AIMS:To investigate the associations of serum immunoglobulin (Ig) and complement levels with incident coronary heart disease (CHD), and to explore the potential mediating role of C-reactive protein (CRP). METHODS AND RESULTS:We measured serum levels of IgA, IgE, IgG, IgM, complement 3 (C3), complement 4 (C4), and CRP in a nested case-control study within the Dongfeng-Tongji cohort, consisting of 1605 CHD cases and 1605 age- and sex-matched controls. We quantified the associations of serum Ig and complement levels with incident CHD using conditional logistic regression and restricted cubic spline models. Mediation analysis was conducted to explore the role of CRP in these associations. The additional predictive ability of an immune indicator score beyond traditional risk factors was also evaluated. Higher IgA and C3 levels were associated with an increased risk of CHD in a linear manner [odds ratio (OR) (95% confidence interval, CI): 1.35 (1.11-1.62), P = 0.002; OR (95% CI): 2.01 (1.17-3.44), P = 0.01, respectively]. Conversely, higher IgG exhibited a significant linear decrease in CHD risk [OR (95% CI): 0.55 (0.36-0.83), P = 0.005]. C-reactive protein mediated 5.70% and 12.51% in the associations of IgA and C3 with incident CHD, respectively. Adding an immune indicator score to the traditional risk model improved CHD prediction more effectively than adding CRP [area under receiver operating characteristic curve (AUC): 0.85% vs. 0.21%; net reclassification improvement (NRI): 15.33% vs. 7.85%; integrated discrimination improvement (IDI): 0.80% vs. 0.17%]. CONCLUSION:Our study identified IgA and C3 as independent risk factors and IgG as a protective factor for CHD. These immune markers may improve CHD risk prediction beyond traditional and CRP models, highlighting their potential for better risk assessment.

BackgroundTuberculosis (TB) remains a global public health burden, and how immune cell subsets regulate host anti-TB immunity and disease progression remains incompletely understood. While previous studies have focused on single-positive (SP) T cells (CD4+ or CD8+) in TB pathogenesis, the association between CD4+CD8+ double-positive (DP) T cells and TB susceptibility, severity, and treatment outcomes have not been fully elucidated. This study aimed to investigate the relationship between DP T cells and other immune cell subsets with TB, and to explore the potential diagnostic and prognostic value of DP T cells in active TB.MethodsA Genome-Wide Association Study (GWAS) was conducted to analyze 731 immune cell traits and a dataset encompassing 895 patients with TB. Subsequently, a cohort including 647 patients with active TB and 632 healthy controls was used to verify the findings of Mendelian randomization (MR). The correlation between the percentage of DP T cells in lymphocytes and TB severity, treatment efficacy, and Mycobacterium tuberculosis (Mtb)-specific IFN-γ production was evaluated. Finally, a random forest model incorporating the percentage of DP T cells in leukocytes and other peripheral blood parameters was constructed to distinguish severe from mild active TB.ResultsMR analysis suggested potential causal links between the percentage of DP T cells among peripheral leukocytes and TB status. Clinical sample validation showed that the percentage of peripheral DP T cell among leukocytes was significantly lower in patients with active TB than in healthy controls (P < 0.001), and was inversely correlated with disease severity. Additionally, the percentage of DP T cells in leukocytes was positively correlated with Mtb-specific antigen-stimulated IFN-γ production. Flow cytometric analysis demonstrated that DP T cells had a significantly higher frequency of IFN-γ-expressing cells compared to CD8+ SP T cells (P < 0.001). The constructed random forest model effectively distinguished severe from mild TB, with good diagnostic performance (AUC = 0.985).ConclusionsOur findings indicate that DP T cells are closely associated with TB severity, and are positively associated with Mtb-specific IFN-γ response. The percentage of peripheral DP T cells in leukocytes could serve as a potential non-invasive biomarker for TB severity stratification.

