Search

Xiang Wen,1,* Xiaohui Wu,1,* Zhishan Deng,1,* Fan Wu,1,2 Huajing Yang,1 Shan Xiao,1 Cuiqiong Dai,1 Changli Yang,3 Shuqing Yu,4 Ruiting Sun,1 Pixin Ran,1,2 Yumin Zhou1 1State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease & National Center for Respiratory Medicine & Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Guangzhou National Laboratory, Guangzhou, Guangdong, People’s Republic of China; 3Wengyuan County People’s Hospital, Shaoguan, People’s Republic of China; 4Lianping County People’s Hospital, Heyuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yumin Zhou; Pixin Ran, Email zhouyumin410@126.com; pxran@gzhmu.edu.cnBackground: The previous findings on the correlation between spirometry and high-density lipoprotein (HDL) cholesterol are intriguing yet conflicting. The aim of this research is to evaluate the relationship between HDL levels and spirometry as well as imaging parameters in patients with chronic obstructive pulmonary disease (COPD) in China.Methods: This study encompasses a total of 907 COPD patients. Participants with complete data from questionnaire interviews, lipid profile examinations, spirometry testing, and computed tomography (CT) scans were included in the analysis. A generalized additive model was employed to identify the non-linear relationship between HDL levels and both spirometry and imaging parameters. In the presence of non-linear correlations, segmented linear regression model was applied to ascertain threshold effects.Results: After adjusting for various factors, we found a non-linear correlation between HDL levels and spirometry/imaging parameters, with an inflection point at 4.2 (66 mg/dL). When Ln (HDL) was below 4.2, each unit increase correlated significantly with reduced post-bronchodilator FEV1 (0.32L, 95% CI: 0.09– 0.55), decreased predicted FEV1% (11.0%, 95% CI: 2.7– 19.3), and lowered FEV1/FVC (8.0%, 95% CI: 4.0– 12.0), along with notable increases in Ln (LAA− 950) by 1.20 (95% CI: 0.60– 1.79) and Ln (LAA− 856) by 0.77 (95% CI: 0.37– 1.17). However, no significant associations were observed when Ln (HDL) was greater than or equal to 4.2.Conclusion: A non-linear correlation existed between HDL levels with lung function and CT imaging in COPD patients. Prior to reaching 66 mg/dL, an elevation in HDL was significantly associated with impaired lung function, more severe gas trapping and emphysema.Keywords: COPD, high-density lipoprotein, lung function, computed tomography imaging

Cuixiang Shao,1,2 Qi Chen,3 Siwen Tang,4 Chaowen Wang,1 Renjuan Sun5 1Department of Obstetrics, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214000, People’s Republic of China; 2Wuxi Medical College, Jiangnan University, Wuxi, Jiangsu, 214122, People’s Republic of China; 3Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214000, People’s Republic of China; 4Department of Intensive Care Unit, First People ‘s Hospital of Pinghu, Pinghu, Zhejiang, 314299, People’s Republic of China; 5Department of Nutrition, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214000, People’s Republic of ChinaCorrespondence: Renjuan Sun, Department of Nutrition, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, Jiangsu, 214000, People’s Republic of China, Tel +86 13813479833, Email sunrj2023rj@163.comPurpose: This study aimed to create, verify and assess the clinical utility of a prediction model for maternal and neonatal adverse outcomes in pregnant women with hypothyroidism.Methods: A prediction model was developed, and its accuracy was tested using data from a retrospective cohort. The study focused exclusively on female patients diagnosed with hypothyroidism who were admitted to a tertiary hospital. The development and validation cohort comprised individuals who gave birth between 1 October 2020 and 31 December 2022. The primary outcome was a combination of crucial maternal and newborn problems (eg premature births, abortions and neonatal asphyxia). The prediction model was developed using logistic regression. Evaluation of the model’s performance was conducted based on its ability to discriminate, calibrate and provide clinical value.Results: In total, nine variables were chosen to develop the predictive model for adverse maternal and neonatal outcomes during pregnancy with hypothyroidism. The area under the curve of the model for predicting maternal adverse outcomes was 0.845, and that for predicting neonatal adverse outcomes was 0.685. The calibration plots showed good agreement between the nomogram predictions and the actual observations in both the training and validation cohorts. Furthermore, decision curve analysis suggested that the nomograms were clinically useful and had good discriminative power to identify high-risk mother–infant cases.Conclusion: Two models to predict the risk probability of maternal and neonatal adverse outcomes in pregnant women with hypothyroidism were developed and verified to assist physicians in evaluating maternal and neonatal adverse outcomes throughout pregnancy with hypothyroidism and to facilitate decision-making regarding therapy.Keywords: pregnancy with hypothyroidism, maternal and neonatal adverse outcomes, nomogram, forecasting model

Rongxin Sun,1 Desheng Duan,2 Renzeng Li2 1Department of Orthopaedics, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Province, People’s Republic of China; 2Second Department of Orthopaedics, Third People’s Hospital of Anyang City, Anyang City, Henan Province, People’s Republic of ChinaCorrespondence: Renzeng Li, Second Department of Orthopaedics, Third People’s Hospital of Anyang City, 363 Dongfeng Road, Beiguan District, Anyang City, Henan Province, People’s Republic of China, Tel +86-13837247813, Email LRZ_doctor@163.comBackground: Recent studies have put forward the viewpoint of “bone immunology”, which holds that the immune system and immune factors play an important regulatory role in the occurrence and development of osteoporosis. This study was intended to identify genetic characteristics of differentially expressed immune-related mRNA and lncRNA in patients combined with osteoporosis and vertebral fracture.Methods: The peripheral blood samples were obtained from 3 groups of subjects: healthy control (HC), osteoporosis patients without vertebral fracture (OWF), and osteoporosis patients combined with vertebral fracture (OVF). The data were integrated to obtain differentially expressed mRNAs (DEmRNAs) and differentially expressed lncRNAs (DElncRNAs). Subsequently, the protein-protein interaction (PPI) networks were constructed. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analyses were performed. Cytoscape-cytoHubba plug-in was used to identify key DEmRNAs. Furthermore, lncRNA-miRNA-mRNA, mRNA-lncRNA co-expression and transcription factors (TFs) networks were constructed. In addition, real-time PCR verification was performed.Results: Totally of 3378 lncRNA-mRNA pairs were obtained, and the lncRNA co-expressed mRNA was mainly enriched in immune-related pathways, especially in GO-biological process (GO-BP) analysis. A total of 8 hub immune-related DEmRNAs were obtained, including IL18R1, IL18RAP, SLC11A1, CSF2RA, CCR3, IL1R2, PGLYRP1, and IL1R1. The TFs network showed that 8 hub immune-related DEmRNAs had interacting TFs. The co-expression network showed that 7 hub immune-related DEmRNAs (IL18R1, IL18RAP, SLC11A1, CSF2RA, IL-1R2, PGLYRP1, and IL1R1) had lncRNA-mRNA co-expression relationship. In addition, the lncRNA-miRNA-mRNA network includes 32 miRNAs, 7 hub immune-related mRNAs (IL18R1, IL18RAP, CSF2RA, CCR3, IL1R2, PGLYRP1, and IL1R1), and 11 lncRNAs.Conclusion: Our study provides a novel and in-depth identification of co-expressed mRNAs and lncRNAs in patients combined with osteoporosis and vertebral fracture at a molecular level. This may provide new candidate biomarkers for the diagnosis of patients with high-risk fractures in the future.Keywords: osteoporosis, vertebral fracture, immune, mRNA, lncRNA, transcriptome

Ruonan Sun,1,&ast; Shuyuan Zhang,1,&ast; Jiarui Si,2 Liming Zhang,1 Haolun Yang,1 Zheng Ye,1 Xin Xiong2 1West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zheng Ye, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, People’s Republic of China, Email zheng_ye@scu.edu.cn Xin Xiong, West China Hospital of Stomatology, Sichuan University, No. 14 Section 3, Renmin South Road, Chengdu, 610041, People’s Republic of China, Tel/Fax +86-28-85503898, Email drxiongxin@scu.edu.cnBackground: Studies have reported correlations between various oral behaviors and painful temporomandibular disorders (TMD), yet comprehensive research on the independent effects of each oral behavior within the general population remains sparse.Objective: This cross-sectional study aimed to investigate the association between painful TMD (PT) and various oral behaviors in general population.Methods: A questionnaire survey was conducted with participants to collect data encompassing demographic characteristics, eight specific oral behaviors, and the 5 major TMD symptoms(5Ts) checklist. Participants were categorized into PT and non-PT (NPT) groups based on their responses to the 5Ts checklist. Those reporting TMJ/facial pain or headaches were assigned to the PT group, while all other participants constituted the NPT group. Both univariate and multivariate logistic regression analyses were employed to evaluate the association between individual oral behavior and the presence of PT, controlling for demographic confounders including age, sex, systemic diseases, and dental treatments history.Results: A total of 441 valid questionnaires were received, including 156 males and 285 females. The prevalence of PT was identified to be 33.33%, with 61.00% of participants engaging in one or more types of oral behaviors. Each oral behavior was more frequently reported in the PT group compared to the NPT group. The univariate logistic regression analysis identified positive correlations between all eight oral behaviors and PT. In the multivariate logistic regression analysis, these associations persisted after adjustment for demographic confounders including age, sex, history of systemic diseases and dental treatments (P< 0.01). The behaviors most strongly associated with PT were “Hold or jut jaw forward/to the side” (OR:4.478), “Hold, tighten or tense muscles without clench” (OR:3.343) and “Hold jaw in rigid or tense position” (OR:3.209).Conclusion: The presence of oral behaviors has significant association with PT. Individuals exhibiting multiple oral behaviors are more likely to experience PT. Additional studies are needed to clarify the effects of reducing oral behaviors on pain-related symptoms.Keywords: oral behaviors, painful temporomandibular disorders, Temporomandibular Joint, general population, cross-sectional study

Yu Z, Chan S, Wang X, et al. Drug Des Devel Ther. 2023;17:993–1006. At the authors request, the Editor and Publisher of the journal Drug Design, Development and Therapy have retracted the published article. Following publication of the article, the authors raised concerns about the duplication of images from Figure 4. Specifically, The images for Figure 4G, HCT116, RUT and 5-FU, have been duplicated. The authors wished to apologize for this error and no longer have confidence in the data and corresponding findings. To maintain academic standards, the authors requested to retract the article and the Editor and Publisher agreed with this decision. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Rui Sun,&ast; Lu Yuan,&ast; Yun Shen,&ast; Ziyang Shen, Bo Ding, Jianhua Ma Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Ding; Jianhua Ma, Email dingbonanjing@sina.com; majianhua196503@126.comAim: To compare the effect of metformin, a fixed combination of metformin and pioglitazone, or dapagliflozin on insulin resistance in patients with newly diagnosed type 2 diabetes.Methods: In this 6-week randomized open-label trial, 58 patients were randomly assigned to insulin with metformin, a fixed combination of metformin and pioglitazone, or dapagliflozin for 4 weeks. Hyperinsulinemic euglycemic clamp tests and FreeStyle Libre Pro Sensor were used to evaluate the insulin sensitivity represented by glucose-infusion rate (M value) and glycemic control, respectively. The main outcome was changes in insulin resistance compared with baseline.Results: The baseline characteristics were well matched among the three groups. When compared to baseline, insulin sensitivity after treatment was significantly improved. Further study revealed that the fixed combination of metformin and pioglitazone provided superior M-value improvement compared with metformin, but not different from dapagliflozin. Moreover, a greater reduction in insulin dose was observed in the fixed combination of metformin and pioglitazone group than the metformin or dapagliflozin group. However, there were no significant differences in the parameters of glycemic control within the groups.Conclusion: In patients with newly diagnosed type 2 diabetes, a fixed combination of metformin and pioglitazone provided greater improvement in insulin resistance than metformin alone and similar changes in insulin resistance to dapagliflozin.Keywords: insulin resistance, metformin, pioglitazone, dapagliflozin, type 2 diabetes

Wenwen Sun,1,&ast; Jun Shen,1,&ast; Ru Sun,1 Dan Zhou,1 Haihong Li2 1Department of Breast Surgery, the First People’s Hospital of Lianyungang, the Affiliated Hospital of XuZhou Medical University, LianYunGang, Jiangsu, 222002, People’s Republic of China; 2Department of Nursing, the First People’s Hospital of Lianyungang, The Affiliated Hospital of XuZhou Medical University, LianYunGang, Jiangsu, 222002, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haihong Li, Department of Nursing, the First People’s Hospital of Lianyungang, the affiliated hospital of XuZhou medical university, No. 6 Zhenhua East Road, High-Tech Square, LianYunGang, Jiangsu Province, 222002, People’s Republic of China, Tel +86 18961322059, Email haihonglired@126.comObjective: In this study, we aim to establish and evaluate a predictive model for post-treatment anxiety state based on basic patient attributes and pre-treatment SAS scores, with the expectation that this model will guide clinical precision intervention.Methods: Data were collected from 606 patients with breast cancer who underwent surgery at our hospital between January 1, 2015 and December 30, 2018 and 144 newly diagnosed patients with breast cancer who were admitted between June 1, 2019 and December 30, 2019, for a total of 750 patients with breast cancer. The relationship between SAS_A scores and prognosis was verified by analyzing patient baseline characteristics, follow-up data, pre-treatment self-rating anxiety scale (SAS) scores, and SAS_A scores in follow-up period after the end of treatment. A risk prediction model was developed in view of the SAS_A scores, which was then screened, validated, and simplified by scoring, with a nomogram plotted.Results: The SAS_A score can be utilized to differentiate prognosis. In K-M analysis, the high SAS_A score group had a significantly poorer progression-free survival rate than the low score group, p-value < 0.0001. Through model feature selection and clinical analysis, all variables were finally incorporated to establish a predictive model with a ROC AUC of 0.721 (0.637– 0.805) for the validation set and external data, and an AUC of 0.810 (0.719– 0.902) for external data, demonstrating good predictive performance. Calibration curves and probability distribution maps were constructed. DCA and CIC analyses demonstrated that model intervention could boost clinical benefits more effectively than intervention for all patients.Conclusion: Using a predictive model to guide clinical management for anxiety in breast cancer patients is feasible, but additional research is required.Keywords: breast cancer, negative emotions, nomogram, predictive model

