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Distant supervised relation extraction which is to extract heterogeneous relations from text data without manual annotation has been widely used in decision-making tasks such as question answering or recommendation system. However, existing distant supervised methods inevitably accompany with the wrong labelling problem. They typically use attention mechanism to select valid instances while ignore the core of relation extraction, i.e., entity pairs and relations. To address this problem, in this paper we incorporate enhanced representations into a gated graph convolutional network to enrich the background information and further improve the attention mechanism to focus on the most relevant relation. Specifically, in the proposed framework, 1) we introduce a triplet enhanced word representation method to focus on not only position information but also entity pair and implicit relation information in a sentence; 2) we use a Gated Rectified Linear Units (GRLU) module to integrate triplet information into an instance so as to achieve the purpose of enhancing sentence-level features; and 3) we employ sentence-relation joint attention over multiple instances and multiple relations, which is expected to dynamically reduce the weights of those noisy instances and enhance the bag representation. Extensive experiments on two popular datasets show that our model achieves significant improvement over all baseline methods.

BACKGROUND: Bronchial reconstruction is one of the most challenging procedures for thoracic surgeons. This study aimed to report the surgical techniques and clinical outcomes of bronchoplastic and sleeve resection for central lung cancer and summarize our center’s experience of this challenging procedure over the past 8 years. METHODS: Between January 2013 and April 2021, 54 patients underwent a sleeve resection or a lobectomy with bronchoplasty, including 11 patients who received video-assisted thoracoscopic surgery (VATS) bronchial sleeve resection (4 via the uniportal approach and 7 via the biportal approach). Perioperative parameters and surgical short-term patient outcomes were analyzed to evaluate the safety and feasibility of this surgical procedure. RESULTS: The average operative time and blood loss were 247.8±73.1 (range, 126–455) minutes and 300.4±321.8 (range, 50–1,500) mL, respectively. The mean postoperative length of stay was 10.5±5.8 (range, 4–29) days. Eleven patients underwent additional pulmonary angioplasty or sleeve resection. For patients who underwent biportal VATS sleeve lobectomy, the median operative time was 255 (interquartile range, 179–360) minutes, the median blood loss was 200 (interquartile range, 100–600) mL, and the median postoperative hospital stay was 5 (interquartile range, 5–8) days. For patients who underwent uniportal VATS sleeve lobectomy, the median operative time was 288 (interquartile range, 241.5–343) minutes, the median blood loss was 75 (interquartile range, 50–100) mL, and the median postoperative hospital stay was 5 (interquartile range, 4.5–5.5) days. No anastomosis-related complications or perioperative mortality was observed. CONCLUSIONS: Both bronchoplastic resection and sleeve resection are safe and feasible procedures. Uniportal thoracoscopic sleeve lobectomy can be performed by skilled surgeons with satisfactory short-term outcomes, although it is surgically complicated.

Xiaobo Shi,1 Xiaoxiao Liu,1 Shupei Pan,1 Yue Ke,1 Yuxing Li,1 Wei Guo,1 Yuchen Wang,1 Qinli Ruan,1 Xiaozhi Zhang,2 Hongbing Ma1 1Department of Radiation Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Department of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of ChinaCorrespondence: Hongbing MaDepartment of Radiation Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157, Xi Wu Road, Xi’an, 710004, Shaanxi, People’s Republic of ChinaTel +86 13991845066Email mhbxian@126.comBackground: Considering the significance of autophagy and long non-coding RNAs (lncRNAs) in the biology of esophageal squamous cell carcinoma (ESCC), the present study aimed to identify a new autophagy-related lncRNA signature to forecast the clinical outcomes of ESCC patients and to guide individualized treatment.Methods: The expression profiles were obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database. We extracted autophagy-related genes from the Human Autophagy Database and identified autophagy-related lncRNAs through Spearman correlation analysis. Univariate, least absolute shrinkage and selection operator and multivariate Cox regression analyses were performed on GSE53625 to construct an autophagy-related lncRNAs prognostic signature. The model was subjected to bootstrap internal validation, and the expression levels of lncRNAs were verified by TCGA database. The potential molecular mechanism of the model was explored by gene set enrichment analysis (GSEA). Spearman correlation coefficient examined the correlation between risk score and ferroptosis-associated genes as well as the response to immunotherapy and chemotherapy.Results: We identified and validated an autophagy-related lncRNAs prognostic signature in 179 patients with ESCC. The prognosis of patients in the low-risk group was significantly better than that in the high-risk group (p-value < 0.001). The reliability of the model was verified by Brier score and ROC. GSEA results showed significant enrichment of cancer- and autophagy-related signaling pathways in the high-risk group and metabolism-related pathways in the low-risk group. Correlation analysis indicated that the model can effectively forecast the effect of immunotherapy and chemotherapy. About 35.41% (74/209) ferroptosis-related genes were significantly correlated with risk scores.Conclusion: In brief, we constructed a novel autophagy-related lncRNAs signature (LINC02024, LINC01711, LINC01419, LCAL1, FENDRR, ADAMTS9-AS1, AC025244.1, AC015908.6 and AC011997.1), which could improve the prediction of clinical outcomes and guide individualized treatment of ESCC patients.Keywords: autophagy, esophageal squamous cell carcinoma, lncRNA, prognosis, therapeutic response

