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Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy. SerpinA3N is mainly associated with the acute phase response and inflammatory response. In our current study, transcriptomics analysis, proteomics analysis, and Western blotting showed that the expression level of Serpin clade A member 3N (SerpinA3N) is significantly increased in the hippocampus of mice with kainic acid (KA)-induced temporal lobe epilepsy, and this molecule is mainly expressed in astrocytes. Notably, in vivo studies using gain- and loss-of-function approaches revealed that SerpinA3N in astrocytes promoted the release of proinflammatory factors and aggravated seizures. Mechanistically, RNA sequencing and Western blotting showed that SerpinA3N promoted KA-induced neuroinflammation by activating the NF-κB signaling pathway. In addition, co-immunoprecipitation revealed that SerpinA3N interacts with ryanodine receptor type 2 (RYR2) and promotes RYR2 phosphorylation. Overall, our study reveals a novel SerpinA3N-mediated mechanism in seizure-induced neuroinflammation and provides a new target for developing neuroinflammation-based strategies to reduce seizure-induced brain injury.

Background Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD), that can improve patients' motor and non‐motor symptoms. However, there are differences in the improvement of patients' emotional symptoms and cognitive function. Objective To investigate the impact of active contact location and the volume of tissue activated (VTA) on patients' emotional symptoms and cognitive function in STN‐DBS in PD. Methods A total of 185 PD patients were included in this study. We evaluated them using the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale, Hamilton Anxiety Scale (HAM‐A), Hamilton Depression Scale (HAM‐D), Montreal Cognitive Assessment (MoCA), and Mini‐Mental State Examination (MMSE) scales at the preoperative, 1‐ and 12‐month postoperative time points. Leads were positioned in standard space using the Lead‐DBS toolbox, and VTA was calculated for analysis. Results When the lead active contact was closer to the ventral side of the STN, the patients' HAM‐A improvement rate was higher, and when the active contact was closer to the anterior and dorsal sides of the STN, the patients' MoCA improvement rate was higher. Stimulation of the sensorimotor zone was more favorable to the improvement of HAM‐A and HAM‐D in patients. And, the stimulation of the associative zone was more favorable to the improvement of MoCA in patients. Conclusion Our results provide evidence that the 12‐month outcomes of cognitive function and emotional symptoms in PD patients with STN‐DBS were closely related to the specific location of the active contacts in the STN and influenced by the VTA. This study models the spatial distribution of activation contacts by correlating the improvement of patients' emotional and cognitive functions with the location of the spatial coordinates of the activation contacts. It was found that the outcomes of cognitive and emotional symptoms in PD patients with STN‐DBS were related to the specific location of active contacts in the STN and influenced by the VTA.

Alternative splicing (AS) is assumed to play important roles in the progression and prognosis of cancer. Currently, the comprehensive analysis and clinical relevance of AS in lower‐grade diffuse gliomas have not been systematically addressed. Here, we gathered alternative splicing data of lower‐grade diffuse gliomas from SpliceSeq. Based on the Percent Spliced In (PSI) values of 515 lower‐grade diffuse glioma patients from the Cancer Genome Atlas (TCGA), we performed subtype‐differential AS analysis and consensus clustering to determine robust clusters of patients. A total of 48 050 AS events in 10 787 genes in lower‐grade diffuse gliomas were profiled. Subtype‐differential splicing analysis and functional annotation revealed that spliced genes were significantly enriched in numerous cancer‐related biological phenotypes and signalling pathways. Consensus clustering using AS events identified three robust clusters of patients with distinguished pathological and prognostic features. Moreover, each cluster was also associated with distinct genomic alterations. Finally, we developed and validated an AS‐related signature with Cox proportional hazards model. The signature, significantly associated with clinical and molecular features, could serve as an independent prognostic factor for lower‐grade diffuse gliomas. Thus, our results indicated that AS events could discriminate molecular subtypes and have prognostic impact in lower‐grade diffuse gliomas.

