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Meng Zhang,1,2 Qi Yuan,1 Peiwen Wang,1 Fan Zhang,1 Dan Wu,1 He Bai,1 Jieting Liu,1 Haifeng Liu,1 Xiaohuan Yuan1 1College of Life Science, Mudanjiang Medical University, Mudanjiang, People’s Republic of China; 2The First Hospital of Qiqihar, Qiqihar, People’s Republic of ChinaCorrespondence: Xiaohuan Yuan, College of Life Science, Mudanjiang Medical University, No. 3 Tongxiang Road, Mudanjiang, 157011, People’s Republic of China, Tel/Fax +86-453-6984401, Email yuanxiaohuan@mdjmu.edu.cnPurpose: Nanovesicles (NVs) derived from bone mesenchymal stem cells (BMSCs) as drug delivery systems are considered an effective therapeutic strategy for diabetes. However, its mechanism of action remains unclear. Here, we evaluated the efficacy and molecular mechanism of BMSC-derived NVs carrying the curcumin analog H8 (H8-BMSCs-NVs) on hepatic glucose and lipid metabolism in type 2 diabetes (T2D).Subjects and Methods: Mouse BMSCs were isolated by collagenase digestion and H8-BMSCs-NVs were prepared by microvesicle extrusion. The effects of H8-BMSCs-NVs on hepatic glucose and lipid metabolism were observed in a T2D mouse model and a HepG2 cell insulin resistance model. To evaluate changes in potential signaling pathways, the PI3K/AKT/AMPK signaling pathway and expression levels of G6P and PEPCK were assessed by Western blotting.Results: H8-BMSCs-NVs effectively improved lipid accumulation in liver tissues and restored liver dysfunction in T2D mice. Meanwhile, H8-BMSCs-NVs effectively inhibited intracellular lipid accumulation in the insulin resistance models of HepG2 cells. Mechanistic studies showed that H8-BMSCs-NVs activated the PI3K/AKT/AMPK signaling pathway and decreased the expression levels of G6P and PEPCK.Conclusion: These findings demonstrate that H8-BMSCs-NVs improved hepatic glucose and lipid metabolism in T2D mice by activating the PI3K/AKT/AMPK signaling pathway, which provides novel evidence suggesting the potential of H8-BMSCs-NVs in the clinically treatment of T2D patients.Keywords: bone mesenchymal stem cell, nanovesicles, curcumin analogue H8, type 2 diabetes

Chaoping Yang,1,* Jing Xie,2,* Qianjun Chen,2 Qiongyin Yuan,3 Jianping Shang,4 Haibo Wu,5 Youhua Yang,6 Mingfang Wang,7 Xiaolan Shu,8 Jing Yue,9 Danna Tu,10 Ying Lin,1,* Ronghao Zheng,4,* Xiaolin Wu4 1Nursing Department, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pediatric Nephrology, Rheumatology, and Immunology, Maternal and Child Health Hospital of Hubei Province, Hubei University of Medicine, Shiyan, Hubei, People’s Republic of China; 3Obstetrical department, Huanggang Maternal and Child Health Hospital, Hubei, People’s Republic of China; 4Department of Pediatric Nephrology, Rheumatology, and Immunology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 5School of Health and Nursing, Wuchang University of Technology, Wuhan, People’s Republic of China; 6Department of Basic Medical Sciences, School of Medicine, Jianghan University, Wuhan, People’s Republic of China; 7Department of Pediatric Gastroenterology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 8Department of Pediatric Intensive Care Unit (PICU), Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 9Emergency Department, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China; 10Department of Pediatric Cardiology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ronghao Zheng, Department of Pediatric Nephrology, Rheumatology, and Immunology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, 745 Wu Luo Road, Hongshan District, Wuhan, Hubei Province, 430070, People’s Republic of China, Email hytwo2001@126.com Ying Lin, Nursing department, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China, Email 523933025@qq.comPurpose: The knowledge, attitude, and practices (KAP) concerning antibiotics by healthcare students have the potential impact on controlling antibiotic abuse and antimicrobial resistance (AMR) growth. This study aims to evaluate the levels and explore the associated factors with KAP on antibiotic use and AMR in Chinese nursing students.Methods: A cross-sectional survey using a self-administered questionnaire consisting of demographics and selected features and KAP on antibiotic use and AMR was conducted to measure KAP levels among nursing students at various universities in Hubei Province, China. The logistic regression analyses were performed to analyze the potential factors associated with the KAP.Results: The survey eventually included a total of 1959 nursing students. The mean scores for KAP were 57.89 ± 26.32, 55.00 ± 12.50, and 71.88 ± 15.63, respectively. Regarding knowledge, 54.3% of participants were unaware that antibiotic was ineffective against viral infections. Regarding attitude, 36% of participants agreed that current antibiotic abuse existed; 96.2% of participants thought it necessary to set up a special course on antibiotics. Regarding practice, only 48.4% of participants usually purchased antibiotics with a prescription. Multivariable analyses indicated that lack of discussion on AMR in school courses was an independent risk factor against KAP, respectively. The main knowledge sources of antibiotic being outside the classroom was an independent risk factor related to knowledge and practice. The average score > 80 points was an independent protective factor related to knowledge and practice.Conclusion: The KAP level on antibiotic use and AMR among Hubei nursing students was general and required further strengthening. Nursing students with risk factors should be prioritized in educational interventions. The findings of our study pointed out some directions for tailored interventions to improve the training on antibiotics.Keywords: antibiotic use, antimicrobial resistance, knowledge, attitude, practice, nursing students

Haishi Zheng,1,2 Yirixiati Aihaiti,2 Yongsong Cai,2 Qiling Yuan,2 Mingyi Yang,2 Zheng Li,2 Ke Xu,2 Peng Xu1,2 1Department of Orthopedics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Department of Joint Surgery, HongHui Hospital, Xi’an Jiaotong University, Xi’an, People’s Republic of ChinaCorrespondence: Peng Xu, Department of Orthopedics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China, Tel +86 13772090019, Email xupeng369@mail.xjtu.edu.cnPurpose: The goal of this study was to explore the expression characteristics of RNA modification-related genes, reveal immune landscapes and identify novel potential diagnostic biomarkers in osteoarthritis (OA) and rheumatoid arthritis (RA) patients.Patients and Methods: RNA microarray and single-cell sequencing (scRNA-seq) data were downloaded from gene expression omnibus (GEO) database. Differentially expressed RNA modification-related genes were identified and then functionally annotated. Univariate logistic regression and lasso regression analysis were used to identify primary disease genes for OA and RA. Validation was done using scRNA-seq analysis and immunohistochemistry (IHC) in human knee synovial tissues and a murine destabilization of the medial meniscus (DMM) model. Through WGCNA analysis, genes associated with cell pyroptosis or autophagy in OA and RA were identified, which were then combined with differentially expressed RNA modification-related genes to construct a PPI interaction network. Furthermore, hub genes were selected for ceRNA interaction network analysis, correlation analysis with OA and RA molecular subtypes, as well as correlation analysis with 22 immune cells.Results: Six RNA modification-related genes (ADAMDEC1, IGHM, OGN, TNFRSF11B, SCARA3 and PTN) were identified as potential OA and RA pathogenesis biomarkers. Their expression was validated in human knee synovial tissues and a murine DMM model. Functional enrichment of differentially expressed RNA modification-related genes between RA and OA was analyzed using GO, KEGG, GSEA, and GSVA. Based on WGCNA and PPI analysis, the six hub genes related to pyroptosis and RNA modification (CXCL10, CXCL9, CCR7, CCL5, CXCL1, and CCR2) were identified as central nodes for ceRNA interaction, correlation with OA and RA molecular subtypes, and association with 22 immune cells.Conclusion: Our research revealed the significance of RNA modification-related genes in the development of OA and RA pathogenesis, thereby providing a novel research direction for understanding the mechanisms, diagnosis, and treatment of OA and RA.Keywords: m6A, m5C, m1A, osteoarthritis, rheumatoid arthritis, single-cell sequencing

