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Abstract The activation of ferroptosis presents a versatile strategy for enhancing the antitumor immune responses in cancer therapy. However, developing ferroptosis inducers that combine high biocompatibility and therapeutic efficiency remains challenging. In this study, we propose a novel approach using biological nanoparticles derived from outer membrane vesicles (OMVs) of Escherichia coli for tumor treatment, aiming to activate ferroptosis and stimulate the immune responses. Specifically, we functionalize the OMVs by anchoring them with ferrous ions via electrostatic interactions and loading them with the STING agonist-4, followed by tumor-targeting DSPE-PEG-FA decoration, henceforth referred to as OMV/SaFeFA. The anchoring of ferrous ions endows the OMVs with peroxidase-like activity, capable of inducing cellular lipid peroxidation by catalyzing H2O2 to •OH. Furthermore, OMV/SaFeFA exhibits pH-responsive release of ferrous ions and the agonist, along with tumor-targeting capabilities, enabling tumor-specific therapy while minimizing side effects. Notably, the concurrent activation of the STING pathway and ferroptosis elicits robust antitumor responses in colon tumor-bearing mouse models, leading to exceptional therapeutic efficacy and prolonged survival. Importantly, no acute toxicity was observed in mice receiving OMV/SaFeFA treatments, underscoring its potential for future tumor therapy and clinical translation.

Abstract Background Acute myeloid leukemia (AML) is an aggressive heterogeneous hematological malignancy with remarkably heterogeneous outcomes. This study aimed to identify potential biomarkers for AML risk stratification via analysis of gene expression profiles. Methods RNA sequencing data from 167 adult AML patients in the Cancer Genome Atlas (TCGA) database were obtained for overall survival (OS) analysis, and 52 bone marrow (BM) samples from our clinical center were used for validation. Additionally, siRNA was used to investigate the role of prognostic genes in the apoptosis and proliferation of AML cells. Results Co‐expression of 103 long non‐coding RNAs (lncRNAs) and mRNAs in the red module that were positively correlated with European Leukemia Network (ELN) risk stratification and age was identified by weighted gene co‐expression network analysis (WGCNA). After screening by uni‐ and multivariate Cox regression, Kaplan–Meier survival, and protein–protein interaction analysis, four genes including the lncRNA LOC541471, GDAP1, SOD1, and STK25 were incorporated into calculating a risk score from coefficients of the multivariate Cox regression model. Notably, GDAP1 expression was the greatest contributor to OS among the four genes. Interestingly, the risk score, ELN risk stratification, and age were independent prognostic factors for AML patients, and a nomogram model constructed with these factors could illustrate and personalize the 1‐, 3‐, and 5‐year OS rates of AML patients. The calibration and time‐dependent receiver operating characteristic curves (ROCs) suggested that the nomogram had a good predictive performance. Furthermore, new risk stratification was developed for AML patients based on the nomogram model. Importantly, knockdown of LOC541471, GDPA1, SOD1, or STK25 promoted apoptosis and inhibited the proliferation of THP‐1 cells compared to controls. Conclusions High expression of LOC541471, GDAP1, SOD1, and STK25 may be biomarkers for risk stratification of AML patients, which may provide novel insight into evaluating prognosis, monitoring progression, and designing combinational targeted therapies.

Abstract Doxorubicin‐induced cardiomyopathy (DIC) brings tough clinical challenges as well as continued demand in developing agents for adjuvant cardioprotective therapies. Here, a zebrafish phenotypic screening with deep‐learning assisted multiplex cardiac functional analysis using motion videos of larval hearts is established. Through training the model on a dataset of 2125 labeled ventricular images, ZVSegNet and HRNet exhibit superior performance over previous methods. As a result of high‐content phenotypic screening, cyanidin chloride (CyCl) is identified as a potent suppressor of DIC. CyCl effectively rescues cardiac cell death and improves heart function in both in vitro and in vivo models of Doxorubicin (Dox) exposure. CyCl shows strong inhibitory effects on lipid peroxidation and mitochondrial damage and prevents ferroptosis and apoptosis‐related cell death. Molecular docking and thermal shift assay further suggest a direct binding between CyCl and Keap1, which may compete for the Keap1‐Nrf2 interaction, promote nuclear accumulation of Nrf2, and subsequentially transactivate Gpx4 and other antioxidant factors. Site‐specific mutation of R415A in Keap1 significantly attenuates the protective effects of CyCl against Dox‐induced cardiotoxicity. Taken together, the capability of deep‐learning‐assisted phenotypic screening in identifying promising lead compounds against DIC is exhibited, and new perspectives into drug discovery in the era of artificial intelligence are provided.

