Identification of CD8+ T-cell exhaustion signatures for prognosis in HBV-related hepatocellular carcinoma patients by integrated analysis of single-cell and bulk RNA-sequencing.

BACKGROUND: HBV infection is the leading risk factor for HCC. HBV infection has been confirmed to be associated with the exhaustion status of CD8+ T cells and immunotherapeutic efficacy in HCC. In this study, we aimed to investigate the prognostic value of the CD8+ T-cell exhaustion signature and immunotherapy response in patients with HBV-related HCC. METHODS: We identified different clusters of HBV-related HCC cells by single-cell RNA sequencing (scRNA-seq) and identified CD8+ T-cell exhaustion-related genes (TERGs) by pseudotime analysis. We conducted differential expression analysis and LASSO Cox regression to detect genes and construct a CD8+ T-cell exhaustion index (TEI). We next combined the TEI with other clinicopathological factors to design a prognostic nomogram for HCC patients. We also analysed the difference in the TEI between the non-responder and responder groups during anti-PD-L1 therapy. In addition, we investigated how HBV induces CD8+ T lymphocyte exhaustion through the inhibition of tyrosine metabolism in HCC using gene set enrichment analysis and RT‒qPCR. RESULTS: A CD8+ T-cell exhaustion index (TEI) was established with 5 TERGs (EEF1E1, GAGE1, CHORDC1, IKBIP and MAGOH). An AFP level > 500 ng, vascular invasion, histologic grade (G3-G4), advanced TNM stage and poor five-year prognosis were related to a higher TEI score, while HBV infection was related to a lower TEI score. Among those receiving anti-PD-L1 therapy, responders had lower TEIs than non-responders did. The TEI also serves as an independent prognostic factor for HCC, and the nomogram incorporating the TEI, TNM stage, and vascular invasion exhibited excellent predictive value for the prognosis in HCC patients. RT‒qPCR revealed that among the tyrosine metabolism-associated genes, TAT (tyrosine aminotransferase) and HGD (homogentisate 1,2 dioxygenase) were expressed at lower levels in HBV-HCC than in non-HBV HCC. CONCLUSION: Generally, we established a novel TEI model by comprehensively analysing the progression of CD8+ T-cell exhaustion, which shows promise for predicting the clinical prognosis and potential immunotherapeutic efficacy in HBV-related HCC patients.

Circular RNAs in non-alcoholic fatty liver disease: Functions and clinical significance.

Nonalcoholic fatty liver disease (NAFLD), which affects approximately 25% of the global population, is an urgent health issue leading to various metabolic comorbidities. Circular RNAs (circRNAs), covalently closed RNA molecules, are characterized by ubiquity, diversity, stability, and conservatism. Indeed, they participate in various biological processes via distinct mechanisms that could modify the natural history of NAFLD. In this review, we briefly introduce the biogenesis, characteristics, and biological functions of circRNAs. Furthermore, we summarize circRNAs expression profiles in NAFLD by intersecting seven sequencing data sets and describe the cellular roles of circRNAs and their potential advantages as biomarkers of NAFLD. In addition, we emphatically discuss the exosomal non-coding RNA sorting mechanisms and possible functions in recipient cells. Finally, we extensively discuss the potential application of targeting disease-related circRNAs and competing endogenous RNA networks through gain-of-function and loss-of-function approaches in targeted therapy of NAFLD.

Acetyl-11-keto-ß-boswellic acid restrains the progression of synovitis in osteoarthritis via the Nrf2/HO-1 pathway.

