We present a unique case of biopsy-proven syphilitic hepatitis which presented as severe acute liver injury with significant elevation in aminotransferases and bilirubin, and improved with antibiotic therapy. However, the patient returned weeks after initial presentation with new-onset acute liver injury and had developed hypergammaglobulinemia, positive autoantibody titers, and repeat liver biopsy demonstrating interface hepatitis, supporting a diagnosis of autoimmune hepatitis. He had an otherwise unrevealing etiologic workup, and responded to glucocorticoid therapy. We believe that syphilitic hepatitis and its treatment subsequently triggered an immunogenic response, leading to autoimmune hepatitis. Autoimmune hepatitis is a chronic liver disease thought to manifest as a result of predisposing genetic factors in combination with environmental insults, especially hepatotropic pathogens. Syphilis is a sexually transmitted disease caused by Treponema pallidum that has been associated with autoimmunity and the development of autoantibodies. We propose that in the setting of syphilitic hepatitis, a molecular mimicry event resulting from structural similarities between T. pallidum and liver antigens, as well as impaired regulatory T-cell function, led to the breakdown of immune tolerance and the onset of autoimmune hepatitis. To support this hypothesis, further molecular analyses and case series are necessary to determine if syphilitic hepatitis and its treatment are risk factors for the onset of autoimmune hepatitis. Autoimmune hepatitis should be considered early as the cause of acute liver injury in susceptible patients with risk factors for the disease, as prompt recognition and appropriate treatment may prevent progression of liver injury and result in improved outcomes.

Despite the advances in therapy, hepatitis B virus (HBV) and hepatitis C virus (HCV) still represent a significant global health burden, both as major causes of cirrhosis, hepatocellular carcinoma, and death worldwide. HBV is capable of incorporating its covalently closed circular DNA into the host cell’s hepatocyte genome, making it rather difficult to eradicate its chronic stage. Successful viral clearance depends on the complex interactions between the virus and host’s innate and adaptive immune response. One encouraging fact on hepatitis B is the development and effective distribution of the HBV vaccine. This has significantly reduced the spread of this virus. HCV is a RNA virus with high mutagenic capacity, thus enabling it to evade the immune system and have a high rate of chronic progression. High levels of HCV heterogeneity and its mutagenic capacity have made it difficult to create an effective vaccine. The recent advent of direct acting antivirals has ushered in a new era in hepatitis C therapy. Sustained virologic response is achieved with DAAs in 85–99% of cases. However, this still leads to a large population of treatment failures, so further advances in therapy are still needed. This article reviews the immunopathogenesis of HBV and HCV, their properties contributing to host immune system avoidance, chronic disease progression, vaccine efficacy and limitations, as well as treatment options and common pitfalls of said therapy.

Houttuynia cordata Thunb, which is a traditional Chinese herbal medicine, is commonly used as an anti-inflammatory, antiviral, and antibacterial agent in China. Emerging evidence shows that extracts of H. cordata Thunb have anticancer activity in human colorectal, leukemic, lung, and liver cancer cells; however, the specific active ingredients or compounds that responsible for these anticancer activities and their mechanism of action remain unknown. Sodium new houttuyfonate (SNH) is an additional product of the active ingredient houttuynin from H. cordata Thunb, which possesses anticancer activity; however, the molecular mechanisms that underlie its action have not been clarified. This study aims to explore the antitumor effect and related molecular mechanism of SNH on human non-small cell lung cancer (NSCLC).

The cytotoxicity of SNH against human lung cancer cells H1299 was investigated using WST-1 and apoptotic assays, and its antitumor molecular mechanism was explored using quantitative proteomics combined with various cellular and biochemical assays.

The results showed that SNH reduced the viability and enhanced the apoptosis of H1299 cells in a dose-dependent manner. Quantitative proteomics and ingenuity pathway analysis revealed that SNH downregulated the expression of cell cycle-related proteins, which included cyclin-dependent kinase 1 (CDK1), protein tyrosine phosphatase type IVA 2 (PTP4A2), and cyclin-dependent kinase 6 (CDK6), and upregulated the expression of Nrf2 (nuclear factor erythroid 2-related factor 2)-mediated oxidative stress response-related proteins in H1299 cells.

