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Shutong Ren,1,&ast; Siyu Chen,2,&ast; Jingru Huang,3 Rong Yu,1 Yunli Wu,4 Xian-E Peng1,4 1Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, 350122, People’s Republic of China; 2State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen, 361104, People’s Republic of China; 3Department of Clinical Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, People’s Republic of China; 4Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xian-E Peng; Yunli Wu, Email fmuxe@163.com; wuyunli422@163.comObjective: This study aimed to explore the association between serum uric acid (sUA) levels and metabolic-associated fatty liver disease (MAFLD) in Southeast China.Methods: We performed a cross-sectional study of 2605 subjects who underwent physical examination between 2015 and 2017 in Southeast China. To explore the association between sUA levels and the risk of MAFLD, we employed logistic regression, restricted cubic spline (RCS), subgroups and multiplicative interaction analysis.Results: Logistic regression analysis showed a positive association between sUA and MAFLD [aOR total population (95% CI)= 1.90 (1.49 ~ 2.42)], [aOR male (95% CI)= 2.01 (1.54 ~ 2.62)], [aOR female (95% CI)= 1.15 (0.62 ~ 2.11)], respectively. The RCS plot presented a significant nonlinear dose–response relationship between sUA levels and MAFLD risk, and the risk of MAFLD increased significantly when sUA> 5.56 mg/dL (Pnonlinear< 0.001). Subgroups analysis revealed that the positive association between sUA and MAFLD was consistent across strata of gender, age, BMI, drinking status, smoking status and tea drinking status. Significant associations between sUA and MAFLD were not only found in males but also existed in subjects whose age ≤ 60, BMI ≥ 24 kg/m2, drinkers, smokers and tea-drinkers. Adjusted ORs were estimated to be 2.01, 1.95, 2.11, 2.29, 2.64 and 2.20, respectively. Multiplicative interactions were not observed between gender, age, drinking status, smoking status, tea drinking status and sUA (all P interaction> 0.05).Conclusion: According to our study, sUA was positively associated with the risk of MAFLD. Additionally, the risk of MAFLD increased significantly when sUA levels exceeded 5.56 mg/dL. Our study may help clarify whether sUA plays a diagnostic role in MAFLD.Keywords: metabolic-associated fatty liver disease, serum uric acid, risk, cross-sectional study

Chuang Cai,1,&ast; Wentan Zeng,2,&ast; Hongwei Wang,3 Shuqi Ren2 1Cancer Research Institute of Zhongshan City, Zhongshan City People’s Hospital, Zhongshan City, Guangdong Province, People’s Republic of China; 2Department of Laboratory Medicine, Tanzhou People’s Hospital of Zhongshan, Zhongshan City Hospital of Integration of TCM & Western Medicine, Zhongshan City, Guangdong Province, People’s Republic of China; 3Department of Pediatrics, Tanzhou People’s Hospital of Zhongshan, Zhongshan City hospital of integration of TCM & western medicine, Zhongshan City, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuqi Ren, Department of Laboratory Medicine, Tanzhou People’s Hospital of Zhongshan, Zhongshan City hospital of integration of TCM & western medicine, No. 10 Dexiu road, Zhongshan City, Guangdong Province, People’s Republic of China, Tel +8615521067602, Fax +860760-23639928, Email shuchijen@163.com Chuang Cai, Cancer Research Institute of Zhongshan City, Zhongshan City People’s Hospital, No. 2 Sunwen East Road, Zhongshan City, Guangdong Province, 528404, People’s Republic of China, Tel +86 18826431030, Fax +86 0760-88823566, Email caich6@foxmail.comPurpose: Hierarchical management is advocated in China to effectively manage chronic obstructive pulmonary disease (COPD) patients and reduce the incidence and mortality of acute exacerbation of COPD (AE-COPD). However, primary and community hospitals often have limited access to advanced equipment and technology. Complete blood count (CBC), which is commonly used in these hospitals, offers the advantages of being cost-effective and easily accessible. This study aims to evaluate the significance of routine blood indicators in aiding of diagnosing AE-COPD.Patients and Methods: In this research, we enrolled a total of 112 patients diagnosed with AE-COPD, 92 patients with stable COPD, and a control group comprising 60 healthy individuals. Clinical characteristics, CBC parameters, and serum CRP levels were collected within two hours. To assess the associations between NLR/PLR/MLR and CRP by Spearman correlation test. The diagnostic accuracy of NLR, PLR and MLR in AE-COPD was assessed using Receiver Operating Characteristic Curve (ROC) and the area under the curve (AUC). Binary Logistic Regression analysis was conducted for the indicators of NLR, PLR and MLR.Results: We found that patients with AE-COPD had significantly higher levels of NLR, PLR and MLR in contrast to patients with stable COPD. Additionally, the study revealed a noteworthy correlation between CRP and NLR (rs=0.5319, P< 0.001), PLR (rs=0.4424, P< 0.001), and MLR (rs=0.4628, P< 0.001). By utilizing specific cut-off values, the amalgamation of NLR, PLR and MLR augmented diagnostic sensitivity. Binary logistic regression analysis demonstrated that heightened NLR and MLR act as risk factors for the progression of AE-COPD.Conclusion: The increasing levels of NLR, PLR and MLR could function as biomarkers, akin to CRP, for diagnosis and assessment of acute exacerbations among COPD patients. Further research is required to validate this concept. Keywords: acute exacerbation of chronic obstructive pulmonary disease, AE-COPD, neutrophil-lymphocyte ratio, NLR, platelet-lymphocyte ratio, PLR, monocyte-lymphocyte ratio, MLR

Yufeng Ling,1 Menglu Duan,1 Wen Lyu,1 Jie Yang,1,2 Yu Liu,1,3 Shuangshuang Ren,1,4 Wenlei Wu1,3 1Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of China; 2Department of Periodontology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of China; 3Department of Senior Specialist, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of China; 4Department of Cariology and Endodontics, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of ChinaCorrespondence: Wenlei Wu; Shuangshuang Ren, Tel +025-83620252 ; +025-83620215, Email wlwu@nju.edu.cn; zjndrenss@163.comIntroduction: Periodontitis, a chronic inflammatory disease prevalent worldwide, is primarily treated through GTR for tissue regeneration. The efficacy of GTR, however, remains uncertain due to potential infections and the intricate microenvironment of periodontal tissue. Herein, We developed a novel core-shell structure multifunctional membrane using a dual-drug-loaded coaxial electrospinning technique (Lys/ACP-CNF), contains L-lysine in the outer layer to aid in controlling biofilms after GTR regenerative surgery, and ACP in the inner layer to enhance osteogenic performance for accelerating alveolar bone repair.Methods: The biocompatibility and cell adhesion were evaluated through CCK-8 and fluorescence imaging, respectively. The antibacterial activity was assessed using a plate counting assay. ALP, ARS, and RT-qPCR were used to examine osteogenic differentiation. Additionally, an in vivo experiment was conducted on a rat model with acute periodontal defect and infection. Micro-CT and histological analysis were utilized to analyze the in vivo alveolar bone regeneration.Results: Structural and physicochemical characterization confirmed the successful construction of the core-shell fibrous structure. Additionally, the Lys/ACP-CNF showed strong antibacterial coaggregation effects and induced osteogenic differentiation of PDLSCs in vitro. The in vivo experiment confirmed that Lys/ACP-CNF promotes new bone formation.Conclusion: Lys/ACP-CNF rapidly exhibited excellent antibacterial activity, protected PDLSCs from infection, and was conducive to osteogenesis, demonstrating its potential application for clinical periodontal GTR surgery. Keywords: anti-microbial therapy, L-lysine, electrospun membrane, osteogenic, periodontal tissue regeneration

Leijuan Gan,1– 3,&ast; Mengran Lang,1– 4,&ast; Xindi Tian,1– 3 Shaohua Ren,1– 3 Guangtao Li,1– 3 Yayue Liu,1– 3 Ruyu Han,1– 3 Kangwei Zhu,1– 3 Huikai Li,1– 3 Qiang Wu,1– 3 Yunlong Cui,1– 3 Wei Zhang,1– 3 Feng Fang,1– 3 Qiang Li,1– 3 Tianqiang Song1– 3 1Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China; 2Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China; 3Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China; 4Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang, Hebei, 065001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tianqiang Song, Tel +86-022-23340123, Fax +86 022-23537796, Email songtianqiangtj@163.comPurpose: The purpose of this study was to investigate the triple-combination therapy of lenvatinib plus sintilimab plus arterially-directed therapy as a conversion therapy for initially unresectable hepatocellular carcinoma (HCC).Patients and Methods: We retrospectively analyzed data from all HCC patients who underwent lenvatinib plus sintilimab plus arterially-directed therapy at Tianjin Medical University Cancer Hospital between December 2018 and October 2020. Of 98 enrolled patients, 37 patients were classified as potentially resectable. We compared the potentially resectable population (PRP) with the non-potentially resectable population (NPRP). The primary study endpoint was conversion rate, and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.Results: The baseline characteristics were comparable between populations except for a higher proportion of patients with extrahepatic metastases in the NPRP versus PRP (23/61 [37.7%] vs 3/37 [8.1%], respectively; p=0.003). For PRP, the ORR was 67.6% based on RECIST v1.1 (75.7% based on mRECIST), conversion rate was 40.5% (15/37). Of the 15 patients who underwent surgical resection, three achieved complete pathological remission. The median follow-up for all patients was 28 months (range: 2– 47). For NPRP, the ORR was 22.9% based on RECIST v1.1 (31.1% based on mRECIST), The median PFS for PRP was significantly longer than that of NPRP (25 vs 13 months, p = 0.0025). The median OS for PRP was significantly longer than that of NPRP (not reached VS 21 months, p=0.014). Hypertension was the most common grade ≥ 3 adverse reaction in both PRP and NPRP. No new safety signals were observed for any of the treatments.Conclusion: The triple-combination therapy of lenvatinib plus sintilimab plus arterially-directed therapy can convert potentially unresectable HCC into resectable disease and improve long-term survival.Keywords: lenvatinib, sintilimab, conversion therapy, unresectable hepatocellular carcinoma, TACE, HAIC

