Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output.

Mitochondria, which play central roles in immunometabolic diseases, have their own genome. However, the functions of mitochondria-located noncoding RNAs are largely unknown due to the absence of a specific delivery system. By circular RNA (circRNA) expression profile analysis of liver fibroblasts from patients with nonalcoholic steatohepatitis (NASH), we observe that mitochondrial circRNAs account for a considerable fraction of downregulated circRNAs in NASH fibroblasts. By constructing mitochondria-targeting nanoparticles, we observe that Steatohepatitis-associated circRNA ATP5B Regulator (SCAR), which is located in mitochondria, inhibits mitochondrial ROS (mROS) output and fibroblast activation. circRNA SCAR, mediated by PGC-1α, binds to ATP5B and shuts down mPTP by blocking CypD-mPTP interaction. Lipid overload inhibits PGC-1α by endoplasmic reticulum (ER) stress-induced CHOP. In vivo, targeting circRNA SCAR alleviates high fat diet-induced cirrhosis and insulin resistance. Clinically, circRNA SCAR is associated with steatosis-to-NASH progression. Collectively, we identify a mitochondrial circRNA that drives metaflammation and serves as a therapeutic target for NASH.

Restoring neuronal iron homeostasis revitalizes neurogenesis after spinal cord injury.

Spinal cord injury (SCI) can lead to iron overloading and subsequent neuronal ferroptosis, which hinders the recovery of locomotor function. However, it is still unclear whether the maintenance of neuronal iron homeostasis enables to revitalize intrinsic neurogenesis. Herein, we report the regulation of cellular iron homeostasis after SCI via the chelation of excess iron ions and modulation of the iron transportation pathway using polyphenol-based hydrogels for the revitalization of intrinsic neurogenesis. The reversed iron overloading can promote neural stem/progenitor cell differentiation into neurons and elicit the regenerative potential of newborn neurons, which is accompanied by improved axon reinnervation and remyelination. Notably, polyphenol-based hydrogels significantly increase the neurological motor scores from ~8 to 18 (out of 21) and restore the transmission of sensory and motor electrophysiological signals after SCI. Maintenance of iron homeostasis at the site of SCI using polyphenol-based hydrogels provides a promising paradigm to revitalize neurogenesis for the treatment of iron accumulation-related nervous system diseases.

Higher TP53BP2 expression is associated with HBsAg loss in peginterferon-α-treated patients with chronic hepatitis B.

BACKGROUND & AIMS: HBsAg loss is only observed in a small proportion of patients with chronic hepatitis B (CHB) who undergo interferon treatment. Investigating the host factors crucial for functional cure of CHB can aid in identifying individuals who would benefit from peginterferon-α (Peg-IFNα) therapy. METHODS: We conducted a genome-wide association study (GWAS) by enrolling 48 patients with CHB who achieved HBsAg loss after Peg-IFNα treatment and 47 patients who didn't. In the validation stage, we included 224 patients, of whom 90 had achieved HBsAg loss, to validate the identified significant single nucleotide polymorphisms. To verify the functional involvement of the candidate genes identified, we performed a series of in vitro and in vivo experiments. RESULTS: GWAS results indicated a significant association between the rs7519753 C allele and serum HBsAg loss in patients with CHB after Peg-IFNα treatment (p = 4.85 × 10-8, odds ratio = 14.47). This association was also observed in two independent validation cohorts. Expression quantitative trait locus analysis revealed higher hepatic TP53BP2 expression in individuals carrying the rs7519753 C allele (p = 2.90 × 10-6). RNA-sequencing of liver biopsies from patients with CHB after Peg-IFNα treatment revealed that hepatic TP53BP2 levels were significantly higher in the HBsAg loss group compared to the HBsAg persistence group (p = 0.035). In vitro and in vivo experiments demonstrated that loss of TP53BP2 decreased interferon-stimulated gene levels and the anti-HBV effect of IFN-α. Mechanistically, TP53BP2 was found to downregulate SOCS2, thereby facilitating JAK/STAT signaling. CONCLUSION: The rs7519753 C allele is associated with elevated hepatic TP53BP2 expression and an increased probability of serum HBsAg loss post-Peg-IFNα treatment in patients with CHB. TP53BP2 enhances the response of the hepatocyte to IFN-α by suppressing SOCS2 expression. IMPACT AND IMPLICATIONS: Chronic hepatitis B (CHB) remains a global public health issue. Although current antiviral therapies are more effective in halting disease progression, only a few patients achieve functional cure for hepatitis B with HBsAg loss, highlighting the urgent need for a cure for CHB. This study revealed that the rs7519753 C allele, which is associated with high expression of hepatic TP53BP2, significantly increases the likelihood of serum HBsAg loss in patients with CHB undergoing Peg-IFNα treatment. This finding not only provides a promising predictor for HBsAg loss but identifies a potential therapeutic target for Peg-IFNα treatment. We believe our results are of great interest to a wide range of stakeholders based on their potential clinical implications.