Meng Zhou,&ast; Fang Lu,&ast; Ling Jiang, Chen Chen, Si Chen, Luhan Geng, Rui Sun, Qing Li, Suyan Duan, Bo Zhang, Huijuan Mao, Changying Xing, Yanggang Yuan Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanggang Yuan; Changying Xing, Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, Jiangsu Province, 210029, Tel/Fax +86-25-6830-6462, Email ygyuan@njmu.edu.cn; cyxing62@126.comAim: Diabetic kidney disease (DKD) continues to be devastating complication of diabetes mellitus. Immune response and inflammatory reaction play essential roles in the progression of DKD. But the specific mechanism of immune cells, and their act on renal innate cells remains unclear. This article focused on immune cells and their communication with renal innate cells to provide bioinformatic evidence for further understanding the immune mechanism in DKD.Methods: Data were analyzed to evaluate the differentially expressed genes (DEGs) and their pathways in DKD patients and mice. Gene set enrichment analysis (GSEA) was used to explore the immune inflammation-related pathways. CIBERSORT was applied to evaluate the distribution of inflammatory cells in different states. Cell-type DEGs and their enrichment pathways were further explored in podocytes, proximal tubule cells and injured tubule cells. Cellchat was used to reveal the cellular communication between immune cells and renal innate cells in DKD.Results: GO and KEGG analysis showed that DEGs were mainly enriched in immune inflammation-related pathways. Monocytes, M2 macrophages and T cells were significantly increased in DKD samples, especially in renal tubule. ScRNA datasets showed that the immune cells number in DKD were significantly increased. Cell-type DEGs were involved in kidney growth and development. In DKD, the interaction numbers and strength between immune cells and innate cells were significantly increased. VISTANT, SPP1 and IGF signal flow were increased in DKD. SPP1-CD44, NRG1-ERBB4, NAMPT-INSR, and Igf1-Igf1r receptor ligand pairs were enhanced in DKD, which mediated the communication between immune-inflammatory cells and innate cells.Conclusion: Our study explored the pathogenesis of renal injury promoted by immunoinflammatory in DKD. VISTANT, SPP1, and IGF signaling pathways and SPP1-CD44, NRG1-ERBB4, NAMPT-INSR, and Igf1- Igf1r receptor ligand pairs might occupy essential place in the occurrence and progress of DKD.Keywords: diabetic kidney disease, immune cells, renal innate cells, bioinformatics

Hongxiang Ji,1 Ziyi Zhao,2 Zeyu Liu,3 Ruitao Sun,3 Yuquan Li,1 Xiaoheng Ding,2 Tongshang Ni4 1College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 2Department of Hand and Foot, Microsurgery, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 3School of Clinical Medicine, Department of Medicine, Qingdao University, Qingdao, People’s Republic of China; 4Center of Integrated Traditional Chinese and Western Medicine, School of Basic Medicine, Qingdao University, Qingdao, People’s Republic of ChinaCorrespondence: Tongshang Ni, Center of Integrated Traditional Chinese and Western Medicine, School of Basic Medicine, Qingdao University, No. 308, Ningxia Road, Qingdao, Shandong, People’s Republic of China, Email neetongshang@126.com Xiaoheng Ding, Department of Hand and Foot, Microsurgery, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao, Shandong, People’s Republic of China, Email dxhqd@126.comAim: To evaluate the real-life effectiveness and safety of Chinese patients with type 2 diabetes mellitus (T2DM) receiving hydrogen inhalation (HI) treatment as a supplementary treatment.Methods: This retrospective, multicenter, observational 6-months clinical study included T2DM patients maintaining HI, visited at 4 time points. The primary outcome is the mean change in glycated hemoglobin (HbA1c) at the end of the study compared to baseline. The secondary outcome is analyzing the mean change of fasting plasma glucose (FPG), weight, lipid profile, insulin dose and homeostasis model assessment. Linear regression and logistics regression are applied to evaluate the effect of HI after the treatment.Results: Of the 431 patients comprised, it is observed a significant decrease in HbA1c level (9.04± 0.82% at baseline to 8.30± 0.99% and 8.00± 0.80% at the end, p< 0.001), FPG (165.6± 40.2 mg/dL at baseline to 157.1± 36.3mg/dL and 143.6± 32.3mg/dL at the end, p< 0.001), weight (74.7± 7.1kg at baseline to 74.8± 10.0kg and 73.6± 8.1kg at the end, p< 0.001), insulin dose (49.3± 10.8U/d at baseline to 46.7± 8.0U/d and 45.2± 8.7U/d, p< 0.001). The individuals in subgroup with higher baseline HbA1c and longer daily HI time duration gain greater HbA1c decrease after 6 months. Linear regression shows that higher baseline HbA1c level and shorter diabetes duration are significantly in relation to greater HbA1c reduction. Logistics regression reveals that lower weight is associated with a higher possibility of reaching HbA1c< 7%. The most common adverse event is hypoglycemia.Conclusion: HI therapy significantly improves glycemic control, weight, insulin dose, lipid metabolism, β-cell function and insulin resistance of patients with type 2 diabetes after 6 months. Higher baseline HbA1c level and shorter diabetes duration is related to greater clinical response to HI.Keywords: type 2 diabetes, observational study, hydrogen inhalation, glycemic control, real-world study

Zhen Yu,1,&ast; Shixin Chan,2,&ast; Xu Wang,2 Rui Sun,2 Ming Wang,1 Zhenglin Wang,2 Xiaomin Zuo,2 Jiajie Chen,3 Huabing Zhang,4 Wei Chen1,2,5 1Department of General Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 2Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 3Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 4Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, 230032, People’s Republic of China; 5Anhui Provincial Institute of Translational Medicine, Hefei, 230022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huabing Zhang, Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, 230032, People’s Republic of China, Email slzhang1977@163.com; huabingzhang@ahmu.edu.cn Wei Chen, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China, Tel +86 13966711566, Fax +86 0551-63633742, Email chenwei366@126.com; chenwei366@ahmu.edu.cnPurpose: To evaluate the effect of 5-fluorouracil (5-FU) combined with rutaecarpine (RUT) on the antiproliferative, anti-migratory, and apoptosis-promoting ability of colorectal cancer (CRC) cells and explore the underlying mechanism.Methods: The antiproliferative effects of RUT and 5-FU on CRC cells were evaluated using MTT and colony formation assays. Anti-migration was assessed by cell scratch and transwell tests. The synergistic effect of RUT and 5-FU was assessed by isobologram and combination index analysis using CompuSyn software. The effects of RUT and 5-FU on cell apoptosis were detected by flow cytometry. Differences in protein expression levels with or without RUT and/or 5-FU treatment were assessed by Western blot. Moreover, a mouse xenograft model of CRC was established to investigate the antitumor effect of RUT and 5-FU in vivo, and Ki67 and cleaved caspase-3 expression was detected by immunofluorescence.Results: In this study, we found that 5-FU combined with RUT can inhibit the proliferative, migratory, and antiapoptotic abilities of CRC cells to a significantly greater extent than either RUT or 5-FU alone both in vivo and in vitro. Western blot analysis showed that the level of signal transducer and activator of transcription 3 (STAT3) phosphorylation in CRC cells was significantly reduced after combination therapy compared with that seen with the respective monotherapies. In addition, combination therapy influenced the STAT3 signaling pathway, namely, it inhibited the expression of c-Myc, CDK4, and Bcl-2 while enhancing that of the proapoptotic protein cleaved caspase-3. Immunofluorescence staining further showed that the expression of Ki67 and cleaved caspase-3 was significantly downregulated and upregulated, respectively, in tumor tissues of mice treated with combination therapy compared with that observed with 5-FU treatment alone.Conclusion: Combined therapy with 5-FU and RUT exerted a superior curative effect in CRC than treatment with either single drug alone and has potential as a novel therapeutic modality for the treatment of CRC.Keywords: 5-fluorouracil, colorectal cancer, rutaecarpine, signal transducer and activator of transcription 3, synergistic therapy

Yuan Ze,1 Huiming Tu,2 Lin Zhang,3,4 Yu Bai,5 Yilin Ren,2 Xin Chen,1 Yuzheng Xue,2 Renjuan Sun,6 Yuling Yang,7 Jie Yang,2 Xuan Zhou,2 Li Liu8 1Wuxi School of Medicine, Jiangnan University, Wuxi, People’s Republic of China; 2Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, People’s Republic of China; 3Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, People’s Republic of China; 4School of Population Medicine and Public Health, Peking Union Medical College/Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 5Department of Gastroenterology, Changhai Hospital of Shanghai, Shanghai, People’s Republic of China; 6Outpatient Nursing department, Affiliated Hospital of Jiangnan University, Wuxi, People’s Republic of China; 7Nursing department of Geriatrics Ward, Affiliated Hospital of Jiangnan University, Wuxi, People’s Republic of China; 8Data Center, Affiliated Hospital of Jiangnan University, Wuxi, People’s Republic of ChinaCorrespondence: Huiming Tu, Department of Gastroenterology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Binhu District, Wuxi, 214122, People’s Republic of China, Tel +86-13861753621, Email tuhuiming1891@163.comObjective: To compare the screening efficacy of colonoscopy and pathologically confirmed single and combined Asia-Pacific colorectal screening (APCS), faecal immunochemical testing (FIT) and stool deoxyribonucleic acid (sDNA) testing protocols.Methods: From April 2021 to April 2022, 842 volunteers participated in primary colorectal cancer (CRC) screenings using APCS scoring, FIT and sDNA testing and 115 underwent a colonoscopy. One hundred high-risk participants were then identified from the results of both processes. The differences in the three CRC screening tests in combination with the colonoscopy pathology diagnostics were evaluated using Cochran’s Q test, the Dunn–Bonferroni test and area under the receiver operating characteristic curve (AUC) value analysis.Results: Both FIT and sDNA testing demonstrated a 100% performance in detecting CRC. For advanced adenoma, the sensitivity of the FIT + sDNA test scheme (double positive) was 29.2%, and the sensitivities of the combined FIT + sDNA test and APCS scoring + sDNA test schemes were 62.5% and 95.8%, respectively. The FIT + sDNA testing kappa value of advanced colorectal neoplasia was 0.344 (p = 0.011). The sensitivity for nonadvanced adenoma of the APCS score + sDNA test scheme was 91.1%. In terms of positive results, the sensitivity of the APCS score + FIT + sDNA detection protocol was significantly higher than that of the APCS score, FIT, sDNA detection, and FIT + sDNA detection methods (adjusted p < 0.001, respectively). For the FIT + sDNA test, the kappa value was 0.220 (p = 0.015) and the AUC was 0.634 (p = 0.037). The specificity of the FIT + sDNA test scheme was 69.0%.Conclusion: The FIT + sDNA test scheme demonstrated superior diagnostic efficacy, and the combined APCS score + FIT + sDNA test scheme demonstrated remarkable improvements in CRC screening efficiency and sensitivity for detecting positive lesions.Keywords: faecal immunochemical testing, stool DNA test, colonoscopy, primary screening, colorectal cancer

Miao Li,1,2 Jiazhao Zhang,3 Chenguang Jiang,2,4 Jun Wang,2 Ruhong Sun,5 Shayu Jin,5 Ning Zhang,1,&ast; Zhenhe Zhou2,&ast; 1Department of Psychology, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Psychiatry, The Affiliated Wuxi Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, People’s Republic of China; 3Grade 2019 Class 6, Basic Medicine College of Jinzhou Medical University, Jinzhou, People’s Republic of China; 4Department of Psychosomatics and Psychiatry, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China; 5Department of Psychiatry, Nanjing Medical University Graduate School, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning Zhang, Department of Psychology, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, People’s Republic of China, Tel +86-13601588630, Email zn6360@126.com Zhenhe Zhou, Department of Psychiatry, The Affiliated Wuxi Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, People’s Republic of China, Tel +86-13358118986, Email zhouzh@njmu.edu.cnPurpose: Deficits in facial emotional intensity recognition have been associated with social cognition in patients with major depression. The study examined multiple event-related potential (ERP) components in patients with major depression and investigated the relationships between ERPs, social cognition, and clinical features.Participants and Methods: Thirty-one patients met DSM-IV diagnosis of depression and 31 healthy participants completed the emotion intensity recognition task (EIRT), while ERPs were recorded. Data on ERP components (P100, N170, P200, and P300) were analyzed.Results: The behavioral results showed that patients with major depression performed worse on EIRT, including all six categories of emotions (sadness, disgust, happiness, surprise, anger, and fear), compared to healthy participants. The ERP results showed that patients with major depression exhibited higher P100 amplitudes for sad and happy faces than healthy participants; P300 amplitudes induced by sad and surprise faces were also higher than in healthy participants, mainly in the central and temporal lobes. A positive correlation was found between sadness intensity scores and P100 amplitudes in patients with major depression.Conclusion: Patients with major depression are biased in their identification of facial expressions indicating emotional intensity. Specifically, they have emotional biases in the early and late stages of cognitive processing, mainly in the form of sensitivity to sad stimuli. It may lead to a persistent rumination of sadness that is detrimental to the remission of depression. Additionally, patients with major depression devote different amounts of cognitive resources for different intensities of sad faces during the preconscious stage of cognitive processing. The more intense their perception of sadness, the more cognitive resources they devote. Therefore, the assessment of the intensity of facial expressions is an important research topic, with clinical implications on social cognitive function in patients with major depression.Keywords: major depression, event-related potentials, emotional intensity recognition, social cognition, emotional tasks