BACKGROUND:Gastric cancer (GC) is a molecularly heterogeneous disease with poor prognosis. DNA methylation plays a critical role in its pathogenesis, and Homeobox genes are known to be frequently dysregulated through epigenetic mechanisms in various cancers. However, the role of the homeobox gene MEIS2 in GC remains unclear. METHOD:Integrated bioinformatics analysis of RNA-seq and DNA methylation data from TCGA and a K19-Wnt1/C2mE transgenic (Gan) mouse model identified MEIS2 as a candidate gene. Its clinical relevance was assessed using GEO datasets and a clinical cohort of 293 GC patients. Functional roles were investigated through in vitro assays, RNA-seq, and metabolic analyses. Methylation-specific PCR, MassARRAY, and ChIP were used to explore the regulatory mechanisms. RESULTS:MEIS2 was significantly downregulated in GC tissues, and its low expression was associated with advanced tumor stage, neural invasion, and poor overall survival. Functional experiments demonstrated that MEIS2 overexpression suppressed GC cell proliferation, migration, and invasion, induced apoptosis, and inhibited glycolysis by reducing glucose uptake, lactate production, and the expression of key glycolytic enzymes. Hypermethylation of the MEIS2 promoter region (-811 to -757 bp) was negatively correlated with its expression. DNMT1 was found to bind directly to this region and promote MEIS2 promoter hypermethylation, leading to its transcriptional downregulation. CONCLUSION:MEIS2 acts as a tumor suppressor in GC, and its downregulation is mediated by DNMT1-driven promoter hypermethylation. These findings highlight MEIS2 as a potential therapeutic target and prognostic biomarker in GC.

Despite effective immunoprophylaxis, hepatitis B vaccine breakthrough infection (VBI) can still occur among individuals born to mothers with HBV infection. This study synthesized evidence on the incidence of post-vaccination HBV infection in this high-risk population. A systematic literature search was conducted in PubMed, Embase, Scopus, China National Knowledge Infrastructure and Wanfang Chinese databases for articles evaluating VBI in individuals born to mothers with HBV infection. The VBI was characterized by seroconversion to HBsAg and/or anti-HBc positivity at or after 2 years of age, following initial post-immunoprophylaxis HBsAg negativity. The incidence of VBI was pooled after quality assessment. The review followed PRISMA 2020 guidelines and was registered in PROSPERO (CRD420251058273). Among 40 included studies, 37 provided HBsAg data (4,776 individuals; 24,434 person-years) and 29 reported anti-HBc (6,190 individuals; 16,663 person-years). The pooled cumulative incidence of HBsAg positivity was 0.24

Alternative treatment for the highly prevalent Helicobacter pylori infection is imperative due to rising antibiotic resistance. We unexpectedly discovered that the anti-H. pylori component in garlic is hydrogen polysulfide (H2Sn, n⩾2), not organic polysulfides. Studies on the mechanism of action (MoA) show that H2Sn specifically inactivates H. pylori glucose-6-phosphate dehydrogenase (G6PDH) by interfering with electron transfer from glucose-6-phosphate (G6P) to nicotinamide adenine dinucleotide phosphate (NADP+). However, low H2Sn yield makes garlic derivatives hard to be a reliable donor of H2Sn to treat H. pylori infection. To address this challenge, we established a polysulfide transformation process from garlic organosulfur compounds into Fe3S4 that generates H2Sn with a 25–58 times increase in yield. Through chitosan encapsulation, we designed a gastric-adaptive H2Sn microreactor (GAPSR) that eradicates H. pylori with 250 times higher efficiency under gastric conditions. A single GAPSR achieves more rapid H. pylori eradication than combined antibiotics therapy without disturbing the gut microbiota. These findings indicate a distinct MoA transformation mediated by polysulfide as an alternative candidate to treat H. pylori infection.

