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Qiu Chen,1 Ji-Lei Zhang,1 Jie-Shun Yang,2 Qing Jin,1 Jun Yang,3 Qiang Xue,1 Xue-feng Guang1 1Department of Cardiology, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, People’s Republic of China; 2Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 3Key Laboratory of Cardiovascular Disease of Yunnan Province, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, People’s Republic of ChinaCorrespondence: Qiang Xue; Xue-feng Guang, Department of Cardiology, Yan’ an Hospital Affiliated to Kunming Medical University, No. 245 Renmin Dong Road, Kunming, Yunnan Province, 650051, People’s Republic of China, Email xueqiang3513@126.com; gxfyayy@163.comPurpose: Necroptosis, a monitored form of inflammatory cell death, contributes to coronary heart disease (CHD) progression. This study examined the potential of using necroptosis genes as diagnostic markers for CHD and sought to elucidate the underlying roles.Methods: Through bioinformatic analysis of GSE20680 and GSE20681, we first identified the differentially expressed genes (DEGs) related to necroptosis in CHD. Hub genes were identified using least absolute shrinkage and selection operator (LASSO) regression and random forest analysis after studying immune infiltration and transcription factor-miRNA interaction networks according to the DEGs. Quantitative polymerase chain reaction and immunohistochemistry were used to further investigate hub gene expression in vivo, for which a diagnostic model was constructed and the predictive efficacy was validated. Finally, the CHD group was categorized into high- and low-score groups in accordance with the single-sample gene set enrichment analysis (ssGSEA) score of the necroptosis genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, GSEA, and further immune infiltration analyses were performed on the two groups to explore the possible roles of hub genes.Results: Based on the results of the LASSO regression and random forest analyses, four genes were used to construct a diagnostic model to establish a nomogram. Additionally, an extensive analysis of all seventeen necroptosis genes revealed notable distinctions in expression between high-risk and low-risk groups. Evaluation of immune infiltration revealed that neutrophils, monocytes, B cells, and activated dendritic cells were highly distributed in the peripheral blood of patients with CHD. Specifically, the high CHD score group exhibited greater neutrophil and monocyte infiltration. Conversely, the high-score group showed lower infiltration of M0 and M2 macrophages, CD8+ T, plasma, and resting mast cells.Conclusion: TLR3, MLKL, HMGB1, and NDRG2 may be prospective biomarkers for CHD diagnosis. These findings offer plausible explanations for the role of necroptosis in CHD progression through immune infiltration and inflammatory response.Keywords: atherosclerosis, cell death, inflammations, diagnostic biomarkers, necroptosis, immune infiltration

Dongqing Yu,1 Jie Huang,1 Jiewen Zhi,2 Qidi Xue1 1Faculty of Education, Northeast Normal University, Changchun, People’s Republic of China; 2School of Foreign Languages, Northeast Normal University, Changchun, People’s Republic of ChinaCorrespondence: Jie Huang, Faculty of Education, Northeast Normal University, Changchun, Jilin, 130024, People’s Republic of China, Tel +86 15536855162, Email huangjie2318@126.comPurpose: The issue of excessive mobile phone use among mothers currently is growing increasingly significant due to the rapid growth of smartphones and other technological items. Given that women are the primary caregivers for preschool-aged children, it is imperative to thoroughly investigate the detrimental impacts of mothers’ problematic mobile phone use on the hyperactive behaviors of their children, as well as the underlying mechanisms.Methods: In this study, 924 Chinese mothers and their children are surveyed. The study looks into the moderating effects of parenting support in this context as well as the chain mediating roles of mothers’ parent-child interaction disorder and work-family conflict in the effects of mothers’ problematic cell phone use on preschoolers’ hyperactive behaviors. Analysis is conducted on the moderating impact of parental support in this as well.Results: The results find that boys have significantly higher levels of hyperactive behavior than girls; maternal problematic cell phone use significantly positively predicts preschoolers’ hyperactive behavior; maternal problematic cell phone use could indirectly affect preschoolers’ hyperactive behavior through the chain-mediated effects of work-family conflict and parent-child interaction disorder, and parenting support moderates the predictive effects of parent-child interaction disorder on preschoolers’ hyperactive behavior.Conclusion: This study reveals potential ways in which mothers’ problematic mobile phone use affects preschoolers’ hyperactivity behaviors in the Chinese context. The findings provide a multidimensional (protective and risk factors) indication of how to reduce the impact of mothers’ problematic mobile phone use on preschoolers’ levels of hyperactivity behaviors, which would contribute to improving children’s mental health. However, this is a cross-sectional study and other factors may also play an important role in this pathway.Keywords: problematic mobile phone use, work-family conflict, parent-child interaction disorder, hyperactive behavior, parenting support

