Hepatic arterioportal fistulas (HAPFs) are abnormal shunts or aberrant functional connections between the portal venous and the hepatic arterial systems. Detection of HAPFs has increased with the advances in diagnostic techniques. Presence of HAPFs over a prolonged period can aggravate liver cirrhosis and further deteriorate liver function. However, the underlying causes of HAPFs and the treatment outcomes are now well characterized. This study aimed to summarize the clinical characteristics of patients with HAPFs, and to compare the outcomes of different treatment modalities.

Data of 97 patients with HAPFs who were admitted to the Second Xiangya Hospital between January 2010 and January 2020 were retrospectively reviewed. Demographic information, clinical manifestations, underlying causes, treatment options, and short-term outcomes were analyzed.

The main cause of HAPF in our cohort was hepatocellular carcinoma (78/97, 80.41%), followed by cirrhosis (10/97, 10.31%). The main clinical manifestations were abdominal distention and abdominal pain. Treatment methods included transcatheter arterial embolization (n=63, 64.9%), surgery (n=13, 13.4%), and liver transplantation (n=2, 2.1%); nineteen (19.6%) patients received conservative treatment. Among patients who underwent transcatheter arterial embolization, polyvinyl alcohol, lipiodol combined with gelatin sponge, and spring steel ring showed comparable efficacy.

Hepatocellular carcinoma and cirrhosis are common causes of HAPFs. Transcatheter arterial embolization is a safe and effective method for the treatment of HAPFs, and polyvinyl alcohol, lipiodol combined with gelatin sponge, and spring steel ring showed comparable efficacy in our cohort.

1,5-Anhydroglucitol (1,5AG) activity has been reported in chronic liver disease. Hepatitis B virus (HBV)-related acute-on-chronic liver failure (HBV-ACLF) patients have a high mortality. We aimed to discover the relationship between serum 1,5AG and the prognosis of HBV-ACLF.

Serum 1,5AG levels were determined in 333 patients with HBV-ACLF, 300 without diabetes were allocated to derivation (n=206) and validation cohorts (n=94), and 33 were recruited to evaluate 1,5AG in those with diabetes. Forty patients with chronic hepatitis B, 40 with liver cirrhosis, and 40 healthy people were controls in the validation cohort.

In the derivation and validation cohorts, serum 1,5AG levels were significantly lower in nonsurvivors than in survivors. The AUC of 1,5AG for 28-day mortality was 0.811. In patients with diabetes, serum 1,5AG levels were also significantly lower in nonsurvivors than in survivors. In multivariate Cox regression analysis, serum 1,5AG levels were independently associated with 28-day mortality. A novel predictive model (ACTIG) based on 1,5AG, age, TB, cholesterol, and INR was derived to predict mortality. In ACTIG, the AUC for 28-day mortality was 0.914, which was superior to some prognostic score models. ACTIG was also comparable to those prognostic score models in predicting 6-month mortality. In mice with D-galactosamine/lipopolysaccharide-induced liver failure, 1,5AG levels were significantly reduced in serum and significantly increased in urine and liver tissue.

Serum 1,5AG levels are a promising predictor of short-term mortality in HBV-ACLF patients. The 1,5AG distribution changed in mice with D-galactosamine/ lipopolysaccharide-induced liver failure.

TMCO3, a member of the monovalent cation:proton antiporter-2 family, has been annotated as a Na+/H+ antiporter, but its pathophysiological role is still unclear. We aimed to investigate the expression profile, prognostic significance, and oncogenic role of TMCO3 in hepatocellular carcinoma (HCC).

Bioinformatic analyses were conducted using transcriptome data from public databases to determine the expression, prognosis, and functional enrichment of TMCO3 in HCC. TMCO3 expression was further validated in an independent HCC cohort from our institution. The oncogenic role of TMCO3 in HCC was evaluated using in vitro and in vivo experiments.