Xincong Li,1,&ast; Shuangshuang Ren,1,&ast; Lutong Song,1 Deao Gu,2 Haoran Peng,1 Yue Zhao,1 Chao Liu,2 Jie Yang,3 Leiying Miao1 1Department of Cariology and Endodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210008, People’s Republic of China; 2Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210008, People’s Republic of China; 3Department of Periodontology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210008, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Leiying Miao; Jie Yang, Email miaoleiying80@163.com; dorothy0314@sina.comIntroduction: Antibacterial photodynamic treatment (aPDT) has indispensable significance as a means of treating periodontal disorders because of its extraordinary potential for killing pathogenic bacteria by generating an overpowering amount of reactive oxygen species (ROS). The elevated ROS that may result from the antibacterial treatment procedure, however, could exert oxidative pressure inside periodontal pockets, causing irreparable damage to surrounding tissue, an issue that has severely restricted its medicinal applications. Accordingly, herein, we report the use of black phosphorus nanosheets (BPNSs) that can eliminate the side effects of ROS-based aPDT as well as scavenge ROS to produce an antibacterial effect.Methods: The antibacterial effect of ICG/aPDT was observed by direct microscopic colony counting. A microplate reader and confocal microscope enabled measurements of cell viability and the quantification of ROS fluorescence. BPNS administration regulated the oxidative environment. IL-1β, IL-6, TNF-α, IL-10, TGF-β, and Arg-1 mRNA expression levels were used to assess the inflammatory response after BPNS treatment. In vivo, the efficacy of the combination of BPNSs and ICG/aPDT was evaluated in rats with periodontal disease by histomorphometric and immunohistochemical analyses.Results: The CFU assay results verified the antibacterial effect of ICG/aPDT treatment, and ROS fluorescence quantification by CLSM indicated the antioxidative ability of the BPNSs. IL-1β, IL-6, TNF-α, IL-10, TGF-β, and Arg-1 mRNA expression levels were significantly decreased after BPNS treatment, confirming the in vitro anti-inflammatory effect of this nanomaterial. The histomorphometric and immunohistochemical analyses showed that the levels of proinflammatory factors decreased, suggesting that the BPNSs had anti-inflammatory effects in vivo.Conclusion: Treatment with antioxidative BPNSs gives new insights into future anti-inflammatory therapies for periodontal disease and other infection-related inflammatory illnesses and provides an approach to combat the flaws of aPDT.Graphical Abstract: Keywords: periodontitis, black phosphorus nanosheets, reactive oxygen species, antibacterial photodynamic therapy, macrophage polarization

Anjun Song,1,&ast; Hui Yang,2,&ast; Guofeng Wu,1 Siying Ren,1 Likun Wang,1 Guannan Qin,1 Yuanhong Mao1 1Emergency Department, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 2Guiyang Public Health Treatment Center, Guiyang, Guizhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Anjun Song, Email 351815967@qq.comObjective: The present study aimed to evaluate the clinical value of minimally invasive surgery for intracranial hematoma removal and high intracranial pressure (ICP) reduction using a novel three-needle brain puncture technique.Methods: A total of 202 cases with supratentorial hematoma were analyzed, 54 of whom received three-needle brain puncture (study group), and the remaining cases received single-needle (control groups 1 and 2) and two-needle brain puncture (control group 3). The amount of intracranial hematoma removed, changes in ICP, retention time of puncture needle, volume of residual blood, the National Institute of Health Stroke Scale (NIHSS) score, and postoperative survival rate were used as indexes to evaluate patient outcomes.Results: We found that three-needle brain puncture (study group) can remove more intracranial hematoma (P < 0.05) and achieve lower ICP (P < 0.05) than single- and two-needle brain puncture (control group). The needle retention time and volume of residual blood significantly decreased in the study group. Additionally, a statistically significant difference was observed in the NIHSS scores and survival rates between the study and control groups (P < 0.05).Conclusion: These data suggest that three-needle minimally invasive stereotactic puncture can effectively remove hematoma, reduce ICP, decrease the degree of brain damage, and improve prognosis.Keywords: cerebral hemorrhage, intracranial pressure monitoring, minimally invasive procedures, three-needle puncture, National Institute of Health Stroke Scale

Xiaoshi Sun, Tianlian Li, Yumeng Tian, Shuying Ren, Ling Li, Ping Li Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of ChinaCorrespondence: Ping Li, Email s6800@163.comPurpose: We investigated the association of omentin with metabolic syndrome (MetS), MetS components, and obesity in adolescents.Methods: A total of 742 middle-school students from Liaoyang City were enrolled in this cross-sectional study using the stratified cluster sampling method. Clinical information and blood samples were collected, and serum omentin levels were measured using enzyme-linked immunosorbent assay.Results: Mean plasma omentin levels were lower in male than in female participants (88.25 (interquartile range 63.02– 133.61) vs 99.46 (interquartile range 69.08– 188.35) ng/L, P = 0.004). The participants were divided into four groups according to the quartile (Q) values of omentin from low to high. With increasing omentin levels from Q1 to Q4, the age of adolescents and the proportion of males gradually increased (P < 0.05), whereas the body mass index (BMI) (P < 0.05) and prevalence of MetS (P > 0.05) tended to decrease. Omentin levels were significantly and negatively correlated with waist circumference and BMI (correlation coefficients of ˗0.099 and ˗0.115, respectively). Regression analysis showed that omentin level was independently associated with the risk of MetS (Odds ratio, OR = 0.639, 95% confidence interval, CI (0.432, 0.945)), which was attributed to the association with central obesity (OR = 0.775, 95% CI (0.605, 0.993)) among MetS components. Increased omentin levels also indicated a reduced risk of obesity (OR = 0.700, 95% CI (0.563, 0.870)).Conclusion: Omentin is an independent predictor of MetS and obesity among adolescents in northeast China.Keywords: metabolic syndrome, omentin, adolescents, obesity, insulin resistance

Linfeng Yu1 &ast;, Xiuding Yang1 &ast;, Wenlong Guan,1 Dongxu Zhang,1 Shuo Ren,2 Yanwei Xing,1 Da An,3 Jian Zhang,1 Yuekun Zhu,1 Anlong Zhu1 1Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 2Department of Gastrointestinal Surgery, Sichuan Cancer Hospital, Chengdu, People’s Republic of China; 3Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Anlong Zhu, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China, Tel/Fax +86 13504848555, Email zhuanlone@163.comPurpose: This study aims to identify key genes in slow transit constipation (STC). We also sought to explore the potential link between STC and colorectal cancer.Patients and Methods: mRNA expression profiles were obtained by RNA sequencing, and differentially expressed genes were identified. Functional enrichment analysis and a protein–protein interaction (PPI) network was explored, and differentially expressed genes common to STC and colorectal cancer were examined. Analysis of the effect of constipation and colorectal cancer common genes on the overall survival of colorectal cancer patients based on GEPIA database.Results: Functional enrichment showed that significantly different genes are related to lymphocyte chemotaxis, positive regulation of inflammatory response, cellular response to tumor necrosis factor, extracellular region, extracellular space and chemokine activity. The hub gene for STC was found in the PPI network. In addition, AQP8 and CFD were common differential genes for STC and colorectal cancer. AQP8 affects overall survival in patients with colorectal cancer.Conclusion: Our findings will contribute to understanding the pathology of STC at the molecular level, with the first discovery that AQP8 may be a hub gene in the transition from STC to colorectal cancer.Keywords: slow transit constipation, RNA sequencing, hub genes, colorectal cancer, AQP8

Leijuan Gan,&ast; Shaohua Ren,&ast; Mengran Lang,&ast; Guangtao Li, Feng Fang, Lu Chen, Yayue Liu, Ruyu Han, Kangwei Zhu, Tianqiang Song Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tianqiang Song, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China, Email songtianqiangtj@163.comPurpose: This study aimed to explore the relationship between the tumor marker score (TMS) and the postoperative recurrence of single small hepatocellular carcinoma (HCC).Patients and Methods: A total of 409 patients with one resectable HCC with a diameter of 3 cm or less who visited Tianjin Medical University Cancer Institute & Hospital from January 2010 to December 2014 were included in this study. Their alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) levels were classified into low and high groups using X-tile software. Each patients’ TMS was calculated as the sum of each tumor marker (low = 0; high = 1).Results: A total of 142 patients were classified as TMS0, 171 as TMS1, and 96 as TMS2. Kaplan–Meier analysis illustrated that TMS could divide the patients into groups with remarkably different prognoses, and the patients with high TMS had worse recurrence-free survival (RFS) than those with low TMS. Multivariate analysis showed that TMS, age, and HBeAg positive were the independent predictors of RFS rate. Subgroup analysis revealed that high TMS was a stable risk factor relative to TMS0. Receiver operating curves showed that the 1-, 3-, and 5-year area under curve (AUC) values of TMS were 0.698, 0.662, and 0.673, respectively. The AUC of TMS was higher than that of other common prognostic models in time-dependent receiver operating curve.Conclusion: TMS was an independent prognostic factor for the postoperative recurrence of a single small HCC and can provide a well-discriminated risk stratification, thus contributing to prognostic prediction and adjuvant therapeutic development.Keywords: hepatocellular carcinoma, recurrence-free survival, tumor marker score, alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 19-9

