Despite promising data showing that circulating tumour DNA (ctDNA) dynamics during treatment can inform real-time tumour response and recurrence risk1, how best to translate these insights into actionable clinical decision-making remains unclear. Here we report results from the EP-STAR trial-a multi-centre, ctDNA-driven, risk-adapted, non-randomized phase II study ( NCT04072107 ; ClinicalTrials.gov) testing whether a risk-adaptive treatment (RAT) strategy guided by on-treatment ctDNA dynamics can meaningfully improve survival, using nasopharyngeal carcinoma as a model. Eligible patients were enrolled and began treatment with standard-of-care gemcitabine-cisplatin neoadjuvant chemotherapy (GP-NAC; the P in this abbreviation stands for platinum)2, followed by RAT or standard-of-care chemoradiotherapy guided by ctDNA clearance trajectory during GP-NAC. Protocol-eligible patients who did not receive RAT, drawn from a prospectively registered ctDNA biomarker cohort ( NCT03855020 )3, served as a non-randomized, contemporaneous no-RAT external cohort. The primary end-point was failure-free survival (FFS) in the RAT group. After a median follow-up of 47.3 months, the 3-year FFS was 89.1% (83.2-95.0%) in the RAT group (n = 110). Patients who received RAT showed significantly improved FFS (P = 0.003, log-rank test) compared with the no-RAT external cohort (hazard ratio = 0.41 [0.23-0.75]; P = 0.004, Cox regression model). The RAT strategy was well-tolerated with no treatment-related deaths. Collectively, these data show that a ctDNA-driven RAT paradigm could be a promising strategy to improve survival, challenging the conventional fixed-course, static treatment approach.

Background Multimorbidity among patients with chronic hepatitis B (CHB) infection has emerged as a priority for healthcare and public health systems worldwide.Objective This study aimed to characterise time-trends in multimorbidities among patients with CHB infection. We identified multimorbidity clusters and combinations and quantified their associations with healthcare services utilisation.Design A retrospective observational study, using electronic medical record data.Setting A large tertiary general hospital in China.Participants The study included 23 137 patients with CHB infection admitted between 2011 and 2023.Outcome measures Latent class analysis and association rule mining (ARM) were performed to identify multimorbidity clusters and combinations, respectively. Multivariable logistic regression quantified associations between the identified multimorbidity patterns and length of stay (LOS), daily expense and 1-year readmission for liver-related conditions (OYRL).Results The mean number of multimorbidities among hospitalised patients with CHB infection was 2.82±1.89. From 2011 to 2023, mean age increased from 44.2±13.7 to 48.4±13.1 (p<0.001). The prevalence of cirrhosis (45.50%–57.10%), hepatocellular carcinoma (HCC) (13.10%–17.10%) and non-alcoholic fatty liver disease (3.15%–5.08%) increased over time. Similar trends were observed for non-liver multimorbidities, including diabetes mellitus (9.86%–11.90%), hypertension (7.34%–10.30%) and chronic kidney diseases (0.96%–1.58%). We identified three multimorbidity clusters: Cluster 1 (43.58%) included patients in the early phase of CHB infection with the lowest overall burden of multimorbidity. Cluster 2 (47.71%) was characterised prominently by cirrhosis and HCC. Patients in cluster 3 (8.70%) were the oldest and exhibited the highest probability of metabolic, circulatory and kidney-related multimorbidities. Three clusters demonstrated different association strengths with healthcare utilisation. Most multimorbidity combinations identified by ARM were significantly associated with higher LOS and OYRL, but lower daily expenses.Conclusions Multimorbidity imposes a substantial burden on CHB-infected patients. Our findings highlight the importance of early diagnosis and treatment of CHB infection, as well as tailored integral strategies for multimorbidity management in individuals with CHB infection.

