Acute-on-chronic liver failure （ACLF） is a form of acute hepatic insufficiency that occurs in the context of a chronic liver disease， with a relatively high mortality rate. To improve the prognosis of ACLF patients， it is essential to early identify the patients with pre-ACLF and constantly optimize and innovate treatment regimens for the disease in the progressive stage. With more than 10 years of research， the Chinese CLIF consortium has developed an early warning model for ACLF and established a system for transferring high-risk patients to tertiary hospitals. At present， the real-world study has also confirmed the consistency between the early warning model and actual conditions in clinical practice， making contributions to the early screening， diagnosis， and treatment of ACLF. The treatment options for the progressive stage of ACLF are also expanding， from the development of innovative pharmaceuticals to the use of artificial liver support and stem cell therapy， and such treatment modalities have made significant achievements in clinical studies and are expected to be implemented in the near future. The development of a more efficient diagnostic system and novel treatment modalities has led to a significant improvement in the diagnosis and treatment of ACLF.

OBJECTIVE: To explore the preparation of nano-silver acupuncture needles and evaluate the appearance, structure and properties. METHODS: Stainless steel acupuncture needles were pretreated by polishing with sandpaper and cleaning with ultrapure water and absolute ethanol. As the working electrodes, the needles were placed in an electrolyte solution contained silver nitrate (AgNO₃), potassium nitrate (KNO₃), and polyvinylpyrrolidone (PVP); and the silver nanoparticles were deposited at a constant voltage of -0.2 V for 1 200 s. The heat-treatment was conducted at 600 ℃ for 15 min in an argon atmosphere to strengthen the adhesion between the nanoparticles and the substrate. The surface appearance and structure of nano-silver acupuncture needles were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The electrical conductivity, thermal conductivity and biocompatibility of the needles were evaluated. The cytotoxicity and biocompatibility of the sample were assessed using the CCK-8 assay. According to the national standard, Acupuncture Needles (GB 2024-2016), the other physicochemical performances of nano-silver acupuncture needles were tested. RESULTS: ①By controlling the AgNO₃ concentration and the molar ratio of AgNO₃ to PVP, it was found that at an AgNO₃ concentration of 2 mmol/L and a molar ratio of 5∶1, silver nanoparticles with the diameter of 50-100 nm, regular appearance, and uniform distribution were obtained. At a lower concentration, the size of silver nanoparticles was smaller and unevenly distributed particles, whereas a higher concentration tended to produce a dendritic structure. ②By sandpaper polishing, acid etching pretreatment, and heat-treatment at 600 ℃ under argon for 15 min, the adhesion of silver nanoparticles on the surface of the needle body was strengthened, and the simulated pig skin puncture test showed the intact coating without shedding. ③SEM found that the silver nanoparticles were uniformly deposited, forming a nanofilm approximately 1.5 μm thick; XRD analysis showed the diffraction peaks corresponding to cubic crystal silver (111), (200), (220) and (311); and XPS detected characteristic peaks of Ag 3d3/2 and Ag 3d5/2, confirming the successful deposition and good crystallinity of the silver nanoparticles. ④Resistivity measurements indicated that the nano-silver acupuncture needles exhibited a resistivity of approximately 0.15 Ω·cm, about three times lower than that of unmodified stainless steel needles. The infrared thermography demonstrated that their thermal conductivity was superior to that of traditional acupuncture needles. In vitro CCK-8 cytotoxicity assay showed that the nano-silver acupuncture needles had no adverse effects on human skin fibroblasts and possessed good biocompatibility. ⑤ The key parameters such as needle tip performance, hardness, and the adhesion between the needle body and handle were in compliance with the requirements in Acupuncture Needles (GB 2024-2016), ensuring a quality guarantee provided for clinical applications. CONCLUSION The preparation of nano-silver acupuncture needles effectively overcomes the insufficient toughness of traditional silver needles and improves the electrical and thermal conductivity of stainless acupuncture needles.