Yonghua Ye,1 Yuping Yang,1 Li Yan,1 Li Zhou,2 Shihui Yu,1 Quan Du,3 Xiaoqiao Dong,3 Qiang Yuan,1 Letian Shan,2,4 Le Guo1 1College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Department of Neurosurgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Cell Resource Bank and Integrated Cell Preparation Center of Xiaoshan District, Hangzhou Regional Cell Preparation Center (Shangyu Biotechnology Co., Ltd), Hangzhou, People’s Republic of ChinaCorrespondence: Letian Shan, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China, Tel +15355015568, Email letian.shan@zcmu.edu.cn Le Guo, College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China, Tel +18986648306, Email le.guo@zcmu.edu.cnPurpose: To explore the pharmacological effects and mechanisms of Qinghao Biejia decoction (QBD) against non-small-cell lung cancer (NSCLC) based on network pharmacology and to verify the anticancer effect of artemisinin B (ART B), the active ingredient of QBD, on H1299 cells.Methods: Ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was applied to explore the chemoprofile of QBD. A zebrafish xenograft model was used to determine the anti-cancer efficacy of QBD. Cell counting kit-8 assay, terminal deoxyribonucleotide transferase-mediated-dUTP nick-end labeling assay; immunofluorescence, and flow cytometry were used to evaluate the in vitro anti-proliferative and pro-apoptotic effects of QBD and ART B on H1299 cells. Subsequently, the related targets and action mechanisms of both QBD and ART B predicted by network pharmacological analyses were experimentally validated by real-time PCR and Western blot assays on H1299 cells.Results: UPLC-QTOF-MS/MS identified a total of 69 compounds (such as ART B, mangiferin, and artemisinic acid) in QBD. The in vivo data showed that QBD significantly inhibited the growth of H1299 cells in xenograft larval zebrafish from 125 to 500 μg/mL. The in vitro data showed that QBD induced apoptosis of H1299 cells, accompanied by down-regulating the expression of BCL-2 and up-regulating the expression of BIM, PUMA, BAX, c-PARP, γ-H2A.X, c-CASP3, and c-CASP8. Alike QBD, ART B exerted similar anti-proliferative and pro-apoptotic effects on H1299 cells. Moreover, ART B inhibited expressions of BCL2L1, AKT1, AKT2, MMP-2, and EGFR, and up-regulated ALB expression. Mechanistically, ART B promoted apoptosis of H1299 cells by inhibiting PI3K/Akt signaling pathway.Conclusion: This study revealed the anti-NSCLC efficacy of QBD. ART B, the effective component of QBD, plays an anti-NSCLC role by down-regulating the PI3K-Akt signaling pathway. It suggests that QBD and ART B are promising drug candidates for NSCLC treatment.Graphical Abstract: Keywords: Qinghao Biejia decoction, non-small-cell lung cancer, larval zebrafish, network pharmacology, artemisinin B

Lanlan Zong,1,* Yanling Wang,1,* Shiyu Song,1 Huiqi Zhang,1 Shengcai Mu,1 Wenshang Liu,1 Yu Feng,1 Shumin Wang,1 Ziwei Tu,1 Qi Yuan,1 Luhui Li,2 Xiaohui Pu1 1School of Pharmacy and Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Henan University, Kaifeng, Henan, 475004, People’s Republic of China; 2Medical school, Henan Technical Institute, Kaifeng, Henan, 475004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qi Yuan; Xiaohui Pu, Tel/Fax +86-371-23880680, Email kaifengYQ2017@163.com; pgh425@163.comIntroduction: Hepatoma is the leading cause of death among liver diseases worldwide. Modern pharmacological studies suggest that some natural monomeric compounds have a significant effect on inhibiting tumor growth. However, poor stability and solubility, and side effects are the main factors limiting the clinical application of natural monomeric compounds.Methods: In this paper, drug-co-loaded nanoself-assemblies were selected as a delivery system to improve the chemical stability and solubility of Tanshinone II A and Glycyrrhetinic acid, and to produce a synergetic anti-hepatoma effect.Results: The study suggested that the drug co-loaded nanoself-assemblies showed high drug loading capacity, good physical and chemical stability, and controlled release. In vitro cell experiments verified that the drug-co-loaded nanoself-assemblies could increase the cellular uptake and cell inhibitory activity. In vivo studies verified that the drug co-loaded nanoself-assemblies could prolong the MRT0-∞, increase accumulation in tumor and liver tissues, and show strong synergistic anti-tumor effect and good bio-safety in H22 tumor-bearing mice.Conclusion: This work indicates that natural monomeric compounds co-loaded nanoself-assemblies would be a potential strategy for the treatment of hepatoma.Graphical Abstract: Keywords: nanoself-assemblies, drug combination, glycyrrhetinic acid, tanshinone IIA, liver cancer

Pan Luo,* Qiling Yuan,* Xianjie Wan, Mingyi Yang, Peng Xu Department of Joint Surgery, HongHui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, 710054, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng Xu, Department of Joint Surgery, HongHui Hospital, Xi’an Jiaotong University, Xi’an, Shanxi, People’s Republic of China, Email sousou369@163.comAbstract: The pathological manifestations of osteoarthritis (OA) involve the destruction of articular cartilage, synovial sac thickening, subchondral osteosclerosis and osteophyte formation. The types of cells involved in OA include chondrocytes, osteoblasts, osteoclasts, synovial fibroblasts, T cells, macrophages, and mesenchymal stem cells (MSCs). There are many effects of immune cells in OA, and innate immune cells such as dendritic cells and macrophages have significant roles in the pathogenesis of OA. On the other hand, the role of adaptive immune cells such as T-cell subsets, B-cell subsets, and NK cells is important in OA pathogenesis. MSCs not only play a key role in the dynamic balance and repair of OA tissue but also inhibit the immune system. Therefore, MSCs are a new potential therapeutic agent for OA. This review mainly summarizes the effects of various immune cells and cytokines on different cells in OA to find new effective therapeutic targets for OA therapy based on the immune system and cytokine activity sites to prevent the development of OA.Keywords: osteoarthritis, immune cells, chondrocytes, mesenchymal stem cells, osteoblasts

