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Hui Ao, Huizhu Song, Jing Li Department of Pharmacy, the Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, People’s Republic of ChinaCorrespondence: Jing Li, Department of Pharmacy, the Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, No. 299, Qingyang Road, Wuxi, Liangxi District, People’s Republic of China, Email lijingwuxi@sina.comPurpose: The increasing multi-drug resistance (MDR) is a serious threat to human health. The appropriate use of antibiotics can control the progression of MDR and clinical pharmacists play an important role in the rational use of antibiotics. There are many factors that influence the effectiveness of multi-drug resistant organisms (MDRO) infection consultations. The study aimed to establish a model to predict the outcome of consultation and explore ways to improve clinical pharmacy services.Patients and methods: Patients diagnosed with MDRO infection and consulted by clinical pharmacists were included. Univariate analysis and multivariate logistic regression analysis were used to identify independent risk factors for MDRO infection consultation effectiveness, and then a nomogram was constructed and validated.Results: 198 patients were finally included. The number of underlying diseases (OR=1.720, 95% CI: 1.260– 2.348), whether surgery was performed prior to infection (OR=8.853, 95% CI: 2.668– 29.373), ALB level (OR=0.885, 95% CI: 0.805~0.974), pharmacist title (OR=3.463, 95% CI: 1.277~9.396) and whether the recommendation was taken up (OR=0.117, 95% CI: 0.030~0.462) were identified as independent influences on the effectiveness of the consultation. The nomogram prediction model was successfully constructed and the AUC of the training set and the verification set were 0.849 (95% CI: 0.780– 0.917) and 0.761 (95% CI: 0.616– 0.907) respectively. The calibration curves exhibited good overlap between the data predicted by the model and the actual data.Conclusion: A nomogram model was developed to predict the risk of consultation failure and was shown to be good accuracy and good prediction efficiency, which can provide proactive interventions to improve outcomes for potentially treatment ineffective patients.Keywords: multi-drug resistance, nomogram, clinical pharmacist, consultation, clinical pharmacy services

Haoyang Tian,1,* Hui Chen,2,* Xiaochun Yin,2 Meiyi Lv,3 Lingling Wei,1 Yuna Zhang,4 Shuhan Jia,5 Jingyuan Li,1 Hui Song1 1School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, People’s Republic of China; 2Department of Endodontics, Jinan Stomatological Hospital, Jinan, People’s Republic of China; 3Department of Pediatric Dentistry, Jinan Stomatological Hospital, Jinan, People’s Republic of China; 4Department of Stomatology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 5Department of Stomatology, Yancheng NO. 1 People’s Hospital, Yancheng, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui Song; Jingyuan Li, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No. 44-1 Wenhua Road West, Jinan, Shandong, 250012, People’s Republic of China, Tel +86-531-88382912, Fax +86-531-88382923, Email songhui@sdu.edu.cn; jingyuan_31@163.comIntroduction: Diabetes has been recognized as an independent risk factor for periodontitis. Increasing evidences indicate that hyperglycemia aggravates inflammatory response of human periodontal ligament cells (hPDLCs). Carbon monoxide-releasing molecule-3 (CORM-3) is a water-soluble compound that can release carbon monoxide (CO) in a controllable manner. CORM-3 has been shown the anti-inflammatory effect in different cell lineages.Methods: We stimulated periodontal ligament cells with LPS and high glucose. The expression of inflammatory cytokine was detected by ELISA. RT-qPCR, Western blot and immunofluorescence were used to detect the expression of TLR2, TLR4, RAGE and the activation of NF-κB pathway. We performed silencing and overexpression treatment of RAGE targeting the role of RAGE. We performed the immunostaining of paraffin sections of the periodontitis model in diabetes rats.Results: The results showed that CORM-3 significantly inhibited the expression of inflammatory cytokine in hPDLCs stimulated with LPS and high glucose. CORM-3 also inhibited LPS and high glucose-induced expression of RAGE/NF-κB pathway and TLR2/TLR4/NF-κB pathway. Silence of RAGE resulted in significantly decreased expression of proteins above. Overexpression of RAGE significantly enhanced the expression of these factors. CORM-3 abrogated the effect of RAGE partially. In animal model, CORM-3 suppressed the inflammatory response of periodontal tissues in experimental periodontitis of diabetic rats.Discussion: Our research proved CORM-3 reduced the inflammatory response via RAGE/NF-κB pathway and TLR2/TLR4/NF-κB pathway in the process of high glucose exacerbated periodontitis. These findings demonstrated the role of RAGE in the process of high glucose exacerbated periodontitis and suggested that CORM3 be a potential therapeutic strategy for the treatment of diabetes patients with periodontitis. Keywords: carbon monoxide-releasing molecules, periodontitis, diabetes, receptor for advanced glycation end products, lipopolysaccharide

Wanjun Bai,1 Xue Sun,1 Bo Qiu,1 Caihui Guo,1 Haojing Song,1 Yiting Hu,1 Xueyuan Zhang,2 Peihua Yin,3 Xiaoru Wang,3 Zhanjun Dong1 1Department of Pharmacy, Hebei General Hospital, Hebei Key Laboratory of Clinical Pharmacy, Shijiazhuang, Hebei, People’s Republic of China; 2Center for Clinical Pharmacology, Shanghai Innovstone Therapeutics Limited, Shanghai, People’s Republic of China; 3Center for Clinical Pharmacology, CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd, Shijiazhuang, People’s Republic of ChinaCorrespondence: Zhanjun Dong, Department of Pharmacy, Hebei General Hospital, Hebei Key Laboratory of Clinical Pharmacy, No. 348 Heping West Road, Xinhua District, Shijiazhuang City, Hebei Province, 050051, People’s Republic of China, Tel +86 311 85988604, Email 13313213656@126.comObjective: This study compared the pharmacokinetics, safety and bioequivalence (BE) of generic and original apremilast tablets in healthy Chinese subjects under fasting and postprandial conditions, providing sufficient evidence for abbreviated new drug application.Methods: A randomized, open-label, two-formulation, single-dose, two-period crossover pharmacokinetic study was performed. Thirty-two eligible healthy Chinese subjects were enrolled in fasting and postprandial studies, respectively. In each trial, subjects received a single 30-mg dose of the test or reference apremilast tablet, followed by a 7-day washout interval between periods. Serial blood samples were obtained for up to 48 h post-intake in each period, and the plasma concentrations of apremilast were determined by a validated method. The primary pharmacokinetic (PK) parameters, including the maximum plasma concentration (Cmax), the areas under the plasma concentration–time curve (AUC0-t, AUC0-∞), were calculated using the non-compartmental method. The geometric mean ratios of the two formulations and the corresponding 90% confidence intervals (CIs) were acquired for bioequivalence analysis. The safety of both formulations was also evaluated.Results: Under fasting and postprandial states, the PK parameters of the test drug were similar to those of the reference drug. The 90% CIs of the geometric mean ratios of the test to reference formulations were 94.09– 103.44% for Cmax, 94.05– 103.51% for AUC0-t, and 94.56– 103.86% for AUC0-∞ under fasting conditions, and 99.18– 112.48% for Cmax, 98.79– 106.02% for AUC0-t, and 98.95– 105.89% for AUC0-∞ under postprandial conditions, all of which were within the bioequivalence range of 80.00– 125.00%. Both formulations were well tolerated, and no serious adverse events occurred during the study.Conclusion: The trial confirmed that the PK parameters of the generic and original apremilast tablets were bioequivalent in healthy Chinese subjects under fasting and postprandial states, which met the predetermined regulatory standards. Both formulations were safe and well tolerated.Clinical Trial Registration: chinaDrugtrials.org.cn, identifier CTR20191056 (July 30, 2019); chictr.org.cn, identifier ChiCTR2300076806 (October 19, 2023).Keywords: apremilast, psoriasis, pharmacokinetics, bioequivalence, safety

Ke Wang,1,2,3 Yuying Kou,4 Xing Rong,1,2 Lingling Wei,5 Jingyuan Li,6 Hongrui Liu,1,2 Minqi Li,1,2 Hui Song31Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, People’s Republic of China; 2Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of China; 3Department of Health Care (Department of General Dentistry II), School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, People’s Republic of China; 4School of Stomatology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China; 5Department of Pediatric Dentistry, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, People’s Republic of China; 6Department of Oral Mucosal Disease, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, People’s Republic of ChinaCorrespondence: Hui Song, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration No.44-1 Wenhua Road West, Jinan, Shandong, 250012, People’s Republic of China, Tel +0086-531-88382912, Email songhui@sdu.edu.cnPurpose: Estrogen deficiency is the main reason of postmenopausal osteoporosis. Eldecalcitol (ED-71) is a new active vitamin D analogue clinically used in the treatment of postmenopausal osteoporosis. We aimed to investigate whether EphrinB2-EphB4 and RANKL/RANK/OPG signaling cooperate in mediating the process of osteoporosis by ED-71.Methods: In vivo, the ovariectomized (OVX) rats were administered orally with 30 ng/kg ED-71 once a day for 8 weeks. HE staining, Masson staining and Immunofluorescence staining were used to evaluate bone mass, bone formation, osteoclastogenesis associated factors and the expression of EphrinB2, EphB4, RANKL and OPG. In vitro, H2O2 stimulation was used to simulate the cell environment in osteoporosis. Immunofluorescence, quantitative real time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and Western Blot were applied to detect the expression of EphrinB2, EphB4, RANKL and OPG. In osteoblasts, EphB4 was knocked down by EphB4 small-interfering RNA (siRNA) transfection. LY294002 (PI3K inhibitor) or ARQ092 (AKT inhibitor) was used to block PI3K/AKT pathway. An indirect co-culture system of osteoblasts and osteoclasts was established. The mRNA and protein expression of osteoclastogenes is associated factors were tested by qRT-PCR and Western Blot.Results: ED-71 increased bone mass and decreased the number of osteoclasts in OVX rats. Moreover, ED-71 promoted the expression of EphrinB2, EphB4, and decreased the RANKL/OPG ratio in osteoblasts. Osteoclastogenesis was restrained when osteoclasts were indirectly co-cultured with ED-71-treated osteoblasts. After silencing of EphB4 expression in osteoblasts, ED-71 inhibited the expression of P-PI3K and P-AKT and increased the ratio of RANKL/OPG. This reversed the inhibitory effect of ED-71 on osteoclastogenes. Therefore, in ED-71-inhibited osteoclastogenes, EphB4 is a key factor affecting the secretion of RANKL and OPG by osteoblasts. EphB4 suppressed the RANKL/OPG ratio through activating PI3K/AKT signaling in osteoblasts.Conclusion: ED-71 inhibits osteoclastogenesis through EphrinB2-EphB4-RANKL/OPG axis, improving bone mass in ovariectomized rats. PI3K/AKT pathway is involved this process.Keywords: osteoporosis, eldecalcitol, osteoclasts, EphrinB2-EphB4, osteoblasts, RANKL/RANK/OPG

Chenghui Tan,1,* Huan Song,2,3,* Shanshan Ma,3,4 Xinyu Liu,3,5 Yuan Zhao6 1Department of Psychology, Renmin University of China, Beijing, People’s Republic of China; 2School of Educational Science, Neijiang Normal University, Neijiang, People’s Republic of China; 3School of Education, Soochow University, Suzhou, People’s Republic of China; 4School of Marxism, Nanjing Forestry University, Nanjing, People’s Republic of China; 5Department of Psychology, Wuhan University, Wuhan, People’s Republic of China; 6Police Officer Academy, Shandong University of Political Science and Law, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuan Zhao, Police Officer Academy, Shandong University of Political Science and Law, Jinan, People’s Republic of China, Email sdjnzhaoyuan@163.comBackground: The existence of aggressive behavior in autism spectrum disorders (ASD) raises questions about whether cognitive and emotional factors in social information processing play a role between autistic traits (ATs) and aggressive behavior in the general population, especially in the context of Chinese culture. Moreover, given a possible gender difference in these variables, the study aimed to examine the effect of ATs on aggressive behavior, and the potential mediating role of hostile attribution bias and alexithymia on this association, as well as gender difference.Methods: 850 Chinese college students participated in the assessment, including their ATs, hostile attribution bias, alexithymia, and aggressive behavior. Pearson correlation, mediation effects analyses, and multiple-group comparison were conducted.Results: The results indicated that ATs indirectly predicted increased aggressive behavior through attribution bias and alexithymia. Gender difference in mediating effects was revealed: ATs indirectly predicted increased aggressive behavior through the serial mediating effect only in males.Conclusion: Hostile attribution bias and alexithymia completely mediated the association between ATs and aggressive behavior, which contained the separate mediating effects of (a) hostile attribution bias and (b) alexithymia and the serial mediating effect of (c) hostile attribution bias and alexithymia. Gender differences in mediating effects were found only in the serial mediating effect, which was significant in males but not in females. The findings revealed the internal mechanism of ATs affecting aggressive behavior and gender difference, which have implications for the intervention of aggressive behavior of individuals with autism and those with high levels of ATs.Keywords: autistic traits, aggressive behavior, hostile attribution bias, alexithymia, serial mediating effect, gender difference