The upregulated expression of TMCO3 was identified and verified in multiple HCC cohorts, and worse overall survival and recurrence-free survival were observed in patients with high TMCO3 expression. The overexpression and knockdown of TMCO3 could affect the proliferation and metastasis of HCC cells, which might be associated with the p53-induced cell cycle regulation and epithelial-mesenchymal transition, respectively. Notably, significant correlations were found between dysregulated TMCO3 and various antitumor agents. Its role in sorafenib sensitivity was further identified by in vitro experiments and the potential mechanism might be related to the regulation of apoptosis. Positive correlations were also identified between upregulation of TMCO3 and the increased infiltration of various immune cells and the elevated expression of multiple immune checkpoint genes in HCC.

Upregulated TMCO3 could act as an oncogenic mediator and promote sorafenib resistance in HCC, providing a potential therapeutic target for HCC treatment.

Visceral obesity is a risk factor for nonalcoholic fatty liver disease (NAFLD). We investigated sex-specific optimal cutoff values for visceral fat area (VFA) associated with lean and overweight/obese NAFLD in an Asian population.

This retrospective study included 678 potential living liver donors (mean age, 30.8±9.4 years; 434 men and 244 women) who had undergone abdominal computed tomography (CT) imaging and liver biopsy between November 2016 and October 2017. VFA was measured using single-slice abdominal CT. NAFLD was evaluated by liver biopsy (≥5% hepatic steatosis). Receiver operating characteristic curve analysis was used to determine cutoff values for VFA associated with lean (body mass index [BMI] <23 kg/m2) and overweight/obese (BMI ≥23 kg/m2) NAFLD.

Area under the curve (AUC) values with 95% confidence intervals (CI) for VFA were 0.82 (95% CI, 0.75–0.88) for lean and 0.74 (95% CI, 0.69–0.79) for overweight/obese men with NAFLD. The AUC values were 0.67 (95% CI, 0.58–0.75) for lean and 0.71 (95% CI, 0.62–0.80) for overweight/obese women with NAFLD. The cutoff values for VFA associated with lean NAFLD were 50.2 cm2 in men and 40.5 cm2 in women. The optimal cutoff values for VFA associated with overweight/obese NAFLD were 100.6 cm2 in men and 68.0 cm2 in women.

Sex-specific cutoff values for VFA may be useful for identifying subjects at risk of lean and overweight/obese NAFLD.

Omics data address key issues in liver transplantation (LT) as the most effective therapeutic means for end-stage liver disease. The purpose of this study was to review the current application and future direction for omics in LT. We reviewed the use of multiomics to elucidate the pathogenesis leading to LT and prognostication. Future directions with respect to the use of omics in LT are also described based on perspectives of surgeons with experience in omics. Significant molecules were identified and summarized based on omics, with a focus on post-transplant liver fibrosis, early allograft dysfunction, tumor recurrence, and graft failure. We emphasized the importance omics for clinicians who perform LTs and prioritized the directions that should be established. We also outlined the ideal workflow for omics in LT. In step with advances in technology, the quality of omics data can be guaranteed using an improved algorithm at a lower price. Concerns should be addressed on the translational value of omics for better therapeutic effects in patients undergoing LT.

Acute liver failure (ALF) is a potentially fatal clinical syndrome with no effective treatment. This study aimed to explore the role of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in modulating the phenotype and immune function of endotoxin-tolerant dendritic cells (ETDCs). In addition, we explored the use of EDTCs in an experimental model of ALF and investigated the associated mechanisms.

In the in vitro experiment, ETDCs were transfected with adenovirus to induce SOCS1+/+ETDCs and SOCS1−/−ETDCs. Thereafter, costimulatory molecules and mixed lymphocyte reaction were assessed. Experimental mice were randomly divided into normal control, ALF, ALF+mock-ETDCs, ALF+SOCS1+/+ETDCs, ALF+AG490, and ALF+AG490+SOCS1+/+ETDCs groups. We examined the therapeutic effect of adoptive cellular immunotherapy by tail-vein injection of target ETDCs 12 h before ALF modeling. AG490, a JAK2/STAT3 inhibitor, was used in the in vivo experiment to further explore the protective mechanism of SOCS1+/+ETDCs.