Fangzhou Hu,1,* Yunfei Zhu,1,* Jingluan Tian,1 Hua Xu,1,2 Qun Xue1 1Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215000, People’s Republic of China; 2Department of Neurology, Affiliated Jintan Hospital of Jiangsu University, Changzhou Jintan First People’s Hospital, Changzhou, Jiangsu, 215006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qun Xue, Email qxue_sz@163.comBackground: Multiple sclerosis (MS) causes chronic inflammation and demyelination of the central nervous system and comprises a class of neurodegenerative diseases in which interactions between multiple immune cell types mediate the involvement of MS development. However, the early diagnosis and treatment of MS remain challenging.Methods: Gene expression profiles of MS patients were obtained from the Gene Expression Omnibus (GEO) database. Single-cell and intercellular communication analyses were performed to identify candidate gene sets. Predictive models were constructed using LASSO regression. Relationships between genes and immune cells were analyzed by single sample gene set enrichment analysis (ssGSEA). The molecular mechanisms of key genes were explored using gene enrichment analysis. An miRNA network was constructed to search for target miRNAs related to key genes, and related transcription factors were searched by transcriptional regulation analysis. We utilized the GeneCard database to detect the correlations between disease-regulated genes and key genes. We verified the mRNA expression of 4 key genes by reverse transcription-quantitative PCR (RT‒qPCR).Results: Monocyte marker genes were selected as candidate gene sets. CD3D, IL2RG, MS4A6A, and NCF2 were found to be the key genes by LASSO regression. We constructed a prediction model with AUC values of 0.7569 and 0.719. The key genes were closely related to immune factors and immune cells. We explored the signaling pathways and molecular mechanisms involving the key genes by gene enrichment analysis. We obtained and visualized the miRNAs associated with the key genes using the miRcode database. We also predicted the transcription factors involved. We used validated key genes in MS patients, several of which were confirmed by RT‒qPCR.Conclusion: The prediction model constructed with the CD3D, IL2RG, MS4A6A, and NCF2 genes has good diagnostic efficacy and provides new ideas for the diagnosis and treatment of MS.Keywords: multiple sclerosis, biomarker, peripheral blood, prediction model

Qian-Qian Nie,1,* Zong-Qing Zheng,2,* Juan Liao,1 Yu-Chao Li,3 Yan-Ting Chen,1 Tian-Ye Wang,1 Gui-Qiang Yuan,4 Zhong Wang,2 Qun Xue1 1Department of Neurology & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 3Department of Nuclear Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, People’s Republic of China; 4Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Changshu Second People’s Hospital, Suzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qun Xue; Zhong Wang, Department of Neurology & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Ganjiang Road, Suzhou, 215021, People’s Republic of China, Email XueQun2578@163.com; wangzhong_8761@163.comBackground: Ischemic injury in stroke is followed by extensive neurovascular inflammation and changes in ischemic penumbra gene expression patterns. However, the key molecules involved in the inflammatory response during the acute phase of ischemic stroke remain unclear.Methods: Gene expression profiles of two rat ischemic stroke-related data sets, GSE61616 and GSE97537, were downloaded from the GEO database for Gene Set Enrichment Analysis (GSEA). Then, GEO2R was used to screen differentially expressed genes (DEGs). Furthermore, 170 differentially expressed intersection genes were screened and analyzed for Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Candidate genes and miRNAs were obtained by DAVID, Metascape, Cytoscape, STRING, and TargetScan. Finally, the rat middle cerebral artery occlusion-reperfusion (MCAO/R) model was constructed, and qRT-PCR was used to verify the predicted potential miRNA molecule and its target genes.Results: GO and KEGG analyses showed that 170 genes were highly associated with inflammatory cell activation and cytokine production. After cluster analysis, seven hub genes highly correlated with post-stroke neuroinflammation were obtained: Cxcl1, Kng1, Il6, AnxA1, TIMP1, SPP1, and Ccl6. The results of TargetScan further suggested that miR-340-5p may negatively regulate SPP1, AnxA1, and TIMP1 simultaneously. In the ischemic penumbra of rats 24 h after MCAO/R, the level of miR-340-5p significantly decreased compared with the control group, while the concentration of SPP1, AnxA1, and TIMP1 increased. Time-course studies demonstrated that the mRNA expression levels of SPP1, AnxA1, and TIMP1 fluctuated dramatically throughout the acute phase of cerebral ischemia-reperfusion (I/R).Conclusion: Our study suggests that differentially expressed genes SPP1, TIMP1, and ANXA1 may play a vital role in the inflammatory response during the acute phase of cerebral ischemia-reperfusion injury. These genes may be negatively regulated by miR-340-5p. Our results may provide new insights into the complex pathophysiological mechanisms of secondary inflammation after stroke.Keywords: SPP1, AnxA1, TIMP1, miR-340-5p, ischemic stroke, acute phase

Gujie Wu,1,* Zhenyu Zhu,1,* Zheng Yang,2,* Min He,1 Kuan Ren,1 Yipeng Dong,1 Qun Xue3 1Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China; 2Department of Respiratory medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China; 3Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qun Xue, Email ntfyxuequn@163.comBackground: Lung squamous cell carcinoma (LUSC) is a malignant tumour of the lung epithelium. A hypoxic environment can promote tumour cell proliferation and invasion. Therefore, this study aims to explore hypoxia-related genes and construct reliable models to predict the prognosis, cellular processes, immune microenvironment and target compounds of lung squamous carcinoma.Methods: The transcriptome data and matched clinical information of LUSC were retrieved from The Cancer Genome Atlas (TCGA) database. The GSVA algorithm calculated each LUSC patient’s hypoxia score, and all LUSC patients were divided into the high hypoxia score group and low hypoxia score group. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were performed to screen out differentially expressed hypoxia-related genes (DE-HRGs) in LUSC microenvironment, and the underlying regulatory mechanism of DE-HRGs in LUSC was explored through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Hereafter, we established a prognosis-related genetic signature for DE-HRGs using univariate and multivariate Cox regression analyses. The relationship between gene signature and immune cells was further evaluated. Finally, the Comparative Toxicogenomics Database (CTD) was utilized to predict the targeted drugs for the prognostic genes.Results: We obtained 376 DE-HRGs. Functional enrichment analysis indicated that the DE-HRGs were involved in the cell cycle-related regulatory processes. Next, we developed and validated 3 HRGs-based prognostic signature for LUSC, including HELLS, GPRIN1, and FAM83A. Risk score is an independent prognostic factor for LUSC. Functional enrichment analysis and immune landscape analysis suggested that the risk scoring system might be involved in altering the immune microenvironment of LUSC patients to influence patient outcomes. Ultimately, a total of 92 potential compounds were predicted for the three prognostic genes.Conclusion: In summary, we developed and validated a hypoxia-related model for LUSC, reflecting the cellular processes and immune microenvironment characteristics and predicting the prognostic outcomes and targeted compounds.Keywords: lung squamous cell carcinoma, hypoxia, prognosis, immune, targeted compounds