This study evaluated the economic and health benefits of hepatitis E (HEV) screening and vaccination in both outbreak and sporadic settings in China. Decision-analytic Markov models were used to evaluate the population impact and cost-effectiveness of HEV screening and vaccination for people with chronic hepatitis B (CHB), older adults, pregnant women, and women of childbearing age. Simulations projected outcomes over six months for outbreak settings and lifetime horizons for sporadic settings. Incremental cost-effectiveness ratios (ICERs) were derived from a health system perspective with costs in 2023 US$. Robustness was examined through sensitivity analyses. Preventive universal screening combined with standard 3-dose HEV 239 vaccine was cost-effective only for people with CHB (Incremental cost-effectiveness ratio [ICER]: $25.38 thousand per Quality-Adjusted Life Year [QALY] gained), reducing symptomatic infections by 58.16% and HEV-related deaths by 57.51% in sporadic settings. This strategy may be economically viable for other vulnerable populations if the vaccine price is below $21 per dose. In outbreak settings, reactive universal screening combined with emergency 2-dose vaccination yielded cost-effective for older adults, pregnant women, and people with CHB (ICERs of $8.80, $26.26, and $31.81 thousand per QALY gained), reducing symptomatic infections and HEV-related deaths by over 70% within six months. In China, where sporadic settings are more common, preventive universal HEV screening combined with standard 3-dose vaccination is cost-effective only for people with CHB. High vaccine costs render this strategy economically unfeasible for older adults, pregnant women, and women of childbearing age.

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) represent a novel class of small non-coding RNAs. Our previous study showed that tsRNA exhibits differential expression patterns in patients with acute-on-chronic liver failure (ACLF), suggesting its potential as a biomarker for ACLF. Nevertheless, the precise role and underlying molecular mechanisms of tsRNA in ACLF remain largely unknown. Using small tsRNA sequencing, the present study revealed that tsRNA-Gly levels were significantly reduced in both plasma exosomes and liver tissues from patients with ACLF. Functionally, robust overexpression of tsRNA-Gly remarkably enhanced liver cell regeneration, while its downregulation inhibited this process. Mechanistically, tsRNA-Gly directly binds to the N-terminal motif domain of acylpeptide hydrolase (ACPH), a non-canonical RNA-binding protein, via a specific recognition sequence (+17-+24). This interaction stabilizes ACPH by suppressing its ubiquitin-proteasome-mediated degradation, thereby increasing its intracellular abundance. The stabilized ACPH forms a functional complex with tsRNA-Gly to activate grainy head-like 1 (GRHL1), driving its nuclear translocation and transcriptional upregulation of Cyclin D1 (CCND1) via direct promoter binding. In summary, our findings demonstrate that tsRNA-Gly serves as a critical regulator of liver regeneration through the ACPH/GRHL1/CCND1 axis. This novel discovery not only enriches our understanding of the molecular mechanisms underlying tsRNA function but also offers new insights into the role of tsRNAs in the pathogenesis of ACLF.

This study explored the role of Mannose-Binding Lectin-Associated Serine Protease 1 (MASP1) in the diagnosis, prognosis, and immune landscape of stomach adenocarcinoma (STAD), with the aim of providing a molecular foundation for developing early, non-invasive diagnostic tools and advancing immunotherapeutic strategies. We analyzed STAD messenger RNA (mRNA) data from The Cancer Genome Atlas (TCGA), immune-related gene data from the ImmPort database, and complement system-related genes from previous studies. Differentially expressed mRNAs (DEmRNAs) relevant to prognosis, immunity, and the complement system were identified using the “limma” and “survival” packages, alongside a Venn diagram. We confirmed MASP1 expression through analysis of external databases, as well as performing quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting (WB) on the normal gastric cell line and various gastric cancer cell lines. The diagnostic performance of MASP1 was evaluated through Receiver Operating Characteristic (ROC) curve analysis using the “pROC” package. Chi-square tests were conducted to examine the association between MASP1 expression and clinicopathological factors. Univariate and multivariate Cox regression analyses were performed to quantify the survival impact of MASP1 expression. Enrichment analyses were conducted to elucidate the functions and pathways associated with MASP1. The relationship between MASP1 expression and tumor immune infiltration was analyzed using single-sample Gene Set Enrichment Analysis (ssGSEA), Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT), Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE), and Spearman correlation methods. Our findings demonstrated that MASP1 is a significant biomarker associated with immune response and prognosis in STAD patients. Elevated MASP1 expression was correlated with poorer clinical outcomes, with ROC curve analysis revealing an Area Under the Curve (AUC) of 0.725 for MASP1. Additionally, MASP1 was identified as an independent prognostic marker for overall survival (OS) in STAD patients. The expression of MASP1 in STAD was predominantly linked to DNA damage repair and cell cycle regulation mechanisms. Furthermore, MASP1 expression showed a significant association with tumor-infiltrating immune cells and immune-related molecules. This study highlights the significant correlation between MASP1 and the immunological landscape of STAD. MASP1 has the potential to serve as a diagnostic and prognostic marker and could be a promising therapeutic target for immunotherapy in STAD.

