The expression of discoidin domain receptor 1 (DDR1) is commonly up-regulated and undergoes collagen-induced ectodomain (N-terminal) shedding during the progression of liver fibrosis. This study aimed to evaluate the clinical utility of N-terminal DDR1 as a diagnostic biomarker for liver fibrosis.

N-terminal DDR1 shedding was evaluated using cell lines, liver fibrosis mouse models, clinical data of 298 patients collected from February 2019 to June 2020. The clinical data were divided into test and validation cohorts to evaluate the diagnostic performance of serum N-terminal DDR1.

Time- and dosage-dependent N-terminal DDR1 shedding stimulated by collagen I was observed in a hepatocyte cell line model. The type I collagen deposition and serum N-terminal DDR1 levels concurrently increased in the development of liver fibrosis in mouse models. Clinical data demonstrated a significant diagnostic power of serum N-terminal DDR1 levels as an accurate biomarker of liver fibrosis and cirrhosis. The diagnostic performance was further increased when applying N-DDR1/albumin ratio, achieving area under the curve of 0.790, 0.802, 0.879, and 0.865 for detecting histological fibrosis stages F ≥2, F ≥3, F 4 with liver biopsy as a reference method, and cirrhosis according to imaging techniques, respectively. With a cut-off of 55.6, a sensitivity, specificity, positive predictive value, and negative predictive value of 82.7%,76.6%, 67.4%, and 88.3% were achieved for the detection of cirrhosis.

Serum N-terminal DDR1 appears to be a novel diagnostic marker for liver fibrosis.

Hepatitis B virus (HBV), one of the well-known DNA oncogenic viruses, is the leading cause of hepatocellular carcinoma (HCC). In infected hepatocytes, HBV DNA can be integrated into the host genome through an insertional mutagenesis process inducing tumorigenesis. Dissection of the genomic features surrounding integration sites will deepen our understanding of mechanisms underlying integration. Moreover, the quantity and biological activity of integration sites may reflect the DNA damage within affected cells or the potential survival benefits they may confer. The well-known human genomic features include repeat elements, particular regions (such as telomeres), and frequently interrupted genes (e.g., telomerase reverse transcriptase [i.e. TERT], lysine methyltransferase 2B [i.e. KMT2B], cyclin E1 [CCNE1], and cyclin A2 [CCNA2]). Consequently, distinct genomic features within diverse integrations differentiate their biological functions. Meanwhile, accumulating evidence has shown that viral proteins produced by integrants may cause cell damage even after the suppression of HBV replication. The integration-derived gene products can also serve as tumor markers, promoting the development of novel therapeutic strategies for HCC. Viral integrants can be single copy or multiple copies of different fragments with complicated rearrangement, which warrants elucidation of the whole viral integrant arrangement in future studies. All of these considerations underlie an urgent need to develop novel methodology and technology for sequence characterization and function evaluation of integration events in chronic hepatitis B-associated disease progression by monitoring both host genomic features and viral integrants. This endeavor may also serve as a promising solution for evaluating the risk of tumorigenesis and as a companion diagnostic for designing therapeutic strategies targeting integration-related disease complications.

Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic disorders. This study aimed to explore the role of metabolic disorders in screening advanced fibrosis in NAFLD patients.

A total of 246 histologically-proven NAFLD patients were enrolled across 14 centers. We compared the severity of fibrosis in patients with different components of metabolic disorders. Based on standard noninvasive tests and metabolic disorders, we developed new algorithms to identify advanced fibrosis.

Metabolic syndrome (MetS) was frequent in NAFLD patients (133/246, 54%). Patients with MetS had a higher proportion of significant fibrosis (p=0.014) and higher LSM values (9.2 kPa, vs. 7.4 kPa, p=0.002) than those without MetS. Patients with more metabolic disorders had higher fibrosis stages (p=0.017). Reduced high-density lipoprotein cholesterol (odds ratio [OR]: 2.241, 95% confidence interval [CI]: 1.004–5.002, p=0.049) and raised fasting glucose (OR: 4.500, 95% CI: 2.083–9.725, p<0.001) were significantly associated with advanced fibrosis. Using these two metabolic disorders as a screening tool, a sensitivity, specificity and accuracy of 92%, 81% and 83% was achieved, respectively. With the new algorithms combining metabolic disorders with noninvasive measurements, the number of patients requiring liver biopsy was reduced, especially in combination with the Fibrosis-4 score and metabolic disorders (36% to 17%, p<0.001). In addition, this stepwise algorithm could achieve a high accuracy (85%) and high negative predictive value (93%).

