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Jing Tang,1,2 Fengyong Liu,2 Hongjun Yuan,2 Xin Li,2 Xiaomei Tian,2 Kan Ji,2 Xueping Li,3 Wei Wang3 1Medical School of Chinese PLA, Beijing, People’s Republic of China; 2Department of Interventional Radiology, The First Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Department of Radiology, The First Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Fengyong LiuDepartment of Interventional Radiology, The First Medical Center, Chinese PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing 100853, People’s Republic of ChinaTel +8613371668617Fax +86-10-66939340Email liufengyong301@163.comPurpose: To evaluate whether the pretreatment apparent diffusion coefficient (ADC) measured with diffusion weighted imaging (DWI) of tumor can be used as an imaging biomarker for predicting prognosis in solitary large hepatocellular carcinomas (HCCs) treated with transcatheter arterial chemoembolization (TACE) immediately combined with radiofrequency ablation (RFA).Patients and Methods: In this single institution retrospective study, 40 solitary large HCCs that underwent treatment with TACE immediately combined with RFA were analyzed. All patients underwent abdominal dynamic contrast-enhanced magnetic resonance imaging within one month before treatment with DWI, and ADC values in the lesions were measured by two independent radiologists. Associations among patients’ preoperative ADC values and objective response (OR), progression-free survival (PFS) and overall survival (OS) were examined. Survival curves were drawn with the Kaplan–Meier method, and differences were determined with the Log rank test. The Cox proportional-hazards model was used for univariate and multivariate analyses of PFS and OS.Results: Forty solitary large HCCs (mean 9.54 cm, range 5.04– 16.06 cm) were successfully treated with TACE in immediate combination with RFA (OR 75%). The ADC values were significantly higher in the response group than the non-response group (1.51± 0.32× 10− 3 mm2/s vs 1.09± 0.17× 10− 3 mm2/s; P< 0.001). As predicted on the basis of the ADC values, the optimal cutoff value for the efficacy of TACE combined with RFA was 1.32× 10− 3 mm2/s, with a predictive sensitivity of 0.63 and a specificity of 1.00. Patients with high ADC had longer PFS than those with low ADC (14.9 months vs 5.3 months; P< 0.001) and had significantly longer survival rates (22.6 months vs 12.1 months; P=0.004).Conclusion: Preoperative ADC values < 1.32× 10− 3 mm2/s are an independent predictor of poorer prognosis in patients with solitary large HCCs who have undergone TACE immediately combined with RFA.Keywords: solitary large hepatocellular carcinoma, apparent diffusion coefficient, TACE, radiofrequency ablation

Xiumei Tian1 ,* Ao Zeng1 ,* Ziying Liu,1 Cunjing Zheng,2 Yuezi Wei,1 Peiheng Yang,1 Minru Zhang,1 Fanwen Yang,1 Fukang Xie1 1School of Basic Medical Sciences, Affiliated Stomatology Hospital, Guangzhou Medical University, Guangzhou 510182, People’s Republic of China; 2Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fukang Xie Tel +86 20 136 4231 6682Email 378141679@qq.comFanwen Yang Tel +86 20 135 0308 0690Fax +86 20 3710 3509Email yangfanwen@163.comBackground: Understanding the biocompatibility and biointeractions of nano-carbon quantum dots (nano-CQDs) in vitro and in vivo is important for assessing their potential risk to human health. In the previous research, the physical properties of CQDs synthesized by the laser ablation in liquid (LAL) method were analyzed in detail; however, possible bioapplications were not considered.Materials and Methods: CQDs were prepared by LAL and characterized by atomic force microscopy, fluorescence lifetime, absorption spectrum, Fourier-transform infrared spectroscopy, and dynamic light scattering. Their biocompatibility was evaluated in vitro using assays for cytotoxicity, apoptosis, and biodistribution and in vivo using immunotoxicity and the relative expression of genes. Cells were measured in vitro using fluorescence-lifetime imaging microscopy to analyze the biointeractions between CQDs and intracellular proteins.Results: There were no significant differences in biocompatibility between the CQDs and the negative control. The intracellular interactions had no impact on the optical imaging of CQDs upon intake by cells. Optical imaging of zebrafish showed the green fluorescence was well dispersed.Conclusion: We have demonstrated that the CQDs have an excellent biocompatibility and can be used as efficient optical nanoprobes for cell tracking and biomedical labeling except for L929 and PC-3M cells.Keywords: nanoprobe, immunotoxicity, biodistribution, biointeraction, optical imaging

Juan Li,1 Lei Zheng,2 Rongmei Wang,1 Deqing Sun,1 Shuang Liang,3 Jing Wu,1 Yongqing Liu,1 Xiaona Tian,1 Tingting Li,4 Yang Yang,5 Leiqiang Han1 1Department of Clinical Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, People’s Republic of China; 2Department of Pharmacy, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250031, People’s Republic of China; 3School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People’s Republic of China; 4Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA; 5China National Center for Biotechnology Development, Beijing 100039, People’s Republic of ChinaCorrespondence: Leiqiang HanDepartment of Clinical Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Road, Jinan, Shandong 250033, People’s Republic of ChinaTel +86-531-85875083Fax +86-531-88962544Email hanlq007@sina.cnBackground: The development of paclitaxel (PTX) resistance seriously restricts its clinical efficacy. An attractive option for combating resistance is inhibiting the expression of P-glycoprotein (P-gp) in tumor cells. We have reported that flavokawain A (FKA) inhibited P-gp protein expression in PTX-resistant A549 (A549/T) cells, indicating that FKA combined with PTX may reverse PTX resistance. However, due to the variable pharmacokinetics of FKA and PTX, the conventional cocktail combination in clinics may cause uncertainty of treatment efficacy in vivo.Materials and Methods: To synergistically elevate the anti-cancer activity of PTX and FKA in vivo, the national medical products administration (NMPA) approved sodium aescinate (Aes) was utilized to stabilize hydrophobic PTX and FKA to form polymer-free twin like PTX-A nanoparticles (NPs) and FKA-A NPs.Results: The resulting nanoparticles prepared simply by nanoprecipitation possessed similar particle size, good stability and ultrahigh drug loadings of up to 50%. With the aid of Aes, these two drugs accumulated in tumor tissue by passive targeting and were efficiently taken up by A549/T cells; this resulted in significant suppression of tumor growth in A549/T homograft mice at a low PTX dose (2.5 mg·kg− 1). Synergistic effects and reversed PTX resistance were achieved by the combination of PTX-A NPs and FKA-A NPs by inhibiting P-gp expression in tumor cells.Conclusion: Using NMPA-approved Aes to prepare twin-like nanoparticles without introducing any new materials provides an efficient platform for combination chemotherapy and clinical translation.Keywords: paclitaxel resistance, flavokawain A, sodium aescinate, polymer-free nanoparticles, combination therapy

