Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

OBJECTIVE: To analyze the efficacy and access safety of extracorporeal membrane oxygenation (ECMO) in series with continuous renal replacement therapy (CRRT) access for critically ill patients using propensity score matching analysis, and to explore the potential influencing factors of infection. METHODS: A total of 200 critically ill patients who received both ECMO and CRRT treatment in the intensive care unit (ICU) of Huai'an Second People's Hospital from December 2020 to December 2024 were retrospectively selected as the research subjects. They were divided into the independent operation group (72 cases) and the series system group (128 cases) according to the access connection mode of ECMO and CRRT. Propensity score matching analysis was used to perform 1 : 1 matching for patients of the two groups. The general data [age, gender, body mass index (BMI), clinical diagnosis, underlying disease, intubation method, intubation position, disease severity, ECMO support duration, catheter indwelling duration, oxygenation index (PaO₂/FiO₂) at 48 hours after ECMO initiation, serum creatinine (SCr), procalcitonin (PCT), hemoglobin (Hb), white blood cell count (WBC), platelet count (PLT)], treatment status [ECMO initiation duration, ECMO operation duration, ECMO flow, left ventricular ejection fraction (LVEF), CRRT initiation duration, CRRT catheter indwelling duration, inflow and outflow volume of replacement fluid], clinical outcome indicators (28-day survival rate, length of ICU stay, renal function recovery, fluid balance compliance rate), and access safety indicators (incidence of ECMO access thrombosis, incidence of infection, and incidence of bleeding events) of all the patients were collected. Subgroup analysis was conducted based on the occurrence of infection, and multivariate Logistic regression analysis was used to screen the potential risk factors for infection in critically ill patients receiving both ECMO and CRRT treatment. RESULTS: Finally, a total of 120 patients were successfully matched, with 60 patients in both the independent operation group and the series system group. No statistically significant differences were observed in the general data between the two groups, indicating comparability. Compared with the independent operation group, the ECMO flow at 48 hours after ECMO initiation, SCr, and alanine transaminase (ALT) of the patients in the series system group were significantly decreased, while the LVEF at 48 hours after ECMO initiation was significantly increased, additionally, the CRRT initiation duration, CRRT catheter indwelling duration, and the length of ICU stay were significantly shortened, and the inflow and outflow volume of replacement fluid were significantly increased. The incidence of infection and bleeding events in the series system group was significantly lower than that in the independent operation group [infection incidence: 11.67% (7/60) vs. 36.67% (22/60), bleeding event incidence: 8.33% (5/60) vs. 48.33% (29/60), both P < 0.05]. No significant difference was found in the other general data, treatment status, clinical outcome indicators, or access safety indicators between the two groups. Among the 120 patients, 29 cases developed infection (accounting for 24.17%), and 91 cases had no infection (accounting for 75.83%). Compared with the non-infection group, the catheter indwelling duration was significantly prolonged and PCT was significantly increased in the infection group, while the PLT and the proportion of patients with ECMO and CRRT access connected via the series system were significantly decreased. Multivariate Logistic regression analysis showed that catheter indwelling duration [odds ratio (OR) = 1.277, 95% confidence interval (95%CI) was 1.001-1.629, P = 0.049], PCT (OR = 1.529, 95%CI was 1.222-1.914, P < 0.001], PLT (OR = 0.953, 95%CI was 0.926-0.981, P = 0.001), and access connection mode (OR = 0.289, 95%CI was 0.090-0.930, P = 0.037) were potential risk factors for infection in critically ill patients. CONCLUSIONS The ECMO-in-series CRRT access can accelerate the initiation of CRRT, avoid local bleeding, stabilize patients' cardiac, hepatic and renal functions, reduce potential infection risks, and improve the prognosis of patients.