Abstract Purpose The aim of this study is to measure the trajectory of healthy ageing among Chinese middle-aged and older population, and explore the disparity of the trajectory, as well as contributing factors, between urban and rural areas in China. Methods A total of 9402 respondents aged 45 years and older interviewed in four waves (2011, 2013, 2015 and 2018) were selected from the China Health and Retirement Longitudinal Study. Healthy ageing score was calculated through item response theory. A latent growth mixture model (LGMM) was applied to distinguish the trajectory of healthy aging. A multinomial logistics regression model (MLRM) was used to explore the relationship between urban-rural areas and healthy aging trajectories, and further to explore associated factors in rural and urban areas separately. Results The healthy ageing score was lower in rural areas than urban areas in each survey wave. Five classes (“continuing-low”, “continuing-middle”, “continuing-middle-to-high”, “significantly-declining”, “continuing-high”) were grouped through LGMM. The MLRM results showed that urban living was significantly associated with a higher likelihood of being healthy (for [continuing-low/continuing-high]: β = − 1.17, RRR = 0.31, P

Abstract Purpose We used targeted capture sequencing to analyze TP53‐mutated circulating tumor DNA (ctDNA) in metastatic breast cancer patients and to determine whether TP53 mutation has predictive value for anti‐human epidermal growth factor receptor 2 (HER2) treatment for in HER2 amplification‐positive patients (HER2+) and HER2 mutation‐positive, amplification‐negative (HER2−/mut) patients. Patients and Methods TP53 mutation features were analyzed in the Geneplus cohort (n = 1184). The MSK‐BREAST cohort was used to explore the value of TP53 mutation in predicting anti‐HER‐2 antibody efficacy. Sequencing of ctDNA in phase Ib, phase Ic, phase II clinical trials of pyrotinib (HER2+ patients), and an investigator‐initiated phase II study of pyrotinib (HER2−/mut patients) were performed to analyze the relationships between TP53 mutation and prognosis for HER2 TKIs. The MSK‐BREAST cohort, MutHER, and SUMMIT cohort were used for verification. Results TP53 mutations were detected in 53.1% (629/1184) of patients in the Geneplus cohort. The TP53 mutation rate was higher in HR‐negative (p

Bamboo surface defect detection provides quality assurance for bamboo product manufacture in industrial scenarios, an integral part of the overall manufacturing process. Currently, bamboo defect inspection predominantly relies on manual operation, but manual inspection is very time-consuming as well as labor-intensive, and the quality of inspection is not guaranteed. A few visual inspection systems based on traditional image processing have been deployed in some factories in recent years. However, traditional machine vision algorithms extract features in tedious steps and have poor performance along with poor adaptability in the face of complex defects. Accordingly, many scholars are committed to seeking deep learning methods to accomplish surface defect detection. However, existing deep learning object detectors struggle with specific industrial defects when directly applied to industrial defect detection, such as sliver defects, especially for ones with extreme aspect ratios. To this end, this paper proposes an improved algorithm based on the advanced object detector YOLOV4-CSP, which introduces asymmetric convolution and attention mechanism. The introduction of asymmetric convolution enhances the feature extraction in the horizontal direction of the bamboo strip surface, improving the performance in detecting sliver defects. In addition, convolutional block attention module(CBAM), a hybrid attention module, which combines channel attention with spatial attention, is utilized to promote the representation ability of the model by increasing the weights of crucial channels and regions. The proposed model achieves outstanding performance in the general categories and excels in the hard-to-detect categories. Some enterprise’s bamboo strip dataset experiments verify that the model can reach 96.74% mAP for the typical six surface defects. Meanwhile, we also observe significant improvements when extending our model to aluminum datasets with similar characteristics.

Abstract Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging. Nasopharyngeal carcinoma (NPC) is a distinctive cancer with poor differentiation and high prevalence of Epstein-Barr virus (EBV) infection. Here, we show that the expression of EBV latent protein LMP1 induces dedifferentiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA. Mechanistically, LMP1 upregulates STAT5A and recruits HDAC1/2 to the CEBPA locus to reduce its histone acetylation. HDAC inhibition restored CEBPA expression, reversing cellular dedifferentiation and stem-like status in mouse xenograft models. These findings provide a novel mechanistic epigenetic-based insight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.

