Although epilepsy is first known as a disease of seizures and convulsions, most patients with epilepsy also suffer from seizure-associated behavioral abnormalities in motor functions, psychiatric status, and cognition. These neurobehavioral comorbidities may have greater impacts on the quality of life of people with epilepsy than the seizures themselves and can profoundly interfere with the treatment compliance. While repeated seizures often lead to behavioral comorbidities, certain types of comorbid conditions may potentially increase the risk for epileptic seizures, indicative of some common mechanisms that might underlie these two conditions. As such, emerging evidence supports that inflammation within the brain might represent a key component of such a shared mechanism, given that neuroinflammation can be induced by seizures and various behavioral stressors, and in turn may exacerbate both conditions. Among inflammatory pathways that arise after prolonged seizures, PGE₂ signaling via the EP2 receptor promotes cytokine induction, blood-brain barrier disruption, reactive gliosis, neuronal death, and eventually, contributes to behavioral dysfunctions. Pharmacological inhibition of EP2 by small-molecule drug-like antagonists affords broad therapeutic benefits including anti-inflammatory and neuroprotective effects in several rodent seizure models, leading to long-lasting alleviation of neurobehavioral comorbidities, particularly cognitive impairments. Targeting this key inflammatory prostaglandin receptor might provide an adjunctive strategy, along with the current anti-seizure medications, to mitigate cognitive dysfunctions associated with seizure disorders.

Objective: To investigate the chemical compositions of Maxing Shigan Decoction (麻杏石甘汤, MXSGD) and elucidate its anti-influenza A virus (IAV) mechanism from prediction to validation. Methods: Ultra high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to analyze the chemical compositions of MXSGD. Network pharmacology theories were used to screen and identify shared targets of both the potential targets of active ingredients of MXSGD and IAV. A protein-protein interaction (PPI) network was then constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The binding stability between core bioactive compounds and key targets was validated by molecular docking and dynamic simulations. A total of 24 BALB/c mice were infected with IAV to build IAV mouse models. After successful modelling, the mouse models were randomly divided into model, MXSGD high-dose (2.8 g/kg), MXSGD low-dose (1.4 g/kg), and oseltamivir (20.14 mg/kg) groups, with an additional normal mice as control group (n = 6 per group). The treatments were administered by gavage daily between 8:00 a.m. and 10:00 a.m. for five consecutive days. Upon completion of the administration, the body weight ratio, lung index, protein content in the bronchoalveolar lavage fluid (BALF), and the levels of inflammatory factors including interleukin (IL)-6 and tumor necrosis factor (TNF)-α in mice were measured to preliminarily analyze the therapeutic efficacy of MXSGD against IAV infection. Furthermore, the expression levels of mechanistic target of rapamycin (mTOR), hypoxia inducible factor (HIF)-1α, and vascular endothelial growth factor (VEGF) proteins in the HIF-1 signaling pathway, which was enriched by network pharmacology, were detected by Western blot. Results: A total of 212 chemical components in MXSGD were identified by the UPLC-MS/MS method. These chemical components can be classified into 9 primary categories and 31 secondary categories. After intersecting the chemical component targets with IAV-related targets, a total of 567 potential MXSGD components targeting IAV were identified. The construction of PPI network and the results of both GO and KEGG enrichment analyses revealed that the anti-IAV effects of MXSGD were associated with multiple pathways, including apoptosis, TNF, HIF-1, and IL-17 signaling pathways. The results of molecular docking demonstrated that the binding energies between the core compound 1-methoxyphaseollin and key targets including HIF-1α, mTOR, and VEGF were all lower than – 5.0 kcal/mol. Furthermore, molecular dynamics simulations confirmed the structural stability of the resulting complexes. Animal experiments showed that compared with the normal controls, IAV-infected mice showed significantly reduced body weight ratio, markedly increased lung index, protein content in BALF, and the levels of inflammatory factors such as IL-6 and TNF-α (P < 0.01), thereby causing damage to the lung tissue; consequently, the expression levels of mTOR, HIF-1α, and VEGF proteins in the lung tissues of these mice were significantly elevated (P < 0.01). However, after MXSGD treatment, the mouse models presented a significant increase in body weight ratio, as well as marked decreases in lung index, protein content in BALF, and the levels of inflammatory factors including IL-6 and TNF-α (P < 0.01). Furthermore, the therapy alleviated IAV-induced injuries and significantly downregulated the expression levels of mTOR, HIF-1α, and VEGF proteins in lung tissues (P < 0.01 or P < 0.05). Conclusion MXSGD exerts anti-IAV effects through multi-component, multi-target, and multi-pathway synergism. Among them, 1-methoxyphaseollin is identified as a potential key component, which alleviates virus-induced lung injury and inflammatory response via the regulation of HIF-1 signaling pathway, providing experimental evidence for the clinical application of MXSGD.