Synovial inflammation plays a key role in osteoarthritis (OA) pathogenesis. Fibroblast-like synoviocytes (FLSs) represent a distinct cell subpopulation within the synovium, and their unique phenotypic alterations are considered significant contributors to inflammation and fibrotic responses. The underlying mechanism by which acetyl-11-keto-ß-boswellic acid (AKBA) modulates FLS activation remains unclear. This study aims to assess the beneficial effects of AKBA through both in vitro and in vivo investigations. Network pharmacology evaluation is used to identify potential targets of AKBA in OA. We evaluate the effects of AKBA on FLSs activation in vitro and the regulatory role of AKBA on the Nrf2/HO-1 signaling pathway. ML385 (an Nrf2 inhibitor) is used to verify the binding of AKBA to its target in FLSs. We validate the in vivo efficacy of AKBA in alleviating OA using anterior cruciate ligament transection and destabilization of the medial meniscus (ACLT+DMM) in a rat model. Network pharmacological analysis reveals the potential effect of AKBA on OA. AKBA effectively attenuates lipopolysaccharide (LPS)-induced abnormal migration and invasion and the production of inflammatory mediators, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS) in FLSs, contributing to the restoration of the synovial microenvironment. After treatment with ML385, the effect of AKBA on FLSs is reversed. In vivo studies demonstrate that AKBA mitigates synovial inflammation and fibrotic responses induced by ACLT+DMM in rats via activation of the Nrf2/HO-1 axis. AKBA exhibits theoretical potential for alleviating OA progression through the Nrf2/HO-1 pathway and represents a viable therapeutic candidate for this patient population.

Hydrophobic Tetracycline Immobilized in Fibrous Hyaluronan Regulates Adhesive Collagen-Based Hydrogel Stability for Infected Wound Healing.

Collagen-based hydrogels have a significant impact on wound healing, but they suffer from structural instability and bacterial invasion in infected wounds. Here, electrospun nanofibers of esterified hyaluronan (HA-Bn/T) are developed to immobilize the hydrophobic antibacterial drug tetracycline by π-π stacking interaction. Dopamine-modified hyaluronan and HA-Bn/T are employed simultaneously to stabilize the structure of collagen-based hydrogel by chemically interweaving the collagen fibril network and decreasing the rate of collagen degradation. This renders it injectable for in situ gelation, with suitable skin adhesion properties and long-lasting drug release capability. This hybridized interwoven hydrogel promotes the proliferation and migration of L929 cells and vascularization in vitro. It presents satisfactory antibacterial ability against Staphylococcus aureus and Escherichia coli. The structure also retains the functional protein environment provided by collagen fiber, inhibits the bacterial environment of infected wounds, and modulates local inflammation, resulting in neovascularization, collagen deposition, and partial follicular regeneration. This strategy offers a new solution for infected wound healing.

Epstein-Barr virus infection: the micro and macro worlds.

Epstein‒Barr virus (EBV) is a DNA virus that belongs to the human B lymphotropic herpesvirus family and is highly prevalent in the human population. Once infected, a host can experience latent infection because EBV evades the immune system, leading to hosts harboring the virus for their lifetime. EBV is associated with many diseases and causes significant challenges to human health. This review first offers a description of the natural history of EBV infection, clarifies the interaction between EBV and the immune system, and finally focuses on several major types of diseases caused by EBV infection.

EMT-Related Gene Signature: A New Method for Personalized Risk Assessment in Patients with Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, accounting for more than 700,000 deaths annually. Epithelial-mesenchymal transition (EMT) is posited to contribute to HCC progression. We, therefore, aimed to elucidate the relationship between EMT-related gene (ERG) expression and prognosis in patients with HCC. METHODS: Univariate and multivariate Cox regression analyses were performed to identify prognostic-related differentially expressed EMT-related genes (DE-ERGs). Time-dependent receiver operating characteristic and Kaplan-Meier curves were used to assess the prognostic performance of the EMT-related signature. pRRophetic R package was used to evaluate sorafenib sensitivity in the GSE14520 cohort. Gene expression in Huh7 and L02 cell lines was detected by real-time PCR and Western blotting. Differential expression of the three genes between HCC tissues and normal tissues was validated using immunohistochemical analyses. RESULTS: Of the 76 identified DE-ERGs, 29 were associated with overall survival. Three prognosis-related ERGs (GOLM1, SOX4, and CD14) were screened out by multivariate Cox regression. A gene signature was identified based on the three prognostic-related ERGs. HCC patients with a low-risk score had a better prognosis and were more sensitive to sorafenib compared to those with a high-risk score. Moreover, we further confirmed increased expression of GOLM1 and SOX4, and decreased expression of CD14, in liver cancer cell line and HCC tissue. CONCLUSIONS: The results of the present study demonstrate the utility of an ERG signature as a potential biomarker informing prognosis in patients with HCC, which may contribute to the implementation of personalized therapies.