Silver/chemistry* ; Needles ; Acupuncture Therapy/instrumentation* ; Metal Nanoparticles/chemistry* ; Humans ; Electric Conductivity ; Animals

BACKGROUND: Treatment with chimeric antigen receptor-T (CAR-T) cells has shown promising effectiveness in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), although the process of preparing for this therapy usually takes a long time. We have recently created CD19 Fast-CAR-T (F-CAR-T) cells, which can be produced within a single day. The objective of this study was to evaluate and contrast the effectiveness and safety of CD19 F-CAR-T cells with those of CD19 conventional CAR-T cells in the management of R/R B-ALL. METHODS: A multicenter, retrospective analysis of the clinical data of 44 patients with R/R B-ALL was conducted. Overall, 23 patients were administered with innovative CD19 F-CAR-T cells (F-CAR-T group), whereas 21 patients were given CD19 conventional CAR-T cells (C-CAR-T group). We compared the rates of complete remission (CR), minimal residual disease (MRD)-negative CR, leukemia-free survival (LFS), overall survival (OS), and the incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) between the two groups. RESULTS: Compared with the C-CAR-T group, the F-CAR-T group had significantly higher CR and MRD-negative rates (95.7% and 91.3%, respectively; 71.4% and 66.7%, respectively; P = 0.036 and P = 0.044). No significant differences were observed in the 1-year or 2-year LFS or OS rates between the two groups: the 1-year and 2-year LFS for the F-CAR-T group vs.C-CAR-T group were 47.8% and 43.5% vs. 38.1% and 23.8% (P = 0.384 and P = 0.216), while the 1-year and 2-year OS rates were 65.2% and 56.5% vs. 52.4% and 47.6% (P = 0.395 and P = 0.540). Additionally, among CR patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) following CAR-T-cell therapy, there were no significant differences in the 1-year or 2-year LFS or OS rates: 57.1% and 50.0% vs. 47.8% and 34.8% (P = 0.506 and P = 0.356), 64.3% and 57.1% vs. 65.2% and 56.5% (P = 0.985 and P = 0.883), respectively. The incidence of CRS was greater in the F-CAR-T group (91.3%) than in the C-CAR-T group (66.7%) (P = 0.044). The incidence of ICANS was also greater in the F-CAR-T group (30.4%) than in the C-CAR-T group (9.5%) (P = 0.085), but no treatment-related deaths occurred in the two groups. CONCLUSION Compared with C-CAR-T-cell therapy, F-CAR-T-cell therapy has a superior remission rate but also leads to a tolerably increased incidence of CRS/ICANS. Further research is needed to explore the function of allo-HSCT as an intermediary therapy after CAR-T-cell therapy.

OBJECTIVE: To screen out the key metabolites related to diabetic foot (DF) by integrating genome-wide association studies (GWAS) and metabolome genome-wide association studies (mGWAS). METHODS: The literature databases such as PubMed and China national knowledge infrastructure(CNKI), as well as genomics databases such as PAN UKBB, FinnGen, and IEU Open GWAS were systematically retrieved from database estobilishment to November 2024 on DF-related single nucleotide polymorphisms and genome-wide association studies. DF-single nucleotide polymorphism-metabolite network was constructed by mGWAS package and mGWAS-Explorer platform. The causal relationship between key factors was evaluated by two-sample Mendelian randomization. The genetic correlation between DF and 575 metabolites (source:IEU Open GWAS) was evaluated by linkage disequilibrium score regression. In vitro experiments were conducted to induce injury of human umbilical vein endothelial cells with 30 mM glucose and intervene with 20 μM γ-tocopherol. Changes in cell migration, scratch healing and tube formation function were detected. RESULTS: Twenty-senen literatures on single nucleotide polymorphism literatures and 3 studies on GWAS were included. Genetic analysis results showed DF-related single nucleotide polymorphisms were enriched in vascular endothelial dysfunction-related pathways (such as fluid shear stress and atherosclerosis). The results of metabolic network analysis screened out 19 associated metabolites, among which 12 such as γ -tocopherol and pyruvate had significant genetic correlations with DF. Mendelian randomization suggested matrix metalloproteinase-9(MMP-9) might be a potential driver of DF (β=0.658, P=0.063 8), and the occurrence of DF could reduce the level of high-density lipoprotein (β=-0.002, P=0.015 2). The results of in vitro experiments confirmed that γ -tocopherol could improve endothelial dysfunction induced by high glucose, specifically manifested as an increase in the number of cell migrations, improvement in the scratch healing rate, and recovery of tubule formation ability (P<0.05). CONCLUSION DF has a genetic basis centered on vascular endothelial dysfunction, and its occurrence can lead to further metabolic disorders. The key single nucleotide polymorphism loci integrated provided molecular markers for the risk stratification of foot ulcers in diabetic patients. In addition, γ -tocopherol has demonstrated clinical application potential as a therapeutic drug for DF by significantly improving the function of vascular endothelial cells in a high-glucose environment.