Metabolic disorders should be taken into consideration in the diagnosis of advanced fibrosis. With further validation and investigation, new algorithms could be recommended in primary care units to spare patients from unnecessary referral and liver biopsies.

Acute liver failure (ALF) is an inflammatory process of acute liver cell injury. Mesenchymal stem cells (MSCs) are undifferentiated, primitive cells with anti-inflammatory, anti-apoptotic, and multi-directional differentiation abilities. This study aimed to explore the therapeutic mechanism of umbilical cord (U)MSCs in ALF.

D-galactosamine (D-GalN) combined with lipopolysaccharide (LPS) was used to establish an ALF model. After model establishment, UMSCs were injected via the tail vein. After UMSC transplantation, the number of mouse deaths was monitored every 12 h. A fully automatic biochemical analyzer was used to detect changes in biochemical analysis. Pathological changes was observed by stained with hematoxylin and eosin.The expression of My D88 was detected by immunohistochemical analysis, quantitative reverse transcription, and western blotting. The expression of NF-κB was detected by quantitative reverse transcription, western blotting.The expression of Bcl-2,Bax were detected by quantitative reverse transcription, western blotting.The expression of TNF-α, IL-1β, IL-6 were detected by enzyme-linked immunosorbent assay.

The 48-h survival rate of the UMSC-treated group was significantly higher than that of the LPS/D-GalN-exposed group. After 24 h of LPS/D-GalN exposure, UMSCs reduced serum alanine aminotransferase and aspartate aminotransferase levels and improved the liver structure. Western blot and real-time fluorescence quantitative nucleic acid amplification analyses showed that UMSCs decreased MyD88 expression, thereby inhibiting LPS/GalN-induced phosphorylation and degradation of inhibitor of nuclear factor (NF)-κB (IκB). Additionally, NF-κB p65 underwent nuclear translocation, inhibiting the production of the inflammatory factors interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α and played a protective role in ALF by down-regulating the pro-apoptotic gene Bax and up-regulating the anti-apoptotic gene Bcl-2. In summary, these findings indicate that UMSCs play a protective role in LPS/GalN-induced acute liver injury via inhibition of the MyD88 pathway and subsequent inhibition of NF-κB-mediated cytokine production.

Through the above mechanisms, UMSCs can effectively reduce LPS/D-GalN-induced ALF, reduce mouse mortality, and restore damaged liver function and damaged liver tissue.

Hepatitis B virus (HBV) infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics, by unknown mechanisms, in the generation of hepatocellular carcinoma. The pregnane X receptor (PXR) is a key regulator of the body’s defense against xenobiotics, including xenobiotic carcinogens and clinical drugs. In this study, we aimed to investigate the molecular mechanisms of HBV X protein (HBx)-PXR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis.

The expression profile of PXR-cytochrome p450 3A4 (CYP3A4) signaling was determined by PCR, western blotting, and tissue microarray. Cell viability and aflatoxin B1 (AFB1) cytotoxicity were measured using the cell counting kit-8 assay. Target gene expression was evaluated using transient transfection and real time-PCR. The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1.

HBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione S-transferase Mu 1 (GSTM1) in cell lines. Activation of PXR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin (IL)-11:IL-11 receptor subunit alpha-1 (IL11RA-1)-mediated inflammation in an HBx transgenic model.

Our finding regarding AFB1 toxicity enhancement by an HBx-PXR-CYP3A4/ GSTM1-KRAS-IL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.

The coronavirus pandemic has resulted in increased rates of hepatic decompensation, morbidity and mortality in patients suffering from existing liver disease, and deranged liver biochemistries in those without liver disease. In patients with cirrhosis with coronavirus disease 2019 (COVID-19), new onset organ failures manifesting as acute-on-chronic liver failure have also been reported. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) also directly binds to enterocytes and cholangiocytes via the angiotensin converting enzyme receptor 2, although the lung remains the portal of entry. Superadded with the COVID-19 related bystander hepatitis, a systemic inflammatory response is noted due to unregulated macrophage activation syndrome and cytokine storm. However, the exact definition and diagnostic criteria of the ‘cytokine storm’ in COVID-19 are yet unclear. In addition, inflammatory markers like C-reactive protein, ferritin, D-dimer and procalcitonin are frequently elevated. This in turn leads to disease progression, activation of the coagulation cascade, vascular microthrombi and immune-mediated injury in different organ systems. Deranged liver chemistries are also noted due to the cytokine storm, and synergistic hypoxic or ischemic liver injury, drug-induced liver injury, and use of hepatotoxic antiviral agents all contribute to deranged liver chemistry. Control of an unregulated cytokine storm at an early stage may avert disease morbidity and mortality. Several immunomodulator drugs and repurposed immunosuppressive agents have been used in COVID-19 with varying degrees of success.