BackgroundPrognostic assessment plays a crucial role in guiding clinical management and treatment decisions for gastric cancer patients. The enrichment characteristics of 5-hydroxymethylcytosine (5hmC) in circulating cell-free DNA (cfDNA) has emerged as potential prognostic epigenetic markers.MethodsUsing 5hmC-Seal combined with next-generation sequencing (NGS), we profiled the genome-wide distribution of 5hmC in plasma cfDNA samples from 51 gastric cancer patients. Prognostic biomarkers were selected via random survival forest and Cox proportion hazards models, and a prognostic model was subsequently constructed.ResultsSeven prognostic biomarker genes were identified, and the 7-gene prognostic model demonstrated a concordance index (C-index) of 0.892 (95% CI = 0.786-0.998). Patients in the high risk group had a significantly worse overall survival (OS) than those in low-risk group (log-rank P = 0.00012). When the cfDNA 5hmC risk-score was integrated with the traditional clinical characteristics, the C-index increased from 0.819 (95% CI = 0.727-0.911) to 0.904 (95% CI = 0.853-0.955). Multivariate analysis adjusted for age, TNM stage, and chemotherapy confirmed that a high risk-score of cfDNA 5hmC model was an independent predictor of poor OS (hazard ratio [HR]=27.47, 95% CI = 3.28-230.25).ConclusioncfDNA 5hmC serves as an effective prognostic biomarker with high predictive value for the long-term survival in postoperative gastric cancer patients.

Glutaminase (GLS), a crucial gene regulating glutaminolysis, has received much attention as it was found to regulate tumor metabolism and copper-induced cell death. However, its biological roles and mechanisms in human cancers remain obscure. Consequently, the integrated pan-cancer analyses and biological experiments were conducted to elucidate its oncological functions. We found GLS was differentially expressed in human cancers and upregulated GLS predicted poor survival, clinicopathological progression, and tumor heterogeneity. Single-cell analysis found GLS was closely related to various biological functions and pathways. Spatial transcriptomic analysis found GLS expression was mainly derived from tumor cells, which implies tumor cells may have a stronger ability to utilize glutamine than antitumor immune cells in the tumor microenvironment (TME). Meanwhile, we noticed GLS expression was strongly related to the infiltration of various immune cells and stromal cells, the expression of immunomodulatory genes, the activity of some conventional antitumor agents, and the therapeutic response of immunotherapy. Moreover, enrichment analyses suggested GLS was related to various metabolic reprogramming, innate and adaptive immunity suppression, and extracellular matrix remodeling. Finally, we observed GLS was highly expressed in our gastric cancer (GC) cohort. As an independent risk factor for GC prognosis, high-GLS was closely related to pathological progression. Inhibiting GLS expression in GC cells effectively prevented proliferation, migration, and invasion and triggered apoptosis. In conclusion, GLS is an underlying biomarker for oncological progression, prognosis, TME, antitumor drug sensitivity, and immunotherapy response. Targeting GLS can facilitate the implementation of individualized and combined treatment strategies.

Occult hepatitis B virus infection (OBI) is defined by the presence of hepatitis B virus (HBV) DNA, while HBsAg (Hepatitis B surface antigen) remains undetectable. The infectivity of OBI and its potential ability to contribute to cirrhosis and hepatocellular carcinoma has been reported, with infection in children potentially leading to more severe outcomes. However, the global prevalence and disease burden remain unclear, and this study aimed to assess the prevalence of OBI in population under 18 years old. We conducted a systematic literature search in PubMed, Embase, Scopus, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Chinese databases for articles evaluating OBI in population under 18 years old. The prevalence of OBI was pooled after quality assessment. A total of 49 studies was included, allowing a meta-analysis of 1,070,526 HBsAg-negative individuals. Data from 28 and 25 studies were extracted for analysis of the high- and low-risk population, respectively. The overall prevalence of OBI in population ≤ 18 years old was 2.1