SNH-induced G0/G1 arrest and apoptosis in H1299 cells by the inhibition of cell cycle-related proteins that included CDK1, PTP4A2, CDK6, and activated the expression of Nrf2-mediated oxidative stress response-related proteins. These findings might provide new molecular mechanisms that underlie the antitumor activity of SNH against NSCLC and could implicate SNH as a novel therapeutic drug for NSCLC in the future.

Correct identification of small hepatocellular carcinomas (HCCs) and benign nodules in cirrhosis remains challenging, quantitative apparent diffusion coefficients (ADCs) have shown potential value in characterization of benign and malignant liver lesions. We aimed to explore the added value of ADCs in the identification of small (≤3 cm) HCCs and benign nodules categorized as Liver Imaging Reporting and Data System (LI-RADS) 3 (LR-3) and 4 (LR-4) in cirrhosis.

Ninety-seven cirrhosis patients with 109 small nodules (70 HCCs, 39 benign nodules) of LR-3 and 4 LR-4 based on major and ancillary magnetic resonance imaging features were included. Multiparametric quantitative ADCs of the lesions, including the mean ADC (ADCmean), minimum ADC (ADCmin), maximal ADC (ADCmax), ADC standard deviation (ADCstd), and mean ADC value ratio of lesion-to-liver parenchyma (ADCratio) were calculated. Regarding the joint diagnosis, a nomogram model was plotted using multivariate logistic regression analysis. The performance was assessed using the area under the receiver operating characteristic curve (AUC).

The ADCmean, ADCmin, ADCratio, and ADCstd were significantly associated with the identification of small HCC and benign nodules (p<0.001). For the joint diagnosis, the LI-RADS category (odds ratio [OR]=12.50), ADCmin (OR=0.14), and ADCratio (OR=0.12) were identified as independent factors for distinguishing HCCs from benign nodules. The joint nomogram model showed good calibration and discrimination, with a C-index of 0.947. Compared with the LI-RADS category alone, this nomogram model demonstrated a significant improvement in diagnostic performance, with AUC increasing from 0.820 to 0.967 (p=0.001).

The addition of quantitative ADCs could improve the identification of small HCC and benign nodules categorized as LR-3 and 4 LR-4 in patients with cirrhosis.

For high morbidity and mortality, hepatocellular carcinoma (HCC) becomes a major health issue worldwide. Nowadays, numerous non-coding RNAs (ncRNAs) are known to regulate the occurrence and pathogenesis of tumors. Some ncRNAs have also been developed as tumor biomarkers and therapeutic targets. However, the potential function of the small Cajal body-specific RNA (scaRNA) SCARNA16, a newly identified ncRNA, remains to be explored in HCC.

In both HCC cell lines and specimens from 120 enrolled patients, the expression values of SCARNA16 were detected. We divided patients into SCARNA16 high and low expression subgroups, and then analyzed the difference of various clinical characteristics and prognosis data between subgroups.

Compared to paired controls, SCARNA16 was significantly down-regulated in HCC cell lines and clinical specimens (p<0.01). Besides, HCC patients with lower SCARNA16 expression commonly presented with larger and more tumor lesions, more vessel carcinoma emboli, more capsular invasion and higher TNM stages (p<0.05). Moreover, SCARNA16 expression was negatively correlated with postoperative prognosis of HCC patients in 5-year follow-up, including tumor-free survival (TFS) (median time of low vs. high subgroups: 14 vs. 48 months, p=0.006) and overall survival (OS) (median time of low vs. high subgroups: 39 vs. 52 months, p=0.001). Besides, SCARNA16 acted as an independent prognostic biomarker in TFS (hazard ratio [HR]: 0.578, 95% CI: 0.345–0.969, p=0.038) and OS (HR: 0.366, 95% CI: 0.178–0.752, p=0.006).

Low expression patterns of SCARNA16 remarkably associated with severe clinical status and poor survival of patients, suggesting that SCARNA16 possesses potency as a novel biomarker for HCC.