Longitudinal change of circulating tumor cell level and its relationship with immune checkpoint inhibitor-based treatment benefits in unresectable, metastatic colorectal cancer patients.

OBJECTIVE: Circulating tumor cell (CTC) exerts diagnostic and prognostic value in colorectal cancer (CRC) patients. This study intended to further investigate the longitudinal change of CTC count, and its correlation with the prognosis of immune checkpoint inhibitor (ICI)-based treatments in unresectable, metastatic CRC patients. METHODS: Fifty-six unresectable, metastatic CRC patients receiving ICI-based treatments were enrolled. CTC count was assessed by the CellSearch system at baseline and month (M)2 in their peripheral blood samples. RESULTS: Forty-one (73.2%) and sixteen (28.5%) patients had CTC count ≥1 and ≥5 at baseline, respectively. Meanwhile, CTC count at M2 was decreased versus that at baseline (median (interquartile range): 1.0 (0.0-3.0) versus 3.0 (0.0-5.0)) (p < 0.001). Besides, increased CTC count at baseline (p = 0.009) and M2 (p = 0.006) associated with a reduced overall response rate. Baseline CTC count ≥5 related to worse progression-free survival (PFS) (p = 0.007), but baseline CTC count ≥1 did not; additionally, baseline CTC count ≥1 (p = 0.043) and ≥5 (p = 0.016) linked to shorter overall survival (OS). Furthermore, M2 CTC count ≥1 (p = 0.002) and ≥5 (p < 0.001) both correlated with poor PFS; meanwhile, M2 CTC count ≥1 (p = 0.006) and ≥5 (p < 0.001) also related to worse OS. After adjustment, only CTC count at M2 ≥ 5 independently associated with unsatisfactory PFS (hazard ratio (HR)=3.218, p = 0.011) and OS (HR = 3.229, p = 0.038). CONCLUSIONS: CTC count is decreased during ICI-based treatments, its reduction represents satisfactory treatment outcomes in unresectable, metastatic CRC patients. Notably, the CTC count at 5 as a cutting threshold after a two-month treatment has an impressive prognostic value.

Ultrabright Renal-Clearable Cyanine-Protein Nanoprobes for High-Quality NIR-II Angiography and Lymphography.

The renal-clearable aspect of imaging agent with minimum toxicity issues and side effects is essential for clinical translation, yet clinical near-infrared-I/II (NIR-I/II) fluorophores with timely renal-clearance pathways are very limited. Herein, we rationally develop the cyanine-protein composite strategy through covalent bonding of ß-lactoglobulin (ß-LG) and chloride-cyanine dye to produce a brilliant and stable NIR-I/II fluorophore (e.g., ß-LG@IR-780). The ß-LG acts as a protecting shell with small molecular weight (18.4 kDa) and ultrasmall size (<5 nm), thus endowing the ß-LG@IR-780 with excellent biocompatibility and renal excretion. Our ß-LG@IR-780 probe enables noninvasive and precise NIR-II visualization of the physiological and pathological conditions of the vascular and lymphatic drainage system, facilitating intraoperative imaging-guided surgery and postoperative noninvasive monitoring. The minimum accumulation of our probes in the main organs improves the overall biosafety. This study provides a facile methodology for new-generation NIR-II fluorophores and largely improves the brightness and pharmacokinetics of small molecular dyes.

CircRNA-PI4KB Induces Hepatic Lipid Deposition in Non-Alcoholic Fatty Liver Disease by Transporting miRNA-122 to Extra-Hepatocytes.