Nan Jiang,1,* Pingting Yang,2,* Shengyun Liu,3,* Hongbin Li,4 Lijun Wu,5 Xiaofei Shi,6 Yongfei Fang,7 Yi Zhao,8 Jian Xu,9 Zhenyu Jiang,10 Zhenbiao Wu,11 Xinwang Duan,12 Qian Wang,1 Xinping Tian,1 Mengtao Li,1 Xiaofeng Zeng1 1Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, People’s Republic of China; 2Department of Rheumatology and Immunology, First Affiliated Hospital, China Medical University, Shenyang, People’s Republic of China; 3Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 4Department of Rheumatology, Affiliated Hospital of Inner Mongolia Medical College, Hohhot, Inner Mongolia, People’s Republic of China; 5Department of Rheumatology and Immunology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region, People’s Republic of China; 6Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, People’s Republic of China; 7Department of Rheumatology, Southwest Hospital, Third Military Medical University, Chongqing, People’s Republic of China; 8Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 9Department of Rheumatology and Immunology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 10Department of Rheumatology, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 11Department of Clinical Immunology and Rheumatology, Xijing Hospital Affiliated to the Fourth Military Medical University, Shanxi, People’s Republic of China; 12Department of Rheumatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaofeng Zeng; Mengtao LiDepartment of Rheumatology, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing Ave, Beijing 100730, People’s Republic of ChinaTel/ Fax + 86-10-69158793Email zengxfpumc@163.com; mengtao.li@cstar.org.cnPurpose: Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by chronic destructive synovitis and possible multisystem involvement. This study aimed to survey the treatment satisfaction of physicians and patients with RA, and to explore the potential factors.Patients and Methods: This cross-sectional study was conducted in 12 centers across China between March 2018 and April 2018. The Treatment Satisfaction Questionnaire for Medication version II was used to assess the treatment satisfaction of patients and physicians. Multivariable regression analysis was used to determine the factors independently associated with treatment satisfaction of patients.Results: The patients’ satisfaction (n=335) with biological disease-modifying antirheumatic drugs (bDMARDs) was higher than physicians’ satisfaction (n=146) regarding the side effects (95.0± 14.3 vs 84.6± 15.7, P< 0.001) and convenience (74.6± 21.2 vs 69.1± 16.5, P=0.002). Among physicians, global satisfaction with bDMARDs was higher than that with conventional synthetic DMARDs (csDMARDs). The multivariable regression analysis showed that age was positively associated with satisfaction of patients, while college or above education and self-assessment of disease severity were inversely associated with satisfaction. Treatment satisfaction was associated positively with the quality of communication with the physician and inversely with treatment costs.Conclusion: For bDMARDs, the treatment satisfaction of patients with RA is generally higher than that of physicians’. Physicians’ satisfaction with bDMARDs is higher than with csDMARDs. Age, education, disease severity, communication with the physician, and treatment costs are independently associated with the treatment satisfaction among patients. Physician–patient communication should be improved in clinical practice. Treatment costs should be taken into account when physicians make decisions.Keywords: patient, physician, rheumatoid arthritis, treatment satisfaction, TSQM-II

Ye Xu,1 Xiangkuo Zheng,2 Weiliang Zeng,2 Tao Chen,1 Wenli Liao,1 Jiao Qian,1 Jie Lin,1 Cui Zhou,1 Xuebin Tian,2 Jianming Cao,2 Tieli Zhou1 1Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China; 2Department of Medical Laboratory Science, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Jianming Cao; Tieli Zhou Tel +86-577-88069595; +86-577-86689885Email wzcjming@163.com; wyztli@163.comBackground: Heteroresistance is a phenomenon that occurs in all bacteria and can cause treatment failure. Yet, the exact mechanisms responsible for heteroresistance still remain unknown. The following study investigated the mechanisms of imipenem-heteroresistance and -resistance in Pseudomonas aeruginosa clinical isolates from Wenzhou, China.Methods: Imipenem resistance was detected by the agar dilution method; heteroresistance was determined by population analysis profiles. Biofilm formation assay and modified carbapenem inactivation methods were also performed. Polymerase chain reaction (PCR) was conducted to detect oprD, and quantitative real-time PCR was used to determine expression levels of oprD, ampC and four efflux pump coding genes (mexB, mexD, mexE and mexY).Results: Six imipenem-heteroresistant and -resistant P. aeruginosa isolates were selected respectively. Deficient oprD was detected in all resistant isolates and two heteroresistant isolates. No strains produced carbapenemases. Expression levels of oprD were down-regulated in heteroresistant isolates. Transcription levels of the mexE and mexY were significantly increased in all heterogeneous subpopulations compared with their respective native ones. Compared with the susceptible group, increased mean relative expression levels of mexE and mexY or the decreased mean relative expression levels of oprD were observed in the resistant group (P < 0.05), whereas transcription levels of the mexB and mexD remained unchanged.Conclusion: Down-regulation of oprD contributed to the resistance and heteroresistance of imipenem in our P. aeruginosa clinical isolates. In addition, the marginal up-regulation of efflux systems may indirectly affect imipenem resistance. Contrarily, defective oprD was less common in our experimental heteroresistant strains than resistant strains.Keywords: Pseudomonas aeruginosa, imipenem, resistance, heteroresistance, molecular mechanism, oprD