Compared with control ETDCs, SOCS1+/+ETDCs had lower expression of costimulatory molecules, weaker allostimulatory ability, lower levels of IL-6 and TNF-α expression and higher IL-10 secretion. SOCS1−/−ETDCs showed the opposite results. In the in vivo experiments, the ALF+SOCS1+/+ETDCs and ALF+AG490+SOCS1+/+ETDCs groups showed less pathological damage and suppressed activation of JAK2/STAT3 pathway. The changes were more pronounced in the ALF+AG490+SOCS1+/+ETDCs group. Infusion of SOCS1+/+ETDCs had a protective effect against ALF possibly via inhibition of JAK2 and STAT3 phosphorylation.

The SOCS1 gene had an important role in induction of endotoxin tolerance. SOCS1+/+ETDCs alleviated lipopolysaccharide/D-galactosamine-induced ALF by downregulating the JAK2/STAT3 signaling pathway.

Transarterial chemoembolization (TACE) is widely applied for the treatment of hepatocellular carcinoma. Repeat TACE is often required in clinical practice because a satisfactory tumor response may not be achieved with a single session. However, repeated TACE procedures can impair liver function and increase treatment-related adverse events, all of which prompted the introduction of the concept of “TACE failure/refractoriness”. Mainly based on evidence from two retrospective studies conducted in Japan, sorafenib is recommended as the first choice for subsequent treatment after TACE failure/refractoriness. Several studies have investigated the outcomes of other subsequent treatments, including locoregional, other molecular targeted, anti-programmed death-1/anti-programed death ligand-1 therapies, and combination therapies after TACE failure/refractoriness. In this review, we summarize the up-to-date information about the outcomes of several subsequent treatment modalities after TACE failure/refractoriness.

Hepatocellular carcinoma (HCC) is a common primary liver neoplasm with high mortality. Dermcidin (DCD), an antimicrobial peptide, has been reported to participate in oncogenesis. This study assessed the effects and underlying molecular events of DCD overexpression and knockdown on the regulation of HCC progression in vitro and in vivo.

The serum DCD level was detected using enzyme-linked immunosorbent assay. DCD overexpression, knockdown, and Ras-related C3 botulinum toxin substrate 1 (Rac1) rescue were performed in SK-HEP-1 cells using plasmids. Immunofluorescence staining, quantitative PCR, and Western blotting were used to detect the expression of different genes and proteins. Differences in HCC cell migration and invasion were detected by Transwell migration and invasion assays. A nude mouse HCC cell orthotopic model was employed to verify the in vitro data.

The level of serum DCD was higher in patients with HCC and in SK-HEP-1 cells. DCD overexpression caused upregulation of DCD, fibronectin, Rac1, and cell division control protein 42 homologue (Cdc42) mRNA and proteins as well as actin-related protein 2/3 (Arp2/3) protein (but reduced Arp2/3 mRNA levels) and activated Rac1 and Cdc42. Phenotypically, DCD overexpression induced HCC cell migration and invasion in vitro, whereas knockout of DCD expression had the opposite effects. A Rac1 rescue experiment in DCD-knockdown HCC cells increased HCC cell migration and invasion and increased the levels of active Rac1/total Rac1, Wiskott-Aldrich syndrome family protein (WASP), Arp2/3, and fibronectin. DCD overexpression induced HCC cell metastasis to the abdomen and liver in vivo.

DCD promotes HCC cell migration, invasion, and metastasis through upregulation of noncatalytic region of tyrosine kinase adaptor protein 1 (Nck1), Rac1, Cdc42, WASP, and Arp2/3, which induce actin cytoskeletal remodeling and fibronectin-mediated cell adhesion in HCC cells.

Hepatitis B surface antigen (HBsAg) clearance is significantly more common in children with chronic hepatitis B (CHB) than in adults; however, the possible influencing factors related to HBsAg loss have yet to be found. This study aimed to explore the efficacy of long-term interferon (IFN)α therapy in treating children with CHB and analyzed the factors influencing functional cure after treatment.

A total of 236 children aged 1–6 years and diagnosed with CHB via liver biopsy were included in the study, all receiving IFNα treatment (IFNα-2b monotherapy, IFNα-2b followed by lamivudine [LAM] or IFNα-2b combined with LAM) and followed up for 144 weeks. A comprehensive analysis was conducted on clinical data, including biochemical items, serum markers of hepatitis B virus (HBV) and immunological indexes, and logistic regression analysis was used to screen the influencing factors related to HBsAg loss.