Yang Y, Ren S, Zhang X, et al. Int J Nanomedicine. 2018;13:3751-3762. The authors have advised that there were some editing errors for Figure 1C on page 3756 and Figure 3D on page 3759. Figure 1C did not clearly depict the boundary of Ag and Fe3O4. Thus, this corrigendum replaces the image 1C with a better resolution, as described in the “Results” section “PLGA(Ag-Fe3O4) nanocomposites preparation and characterization)” on pages 3755-3756. Image 3D has reported to have repeated region in the PLGA(Ag-Fe3O4) on the published proof. After a thorough check to the original images and raw data, the authors found out that there was no repeated region and hereby present the updated image for Figure 3. Page 3756, Figure 1, the correct figure is shown in Download Article. Page 3759, Figure 3, the correct figure is shown in Download Article. The authors apologize for these errors and advise they do not affect the results of the paper. Read the original article

Xin Liu,1 Lili An,2 Shuaijun Ren,2 Yonghui Zhou,1 Wei Peng1 1College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, 550025, People’s Republic of China; 2Dermatology Department, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, 550025, People’s Republic of ChinaCorrespondence: Xin Liu, College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, 550025, People’s Republic of China, Tel +8618886056643, Email 1046977102@qq.comPurpose: As a kind of opportunist pathogen, Staphylococcus epidermidis (MRSE) can cause nosocomial infections and easily evolve into resistant bacteria. Among these, methicillin-resistant Staphylococcus epidermidis (MRSE) exhibit significantly higher rates. Our previous study showed that Patrinia scabiosaefolia (PS) possessed strong antibacterial activity against MRSE. However, the mechanism of PS against MRSE is not clear.Methods: Here, a tandem mass tag-based (TMT) proteomic analysis was performed to elucidate the potential mechanism of PS against MRSE. We compared the differential expression proteins of MRSE under PS stress.Results: Based on a fold change of > 1.2 or < 1/1.2 (with p value set at < 0.05), a total of 248 proteins (128 up-regulated proteins, 120 down-regulated proteins) were identified. Bioinformatic analysis showed that proteins including arginine deiminase (arcA), ornithine carbamoyltransferase (arcB) and carbamate kinase (arcC), serine–tRNA ligase (serS), phenylalanine–tRNA ligase beta and subunit (pheT), DltD (dlt), d-alanyl carrier protein (dlt), accumulation-associated protein (SasG), serine-aspartate repeat-containing protein C (SdrC) and hemin transport system permease protein HrtB (VraG) played important roles in mechanism of PS against MRSE.Conclusion: In summary, these results indicated that arginine deiminase pathway (ADI) pathway, protein synthesis, cell wall synthesis, biofilm formation and uptake of iron were related to mechanisms of PS against MRSE. Our findings provide an insight into the the mechanism of PS against MRSE, and may be valuable in offering new targets to develop more anti-MRSE drugs.Keywords: methicillin-resistant Staphylococcus epidermidis, Patrinia scabiosaefolia, proteomic

Liting Wu,1,&ast; Wenting Luo,1,&ast; Haisheng Hu,1 Xianhui Zheng,1 Zhangkai J Cheng,1 Dongming Huang,2 Xiaowen Huang,2 Hong Zhang,3 Yang Liu,3 Rongfang Zhang,4 Hui Yang,4 Yun Sun,5 Yi Wang,5 JinHai Ma,6 Jing Liu,6 Xin Sun,7 Huajie Wu,7 Chunhua Wei,8 Shuping Zhang,8 Xiaoluan Li,9 Shuang Ren,9 Chuangli Hao,10 Baoqing Sun1 1Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510120, People’s Republic of China; 2Department of Pediatrics, Boai Hospital of Zhongshan City, Zhongshan, 528400, People’s Republic of China; 3Gansu Provincial Hospital, Lanzhou, 730000, People’s Republic of China; 4Gansu Provincial Maternity and Child Care Hospital, Lanzhou, 730000, People’s Republic of China; 5Yinchuan Maternal and Child Health Care Hospital, Yinchuan, 750000, People’s Republic of China; 6Ningxia Medical University General Hospital, Yinchuan, 750000, People’s Republic of China; 7Department of Pediatrics, Xijing Hospital, the Fourth Military Medical University, Xian, 710032, People’s Republic of China; 8Weifang Weien Hospital, Weifang, 261000, People’s Republic of China; 9The First Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China; 10Department of Respirology, Children’s Hospital, Soochow University, Suzhou, 215025, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Baoqing SunFirst Affiliated Hospital of Guangzhou Medical University, 151 Yanjiangxi Road, Guangzhou, 510120, Guangdong, People’s Republic of ChinaTel +86 20 8306 2865Fax +86 20 8306 2729Email sunbaoqing@vip.163.comChuangli HaoDepartment of Respirology, Children’s Hospital, Soochow University, Suzhou, 215025, Jiangsu, People’s Republic of ChinaTel +86-51280693588Fax +86-512-80696309Email hcl_md@163.comBackground: Up to now, epidemiological studies on allergy rhinitis (AR) have primarily focused on determining the risk of disease in Chinese adults, with the majority of them designed by single centers, while cross-sectional and epidemiological data describing allergic sensitization in children with self-reported AR are scarce.Objective: This study was estimating of the latest information about the sensitization patterns and risk factors of clinical AR to develop effective strategies for the prevention and treatment of AR.Methods: We conducted a cross-sectional survey between January 2020 and June 2021 involving children from seven cities in China who reported AR. A total of 762 children participated in this survey. To evaluate the risk factors and specific sensitization patterns of clinical AR through questionnaires and specific immunoglobulin E to 11 aeroallergens.Results: Of the 762 patients, 593 (77.8%) had at least one positive IgE level. Aged 7– 14 years (OR 1.503, (95% CI 1.058– 2.136), P = 0.023); With allergic conjunctivitis (OR 1.843, (95% CI 1.297– 2.620), P = 0.001) and living in the Eastern (OR 1.802, (95% CI 1.263– 2.573), P = 0.001) all elevated the risk of clinical AR associated with aeroallergens. The sensitization rates of D. pteronyssinus and D. farinae were higher than those of other allergens in the 0– 6 and 7– 14 years old age groups. The most common aeroallergens among self-reported children with AR in the eastern were D. farinae (74.9%) and D. pteronyssinus (74.3%), while in the western were mugwort (60.0%) and marguerite (56.6%). Majority of sIgE-positive subjects were sensitized to three or more of the tested pollen allergens in the Western (52.1%), compared with 5.7% in the Eastern.Conclusion: There was an apparent geographic variation in childhood allergies in China. Age factors also had strong impacts on the allergen sensitization rate of children, but these impacts differed across regions.Keywords: allergic rhinitis, specific immunoglobulin E, cross-sectional survey, aeroallergen, children

Shuai Ren, Lina Song, Ying Tian, Li Zhu, Kai Guo, Huifeng Zhang, Zhongqiu Wang Department of Radiology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210029, People’s Republic of ChinaCorrespondence: Shuai Ren; Zhongqiu WangDepartment of Radiology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Nanjing, Jiangsu Province, 210029, People’s Republic of ChinaEmail sren001@163.com; zhongqiuwang0815@163.comBackground: Pancreatic cancer (PC) remains a difficult tumor to diagnose and treat. It is often diagnosed as advanced by reason of the anatomical structure of the deep retroperitoneal layer of the pancreas, lack of typical symptoms and effective screening methods to detect this malignancy, resulting in a low survival rate. Emodin (EMO) is an economical natural product with effective treatment and few side effects of cancer treatment. Magnetic nanoparticles (MNPs) can achieve multiplexed imaging and targeted therapy by loading a wide range of functional materials such as fluorescent dyes and therapeutic agents.Purpose: The purpose of this study was to design and evaluate a multifunctional theranostic nanoplatform for PC diagnosis and treatment.Methods: In this study, we successfully developed EMO-loaded, Cy7-functionalized, PEG-coated Fe3O4 (Fe3O4-PEG-Cy7-EMO). Characteristics including morphology, hydrodynamic size, zeta potentials, stability, and magnetic properties of Fe3O4-PEG-Cy7-EMO were evaluated. Fluorescence imaging (FI)/magnetic resonance imaging (MRI) and therapeutic treatment were examined in vitro and in vivo.Results: Fe3O4-PEG-Cy7-EMO nanoparticles had a core size of 9.9 ± 1.2 nm, which showed long-time stability and FI/MRI properties. Bio-transmission electron microscopy (bio-TEM) results showed that Fe3O4-PEG-Cy7-EMO nanoparticles were endocytosed into BxPC-3 cells, while few were observed in hTERT-HPNE cells. Prussian blue staining also confirmed that BxPC-3 cells have a stronger phagocytic ability as compared to hTERT-HPNE cells. Additionally, Fe3O4-PEG-Cy7-EMO had a stronger inhibition effect on BxPC-3 cells than Fe3O4-PEG and EMO. The hemolysis experiment proved that Fe3O4-PEG-Cy7-EMO can be used in vivo experiments. In vivo analysis demonstrated that Fe3O4-PEG-Cy7-EMO enabled FI/MRI dual-modal imaging and targeted therapy in pancreatic tumor xenografted mice.Conclusion: Fe3O4-PEG-Cy7-EMO may serve as a potential theranostic nanoplatform for PC.Keywords: pancreatic cancer, emodin, magnetic nanoparticles, passive targeting