Interferon-γ+ Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization.

The immune mechanism underlying hepatitis B surface antigen (HBsAg) loss, particularly type I inflammatory response, during pegylated interferon-α (PEG-IFN) therapy remains unclear. In this study, we aimed to elucidate such immune mechanisms. Overall, 82 patients with chronic hepatitis B (CHB), including 41 with HBsAg loss (cured group) and 41 uncured patients, received nucleos(t)ide analogue and PEG-IFN treatments. Blood samples from all patients, liver tissues from 14 patients with CHB, and hepatic perfusate from 8 liver donors were collected for immune analysis. Jurkat, THP-1 and HepG2.2.15 cell lines were used in cell experiments. The proportion of IFN-γ+ Th1 cells was higher in the cured group than in the uncured group, which was linearly correlated with HBsAg decline and alanine aminotransferase (ALT) levels during treatment. However, CD8+ T cells were weakly associated with HBsAg loss. Serum and intrahepatic levels of Th1 cell-associated chemokines (C-X-C motif chemokine ligand [CXCL] 9, CXCL10, CXCL11, IFN-γ) were significantly lower in the cured patients than in patients with a higher HBsAg quantification during therapy. Serum from cured patients induced more M1 (CD68+CD86+ macrophage) cells than that from uncured patients. Patients with chronic HBV infection had significantly lower proportions of CD86+ M1 and CD206+ M2 macrophages in their livers than healthy controls. M1 polarization of intrahepatic Kupffer cells promoted HBsAg loss by upregulating the effector function of tissue-resident memory T cells with increased ALT levels. IFN-γ+ Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization.

Mesenchymal Stem Cells Promote Polarization of M2 Macrophages in Mice with Acute-On-Chronic Liver Failure via Mertk/JAK1/STAT6 Signaling.

Acute-on-chronic liver failure (ACLF) is a severe disease with a high mortality. Macrophage-related inflammation plays a crucial role in ACLF development. Mesenchymal stem cells (MSCs) treatment was demonstrated to be beneficial in ACLF in our previous study; however, the underlying mechanisms remain unknown. Therefore, mouse bone marrow-derived MSCs were used to treat an ACLF mouse model or cocultured with RAW264.7/J774A.1 macrophages that were stimulated with LPS. Histological and serological parameters and survival were analyzed to evaluate efficacy. We detected changes of Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and markers of macrophage polarization in vitro and in vivo. In ACLF mice, MSCs improved liver function and 48-h survival of ACLF mice and alleviated inflammatory injury by promoting M2 macrophage polarization and elevated Mertk expression levels in macrophages. This is significant, as Mertk regulates M2 macrophage polarization via the JAK1/STAT6 signaling pathway.

Vpr driving DNA methylation variation of CD4 + T cells in HIV-1 infection.