The cumulative loss rates of HBsAg were 79.5%, 62.1% and 42.1% at 144 weeks after the start of treatment in the 1–3 years-old group, 3–5 years-old group and 5–7 years-old group, respectively (p<0.05). IFNα-2b combined with LAM treatment displayed the highest HBsAg loss rates compared with monotherapy and sequential treatment (p=0.011). Younger baseline age and lower HBsAg levels were independent factors for the prediction of HBsAg loss (p<0.05). The baseline PreS1 and hepatitis B core antibody levels in the HBsAg loss group were lower than those in the HBsAg non-loss group. In addition, the PreS1 level was positively corelated with the level of HBsAg, HBV DNA and liver inflammation.

Long-term treatment with IFNα was effective in achieving HBsAg loss in CHB children aged 1–6 years-old. Age less than 3 years-old and lower HBsAg levels are independent predictors of functional cure in children with CHB.

Cirrhosis patients exhibit cytopenia, and, at times refractory neutropenia to granulocyte colony-stimulating factor (G-CSF), which acts through the CSF3-receptor (CSF3R), and changes in CSF3R can affect the response. We conducted this study to assess the CSF3R status and its relevance in cirrhotic patients.

Cirrhotic patients (n=127) and controls (n=26) with clinically indicated bone marrow (BM) examination were studied. BM assessment was done by qRT-PCR and immunohistochemistry (IHC) for CSF3R. Circulating G-CSF, CSF3R, and carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) were measured. BM hematopoietic precursor cells and their alterations were examined by flow cytometry. The findings were validated in liver cirrhosis patients who received G-CSF for severe neutropenia.

The mean age was 48.6±13.4 years, and 80.3% were men. Circulatory CSF3R reduction was noted with the advancement of cirrhosis, and confirmed by qRT-PCR and IHC in BM. CSF3R decline was related to decreased hematopoietic stem cells (HSCs) and downregulation of CSF3R in the remaining HSCs. Cocultures confirmed that CEACAM1 led to CSF3R downregulation in BM cells by possible lysosomal degradation. Baseline low peripheral blood-(PB)-CSF3R also predisposed development of infections on follow-up. Decreased CSF3R was also associated with nonresponse to exogenous G-CSF treatment of neutropenia.

Advanced liver cirrhosis was associated with low CSF3R and high CEACAM1 levels in the BM and circulation, making patients prone to infection and inadequate response to exogenous G-CSF.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and causes major economic and health burdens throughout the world. Although the incidence of ICC is relatively low, an upward trend has been seen over the past few decades. Owing to the lack of specific manifestations and tools for early diagnosis, most ICC patients have relatively advanced disease at diagnosis. Thus, neoadjuvant therapy is necessary to evaluate tumor biology and downstage these patients so that appropriate candidates can be selected for radical liver resection. However, even after radical resection, the recurrence rate is relatively high and is a main cause leading to death after surgery, which makes adjuvant therapy necessary. Because of its low incidence, studies in both neoadjuvant and adjuvant settings of ICC are lagging compared with other types of malignancy. While standard neoadjuvant and adjuvant regimens are not available in the current guidelines due to a lack of high-level evidence, some progress has been achieved in recent years. In this review, the available literature on advances in neoadjuvant and adjuvant strategies in ICC are evaluated, and possible challenges and opportunities for clinical and translational investigations in the near future are discussed.

Patients with hepatocellular carcinoma (HCC) surgically resected are at risk of recurrence; however, the risk factors of recurrence remain poorly understood. This study intended to establish a novel machine learning model based on clinical data for predicting early recurrence of HCC after resection.

A total of 220 HCC patients who underwent resection were enrolled. Classification machine learning models were developed to predict HCC recurrence. The standard deviation, recall, and precision of the model were used to assess the model’s accuracy and identify efficiency of the model.

