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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

Minglu Xu,1,2,* Lingli Fang,1,2,* Qin Xue,1,2 Xuyang Zhang,1,2 Yao He1,3 1Department of Orthodontics, Stomatological Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Oral Disease and Biomedical Sciences, Stomatological Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yao He, Department of Orthodontics, Stomatological Hospital of Chongqing Medical University, 426 North of Songshi Avenue, Chongqing, 401147, People’s Republic of China, Email yaohe@hospital.cqmu.edu.cnObjective: Oxidative stress is involved in the mechanisms associated with temporomandibular joint (TMJ) diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial oxidative stress marker, but the specific mechanisms of its regulation in the early stages of mandibular condylar cartilage (MCC) degeneration remain unclear. This study aimed to explore the regulatory role of Nrf2 and its related oxidative stress signaling pathway in the early stage of MCC degeneration.Materials and Methods: Overloading force-induced MCC degeneration was performed in wild-type and Nrf2 knockout mice, as well as in mice after treatment with the Nrf2 activator cardamonin. Changes in MCC degeneration and the expression of oxidative stress markers in the corresponding situations were observed.Results: Nrf2 and NADPH oxidase 2 (NOX2) expression were elevated during early MCC degeneration induced by an overloading force. MCC degeneration was aggravated when Nrf2 was knocked out, accompanied by increased NOX2 and superoxide dismutase 2 (SOD2) expression. The MCC degeneration process was alleviated after cardamonin treatment, with activation of the Nrf2 pathway and decreased NOX2 and SOD2 expression.Conclusion: Early MCC degeneration is accompanied by mild oxidative stress progression. Activated Nrf2 and related pathways could alleviate the degeneration of MCC.Keywords: NF-E2-related factor 2, oxidative stress, temporomandibular joint, cartilage, mechanical force

Qiao Xue,1 Jie Ji,2 Wen-Ge Fan,1 Jian-Peng Pan,3 Mei Wei,1 Hao Ding,1 Jun Zhao1 1Department of Dermatology, Changshu No. 1 People’s Hospital, Changshu Hospital Affiliated to Soochow University, Changshu, Jiangsu Province, 215500, People’s Republic of China; 2Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, 210000, People’s Republic of China; 3Department of Hand Surgery, Changshu No. 2 People’s Hospital, Changshu Hospital Affiliated to Yangzhou University, Changshu, Jiangsu Province, 215500, People’s Republic of ChinaCorrespondence: Jun Zhao, Department of Dermatology, Changshu Hospital Affiliated to Soochow University, Changshu No. 1 People’s Hospital, No. 1 Shuyuan Street, Yushan Town, Changshu, Jiangsu Province, 215500, People’s Republic of China, Tel +86-15051774136, Email zhaojunzhjzzzj@126.comObjective: To understand the situation and risk factors of skin lesions following the eruption of shingles.Methods: We selected 275 patients with shingles who had been diagnosed and treated in the Dermatology Department of Changshu No. 1 People’s Hospital between July 2017 and March 2022. Age, gender, skin lesion site, skin lesion type, prodromal pain, history of diabetes, history of hypertension, history of other immune diseases, as well as other pertinent clinical data, were collected. The severity and pain of patients with severe shingles were evaluated, and their fasting blood sugar and plasma albumin were measured for routine antiviral treatment. They were followed up 6 months—the types of skin lesions and pertinent clinical data were compared, and the risk factors for skin lesions were analyzed.Results: There were no statistically significant differences in gender, age, or site among the different types of skin lesions (P > 0.05). The severity of skin lesions, acute pain, history of diabetes, history of scars, low immune function, combined with hypoproteinemia, squeezing and stripping behavior, and post-herpetic neuralgia (PHN) were significantly associated with skin lesions (P < 0.05). The results of multivariate analysis showed that: age ≥ 60 years old, severe skin injury combined with diabetes, low immune function, scar history, squeezing and stripping were independent risk factors for the development of skin lesions due to shingles.Conclusion: There is no significant difference in age, gender, site, or other characteristics between the types of skin lesions due to shingles. The independent risk factors of skin lesions due to shingles are old age, severe rash, history of scars, diabetes, low immunity, squeezing, and peeling.Keywords: risk factors, skin lesions due to shingles