Humans ; Diabetic Foot/drug therapy* ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; Genomics ; Metabolomics ; Metabolome

OBJECTIVES: To assess the preliminary efficacy and safety of a dose-intensified C5VD regimen (cisplatin, 5-fluorouracil, vincristine, and doxorubicin) in children with locally advanced hepatoblastoma. METHODS: This prospective study enrolled 24 children with newly diagnosed, locally advanced hepatoblastoma who received the dose-intensified C5VD regimen at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, and Shanghai Children's Hospital between January 2020 and December 2023. Clinical characteristics, treatment outcomes, and chemotherapy-related toxicities were analyzed. RESULTS: Of the 24 patients, 13 were male and 11 were female, with a median age at diagnosis of 18.7 months (range: 3.5-79.4 months). All patients achieved complete macroscopic resection of hepatic lesions without liver transplantation. Serum alpha-fetoprotein levels decreased significantly after two chemotherapy cycles. During a median follow-up of 38.4 months (range: 15.8-50.7 months), all patients maintained continuous complete remission, with 3-year event-free survival and overall survival rates of 100%. Across 144 chemotherapy cycles, the incidence rates of grade 3-4 neutropenia, thrombocytopenia, and infections were 97%, 77%, and 71%, respectively; no treatment-related deaths occurred. Notably, 5 patients (21%) developed Brock grade ≥3 hearing loss, of whom 1 required a hearing aid. CONCLUSIONS The dose-intensified C5VD regimen demonstrates significant efficacy with an overall favorable safety profile in the treatment of newly diagnosed, locally advanced pediatric hepatoblastoma. Grade 3-4 myelosuppression and infection are the predominant toxicities. However, high‑dose cisplatin-induced ototoxicity remains a concern, highlighting the need for improved otoprotective strategies.