BACKGROUND: Despite the existence of available therapeutic interventions for HIV-1, this virus remains a significant global threat, leading to substantial morbidity and mortality. Within HIV-1-infected cells, the accessory viral protein r (Vpr) exerts control over diverse biological processes, including cell cycle progression, DNA repair, and apoptosis. The regulation of gene expression through DNA methylation plays a crucial role in physiological processes, exerting its influence without altering the underlying DNA sequence. However, a thorough examination of the impact of Vpr on DNA methylation in human CD4 + T cells has not been conducted. METHODS: In this study, we employed base-resolution whole-genome bisulfite sequencing (WGBS), real-time quantitative RCR and western blot to explore the effect of Vpr on DNA methylation of host cells under HIV-1 infection. RESULTS: We observed that HIV-1 infection leads to elevated levels of global DNA methylation in primary CD4 + T cells. Specifically, Vpr induces significant modifications in DNA methylation patterns, particularly affecting regions within promoters and gene bodies. These alterations notably influence genes related to immune-related pathways and olfactory receptor activity. Moreover, Vpr demonstrates a distinct ability to diminish the levels of methylation in histone genes. CONCLUSIONS: These findings emphasize the significant involvement of Vpr in regulating transcription through the modulation of DNA methylation patterns. Together, the results of this investigation will considerably enhance our understanding of the influence of HIV-1 Vpr on the DNA methylation of host cells, offer potential avenues for the development of more effective treatments.

Impact of nonalcoholic fatty liver disease status change on antiviral efficacy of nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B.

Data on the dynamic changes in chronic hepatitis B (CHB) patients with nonalcoholic fatty liver disease (NAFLD) during antiviral therapy are scarce. We aimed to investigate the evolution of NAFLD status change in CHB patients treated with nucleos(t)ide analogues (NAs) and its influence on therapeutic outcomes. This retrospective study included 164 HBeAg-positive CHB patients from a randomized controlled trial who were treated with NAs for 104 weeks and underwent paired liver biopsies. Histological evaluation was performed at baseline and Week 104. The patients were divided into four groups according to NAFLD status changes. From baseline to Week 104, the overall percentage of CHB patients with concurrent NAFLD increased from 17.1% to 26.2% (p = 0.044). Among them, 7 of 28 patients (25.0%) with NAFLD at baseline showed NAFLD remission at week 104, while 22 of 136 patients (16.2%) without NAFLD at baseline developed new-onset NAFLD. In subgroup analyses, the new-onset and sustained NAFLD groups showed significantly lower rates of biochemical response at week 104 as compared to the sustained non-NAFLD group (77.3% and 57.1% vs. 93.9%, respectively; all p < 0.05), as well as fibrosis improvement (31.8% and 42.9% vs. 69.3%, respectively; all p < 0.05). NAFLD status changes did not influence the virological response, HBeAg seroconversion, and necroinflammation improvement (all p > 0.05). In HBeAg-positive CHB patients receiving NAs therapy, new-onset and sustained NAFLD may counteract the benefits of antiviral therapy, reducing the rate of biochemical response and fibrosis improvement.

Landslide Monitoring along the Dadu River in Sichuan Based on Sentinel-1 Multi-Temporal InSAR.

The Dadu River travels in the mountainous areas of southwestern China, one of regions with the most hazards that has long suffered from frequent geohazards. The early identification of landslides in this region is urgently needed, especially after the recent Luding earthquake (MS 6.8). While conventional ground-based monitoring techniques are limited by the complex terrain conditions in these alpine valley regions, space interferometric synthetic aperture radar (InSAR) provides an incomparable advantage in obtaining surface deformation with high precision and over a wide area, which is very useful for long-term and slow geohazard monitoring. In this study, more than 500 Sentinel-1 SAR images with four frames acquired during 2017~2022 were collected to detect the hidden landslide regions from the Jinchuan to Ebian Section along the Dadu River, based on joint-scatterer InSAR (JS-InSAR) and small baseline subset (SBAS) techniques. The results showed that our method could be successfully applied for landslide monitoring in complex mountainous regions. Furthermore, 143 potential landslide regions spreading over an 800 km area along the Dadu River were extracted by integrating the deformation measurements and optical images. Our study can provide a reference for large-scale geological hazard surveys in mountainous areas, and the InSAR technique will be encouraged for the local government in future long-term monitoring applications in the Dadu River Basin.