Xiaoxiao Liu,1 Xiaobo Shi,1 Wei Guo,1 Yue Ke,1 Yuxing Li,1 Shupei Pan,1 Xiaona Li,2 Mei Liu,3 Mingzhu Liu,4 Yuchen Wang,1 Qinli Ruan,1 Hongbing Ma1 1Department of Radiation Oncology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China; 2Department of Dermatology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China; 4Department of Gastroenterology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of ChinaCorrespondence: Hongbing MaDepartment of Radiation Oncology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of ChinaTel +86 13991845066Email mhbxian@126.comPurpose: Ferroptosis and long non-coding RNA (lncRNA) expression signatures have been associated with the clinical progression and immune-contexture of different solid tumors. The study aimed to identify a prognostic signature of ferroptosis-related lncRNAs (falncRNAs) to forecast the immune scenery and immunotherapy response in esophageal cancer (EC).Patients and Methods: Gene expression profiles of EC were extracted from The Cancer Genome Atlas (TCGA) database, and ferroptosis-related genes were downloaded from the FerrDb database, which identified differentially expressed falncRNAs (DEfalncRNAs) via differential analysis. DEfalncRNA pairs associated with prognosis were identified by constructing a matrix, univariate and least absolute shrinkage and selection operator (LASSO) analysis. The prognostic signature was constructed by multivariate analysis. We appraised the forecasting capability of prognostic signature in survival, clinicopathological features, immune landscape, efficacy of immunotherapy, and drug sensitivity. The potential molecular mechanism of signature was investigated by gene set enrichment analysis (GSEA).Results: We obtained 18 DEfalncRNA pairs to define a novel prognostic signature that was determined on a discovery cohort of 158 tumor samples and 11 adjacent normal tissues from TCGA and internally validated, with the definition of high- vs low-risk groups based on 3 years overall survival. We demonstrated that the high- vs low-risk groups differed for clinical parameters and computationally predicted drug sensitivity and tumor immune contexture, with the high-risk group having worse survival, more aggressive disease (node involvement, metastasis), reduced drug sensitivity, higher tumor mutation load, and gene signatures of infiltration of pro-tumoral immune cell subsets. The GSEA results revealed that ferroptosis and immunoregulatory pathways were significantly enriched in the high-risk group.Conclusion: The prognostic signature based on falncRNAs has the potential to forecast the survival, immune scenery, efficacy of immunotherapy, and drug sensitivity of EC, which is helpful for clinical prediction and individualized treatment.Keywords: esophageal cancer, ferroptosis, lncRNA, immune, signature, prognosis