B cell-mediated humoral immunity plays a vital role in viral infections, including chronic hepatitis B virus (HBV) infection, which remains a critical global public health issue. Despite hepatitis B surface antigen-specific antibodies are essential to eliminate viral infections, the reduced immune functional capacity of B cells was identified, which was also correlated with chronic hepatitis B (CHB) progression. In addition to B cells, T follicular helper (Tfh) cells, which assist B cells to produce antibodies, might also be involved in the process of anti-HBV-specific antibody production. Here, we provide a comprehensive review of the role of various subsets of B cells and Tfh cells during CHB progression and discuss current novel treatment strategies aimed at restoring humoral immunity. Understanding the mechanism of dysregulated B cells and Tfh cells will facilitate the ultimate functional cure of CHB patients.

Spontaneous bacterial peritonitis (SBP) is one of the leading causes of death in patients with liver cirrhosis. We aimed to establish a prognostic model to evaluate the 1-year survival of cirrhosis patients after the first episode of SBP.

A prognostic model was developed based on a retrospective derivation cohort of 309 cirrhosis patients with first-ever SBP and was validated in a separate validation cohort of 141 patients. We used Uno’s concordance, calibration curve, and decision curve (DCA) analysis to evaluate the discrimination, calibration, and clinical net benefit of the model.

A total of 59 (19.1%) patients in the derivation cohort and 42 (29.8%) patients in the validation cohort died over the course of 1 year. A prognostic model in nomogram form was developed with predictors including age [hazard ratio (HR): 1.25; 95% confidence interval (CI): 0.92–1.71], total serum bilirubin (HR: 1.66; 95% CI: 1.28–2.14), serum sodium (HR: 0.94; 95% CI: 0.90–0.98), history of hypertension (HR: 2.52; 95% CI: 1.44–4.41) and hepatic encephalopathy (HR: 2.06; 95% CI: 1.13–3.73). The nomogram had a higher concordance (0.79) compared with the model end-stage liver disease (0.67) or Child-Turcotte-Pugh (0.71) score. The nomogram also showed acceptable calibration (calibration slope, 1.12; Bier score, 0.15±0.21) and optimal clinical net benefit in the validation cohort.

This prediction model developed based on characteristics of first-ever SBP patients may benefit the prediction of patients’ 1-year survival.

Thioredoxin domain-containing 5 (TXNDC5) is an endoplasmic reticulum (ER) residing chaperon that is associated with the inflammatory phenotype of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs), such as high proliferation, cytokine production and invasion. However, if TXNDC5 is involved in communication between RA FLSs remains unknown.

Exosomes were separated and TXNDC5 expression in exosomes was detected by Western blotting, immunofluorescent staining, and flow cytometry. Cell Counting Kit-8 (CCK-8), Annexin V-APC/7-amino-actinomycin D staining, Western blotting, and enzyme-linked immuno sorbent assay (ELISA) were applied to detect the effects of exosomes on cell viability, apoptosis, activation of signaling pathways, and the production of inflammatory factors.

TXNDC5 protein was detected in the exosomes from RA FLSs and its content in exosomes increased when RA FLSs were stimulated by ER stress inducers. Functionally, TXNDC5 overexpressing RA FLSs-derived exosomes (TXNDC5-containing Exo) increased the production of inflammatory factors and the phosphorylated levels of extracellular regulated protein kinases (ERK), protein kinase B (PKB/Akt), p65 nuclear factor kappa beta (NF-κB), and p38 mitogen-activated protein kinase (MAPK) signaling pathways in recipient FLSs. In addition, recipient FLSs with increased TXNDC5 expression were characterized by enhanced cell viability but a decrease in apoptosis in response to ER stress. More importantly, the introduction of TXNDC5-containing Exo protected recipient RA FLSs against the toxicity of methotrexate for viability, cytokine production, and apoptosis.

In combination, these results could provide a novel approach for TXNDC5 to communicate via exosomes between RA FLSs to exacerbate inflammation of RA and specific inhibition of exosome-mediated delivery of TXNDC5 has potential as a novel treatment strategy for RA.

The efficacy of targeted programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs) has been confirmed in many solid malignant tumors. The overexpression of PD-1/PD-L1 serves as a biomarker to predict prognosis and clinical progression. However, the role of PD-1 in patients with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) remains indeterminate. Given that HBV is the most important cause for HCC, this study aimed to investigate the prognostic and clinicopathological value of PD-1 in HBV-HCC via a meta-analysis.