Jia-Wei Wang,1 Qing Yuan,1 Li Li,2 Kai-Hua Cao,1 Qi Liu,1 Hong-Liang Wang,3 Ke Hu,1,* Xi Wu,4,* Jing-Hai Wan1 1Department of Neurosurgery, 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; 2Medical Records Department, 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; 3Department of Neurosurgery, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China; 4General Department, 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*These authors contributed equally to this workCorrespondence: Ke Hu, Department of Neurosurgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Nanli Panjiayuan, Chaoyang District, Beijing, 100021, People’s Republic of China, Tel/Fax +86-10-87787350, Email huke6668@163.com Xi Wu, General Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Nanli Panjiayuan, Chaoyang District, Beijing, 100021, People’s Republic of China, Tel/Fax +86-10-87788200, Email wuxiamg@163.comPurpose: Several biomarkers, such as baseline neutrophil-to-lymphocyte ratio (NLR), have been more investigated in patients with brain metastases (BM), while their role in patients with leptomeningeal metastases (LM) has not been clarified. Considering the difference between the clinical behaviour of BM and LM, there is the need for addressing the role of these biomarkers in LM.Methods: The present study retrospectively analyzed 95 consecutive patients with LM from lung cancer who were diagnosed at the National Cancer Center, Cancer Hospital of Chinese Academy of Medical Sciences between January 2016 and December 2019. Baseline NLR, platelet-to-lymphocyte ratio (PLR), systemic immunoinflammation index (SII), and lymphocyte‐to-monocyte ratio at diagnosis of LM were calculated based on complete blood count and correlated, along with other characteristics, with overall survival (OS) using univariate and multivariate analyses. The best cutoff values for systemic immunoinflammation biomarkers were derived using the surv_cutpoint function in R software, which optimized the significance of the split between Kaplan–Meier survival curves.Results: Median OS of patients with LM was 12 months (95% CI 9– 17 months). On univariate analysis, NLR, PLR, SII, LMR, sex, smoking history, ECOG performance status (PS) scores, histological subtypes and targeted therapy were all significantly associated with OS. Only NLR (P=0.034, 95% CI 1.060– 4.578) and ECOG PS scores (P=0.019, 95% CI 0.137– 0.839) maintained a significant association with OS on multivariate analysis. Furthermore, patients with baseline NLR > 3.57 had significantly worse OS than patients with NLR ≤ 3.57 (median OS 7 vs 17 months), as did patients with ECOG PS scores > 2 vs ≤ 2 (median OS 4 vs 15 months).Conclusion: Both baseline NLR and PS scores at the time of LM diagnosis are helpful and available prognostic biomarkers for patients with LM from lung cancer.Keywords: systemic immunoinflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte‐to-monocyte ratio, leptomeningeal metastases, lung cancer

Tingting Xu,1,&ast; Wei Sun,2,&ast; Hongqing Zhao,3,&ast; Xinmin Wang,4 Qi Yuan,1 Xijie Zhang,1 Shan Mao,5 Xiuwei Zhang,6 Mingming Zhao,7 Zebo Sheng,8 Mingshun Zhang,9 Mao Huang,1 Ningfei Ji1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Xishan People’s Hospital of Wuxi City, Wuxi, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Wuxi Second People’s Hospital, Wuxi, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Shuyang Hospital of Traditional Chinese Medicine, Suqian, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, Nanjing First Hospital, Nanjing, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Nanjing Jiangning Hospital, Nanjing, People’s Republic of China; 7Department of Respiratory and Critical Care Medicine, Nanjing Gaochun People’s Hospital, Nanjing, People’s Republic of China; 8Department of Respiratory and Critical Care Medicine, Changshu First People’s Hospital, Suzhou, People’s Republic of China; 9Department of Immunology, Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mao Huang; Ningfei Ji, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Road, Nanjing, 210029, People’s Republic of China, Tel/Fax +86-13813886116 ; +86-18951080699, Email hm6114@163.com; jiningfei@163.comPurpose: Hospitalization for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is considered as severe exacerbations. Readmission for severe exacerbations is a crucial event for COPD patients. However, factors associated with readmission for severe exacerbations are incomplete. The study aimed to investigate different characteristics between the severe and non-severe exacerbation groups.Patients and Methods: Patients hospitalized for severe AECOPD were included in multi-centers, and their exacerbations in next 12 months after discharge were recorded. According to exacerbations, patients were separated into the severe-exacerbation group and the non-severe exacerbation group. Propensity-score matching (PSM) and multivariable analyses were performed to compare the baseline characteristics of two groups. The Hosmer-Lemeshow test and receiver operating characteristic curve were applied to evaluate how well the model could identify clusters.Results: The cohort included 550 patients with severe AECOPD across 27 study centers in China, and 465 patients were finally analyzed. A total of 41.5% of patients underwent readmission for AECOPD within 1 year. There were no significant differences in baseline characteristics between groups after PSM. Severe exacerbations in the 12 months were related to some factors, eg, the duration of COPD (13 vs 8 years, P< 0.001), the COPD Assessment Test (CAT) score (20 vs 17, P< 0.001), the blood eosinophil percentage (1.5 vs 2.0, P< 0.05), and their inhaler therapies. Patients readmitted with AECOPD had a longer time of diagnosis (≥ 9 years), more symptoms (CAT ≥ 10), and lower blood eosinophils (Eos < 2%). A clinical model was derived to help identify patients at risk of readmission with severe exacerbations.Conclusion: These analyses confirmed the relevance of COPD at admission with future severe exacerbations. A lower blood eosinophils percentage appears to be related to readmission when combined with clinical history. Further studies are needed to evaluate whether this study can predict the risk of exacerbations.Keywords: chronic obstructive pulmonary disease, acute exacerbation, eosinophils, prognosis

Anish Maskey,1 Kamal Srivastava,1,2 Gary Soffer,3 David Dunkin,4 Qian Yuan,5 Xiu-Min Li1,6 1Department of Pathology, Microbiology & Immunology, New York Medical College, Valhalla, NY, USA; 2General Nutraceutical Technology, LLC, Elmsford, NY, USA; 3Department of Allergy and Immunology, Yale University, New Haven, CT, USA; 4Division of Pediatric Gastroenterology and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 5Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Boston, MA, USA; 6Department of Otolaryngology, New York Medical College, Valhalla, NY, USACorrespondence: Xiu-Min Li, Department of Pathology, Microbiology & Immunology, New York Medical College, 40 sunshine cottage Road, BSB 319, Valhalla, NY, 10595, USA, Tel +1-914-594-4197, Email XiuMin_Li@nymc.eduBackground: Eosinophilic Esophagitis (EoE) is an increasingly common chronic inflammatory disease. The pathological mechanisms underlying EoE are largely unknown.Objective: We sought to understand the mechanisms underlying aeroallergen-induced EoE in Sharpin gene deficient (Sharpin-/-) mice that is prone to inflammatory response.Methods: Sharpin-/-mice were exposed with Aspergillus fumigatus and ovalbumin intranasally every alternate day for 4 weeks. Wild type (WT) naïve mice, WT exposed, and un-exposed Sharpin-/- mice were controls. Histopathological analysis was performed by H&E, trichrome and major basic protein staining. Total and specific IgE, IgG, and IgA levels were measured by ELISA and Th2 cytokine and CCL11 chemokine gene expression were determined.Results: Airborne allergen exposed Sharpin-/- mice showed severe eosinophilic inflammation in the esophagus (p < 0.001), and markedly increased epithelial thickening (p < 0.0001) compared to WT normal controls, whereas airborne allergen exposed WT mice and unexposed Sharpin-/- mice only showed mild eosinophilic inflammation in the esophagus. These exposed Sharpin-/- mice also showed over 7-fold increase in blood eosinophils (p < 0.0001), 60-fold increase in eosinophils in bronchoalveolar lavage fluid (p < 0.0001) and 4-fold increase in eosinophils in the skin (p < 0.0001) compared to normal controls. Surprisingly, exposed Sharpin-/- mice did not show elevation of serum total or antigen-specific IgE levels but reduced total IgA and IgG levels than normal controls There was a marked increase in IL-4, IL-13 and CCL11 gene expression in esophageal tissue (p < 0.001) in exposed Sharpin-/- mice compared to WT normal mice.Conclusion: Th2 cytokines and chemokines, but not IgE may play an important pathologic role in aeroallergen-induced EoE. This study may provide insight into new therapeutics for EoE.Keywords: aeroallergen, eosinophilic esophagitis, non-IgE, Th2