Yajie Zhu,1 Xiaoli Ge,1 Di Xie,1 Shangyuan Wang,1 Feng Chen,2 Shuming Pan1 1Department of Emergency Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of China; 2Division of Medical Microbiology, Department of Clinical Laboratory, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of ChinaCorrespondence: Shuming PanDepartment of Emergency Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, People’s Republic of ChinaTel +862125076045Fax +862165030840Email panshuming@xinhuamed.com.cnFeng ChenDivision of Medical Microbiology, Department of Clinical Laboratory, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, People’s Republic of ChinaTel +862125078999Fax +862165030840Email chenfeng@xinhuamed.com.cnBackground: Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are most often caused by bacterial pneumonia and characterized by severe dyspnea and high mortality. Knowledge about the lung injury effects of current clinical bacterial strains is lacking. The aim of this study was to investigate the ability of representative pathogenic bacteria isolated from patients to cause ALI/ARDS in mice and identify the major virulence factor.Methods: Seven major bacterial species were isolated from clinical sputum and unilaterally instilled into the mouse airway. A histology study was performed to determine the lung injury effect. Virulence genes were examined by PCR. Sequence types of P. aeruginosa strains were identified by MLST. LC-MS/MS was used to analysis the bacterial exoproducts proteome. LasB was purified through a DEAE-cellulose column, and its toxicity was tested both in vitro and in vivo.Results: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus agalactiae, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli were randomly separated and tested 3 times. Among them, gram-negative bacteria have much more potential to cause acute lung injury than gram-positive bacteria. However, P. aeruginosa is the only pathogen that induces diffuse alveolar damage, hemorrhage and hyaline membranes in the lungs of mice. The lung injury effect is associated with the excreted LasB elastase. Purified LasB recapitulated lung injury similar to P. aeruginosa infection in vivo. We found that this was due to the powerful degradation effect of LasB on the extracellular matrix of the lung and key proteins in the coagulation cascade without inducing obvious cellular apoptosis. We also report for the first time that LasB could induce DIC-like coagulopathy in vitro.Conclusion: P. aeruginosa strains are most capable of inducing ALI/ARDS in mice among major clinical pathogenic bacteria tested, and this ability is specifically attributed to their LasB production.Keywords: unilateral lung injury, LasB elastase, Pseudomonas aeruginosa, ALI/ARDS

Zhiqi Shi,1,2 Shugang Pan,3,4 Luolin Wang,5 Sha Li2 1School of Pharmacy, Changzhou Institute of Industry and Technology, Changzhou, Jiangsu, People’s Republic of China; 2Longsha Medical Research Institute, Wuxi Hospital of Traditional Chinese Medicine, Wuxi, Jiangsu, People’s Republic of China; 3School of Pharmacy, Changzhou Institute of Technology, Changzhou, 213022, People’s Republic of China; 4Key Laboratory for Soft Chemistry and Functional Materials of Ministry Education, Nanjing University of Science and Technology, Nanjing, People’s Republic of China; 5Department of Pharmacy, Guangdong Provincial Institute of Traditional Chinese Medicine, Guangzhou, People’s Republic of ChinaCorrespondence: Zhiqi ShiSchool of Pharmacy, Changzhou Institute of Industry and Technology, No. 28#, Mingxin Road, Changzhou, Jiangsu Province, 213164, People’s Republic of ChinaTel +86 519-86335118Email shi_mars@foxmail.comSha LiLongsha Medical Research Institute, Wuxi Hospital of Traditional Chinese Medicine, No. 8#, Zhongnan Road, Wuxi, Jiangsu Province, 214071, People’s Republic of ChinaTel +86 510-88859999Email sl0426@foxmail.comIntroduction: Oleanolic acid (OA) has been shown to be useful for the treatment of mental disorders.Methods: In this study, we investigated the effects of OA in animal models of spontaneous withdrawal and naloxone-precipitated withdrawal and evaluated the effects of OA on the acquisition, extinction, and reinstatement of morphine-induced conditioned place preference (CPP).Results: OA significantly improved symptoms of withdrawal, and significantly reduced the acquisition and reinstatement of morphine-induced conditioned place preference. Moreover, OA significantly reduced the serum content of 5-hydroxy tryptamine (5-HT) and dopamine (DA) in a dose-dependent manner, and reduced norepinephrine (NE) and 5-HT content in the frontal cortex (PFC), while significantly increasing endorphin content in rats. OA also significantly reduced serum DA content in mice.Conclusion: These results indicate that OA can improve the withdrawal symptoms of rats and mice by regulating the DA system and suggest that OA may be useful in treatment of morphine addiction.Keywords: OA, withdrawal, morphine-induced, rats, mice

The discharged saline wastewater has severely influenced the aquatic environment as the treatment performance of many wastewater treatment techniques is limited. In addition, the sources of saline wastewater are also plentiful from agricultural and various industrial fields such as food processing, tannery, pharmaceutical, etc. Although high salinity levels negatively impact the performance of both physicochemical and biological processes, membrane bioreactor (MBR) processes are considered as a potential technology to treat saline wastewater under different salinity levels depending on the adaption of the microbial community. Therefore, this study aims to systematically review the application of MBR widely used in the saline wastewater treatment from the perspectives of microbial structure and treatment efficiencies. At last, the concept of carbon dioxide capture and storage will be proposed for the MBR-treating saline wastewater technologies and considered toward the circular economy with the target of zero emission.