Engineering Poly(ethylene glycol) Nanoparticles for Accelerated Blood Clearance Inhibition and Targeted Drug Delivery.

Surface modification with poly(ethylene glycol) (PEGylation) is an effective strategy to improve the colloidal stability of nanoparticles (NPs) and is often used to minimize cellular uptake and clearance of NPs by the immune system. However, PEGylation can also trigger the accelerated blood clearance (ABC) phenomenon, which is known to reduce the circulation time of PEGylated NPs. Herein, we report the engineering of stealth PEG NPs that can avoid the ABC phenomenon and, when modified with hyaluronic acid (HA), show specific cancer cell targeting and drug delivery. PEG NPs cross-linked with disulfide bonds are prepared by using zeolitic imidazolate framework-8 NPs as templates. The reported templating strategy enables the simultaneous removal of the template and formation of PEG NPs under mild conditions (pH 5.5 buffer). Compared to PEGylated liposomes, PEG NPs avoid the secretion of anti-PEG antibodies and the presence of anti-PEG IgM and IgG did not significantly accelerate the blood clearance of PEG NPs, indicating the inhibition of the ABC effect for the PEG NPs. Functionalization of the PEG NPs with HA affords PEG NPs that retain their stealth properties against macrophages, target CD44-expressed cancer cells and, when loaded with the anticancer drug doxorubicin, effectively inhibit tumor growth. The innovation of this study lies in the engineering of PEG NPs that can circumvent the ABC phenomenon and that can be functionalized for the improved and targeted delivery of drugs.

Chloride intercellular channel 3 suppression-mediated macrophage polarization: a potential indicator of poor prognosis of hepatitis B virus-related acute-on-chronic liver failure.

Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) are characterized by immune paralysis and susceptibility to infections. Macrophages are important mediators of immune responses can be subclassified into two main phenotypes: classically activated and alternatively activated. However, few studies have investigated changes to macrophage polarization in HBV-related liver diseases. Therefore, we investigated the functional status of monocyte-derived macrophages (MDMs) from patients with mild chronic hepatitis B (n = 226), HBV-related compensated cirrhosis (n = 36), HBV-related decompensated cirrhosis (n = 40), HBV-ACLF (n = 62) and healthy controls (n = 10), as well as Kupffer cells (KCs) from patients with HBV-ACLF (n = 3). We found that during the progression of HBV-related liver diseases, the percentage of CD163+ CD206+ macrophages increased, while the percentage of CD80+ human leukocyte antigen-DR+ macrophages decreased significantly. MDMs and KCs mainly exhibited high CD163+ CD206+ expression in patients with HBV-ACLF, which predicted poor clinical outcome and higher liver transplantation rate. Transcriptome sequencing analysis revealed that chloride intracellular channel-3 (CLIC3) was reduced in patients with HBV-ACLF, indicating a poor prognosis. To further study the effect of CLIC3 on macrophage polarization, human monocytic THP-1 cell-derived macrophages were used. We found that classical and alternative macrophage activation occurred through nuclear factor kappa B (NF-κB) and phosphoinositide 3-kinase/protein kinase B pathways, respectively. CLIC3 suppression inhibited NF-κB activation and promoted the alternative activation. In conclusion, macrophage polarization gradually changed from classically activated to alternatively activated as HBV-related liver diseases progressed. Both CLIC3 suppression and increased alternatively activated macrophage percentage were potential indicators of the poor prognosis of patients with HBV-ACLF.

Role of hepatitis B surface antibody in seroreversion of hepatitis B surface antigen in patients achieving hepatitis B surface antigen loss with pegylated interferon-based therapy.