Yanxiang Shao,1,&ast; Xiang Tu,1,&ast; Yang Liu,1,&ast; Yige Bao,1 Shangqing Ren,1,2 Zhen Yang,1,3 Xu Hu,1 Kan Wu,1 Hao Zeng,1 Qiang Wei,1 Xiang Li1 1Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Robotic Minimally Invasive Surgery Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, People’s Republic of China; 3Department of Urology, Chengdu Second People’s Hospital, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiang LiDepartment of Urology, West China Hospital, Sichuan University, 37 GuoXueXiang, Chengdu, Sichuan, People’s Republic of ChinaTel +86 18980601428Email xiangli87@hotmail.comObjective: To investigate the predictive factors of lymph node metastasis (LNM) and evaluate the usefulness of prediction nomograms.Methods: This study included 300 patients diagnosed with penile squamous cell carcinoma at West China Hospital (WCH) of Sichuan University (Chengdu, China) and 412 cases acquired from the Surveillance, Epidemiology, and End Results (SEER) program. Logistic regression analysis was performed on these cohorts to investigate the predictive factors of LNM. We evaluated a recently developed prediction nomogram for LNM, which was established based on the National Cancer Database (NCDB). Moreover, we developed a novel nomogram using cases from the WCH for the prediction of lymphatic metastasis.Results: Logistic analysis identified that younger age at diagnosis, invasion of the penis body, poorer pT stage, cN stage, nuclear grade and the presence of lymph vascular invasion (LVI) were significantly correlated with LNM in WCH cases; however, only race, poorer T stage and cN stage were significantly associated with LNM among the cases from the SEER. Multivariate analysis demonstrated that younger age, poorer T stage, cN stage and nuclear grade were independent predictors of LNM. Receiver operating characteristic curve analysis of WCH cases showed that the tumor T stage 8th edition has better area under the curve than 7th stage (0.672 vs 0.636, respectively). Moreover, well AUC was seen in external validation of NCDB nomogram in WCH cohorts and SEER series (0.833 vs 0.795). The new nomogram included the aforementioned independent predictors and the bootstrap-corrected concordance was 0.876.Conclusion: Younger diagnose age, poorer pT stage, cN stage, nuclear grade and LVI were the most important predictors of LNM in patients with penile cancer. 8th T stage performed better than 7th version in predicting LNM. NCDB nomogram has some application values in both WCH and SEER cases, and our novel model further improved the predictive accuracy.Keywords: penile cancer, lymph node metastasis, prediction model, nomogram, SEER

Yanxiang Shao,1,&ast; Thongher Lia,1,&ast; Yaohui Wang,1,&ast; Kan Wu,1 Xu Hu,1 Yang Liu,1 Shuyang Feng,1 Shangqing Ren,1,2 Zhen Yang,1,3 Sanchao Xiong,1 Weixiao Yang,1 Qiang Wei,1 Hao Zeng,1 Xiang Li1 1Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Robotic Minimally Invasive Surgery Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, 610072, People’s Republic of China; 3Department of Urology, Chengdu Second People’s Hospital, Chengdu, 610021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiang LiDepartment of Urology, Institute of Urology, West China Hospital, Sichuan University, 37 GuoXueXiang, Chengdu, 610041, People’s Republic of ChinaEmail xiangli87@hotmail.comObjective: To evaluate the prognostic factors of penile cancer and the utility of prognostic models.Methods: We analyzed postoperatively collected data of 311 patients diagnosed with penile cancer. Survival analysis (Kaplan–Meier and cox regression methods) was performed on this cohort. The c-index was used to determine the predictive accuracies of potential prognostic factors. The accuracies of four prognostic models were also evaluated, which were AJCC prognostic stage group for three recent editions, and four nomograms constructed by the Surveillance, Epidemiology, and End Results program (SEER). Two novel nomograms using our data were created and AUC of 2-year survival were determined to compare existing and newly established models.Results: Tumor site, T and N stages, nuclear grade and lymph vascular invasion (LVI) significantly influenced prognosis. The 8th T and N stages had better c-indexes than former editions, while no improvement was seen in the 8thAJCC stage group. 6th AJCC+grade nomogram had a higher c-index than other three nomograms (SEER+grade, 6th TNM+grade, and 6th T1-3N0-3+grade nomograms; c-index: 0.831 vs 0.738, 0.792 and 0.781). New nomogram 1 included the 8th T and N stages, tumor site, nuclear grade, and LVI, with a c-index of 0.870. Novel nomogram 2 replaced the T and N stages with the AJCC stage group, which had a lower c-index of 0.855. The order of prediction accuracy of 2-year survival in the old and new models is consistent with the c-index results.Conclusion: Tumor site, stages, grade, and LVI play important roles in predicting survival of penile cancer. The 8th stages have better predictive accuracy than former editions. We proposed two models with better predictive accuracy than former models; specifically, nomogram 1 may be a more precise and convenient tool for predicting penile cancer outcomes.Keywords: penile cancer, TNM stage, survival, nomogram, external validation

Wenjuan Yan,1,&ast; Qi Zhang,1,&ast; Yingjie Zhu,1 Nan Jing,1 Youhua Yuan,1 Yi Zhang,2 Siying Ren,3 Dongmei Hu,4 Wenmin Zhao,5 Xiaojuan Zhang,6 Caiqin Shi,7 Meiyun Wang,8 Yi Li1 1Department of Clinical Microbiology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, People’s Republic of China; 2Department of Clinical Laboratory, Zhengzhou Central Hospital, Affiliated to Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Clinical Laboratory, Kaifeng People’s Hospital, Kaifeng, Henan, People’s Republic of China; 4Department of Clinical Laboratory, Zhumadian First People’s Hospital, Zhumadian, People’s Republic of China; 5Department of Clinical Laboratory, Kaifeng Central Hospital, Kaifeng, Henan, People’s Republic of China; 6Department of Clinical Laboratory, Gongyi People’s Hospital, Zhengzhou, Henan, People’s Republic of China; 7Department of Microbiology Laboratory, KingMed Diagnostics, Zhengzhou, Henan, People’s Republic of China; 8Department of Medical Imaging, Henan Provincial People’s Hospital & the People’s Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi LiDepartment of Clinical Microbiology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, People’s Republic of ChinaTel +86 159 39039006Email liyilabmed@henu.edu.cnPurpose: To evaluate polymyxin-resistant Klebsiella pneumoniae and Escherichia coli prevalence and characteristics in the Henan province, China.Materials and Methods: A total of 2301 bacterial isolates collected at six hospitals were assessed. Their response to polymyxin was evaluated by minimum inhibitory concentration (MIC) analysis, and the mobilized colistin resistance (mcr) and carbapenemase gene were explored. Mutations on mgrB, phoPQ, pmrAB, and crrAB in polymyxin-resistant K. pneumoniae were detected by PCR. phoP, phoQ, pmrK, pmrA, pmrB, and pmrC transcriptional levels were quantified by RT-qPCR. Pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing were performed to determine the phylogenetic relationship between the polymyxin-resistant isolates.Results: Of the E. coli and K. pneumoniae isolates identified, 0.3% and 1.4% were polymyxin-resistant, respectively, with MICs of 4– 64 μg/mL. All polymyxin-resistant isolates were susceptible to tigecycline. Four E. coli isolates were mcr-1-positive and one was carbapenem-resistant, carrying blaNDM-5 and mcr-1. One K. pneumoniae isolate was mcr-1-positive and nine were carbapenem-resistant (PRCRKP), carrying blaKPC-2 but not mcr-1. The five E. coli isolates belonged to four sequence types (ST2, ST132, ST632, and ST983). All PRCRKP isolates belonged to ST11. However, all 16 isolates belonged to different PFGE types with < 95% genetic similarity. Insertion sequences in mgrB were detected in nine (81.8%) polymyxin-resistant K. pneumoniae samples. Colistin resistance was linked with pmrHFIJKLM operon upregulation, with phoP, phoQ, and pmrK being overexpressed in all but one of the polymyxin-resistant K. pneumoniae samples. Furthermore, 33.3% of patients carrying polymyxin-resistant isolates had previously used polymyxin, and 66.7% patients displayed good clinical outcomes.Conclusion: The K. pneumoniae polymyxin resistance rate was slightly higher than that of E. coli and mcr-1 was more common in E. coli than in K. pneumoniae. Moreover, the insertion of ISkpn14 into mgrB may be the main contributor to polymyxin-resistance in K. pneumoniae in Henan.Keywords: polymyxin, Escherichia coli, Klebsiella pneumoniae, mcr, Henan province