Xin Tian, Ying Xuan, Rong Wu, Song Gao Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, People’s Republic of ChinaCorrespondence: Song GaoDepartment of Clinical Oncology, Shengjing Hospital of China Medical University, 36 San Hao Street, Shenyang 110004, People’s Republic of ChinaEmail gaogao0229@hotmail.comObjective: To investigate the curative and adverse effects (AEs) of additional use of nimotuzumab combined with induction chemotherapy and concurrent chemoradiotherapy in unresectable locoregionally advanced hypopharyngeal carcinoma.Patients and Methods: We retrospectively evaluated 36 patients with stage III or IVA hypopharyngeal carcinoma who received induction chemotherapy followed by concurrent chemoradiotherapy with or without nimotuzumab. The induction chemotherapy included two or three cycles of TPF regimen. The intensity-modulated radiation therapy (IMRT) dose was 70 Gy to the planning target volume. Concurrent with radiotherapy, patients received chemotherapy consisting of cisplatin q3w. Adjuvant chemotherapy consisting of TPF regimen was administered 1 month later after concurrent chemoradiotherapy. Nimotuzumab (200 mg day 1, q3w) was given to patients concurrently with induction chemotherapy and was administered concurrently with IMRT at a weekly dose of 200 mg.Results: After induction chemotherapy, the objective response rate in patients treated with nimotuzumab (group A) versus those treated without nimotuzumab (group B) was 91.7% versus 58.3% (p=0.029). After concurrent chemoradiotherapy, the objective response rate was 95.8% in group A versus 83.3% in group B (p=0.253). The median follow-up was 22.6 months (range 8.9– 39.5 months). The 2-year OS rate in group A and group B were 62.5% (95% CI 55– 70%) and 51.8% (95% CI 45– 59%), respectively, the 2-year OS rate in group A was better than group B, P< 0.05. PFS was 23 months (95% CI 19– 27) in group A versus 18 months (95% CI 12– 22) in group B, PFS was longer in group A than group B, P< 0.05. There was no significant difference in AEs between the two groups.Conclusion: Additional use of nimotuzumab combined with induction chemotherapy and concurrent chemoradiotherapy in unresectable locoregionally advanced hypopharyngeal carcinoma yielded better short-term efficacy, also may improve overall survival and progression-free survival than patients without using nimotuzumab. The toxicity was tolerable.Keywords: nimotuzumab, induction chemotherapy, chemoradiotherapy, unresectable, locoregionally advanced, hypopharyngeal carcinoma

Xuebin Tian, 1, 2 Xiangkuo Zheng, 2 Yao Sun, 1 Renchi Fang, 1 Siqin Zhang, 1 Xiucai Zhang, 1 Jie Lin, 1 Jianming Cao, 2 Tieli Zhou 1 1Department of Clinical Laboratory, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China; 2School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Tieli ZhouDepartment of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaTel +86-0577-86699370Email wyztli@163.com Jianming CaoSchool of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, People’s Republic of ChinaTel +86-0577-88069595Email wzcjming@163.comBackground: The emergence and spread of carbapenem-resistant Escherichia coli (E. coli) pose a serious threat to human health worldwide. This study aimed to investigate the molecular mechanisms underlying carbapenem resistance and their prevalence among E. coli in China.Methods: A collection of 5796 E. coli clinical isolates were collected from the First Affiliated Hospital of Wenzhou Medical University from 2002 to 2017. Sensitivity to antibiotics was determined using the agar dilution method. The detection of carbapenemases production and the prevalence of resistance-associated genes were investigated through modified carbapenem inactivation method (mCIM), PCR and sequencing. The mutations in outer membrane porins genes (ompC and ompF) were also analyzed by PCR and sequencing assays. The effect of efflux pump mechanism on carbapenem resistance was also tested. E. coli were typed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST).Results: A total of 58 strains (1.0%) of carbapenem-resistant E. coli were identified. The strains carrying blaKPC-2 and blaNDM accounted for 22.4% (13/58) and 51.7% (30/58), respectively. Among blaNDM- positive strains, 27 blaNDM genes were assigned to blaNDM-5, while the remaining three strains were blaNDM-1, whereas blaVIM, blaIMP, blaOXA-48, and blaSHV were not found. The CTX-M-type β-lactamase genes accounted for 96.6% (56/58). In addition, blaTEM-1 genes were identified in 58.6% of tested strains. In carbapenem-resistant isolates, mutations in OmpC (the majority of mutated sites were D192G and Q104_F141del, accounting for 54.5%) and OmpF (large deletions S75_V127del, W83_D135del and Q88_D135del) were detected. Of note, the antibiotic resistance was not associated with overexpression of efflux pump. Moreover, MLST categorized the 58 carbapenem-resistant isolates into 19 different sequence types. PFGE analysis revealed that homology among the carbapenem-resistant isolates was low and sporadic.Conclusion: The blaNDM was the principal resistance mechanism of carbapenem-resistant E. coli in the hospital. blaNDM-5 is becoming a new threat to public health and the alteration of outer membrane porins might help further increase the MIC of carbapenem.Keywords: Escherichia coli, carbapenem-resistant, carbapenemase, outer membrane porin, epidemiology