We searched PubMed, Embase, Scopus, the Cochrane Library, Web of Science and Google Scholar up to January 2021 for studies on the correlation between clinicopathology/prognosis and PD-1 in patients with HBV-HCC. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to investigate the prognostic significance of PD-1 expression. The odds ratios (ORs) and 95% CIs were determined to explore the association between PD-1 expression and clinicopathological features.

Our analysis included seven studies with 658 patients, which showed that high PD-1 expression was statistically correlated with poorer overall survival (HR=2.188, 95% CI: [1.262–3.115], p<0.001) and disease-free survival (HR=2.743, 95% CI: [1.980–3.506], p<0.001). PD-1 overexpression was correlated with multiple tumors (OR=2.268, 95% CI: [1.209–4.257], p=0.011), high level of alpha fetoprotein (AFP; OR=1.495, 95% CI: [1.005–2.223], p=0.047) and advanced Barcelona Clinic Liver Cancer (BCLC) stage (OR=3.738, 95% CI: [2.101–6.651], p<0.001).

Our meta-analysis revealed that the high level of PD-1 expression was associated with multiple tumors, high level of AFP and advanced BCLC stage. It significantly predicted a poor prognosis of HBV-HCC, which suggests that anti-PD-1 therapy for HBV-HCC patients is plausible.

The prognosis of hepatocellular carcinoma (HCC) is extremely poor; therefore, there is an urgent need for novel prognostic molecular biomarkers of HCC. The current investigation utilized circular (circ)RNA-associated competing endogenous (ce)RNAs analysis in order to identify significant prognostic biomarkers of HCC.

CircRNAs and mRNAs that were differentially expressed between normal and HCC tissues were identified. Their respective functions were predicted with Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. A nomogram was used for model verification.

A ceRNA network composed of differentially expressed circRNAs and mRNAs was constructed. Significant hub nodes in the ceRNA network were hsa_circ_0004662, hsa_circ_0005735, hsa_circ_0006990, hsa_circ_0018403 and hsa_circ_0100609. By using this information, a prognostic risk assessment tool was developed based on the expressions of seven genes (PLOD2, TARS, RNF19B, CCT2, RAN, C5orf30 and MCM10). Furthermore, multivariate Cox regression analysis revealed risk and T-stage parameters as independent prognostic factors. The nomograms that were constructed from risk and T-stage groups were used to further assess the prediction of HCC patient survival rates. The nomogram, which consisted of risk and T-stage scores assessment models, was found to be an independent factor for predicting prognosis of HCC.

Five circRNAs, including hsa_circ_0004662, hsa_circ_0005735, hsa_circ_0006990, hsa_circ_0018403 and hsa_circ_0100609, that may play key roles in the progression of HCC were identified. Seven gene signatures were identified, which were associated with the aforementioned circRNAs, including PLOD2, TARS, RNF19B, CCT2, RAN, C5orf30 and MCM10, all of which were significant genes involved in the pathophysiology of HCC. These genes may be used as a prognosticating tool in HCC patients.

Alzheimer’s disease (AD) is a neurodegenerative disorder with a complex pathology that is not completely understood. Over time, AD reduces one’s cortical and subcortical functioning. The incidence and prevalence of AD is projected to increase as the worldwide population continues to grow older. While advances in the field of neurology and medicine continue to improve, there are presently no novel therapeutic agents to prevent, halt, or cure patients suffering from AD. The utilization of biomarkers that aid the diagnostic algorithm, drug response monitoring and disease progression that add to further our understanding of the pathophysiology of neurodegenerative disease is vastly expanding. The significance of amyloid plaque deposition, tau pathology, and neurofibrillary tangle accumulation have been well-studied in the realm of neurodegenerative diseases for decades and are proposed biomarkers. However, it has been difficult to stratify physiological biomarkers of blood/plasma, cerebrospinal fluid, saliva/urine/hair/nail for diagnostic utility and overall understanding in the pathogenesis of neurodegeneration. We aim to review the most relevant, up-to-date biomarkers and their implications in AD.

It remains difficult to forecast the 180-day prognosis of patients with hepatitis B virus-acute-on-chronic liver failure (HBV-ACLF) using existing prognostic models. The present study aimed to derive novel-innovative models to enhance the predictive effectiveness of the 180-day mortality in HBV-ACLF.

