Despite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.

This study aimed to determine the drug resistance phenotype and genetic characteristics of Listeria monocytogenes ST5 LK100 isolated from a neonate,which provided a basis for the diagnosis and treatment of L.monocyto-genes infection and to enhance the understanding of the genomic characteristics of this strain.A suspected L.monocytogenes strain was isolated from the gastric juice sample of an infected neonate,and identified with a VITEK2 Compact automatic mi-crobial identification instrument and 16S RNA sequencing.Five drug sensitivity tests were conducted on the identified strain with the E-test method.Additionally,the whole genome of the strain was sequenced using a third-generation sequencing plat-form.The antibiotic resistance elements of the strain were identified by BlastN with the CARD antibiotic resistance gene data-base.The multilocus sequence typing(MLST),serotyping,and virulence genes of the strain was determined by Pasteur da-tabase,the virulence gene distribution was analyzed using the virulence analysis website.The prophages of the strain were predicted and annotate by PHASTER online website.The strain(LK100)isolated from the neonate was identified as L.monocytogenes.This strain was sensitive to penicillin,ampicil-lin,meropenem,erythromycin,and trimethoprim-sulfame-thoxazole antibiotics.The MLST type and serotype was ST5 and 1/2b-3b,respectively.The total length of the chromoso-mal genome of LK100 was 3 032 582 bp with a GC content of 37.91％,and it contained a complete circular plasmid with a se-quence length of 52 822 bp.The strain LK100 carried complete InlA protein,LIPI-1 pathogenicity island,SSI-1 stress survival island,and an LGI2 genomic island.The intrinsic antibiotic resistance genes were mainly located on the chromosome.Five prophage sequences were predicted in the LK100 genome.This study identified a strain of ST5 L.monocytogenes LK100 from an infected neonate and characterized its genome and antibiotic sensitivity,laying the foundation for further research on ST5 L.monocytogenes.

As artificial intelligence technology rapidly advances, its deployment within the medical sector presents substantial ethical challenges. Consequently, it becomes crucial to create a standardized, transparent, and secure framework for processing medical data. This includes setting the ethical boundaries for medical artificial intelligence and safeguarding both patient rights and data integrity. This consensus governs every facet of medical data handling through artificial intelligence, encompassing data gathering, processing, storage, transmission, utilization, and sharing. Its purpose is to ensure the management of medical data adheres to ethical standards and legal requirements, while safeguarding patient privacy and data security. Concurrently, the principles of compliance with the law, patient privacy respect, patient interest protection, and safety and reliability are underscored. Key issues such as informed consent, data usage, intellectual property protection, conflict of interest, and benefit sharing are examined in depth. The enactment of this expert consensus is intended to foster the profound integration and sustainable advancement of artificial intelligence within the medical domain, while simultaneously ensuring that artificial intelligence adheres strictly to the relevant ethical norms and legal frameworks during the processing of medical data.
Artificial Intelligence/legislation & jurisprudence* ; Humans ; Consensus ; Computer Security/standards* ; Confidentiality/ethics* ; Informed Consent/ethics*

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aβ neurotoxicity and promotes Aβ clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.
Mice ; Animals ; Alzheimer Disease/pathology* ; Receptor, Nerve Growth Factor ; Amyloid beta-Peptides ; Autoantibodies ; Mice, Transgenic

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult ; Humans ; Adolescent ; Imatinib Mesylate/adverse effects* ; Incidence ; Antineoplastic Agents/adverse effects* ; Retrospective Studies ; Pyrimidines/adverse effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Treatment Outcome ; Benzamides/adverse effects* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Aminopyridines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*

OBJECTIVE: To explore the chronic injury and its possible mechanism of ionizing radiation on multipotent hematopoietic progenitor cells (MPPs) by determining the related indicators of MPPs in bone marrow of mice post-radiation. METHODS: Sixteen C57BL/6 adult mice were randomly divided into normal control and irradiation groups, 8 mice in each group. The mice in irradiation group were exposed to 6 Gy X-ray. The proportion of bone marrow MPPs, their apoptosis and proliferation 2 months after irradiation were detected by flow cytometry. Mitochondrial activity and levels of reactive oxygen species (ROS) in each MPPs population were detected by Mitotracker Red and DCFDA probes, and the senescent state of MPPs in the bone marrow was analyzed. RESULTS: Ionizing radiation could reduce the proportion of MPPs in mouse bone marrow. The proportions and numbers of MPP1, MPP3 and MPP4 in the bone marrow were significantly decreased after whole-body irradiation with 6 Gy X-ray (P<0.05). In addition, radiation significantly reduced the colony-forming capacity of MPPs in bone marrow (P<0.05), the proportions of apoptotic cells in the MPP1 and MPP4 cell populations increased significantly in the bone marrow (P<0.05). The activity of mitochondria was significantly reduced in the bone marrow MPP2, MPP3 and MPP4 cell populations compared with that of the control group (P<0.05). It was also found that the radiation could significantly increase the ROS levels of MPPs in bone marrow, and the content of ROS in the MPP2, MPP3 and MPP4 cell population of the bone marrow was significantly increased(P<0.05). The senescent cells ratios of MPP1, MPP3 and MPP4 cells in the bone marrow after irradiation were significantly higher than those in the control group (P<0.05). CONCLUSION Ionizing radiation can cause chronic MPPs damage in mice, which is closely associated with persistent oxidative stress, cells apoptosis, and cellular senescence.
Mice ; Animals ; Bone Marrow ; Reactive Oxygen Species ; Mice, Inbred C57BL ; Hematopoietic Stem Cells ; Whole-Body Irradiation ; Radiation, Ionizing ; Bone Marrow Cells