Xiaofei Yu,1,* Zhengwei Dong,2,* Wanying Wang,1 Shiqi Mao,1 Yingying Pan,1 Yiwei Liu,1 Shuo Yang,1 Bin Chen,1 Chunyan Wang,1 Xuefei Li,3 Chao Zhao,3 Keyi Jia,1 Chuchu Shao,1 Chunyan Wu,2 Shengxiang Ren,1 Caicun Zhou1 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 2Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 3Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shengxiang RenDepartment of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of ChinaTel +86-21-65115006Fax +86-21-65111298Email harry_ren@126.comChunyan WuDepartment of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507, Zheng Min Road, Shanghai, 200433, People’s Republic of ChinaFax +86-21-65111298Email wuchunyan581@163.comPurpose: High-grade patterns (micropapillary/solid/complex gland) are associated with a higher recurrence rate and shorter disease-free survival. Thus far, it remains unclear whether the efficacy of first-line anticancer therapy is different from that of the other adenocarcinoma subgroups for patients with high-grade patterns. The study aimed to investigate the association between an adenocarcinoma with high-grade patterns with the outcomes of first-line treatment in patients with lung cancer.Patients and Methods: Patients with a high-grade pattern adenocarcinoma (more than 20% of micropapillary/solid components/complex glandular patterns) were retrospectively analyzed between June 2015 and June 2017. Patients’ clinical characteristics and treatment outcomes were compared with those of the remaining control adenocarcinoma subgroups.Results: In total, 239 patients with adenocarcinoma, including 115 (48.1%) high-grade patterns and 124 (51.9%) control groups, were enrolled. Patients’ clinical characteristics such as age, sex, smoking status, and stage were similar between the two groups. Among them, 108 patients received first-line chemotherapy, and 131 received epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs). In the chemotherapy group, adenocarcinoma of high-grade patterns had a significantly lower objective response rate (ORR; 15.6% vs 36.4%, P=0.045), shorter progression-free survival (PFS; median 4.1 vs 5.4 months, P=0.007) and overall survival (OS, median 19.6 vs 23.8 months, P=0.048) compared with the control group. As for these treated with EGFR-TKIs, a similar ORR (70.7% vs 72.1%, P=0.703), PFS (median 11.3 vs 13.9 months, P=0.065) and OS (median 34.1 vs 29.6%, p=0.575) were observed between these two groups.Conclusion: An adenocarcinoma with high-grade patterns is associated with inferior outcomes to first-line chemotherapy in relapsed lung cancer. Patients who received chemotherapy had a significantly shorter PFS and OS and lower ORR than control subjects, while there was no difference in the EGFR-TKI cohort. This study is the first to report the distribution of adenocarcinoma with high-grade patterns.Keywords: adenocarcinoma, micropapillary, solid, chemotherapy, EGFR-TKIs

Minhua Ye1 *,* Sijia Ren2 *,* Chunguo Wang,1 Xiaoshun Shi,3 Jianfei Shen1 1Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Wenzhou, 317000, People’s Republic of China; 2Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Zhejiang University School of Medicine, Hangzhou, 310000, People’s Republic of China; 3Department of Thoracic Surgery, Nafang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianfei ShenDepartment of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Wenzhou, 317000, People’s Republic of ChinaEmail jianfei051@163.comXiaoshun ShiDepartment of Thoracic Surgery, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou Avenue, Guangzhou, 510515, People’s Republic of ChinaEmail sxs917@163.comBackground: Primary adenoid cystic carcinoma (ACC) of the lung, which arises from the bronchial gland and is rare, accounting for only 0.04– 0.2% of all primary lung tumors. The genetic profiling of bilateral ACC of unknown primary site and application in postoperative decision-making are less reported.Case Presentation: A 57-year-old male with a smoking history of over 30 years and multiple nodules in both lungs was present to our department. After assessing the bilateral solid nodules in his Positron Emission Tomography–Computed Tomography (PET/CT) scan, malignant lesions at the left lower lung, right lower lung, and right middle lung are suspected. Sequential selective video-assisted thoracoscopic surgeries (VATS) were performed. A genetic alteration test of 425 cancer-related genes and global gene expression profile of the specimens revealed intrapulmonary metastasis existed. The patient was followed up for three years without recurrence and tissue mutations in liquid biopsy.Conclusion: We present a way of omics-based multiple pulmonary lesions origin assessment, facilitating post-operative differential diagnosis and treatment decision for difficult cases.Keywords: adenoid cystic carcinoma, next-generation sequencing, lung cancers of unknown primary site, PIK3R1

FanYan Meng,1 Shuang Ren,1 Yun Meng,1 Ning Tao,1,2 Jie Zhang1 1Traditional Chinese Medicine Department, The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Clinical Medicine of Traditional Chinese and Western Medicine, China Medical University, Shenyang 110122, People’s Republic of ChinaCorrespondence: Jie ZhangTraditional Chinese Medicine Department, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province, People’s Republic of ChinaTel +86-24-83283687Email zhangjie945@outlook.comPurpose: Previous evidence has shown that psychological stress can trigger the onset of autoimmune disease. This study aimed to investigate the prevalence of stressful life events preceding the onset of symptoms in female primary Sjogren’s syndrome (pSS) in China compared to controls and the possible associations of stressful life events with disease activity.Patients and Methods: This was a hospital-based retrospective case–control study. Sixty-seven consecutive female pSS patients and an equal number of age-matched (± 3 years) healthy controls were recruited for assessment using the related Stressful Life Events Scale. The pSS disease activity was measured by the EULAR Sjogren’s syndrome disease activity index. Data were analyzed by SPSS, version 23, using chi-square, univariate logistic regression, multiple logistic regression, and partial correlation.Results: A higher number of negative stressful life events before disease onset in pSS patients compared with healthy controls suggest that these play a role in increasing the risk of disease occurrence (OR = 2.59, 95% CI: 1.87– 3.58, p < 0.05). The number of positive life events did not differ between the two groups. Both the number and severity of the negative stressful life events were also significantly correlated with disease activity.Conclusion: Patients with pSS experienced more negative stressful life events in the year preceding the onset of symptoms than controls. Negative stressful life events before symptom onset may be risk factors for pSS and may affect pSS disease activity.Keywords: primary Sjogren’s syndrome, stressful life events, retrospective case-control study, risk factors

Siling Ren,1,* Jingxian Wu,2,* Wanchun Yin,1 Qianqian Liao,1 Sailan Gong,1 Beibei Xuan,1 Xiaoling Mu1 1Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China; 2Department of Pathology, Chongqing Medical University, Chongqing 400016, People’s Republic of China*These authors contributed equally to this work.Correspondence: Xiaoling MuDepartment of Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of ChinaEmail mxl@hospital.cqmu.edu.cnObjective: In this study, 345 patients with endometrial carcinoma (EC) were selected to investigate the correlation between ER/PR status and the EC disease-free survival (DFS) rate.Methods: The intensity and proportion of tumor cell expression of estrogen receptors and progesterone receptors (ER/PR) status of 345 postoperative tumor specimens in ECs were independently assessed semi-quantitatively by two pathologists using immunohistochemistry, the summed score ranged from 0 to 8 points was worked out by adding proportion score and intensity score based on the breast cancer hormone receptor immunohistochemical Allred scoring system. The association between DFS in ECs and ER/PR expression (intensity, proportion and summed score) was assessed using Cox regression analysis. Gene expression data were obtained from The Cancer Genome Atlas research network (TCGA).Results: According to inclusion criteria, 201 type I and 144 type II EC patients were enrolled in this study. In the univariate analysis of type I endometrial carcinoma, the intensity, proportion and summed score of ER/PR status were significantly correlated with DFS. After adjusting for factors known to significantly impact survival, the influence of ER/PR status on DFS is generally decreased but the correlation is still significant. In the univariate analysis of type II endometrial carcinoma, the intensity, proportion and summed score of ER/PR status were significantly correlated with DFS. After adjusting for factors known to significantly impact survival, the influence of ER status on DFS is generally decreased, but the correlation is still significant, the effect of PR expression on DFS is not statistically significant.Conclusion: Higher ER/PR expression status was associated with better DFS in patients with type I endometrial cancer after adjusting for known factors that significantly affect survival. In patients with type II endometrial cancer, patients with positive ER expression were significantly associated with better DFS. However, the effect of PR expression on DFS was not statistically significant.Keywords: endometrial cancer, endometrioid carcinoma, disease-free survival rate, hormone receptor status, ER, PR