Background To investigate the symptoms, the level of antibody, the progression of liver disease after SARS-CoV-2 infection in middle-aged and elderly population infected with hepatitis virus. Methods The study was based on a cohort of high-risk liver cancer and the participants was recruited in April 2023. Blood sample were collected and information was obtained through questionnaires. Data on reinfection was obtained by follow-up until July 31, 2023. The SARS-CoV-2-specific neutralizing antibody and IgG were measured. Results A total of 599 participants infected with hepatitis virus were included and the mean age was 61.3 ± 7.4 years. The SARS-CoV-2 infection rate was 94.7%. Among the infected, 132 were asymptomatic, 435 were symptomatic, no severe cases occurred. Four months after infection, no difference was in liver function and aMAP score between the infected and uninfected. The infected had higher seropositivity rates of both antibodies than the uninfected (neutralizing antibody: uninfected: 93.7%, infected: 99.6%; IgG: uninfected: 59.4%, infected: 98.9%). The levels of both antibodies in the symptomatic were higher than those the asymptomatic and the uninfected (neutralizing antibody: uninfected: 0.75 AU/mL, asymptomatic: 15.46 AU/mL, symptomatic: 24.76 AU/mL; IgG: uninfected: 15.10 AU/mL, asymptomatic: 263.84 AU/mL, symptomatic: 291.83 AU/mL). By July 31, 2023, the incidence of reinfection was 17.5%. Conclusions Although the infection rate of SARS-CoV-2 was high, no severe cases occurred. Omicron infection may not aggravate progression of hepatitis. Four months after infection, the population showed high positivity rate in neutralizing antibody and IgG. Monitoring of virus mutations and targeted prevention and care strategies is crucial for vulnerable populations.

This study explores new screening strategies to enhance liver cancer screening effectiveness. In a prospective study, 2605 participants underwent baseline, 6-months self-reported, and 1-year follow-up screenings using abdominal ultrasonography, AFP, AFP-L3%, and DCP. The results demonstrated the GALADUS protocol exhibited superior performance with higher AUC (0.935 vs. 0.836; DeLong P < 0.001), sensitivity (91.0% vs. 70.8%; P < 0.001), detection (3.1% vs. 2.4%; P < 0.001), and early diagnosis rates (64.2% vs. 58.7%) compared to the AFP/US protocol. Notably, among individuals with an aMAP score ≥ 60, GALADUS had significantly outperformed AFP/US in AUC (0.923 vs. 0.826; DeLong P < 0.001), sensitivity (94.2% vs. 69.6%; P < 0.001), detection (9.7% vs. 7.2%; P < 0.001), and early diagnosis rates (63.1% vs. 54.2%). However, for those with an aMAP score < 60, GALADUS offered no significant advantages. Introducing the "aMAP triage" protocol, combining GALADUS for aMAP ≥ 60 and AFP/US for aMAP < 60, further enhanced AUC to 0.925 (DeLong P < 0.001), improved sensitivity by 19.1% (89.9% vs. 70.8%; P < 0.001), and increased detection (3.1% vs. 2.4%; P < 0.001) and early diagnosis rates (65.0% vs. 58.7%), being cost-effective compared to GALADUS. In conclusion, this study highlights the potential of a stratified precision screening strategy in identifying high-risk individuals, applying tailored early detection protocols to improve liver cancer screening efficacy.

BACKGROUND:Glucose metabolism plays a critical role in tumor progression. When glucose intake is insufficient and the tumor's growth rate exceeds its energy supply, tumor cells typically adapt and overcome the energy stress through compensatory mechanisms to maintain the survival of tumor cells, which may also be related to tumor recurrence or metastasis. METHODS:Different concentrations of glucose were selected as the basis for the energy stress model of gastric cancer. Then CCK-8 and flow cytometry were used to detect its effects on cell proliferation, apoptosis, and cell cycle. Differentially expressed genes (DEGs) were screened by RNA sequencing and the regulated pathways were identified by gene set enrichment analysis. The regulatory relationship between the gene PPP1R15A and its transcription factor JUN was proved by ChIP-qPCR and dual-luciferase reporter assay. The gain and loss of function assays were conducted to examine the effects of PPP1R15A under energy stress in vivo and in vitro. Potential regulatory mechanisms of PPP1R15A were further analyzed through a combination of online databases, RNA sequencing, and metabolite sequencing. The regulation of PPP1R15A on cell autophagy under energy stress was detected by western blot, transmission electron microscope, mRFP-GFP-LC3 adenovirus and laser scanning confocal microscopy. RESULTS:PPP1R15A and the transcription factor JUN were significantly upregulated by glucose deprivation (0 mM vs. 25 mM), JUN combined with the promoter of PPP1R15A and activated its expression. Both PPP1R15A and JUN were highly expressed in gastric cancer tissues and were independent risk factors for prognosis in the gastric cancer cohort. Overexpression of PPP1R15A promoted cell proliferation, inhibited apoptosis, and was involved in cell cycle arrest. Further RNA and metabolite sequencing suggested that PPP1R15A was associated with cell autophagy. In vitro experiments confirmed that both glucose deprivation and overexpression of PPP1R15A promoted the biosynthesis of autolysosome and autophagosome, and activated the cleavage of LC3 complex in gastric cancer cells. Moreover, PPP1R15A knockdown inhibited cell autophagy induced by glucose deprivation. CONCLUSIONS:PPP1R15A sustained the survival of gastric cancer cells by regulating autophagy under energy stress to resist or adapt to harsh environments.