Shujie Wang,1,2 Chunyan Shao,2 Xingkai Zhao,1 Yizhe Guo,1 Houhui Song,2 Lida Shen,3 Zhenlei Zhou,1 Zhen Li4,5 1College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, People’s Republic of China; 2College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang Agriculture and Forestry University, Hangzhou, Zhejiang, 311300, People’s Republic of China; 3College of Mechanical and Electrical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, Jiangsu, 210016, People’s Republic of China; 4College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, People’s Republic of China; 5State Key Laboratory of Palaeobiology and Stratigraphy, Nanjing Institute of Geology and Palaeontology and Center for Excellence in Life and Paleoenvironment, Chinese Academy of Sciences, Nanjing, Jiangsu, 210008, People’s Republic of ChinaCorrespondence: Zhenlei Zhou, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, People’s Republic of China, Tel +86 (25) 84395505, Email zhouzl@njau.edu.cn Zhen Li, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, People’s Republic of China, Tel/Fax +86 (25) 84399827, Email lizhen@njau.edu.cnIntroduction: Hydroxylapatite (HAp) is a biodegradable bone graft material with high biocompatibility. However, the clinical application of HAp has been limited due to the poor absorption rate in vivo.Methods: In this study, carbonated hydroxylapatite (CHAp) with a chemical composition similar to natural bone was synthesized. HAp and CHAp scaffolds were fabricated by 3D printing. Each material was designed by two types of scaffold model with a maximum width of 8 mm and a thickness of 2 mm, ie, structure I (round shape) and structure II (grid shape). Then, the HAp scaffolds were loaded with lutein. These scaffolds were implanted into the 8 mm bone defect on the top of the rabbit skull within 3 hours in the morning. The curative effects of the scaffolds were assessed two months after implantation.Results: The 3D printed scaffolds did not cause severe inflammation or rejection after implantation. It showed that the porous structures allow bone cells to enter into the scaffolds. Furthermore, CHAp scaffolds were more biocompatible than HAp scaffolds, and showed a higher level of degradation and new bone formation after implantation. Structure II scaffolds with a smaller mineral content degraded faster than structure I, while structure I had better osteoconductive properties than structure II. Besides, the addition of lutein significantly enhanced the rate of new bone formation.Discussion: The uniqueness of this study lies in the synthesis of 3D printed CHAp scaffolds and the implantation of CHAp in rabbit bone defects. The incorporation of suitable carbonate and lutein into HAp can enhance the osteoinductivity of the graft, and CHAp has a faster degradation rate in vivo, all of which provide a new reference for the research and application of apatite-based composites.Keywords: bone, 3D printing, hydroxylapatite, lutein, repair

Zhao Guo,1,* Haoyun Song,1,* Yingxia Tian,2,* Jie Xu,3 Guokun Zhang,1 Yanan Guo,1 Rong Shen,1 Degui Wang1 1Department of Anatomy and Histology, Lanzhou University School of Basic Medical Sciences, Lanzhou, 730000, People’s Republic of China; 2Department of Internal Medicine, Gansu Provincial Academic Institute for Medical Research, Lanzhou, 730050, People’s Republic of China; 3Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu, 730030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Degui Wang; Rong Shen, Department of Anatomy and Histology, Lanzhou University School of Basic Medical Sciences, Lanzhou, 730000, People’s Republic of China, Tel +86 13893609120 ; +86 13909483373, Fax +86 931 8915023, Email wangdegui@lzu.edu.cn; shenr@lzu.edu.cnBackground: The evident side effects and decreased drug sensitivity significantly restrict the use of chemotherapy. However, nanoparticles based on biomaterials are anticipated to address this challenge.Methods: Through bioinformatics analysis and colon cancer samples, we initially investigated the expression level of RNF8 in colon cancer. Next, we constructed nanocarrier for delivering siRNF8 based on DNA tetrahedron (si-Tet), and Doxorubicin (DOX) was further intercalated into the DNA structure (si-DOX-Tet) for combination therapy. Further, the effects and mechanism of RNF8 inhibition on the sensitivity of colon cancer cells to DOX chemotherapy have also been studied.Results: RNF8 expression was increased in colon cancer. Agarose gel electrophoresis, transmission electron microscopy, and size distribution and potential analysis confirmed the successful preparation of the two nanoparticles, with particle sizes of 10.29 and 37.29 nm, respectively. Fluorescence imaging reveals that the carriers can be internalized into colon cancer cells and escape from lysosomes after 12 hours of treatment, effectively delivering siRNF8 and DOX. Importantly, Western blot analysis verified treatment with 50nM si-Tet silenced RNF8 expression by approximately 50% in colon cancer cells, and combined treatment significantly inhibited cell proliferation. Furthermore, the CCK-8 assay demonstrated that si-Tet treatment enhanced the sensitivity of colon cancer cells to the three chemotherapeutic drugs. Significant more DNA damage was detected after treatment with both si-Tet or si-DOX-Tet. Further flow cytometry analysis revealed that si-DOX-Tet treatment led to significantly more apoptosis, approximately 1.6-fold higher than treatment with DOX alone. Mechanistically, inhibiting RNF8 led to decreased ABCG2 expression and DOX efflux, but increased DNA damage, thereby enhancing the chemotherapeutic effect of DOX.Conclusion: We have successfully constructed si-DOX-Tet. By inhibiting the expression of RNF8, it enhances the chemotherapy sensitivity of DOX. Therefore, this tetrahedral FNA nanocarrier offers a new approach for the combined treatment of colon cancer. Keywords: DNA framework nucleic acid, RNF8, chemosensitivity, RNAi, colorectal cancer

Haojing Song, Bo Qiu, Xue Sun, Caihui Guo, Yiting Hu, Wanjun Bai, Zhanjun Dong Department of Medicine, Hebei General Hospital, Shijiazhuang, 050051, People’s Republic of ChinaCorrespondence: Wanjun Bai; Zhanjun Dong, Department of Medicine, Hebei General Hospital, Shijiazhuang, 050051, People’s Republic of China, Tel +86-0311-85988326 ; +86-0311-85988604, Fax +86-0311-85988604, Email baiwanjun0311@163.com; yqlcdzj@163.comBackground: The objective of this study was to evaluate the effect of a high-fat meal on the pharmacokinetics and safety of 80/5 mg valsartan/amlodipine tablets in healthy subjects.Subjects and Methods: These results were derived from a bioequivalence trial where subjects were randomly assigned to take valsartan/amlodipine 80/5mg under fed conditions or after a high-fat meal contained 978.6 kilocalories (54.6% from fat). The blood samples were collected and plasma concentrations of valsartan/amlodipine were measured using high-performance liquid chromatography-mass spectrometry. The non-compartmental module of Phoenix WinNonlin Version 8.2 was used to calculate pharmacokinetic parameters. The BE module of WinNonLin was used to analyze the statistics of the maximum plasma concentration (Cmax), the area under the concentration-time curve from zero to the last quantifiable time point (AUC0-t), and the area under the concentration-time curve from zero to infinity(AUC0–∞) in plasma. 88 healthy subjects were enrolled and divided into in a fasted group and a fed group.Results: The Cmax, AUC0–t, and AUC0–∞ of valsartan in plasma under fed conditions were 51%, 56%, and 57% lower, respectively, than those under fasted conditions, and the 90% confidence interval (90% CI) were outside the 80.00– 125.00% range. All the pharmacokinetic parameters for amlodipine under fed conditions were similar to those observed under fasted conditions, and the 90% CIs were within the 80.00– 125.00% range. The incidence of treatment emergent adverse events (TEAE) was similar between the fasted group and the fed group, while adverse drug reaction (ADR) was more frequent in the fasted group which may be related to the higher blood concentrations of valsartan, but all were mild.Conclusion: The result indicated that the high-fat meal had a significant effect on the pharmacokinetics of valsartan, but no effect on amlodipine. All treatments were safe and well tolerated in healthy subjects under fed and fasted conditions.Keywords: amlodipine, valsartan, high-fat meal, pharmacokinetics

Haiyan Song,1,2 Hui Zhang,1 Ding Zhang,1 Bo Liu,2 Pengcheng Wang,3 Yanyan Liu,1,4,5 Jiabin Li,1,4– 6 Ying Ye1 1Department of Infectious Disease, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Infectious Disease, the 901st Hospital, Hefei, Anhui, People’s Republic of China; 3Department of Clinical Laboratory, the 901st Hospital, Hefei, Anhui, People’s Republic of China; 4Anhui Center for Surveillance of Bacterial Resistance, Hefei, Anhui, People’s Republic of China; 5Institute of Bacterial Resistance, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 6Department of Infectious Diseases, the Chaohu Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of ChinaCorrespondence: Ying Ye; Jiabin Li, Tel +86-551-62922713, Fax +86-551-62922281, Email yeying2@139.com; lijiabin@ahmu.edu.cnPurpose: This study aims to establish a valuable risk prediction model for mortality in patients with Acinetobacter baumannii (A. baumannii).Patients and Methods: The 622 patients with A. baumannii infection from the First Affiliated Hospital of Anhui Medical University were enrolled as the study cohort. Univariate and multivariate logistic regression analysis was used to preliminarily screen the independent risk factors of death caused by A. baumannii infection, followed by LASSO regression analysis to determine the risk factors. According to the calculated regression coefficient, the Nomogram death prediction model is established. The area under the curve (AUC) and decision curve analysis (DCA) of the operating characteristic (ROC) curve of the subjects are used to evaluate the discrimination of the established prediction model. The calibration degree of the prediction model is represented by a calibration chart. A validation cohort that consisted of 477 patients admitted to the 901st Hospital was also included.Results: Our results revealed that the source of infection, carbapenem-resistant A. baumannii, mechanical ventilation, serum albumin value, and Charlson comorbidity index were independent risk factors for death caused by A. baumannii infection. The AUC value of ROC curves of study cohort and validation cohort were 0.76 and 0.69, respectively. The probability range (30– 80%) indicated a high net income of the modified model and strong capacity of discrimination. The calibration curve obtained by analysis swings up and down around the 45 diagonal line, which shows that the calibration degree of the prediction model is very high.Conclusion: In this study, we have reconstructed a risk prediction model for mortality in patients with A. baumannii infections. This model provides useful information to predict the risk of death in patients with A. baumannii infection, but the specificity is not optimistic. If this prediction model is wanted to be applied to clinical practice, more analysis and research are necessary.Keywords: A. baumannii, prediction model, risk factors, carbapenem resistance

Hanbing Song,* Hongpeng Liu,* XiaoDong Li, Bing Lv, Zonghan Tang, Qipeng Chen, Danqi Zhang, Fei Wang Department of Orthopedics, Heilongjiang University of Traditional Chinese Medicine, Harbin, 150000, Heilongjiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Danqi Zhang; Fei Wang, Surgery Building, Department of Orthopedics, Heilongjiang University of Traditional Chinese Medicine, No. 26 Heping Road, Xiangfang District, Harbin, Heilongjiang Province, People’s Republic of China, Email hljzymzdq@163.com; wangfei631@126.comBackground: This study aims to identify new therapeutic targets and explore the molecular mechanism of ankylosing spondylitis (AS), a rheumatic immune disease that mainly affects the sacroiliac and spinal joints. Despite extensive research, the exact cause of AS is still unknown. The research team utilized a bioinformatics approach to achieve their objectives.Methods: The GSE73754 dataset was downloaded from GEO database. Autophagy-related genes (ARGs) were collected from the Human Autophagy-dedicated Database. The limma package was used to screen for differentially expressed genes (DEGs), which were then intersected with the autophagy-related genes (ARGs) to identify differentially expressed autophagy-related genes (DEARGs). Subsequently, the DEARGs associated with AS were subjected to GO-BP and KEGG enrichment analyses using the clusterProfiler package. Core genes were identified using the cytoHubba plug-in of Cytoscape and were validated by clinical blood samples. Additionally, the Cell algorithm was utilized to evaluate the proportion of immune cell infiltration.Results: A total of 29 DEARGs were identified, which were found to be mainly enriched in autophagy, apoptosis, and necroptosis through functional enrichment analysis. Two core genes, HSPA5 and SQSTM1, were confirmed to have diagnostic value in AS. Immune cell infiltration analysis revealed CD8+ T cells, CD8+ T effector memory (Tem), natural killer (NK) cells, T gamma delta (Tgd) cells, and T-helper 1 (Th1) cells as major participants in AS development. Furthermore, HSPA5 expression was significantly correlated with Th1 cells, CD8+ T cells, CD4+ memory cells, and macrophages.Conclusion: This study suggested that HSPA5 and SQSTM1 can serve as useful diagnostic biomarkers for AS. These findings lay the foundation for identifying crucial mRNAs in the whole blood of AS patients, which may aid in the development of novel markers for AS.Keywords: diagnostic biomarkers, autophagy, immune cell, ankylosing spondylitis