Yan Zhang,1 Wenjie Li,1 Xiaomin Tian,1 Ruanyang Sun,1 Shidan Zhou,2 Ling Jia,1 Jian Sun,1,3,4 Xiao-Ping Liao,1,3,4 Ya-Hong Liu,1,3,4 Yang Yu1,3,4 1Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, People’s Republic of China; 2Intensive Care Unit, Huizhou Municipal Central Hospital, Huizhou, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Microbial Safety and Health, Guangdong Institute of Microbiology, Guangdong Academy of Science, Guangzhou, People’s Republic of China; 4Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, People’s Republic of ChinaCorrespondence: Yang Yu, Email graceyyu@scau.edu.cnObjective: Carbapenem-resistant Enterobacteriaceae (CRE) have become an increasingly common cause of healthcare-related infections and present a serious challenge to clinical treatment. This study examined the phenotypic, genotypic characterization, clinical, and microbiological data of CRE in the Huizhou Municipal Central Hospital.Methods: We conducted a phenotypic susceptibility evaluation and whole genome sequence analysis for 52 CRE strains isolated from 37 patients and 2 medical device-related samples during 2013– 2017 to characterize risk factors, antimicrobial resistance profiles, dominant clones and hospital transmission.Results: Long-term hospitalization, treatment time with antibiotics and use of invasive devices were linked to the risk of CRE infection. The carbapenem resistance genes (CRGs) we found included blaNDM (82.7%), blaIMP (19.2%) and blaKPC (3.8%), Escherichia coli (44.2%) and Klebsiella pneumoniae (44.2%) were the dominant species we identified, and the type of CRG carried by isolates was highly correlated with species. The coexistence of CRGs with a variety of other antibiotic resistance genes leads to an increased prevalence of high resistance levels for CRE to β-lactams and other antibiotic classes such as aminoglycosides and fluoroquinolones. These isolates were sensitive only to colistin and tigecycline. In addition to this, we observed significantly genomic diversity of CRE isolates in this hospital. Importantly, we found that long-term transmission of multiple CRE clones had occurred at this hospital between various wards.Conclusion: Evaluating and improving the current infection control strategies may be necessary, and reducing nosocomial transmission remains the primary control element for CRE infections in China.Keywords: carbapenem-resistant Enterobacteriaceae, bacteremia, carbapenem resistance genes, nosocomial transmission

Lanyao Yang1,2 &ast;, Lanlan Wu3 &ast;, Yao Liu,3 Hengying Chen,4 Yuanhuan Wei,3 Ruifang Sun,3 Siwen Shen,3 Bowen Zhan,1,2 Jianjun Yang,1,2 Guifang Deng3 1Department of Nutrition and Food Hygiene, School of Public Health and Management, Ningxia Medical University, Yinchuan, People’s Republic of China; 2Key Laboratory of Environmental Factors and Chronic Disease Control, School of Public Health and Management, Ningxia Medical University, Yinchuan, People’s Republic of China; 3Department of Clinical Nutrition, Union Shenzhen Hospital of Huazhong University of Science and Technology, Shenzhen, People’s Republic of China; 4Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guifang Deng, Department of Clinical Nutrition, Union Shenzhen Hospital of Huazhong University of Science and Technology, No. 89 Taoyuan Road, Shenzhen, Guangdong, 518052, People’s Republic of China, Email misyfly@163.com Jianjun Yang, Department of Nutrition and Food Hygiene, School of Public Health and Management, Ningxia Medical University, No. 1160 Shengli Road, Yinchuan, Ningxia, 750004, People’s Republic of China, Email yangjj@nxmu.edu.cnObjective: This study evaluated the associations of serum ferritin (SF) concentration during pregnancy with the risk of adverse maternal and fetal pregnancy outcomes.Methods: We conducted a retrospective study of 2327 pregnant women from 2015 to 2020 in Guangdong, China. SF concentrations were measured at 16– 18th and 28– 32th week of gestation. Logistic regression models were applied to estimate the association between SF concentration and the risk of adverse pregnancy outcomes.Results: After multivariable adjustment, the odds ratio (OR) of the highest quartile of SF concentration at 16– 18th week of gestation was 1.43 (95% confidence interval [CI]: 1.09, 1.89) for gestational diabetes mellitus (GDM) and 1.79 (95% CI: 1.15, 2.79) for small for gestational age (SGA) when compared with the lowest quartile. At 28– 32th week of gestation compared with the lowest quartile, women with SF in the highest quartile had an increased risk of SGA (OR: 1.62; 95% CI: 1.01, 2.62). Moreover, the lowest quartile of SF concentration decreased risk of SGA by 90% (95% CI: 0.01, 0.80) when compared with the highest quartile among pregnancy women with GDM.Conclusion: Elevated SF concentrations increased the risk of GDM and SGA during pregnancy. Maintaining an appropriately low level of maternal SF at 28– 32th week of gestation in women with GDM could reduce the risk of SGA.Keywords: ferritin, adverse pregnancy outcomes, gestational diabetes mellitus, small for gestational age

Hanrui Liu,1 Chengyong Ma,2 Huayan Xu,1 Huan Zhang,3 Rong Xu,1 Kun Zhang,1 Ran Sun,1 Kuan Li,1 Qihong Wu,1 Lingyi Wen,1 Lizhi Zhang,2 Yingkun Guo1 1West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3College of Chemistry and Materials Science, Northwest University, Xi’an, People’s Republic of ChinaCorrespondence: Yingkun Guo, Development and Related Diseases of Women and Children Key Laboratory, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin South Road, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86+18180609256, Email gykpanda@163.com Lizhi Zhang, Department of Radiology, West China Hospital of Sichuan University, No. 37, Guoxue Road, Chengdu, Sichuan, 610041, People’s Republic of China, Email littche_2000@163.comIntroduction: Free radicals in oxidative stress are known to play a pathogenic role in sepsis. A major clinical challenge associated with sepsis is sepsis-associated encephalopathy (SAE). The rapid increase of free radicals in the brain promotes SAE progression. Here, macromolecule free radicals in the mouse brain were uniquely detected by immunospin trapping (IST) and magnetic resonance imaging (MRI).Methods: The new strategy uses spin trapping agent DEPMPO-biotin to capture macromolecule free radicals in lesions and form biotin-DEPMPO-radical adducts. Then, a targeting MRI probe, avidin-BSA@Gd-ESIO, was used to detect the radical adducts through the highly specific binding of avidin and biotin. The avidin-BSA@Gd-ESIO probe was synthesized and systematically characterized. The detection capability of the new strategy was evaluated in vitro and in vivo using a confocal microscope and a 7T MRI, respectively.Results: In reactive oxygen species (ROS)–induced microglial cells, the accumulation of the avidin-BSA@Gd-ESIO probe in the DEPMPO-biotin-treated group was significantly higher than that of control groups. In vivo MRI T1 signal intensities were significantly higher within the hippocampus, striatum, and medial cortex of the brain in mice with a mild or severe degree of sepsis compared with the sham control group. Histological analysis validated that the distribution of the avidin-BSA@Gd-ESIO probe in brain tissue slices was consistent with the MRI images. The fluorescence signals of ROS and avidin-BSA@Gd-ESIO probe were overlapped and visualized using immunofluorescent staining. By evaluating the T1 signal changes over time in different areas of the brain, we estimated the optimal MRI detection time to be 30 minutes after the probe administration.Discussion: This method can be applied specifically to assess the level of macromolecular free radicals in vivo in a simple and stable manner, providing a pathway for a more comprehensive understanding of the role of free radicals in SAE.Graphical-Abstract: Keywords: macromolecule radical, ESIO, spin trapping, sepsis-associated encephalopathy

Li Li,1 Rongjin Sun,1 Joseph Zenga,2 Heather Himburg,3 Lu Wang,1 Shengnan Duan,1 Jingwen Liu,1 Dinh Bui,1 Zuoxu Xie,1 Ting Du,4 Lijun Xie,1 Taijun Yin,1 Stu Wong,2 Song Gao,4 Ming Hu1 1Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA; 2Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, USA; 3Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 4Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USACorrespondence: Ming Hu, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA, Email mhu@uh.edu Song Gao, Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA, Email Song.Gao@tsu.eduObjective: We aim to quantify the absolute protein expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in various cells and tissues to determine the relative contribution of COX-1 and COX-2 to PGE2 production.Methods: An LC-MS method was developed and validated, then used for quantifying the absolute amounts of COX-1 and COX-2 in recombinant human COX-1 and COX-2, lysates from different cells, tissue microsomes of rodents and humans, Pirc rat colonic polyps, and biopsy specimens from squamous cell carcinoma (SCC) patients. The COX-1 and COX-2 turnover numbers were subsequently calculated based on apparent formation rates of PGE2.Results: A robust LC-MS method for quantification of COX-1 and COX-2 was developed and validated and then used to calculate their apparent turnover numbers. The results showed that COX-1 expression levels were much higher than that of COX-2 in all the tested tissues including the colonic epithelium of F344 (28-fold) and Pirc rats (20-fold), colonic polyps of Pirc rats (8-fold), and biopsy specimens of SCC patients (11– 17-fold). In addition, both COX-1 and COX-2 were higher in polyps when compared to adjacent mucosa of Pirc rats. The turnover number of recombinant human COX-2 was 14-fold higher than that of recombinant human COX-1. LPS stimulation increased COX-2 protein expression in three cell lines (Raw 264.7, SCC9 and EOMA) as expected but unexpectedly increased COX-1 protein expression (13.8-fold) in EOMA cells.Conclusion: In human oral cancer tissues and cells as well as Pirc rat colon, COX-1 plays an unexpectedly but more important role than COX-2 in abnormal PGE2 production since COX-1 expression is much higher than COX-2. In addition, COX-1 expression levels are inducible in cells, and higher in polyps than surrounding mucosa in Pirc rat colon. These results indicate that targeted suppression of local COX-1 should be considered to reduce colon-specific PGE2-mediated inflammation.Graphical Abstract: Keywords: cyclooxygenase-1, cyclooxygenase-2, turnover number, inflammation, absolute quantification, liquid chromatography with tandem mass spectrometry

Yunfan Xia,1 Ruohan Sun,1 Rongrong Li,1 Leilei Ren,1 Yiyi Wang,1 Jianqiao Fang2 1The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China; 2The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of ChinaCorrespondence: Jianqiao Fang, 23 Qingchun Road, Hangzhou City, People’s Republic of China, Tel +86(0)571-87238254, Fax +86(0)571-87238005, Email fangjianqiao7532@163.comBackground: Accumulate evidence indicated that moxibustion has a positive effect on pain treatment. However, the bibliometric analysis of moxibustion on pain remains uncertain. Herein, this study aimed to explore the current hotspots and the research trends over the past decade to bring a great panorama in this field.Methods: Publications were retrieved from the database Web of Science Core Collection (WoSCC) related to moxibustion therapy for pain treatment from January 1, 2012, to December 31, 2021. CiteSpace and Excel were applied to analyze the volume of publications, journals, cited journals, dual-map analysis, countries, institutes, authors, references, and keywords with citation bursts.Results: A total of 360 publications were retrieved from 2012 to 2021. The annual number of publications increased steadily with some fluctuations over the past 10 years. “The Evid Based Complement Alternat Med” and “the Gut” were the top-cited journals in frequency and centrality. China and Shanghai University of Traditional Chinese Medicine were the most prolific country and institutions, respectively. Among authors, Huangan Wu was the most active author with the highest cited frequency. Jun Xiong, Fanrong Liang and Guixing Xu held the articles with higher centrality. In the ranking of frequency and centrality in cited references, the top one was the article published by Shamseer L and Deng HY, respectively. “Acupuncture” was the keyword with the highest frequency. Pain disease (including rheumatoid arthritis, knee osteoarthritis, herpes zoster), research method (including randomized controlled trial), and risk (including quality of life, economic burden, physical and psychological problems) were the hotspots and frontier trends in this field.Conclusion: This bibliometric study reveals the current status and research trend in the treatment of pain with moxibustion. The formulation with bibliometric analysis further elicits hot spots and frontier issues in this field.Keywords: moxibustion, pain, CiteSpace, bibliometric analysis

Rongrong Sun,1 Zhixin Yan,2 Wenxia Yi,2 Wenqiu Tian,2 Mei Sun,2 Jing Zhang1 1Children’s Ward, Cangzhou Central Hospital, Cangzhou, Hebei Province, People’s Republic of China; 2Cangzhou Central Hospital, Cangzhou, Hebei Province, People’s Republic of ChinaCorrespondence: Jing Zhang, Children’s Ward, Cangzhou Central Hospital, Cangzhou City, Hebei Province, 061001, People’s Republic of China, Tel +86 15031730097, Email wuwo681230754@163.comObjective: To study serum levels of vitamins A, D and E in children with recurrent respiratory tract infections of different ages and the correlation.Methods: The clinical data of two groups of children of different ages were collected. The serum levels and deficiencies of vitamins A, D and E in children were statistically analyzed.Results: The proportions of premature infants, low body weight infants, special physique, hospitalization history, hypocalcemia, living in a bungalow, and daily outdoor activities in less than 30 minutes in the case group were higher than those in the control group (χ2=4.507, 5.165, 7.040, 14.907, 4.267, 33.800, 4.507, 8.571, P < 0.05). The serum levels of vitamins A, D and E of children aged 0– 1, 2– 5, and 6– 12 in the case group were lower than those in the control group (P < 0.05). Compared with the control group, the serum vitamin A level of children in the case group was lower (t = 2.631, P < 0.05), and the deficiency rate was higher (χ2=24.200, P < 0.05).Conclusion: Serum levels of vitamins A, D and E, which are related to birth mode, physical fitness, hospitalization history, hypocalcemia, vitamin deficiency, living environment, and daily outdoor activity time, vary in children with recurrent respiratory tract infections of different ages, and are lower in children with recurrent respiratory tract infections than in healthy children.Keywords: different age groups, recurrent respiratory tract infections, children, serum vitamins A, D and E levels, correlation

