Inverse relationship between HBV DNA levels and liver histopathological changes in immune-tolerant CHB patients.

Limited data exist regarding the association between hepatitis B virus (HBV) DNA levels and liver histopathological changes in patients with chronic hepatitis B (CHB) during the immune tolerant (IT) phase. In this study, we retrospectively analysed liver biopsy results from 150 adult IT-CHB patients. The liver tissue necroinflammation and fibrosis were evaluated by the Scheuer scoring system. Multivariate logistic regression, smooth curve fitting, and segmented regression models were used to examine the association between HBV DNA levels and liver histopathological changes. A total of 26%, 30.67% and 42% of IT patients had significant necroinflammation (≥G2), significant fibrosis (≥S2) and significant histopathological changes (≥G2 and/or ≥S2), respectively. HBV DNA levels were independently and non-linear inversely associated with significant necroinflammation and histopathological changes in IT-CHB patients. Patients with HBV DNA levels <107 IU/mL had a higher risk of significant histopathological changes compared to those with levels >107 IU/mL. The findings were further confirmed by smooth curve fitting analyses, subgroup and sensitivity analyses. In segmented regression model analyses, the optimal DNA value for the lowest odds ratio of significant histopathological changes was 7.26 log10 IU/mL. A non-linear inverse association between HBV DNA levels and significant histopathological changes in IT-CHB patients. DNA 7.26 log10 IU/mL may serve as a potential cut-off point to define a 'true immune tolerant phase' with minimal liver histopathological changes.

A signature based on circadian rhythm-associated genes for the evaluation of prognosis and the tumour microenvironment in HNSCC.

The morbidity and mortality rates of head and neck squamous cell carcinoma (HNSCC) remain high worldwide. Therefore, there is an urgent need to identify a new prognostic biomarker to guide the personalized treatment of HNSCC patients. Increasing evidence suggests that circadian rhythm genes play an important role in the development and progression of cancer. We aimed to explore the value of circadian rhythm genes in predicting prognosis and guiding the treatment of HNSCC. We first obtained a list of circadian rhythm genes from previous research. The sequencing data were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Finally, univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox proportional hazard analysis were performed to develop a prognostic signature (Circadian Rhythm-Related Gene Prognostic Index, CRRGPI) consisting of nine circadian rhythm genes. The signature exhibited good performance in predicting overall survival. Patients with low CRRGPI scores had lower metabolic activities and an active antitumour immunity ability. Additionally, a clinical cohort was used to further evaluate the ability of the CRRGPI to predict the efficacy of immune checkpoint inhibitors. In conclusion, the novel circadian rhythm-related gene signature can provide a precise prognostic evaluation with the potential capacity to guide individualized treatment regimens for HNSCC patients.

Genomic, transcriptomic, and epigenomic analysis of a medicinal snake, Bungarus multicinctus, to provides insights into the origin of Elapidae neurotoxins.

The many-banded krait, Bungarus multicinctus, has been recorded as the animal resource of JinQianBaiHuaShe in the Chinese Pharmacopoeia. Characterization of its venoms classified chief phyla of modern animal neurotoxins. However, the evolutionary origin and diversification of its neurotoxins as well as biosynthesis of its active compounds remain largely unknown due to the lack of its high-quality genome. Here, we present the 1.58 Gbp genome of B. multicinctus assembled into 18 chromosomes with contig/scaffold N50 of 7.53 Mbp/149.8 Mbp. Major bungarotoxin-coding genes were clustered within genome by family and found to be associated with ancient local duplications. The truncation of glycosylphosphatidylinositol anchor in the 3'-terminal of a LY6E paralog released modern three-finger toxins (3FTxs) from membrane tethering before the Colubroidea divergence. Subsequent expansion and mutations diversified and recruited these 3FTxs. After the cobra/krait divergence, the modern unit-B of ß-bungarotoxin emerged with an extra cysteine residue. A subsequent point substitution in unit-A enabled the ß-bungarotoxin covalent linkage. The B. multicinctus gene expression, chromatin topological organization, and histone modification characteristics were featured by transcriptome, proteome, chromatin conformation capture sequencing, and ChIP-seq. The results highlighted that venom production was under a sophisticated regulation. Our findings provide new insights into snake neurotoxin research, meanwhile will facilitate antivenom development, toxin-driven drug discovery and the quality control of JinQianBaiHuaShe.

Clinical Predictors of Functional Cure in Children 1-6 Years-old with Chronic Hepatitis B.