Wanjun Bai,1 Haojing Song,1 Yiting Hu,1 Xueyuan Zhang,2 Xiaoru Wang,3 Caihui Guo,1 Bo Qiu,1 Zhanjun Dong1 1Department of Pharmacy, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of China; 2Shanghai Innovstone Therapeutics Limited, Shanghai, People’s Republic of China; 3CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd, Shijiazhuang, People’s Republic of ChinaCorrespondence: Zhanjun Dong, Department of Pharmacy, Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang City, Hebei Province, 050051, People’s Republic of China, Tel +86 311 85988604, Email 13313213656@126.comObjective: This study compared the pharmacokinetic and safety profiles of generic and original vortioxetine hydrobromide tablets under fasting and fed conditions, and evaluated the bioequivalence of two vortioxetine formulations to obtain sufficient evidence for abbreviated new drug application.Methods: A randomized, open-label, two-formulation, single-dose, two-period crossover bioequivalence study was conducted under fasting and fed conditions (n = 32 per study). Eligible healthy Chinese subjects received a single 10-mg dose of the test or reference vortioxetine hydrobromide tablet, followed by a 28-day washout interval between periods. Serial blood samples were collected up to 72 h after administration in each period, and the plasma concentrations of vortioxetine were detected using a validated method. The primary pharmacokinetic (PK) parameters were calculated using the non-compartmental method. The geometric mean ratios for the PK parameters of the test drug to the reference drug and the corresponding 90% confidence intervals were acquired for bioequivalence analysis. A safety evaluation was performed throughout the study.Results: Under fasting and fed conditions, the PK parameters of the test drug were similar to those of the reference drug. The 90% confidence intervals (CIs) of the geometric mean ratios of the test to reference formulations were 96.44– 105.81% for peak concentration (Cmax), 97.94– 105.05% for the area under the curve truncated at 72 hours (AUC0-72 h) under fasting conditions, 93.92– 104.15% for Cmax, and 96.67– 102.55% for AUC0-72 h under fed conditions, all of which were within the accepted bioequivalence range of 80.00– 125.00%. Both the test and reference formulations were well-tolerated, and no serious adverse events related to the study drug were reported during the study.Conclusion: The PK bioequivalence of the test and reference vortioxetine hydrobromide tablets in healthy Chinese subjects was established under fasting and fed conditions, which met the predetermined regulatory criteria. Both formulations were safe and well tolerated.Keywords: vortioxetine, bioequivalence, pharmacokinetics, safety

Yun-E Xu,1,* Di-Shu Ao,1,* Xin Sun,1 Wei Chen,2 Xue Luo,1 Can Zhao,1 Sheng-Yu Wang,1 Hong Song1 1Department of Microbiology, School of Basic Medical Sciences, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 2Department of Hepatobiliary Surgery, Third Affiliated Hospital of Zunyi Medical University (The First People’s Hospital of Zunyi), Zunyi, 563000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong Song, Department of Microbiology, School of Basic Medical Sciences, Zunyi Medical University, Zunyi, 563000, People’s Republic of China, Tel +86-18985259977 ; +86-0851-28643582, Email hongsong@zmu.edu.cnPurpose: Hydrogels containing the nano-self-assembling peptide RADA16-I (Nanogels) were utilized as scaffolds to establish airway organoids and an adenovirus-infected model. The results support in vitro adenovirus studies, including isolation and culture, pathogenesis research, and antiviral drug screening.Methods: HSAEC1-KT, HuLEC-5a and HELF cells were cocultured in RADA16-I hydrogel scaffolds to construct an airway organoid model. Adenovirus was used to infect this model for adenovirus-related studies. The morphological characteristics and the proliferation and activity of airway organoids before and after adenovirus infection were evaluated. The expression of the airway organoid marker proteins CC10, KRT8, AQP5, SPC, VIM and CD31 was detected. TEM and qPCR were used to detect adenovirus proliferation in airway organoids.Results: HSAEC1-KT, HuLEC-5a and HELF cells cocultured at 10:7:2 self-assembled into airway organoids and maintained long-term proliferation in a RADA16-I hydrogel 3D culture system. The organoids stably expressed the lumen-forming protein KRT8 and the terminal airway markers AQP5 and SPC. Adenoviruses maintained long-term proliferation in this model.Conclusion: An airway-organoid model of adenovirus infection was constructed in vitro from three human lung-derived cell lines on RADA16-I hydrogels. The model has potential as a novel research tool for adenovirus isolation and culture, pathogenesis research, and antiviral drug screening.Keywords: nano-self-assembling peptide, RADA16-I hydrogels, airway organoids, adenovirus

Haojie Song,1 Yueyang Li,1 Qiang Zhang,2 Yanyuan Cheng3 1School of Business, Zhengzhou University, Zhengzhou City, People’s Republic of China; 2Department of Health Policy & Management, Shenzhen Health Development Research and Data Management Center, Shenzhen City, People’s Republic of China; 3School of Labor and Human Resources, Renmin University of China, Beijing City, People’s Republic of ChinaCorrespondence: Qiang Zhang, Department of Health Policy & Management, Shenzhen Health Development Research and Data Management Center, No.8 Yuanling of 5th Street, Futian District, Shenzhen City, Guangdong Province, 518028, People’s Republic of China, Tel +86 0755 22209945, Email zhangqiang110663@sina.comPurpose: This study explored the J-shaped effect of compulsory citizenship behavior on counterproductive work behavior of new generation employees, as well as the separate and joint moderating effects of trust and felt trust on the J-shaped relationship between compulsory citizenship behavior and counterproductive work behavior.Methods: Three waves of data were collected from 659 new generation employees in China. A self-report method was used to measure compulsory citizenship behavior, counterproductive work behavior, trust and felt trust. Then, based on the cognitive appraisal theory of stress and social information processing theory, a nonlinear model was constructed and tested.Results: (1) Compulsory citizenship behavior had a J-shaped effect on job performance. That is, when the compulsory citizenship behavior level was lower, the effect of compulsory citizenship behavior on counterproductive work behavior was not significant; but when it increased to medium and higher levels, the effect was significant and stronger. (2) The moderating effect of trust (employees’ perceived trust in leader) or felt trust (employees’ perception of being trusted by leader) was significant. That is, when trust or felt trust was lower, the J-shaped effect was stronger; conversely, the J-shaped effect was weak. (3) The joint moderating effect of trust and felt trust was significant. That is, when trust was high, the moderation effect of felt trust was significant; conversely, the moderation effect of felt trust was not significant.Conclusion: The results identify the nonlinear effect of compulsory citizenship behavior through exploring the J-shaped effect of compulsory citizenship behavior on counterproductive work behavior and the boundary conditions in the nonlinear relationship. Meanwhile, the study provide implications for organizations regarding how to manage employees’ work behavior.Keywords: compulsory citizenship behavior, counterproductive work behavior, trust, felt trust

Haojie Song,1 Qian Yin,1 Qiang Zhang,2 Yongxin Li3 1School of Business, Zhengzhou University, Zhengzhou City, People’s Republic of China; 2Department of Health Policy & Management, Shenzhen Health Development Research and Data Management Center, Shenzhen City, People’s Republic of China; 3School of Psychology, Henan University, Kaifeng City, People’s Republic of ChinaCorrespondence: Qiang Zhang, Department of Health Policy & Management, Shenzhen Health Development Research and Data Management Center, No. 8, Yuanling of 5th Street, Futian District, Shenzhen City, Guangdong Province, 518028, People’s Republic of China, Tel +86 755 22209945, Email zhangqiang110663@sina.comPurpose: Based on ego depletion theory and interaction ritual theory, this research explores the impact of compulsory citizenship behavior on new-generation knowledge workers’ job performance via the mediating role of ego depletion and the moderating role of relational energy employees experienced in interactions with coworkers.Methods: Two studies were conducted to explore the impact of compulsory citizenship behavior on job performance. Study 1 used a 10-day daily diary Survey (N=112) and Study 2 used a questionnaire survey conducted multiple times (N=356) to test the hypotheses.Results: The results of Study 1 and Study 2 were almost convergent. Compulsory citizenship behavior had a negative effect on job performance through the mediating effect of ego depletion. In addition, relational energy negatively moderated the effect of compulsory citizenship behavior on ego depletion and negatively moderated the mediating effect of ego depletion between compulsory citizenship behavior and job performance.Conclusion: The results deepen our understanding of the mechanism underlying the effect of compulsory citizenship behavior on job performance from the theoretical perspective of psychological energy, and also provide practical implications on how to manage new-generation knowledge employees’ work behavior and job performance.Keywords: compulsory citizenship behavior, ego depletion, job performance, relational energy, new-generation knowledge workers

Yi Geng,1 Yu-Jie Sun,1 Hao Song,1 Qiu-Ju Miao,1 Yi-Fei Wang,1 Jin-Liang Qi,2 Xiu-Lian Xu,1 Jian-Fang Sun1 1Institute of Dermatology, Peking Union Medical College and Chinese Academy of Medical Sciences, Nanjing, 210042, People’s Republic of China; 2State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, People’s Republic of ChinaCorrespondence: Xiu-Lian Xu; Jian-Fang Sun, Email xxlqjl@sina.com; fangmin5758@aliyun.comBackground: Skin cutaneous melanoma (SKCM) is the deadliest dermatology tumor. Ongoing researches have confirmed that the NOD-like receptors (NLRs) family are crucial in driving carcinogenesis. However, the function of NLRs signaling pathway-related genes in SKCM remains unclear.Objective: To establish and identify an NLRs-related prognostic signature and to explore its predictive power for heterogeneous immune response in SKCM patients.Methods: Establishment of the predictive signature using the NLRs-related genes by least absolute shrinkage and selection operator-Cox regression analysis (LASSO-COX algorithm). Through univariate and multivariate COX analyses, NLRs signature’s independent predictive effectiveness was proven. CIBERSORT examined the comparative infiltration ratios of 22 distinct types of immune cells. RT-qPCR and immunohistochemistry implemented expression validation for critical NLRs-related prognostic genes in clinical samples.Results: The prognostic signature, including 7 genes, was obtained by the LASSO-Cox algorithm. In TCGA and validation cohorts, SKCM patients with higher risk scores had remarkably poorer overall survival. The independent predictive role of this signature was confirmed by multivariate Cox analysis. Additionally, a graphic nomogram demonstrated that the risk score of the NLRs signature has high predictive accuracy. SKCM patients in the low-risk group revealed a distinct immune microenvironment characterized by the significantly activated inflammatory response, interferon-α/γ response, and complement pathways. Indeed, several anti-tumor immune cell types were significantly accumulated in the low-risk group, including M1 macrophage, CD8 T cell, and activated NK cell. It is worth noting that our NLRs prognostic signature could serve as one of the promising biomarkers for predicting response rates to immune checkpoint blockade (ICB) therapy. Furthermore, the results of expression validation (RT-qPCR and IHC) were consistent with the previous analysis.Conclusion: A promising NLRs signature with excellent predictive efficacy for SKCM was developed.Keywords: cutaneous melanoma, NLR proteins, immune, survival analysis, prognosis