Ting Zhan, 1,* Qingxi Zhu, 1,* Zheng Han, 1 Jie Tan, 1 Meng Liu, 1 Weijie Liu, 1 Wei Chen, 1 Xiaoli Chen, 1 Xueting Chen, 2 Junsheng Deng, 2 Xia Tian, 1 Xiaodong Huang 1 1Department of Gastroenterology, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan 430060, People’s Republic of China; 2Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan 430060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaodong Huang; Xia Tian Tel +86 1388619054; +86 13871480868Email 13297056720@163.com; hcwy100@163.comBackground: Pancreatic cancer (PC) is a highly invasive tumor with a poor prognosis, short overall survival rate and few chemotherapeutic choices. Despite the importance of finding ways to treat pancreatic cancer, the mechanisms of tumor progression have not been fully elucidated. microRNA-455-3p (miR-455-3p) has been reported to play an important role in several cancers, but its function in pancreatic cancer remains unclear.Methods: To investigate the biological functions, miRNAs mimics or inhibitors were transfected into pancreatic cancer cells. Flow cytometry was used to detect cell apoptosis. Wound healing and Transwell assays were employed to observe cell invasion and migration abilities. The expression of Bcl-2, Bax, caspase-3, E-cadherin, N-cadherin, Snail, β-Catenin, c-Myc and Cyclin D1 were evaluated by qPCR and Western blot.Results: We confirmed that inhibition of miR-455-3p decreases cell apoptosis and increases cell migration, invasion and EMT of pancreatic cancer, whereas forced overexpression of miR-455-3p has the opposite effect. Furthermore, we demonstrated that the tumor suppression effects of miR-455-3p were partially reversed by TAZ overexpression. In addition, miR-455-3p led to inactivation of Wnt/β-catenin signaling in pancreatic cancer cells, and TAZ overexpression restored the inhibition of Wnt/β-catenin signaling.Conclusion: Taken together, our data demonstrated that miR-455-3p functions as an important tumor suppressor that suppresses the Wnt/β-catenin signaling pathway via TAZ to inhibit tumor progression in pancreatic cancer. We conclude that the miR-455-3p/TAZ/Wnt axis may be a potential therapeutic target for pancreatic cancer.Keywords: miR-455-3p, Wnt, apoptosis, metastasis, EMT

Xiaolang Tian, Changwu Huang, Xiaoli Ye, Hongyan Jiang, Rufang Zhang, Xiaofang Hu, Dongshuang Xu Department of Clinical Laboratory, University of Chinese Academy of Sciences Chongqing Renji Hospital (Fifth People’s Hospital of Chongqing), Chongqing, People’s Republic of ChinaCorrespondence: Dongshuang XuDepartment of Clinical Laboratory, University of Chinese Academy of Sciences Chongqing Renji Hospital (Fifth People’s Hospital of Chongqing), No. 24 Renji Road, Nanan District, Chongqing 400062, People’s Republic of ChinaTel +86 023-62895125Fax +86 023-62881980Email dongshuang_xu@163.comBackground: The emergence and spread of carbapenem-resistant Enterobacter cloacae (CR-ECL) have posed a serious threat to clinical management. This retrospective study assessed the epidemiological characteristics of CR-ECL to explore the risk factors and predictors of mortality in patients with CR-ECL infection.Methods: We performed a retrospective 1:2 case-control study of hospitalized patients from January 2014 to December 2017. A total of 85 consecutive unique CR-ECL strains comprised the case group, and 170 matched patients with carbapenem-susceptible Enterobacter cloacae (CS-ECL) infection at the same period as the control group. Isolates were screened for potential resistance genes by polymerase chain reaction (PCR) and molecular typing was performed by multilocus sequence typing (MLST).Results: The results of drug resistance gene detection showed that blaNDM-1 was the most common carbapenem resistance gene. The MLST results showed that ST51 was the predominant epidemic type, followed by ST88. ICU admission (P< 0.001), drainage tube (P=0.002), central venous catheter (P=0.005), and carbapenem exposure (P=0.003) were independent risk factors for CR-ECL infection. Significant predictors for 28-day mortality included solid tumours (P=0.005), septic shock (P=0.019), and mechanical ventilation (P=0.027).Conclusion: Our study indicated that ST51 and ST88, which are closely related, were the predominant epidemic types of CR-ECL producing blaNDM-1 in southwestern China. Strengthening the surveillance of patients with solid tumours, septic shock and mechanical ventilation is an urgent need.Keywords: carbapenem-resistant Enterobacter cloacae, epidemiological characteristics, risk factors, predictors of mortality

Xinyu Dai,1 Jingqing Yao,1 Yuejiao Zhong,2 Yuntao Li,3 Qianling Lu,4 Yan Zhang,1 Xue Tian,1 Zhirui Guo,5 Tingting Bai5 1Department of Neurology, Second Affiliated Hospital of Nanjing Medical University, Nanjing 210000, People’s Republic of China; 2Department of Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210000, People’s Republic of China; 3Department of General Practice, Second Affiliated Hospital of Nanjing Medical University, Nanjing 210000, People’s Republic of China; 4Department of Neurology, Third Affiliated Hospital of Nanjing Medical University, Nanjing 210000, People’s Republic of China; 5Department of Geratology, Second Affiliated Hospital of Nanjing Medical University, Nanjing 210000, People’s Republic of ChinaCorrespondence: Yuejiao ZhongDepartment of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Baiziting 42, Nanjing 210009, People’s Republic of ChinaEmail zhongyuejiao2019@163.com Yuntao LiDepartment of General Practice, Second Affiliated Hospital of Nanjing Medical University, No. 121 Jiangjiayuan Road, Nanjing, Jiangsu, People’s Republic of ChinaTel/Fax +86 25 5850 9989Email 18951762737@163.comBackground: Primary central nervous system lymphomas (PCNSL) are extranodal malignant non-Hodgkin lymphomas (NHL) that arise exclusively in central nervous system (CNS). Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype.Purpose: To evaluate whether nano drug-loading system-mediated magnetic-targeted thermochemotherapy could produce a better therapeutic effect than single chemotherapy while reducing the use of chemotherapeutic drugs.Methods: Six groups (control, Fe3O4, MTX, Fe3O4@MTX, Fe3O4 with hyperthermia and Fe3O4@MTX with hyperthermia) were set. Tumor cell apoptosis in each treatment group was detected by flow cytometry. Apoptosis-related gene expressions Caspase-3, Bax and Bcl-2 were detected by qPCR and Western blot; intracranial tumor model of PCNSL was established by intracranial injection of OCI-LY18 tumor cells into BALB/c-Nude mice. Magnetic resonance imaging (MRI) was used to monitor tumor progression and H&E staining was used to observe pathological changes of the tumor tissue.Results: In vitro, compared with chemotherapy alone, apoptosis rate of Fe3O4@MTX mediated thermochemotherapy group was significantly increased, and expression of apoptosis-inducing gene Caspase-3 and Bax were significantly upregulated in OCI-LY18 cells, while expression of apoptosis-inhibiting Bcl-2 gene was significantly downregulated. In vivo, MRI showed successful generation of intracranial tumor, and tumor volume was significantly smaller in combined thermochemotherapy group than in single chemotherapy group. H&E staining result of tumor tissues in each group was consistent with MRI; tumor cells were significantly reduced in thermochemotherapy group. Expression of apoptosis-related gene Caspase-3 and Bax were significantly upregulated in tumor tissues, while expression of Bcl-2 gene was significantly downregulated.Conclusion: These results demonstrated in vivo and in vitro that the combined thermochemotherapy of Fe3O4@MTX MNPs was superior to the single MTX chemotherapy with less dosage, which may promote apoptosis of DLBCL cells through the mitochondrial apoptotic pathway and provided a new way for the treatment of PCNSL.Keywords: primary central nervous lymphoma, PCNSL, Fe3O4@MTX magnetic nanoparticles, MNPs, hyperthermia, OCI-LY18 cells