Humans ; Extracorporeal Membrane Oxygenation/adverse effects* ; Critical Illness/therapy* ; Retrospective Studies ; Continuous Renal Replacement Therapy ; Male ; Female ; Intensive Care Units ; Propensity Score ; Middle Aged ; Renal Replacement Therapy ; Adult ; Aged ; Risk Factors

Objective:To investigate the clinical manifestations, endoscopic characteristics, and prognostic factors of patients with colorectal extranodal NK/T cell lymphoma.Methods:The clinical data of 52 patients with colorectal extranodal NK/T cell lymphoma admitted to the First Affiliated Hospital of Zhengzhou University from January 2013 to January 2023 were retrospectively analyzed. Their clinical manifestations and endoscopic characteristics were summarized, and the prognostic factors were analyzed by Cox regression model.Results:Among the 52 patients with colorectal extranodal NK/T cell lymphoma, there were 35 males and 17 females, with a male-to-female ratio of 2.06∶1. Among the general symptoms, abdominal pain was the most common (39 cases), and B symptoms occurred in 47 patients, among which fever was the most common lymphoma B symptom (42 cases), and gastrointestinal perforation was the most common complication (18 cases). Forty-three patients underwent colonoscopy, and the main manifestations under endoscopy were the ulceration type (24 cases). The ulcers were irregular at the edges and often covered with moss at the bottom. The median survival time was 4.3 months. Multivariate Cox regression analysis showed that hemocytic syndrome ( HR=8.50,95% CI: 1.679-8.328, P=0.001), serum albumin ( HR=3.59,95% CI: 1.017-6.551, P=0.048), and with or without chemotherapy ( HR=0.31, 95% CI: 0.246-1.061, P=0.025) were independent factors influencing the overall survival of patients with colorectal extranodal NK/T cell lymphoma. Conclusions:Colorectal extranodal NK/T cell lymphoma is a rare disease with a very poor prognosis. When patients present with abdominal pain and lymphoma B symptoms, and when ulcers with irregular edges and moss covering the bottom are found under endoscopy, the disease should be considered, and endoscopic biopsy should be taken in time for pathological diagnosis. The prognosis of patients with hemophagocytic syndrome and hypoproteinemia is poor. This disease should be treated with chemotherapy and surgery, and on this basis, hemophagocytic syndrome and hypoproteinemia should be treated to improve the prognosis of patients.

Objective Exploring the mechanisms of Sanwu Huangqin Decoction in the treatment of liver tumors based on network pharmacology and molecular docking technologies and experimental observations.Methods TCMSP database was used to screen the effective compounds contained in Sanwu Huangqin decoction,Drug bank,Pharm mapper,Uniport,PubMed and other databases were used to obtain the action targets of Sanwu Huangqin decoction,gene cards and TCGA databases were used to obtain the related targets of hepatocellular carcinoma,and the"drug-disease"target genes were obtained after the intersection with the action targets of Sanwu Huangqin decoction,and the protein interaction network was constructed using string database,David and KEGG databases were used for go and KEGG enrichment analysis,Cytoscape software was used to build the corresponding network,and discovery studios software was used for molecular docking to verify the above network pharmacology related results.The effects of Sanwu Huangqin decoction on the proliferation,the metastasis and the expression of IL-6 of cancer cells were observed.Results 81 effective components and 10 key components of Sanwu Huangqin decoction,249 targets,1420 differential targets between tumor samples and normal samples were obtained,and 59 overlapping targets were obtained.Frequency analysis of protein interaction network:the potential mechanism of Sanwu Huangqin Decoction in treating hepatocellular carcinoma is related to ESR1,Myc,Jun,IL-6,MMP9,EGF,etc.Through GO and KEGG enrichment analysis,IL-17 signaling pathway,TNF signaling pathway,Toll like receptor signaling pathway may play important roles.The results of molecular docking showed that acacetin,wogonin,baicalein,oroxylin a,beta sitosterol,8-isoopenenyl-kaempferol,formononetin,luteolin,quercetin,and stigmastrol bound to IL-6 protein,which further confirmed the above results.Animal experiments showed that Sanwu Huangqin decoction could inhibit the tumor size and the pulmonary metastasis,and the content of IL-6 in cancer cells was decreased,which preliminarily verified the anti-tumor effects and mechanism of Sanwu Huangqin decoction.Conclusion In this study,we found that IL-6 was the key target of Sanwu Huangqin decoction by network pharmacology and molecular docking technology.Sanwu Huangqin decoction could reduce the content of IL-6 in tumor tissues to inhibit liver cancer in vivo.These results provided a theoretical basis for the application of Sanwu Huangqin decoction in the treatment of liver cancer.