Runjie Sun,1 Jiang Liu,2 Manya Yu,1 Mengting Xia,3 Yanyu Zhang,1 Xiaoqi Sun,1 Yunsheng Xu,4 Xing Cui4 1College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China; 2Department of Foreign Affairs Office, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China; 3First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China; 4Second School of Clinical Medicine, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250001, People’s Republic of ChinaCorrespondence: Yunsheng Xu; Xing Cui, Second School of Clinical Medicine, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, 1 Jingba Road, Jinan, 250001, People’s Republic of China, Email xys65@126.com; cdz45@foxmail.comBackground: Bortezomib-induced peripheral neuropathy (BiPN) is a common complication of multiple myeloma (MM) treatment that seriously affects the quality of life of patients. The purpose of the present study was to explore the therapeutic effect of paeoniflorin on BiPN and its possible mechanism.Methods: ELISA was used to measure the level of interleukin-6 (IL6) in the plasma of MM patients, and bioinformatics analysis was used to predict the mechanism underlying the effect of paeoniflorin on peripheral neuropathy. Cell and animal models of BiPN were constructed to evaluate mitochondrial function by measuring cell viability and mitochondrial quality and labeling mitochondria with MitoTracker Green. Nerve injury in mice with BiPN was assessed by behavioral tests, evaluation of motor nerve conduction velocity, hematoxylin-eosin (HE) staining, electron microscopy and analysis of the levels of reactive oxygen species (ROS). Western blotting and immunohistochemistry (IHC) were used to assess the expression of autophagy-related proteins.Results: In MM patients, IL6 levels were positively correlated with the degree of PN. The results of bioinformatics analysis suggested that paeoniflorin ameliorated PN by altering inflammation levels and mitochondrial autophagy. Paeoniflorin increased PC12 cell viability and mitochondrial autophagy levels, alleviated mitochondrial damage, and reduced IL6 levels. In addition, paeoniflorin effectively improved the behavior of mice with BiPN, relieved sciatic nerve injury in mice, increased the expression of LC3II/I, beclin-1, and Parkin in sciatic nerve cells, and increased the expression of LC3B and Parkin in the nerve tissue.Conclusion: The present study confirmed that paeoniflorin significantly ameliorated peripheral neuropathy (PN) caused by bortezomib, possibly by reducing IL6 levels to regulate PARKIN-mediated mitochondrial autophagy and mitochondrial damage.Keywords: multiple myeloma, paeoniflorin, peripheral neuropathy, mitochondria, autophagy

Xue C, He Y, Hu Q, et al. Cancer Manag Res. 2018;10:5101–5112. We, the Editors and Publisher of Cancer Management and Research, have retracted the published article. Concerns were raised about the integrity of the data in the article following the author’s request to correct images in Figures 2 and 3. It was found images from these figures had been duplicated within the article and with those from another article. Specifically, The images for Figure 2D, GBC-SD, NC and PIM1-siRNA, have been duplicated with the images for Figure 3C, GBC-SD, NC and NOZ, PIM1-siRNA, respectively. The images for Figure 2D, NOZ, NC, have been duplicated with the images from Figure 5d, Hep3B, PLK-4 from Bao J, Yu Y, Chen J, et al. MiR-126 negatively regulates PLK-4 to impact the development of hepatocellular carcinoma via ATR/CHEK1 pathway. Cell Death Dis. 2018;9:1045. https://doi.org/10.1038/s41419-018-1020-0. When approached for an explanation, the authors were cooperative and provided some original data for their study, however, the provided data was not satisfactory, and the results could not be adequately verified. As verifying the validity of the published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors do not agree with this decision. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Zhirui Wang,&ast; Rui Sun,&ast; Cheng Mu, Chunhua Wang, Hui Zhao, Lina Jiang, Hanfang Ju, Wenxi Dai, Fan Zhang Tuberculosis Reference Laboratory, Tianjin Center for Tuberculosis Control, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fan Zhang, Tuberculosis Reference Laboratory, Tianjin Center for Tuberculosis Control, No. 124, Chifeng Road, Heping District, Tianjin, 300041, People’s Republic of China, Tel +86-22-27124491, Fax +86-22-27117595, Email jncdczhf@126.comObjective: Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a global concern. This study aimed to determine the molecular characteristics of fluoroquinolone-resistant and multidrug-resistant M. tuberculosis strains using whole-genome sequencing to predict drug resistance in M. tuberculosis in Tianjin, China, which has not been established previously.Methods: Twenty-one fluoroquinolone-resistant and multidrug-resistant M. tuberculosis strains were isolated from sputum samples. Phenotypic drug resistance against 12 anti-tuberculosis drugs was determined using drug susceptibility testing. Whole-genome sequencing was performed to predict drug resistance in M. tuberculosis based on genome regions associated with drug resistance. The sensitivity of whole-genome sequencing for predicting drug resistance was calculated based on phenotypic drug susceptibility testing information.Results: Among the 21 isolates, mutations in 15 genome regions associated with drug resistance, including rpoB for rifampicin; katG and inhA promoter for isoniazid; gyrA and gyrB for ofloxacin and moxifloxacin; rpsL for streptomycin; rrs for streptomycin, amikacin, kanamycin and capreomycin; pncA and panD for pyrazinamide; embB, embC-embA, aftA, and ubiA for ethambutol; ethA for protionamide; and folC for para-aminosalicylic acid, were detected. Compared with traditional drug susceptibility testing results, the sensitivities for whole-genome sequencing of rifampin, isoniazid, ofloxacin, moxifloxacin, streptomycin, ethambutol, pyrazinamide, kanamycin, and amikacin resistance were 100%, 90.48%, 95.24%, 92.86%, 95.27%, 85.71%, 66.67%, 50%, and 50%, respectively. The sensitivities for whole-genome sequencing of capreomycin, protionamide, and para-aminosalicylic acid were not calculated because only one isolate showed phenotypic drug resistance. Mutations determined in drug susceptibility-associated genes can explain phenotypic drug resistance in most isolates. Notably, these mutations were absent in certain drug-resistant isolates, indicating other drug resistance mechanisms.Conclusion: Whole-genome sequencing represents an effective diagnostic tool for fluoroquinolone-resistant and multidrug-resistant TB though it has some obstacles. Whole-genome sequencing should be used to predict drug resistance prior to performing traditional phenotypic drug susceptibility testing in Tianjin, China.Keywords: Mycobacterium tuberculosis, tuberculosis, fluoroquinolone, mutation, drug resistance, whole-genome sequencing

Ruohan Sun,1,2,&ast; Shimin Li,1,&ast; Leilei Ren,2 Yunfan Xia,2 Yiyi Wang,2 Zhiyuan Bian,2 Jianqiao Fang,2 Zuyong Zhang1 1Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Acupuncture, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zuyong Zhang, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, No. 38 West Lake Road, Hangzhou, Zhejiang, People’s Republic of China, Email zzynwk@126.com Jianqiao Fang, The Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 23 Qinchun Road, Hangzhou, Zhejiang, People’s Republic of China, Email fangjianqiao7532@163.comIntroduction: Postherpetic neuralgia (PHN) is a severe complication of herpes zoster (HZ), representing an important burden of disease in the elderly. Electroacupuncture (EA) has become growingly appreciated as a therapy of PHN with the situation that effectiveness of conventional therapy of PHN is less than ideal. Owing to its low price, no side effects, high safety and high patients acceptance, EA has been used in treating PHN more frequently. Therefore, the randomized controlled trial which is to evaluate the effectiveness and safety of EA in patients with PHN and whether EA could be an alternative therapy of medication is needed.Patients and Methods: A total of 88 patients with PHN will be recruited from 2 hospitals and randomized assigned to EA group or Medication group in a 1:1 ratio, utilizing a central randomization system. The trial will involve a 4-week treatment period, and a 4-week follow-up period. All variables will be evaluated at week 0 (baseline), week 2 (treatment), week 4 (treatment), week 8 (follow-up) and week 16 (follow-up). Primary outcomes will be pain intensity. Secondary outcomes will contain quality of life, mood state and sleep quality. All adverse effects will be assessed during the trial.Conclusion: This study will provide significant evidence that whether EA therapy is effective and safe for patients with PHN and whether EA could be an alternative therapy of medication.Ethics and Dissemination: Ethics approval has been obtained from the Ethics Committee of the Hangzhou Third People’s Hospital (No. 2021KAO43). Informed consent will be signed before enrolment. Results of this trial will be presented to international journals for publication and be reported in relevant international conferences.Trial Registration Number: This protocol has been registered in the Chinese Clinical Trial registry with the identification code ChiCTR2100054592.Keywords: postherpetic neuralgia, electroacupuncture, pain, randomized controlled trial, protocol

Liang Zhang,1,&ast; Zhentao Yang,1,&ast; Shiyu Zhang,1 Ke Zhou,1 Wu Zhang,2 Sunbin Ling,1 Ruiqi Sun,1 Hong Tang,1 Xue Wen,3 Xiaowen Feng,1 Penghong Song,1 Xiao Xu,1 Haiyang Xie,1 Shusen Zheng1,2 1Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China; 2Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, Zhejiang, 310004, People’s Republic of China; 3Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiyang Xie; Shusen ZhengSchool of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, Zhejiang, 310000, People’s Republic of ChinaTel/Fax +86 571 87236570; +86 571 87236466Email xiehy@zju.edu.cn; shusenzheng@zju.edu.cnPurpose: Patients receiving liver transplantation (LT) for hepatocellular carcinoma (HCC) are at high risk of tumor recurrence. Polyploidy is a fascinating characteristic of the liver and correlates with HCC development and progression. This study aims to investigate the association between hepatocyte polyploidy spectrum and HCC recurrence after LT.Patients and Methods: Thirty-two paired HCC, peritumoral, cirrhotic, and normal liver specimens were employed to examine the hepatocyte polyploidization pattern during liver tumorigenesis. Clinicopathological implications of polyploidy spectrum for LT recipients with HCC were investigated in 205 patients from two transplant centers. Immunofluorescence staining was performed on paraffin-embedded tissue sections to determine the ploidy profiles in situ. Expression levels of CD4, CD8, forkhead box protein 3 (Foxp3) and programmed death-ligand 1 (PD-L1) were measured using immunohistochemistry. An array-based multiplex ELISA system was used for the quantitative measurement of 40 unique inflammatory cytokines.Results: The fraction of mononuclear polyploidy increased, whereas that of binuclear polyploidy reduced during hepatocarcinogenesis. Recipients with highly mononuclear polyploid HCC (HMP–HCC) had inferior recurrence-free survival and HCC-specific survival than poorly mononuclear polyploid HCC recipients. These two groups differed in abundance of infiltrative CD8+ cytotoxic T cells and FoxP3+ Treg cells, and PD-L1 expression, as well as circulating granulocyte–macrophage colony-stimulating factor, interferon-γ and interleukin-10 levels. HMP–HCC constituted an independent recurrence predictor and could improve the discriminative efficacy of clinical prediction models (Milan criteria, AFP model, and Metroticket 2.0 criteria). A scoring system incorporating the ploidy signature was developed and validated, allowing for an improved risk prediction relative to the RETREAT score and post-MORAL score.Conclusion: Polyploid spectra are associated with tumor immunophenotype and provide supplementary prognostic information in LT for HCC.Keywords: polyploidy, immunosurveillance, tumor-infiltrating lymphocytes, cytokines, tumor recurrence

Weifeng Zou,1 Xiaoqian Wang,2 Ruiting Sun,3 Jinxing Hu,1 Dong Ye,4 Ge Bai,3 Sha Liu,5 Wei Hong,6 Meihua Guo,1 Pixin Ran3 1State Key Laboratory of Respiratory Disease, Guangzhou Chest Hospital, Guangzhou, Guangdong, People’s Republic of China; 2The Third Hospital of Mianyang, Mianyang, Sichuan, People’s Republic of China; 3National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 4State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 5The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, People’s Republic of China; 6GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Pixin RanNational Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, Guangdong, 510120, People’s Republic of ChinaTel +86 13922765811Email pxran@gzhmu.edu.cnBackground: Fine-particulate matter ≤ 2.5 μm in diameter (PM2.5)-associated airway remodeling has recently been recognized as a central feature of COPD. Activation of the Wnt/β-catenin pathway is closely related to the occurrence of airway remodeling. Accordingly, the goal of this study was to determine whether the Wnt5a/β-Catenin pathway is involved in PM2.5-induced smooth muscle proliferation in vivo and in vitro, which promotes the development of airway remodeling in subjects with COPD.Methods: The effect of Wnt5a on β-Catenin-mediated airway remodeling was assessed using an in vivo model of PM2.5-induced COPD and PM2.5-exposed human bronchial smooth muscle cells (HBSMCs) in vitro. Small animal spirometry was used to measure lung function in mice. H&E staining and immunohistochemistry were performed to inspect emphysema and airway remodeling indices. Real-time PCR was used to detect Wnt5a, β-Catenin, TGF-β 1, CyclinD1 and c-myc mRNA expression. The CCK8 assay was performed to detect cellular activity. Western blotting was performed to assess PCNA, α-SMA, Wnt5a, β-Catenin, PDGFRβ and TenascinC protein expression. β-Catenin expression was detected using cellular immunofluorescence.Results: Exposure to PM2.5 led to emphysema, airway wall thickening, an increased smooth muscle layer thickness, decreased lung function and increased expression of the Wnt5a, β-Catenin, PDGFRβ and Tenascin C proteins in the mouse lung tissue. BOX5 (a Wnt5a antagonist) alleviated these PM2.5-induced outcomes in mice. Moreover, PM2.5 induced the expression of the Wnt5a, β-Catenin, TGF-β 1, CyclinD1 and c-myc mRNAs in HBSMCs. BOX5 also inhibited the PM2.5-induced increases in PCNA, α-SMA, Wnt5a, β-Catenin, PDGFRβ and Tenascin C protein expression in HBSMCs.Conclusion: Our findings suggest that PM2.5 exposure induces HBSMC proliferation, contributing to airway remodeling via the Wnt5a/β-Catenin signaling pathway in vivo and in vitro, which might be a target for COPD treatment.Keywords: COPD, airway remodeling, PM2.5, Wnt5a/β-Catenin

Xuan Wang, Dongyu Hua, Xiaole Tang, Shan Li, Rao Sun, Zheng Xie, Zhiqiang Zhou, Yilin Zhao, Jintao Wang, Shiyong Li, Ailin Luo Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of ChinaCorrespondence: Shiyong Li; Ailin Luo Email shiyongli@hust.edu.cn; alluo@tjh.tjmu.edu.cnAbstract: Postoperative neurocognitive disorder (PND) increases the length of hospital stay, mortality, and risk of long-term cognitive impairment. Perioperative sleep disturbance is prevalent and commonly ignored and may increase the risk of PND. However, the role of perioperative sleep disturbances in PND remains unclear. Nocturnal sleep plays an indispensable role in learning, memory, and maintenance of cerebral microenvironmental homeostasis. Hospitalized sleep disturbances also increase the incidence of postoperative delirium and cognitive dysfunction. This review summarizes the role of perioperative sleep disturbances in PND and elucidates the potential mechanisms underlying sleep-deprivation-mediated PND. Activated neuroinflammation and oxidative stress; impaired function of the blood-brain barrier and glymphatic pathway; decreased hippocampal brain-derived neurotrophic factor, adult neurogenesis, and sirtuin1 expression; and accumulated amyloid-beta proteins are associated with PND in individuals with perioperative sleep disorders. These findings suggest that the improvement of perioperative sleep might reduce the incidence of postoperative delirium and postoperative cognitive dysfunction. Future studies should further investigate the role of perioperative sleep disturbance in PND.Keywords: perioperative sleep disturbance, cognitive impairment, postoperative delirium, postoperative cognitive dysfunction, neuroinflammation