Yingjian Song,1,* Huimin Liu,2,* Chunling Cui,3 Xiaonu Peng,1 Chaoyang Wang,1 Xudong Tian,4 Wenjun Li1 1Department of Thoracic Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, People’s Republic of China; 2Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, People’s Republic of China; 3Library, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, People’s Republic of China; 4Department of Thoracic Surgery, Liaocheng People’s Hospital, Liaocheng 252000, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xudong TianDepartment of Thoracic Surgery, Liaocheng People’s Hospital, No. 67, Changxi Road, Liaocheng, Shandong 252000, People’s Republic of ChinaTel +86-15653112705Email zhangding553977@126.comWenjun LiDepartment of Thoracic Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhungding East Road, Zhifu District, Yantai 264000, Shandong, People’s Republic of ChinaTel +86-18653525277Email liwenjun90808@163.comObjective: To study the effect of peroxiredoxin 1 (PRDX1) on esophageal squamous carcinoma cells and determine whether it plays a role in regulating the PI3K/AKT signaling pathway.Methods: Three esophageal squamous cell carcinoma cell lines (Eca-109, EC9706, and KYSE150) and one normal cell line (human esophageal epithelial cells) were selected. The protein expression of peroxiredoxin 1 (PRDX1) and the activity of the PI3K/AKT pathway were detected via Western blotting. The proliferation ability of cells was detected through the MTT assay and cell clone formation. Apoptosis was detected using flow cytometry. Subsequently, cells were treated with a PI3K/AKT pathway inhibitor and activator, alone or in combination with silencing of PRDX1, and the above indicators were re-tested.Results: The expression of PRDX1 and activity of PI3K/AKT pathway-associated proteins were higher in esophageal cancer cells than in normal esophageal epithelial cells. Compared with normal human esophageal epithelial cells, the proliferation of the three types of esophageal cancer cells was increased, whereas their level of apoptosis was decreased (p

Tian X, Zeng A, Liu Z, et al. Int J Nanomedicine. 2020;15:6519–6529. The authors have advised that there was an error in the Funding section on page 6528. Line 4, the text “(grant Q195026028)” should read “(grant 2019A1515011800)”. The authors apologize for this error. Read the original article

Background Adenosine is used to treat no‐reflow in the infarct‐related artery (IRA) during ST‐segment–elevation myocardial infarction intervention. However, the physiological effect of adenosine in the IRA is variable. Coronary steal—a reduction of blood flow to the distal coronary bed—can occur in response to adenosine and this is facilitated by collaterals. We investigated the effects of adenosine on coronary flow reserve (CFR) in patients presenting with ST‐segment–elevation myocardial infarction to better understand the physiological mechanism underpinning the variable response to adenosine. Methods and Results Pressure‐wire assessment of the IRA after percutaneous coronary intervention was performed in 93 patients presenting with ST‐segment–elevation myocardial infarction to calculate index of microvascular resistance, CFR, and collateral flow index by pressure. Modified collateral Rentrop grade to the IRA was recorded, as was microvascular obstruction by cardiac magnetic resonance imaging. Coronary steal (CFR 1.1) after adenosine occurred in 19 (20%), 15 (16%), and 59 (63%) patients, respectively. Patients with coronary steal had higher modified Rentrop score to the IRA (1 [0, 1.75] versus 0 [0, 1], P50%) in the donor arteries (52.63% versus 22.03%, P=0.02) than the hyperemic group. Conclusions Adenosine‐induced coronary steal may be responsible for a reduction in coronary flow reserve in a proportion of patients presenting with ST‐segment–elevation myocardial infarction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03145194. URL: https://www.isrctn.com; Unique identifier: ISRCTN3176727.

