Reactive astrocytes, which exhibit a correlation with the degeneration of dopaminergic neurons, are present in a considerable number during the progression of Parkinson's disease (PD). However, the underlying factors shaping astrocyte reactivity and neuroinflammation in PD remain inadequately elucidated. Here, we demonstrate that fibroblast growth factor 7 (FGF7)/FGF receptor 2 (FGFR2) autocrine signaling intensifies astrocyte reactivity and inflammation. Genetic deletion of Arrb2, β-Arrestin2 encoding gene, led to escalated astrocyte reactivity in MPTP-treated mice, which was further substantiated in astrocyte-specific Arrb2 knockdown mice. RNA sequencing profiling of Arrb2 knockout astrocytes identified Fgf7 as a critical effector of astrocyte reactivity. Subsequently, conditional knockdown of Fgf7 and its receptor Fgfr2 in astrocytes elicited advantageous effects for MPTP-treated mice by restraining the inflammatory phenotypic transition of reactive astrocytes. Furthermore, deletion of astrocytic Fgf7 mitigated MPTP-induced pathology in Arrb2 knockout mice. Mechanistically, STAT1 was distinguished as the transcription factor suppressing Fgf7 expression, while β-Arrestin2 counteracted the proteasomal degradation of STAT1 by binding to RNF220, an E3 ubiquitin ligase for STAT1. More importantly, selectively engaging dopamine D2 receptor (Drd2)/β-Arrestin2-biased signaling using the agonist UNC9995 exhibited therapeutic potential in MPTP-treated mice via moderation of astrocytic FGF7 production, thereby restoring balance in astrocyte reactivity. Collectively, our study bridges a crucial knowledge gap by elucidating the novel functions of FGF family members within the central nervous system, particularly within the context of PD. The autocrine signaling of FGF7/FGFR2 represents a novel mechanism and a potential druggable target for modulating astrocyte-derived inflammation.

Objective To explore the predictive value of combined serum soluble hemoglobin scavenger receptor 163(sCD163),hypersensitive C-reactive protein(hs-CRP),and procalcitonin(PCT)for stroke-associated pneumonia(SAP).Methods A total of 100 patients with acute ische-mic stroke admitted to the First Hospital of Zhangjiakou from October 2021 to January 2023 were se-lected as the study subjects.According to whether they developed SPA within 7 days of admission,they were divided into SAP group(n=64)and non-SAP group(n=36).Based on pneumonia se-verity index(PSI),patients in the SAP group were further divided into mild SAP group and severe SAP group.Enzyme-linked immunosorbent assay(ELISA)was used to detect the serum levels of sCD163,hs-CRP,and PCT.The clinical data of the patients were collected and compared.Pearson's method was used to analyze the correlation between the PSI score and the serum levels of sCD163,hs-CRP,and PCT in SAP patients.Multivariate Logistic regression analysis was employed to screen for factors influencing the occurrence of SAP.Receiver operating characteristic(ROC)curve analy-sis was used to evaluate the predictive efficacy of serum sCD163,hs-CRP,and PCT for the occur-rence of SAP.Results The proportion of patients with dysphagia and the National Institutes of Health Stroke Scale(NIHSS)score in the SAP group were significantly higher than those in the non-SAP group(P＜0.05).The serum levels of sCD163,hs-CRP,and PCT in the SAP group were significantly higher than those in the non-SAP group(P＜0.05).The serum levels of sCD163,hs-CRP,and PCT in the severe SAP group were significantly higher than those in the mild SAP group(P＜0.05).Pearson's correlation analysis showed that the PSI score was positively correlated with the serum levels of sCD163,hs-CRP and PCT in SAP patients(r=0.356,0.413,0.391,P＜0.001).Logistic regression analysis revealed that serum sCD163,hs-CRP,PCT,NIHSS score,and dysphagia were all influencing factors for the occurrence of SAP(P＜0.05).The areas under the curve(AUC)for predicting SAP using serum sCD163,hs-CRP,PCT and their combina-tion were 0.842,0.924,0.866 and 0.973,respectively,with sensitivities of 73.44％,84.37％,67.19％and 90.62％,and specificities of 88.89％,83.33％,97.22％and 94.44％,respectively.The predictive value of the combined detection was superior to that of the individual detection of ser-um sCD163,hs-CRP and PCT(P＜0.05).Conclusion The serum levels of sCD163,hs-CRP,and PCT are elevated in SAP patients,and their changes are closely related to the severity of the disease.The combined detection of these three indicators has a high value in predicting the occur-rence of SAP and may serve as auxiliary markers for predicting early SAP.