Objective:To investigate the clinical manifestations, endoscopic characteristics, and prognostic factors of patients with colorectal extranodal NK/T cell lymphoma.Methods:The clinical data of 52 patients with colorectal extranodal NK/T cell lymphoma admitted to the First Affiliated Hospital of Zhengzhou University from January 2013 to January 2023 were retrospectively analyzed. Their clinical manifestations and endoscopic characteristics were summarized, and the prognostic factors were analyzed by Cox regression model.Results:Among the 52 patients with colorectal extranodal NK/T cell lymphoma, there were 35 males and 17 females, with a male-to-female ratio of 2.06∶1. Among the general symptoms, abdominal pain was the most common (39 cases), and B symptoms occurred in 47 patients, among which fever was the most common lymphoma B symptom (42 cases), and gastrointestinal perforation was the most common complication (18 cases). Forty-three patients underwent colonoscopy, and the main manifestations under endoscopy were the ulceration type (24 cases). The ulcers were irregular at the edges and often covered with moss at the bottom. The median survival time was 4.3 months. Multivariate Cox regression analysis showed that hemocytic syndrome ( HR=8.50,95% CI: 1.679-8.328, P=0.001), serum albumin ( HR=3.59,95% CI: 1.017-6.551, P=0.048), and with or without chemotherapy ( HR=0.31, 95% CI: 0.246-1.061, P=0.025) were independent factors influencing the overall survival of patients with colorectal extranodal NK/T cell lymphoma. Conclusions:Colorectal extranodal NK/T cell lymphoma is a rare disease with a very poor prognosis. When patients present with abdominal pain and lymphoma B symptoms, and when ulcers with irregular edges and moss covering the bottom are found under endoscopy, the disease should be considered, and endoscopic biopsy should be taken in time for pathological diagnosis. The prognosis of patients with hemophagocytic syndrome and hypoproteinemia is poor. This disease should be treated with chemotherapy and surgery, and on this basis, hemophagocytic syndrome and hypoproteinemia should be treated to improve the prognosis of patients.

BACKGROUND:High-methionine diet can cause liver injury in Cbs+/-mice,and hyperhomocystinemia is related to the occurrence and progression of various liver-related diseases,such as hepatic steatosis,autoimmune hepatitis,and alcoholic fatty liver disease.MicroRNAs(miRNAs)are involved in various cellular processes including cell survival,differentiation and autophagy,which are of great significance. OBJECTIVE:To investigate the critical role of miR-144-3p on Cbs+/-mouse hepatocyte autophagy induced by high methionine die. METHODS:(1)Ten male cystathione-β-synthase normal(Cbs+/+)mice and another 10 male mice with single gene knockout(Cbs+/-)of similar body mass,4 weeks of age,were fed a high-methionine diet and executed after 12 weeks to take liver tissue.(2)Human hepatocytes(HL-7702)were cultured in vitro and divided into control[0 μmol/L homocysteine(Hcy)],Hcy(100 μmol/L Hcy),mimic-NC(transfected with mimic-NC),mimic-NC + Hcy(mimic-NC transfecton+100 μmol/L Hcy),miR-144-3p mimic(transfected with miR-144-3p mimic),and miR-144-3p mimic + Hcy(miR-144-3p mimic transfection+100 μ mol/L Hcy),inhibitor-NC(transfected with inhibitor-NC),inhibitor-NC + Hcy(inhibitor-NC transfection + 100 μmol/L Hcy),miR-144-3p inhibitor(transfected with miR-144-3p inhibitor),and miR-144-3p inhibitor + Hcy(miR-144-3p inhibitor transfection + 100 μmol/L Hcy).Quantitative real-time PCR was used to detect the expression