Humans ; Hepatoblastoma/pathology* ; Male ; Female ; Infant ; Liver Neoplasms/pathology* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Child, Preschool ; Prospective Studies ; Doxorubicin/adverse effects* ; Child ; Cisplatin/adverse effects* ; Vincristine/adverse effects* ; Fluorouracil/adverse effects*

OBJECTIVE: To analyze the Epstein-Barr virus (EBV) load in different lymphocyte subsets, as well as clinical characteristics and outcomes in patients with hematologic malignancies experiencing EBV reactivation. METHODS: Peripheral blood samples from patients were collected. B, T, and NK cells were isolated sorting with magnetic beads by flow cytometry. The EBV load in each subset was quantitated by real-time quantitative polymerase chain reaction (RT-qPCR). Clinical data were colleted from electronic medical records. Survival status was followed up through outpatient visits and telephone calls. Statistical analyses were performed using SPSS 25.0. RESULTS: A total of 39 patients with hematologic malignancies were included, among whom 35 patients had undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). The median time to EBV reactivation was 4.8 months (range: 1.7-57.1 months) after allo-HSCT. EBV was detected in B, T, and NK cells in 20 patients, in B and T cells in 11 patients, and only in B cells in 4 patients. In the 35 patients, the median EBV load in B cells was 2.19×10⁴ copies/ml, significantly higher than that in T cells (4.00×10³ copies/ml, P <0.01) and NK cells (2.85×10² copies/ml, P <0.01). Rituximab (RTX) was administered for 32 patients, resulting in EBV negativity in 32 patients with a median time of 8 days (range: 2-39 days). Post-treatment analysis of 13 patients showed EBV were all negative in B, T, and NK cells. In the four non-transplant patients, the median time to EBV reactivation was 35 days (range: 1-328 days) after diagnosis of the primary disease. EBV was detected in one or two subsets of B, T, or NK cells, but not simultaneously in all three subsets. These patients received a combination chemotherapy targeting at the primary disease, with 3 patients achieving EBV negativity, and the median time to be negative was 40 days (range: 13-75 days). CONCLUSION In hematologic malignancy patients after allo-HSCT, EBV reactivation commonly involves B, T, and NK cells, with a significantly higher viral load in B cells compared to T and NK cells. Rituximab is effective for EBV clearance. In non-transplant patients, EBV reactivation is restricted to one or two lymphocyte subsets, and clearance is slower, highlighting the need for prompt anti-tumor therapy.
Humans ; Hematologic Neoplasms/virology* ; Herpesvirus 4, Human/physiology* ; Epstein-Barr Virus Infections ; Hematopoietic Stem Cell Transplantation ; Virus Activation ; Lymphocyte Subsets/virology* ; Flow Cytometry ; Killer Cells, Natural/virology* ; Male ; Female ; B-Lymphocytes/virology* ; Viral Load ; Adult ; T-Lymphocytes/virology* ; Middle Aged

BACKGROUND: Based on the China-VHD database, this study sought to develop and validate a Valvular Heart Disease- specific Age-adjusted Comorbidity Index (VHD-ACI) for predicting mortality risk in patients with VHD. METHODS & RESULTS: The China-VHD study was a nationwide, multi-centre multi-centre cohort study enrolling 13,917 patients with moderate or severe VHD across 46 medical centres in China between April-June 2018. After excluding cases with missing key variables, 11,459 patients were retained for final analysis. The primary endpoint was 2-year all-cause mortality, with 941 deaths (10.0%) observed during follow-up. The VHD-ACI was derived after identifying 13 independent mortality predictors: cardiomyopathy, myocardial infarction, chronic obstructive pulmonary disease, pulmonary artery hypertension, low body weight, anaemia, hypoalbuminaemia, renal insufficiency, moderate/severe hepatic dysfunction, heart failure, cancer, NYHA functional class and age. The index exhibited good discrimination (AUC, 0.79) and calibration (Brier score, 0.062) in the total cohort, outperforming both EuroSCORE II and ACCI (P < 0.001 for comparison). Internal validation through 100 bootstrap iterations yielded a C statistic of 0.694 (95% CI: 0.665-0.723) for 2-year mortality prediction. VHD-ACI scores, as a continuous variable (VHD-ACI score: adjusted HR (95% CI): 1.263 (1.245-1.282), P < 0.001) or categorized using thresholds determined by the Yoden index (VHD-ACI ≥ 9 vs. < 9, adjusted HR (95% CI): 6.216 (5.378-7.184), P < 0.001), were independently associated with mortality. The prognostic performance remained consistent across all VHD subtypes (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid valve disease, mixed aortic/mitral valve disease and multiple VHD), and clinical subgroups stratified by therapeutic strategy, LVEF status (preserved vs. reduced), disease severity and etiology. CONCLUSION The VHD-ACI is a simple 13-comorbidity algorithm for the prediction of mortality in VHD patients and providing a simple and rapid tool for risk stratification.