Lin Cheng, Pu Yao, Hongping Wang, Qian Yuan, Xiaowen Wang, Wei Feng, Fengjun Sun, Qian Wang Department of Pharmacy, The First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, 400038, People’s Republic of ChinaCorrespondence: Qian Wang; Fengjun Sun, Email xqwq411@126.com; fengj_sun@163.comObjective: In this study, the Lactobacillus plantarum HFY15 (LP-HFY15) strain isolated from naturally fermented yak yogurt was investigated. An animal model of lupus nephritis was established by pristane to verify the interventional effect of LP-HFY15 on mouse lupus nephritis by regulating the transforming growth factor-β 1 (TGF-β 1) signaling pathway.Materials and Methods: Indexes in mouse serum and tissues were detected by kits, pathological changes in mouse kidney were observed by hematoxylin-eosin (H&E) staining, and quantitative polymerase chain reaction (qPCR) was used to detect TGF-β 1-related expression in mouse kidney tissue, which further elucidated the mechanism of LP-HFY15.Results: LP-HFY15 decreased the elevation of urinary protein and the levels of interleukin-6 (IL-6), IL-12, tumor necrosis factor alpha (TNF-α), and interferon γ (IFN-γ) in serum and kidney tissue. LP-HFY15 also reduced serum creatinine (SCr), blood urea nitrogen (BUN), total cholesterol (TC), triglyceride (TG), and raised total protein (TP), and albumin (ALB) levels in mice with nephritis. In addition, LP-HFY15 inhibited the positive rate of double-stranded deoxyribonucleic acid (dsDNA) antibodies in mice with nephritis. The observation of H&E sections showed that LP-HFY15 alleviated the glomerulus morphological incompleteness and inflammatory infiltration caused by nephritis. Further results showed that LP-HFY15 downregulated the mRNA expression of TGF-β 1, vascular endothelial growth factor (VEGF), and nuclear factor kappa-B (NF-κB) in the kidneys of lupus nephritis mice, and the expression of inhibitor of NF-κB (IκB-α), copper/zinc superoxide dismutase (Cu/Zn-SOD), and manganese superoxide dismutase (Mn-SOD) was also upregulated.Conclusion: These results indicated that LP-HFY15 plays a significant role in experimental intervention for lupus nephritis. The effect of LP-HFY15 was positively correlated with its concentration, and the effect was similar to that of prednisone at 109 CFU/kg.Keywords: lactic acid bacteria, lupus nephritis, TGF-β 1, dsDNA, pristane

Quangang Yuan,1,&ast; Jiang Guo,2,&ast; Long He,1 Qiulin Chen,1 Xianhong Zou,1 Siming Yang,1 Zhenyang Zhang1 1Department of Urology, Chongqing Hechuan Hongren Hospital, Chongqing, 401520, People’s Republic of China; 2Department of Urology, Anyue People’s Hospital of Ziyang City, Ziyang City, Sichuan Province, 642300, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhenyang Zhang, Tel/Fax +86 23-67710675, Email urinaryzhang@163.comObjective: To investigate the risk factors, pathogen distribution, and drug resistance of systemic inflammatory response syndrome (SIRS) after holmium laser ureteroscopic lithotripsy for impacted ureteral calculi (HLULIUC).Patients and Methods: The clinical data of 293 patients with HLULIUC in our hospital from October 2017 to February 2021 were retrospectively collected, including age, BMI, stone size, operation time, urine routine, urine culture, basic illness, complete blood count, liver and kidney function, etc. Patients were divided into SIRS and non-SIRS groups according to whether they had SIRS or not. Then the differences in clinical data, blood and urine bacterial culture results, and drug resistance between the two groups were analyzed.Results: The incidence of SIRS after HLULIUC was 17.75%. Logistic regression analysis showed that the risk factors of SIRS after HLULIUC include ureteral calculi≥ 1cm (OR=2.839, 95% CI=1.341– 5.647, P=0.021), long operation time (OR=4.534, 95% CI=2.597– 12.751, P=0.017), diabetes mellitus (OR=3.137, 95% CI=1.142– 7.319, P=0.012), increased preoperative C-reactive protein (OR=1.864, 95% CI=1.05– 4.347, P=0.032), and positive urine leukocytes (OR=3.514, 95% CI=1.7237– 9.734, P=0.007) and culture (OR=6.034, 95% CI=3.097– 15.751, P< 0.001) before operation. The main pathogens causing SIRS after HLULIUC were Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Enterococcus faecalis, and Pseudomonas aeruginosa. The pathogenic bacteria are sensitive to drugs including piperacillin/tazobactam, meropenem, tigecycline, teicoplanin, vancomycin, and imipenem. The resistance rates to quinolones (such as levofloxacin) and to the second- and third-generations of cephalosporins were as high as 52.94%– 90.19%.Conclusion: Ureteral calculi≥ 1cm, long operation time, diabetes, increased C-reactive protein, and preoperative positive urine leukocytes and culture are independent risk factors of SIRS after HLULIUC. Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Enterococcus faecalis, and Pseudomonas aeruginosa are the main pathogenic bacteria for SIRS after HLULIUC. The pathogenic bacteria are sensitive to drugs, including piperacillin/tazobactam, meropenem, tigecycline, teicoplanin, vancomycin, and imipenem.Keywords: impacted ureteral calculi, holmium laser ureteroscopic lithotripsy, systemic inflammatory response syndrome, risk factors, drug resistance, sensitivity

Juan Du,1 Lanlan Zong,2 Mengmeng Li,2 Keke Yu,2 Yonghui Qiao,3 Qi Yuan,2 Xiaohui Pu2 1Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, People’s Republic of China; 2Institute of Pharmacy, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, People’s Republic of China; 3Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, People’s Republic of ChinaCorrespondence: Juan Du; Xiaohui Pu, Tel/Fax +86-371-23880680, Email jindalai66@163.com; pgh425@163.comIntroduction: Cancerous tumors are still a major disease that threatens human life, with tumor multidrug resistance (MDR) being one of the main reasons for the failure of chemotherapy. Thus, reversing tumor MDR has become a research focus of medical scientists.Methods: Here, a reduction-sensitive polymer prodrug micelle, mPEG-DCA-SS-PTX (PDSP), was manufactured with a new polymer inhibitor of drug resistance as a carrier to overcome MDR and improve the anti-tumor effect of PTX.Results: The PDSP micelles display good stability, double-responsive drug release, and excellent biocompatibility. The PDSP micelles reduced the cytotoxicity of PTX to normal HL-7702 cells and enhanced that to SMMC-7721 and MCF-7 cells in vitro. Improved sensitivity of A549/ADR to PDSP was also observed in vitro. Furthermore, in vivo experiments show reduced systemic toxicity and enhanced therapeutic efficacy of PTX to H22 subcutaneous tumor-bearing mice.Conclusion: This work proves that the reduction-sensitive polymer prodrug micelles carried by the new polymer inhibitor can be used as an alternative delivery system to target tumors and reverse MDR for paclitaxel and other tumor-resistant drugs.Keywords: anti-multidrug resistance, polymer prodrug micelles, paclitaxel, reduction sensitivity, liver targeting