ABSTRACT Hepatitis B virus (HBV) infection remains a significant global public health challenge, contributing to both hepatic and extrahepatic disease burdens. This study aims to estimate the global disease and economic burden of HBV‐attributable noncommunicable diseases (NCDs). The study included hepatic NCDs (cirrhosis and other chronic liver diseases [CCLDs] and hepatocellular carcinoma [HCC]) and nonhepatic NCDs (NHNCDs). Nine NHNCDs were identified by integrating the Global Burden of Disease Study (GBD) 2021 database cause list with narrative reviews from January 1, 2013, to May 31, 2024. The economic impacts of HBV‐attributable NCDs in 159 countries were estimated and projected to 2035 using a cost‐of‐illness approach, encompassing healthcare costs and productivity losses due to mortality. Country‐specific data were sourced from public and global databases. In 2021, the global HBV‐attributable age‐standardized incidence rates (ASIRs) and disability‐adjusted life‐years (DALYs) rates (ASDRs) were: hepatic CCLDs (61.51 and 161.92/100 000 persons), HCC (2.37 and 65.36/100 000 persons), and NHNCDs (7.75 and 33.04/100 000 persons). The global economic cost of HBV‐attributable NCDs was conservatively estimated at $40.99 billion in 2021, including $37.42 billion in healthcare costs and $3.57 billion in productivity losses, equivalent to 0.027% of global GDP. Of the healthcare costs, 55.5% ($20.78 billion) were borne by the public healthcare providers, 13.2% ($4.94 billion) by the private healthcare providers, and 31.3% ($11.71 billion) by patients' out‐of‐pocket spending. If current trends persist, the global economic costs were projected to increase from $42.94 billion (0.028% of global GDP) in 2022 to $83.74 billion (0.035% of global GDP) in 2035, with a cumulative cost $847.10 billion (0.031% of global GDP) over this period. Central and Western Sub‐Saharan Africa would bear the heaviest HBV‐attributable NCDs costs relative to GDP, while the Caribbean and Latin America would experience the most rapid growth of economic impact. The economic burden of HBV‐attributable NCDs is projected to increase over the next decade and disproportionately affect resource‐limited settings. Targeted and sustained efforts will be essential to mitigate widening health and economic disparities.

Background The estrogen related receptor alpha (ESRRA), a key member of the estrogen receptor-related receptor (ERR) family, has been extensively implicated in tumor progression across multiple cancers. Existing studies highlight its pivotal role in cancer cell proliferation and migration. However, its specific function and underlying molecular mechanisms in hepatocellular carcinoma (HCC) remain incompletely understood. Methods The effects of ESRRA on HCC cells proliferation and migration were investigated in vitro (CCK-8, colony formation, EdU proliferation, wound-healing, transwell assays, and Epithelial-mesenchymal transition (EMT) marker analysis) and in vivo (Balb/c nude mouse subcutaneous xenograft and lung metastasis models). RNA sequencing and dual-luciferase reporter assays were employed to identify ESRRA’s downstream targets and pathways. Results ESRRA promoted HCC cell proliferation and migration in vitro and in vivo . Mechanistically, ESRRA transcriptionally upregulated PHD finger protein 5A (PHF5A), which subsequently activated the PI3K/AKT signaling cascade. The cholesterol-lowering drug rosuvastatin exerted anti-tumor effects on HCC by downregulating ESRRA and, meanwhile, suppressing its transcriptional activity through depleting intracellular cholesterol. Conclusion ESRRA promotes HCC progression via the PHF5A /PI3K/AKT axis and mediates rosuvastatin's anti-tumor effect. Targeting ESRRA-PHF5A may be a therapeutic strategy for HCC.