Zhongyuan Xin,1,2,&ast; Mengya Zhang,2,&ast; Hengqing Cui,3,&ast; Xiuwen Ding,2,&ast; Tinglin Zhang,2 Lili Wu,2 Haipo Cui,1 Qian Xue,2 Cuimin Chen,2 Jie Gao2 1School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China; 2Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China; 3Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, ‎People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Gao; Cuimin Chen, Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China, Tel +86 21 31162092, Fax +86 21 31161111, Email gaojiehighclea@smmu.edu.cn; 535428425@qq.comAbstract: Cancer is the second leading cause of death worldwide. Its incidence has been increasing in recent years, and it is becoming a major threat to human health. Conventional cancer treatment strategies, including surgery, chemotherapy, and radiotherapy, have faced problems such as drug resistance, toxic side effects and unsatisfactory therapeutic efficacy. Therefore, better development and utilization of biomaterials can improve the specificity and efficacy of tumor therapy. Algae, as a novel living material, possesses good biocompatibility. Although some reviews have elucidated several algae-based biomaterials for cancer treatment, the majority of the literature has focused on a limited number of algae. As a result, there is currently a lack of comprehensive reviews on the subject of anticancer algae. This review aims to address this gap by conducting a thorough examination of algal species that show potential for anticancer activity. Furthermore, our review will also elucidate the engineering strategies of algae and discuss the challenges and prospects associated with their implementation.Keywords: algae, neoplasms, engineering strategies, biomaterials, anticancer mechanism

Hongli Yang,1,&ast; Fajuan Rui,2,&ast; Rui Li,3,&ast; Shengxia Yin,4 Qi Xue,1 Xinyu Hu,5 Yayun Xu,5 Chao Wu,4 Junping Shi,6 Jie Li2,4 1Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji’nan, People’s Republic of China; 2Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing, People’s Republic of China; 3Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, People’s Republic of China; 4Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 5Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Ji’nan, People’s Republic of China; 6Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Wenzhou Road, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Li, Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, People’s Republic of China, Email lijier@sina.com Junping Shi, Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Wenzhou Road, Hangzhou, Zhejiang, People’s Republic of China, Email 20131004@hznu.edu.cnAbstract: Background and Aims: Changes in living standards and diet structure, non-alcoholic fatty liver disease (NAFLD) is prevalent globally, including in Asia, where chronic hepatitis B (CHB) is endemic. As such, cooccurrence of NAFLD with CHB is common in Asia. However, the pathogenesis underlying the onset of fatty liver in CHB prognosis has not been fully elucidated. Therefore, we aimed to investigate the effects and mechanisms of lipotoxicity on hepatitis B virus (HBV) DNA replication.Methods: The expression of adenosine deaminase acting on RNA-1 (ADAR1) and miR-122 was evaluated in liver tissues from patients with CHB concurrent NAFLD. Palmitic acid-treated HepG2.2.15 cells were used as the cell model. The effect of lipotoxicity on HBV DNA replication was evaluated in vitro by transfecting the ADAR1 overexpression or knockdown lentiviral vector into HepG2.2.15 cells, respectively. qRT-PCR, western blotting and immunofluorescence were performed to determine ADAR1 expression.Results: The expression of ADAR1 in the liver tissues of CHB patients with concurrent NAFLD was significantly down-regulated compared with that in CHB patients. Enforced expression of ADAR1 inhibited the HBV DNA replication, whereas ADAR1 knockdown resulted in increased HBV DNA expression in palmitic acid - treated HepG2.2.15 cells. Additionally, ADAR1 inhibited the HBV DNA replication by upregulating miR-122, which is most abundant in the liver and mainly inhibits HBV DNA replication.Conclusions: ADAR1 may act as a suppressor of HBV replication in palmitic acid -treated HepG2.2.15 cells by increasing miR-122 levels. Thus, ADAR1 may serve as a potential biomarker and therapeutic target for CHB with concurrent NAFLD.Graphical Abstract: Keywords: chronic hepatitis B, non-alcoholic fatty liver disease, ADAR1, miR-122, HBV DNA