Background The chronic injury of the hematopoietic system caused by ionizing radiation (IR) is often ignored. The essential cause of this injury is the damage of hematopoietic stem and progenitor cells (HSPCs). Objective To explore the long-term effects of IR at different radiation doses and at different radiation fractions of the same radiation dose on HSPCs in the bone marrow of mice, and to provide a scientific basis for reducing the chronic damage to the hematopoietic system caused by IR. Methods A total of 16 male C57BL/6 mice aged 8-10 weeks were randomly divided into four groups that received different doses or fractions of total body X-ray irradiation, including 1.5 Gy×4 irradiation group (n=5), 3 Gy irradiation group (n=4), 6 Gy irradiation group (n=4), and non-irradiation group (n=3). Two months after irradiation, bone marrow cells from each mouse were collected and counted. The clone forming ability of bone marrow cells was analyzed by cobblestone area-forming cell (CAFC) assay. The proportion of HSPCs was measured by flow cytometry. The cell cycle of HSPCs was assessed by antigen identified by monoclonal antibody Ki 67 (Ki-67) and 7-amino-actinomycin D (7-AAD) double staining. The reactive oxygen species (ROS) levels of HSPCs were estimated with a 2,7-dichlorodihydrofluorescein diacetate (DCFDA) probe. The cellular senescence of HSPCs was evaluated with a 5-dodecanoylaminofluorescein di-β-D-galactopyranoside (C12FDG) probe. The expression of senescence related genes such as P16, P19, P21, and P27 was measured by real-time fluorescence quantitative PCR. Results There was no significant change in the numbers of bone marrow cells 2 months after different doses and fractions of radiation (P>0.05). The clone forming ability of bone marrow cells was significantly decreased after 3 Gy and 6 Gy irradiation when compared to non-irradiated mice (P<0.01). HSPCs responded inconsistently to different doses and fractions of irradiation. Overall, there was no significant change in long-term hematopoietic stem cells (LT-HSCs) proportion after irradiation (P>0.05), the proportions of hematopoietic progenitor cells (HPCs), hematopoietic stem cells (HSCs), short-term hematopoietic stem cells (ST-HSCs), and multipotent progenitors 2 (MPP2) increased after irradiation (P<0.05), and the proportions of LSK, MPP1, MPP3, and MPP4 cells decreased after irradiation (P<0.05); except for HPCs and MPP2, the proportion of HSPCs in G0 phase was decreased (P<0.05). The ROS production in HSPCs was increased significantly after 6 Gy irradiation (P<0.05), while the ROS levels after 3 Gy and 1.5 Gy×4 irradiation were similar to that of the non-radiation group (P>0.05). The cellular senescent proportion of HPCs, LSK, and HSCs increased after irradiation (P<0.05). The expression levels of senescence related genes P16, P19, and P21 in HSCs were significantly increased (P<0.05). Conclusion The responses of HSPCs in bone marrow to IR vary depending on doses and fractions of irradiation. Increased ROS production and cellular senescence may be involved in the damage process of HSPCs under radiation settings.

Increased neuronal apoptosis is an important pathological feature of Alzheimer's disease (AD). The Bcl-2-interacting mediator of cell death (Bim) mediates amyloid-beta (Aβ)-induced neuronal apoptosis. Naturally-occurring antibodies against Bim (NAbs-Bim) exist in human blood, with their levels and functions unknown in AD. In this study, we found that circulating NAbs-Bim were decreased in AD patients. Plasma levels of NAbs-Bim were negatively associated with brain amyloid burden and positively associated with cognitive functions. Furthermore, NAbs-Bim purified from intravenous immunoglobulin rescued the behavioral deficits and ameliorated Aβ deposition, tau hyperphosphorylation, microgliosis, and neuronal apoptosis in APP/PS1 mice. In vitro investigations demonstrated that NAbs-Bim were neuroprotective against AD through neutralizing Bim-directed neuronal apoptosis and the amyloidogenic processing of amyloid precursor protein. These findings indicate that the decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim hold promise for the treatment of AD.
Alzheimer Disease/pathology* ; Amyloid beta-Peptides/metabolism* ; Amyloid beta-Protein Precursor/metabolism* ; Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic

Gastrointestinal Tract ; Humans ; Lymphoproliferative Disorders ; T-Lymphocytes

OBJECTIVE: To investigate the expression of PCGF1 in rectal adenocarcinoma (READ) and the effect of PCGF1 silencing on proliferation READ cells in vitro. METHODS: The UALCAN and ENCORI online databases were used to analyze the expression level of PCGF1 in READ tissues and normal tissues and its association with the clinicopathological parameters and survival outcomes of patients with READ. The expression levels of PCGF1 were detected in two READ cell lines and a normal rectal epithelial cell line (HcoEpiC cells) using qPCR and Western blotting. Lentiviral vectors were used to construct PCGF1-overexpressing and PCGF1-silenced cell lines, and the proliferative activity of the cells was assessed using CCK-8 assay. The effect of PCGF1 silencing on tumor proliferation in vivo was also evaluated by observing tumorigenicity of the cells in nude mice. RESULTS: PCGF1 was highly expressed in READ tissue (P < 0.001), and its expression levels was correlated with READ stage, differentiation and lymph node metastasis (P < 0.001). A high PCGF1 expression level was associated with a poor survival outcome of READ patients (P < 0.05). In SW837 and SW1463 cells, PCGF1 silencing significantly lowered the proliferative activity of the cells both in vitro (P < 0.05) and in nude mice (P < 0.01). CONCLUSION PCGF1 is highly expressed in READ tissue and may potentially serve as a prognostic biomarker as well as a therapeutic target for READ.
Adenocarcinoma/genetics* ; Animals ; Biomarkers ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Mice ; Mice, Nude ; Polycomb Repressive Complex 1 ; Sincalide