Ectopic fat deposition in the liver, known as non-alcoholic fatty liver disease (NAFLD), affects up to 30% of the worldwide population. miRNA-122, the most abundant liver-specific miRNA, protects hepatic steatosis and inhibits cholesterol and fatty acid synthesis in NAFLD. Previously, we have shown that compared with its expression in healthy controls, miRNA-122 decreased in the liver tissue but gradually increased in the serum of patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, suggesting that miRNA-122 could have been transported to the serum. Here, we aimed to confirm and unravel the mechanism of transportation of miRNA-122 to extra-hepatocytes. Our findings showed a decrease in the intra-hepatocyte miRNA-122 and an increase in the extra-hepatocyte (medium level) miRNA-122, suggesting the miRNA-122 "escaped" from the intra-hepatocyte due to an increased extra-hepatocyte excretion. Using bioinformatics tools, we showed that miRNA-122 binds to circPI4KB, which was further validated by an RNA pull-down and luciferase reporter assay. The levels of circPI4KB in intra- and extra-hepatocytes corresponded to that of miRNA-122, and the overexpression of circPI4KB increased the miRNA-122 in extra-hepatocytes, consequently accomplishing a decreased protective role of miRNA-122 in inhibiting the lipid deposition. The present study provides a new explanation for the pathogenesis of the hepatic lipid deposition in NAFLD.

Pegylated interferon-α-2b combined with tenofovir disoproxil fumarate, granulocyte-macrophage colony-stimulating factor, and hepatitis B vaccine treatment for naïve HBeAg-positive chronic hepatitis B patients: A prospective, multicenter, randomized controlled study.

Hepatitis B surface antigen (HBsAg) loss or seroconversion is an ideal treatment endpoint for patients with chronic hepatitis B but is rarely achievable in  hepatitis B e-antigen (HBeAg)-positive patients using existing treatment strategies. In this study, the effect of pegylated interferon (peg-IFN) alfa-2b plus tenofovir disoproxil fumarate (TDF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and hepatitis B vaccine was evaluated. This randomized controlled trial was conducted at nine liver centers in Chinese university hospitals from May 2018 to July 2020. Patients (n = 303) enrolled were randomly administered peg-IFN-α-2b combined with TDF, GM-CSF, and hepatitis B vaccine (experimental group); peg-IFN-α-2b plus TDF (control group 2); or interferon-α-2b alone (control group 1). The primary efficacy endpoint was HBsAg seroconversion at 48 weeks and the secondary endpoint included safety. No differences in baseline HBsAg levels were observed among the groups. The primary endpoint was achieved in three (3.0%), one (1.03%), and one (1.19%) patient in the experimental group, control group 2, and control group 1, respectively. The incidence of HBsAg seroconversion at week 48 was not significantly different among the three groups (p = 0.629). However, the decrease in serum levels of HBsAg at week 48 was significantly higher in the experimental and control group 2 compared with that in control group 1 (p = 0.008 and 0.006, respectively). No significant difference between the experimental and control group 2 was observed (p = 0.619). Adverse events were not significantly different among the groups except for the lower incidence of neutropenia in the experimental group. Peg-IFN-α-2b combined with TDF, GM-CSF, and hepatitis B vaccine is not superior to peg-IFN-α-2b combined with TDF in HBeAg-positive naïve patients. Clinical Trials Registration: ChiCTR1800016173.

Predicting progression to severe COVID-19 using the PAINT score.

OBJECTIVES: One of the major challenges in treating patients with coronavirus disease 2019 (COVID-19) is predicting the severity of disease. We aimed to develop a new score for predicting progression from mild/moderate to severe COVID-19. METHODS: A total of 239 hospitalized patients with COVID-19 from two medical centers in China between February 6 and April 6, 2020 were retrospectively included. The prognostic abilities of variables, including clinical data and laboratory findings from the electronic medical records of each hospital, were analysed using the Cox proportional hazards model and Kaplan-Meier methods. A prognostic score was developed to predict progression from mild/moderate to severe COVID-19. RESULTS: Among the 239 patients, 216 (90.38%) patients had mild/moderate disease, and 23 (9.62%) progressed to severe disease. After adjusting for multiple confounding factors, pulmonary disease, age > 75, IgM, CD16+/CD56+ NK cells and aspartate aminotransferase were independent predictors of progression to severe COVID-19. Based on these five factors, a new predictive score (the 'PAINT score') was established and showed a high predictive value (C-index = 0.91, 0.902 ± 0.021, p < 0.001). The PAINT score was validated using a nomogram, bootstrap analysis, calibration curves, decision curves and clinical impact curves, all of which confirmed its high predictive value. CONCLUSIONS: The PAINT score for progression from mild/moderate to severe COVID-19 may be helpful in identifying patients at high risk of progression.