Qian-Qian Nie,1,&ast; Zong-Qing Zheng,2,&ast; 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&ast;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

Qineng Xue,&ast; Junming Xia,&ast; Jin Lu, Xia Shen Department of Anesthesiology, Eye & and ENT Hospital, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xia Shen, Department of Anesthesiology, Eye & and ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, People’s Republic of China, Tel +86-21-64377134, Fax +86-21-64373416, Email zlsx@yahoo.comPurpose: To investigate the tolerability of midazolam intravenous (IV) solution by masking its bitter taste through the addition of syrup.Methods: In the waiting area before surgery at our institution, Eye and ENT Hospital, from May to November of 2021, pediatric patients scheduled for anterior ear fistula removal or eardrum catheterization were randomly assigned to receive a mixture of IV midazolam and water (Group C) or IV midazolam and syrup (Group S) in equal volumes. We measured the difference between the groups in terms of drug tolerability with a 5-point facial hedonic scale given to every patient, parent, and nurse involved in the study. Secondary outcomes included sedation and anxiety levels, which were assessed at separation from the parents and general anesthesia induction via a mask.Results: In total, 180 patients were enrolled. The facial hedonic scales were higher in Group S as evaluated by the children (p=0.046), parents (p=0.020), and nurses (p=0.026). More patients were willing to take the same solution again in Group S than in Group C (p=0.024). The levels of sedation and anxiety at two timepoints were similar between the groups (all p> 0.05). No adverse events were noted preoperatively.Conclusion: The tolerability of IV midazolam administered orally was increased in a pediatric population by adding syrup. The sedative and anxiolytic effects were comparable for both midazolam mixtures.Trial Registry Number: China Clinical Research Information Service, ChiCTR2000040229.Keywords: oral midazolam, pediatric preoperative sedation, pediatric preoperative anxiety

Gujie Wu,1,&ast; Zhenyu Zhu,1,&ast; Zheng Yang,2,&ast; 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&ast;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,&ast; Min He,1,&ast; Kuan Ren,1,&ast; 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&ast;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

BackgroundChimeric Antigen Receptor T cell(CAR T-cell) therapy has been a great success in relapsed/refractory acute B lymphoblastic leukemia and B-cell lymphoma. At the same time, there are also related adverse reactions, especially cytokine release syndrome(CRS) and immune effector cell associated neurotoxicity syndrome(ICANS). However, Double CRS caused by CRA T cells are very rare.Case reportHere, we report a 33-year-male with secondary central diffuse large B-cell lymphoma(CNSL) who develpoed double CRS following sequential infusion of Anti-CD22 and Anti-CD19 CAR T cells after autologous hematopoietic stem cell transplantation(ASCT). On d+5, the patient developed high fever, along with chilly sensation, shivering, headache, blood oxygen desaturation, shock, weakness, severe thirst, and heart rate decline. IL-6 and ferritin increased significantly. The patient was diagnosed with the first CRS (grade 3). On d+36, the patient again had a persistent fever(T>39C) and limbs rash. IL-6 and ferritin again increased significantly on d+38. After exclusion of infection, a diagnosis of double CRS was made. The patient’s symptoms were completely relieved after receiving tocilizumab, glucocorticoids, and other supportive treatments on d+45.On d+90, contrast-enhanced MR angiogram shows that the lesion basically disappeared, indicating the patient had achieved CR. At the end of the follow-up at d+150, the patient was functioning normally without any sequelae.ConclusionThis is the first reported case worldwide where the patient with secondary CNSL suffered double CRS after CAR T-cell infusion. Our findings showed that it is important to increase awareness of early detection and diagnosis of double CRS and adopt appropriate treatment strategies.