Gaoliang Yan, Renhua Sun, Zhongpu Chen, Xiaodong Pan, Zulong Sheng, Chengchun Tang Department of Cardiology, Zhongda Hospital of Southeast University Medical School, Nanjing, 210009, People’s Republic of ChinaCorrespondence: Gaoliang YanDepartment of Cardiology, Zhongda Hospital of Southeast University Medical School, Nanjing, 210009, People’s Republic of ChinaTel +86 18761890380Email yangaol@hotmail.comPurpose: Pulmonary hypertension (PH) is a pathological process mainly characterized by the progressive increase in pulmonary vascular resistance. The degradation of pulmonary artery smooth muscle cells (PASMCs) from contractile/differentiated phenotype to synthetic/dedifferentiated phenotype is a key factor for hypoxic pulmonary hypertension.Materials and Methods: In this study, qPCR was performed to evaluate the gene expression of mRNAs. Western blot, immunofluorescence and RNA pull down were used to detect gene expression levels.Results: We found that the gene expression of polypyrimidine tract-binding protein1 (PTBP1) was increased significantly in a time-dependent manner in rats PA tissues and PASMCs after hypoxia. PTBP1 knockdown can inhibit the phenotypic transition of PASMCs. PTBP1 inhibits the phenotypic transition of PASMCs. In addition, PTBP1 inhibits the integrin-linked kinase (ILK) expression under hypoxic conditions, thereby down-regulating the expression of downstream proteins. It inhibits the phenotypic transition of PASMCs and alleviates pulmonary hypertension.Conclusion: In conclusion, PTBP1/ILK axis promotes the development of PH via inducing phenotypic transition of PASMCs. This may provide a novel therapy for PH.Keywords: pulmonary hypertension, polypyrimidine tract-binding protein 1, integrin-linked kinase, pulmonary artery smooth muscle cells

Rui Sun,* Jinhui Liu,* Sipei Nie,* Siyue Li, Jing Yang, Yi Jiang, Wenjun Cheng Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenjun ChengDepartment of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, People’s Republic of ChinaEmail wenjunchengdoc@163.comIntroduction: This bioinformatic study confirmed a new miRNA-mRNA regulatory network and a prognostic signature in endometrial cancer (EC).Materials and Methods: We downloaded RNA-seq and miRNA-seq data of EC from the TCGA database, then used EdegR package to screen differentially expressed miRNAs and mRNAs (DE-miRNAs and DE-mRNAs). Then, we constructed a regulatory network of EC-associated miRNAs and hub genes by Cytoscape, and determined the expression of unexplored miRNAs in EC tissues and normal adjacent tissues by quantitative Real-Time PCR (qRT-PCR). A prognostic signature model and a predictive nomogram were constructed. Finally, we explored the association between the prognostic model and the immune cell infiltration.Results: A total of 11,531 DE-mRNAs and 236 DE-miRNAs, as well as 275 and 118 candidate DEGs for upregulated and downregulated DE-miRNAs were screened out. The miRNA-mRNA network included 5 downregulated and 13 upregulated DE-miRNAs. qRT-PCR proved that the expression levels of miRNA-18a-5p, miRNA-18b-5p, miRNA-449c-5p and miRNA-1224-5p and their target genes (NR3C1, CTGF, MYC, and TNS1) were consistent with our predictions. Univariate and multivariate Cox proportional hazards regression analyses of the hub genes revealed a significant prognostic value of NR3C1, EZH2, AND GATA4, and these genes were closely related to eight types of immune infiltration cells.Conclusion: We identified three genes as candidate biomarkers for EC, which may provide a theoretical basis for targeted therapy.Keywords: TCGA, endometrial cancer, miRNA-mRNA network, prognostic model, immune infiltration cell

Zhiqiang Luo,1,* Guohua Yu,1,* Wubin Wang,1,* Rui Sun,1 Binbin Zhang,1 Jing Wang,2 Jing Liu,1 Shan Gao,1 Peng Wang,3 Yuanyuan Shi1,4 1School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China; 2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People’s Republic of China; 3The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, People’s Republic of China; 4Shenzhen Research Institute, Beijing University of Chinese Medicine, Shenzhen, 518118, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng WangThe First Affiliated Hospital of Guangzhou Medical University, No. 151 Yanjiang Road, Yuexiu District, Guangzhou, 510120, People’s Republic of ChinaEmail mrwp0022@163.comYuanyuan ShiShenzhen Research Institute, Beijing University of Chinese Medicine, No. 16 Lanjingzhong Road, Pingshan District, Shenzhen, 518118, People’s Republic of ChinaTel +86 18565780299Email yshi@bucm.edu.cnIntroduction: Gu-Ben-Ke-Chuan (GBKC) decoction, a well-known prescription composed of seven herbs, has been widely used for treating chronic bronchitis (CB). However, the pharmacological constituents of GBKC and the underlying mechanisms by which these components act on CB remain unclear.Methods: Ultra-high-pressure liquid chromatography coupled with linear ion trap–Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap) was first employed to rapidly identify compounds from GBKC. Thereafter, network pharmacology and molecular docking analyses were performed to identify the potential active constituents, candidate targets, and major pathways. Finally, the affinities between the key compounds and targets were verified via surface plasmon resonance (SPR) analysis. In addition, the anti-inflammatory effect of GBKC was verified using an LPS-induced inflammatory cell model based on the predicted results.Results: A total of 53 major compounds were identified in the GBKC decoction. After network pharmacology-based virtual screening, 141 major targets and 39 main compounds were identified to be effective in the treatment of CB. The major targets were highly enriched in the tumor necrosis factor (TNF) signaling pathway, suggesting that GBKC could attenuate the inflammatory response in patients with CB. Furthermore, molecular docking results indicated that 20 pairs of components and target proteins relevant to the TNF pathway exhibited notable interactions. Among them, eight compound-target pairs exhibited good affinity as per SPR analysis. In addition, the production of interleukin 6 and TNF-α in LPS-induced MH-S cells was suppressed after GBKC treatment.Conclusion: This study successfully clarified the mechanism of action of GBKC against CB, which demonstrated that the integrated strategy described above is reliable for identifying the active compounds and mechanisms responsible for the pharmacological activities of GBKC decoction.Keywords: Gu-Ben-Ke-Chuan decoction, chronic bronchitis, UHPLC-LTQ-Orbitrap, network pharmacology, surface plasmon resonance

Wenfeng Lin,1,* Chaoming Li,1,2,* Naijin Xu,1,3 Masami Watanabe,1,4 Ruizhi Xue,1 Abai Xu,2 Motoo Araki,1 Ruifen Sun,5 Chunxiao Liu,2 Yasutomo Nasu,1 Peng Huang1,2,6 1Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 2Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan; 5Center for Scientific Research, Yunnan University of Chinese Traditional Medicine, Kunming, People’s Republic of China; 6Okayama Medical Innovation Center, Okayama University, Okayama, Japan*These authors contributed equally to this workCorrespondence: Peng HuangDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, JapanTel + 81-86-235-7997Fax +81-86-235-7884Email huangpeng509@gmail.comPurpose: With the advance of screening techniques, there is a growing number of low-risk or intermediate-risk prostate cancer (PCa) cases, remaining a serious threat to men’s health. To obtain better efficacy, a growing interest has been attracted to develop such emerging treatments as immunotherapy and focal therapy. However, few studies offer guidance on whether and how to combine these modalities against PCa. This study was designed to develop dual-functional nanoparticles (NPs) which combined photothermal therapy (PTT) with immunotherapy and determine the anti-tumor efficacy for PCa treatment.Methods: By a double emulsion technique, the drug nanocarrier, poly(lactic-co-glycolic acid) or PLGA, was applied for co-loading of a fluorescent dye, indocyanine green (ICG) and a toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) to synthesize PLGA-ICG-R848 NPs. Next, we determined their characteristic features and evaluated whether they inhibited the cell viability in multiple PCa cell lines. After treatment with PLGA-ICG-R848, the maturation markers of bone marrow-derived dendritic cells (BMDCs) were detected by flow cytometry. By establishing a subcutaneous xenograft model of mouse PCa, we explored both the anti-tumor effect and immune response following the NPs-based laser ablation.Results: With a mean diameter of 157.7 nm, PLGA-ICG-R848 exhibited no cytotoxic effect in PCa cells, but they significantly decreased RM9 cell viability to (3.9± 1.0)% after laser irradiation. Moreover, PLGA-ICG-R848 promoted BMDCs maturation with the significantly elevated proportions of CD11c+CD86+ and CD11c+CD80+ cells. Following PLGA-ICG-R848-based laser ablation in vivo, the decreased bioluminescent signals indicated a significant inhibition of PCa growth, while the ratio of splenic natural killer (NK) cells in PLGA-ICG-R848 was (3.96± 1.88)% compared with (0.99± 0.10)% in PBS group, revealing the enhanced immune response against PCa.Conclusion: The dual-functional PLGA-ICG-R848 NPs under laser irradiation exhibit the anti-tumor efficacy for PCa treatment by combining PTT with immunotherapy.Keywords: prostate cancer, PLGA, indocyanine green, resiquimod, photothermal therapy, immunotherapy

Wei Luo,1,* Ruifen Sun,2,* Xin Chen,3,* Ju Li,4 Jike Jiang,4 Yuxiao He,4 Shaoqing Shi,2 Heling Wen5 1Department of Respiratory and Critical Care Medicine, The People’s Hospital of Leshan, Leshan, Sichuan, People’s Republic of China; 2Center for Scientific Research, Yunnan University of Chinese Traditional Medicine, Kunming, Yunnan, People’s Republic of China; 3College of Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, People’s Republic of China; 4College of Basic Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, People’s Republic of China; 5Department of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Heling WenDepartment of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, No. 32th West Second Section First Ring Road, Qingyang District, Chengdu, Sichuan 610072, People’s Republic of ChinaTel/Fax +86-28-87394174Email wenheling2008@163.comShaoqing ShiCenter for Scientific Research, Yunnan University of Chinese Traditional Medicine, No. 1076th Yuhua Road, Chenggong District, Kunming, Yunnan 650500, People’s Republic of ChinaTel +86-871-65918050Fax +86-871-65918049Email sqs621@yeah.netIntroduction: The incidence and mortality rates of lung cancer rank top in the different types of cancers in China. Licochalcone A (LA) is a flavonoid extracted from the roots of licorice with antitumor effects in various cancers in vitro and in vivo. However, the role of LA in non-small cell lung cancer (NSCLC) remains largely unclear.Methods: The cell viability was measured by MTT assay, Edu staining and colony formation assay. Apoptosis was investigated using Annexin V/PI double-stained assays with flow cytometry. Real-time quantitative RT-PCR was carried out to investigate the expression of mRNA of related proteins. Western blotting was used to investigate the expression of related proteins.Results: The results show that LA inhibits the proliferation of NSCLC cells in a dose-dependent manner and induces apoptotic cell death. Moreover, LA significantly suppresses the expression of c-IAP1, c-IAP2, XIAP, Survivin, c-FLIPL and RIP1 without influencing the level of mRNA. Cycloheximide chase assay demonstrates that LA greatly decreases the stability of Survivin, XIAP and RIP1. Mechanistic studies indicate that LA induces cytoprotective autophagy since block of autophagy with CQ greatly enhances LA-induced anticancer activities. Furthermore, LA rapidly induces ERK and p38 activation in a time-dependent manner in both A549 and H460 cells, but suppresses the activities of c-Jun N-terminal kinase (JNK); suppression of ERK not p38 with inhibitor attenuates LA-induced autophagy, while it remarkably enhances LA-induced cytotoxicity in lung cancer cells and further promotes the degradation of apoptosis-related proteins.Discussion: The results of this study provide novel insights on the role of apoptosis-related proteins and the MAPKs pathway in the anticancer activities of LA.Keywords: non-small cell lung cancer, NSCLC, licochalcone A, LA, inhibitors of apoptosis proteins, IAPs, RIP1, ERK, autophagy

Yan Li,1,* Tingwei Yu,2,* Zengyou Liu,2 Hengying Chen,3 Yao Liu,4 Yuanhuan Wei,4 Ruifang Sun,4 Hongmei Zhang,2 Wei Wang,2 Yihua Lu,2 Yingyu Zhou,1 Guifang Deng,4 Zheqing Zhang1 1Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Obstetrics, Union Shenzhen Hospital of Huazhong University of Science and Technology, Shenzhen, People’s Republic of China; 3Injury Prevention Research Center, Shantou University Medical College, Shantou, People’s Republic of China; 4Department of Clinical Nutrition, Union Shenzhen Hospital of Huazhong University of Science and Technology, Shenzhen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zheqing ZhangDepartment of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, No. 1023-1063, Shatai South Road, Baiyun District, Guangzhou, Guangdong 510515, People’s Republic of ChinaEmail zzqaa501@smu.edu.cnGuifang DengDepartment of Clinical Nutrition, Union Shenzhen Hospital of Huazhong University of Science and Technology, No. 89 Taoyuan Road, Shenzhen, Guangdong 518052, People’s Republic of ChinaEmail misyfly@163.comObjective: To evaluate the associations of serum uric acid (UA), urea nitrogen (UN), and urine specific gravity (USG) levels in the first trimester of pregnancy with the risk of gestational diabetes mellitus (GDM).Patients and Methods: A retrospective cohort study was conducted in 1,769 pregnant women aged 31.55 ± 3.91 years. UA, UN, and USG levels were measured during the 16– 18th week of gestation. GDM was diagnosed by an oral 75 g glucose tolerance test during the 24– 28th week of gestation.Results: A multivariate adjusted logistic regression analysis showed that UA levels in the highest quartile increased the risk of GDM by 55.7% (odds ratio [OR]: 1.557, 95% confidence interval [CI]: 1.055– 2.298; p = 0.026) compared to those in the lowest quartile. USG levels in the second, third, and fourth quartiles increased the risk of GDM by 67.6% (95% CI: 1.090– 2.421), 112.4% (95% CI: 1.446– 3.119), and 94.5% (95% CI: 1.314– 2.880), respectively, compared to those in the first quartile (p trend = 0.001). No significant association between UN levels and the GDM risk was observed. When the extreme composite biomarker score quartiles were compared, the adjusted OR (95% CI) for GDM was 1.909 (95% CI: 1.332– 2.736). Age-stratified analyses revealed similar results in women aged ≤ 35 years only, but not in those aged > 35 years.Conclusion: Higher levels of UA and USG and a higher composite kidney function biomarker score during the 16– 18th week of gestation were positively and independently associated with an increased risk of GDM.Keywords: uric acid, urea nitrogen, urine specific gravity, gestational diabetes mellitus, retrospective cohort study