Determinants of suboptimal immune recovery among a Chinese Yi ethnicity population with sustained HIV suppression.

OBJECTIVES: Despite sustained viral suppression with effective antiretroviral therapy (ART), HIV-infected patients with suboptimal immune recovery are still at high risk of both non-AIDS-related and AIDS-related events. The aim of this study was to investigate determinants potentially associated with suboptimal CD4 + T cell count recovery during free ART with sustained viral suppression among an HIV-infected Yi ethnicity population in Liangshan Prefecture, an area in China with high HIV prevalence. METHODS: This retrospective study included HIV-infected Yi adults (≥ 18 years and baseline CD4 + T cell count less than 500 cells/µL) for whom ART supported by National Free Antiretroviral Treatment Program was initiated between January 2015 and December 2018 in Zhaojue County, Liangshan Prefecture. Virological suppression (viral load < 50 copies/mL) was achieved within 12 months after ART initiation, and sustained virological suppression was maintained. Multivariate log-binomial regression analysis was used to assess determinants of suboptimal immune recovery. RESULTS: There were 140 female and 137 male patients in this study, with a mean age of 36.57 ± 7.63 years. Most of the Yi patients were infected through IDU (48.7%) or heterosexual contact (49.8%), and the anti-HCV antibody prevalence was high (43.7%, 121/277). Of the 277 patients with a mean ART duration of 3.77 ± 1.21 years, complete immune recovery occurred in only 32.9%. The baseline CD4 + T cell count in patients with suboptimal and intermediate immune recovery was 248.64 ± 108.10 and 288.59 ± 108.86 cells/µL, respectively, which was much lower than the baseline 320.02 ± 123.65 cells/µL in patients who achieved complete immune recovery (p < 0.001). Multivariable analysis demonstrated that low pre-ART CD4 + cell count and coinfection with HCV were associated with immune recovery of the HIV patients. CONCLUSIONS: Our study suggests that for HIV-infected Yi patients in Liangshan Prefecture, prompt ART initiation after diagnosis of HIV infection should be applied, and curative HCV treatment should be given to patients with HCV/HIV coinfection to improve the immunological effectiveness of ART. Trial registration None.

[Assessment Value of Short-Term Prognosis of Six Predictive Models for Patients with Acute-on-Chronic Liver Failure Treated with Artificial Liver Support System].

Objective: To apply 6 predictive models on acute-on-chronic liver failure (ACLF) patients treated with artificial liver support system (ALSS), and to compare their assessment values for the short-term prognosis of patients. Methods: A total of 258 ACLF patients who underwent ALSS therapy between January 2018 and December 2019 were selected from the ALSS clinical database established by West China Hospital, Sichuan University, and their clinical data and 90-day prognosis information were collected. Cox proportional hazards model was used to estimate the association between the six predictive models, including Chinese Group on the Study of Severe Hepatitis B-ACLF (COSSH ACLF), European Association for the Study of the Liver--Chronic Liver Failure-Consortium (CLIF-C) ACLF, CLIF-C Organ Failure (OF), Asian Pacific Association for the Study of the Liver (APASL) ACLF Research Consortium (AARC) ACLF, Model for End-Stage Liver Disease (MELD) and Simplified MELD (sMELD), and 90-day mortality, which included death or receiving liver transplantation. The area under the receiver operating characteristic (ROC) curve ( AUC), Harrell's C-index and Brier scores were calculated and compared to evaluate the predictive power. Results: A total of 258 ACLF patients were enrolled. Of these patients, who had a mean age of (46.2±11.7) years old, 37 (14.3%) patients were female, 202 (78.3%) patients had a diagnosis of liver cirrhosis, and 107 (41.5%) patients died during the 90-day follow-up period. The six predictive models all yielded higher scores for patients who died than those for patients who survived (all P<0.001). The six predictive models were all independent risk factors for the short-term prognosis of ACLF patients treated with ALSS (all adjusted hazard ratio [HR]>1, all P<0.001). The AUC (0.806, 95% confidence interval [CI]: 0.753-0.853) and Harrell's C-index (0.772, 95% CI: 0.727-0.816) of COSSH ACLF were much higher than those of the five other predictive models (all AUCs<0.750, P<0.01; all Harrell's C-indices<0.750, P<0.001). The Brier score of COSSH ACLF was 0.18 (95% CI: 0.15-0.20). The 90-day mortality of patients defined as having low risk, moderate risk, and high risk according to the risk stratification of COSSH ACLF were 22.2%, 56.3%, and 90.2%, respectively. Conclusion: The COSSH ACLF could more accurately predict short-term prognosis in ACLF patients who received ALSS therapy, and could facilitate clinical decision-making.