Gujie Wu,1,* Min He,1,* Kuan Ren,1,* Huiyun Ma,1 Qun Xue2 1Medical School of Nantong University, Nantong, People’s Republic of China; 2Cardiothoracic Surgery Department, Affiliated Hospital of Nantong University, Nantong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qun Xue, Email ntfyxuequn@163.comBackground: Inducible co-stimulator (ICOS) is a cell-enhanced co-stimulatory receptor that has shown great potential in the regulation of innate and adaptive immunity. However, the role of ICOS in lung adenocarcinoma (LUAD) remains unclear.Methods: We used data from the Cancer Genome Atlas(TCGA) database to identify the expression and prognostic role of ICOS in LUAD. The results were validated using Gene Expression Omnibus(GEO) and Kaplan-Meier plotter databases. A model with predictive performance for overall survival of LUAD patients was constructed using fitted ICOS expression and other clinical parameters. We explored the biological function of ICOS. Subsequently, we further analysed and validated the effect of ICOS expression on tumour immune microenvironment (TIME) and survival. Finally, the CellMiner database was used to determine the relationship between ICOS expression and drug sensitivity.Results: ICOS expression is significantly associated with poor prognosis in multiple cancers, especially LUAD, and is a good predictor of overall survival in LUAD patients. The biological function is to promote autoimmunity and inhibit cell proliferation. ICOS-related survival prediction model developed to more accurately predict 1-, 3- and 5-year survival probabilities for LUAD patients. In addition, we can use the expression of ICOS to effectively assess patient malignancy, prognosis, TIME status and clinical combination of drugs.Conclusion: Our results suggest that ICOS is correlated with prognosis and immune infiltrating levels in LUAD. Higher ICOS expression predicts better TIME. This study provides a novel strategy for the development of immunotherapeutic and prognostic markers in LUAD.Keywords: ICOS, lung adenocarcinoma, prognosis, immune infiltration, drug sensitivity

Qing Xue,1 Jinxin Yang,2 Huatian Wang,3 Deyu Zhang4 1Shandong Youth University of Political Science, Jinan, People’s Republic of China; 2University of Jinan, Jinan, People’s Republic of China; 3Industrial Engineering and Innovation Science, Eindhoven University of Technology, Eindhoven, the Netherlands; 4College of Foreign Languages, Ocean University of China, Qingdao, People’s Republic of ChinaCorrespondence: Huatian Wang, Eindhoven University of Technology, De Zaale, Eindhoven, 5600 MB, the Netherlands, Tel +31 040 247 9111, Email h.wang4@tue.nlPurpose: College students’ well-being is important for their self-growth and the whole society. However, we still know relatively little about how college students could proactively, strategically improve their well-being in the leisure context. Following the self-determination theory and proactivity literature, this study examines how and when leisure crafting (ie, a proactive act whereby individuals balance their leisure resources and demands by utilizing their personal abilities and needs) can enhance college students’ well-being.Methods: Conducting a quantitative weekly diary study of 80 Chinese students in an engineering college (320 observations), we drew a moderated mediation model.Results: We found that weekly leisure crafting behaviors (ie, seeking structural leisure resources, seeking social leisure resources, seeking leisure challenges, and reducing hindering leisure demands) were positively related to weekly intrinsic need satisfaction (ie, need for competence, autonomy, and relatedness), then resulting in higher weekly subjective well-being (ie, physical thriving, mental health, and life meaningfulness). Moreover, this indirect effect was stronger for those who had a higher level of leisure boredom.Conclusion: Our study contributes to student development and well-being literature by focusing on the students’ leisure context and providing a means to enhance their well-being. We unfold how the leisure crafting strategy boosts college students’ well-being via increasing their intrinsic need satisfaction. We also highlight the compensating role of leisure crafting when one is in an unfavorable personal state (eg, leisure boredom).Keywords: leisure crafting, intrinsic need satisfaction, leisure boredom, college student, well-being, diary study