Approximately 20% to 30% of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) experience disease relapse despite definitive chemoradiotherapy. The programmed cell death 1 (PD-1) blockade camrelizumab has demonstrated considerable value in recurrent or metastatic NPC, while its role in locoregionally advanced NPC is unclear. To evaluate the efficacy and safety of adjuvant camrelizumab for patients with locoregionally advanced NPC. Randomized, open-label, multicenter, phase 3 clinical trial conducted from August 2018 to November 2021 at 11 centers in China and enrolling 450 patients with T4N1M0 or T1-4N2-3M0 NPC who had completed induction-concurrent chemoradiotherapy. The final date of follow-up was March 20, 2024. Patients were randomized (1:1) to receive adjuvant camrelizumab (200 mg intravenously once every 3 weeks for 12 cycles; n = 226) or observation (standard therapy group; n = 224). The primary end point was event-free survival (freedom from distant metastasis, locoregional relapse, or death due to any cause). Secondary end points included distant metastasis–free survival, locoregional relapse–free survival, overall survival, safety, and health-related quality of life. Among the 450 participants (mean age, 45 [SD, 10] years; 24% women), after a median follow-up of 39 (IQR, 33-50) months, the camrelizumab group had a 3-year event-free survival rate of 86.9%, whereas the standard therapy group had a rate of 77.3% (stratified hazard ratio, 0.56; 95% CI, 0.36-0.89; P = .01). Grade 3 or 4 adverse events were reported in 23 patients (11.2%) in the camrelizumab and 7 (3.2%) in the standard therapy group. Reactive capillary endothelial proliferation was the most common adverse event related to camrelizumab, occurring in 85.8% of patients at grade 1 or 2, while 2% of patients had grade 3 or 4 events. There was no significant deterioration in quality of life associated with camrelizumab treatment. Adjuvant PD-1 blockade with camrelizumab significantly improved event-free survival with manageable toxicities, highlighting its potential role in the management of locoregionally advanced NPC. ClinicalTrials.gov Identifier: NCT03427827

Antiviral treatment reduces, but does not eliminate, the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Predicting HCC risk in this population remains challenging. This study aimed to use dynamic changes in liver stiffness measurement (LSM) obtained using two-dimensional (2D) shear-wave elastography (SWE) to predict HCC in patients with non-cirrhotic and cirrhotic CHB who had well-controlled viremia. We retrospectively enrolled 303 patients with CHB (45 patients with cirrhosis) who had well-controlled viremia (hepatitis B virus DNA < 100 IU/mL for ≥ 6 months) during antiviral treatment. Patients were followed up every 3–6 months and had two to twelve reliable LSMs using 2D SWE. Clinical and laboratory variables, single LSM, change between two LSMs, and dynamic LSM changes were analyzed using least absolute shrinkage and selection operator and multivariable Cox regression analysis to identify risk factors for HCC. Dynamic LSM changes were classified into sustained low LSM (all LSMs ≤ 8.1 kPa), unstable LSM (LSM ≤ 8.1 kPa at least once and > 8.1 kPa at least once), and sustained high LSM (all LSMs > 8.1 kPa). Among the 303 patients, 27 developed HCC. In the multivariable analysis, sustained high LSM in dynamic LSM changes (HR = 11.624, 95

Importance With the programmed cell death protein 1 (PD-1) blockade toripalimab, omitting highly toxic concurrent cisplatin may be feasible for nasopharyngeal carcinoma (NPC) without compromising survival. Objective To evaluate the efficacy and safety of toripalimab incorporated into induction chemotherapy and radiotherapy, without concurrent cisplatin, for locoregionally advanced NPC. Design, Setting, and Participants Open-label, multicenter, randomized phase 3 clinical trial conducted from August 2021 to July 2022 at 13 hospitals in China, enrolling 532 patients with T4N1M0 or T1-4N2-3M0 NPC; 400 (75.2%) completed the trial per protocol. The final date of follow-up was March 21, 2025. Interventions Patients were randomly assigned to either the standard therapy group (n = 266), receiving toripalimab with gemcitabine-cisplatin induction chemotherapy and concurrent cisplatin-radiotherapy (100 mg/m(2) triweekly for 2 cycles), or the concurrent cisplatin-sparing group (n = 266), receiving the same regimen without concurrent cisplatin. The 17 cycles of toripalimab (240 mg triweekly) were distributed across the induction, radiotherapy, and adjuvant phases as 3, 3, and 11 cycles, respectively. Main Outcomes and Measures Coprimary end points were failure-free survival (noninferiority margin, 8%) and incidence of all-grade vomiting (superiority design). Secondary end points included overall survival, locoregional recurrence-free survival, distant metastasis-free survival, safety, tumor response, quality of life, and tolerability. Results In the 532 patients in the intention-to-treat population (median [IQR] age, 47 [39-54] years; 25.2% women), after a median follow-up of 37.0 (range, 4.0-50.0) months, the concurrent cisplatin-sparing group had a 3-year failure-free survival rate of 88.3% vs 87.6% in the standard therapy group, a difference of 0.7% (lower limit of the 1-sided 95% CI, -3.9%; P = .002 for noninferiority; stratified hazard ratio, 0.92 [95% CI, 0.66-1.79]; log-rank P = .73). In the safety analysis, the incidence of all-grade vomiting was significantly lower in the concurrent cisplatin-sparing group vs the standard therapy group (26.2% [68/260] vs 59.8% [156/261]; difference, 33.6% [1-sided 95% CI, 26.9%-infinity]; P < .001). Patient-reported quality of life (participation rate, 87.5%) and tolerability (participation rate, 94.7%) were better in the concurrent cisplatin-sparing group, primarily in gastrointestinal, functional, and global health status. Conclusions and Relevance In this phase 3 randomized clinical trial, among patients with locoregionally advanced NPC, toripalimab combination therapy without concurrent cisplatin was a feasible treatment with high efficacy in failure-free survival and low toxicity. Trial Registration ClinicalTrials.gov Identifier: NCT04907370