The present cohort study examined 171 HBV-ACLF patients (non-survivors, n=62; survivors, n=109). The 27 retrospectively collected parameters included the basic demographic characteristics, clinical comorbidities, and laboratory values. Backward stepwise logistic regression (LR) and the classification and regression tree (CART) analysis were used to derive two predictive models. Meanwhile, a nomogram was created based on the LR analysis. The accuracy of the LR and CART model was detected through the area under the receiver operating characteristic curve (AUROC), compared with model of end-stage liver disease (MELD) scores.

Among 171 HBV-ACLF patients, the mean age was 45.17 years-old, and 11.7% of the patients were female. The LR model was constructed with six independent factors, which included age, total bilirubin, prothrombin activity, lymphocytes, monocytes and hepatic encephalopathy. The following seven variables were the prognostic factors for HBV-ACLF in the CART model: age, total bilirubin, prothrombin time, lymphocytes, neutrophils, monocytes, and blood urea nitrogen. The AUROC for the CART model (0.878) was similar to that for the LR model (0.878, p=0.898), and this exceeded that for the MELD scores (0.728, p<0.0001).

The LR and CART model are both superior to the MELD scores in predicting the 180-day mortality of patients with HBV-ACLF. Both the LR and CART model can be used as medical decision-making tools by clinicians.

Previous studies reported that serum resistin levels were remarkably changed in patients with nonalcoholic fatty liver disease (NAFLD) but the conclusions were inconsistent. The aim of this study was to investigate accurate serum resistin levels in adult patients with NAFLD.

A complete literature research was conducted in the PubMed, Embase, and Cochrane Library databases, and all the available studies up to 7 May 2020 were reviewed. The pooled standardized mean difference (SMD) values were calculated to investigate the serum resistin levels in patients with NAFLD and healthy controls.

A total of 28 studies were included to investigate the serum resistin levels in patients with NAFLD. Patients with NAFLD had higher serum resistin levels than controls (SMD=0.522, 95% confidence interval [CI]: 0.004–1.040, I2=95.9%). Patients with nonalcoholic steatohepatitis (NASH) had lower serum resistin levels than the healthy controls (SMD=−0.44, 95% CI: −0.83–0.55, I2=74.5%). In addition, no significant difference of serum resistin levels was observed between patients with NAFL and healthy controls (SMD=−0.34, 95% CI: −0.91–0.23, I2=79.6%) and between patients with NAFL and NASH (SMD=0.15, 95% CI: −0.06–0.36, I2=0.00%). Furthermore, subgroup and sensitivity analyses suggested that heterogeneity did not affect the results of meta-analysis.

This meta-analysis investigated the serum resistin levels in adult patients with NAFLD comprehensively. Patients with NAFLD had higher serum resistin levels and patients with NASH had lower serum resistin levels than healthy controls. Serum resistin could serve as a potential biomarker to predict the development risk of NAFLD.

The pathogenesis of liver fibrosis involves liver damage, inflammation, oxidative stress, and intestinal dysfunction. Indole-3-propionic acid (IPA) has been demonstrated to have antioxidant, anti-inflammatory and anticancer activities, and a role in maintaining gut homeostasis. The current study aimed to investigate the role of IPA in carbon tetrachloride (CCl4)-induced liver fibrosis and explore the underlying mechanisms.

The liver fibrosis model was established in male C57BL/6 mice by intraperitoneal injection of CCl4 twice weekly. IPA intervention was made orally (20 mg/kg daily). The degree of liver injury and fibrosis were assessed by serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and histopathology. Enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction (qPCR) were used to detect the inflammatory cytokines. The malondialdehyde (MDA), glutathione, glutathione peroxidase, superoxide dismutase, and catalase were determined via commercial kits. Hepatocyte apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The expression of mRNA and protein was assayed by qPCR, Western blotting, or immunohistochemical staining.

After IPA treatment, the ALT and AST, apoptotic cells, and pro-inflammatory factor levels were enhanced significantly. Moreover, IPA intervention up-regulated the expression of collagen I, α-smooth muscle actin, tissue inhibitor of matrix metalloproteinase-1, matrix metalloproteinase-2, transforming growth factor-β1 (TGF-β1), Smad3, and phosphorylated-Smad2/3. Additionally, IPA intervention did not affect the MDA level. Attractively, the administration of IPA remodeled the gut flora structure.