ObjectiveAccording to the General Strain Theory, stress can lead to a range of problem behaviors. In the current study, we focused on the association between perceived stress and mobile phone addiction. We hypothesized that this association is mediated by low self-control and that the first path of the mediation is moderated by security.MethodsCollege students (N = 397; ages 16–21; 51.89% females) from a university in Hunan Province, China, were surveyed by cluster sampling method. The students completed the Smartphone Addiction Scale-Short Version (SAS-SV), the Depression Anxiety Stress Scale (DASS-21), the Self-Control Scale (SCS), and the Security Questionnaire (SQ) during regular class time. SPSS26.0 statistical software was used for descriptive statistics and Pearson correlation analyses, the SPSS macro PROCESS was used to test the mediating effects of self-control and the moderating role of security.ResultsMediation analysis showed that as expected, perceived stress was associated with lower self-control, which in turn was associated with a higher risk for mobile phone addiction. Also as expected, moderated mediation analysis indicated that the association between perceived stress and self-control was moderated by security. Specifically, the relationship between perceived stress and self-control was stronger for low security.ConclusionThis study provides useful insight into the understanding of how perceived stress increases the risk of mobile phone addiction. The results are consistent with the General Strain Theory and further indicate that concrete approaches are required for the prevention and intervention to reduce mobile phone addiction among college students.

Abstract Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma (HCC) in individuals infected with the hepatitis virus. However, the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined. Here, we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1 (AFB1) targets. Among the most significant hits was the aryl hydrocarbon receptor (AHR), a ligand-binding transcription factor regulating cell metabolism, differentiation, and immunity. AHR-deficient cells tolerated high concentrations of AFB1, in which AFB1 adduct formation was significantly decreased. AFB1 triggered AHR nuclear translocation by directly binding to its N-terminus. Furthermore, AHR mediated the expression of P450 induced by AFB1. AHR expression was also elevated in primary tumor sections obtained from AFB1-HCC patients, which paralleled the upregulation of PD-L1, a clinically relevant immune regulator. Finally, anti-PD-L1 therapy exhibited greater efficacy in HCC xenografts derived from cells with ectopic expression of AHR. These results demonstrated that AHR was required for the AFB1 toxicity associated with HCC, and implicate the immunosuppressive regimen of anti-PD-L1 as a therapeutic option for the treatment of AFB1-associated HCCs.

Summary: Background: Multiple approaches based on cell-free DNA (cfDNA) have been applied to detect minimal residual disease (MRD) and to predict prognosis or recurrence. However, a comparison of the approaches used in different cohorts and studies is difficult. We aimed to compare multiple approaches for MRD analysis after neoadjuvant therapy (NAT) in patients with locally advanced rectal cancer (LARC). Methods: Sixty patients with LARC from a multicentre, phase II/III randomized trial were included, with tissue and blood samples collected. For each cfDNA sample, we profiled MRD using 3 approaches: personalized assay targeting tumour-informed mutations, universal panel of genes frequently mutated in colorectal cancer (CRC), and low depth sequencing for copy number alterations (CNAs). Findings: Positive MRD based on post-NAT personalized assay was significantly associated with an increased risk of recurrence (HR = 27.38; log-rank P < 0.0001). MRD analysis based on universal panel (HR = 5.18; log-rank P = 0.00086) and CNAs analysis (HR = 9.24; log-rank P = 0.00017) showed a compromised performance in predicting recurrence. Both the personalized assay and universal panel showed complementary pattern to CNAs analysis in detecting cases with recurrence and the combination of the two types of biomarkers may lead to better performance. Interpretation: The combination of mutation profiling and CNA profiling can improve the detection of MRD, which may help optimize the treatment strategies for patients with LARC.

ObjectivesThis study aims to examine the mediation role of satisfaction with children on the association between contact with children (CCT) and healthy aging among middle-aged and older parents in China.MethodsData from 9,575 parents over 45 years old were obtained from the 2018 China Health and Retirement Longitudinal Survey. A multinomial logistic regression model was applied to measure the association between contact, satisfaction, and healthy aging with potential confounders controlled. We used the Sobel–Goodman Mediation test to analyze the mediation role of satisfaction on the association between types of CCT and healthy aging.ResultsParents with contact with adult children had higher satisfaction with children [for contact weekly (satisfied/unsatisfied): relative risk ratio (RRR) = 2.44, CI = 1.92–3.10] and higher healthy aging [for contact weekly (Q5/Q1): RRR = 1.41, CI = 1.13–1.77]. Satisfaction was strongly related to healthy aging [for satisfied (Q5/Q1): RRR = 3.44, CI = 2.14–5.51], and mediated 19.05% of healthy aging for weekly contact (Sobel test z = 4.338; indirect role = 0.014, CI = 0.011–0.018; direct role = 0.061, CI = 0.029–0.094). Subgroup analysis further revealed that satisfaction with contact played a partial mediating role between monthly contact and healthy aging in female and rural groups.ConclusionsMonthly CCT is more appropriate for older parents. Satisfaction with children in older parents seems to act as a significant and partial mediator of the relationship between contact and healthy aging. The contribution of satisfaction to healthy aging could be important to be considered and promoted in women and rural older parents, independent of CCT.