Objective:To reassess the prognostic value of minimal residual disease (MRD) and IKZF1 gene deletions in adults with B-cell acute lymphoblastic leukemia (B-ALL) who received pediatric-specific chemotherapy regimens during the Nanfang Hospital PDT-ALL-2016 trial.Methods:We retrospectively analyzed the prognosis of 149 adult patients with B-ALL who were admitted to Nanfang Hospital from January 2016 to September 2020. Prognostic factors were identified using Cox regression models.Results:The complete remission rate was 93.2% in 149 patients, with a 5-year overall survival (OS) rate of (54.3±5.0) % and a cumulative incidence of relapse (CIR) of (47.5±5.2) %. The Cox regression analysis revealed that MRD positivity at day 45 (MRD 3) after induction therapy was independently associated with relapse risk ( HR=2.535, 95% CI 1.122-5.728, P=0.025). Deletion of IKZF1 gene was independently associated with mortality risk ( HR=1.869, 95% CI 1.034-3.379, P=0.039). Based on MRD 3 and IKZF1 gene status, we categorized adult patients with B-ALL into the low-risk (MRD 3-negative and IKZF1 gene deletion-negative) and high-risk (MRD 3-positive and/or IKZF1 gene wild type) groups. The 5-year OS and CIR rates were (45.5±6.0) % vs (69.4±8.6) % ( P<0.001) and (61.6±8.3) % vs (25.5±6.5) % ( P<0.001), respectively, in the high-risk and low-risk groups, respectively. The multivariate analysis showed that the high-risk group was an independent risk factor for OS ( HR=3.937, 95% CI 1.975-7.850, P<0.001) and CIR ( HR=4.037, 95% CI 2.095-7.778, P<0.001) . Conclusion:The combined use of MRD and IKZF1 gene in prognostic stratification can improve clinical outcome prediction in adult patients with B-ALL, helping to guide their treatment.

Objective:To invastigate the targets and signaling pathways of Gubiao Fanggan Modified Formula in regulating the defense against influenza A virus in immunosuppressed mice by network pharmacology,and the key targets were verified by immuno-suppressive mice model.Methods:TCMSP database was used to search the active ingredients of Gubiao Fanggan Modified Formula,and GeneCard,OMIM,PharmGkb databases were used to obtain the potential targets of the active ingredients to prevent influenza,and take their intersection targets were taken;STRING11.5 database was used to make protein-protein interaction network analyzed and finded the core targets;Cytoscape3.8.1 was used to build a traditional Chinese medicine-ingredient-disease target network,and GO enrichment analysis and KEGG enrichment analysis were performed.Intraperitoneal injection of cyclophosphamide was used to construct a mouse model of immune function suppression,normal group,model control group,Gubiao Fanggan Modified Formula group and oseltamivir group were set up,followed by prophylactic administration,and influenza virus intervention was performed on the fourth day.After 7 days of intragastric administration,the key targets were verified by mouse spleen index,HE staining,RT-qPCR and immunohistochemistry.Results:There were 82 active ingredients in five traditional Chinese medicines in Gubiao Fanggan Modi-fied Formula,and 72 common targets of drugs and diseases such as IL-6,TNF-α,IL-2,etc,mainly involving IL-17,TNF and AGE-RAGE signaling pathway.Gubiao Fanggan Modified Formula could increase spleen index and significantly reduce mRNA and protein expressions of IL-6 and TNF-α in spleen tissue of mice(P<0.05 or P<0.01).Conclusion:Gubiao Fanggan Modified Formula may regulate body's immune function through targets such as IL-6 and TNF-α,thereby preventing influenza virus infection.