of miR-144-3p in liver tissue and hepatocytes.After transfection of miR-144-3p mimic or inhibitor,quantitative real-time PCR and western blot were used to detect the transfection efficiency of miR-144-3p and its effect on the expression of autophagy-related proteins LC3B and p62.The levels of alanine transferase and aspartate aminotransferase in hepatocyte supernatants were determined by enzyme linked immunosorbent assay.The correlation between the expression of miR-144-3 in hepatocyte and the levels of alanine transferase and aspartate aminotransferase in hepatocyte supernatants were analyzed by Pearson correlation analysis. RESULTS AND CONCLUSION:Compared with the Cbs+/+ group and control group,the expression of miR-144-3p in the liver tissue of the Cbs+/-group and in hepatocytes of the Hcy group was decreased(P<0.01).The expression of LC3B-Ⅱ/Ⅰ was decreased in hepatocyte after transfection of miR-144-3p mimic,while the protein expression of p62 was increased(P<0.01).The opposite results were obtained after transfection of miR-144-3p inhibitor(P<0.01).Compared with the mimic-NC group,the levels of alanine transferase and aspartate aminotransferase were decreased in the miR-144-3p mimic group(P<0.01),while the opposite results were obtained in the inhibitor-NC group(P<0.01).The expression of miR-144-3p in hepatocytes was negatively correlated with the levels of alanine transferase(P<0.01,r=-0.887 6)and aspartate aminotransferase(P<0.01,r=-0.829 9)in the supernatant of hepatocytes.To conclude,Hcy promotes hepatocyte autophagy by inhibiting the expression of miR-144-3p,which subsequently aggravates liver injury.

Objective To investigate the effects of long non-coding RNA (lncRNA) taurine up-regulated gene 1 (TUG1) on the proliferation, migration, and angiogenesis of gastric cancer cells. Methods The expression levels of LncRNA TUG1 in gastric cancer tissues and adjacent non-cancerous tissues were analyzed based on public databases. The expression of lncRNA TUG1 in gastric cancer cell lines was detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). SGC-7901 gastric cancer cells were transfected with si-TUG1 and si-NC, and the effects of knocking down lncRNA TUG1 on cell proliferation, colony formation, migration, and angiogenesis were analyzed using the Cell Counting Kit-8 (CCK-8) assay, colony formation assay, Transwell assay, and Matrigel tube formation assay. The correlation between alkB homolog 5 (ALKBH5) gene and lncRNA TUG1 was analyzed based on public databases. The regulatory relationship between ALKBH5 and lncRNA TUG1 was verified using Actinomycin D experiments. The effects of knocking down ALKBH5 on the proliferation, colony formation, migration, and angiogenesis of gastric cancer cells were analyzed through cell function experiments. Results LncRNA TUG1 was up-regulated in gastric cancer tissues and cell lines. After knocking down lncRNA TUG1, the proliferation, colony formation, migration, and angiogenesis abilities of SGC-7901 cells were lower than those of control cells(P < 0.05). Database analysis results showed that ALKBH5 was positively correlated with lncRNA TUG1 expression in gastric cancer (r=0.37, P < 0.05). Compared with control cells, the RNA stability of lncRNA TUG1 in SGC-7901 cells with knocked-down ALKBH5 decreased, and the cell proliferation, colony formation, migration, and angiogenesis abilities were also reduced (P < 0.05). Conclusion ALKBH5 promotes the proliferation, colony formation, migration, and angiogenesis of gastric cancer cells by inducing the expression of lncRNA TUG1.