Importance Approximately 20% to 30% of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) experience disease relapse despite definitive chemoradiotherapy. The programmed cell death 1 (PD-1) blockade camrelizumab has demonstrated considerable value in recurrent or metastatic NPC, while its role in locoregionally advanced NPC is unclear. Objective To evaluate the efficacy and safety of adjuvant camrelizumab for patients with locoregionally advanced NPC. Design, Setting, and Participants Randomized, open-label, multicenter, phase 3 clinical trial conducted from August 2018 to November 2021 at 11 centers in China and enrolling 450 patients with T4N1M0 or T1-4N2-3M0 NPC who had completed induction-concurrent chemoradiotherapy. The final date of follow-up was March 20, 2024. Interventions Patients were randomized (1:1) to receive adjuvant camrelizumab (200 mg intravenously once every 3 weeks for 12 cycles; n = 226) or observation (standard therapy group; n = 224). Main Outcomes and Measures The primary end point was event-free survival (freedom from distant metastasis, locoregional relapse, or death due to any cause). Secondary end points included distant metastasis-free survival, locoregional relapse-free survival, overall survival, safety, and health-related quality of life. Results Among the 450 participants (mean age, 45 [SD, 10] years; 24% women), after a median follow-up of 39 (IQR, 33-50) months, the camrelizumab group had a 3-year event-free survival rate of 86.9%, whereas the standard therapy group had a rate of 77.3% (stratified hazard ratio, 0.56; 95% CI, 0.36-0.89; P = .01). Grade 3 or 4 adverse events were reported in 23 patients (11.2%) in the camrelizumab and 7 (3.2%) in the standard therapy group. Reactive capillary endothelial proliferation was the most common adverse event related to camrelizumab, occurring in 85.8% of patients at grade 1 or 2, while 2% of patients had grade 3 or 4 events. There was no significant deterioration in quality of life associated with camrelizumab treatment. Conclusions and Relevance Adjuvant PD-1 blockade with camrelizumab significantly improved event-free survival with manageable toxicities, highlighting its potential role in the management of locoregionally advanced NPC.

With the programmed cell death protein 1 (PD-1) blockade toripalimab, omitting highly toxic concurrent cisplatin may be feasible for nasopharyngeal carcinoma (NPC) without compromising survival. To evaluate the efficacy and safety of toripalimab incorporated into induction chemotherapy and radiotherapy, without concurrent cisplatin, for locoregionally advanced NPC. Open-label, multicenter, randomized phase 3 clinical trial conducted from August 2021 to July 2022 at 13 hospitals in China, enrolling 532 patients with T4N1M0 or T1-4N2-3M0 NPC; 400 (75.2%) completed the trial per protocol. The final date of follow-up was March 21, 2025. Patients were randomly assigned to either the standard therapy group (n = 266), receiving toripalimab with gemcitabine-cisplatin induction chemotherapy and concurrent cisplatin-radiotherapy (100 mg/m2 triweekly for 2 cycles), or the concurrent cisplatin–sparing group (n = 266), receiving the same regimen without concurrent cisplatin. The 17 cycles of toripalimab (240 mg triweekly) were distributed across the induction, radiotherapy, and adjuvant phases as 3, 3, and 11 cycles, respectively. Coprimary end points were failure-free survival (noninferiority margin, 8%) and incidence of all-grade vomiting (superiority design). Secondary end points included overall survival, locoregional recurrence-free survival, distant metastasis–free survival, safety, tumor response, quality of life, and tolerability. In the 532 patients in the intention-to-treat population (median [IQR] age, 47 [39-54] years; 25.2% women), after a median follow-up of 37.0 (range, 4.0-50.0) months, the concurrent cisplatin–sparing group had a 3-year failure-free survival rate of 88.3% vs 87.6% in the standard therapy group, a difference of 0.7% (lower limit of the 1-sided 95% CI, −3.9%; P = .002 for noninferiority; stratified hazard ratio, 0.92 [95% CI, 0.66-1.79]; log-rank P = .73). In the safety analysis, the incidence of all-grade vomiting was significantly lower in the concurrent cisplatin–sparing group vs the standard therapy group (26.2% [68/260] vs 59.8% [156/261]; difference, 33.6% [1-sided 95% CI, 26.9%-∞]; P < .001). Patient-reported quality of life (participation rate, 87.5%) and tolerability (participation rate, 94.7%) were better in the concurrent cisplatin–sparing group, primarily in gastrointestinal, functional, and global health status. In this phase 3 randomized clinical trial, among patients with locoregionally advanced NPC, toripalimab combination therapy without concurrent cisplatin was a feasible treatment with high efficacy in failure-free survival and low toxicity. ClinicalTrials.gov Identifier: NCT04907370