Objective To detect the serum levels of CC chemokine receptor 2(CCR2)and C-reactive pro-tein(CRP)in stroke patients,and analyze their relationship with the severity of stroke associated pneumonia and their clinical significance.Methods A total of 78 patients with stroke associated pneumonia who were di-agnosed and treated in the hospital from October 2022 to February 2023 were collected as the study group,ac-cording to the severity of pneumonia,the study group was divided into mild group(31 cases),moderate group(29 cases),and severe group(18 cases),78 stroke patients who did not develop pneumonia were included into control group.Pearson method was applied to analyze the correlation between serum CCR2 and CRP levels in stroke associated pneumonia patients.Multivariate Logistic regression was applied to analyze the factors influ-encing the occurrence of stroke associated pneumonia.Receiver operating characteristic(ROC)curve was ap-plied to analyze the diagnostic value of serum CCR2 and CRP for stroke associated pneumonia.Results The National Institute of Health stroke scale(NIHSS)score,serum CCR2,and CRP levels in the study group were obviously higher than those in the control group(P<0.05).The levels of serum CCR2 and CRP increased with the aggravation of pneumonia(P<0.05).The levels of serum CCR2 and CRP in the study group were positively correlated(r=0.799,P<0.05).NIHSS score,CCR2,and CRP levels were risk factors for stroke associated pneumonia in stroke patients(P<0.05).The area under the curve(AUC)for the diagnosis of stroke associated pneumonia using serum CCR2 and CRP alone was 0.873 and 0.888,respectively,and the AUC for the combined detection of the two was 0.936,the combined detection of the two was superior to the individual detection of serum CCR2 and CRP(Zcombination-CCR2=1.987,Zcombination-CRP=1.832,P=0.041,0.047).Conclusion Serum CCR2 and CRP are closely related to the severity of stroke associated pneumonia,and their combined detection has high diagnostic value for stroke associated pneumonia.

Objective To investigate the diagnostic value of serum soluble fms-like tyrosine kinase 1(sFlt-1)and soluble differentiation cluster 14(sCD14)in stroke-associated pneumonia(SAP).Methods A total of 67 SAP patients admitted to the hospital from March 2022 to January 2023 were selected as the study group,and 50 stroke patients without pneumonia during the same period were selected as the control group.Enzyme-linked immunosorbent assay was used to measure serum sFlt-1 and sCD14 levels.Pearson correlation analysis was used to analyze the correlation between serum sFlt-1,sCD14 levels and clinical data.Multivariate Logistic regression was used to analyze the influencing factors of SAP in patients with stroke.Receiver operating char-acteristic(ROC)curve was used to analyze the diagnostic value of serum sFlt-1 and sCD14 levels in predicting SAP in patients with stroke.Results The serum levels of sFlt-1 and sCD14 in SAP patients were higher than those in stroke patients without pneumonia and stroke patients with pneumonia alone(P＜0.05).SAP in stroke patients was associated with age,atrial fibrillation,heart failure,aspiration,dysphagia,brain stem stroke,proton pump inhibitor use,fever,cough,dyspnea,low-density lipoprotein cholesterol,procalcitonin(PCT),C-reactive protein,white blood cell count,national institutes of health stroke scale(NIHSS)score,clinical pulmonary infection(CPIS)score(P＜0.05).Correlation analysis showed that serum sFlt-1 level was positively correlated with sCD14(r=0.439,P＜0.001),and serum sFlt-1 and sCD14 levels were positively correlated with NIHSS score and CPIS score(P＜0.05).Multivariate Logistic regression analysis showed that sFlt-1,sCD14,proton pump inhibitor use,PCT,dysphagia,and age were the influencing factors of SAP in stroke patients(P＜0.05).ROC curve results showed that the area under the curve of serum sFlt-1 and sCD14 combined to evaluate SAP in stroke patients was higher than that of single detection(ZsFlt-1-combined=2.194,P=0.028,ZscD14-combined=2.310,P=0.002).Conclusion The serum levels of sFlt-1 and sCD14 are in-creased in SAP patients,and the combination of the two has a good diagnostic value for predicting the occur-rence of SAP.