Bo Yuan,1 Rongqing Sun,1 Yuming Du,1 Zhankui Jia,2 Wencheng Yao,2 Jinjian Yang2 1Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, People’s Republic of China; 2Urinary Surgery Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, People’s Republic of ChinaCorrespondence: Jinjian YangUrinary Surgery Department, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou, Henan Province 450052, People’s Republic of ChinaEmail yangjj_2011@126.comObjective: Long non-coding RNA (lncRNA) cancer susceptibility candidate 9 (CASC9) has been reported to play a vital role in tumorigenesis. This study explored the biological role of CASC9 and its regulation mechanism in bladder cancer (BC).Methods: Gene expression was evaluated using quantitative reverse transcription polymerase chain reaction and Western blot. The functional role of CASC9 in BC was studied using Cell Counting Kit-8, colony formation assay, scratch wound healing assay, transwell invasion assay, and xenograft tumor assay. In addition, the mechanism of CASC9 function in BC was determined using RNA immunoprecipitation assay and chromatin immunoprecipitation assay.Results: CASC9 was upregulated in BC tissues and cell lines, and correlated with the staging and metastasis in BC. Knockdown of CASC9 inhibited the proliferation, migration, and invasion of BC cells. Similarly, silencing of CASC9 inhibited tumor growth in vivo. Signal transducer and activator of transcription 3 (STAT3) was upregulated in BC tissues and cell lines, and positively correlated with CASC9 in BC tissues. Moreover, CASC9 was shown to be regulated by STAT3 in BC cells. Furthermore, CASC9 regulated phosphatase and tensin homolog (PTEN) expression by interacting with enhancer of zeste homolog 2 (EZH2). More significantly, CASC9 silencing-mediated inhibition of BC progression was partly reversed by EZH2 overexpression or PTEN inhibition.Conclusion: Upregulation of CASC9 induced by STAT3 promoted the progression of BC by interacting with EZH2 and affecting the expression of PTEN, representing a novel regulatory mechanism for BC progression.Keywords: bladder cancer, cancer susceptibility candidate 9, signal transducer and activator of transcription 3, phosphatase and tensin homolog, enhancer of zeste homolog 2

Lanxiang Bai1 ,* Xiaonu Peng2 ,* Ruimei Sun3 1Disinfection Supply Center, Yantai Yuhuangding Hospital, Yantai 264000, Shandong, People’s Republic of China; 2Department of Thoracic Surgery, Yantai Yuhuangding Hospital, Yantai 264000, Shandong, People’s Republic of China; 3Department of Laboratory, Weifang No.2 People’s Hospital, Weifang 261041, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ruimei Sun Email sunruimeiweifang@163.comBackground: Protein kinase Cα (PRKCA) is an oncogene in multiple cancers including non-small-cell lung cancer (NSCLC) and can be transcribed into a number of circular PRKCAs (circPRKCAs). Here, we aimed to elaborate the role and mechanism of circPRKCA_024 (circPRKCA) in malignant progression of NSCLC.Methods: Expression of circPRKCA, miRNA (miR)-330-5p and 3-phosphoinositide-dependent protein kinase-1 (PDK1) was measured by real-time quantitative PCR and Western blotting, and their relationship was testified by dual-luciferase reporter assay, RNA immunoprecipitation, and RNA pull-down assay. Cell behaviors were evaluated by cell counting kit (CCK)-8, flow cytometry, and transwell assays. AKT activity was confirmed by Western blotting. Xenograft experiment assessed tumor growth.Results: Expression of circPRKCA and PDK1 was upregulated, and miR-330-5p was downregulated in NSCLC tissues and cell lines. High circPRKCA was correlated with TNM stage and lymph node metastasis of NSCLC patients. Silencing circPRKCA could suppress cell viability, migration, and invasion in A549 and H1299 cells, accompanied with apoptosis rate promotion. Moreover, circPRKCA knockdown retarded tumor growth of A549 cells in vivo. Molecularly, miR-330-5p was sponged by circPRKCA, and PDK1 was a target of miR-330-5p. Inhibiting miR-330-5p could attenuate the suppression of circPRKCA knockdown on cell growth, migration, and invasion; contrarily, promoting miR-330-5p caused inhibition on those cell behaviors by downregulating PDK1. Analogously, AKT activity was suppressed by circPRKCA downregulation and miR-330-5p upregulation in NSCLC cells both in vitro and in vivo.Conclusion: Depleting circPRKCA inhibited PDK1 to suppress NSCLC cell malignant behaviors through miR-330-5p/PDK1/AKT pathway.Keywords: circPRKCA, miR-330-5p, PDK1, AKT, NSCLC

Hongmei Luo,1,* Ruixue Sun,1,* Yuhuan Zheng,1,2,* Jingcao Huang,1 Fangfang Wang,1 Dan Long,3 Yu Wu1 1Department of Hematology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, People’s Republic of China; 3Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu Wu Tel +86-28-85422370Fax +86-28-85423921Email wu_yu@scu.edu.cnPurpose: Acute myeloid leukemia (AML) is associated with a poor overall prognosis. PIM family genes, including PIM1, PIM2, and PIM3, are proto-oncogenes that are aberrantly overexpressed in different types of human cancers. In this study, we aimed to explore and clarify the function of PIM3 in AML.Patients and Methods: The expression of the three PIM genes in AML was detected using the Gene Expression Omnibus. The expression of PIM3 and PIM3 in patient samples and AML cell lines was measured using quantitative real-time polymerase chain reaction or Western blot analyses. The cellular behaviors of PIM3-overexpressing AML cell lines were detected using a CCK-8 assay, flow cytometry, Western blotting, immunofluorescence staining, and a cell migration assay. The interactions between PIM3 and phosphorylated CXCR4 (pCXCR4) were explored via immunoprecipitation.Results: Higher PIM3 expression was detected in primary AML cells than in healthy donor cells. Second, PIM3 overexpression promoted AML cell proliferation and protected against spontaneous apoptosis by phosphorylating BAD (pBAD) at Ser112. Furthermore, PIM3 overexpression might promote the migration of AML cells via CXCR4. PIM3-overexpressing AML cell lines exhibited increased CXCR4 phosphorylation at Ser339, and pCXCR4 interacted with PIM3.Conclusion: Our findings suggest that PIM3 regulates the proliferation, survival, and chemotaxis of AML cell lines. Moreover, pCXCR4 might mediate the regulation of PIM3-induced chemotaxis. Therefore, the inhibition of PIM3 expression may be a promising therapeutic target in AML.Keywords: pBAD, pCXCR4, PIM1, PIM2, PIM3

Rongrong Li,1,* Jing Sun,1,2,* Hantong Hu,1,2 Qifei Zhang,1 Ruohan Sun,1 Shuning Zhou,1 Haijuan Zhang,1 Jianqiao Fang1,2 1The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou City, Zhejiang Province, People’s Republic of China; 2The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, Zhejiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianqiao Fang Email fangjianqiao7532@163.comBackground: Acupuncture has been widely applied to relieve knee osteoarthritis (KOA) in many countries. However, the bibliometric analysis of the global use of acupuncture on KOA is largely unknown. Therefore, this study aimed to explore the current status and trends of the global use of acupuncture on KOA in recent 10 years by using CiteSpace (5.6.R3).Methods: Publications regarding acupuncture therapy for treating KOA between 2010 and 2019 were extracted from the Web of Science database. CiteSpace was used to analyze the number of publications, countries, institutions, journals, authors, cited references and keywords by using standard bibliometric indicators.Results: A total of 343 publications were retrieved from 2010 to 2019. The total number of publications continually increased over the past four years, and the most active journals, countries, institutions and authors in the field of acupuncture therapy on patients with KOA were identified. The Evid Based Complement Alternat Med (28) was the most prolific journal, and the Ann Intern Med (202) was the most cited journal. The most productive country and institution in this field was China (115) and University of York (18), respectively. Hugh Macpherson (18) was the most prolific author and Witt C ranked the first in the cited authors. In the ranking of frequency in cited reference, the first article was published by Scharf HP (54). The keyword of ‘randomized controlled trial’ ranked first for research developments with the highest citation burst (3.9486). Besides, there were three main frontiers in keywords for KOA research, including ‘research method, ‘age’ and ‘measure of intervention’.Conclusion: The findings from this bibliometric study provide current status and trends in clinical research of acupuncture therapy on patients with KOA over the past ten years, which may help researchers identify hot topics and explore new directions for future research in this field.Keywords: acupuncture, knee osteoarthritis, bibliometric analysis, CiteSpace

Yang Yang,1 Dan Li,2 Yulong Li,3 Qiuyu Jiang,4 Ruifang Sun,5 Jinren Liu,1 Fei Wu,4 Jiyu Miao,4 Lei Ni,4 Xingmin Shi,1 Chen Huang4 1Department of Toxicology and Sanitary Analysis, School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an 710061, People’s Republic of China; 2Department of Clinical Medicine, Medical College of Yan’an University, Yan’an 716000, Shanxi Province, People’s Republic of China; 3Department of Gastroenterology, Shaanxi Provincial People’s Hospital, Xi’an 710068, People’s Republic of China; 4Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an Jiaotong University, Xi’an 710061, People’s Republic of China; 5Department of Pathology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an Jiaotong University, Xi’an 710061, People’s Republic of ChinaCorrespondence: Xingmin ShiSchool of Public Health, Xi’an Jiaotong University Health Science Center, Yanta Western Road 76, Xi’an 710061, People’s Republic of ChinaEmail shixingmin142@163.comChen HuangXi’an Jiaotong University Health Science Center, Yanta Western Road 76, Xi’an 710061, People’s Republic of ChinaTel +86-29-82655077Email hchen@mail.xjtu.edu.cnAim: Low-temperature plasma (LTP) has potential applications in cancer therapy. Herein, we explored the molecular mechanisms of proliferation inhibition induced by LTP.Methods: LTP was generated by a helium atmospheric-pressure plasma jet and used to treat A549 and H1299 cells. CCK-8 and cell apoptosis assays were performed to evaluate the effects of LTP treatment on A549 and H1299 cells. The qRT-PCR was performed to measure the expression of miR-203a after treating with LTP. CCK-8, colony formation, cell apoptosis assays, and Western blotting were performed to analyse the function of miR-203a in the development of lung cancer. Dual-luciferase assay and Western blotting were used to probe the relationship between miR-203a and BIRC5, and gene silencing using si-BIRC5 was carried out to explore the effect of knocking down BIRC5 on lung cancer cells.Results: We found that LTP significantly suppressed proliferation and promoted apoptosis in A549 and H1299 cells. The miR-203a expression was increased after cells were treated with LTP. The miR-203a expression was downregulated among lung cancer tissue samples, and overexpression of miR-203a suppressed cell growth and induced apoptosis in lung cancer cells. We showed that miR-203a targeted BIRC5. Moreover, silencing of BIRC5 caused proliferation inhibition and induced apoptosis in lung cancer cells.Conclusion: Our study revealed that LTP inhibited proliferation and induced apoptosis in A549 and H1299 cells through the miR-203a/BIRC5 axis. These findings showed that LTP could potentially be used to treat lung cancer.Keywords: low-temperature plasma, lung cancer, proliferation, miR-203a, BIRC5

Xin Kang,1,2 Libin Zhan,1,3 Xiaoguang Lu,2 Jianbo Song,2 Yilong Zhong,2 Yi Wang,1 Yilun Yang,4 Zhiwei Fan,2 Xiaozheng Jiang,2 Ruru Sun2 1Institute of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 2Department of Emergency Medicine, Affiliated Zhongshan Hospital, Dalian University, Dalian, Liaoning, People’s Republic of China; 3Basic Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 4Graduate School, Zunyi Medical University, Zunyi, Guizhou, Republic of ChinaCorrespondence: Libin ZhanInstitute of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, People’s Republic of China, Basic Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of ChinaTel +86 25-85811569Email zlbnj@njucm.edu.cnXiaoguang LuDepartment of Emergency Medicine, Affiliated Zhongshan Hospital, Dalian University, Dalian, Liaoning, People’s Republic of ChinaEmail luxiaoguang@dlu.edu.cnBackground: The Goto-Kakizaki (GK) rat, developed from repeated inbreeding of glucose-intolerant Wistar rats, has been widely used to explore the development of spontaneous type-2 diabetes mellitus (T2DM). However, the gastric microbiota of GK and Wistar rats are still unclear. This study aimed to understand the gastric microbiota characteristics of GK rats by comparing it with non-diabetic Wistar rats.Materials and Methods: Male Wistar rats and GK rats were housed in specific pathogen-free (SPF) environment for 12 weeks with free access to sterilized food and water. Body weight and random blood glucose (BG) levels were determined. At the end of the experiment, the gastric contents of the rats were collected for the identification of gastric microbiota using 16S rRNA gene sequencing.Results: The richness of gastric microbiota in GK rats was similar to that of Wistar rats (P > 0.05). The results of Shannon, Simpson, beta diversity indices, and ANOSIM analysis showed that alpha and beta diversity of gastric microbiota in GK rats were significantly lower than that of Wistar rats (P < 0.01). Firmicutes (96.0%), Proteobacteria (1.9%) and Cyanobacteria (0.8%) were the dominant gastric microbiota in GK rats accounting for 72.9%, 14.7% and 10.9%, respectively. Linear discriminant analysis effect size (LEfSe)  revealed  that phylum Firmicutes and four genera (Anaerovibrio, Collinsella, Prevotellaceae_UCG_001, and Lactobacillus) were significantly abundant in the stomachs of GK rats. In contrast, seven genera (unidentified_Chloroplast, Porphyromonas, Neisseria, Rubrobacter, Veillonella, Lachnospiraceae_UCG_005, and unidentified_Erysipelotrichaceae) were significantly abundant in the stomachs of Wistar rats. Blood glucose was positively correlated with Anaerobibrio and Lactobacillus, and negatively correlated with four genera (Porphyromonas, Rubrobacter, Lachnospiraceae_UCG_005, and unidentified_Erysipelotrichaceae). In addition, chemoheterotrophy and fermentation were the most important functions of gastric microbiota.Conclusion: The gastric microbiota of GK rats with spontaneous T2DM showed the typical characteristics of low diversity and significant enrichment of Firmicutes phylum and four genera (Anaerovibrio, Collinsella, Prevotellaceae_UCG_001, and Lactobacillus) compared with gastric microbiota of Wistar rats.Keywords: gastric microbiota, type-2 diabetes mellitus, GK rat, wistar rat, 16S rRNA gene sequencing