Corona virus disease (COVID)-19 is caused by the novel severe acute respiratory syndrome coronavirus-2 (commonly referred to as SARS-CoV-2). In March 2020, the World Health Organization declared the COVID-19 outbreak a pandemic. Though the target organ for the virus is primarily the lungs, with the recent understanding of the pathobiology of this disease and the immune dysregulation associated with it, it is now clear that COVID-19 affects multiple organ systems. Several drugs and therapies have been tried or repurposed to combat the wrath posed by this disease. On October 22, 2020, the USA Food and Drug Administration approved remdesivir for use in adults and pediatric patients (12 years of age and older). Several of the drugs being tried against COVID-19 have hepatotoxicity as their potential side effect. This review aims to provide the latest insights on various drugs being used in the treatment of COVID-19 and their effects on the liver.

Multiple regulatory mechanisms play an important role in arsenic-induced liver injury. To investigate whether histone H3 lysine 4 (H3K4) methyltransferase (SET7/9) and histone H3K4 demethyltransferase (LSD1/KDM1A) can regulate endoplasmic reticulum stress (ERS)-related apoptosis by modulating the changes of H3K4 methylations in liver cells treated with arsenic.

Apoptosis, proliferation and cell cycles were quantified by flow cytometry and real-time cell analyzer. The expression of ERS- and epigenetic-related proteins was detected by Western blot analysis. The antisense SET7/9 expression vector and the overexpressed LSD1 plasmid were used for transient transfection of LO2 cells. The effects of NaAsO2 on the methylation of H3 in the promoter regions of 78 kDa glucose-regulated protein, activating transcription factor 4 and C/EBP-homologous protein were evaluated by chromatin immunoprecipitation assay.

The protein expression of LSD1 (1.25±0.08 vs. 1.77±0.08, p=0.02) was markedly decreased by treatment with 100 µM NaAsO2, whereas the SET7/9 (0.68±0.05 vs. 1.10±0.13, p=0.002) expression level was notably increased, which resulted in increased H3K4me1/2 (0.93±0.64, 1.19±0.22 vs. 0.71±0.13, 0.84±0.13, p=0.03 and p=0.003). After silencing SET7/9 and overexpressing LSD1 by transfection, apoptosis rate (in percentage: 3.26±0.34 vs. 7.04±0.42, 4.80±0.32 vs. 7.52±0.38, p=0.004 and p=0.02) was significantly decreased and proliferation rate was notably increased, which is reversed after inhibiting LSD1 (in percentage: 9.31±0.40 vs. 7.52±0.38, p=0.03). Furthermore, the methylation levels of H3 in the promoter regions of GRP78 (20.80±2.40 vs. 11.75±2.47, 20.46±2.23 vs. 14.37±0.91, p=0.03 and p=0.01) and CHOP (48.67±4.04 vs. 16.67±7.02, 59.33±4.51 vs. 20.67±3.06, p=0.004 and p=0.001) were significantly increased in LO2 cells exposed to 100 µM NaAsO2 for 24 h.

Histone methyltransferase SET7/9 and histone demethyltransferase LSD1 jointly regulate the changes of H3K4me1/me2 levels in arsenic-induced apoptosis. NaAsO2 induces apoptosis in LO2 cells by activating the ERS-mediated apoptotic signaling pathway, at least partially by enhancing the methylation of H3 on the promoter regions of ERS-associated genes, including GRP78 and CHOP.

Acute-on-chronic liver failure (ACLF) is acute decompensation of liver function in the setting of chronic liver disease, and characterized by high short-term mortality. In this study, we sought to investigate the clinical course of patients at specific time points, and to propose dynamic prognostic criteria.

We assessed the clinical course of 453 patients with ACLF during a 12-week follow-up period in this retrospective multicenter study. The clinical course of patients was defined as disease recovery, improvement, worsening or steady patterns based on the variation tendency in prothrombin activity (PTA) and total bilirubin (TB) at different time points.