Background and Aims: Hepatitis B surface antigen (HBsAg) clearance is significantly more common in children with chronic hepatitis B (CHB) than in adults; however, the possible influencing factors related to HBsAg loss have yet to be found. This study aimed to explore the efficacy of long-term interferon (IFN)α therapy in treating children with CHB and analyzed the factors influencing functional cure after treatment. Methods: A total of 236 children aged 1-6 years and diagnosed with CHB via liver biopsy were included in the study, all receiving IFNα treatment (IFNα-2b monotherapy, IFNα-2b followed by lamivudine [LAM] or IFNα-2b combined with LAM) and followed up for 144 weeks. A comprehensive analysis was conducted on clinical data, including biochemical items, serum markers of hepatitis B virus (HBV) and immunological indexes, and logistic regression analysis was used to screen the influencing factors related to HBsAg loss. Results: The cumulative loss rates of HBsAg were 79.5%, 62.1% and 42.1% at 144 weeks after the start of treatment in the 1-3 years-old group, 3-5 years-old group and 5-7 years-old group, respectively (p<0.05). IFNα-2b combined with LAM treatment displayed the highest HBsAg loss rates compared with monotherapy and sequential treatment (p=0.011). Younger baseline age and lower HBsAg levels were independent factors for the prediction of HBsAg loss (p<0.05). The baseline PreS1 and hepatitis B core antibody levels in the HBsAg loss group were lower than those in the HBsAg non-loss group. In addition, the PreS1 level was positively corelated with the level of HBsAg, HBV DNA and liver inflammation. Conclusions: Long-term treatment with IFNα was effective in achieving HBsAg loss in CHB children aged 1-6 years-old. Age less than 3 years-old and lower HBsAg levels are independent predictors of functional cure in children with CHB.

A non-invasive model for predicting liver fibrosis in HBeAg-positive patients with normal or slightly elevated alanine aminotransferase.

ABSTRACT: Early and accurate diagnosis of liver fibrosis is necessary for HBeAg-positive chronic hepatitis B (CHB) patients with normal or slightly increased alanine aminotransferase (ALT), Liver biopsy and many non-invasive predicting markers have several application restrictions in grass-roots hospitals. We aimed to construct a non-invasive model based on routinely serum markers to predict liver fibrosis for this population.A total of 363 CHB patients with HBeAg-positive, ALT ≤2-fold the upper limit of normal and liver biopsy data were randomly divided into training (n = 266) and validation groups (n = 97). Two non-invasive models were established based on multivariable logistic regression analysis in the training group. Model 2 with a lower Akaike information criterion (AIC) was selected as a better predictive model. Receiver operating characteristic (ROC) was used to evaluate the model and was then independently validated in the validation group.The formula of Model 2 was logit (Model value) = 5.67+0.08 × Age -2.44 × log10 [the quantification of serum HBsAg (qHBsAg)] -0.60 × log10 [the quantification of serum HBeAg (qHBeAg)]+0.02 × ALT+0.03 ×  aspartate aminotransferase (AST). The area under the ROC curve (AUC) was 0.89 for the training group and 0.86 for the validation group. Using 2 cut-off points of -2.61 and 0.25, 59% of patients could be identified with liver fibrosis and antiviral treatment decisions were made without liver biopsies, and 149 patients were recommended to undergo liver biopsy for accurate diagnosis.In this study, the non-invasive model could predict liver fibrosis and may reduce the need for liver biopsy in HBeAg-positive CHB patients with normal or slightly increased ALT.

Increased Platelet-CD4+ T Cell Aggregates Are Correlated With HIV-1 Permissiveness and CD4+ T Cell Loss.

Chronic HIV-1 infection is associated with persistent inflammation, which contributes to disease progression. Platelet-T cell aggregates play a critical role in maintaining inflammation. However, the phenotypic characteristics and clinical significance of platelet-CD4+ T cell aggregates remain unclear in different HIV-infected populations. In this study, we quantified and characterized platelet-CD4+ T cell aggregates in the peripheral blood of treatment-naïve HIV-1-infected individuals (TNs), immunological responders to antiretroviral therapy (IRs), immunological non-responders to antiretroviral therapy (INRs), and healthy controls (HCs). Flow cytometry analysis and immunofluorescence microscopy showed increased platelet-CD4 + T cell aggregate formation in TNs compared to HCs during HIV-1 infection. However, the frequencies of platelet-CD4 + T cell aggregates decreased in IRs compared to TNs, but not in INRs, which have shown severe immunological dysfunction. Platelet-CD4 + T cell aggregate frequencies were positively correlated with HIV-1 viral load but negatively correlated with CD4 + T cell counts and CD4/CD8 ratios. Furthermore, we observed a higher expression of CD45RO, HIV co-receptors, HIV activation/exhaustion markers in platelet-CD4 + T cell aggregates, which was associated with HIV-1 permissiveness. High levels of caspase-1 and caspase-3, and low levels of Bcl-2 in platelet-CD4+ T cell aggregates imply the potential role in CD4+ T cell loss during HIV-1 infection. Furthermore, platelet-CD4 + T cell aggregates contained more HIV-1 gag viral protein and HIV-1 DNA than their platelet-free CD4 + T cell counterparts. The platelet-CD4 + T cell aggregate levels were positively correlated with plasma sCD163 and sCD14 levels. Our findings demonstrate that platelet-CD4 + T cell aggregate formation has typical characteristics of HIV-1 permissiveness and is related to immune activation during HIV-1 infection.