This study aims to identify specific molecular targets sensitive to AZD6738 through the integration of network pharmacology and transcriptomic methods, and to assess their potential role in the treatment of hepatocellular carcinoma (HCC). Additionally, we explore the specific effects of AZD6738 on the tumor microenvironment and its ability to regulate immune responses. We employed a combination of network pharmacology and transcriptomic analysis to identify specific molecules associated with HCC, including EZH2, CCNB1, PRKDC, CTSL, PSEN1, SLC6A3, and FKBP1A. Using these molecules and clinical features, we constructed a robust prognostic model for HCC. We further used single-cell transcriptomic technology to screen for core targets and performed spatial transcriptomic analysis to determine their spatial distribution. To validate the efficacy of AZD6738 in vivo, we established a subcutaneous tumor model, with the experimental group receiving oral administration of AZD6738 (75 mg/kg). Finally, we assessed the changes in the immune cell expression profile in tumor tissues post-AZD6738 treatment using flow cytometry. Our study indicates that the high expression of genes such as EZH2, CCNB1, PRKDC, and PSEN1 is associated with poor prognosis in HCC patients. Molecular docking and RT-PCR validation demonstrated that AZD6738 exhibits high affinity for these targets and significantly reduces the mRNA levels of EZH2, PRKDC, and CCNB1 in HCC cell lines, with EZH2 showing the most pronounced decrease. Animal experiments revealed that AZD6738 can enhance the immune microenvironment in liver cancer; specifically, AZD6738 not only promotes the proliferation of CD8+ T cells but also enhances their differentiation into effector memory T cells, indicating that the drug can potentiate anti-tumor immune responses. This study reveals that AZD6738 demonstrates significant therapeutic efficacy by targeting the key molecule EZH2, thereby modulating the tumor microenvironment and enhancing anti-tumor immunity.

Inhibitors of immune checkpoints have shown little effect in clinical trials involving glioma patients. Here, we explored novel targets for use in future treatments. Previous studies showed the sialic acid-binding Ig-like lectin (Siglec) family to have a specific role in immunosuppression. We aimed to study the characteristics and immune function of Siglec family members. Transcriptome data from 1024 glioma samples and 1551 glioma single cells were used in our study. Clinical and molecular pathology information was also included. Statistical, bioinformatical methods, and single-cell sequencing analysis were applied to investigate the role of Siglec family members. Siglecs-5, -7, -9, and -16 showed a significant correlation with immunosuppression in glioma. They are typically expressed in higher grade, IDH-wildtype, and mesenchymal subtype gliomas. Siglec-5, -7, and -9 had a similar immune function to TIM-3, while Siglec-16 was similar to PD-L1, suppressing tumor immunity via different mechanisms. Joint use of Siglec-inhibitors and immune checkpoint inhibitors could prolong the survival of glioma patients. Siglec-5, -7, -9, and -16 suppressed tumor immunity in different ways. Joint usage of inhibitors may be an effective means to improve the efficacy of glioma immunotherapy.

Although hypothermia therapy is effective to treat neonatal hypoxic-ischemic encephalopathy,many neonatal patients die or suffer from severe neurological dysfunction.Erythropoietin is considered one of the most promising neuroprotective agents.We hypothesized that erythropoietin combined with hypothermia will improve efficacy of neonatal hypoxic-ischemic encephalopathy treatment.In this study,41 neonates with moderate/severe hypoxic-ischemic encephalopathy were randomly divided into a control group（hypothermia alone for 72 hours,n = 20） and erythropoietin group（hypothermia ＋ erythropoietin 200 IU/kg for 10 days,n = 21）.Our results show that compared with the control group,serum tau protein levels were lower and neonatal behavioral neurological assessment scores higher in the erythropoietin group at 8 and 12 days.However,neurodevelopmental outcome was similar between the two groups at 9 months of age.These findings suggest that erythropoietin combined with hypothermia reduces serum tau protein levels and improves neonatal behavioral neurology outcome but does not affect long-term neurodevelopmental outcome.