Beina Hui,1 Shupei Pan,2 Shaomin Che,1 Yuchen Sun,1 Yanli Yan,1 Jia Guo,1 Tuotuo Gong,1 Juan Ren,1 Xiaozhi Zhang1 1Department of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, People’s Republic of China; 2Department of Radiation Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710004, People’s Republic of ChinaCorrespondence: Juan Ren; Xiaozhi Zhang Tel +86 2985324029; +86 2985324621Email 869491533@qq.com; zhangxiaozhi@xjtu.edu.cnPurpose: Resistance to radiotherapy results in a high treatment failure rate for locally advanced esophageal squamous cell carcinoma (ESCC). Ubiquitin-like with plant homeodomain and ring-finger domains 1 (UHRF1), is associated with poor prognosis in ESCC. The present study aims to characterize the effect of UHRF1 silencing on the radiosensitivity of ESCC and its potential mechanism.Methods: Both in vitro and in vivo experiments were conducted to observe the effects of UHRF1 silencing on the radiosensitivity of ESCC. The effects of UHRF1 silencing on the apoptosis of ESCC cells were assessed by flow cytometry. The expression of apoptosis-related factors (caspase-3 and Bcl-2), PI3K/Akt/mTOR signaling pathway-related factors (PTEN, p-Akt and Akt, p-mTOR and mTOR), and DNMT1 were measured via Western blot, and the status of PTEN methylation was detected by methylation-specific PCR. Immunohistochemistry was used to detect the expressions of PTEN, p-AKT, and p-mTOR in xenograft tumor tissues.Results: In vitro and in vivo experiments showed that UHRF1 knock-down inhibited ESCC cell growth and enhanced their radiosensitivity. shUHRF1 combined with radiation significantly increased ESCC cell apoptosis. Meanwhile, it activated the expression of caspase-3 and inhibited the expression of Bcl-2. shUHRF1 inhibited the expression of DNMT1 and reduced the methylation of PTEN, and then upregulated the expression of PTEN to inhibit the PI3K/Akt/mTOR signaling pathway. On the contrary, the PI3K/Akt/mTOR signaling pathway can be activated by upregulation of UHRF1.Conclusion: Our findings provide a theoretical basis for UHRF1 as a target to improve the radiosensitivity of ESCC.Keywords: radiosensitivity, UHRF1, esophageal squamous carcinoma, shRNA, PI3K/Akt/mTOR

Huanhuan Zhao,1– 5,* Lulu Liang,1– 5,* Shaokang Pan,1 Zhenjie Liu,1 Yan Liang,1 Yingjin Qiao,1 Dongwei Liu,1– 5 Zhangsuo Liu1– 5 1Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 2Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 3Research Center for Kidney Disease, Zhengzhou, 450052, Henan Province, People’s Republic of China; 4Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People’s Republic of China; 5Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhangsuo Liu; Dongwei LiuDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, Henan Province, People’s Republic of ChinaTel +86-0371-66295921Email Lzs58055@163.com; dongweiliu01@163.comPurpose: Acute kidney injury is very common in hospitalized patients and carries a significant risk of mortality. Although timely intervention may improve patient prognosis, studies on the development of acute kidney disease in patients with acute kidney injury remain scarce. Thus, we constructed a prediction model to identify patients likely to develop acute kidney disease.Patients and Methods: Among 474 patients screened for eligibility, 261 were enrolled and randomly divided into training (185 patients) and independent validation cohorts (76 patients). Least absolute shrinkage and selection operator regression and multivariate logistic regression analyses were used to select features and build a nomogram incorporating the selected predictors: diabetes, anemia, oliguria, and peak creatinine. Calibration, discrimination, and the clinical usefulness of the model were assessed using calibration plots, the C-index, receiver operating characteristic curves, and decision curve analysis.Results: Diabetes was significantly associated with the presence of AKD. Peak creatinine, oliguria, and anemia also contributed to the progression of acute kidney injury. The model displayed good predictive power with a C-index of 0.834 and an AUC of 0.834 (95% confidence interval (CI): 0.773– 0.895) in the training cohort and a C-index of 0.851 and an AUC of 0.851 (95% CI: 0.753– 0.949) in the validation cohort. The calibration curves also showed that the model had a medium ability to predict acute kidney disease risk. Decision curve analysis showed that the nomogram was clinically useful when interventions were decided at the possibility threshold of 22%.Conclusion: This novel prediction nomogram may allow for convenient prediction of acute kidney disease in patients with acute kidney injury, which may help to improve outcomes.Keywords: diabetes mellitus, acute kidney injury, anemia, oliguria, nomogram