Tongsong Zhang,1,* Fangfang Shang,2,* Yanhui Ma,3 Yanxia Xu,1 Weihong Sun,4 Haiping Song1 1Department of Oncology, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, Qingdao, Shandong, 266042, People’s Republic of China; 2Department of Pathology, No. 971 Hospital of People’s Liberation Army Navy, Qingdao, 266071, People’s Republic of China; 3Department of Clinical Laboratory, Biotherapy Center, Affiliated Qingdao Central Hospital, Qingdao University, Qingdao, 266042, People’s Republic of China; 4Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, Qingdao, Shandong, 266042, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haiping Song; Yanxia Xu, Department of Oncology, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, 127 Siliu South Road, Qingdao, 266042, People’s Republic of China, Tel +86 532 8496 2202 ; +86 532 84962203, Fax +86 532-84963506, Email yanguangcanlanning@163.com; xyx1021@126.comObjective: To investigate whether the expression of Hsp70 is associated with Cav-1 in promoting the imbalance of Th17/Treg cells in COPD.Methods: The plasma Cav-1, Hsp70 expression were quantified by enzyme-linked immunosorbent assay (ELISA). The frequencies of circulating Th17, Treg cells and Th17/Treg ratio were determined by flow cytometry. Peripheral blood mononuclear cells (PBMCs) from subjects were transfected with Cav-1 or control plasmids and Hsp70 plasmid.Results: We found that Cav-1 expression was lower but the levels of Hsp70 and Th17 cells were higher in COPD than in healthy control (HC). Hsp70 expressions were positively correlated with Cav-1 levels, Th17 cells, and Th17/Treg ratio in COPD but not in HC. Cav-1 over-expression resulted in an increase in Hsp70 and Th17 levels. Suppressing Hsp70 expressing by small interfering RNA (siRNA), the decline of Th17 frequency was observed in Cav-1-overexpressed PBMCs.Conclusion: Collectively, our results illuminate that Cav-1 contributes to the imbalance of Th17/Treg through potentially regulating Hsp70 expression.Keywords: caveolin-1, COPD, Hsp70, IL-17+ Th17 cells, Foxp3+ Treg cells

Guanghui Qiao, Hanqi Song, Songhe Hou, Jinyi Xu School of Tourism and Urban-Rural Planning, Zheshang Research Institute, Zhejiang Gongshang University, Hangzhou, People’s Republic of ChinaCorrespondence: Guanghui Qiao, School of Tourism and Urban-Rural Planning, Zheshang Research Institute, Zhejiang Gongshang University, 18 Xuezheng Street, Qiantang District, Hangzhou, 310018, People’s Republic of China, Tel +86 158 6882 5564, Fax +86 571 2800 8166, Email qiaoguanghuileo@outlook.comAbstract: As the continuous public health crisis, the communicable diseases of COVID-19, OMI and Monkeybox fallout are striking parallels to the whole world. The scope and duration of these disasters are unprecedented. The tourism industry has become one of the hit hardest industries, and research on tourism risks and safety of public health are more of big concerns in recent years. In this study, 751 SSCI articles on risk and tourism from 2008 to 2022 were selected through literature retrieval using the Web of Science core collection database, and visual analysis was performed using CiteSpace to show the knowledge evolution process, research hotspots and future trends in this field. The analysis results show that there has been an overall upward trend in the number of research studies on risk and tourism in the past 15 years. Secondly, there is an international trend toward cooperation between scholars. The main cooperation network centers are Australia, England, the United States and China. In addition, there are seven main clusters of research topics in the field of risk and tourism. Finally, the change of research hotspots is also closely related to catastrophic events. After the outbreak of the COVID-19, public health and the recovery of the tourism industry has attracted more and more scholars’ attention. By examining and analyzing the research content of risk, public health and tourism studies over the past 15 years, this study provides suggestions for the risk management of tourism and tries to predict the new development trend of tourism in the post-COVID-19 era.Keywords: risk, public health, tourism sustainable development, post-covid-19, bibliometrics, CiteSpace

Jing Zhang,1 Haijing Song,2 Yanan Dong,1 Ganghui Li,3 Jun Li,1 Qizhe Cai,4 Shoujun Yuan,5 Yi Wang,1 Haifeng Song1 1State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, People’s Republic of China; 2Emergency Medicine, PLA Strategic Support Force Medical Center, Beijing, 100101, People’s Republic of China; 3China Pharmaceutical University, Nanjing, 211198, People’s Republic of China; 4Department of Echocardiography, Beijing Chao Yang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China; 5Beijing Institute of Radiation Medicine, Beijing, 100850, People’s Republic of ChinaCorrespondence: Haifeng Song; Yi Wang, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, People’s Republic of China, Tel +86 10 81139169, Fax +86 10 81139169, Email songhf@vip.163.com; yves.wangy@vip.163.comBackground: Extracellular vesicles (EVs) are considered a promising drug delivery platform. Naïve EVs face numerous issues that limit their applications, such as fast clearance, hepatic accumulations, and a lack of target-specific tropism. We aimed to explore a series of surface engineering approaches to: 1) reduce the non-specific adhesion of EVs, and 2) improve their enrichment in the target tissue. As a proof-of-concept, we investigated the therapeutic potentials of a multi-modal EVs system carrying a tumor-specific nanobody and the immuno-stimulant interleukin-12 (IL12) using in vivo models of hepatocellular carcinoma.Methods: The major cell adhesion molecule on the HEK293-derived EVs, integrin β 1 (ITGB1), was knocked out (KO) by CRISPR/Cas9-mediated gene editing, followed by deglycosylation to generate ITGB1−Deg EVs for the subsequent pharmacokinetic and biodistribution analyses. ITGB1−Deg EVs were further loaded with glypican-3 (GPC3)-specific nanobody (HN3) and mouse single-chain IL12 (mscIL12) to generate ITGB1−mscIL12+HN3+Deg EVs, for evaluation of tumor tropism and therapeutic potential in a mice model of hepatocellular carcinoma.Results: Removal of ITGB1 led to the broad suppression of integrins on the EVs surface, resulting in a decrease in cellular uptake. Deglycosylation of ITGB1− EVs gave rise to inhibition of the EVs uptake by activated RAW264.7 cells. ITGB1 removal did not significantly alter the pharmacokinetic behaviors of HEK293-EVs, whereas the ITGB1−Deg EVs exhibited enhanced systemic exposure with reduced hepatic accumulation. Loading of HN3 conferred the ITGB1−Deg EVs with tumor-specific tropism for both subcutaneous and metastasized tumors in mice. The ITGB1−mscIL12+HN3+Deg EVs activated mouse splenocytes with high potency. Systemic administration of the EVs with the equivalent dose of 1.5μg/kg of exosomal IL12 achieved satisfactory tumor growth inhibition and good tolerability.Conclusion: The combinatorial approach of EVs surface engineering conferred HEK293-EVs with reduced non-specific clearance and enhanced tumor targeting efficacy, which constituted an efficient delivery platform for critical cancer therapeutics like IL12.Keywords: exosome, glycosylation, glycan, drug delivery

Jingyuan Li,1 Qingbin Han,2 Hui Chen,3 Tingting Liu,1 Jiahui Song,1 Meng Hou,4 Lingling Wei,1 Hui Song1 1School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, Shandong Linyi People’s Hospital, Linyi, People’s Republic of China; 3Department of Endodontics, Jinan Stomatological Hospital, Jinan, People’s Republic of China; 4School of Stomatology, Jining Medical College, Jining, People’s Republic of ChinaCorrespondence: Hui Song, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, 250012, People’s Republic of China, Tel +86-531-88382912, Fax +86-531-88382923, Email songhui@sdu.edu.cnPurpose: Bone marrow-derived mesenchymal stem cells (BMSCs) are hopeful in promoting bone regeneration as their pluripotency in differentiation. Our previous study showed that carbon monoxide-releasing molecule-3 (CORM-3) increased the osteogenic differentiation of rat BMSCs in vitro. However, the mechanism remained unclear. MicroRNAs (miRNAs) play a very important role in modulating the osteogenic differentiation of BMSCs. Therefore, we researched the miRNAs involved in CORM-3-stimulated osteogenic differentiation.Methods: The CORM-3-stimulated osteogenic differentiation of rat BMSCs was further studied in vivo. Based on the gene sequencing experiment, the rat BMSCs were transfected with miR-195-5p mimics and inhibitor, pcDNA3.1-Wnt3a and Wnt3a siRNA. The osteogenic differentiation of rat BMSCs was measured by quantitative real-time polymerase chain reaction, Western blot and alizarin red staining. Additionally, the targeting relationship between miR-195-5p and Wnt3a was confirmed by the dual-luciferase assay.Results: MiR-195-5p was down-expressed during the CORM-3-stimulated osteogenic differentiation of rat BMSCs. CORM-3-stimulated osteogenic differentiation of rat BMSCs was inhibited with miR-195-5p overexpression, evidenced by significantly reduced mRNA and protein expressions of runt-related transcription factor 2 and osteopontin, and matrix mineralization demonstrated. On the contrary, the osteogenic differentiation was enhanced with inhibition of miR-195-5p. CORM-3-stimulated osteogenic differentiation of rat BMSCs was increased by overexpression of Wnt3a, while the opposite was observed in the Wnt3a-deficient cells. Moreover, the decreased osteogenic differentiation capacity by increased expression of miR-195-5p was rescued by Wnt3a overexpression, showing miR-195-5p directly targeted Wnt3a.Conclusion: These results demonstrate that CORM-3 promoted osteogenic differentiation of rat BMSCs via miR-195-5p/Wnt3a, which bodes well for the application of CORM-3 in the treatment of periodontal disease and other bone-defect diseases.Graphical Abstract: Keywords: carbon monoxide-releasing molecule-3, microRNA-195-5p, Wnt3a, osteogenic differentiation, bone marrow mesenchymal stem cells

Hao-ze Shi, Yi-qun Jiang, Xiu-lian Xu, Wei Zhang, Hao Song, Xiao-po Wang, Xue-si Zeng, Jian-fang Sun, Hao Chen Department of Pathology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, People’s Republic of ChinaCorrespondence: Hao Chen; Jian-fang Sun, Department of Pathology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, Email ch76ch@163.com; fangmin5758@aliyun.comBackground: Hypopigmented mycosis fungoides (hMF) is gradually acknowledged by more dermatologists, yet a consensus regarding its characteristics is not reached. The profile of Chinese hMF patients has not been deeply reviewed previously. Our research may contribute to the understanding of hMF, especially the Chinese patients with Fitzpatrick phototypes of III and IV.Aim: To have a better understanding of hMF in terms of clinical, histopathological and immunohistochemical features in the Chinese population and to determine if there are differences between the Chinese population and other ethnic groups.Methods: We made a retrospective analysis of clinical, histopathological and immunohistochemical features of 32 hMF patients in our hospital from 2010 to 2020. These features were then summarized and compared with previous reports.Results: All patients belonged to Fitzpatrick phototypes of III or IV. Twenty-one male (65.63%) patients and 11 female (34.37%) patients were analyzed, and the male to female ratio was 1.9:1. The age at diagnosis of patients ranged from 4 to 39 years, and the average age at diagnosis of these patients was 18 years, the median age was 16.5. Back was the most frequent site (34.37%). The clinical and histological results of lesions had no distinctive points. Immunohistochemically, among these 32 patients, there were 30 patients whose information was complete, there was 19 patients (63.33%) who were CD8 positive lymphocytes predominance, 9 patients (30%) had CD8 and CD4 positive lymphocyte mixed infiltration, and other 2 patients (6.67%) had CD4 positive lymphocytes predominance. Partial loss of CD7 was only observed in 1 patient (3.33%). Nearly all patients adopted topical nitrogen mustard and topical steroid and most of them had an excellent prognosis.Conclusion: The clinical profiles of hMF in Chinese population shared differences with other ethnic groups, but its histopathological, immunohistochemical results and prognosis condition were resembled with other previous reports. Hence, more patients were needed to find the characteristics of hMF.Keywords: hypopigmented, mycosis fungoides, cutaneous, MF