IPA aggravated CCl4-induced liver damage and fibrosis by activating HSCs via the TGF-β1/Smads signaling pathway.

In the last decade, several second-line therapies followed by sorafenib in patients with advanced hepatocellular carcinoma (HCC) have been reported. But the outcomes were different from each other. This meta-analysis aimed to evaluate the efficacy and safety of the second-line therapies followed by sorafenib in patients with advanced HCC.

Embase (1974 to October 2019) and Ovid MEDLINE (1946 to October 2019) were searched for randomized clinical trials on second-line therapies followed by sorafenib in patients with advanced HCC. The quality of each study was assessed by the modified Jadad scale. Statistical analysis was carried out by RevMan5.3 software. Efficacy and safety were analyzed. Efficacy included overall survival (OS), disease control rate, time to progression, and progression-free survival.

Eight studies involving 3,173 patients were eligible. No difference in OS was found between the second-line treatment group and the control group (HR=0.87, 95% CI: 0.74–1.01, p=0.06). Disease control rate (relative risk (RR)=1.36, 95% CI: 1.16–1.60, p=0.0002), time to progression (HR=0.64, 95% CI: 0.51–0.81, p=0.0002) and progression-free survival (HR=0.60, 95% CI: 0.46–0.77, p<0.0001) were significantly improved by the second-line therapies. There was a slight difference in adverse events of any grade (RR=1.07, 95% CI: 1.00–1.14, p=0.03) between the two groups.

These second-line therapies followed by sorafenib may potentially improve the prognosis in patients with advanced HCC. Compared with other second-line therapies, regorafenib seemed to be more effective.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in the world. The rising prevalence of nonalcoholic steatohepatitis (NASH) has led to a 170% increase in NASH cirrhosis as the listing indication for liver transplantation from 2004 to 2013. As of 2018, NASH has overtaken hepatitis C as an indication for liver transplantation in the USA. After liver transplantation, the allograft often develops recurrent NAFLD among patients with known NASH cirrhosis. In addition to recurrent disease, de novo NAFLD has been reported in patients with other indications for liver transplantation. In this review, we will discuss the risk factors associated with recurrent and de novo NAFLD, natural course of the disease, and management strategies after liver transplantation.

The ongoing coronavirus disease-2019 (COVID-19) pandemic has necessitated special considerations in the management of diseases. The way presence of pre-existing diseases or treatment for it predisposes to, alters course of, and changes the management of COVID-19, is of relevance and is being extensively studied. Autoimmune hepatitis (AIH) is unique in that it is an autoimmune disease mandating treatment with immunosuppressive drugs, as well as a liver disease with potential for varying degrees of underlying fibrosis. The use of immunosuppressive drugs could alter the risk of acquiring COVID-19, the clinical course and severity of COVID-19 and the degree of underlying liver fibrosis could alter the clinical outcomes of patients with COVID-19. In this review, we try to summarize key areas relevant in understanding and improving the clinical care of patients with AIH in the current pandemic. Special considerations required in the management of patients with AIH in COVID-19 hotspots have been outlined based on the current evidence.

The overall survival (OS) of hepatocellular carcinoma (HCC) remains dismal. Bioinformatic analysis of transcriptome data could identify patients with poor OS and may facilitate clinical decision. This study aimed to develop a prognostic gene model for HCC.

GSE14520 was retrieved as a training set to identify differential expressed genes (DEGs) between tumor and adjacent liver tissues in HCC patients with different OS. A DEG-based prognostic model was then constructed and the TCGA-LIHC and ICGC-LIRI datasets were used to validate the model. The area under the receiver operating characteristic curve (AUC) and hazard ratio (HR) of the model for OS were calculated. A model-based nomogram was established and verified.