Infants born to HBsAg/HBeAg-positive mothers remain risk for hepatitis B virus vaccine breakthrough infection (VBI). In this multicenter prospective cohort study, we assessed whether increased neonatal vaccine dose (20 μg vs. 10 μg) or booster immunization could reduce VBI among these children. Infants were vaccinated after birth and followed up to age 5. The 20 μg non-booster group sustained higher anti-HBs levels and lower seronegative rates at all follow-ups compared to the 10 μg non-booster group. Booster immunization increased antibody levels in both dose groups. By age 5, VBI incidence was highest in the 10 μg non-booster group, whereas all overt/occult infections occurred among non-booster children. Multivariate analysis suggested that both higher neonatal dose and booster immunization were associated with a reduced VBI risk, with the lowest risk observed when both strategies were combined. These findings suggest that increased neonatal vaccine dose and booster immunization may help sustain anti-HBs and reduce VBI in high-risk population.

Background: According to the 2022 Global Cancer Statistics, lung cancer is the leading cause of cancer-related mortality worldwide. Lung adenocarcinoma (LUAD), which is a histological subtype of Non- Small Cell Lung Cancer (NSCLC), accounts for 40% of primary lung cancer. Therefore, there is an urgent need to identify new prognostic markers as clinical predictive markers for LUAD. Objective: This study aimed to investigate the role of Keratin 80 (KRT80) in the prognosis of LUAD and its underlying mechanisms. Methods: Bioinformatics analysis was conducted using data retrieved from The Cancer Genome Atlas (TCGA) databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were employed to predict the involved biological processes and signaling pathways, respectively. The LinkedOmics database was utilized to identify differentially expressed genes (DEGs) correlated with KRT80. Nomograms and Kaplan-Meier plots were constructed to evaluate the survival outcomes of patients diagnosed with LUAD. Moreover, TIMER was employed to conduct correlation analyses between KRT80 expression and immune cell infiltration, shedding light on the intricate interplay between KRT80 and the tumor microenvironment in LUAD. To ascertain the RNA and protein expression levels of KRT80 in LUAD and adjacent normal tissues, Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) and immunohistochemistry techniques were employed, respectively. Results: Scrutiny of the TCGA dataset revealed KRT80 up-regulation across pan-cancer tissues, notably elevated in LUAD compared to healthy lung tissues. This finding was validated in our clinical samples, where Kaplan-Meier survival curves indicated poorer survival rates for high KRT80 expression in LUAD. A positive correlation was found between the transcription level of KRT80 in LUAD samples and clinical parameters, such as lymph node metastasis stage, distant metastasis, and pathological stage. Survival, logistic regression, and Cox regression analyses emphasized the clinical prognostic significance of high KRT80 expression in LUAD. Nomogram results underscored the robust predictive potential of KRT80 for the survival of LUAD patients. Gene functional enrichment analyses mainly associated KRT80 with cytokine-cytokine receptor interactions, cell cycle, apoptosis, and chemokine signaling pathways. Based on the results of the immune infiltration analysis, it can be found that the expression of KRT80 is related to the immune cell subsets and survival rate of patients with LUAD. Conclusion: Our research revealed a significant upregulation of KRT80 in LUAD, with heightened KRT80 expression correlating with unfavorable prognosis. This study represents a comprehensive and systematic evaluation of KRT80 expression in LUAD, encompassing its prognostic and diagnostic significance, as well as underlying mechanisms. Our findings suggest that KRT80 may emerge as a novel prognostic and predictive biomarker in LUAD.

Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation. We report that the histone H3-specific demethylase KDM4 is expressed as human stromal cells undergo senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation correlate with poorer survival of patients with prostate cancer after chemotherapy. Global chromatin accessibility mapping via assay for transposase-accessible chromatin with high-throughput sequencing, and expression profiling through RNA sequencing, reveals global changes of chromatin openness and spatiotemporal reprogramming of the transcriptomic landscape, which underlie the senescence-associated secretory phenotype (SASP). Selective targeting of KDM4 dampens the SASP of senescent stromal cells, promotes cancer cell apoptosis in the treatment-damaged tumor microenvironment, and prolongs survival of experimental animals. Our study supports dynamic changes of H3K9/H3K36 methylation during senescence, identifies an unusually permissive chromatin state, and unmasks KDM4 as a key SASP modulator. KDM4 targeting presents a new therapeutic avenue to manipulate cellular senescence and limit its contribution to age-related pathologies, including cancer.

Gastric cancer (GC) remains a prevalent and aggressive malignancy worldwide, characterized by significant morbidity and mortality. The regulator of G-protein signaling 1 (RGS1) plays an oncogenic role in various cancers, including GC, but its clinical relevance and mechanisms remain underexplored. In this pilot study, we investigated RGS1 expression in GC tissues and its potential as a prognostic marker, laying the groundwork for future research. Our analysis of patient data from the TCGA data and our cohort of 375 surgically resected GC patients revealed that RGS1 was upregulated in GC tissues and had prognostic significance (TCGA: adjusted HR:1.49, 95%CI: 1.02-2.18; GC cohort: adjusted HR: 1.38, 95%CI: 1.02-1.85). GO function and KEGG enrichment analyses suggest that RGS1 is involved in macrophage-mediated immune responses in GC. We observed a positive correlation between RGS1 expression and M2 macrophage infiltration. Furthermore, co-occurrence of elevated RGS1 expression and M2 macrophage infiltration predicts a worse prognosis (adjusted HR: 1.73, 95%CI: 1.24-2.42 in our cohort). In vitro, RGS1 upregulation and the presence of M2 macrophages enhanced malignant phenotypes of GC cells. Additionally, we confirmed that RGS1 promoted macrophage recruitment and M2 polarization via upregulation of CCL4 expression in vivo. In conclusion, this study suggests that RGS1 could serve as a promising prognostic marker for GC and a potential target for immunotherapy. However, further investigation with more advanced experimental models is needed to confirm these preliminary findings.

Gastric cancer (GC) is a leading cause of cancer-related mortality globally. Histone lactylation, an emerging post-translational modification, holds promise as a therapeutic target and prognostic biomarker, though its expression patterns and clinical relevance in GC are underexplored. Pan-lactylation was quantified by IHC in tumor/adjacent normal tissues and validated via Western blot in GC/normal cell lines. Systematic profiling of lactylome and proteome of tumor-normal pairs (n = 3) identified 127 lactylation-regulated genes. Four prognostic models (stepCOX, LASSO, RSF, GBM) were built using these lactylation-regulated genes from GPL6947 data sets and validated independently in GPL570 data sets. IHC results confirmed elevated pan-lactylation in GC tissues and high pan-lactylation level correlated with larger tumor diameter (P = 0.041) and vascular invasion (P = 0.032). In addition, pan-lactylation level was an independent prognostic predictor (HR = 2.06, 95%CI: 1.51-2.80). Four prognostic models were constructed with different advantages, while the RSF model achieved superior training performance (5-year C-index = 0.837), while COX regression demonstrated optimal validation robustness (5-year C-index = 0.624). Pan-lactylation is a novel prognostic biomarker for GC. The lactylation-driven prognostic signature facilitates precise risk stratification in GC patients, providing a framework for personalized therapeutic intervention.