BACKGROUND:Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS:This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS:Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION:Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING:National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

While micronutrients are crucial for immune function, their impact on humoral responses to inactivated COVID-19 vaccination remains unclear. We investigated the associations between seven key micronutrients and antibody responses in 44 healthy adults with two doses of an inactivated COVID-19 vaccine. Blood samples were collected pre-vaccination and 28 days post-booster. We measured circulating minerals (iron, zinc, copper, and selenium) and vitamins (A, D, and E) concentrations alongside antibody responses and assessed their associations using linear regression analyses. Our analysis revealed inverse associations between blood iron and zinc concentrations and anti-SARS-CoV-2 IgM antibody binding affinity (AUC for iron: beta = -258.21, p < 0.0001; zinc: beta = -17.25, p = 0.0004). Notably, antibody quality presented complex relationships. Blood selenium was positively associated (beta = 18.61, p = 0.0030), while copper/selenium ratio was inversely associated (beta = -1.36, p = 0.0055) with the neutralizing ability against SARS-CoV-2 virus at a 1:10 plasma dilution. There was no significant association between circulating micronutrient concentrations and anti-SARS-CoV-2 IgG binding affinity. These findings suggest that circulating iron, zinc, and selenium concentrations and copper/selenium ratio, may serve as potential biomarkers for both quantity (binding affinity) and quality (neutralization) of humoral responses after inactivated COVID-19 vaccination. Furthermore, they hint at the potential of pre-vaccination dietary interventions, such as selenium supplementation, to improve vaccine efficacy. However, larger, diverse studies are needed to validate these findings. This research advances the understanding of the impact of micronutrients on vaccine response, offering the potential for personalized vaccination strategies.

Background and Aims: As a subunit of the condensin com-plex, NCAPG has an important role in maintaining chromo-some condensation, but its biological function and regulatory mechanism in hepatocellular carcinoma (HCC) remains un-defined. Methods: The prognostic ability of NCAPG in HCC patients was examined by univariate and multivariate Cox regression analysis. ROC curves were plotted to compare the predictive ability of NCAPG and AFP. Double luciferase reporter system, and ChIP were used to investigate tran-scriptional potential of E2F1 to NCAPG. Pyroptosis was ob-served by scanning electron microscopy. Protein expression of NCAPG, E2F1, and major proteins constituting NLRP3 in-flammasome was determined by western blotting and ELISA. An in vivo tumor formation assay was conducted to verify the in vitro results. Results: Up-regulated NCAPG was identi-fied in HCC tissues compared with adjacent tissue and high NCAPG was positively correlated with poor prognosis. Serum NCAPG mRNA level was a prognostic factor in HCC patients and also a diagnostic factor with higher predictive ability compared with AFP [AUROC 0.766 (95% CI: 0.650-0.881) vs. 0.649 (95% CI 0.506-0.793)]. HBx transfection resulted in concomitant up-regulation of E2F1 and NCAPG. E2F1 sig-nificantly increased the activity of luciferase reporter fused with NCAPG reporter, and the interaction of E2F1 and NCAPG gene was confirmed by ChIP. Silencing of E2F1 resulted in significant down-regulation of NCAPG. Knockdown of NCAPG promote pyroptosis mediated by NLRP3 inflammasome acti-vation in multiple HCC cell lines and also suppressed tumo-rigenesis in vitro. Conclusions: We identified a novel role of NCAPG in the regulation of NLRP3 inflammasome-mediated pyroptosis, which was regulated by its upstream transactiva-tor, E2F1. The role of E2F1-NCAPG-NLRP3 regulation of py-roptosis network may be a potential target in HCC treatment.