Patients with pancreatic ductal adenocarcinoma (PDAC) have a grim prognosis despite complete surgical resection and intense systemic therapies. While immunotherapies have been beneficial with many different types of solid tumors, they have almost uniformly failed in the treatment of PDAC. Understanding how therapies affect the tumor immune microenvironment (TIME) can provide insights for the development of strategies to treat PDAC. We used quantitative multiplexed immunofluorescence (qmIF) quantitative spatial analysis (qSA), and immunogenomic (IG) analysis to analyze formalin-fixed paraffin embedded (FFPE) primary tumor specimens from 44 patients with PDAC including 18 treated with neoadjuvant chemoradiation (CRT) and 26 patients receiving no treatment (NT) and compared them with tissues from 40 treatment-naïve melanoma patients. We find that relative to NT tumors, CD3

Saibo Pan,* Shijie Wang,* Wenshan Li, Ying Chai Department of Thoracic Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ying ChaiDepartment of Thoracic Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, # 88 Jiefang Road, Hangzhou, 310009, People’s Republic of ChinaTel +86-571-87783642Fax +86-571-87068001Email chaiy@zju.edu.cnPurpose: The superior efficacy of first-line treatment with icotinib over that of standard chemotherapy has been well demonstrated in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation. However, whether icotinib is superior to cisplatin plus docetaxel as adjuvant chemotherapy in patients with stage II (N1+) NSCLC selected by EGFR mutation is controversial.Methods: A total of 43 patients with completely resected stage II (T1-2N1M0) NSCLC and proven sensitive EGFR mutation (19Del or L858R) between January 2010 and December 2019 were included in our study. The disease-free survival (DFS) and overall survival (OS) were analyzed in 22 patients treated with icotinib and 21 patients treated with cisplatin plus docetaxel. Factors affecting DFS and OS were assessed by the Kaplan-Meier (KM) estimator and univariate Cox regression analysis.Results: Our cohort included 22 icotinib patients and 21 cisplatin plus docetaxel patients with a median follow-up of 35.5 months and 38 months, respectively. Survival time was significantly longer in the icotinib group than in the chemotherapy group, with a median DFS of 47 months (95% CI, not reached) versus 18 months (95% CI, 12.4– 23.6; HR 0.16; 95% CI, 0.07– 0.35; log-rank p< 0.0001). In the icotinib group, the most common adverse effects (AEs) were skin rash (40.9%) and elevated alanine aminotransferase (22.7%), whereas in the cisplatin plus docetaxel group, the most common AEs were nausea or vomiting (90.5%), anorexia (71.4%), and fatigue (71.4%). No deaths were treatment-related.Conclusion: In this study, we demonstrated that in EGFR mutation-positive patients with completely resected stage II (T1-2N1M0) NSCLC, icotinib might provide DFS benefits, and reduced drug toxicity compared to cisplatin plus docetaxel. Thus, icotinib may be a reasonable option for adjuvant chemotherapy in patients with pathological stage II (N1+) NSCLC with EGFR mutation.Keywords: icotinib, adjuvant therapy, EGFR-TKI, lung cancer, survival analysis, adverse events