Longyan Yang,1,* Yan Wang,1,* Rongxin Sun,1,* Yuanyuan Zhang,1 Ying Fu,1 Zhaohui Zheng,1 Zhili Ji,2 Dong Zhao1 1Beijing Key Laboratory of Diabetes Research and Care, Center for Endocrine Metabolism and Immune Diseases, Luhe Hospital Capital Medical University, Beijing 101149, People’s Republic of China; 2Department of General Surgery, Luhe Hospital Capital Medical University, Beijing 101149, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dong Zhao; Zhili Ji Tel +86-10-69543901Fax +86-10-69531069Email zhaodong@ccm.edu.cn; lhyyjzl@163.comPurpose: Although papillary thyroid carcinoma (PTC) is associated with a generally favorable prognosis, about 15% of patients present recurrence and distant metastasis in the next decade leading to death. Angiopoietin-like 4 (ANGPTL4) is secreted to circulation and belongs to the angiopoietin-like proteins. The expression of ANGPTL4 was increased in several solid tumor tissues compared to corresponding paracancerous tissues. ANGPTL4 was identified as pro-tumorigenic protein, including stimulating tumor cell growth, promoting tumor metastasis. However, the clinical significance and biological function of ANGPTL4 in PTC is still unclear. Hence, the purpose of this study was to evaluate the role of ANGPTL4 in PTC, investigating the possibility of whether ANGPTL4 could become a novel target for PTC therapy.Methods: We investigated the expression level of ANGPTL4 and pAKT in PTC and paracancerous tissue by immunohistochemistry. We determined the effect of ANGPTL4 in PTC cell proliferation through cell counting kit-8 (CCK-8) and cell cycle by flow cytometry analysis. Furthermore, the correlation between ANGPTL4 expression levels and PTC cell proliferation from the TCGA data set was analyzed by GSEA. We explored the role of ANGPTL4 on the phosphorylation of AKT and proliferation in PTC cells via overexpression or knockdown assays and AKT inhibitor assay.Results: In the present study, we found that ANGPTL4 was highly expressed in both protein and mRNA level in PTC compared with adjacent noncancerous tissues or benign nodule. ANGPTL4 expression increased according to thyroid tumor progression. ANGPTL4 level was positively correlated with the size of PTC. ANGPTL4 increased cell proliferation and decreased cell cycle arrest of PTC. Knockdown of ANGPTL4 inhibited the phosphorylation of AKT. ANGPTL4 regulated PTC cell proliferation through AKT signaling pathway.Conclusion: Our findings suggested that ANGPTL4 was increased in PTC compared with adjacent noncancerous tissues, and ANGPTL4 increased cell proliferation and inhibited cell cycle arrest in PTC cells via promoting AKT phosphorylation. The study may provide fundamental information to suggest its suitability as a target for the treatment of PTC.Keywords: papillary thyroid carcinoma, angiopoietin-like 4, AKT, proliferation

Ru Sun, 1 Chengwu Shen, 1 Shumaila Shafique, 2 Omer Mustapha, 2 Talib Hussain, 3 Ikram Ullah Khan, 4 Yasir Mehmood, 4 Khaleeq Anwer, 5 Yasser Shahzad, 3 Abid Mehmood Yousaf 3 1Department of Pharmacy, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250000, People’s Republic of China; 2Faculty of Pharmaceutical Sciences, Dow College of Pharmacy, Dow University of Health Sciences, Karachi 74200, Pakistan; 3Department of Pharmacy, COMSATS University Islamabad, Lahore 54000, Pakistan; 4Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad 38000, Pakistan; 5Office of Chief Executive Officer, District Health Authority, Pakpattan 57400, PakistanCorrespondence: Abid Mehmood Yousaf; Talib HussainDepartment of Pharmacy, COMSATS University Islamabad, Lahore Campus, Lahore 54000, PakistanTel +92-300-4774147; +92-345-7220536Email abid.ucp@hotmail.com; talib.hussain@cuilahore.edu.pkBackground: Bezafibrate is a BCS class II drug as it presents very low solubility in water; therefore, its bioavailability after oral administration is very poor. The aim of this work was to enhance solubility and dissolution rate of bezafibrate in water in order to enhance its oral bioavailability.Methods: Several formulations were prepared using PVP K30 and Cremophor ELP employing the solvent-evaporation method and the electrospraying technique. Solubility, release rate, bioavailability in male Sprague Dawley rats, and lipid profile attributes in Wistar rats were assessed in comparison with bezafibrate plain powder. Solid-state characterization was carried out using X-ray diffraction (XRD) analysis, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM).Results: All the formulations exerted positive effect towards the desired goal. In particular, the optimized formulation furnished about 14-fold enhanced solubility and 85.48 ± 10.16% drug was released in 10 min as compared with bezafibrate alone (4.06 ± 2.59%). The drug existed in the amorphous state in the prepared sample as confirmed by XRD and DSC, whilst no drug-excipient interactions were observed through FTIR analysis. Moreover, SEM revealed smooth-surfaced spherical particles of the optimized formulation. A 5.5-fold higher oral bioavailability was achieved with the optimized formulation in comparison with bezafibrate plain powder. Also, TG, LDL and TC were decreased, and HDL was increased considerably in HFD-treated rats.Conclusion: The optimized formulation consisting of bezafibrate, PVP K30 and cremophor ELP (1/12/1.5, w/w/w) might be a capable drug delivery system for orally administering poorly water-soluble bezafibrate with improved bioavailability and antihyperlipidemic effects.Keywords: aqueous solubility, bezafibrate, electrospraying, lipid profile, oral bioavailability, solid dispersion

Ruimei Sun,1 Xiujiang Sun,2 Hua Liu,3 Peirui Li2 1Department of Radiotherapy, The Affiliated Hospital of Weifang Medical University, Weifang 261041, People’s Republic of China; 2Department of Thyroid and Breast Surgery, The Affiliated Hospital of Weifang Medical University, Weifang 261041, People’s Republic of China; 3Department of Gynaecology, The Affiliated Hospital of Weifang Medical University, Weifang 261041, People’s Republic of ChinaCorrespondence: Peirui LiDepartment of Thyroid and Breast Surgery, The Affiliated Hospital of Weifang Medical University, No. 2428, Yuhe Road, Weifang 261041, People’s Republic of ChinaTel +86-0536-3081399Email lipeirui536@sina.comBackground and objective: Endometrial carcinoma (EC) is one of the most frequently diagnosed malignancies in females. Dysregulation of lncRNA TDRG1 has been widely documented in several cancers, including EC. However, the mechanism of this lncRNA involving in EC progression remains to be further elucidated.Materials and methods: The enrichment levels of TDRG1 in EC tissues and cell lines were examined by RT-qPCR. Flow cytometry, cell counting kit-8 (CCK-8), transwell, and Western blot assays were conducted to assess whether TDRG1 knockdown could affect cell cycle arrest, proliferation, migration, invasion, and apoptosis of EC cells. The phosphorylation levels of mTOR, AKT and PI3K that associated with PI3K/Akt/mTOR pathway were determined by Western blot assay.Results: TDRG1 expression was markedly upregulated in EC tissues and cell lines. Knockdown of TDRG1 significantly induced cell cycle arrest and apoptosis, inhibited cell proliferation, restrained the invasion and migration abilities in EC cells. Moreover, TDRG1 silencing decreased the protein levels of p-AKT, p-PI3K, and p-mTOR of EC cells.Conclusion: Our data underlined the implication of TDRG1 in EC progression, proposing that targeting TDRG1 might be a potential therapeutic avenue in EC.Keywords: endometrial carcinoma, TDRG1, PI3K/AKT/mTOR pathway

Hongwei Guan,1,* Juan Li,1,* Rui Sun,1 Wei Liu,1 Mei Feng,2 Hui Ma,3 Changzhong Li1 1Department of Obstetrics and Gynecology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, People’s Republic of China; 2Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People’s Republic of China; 3Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changzhong LiDepartment of Obstetrics and Gynecology, Shandong Provincial Hospital affiliated to Shandong University, 324 Jingwuweisi Road, Jinan 250021, People’s Republic of ChinaTel +86 531 15168888909Email 15168888909@163.comPurpose: The aim of our research was to investigate the expression of BMP7 in ovarian cancer (OC) and the biological effect of knocking down BMP7 on ovarian cancer A2780 cells.Methods: We detected BMP7 expression in ovarian cancer and normal ovarian tissue by immunohistochemistry (IHC). We downregulated BMP7 expression using lentivirus-mediated RNAi and then examined the effects of knocking down BMP7 on the cell growth and invasion, cell cycle and paclitaxel sensitivity of A2780 cells. The mRNA and protein levels were detected by total RNA extraction and quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. Cell proliferation was measured by CCK-8 and colony formation assays. The number of cells in each cell cycle stage and those undergoing apoptosis were measured by flow cytometry.Results: BMP7 expression was significantly higher in the ovarian cancer tissues than it was in the normal ovarian tissues. Knocking down BMP7 in ovarian cancer A2780 cells inhibited cell proliferation, migration and invasion; led to G1 cell cycle arrest; and reversed the epithelial-mesenchymal transformation (EMT) process. In addition, downregulating BMP7 increased the sensitivity of the A2780 cells to paclitaxel. Moreover, BMP7 downregulation resulted in decreased expression of Smad1/5/9, p-Smad1/5/9, ID2 and cyclin D1 protein.Conclusion: The results presented here are expected to contribute to the development of possible therapeutic targets for patients with ovarian cancer.Keywords: BMP7, ovarian cancer, EMT, drug sensitivity, proliferation, cell cycle

Du Meng,1,* Hongwei Lei,2,* Xiaoqiang Zheng,3 Yaxuan Han,4 Ronggang Sun,5 Dongli Zhao,1 Rui Liu11Department of Radio Oncology, The First Affiliated Hospital of Xi’an Jiaotong University School of Medicine, Xi’an, Shaanxi Province, 710061, People’s Republic of China; 2Department of Radio Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, 116027, People’s Republic of China; 3Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University School of Medicine, Xi’an, Shaanxi Province, 710061, People’s Republic of China; 4Department of Oncology, The Xi’an Chest Hospital, Xi’an, Shaanxi Province, 710000, People’s Republic of China; 5Department of Radio Oncology, The People’s Hospital of YangZhong City, YangZhong, Jiangsu Province, 212200, People’s Republic of China*These authors contributed equally to this workBackground: Breast cancer is one of the foremost threats to female health nowadays. Tamoxifen, an antagonist of estrogen receptor-α (ERα), is the first choice for endocrine-dependent breast cancer (ERα-positive breast cancer) treatment. However, ERα has an important function in the normal physical regulation of estrogen, and current oral administration of tamoxifen has potential side effects on normal endocrine secretion. In the present work, we aim to develop novel approaches to increase the antitumor effect of tamoxifen on breast cancer cells and decrease the potential side effects in the human body during treatment.Methods: A temperature-sensitive phase-change hydrogel for tamoxifen (Tam-Gel) was generated. After establishing subcutaneous tumors formed by MCF-7, an ERα-positive breast cancer cell line, in nude mice, an intratumoral injection of Tam-Gel was performed to examine whether Tam-Gel facilitated the slow-release or antitumor effect of tamoxifen. A metastatic breast cancer model was established using the intrahepatic growth of MCF-7 cells in immunodeficient rats.Results: Tam-Gel can transform from liquid to hydrogel at room temperature. An intratumoral injection of Tam-Gel facilitated the slow-release or antitumor effect of tamoxifen. Once Tam-Gel, but not Tam-Sol, was administered by intratumoral injection, it significantly decreased the uptake of radionuclide probes (18F-fluoroestradiol or 18F-fluorodeoxyglucose) by cells in rats’ livers and the intrahepatic growth of MCF-7 cells in rats’ livers.Conclusion: A novel slow-release system was successfully prepared to facilitate the long-term release of tamoxifen in breast cancer tissues, and achieved an antitumor effect in the long term.Keywords: breast cancer, estrogen receptor-α, tamoxifen nanoparticle, temperature-sensitive phase-change hydrogel

Premal Patel,1 Ryan Sun,1 Benjamin Shiff,1 Kiril Trpkov,2 Geoffrey Thomas Gotto3 1Section of Urology, University of Manitoba, Winnipeg, MB, Canada; 2Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada; 3Department of Surgery, University of Calgary, Calgary, AB, Canada Objective: To assess the impact of time between prostate cancer diagnosis on biopsy and definitive intervention with radical prostatectomy (RP) in regard to adverse pathologic outcomes using a large multi-surgeon database.Materials and methods: We retrospectively reviewed 2,728 patients who underwent RP between 2005 and 2014. Patients were stratified according to biopsy Grade Group (GG). Pathologic outcomes were evaluated for patients with Results: In total 2,310 patients met the inclusion criteria. Median time from biopsy to surgery was 83 days (range: 61–109 days). No difference was observed for patients in any risk category regarding the adverse pathologic outcomes, including GG upgrade from biopsy to prostatectomy, presence of EPE, SVI, positive surgical margins, and positive lymph node involvement, with delays of up to 6 months between biopsy and RP. Surgical margins were positive in 25% of cases with pT2 disease and 50.2% of cases with pT3 and greater disease. EPE and SVI were present in 24.5% and 7.5% of specimens, respectively.Conclusion: Surgical delays of up to 6 months following prostate biopsy were not associated with an increased risk of GG upgrading, EPE, SVI, positive surgical margins, or lymph node involvement. Keywords: radical prostatectomy, prostate cancer, surgical wait time, surgical delay, pathologic outcomes, prostate biopsy