N6-methyladenosine (m6A) modification, a eukaryotic messenger RNA modification catalyzed by methyltransferase-like 3 (METTL3), plays a pivotal role in stem cell fate determination. Calvarial bone development and maintenance are orchestrated by the cranial sutures. Cathepsin K (CTSK)–positive calvarial stem cells (CSCs) contribute to mice calvarial ossification. However, the role of m6A modification in regulating Ctsk+ lineage cells during calvarial development remains elusive. Here, we showed that METTL3 was colocalized with cranial nonosteoclastic Ctsk+ lineage cells, which were also associated with GLI1 expression. During neonatal development, depletion of Mettl3 in the Ctsk+ lineage cells delayed suture formation and decreased mineralization. During adulthood maintenance, loss of Mettl3 in the Ctsk+ lineage cells impaired calvarial bone formation, which was featured by the increased bone porosity, enhanced bone marrow cavity, and decreased number of osteocytes with the less-developed cellular outline. The analysis of methylated RNA immunoprecipitation sequencing and RNA sequencing data indicated that loss of METTL3 reduced Hedgehog (Hh) signaling pathway. Restoration of Hh signaling pathway by crossing Sufufl/+ alleles or by local administration of SAG21 partially rescued the abnormity. Our data indicate that METTL3 modulates Ctsk+ lineage cells supporting calvarial bone formation by regulating the Hh signaling pathway, providing new insights for clinical treatment of skull vault osseous diseases. [ABSTRACT FROM AUTHOR]

Ling-Wang An,1 Xiang-Lan Li,1 Lin-Hui Chen,2 Hong Tang,3 Qun Yuan,4 Yan-Jun Liu,5 Yu Ji,6 Ju-Ming Lu1,7 1Department of Endocrinology, Beijing Ruijing Diabetes Hospital, Beijing, 100079, People’s Republic of China; 2Department of Endocrinology, Taiyuan Diabetes Hospital, Taiyuan, 030013, People’s Republic of China; 3Department of Share-Care Center, Chengdu Ruien Diabetes Hospital, Chengdu, 610000, People’s Republic of China; 4Department of Endocrinology, Heilongjiang Ruijing Diabetes Hospital, Harbin, 150009, People’s Republic of China; 5Department of Endocrinology, Lanzhou Ruijing Diabetes Hospital, Lanzhou, 730000, People’s Republic of China; 6Department of Endocrinology, Beijing Aerospace General Hospital, Beijing, 100076, People’s Republic of China; 7Department of Endocrinology, The General Hospital of the People’s Liberation Army, Beijing, 100853, People’s Republic of ChinaCorrespondence: Ju-Ming LuDepartment of Endocrinology, The General Hospital of the People’s Liberation Army, No. 28 of Fuxing Road, Haidian District, Beijing, 100853, People’s Republic of ChinaTel +86 10 8822 9999Email lujm666_1@21cn.comObjective: To analyse diabetes treatment, treatment change and self-management behaviours in association with 2-year glycaemic trajectories in patients with non-newly diagnosed type 2 diabetes mellitus in Chinese primary care.Methods: This was an observational, multi-centre, longitudinal, retrospective cohort study. Clinical data of 4690 subjects were extracted from electronic medical records, including serial glycated haemoglobin A1c (HbA1c) measurements, antidiabetic medication records and compliance to exercise, diet, medications and self-monitoring of blood glucose (SMBG). Patterns of longitudinal HbA1c trajectories were identified using the percentage of HbA1c measurements < 7.5% from the second available HbA1c measurement. Clinical relevance of the clusters was assessed through multivariable analysis.Results: Approximately half of the participants demonstrated good glycaemic control; of these, 34.5% demonstrated stable, good control, and 13.7% demonstrated relatively good control. About 16.2% demonstrated moderate control, and 35.6% demonstrated poor control. From the good to poor control groups, the percentage of subjects treated with insulin at baseline and during the follow-up period increased gradually, while the percentage of subjects adhering to exercise, diet, medications and SMBG decreased gradually. Compared with baseline, the adherence to exercise, diet, medications and SMBG improved significantly. Approximately 50% and 26% of subjects in the two poorest control groups, respectively, experienced treatment changes. After multivariable adjustments, baseline HbA1c ≥ 7.5%, HbA1c change ≥− 0.5% from baseline to visit 1, insulin treatment, treatment change, poor adherence to diet, exercise, SMBG during the follow-up period and HbA1c measurements < 3 per year were significantly associated with poorer glycaemic control.Conclusion: We identified four longitudinal HbA1c trajectories in patients with non-newly diagnosed type 2 diabetes. Even if baseline HbA1c is suboptimal, aggressive treatment changes, good adherence during the follow-up period, ≥ 3 HbA1c measurements per year and reducing HbA1c levels to a certain extent by the first follow-up visit were important for good, stable, long-term glycaemic control.Keywords: haemoglobin A1c, self-monitoring of blood glucose, diabetes, glycaemic trajectories, glycaemic control

Yuanyuan Dai,1 Wenjiao Chang,1 Xin Zhou,1 Wei Yu,2 Chen Huang,2 Yunbo Chen,2 Xiaoling Ma,1 Huaiwei Lu,1 Rujin Ji,2 Chaoqun Ying,2 Peipei Wang,2 Zhiying Liu,2 Qingfeng Yuan,1 Yonghong Xiao2 1Department of Laboratory, First Affiliated Hospital of University of Science and Technology of China, Hefei, People’s Republic of China; 2State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Yonghong Xiao Tel/Fax +865 718 723 6421Email xiao-yonghong@163.comPurpose: To evaluate the administration regimen of ceftazidime/avibactam (CZA) for bloodstream infections caused by Enterobacteriaceae and Pseudomonas aeruginosa.Methods: The minimal inhibitory concentrations (MICs) of CZA against Enterobacteriaceae and P. aeruginosa isolated from blood cultures at member hospitals in BRICS (Blood Bacterial Resistant Investigation Collaborative System) in 2019 were determined by broth micro-dilution methodology. A 10,000-patient Monte Carlo simulation (MCS) was used to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) for different CZA dosage regimens to evaluate their efficacies and optimize the best initial dosage regimen.Results: Altogether, 6487 Enterobacteriaceae and P. aeruginosa strains were isolated from the blood cultures. The overall CZA resistance rate was 2.31%, of which the Enterobacteriaceae and P. aeruginosa rates were 1.57% and 14.29%, respectively. The MCS showed that the greater the MIC value, the worse the therapeutic effect. When the CZA MIC was ≤ 8 mg/L, the standard dose (2.5g iv q8h) achieved 90% PTA in the subset of patients with creatinine clearance (CrCl) values from 51 to 120 mL/min. Although the high-dose regimen (3.75g iv q8h) achieved 90% PTA in patients with CrCl values from 121 to 190 mL/min, implementing the low-dose regimen (1.25g iv q8h) was also effective for patients in the 51– 89 mL/min CrCl range. Generally, the high-dose regimen (3.75g iv q8h) reached 90% CFR against all of the strains. Conversely, in patients with CrCl values of 121– 190 mL/min, the standard dose (2.5g iv q8h) failed to reach 90% CFR against some Enterobacteriaceae members and P. aeruginosa. When the dose was reduced to the low-dose regimen (1.25g iv q8h), no patients reached 90% CFR against some Enterobacteriaceae members and P. aeruginosa.Conclusion: CZA has good antibacterial activity against Enterobacteriaceae and P. aeruginosa in bloodstream infections. Clinicians could make individualized treatment regimens in accordance with the sensitivity of the strains and the level of renal function in their patients to best predict the drug-related clinical responses.Keywords: Gram-negative bacteria, extended-spectrum β-lactamase, dosage regimens, pharmacokinetics, pharmacodynamics, minimum inhibitory concentration