Gu Jie Wu,1,2,* Kuan Ren,1,2,* Min He,1,2 Jian Xun Xu,1,2 Zhen Qing Li,1,2 Ding Bo,1,2 Qun Xue3 1Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People’s Republic of China; 2Medical College of Nantong University, Nantong, 226001, Jiangsu, People’s Republic of China; 3Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qun XueDepartment of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, People’s Republic of ChinaEmail ntfyxuequn@163.comBackground: Sorting nexin-20 (SNX20) is a member of the sorting nexin family of proteins. It plays a crucial role in the regulation of innate immunity. However, the prognostic risk, potential mechanisms, immunotherapy, and other functions of SNX20 in lung adenocarcinoma (LUAD) remain unclear.Methods: We analyzed and validated the expression and prognostic role of SNX20 in LUAD through a combination of The Cancer Genome Atlas, Gene Expression Omnibus, Oncomine, TIMER, and Human Protein Atlas databases. Further, we analyzed the correlation between SNX20 expression and clinical characteristics of LUAD, and the prognostic value of SNX20 in LUAD was evaluated. Using fitted SNX20 expression and other clinical parameters, a predictive model with predictive performance for the overall survival of patients with LUAD was constructed. The potential biological function of SNX20 in LUAD was explored using gene set enrichment analysis. In addition, we analyzed the correlation between SNX20 expression and the immune microenvironment and survival.Results: SNX20 was downregulated in most cancer types, was associated with poor prognosis in LUAD and could be an independent prognostic factor for patients with LUAD. The predictive model developed by us had good predictive power for determining the overall survival of patients with LUAD. Biofunctional analysis revealed that genes co-expressed with SNX20 mainly promoted the immune process and inhibited the cell proliferation process in LUAD. We observed that high expression of SNX20 was accompanied by a better immune microenvironment and survival in patients with LUAD. Furthermore, the LUAD immune response was elevated with an increase in SNX20 expression. Finally, we found that SNX20 expression was significantly associated with various tumor-infiltrating immune cells, and it was widely involved in regulating various immune molecules in LUAD and affecting immune infiltration in the tumor microenvironment.Conclusion: Our results suggested that SNX20 is a potential immune-related biomarker and therapeutic target associated with the prognosis of patients with LUAD. This provided a new strategy for the development of immunotherapeutic and prognostic markers in LUAD.Keywords: SNX20, biomarkers, lung adenocarcinoma, prognosis, immune infiltration

Yao Tong,* Chengrong Bao,* Yi-Qiong Xu,* Lei Tao,* Yao Zhou, Lei Zhuang, Ying Meng, Hui Zhang, Jingjing Xue, Weijun Wang, Lele Zhang, Qingbo Pan, Zhenzhen Shao, Tianran Hu, Qian Guo, Qingsheng Xue, Han Lu, Yan Luo Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Luo; Han Lu Email ly11087@rjh.com.cn; luhan0301@163.comBackground: Acute lung injury (ALI) is a severe respiratory disease with high rates of morbidity and mortality. Many mediators regarding endogenous or exogenous are involved in the pathophysiology of ALI. Here, we have uncovered the involvement of integrins and matrix metalloproteinases, as critical determinants of excessive inflammation and endothelial permeability, in the regulation of ALI.Methods: Inflammatory cytokines were measured by quantitative real-time PCR for mRNA levels and ELISA for secretion levels. Endothelial permeability assay was detected by the passage of rhodamine B isothiocyanate-dextran. Mice lung permeability was assayed by Evans blue albumin (EBA). Western blot was used for protein level measurements. The intracellular reactive oxygen species (ROS) were evaluated using a cell-permeable probe, DCFH-DA. Intratracheal injection of lipopolysaccharide (LPS) into mice was conducted to establish the lung injury model.Results: Exogenous MMP-9 significantly aggravated the inflammatory response and permeability in mouse pulmonary microvascular endothelial cells (PMVECs) treated by LPS, whereas knockdown of MMP-9 exhibited the opposite phenotypes. Knockdown of integrin β 3 or β 5 in LPS-treated PMVECs significantly downregulated MMP-9 expression and decreased inflammatory response and permeability in the presence or absence of exogenous MMP-9. Additionally, the interaction of MMP-9 and integrin β 5 was impaired by a ROS scavenger, which further decreased the pro-inflammatory cytokines production and endothelial leakage in PMVECs subjected to co-treatment (LPS with exogenous MMP-9). In vivo studies, exogenous MMP-9 treatment or knockdown β 3 integrin significantly decreased survival in ALI mice. Notably, knockdown of β 5 integrin alone had no remarkable effect on survival, but which combined with anti-MMP-9 treatment significantly improved the survival by ameliorating excessive lung inflammation and permeability in ALI mice.Conclusion: These findings support the β 3/5 integrin-MMP-9 axis as an endogenous signal that could play a pivotal role in regulating inflammatory response and alveolar-capillary permeability in ALI.Keywords: acute lung injury, endothelial cells, integrin, MMP-9

Aixia Song,1 Yuying Yang,2 Hongmei He,1 Jian Sun,1 Qing Chang,1 Qian Xue1 1Department of Neurology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, 075000, People’s Republic of China; 2Stroke Office, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, 075000, People’s Republic of ChinaCorrespondence: Qian XueDepartment of Neurology, The First Affiliated Hospital of Hebei North University, No. 12 Changqing Road, Qiaoxi District, Zhangjiakou, Hebei, 075000, People’s Republic of ChinaEmail qianyanxin7@163.comBackground: Neuroinflammation and neuronal apoptosis are considered as the critical factors in the pathogenesis of multiple neurological diseases. Recent studies have shown that long non-coding RNA (lncRNA) plays a crucial part in neuroinflammation and neuronal apoptosis.Methods: The expression levels of lncRNA KCNQ1OT1, miR-30e-3p and NLRP3 in lipopolysaccharide (LPS)-induced HMC3 cells were analyzed using RT-qPCR. MTT assay, LDH release assay and ELISA were used to assess the effect of KCNQ1OT1 and miR-30e-3p on neuroinflammation and neuronal apoptosis. The targeted regulatory relationships among KCNQ1OT1, miR-30e-3p and NLRP3 were evaluated by bioinformatics analysis, dual-luciferase reporter gene assay, RT-qPCR and Western blot.Results: In LPS-induced HMC3 cells, the expression levels of KCNQ1OT1 and NLRP3 were increased, while the expression level of miR-30e-3p was reduced. Knockdown of KCNQ1OT1 alleviated LPS-induced apoptosis and neuroinflammation of HMC3 cells, accompanied by increased cell viability, low LDH release and reduced cell apoptosis rate, and reduced levels of TNF-α, IL-1β and IL-6. Overexpression of miR-30e-3p had a similar effect. Additionally, KCNQ1OT1 could bind with miR-30e-3p and repress its expression in HMC3 cells, and KCNQ1OT1 overexpression counteracted miR-30e-3p’s inhibitory effect on LPS-induced neuronal damage and inflammatory response in HMC3 cells. Furthermore, KCNQ1OT1 could positively regulate the expression of NLRP3 via repressing miR-30e-3p.Conclusion: Inhibition of KCNQ1OT1 could reduce neuroinflammation and neuronal apoptosis induced by LPS in HMC3 cells by regulating miR-30e-3p/NLRP3 pathway, suggesting that KCNQ1OT1 and miR-30e-3p could serve as promising therapeutic targets for treating neurological diseases.Keywords: NLRP3, KCNQ1OT1, miR-30e-3p, neuroinflammation