Resolution of PTA was observed in 231 patients (51%) at 12 weeks after the diagnosis of ACLF. Among the remaining patients, 66 (14.6%) showed improvement and 156 (34.4%) showed a steady or worsening course. In patients with resolved PTA, the clinical course of TB exhibited resolved pattern in 95.2%, improved in 3.9%, and steady or worse in 0.8%. Correspondingly, in patients with improved PTA, these values for TB were 28.8%, 27.3%, and 43.9%, respectively. In patients with steady or worsening PTA, these values for TB were 5.7%, 32.3%, and 65.6%, respectively. Dynamic prognostic criteria were developed by combining the clinical course of PTA/TB and the clinical outcomes at 4 and 12 weeks after diagnosis in ACLF patients.

We propose the following dynamic prognostic criteria: rapid progression, slow progression, rapid recovery, slow recovery, and slow persistence, which lay the foundation for precise prediction of prognosis and the improvement of ACLF therapy.

The survival rate of patients with hepatocellular carcinoma is variable. The abnormal expression of RNA-binding proteins (RBPs) is closely related to the occurrence and development of malignant tumors. The primary aim of this study was to identify RBPs related to the prognosis of liver cancer and to construct a prognostic model of liver cancer.

We downloaded the hepatocellular carcinoma gene sequencing data from The Cancer Genome Atlas (cancergenome.nih.gov/) database, constructed a protein-protein interaction network, and used Cytoscape to realize the visualization. From among 325 abnormally expressed genes for RBPs, 9 (XPO5, enhancer of zeste 2 polycomb repressive complex 2 subunit [EZH2], CSTF2, BRCA1, RRP12, MRPL54, EIF2AK4, PPARGC1A, and SEPSECS) were selected for construction of the prognostic model. Then, we further verified the results through the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo/ ) database and in vitro experiments.

A prognostic model was constructed, which determined that the survival time of patients in the high-risk group was significantly shorter than that of the low-risk group (p<0.01). Univariate and multivariate Cox regression analysis suggested that the risk score was an independent prognostic factor (p<0.01). We also constructed a nomogram based on the risk score, survival time, and survival status. At the same time, we verified the high expression and cancer-promoting effects of EZH2 in tumors.

Survival, receiver operating characteristic curve and independent prognostic analyses demonstrated that we constructed a good prognostic model, which might be useful for estimating the survival of patients with hepatocellular carcinoma.

Unfractionated heparin (UFH) and bivalirudin are widely used as anticoagulants in cardiovascular medicine, including for thrombosis prevention during coronary angiography (CAG) and percutaneous coronary intervention (PCI). Little is known of the effects of UFH and bivalirudin on liver and kidney function in patients subjected to these procedures. This study compared the effects of bivalirudin and UFH on liver/renal function in patients with coronary artery disease who underwent CAG, with or without PCI.

The study comprised 134 consecutive patients (40–89 years-old), who underwent CAG (or CAG and PCI); among them, 66 and 68 patients were subject to, respectively, bivalirudin or UFH. The following indicators of liver/renal function were measured before and after the procedures: plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, estimated glomerular filtration rate (eGFR), creatinine clearance, and serum creatinine. Patients were further stratified by severity of chronic kidney disease (CKD), based on original eGFR.

Relative to baseline, in the bivalirudin group, ALT and AST were higher after CAG (p=0.005, 0.025), while blood urea nitrogen and serum creatinine were lower (p=0.049, <0.001). In the UFH group, ALT, AST, eGFR, and creatinine clearance were lower after CAG (p≤0.001, all). Patients given bivalirudin with moderate or severe CKD, but not those with mild CKD, gained significant improvement in kidney function.

Relative to UFH, bivalirudin may better safeguard the renal function of patients with coronary artery disease who undergo CAG, especially patients with moderate-to-severe renal insufficiency. UFH may cause less liver damage than bivalirudin.

The coronavirus disease 2019 (COVID-19) pandemic continues worldwide. We report here two cases of chronic hepatitis B patients with acute respiratory syndrome coronavirus 2 infection treated with tenofovir disoproxil fumarate who demonstrated a favorable outcome. This report adds some evidence that concurrent HBV infection may not worsen COVID-19 infection and tenofovir disoproxil fumarate treatment may have partial positive effect on COVID-19 rapid recovery.

This study was performed to determine whether atrial fibrillation (AF) is related to the precise location of a coronary artery lesion.

A single-center retrospective study was conducted to compare data from clinical, laboratory, and instrumental examinations of 89 patients with AF (main group) who were admitted to the department between October 2015 and October 2019. One-hundred-and-sixty patients (comparison group) were selected according to balanced matching.