Objective:To investigate the efficacy and safety of posaconazole in the prevention of invasive pulmonary aspergillosis (IPA) in patients with liver failure treated with glucocorticoids (GC).Methods:The study was an observational study. Patients with early and middle stages of liver failure hospitalized in the Department of Infectious Diseases of Hebei Medical University Third Hospital, who received GC treatment between February 2016 and February 2022 were included. The patients were divided into trial group (with posaconazole suspension (200 mg each time, three times daily)) and control group (without posaconazole) according to whether posaconazole was used during treatment. Two groups of patients were matched of 1∶2 ratio according to age, gender and baseline model for end-stage liver disease (MELD) score. The basic information, laboratory examination results, adverse reactions of posaconazole, incidence of invasive Aspergillus infection and therapeutic effect of patients were collected. Statistical analysis was performed using the chi-square test, logistic regression analysis was used to screen risk factors for IPA, the receiver operator characteristic (ROC) curve was used to evaluate the predictive ability of the risk factors, Kaplan-Meier survival curves was used to analyze patient′s survival, and Log-rank test was used to compare the survival rates between the trial group and control group. Results:A total of 108 patients (36 in trial group and 72 in control group) were enrolled. There were no statistical differences between the two groups in terms of the etiology of liver diseases, baseline laboratory findings and risk factors for invasive Aspergillus infection (all P>0.05). There were 21 cases of IPA during hospitalization, with a total infection rate of 19.4%(21/108), including 5.6%(2/36) in the trial group and 26.4%(19/72) in the control group. The difference of IPA incidences between the two groups was statistically significant ( χ2=6.65, P=0.010). Logistic regression analysis suggested that elevated C-reactive protein, GC application more than seven days and cumulative dose of GC were independent risk factors for IPA in patients with liver failure treated with GC (odds ratio ( OR)=1.080, 15.266, 1.004, respectively, all P<0.05). The ROC curve showed that the cut-off value of C-reactive protein was 6.00 mg/L, and cumulative dose of GC was 490 mg. There were no statistical differences between the two groups in terms of adverse effects such as neutropenia, thrombocytopenia, gastrointestinal bleeding, nausea and vomiting rates (all P>0.05), and there were no patients with visual disturbances or discontinuation of medication. Cumulative deaths were 20(18.5%), and 88(81.5%) patients survived in this study. There were 11(52.4%) deaths among 21 patients with IPA and nine (10.3%) deaths among 87 patients without IPA. The difference of survival rates between patients who developed and did not develop IPA was statistically significant ( χ2=21.31, P<0.001). Conclusions:Posaconazole may be helpful in reducing the incidence of concurrent IPA morbidity in patients with liver failure treated with GC, thereby improving survival rates with few adverse effects.

Chronic refractory wound (CRW) is one of the most challengeable issues in clinic due to complex pathogenesis, long course of disease and poor prognosis. Experts need to conduct systematic summary for the diagnosis and treatment of CRW due to complex pathogenesis and poor prognosis, and standard guidelines for the diagnosis and treatment of CRW should be created. The Guideline forthe diagnosis and treatment of chronic refractory wounds in orthopedic trauma patients ( version 2023) was created by the expert group organized by the Chinese Association of Orthopedic Surgeons, Chinese Orthopedic Association, Chinese Society of Traumatology, and Trauma Orthopedics and Multiple Traumatology Group of Emergency Resuscitation Committee of Chinese Medical Doctor Association after the clinical problems were chosen based on demand-driven principles and principles of evidence-based medicine. The guideline systematically elaborated CRW from aspects of the epidemiology, diagnosis, treatment, postoperative management, complication prevention and comorbidity management, and rehabilitation and health education, and 9 recommendations were finally proposed to provide a reliable clinical reference for the diagnosis and treatment of CRW.