Chunyan Shao,1– 5,* Ziwei Yu,1– 5,* Tongwang Luo,1– 5,* Bin Zhou,1– 5 Quanjiang Song,1– 5 Zhuoyue Li,1– 5 Xiaoqiang Yu,1– 5 Sheng Jiang,1– 5 Yingshan Zhou,1– 5 Wanyu Dong,1– 5 Xingdong Zhou,1– 5 Xiaodu Wang,1– 5 Houhui Song1– 5 1Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Hangzhou, Zhejiang, 311300, People’s Republic of China; 2Zhejiang Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Hangzhou, Zhejiang, 311300, People’s Republic of China; 3Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, Hangzhou, Zhejiang, 311300, People’s Republic of China; 4China-Australia Joint Laboratory for Animal Health Big Data Analytics, Hangzhou, Zhejiang, 311300, People’s Republic of China; 5College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, 311300, People’s Republic of China*These authors contributed equally to this workCorrespondence: Houhui Song; Xiaodu Wang, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, 311300, People’s Republic of China, Tel +86 15064890670 ; +86 18806537583, Email songhh@zafu.edu.cn; xdwang@zafu.edu.cnIntroduction: Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly prevalent and endemic swine pathogen that causes significant economic losses to the global swine industry. Selenium nanoparticles (SeNPs) have attracted increasing attention in the biomedical field, given their antiviral effects. This study aimed to investigate the inhibitory effect of chitosan-coated SeNPs (CS-SeNPs) on PRRSV replication.Methods: In this study, CS-SeNPs were synthesized by chemical reduction and characterized by assessing the morphology, size distribution, zeta potential, and element composition. Marc-145 cells were infected with r-PRRSV-EGFP (0.1 MOI) and inoculated with CS-SeNPs (10 μM). Subsequently, the concentrations of hydrogen peroxide (H2O2) and glutathione (GSH), and glutathione peroxidase (GSH-Px) activity were measured using specific commercial assay kits. ORF5 RNA expression, viral titer, and nucleocapsid (N) protein expression were assessed using qRT-PCR, TCID50, and Western blot. ROS generation, apoptosis rates, and JNK /caspase-3/PARP protein expression were evaluated using dihydroethidium staining, flow cytometry, and Western blot.Results: The results showed that CS-SeNPs treatment significantly suppressed oxidative stress induced by r-PRRSV-EGFP infection by increasing GSH-Px activity, promoting GSH production, and inhibiting H2O2 synthesis. CS-SeNPs treatment significantly inhibited ORF5 gene expression, viral titers, and N protein of r-PRRSV-EGFP at 24 and 48 hours post-infection (hpi) in Marc-145 cells. The increase in apoptosis rates induced by r-PRRSV-EGFP infection was significantly decreased by CS-SeNPs inoculation through inhibiting ROS generation, JNK phosphorylation levels, and cleavage of caspase-3 and PARP mainly at 48 hpi.Conclusion: These results demonstrated that CS-SeNPs suppress PRRSV-induced apoptosis in Marc-145 cells via the ROS/JNK signaling pathway, thereby inhibiting PRRSV replication, which suggested the potential antiviral activity of CS-SeNPs that deserves further investigation for clinical applications.Keywords: chitosan-coated selenium nanoparticles, PRRSV, apoptosis, ROS, JNK signaling pathways

Lin Sun,1– 3,* Bo Peng,1– 3,* Jun Zhou,1– 3 Ping Wang,1 Yuqing Mo,4 Guofang Xu,1 Yi Tao,1 Hejie Song,1– 3 Wei Tang,1– 3 Meiling Jin4 1Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Tang, Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Email tina_tangwei@163.com Meiling Jin, Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China, Email mljin118@163.comPurpose: Allergic asthma is a heterogeneous disease with complex underlying mechanisms. Cytokines are key mediators in immune system and potential indicators of disease status. The aim of this study is to compare the difference of serum cytokine profile in allergic asthma patients with different disease severity and explore candidate biomarkers for disease monitoring and targeting therapeutic agents.Patients and Methods: A total of 40 allergic asthmatics (mild, n=22; moderate-to-severe, n=18) were included in this study. Serum samples, lung function and exhaled nitric oxide data were collected from each subject. A Meso Scale Discovery (MSD) electrochemiluminescence platform was applied to access serum levels of 33 cytokines. Serum cytokine profile was compared between mild and moderate-to-severe allergic asthmatics, and the correlation between serum cytokine levels, lung function and exhaled nitric oxide were analyzed.Results: Moderate-to-severe allergic asthmatics displayed higher levels of eotaxin-1, eotaxin-2, MCP-1, MCP-2, MCP-3, YKL-40 and lower IL-23, IL-31 and TRAIL in serum in comparison with mild allergic asthmatics. Serum YKL-40, eotaxin-1 and MCP-1 had the best ability to discriminate mild and moderate-to-severe allergic asthmatics, with an AUC of 0.833, 0.811 and 0.760. Serum IP-10 was positively correlated with FeNO levels, while FnNO displayed a strong positive correlation with serum IL-25.Conclusion: Compared with mild allergic asthmatics, significant increase in serum eotaxin-1, eotaxin-2, MCP-1, MCP-2, MCP-3, YKL-40 and decrease in serum IL-23, IL-31 and TRAIL was noted in moderate-to-severe allergic asthmatics. YKL-40, eotaxin-1 and MCP-1 might be candidate biomarkers in reflecting severity in allergic asthma patients.Keywords: allergic asthma, cytokine, YKL-40, eotaxin, MCP

Hyunjong Song,1 Jin-Hwa Park2 1Department of Health Policy and Management, College of Health Sciences, Sangji University, Gangwon-do, Republic of Korea; 2College of Nursing, Institute of Nursing Science, Daegu Catholic University, Daegu, Republic of KoreaCorrespondence: Jin-Hwa Park, Tel +82 53 650 4754, Fax +82 53 650 4392, Email parkjh07@cu.ac.krPurpose: The rapidly increasing older adults’ population of South Korea has increased the socioeconomic burden on society due to cognitive decline. In this study, we examined the association between changes in physical activity in the older adults and their cognitive function, a primary criterion for the diagnosis of dementia, using panel data from the 2012– 2018 Korean Longitudinal Study of Aging.Patients and Methods: This study used baseline (2012) and biennial assessment of follow-up data (2014, 2016, 2018) from Korean Longitudinal Study of Aging. A total of 1733 older adults with the Korean version of the Mini Mental State Examination (K-MMSE) scores in the normal range at the time of the first investigation were included in the study. Physical activity was classified into three categories: inactivity, low physical activity, and high physical activity. Changes in physical activity from 2012 were classified into five groups: remained active, became active in 2016, became active in 2014, became inactive, and remained inactive. Participants’ general and health-related characteristics were used as control variables. Descriptive statistics, chi-square tests, and logistic regression analysis were used for analysis.Results: The baseline mean age of the older adults in 2012 was 71.63 years; of the total 1733 participants, 57.1% were inactive, 5.7% had low physical activity, and 37.3% had high physical activity. Changes in physical activity were significantly associated with cognitive decline. Compared to the group that continued regular physical activity, the risk of cognitive decline increased in the case of participants who became or remained inactive.Conclusion: Results highlighted the importance of continuous physical activity and its relation to cognitive function. Encouraging continuous physical activity in the older adults has a positive effect on the prevention of cognitive impairment and dementia. Thus, exercise-based interventions should be implemented a community health service.Keywords: aging, cognition disorders, older adults, physical activity

Mingkai Gong,1 Xiangping Liu,2 Wu Yang,3 Hongming Song,1 Xian Zhao,1 Xiancheng Ai,1 Shuo Wang,1 Haibo Wang1 1Center of Diagnosis and Treatment of Breast Disease, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China; 2Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China; 3Department of International Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of ChinaCorrespondence: Haibo WangCenter of Diagnosis and Treatment of Breast Disease, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of ChinaEmail hbwang66@126.comBackground: Cancer metabolism and specifically lipid metabolism play an important role in breast cancer (BC) progression and metastasis. However, the role of lipid metabolism-associated genes (LMGs) in the prognosis of breast cancer remains unknown.Methods: The expression profiles and clinical follow-up information of 1053 BC were downloaded from The Cancer Genome Atlas (TCGA), and metabolic genes were downloaded from the Gene Set Enrichment Analysis (GSEA) dataset. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed on the differentially expressed metabolism-related genes. Then, the formula of the metabolism-related risk model was composed, and the risk score of each patient was calculated. The breast cancer patients were divided into high-risk and low-risk groups with a cutoff of the median expression value of the risk score, and the prognostic analysis was also used to analyze the survival time between these two groups. Finally, we analyzed the expression, interaction and correlation among the lipid metabolism-associated genes risk model.Results: The results from the prognostic analysis indicated that the survival was significantly poorer in the high-risk group than in the low-risk group in TCGA, and single-sample gene set enrichment analysis (ssGSEA) shows it is plausible that lipid metabolism is highly correlated with tumor immunity.Conclusion: Lipid metabolism-associated genes may become a new prognostic indicator predicting the survival of BC patients. The prognostic genes (n = 16) may help provide new strategies for tumor therapy.Keywords: bioinformatics, lipid metabolism-associated genes, breast cancer, lipid metabolism, TCGA

Jong Min Han,1 Hyunjong Song2 1Convergence Innovation Support Center, Gangwon Technopark, Chuncheon, South Korea; 2Department of Health Policy and Management, Sangji University, Wonju, South KoreaCorrespondence: Hyunjong SongDepartment of Health Policy and Management, Sangji University, 83, Sangjidae-gil, Wonju, Gangwon-do, 26339, South KoreaTel +82 33 738 7916Fax +82 33 738 7910Email igypop@hanmail.netPurpose: This study identified the relationships between perceived household economic status and household economic downturn due to COVID-19 and adolescent depressive symptoms and suicidal ideation.Methods: Participants for this study were extracted from the 13th Korea Youth Risk Behavior Web-Based Survey, conducted from August to November 2020. The participants comprised 54,948 middle and high school students selected by stratified random cluster sampling.Results: The prevalence rates of depressive symptoms and suicidal ideation were 25.2% and 10.9%, respectively. Multivariate logistic regression analysis showed that lower perceived household economic status significantly predicted higher prevalence of depressive symptoms and suicidal ideation. Participants who perceived that their household economic status had declined because of COVID-19 were more likely to have experienced depression and suicidal ideation. These results were similar regardless of the participants’ perceptions of household economic status.Conclusion: This study found that in the ongoing pandemic, there is a need for an active mental health promotion program for adolescents from low-income households, especially those who experienced a recent decline in the household economy.Keywords: COVID-19, adolescent, depression, suicidal ideation, economic condition

Donglu Zhao, Qi Xing, Hang Song, Yan Zhao, Guiying Guo No. 4 Ward of Hematology Department, Institute of Hematology and Oncology, Harbin First Hospital, Harbin 150010, Heilongjiang Province, People’s Republic of ChinaCorrespondence: Donglu ZhaoNo. 4 Ward of Hematology Department, Institute of Hematology and Oncology, Harbin First Hospital, No. 149 Diduan Street, Daoli District, Harbin 150010, Heilongjiang Province, People’s Republic of ChinaTel +86-13936254716Email zhaodonglu123@163.comBackground: Long noncoding RNA LINC00265 or miR-4500 is involved in the pathogenesis of many cancers. However, their functions in acute lymphoblastic leukemia (ALL) remain unknown. In this study, we investigated how LINC00265 and miR-4500 regulate the malignant characteristics of ALL.Methods: Real-time PCR was used in examining the expression of LINC00265 in ALL cell lines and blood of patients with ALL. Cell proliferation, cell migration, and xenograft tumor assays were performed to verify the function of LINC00265 subjected to overexpressing and silencing experiments. The ceRNA mechanism with LINC00265/miR-4500/STAT3 was investigated through luciferase and RNA pull-down assays. Finally, the function of the LINC00265/miR-4500/STAT3 axis subjected to overexpressing and silencing assays was determined through cell proliferation, cell migration, and xenograft tumor assays.Results: LINC00265 was highly expressed in ALL cell lines and blood of patients with ALL and facilitated the proliferation, migration, invasion, and growth of xenograft tumors of ALL cells. The silencing of LINC00265 expression with LINC00265 siRNA significantly inhibited the malignancy of the ALL cells. RNA pull-down and luciferase assays demonstrated that LINC00265 competitively targeted miR-4500 and enhanced STAT3 expression. Furthermore, miR-4500 inhibitors or overexpressed LINC00265 up-regulated STAT3 expression, and miR-4500 mimics or STAT3 shRNAs eliminated the LINC00265-induced malignancy of the ALL cells.Conclusion: Mechanistically, LncRNA LINC00265 can competitively interact with miR-4500 and thereby up-regulates STAT3 signaling and enhances the malignancy of tumors.Keywords: acute lymphoblastic leukemia, LINC00265, miR-4500, cell proliferation