Ling-Zhi Hong,1,* Qi Xue,2,* Hong Shao2 1Emergency Department, Chun’an First People’s Hospital (Zhejiang Provincial People’s Hospital Chun’an Branch), Hangzhou, 311700, Zhejiang Province, People’s Republic of China; 2Department of Cardiology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong ShaoDepartment of Cardiology, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), No. 158 Shangtang Road, Hangzhou, 310014, Zhejiang Province, People’s Republic of ChinaTel/Fax +86-571-85894283Email shaohong@hmc.edu.cnAbstract: Several lines of evidence have linked a dysregulated inflammatory setting to the pathogenesis of atherosclerosis, which is a form of chronic vascular inflammation. Various inflammatory biomarkers have been associated with inflammation and are recognized as potential tools to monitor the progression of atherosclerosis. A well-studied inflammatory marker in the context of cardiovascular diseases is C-reactive protein (CRP) or, more accurately, highly sensitive-CRP (hs-CRP), which has been established as an inflammatory biomarker for atherosclerotic events. In addition, a growing body of investigations has attempted to disclose the potential of inflammatory cytokines, enzymes, and genetic polymorphisms related to innate and adaptive immunity as biomarkers for predicting the development of atherosclerosis. In this review article, we clarify both traditional and novel inflammatory biomarkers related to components of the innate and adaptive immune system that may mirror the progression or phases of atherosclerotic inflammation/lesions. Furthermore, the contribution of the inflammatory biomarkers in developing potential therapeutics against atherosclerotic treatment will be discussed.Keywords: atherosclerosis, inflammation, immune response, biomarker, hs-CRP

Ming Zhang,1– 3 Wei Han,3,4 Yuhao Xu,3,4 Dapeng Li,3 Qun Xue1 1Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People’s Republic of China; 2Department of Geriatric Psychiatry, Changzhou Dean Hospital, Changzhou, Jiangsu 213000, People’s Republic of China; 3Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, People’s Republic of China; 4Department of Neurology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, People’s Republic of ChinaCorrespondence: Qun XueDepartment of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People’s Republic of ChinaTel + 86- 13013813620Email qxue_sz@163.comBackground: Although numerous microRNAs (miRNAs) have been discovered to participate in the progression of Alzheimer’s disease (AD), they are still difficult to apply in clinical work. Thus, the identification of novel miRNAs and clarification of their clinical significance are importing for improving the diagnosis and treatment of AD. The purpose of this study was to analyze the expression of miR-128 and its diagnostic value in patients with AD.Patients and Methods: In this study, 117 AD patients and 106 controls were enrolled, and the demographic data, biochemical parameters and serum miR-128 levels were collected. These data were then used to build a logistic regression model, and receiver operating characteristic (ROC) curves were drawn to evaluate the diagnostic value of miR-128. The relationships between miR-128 and inflammatory factors (IL-1β/TNF-α) were also analyzed from clinical serum data.Results: Our study found that miR-128 was significantly upregulated in the serum samples of AD patients compared with controls, and that this upregulation was negatively correlated with Mini-Mental State Examination (MMSE) scores (r = − 0.687, P< 0.01). ROC curve showed that the area under the curve of miR-128 was 0.831. Logistic regression analyses showed that glycosylated hemoglobin (HbA1c) levels, low-density lipoprotein (LDL) levels, MMSE scores and serum miR-128 levels were statistically significant (P< 0.01), and the ROC curve of the combined detection of these variables was 0.906. The serum miR-128 levels in AD patients were positively correlated with the serum IL-1β (r=0.798, P< 0.01) and serum TNF-α levels (r=0.733, P< 0.01).Conclusion: Serum miR-128 is a candidate diagnostic biomarker in AD patients who achieved good diagnostic performance when used alone or in combination with other factors and may have the potential to be a novel therapeutic target for neuroinflammation.Keywords: Alzheimer’s disease, miR-128, logistic regression, ROC curve