Aim： To develop a combined population pharmacokinetic model （PPK） to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters. Methods： Relevant patient concentration data （eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc） were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medi- cations as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors. Results： A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients （74 males, 88 females） at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population-predicted clearance of clozap- ine and norclozapine in female nonsmokers were 21.9 and 32.7 L/h, respectively. The population＊predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance （clozapine by 45%; norclozapine by 54.3%）. The clearance was significantly greater in males than in females （clozapine by 20.8%; nor- clozapine by 24.2%）. The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients. Conclusion： Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring.

Aim： To develop a population pharmacokinetic （PopPK） model of tacrolimus in healthy Chinese volunteers and liver transplant recipients for investigating the difference between the populations, and for potential individualized medication. Methods： A set of 1100 sparse trough concentration data points from 112 orthotopic liver transplant recipients, as well as 851 dense data points from 40 healthy volunteers receiving a single dose of tacrolimus （2 mg, po） were collected. PopPK model of tacrolimus was constructed using the program NONMEM. Related covariates such as age, hepatic and renal functions that were potentially associated with tacrolimus disposition were evaluated. The final model was validated using bootstrapping and a visual predictive check. Results： A two-compartment model of tacrolimus could best describe the data from the two populations. The final model including two covariates, population （liver transplant recipients or volunteers） and serum ALT （alanine aminotransferase） level, was verified and adequately described the pharmacokinetic characteristics of tacrolimus. The estimates of V2/F, Q/F and V3/F were 22.7 L, 76.3 L/h and 916 L, respectively. The estimated CL/F in the volunteers and liver transplant recipients was 32.8 and 18.4 L/h, respectively. Serum ALT level was inversely related to CL/F, whereas age did not influence CL/F. Thus, the elderly （≥65 years） and adult （〈65 years） groups in the liver transplant recipients showed no significant difference in the clearance of tacrolimus. Conclusion： Compared with using the sparse data only, the integrating modeling technique combining sparse data from the patients and dense data from the healthy volunteers improved the PopPK analysis of tacrolimus.

Aim： Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib （ER） with VEGFR TKI sunitinib （SU） did not improve the overall survival in patients with non-small-cell lung cancer （NSCLC）. In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen. Methods： ER （20, 50 mg·kg-1·d-1） or SU （5, 10, 20 mg·kg-1·d-1） alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen. Results： The in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index （φ） of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER （≤5 mg.kg-1.d-1） and adjusting the dose of SU might yield a better dosage regimen for clinical research. Conclusion： The experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.

Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy. SerpinA3N is mainly associated with the acute phase response and inflammatory response. In our current study, transcriptomics analysis, proteomics analysis, and Western blotting showed that the expression level of Serpin clade A member 3N (SerpinA3N) is significantly increased in the hippocampus of mice with kainic acid (KA)-induced temporal lobe epilepsy, and this molecule is mainly expressed in astrocytes. Notably, in vivo studies using gain- and loss-of-function approaches revealed that SerpinA3N in astrocytes promoted the release of proinflammatory factors and aggravated seizures. Mechanistically, RNA sequencing and Western blotting showed that SerpinA3N promoted KA-induced neuroinflammation by activating the NF-?B signaling pathway. In addition, co-immunoprecipitation revealed that SerpinA3N interacts with ryanodine receptor type 2 (RYR2) and promotes RYR2 phosphorylation. Overall, our study reveals a novel SerpinA3N-mediated mechanism in seizure-induced neuroinflammation and provides a new target for developing neuroinflammation-based strategies to reduce seizure-induced brain injury. Keywords: Astrocytes, SerpinA3N, Neuroinflammation, Epileptic seizures, Temporal lobe epilepsy, Multi-omics analysis