Jing Xu,1,* Fengyuan Chen,1,* Guoquan Wang,1,* Bin Liu,2 Hang Song,1 Teng Ma2 1Department of Biochemistry and Molecular Biology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, People’s Republic of China; 2Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China*These authors contributed equally to this workCorrespondence: Teng Ma; Hang Song Email mateng82913@163.com; hangsong@ahtcm.edu.cnAbstract: G. lucidum has a long history of thousands of years in China and is closely related with the lives of the Chinese people. It is reported to cure various diseases due to its high nutritional value and wide range of uses. The fascinating effects of G. lucidum have tethered a multitude of efforts to explore its effective ingredients and supplement functions. At present, many cancer research studies have reported the G. lucidum polysaccharides (GLPs) and G. lucidum triterpenes (GLTs) as the main active ingredients in G. lucidum, which have shown positive effects on radiotherapy and chemotherapy. GLPs or GLTs treatment synergizes with radiotherapy and chemotherapy through multiple pathways, including oxidative stress, apoptosis, immune microenvironment, etc. Therefore, this review aims to analyze and summarize these complex molecules from G. lucidum in order to create more treatment options for cancer patients in the future.Keywords: GLP, GLTs, pharmacology, general structure, radiotherapy and chemotherapy

Xishuai Wang,1,2 Hanan Song,1 Shiyu Zhao,1 Weijun Guan,1 Yang Gao3 1Department of Animal Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, People’s Republic of China; 2College of P.E and Sport, Beijing Normal University, Beijing, 100875, People’s Republic of China; 3Institute of Physical Educational and Training, Capital University of Physical Education and Sport, Beijing, 100191, People’s Republic of ChinaCorrespondence: Weijun Guan; Yang Gao Email guanweijun1967@163.com; gaoyang195528@126.comObjective: In the present study, we separated and characterized mouse gingival-derived mesenchymal stem cells (GMSCs) and investigated whether GMSCs can improve lipopolysaccharide (LPS)-induced sepsis and its complications.Methods: Ninety-six ICR mice were randomly divided into the following groups: the control (Sham), LPS, and LPS + MSC groups. Mice received 5 mg/kg LPS intraperitoneally to induce sepsis. Histopathological micrographs illustrated organ injury. We detected systemic inflammation, blood glucose levels, and serum levels of high-mobility group box 1 (HMGB1) and lactate. In addition, pulmonary inflammation, lung permeability, and oxidative stress-related indicators in lung tissue were measured.Results: We successfully separated a novel population of MSCs from mouse gingiva. These cells had MSC-associated properties, such as a typical fibroblast-like morphology, multiple differentiation potential, and certain phenotypes. Cell-based therapy using GMSCs significantly improved the survival rate, systemic inflammation, hypoglycemia, multiple organ dysfunction syndrome (MODS), and aortic injury during sepsis. GMSCs administration reduced pulmonary inflammation, lung permeability, and oxidative stress injury. GMSCs administration reduced neutrophil infiltration partly because GMSCs inhibited neutrophil chemoattractants tumor necrosis factor (TNF-α), C-X-C motif chemokine ligand (CXCL-1), and Interleukin (IL-8). GMSCs impaired LPS-induced HMGB1 and lactate release during sepsis.Conclusion: GMSCs administration is a novel therapeutic strategy targeting aerobic glycolysis for the treatment of sepsis because GMSCs impair LPS-induced HMGB1 and lactate release. GMSCs alleviate lung injury partly because GMSCs exert immune effects, inhibit neutrophilic inflammation, and reduce oxidative stress injury.Keywords: mesenchymal stem cells, sepsis, ALI, neutrophilic inflammation, oxidative stress, Warburg effect

Wenqian Shang,1 Jing Zhang,2 Haibo Song,2 Shunfei Zhu,3 Aimin Zhang,1 Yushuang Hua,1 Shujun Han,4 Yan Fu5 1Department of Traditional Chinese Medicine, Zibo Maternal and Child Health Hospital, Zibo, Shandong, 255000, People’s Republic of China; 2Translational Medicine Center, Zibo Maternal and Child Health Hospital, Zibo, Shandong, 255000, People’s Republic of China; 3Clinical Laboratory, Zibo Maternal and Child Health Hospital, Zibo, Shandong, 255000, People’s Republic of China; 4Surgical Department, Zhangdian District Hospital of Traditional Chinese Medicine, Zibo, 255000, Shandong, People’s Republic of China; 5Shandong University of Technology, Zibo, 255000, Shandong, People’s Republic of ChinaCorrespondence: Aimin Zhang; Wenqian ShangDepartment of Traditional Chinese Medicine, Zibo Maternal and Child Health Hospital, No. 66 North Tianjin Road, Zhangdian District, Zibo, Shandong, People’s Republic of ChinaTel +86 18505330408; +86 15053358995Email purplesunk@163.com; shanzhongyiwanyi@126.comBackground: Endometrial cancer (EC) is one of the most common gynaecological malignancies, and its incidence has been rising over the past decade. Tetrandrine, a bisbenzylisoquinoline alkaloid, has been isolated from a vine used in traditional Chinese medicine, Stephania tetrandra. However, the key mechanism of tetrandrine in EC is still unclear.Purpose: This research was designed to predict the molecular mechanisms of tetrandrine against EC based on network pharmacology and to further verify these predictions by in vitro experiments.Methods: The potential therapeutic targets of tetrandrine against EC were predicted by using public databases. Afterwards, the protein–protein interaction (PPI) network of the common targets was constructed, and the key gene targets were obtained. Biological function and pathway enrichment analyses were performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Furthermore, molecular docking and in vitro experiments were carried out to verify the predictions. The cell counting kit‑8 (CCK‑8) assay, Hoechst 33258 staining, flow cytometry analysis, qRT-PCR, Western blot analysis and an immunofluorescence assay were performed.Results: Our findings identified 111 potential therapeutic targets of tetrandrine against EC. We obtained 7 key gene targets from the PPI network analysis. Furthermore, GO enrichment analysis indicated that these targets were mainly associated with metabolic processes, responses to stimulus, and biological regulation. The KEGG pathway analysis showed that the common targets were mainly distributed in the PI3K/Akt signalling pathway. A potential interaction of tetrandrine with Akt1 was revealed by molecular docking. In addition, in vitro experiments showed that tetrandrine significantly inhibited cell proliferation and induced apoptosis in Ishikawa and HEC-1-B cells in dose- and time-dependent manners. The results also revealed that tetrandrine can downregulate the expression of Bcl-2 and upregulate the expression of Bax at the mRNA level. The mRNA levels of Akt were not significantly different in the various tetrandrine (0, 10 and 20μM) groups. However, Western blot analysis demonstrated that the protein expression ratios of p-Akt/Akt decreased at the protein level. The results were further confirmed by immunofluorescence assays.Conclusion: Based on bioinformatic analysis and experimental verification, our findings demonstrated that tetrandrine exerted tumour-suppressive effects on EC by regulating the PI3K/Akt signalling pathway.Keywords: endometrial carcinoma, mechanism, network pharmacology, tetrandrine

Yue Yang, Qinghua Tian, Dan Wang, Fei Yi, Hongmei Song, Wenbin Li, Chungen Wu Department of Diagnostic and Interventional Radiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Chungen Wu; Wenbin LiDepartment of Diagnostic and Interventional Radiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yi Shan Road, Shanghai, People’s Republic of ChinaTel/Fax +86 18930177559; +86 18930177524Email wucgsh@163.com; liwenbin@sjtu.edu.cnObjective: To report our experience of treating painful C1 osteolytic lesions with cement augmentation via a lateral approach under fluoroscopic guidance.Materials and Methods: Nine consecutive patients (eight men and one woman; mean age: 56.7± 13.2 years) with osteolytic lesions of the atlas who underwent cementoplasty via a lateral approach were enrolled in this study. The technical success rate, operation time, and complications were recorded. Visual analogue scale (VAS) and Neck disability index (NDI) were used to evaluate the pain relief and neck function status pre-procedure (baseline) and post-procedure (at 3 days; after 1, 3, 6, 12, 18, and 24 months; and at the last follow-up).Results: The procedure was technically successful without any complications in all patients. The mean procedure time was 44.3± 7.8 min. There were three cases of bone cement leakage, but no clinical symptoms. The mean VAS score decreased from 6.7± 1.0 before the procedure to 3.7 three days after the procedure. The mean NDI score decreased from 67.3± 11.2 before the procedure to 39.3± 13.7 three days after the procedure. The VAS and NDI scores decreased at each follow-up time point, and the difference was statistically significant compared with the scores before the procedure (P< 0.01).Conclusion: Fluoroscopy-guided lateral approach is a feasible, safe, and effective method for treatment of osteolytic lesions of the atlas and can relieve pain and stabilize the bone.Keywords: atlas, C1, lateral, vertebroplasty, fluoroscopy

Hualei Song,1,&ast; Yuntao Zhang,2,&ast; Zihan Zhang,2,&ast; Shijiang Xiong,3 Xiangrui Ma,2 Yourui Li2 1Department of Laboratory, Binzhou Medical University Hospital, Binzhou, 256603, People’s Republic of China; 2Department of Stomatology, Binzhou Medical University Hospital, Binzhou, 256603, People’s Republic of China; 3Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, 250012, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yourui LiDepartment of Stomatology, Binzhou Medical University Hospital, 661#, 2nd Huanghe Road, Binzhou, 256603, Shangdong Province, People’s Republic of ChinaTel +86 543 3256715Email carylee37@qq.comBackground: As commonly bone defect is a disease of jaw that can seriously affect implant restoration, the bioactive scaffold can be used as potential systems to provide effective repair for bone defect.Purpose: A osteoinductive bone tissue engineering scaffold has been prepared in order to explore the effect of bioactive materials on bone tissue engineering.Methods: In this study, NELL-1 nanoparticles (Chi/NNP) and nano hydroxyapatite were incorporated in composite scaffolds by electrospinning and characterized using TEM, SEM, contact angle, tensile tests and in vitro drug release. In vitro biological activities such as MC3T3-E1 cell attachment, proliferation and osteogenic activity were studied.Results: With the addition of nHA and nanoparticles, the fiber diameter of PCL/BNPs group, PCL/NNPs group and PCL/nHA/NNPs group was significantly increased. Moreover, the hydrophilic hydroxyl group and amino group presented in nHA and nanoparticles had improved the hydrophilicity of the composite fibers. The composite electrospun containing Chi/NNPs can form a double protective barrier which can effectively prolong the release time of NELL-1 growth factor. In addition, the hydroxyapatite/NELL-1 nanoparticles electrospun fibers can promote attachment, proliferation, differentiation of MC3T3-E1 cells and good cytocompatibility, indicating better ability of inducing osteogenic differentiation.Conclusion: A multi-functional PCL/nHA/NNPs composite fiber with long-term bioactivity and osteoinductivity was successfully prepared by electrospinning. This potential composite could be used as scaffolds in bone tissue engineering application after in vivo studies.Keywords: polycaprolactone, nanoscaffold, MC3T3-E1 cells, osteogenic activity

Hui Chen,1,2 Yan Dai,1,3 Jing Cui,4 Xiaochun Yin,2 Wei Feng,2 Meiyi lv,1,5 Hui Song1 1Department of VIP Center, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, 250012, Shandong, People’s Republic of China; 2Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong Province, People’s Republic of China; 3Department of Oral and Maxillofacial Surgery, Zibo Central Hospital, Zibo, Shandong Province, People’s Republic of China; 4Department of Oral and Maxillofacial Surgery, Jinan Stomatological Hospital, Jinan, Shandong Province, People’s Republic of China; 5Pediatric Dentistry, Jinan Stomatological Hospital, Jinan, Shandong Province, People’s Republic of ChinaCorrespondence: Hui SongDepartment of VIP Center, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1 Wenhua Road West, Jinan, 250012, Shandong, People’s Republic of ChinaTel +86 53188382923Fax +86 53188382923Email songhui@sdu.edu.cnPurpose: Limited intrinsic regeneration capacity following bone destruction remains a significant medical problem. Multiple regulatory effects of carbon monoxide releasing molecule-3 (CORM-3) have been reported. The aim of this study was to investigate the effect of CORM-3 on the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) during osteogenesis.Patients and Methods: hPDLSCs obtained from healthy periodontal ligament tissues were cultured and identified with specific surface antigens by flow cytometry. Effect of CORM-3 on the proliferation of hPDLSCs was determined by CCK-8 assay. Alizarin red staining and alkaline phosphatase (ALP) activity were used to assess the osteogenic differentiation of hPDLSCs. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were used to detect the expression of the indicated genes. Critical-sized skull defect was made in Balb/c-nude mice, microcomputed tomography (Micro-CT) and Masson trichrome staining were used to assess the new bone regeneration in mice.Results: CORM-3 (400 μmol/l) significantly promoted the proliferation of hPDLSCs. CORM-3 pretreatment not only notably enhanced the mRNA and protein expression of osteo-specific marker OPN, Runx2 and ALP, but also increased mineral deposition and ALP activity by the release of CO on day 3, 7 and 14 (P< 0.05). Degassed CORM-3 did not show the same effect as CORM-3. In animal model, application of CORM-3 with hPDLSCs transplantation highly increased new bone formation in skull defect region.Conclusion: CORM-3 promoted osteogenic differentiation of hPDLSCs, and increased hPDLSCs-induced new bone formation in mice with critical-sized skull defect, which suggests an efficient and promising strategy in the treatment of disease with bone defect.Keywords: CORM-3, hPDLSC, osteo-specific marker, micro-computed tomography, osteopontin, Runx2