Abstract Background Type 2 diabetes mellitus (T2DM) increases the risk of liver cancer among people living with hepatitis B virus (HBV). Our study aimed to estimate the global burden and trends of liver cancer attributable to comorbid T2DM among people living with HBV from 1990 to 2019. Methods We calculated the population attributable fractions (PAFs) of liver cancer attributable to comorbid T2DM among the burden of HBV-related liver cancer. We applied the PAFs to the burden of HBV-related liver cancer derived from the Global Burden of Disease (GBD) 2019 database to obtain the burden of liver cancer attributable to HBV–T2DM comorbidity. The prevalence, disability-adjusted life year (DALY), and deaths of liver cancer attributable to the comorbidity were assessed at the global, regional, and country levels and then stratified by the sociodemographic index (SDI), sex, and age group. Estimated annual percentage changes (EAPCs) were calculated to quantify the temporal trends. Results In 2019, the global age-standardized prevalence and DALY rates of liver cancer attributable to HBV–T2DM comorbidity were 9.9 (8.4–11.5) and 182.4 (154.9–212.7) per 10,000,000 individuals, respectively. High-income Asia Pacific and East Asia had the highest age-standardized prevalence and DALY rates of liver cancer attributable to HBV–T2DM comorbidity, respectively. From 1990 to 2019, age-standardized prevalence and DALY rates increased in 16 out of 21 GBD regions. High-income North America had the largest annual increases in both age-standardized prevalence rates (EAPC = 6.07; 95% UI, 5.59 to 6.56) and DALY rates (EAPC = 4.77; 95% UI, 4.35 to 5.20), followed by Australasia and Central Asia. Across all SDI regions, the high SDI region exhibited the most rapid increase in age-standardized prevalence and DALY rates from 1990 to 2019. Additionally, men had consistently higher disease burdens than women across all age groups. The patterns of mortality burden and trends are similar to those of DALYs. Conclusions The burden of liver cancer attributable to comorbid T2DM among people living with HBV has exhibited an increasing trend across most regions over the last three decades. Tailored prevention strategies targeting T2DM should be implemented among individuals living with HBV.

The liver is the largest glandular organ in the body and has a unique distribution of cells and biomolecules. However, the treatment outcome of end-stage liver disease is extremely poor. Single-cell sequencing is a new advanced and powerful technique for identifying rare cell populations and biomolecules by analyzing the characteristics of gene expression between individual cells. These cells and biomolecules might be used as potential targets for immunotherapy of liver diseases and contribute to the development of precise individualized treatment. Compared to whole-tissue RNA sequencing, single-cell RNA sequencing (scRNA-seq) or other single-cell histological techniques have solved the problem of cell population heterogeneity and characterize molecular changes associated with liver diseases with higher accuracy and resolution. In this review, we comprehensively summarized single-cell approaches including transcriptomic, spatial transcriptomic, immunomic, proteomic, epigenomic, and multiomic technologies, and described their application in liver physiology and pathology. We also discussed advanced techniques and recent studies in the field of single-cell; our review might provide new insights into the pathophysiological mechanisms of the liver to achieve precise and individualized treatment of liver diseases.

BackgroundPrevious studies have suggested the potential of PD-1/PD-L1 inhibitors in the treatment of chronic HBV infection. However, since phase III clinical trials have not yet been announced, additional clinical insights may be obtained by observing changes in serum hepatitis B surface antigen (HBsAg) and HBV-DNA levels in cancer patients undergoing PD-1 inhibitor therapy.ObjectiveTo explore the effects of PD-1 inhibitor combinational therapy on serum HBsAg and HBV-DNA levels, investigate the incidence of HBsAg loss, HBV reactivation (HBVr), and immune-related adverse events (irAEs), and identify the risk factors associated with significant HBsAg fluctuations and HBVr. MethodsA retrospective study including 1195 HBsAg-positive cancer patients who received PD-1 inhibitors between July 2019 and June 2023 was conducted, and 180 patients were enrolled in this study. Serum HBsAg levels before and after PD-1 inhibitor administration were compared across different subgroups. The Pearson χ2 or Fisher exact test was performed to investigate the relationships between categorical variables. Univariable and multivariable analysis were performed to identify the risk factors associated with significant HBsAg fluctuations and HBVr. ResultsWith the concurrent use of antiviral agents, serum HBsAg levels decreased (Z=-3.966, P < 0.0001) in 129 patients and increased (t=-2.047, P=0.043) in 51 patients. Additionally, 7 patients (3.89%) achieved serum HBsAg loss. Virus replication was suppressed in most of the enrolled patients. When divided patients into different subgroups, significant HBsAg decreases after PD-1 inhibitor administration were discovered in lower baseline HBsAg group (Z=-2.277, P=0.023), HBeAg-seronegative group (Z=-2.200, P=0.028), non-irAEs occurrence group (Z=-2.007, P=0.045) and liver cancer group (Z=-1.987, P=0.047). Of note, 11 patients and 36 patients experienced HBVr (6.11%) and irAEs (20%), respectively, which could lead to discontinuation or delayed use of PD-1 inhibitors. After multivariable analysis, HBeAg-seropositive (OR, 7.236 [95% CI, 1.757-29.793], P=0.01) and the occurrence of irAEs (OR, 4.077 [95% CI, 1.252-13.273], P=0.02) were identified as the independent risk factors for significant HBsAg increase, the occurrence of irAEs (OR, 5.560 [95% CI, 1.252-13.273], P=0.01) was identified as the only independent risk factor for HBVr. ConclusionPD-1 inhibitors combined with nucleos(t)ide analogues (NAs) may exert therapeutic potential for chronic HBV infection in cancer patients. However, attention also should be paid to the risk of significant elevation in HBsAg levels, HBVr, and irAEs associated with PD-1 inhibitor combinational therapy.