Ruilin Sun,1 Xi Lu,1 Li Gong,2 Faguang Jin1 1Department of Respiratory Medicine, The Second Affiliated Hospital of Air Force Medical University, Xi’an, People’s Republic of China; 2Department of Pathology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, People’s Republic of China Background: Lung cancer is the most common and lethal malignancy worldwide. TCTP is highly expressed in various cancers including lung cancer. Epithelial–mesenchymal transition (EMT) could increase cancer cell invasion. Whether TCTP’s expression is associated with EMT in lung adenocarcinoma is largely unknown.Methods: Several Gene Expression Omnibus datasets were used to analyze the correlation between TCTP expression and overall survival of lung adenocarcinoma patients by Kaplan–Meier survival analysis. Then, 24 surgically removed fresh lung adenocarcinoma tissue samples and paired paracancer tissue samples were used to analyze the correlation between TCTP expression and tumor stage by immunohistochemical analysis. Furthermore, stable cell lines were generated using lentiviral transduction systems to knock down or overexpress TCTP in A549 cells. Cell migration and invasion were measured by scratch and transwell assays, and EMT marker proteins such as α-SMA, ZEB1, and E-cadherin were quantitated by Western blot. The expression levels of miR-200a, miR-141, and miR-429 were determined by real-time quantitative PCR, and their target genes were predicted by an online database miRTarBase. The interaction between TCTP and these genes was analyzed by String database and visualized by Cytoscape.Results: TCTP was highly expressed in tumor tissues compared to paracancer tissues. The expression of TCTP was associated with shorter overall survival. TCTP knockdown experiment in A549 cells suggested that TCTP knockdown could decrease the migration and invasion of lung cancer cells, and the expression level of ZEB1 and α-SMA, but increase the expression of E-cadherin and p53. Vice versa, overexpression of TCTP could increase the migration and invasion of cancer cells, and the expression level of ZEB1 and α-SMA, but decrease the expression of E-cadherin and p53. Furthermore, we found the expression of miR-200a, miR-141, and miR-429 was associated with TCTP expression.Conclusion: TCTP promotes EMT in lung adenocarcinoma, and this effect may be associated with miR-200 family members like miR-200a, miR-141, and miR-429. Keywords: TCTP, lung adenocarcinoma, epithelial–mesenchymal transition, miR-200

Wei Luo,1 Ru-xin Sun,2 Han Jiang,3 Xin-long Ma1 1Department of Orthopedics, Tianjin Hospital, Tianjin 300211, People’s Republic of China; 2Department of Gynaecology and Obstetrics, Tianjin Hongqiao Hospital, Tianjin 300131, People’s Republic of China; 3Department of Orthopedics, Tianjin Third Central Hospital, Tianjin 300170, People’s Republic of China Background: Degenerative spinal diseases and diabetes mellitus (DM) have increasingly become a social and economic burden. The effect of DM on spinal surgery complications reported by previous studies remains controversial. Methods: We searched MEDLINE, Cochrane CENTRAL, ScienceDirect, EMBASE, and Google Scholar to identify studies reporting the relationship between DM and spinal surgery complications. Two independent reviewers performed independent data abstraction. The I2 statistic was used to assess heterogeneity. A fixed-effects or random-effects model was used for the meta-analysis. Results: Twenty-four studies met the inclusion criteria. Surgical site infection and the incidence of deep venous thrombosis after spinal surgery were significantly higher in patients with than in patients without diabetes, and the length of hospital stay was significantly longer in patients with diabetes (P0.05). Conclusion: Patients with diabetes have a higher risk when undergoing spinal surgery than patients without diabetes. Diabetes increases the risks of postoperative mortality, surgical site infection, deep venous thrombosis, and a prolonged hospitalization time after spinal surgery. Keywords: diabetes mellitus, spine, surgery, complication

Yan Shen,1,* Yinglan Yu,1,* Birendra Chaurasiya,1 Xiaolian Li,1 Ying Xu,2 Thomas J Webster,3 Jiasheng Tu,1 Runing Sun4 1Department of Pharmaceutics, Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, School of Pharmacy, China Pharmaceutical University, Nanjing, China; 2College of Pharmacy, Jiangsu University, Zhenjiang, China; 3Department of Chemical Engineering, Northeastern University, Boston, MA, USA; 4School of Engineering, China Pharmaceutical University, Nanjing, China *These authors contributed equally to this work Introduction: Cyclosporine-A (CsA) is generally used as an immunosuppressant and is also prescribed for some ophthalmic applications such as vernal keratoconjunctivitis and dry eye. However, it is limited clinically due to its low aqueous solubility and ocular bioavailability.Methods: In this work, lyophilized methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA) polymer micelles were prepared for ophthalmic formulations as a promising nano-carrier for hydrophobic drugs like CsA. A mPEG-PLA diblock polymer was synthesized by ring opening polymerization and CsA was loaded into mPEG-PLA micelles by a simple film dispersion method. A uniform design of experiments was utilized to optimize the final formulation. The obtained formulation was characterized for diameter (57.0±3.2 nm), entrapment efficiency % (98.51±1.4), and in vitro release. Moreover, incorporating the stabilizer mPEG2000 could increase the in vitro stability of the lyophilized CsA-loaded mPEG-PLA micelles.Results: Results showed a sustained release of CsA from the micelles. Drug concentration and time-dependent cytotoxicity of human corneal epithelial-2 cells was observed. Additionally, the transcorneal mechanism of mPEG-PLA micelles was studied and the results showed that the mPEG-PLA micelles mainly absorbed by a paracellular pathway via corneal epithelial cells.Conclusion: Taken together, the results proved that this mPEG-PLA diblock polymer can be potentially used as a nanoscopic carrier to deliver hydrophobic drugs in a controlled manner to the ocular region and, thus, deserves further attention. Keywords: CsA, mPEG-PLA micelles, lyophilization, physicochemical characteristics, transcorneal mechanism

Rongxin Sun,1,2 Aikeremujiang Muheremu,3 Yihe Hu1 1Department of Orthopedics, Xiangya Hospital, CentralSouth University, Kaifu District, Changsha, Hunan 86410008, China; 2Department of Orthopedics, Sixth Affiliated Hospital of Xinjiang Medical University, Tianshan District, Urumqi, Xinjiang 86830001, China; 3Department of Spine Surgery, Sixth Affiliated Hospital of Xinjiang Medical University, Tianshan District, Urumqi, Xinjiang 86830001, China Objective: Osteosarcoma is a highly malignant osseous sarcoma with poor prognosis. Previous studies indicated that miRNA-30c may play an important role in the development of osteosarcoma, but its mechanism is not yet clear. The current research was carried out to explore the potential applications of miR-30c in the diagnosis and treatment of osteosarcoma.Materials and methods: Real-time PCR and in situ hybridization were used to test the correlation between miR-30c and the onset of osteosarcoma. In vitro transfection of miR-30 mimic was used to test the effect of miR-30c on the development of osteosarcoma. Cell Counting Kit-8, formation of Petri dish clones, in vivo formation of tumor, flow cytometry tests and Transwell analysis were used to assess the effect of miR-330c on the metastatic potential and invasiveness of osteosarcoma.Results: Reverse transcriptase-PCR analysis and in situ hybridization tests revealed that the expression of miR-30c was lower in the osteosarcoma tissue than in normal bone tissue (P

Ling-bin Shu,1,* Qun Lu,2,* Ren-hua Sun,3 Le-qing Lin,4 Qiao-ling Sun,1 Jie Hu,1 Hong-wei Zhou,1 Edward Wai-Chi Chan,5,6 Sheng Chen,5,6 Rong Zhang11Department of Clinical Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; 2Department of Hospital Infection Management, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; 3Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China; 4Department of Intensive Care Unit, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China; 5Shenzhen Key Lab for Food Biological Safety Control, Food Safety and Technology Research Center, Hong Kong PolyU Shen Zhen Research Institute, Shenzhen, China; 6State Key Lab of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong *These authors contributed equally to this work Objective: To understand the prevalence and transmission of carbapenem-resistant Klebsiella pneumoniae (CRKP) in ICU patients in Zhejiang Province, China, and determined the genetic and phenotypic characteristics of these CRKP strains. Materials and Methods: A total of 202 ICU patients from eight tertiary hospitals were recruited and 55 non-duplicate CRKP strains were collected during July and August in 2017. These strains were subjected to determination of MICs, carriage of carbapenemase genes and tet(A) variants, PFGE, MLST and virulence potential using G. mellonella larvae infection model. Results: A total of 55 CRKP strains were recovered from 42 patients, representing a carriage rate of 20.8%. CRKP strains were recovered from both the intestinal and respiratory tract of 13 patients. Importantly, strains isolated from sputum and fecal samples often displayed identical PFGE profiles, suggesting that CRKP may also colonize the respiratory tract. The most dominant ST type of these CRKP strains was ST11, accounting for 78% (43/55) of the test strains. The majority of CRKP strains were resistant to multiple antibiotics, with the exception of tigecycline and ceftazidime/avibactam. Interestingly, 32 strains were found to harbor the tet(A) variant, which is known to confer reduced tigecycline susceptibility. Assessment of the virulence potential of these CRKP strains by string test showed that results were negative for 53 of the 55 test strains. However, further assessment of virulence potential using a G. mellonella larvae infection model showed that CRKP isolated from sputum consistently exhibited a higher virulence level than strains recovered from fecal samples. Conclusion: CRKP is highly prevalent in ICU patients in Zhejiang Province with strains isolated from respiratory exhibiting higher virulence potential than those from GI tract. These data provide essential insight into development of new infection control measures to halt the transmission of CRKP in clinical settings. Keywords: carbapenem-resistant Klebsiella pneumoniae, surveillance, sputum, feces, ICU, resistance, virulence

Song Chai,1,* Shifeng Kan,1,* Ran Sun,1 Ruijuan Zhou,1 Yi Sun,2 Wenhua Chen,1 Bo Yu1,3 1Department of Rehabilitation, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China; 2Department of Rehabilitation, Shanghai Sunshine Rehabilitation Center, Yangzhi Affiliated Rehabilitation Hospital of Tongji University, Shanghai 201209, China; 3Department of Rehabilitation Therapy, School of International Medical Technology, Shanghai Sanda University, Shanghai 201209, China *These authors contributed equally to this work Background: Integration of several types of therapeutic agents into one nanoplatform to enhance treatment efficacy is being more widely used for cancer therapy. Methods: Herein, a biocompatible polydopamine (PDA)-coated MoSe2-wrapped doxorubicin (DOX)-loaded hollow mesoporous silica nanoparticles (HMSNs) nanoplatform (PM@HMSNs-DOX) was fabricated for dual-sensitive drug release and chemo-photothermal therapy for enhancing the therapeutic effects on breast cancer. The HMSNs were obtained by a “structural difference-based selective etching” strategy and served as the drug carrier, exhibiting a high DOX loading capacity of 427 mg/g HMSNs-NH2, and then wrapped with PDA-coated MoSe2 layer to form PM@HMSNs-DOX. Various techniques proved the successful fabrication of the nanocomposites. Results: The formed PM@HMSNs-DOX nanocomposites exhibited good biocompatibility, good stability, and super-additive photothermal conversion efficiency due to the cooperation of MoSe2 and PDA. Simultaneously, the pH/near-infrared-responsive drug release profile was observed, which could enhance the synergistic therapeutic anticancer effect. The antitumor effects of PM@HMSNs-DOX were evaluated both in vitro and in vivo, demonstrating that the synergistic therapeutic efficacy was significantly superior to any monotherapy. Also, in vivo pharmacokinetics studies showed that PM@HMSNs-DOX had a much longer circulation time than free DOX. In addition, in vitro and in vivo toxicity studies certified that PM@HMSNs are suitable as biocompatible agents. Conclusion: Our nanoplatform loaded with DOX displays pH/near-infrared-induced chemotherapy and excellent photothermal therapy, which hold great potential for cancer treatment. Keywords: hollow mesoporous silica nanoparticles, MoSe2, polydopamine, chemo-photothermal therapy

Yi Sheng,1,* Wei Wang,2,* Bo Hong,2 Xingwang Jiang,1 Ruochuan Sun,1 Qiang Yan,1 Shangxin Zhang,1 Mingdian Lu,1 Shengyi Wang,1 Zhen Zhang,1 Wenchu Lin,2 Yongxiang Li1 1Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; 2High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, China *These authors contributed equally to this work Background: KIF20A is well known as one of the key proteins in mitosis. Recently, a number of studies illustrated that KIF20A might function as an oncogene in some carcinomas. However, its expression levels and clinical value remained unclear in gastric cancer (GC). Patients and methods: In this study, we investigated the expression of KIF20A in samples from GC patients and cell lines by quantitative real-time PCR and Western blot. The function of KIF20A in cell proliferation of GC cell lines was examined via cell viability and colony formation assays. Immunohistochemistry assay based on a tissue microarray consisting of 146 cases was performed to evaluate the prognostic value of KIF20A. The overall survival rate of 122 GC patients based on KIF20A expression was analyzed as well. Finally, using KIF20A inhibitor, genistein, and combining it with cisplatin or fluorouracil, the antitumor effects were studied. Results: Most GC samples (56.76%) showed higher KIF20A expression level compared to their corresponding normal specimens, which demonstrated the potential oncogenic role of KIF20A in GC. The functional studies elucidated the essential role of KIF20A in GC cell proliferation. Besides, tissue microarray result showed that the expression level of KIF20A was significantly related to the histological grades (P=0.036). Furthermore, we found the expression of KIF20A was related to poor overall survival rate, which is coincident with the results from Kaplan–Meier plotter database. In addition, we found that a KIF20A inhibitor, genistein, could enhance the antitumor activity of cisplatin and fluorouracil, which might be considered as a chemosensitive agent in GC. Conclusion: KIF20A can promote cell proliferation in GC, which might be used as an independent prognostic factor and a potential therapeutic target. Keywords: KIF20A, genistein, gastric cancer, prognosis