It is unclear whether hepatitis B surface antibody (HBsAb) confers clinical benefits after HBsAg seroclearance, especially in hepatitis B surface antigen (HBsAg) seroreversion and maintenance of HBsAb. We evaluated this in patients (n = 222) with HBsAg loss following treatment with pegylated interferon (PEG-IFN)-based therapy who completed a 48-week follow-up period. Serum hepatitis B virus (HBV) markers and biochemical indicators were evaluated every 3 months. The primary endpoint was HBsAg seroreversion. Factors associated with HBsAg seroreversion were also investigated. HBsAb ≥100 mIU/ml resulted in a lower HBsAg seroreversion rate than an HBsAb-negative status (5.5% vs. 29.5%, p < .001); however, the seroreversion rate was not significantly different between patients with HBsAb 10-100 mIU/ml and those in the HBsAb-negative group. Patients with HBsAb ≥100 mIU/ml had a lower HBsAb loss rate than those with HBsAb 10-100 mIU/ml (7.3% vs. 21.7%, p = .005). The final HBsAg seroreversion and HBV DNA relapse rates were 13.5% and 1.8%, respectively. HBsAb ≥100 mIU/ml at the off-treatment time (odds ratio [OR] 0.110, 95% confidence interval [CI]: 0.034-0.353, p < .001) and treatment time to attain HBsAg loss >28 weeks (OR 2.508, 95% CI: 1.068-5.890, p = .035) were predictors of HBsAg seroreversion. Consolidation therapy for 12-24 weeks resulted in higher HBsAb titres than consolidation therapy for ≤12 weeks in HBsAb-negative patients at the off-treatment time (p < .001). HBsAg seroconversion with HBsAb ≥100 mIU/ml decreases HBsAg seroreversion and provides an efficient maintenance rate of HBsAb. HBsAg seroconversion with high HBsAb titres may be clinically beneficial for chronic hepatitis B treated with PEG-IFN-based therapy.

Real-world study on HBsAg loss of combination therapy in HBeAg-negative chronic hepatitis B patients.

Combination therapy with pegylated interferon (PEG-IFN) and nucleos(t)ide analogues (NAs) can enhance hepatitis B surface antigen (HBsAg) clearance. However, the specific treatment strategy and the patients who would benefit the most are unclear. Therefore, we assessed the HBsAg loss rate of add-on PEG-IFN and explored the factors associated with HBsAg loss in chronic hepatitis B (CHB) patients. This was a real-world cohort study of adults with CHB. Hepatitis B e antigen (HBeAg)-negative NAs-treated patients with baseline HBsAg ≤1500 IU/ml and HBV DNA < the lower limit of detection, or 100 IU/ml, received 48 weeks of add-on PEG-IFN. The primary outcome of the study was the rate of HBsAg loss at 48 weeks of combination treatment. Using multivariable logistic regression analysis, we determined factors associated with HBsAg loss. HBsAg loss in 2579 patients (mean age: 41.2 years; 80.9% male) was 36.7% (947 patients) at 48 weeks. HBsAg loss was highest in patients from south-central and southwestern China (40.0%). Factors independently associated with HBsAg loss included: increasing age (odds ratio = 0.961); being male (0.543); baseline HBsAg level (0.216); HBsAg decrease at 12 weeks (between 0.5 and 1.0 log10 IU/ml [2.405] and >1.0 log10 IU/ml [7.370]); alanine aminotransferase (ALT) increase at 12 weeks (1.365); haemoglobin (HGB) decrease at 12 weeks (1.558). There was no difference in the primary outcomes associated with the combination regimen. In conclusion, HBsAg loss by combination therapy was higher in patients from southern China than those from the north. An increased chance of HBsAg loss was associated with baseline characteristics and dynamic changes in clinical indicators.

Modulation of Colloidal Particle Stiffness for the Exploration of Bio-Nano Interactions.