In the training set, differential expression analysis identified 80 genes dysregulated in oxidation-reduction and metabolism regulation. After univariate Cox and LASSO regression, eight genes (LPCAT1, DHRS1, SORBS2, ALDH5A1, SULT1C2, SPP1, HEY1 and GOLM1) were selected to build the prognostic model. The AUC for 1-, 3- and 5-year OS were 0.779, 0.736, 0.754 in training set and 0.693, 0.689, 0.693 in the TCGA-LIHC validation set, respectively. The AUC for 1- and 3-year OS were 0.767 and 0.705 in the ICGC-LIRI validation set. Multivariate analysis confirmed the model was an independent prognostic factor (training set: HR=4.422, p<0.001; TCGA-LIHC validation set: HR=2.561, p<0.001; ICGC-LIRI validation set: HR=3.931, p<0.001). Furthermore, a nomogram combining the model and AJCC stage was established and validated, showing increased OS predictive efficacy compared with the prognostic model (p=0.035) or AJCC stage (p<0.001).

Our eight-gene prognostic model and the related nomogram represent as reliable prognostic tools for OS prediction in HCC patients.

Protein phosphatase 2A (PP2A) is associated with many cancers. This study aimed to clarify whether PPP2CA, which encodes the alpha isoform of the catalytic subunit of PP2A, plays a role in hepatocellular carcinoma (HCC) and to identify the potential underlying molecular pathways.

Based on bioinformatics, public databases and our in-house RNA-Seq database, we analyzed the clinical value and molecular mechanism of PPP2CA in HCC.

Data were analyzed from 2,545 patients with HCC and 1,993 controls without HCC indexed in The Cancer Genome Atlas database, the Gene Expression Omnibus database and our in-house RNA-Seq database. PPP2CA expression was significantly higher in HCC tissue than in non-cancerous tissues (standardized mean difference: 0.69, 95% confidence interval [CI]: 0.50–0.89). PPP2CA expression was able to differentiate HCC from non-HCC, with an area under the summary receiver operator characteristic curve of 0.79 (95% CI: 0.75–0.83). Immunohistochemistry of tissue sections confirmed that PPP2CA protein was up-regulated in HCC tissues. High PPP2CA expression in HCC patients was associated with shorter overall, progression-free and disease-free survival. Potential molecular pathways through which PPP2CA may be involved in HCC were determined using miRWalk 2.0 as well as analysis of Gene Ontology categories, Kyoto Encyclopedia of Genes and Genomes pathways, and protein-protein interaction networks.

PPP2CA is up-regulated in HCC and higher expression correlates with worse prognosis. PPP2CA shows potential as a diagnostic marker for HCC. Future studies should examine whether PPP2CA contributes to HCC through the candidate microRNAs, pathways and hub genes identified in this study.

The impact of coronavirus disease-2019 (COVID-19) on liver function remains to be fully elucidated. This study was designed to investigate such and determine the clinical significance in determining mortality risk.

A retrospective study was conducted in patients with COVID-19 from March 2020 to July 2020. Clinical details were retrieved from electronic medical records to obtain clinical characteristics, medical history, laboratory tests, therapeutic intervention, and outcome data.

A total of 184 patients with COVID-19 were included (median age: 45.5 years), comprised of 62.5% men. In total, 22 (12.0%) patients had severe infection and 162 (88.0%) had mild to moderate infection. Overall, 95 (51.6%) showed abnormal liver function test (LFT) and 17 (9.2%) showed normal LFT at admission. The median age, hospital stay, and LFT were significantly higher in severe vs. non-severe infection (p<0.001). Out of 12 deaths, the majority were due to severe infection (n=11). Deaths were also due to acute respiratory distress syndrome (n=5), cardiac reasons (n=3), and sepsis with multiorgan failure (n=3). The median age, hospital stay and number of intensive care unit admissions were higher in patients having abnormal LFT compared to normal LFT. Incidence of elevated aspartate aminotransferase (42.8% and 40.4%), alanine transaminase (43.7% and 41.6%), and hypoalbuminemia (71.4% and72.7%) at admission and discharge were more common in severe infection. The mean survival was significantly lower in severe infection compared to those with non-severe disease (17.2 vs. 52.3 days; p<0.001).

Incidence of abnormal liver function was higher in patients with severe COVID-19 and was associated with prolonged hospital stay; mortality was associated with severity of COVID-19. For ruling out the risk of liver injury, it is crucial to vigilantly monitor the liver function parameters in patients with COVID-19 admitted to hospital.