Wenbin Xu,* Shangdan Xie,* Xin Chen, Shuya Pan, Hongfei Qian, Xueqiong Zhu Center of Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xueqiong ZhuCenter of Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, Zhejiang, 325027, People’s Republic of ChinaTel +86 577 88002796 (office)Fax +86 577 88002796Email zjwzzxq@163.comPurpose: This study aimed to investigate the effects of quercetin on the efficacy of various chemotherapeutic drugs in cervical cancer cells.Methods: All drug experiments were performed in HeLa and SiHa cells. The cell viability was detected by Cell Counting Kit-8 assay, and cell proliferation was estimated by bromodeoxyuridine assay. CompuSyn software was utilized to calculate the combination index (CI) and evaluate the synergistic or antagonistic effect of quercetin with cisplatin, paclitaxel, 5-fluorouracil and doxorubicin on cell viability. Cell migration and invasion abilities were detected by transwell assays, and cell apoptosis was measured by flow cytometry. The expression levels of matrix metallopeptidase 2 (MMP2), ezrin, P-glycoprotein (P-Gp) and methyltransferase-like 3 (METTL3) protein treated with various drugs were analyzed by Western blotting.Results: Quercetin inhibited the viability of HeLa and SiHa cells in a dose- and time-dependent manner. The CI values of quercetin with cisplatin, paclitaxel, 5-fluorouracil and doxorubicin were < 1, > 1, > 1 and > 1, respectively. The effect of combination of quercetin and cisplatin on cell proliferation was stronger than their individual effects. Co-treatment group could inhibit more cell migration and invasion in contrast to single-drug group. Besides, quercetin combined with cisplatin group induced more cell apoptosis in contrast to single-drug group. The results of Western blotting showed that the expression levels of MMP2, ezrin, P-Gp and METTL3 in co-treatment group were lower than in cisplatin group, respectively.Conclusion: Quercetin and cisplatin had synergistic inhibitory effect on cervical cancer cells. Quercetin might enhance the antitumor effect of cisplatin via inhibiting proliferation, migration and invasion and elevating apoptosis through weakening MMP2, ezrin, METTL3 and P-Gp expression of cancer cells.Keywords: quercetin, cisplatin, cervical cancer, chemosensitivity

Yuexia Wang,1,* Shengli Pan,2,* Xinhong He,3 Ying Wang,3 Haozhe Huang,3 Junxiang Chen,3 Yuhao Zhang,2 Zhijin Zhang,2 Xianju Qin2 1Department of General Surgery, Shanghai Eighth People’s Hospital, Jiangsu University, Shanghai, People’s Republic of China; 2Department of General Surgery, Shanghai Eighth People’s Hospital, Shanghai, People’s Republic of China; 3Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shengli Pan; Xianju QinDepartment of General Surgery, Shanghai Eighth People’s Hospital, Caobao Road No. 8, Shanghai 200232, People’s Republic of ChinaTel +86-21-34284588Email panshengli171107@163.com; qinxj@hotmail.comIntroduction: Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide. Copines-1 (CPNE1) has been shown to be overexpressed in various cancers; however, the role of CPNE1 in CRC remains unknown. Therefore, it is of great importance to elucidate the role of CPNE1 in CRC and its underlying mechanism of action.Methods: CPNE1 expression in CRC tissues was measured by quantitative real-time PCR and immunohistochemical (IHC) staining. CPNE1 was knocked down (KD) or overexpressed using small inferring RNAs or lentiviral transduction in CRC cells. The proliferation, apoptosis, glycolysis, and mitochondrial respiration of CRC cells were assessed by cell counting kit-8, flow cytometry, and Xfe24 extracellular flux analyzer assays, respectively. The role of CPNE1 in tumor growth and chemoresistance was further confirmed in xenograft and patient-derived tumor xenograft models, respectively.Results: CPNE1 mRNA and protein were upregulated in CRC tissues. CPNE1 promoted proliferation, inhibited apoptosis, increased mitochondrial respiration, enhanced aerobic glycolysis by activating AKT signaling, upregulated glucose transporter 1 (GLUT1) and hexokinase 2 (HK2), and downregulated the production of cleaved Caspase-3 (c-Caspase 3). CPNE1 also contributed to chemoresistance in CRC cells. CPNE1 KD inhibited tumor growth and increased the sensitivity of tumors to oxaliplatin in vivo.Conclusion: CPNE1 promotes CRC progression by activating the AKT-GLUT1/HK2 cascade and enhances chemoresistance.Keywords: copines-1, colorectal cancer, aerobic glycolysis, mitochondrial respiration