Tuning the physicochemical parameters (e.g., size, shape, and surface chemistry) of colloidal particles (CPs) for the engineering of drug carriers has proven to be a promising approach to improve drug delivery efficacy. Recently, the stiffness of CPs has attracted widespread attention for modulating bio-nano interactions. In this perspective, we outline the strategies for the modulation and characterization of CP stiffness and highlight the importance of CP stiffness in the control over biological interactions. Challenges and opportunities of current and future developments in the modulation of CP stiffness for the exploration of bio-nano interactions in therapeutic delivery are also discussed. This perspective is expected to help thoroughly understand the role of CP stiffness in bio-nano interactions and facilitate the design of CPs as carriers for improved drug and vaccine delivery.

The impact of serum thyroid-stimulation hormone levels on the outcome of hepatitis B virus related acute-on-chronic liver failure: an observational study.

BACKGROUND: Thyroid dysfunction has been reported in severe liver diseases. The aim of this study was to analyze the impact of serum thyroid-stimulation hormone (TSH) levels on the prognosis of patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). METHODS: This retrospective cohort study included 1,862 patients with HBV-related ACLF. Risk factors associated with 30-day and 90-day survival, hazard ratios (HRs), and 95% confidence intervals (CIs) for TSH were estimated using Cox proportional hazards regression. The Area Under the ROC curve (AUROC) analysis was carried out, and the cut-off values were calculated. After grouping by the cut-off value, survival was compared between the groups using the log-rank test. This study data is from the "Survival Cohort Study (SCS)", which has been registered at ClinicalTrials.gov (NCT03992898). RESULTS: Multivariate analysis indicated that an elevated TSH level was a highly significant predictor for 30-day survival (HR = 0.743, 95% CI: 0.629-0.878, P < 0.001) and 90-day survival (HR = 0.807, 95% CI: 0.717-0.909, P < 0.001). The AUROC of TSH level for 30-day and 90-day mortality were 0.655 and 0.620, respectively, with the same best cut-off values of 0.261 µIU/mL. Log-rank test showed that the group with higher TSH level had higher 30-day (78.5%, 95% CI: 76.1%-80.9% vs. 56.9%, 95% CI: 53.4%-60.4%; P < 0.001) and 90-day survival rate (61.5%, 95% CI: 58.6%-64.4% vs. 42.8%, 95% CI: 39.3%-46.3%; P < 0.001). Similar findings were observed in subgroups analysis. After adjusting for age and other risk factors, the higher level of TSH remained associated with 30-day survival (HR = 0.602, 95% CI: 0.502-0.721, P < 0.001) and 90-day survival (HR = 0.704, 95% CI, 0.609-0.814, P < 0.001). CONCLUSIONS: Serum TSH level significantly correlate with HBV-related ACLF patients' survival and may be of value for predicting 30-day and 90-day survival of patients with HBV-related ACLF.

Clinical features and risk factors of surgical site infections in HIV-negative patients with cryptococcal meningitis underwent ventriculoperitoneal shunt operations: a retrospective study.

BACKGROUND: To investigate the clinical features and risk factors of ventriculoperitoneal shunt (VPS) associated surgical site infections (SSIs) in HIV-negative patients with cryptococcal meningitis (CM). METHODS: We retrospectively reviewed the medical records of HIV-negative patients with CM underwent VPS operation admitted to The Third Affiliated Hospital of Sun Yat-sen University in Southwest China over the past 7 years. RESULTS: 193 patients were included, of whom 25 (12.95%) had SSIs in 6 (median duration, 1-48 days) days after operation. Compared with patients without SSIs, patient with SSIs tended to be shorter preoperative stay. 52% patients in SSIs group and 25% patients in no-SSIs group underwent VPS operations within 3 days after admission (p = 0.017). Although body temperature and infectious indicators slightly elevated postoperative in both groups. The patients with SSIs experienced more fever; more central nervous system symptoms; higher PCT value and lower cerebrospinal fluid (CSF) glucose in contrast to the no-SSIs group. Multivariate regression analysis found a 2.653 fold increase in the risk of infection for every 1 °C increase in postoperative body temperature. Among the 25 patients, 9 patients had positive culture results, three samples reported to be oxacillin resistant coagulase-negative Staphylococci. CONCLUSIONS: SSIs was one of the serious surgical complications after VPS operation. High body temperature, the occurrence of dizziness and headache, low postoperative hemoglobin are risk factors. Postoperative patients with high fever, high PCT and low CSF glucose should be paid more attention to.