OBJECTIVE: To investigate the effect of Tongmai Hypoglycemic Capsule (THC) on myocardium injury in diabetic cardiomyopathy (DCM) rats. METHODS: A total of 24 Sprague Dawley rats were fed for 4 weeks with high-fat and high-sugar food and then injected with streptozotocin intraperitoneally for the establishment of the DCM model. In addition, 6 rats with normal diets were used as the control group. After modeling, 24 DCM rats were randomly divided into the model, L-THC, M-THC, and H-THC groups by computer generated random numbers, and 0, 0.16, 0.32, 0.64 g/kg of THC were adopted respectively by gavage, with 6 rats in each group. After 12 weeks of THC administration, echocardiography, histopathological staining, biochemical analysis, and Western blot were used to detect the changes in myocardial structure, oxidative stress (OS), biochemical indexes, protein expressions of myocardial fibrosis, and nuclear factor erythroid 2-related faactor 2 (Nrf2) element, respectively. RESULTS: Treatment with THC significantly decreased cardiac markers such as creatine kinase, lactate dehydrogenase, and creatine kinase-MB, etc., (P<0.01); enhanced cardiac function indicators including heart rate, ejection fraction, cardiac output, interventricular septal thickness at diastole, and others (P<0.05 or P<0.01); decreased levels of biochemical indicators such as fasting blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, aspartate transaminase, (P<0.05 or P<0.01); and decreased the levels of myocardial fibrosis markers α-smooth muscle actin (α-SMA), and collagen I (Col-1) protein (P<0.01), improved myocardial morphology and the status of myocardial interstitial fibrosis. THC significantly reduced malondialdehyde levels in model rats (P<0.01), increased levels of catalase, superoxide dismutase, and glutathione (P<0.01), and significantly increased the expression of Nrf2, NAD(P)H:quinone oxidoreductase 1, heme oxygenase-1, and superoxide dismutase 2 proteins in the left ventricle of rats (P<0.01). CONCLUSION THC activates the Nrf2 signaling pathway and plays a protective role in reducing OS injury and cardiac fibrosis in DCM rats.
Animals ; Diabetic Cardiomyopathies/physiopathology* ; Oxidative Stress/drug effects* ; Drugs, Chinese Herbal/therapeutic use* ; Rats, Sprague-Dawley ; Myocardium/metabolism* ; Fibrosis ; Male ; Capsules ; Hypoglycemic Agents/therapeutic use* ; NF-E2-Related Factor 2/metabolism* ; Rats ; Diabetes Mellitus, Experimental/drug therapy*

Eightly-four novel thioheterocyclic nucleoside derivatives were designed, synthesized, and evaluated for antitumor activity in vitro and in vivo. Most of the compounds inhibited the growth of HCT116 and HeLa cancer cells in vitro, among them 33a and 36b exhibited potent activity against HCT116 cells (IC₅₀ = 0.27 and 0.49 μmol/L, respectively). Both compounds 33a and 36b inhibited cell metastasis, arrested the cell cycle in the G₂/M phase, and induced apoptosis in vitro. Mechanistic studies revealed that 33a and 36b increased ROS levels, led to DNA damage, ER stress, and mitochondrial dysfunction, and inhibited autophagy in HCT116 cells. Biological information analysis, RNA-sequencing, Gene Set Enrichment Analysis (GSEA), drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and SPR experiments identified that compounds 33a and 36b showed antitumor activity by suppressing the c-MYC pathway. c-MYC silencing assays indicated that c-MYC proteins participated in 33a-mediated anticancer activities in HCT116 cells. More importantly, compound 33a presented favorable pharmacokinetic properties in mice (T _1/2 = 6.8 h) and showed significant antitumor efficacy in vivo without obvious toxicity, showing promising potential for further clinical development.