Xiaoqing Tian,1 YinFeng He,2 Zhe Han,3 HongMin Su,4 Chao Chu4 1Department of Orthopeadic Surgery, Heze Mudan People’s Hospital, Heze City, Shandong 274000, People’s Republic of China; 2Department of Joint Surgery, Heze Municipal Hospital, Heze City, Shandong 274000, People’s Republic of China; 3Department of Traumatic Surgery, Heze Municipal Hospital, Heze City, Shandong 274000, People’s Republic of China; 4Department of Spinal Surgery, Heze Municipal Hospital, Heze City, Shandong 274000, People’s Republic of ChinaCorrespondence: Chao ChuDepartment of Spinal Surgery, Heze Municipal Hospital, 2888 Caozhou West Road, Heze City, Shandong 274000 People’s Republic of ChinaEmail chaochuaaa@126.comBackground: To date, the impact and potential molecular mechanisms of CLDN12 and its association with malignancy in osteosarcoma have not been determined.Materials and methods: In the present study, the expression profiles of CLDN12 in osteosarcoma cell lines and tissues were explored by immunohistochemistry. A fetal osteoblast cell line was transfected with a eukaryotic expression plasmid, and endogenous CLDN12 in osteosarcoma cells were silenced through an RNA interference (RNAi) method. These transfections were verified, and the activation state of Thr308 site in protein kinase B (Akt) was explored by Western blotting. Moreover, the malignant phenotype of osteosarcoma cells was evaluated by cell counting kit-8 (CCK-8), colony formation, Transwell, and wound-healing assays. Furthermore, osteoblast cells were treated with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 to determine the impact of the PI3K/Akt signaling pathway on cell migration ability.Results: The results revealed that CLDN12 was overexpressed and localized in the cytoplasm of osteosarcoma cells, and its overexpression was associated with an unfavorable prognosis, irrespective of tumor node metastasis stage. In addition, the knockdown of CLDN12 in cultured osteosarcoma cells markedly attenuated cell proliferation and migration, as indicated by the Cell Counting Kit-8 assay, colony formation assay, scratch wound healing assay and Transwell migration assay. The results also demonstrated that the overexpression of CLDN12 increased the activation of Thr308 site in Akt in fetal osteoblast cells, and the PI3K inhibitor LY294002 partially decreased CLDN12-promoted proliferation and metastasis.Conclusion: In conclusion, the results of the present study indicated that CLDN12 promoted cell proliferation and migration through the PI3K/Akt signaling pathway in osteosarcoma cells, suggesting that CLDN12 may be a potential agent in the treatment of patients with osteosarcoma.Keywords: tight junction, claudin-12, osteosarcoma, metastasis, protein kinase B

Di Feng,1 Xiaoyu Yu,1 Xing Tian,2 Hongxue Meng,1 Yang Jiang,1 HongTao Song,1 WenQi Li,1 HaoCheng Zhang,3 Jingshu Geng1 1Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, People’s Republic of China; 2Department of Microbiology and Center of Infectious Disease, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150070, People’s Republic of ChinaCorrespondence: Jingshu GengDepartment of Pathology, Harbin Medical University Cancer Hospital, 7th Floor, Outpatient Building, Harbin, Heilongjiang 150081, People’s Republic of ChinaEmail gengjingshu@yeah.netPurpose: Metadherin (MTDH), as an oncogene, is associated with metastasis and poor prognosis. This study investigated MTDH expressions and development of gastric cancer (GC) cell phenotypes and the contribution of MTDH to epithelial–mesenchymal transition (EMT).Patients and methods: MTDH expression was assayed in human GC cell lines and tumor tissue from 92 GC patients. Functional experiments were performed to characterize MTDH activity. Expressions of EMT-related proteins (vimentin and E-cadherin), phosphorylated β-catenin and β-catenin were assayed by immunohistochemistry, Western blotting, immunofluorescence, and co-immunoprecipitation, respectively.Results: MTDH expressions were higher in GC tissue than that in gastric mucosa from the same patient. MTDH overexpression was correlated with metastasis and enhanced malignant GC phenotypes, i.e., proliferation, migration, invasiveness, and chemoresistance. MTDH overexpression was associated with expressions of vimentin, E-cadherin and cancer stem-cell biomarkers including CD44, CD133, and Oct4. MTDH complexed with β-catenin and decreased phosphorylated β-catenin levels to facilitate β-catenin translocation into the nucleus and expressions of downstream genes.Conclusion: MTDH overexpression in GC cells is associated with EMT and development of cancer stem cell malignant phenotypes and affects the subcellular translocation of β-catenin. The results warrant investigation of the prognostic value of MTDH in GC and as a therapeutic target.Keywords: metadherin, gastric cancer, CD44, β-catenin, cancer stem cells

Weiyan Cheng,1,2,* Suhua Wang,1,2,* Zhiheng Yang,1,2 Xin Tian,1,2 Yongzhou Hu31Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of China; 2Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; 3Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People’s Republic of ChinaCorrespondence: Xin TianDepartment of Pharmacy, The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Road, Zhengzhou 450052, People’s Republic of ChinaEmail tianx@zzu.edu.cnYongzhou HuZhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, People’s Republic of ChinaEmail huyz@zju.edu.cn*These authors contributed equally to this workPurpose: In order to get novel EGFR inhibitors exerting more potency in tumor hypoxia than in normoxia.Methods: A series of 4-[(2-nitroimidazole-1H-alkyloxyl)aniline]-quinazolines were designed and synthesized, and their in vitro cytotoxicity and EGFR inhibitory activity were evaluated. Molecule docking study was performed for the representative compound.Results: The structure-activity relationship (SAR) studies revealed that compounds bearing both meta-chloride and para-(2-nitroimidazole-1H-alkyloxy) groups on the aniline displayed potent inhibitory activities both in enzymatic and cellular levels. The most promising compound 16i potently inhibited EGFR with an IC50 value of 0.12 μM. Meanwhile, it manifested more potent cytotoxicity than the positive control lapatinib under tumor normoxia and hypoxia conditions (IC50 values of 1.59 and 1.09 μM against A549 cells, 2.46 and 1.35 μM against HT-29 cells, respectively). The proposed binding model of 16i in complex with EGFR was displayed by the docking results.Conclusion: This study provides insights for developing hypoxia-activated kinase inhibitors.Keywords: EGFR inhibitor, hypoxia, tumor, 4-anilinoquinazoline, 2-nitroimidazole