Reappraisal of the diagnostic value of alpha-fetoprotein for surveillance of HBV-related hepatocellular carcinoma in the era of antiviral therapy.

This study was designed to explore if antiviral treatment influences the performance of serum alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) among the high-risk chronic HBV-infected patients. A total of 5936 patients who had evidence of chronic HBV infection were enrolled from four independent centres in this retrospective study, including 1721 chronic hepatitis B (CHB), 2286 liver cirrhosis (LC), 798 HCC within Milan criteria and 1131 HCC beyond Milan criteria patients. Stratified by whether they received treatment or not, the patients were further divided into antiviral and non-antiviral groups. Then, the performance of AFP for discriminating HCC was evaluated. Patients receiving antivirals had significantly lower median levels of AFP compared with the non-antiviral patients (P < .001), and there were significantly less patients with abnormal AFP levels in antiviral groups (P < .001). Antiviral therapy improved the AUROCs of AFP for discriminating HCC within Milan criteria. When setting the cut-off values at 20 ng/mL and 100 ng/mL as surveillance and confirmatory tests respectively for HCC among patients receiving antiviral treatment, AFP exhibited a significantly higher sensitivity than those of 200 ng/mL and 400 ng/mL, which are currently recommended by some guidelines, without compromising specificity. Further analysis in antiviral patients revealed that serum AFP had better performance for discriminating HCC within Milan criteria in ALT ≤ 1ULN patients than that in ALT > 1ULN patients. In conclusion, in the era of antiviral therapy, serum AFP's surveillance performance was substantially improved for HCC within Milan criteria among the high-risk population of CHB and LC patients.

Changes of cytokine levels and T cell surface molecules in patients with chronic hepatitis B and the association with functional cure.

This study aimed to examine changes in levels of cytokine and T cell surface molecules in chronic hepatitis B (CHB) patients receiving sequential interferon therapy following 1-year nucleos(t)ide analogs (NAs) treatment. Cytokine levels were measured in 30 patients, and T cell surface molecule expression was measured in 48 patients receiving sequential interferon therapy and 24 patients only receiving NA mono-therapy. An HBsAg titer of <0.05 IU/ml was defined as a "functional cure." In the cured group (HBsAg < 0.05 IU/ml), a decreasing probability was observed in IFN-γ (after Week 0), and IL-22 and IP-10 (after Week 12). In the non-cured group (HBsAg ≥ 0.05 IU/ml), a probability of slightly decreasing was observed for IFN-γ (after Week 12), and a probability of increasing IP-10 concentration (after Week 0) was observed. Generalized estimating equation (GEE) analyses showed significant differences in the levels of IL-10, IL-23, CCL-3, IL-1ß, IL-2, and IL-12P70 between the two groups. In GEE analysis, there were significant differences in expressions of CD45RO+ between the cured group and the non-cured group. The frequencies of T cells expressing Tim-3, CD62L, and CD152 were significantly lower in the sequential interferon therapy group than in the NA mono-therapy group. Changes in cytokine levels (IFN-γ, IP-10, IL-10, IL-23, CCL-3, IL-1ß, IL-2, and IL-12P70) and T cell surface molecules (CD45RO+ ) may predict HBsAg seroconversion in CHB patients receiving sequential interferon therapy. The period from Weeks 12 to 24 during sequential interferon therapy may be a critical time of immune status change.

Encapsulation of Enzymes in Metal-Phenolic Network Capsules for the Trigger of Intracellular Cascade Reactions.