Objective:To investigate the clinicopathological features and molecular characteristics of β-catenin-deficient colorectal cancer.Methods:The clinical, pathological and molecular features of 11 colorectal cancers with β-catenin protein loss diagnosed at the 960th Hospital of People′s Liberation Army of China, from January 2012 to November 2022 were analyzed.Results:Among the 11 patients, 3 were males and 8 were females. Their age ranged from 43 to 74 years, with the median age of 59 years. Six were in the left colon and 5 were in the right colon. One of the 11 cases had lymph node metastasis, 10 cases were well and moderately differentiated adenocarcinoma, and 1 was mucinous adenocarcinoma. Eight cases were of TNM stage T4, 2 of T1 stage and 1 of Tis stage. β-catenin protein was not detected using immunohistochemistry. Sanger sequencing revealed the presence of fragment-deletion mutation in exon 3 of CTNNB1 gene, resulting in loss of β-catenin protein expression.Conclusion:β-catenin deficiency is present in a small number of colorectal cancers and may be associated with exon 3 mutations of CTNNB1 gene.

Objective:To explore the effect of SQLE on the biological characteristics of pan-cancer,using bioinformatics methods to predict and analyze the correlation between SQLE and the clinical prognosis and immunity of pan-cancer.Methods:The ex-pression level of SQLE in tumor and normal tissues and its correlation with different clinical stages of pan-cancer were analyzed,and the relationship between SQLE expression and overall survival and tumor microenvironment were evaluated.Gene enrichment analysis was conducted to study the biological functions and signaling pathways related to SQLE gene,then,calculate the correlation between SQLE gene and tumor mutation load and microsatellite instability,and analyze the correlation between SQLE gene and immunomodula-tory genes.Results:SQLE gene was highly expressed in variety of tumors,and differentially expressed in different tumor stages.High expression of SQLE was a risk factor in variety of tumors.Patients with high expression of SQLE hade a worse prognosis.SQLE was cor-related with TMB and MSI,and involved in tumor development through different pathways.Conclusion:SQLE,as a valuable prognos-tic biomarker and new therapeutic target for variety of cancers,has certain application value in basic research and clinical treatment of various cancers.