There were no statistically significant differences in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), troponin, or creatine kinase-myocardial band (CK-MB) between the two groups. However, the levels of homocysteine (17.0 ± 1.7 µmol/L vs. 13.7 ± 1.0 µmol/L, p = 0.001), uric acid (342.8 ± 16.7 µmol/L vs. 308.5 ± 15.1 µmol/L, p = 0.003) and creatinine (79.3 ± 4.7 µmol/L vs. 72.9 ± 3.1 µmol/L, p = 0.017) were higher in the AF group compared to the non-AF group. Moreover, the left atrium (LA) diameter (40.2 ± 1.4 mm vs. 33.5 ± 0.8 mm, p = 0.001) was larger in the AF group compared to the non-AF group. Patients with AF compared to those without AF had no significant differences in the degree or location of coronary artery lesions.

AF in patients was not associated with specific coronary artery lesions in the current study.

The recognition of transarterial chemoembolization (TACE) failure/refractoriness among Chinese clinicians remains unclear. Using an online survey conducted by the Chinese College of Interventionalists (CCI), the aim of this study was to explore the recognition of TACE failure/refractoriness and review TACE application for hepatocellular carcinoma (HCC) treatment in clinical practice.

From 27 August 2020 to 30 August 2020 during the CCI 2020 annual meeting, a survey with 34 questions was sent by email to 264 CCI clinicians in China with more than 10 years of experience using TACE for HCC treatment.

A total of 257 clinicians participated and responded to the survey. Most participants agreed that the concept of “TACE failure/refractoriness” has scientific and clinical significance (n=191, 74.3%). Nearly half of these participants chose TACE-based combination treatment as subsequent therapy after so-called TACE failure/refractoriness (n=88, 46.1%). None of the existing TACE failure/refractoriness definitions were widely accepted by the participants; thus, it is necessary to re-define this concept for the treatment of HCC in China (n=235, 91.4%). Most participants agreed that continuing TACE should be performed for patients with preserved liver function, presenting portal vein tumor thrombosis (n=242, 94.2%) or extrahepatic spread (n=253, 98.4%), after the previous TACE treatment to control intrahepatic lesion(s).

There is an obvious difference in the recognition of TACE failure/refractoriness among Chinese clinicians based on existing definitions. Further work should be carried out to re-define TACE failure/refractoriness.

In recent years, with a gradual increase of health awareness, society has become more concerned about the frequent occurrence of air pollution. As is known to all, fine particulate matter (particles less than 2.5 micrometers in diameter [PM2.5]) is the main cause of haze, which is suspended in the air and generated through a series of physical and chemical changes. Of note, different components and sources of PM2.5 cause different kinds of damage. Identification of the components and analysis of the sources have guiding significance for the prevention of PM2.5 damage. Indoor PM2.5 that is mainly from smoking and biomass combustion also has an adverse influence on human health. The prediction of indoor PM2.5 sedimentation and suspension is of great significance for maintaining good indoor air quality. Thus, the present review was conducted to provide a brief overview of new insights into the composition analysis, source analysis, indoor diffusion and deposition model, and the pathogenic mechanism of PM2.5, which have been explored with new technologies in recent years. This review will help to provide reference for PM2.5 related policy formulation.

The role of runt-related transcription factor 2 (RUNX2) in tumorigenesis and tumor progression in many cancers has been identified except for lung cancer. This study aimed to explore the expression level, functions and prognostic values of RUNX2 in lung cancer.

ONCOMINE was utilized to compare RUNX2 expression difference between cancers and normal tissue. GEPIA was used to further detect the expression pattern of RUNX2 between lung cancer and corresponding normal lung tissue. Then, the prognosis value of RUNX2 in lung cancer was evaluated through Kaplan-Meier Plots. The genomic alterations of RUNX2 neighbor genes were analyzed by cBioPortal, and GO enrichment was conducted to identify functional categories of RUNX2 and genes associated with RUNX2 alterations.

ONCOMINE and GEPIA revealed the upregulated expression level of RUNX2 in lung cancer compared to normal lung tissue. Higher RUNX2 level was associated with lower progression-free survival and overall survival in lung cancer patients. GO enrichment implicated that cell proliferation, invasion and metastasis-related genes as well as the functions of cell adhesion, cell migration, and cell proliferation were significantly associated with RUNX2 alterations.

Our findings indicated the value of RUNX2 as a novel prognostic biomarker and a potential therapeutic target for lung cancer.