Ribosome-targeting antibacterial agents: Advances, challenges, and opportunities.

Ribosomes, which synthesize proteins, are critical organelles for the survival and growth of bacteria. About 60% of approved antibiotics discovered so far combat pathogenic bacteria by targeting ribosomes. However, several issues, such as drug resistance and toxicity, have impeded the clinical use of ribosome-targeting antibiotics. Moreover, the complexity of the bacteria ribosome structure has retarded the discovery of new ribosome-targeting agents that are considered as the key to the drug-resistance and toxicity. To deal with these challenges, efforts such as medicinal chemistry optimization, combination treatment, and new drug delivery system have been developed. But not enough, the development of structural biology and new screening methods bring powerful tools, such as cryo-electron microscopy technology, advanced computer-aided drug design, and cell-free in vitro transcription/translation systems, for the discovery of novel ribosome-targeting antibiotics. Thus, in this paper, we overview the research on different aspects of bacterial ribosomes, especially focus on discussing the challenges in the discovery of ribosome-targeting antibacterial drugs and advances made to address issues such as drug-resistance and selectivity, which, we believe, provide perspectives for the discovery of novel antibiotics.

Efficacy of different nucleoside analog rescue therapies for entecavir-resistant chronic hepatitis B patients.

BACKGROUND: Entecavir (ETV) is recommended as a first-line anti-HBV treatment. However, many chronic hepatitis B patients initiate anti-HBV treatment such as lamivudine and telbivudine with low genetic barriers in China, which leads to compensatory mutations and increases the rate of ETV resistance. The management of ETV resistance in China is an essential clinical issue. METHODS: Patients from 2011 to 2017 with nucleos(t)ide analog resistance were screened and 72 patients with ETV resistance were included. These patients received different rescue therapies including an ETV and adefovir (ADV) combination therapy group (n = 25), a tenofovir (TDF) monotherapy group (n = 27), and an ETV and TDF combination therapy group (n = 20). Virologic, biochemical, and serologic responses were compared among the three groups. RESULTS: The rate of ETV resistance among all HBV-resistant variants increased from 6.04% in 2011 to 15.02% in 2017. TDF monotherapy and TDF combination groups showed similar rates of negative HBV DNA at 48 weeks (74.07% vs 70.00%, P > 0.05), while the ETV and ADV group showed the worst virologic response (28.00%). Also, TDF monotherapy and TDF combination therapy showed similar decline of HBV DNA at weeks 12, 24, and 48. There was no significant difference in the rates of HBeAg clearance, ALT normalization, and abnormal renal function among the three groups. CONCLUSIONS: TDF monotherapy showed a comparable virologic response to TDF and ETV combination therapy and a better virologic response than ETV and ADV combination therapy. Thus, TDF monotherapy is the preferred rescue therapy for ETV resistance.