Xiaohan Ren,1,* Shangqian Wang,1,* Xinglin Chen,1,* Xiyi Wei,1,* Guangyao Li,1,* Shancheng Ren,2 Tongtong Zhang,1 Xu Zhang,1 Zhongwen Lu,1 Zebing You,1 Zengjun Wang,1 Ninghong Song,1 Chao Qin1 1The State Key Laboratory of Reproductive; Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China; 2Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chao Qin; Ninghong SongThe State Key Laboratory of Reproductive; Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of ChinaTel +86 13776678978; +86 15651728807Email nmuqinchao@163.com; songninghong_urol@163.comBackground: Since December 2019, the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first spread quickly in Wuhan, China, then globally. Based on previously published evidence, ACE2 and TMPRSS2 are both pivotal entry molecules that enable cellular infection by SARS-CoV-2. Also, increased expression of pro-inflammatory cytokines, or a “cytokine storm,” is associated with multiple organ dysfunction syndrome often observed in critically ill patients.Methods: We investigated the expression pattern of ACE2 and TMPRSS2 in major organs in the human body, especially in specific disease conditions. Multiple sequence alignment of ACE2 in different species was used to explain animal susceptibility. Moreover, the cell-specific expression patterns of ACE2 and cytokine receptors in the urinary tract were assessed using single-cell RNA sequencing (scRNA-seq). Additional biological relevance was determined through Gene Set Enrichment Analysis (GSEA) using an ACE2-specific signature.Results: Our results revealed that ACE2 and TMPRSS2 were highly expressed in genitourinary organs. ACE2 was highly and significantly expressed in the kidney among individuals with chronic kidney diseases or diabetic nephropathy. In single cells, ACE2 was primarily enriched in gametocytes in the testis and renal proximal tubules. The receptors for pro-inflammatory cytokines, especially IL6ST, were notably concentrated in endothelial cells, macrophages, spermatogonial stem cells in the testis, and renal endothelial cells, which suggested the occurrence of alternative damaging autoimmune mechanisms.Conclusion: This study provided new insights into the pathogenic mechanisms of SARS-CoV-2 that underlie the clinical manifestations observed in the human testis and kidney. These observations might substantially facilitate the development of effective treatments for this rapidly spreading disease.Keywords: genitourinary organs, pro-inflammatory cytokine receptors, kidney, testis, SARS-CoV-2

Liuqing Yang,1,2 Guanghui Li,3 Ya Gao,4 Nini Ou,1 Tingting Yu,5 Shirong Ren1 1Department of Stomatology, Ningbo Dental Hospital, Ningbo City, Zhejiang Province 315000, People’s Republic of China; 2Ningbo Institute of Oral Health, Ningbo City, Zhejiang Province 315000, People’s Republic of China; 3Department of Stomatology, Fujian Medical University, Fuzhou City, Fujian Province 350122, People’s Republic of China; 4Department of Stomatology, Shanghai First People’s Hospital, Shanghai 201600, People’s Republic of China; 5Department of Stomatology, Yinzhou Dental Hospital, Ningbo City, Zhejiang Province 315000, People’s Republic of ChinaCorrespondence: Liuqing YangDepartment of Stomatology, Ningbo Dental Hospital, No. 1821 Ningchuan Road, Ningbo City, Zhejiang Province 315000, People’s Republic of ChinaEmail sb7390@163.comBackground: Cell proliferation of oral squamous cell carcinoma (OSCC) is precisely regulated with a cascade of genes and pathways. Previous studies have identified NR4A1 as an oncogene and plays a crucial role in colorectal cancer development and progression. This study was performed to investigate the potential interaction between lncRNA NR4A1AS and miR-221 and how their interaction is modulated in periodontitis.Patients and Methods: Research subjects of this study included 62 OSCC patients. Cell transfection and RT-qPCR were applied to detect the expression levels of NR4A1AS and miR-221. Methylation-specific PCR (MSP) was carried out to determine the demethylation of miR-221 by NR4A1AS. CCK-8 assay was used to detect the proliferation of OSCC cells with the overexpression of NR4A1AS or/and overexpression of miR-221.Results: In this study, we observed that NR4A1AS was upregulated in tumor tissue samples of OSCC, and its high expression levels were significantly correlated with poor survival in patients with OSCC. In addition, miR-221 was significantly down-regulated in OSCC tumors. NR4A1AS and miR-221 were significantly and positively correlated in OSCC tumors but not in non-dysplastic tissue. In OSCC cells, overexpression of NR4A1AS led to upregulation of miR-221 and decreased the methylation of miR-221 gene. However, overexpression of miR-221 did not affect the expression of NR4A1AS in OSCC cells. In addition, overexpression of NR4A1AS or miR-221 increased the proliferation rate of OSCC cells.Conclusion: This study is the first to report that NR4A1AS is upregulated in OSCC. Moreover, we also propose that miR-221 is modulated by NR4A1AS through demethylation and the upregulation of NR4A1AS or miR-221 promotes the proliferation of OSCC cells, which suggests that anti-NR4A1AS might be a perspective approach for the therapy of OSCC.Keywords: oral squamous cell carcinoma, lncRNA NR4A1AS, miR-221, proliferation

Lu-Huai Feng,1 Kun-Peng Bu,1 Shuang Ren,1 Zhenhua Yang,2 Bi-Xun Li,1 Cheng-En Deng3 1Department of Comprehensive Internal Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 2Department of Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 3Department of Urology, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of ChinaCorrespondence: Cheng-En DengDepartment of Urology, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaTel +86 18775391817Fax +86 771-5719573Email dengchengen66@126.comBi-Xun LiDepartment of Comprehensive Internal Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaTel +86 18977100069Fax +86 771-5719573Email libixun@126.comPurpose: Digestive carcinomas remain a major health burden worldwide and are closely related to type 2 diabetes. The aim of this study was to develop and validate a digestive carcinoma risk prediction model to identify high-risk individuals among those with type 2 diabetes.Patients and Methods: The prediction model was developed in a primary cohort that consisted of 655 patients with type 2 diabetes. Data were collected from November 2013 to December 2018. Clinical parameters and demographic characteristics were analyzed by logistic regression to develop a model to predict the risk of digestive carcinomas; then, a nomogram was constructed. The performance of the nomogram was assessed with respect to calibration, discrimination, and clinical usefulness. The results were internally validated by a bootstrapping procedure. The independent validation cohort consisted of 275 patients from January 2019 to December 2019.Results: Predictors in the prediction nomogram included sex, age, insulin use, and body mass index. The model showed good discrimination (C-index 0.747 [95% CI, 0.718– 0.791]) and calibration (Hosmer–Lemeshow test P=0.541). The nomogram showed similar discrimination in the validation cohort (C-index 0.706 [95% CI, 0.682– 0.755]) and good calibration (Hosmer–Lemeshow test P=0.418). Decision curve analysis demonstrated that the nomogram would be clinically useful.Conclusion: We developed a low-cost and low-risk model based on clinical and demographic parameters to help identify patients with type 2 diabetes who might benefit from digestive cancer screening.Keywords: type 2 diabetes, digestive cancer, prediction, demographic

Ren S, Song L, Tian Y, et al. Int J Nanomedicine. 2021;16:7463–7478. Page 7466, Cell Viability Assay and Apoptosis Analyses section, 3rd sentence, the text “Next, different concentrations of Fe3O4-PEG and Fe3O4-PEG-Cy7-EMO (0, 12.5, 25, 50, 80, 100 μg/mL) were added to the plates and incubated for 24 hours” should read “Next, different concentrations of Fe3O4-PEG and Fe3O4-PEG-Cy7-EMO (0, 6, 12, 25, 50, 80, 100 μg/mL) were added to the plates and incubated for 48 hours”. Page 7473, Table 1, the value “62.23%” in the BxPC-3 row for the Fe3O4-PEG-Cy7-EMO (80µg/mL) column should read “62.63%”. Page 7474, Figure 7A, due to an error at the time of figure assembly, the images for spleen and lung in the second and the third rows are identical. The correct Figure 7 is shown in Download Article. The authors apologize for these errors and advise they do not affect the results of the paper. Read the original article

Wenli Qiu,1 Na Duan,1 Xiao Chen,1 Shuai Ren,1 Yifen Zhang,2 Zhongqiu Wang,1 Rong Chen3 1Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Department of Pathology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 3Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USACorrespondence: Zhongqiu WangDepartment of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing 210029, Jiangsu Province, People’s Republic of ChinaTel +86 25 8661 8472Fax +86 25 8661 8139Email zhq200105@sina.comPurpose: To assess the performance of combining computed tomography (CT) texture analysis with machine learning for discriminating different histopathological grades of pancreatic ductal adenocarcinoma (PDAC).Methods: From July 2012 to August 2017, this retrospective study comprised 56 patients with confirmed histopathological PDAC (32 men, 24 women, mean age 64.04±7.82 years) who had undergone preoperative contrast-enhanced CT imaging within 1 month before surgery. Two radiologists blinded to the histopathological outcome independently segmented lesions for quantitative texture analysis. Histogram features, co-occurrence, and run-length texture were calculated. A support-vector machine was constructed to predict the pathological grade of PDAC based on preoperative texture features.Results: Pathological analysis confirmed 37 low-grade PDAC (five well-differentiated/grade I and 32 moderately differentiated/grade II) and 19 high-grade PDAC (19 poorly differentiated/grade III) tumors. There were no significant differences in clinical or biological characteristics between patients with high-grade and low-grade tumors (P>0.05). There were significant differences between low-grade PDAC and high-grade PDAC on nine histogram features, seven run-length features, and two co-occurrence features. Cluster shade was the most important predictor (sensitivity 0.315). Using these texture features, the support-vector machine achieved 86% accuracy, 78% sensitivity, 95% and specificity.Conclusion: Machine learning–based CT texture analysis accurately predicted histopathological differentiation grade of PDAC based on preoperative texture features, leading to maximization patient survival and achievement of personalized precision treatment.Keywords: computed tomography, texture analysis, machine learning, pancreatic ductal adenocarcinoma, histopathological grade