Background China bears a high burden of both hepatitis B virus (HBV) infection and type 2 diabetes mellitus (T2DM). T2DM accelerates the progression of liver disease among individuals infected with HBV. This study aims to assess the excess disease burden caused by comorbid T2DM among HBV-infected individuals in China. Methods We estimated the disease burden of HBV and its complications in China from 2006 to 2030 using individual-based Markov models. The baseline population consisted of 93 million HBV-infected individuals derived from the 2006 National Serological Epidemiological Survey. We developed two models: one incorporated the impact of T2DM on the disease progression of HBV infection, while the other did not consider the impact of T2DM. By comparing the outcomes between these two models, we estimated the excess disease burden attributable to comorbid T2DM among HBV-infected individuals. Results The incidence of severe HBV complications, including cirrhosis, hepatocellular carcinoma (HCC), and liver-related deaths, exhibited an increasing trend from 2006 to 2030 among the Chinese HBV-infected population. Comorbid T2DM increased the annual incidence and cumulative cases of severe HBV complications. From 2006 to 2022, comorbid T2DM caused 791,000 (11.41%), 244,000 (9.27%), 377,000 (8.78%), and 796,000 (12.19%) excess cases of compensated cirrhosis, decompensated cirrhosis, HCC, and liver-related deaths, respectively. From 2023 to 2030, comorbid T2DM is projected to result in an 8.69% excess in severe HBV complications and an 8.95% increase in liver-related deaths. Among individuals aged 60 and older at baseline, comorbid T2DM led to a 21.68% excess in severe HBV complications and a 28.70% increase in liver-related deaths from 2006 to 2022, with projections indicating a further 20.76% increase in severe HBV complications and an 18.31% rise in liver-related deaths over the next seven years. Conclusions Comorbid T2DM imposes a substantial disease burden on individuals with HBV infection in China. Healthcare providers and health policymakers should develop and implement tailored strategies for the effective management and control of T2DM in individuals with HBV infection.

Background and aims:There is currently no single model for predicting Wilson's disease (WD). We aimed to create a nomogram using daily clinical parameters to improve the accuracy of WD diagnosis in patients with abnormal liver function. Methods:Between July 2016 and December 2020, we identified 90 WD patients with abnormal liver function who had homozygous or compound heterozygous mutations in the ATP7B gene. The control group included 128 patients with similar liver function but no WD during the same time period. To create a nomogram, we screened potential predictive variables using the least absolute shrinkage and selection operator model and multivariate logistic regression. Results:We developed a nomogram for screening for WD based on six predictive factors: serum copper, direct bilirubin, uric acid, cholinesterase, prealbumin, and reticulocyte percentage. In the training cohort, the area under curve (AUC) of the nomogram reached 0.967 (95% confidence interval (CI) 0.946-0.988), while the area under the precision-recall curve was 0.961. Based on the optimal cutpoint of 213.55, our nomogram performed well, with a sensitivity of 96% and a specificity of 87%. In the validation cohort, the AUC of the nomogram was as high as 0.991 (95% CI 0.970-1.000). Conclusions:We developed a nomogram that can predict the risk of WD prior to the detection of serum ceruloplasmin or urinary copper, greatly increasing screening efficiency for patients with abnormal liver function.