Simple non-invasive scoring systems and histological scores in predicting mortality in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: There is debate among the hepatology community regarding the simple non-invasive scoring systems and histological scores (even it was developed for histological classification) in predicting clinical outcomes in patients with non-alcoholic fatty liver disease (NAFLD). This study aimed to determine whether the presence of simple non-invasive scoring systems and histological scores could predict all-cause mortality, liver-related mortality, and liver disease decompensation (liver failure, cirrhosis, hepatocellular carcinoma, or decompensated liver disease). METHODS: The pooled hazard ratio of prognostic factors and incidence rate per 1000 person-years in patients with NAFLD was calculated and further adjusted by two different models of handling the duplicated data. RESULTS: A total of 19 longitudinal studies were included. Most simple non-invasive scoring systems (Fibrosis-4 Score, BARD, and aspartate aminotransferase-to-platelet ratio index ) and histological scores (NAFLD activity score, Brunt, and "steatosis, activity, and fibrosis" ) failed in predicting mortality, and only the NAFLD fibrosis score > 0.676 showed prognostic ability to all-cause mortality (four studies, 7564 patients, 118 352 person-years followed up, pooled hazard ratio 1.44, 95% confidence interval [CI] 1.05-1.96). The incidence rate per 1000 person-years of all-cause mortality, liver-related mortality, cardiovascular-related mortality, and liver disease decompensation resulted in a pooled incidence rate per 1000 person-years of 22.65 (14 studies, 95% CI 9.62-53.31), 3.19 (7 studies, 95% CI 1.14-8.93), 6.02 (6 studies, 95% CI 4.69-7.74), and 11.46 (4 studies, 95% CI 5.33-24.63), respectively. CONCLUSION: Non-alcoholic fatty liver disease fibrosis score showed promising prognostic value to all-cause mortality. Most present simple non-invasive scoring systems and histological scores failed to predict clinical outcomes.

Exosomal Interferon-Induced Transmembrane Protein 2 Transmitted to Dendritic Cells Inhibits Interferon Alpha Pathway Activation and Blocks Anti-Hepatitis B Virus Efficacy of Exogenous Interferon Alpha.

The negative regulators in the interferon (IFN) signaling pathway inhibit intrahepatic immune response, resulting in suboptimal therapeutic response to IFNα treatment in chronic hepatitis B (CHB) patients. Identifying the key negative factors and elucidating the regulating mechanism are essential for improving anti-HBV (hepatitis B virus) efficacy of IFNα. From the Gene Expression Omnibus (GEO) database, we downloaded and analyzed gene expression profiles of CHB patients with different responses to IFNα (GSE54747), and found that innate immune status was associated with the IFNα-based therapeutic response in CHB patients. Through PCR array, we found higher baseline level of IFN-induced transmembrane protein 2 (IFITM2) mRNA and lower baseline level of IFNα mRNA in peripheral blood mononuclear cells (PBMCs) of CHB patients with suboptimal response to IFNα treatment. Increased IFITM2 protein was also found in the serum of IFNα nonresponsive patients. With further experiments, we found that overexpressing IFITM2 in Huh7 cells suppressed endogenous IFNα synthesis by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3); knocking out IFITM2 enhanced activation of the endogenous IFNα synthesis pathway, exhibiting better inhibition on HBV replication. We also found that IFITM2 protein was shuttled by exosomes to dendritic cells (DCs), the main source of endogenous IFNα. Exosome-mediated transport of IFITM2 inhibited synthesis of endogenous IFNα in DCs whereas the inhibitory effect was abolished when IFITM2 was knocked out. Furthermore, we demonstrated that both palmitoylation inhibitor and mutation on 70/71 sites of IFITM2 protein influenced its incorporation into exosomes. Mutated IFITM2 protein increased the effect of IFNα against HBV. Conclusion: Exosome-mediated transport of IFITM2 to DCs inhibits IFNα pathway activation and blocks anti-HBV efficacy of exogenous IFNα. The findings provide an explanation to the suboptimal response of CHB patients to IFNα treatment.

Elevated cardiac biomarkers may be effective prognostic predictors for patients with COVID-19: A multicenter, observational study.