Shuai Ren,1 Xiao Chen,1 Wenjing Cui,1 Rong Chen,2 Kai Guo,1 Huifeng Zhang,1 Shuai Chen,1 Zhongqiu Wang11Department of Radiology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province 210029, People’s Republic of China; 2Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USACorrespondence: Zhongqiu WangDepartment of Radiology, The Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Nanjing, Jiangsu Province 210029, People’s Republic of ChinaTel +86 258 086 1278Email zhqwang001@126.comPurpose: Both chronic mass-forming pancreatitis (CMFP) and pancreatic ductal adenocarcinoma (PDAC) are focal pancreatic lesions and share very similar clinical symptoms and imaging performance. There is great clinical value in preoperative differentiation of those two lesions. The purpose of this study was to investigate the value of computed tomography (CT) features in discriminating CMFP from PDAC.Patients and methods: Forty-seven patients with pathologically confirmed PDAC and 21 patients with CMFP were included in this study. Demographic and CT features, including tumor location, size, margin, pancreatic or bile duct dilatation, vascular invasion, cystic necrosis, pancreatic atrophy, calcification, and tumor contrast enhancement, were retrospectively analyzed and compared. Multivariate logistic regression analyses were adopted to identify relevant CT imaging features to discriminate CMFP from PDAC.Results: There were significant differences between CMFP and PDAC with respect to main pancreatic duct dilatation, vascular invasion, cystic necrosis, pancreatic atrophy, calcification, and tumor contrast enhancement. Delayed contrast enhancement (>70.5 Hounsfield units) showed high sensitivity and specificity of 84.2% and 84.7%. The areas under the curve (AUCs) of the predicting models based on qualitative and quantitative variables were 0.770 (95% CI: 0.660–0.880) and 0.943 (95% CI: 0.888–0.999), respectively. When all significant variables were used in combination to build a predicting model, the AUC was 0.969 (95% CI: 0.930–1.000) with 84.2% sensitivity and 94.7% specificity.Conclusion: Main pancreatic duct dilatation, vascular invasion, cystic necrosis, pancreatic atrophy, calcification, tumor size, and tumor contrast enhancement were shown to be useful CT imaging features in discriminating CMFP from PDAC.Keywords: pancreas, adenocarcinoma, pancreatitis, computed tomography

Chuan-gen Guo,1,* Shuai Ren,2,* Xiao Chen,2 Qi-dong Wang,1 Wen-bo Xiao,1 Jing-feng Zhang,1 Shao-feng Duan,3 Zhong-qiu Wang2 1Department of Radiology, The First Affiliated Hospital, College of Medicine Zhejiang University, Hangzhou 310003, China; 2Department of Radiology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; 3GE Healthcare, Shanghai 201203, China *These authors contributed equally to this work Purpose: The purpose of this study was to evaluate the performance of magnetic resonance imaging (MRI) findings and texture parameters for prediction of the histopathologic grade of pancreatic neuroendocrine tumors (PNETs) with 3-T magnetic resonance.Patients and methods: PNETs are classified into Grade 1 (G1), Grade 2 (G2), and Grade 3 (G3) tumors based on the Ki-67 proliferation index and the mitotic activity. A total of 77 patients with pathologically confirmed PNETs met the inclusion criteria. Texture analysis (TA) was applied to T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) maps. Patient demographics, MRI findings, and texture parameters were compared among three different histopathologic subtypes by using Fisher’s exact tests or Kruskal–Wallis test. Then, logistic regression analysis was adopted to predict tumor grades. ROC curves and AUCs were calculated to assess the diagnostic performance of MRI findings and texture parameters in prediction of tumor grades.Results: There were 31 G1, 29 G2, and 17 G3 patients. Compared with G1, G2/G3 tumors showed higher frequencies of an ill-defined margin, a predominantly solid tumor type, local invasion or metastases, hypo-enhancement at the arterial phase, and restriction diffusion. Four T2-based (inverse difference moment, energy, correlation, and differenceEntropy) and five DWI-based (correlation, contrast, inverse difference moment, maxintensity, and entropy) TA parameters exhibited statistical significance among PNETs (P

Xiao-jie Chen,1 Shu-min Ren,2 Jian-zeng Dong,1 Chun-guang Qiu,1 Ying-wei Chen,1 Hai-long Tao1 1Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; 2Department of Genetics and Prenatal Diagnosis, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China Objective: The aim of this study was to investigate the protective effect and mechanism of Ginkgo biloba extract-761 (EGb 761) in the rat with myocardial ischemia–reperfusion injury (MIRI).Materials and methods: Forty Sprague Dawley rats were randomly divided into following four groups: sham group, I/R group and EGb 761 groups (20 and 40 mg/kg). MIRI model was established after 14 days of administration. The myocardial infarct size and myocardial histology were measured and compared. Meanwhile, the levels of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin T (TnT), TNF-α, IL-6, IL-1β, superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) were evaluated. Western blot was used to detect the expression of Caspase-3, Bax, Bcl-2, HO-1, Nrf2, Akt, p-Akt and nuclear protein Nrf2.Results: The levels of infarct size, CK-MB, LDH, TnT, TNF-α, IL-6 and IL-1β in the EGb 761 groups were significantly lower than those in the ischemia/reperfusion (I/R) group. The content of MDA was lower in the myocardium, whereas the activities of SOD and GSH-Px were higher than those in the I/R group. The expressions of Caspase-3 and Bax in the EGb 761 groups were significantly lower than those in the I/R group, whereas the expressions of Bcl-2, p-Akt and HO-1 and nuclear protein Nrf2 in the EGb 761 groups were higher than those in the I/R group.Conclusion: EGb 761 might inhibit the apoptosis of myocardial cells and protect the myocardium by activating the Akt/Nrf2 pathway, increasing the expression of HO-1, decreasing oxidative stress and repressing inflammatory reaction. Keywords: Ginkgo biloba extract, myocardial ischemia-reperfusion injury, oxidative stress, superoxide dismutase

Shihong Ren,1 Zhan Wang,2 Xin Huang,2 Lingling Sun,2 Jinxiang Shao,1 Zhaoming Ye2 1Department of Orthopedics, The First People’s Hospital of Wenling, Wenling 317500, China; 2Department of Orthopedics, Centre for Orthopedic Research, Orthopedics Research Institute of Zhejiang University, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China Background: Rhabdomyosarcoma (RMS) is a rare malignant soft tissue sarcoma with a poor outcome and unclear prognostic factors. The purpose of this study was to analyze the prognostic postoperative survival factors among patients with RMS of the limbs. Methods: Postoperative data on patients with RMS of the limbs from 1983 to 2013 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database of the US National Cancer Institute. Both overall survival (OS) and cancer-specific survival (CSS) were assessed using the Kaplan–Meier method (to obtain OS and CSS curves) and a Cox proportional hazards regression model. Results: In total, 385 cases were obtained from the SEER database. The 5- and 10-year OS rates of the entire group were 51.5% and 42.2%, respectively. The 5- and 10-year CSS rates were 56.7% and 50.7%, respectively. Univariate analysis revealed that age, location, tumor stage, tumor size, and radiation therapy (RT) were associated with OS. Age, tumor stage, tumor size, and RT were associated with CSS. Age, tumor stage, tumor size, and RT were also independent predictors of both OS and CSS. Conclusion: Young age, no metastasis at presentation, smaller tumor size, and RT are favorable factors for prolonging survival among patients with RMS of the limbs after surgery. Keywords: rhabdomyosarcoma, SEER, prognosis, survival

Yaping Yang,1,* Shuangshuang Ren,2,* Xuan Zhang,2 Yijun Yu,1 Chao Liu,3 Jie Yang,2 Leiying Miao1 1Department of Cariology and Endodontics, 2Department of Periodontology, 3Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China *These authors contributed equally to this work Introduction: The placement of dental implants is performed in a contaminated surgical field in the oral cavity, which may lead to implant failure. Bacterial adhesion and proliferation (Streptococcus mutans, Porphyromonas gingivalis) often lead to implant infections. Although Ag nanoparticles hold great promise for a broad spectrum of antibacterial activities, their runoff from dental implants compromises their antibacterial efficacy and potentially impairs osteoblast proliferation. Thus, this aspect remains a primary challenge and should be controlled. Materials and methods: In this study, PLGA(Ag-Fe3O4) was modified on the implanted tooth surface and was characterized by transmission electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The magnetic and antibacterial properties were also determined. Results: Results showed that Ag successfully bonded with Fe3O4, and Ag-Fe3O4 not only exerted superparamagnetism but also exhibited antibacterial activity almost identical to silver nanoparticles (nano-Ag). The PLGA(Ag-Fe3O4) coating could significantly maintain the antibacterial activity and avoid bacterial adhesion to the implant. Compared with the blank control group, PLGA(Ag-Fe3O4) under magnetic field-coated samples had a significantly lower amount of colonized S. mutans (P