Background The physical appearance of tongue coatings is vital for traditional Chinese medicine (TCM) to diagnose health and disease status. The microbiota of different tongue coatings could also influence coating formation and be further associated with specific diseases. Previous studies have focused on bacteria from different tongue coatings in the context of specific diseases, but the normal variations in healthy individuals remain unknown.Aim: We examined the tongue microbiota by metagenomics in 94 healthy individuals classified into eight different tongue types.Results: The overall composition of the tongue coating microbiome is not drastically different among different coating types, similar to the findings of previous studies in healthy populations. Further analysis revealed microbiota characteristics of each coating type, and many of the key bacteria are reported to be implicated in diseases. Moreover, further inclusion of diabetic patients revealed disease-specific enrichment of Capnocytophaga, even though the same tongue coatings were studied.Conclusions: This work revealed the characteristic compositions of distinctive tongue coatings in a healthy population, which serves as a basis for understanding the tongue coating formation mechanism and provides a valuable reference to further investigate disease-specific tongue coating bacterial markers.

Background: Central venous catheters are convenient for drug delivery and improved comfort for cancer patients, but they also cause serious complications. The most common complication is catheter-related thrombosis (CRT).Objectives: This study aimed to evaluate the incidence and risk factors for CRT in cancer patients and develop an effective prediction model for CRT in cancer patients.Methods: The development of our prediction model was based on a retrospective cohort (n = 3,131) from the National Cancer Center. Our prediction model was confirmed in a prospective cohort from the National Cancer Center (n = 685) and a retrospective cohort from the Hunan Cancer Hospital (n = 61). The predictive accuracy and discriminative ability were determined by receiver operating characteristic (ROC) curves and calibration plots.Results: Multivariate analysis demonstrated that sex, cancer type, catheter type, position of the catheter tip, chemotherapy status, and antiplatelet/anticoagulation status at baseline were independent risk factors for CRT. The area under the ROC curve of our prediction model was 0.741 (CI: 0.715–0.766) in the primary cohort and 0.754 (CI: 0.704–0.803) and 0.658 (CI: 0.470–0.845) in validation cohorts 1 and 2, respectively. The model also showed good calibration and clinical impact in the primary and validation cohorts.Conclusions: Our model is a novel prediction tool for CRT risk that accurately assigns cancer patients into high- and low-risk groups. Our model will be valuable for clinicians when making decisions regarding thromboprophylaxis.

Abstract Background An increasing number of cancer patients die of cardiovascular diseases. The cardiotoxicity of chemotherapy is particularly important in triple-negative breast cancer (TNBC) with limited therapeutic options. Cardiac autophagy is an important mechanism of cardiotoxicity. This research was aimed to investigate the cardiotoxicity of chemotherapy in TNBC, screen the susceptible population, and determine the relationship between cardiotoxicity and autophagy-related polymorphisms. Methods From a total of 2450 stage I-III TNBC patients, 147 met the inclusion criteria and finally recruited. Electrocardiography (ECG) was performed before most chemotherapy cycles, and echocardiography (UCG) was performed according to clinical needs. All ECG and UCG records were re-interpreted by cardiologists at the National Center for Cardiovascular Disease, Fuwai Hospital. According to the National Center for Biotechnology Information and the Catalog of Somatic Mutations in Cancer database, we selected 25 single nucleotide polymorphisms (SNPs) related to autophagy and genotyped the 147 TNBC patients. Paired-sample T tests, Chi squared tests, and logistic regression models were employed for the analysis. Results Only 46 (31.3%) patients had normal ECG records after every chemotherapy cycle. Among the 16 patients who underwent UCG, 2 (12.5%) had a reversible decrease of left ventricular ejection fraction. The use of anthracyclines and excessive alcohol consumption were risk factors of ECG abnormalities. With the continuation of chemotherapy, heart rate gradually increased. Anthracyclines were associated with QRS duration abnormalities (P = 0.043). After genotyping for 25 autophagy-related SNPs, we found that the G allele of autophagy-related 13 (ATG13) rs10838611 was significantly associated with ECG abnormalities (odds ratio = 2.258, 95% confidence interval = 1.318–3.869; P = 0.003). Conclusion ECG abnormalities caused by chemotherapy are common in the real world. Autophagy-related SNPs are associated with chemotherapy-induced cardiotoxicity, thereby providing new evidence for autophagy as a cause of chemotherapy-induced cardiac damage.