Qingpeng Zeng,1 Bingzhi Wang,2 Jiagen Li,1 Jun Zhao,1 Yousheng Mao,1 Yushun Gao,1 Qi Xue,1 Shugeng Gao,1 Nan Sun,1 Jie He1 1Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Jie HeDepartment of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Beijing 100021, People’s Republic of ChinaEmail prof.jiehe@gmail.comObjective: Spread through air spaces (STAS) has been reported to be an invasive histological pattern with poor prognosis in lung cancer; however, little is known about its intrinsic risk factors. This work analyzed the correlation between pathological and radiological features and STAS in resected lung adenocarcinomas.Patients and Methods: We retrospectively reviewed 1821 consecutive surgically treated patients with histologically diagnosed lung adenocarcinoma (174 positive for STAS and 1647 negative for STAS) from December 2017 to November 2018 at our institution. Propensity score matching identified 170 well-balanced pairs of patients. The correlations between pathological and radiological features and the presence of STAS were analyzed.Results: Before propensity matching, the incidence rate of STAS was 9.6% in all patients. In matched cohorts, multivariate analysis showed that the presence of STAS was significantly correlated with pure solid nodules (SNs) (p = 0.001) and solid/micropapillary patterns (SMPs) (p = 0.002). The odds ratio for STAS in SN-positive and SMP-positive adenocarcinoma against that in SN-negative and SMP-negative adenocarcinoma was 10.922 (95% confidence interval, 5.826– 20.475; p < 0.001). Tumor differentiation, visceral pleural invasion (VPI), lymphovascular invasion (LVI), invasive adenocarcinoma, and non-lepidic subtype were significantly associated with STAS in the univariate analysis (p < 0.05); however, the differences failed to reach a significant level in the multivariate analysis.Conclusion: We found that STAS was significantly correlated with several invasive clinicopathological patterns. The presence of SNs and SMPs were revealed as independent predictors for STAS, which could offer clinicians clues to identify STAS-positive adenocarcinoma.Keywords: lung adenocarcinoma, spread through air spaces, solid pulmonary nodule

In this study, the adsorption performance of rice wine lees on reactive brilliant red (X-3B) was studied. Five aspects of SEM, FTIR characterization of rice wine lees, initial X-3B pH, rice wine lees dosage and initial dye concentration were studied. The characterization of rice wine lees indicated that it was a good adsorbent due to its larger specific surface area. And the experiment results showed that pH had a great influence on the adsorption effect of rice wine lees, and the adsorption performance decreased with the increase of pH. At the same time, the removal rate of reactive brilliant red X-3B increased with the increase of the dosage of rice wine lees and decreased with the increase of initial concentration of dyes. In the meanwhile, the experimental data were fitted to find that the adsorption of Reactive Brilliant Red X-3B by rice wine lees followed the Langmuir isotherm model. The adsorption kinetics was consistent with the intraparticle diffusion model and the maximum adsorption capacity was 12.376 mg/g.

Yan Yu,1,* Lili Zhao,1,* Yu Xie,1 Yu Xu,1 Weike Jiao,2 Jianhui Wu,2 Xinyu Deng,2 Guiju Fang,2 Qing Xue,2 Yali Zheng,1,3 Zhancheng Gao1,3 1Department of Respiratory and Critical Care Medicine, Peking University People’s Hospital, Beijing 100044, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Ningde Municipal Hospital Affiliated to Fujian Medical University, Ningde, Fujian 352100, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Xiang’An Hospital of Xiamen University, Xiamen, Fujian 361100, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhancheng Gao; Yali Zheng Tel +86 18810900430; Tel +86 15011451515Email zcgao@bjmu.edu.cn; yali_zheng@126.comBackground: T helper (Th) cell cytokine imbalances have been associated with the pathophysiology of chronic obstructive pulmonary disease (COPD), including the Th1/Th2 and Th17/T regulatory cells (Treg) paradigms. Clarifying cytokine profiles during COPD acute exacerbation (AE) and their relationships with clinical manifestations would help in understanding the pathogenesis of disease and improve clinical management.Materials and Methods: Eighty seven patients admitted to the hospital with AEs of COPD were included in this study, and follow-up was conducted after discharge (every 30 days, for a total of 120 days). Sputum samples of patients at different time points (including at admission, discharge, and follow-up) were collected, and sputum cytokine profiling (12 cytokines in total) was performed using a Luminex assay.Results: According to the cytokine profiles at admission, patients were divided into three clusters by a k-means clustering algorithm, namely, Th1high Th17high (n=26), Th1lowTh17low (n=56), and Th1high Th17low (n=5), which revealed distinct clinical characteristics. Patients with Th1high Th17low profile had a significantly longer length of non-invasive ventilation time and length of hospital stay than patients with Th1high Th17high profile (7 vs 0 days, 22 vs 11 days, respectively, p < 0.05), and had the highest AE frequency. Sputum levels of Th17 cytokines (IL-17A, IL-22, and IL-23) during AE were negatively correlated with AE frequency in the last 12 months (r = − 0.258, − 0.289 and − 0.216, respectively, p < 0.05). Moreover, decreased sputum IL-17A levels were independently associated with increased AE frequency, with an OR (95% CI) of 0.975 (0.958– 0.993) and p = 0.006.Conclusion: Th1/Th17 imbalance during AE is associated with the severity of COPD. Decreased Th17 cytokine expression is correlated with increased AE frequency. The Th1/Th17 balance may be a specific target for the therapeutic manipulation of COPD.Keywords: chronic obstructive pulmonary disease, acute exacerbation, Th1 cytokines, Th17 cytokines, therapeutic