Xue He,1–3 Tiao Li,1–3 Naixin Kang,1–3 Huihui Zeng,1–3 Siying Ren,1–3 Dandan Zong,1–3 Jinhua Li,1–3 Shan Cai,1–3 Ping Chen,1–3 Yan Chen1–3 1Department of Respiratory Medicine, The Second Xiangya Hospital, 2Research Unit of Respiratory Disease, 3Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan, China Background: Cigarette smoke exposure is the most common risk factor for emphysema, which is one of the major pathologies of COPD. Protein arginine methyltransferase 6 (PRMT6) is a nuclear enzyme that specially catalyzes dimethylation of R2 in histone H3 (H3R2me2a). H3R2me2a prevents trimethylation of H3K4 (H3K4me3), which is located in the transcription start sites of genes in mammalian genomes. We attempted to determine the expression of PRMT6 in human samples, and investigate whether the upregulation of PRMT6 expression can attenuate the development of cigarette smoke extract (CSE)-induced emphysema. Further experiments were performed to elucidate the molecular mechanisms involved.Materials and methods: Human lung tissues were obtained from patients undergoing pneumonectomy for benign pulmonary lesions. BALB/c mice were treated with lentiviral vectors intratracheally and injected with CSE three times. The protein expression of PRMT6, H3R2me2a, and H3K4me3 in human and mouse samples, as well as B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and endothelial nitric oxide synthase (eNOS) in mice were detected in lung homogenates by Western blotting. The mRNA expression of cyclooxygenase-2, interleukin-6, Bcl-2, Bax, and eNOS in mice was measured by quantitative real-time polymerase chain reaction.Results: The expression of PRMT6 was significantly downregulated in the pulmonary parenchyma in smokers with COPD as well as in mice treated with CSE. Overexpression of PRMT6 was detected in the CSE + Lenti-PRMT6 group of mice, which reversed the expression of H3R2me2a and H3K4me3. Inflammation, apoptosis, and oxidative stress levels were severe in the CSE-treated emphysema mice compared with the control group, which was inhibited by the overexpression of PRMT6.Conclusion: The overexpression of PRMT6 might inhibit inflammation, apoptosis, and oxidative stress in CSE-induced emphysema mediated by H3R2me2a. Keywords: COPD, cigarette smoke extract, inflammation, apoptosis, oxidative stress, PRMT6

Xiangwei Liu,1,* Naiwen Tan,1,* Yuchao Zhou,1 Hongbo Wei,1,* Shuai Ren,1 Fan Yu,2 Hui Chen,3 Chengming Jia,4 Guodong Yang,5 Yingliang Song1 1State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Implant Dentistry, 2Department of Prosthodontics, School of Stomatology, 3Department of Plastic Surgery, Tangdu Hospital, 4Department of Traditional Chinese Medicine, Xijing Hospital, 5Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, China *These authors contributed equally to this work Abstract: Impaired osseointegration of the implant remains the big hurdle for dental implant therapy in diabetic patients. In this study, the authors first identified that miR204 was strikingly highly expressed in the bone mesenchymal stem cells (BMSCs) of diabetic rats. Forced expression of miR204 repressed the osteogenic potential of BMSCs, while inhibition of miR204 significantly increased the osteogenic capacity. Moreover, the miR204 inhibitor was conjugated with gold nanoparticles (AuNP-antagomiR204) and dispersed them in the poly(lactic-co-glycolic acid) (PLGA) solution. The AuNP-antagomiR204 containing PLGA solution was applied for coating the surface of titanium implant. Electron microscope revealed that an ultrathin sheet was formed on the surface of the implant, and the AuNPs were evenly dispersed in the coated PLGA sheet. Cellular experiments revealed that these encapsulated AuNP-antagomiR204 were able to be released from the PLGA sheet and uptaken by adherent BMSCs. In vivo animal study further confirmed that the AuNP-antagomiR204 released from PLGA sheet promoted osseointegration, as revealed by microcomputerized tomography (microCT) reconstruction and histological assay. Taken together, this study established that miR204 misexpression accounted for the deficient osseointegation in diabetes mellitus, while PLGA sheets aided the release of AuNP-antagomiR204, which would be a promising strategy for titanium implant surface functionalization toward better osseointegration. Keywords: osseointegration, miR204, PLGA sheets, gold nanoparticles, diabetes mellitus, titanium implant

Naiwen Tan,1–3,* Xiangwei Liu,1,2,* Yanhui Cai,4 Sijia Zhang,1,2 Bo Jian,1,2 Yuchao Zhou,1,2 Xiaoru Xu,1,2 Shuai Ren,1,2 Hongbo Wei,1,2 Yingliang Song1,2 1State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Xi’an, Shaanxi, China; 2Department of Implant Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China; 3Department of Stomatology, Hospital 463 of PLA, Xi’an, Shaanxi, China; 4Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, China *These authors contributed equally to this work Background: High failure rates of oral implants have been reported in diabetic patients due to the disruption of osseointegration. The aim of this study was to investigate whether direct laser metal sintering (DLMS) could improve osseointegration in diabetic animal models. Methods: Surface characterizations were carried out on two types of implants. Cell morphology and the osteogenic-related gene expression of MG63 cells were observed under conditions of DLMS and microarc oxidation (MAO). A diabetes model in mini-pigs was established by intravenous injection of streptozotocin (150 mg/kg), and a total of 36 implants were inserted into the mandibular region. Micro-computed tomography (micro-CT) and histologic evaluations were performed 3 and 6 months after implantation. Results: The Ra (the average of the absolute height of all points) of MAO surface was 2.3±0.3 µm while the DLMS surface showed the Ra of 27.4±1.1 µm. The cells on DLMS implants spread out more podia than those on MAO implants through cell morphology analysis. Osteogenic-related gene expression was also dramatically increased in the DLMS group. Obvious improvement was observed in the micro-CT and Van Gieson staining analyses of DLMS implants compared with MAO at 3 months, although this difference disappeared by 6 months. DLMS implants showed a higher bone–implant contact percentage (33.2%±11.2%) at 3 months compared with MAO group (18.9%±7.3%) while similar results were showed at 6 months between DLMS group (42.8%±10.1%) and MAO group (38.3%±10.8%). Conclusion: The three-dimensional environment of implant surfaces with highly porous and fully interconnected channel and pore architectures can improve cell spreading and accelerate the progress of osseointegration in diabetic mini-pigs. Keywords: laser manufacturing, dental implants, diabetes mellitus, osseointegration

Kaixiu Fang,1,* Wen Song,2,* Lifeng Wang,1 Sen Jia,3 Hongbo Wei,1 Shuai Ren,1 Xiaoru Xu,1 Yingliang Song1 1State Key Laboratory of Military Stomatology, Department of Implant Dentistry, School of Stomatology, Fourth Military Medical University, Xi’an, People’s Republic of China; 2State Key Laboratory of Military Stomatology, Department of Prosthetic Dentistry, School of Stomatology, Fourth Military Medical University, Xi’an, People’s Republic of China; 3State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, People’s Republic of China *These authors contributed equally to this work Abstract: Improving osseointegration of extensively used titanium (Ti) implants still remains a main theme in implantology. Recently, grafting biomolecules onto a Ti surface has attracted more attention due to their direct participation in the osseointegration process around the implant. Semaphorin 3A (Sema3A) is a new proven osteoprotection molecule and is considered to be a promising therapeutic agent in bone diseases, but how to immobilize the protein onto a Ti surface to acquire a long-term effect is poorly defined. In our study, we tried to use chitosan to wrap Sema3A (CS/Sema) and connect to the microarc oxidized Ti surface via silane glutaraldehyde coupling. The microarc oxidization could formulate porous topography on a Ti surface, and the covalently bonded coating was homogeneously covered on the ridges between the pores without significant influence on the original topography. A burst release of Sema3A was observed in the first few days in phosphate-buffered saline and could be maintained for >2 weeks. Coating in phosphate-buffered saline containing lysozyme was similar, but the release rate was much more rapid. The coating did not significantly affect cellular adhesion, viability, or cytoskeleton arrangement, but the osteogenic-related gene expression was dramatically increased and calcium deposition was also abundantly detected. In conclusion, covalent bonding of CS/Sema could strongly improve osteogenic differentiation of osteoblasts and might be applied for Ti implant surface biofunctionalization. Keywords: titanium, semaphorin 3A, silane reaction, microarc oxidation, osteogenic differentiation

The hydrodynamic coefficient of an underwater manipulator varies with changes in posture and flow field, presenting significant challenges for precise control and localization. This study, conducted numerical simulations to investigate the patterns of variation in flow field and hydrodynamic coefficients. Results showed that hydrodynamic performance remained consistent when the posture of the manipulator was either axisymmetric or origin-symmetric. Upon rotation, axial flow extended across the entire downstream surface, and the Karman vortex street entirely eliminated. Pressure coefficients on the back pressure surface of the manipulator increased with the Reynolds number within the range of 6x10³ ≤ Re ≤ 3x104, while the pressure coefficient on the upstream surface remained unchanged. Within this range, drag coefficients for the upper and lower arms decreased by 27.4% and 23.9%, respectively. The hydrodynamic performance of the lower arm was independent of the upper arm's posture, with a maximum drag coefficient of 1.48 achieved at α = -90°. As the posture angle of the manipulator varied from 30° to 60°, the pressure coefficient on the upstream surface decreased from 0.75 to 0.25. [ABSTRACT FROM AUTHOR]