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,&ast; Kuan Ren,1,2,&ast; 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&ast;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,&ast; Chengrong Bao,&ast; Yi-Qiong Xu,&ast; Lei Tao,&ast; 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&ast;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

Shenqi Zhang,1– 3 Chengbin Wang,3 Lei Shi,1 Qingyun Xue1,2 1Department of Orthopedics, Beijing Hospital, National Center of Gerontology, Beijing, People’s Republic of China; 2Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Department of Joint and Sports Medicine, Zaozhuang Municipal Hospital Affiliated to Jining Medical University, Shandong, People’s Republic of ChinaCorrespondence: Qingyun XueBeijing Hospital, National Center of Gerontology, No. 1 Dongdan Dahua Road, Dongcheng District, Beijing, 100730, People’s Republic of ChinaTel +8613188929900Email bjyyxqy@163.comSummary: The recent outbreak of coronavirus disease 2019 (COVID-19) has become a global epidemic. Corticosteroids have been widely used in the treatment of severe acute respiratory syndrome (SARS), and the pathological findings seen in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are very similar to those observed in severe acute respiratory syndrome-related coronavirus (SARS-CoV) infection. However, the long-term use of corticosteroids (especially at high doses) is associated with potentially serious adverse events, particularly steroid-induced avascular necrosis of the femoral head (SANFH). In today’s global outbreak, whether corticosteroid therapy should be used, the dosage and duration of treatment, and ways for the prevention, early detection, and timely intervention of SANFH are some important issues that need to be addressed. This review aims to provide a reference for health care providers in COVID-19 endemic countries and regions.Article Focus: Hormones are a double-edged sword. This review aims to provide a reference for health care providers in coronavirus disease 2019 (COVID-19) endemic countries and regions, especially with respect to the pros and cons of corticosteroid use in the treatment of patients with COVID-19.Key Messages: In today’s global outbreak, whether corticosteroid therapy should be used, the dosage and duration of treatment, and ways for the prevention, early detection, and timely intervention of SANFH are some important issues that need to be addressed.Strengths and Limitations: Since SARS was mainly prevalent in China at that time, many evidences in this paper came from the reports of Chinese scholars. There is a bias in the selection of data, which may ignore the differences in environment, race, living habits, medical level and so on. SANFH may be the result of multiple factors. Whether the virus itself is an independent risk factor for SANFH has not been confirmed. In this paper, through literature retrieval, some reference opinions on glucocorticoid usage, diagnosis and treatment of SANFH are given. However, due to the lack of large-scale research data support, it can not be used as the gold standard for the above problems.Keywords: COVID-19, steroid, necrosis of the femoral head, SARS

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

Liang Zhao, Gefei Zhao, Qi Xue Department of Thoracic Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, People’s Republic of ChinaCorrespondence: Qi XueDepartment of Thoracic Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, People’s Republic of ChinaTel +86-13801204967Email qixue02@sina.comPurpose: Tizanidine hydrochloride (TZN) is a centrally acting α 2-adrenergic agonist. In this study, we aimed to explore the role of TZN on human lung cancer and to elucidate its underlying mechanisms.Methods: The effect of TZN treatment in A549 cell proliferation, migration, invasion and apoptosis was evaluated by CCK8, transwell and flow cytometer assays. The expression of apoptosis-related proteins and the activation of AKT and Wnt3a/β-catenin pathways were detected by Western blot. From the data of DrugBank, TZN could act as an agonist to target Nischarin in humans. We next investigated the function of Nischarin receptor in lung cancer and its role in the anti-tumor activity of TZN.Results: The treatment of TZN inhibited the proliferation, migration and invasion of A549 cells, and induced apoptosis. These results were further confirmed by that TZN treatment increased the Bax/Bcl-2 ratio in A549 cells. We also observed that TZN treatment changed the expression and phosphorylation of proteins of AKTand Wnt3a/β-catenin signaling pathway members. By bioinformatics analysis, we found that Nischarin was down-regulated in human lung cancer tissues and patients with high Nischarin expression had a better survival. Moreover, Nischarin functioned as a tumor suppressor in the survival and metastasis of A549 cells through the regulation of AKT and Wnt3a/β-catenin pathways. Knockdown of Nischarin promoted the proliferation, invasion, migration of A549 cells and inhibited the apoptosis, which were reversed by the TZN treatment.Conclusion: Summary, our data revealed that treatment of TZN inhibited the growth of lung cancer cell line A549 and may be used as a novel strategy for lung cancer therapy.Keywords: Tizanidine, lung cancer, A549, apoptosis, AKT pathway