Abstract Background Primary hepatic angiosarcoma (PHA) is a rare and aggressive solid tumor, with high rates of local recurrence and distant metastasis, and poor prognosis. There are no established treatment guidelines for PHA. Case presentation A 78-year-old asymptomatic man with PHA that was successfully treated with pazopanib plus PD-1 inhibitor and RetroNectin-activated killer cells (RAK cells). After one month of treatment, there was a clear reduction in the size and number of the liver metastases; and after nearly 15 months, most of the lesions were stable, no new lesions had developed, and the side effect of treatment was minor. Conclusion Pazopanib, PD-1 inhibitor and RAK cells could serve as a potential option for the treatment of advanced PHA.

Epstein–Barr virus (EBV) was the first human virus proved to be closely associated with tumor development, such as lymphoma, nasopharyngeal carcinoma, and EBV-associated gastric carcinoma. Despite many efforts to develop prophylactic vaccines against EBV infection and diseases, no candidates have succeeded in effectively blocking EBV infection in clinical trials. Previous investigations showed that EBV gp350 plays a pivotal role in the infection of B-lymphocytes. Nevertheless, using monomeric gp350 proteins as antigens has not been effective in preventing infection. Multimeric forms of the antigen are more potently immunogenic than monomers; however, the multimerization elements used in previous constructs are not approved for human clinical trials. To prepare a much-needed EBV prophylactic vaccine that is potent, safe, and applicable, we constructed an Fc-based form of gp350 to serve as a dimeric antigen. Here, we show that the Fc-based gp350 antigen exhibits dramatically enhanced immunogenicity compared with wild-type gp350 protein. The complete or partial gp350 ectodomain was fused with the mouse IgG2a Fc domain. Fusion with the Fc domain did not impair gp350 folding, binding to a conformation-dependent neutralizing antibody (nAb) and binding to its receptor by enzyme-linked immunosorbent assay and surface plasmon resonance. Specific antibody titers against gp350 were notably enhanced by immunization with gp350-Fc dimers compared with gp350 monomers. Furthermore, immunization with gp350-Fc fusion proteins elicited potent nAbs against EBV. Our data strongly suggest that an EBV gp350 vaccine based on Fc fusion proteins may be an efficient candidate to prevent EBV infection in clinical applications.

Based on the ERG (Existence, Relatedness and Growth) theory, a scale was developed to evaluate the professional needs of psychological counsellors in China and its related factors were explored. A total of 209 counsellors participated in the study and completed two online questionnaires. The majority of participants were female (n = 163, 78%). The average age of participants is 41.00 (SD = 8.66). The results showed that the existence needs ([x-bar] = 4.49, SD = 0.60), relatedness needs ([x-bar] = 4.20, SD = 0.65) and growth needs ([x-bar] = 4.66, SD = 0.50) of counsellors were all at a high level. Work setting, marital status and regular supervision had a significant influence on the professional needs of counsellors. Counsellors working in private practice had more existence and growth needs compared to those working in institutions. Counsellors, who were married, had more existence and relatedness needs than those who were single. Counsellors without regular supervision had more existence, relatedness and growth needs.

Although it is well known that nasopharyngeal carcinoma (NPC) is closely related with Epstein-Barr virus (EBV), few data are available about which and how EBV-expressed gene is involved in the carcinogenesis of human nasopharyngeal epithelial cells. EBV-encoded BARF1 (BamH I-A right frame 1) gene has been shown to be oncogenic and capable of inducing malignant transformation in BALB/c3T3 and NIH3T3 cells as well as in human B-cell lines Louckes and Akata. It remains unclear, however, whether BARF1 can transform primate or human epithelial cells. Here, we have shown that overexpression of H-Ras gene transformed BARF1-immortalized PATAS cells into malignant cell line. Furthermore, we found that cooperation of BARF1 with H-Ras and SV40 T antigens was sufficient to transform nonmalignant human nasopharyngeal epithelial NP69 cells when serially introduced BARF1 and H-Ras into the SV40 T antigens-immortalized NP69 cells. Taken together, these results demonstrated that the cooperation of BARF1 with Ras suffices to transform primary primate epithelial cell PATAS. Similarly, BARF1 together with H-Ras and SV40 T can transform human epithelial cell NP69, thereby indicating that BARF1 could be involved in the NPC pathogenesis in combination with additional genetic changes.