Objective To rescue a recombinant oncolytic influenza virus chimeric with IL-21 and evaluate its inhibitory effects and safety against hepatocell ular carcinoma(HCC)both in vitro and in vivo,and to explore the mechanism by which this virus enhances antitumor effects when combined with anti-programmed cell death protein 1(anti-PD-1)antibody.Methods The IL-21 gene fragment was inserted into the nonstructural protein(NS)sequence of the influenza virus PR8 using reverse genetics(RG)technology to rescue the recombinant oncolytic influenza virus rOV-IL-21-NS.The virus titer and virulence were determined using the 50％tissue culture infectious dose(TCID50)and hemagglutination assays.The successful insertion of the exogenous gene into the NS sequence was verified using RT-qPCR,gel electrophoresis,and sequencing analysis.Viral morphology and size were observed with transmission electron microscopy.The impact of the virus on the viability of hepatocellular carcinoma cells was assessed with CCK-8 assay.A subcutaneous tumor model of HCC was established in 45 female C57BL/6 mice(8 weeks old,weighing 16～20 g),and then the mice were randomly assigned into PBS,PR8,anti-PD-1,rOV-IL-21-NS,and the rOV-IL-21-NS+anti-PD-1 treatment groups,with 9 mice in each group,to evaluate the anti-tumor effects of monotherapy versus combination therapy.Flow cytometry was conducted to assess the regulatory effects of monotherapy and combination therapy on the tumor immune microenvironment.Results RG technology successfully rescued the recombinant oncolytic influenza virus rOV-IL-21-NS.Sequencing confirmed the successful insertion of IL-21 into the target sequence,and the obtained virus could be stably propagated,with its sixth passage reaching a hemagglutination titer of 211,and a viral titer of 6 Log10(TCID50/mL).Oncolytic virus rOV-IL-21-NS,at a multiplicity of infection(MOI)of 3,selectively reduced the viability of HCC cells without significantly affecting normal liver cells.Compared to the control group,the combination of rOV-IL-21-NS and anti-PD-1 antibodies significantly inhibited tumor growth(P＜0.001)and increased the proportions of CD4+T and CD8+T cells in the spleen tissue of the mouse model of subcutaneous HCC tumor(P＜0.001).Conclusion The recombinant oncolytic influenza virus rOV-IL-21-NS chimeric with IL-21 can effectively and safely exert targeted killing to HCC cells,enhance T cell activation by synergizing with anti-PD-1 antibodies,and improve the immune microenvironment.

ObjectiveTo characterize the chemical constituents of Dayuanyin based on ultra-performance liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry（UPLC-Q-Exactive Orbitrap MS）. MethodThe detection was performed on a Thermo Acclaim™ RSLC 120 C₁₈ column（2.1 mm×100 mm， 2.2 μm）， the mobile phase was acetonitrile（A）-0.1% formic acid aqueous solution（B） for gradient elution （0-7.5 min， 10%-19%A； 7.5-12 min， 19%-22.5%A； 12-23 min， 22.5%-27%A； 23-27 min， 27%-56%A； 27-35 min， 56%-84%A； 35-36 min， 84%-90%A）， the flow rate was 0.3 mL·min^-1， and the column temperature was 30 ℃. The data were collected in the positive and negative ion modes by heated electrospray ionization（HESI）， and the detection range was m/z 80-1 200. Combining the retention time of the reference substance， fragment ions， databases such as PubChem and related literature， Xcalibur 3.0 was used to identify the chemical constituents of Dayuanyin. ResultA total of 161 compounds were identified， including 14 alkaloids， 60 flavonoids， 16 terpenoids， 26 saponins， 18 phenylpropanoids， 16 organic acids and 11 others. ConclusionThe established method can effectively and quickly identify the chemical components in Dayuanyin， and clarify its chemical composition， which can provide a basis for the development of compound preparations of this famous classical formula.