Objective:To explore the feasibility of the AI intelligent reconstruction model based on knee joint magnetic resonance data developed by Nuctech Company Limited for evaluating knee cartilage injury.Methods:Thirty-three patients (a total of forty-one knees) who were hospitalized with severe knee osteoarthritis in Beijing Tsinghua Changgung Hospital from May 2021 to April 2022 were selected. All of them were planned to be performed total knee arthroplasty (TKA) for the treatment of knee osteoarthritis. Fifteen males with an average age of 71±5 years old and twenty six females with an average age of 71±9 years old were included in this study. There were 19 cases of left knee and 22 cases of right knee. Thin layer MRI examination on the patients' knee joints was performed before the surgery, and artificial intelligence model based on the thin layer MRI data of the knee joint was reconstructed. The cartilage part of the model was selected and corrected by Principal Component Analysis (PCA) in order to realize model straightening. The tibial plateau cartilage of knee joint which intercepted during operation was classified according to the International Cartilage Repair Society (ICRS). Finally the results were compared with the ICRS classification results of knee artificial intelligence reconstruction model and artificial recognition of knee joint MRI images.Results:Compared with the grade of cartilage injury intercepted during our operation which was according to the ICRS classification, the sensitivity of artificial intelligence reconstruction model for the diagnosis of cartilage injury with ICRS classification grade four was 93.1%. The specificity of artificial intelligence reconstruction model was 91.4%. The positive predictive value (PPV) of artificial intelligence reconstruction model was 92.2%. And the negative predictive value (NPV) of artificial intelligence reconstruction model was 80.3%. The area under ROC curve (AUC) was 0.92. The ICRS classification consistency between artificial intelligence model and physical inspection results was good with kappa value 0.81 ( P<0.001) . In the aspect of artificial recognition of cartilage injury grading in MRI images, the sensitivity of artificial recognition was 92.10% compared with the manual identification of cartilage injury classification in MRI images. The specificity of artificial recognition was 91.60%. The positive predictive value (PPV) of artificial recognition was 97.20% and the negative predictive value (NPV) of artificial recognition was 78.8%. The kappa value of the cartilage injury classification in MRI images consistency between artificial recognition and manual identification was 0.79 ( P<0.001). Conclusion:Based on the evaluation of cartilage injury by AI reconstruction model of knee joint, the sensitivity and specificity of the diagnosis of ICRS grade IV cartilage injury can be acceptable, but still needs to be improved.

Influenza is an acute viral respiratory infection that has caused high morbidity and mortality worldwide. Influenza A virus (IAV) has been found to activate multiple programmed cell death pathways, including ferroptosis. Ferroptosis is a novel form of programmed cell death in which the accumulation of intracellular iron promotes lipid peroxidation, leading to cell death. However, little is known about how influenza viruses induce ferroptosis in the host cells. In this study, based on network pharmacology, we predicted the mechanism of action of Maxing Shigan decoction (MXSGD) in IAV-induced ferroptosis, and found that this process was related to biological processes, cellular components, molecular function and multiple signaling pathways, where the hypoxia inducible factor-1(HIF-1) signaling pathway plays a significant role. Subsequently, we constructed the mouse lung epithelial (MLE-12) cell model by IAV-infected in vitro cell experiments, and revealed that IAV infection induced cellular ferroptosis that was characterized by mitochondrial damage, increased reactive oxygen species (ROS) release, increased total iron and iron ion contents, decreased expression of ferroptosis marker gene recombinant glutathione peroxidase 4 (GPX4), increased expression of acyl-CoA synthetase long chain family member 4 (ACSL4), and enhanced activation of hypoxia inducible factor-1α (HIF-1α), induced nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) in the HIF-1 signaling pathway. Treatment with MXSGD effectively reduced intracellular viral load, while reducing ROS, total iron and ferrous ion contents, repairing mitochondrial results and inhibiting the expression of cellular ferroptosis and the HIF-1 signaling pathway. Finally, based on animal experiments, it was found that MXSGD effectively alleviated pulmonary congestion, edema and inflammation in IAV-infected mice, and inhibited the expression of ferroptosis-related protein and the HIF-1 signaling pathway in lung tissues.
Animals ; Mice ; Ferroptosis ; Network Pharmacology ; Reactive Oxygen Species ; Vascular Endothelial Growth Factor A ; Influenza A virus ; Iron ; Hypoxia