Abstract Objective Ligation-Mediated Amplification (LMA) is a versatile biochemical tool for amplifying selected DNA sequences. LMA has increased in popularity due to its integration within chromosome conformation capture (5C) and chromatin immunoprecipitation (2C-ChIP) methodologies. The output of either 5C or 2C-ChIP protocols is a single-read sequencing library of ligated primer pairs that may or may not be multiplexed. While many computational tools currently exist for read mapping and analysis, these tools neither fully support multiplexed libraries nor provide qualitative reporting on the LMA primers involved. Typically, the task of library demultiplexing or primer analysis is offloaded on to the user. Our aim was to develop an easy-to-use pipeline for processing (multiplexed) single-read sequencing data produced by sequence-specific LMA. Results Here, we describe the Ligation-mediated Amplified, Multiplexed Primer-pair Sequence (LAMPS) analysis pipeline. LAMPS facilitates the analysis of multiplexed LMA sequencing data and provides a thorough assessment of a library’s reads for a variety of experimental parameters (e.g., primer-pair efficiency). The standardized output of LAMPS allows for easy integration with downstream analyses, such as data track visualization on a genome browser. LAMPS is made publicly available on GitHub: https://github.com/BlanchetteLab/LAMPS

Yong Liu,1 Yan-Ping Zhu,2 Ming-Zhi Cai,1 Bin Ke,1 Bin Li,1 Ning Liu,1 Qiang Xue,1 Hong-Jie Zhan,1 Jing-Yu Deng,1 Li Zhang,1 Yan-Peng Hao,2 Zhi-Qiang Wang,2 Li Wang,2 Han Liang1 1Department of Gastroenterology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, People’s Republic of China; 2Nanjing Personal Oncology Biological Technology Co. Ltd., Nanjing 211100, Jiangsu, People’s Republic of ChinaCorrespondence: Han LiangDepartment of Gastroenterology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Huan-Hu-Xi Road, Ti-Yuan-Bei, He Xi District, Tianjin 300060, People’s Republic of ChinaTel +86 22 2334 0123-1061Fax +86 22 2334 0123Email liangh95247@163.comObjective: The current study aims to explore the establishment of the patient-derived tumor xenograft (PDTX) model.Materials and Methods: Twenty patients with gastric cancer, 10 males and 10 females, were enrolled in the current study. Firstly, the volume, invasion and metastasis of the xenografts were observed. Subsequently, the correlation between tumor tissues of the PDTX mouse model and the patients’ primary tumor tissues was evaluated by pathological H&E staining and immunohistochemistry.Results: The results showed that the PDTX models corresponding to 15 of the 20 patients were successfully established, and the success rate of PDTX model establishment was 75%. Furthermore, the PDTX models maintained the differentiation degree, morphological characteristics and structural characteristics of tumor cells.Conclusion: A PDTX model can be used as a substitute for cancer patients in clinical practice and may be suitable for clinical pharmacodynamic screening and new drug development.Keywords: gastric tumor, PDTX, xenotransplantation model

Fan Gao,1 Hua Qiang,2 Xiao-Juan Fan,2 Qi Xue,3 Ling Bai21Clinical Research Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 3Institut des Sciences de la Terre, Centre National de la Recherche Scientifique, Saint-Martin-d’Hères, FrancePurpose: Previous research findings on the association between serum total bilirubin (TB) and cardiovascular events varied with different study populations. Our objective was to clarify the association between serum TB at admission and long-term adverse outcomes in patients with acute coronary syndrome (ACS) and stable angina (SA) undergoing percutaneous coronary intervention (PCI).Patients and methods: This prospective cohort study included 2,502 patients who underwent PCI. Information on the study population was obtained from the Dryad Digital Repository. The patients were divided into two groups: high (>0.60 mg/dL) and low TB groups (≤0.60 mg/dL) based on the optimal cutoff value achieved in the receiver operating characteristic curve analysis. The relationships between serum TB at admission and clinical outcomes after PCI were analyzed in multivariable logistic regression models and restricted cubic spline.Results: In all patients undergoing PCI, TB>0.60 mg/dL was associated with major adverse cardiovascular events (MACE) and cardiovascular death during a 3-year follow-up. The odds ratio (95% confidence interval) was 1.60 (1.22–2.10) and 1.81 (1.22–2.70) for MACE and cardiovascular death, respectively. The association between TB and MACE was not altered by clinical presentation (p for interaction=0.949).Conclusion: In patients with ACS and SA undergoing PCI, elevated serum TB was associated with increased risk of MACE and cardiovascular death.Keywords: bilirubin, acute coronary syndrome, stable angina, primary percutaneous coronary intervention, major adverse cardiovascular; cerebrovascular events

Qi Xue, Ming-zhao Qin, Jing Jia, Jin-ping Liu, Yun Wang Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China Purpose: Frailty and atherosclerotic diseases are prevalent among the older people and usually present the same pathogenesis and risk factors. Therefore, the aim of this study was to determine the association between frailty and atherosclerosis.Patients and methods: The enrolled participants were 171 patients aged 60–96 years in Beijing Tongren Hospital. Data that were collected included sex, age, height, weight, calculated body mass index (BMI), past medical history, comorbidities (including hypertension, coronary heart disease [CHD], and diabetes), ability to perform activities of daily living (ADL) as measured using the Barthel index, handgrip strength, 15-feet (4.57 m) walking speed, body composition features determined by bioelectrical impedance analysis, the ankle–brachial index (ABI), and atherosclerosis determined by the cardio-ankle vascular index (CAVI). Patients were divided into frail, pre-frail, and non-frail groups using Fried’s frailty index. ANOVA was used to assess the differences among these groups. Linear correlation analysis was used to examine the relationship between the CAVI and frailty phenotype. Ordinal multivariate logistic regression analysis was used to examine the factors affecting frailty and the relationship between frailty and atherosclerosis.Results: The population was categorized as 21.3% frail, 38.4% pre-frail, and 40.3% non-frail. Patients in the frail group were older, had lower handgrip strength, slower walking speed, and a lower ABI and a higher proportion of carotid intima-media thickening with values of at least 1 mm compared with those in the pre-frail and non-frail groups. The CAVI score was higher in the frail group than that in the other two groups. There were significant inverse linear correlations between grip strength, walking speed, and the CAVI. CAVI showed an independent risk factor for frailty (OR: 2.013, 95% CI 1.498–2.703, p