Recurrent HCC developed in 89 (40.45%) patients at a median time of 14 months from primary resection. In principal component analysis, tumor size, tumor grade differentiation, portal vein tumor thrombus, alpha-fetoprotein, protein induced by vitamin K absence or antagonist-II (PIVKA-II), aspartate aminotransferase, platelet count, white blood cell count, and HBsAg were positive prognostic factors of HCC recurrence and were included in the preoperative model. After comparing different machine learning methods, including logistic regression, decision tree, naïve Bayes, deep neural networks, and k-nearest neighbor (K-NN), we choose the K-NN model as the optimal prediction model. The accuracy, recall, precision of the K-NN model were 70.6%, 51.9%, 70.1%, respectively. The standard deviation was 0.020.

The K-NN classification algorithm model performed better than the other classification models. Estimation of the recurrence rate of early HCC can help to allocate treatment, eventually achieving safe oncological outcomes.

Microvascular invasion (MVI) is a major risk factor for the early recurrence of hepatocellular carcinoma (HCC) and it seriously worsens the prognosis. Accurate preoperative evaluation of the presence of MVI could greatly benefit the treatment management and prognosis prediction of HCC patients. The study aim was to evaluate the diagnostic performance of the apparent diffusion coefficient (ADC), a quantitative parameter for the preoperative diagnosis MVI in HCC patients.

Original articles about diffusion-weighted imaging (DWI) and/or intravoxel incoherent motion (IVIM) conducted on a 3.0 or 1.5 Tesla magnetic resonance imaging (MRI) system indexed through January 17, 2021were collected from MEDLINE/PubMed, Web of Science, EMBASE, and the Cochrane Library. Methodological quality was evaluated using Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). The pooled sensitivity, specificity, and summary area under the receiver operating characteristic curve (AUROC) were calculated, and meta-regression analysis was performed using a bivariate random effects model through a meta-analysis.

Nine original articles with a total of 988 HCCs were included. Most studies had low bias risk and minimal applicability concerns. The pooled sensitivity, specificity and AUROC of the ADC value were 73%, 70%, and 0.78, respectively. The time interval between the index test and the reference standard was identified as a possible source of heterogeneity by subgroup meta-regression analysis.

Meta-analysis showed that the ADC value had moderate accuracy for predicting MVI in HCC. The time interval accounted for the heterogeneity.

Liver injury is an important complication that may arise in patients suffering from coronavirus disease 2019 (COVID-19) and is accompanied by a transient increase of transaminases and/or other liver enzymes. Liver function test (LFT) abnormalities generally disappear when the COVID-19 resolves or hepatotoxic drugs are discontinued. The LFT abnormalities are associated with drug-induced liver injury (DILI), due to the overuse of antimalarials, antivirals, and antimicrobials. Studies have reported varying levels of these liver injuries in COVID-19 patients; however, most involve elevated serum aminotransferases. Hepatic dysfunction is significantly high in patients with severe illness and has poor outcome. Normally, the liver is involved in the metabolism of many drugs, including nucleoside analogs and protease inhibitors, which are currently repurposed to treat COVID-19. In addition to the manifestation of COVID-19, drugs implemented in its treatment may aggravate liver injuries. Thus, DILI should be considered especially in those COVID-19 patients with underlying liver disease. It was unclear whether the elevated liver enzymes have originated from the underlying disease or DILI in this population. Furthermore, it is difficult to establish a direct relationship between a specific drug and liver injury. Another possible effect of liver damage may due to inflammatory cytokine storm in severe COVID-19. Liver injury can change metabolism, excretion, dosing, and expected concentrations of the drugs, which may make it difficult to achieve a therapeutic dose of the drug or increase the risk of adverse effects. These repurposed drugs have shown limited efficacy against the virus and the disease itself; however, they still pose risk of adverse effects. Careful and close monitoring of LFTs in COVID-19 patients can provide early diagnosis of liver injury, and the risk of DILI could be reduced. Also, drug interactions in liver-transplanted patients should always be kept in mind for certain immunosuppressive therapies and their known signs of DILI. Altogether, abnormal LFTs should not be regarded as a contraindication to use COVID-19 experimental therapies if needed under emergent status.

We compared lung function parameters in nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD), and examined the association between lung function parameters and fibrosis severity in MAFLD.