As the main weapon of cellular immunity,CD4+ T cells play a vital role in controlling and eliminating infections,and are an important barrier for the body to resist infections.Respiratory tract infectious diseases caused by influenza virus infection have extremely high infectivity,morbidity and mortality.The infection mechanism is relatively complicated and has not been fully ex-plained.The exuberant immune response induced by the body after influenza virus infection is described as a"cytokine storm"which is related to pro-inflammatory cytokines and tissue damage,which may eventually lead to acute lung injury.Therefore,this article sum-marizes the current research progress,focusing on the mechanism of CD4+T cells in the cytokine storm induced by influenza virus in-fection and the impact of acute lung injury,providing relevant ideas and theoretical guidance for follow-up research,with a view to the disease caused by influenza virus bring new and effective methods of diagnosis and treatment.

Objective:To explore the regulatory effect of cellular FLICE-like inhibitory protein (cFLIP) on myocardial ischemia-reperfusion injury based on the RIPK1/RIPK3/MLKL-mediated necroptosis pathway.Methods:The cardiomyocyte hypoxia/reoxygenation (H/R) model was constructed by hypoxia for 4 h/reoxygenation for 12 h, and the rat ischemia reperfusion (I/R) model was constructed by ligating the left anterior descending artery for 30 min and reperfusion for 3 h. CCK-8 method was used to detect the viability of cardiomyocytes in each group. DAPI/PI double staining was used to observe changes in necrosis rate of myocardial cell. STRING database was used to predict the protein interaction network of cFLIP. TTC staining was used to detect the area of myocardial infarction in each group of rats, and the protein expression of cFLIPL, cFLIPS, p-RIPK1, p-RIPK3 and p-MLKL were detected by Western blot.Results:In cardiomyocyte H/R injury and myocardial tissue I/R injury, the protein expressions of cFLIPL and cFLIPS were significantly down-regulated, while the levels of p-RIPK1, p-RIPK3 and p-MLKL were increased significantly. Up-regulating the protein expression of cFLIPL and cFLIPS could significantly reduce the damage of cardiomyocytes and the rate of cell necrosis induced by H/R, and decrease the area of myocardial infarction caused by I/R. STRING database results showed that cFLIP had direct protein interactions with RIPK1 and RIPK3. Overexpression of cFLIP in cardiomyocyte and myocardial tissue significantly inhibited H/R or I/R induced the phosphorylation levels of RIPK1, RIPK3 and MLKL.Conclusions:Overexpression of cFLIP can significantly inhibit the RIPK1/RIPK3/MLKL-mediated necroptosis, thereby reducing myocardial cell damage and decreasing the area of myocardial infarction.

Objective:To compare 5-year overall survival (OS) and disease free survival (DFS) between preoperative three dimensional conformal radiotherapy (3DCRT) and volumetric medulated arc therapy (VMAT) concurrently combined with chemotherapy for locally advanced rectum cancer (LARC), and analyze the value of induction and/or consolidation chemotherapy in these circumstances.Methods:334 patients with LARC treated with preoperative 3DCRT (172 cases) and VMAT (162 cases) concurrently combined with chemotherapy, main protocol XELOX (capecitabine plus oxaplatin), and subsequent surgery in Sun Yat-sen University from May 2007 to April 2013 were retrospectively analyzed. The radiation prescription dose for VMAT group was 50 Gy 25 fractions for planning target volume1(PTV 1), and 46 Gy 25 fractions for PTV 2. The radiation prescription dose for 3DCRT group was 46 Gy 23 fractions for PTV 2. One hundred and eighty-five cases of all received preoperative concurrent chemoradiotherapy (namely, CCRT group), 149 cases received preoperative concurrent chemoradiotherapy plus median 2 courses (1-7 courses) induction and/or consolidation chemotherapy (namely, CCRT±induction chemotherapy±consolidation chemotherapy group), whose main chemotherapy protocol was XELOX. Difference of 5-year OS and DFS between 3DCRT and VMAT group was compared. The rate differences of acute toxicity during chemoradiotherapy, postoperative complications, ypCR, and survival between CCRT group and CCRT±induction chemotherapy±consolidation chemotherapy group were analyzed. Results:After a median follow-up of 62.3 months (2.4-119months) for the 334 patients, no any significant difference for 5-year OS (79.0% vs. 83.2%, P=0.442) and 5-year DFS (77.0% vs. 82.1%, P=0.231) between 3DCRT and VMAT group was observed. There was no any significant difference for the Grade 3 hematological toxicity (7.0% vs. 12.1%, P=0.114) and non-hematological toxicity (14.1% vs. 16.8%, P=0.491) during chemoradiotherapy, postoperative complications (17.3% vs. 17.4%, P=0.971), ypCR rate (25.4% vs. 30.2%, P=0.329), 5-year OS (80.5% vs. 82.0%, P=0.714) and 5-year DFS (78.8% vs. 81%, P=0.479) between CCRT group and CCRT±induction chemotherapy±consolidation chemotherapy group. Conclusions:Compared with 3DCRT, the physics advantage of VMAT technique does not significantly convert into clinical benefits and improve 5-year OS and DFS, even further boosting radiation dose to the gross tumor volume. It is safe for median 2 courses of induction and/or consolidation chemotherapy before and or after preoperative concurrent chemoradiotherapy in the treatment of LARC, though it does not significantly improve ypCR rate and survival.