Can Cui,1 Xiaojing Cheng,2 Liang Yan,1 Huirong Ding,3 Xiaoya Guan,1 Wenlong Zhang,4 Xiuyun Tian,1 Chunyi Hao11Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Carcinoma Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 3Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Central Laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China; 4Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Laboratory Animal, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaBackground: Colorectal cancer (CRC) is one of the most prevalent gastrointestinal malignancies. The incidence of CRC has been rapidly increasing in China. Transferrin receptor 1 (TfR1) is a key regulator of cellular iron homeostasis. Several studies have demonstrated TfR1 overexpression in a variety of human tumors, but the association between TfR1 and CRC remains unclear.Methods: TfR1 expression was evaluated in six CRC cell lines and tumor tissues. A total of 201 CRC patients were included for immunohistochemistry and 19 pairs of frozen tissues were used for real-time PCR. Cell proliferation, cell cycle, cell migration and invasion, and in vivo carcinogenesis were tested after downregulation of TfR1 by lentivirus. Protein microarray and Western blot analyses were used to explore the underlying mechanisms of TfR1 in CRC.Results: TfR1 expression was higher in CRC tissues than in normal tissues (57.2% vs 22.9%, P＜0.001). TfR1 expression was obviously higher in CRC tissues with well differentiation (P＝0.008), no lymph node metastasis (P＝0.002), no distant metastasis (P＝0.006), no vascular invasion (P＜0.001) and early TNM stage (P＝0.013). CRC patients with TfR1-positive expression had a better survival than those with TfR1-negative expression (P＝0.044). Downregulation of TfR1 expression inhibited cell proliferation, promoted cells from G1 phase to S phase and facilitated cell migration and invasion. Knockdown of TfR1 also suppressed tumor growth in BALB/C-nu mice. Protein microarray and Western blot analyses showed that the Janus protein tyrosine kinase/signal transducer and activator of transcription pathway was activated along with downregulation of TfR1 expression.Conclusion: Though TfR1 was overexpressed in colorectal cancer tissues, there was evidence that downregulation of TfR1 could promote cancer progression.Keywords: colorectal cancer, transferrin receptor 1, tumor progression, JAK/STAT pathway

Xiaodong Tian, Yongsu Ma, Hongqiao Gao, Yan Zhuang, Yinmo YangDepartment of General Surgery, Peking University First Hospital, Beijing 100034, People’s Republic of ChinaBackground: Long lasting and unbearable abdominal pain is the most common symptom of chronic pancreatitis (CP). This study aimed to evaluate surgical options for the control of chronic pancreatic pain based on anatomical morphological changes.Methods: A retrospective review of patients who underwent surgery for treatment of chronic pancreatic pain in Peking University First Hospital between January 2000 and December 2017 was performed. The surgical options included modified Puestow procedure, Frey procedure, Beger procedure, pancreaticoduodenectomy (PD) or pylorus preserving pancreaticoduodenectomy (PPPD), distal pancreatectomy and total pancreatectomy.Results: Among 116 patients, pain relief rate after surgery was 82.6% (95/115) while 22 (23.2%) cases suffered recurrent chronic pancreatic pain during follow-up. Pain relief rate was 83.1% (54/65) after modified Puestow procedure, 63.6% (7/11) after distal pancreatectomy, 83.3% (10/12) after PD/PPPD, 86.7% (13/15) after Frey procedure, and 90% (9/10) after Beger procedure. Pain recurrence rate was 27.8% (15/54) after modified Puestow procedure, 42.9% (3/7) after distal pancreatectomy, 10% (1/10) after PD/PPPD, 15.4% (2/13) after Frey procedure, and 11.1% (1/9) after Beger procedure.Conclusion: The surgical options for the control of chronic pancreatic pain according to the anatomical morphological changes of CP is reasonable and effective. The procedure of distal pancreatectomy alone should be cautiously used for pain relief.Keywords: chronic pancreatitis, abdominal pain, surgical treatment, pathological anatomy

Xiaoyu Xu,1 Songcheng Yin,2,3 Hongling Guo,1 Mengxiong Li,1 Zhirong Qian,4 Xiaohui Tian,1 Tian Li11Department of Gynecology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, People’s Republic of China; 2Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, People’s Republic of China; 3Department of Surgical Oncology, First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 4Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, People’s Republic of ChinaBackground: The number of published randomized clinical trials (RCTs) using targeted maintenance therapy for newly diagnosed epithelial ovarian cancer is increasing. Our objective was to evaluate the comparative effectiveness of each maintenance therapy using a network meta-analysis.Materials and methods: A systematic search for RCTs was conducted using Medline, Embase, and CENTRAL databases followed by a Bayesian network meta-analysis. The primary outcome was progression-free survival (PFS) and the secondary outcome was overall survival (OS). Pooled hazard ratios (HRs) with 95% credible intervals (95% CrIs) were used to estimate outcomes.Results: A total of 11 RCTs involving 6631 patients were included. Network meta-analysis showed that pure maintenance therapy with pazopanib resulted in a significantly better PFS compared with placebo (HR, 0.77; 95% CrI, 0.65–0.92). Bevacizumab-throughout treatment was also associated with a better PFS (HR, 0.76, 95% CrI, 0.69–0.84). However, anti-CA-125 monoclonal antibodies (abagovomab and oregovomab) showed no significant survival benefit. Moreover, combined analysis showed that targeted-throughout was not significantly superior to pure targeted maintenance therapy for PFS and OS. Stratified analysis showed paralleled results with no significant difference between pazopanib pure maintenance and bevacizumab-throughout treatments.Conclusion: Our study showed a survival advantage conferred by pazopanib and bevacizumab as maintenance therapy in newly diagnosed epithelial ovarian cancer. Further clinical trials are essential to both determine the effect of bevacizumab in the maintenance stage and identify the specific subgroup(s) that benefit.Keywords: targeted treatment, maintenance therapy, ovarian cancer, network meta-analysis