Ying Zhou,1,2,&ast; Ningbo Hao,2,&ast; Zhongping Duan,3 Ming Kong,3 Manman Xu,3 Dan Zhang,2 Xiangxiang Xu,2 Qingwen Yuan,1,2 Changzheng Li2 1Postgraduate Training Base of Jinzhou Medical University, Jinzhou, People’s Republic of China; 2Department of Gastroenterology and Hepatology, The PLA Rocket Force Characteristic Medical Center, Beijing, People’s Republic of China; 3Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, You’an Hospital Affiliated to Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changzheng LiDepartment of Gastroenterology and Hepatology, The PLA Rocket Force Characteristic Medical Center, 16 Xinjiekouwai Street, Beijing, 100088, People’s Republic of ChinaEmail licz007@aliyun.comObjective: The aim of this study was to investigate the possible association of muscle and adipose parameters with the severity and prognosis of patients hospitalized with acute pancreatitis (AP).Methods: A total of 392 hospitalized patients and 309 controls were enrolled in the study analysis from April 1, 2016, to February 1, 2021. The computed tomography scans of each population were evaluated for muscle and adipose parameters. The effects of parameters on developing moderately severe acute pancreatitis (MSAP) or severe acute pancreatitis (SAP) were evaluated using univariate and multivariate logistic regression analyses. Associations with disease recurrence and death were analyzed through Cox regression analysis.Results: The AP patients had higher levels of visceral adipose tissue (144.25 vs 97.81 cm2, p < 0.001) and subcutaneous adipose tissue (135 vs 120 cm2, p < 0.001) but lower levels of adipose tissue attenuation (visceral and subcutaneous) and skeletal muscle attenuation (SMA) than the controls (p < 0.05, respectively). Visceral adipose tissue (VAT) and SMA differed significantly with p-values of 0.014 and 0.003 in the different severity groups of AP. In multivariate analysis, VAT and SMA were associated with MSAP or SAP, with odds ratios of 1.003 and 0.973, respectively (95% CI 1.000– 1.006, p = 0.041; 95% CI 0.953– 0.993, p = 0.010). Cox regression analysis showed that low SMA was strongly associated with an increased mortality in MSAP and SAP patients (HR 10.500, 95% CI 1.344– 82.025, p = 0.025). Regression analysis also showed an association of VAT loss of more than 17% with reduced 1-year recurrence of acute pancreatitis (HR 0.427, 95% CI 0.189– 0.967, p = 0.041).Conclusion: VAT and SMA were influential factors for the severity and prognosis of patients with AP. Patients should proper diet and exercise after discharge to reduce VAT and strengthen muscle function to improve prognosis.Keywords: skeletal muscle attenuation, visceral adipose tissue, subcutaneous adipose tissue, recurrent acute pancreatitis

Chen Shi,1,2 Xiong Wang,1,2 Changdong Diao,1,2 Haixia Zhu,1,2 Qi Yuan,1,2 Jinmei Liu,1,2 Shijun Li,1,2 Ming Gu,1,2 Yu Zhang1,2 1Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People’s Republic of China; 2Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, People’s Republic of ChinaCorrespondence: Ming Gu; Yu ZhangDepartment of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People’s Republic of ChinaEmail gimyonline@163.com; whxhzy@163.comObjective: Although temozolomide has been extensively used to treat various tumors, there is a lack of large-cohort studies on temozolomide’s toxicity profile. The toxicity profiles and associated factors in patients treated with temozolomide-containing regimens were analyzed.Patients and Methods: Patients treated with temozolomide-containing regimens in the Affiliated Union Hospital of Huazhong University of Science and Technology from January 2008 to December 2019 were included. A retrospective analysis of the clinical data of patients treated with temozolomide-containing regimens was performed. Univariate chi-square test and multivariate logistic regression analysis were employed to identify factors associated with the occurrence of toxicities.Results: Among the 1057 patients received temozolomide-containing regimens, 922 patients were included in our analyses. Of the 922 patients, 484 patients (52.5%) experienced toxicities. Univariate analysis revealed that radiotherapy, chemotherapy cycle, chemotherapy regimen, and clinical stage were significantly associated with the toxicity during temozolomide treatment (P < 0.05). The chemotherapy regimen, chemotherapy cycle, and clinical stage were significantly associated with the overall occurrence of toxicities (P < 0.05). A chemotherapy regimen, chemotherapy cycle, and clinical stage were associated with the hematological system’s toxicities, whereas gender, age, clinical diagnosis, and clinical stage were related to gastrointestinal toxicities (P < 0.05). Clinical diagnosis, chemotherapy regimen, and age were associated with liver toxicity (P < 0.05).Conclusion: Toxicities are common among patients receiving temozolomide-containing regimens. Clinicians should be aware of factors associated with toxicities to minimize the impact of the toxicity.Keywords: temozolomide, toxicity, hematological system, gastrointestinal system, liver toxicity

Regarding the airfoil optimization design of multi-rotor unmanned aerial vehicles, this paper proposes an integral airfoil design method based on upper airfoil contour optimization. Firstly, by designing concave descent input curves with 0-1 distribution, the upper arc of different optimized airfoils is obtained using the Tangent circles method. Secondly, an integral airfoil generation method is developed after establishing the middle arc. As the upper and lower arcs of different shapes are randomly combined, various airfoil profiles are obtained by random assortment. Finally, the effectiveness and accuracy of the designed airfoil are validated through Python programming. The airfoil is generated by the XFOIL program, and the optimal airfoil is output with a lift-todrag ratio as the target. Meanwhile, an accurate Fluent analysis model is established, and a comparison verification is conducted on the data with the attack angle falling within [-8.02, 12.04] and lift-to-drag ratio falling within [- 50, 100]. After Fluent modeling of the designed airfoil, the Euclidean distance between the calculated angle-lift-drag ratio data curve and the data curve tested by the wind tunnel is 0.0331, while the Euclidean distance between the simulated data in the literature and the wind tunnel data is 0.0408. It indicates that our precise model achieves 18.9% higher accuracy than the literature model. Testing and verification results indicate that our designed airfoil based on upper arc optimization and its corresponding airfoil library can meet the design requirements for the aerodynamic performance of airfoils in practical applications. It provides a valuable reference for the development of airfoil design, optimization, and generation methods. [ABSTRACT FROM AUTHOR]