In this cross-sectional study, we randomly recruited 2,543 middle-aged individuals from 25 communities across four cities in China during 2016 and 2020. All participants received a health check-up including measurement of anthropometric parameters, biochemical variables, liver ultrasonography, and spirometry. The severity of liver disease was assessed by the fibrosis (FIB)-4 score.

The prevalence of MAFLD was 20.4% (n=519) and that of NAFLD was 18.4% (n=469). After adjusting for age, sex, adiposity measures, smoking status, and significant alcohol intake, subjects with MAFLD had a significantly lower predicted forced vital capacity (FVC, 88.27±17.60% vs. 90.82±16.85%, p<0.05) and lower 1 s forced expiratory volume (FEV1, 79.89±17.34 vs. 83.02±16.66%, p<0.05) than those with NAFLD. MAFLD with an increased FIB-4 score was significantly associated with decreased lung function. For each 1-point increase in FIB-4, FVC was diminished by 0.507 (95% CI: −0.840, −0.173, p=0.003), and FEV1 was diminished by 0.439 (95% CI: −0.739, −0.140, p=0.004). The results remained unchanged when the statistical analyses was performed separately for men and women.

MAFLD was significantly associated with a greater impairment of lung function parameters than NAFLD.

Hepatic regenerative nodules are reactive hepatocellular proliferations that develop in response to liver injury. Giant hepatic regenerative nodules of 10 cm or more are extremely rare and have only been reported in patients with biliary atresia or Alagille syndrome. A 50-year-old man presented with a pathologically confirmed giant 11.3×9.4×11.2 cm hepatic regenerative nodule and hepatitis B virus-related cirrhosis. Imaging of intrahepatic nodule included mild hyperenhancement in the portal phase of contrast-enhanced CT and the hepatobiliary phase in the gadoxetic acid-enhanced MRI scan, as well as the portal vein crossing through sign in the setting of liver cirrhosis. This case highlights the imaging characteristics of giant hepatic regenerative nodules in hepatitis cirrhosis.

Alcohol-associated liver disease (ALD) is the most common cause of advanced liver disease worldwide, including in the USA. Alcohol use and cirrhosis mortality is higher in American Indian/Alaska Native (AI/AN) compared to Whites. Data are scanty on ALD as a liver disease etiology in AI/AN compared to other races and ethnicities.

The National Inpatient Sample on 199,748 cirrhosis-related hospitalizations, 14,241 (2,893 AI/AN, 2,893 Whites, 2,882 Blacks, 2,879 Hispanics, and 2,694 Asians or other races) matched 1:1 for race/ethnicity on demographics, insurance, and income quartile of the residence zip code analyzed.

After controlling for geographic location and hospital type, odds ratio (OR) and 95% confidence interval (CI) for ALD as cirrhosis etiology was higher among admissions in AI/AN vs. Whites [1.55 (1.37–1.75)], vs. Blacks [1.87 (1.65–2.11)], vs. Hispanic [1.89 (1.68–2.13)] and Asians/other races [2.24 (1.98–2.53)]. OR was also higher for AI/AN vs. all other races for alcohol-associated hepatitis (AH) as one of the discharge diagnoses. The findings were similar in a subgroup of 4,649 admissions with decompensated cirrhosis and in a cohort of 350 admissions with acute-on-chronic liver failure as defined by EASL-CLIF criteria. Alcohol use disorder diagnosis was present in 38% of admissions in AI/AN vs. 24–30% in other races, p<0.001. A total of 838 (5.9%) admissions were associated with in-hospital mortality. OR (95% CI) for in-hospital mortality in AI/AN individuals was 34% reduced vs. Blacks [0.66 (0.51–0.84)], but no difference was observed on comparison with other races.

ALD, including AH, is the most common etiology among cirrhosis-related hospitalizations in the USA among AI/AN individuals. In-hospital mortality was observed in about 6% of admissions, which was higher for Blacks and similar in other races compared to admissions for AI/AN. Public health policies should be implemented to reduce the burden of advanced ALD among AI/AN individuals.

Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors. Spindle and kinetochore-associated (SKA) family genes are essential for the maintenance of the metaphase plate and spindle checkpoint silencing during mitosis. Recent studies have indicated that dysregulation of SKA family genes induces tumorigenesis, tumor progression, and chemoresistance via modulation of cell cycle and DNA replication. However, the differential transcription of SKAs in the context of HCC and its prognostic significance has not been demonstrated.

Bioinformatics analyses were performed using TCGA, ONCOMINE, HCCDB, Kaplan-Meier plotter, STRING, GEPIA databases. qRT-PCR, western blot, and functional assays were utilized for in vitro experiments.

We found remarkable upregulation of transcripts of SKA family genes in HCC samples compared with normal liver samples on bioinformatics analyses and in vitro validation. Interaction analysis and enrichment analysis showed that SKA family members were mainly related to microtubule motor activity, mitosis, and cell cycle. Immuno-infiltration analysis showed a correlation of all SKA family genes with various immune cell subsets, especially T helper 2 (Th2) cells. Transcriptional levels of SKA family members were positively associated with histologic grade, T stage, and α-fetoprotein in HCC patients. Receiver operating characteristic curve analysis demonstrated a strong predictive ability of SKA1/2/3 for HCC. Increased expression of these SKAs was associated with unfavorable overall survival, progression-free survival, and disease-specific survival. On Cox proportional hazards regression analyses, SKA1 upregulation and pathological staging were independent predictors of overall survival and disease-specific survival of HCC patients. Finally, clinical tissue microarray validation and in vitro functional assays revealed SKA1 acts an important regulatory role in tumor malignant behavior.

SKA family members may potentially serve as diagnostic and prognostic markers in the context of HCC. The correlation between SKAs and immune cell infiltration provides a promising research direction for SKA-targeted immunotherapeutics for HCC.

As a hepatocellular carcinoma biomarker, serum Golgi protein 73 (GP73) is reportedly related to inflammation. Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation. In this study, we aimed to explore the association between the GP73 level and short-term mortality in patients with alcohol-associated liver disease-related ACLF (ALD-ACLF).

This retrospective cohort study involved 126 Chinese adults with ALD-ACLF. Baseline serum GP73 level was measured using enzyme-linked immunosorbent assay. Patients were followed-up for 90 d and outcomes were assessed. Data were analyzed using multivariate Cox regression and piecewise linear regression analyses. The predictive value of GP73 and classic models for the short-term prognosis of participants were evaluated and compared using receiver operating characteristic curves.

The serum GP73 level was independently associated with an increased mortality risk in patients with ALD-ACLF. Compared with the lowest tertile, the highest serum GP73 level predisposed patients with ALD-ACLF to a higher mortality risk in the fully adjusted model [at 28 days: hazard ratio (HR): 4.29 (0.99–18.54), p=0.0511; at 90 days: HR: 3.52 (1.15–10.79), p=0.0276]. Further analysis revealed a positive linear association. GP73 significantly improved the accuracy of the Child-Turcotte-Pugh score, model for end-stage liver disease score, and model for end-stage liver disease-sodium score in predicting short-time prognosis of patients with ALD-ACLF.

The serum GP73 level is a significant predictor of the subsequent risk of death in patients with ALD-ACLF. GP73 improved the predictive value of classic prognostic scores.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide, reflecting the current epidemics of obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome. NAFLD is characterized by the accumulation of fat in the liver, and is known to be a cause of cirrhosis. Although many pathways have been proposed, the cause of NAFLD-linked fibrosis progression is still unclear, which posed challenges for the development of new therapies to prevent NASH-related cirrhosis and hepatocellular carcinoma. Cirrhosis is associated with activation of hepatic stellate cells (HSC) and accumulation of excess extracellular matrix proteins, and inhibiting the activation of HSCs would be expected to slow the progression of NAFLD-cirrhosis. Multiple molecular signals and pathways such as oxidative stress and glutaminolysis have been reported to promote HSC activation. Both mechanisms are plausible antifibrotic targets in NASH, as the activation of HSCs the proliferation of myofibroblasts depend on those processes. This review summarizes the role of the glutaminolysis-ammonia-urea cycle axis in the context of NAFLD progression, and shows how the axis could be a novel therapeutic target.