Nanoengineered capsules encapsulated with functional cargos (e.g., enzymes) are of interest for various applications including catalysis, bioreactions, sensing, and drug delivery. Herein, we report a facile strategy to engineer enzyme-encapsulated metal-phenolic network (MPN) capsules using enzyme-loaded zeolitic imidazolate framework nanoparticles (ZIF-8 NPs) as templates, which can be removed in a mild condition (e.g., ethylenediaminetetraacetic acid (EDTA) solution). The capsule size (from 250 nm to 1 µm) and thickness (from 9.8 to 33.7 nm) are well controlled via varying the template size and coating time, respectively. Importantly, MPN capsules encapsulated with enzymes (i.e., glucose oxidase) can trigger the intracellular cascade reaction via the exhaustion of glucose to produce H2O2 and subsequently generate toxic hydroxyl radicals (•OH) based on the Fenton reaction via the reaction between H2O2 and iron ions in MPN coatings. The intracellular cascade reaction for the generation of •OH is efficient to inhibit cancer cell viability, which is promising for the application in chemodynamic therapy.

Sono-Fenton Chemistry Converts Phenol and Phenyl Derivatives into Polyphenols for Engineering Surface Coatings.

We report a sono-Fenton strategy to mediate the supramolecular assembly of metal-phenolic networks (MPNs) as substrate-independent coatings using phenol and phenyl derivatives as building blocks. The assembly process is initiated from the generation of hydroxyl radicals (. OH) using high-frequency ultrasound (412 kHz), while the metal ions synergistically participate in the production of additional . OH for hydroxylation/phenolation of phenol and phenyl derivatives via the Fenton reaction and also coordinate with the phenolic compounds for film formation. The coating strategy is applicable to various phenol and phenyl derivatives and different metal ions including FeII , FeIII , CuII , and CoII . In addition, the sono-Fenton strategy allows real-time control over the assembly process by turning the high-frequency ultrasound on or off. The properties of the building blocks are maintained in the formed films. This work provides an environmentally friendly and controllable method to expand the application of phenolic coatings for surface engineering.

Outcomes of Long-term Treatment of Chronic HBV Infection With Entecavir or Other Agents From a Randomized Trial in 24 Countries.

BACKGROUND & AIMS: Treatment of chronic hepatitis B virus (HBV) infection with entecavir suppresses virus replication and reduces disease progression, but could require life-long therapy. To investigate clinical outcome events and safety associated with long-term treatment with entecavir, we followed up patients treated with entecavir or another standard-of-care HBV nucleos(t)ide analogue for up to 10 years. We assessed long-term outcomes and relationships with virologic response. METHODS: Patients with chronic HBV infection at 299 centers in Asia, Europe, and North and South America were assigned randomly to groups that received entecavir (n = 6216) or an investigator-selected nonentecavir HBV nucleos(t)ide analogue (n = 6162). Study participants were followed up for up to 10 years in hospital-based or community clinics. Key end points were time to adjudicated clinical outcome events and serious adverse events. In a substudy, we examined relationships between these events and virologic response. RESULTS: There were no significant differences between groups in time to event assessments for primary end points including malignant neoplasms, liver-related HBV disease progression, and death. There were no differences between groups in the secondary end points of nonhepatocellular carcinoma malignant neoplasms and hepatocellular carcinoma. In a substudy of 5305 patients in China, virologic response, regardless of treatment group, was associated with a reduced risk of liver-related HBV disease progression (hazard ratio, 0.09; 95% CI, 0.038-0.221) and hepatocellular carcinoma (hazard ratio, 0.03; 95% CI, 0.009-0.113). Twelve patients given entecavir (0.2%) and 50 patients given nonentecavir drugs (0.8%) reported treatment-related serious adverse events. CONCLUSIONS: In a randomized controlled trial of patients with chronic HBV infection, we associated entecavir therapy with a low rate of adverse events over 10 years of follow-up evaluation. Patients receiving entecavir vs another nucleos(t)ide analogue had comparable rates of liver- and non-liver-related clinical outcome events. Participants in a China cohort who maintained a virologic response, regardless of treatment group, had a reduced risk of HBV-related outcome events including hepatocellular carcinoma. ClinicalTrials.gov identifier no: NCT00388674.