Zhou Zhou,1– 3 Pei-Wen Zhu,3 Wen-Qing Shi,3 You-Lan Min,3 Qi Lin,3 Qian-Min Ge,3 Biao Li,3 Qing Yuan,3 Yi Shao3 1Institute of Pathogenic Biology, Medical College, University of South China, Hengyang 421001, Hunan, People’s Republic of China; 2Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hengyang 421001, Hunan, People’s Republic of China; 3Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, People’s Republic of ChinaCorrespondence: Yi ShaoDepartment of Ophthalmology, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Donghu District, Nanchang 330006, Jiangxi Tel/ Fax +86 791-88692520Email freebee99@163.comPurpose: Brain function in patients with acute eye pain (EP) has not been extensively studied. An understanding of the alterations in short-range functional connectivity density (shortFCD) and long-range functional connectivity density (longFCD) in patients with EP remains elusive. The aim of the present study was to compare the functional connectivity density (FCD) between patients with EP and healthy controls (HCs) using resting-state functional connectivity.Methods: A total of 40 patients with EP (26 males and 14 females) and 40 HCs (26 males and 14 females) of similar age underwent functional magnetic resonance (MR) examination at the resting state. The shortFCD and longFCD values were compared using the one-sample t-test. The differences between patients with EP and the HCs were evaluated using receiver operating characteristic (ROC) curves.Results: In the patients with EP, significantly reduced shortFCD values were observed in the left posterior lobe of the cerebellum, right inferior parietal lobule, and left anterior lobe of the cerebellum, and significantly reduced longFCD values were observed in both the left and right posterior lobe of the cerebellum. Significantly increased shortFCD values were also observed in both superior frontal gyri (Brodmann area 6), and increased longFCD values were observed in the left inferior temporal gyrus and left superior frontal gyri (Brodmann area 11). Compared with the HCs, less reduction was noted among the shortFCD values of patients with EP in the right posterior lobe of the cerebellum, right supramarginal gyrus, left middle temporal gyrus, bilateral superior frontal gyri, and bilateral caudate nuclei.Conclusion: EP patients shown variation of binarized shortFCD and long FCD in brain areas including premotor cortex, ventral cortical visual system, newest part of the cerebellum, cerebellum control unconscious proprioception, inhibition of involuntary movement, somatosensory association cortex, nucleus involving reward system and ventral cortical visual system which might provide an explanation of brain functional compensation for chronic eye pain and visual impairment in the EP patients.Keywords: eye pain, magnetic resonance imaging, functional connectivity density

Yebei Qiu,1,2,* Xiaocheng Cao,1,2,* Lihua Liu,3,4 Xiaozheng Cao,3,4 Qing Yuan,5 Xiang Li,5 Yinghong Cui,1,5 Chang Xu,1,2 Chang Zou,4,6 Kaiqun Ren,1,2 Jianguo Cao1,2 1The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal University, Changsha 410013, People’s Republic of China; 2The Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha 410013, People’s Republic of China; 3Pharmacy Department, The Second Clinical Medical School of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, People’s Republic of China; 4Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen People’s Hospital, Shenzhen 518020, People’s Republic of China; 5Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha, Hunan 410013, People’s Republic of China; 6Clinical Medical Research Center, The Second Clinical Medical School of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianguo Cao; Kaiqun RenKaiqun Ren the Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal University, Changsha 410013, People’s Republic of ChinaTel +86-0731-88912434Email caojianguo2005@126.com; kaiqunren@126.comBackground: Manganese superoxide dismutase (MnSOD) induces FoxM1 expression, subsequently contributing to migration in several cancer cells. Isovitexin (ISOV) was recently found to downregulate MnSOD and FoxM1, decreasing stemness in hepatocellular carcinoma (HCC) stem-like cells (HCSLCs). The current study aimed to determine whether inhibition of migration, invasion and EMT in HCSLCs by ISOV results from MnSOD/FoxM1 signaling blockade and subsequent Twist1, Slug, ZEB1 and MMP-2 downregulation.Materials and Methods: We examined the migratory and invasive capabilities and EMT phenotype in HCC cells and their HCSLCs, respectively, by wound-healing assay, transwell invasion assay and Western blot after treatment with non-cytotoxic concentrations of ISOV, and explored the mechanism by which ISOV affects migration, invasion and EMT by MnSOD or FoxM1 knockdown and/or overexpression in HCSLCs or HCC cells.Results: The results showed that ISOV not only downregulated MnSOD and FoxM1 but also suppressed the migratory and invasive capabilities and reversed the EMT phenotype in HCSLCs, which was reflected by elevated E-cadherin protein amounts, and reduced N-cadherin, Twist1, Slug, ZEB1 and MMP-2 protein levels. The suppressive effects of ISOV on the migratory and invasive capabilities and EMT phenotype could be potentiated by MnSOD or FoxM1 knockdown in HCSLCs, and attenuated by MnSOD or FoxM1 overexpression in HCC cells. Importantly, FoxM1 overexpression reversed MnSOD knockdown combined with ISOV suppression on the migratory and invasive capabilities and EMT phenotype in HCSLCs, while having little effects on MnSOD expression.Conclusion: Collectively, the above findings demonstrated that ISOV suppresses migration, invasion and EMT in HCSLCs by blocking MnSOD/FoxM1 signaling subsequently inhibiting the expression of EMT-related transcription factors and MMP-2.Keywords: hepatocellular carcinoma, cancer stem cell, isovitexin, epithelial-mesenchymal transition, MnSOD, FoxM1, Twist1, MMP-2

Zhenli Min,1,2,* Yue Zhu,1,3,* Xing Hong,1 Zhijun Yu,1,2 Min Ye,1,2 Qiong Yuan,1,2 Xiamin Hu4 1Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan 430081, People’s Republic of China; 2New Medicine Innovation and Development Institute, College of Medicine, Wuhan University of Science and Technology, Wuhan 430081, People’s Republic of China; 3Stem Cell Lab, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 4College of Pharmacy, Shanghai University of Medicine & Health Sciences, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiamin Hu; Qiong Yuan Tel +862165883592; +86 27 68893640Email huxm@sumhs.edu.cn; yuanqiong@wust.edu.cnPurpose: The monocarbonyl analogs of curcumin (MCACs) have been widely studied for their promising antitumor activity. Pyrazole is a five-membered aromatic heterocyclic system with various bioactivities incorporated frequently in drugs. However, few of MCACs inspired pyrazole analogues were investigated. To search for more potent cytotoxic agents based on MCACs, a series of new 1,5-diaryl/heteroaryl-1,4-pentadien-3-ones inspired pyrazole moiety was synthesized and evaluated on their anti-colon cancer activities.Methods: Fifteen new compounds were synthesized and characterized by spectral datum, and then they were tested preliminarily by MTT assay for their cytotoxic activities against a panel of four human cancer cell lines, namely, gastric (SGC-7901), liver (HepG2), lung (A549), and colon (SW620) cancer cells. Compound 7h exhibited excellent selectivity and outstanding anti-proliferation activity against SW620 cells among these 15 compounds. Further, the mechanisms were investigated by transwell migration and invasion assay, clonogenic assay, cell apoptosis analysis, cell cycle analysis, Western blot analysis.Results: The IC50 value of 7h against SW620 cells was 12 nM, being more potent than curcumin (IC50 = 9.36 μM), adriamysin (IC50 = 3.28 μM) and oxaliplatin (IC50 = 13.33 μM). Further assays showed that 7h inhibited SW620 cell migration, invasion and colony formation obviously, which was due to its ability to induce cell cycle arrest in the G2/M and S phases and apoptosis. Western blot assay revealed that 7h decreased the protein expression of ATM gene, which may primarily contribute to its anticancer activity against SW620 cells.Conclusion: A new MCACs 7h was synthesized and found to exhibit excellent anti-proliferation activity against SW620 cells. Further studies indicated that 7h exerted its anticancer activity against SW620 cells probably via decreasing the ATM protein expression. The present study suggested that 7h was a promising candidate as an anti-colon cancer drug for future development.Keywords: 1, 5-diheteroarylpenta-1, 4-dien-3-one, colon cancer, cell proliferation, cell apoptosis, ATM gene