Background: The capsaicin receptor, transient receptor potential vanilloid type -1 (TRPV1) directs complex roles in signal transduction including the detection of noxious stimuli arising from cellular injury and inflammation. Under pathophysiologic conditions, TRPV1 mRNA and receptor protein expression are elevated in dorsal root ganglion (DRG) neurons for weeks to months and is associated with hyperalgesia. Building on our previous isolation of a promoter system for the rat TRPV1 gene, we investigated the proximal TRPV1 P2-promoter by first identifying candidate Sp1-like transcription factors bound in vivo to the P2-promoter using chromatin immunoprecipitation (ChIP) assay. We then performed deletion analysis of GC-box binding sites, and quantified promoter activity under conditions of Sp1 / Sp4 over-expression versus inhibition/knockdown. mRNA encoding Sp1, Sp4 and TRPV1 were quantified by qRT-PCR under conditions of Sp1/Sp4 over-expression or siRNA mediated knockdown in cultured DRG neurons.Results: Using ChIP analysis of DRG tissue, we demonstrated that Sp1 and Sp4 are bound to the candidate GC-box site region within the endogenous TRPV1 P2-promoter. Deletion of GC-box "a" or "a + b" within the P2- promoter resulted in a complete loss of transcriptional activity indicating that GC-box "a" was the critical site for promoter activation. Co-transfection of Sp1 increased P2-promoter activity in cultured DRG neurons whereas mithramycin-a, an inhibitor of Sp1-like function, dose dependently blocked NGF and Sp1-dependent promoter activity in PC12 cells. Co-transfection of siRNA directed against Sp1 or Sp4 decreased promoter activity in DRG neurons and NGF treated PC12 cells. Finally, electroporation of Sp1 or Sp4 cDNA into cultures of DRG neurons directed an increase in Sp1/Sp4 mRNA and importantly an increase in TRPV1 mRNA. Conversely, combined si-RNA directed knockdown of Sp1/Sp4 resulted in a decrease in TRPV1 mRNA.Conclusion: Based on these studies, we now propose a model of TRPV1 expression that is dependent on Sp1-like transcription factors with Sp4 playing a predominant role in activating TRPV1 RNA transcription in DRG neurons. Given that increases of TRPV1 expression have been implicated in a wide range of pathophysiologic states including persistent painful conditions, blockade of Sp1-like transcription factors represents a novel direction in therapeutic strategies. © 2011 Chu et al; licensee BioMed Central Ltd.

Yinbing Zhang,1,2 Haifeng Liu,3 Yingqian Zhang,4 Qiong Wu,1 Yanyan Zhang,1,2 Jie Zhang,1,2 Xiangshan Zhou,3 He Jiao,5 Feng Fan,6 Qi Xue,7 Xin Wang,1,2 Zhihui Zhong1,2 1Laboratory of Nonhuman Primate Disease Modeling Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; 2Sichuan Kangcheng Biomed Co., Ltd., Chengdu, China; 3Angde Biotech Pharmaceutical Co., Ltd., Liaocheng, China; 4Department of Physiology, Southwest Medical University, Luzhou, China; 5Department of Interventional therapy, West China Hospital, Sichuan University, Chengdu, China; 6Department of Neurointervention, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; 7Food and Drug Administration of Shibei District Government, Qingdao, China Purpose: In order to evaluate the thrombolytic effects of reteplase in pulmonary thromboembolism (PTE), we developed a novel canine PTE model. The efficacy of reteplase against PTE in comparison to alteplase was clarified for the first time, and this PTE model could be further applied to studies of novel thrombolytic therapies. Patients and methods: Twenty-four dogs were divided into four groups: sham operation, vehicle, alteplase, and reteplase. Autologous thrombi/saline were injected into the pulmonary artery, and thrombolytic agents were administrated. Thrombus formation and dissolution were monitored by real-time digital subtraction angiography (DSA), and pulmonary pressures were measured simultaneously. Blood coagulation, blood gas, hematology, and histopathologic examinations were used as subsidiary methods. Results: The canine PTE model was established with a significant decrease of blood flow and ~75% blocking area. Administration of reteplase (0.6 mg/kg) resulted in effective thrombus dissolution with a recovery of over 80% blood flow, as effective as alteplase (1.6 mg/kg). Correspondingly, the elevated pulmonary systolic, diastolic, and mean arterial pressures declined to the normal level. Blood coagulation was changed by reteplase, with a dramatic elongation of prothrombin time, activated partial thromboplastin time, and thrombin time, even longer than alteplase. In contrast to the vehicle group, no obvious pathological changes were found in the two thrombolytic groups. Hematological, blood biochemical, and blood gas results also indicated that reteplase had no adverse reactions in this PTE model. Conclusion: Reteplase proved to be an effective and safe therapy for PTE for the first time, and a small dosage of reteplase exerted an efficacy comparable to the routine dosage of alteplase. Our findings indicated the potential of reteplase as clinical treatment against PTE. This technically innovative, stability- and validity-proved canine PTE model developed by minimally invasive surgery and DSA resembled major clinical features. This may further facilitate our understanding of thrombotic disorders and development of prophylactic and therapeutic approaches. Keywords: reteplase, canine pulmonary thromboembolism model, thrombolytic therapy