Wanguo Feng,1 Ruixi Zhu,2 Junlong Ma,3 Han Song2 1Department of Refractive Surgery, Dalian Aier Eye Hospital, Dalian, 116092, People’s Republic of China; 2Department of Ophthalmology, Heilongjiang Provincial Hospital, Harbin Institute of Technology, Harbin, 150036, People’s Republic of China; 3Department of Ophthalmology, Dalian University Affiliated Xinhua Hospital, Dalian, 116021, People’s Republic of ChinaCorrespondence: Han SongDepartment of Ophthalmology, Heilongjiang Provincial Hospital, Harbin Institute of Technology, Harbin, 150036, People’s Republic of ChinaEmail songhan00111@163.comBackground: Long noncoding RNA (lncRNA) has been reported to play important roles in tumor initiation. However, how lncRNA ELFN1-AS1 affects retinoblastoma development remains unclear. Thus, we sought to elucidate its functions in retinoblastoma progression.Methods: ELFN1-AS1 expression was measured in retinoblastoma tissues and normal tissues by qRT-PCR. CCK8, colony formation and Transwell assay were carried out to investigate the effects of ELFN1-AS1 knockdown on cell malignant behaviors. Bioinformatics analyses were performed to predict the relationship among ELFN1-AS1, miR-4270 and SBK1.Results: ELFN1-AS1 was highly expressed in retinoblastoma tissues and cell lines. ELFN1-AS1 was positively correlated with retinoblastoma progression and prognosis. ELFN1-AS1 knockdown curtailed retinoblastoma proliferation, migration and invasion. ELFN1-AS1 was the competing endogenous RNA for miR-4270 and promoted SBK1expression.Conclusion: Altogether, our findings demonstrated that ELFN1-AS1 promotes retinoblastoma progression through mediating miR-4270/SBK1 axis and might be a promising therapeutic target.Keywords: ELFN1-AS1, miR-4270, SBK1, retinoblastoma, progression

Jinyan Shi,1,* Bilin Tao,2,* Zhongqi Li,2 Huan Song,2 Jizhou Wu,2 Beibei Qiu,2 Jianming Wang2 1Department of Clinical Laboratory, The Fourth People’s Hospital of Lianyungang, Lianyungang, Jiangsu, People’s Republic of China; 2Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianming WangDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People’s Republic of ChinaTel +86-25-86868438Email jmwang@njmu.edu.cnObjective: Drug-resistant tuberculosis (DR-TB) is a growing problem worldwide. The rapid drug susceptibility test (DST) of DR-TB enables the timely administration of a chemotherapy regimen that effectively treats DR-TB. GeneChip has been reported as a novel molecular diagnostic tool for rapid diagnosis but has limited data on the performance of subgroup patients with DR-TB. This study aims to assess the diagnostic value of GeneChip in patients with different sexes, ages, treatment histories, treatment outcomes, and places of residence.Methods: We recruited newly registered sputum smear-positive pulmonary TB patients from January 2011 to September 2020 in Lianyungang City, Jiangsu Province, China. We applied both GeneChip and DST to measure drug resistance to rifampin (RIF) and isoniazid (INH). The kappa value, sensitivity, specificity, and agreement rate (AR) were calculated. We also applied a Classification and Regression Tree to explore factors related to the performance of GeneChip.Results: We observed that sex, age, treatment history, treatment outcomes, and drug resistance type were significantly associated with the performance of GeneChip. For RIF resistance, there was significant accordance in young patients (kappa: 0.79) and cases with the treatment failure outcome (kappa: 0.92). For multidrug resistance (MDR), there was significant accordance in young cases (kappa: 0.77). Compared with previously treated patients, the newly treated patients had a significantly higher AR in detecting RIF resistance (0.97 vs 0.92), INH resistance (0.95 vs 0.89), and MDR (0.98 vs 0.92). The overall sensitivity, specificity, AR and kappa value for the diagnosis of MDR-TB were 0.70 (95% CI: 0.63– 0.70), 0.99 (95% CI: 0.98– 0.99), 0.98 (95% CI: 0.97– 0.98), and 0.72 (95% CI: 0.67– 0.78), respectively.Conclusion: We observed a high concordance between GeneChip and DST among TB patients with different characteristics, indicating that GeneChip can be a potential alternative tool for rapid MDR-TB detection.Keywords: tuberculosis, drug resistance, GeneChip, diagnosis, drug susceptibility test

Dongdong Yin,1,2,* Yanfeng Lin,1,3,* Zhonghong Li,1,4,* Hui Ma,5,* Lanfen Lu,6 Kaiying Wang,1,3 Lang Yang,1,3 Xinying Du,1 Peng Li,1 Kezong Qi,2 Hongbin Song1,* 1Center for Disease Control and Prevention of PLA, Beijing, People’s Republic of China; 2Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control College of Animal Science and Technology, Anhui Agricultural University, Hefei, People’s Republic of China; 3Institute for Disease Control and Prevention, AMMS, Beijing, People’s Republic of China; 4College of Environmental and Chemical Engineering, Nanchang Hangkong University, Nanchang, People’s Republic of China; 5The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China; 6Department of Laboratory Diagnosis, Sun Yat-Sen University Affiliated Zhongshan Hospital, Zhongshan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng Li; Kezong Qi Email jiekenlee@126.com; qkz@ahau.edu.cnBackground: A carbapenem-resistant Escherichia coli (sequence type 5415) strain was isolated from a male patient through routine surveillance in 2018 in Guangzhou, China.Materials and Methods: Bacteria were isolated from a sputum culture and identified by using the Vitek 2 compact system. The blaNDM-5 gene was amplified and confirmed by sequencing. Antimicrobial susceptibility testing was determined by a Vitek 2 compact system. The blaNDM-5 gene was located by Southern blotting. Whole-genome sequencing was carried out using both Illumina MiSeq and Oxford Nanopore MinION.Results: S1-PFGE and Southern blotting showed that the blaNDM-5 gene was located on a novel 66-kb IncFII [F2:A-:B-] plasmid. Conjugation assays revealed that the blaNDM-5-bearing plasmid was self-transferrable. Genomic sequencing and comparative analysis suggested that plasmid p2947-NDM5 likely originated from a combination of an IncFII-type backbone and the blaNDM-5 flanking genetic elements.Conclusion: This is the first report of an ST5414 E. coli strain expressing an NDM-5 β-lactamase. This study highlights the genetic complexity of blaNDM-5 carrying plasmids and the urgent need for continuous active monitoring.Keywords: Escherichia coli, ST5415, NDM-5, IncFII, carbapenem resistant

Huachen Song, Xiaonan Tang, Xiang Li, Yufei Wang, Anjun Deng, Wenjie Wang, Haijing Zhang, Hailin Qin, LianQiu Wu State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of ChinaCorrespondence: Haijing Zhang; LianQiu Wu Tel +86 10-63031589Fax +86 10-63035779Email zhanghaijing@imm.ac.cn; wlq@imm.ac.cnIntroduction: Colitis-associated cancer (CAC) accounts for approximately 15% of IBD patient mortalities. However, currently available anti-CAC drugs possess many disadvantages including safety, specificity and side effects. Therefore, the development of novel anti-CAC compounds is imperative. HLJ2 was a monomeric compound synthesized by our institute and reported to have an effect on ulcer colitis.Methods: In vivo the AOM/DSS-induced CAC model was used to evaluate the effects of HLJ2 on ameliorating CAC symptoms, immunohistochemical analysis was used to analyze the pathological damage to colons and epithelial–mesenchymal transition was for changes of cytokines. In vitro, flow cytometric analysis, immunofluorescence and Western blot were used to detect the inhibition effect of HLJ2 on nuclear factor-κB and epithelial–mesenchymal transition in TGF-β 1-stimulated SW480 cells.Results: In the AOM/DSS animal model, HLJ2 was demonstrated to inhibit the secretion of inflammatory cytokines and nuclear factor-κB, levels of tumorigenesis-related proteins including snail, and finally inhibited a key step in metastasis, epithelial–mesenchymal transition. In vitro, HLJ2 was also shown to inhibit nuclear factor-κB and epithelial–mesenchymal transition in TGF-β 1-stimulated SW480 cells in accordance with in vivo results. Meanwhile, the nuclear factor-κB inhibitor could interrupt the effect of HLJ2 on epithelial–mesenchymal transition.Discussion: HLJ2 may ameliorate CAC through inhibiting nuclear factor-κB and then downstream epithelial–mesenchymal transition. The combination of the obvious improvement in effects on CAC without obvious side effects suggests that HLJ2 could be developed as a potential CAC therapeutic candidate.Keywords: inflammatory bowel disease, colitis-associated cancer, EMT

Particle dark matter could belong to a multiplet that includes an electrically charged state. WIMP dark matter (χ0) accompanied by a negatively charged excited state (χ−) with a small mass difference (e.g. < 20 MeV) can form a bound-state with a nucleus such as xenon. This bound-state formation is rare and the released energy is O(1−10) MeV depending on the nucleus, making large liquid scintillator detectors suitable for detection. We searched for bound-state formation events with xenon in two experimental phases of the KamLAND-Zen experiment, a xenon-doped liquid scintillator detector. No statistically significant events were observed. For a benchmark parameter set of WIMP mass mχ0=1 TeV and mass difference Δm=17 MeV, we set the most stringent upper limits on the recombination cross section times velocity 〈σv〉 and the decay-width of χ− to 9.2×10−30 cm3/s and 8.7×10−14 GeV, respectively at 90% confidence level.