Jiduo Liu,* Yingchun Zhou,* Qing Yuan, Mingfeng Xiao Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingfeng Xiao Email beef168@163.comAbstract: Lineage switch is very rare in blastic crisis of chronic myeloid leukemia (CML-BC). Here, we report a case of CML-BC in which the blast lineage switched from myeloid to B-lymphoid. A 35-year-old male was initially admitted to our hospital because of abdominal distention for over a year and dizziness for one week. Prior to presentation at our hospital, he visited a local hospital because of abdominal distention where his white blood cell count and bone marrow (BM) smear indicated CML. Results from peripheral blood (PB) counts, bone marrow analysis, immunophenotyping by flow cytometry, and the detection of the Philadelphia chromosome were consistent with a diagnosis of myeloid blast crisis from CML. The patient received chemotherapy with imatinib for induction, which diminished the number of blasts. However, after three months, the blasts were increased in the PB and BM. The BM study and immunophenotyping by flow cytometry revealed B-lymphoblastic leukemia. In accordance with his first admission, a chromosome study revealed a karyotype of 46, XY, t(9; 22)(q34; q11) in all 20 cells analyzed, and B-lymphoblastic transformation from CML was diagnosed. Despite three months of treatment with DVCP (daunorubicin, vincristine, cyclophosphamide and prednisone) chemotherapy in combination with dasatinib, the patient did not achieve complete remission. The patient decided to stop treatment and was discharged from the hospital for financial reasons. This case implicates the Philadelphia chromosome with p210 BCR-ABL1 fusion proteins as a key molecule in CML-BC. Further research is needed to assess the frequency, treatment, and prognosis of CML-BC patients with lineage switch.Keywords: CML, myeloid blastic crisis, B-lymphoblastic transformation, Philadelphia chromosome, BCR-ABL1 fusion gene

Shuhan Liu,1 Rongjuan Guo,2 Fei Liu,3 Qingjie Yuan,4 Yao Yu,1 Feifei Ren1 1Second Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, People’s Republic of China; 2Department of Neurology, Dongfang Hospital Beijing University of Chinese Medicine, Beijing 100078, People’s Republic of China; 3College of Acupuncture and Massage, Changchun University of Chinese Medicine, Changchun 130117, People’s Republic of China; 4Department of Traditional Chinese Medicine, Tsinghua University Yuquan Hospital, Beijing 100040, People’s Republic of ChinaCorrespondence: Rongjuan GuoDepartment of Neurology, Dongfang Hospital Beijing University of Chinese Medicine, No. 6 Fangxingyuan 1st Block, Fengtai District, Beijing City, People’s Republic of ChinaTel +86 1 861 137 7633Fax +86 1064286498Email dfguorongjuan@163.comPurpose: Gut microbiota affects various physiological functions in the host and has crucial effects on the nervous system. There is increasing evidence of a correlation between gut microbiota and depression; however, the mechanisms underlying the regulation of depression-like behavior by gut microbiota remain unclear. In this study, we assessed the regulatory mechanism of gut microbiota on depression-like behavior in rats.Methods: We transplanted fecal microbiota obtained from patients with depression and healthy individuals into germ-free (GF) rats (n=18) through fecal microbiota transplantation technology. Next, we assessed the affective behavior in the rats using the forced swimming test and a sucrose preference test. We used enzyme-linked immunosorbent assay (ELISA) to determine the hippocampal levels of 5-hydroxytryptamine (5-HT), dopamine (DA), and noradrenaline (NE) and the serum levels of corticosterone (CORT), adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-6 (IL-6), interleukin-1 (IL-1), interleukin-1 (IL-4), and interleukin-1 (IL-10). The mitochondrial morphology of small intestinal epithelial cells was observed through transmission electron microscopy.Results: Rats that received fecal microbiota from patients with depression (depression microbiota) exhibited depression-like behavior. They presented decreased levels of hippocampal neurotransmitters, serum CORT levels, and anti-inflammatory cytokine levels, as well as increased ACTH, CRH, and serum levels of multiple pro-inflammatory cytokines. Observation of the mitochondria ultrastructure showed damaged mitochondria in the intestinal epithelial cells, significant endoplasmic reticulum expansion, and border aggregation of nuclear chromatin.Conclusion: Our findings suggested that the depression-like behaviors induced by the depression microbiota through the neuroendocrine-immune-mitochondrial pathway, which were associated with neuroendocrine disorders, inflammatory responses, and mitochondrial damage.Keywords: gut microbiota, depression, neurotransmitter, HPA axis, immune, mitochondrial

Qian-Min Ge,* Yu-Ting Zou,* Wen-Qing Shi, Yu-Qing Zhang, Biao Li, You-Lan Min, Qing Yuan, Yi Shao Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province Ocular Disease Clinical Research Center, Nanchang, Jiangxi 330006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi ShaoDepartment of Ophthalmology, The First Affiliated Hospital of Nanchang University, No. 17, YongWaiZheng Street, DongHu District, Nanchang, Jiangxi 330006, People’s Republic of ChinaTel/Fax +86 791-88692520Email freebee99@163.comObjective: At present, little is known regarding the specific risk factors of ocular metastasis (OM) in elderly patients with lung cancer. This study aimed to find out the risk factors of ocular metastasis.Methods: A total of 1615 elderly patients with lung cancer were recruited into this retrospective study between April 2001 and July 2016. These patients were divided into two groups, namely OM and non-ocular metastasis (NOM). Student’s t-tests, nonparametric rank sum tests, and Chi-square tests were applied to describe whether there were significant differences between the OM group and NOM group. We compared a range of serum biomarkers between the two groups of patients, including alkaline phosphatase, calcium, hemoglobin, alpha-fetoprotein, carcinoembryonic antigen, CA-125, CA-199, CA-153, CA-724, cytokeratin-19 fragment (CYFRA21-1), TPSA and neuron specific enolase (NSE). We used binary logistic regression analysis to determine the risk factors and receiver operating curve (ROC) analyses to assess the diagnostic value for OM in CRC patients.Results: The incidence of OM in elderly patients with lung cancer was 2.0%. Binary logistic regression indicated that CA-125, CA-153, and total prostate specific antigen (TPSA) were identified as independent risk factors of OM in patients with lung cancer (P< 0.001, P< 0.001, and P=0.003, respectively). The sensitivity and specificity of OM diagnosis were as follows: CA-125, 81.25% and 81.57%; CA-153, 68.75% and 83.78%; and TPSA, 81.25% and 90.03%, respectively.Conclusion: The serum concentrations of CA-125, CA-153, and TPSA have predictive value in the diagnosis of OM in elderly patients with lung cancer.Keywords: elderly people, lung cancer, ocular metastases, risk factors