Objective:To screen the key exosomal long non-coding RNAs (lncRNAs) molecules that cause nasopharyngeal carcinoma cells to develop chemoradiotherapy resistance.Methods:In vitro, a model of concurrent chemoradiotherapy for human nasopharyngeal carcinoma cells was constructed, and the continuous shock method of high-dose concurrent chemoradiotherapy was used to induce the establishment of chemoradiotherapy-resistant nasopharyngeal carcinoma cell lines, and its resistance formation was verified. Exosomes produced by chemoradiotherapy-resistant cell lines and respective mother cell lines for nasopharyngeal carcinoma were extracted and identified. Finally, biochip technology was used to detect the differential expression levels of exosomal lncRNAs. Results:After 10 repeated treatments of concurrent chemoradiotherapy, CNE-1 CRR and CNE-2 CRR were successfully obtained. Compared with the mother cell lines, CNE-1 CRR and CNE-2 CRR had a tendency to transform from epithelial to interstitial morphology, and the number of cell clones was higher, and the values of average lethal dose (D 0), quasi-threshould dose (D q), survival fraction after 2 Gy irradiation (SF 2) and cell survival rate were higher. Nasopharyngeal carcinoma cells were detected by PCR chip of exosomal lncRNAs. Compared with their respective mother cell lines, 18 lncRNAs in CNE-1 CRR exosomes were significantly up-regulated and 31 lncRNAs were significantly down-regulated, and 15 lncRNAs were significantly up-regulated and 38 lncRNAs were significantly down-regulated in CNE-2 CRR exosomes. CNE-1 CRR also had similar expression profiles to CNE-2 CRR. Conclusion:There are significantly up-regulated and down-regulated lncRNAs in the exosomes of CNE-1 CRR and CNE-2 CRR.

Objective:To investigate the efficacy of neostigmine combined with raw rhubarb enema on severe acute pancreatitis (SAP) patients with intra-abdominal hypertension (IAH).Methods:The clinical data of 89 SAP patients, who were admitted and underwent continuous renal replacement treatment (CRRT) in intensive care unit (ICU) department of the First Affiliated Hospital of Hebei North University from January 2018 to June 2022, were retrospectively analyzed. Patients were divided into control group ( n=44) and experimental group ( n=45) according to the treatment mode. Raw rhubarb enema plus sodium sulfate topical application were administrated twice a day for 7 days in control group; besides the treatment above, intramuscular injection of neostigmine 0.5 mg twice a day for 7 days was given in experimental group. Intra-abdominal pressure was monitored, acute physiology and chronic health evaluation (APACHE)Ⅱ, kidney disease: improving global outcome stage (KDIGO), lung injury score (LIS) were recorded, and serum leukocyte, CRP, procalcitonin (PCT), IL-6, IL-8 and tumor necrosis factor (TNF)-ɑ level were examined before and after treatment in both groups. The primary endpoint was the amount change of intra-abdominal pressure within 24 hours, and secondary endpoints included increased fecal volume within 7 days after treatment, new abdominal compartment syndrome (ACS), new organ dysfunction, vascular complications, length of ICU stay, total length of stay, survival rate and treatment intervention and occurrence of complications within 6 months after the end of treatment. Results:Intra-abdominal pressure began to decrease at 9 hours after treatment both in control group and experimental group. Compared with that before treatment, the intra-abdominal pressure of the two groups decreased significantly after 7 days of treatment, and the decrease rate of the experimental group within 7 days was obviously higher than that of the control group, with statistical significance (all P values <0.05). Compared with those before treatment, APACHEⅡ, KDIGO and LIS in both groups were significantly decreased, but the decreases in experimental group were more remarkable than those in control group (all P values <0.05). After treatment, the serum WBC count and the levels of inflammatory factors CRP, PCT, IL-6, IL-8, TNF-ɑ in experimental group were obviously lower than those in control group with statistical significance (all P values <0.05). Compared with control group, the change of intra-abdominal pressure in experimental group was significantly increased after 24-hour treatment, and the fecal volume was also obviously increased on day 1, 2, 3, 5 and 7 after treatment (all P values <0.05). However, there were no significantly statistical differences on the severity of intra-abdominal pressure, new occurrence of ACS and organ failure, vascular complication, ICU hospitalization and total length of stay and survival rate between two groups. After 6-month follow-up, the recurrence of pancreatitis and its treatment intervention between two groups were not statistically significant. Conclusions:The adjuvant treatment of neostigmine could reduce intra-abdominal pressure, increase defecation volume in SAP patients and alleviate SAP condition, which might be related to reducing the release of inflammatory cytokines.