Di-Shu Ao,1,* Lu-Yao Gao,1,* Jing-Han Gu,1 Jun-Hua Qiao,1 Huan Wang,1 Yan-Fei Liu,2 Hong Song1 1Department of Microbiology, School of Basic Medical Sciences, Zunyi Medical University, Zunyi 563000, People’s Republic of China; 2Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan-Fei LiuKey Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, ChinaTel +86-18286276104Email l_yfei@163.comHong SongDepartment of Microbiology, School of Basic Medical Sciences, Zunyi Medical University, Zunyi 563000, People’s Republic of ChinaTel +86-18985259977Email hongsong@zmu.edu.cnPurpose: To construct a three-dimensional (3D) culture model of adenovirus in vitro using the nanoself-assembling peptide RADA16-I as a 3D cell culture scaffold combined with virology experimental technology to provide a novel research method for virus isolation and culture, pathogenesis research, antiviral drug screening and vaccine preparation.Methods: The nanoself-assembling peptide RADA16-I was used as a 3D scaffold material for 293T cell culture, and adenovirus was cultured in the cells. The growth, morphological characteristics and pathological effects of 3D-cultured 293T cells after adenovirus infection were observed with an inverted microscope and MTS. The proliferation of adenovirus in 293T cells was observed by TEM and detected by qPCR. The levels of TNF-α and IL-8 secreted by adenovirus-infected 293T cells in the RADA16-I 3D culture system were detected by ELISA.Results: The 293T cells grew well in the RADA16-I 3D culture system for a prolonged period of time. The adenovirus infection persisted for a long time with multiple proliferation peaks, which closely resembled those of in vivo infections. The adenovirus virions amplified in the 3D system remained infectious. There were multiple secretion peaks of TNF-α and IL-8 secretion levels in adenovirus-infected 293T cells cultured in 3D culture systems.Conclusion: The nanoself-assembling peptide RADA16-I can be used as a 3D scaffold for adenovirus isolation, culture and research. The 3D culture system shows more realistic in vivo effects than two-dimensional (2D) culture.Keywords: nanoself-assembling peptide, 3D culture, adenovirus, 293T cells

Huan Song,1,* Jian Sun,2,* Weimin Kong,2,* Ye Ji,1 Dian Xu,1 Jianming Wang1 1Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, People’s Republic of China; 2Department of Thoracic Surgery, The First People’s Hospital of Yancheng City, Yancheng 224006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianming Wang Department of EpidemiologyCenter for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, People’s Republic of ChinaTel +86-25-86868438Email jmwang@njmu.edu.cnPurpose: Accumulating evidence has indicated that circRNAs are closely involved in tumorigenesis and progression of human cancers. However, the molecular mechanism underlying function of circRNAs in breast cancer has not been thoroughly elucidated. Currently, we aimed to characterize the circRNA-related competing endogenous RNA (ceRNA) regulatory network in breast cancer and to construct prognostic model.Materials and Methods: First, we constructed circRNA expression profiles for paired breast cancer in a Chinese population using a human circRNA microarray. Expression profiles of circRNAs, miRNAs, and mRNAs were retrieved from our circRNA dataset, the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. We applied the limma and edgeR packages to identify differentially expressed RNAs. Weighted gene correlation network analysis (WGCNA) was used to identify critical modules of mRNAs. Next, a ceRNA network was established based on circRNA–miRNA and miRNA–mRNA intersections. Both Cox regression analysis and ROC curve analysis were performed to generate prognostic model. Additionally, we performed Gene Set Enrichment Analysis (GSEA) on prognostic signatures.Results: Total of 59 circRNAs, 98 miRNAs and 3966 mRNAs were identified as differentially expressed RNAs. We first identified 38 miRNA-mRNA pairs and 38 circRNA-miRNA pairs to construct the circRNA–miRNA-mRNA regulatory network and then generated a prognostic model based on 7 signatures (MMD, SLC29A4, CREB5, FOS, ANKRD29, MYOCD, and PIGR), and patients with high-risk scores presented poor prognosis. Several cancer-related pathways were enriched, including the TGF-β pathway, the focal adhesion pathway, and the JAK-STAT signaling pathway, and 20 prognostic ceRNA regulatory networks were subsequently identified.Conclusion: In all, we screened a series of dysregulated circRNAs, miRNAs, and mRNAs, and constructed circRNA-related ceRNA network in breast cancer. Our findings may help to deepen the understanding of circRNA-related regulatory mechanisms. Moreover, we generated a prognostic model that provided new insight into postoperative management for breast cancer.Keywords: ncRNA, ceRNA, circRNA, miRNA, mRNA, breast cancer, TCGA

He Song, Ming Dong Department of Gastrointestinal Surgery of the First Hospital of China Medical University, Shenyang 110001, People’s Republic of ChinaCorrespondence: Ming Dong Tel +8613804900651Fax +862483282881Email dongming@cmu.edu.cnIntroduction: Solid pseudopapillary tumors of pancreas (SPTP) is an indolent rare tumor with malignant potential. The prediction of malignancy is an enigma. The aim of this study is to explore the relationship between operative measurements and malignancy prognosis of SPTP patients.Methods: A cohort of consecutive 102 patients were enrolled in this study. Preoperative measurements and clinical outcomes were analyzed.Results: Eighteen patients (17.6%) were confirmed as malignant. The malignant SPTP of the optimal cut-off value was 47.9 (p=0.012) for prognostic nutritional index (PNI). The value of PNI≤ 47.9 and incomplete capsule were significantly correlated with malignancy. Univariate analysis showed that the PNI≤ 47.9 (p=0.013) and incomplete capsule (p< 0.001) were predictors of disease-specific survival (DSS). Multivariate analysis identified the PNI≤ 47.9 (p=0.036) and incomplete capsule (p=0.023) as the independent prognostic factors of DSS. The new score of 0,1,2 based on PNI and capsule presence stratified the patients into 3 groups. The patients with low PNI and incomplete capsule achieved the worst prognosis.Conclusion: The combination test of operative PNI and capsule presence would be a reliable indicator of the aggressive natural history of SPTP.Keywords: solid pseudopapillary tumor, pancreas, prognostic nutritional index, disease-specific survival

Ting Ye,1,* Hua-Wu Gao,1,* Wei-Ting Xuan,1 Shu Ye,1– 3 Peng Zhou,1– 3 Xin-Quan Li,1 Yan Wang,1– 3 Hang Song,1,2 Yan-Yan Liu,1,2 Biao Cai1– 3 1School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, People’s Republic of China; 2Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei 230012, People’s Republic of China; 3Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei 230012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan-Yan Liu; Biao Cai Email liuyan2027@163.com; caibiao@ahtcm.edu.cnObjective: To investigate the neuroprotective effect of chrysophanol (CHR) on PC12 treated with Aβ25-35, and the involved mechanism.Methods: After the establishment of an AD cell model induced by Aβ25-35, the cell survival rate was detected by MTT, cell apoptosis was assayed by Hoechst 33342 staining, mRNA expressions of calmodulin (CaM), calcium/calmodulin-dependent protein kinase kinase (CaMKK), calcium/calmodulin-dependent protein kinase IV (CaMKIV) and tau (MAPT; commonly known as tau) were determined by qRT-PCR, and protein levels of CaM, CaMKK, CaMKIV, phospho-CaMKIV (p-CaMKIV), tau and phospho-tau (p-tau) were detected by Western blot analysis.Results: When pretreated with CHR before exposure to Aβ25-35, PC12 cells showed that increased cell viability and reduced apoptosis. The qRT-PCR results indicated that the deposition of Aβ25-35 triggers a decrease in levels of CaM, CaMKK, CaMKIV, and tau in PC12 cells. In addition, Western blot results also suggested that Aβ25-35 decreases the protein expression of CaM, CaMKK, CaMKIV, p-CaMKIV, and the ratio of p-tau to tau in PC12 cells. However, the above effects were significantly alleviated after the treatment of CHR.Conclusion: CHR plays a neuroprotective role in AD though decreasing the protein level of CaM-CaMKK-CaMKIV and the expression of p-tau downstream.Keywords: chrysophanol, Alzheimer’s disease, CaM-CaMKK-CaMKIV, p-tau

Honghai Song,1,2,* Yang Zhou,1,* Aifen Peng,3 Jiaming Liu,1,2,4 Xin Wu,1 Wenzhao Chen,1 Zhili Liu1,2,5 1Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of China; 2Institute of Spinal and Spinal Cord Diseases, Nanchang University, Nanchang 330031, People’s Republic of China; 3College of Humanities, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, People’s Republic of China; 4Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, People’s Republic of China; 5Division of Science and Technology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhili LiuDepartment of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, People’s Republic of ChinaTel/ Fax +86-79188693201Email zgm7977@163.comPurpose: Osteosarcoma (OS) is the most common primary malignant tumor of the bone in young adolescents and children. We explored the underlying mechanism of Aurora-B in promoting OS cell proliferation and metastasis.Patient and Methods: Bioinformatics was employed to predict the substrate of Aurora-B. IHC and Western blot were used to confirm the correlation between Aurora-B and NPM1. ERK/NF-κβ pathway-related proteins were detected by Western blot and immunofluorescence (IF). CCK8, wound healing, transwell, and Tunel assays were used to identify the cell proliferation, migration and apoptosis potential. Spontaneous metastasis xenografts were established to confirm the role of Aurora-B and NPM1.Results: Aurora-B promotes NPM1 phosphorylation on Ser125. The phosphorylation of NPM1Ser125 induced by Aurora-B activates the ERK/NF-κβ signaling. Further study revealed that Aurora-B promotes proliferation, migration and inhibits apoptosis via phosphorylating NPM1 in vitro and in vivo.Conclusion: Aurora-B promotes OS malignancy via phosphorylating NPM1Ser125 and activating ERK/NF-κβ signaling.Keywords: Aurora-B, osteosarcoma, NPM1, ERK, NF-κβ

Pinli Yue,1,* Menglan Zhou,1– 3,* Lintao Zhang,1,* Qiwen Yang,1 Hongmei Song,1 Zhipeng Xu,1 Ge Zhang,1 Xiuli Xie,1 Yingchun Xu1 1Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China; 2Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China; 3Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiwen Yang; Yingchun Xu Email yangqiwen81@vip.163.com; xycpumch@139.comBackground: The aim of this study was to evaluate the clinical performance of the BD Kiestra InoqulA automated specimen processing system with commonly encountered clinical microbiology specimens.Materials and Methods: Four types of clinical specimens (sputum, urine, normally sterile body fluids, and feces) were inoculated onto relevant agar plates using a manual method and the BD Kiestra automated system. The number of isolated pathogen species, number of isolated single colonies and uniformity of plate streaking were calculated and compared between two methods.Results: Significantly more isolated colonies were observed on plates inoculated by InoqulA for all specimen types and media with the exception of sputum specimens inoculated onto chocolate agar with vancomycin (P =0.076) and urine onto China blue agar (P =0.856). The quality of plate streaking was also better with InoqulA for all specimen types and media with the exception of urine specimens (P =1.000) and sterile body fluids (P =0.56) inoculated onto China blue agar.Conclusion: This is the first evaluation study of InoqulA with 4 types of clinical specimens in China. It focused on the effect of streaking plates automatically with the magnetic bead. Inoculation of clinical specimens with the BD Kiestra InoqulA system is superior to the manual method for recovery of single colonies and the overall quality of semi-quantitative plate streaking.Keywords: BD Kiestra, InoqulA, microbiology automation

Kaiying Wang,1,2,* Peihan Li,1,2,* Jinhui Li,2,* Xiaofeng Hu,2,* Yanfeng Lin,1,2 Lang Yang,1,2 Shaofu Qiu,2 Hui Ma,*,3 Peng Li,2 Hongbin Song2 1College of Military Medicine, Academy of Military Sciences, Beijing, People’s Republic of China; 2Center for Disease Control and Prevention of PLA, Beijing, People’s Republic of China; 3The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng Li; Hongbin Song Tel/ Fax +86-10-66948475Email jiekenlee@126.com; hongbinsong@263.netBackground: The New Delhi metallo-β-lactamase-1 (NDM-1)-positive plasmid and its variants pose daunting threats to public health. Hospital sewage was considered as an important reservoir of antibiotic genes. Numerous and diverse taxa of multidrug-resistant (MDR) bacteria carrying NDM-1-positive plasmids have been identified during routine surveillance of hospital sewage. We herein report a carbapenem-resistant Acinetobacter towneri strain AeBJ009 with an NDM-1-positive plasmid isolated from hospital sewage.Materials and Methods: Bacteria were isolated from cultures of hospital sewage and identified by using the Vitek 2 compact system and 16S rRNA sequencing. The blaNDM-1 gene was amplified and confirmed by sequencing. Antimicrobial susceptibility testing was performed using AST-GN14 on the Vitek2 compact system. In addition, the blaNDM-1 gene was located by Southern blotting. Conjugation experiment and whole-genome sequencing were performed for further analysis.Results: Strain AeBJ009 was isolated from hospital sewage and identified as A. towneri. Antimicrobial susceptibility testing revealed an MDR phenotype. Pulsed-field gel electrophoresis and Southern blotting showed that strain AeBJ009 carries three plasmids and that blaNDM-1 is located on the 47kb plasmid pNDM-AeBJ009. However, the conjugation experiment to transfer pNDM-AeBJ009 to Escherichia coli strain J53 was unsuccessful. Whole-genome sequencing found that pNDM-AeBJ009 contains a Tn 125 element carrying blaNDM-1. The ble gene downstream of blaNDM-1 displayed a single-nucleotide polymorphism compared to its homologue on plasmid pM131_NDM1. BLAST analysis using the Comprehensive Antibiotic Resistance Database identified no gene polymorphisms with 100% identity to our ble variant.Conclusion: The A. towneri strain AeBJ009 exhibiting an extended spectrum of antibiotic resistance was isolated from hospital sewage and may potentially exacerbate the risk of MDR bacterial infections. The prevention of nosocomial infections due to drug-resistant bacteria will require enhanced monitoring and control of MDR pathogens in environmental reservoirs.Keywords: NDM-1, ble, Acinetobacter towneri, drug resistance