PURPOSE: The coronavirus disease 19 (COVID-19) has become a global health event. Cardiac biomarkers like creatine kinase isoenzyme (CK-MB), myoglobin, and high-sensitivity troponin T were usually elevated in early stages. This study aimed to investigate whether the elevated cardiac biomarkers could become effective prognostic predictors for COVID-19 patients. METHODS: The present study involved 357 COVID-19 patients. The potential predictors for two study outcomes (in-hospital death and recovery status) in 28 days were selected by LASSO regression analysis. Prognostic values of cardiac biomarkers selected were evaluated using the receiver operating characteristic curve (ROC) and the area under ROC (AUC). RESULTS: After 28-day follow-up, overall 357 patients were divided into death group (n = 25) and survival group (n = 332), or non-recovery group (n = 43) and recovery group (n = 314). The LASSO regression analysis showed elevated CK-MB and myoglobin were independent risk predictors for in-hospital death, and CK-MB and myoglobin were also independent risk predictors for non-recovery. The AUC of CK-MB and myoglobin for in-hospital death were 0.862 (95%CL: 0.804-0.920, p < 0.001) and 0.838 respectively (95%CL: 0.729-0.947, p < 0.001). The AUC of CK-MB and myoglobin for non-recovery were 0.839 (95%CL: 0.786-0.892, p < 0.001) and 0.841 (95%CL: 0.765-0.918, p < 0.001) respectively. We also found AUC of combined use of CK-MB and myoglobin for in-hospital death and non-recovery were 0.883 (95CL: 0.813-0.952, p < 0.001), and 0.873 (95%CL: 0.817-0.930, p < 0.001) respectively. CONCLUSIONS: In patients with COVID-19, elevated CK-MB and myoglobin on admission may be effective predictors for adverse outcomes, and combined use of CK-MB and myoglobin had a better performance for prediction.

The Prognostic Nutritional Index is associated with mortality of COVID-19 patients in Wuhan, China.

BACKGROUND: Declared as pandemic by WHO, the coronavirus disease 2019 (COVID-19) pneumonia has brought great damage to human health. The uncontrollable spread and poor progression of COVID-19 have attracted much attention from all over the world. We designed this study to develop a prognostic nomogram incorporating Prognostic nutritional index (PNI) in COVID-19 patients. METHODS: Patients confirmed with COVID-19 and treated in Renmin Hospital of Wuhan University from January to February 2020 were included in this study. We used logistic regression analysis to find risk factors of mortality in these patients. A prognostic nomogram was constructed and receiver operating characteristics (ROC) curve was drawn to evaluate the predictive value of PNI and this prognostic model. RESULTS: Comparison of baseline characteristics showed non-survivors had higher age (P < .001), male ratio (P = .038), neutrophil-to-lymphocyte ratio (NLR) (P < .001), platelet-to-lymphocyte ratio (PLR) (P < .001), and PNI (P < .001) than survivors. In the multivariate logistic regression analysis, independent risk factors of mortality in COVID-19 patients included white blood cell (WBC) (OR 1.285, P = .039), PNI (OR 0.790, P = .029), LDH (OR 1.011, P < .015). These three factors were combined to build the prognostic model. Area under the ROC curve (AUC) of only PNI and the prognostic model was 0.849 (95%Cl 0.811-0.888) and 0.950 (95%Cl 0.922-0.978), respectively. And calibration plot showed good stability of the prognostic model. CONCLUSION: This research indicates PNI is independently associated with the mortality of COVID-19 patients. Prognostic model incorporating PNI is beneficial for clinicians to evaluate progression and strengthen monitoring for COVID-19 patients.

Hepatitis B Virus Infection: Overview.

Hepatitis B virus (HBV) is a DNA virus, belonging to the Hepadnaviridae family. It is a partially double-stranded DNA virus with a small viral genome (3.2 kb). Chronic HBV infection remains a global public health problem. If left untreated, chronic HBV infection can progress to end-stage liver disease, such as liver cirrhosis and hepatocellular carcinoma (HCC). In recent years, tremendous advances in the field of HBV basic and clinical research have been achieved, ranging from the HBV biological characteristics, immunopathogenesis, and animal models to the development of new therapeutic strategies and new drugs against HBV. In this overview, we begin with a brief history of HBV discovery and treatment milestones. We then briefly summarize the HBV research advances, which will be detailed in the following chapters.