Objective:To establish a nomogram model for predicting the risk of coronary artery disease in elderly patients with acute myocardial infarction (AMI).Methods:The clinical data of elderly patients with AMI who underwent coronary angiography in the department of cardiology of Cangzhou Central Hospital from July 2015 to March 2020 were analyzed, including age, gender, smoking history, underlying diseases, family history, blood pressure, left ventricular ejection fraction (LVEF), and several biochemical indicators at admission, such as total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein [Lp(a)], apolipoproteins (ApoA, ApoB), ApoA/B ratio, total bilirubin (TBil), direct bilirubin (DBil), indirect bilirubin (IBil), fasting blood glucose (FBG) and uric acid (UA). Patients were divided into model group (2 484 cases) and validation group (683 cases) according to the ratio of 8∶2. According to Gensini score, the model group and validation group were divided into mild lesion group (0-20 points) and severe lesion group (≥81 points). The differences of each index between different coronary lesion degree groups were compared. Lasso regression and Logistic regression were used to analyze the risk factors of aggravating coronary lesion risk in elderly patients with AMI, and then the nomogram prediction model was established for evaluation and external validation.Results:① In the model group, there were significant differences in the family history of coronary heart disease, FBG and HDL-C between the mild lesion group (411 cases) and the severe lesion group (417 cases) [family history of coronary heart disease: 3.6% vs. 7.7%, FBG (mmol/L): 5.88±1.74 vs. 6.43±2.06, HDL-C (mmol/L): 1.48±0.69 vs. 1.28±0.28, all P < 0.05]. In the validation group, there were significant differences between the mild lesion group (153 cases) and the severe lesion group [132 cases; FBG (mmol/L): 5.58±0.88 vs. 6.85±0.79, HDL-C (mmol/L): 1.59±0.32 vs. 1.16±0.21, both P < 0.05]. ② Lasso regression analysis showed that family history of coronary heart disease, FBG, and HDL-C were risk factors of coronary artery disease in elderly patients with AMI, with coefficients 0.118, 0.767, and -0.558, respectively. Logistic regression analysis showed that FBG [odds ratio ( OR) = 1.479, 95% confidence interval (95% CI) was 1.051-2.082, P = 0.025] and HDL-C ( OR = 0.386, 95% CI was 0.270-0.553, P < 0.001] were independent risk factors of coronary artery disease in elderly patients with AMI. ③ According to the rank score of FBG and HDL-C, the nomogram prediction risk model of aggravating coronary artery disease degree was established for each patient. It was concluded that the risk of coronary artery disease in elderly people with higher FBG level and (or) lower HDL-C level was significantly increased. ④ The nomogram model constructed with the model group data predicted the risk concordance index (C-index) was 0.689, and the C-index of the external validation group was 0.709. Conclusions:FBG and HDL-C are independent risk factors for aggravating coronary artery disease in elderly patients with AMI. The nomogram model of aggravating coronary artery disease in elderly patients with AMI has good predictive ability, which can provide more intuitive research methods and clinical value for preventing the aggravation of coronary artery disease in elderly patients.