Junxiu Cai,1,2,* Yan Zhang,3,* Rebiya Nuli,4 Yangyi Zhang,5 Manfutong Abudusemaiti,5 Aizhatiguli Kadeer,6 Xiaoli Tian,5 Hui Xiao5 1Department of Occupational and Environmental Health, School of Public Health, Xinjiang Medical University, Urumqi 830011, Xinjiang Uygur Autonomous Region, China; 2Medical Department, Fifth Affiliated Hospital, Xinjiang Medical University, Urumqi 830011, Xinjiang Uygur Autonomous Region, China; 3Department of Pathology, Basic Medical Science Institute, International Education College, Xinjiang Medical University, Urumqi 830011, Xinjiang Uygur Autonomous Region, China; 4Department of Human Parasitology, Basic Medical Science Institute, Xinjiang Medical University, Urumqi 830011, Xinjiang Uygur Autonomous Region, China; 5Department of Nutrition and Food Hygiene, School of Public Health, Xinjiang Medical University, Urumqi 830011, Xinjiang Uygur Autonomous Region, China; 6Department of Epidemiology and Statistics, School of Public Health, Xinjiang Medical University, Urumqi 830011, Xinjiang Uygur Autonomous Region, China *These authors contributed equally to this work Purpose: This study aimed to characterize dietary patterns in the Uyghur population and examined the relationship between dietary pattern, TCF7L2 single-nucleotide polymorphisms (SNPs), and the risk of type 2 diabetes mellitus (T2DM).Patients and methods: Dietary patterns were defined using factor analysis, and associations between dietary patterns were evaluated using multivariate logistic regression analyses. Genotyping of seven SNPs of TCF7L2 (rs11196205, rs12255372, rs12573128, rs4506565, rs7895340, rs7901695, and rs7903146) was conducted, and the association between these seven SNPs and the risk of T2DM was evaluated. Interactions between SNPs, homeostasis model assessment-insulin resistance, and dietary patterns were also analyzed.Results: A total of 828 participants were enrolled in this study, including 491 people with T2DM and 337 healthy controls. Five dietary patterns were defined, and the results indicated that the “fruit” and “vegetables” dietary patterns were associated with a significant decrease in the risk of T2DM, whereas the “meats” and “grains” dietary patterns were associated with an increased risk of T2DM. Moreover, the “dairy product” dietary pattern showed no association with the risk of T2DM. Furthermore, our results revealed that the TCF7L2 SNP, rs12573128, is associated with an increased risk of T2DM. SNPs rs4506565 and rs7903146 significantly interacted with dietary pattern.Conclusion: Our studies suggest that dietary pattern and genetic polymorphisms of TCF7L2 are associated with the development of T2DM in the Uyghur population of China. Keywords: type 2 diabetes mellitus, dietary patterns, TCF7L2, polymorphism, Uyghur

Nannan Gao,1 Chunhou Li,2 Jiadong Ji,3 Yanli Yang,1 Shaoting Wang,1 Xinlun Tian,1 Kai-Feng Xu1 1Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China; 2Office of Medical Insurance, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China; 3School of Statistics, Shandong University of Finance and Economics, Jinan, China Purpose: Evidence between air pollution and COPD admissions is inconsistent and limited in China. In this study, we aimed to explore the effects of air pollutants on COPD admissions in Beijing, China.Patients and methods: Daily COPD hospital admission visits derived from tertiary and secondary hospitals in Beijing were retrieved from January 2013 to February 2017. Air pollutant levels and meteorological data over the same periods were also achieved. Generalized additive model was applied to estimate the percentage changes with 95% CIs in daily admissions corresponding to 10 µg/m3 increases in pollutants levels [1 mg/m3 in carbon monoxide (CO)], stratified by age, gender, and season.Results: Seventy-three thousand seventy-six COPD hospital admission visits were included with mean daily visits of 48 (21). Cumulative lag effect with per 10 µg/m3 increase in air pollutant levels was largest for nitrogen dioxide (NO2) with 3.03% (95% CI: 1.82%–4.26%) at lag 06, for sulfur dioxide (SO2) with 2.07% (95% CI: 1.00%–3.15%) at lag 01, for particulate matter ≤10 µm in aerodynamic diameter (PM10) with 0.92% (95% CI: 0.55%–1.30%) at lag 07, and for particulate matter ≤2.5 µm in aerodynamic diameter (PM2.5) with 0.82% (95% CI: 0.38%–1.26%) at lag 06, respectively. Percentage increase for each 1 mg/m3 increase in CO was 5.99% (95% CI: 2.74%–9.34%) at lag 06. Further, stronger effects on COPD admissions were found in warm seasons than in cold seasons.Conclusion: Short-term exposures to PM2.5, PM10, NO2, SO2, and CO had adverse effects on COPD hospitalizations in Beijing with different magnitudes and lag days. Keywords: adverse effects, air pollution, COPD, time series analysis, hospital visits

Xiaolang Tian,* Shan Sun,* Xiaojiong Jia,* Hua Zou, Shuang Li, Liping Zhang Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China *These authors contributed equally to this work Purpose: Carbapenem-resistant Enterobacteriaceae (CRE) have been increasingly reported worldwide and pose a serious public threat, but the clinical significance of extended-spectrum β-lactamase (ESBL) production in CRE is not well established. Patients and methods: A retrospective case–case–control study was conducted to identify the clinical characteristics of patients with ESBL-CRE. The susceptibility of isolates obtained from these patients was assessed. The detection of ESBL and carbapenemase-related genes was performed by PCR methods. Predictors of 30-day mortality in patients with ESBL-CRE infection were also identified in our study. Results: A total of 149 patients with CRE infection caused by Enterobacter cloacae (n=74), Escherichia coli (n=38), and Klebsiella pneumoniae (n=37) were identified in Chongqing, Southwestern China, between January 2011 and December 2014. Of the 35 isolates detected with carbapenemase-related genes, 16 isolates had New Delhi metallo-β-lactamase (NDM), nine isolates had K. pneumoniae carbapenemase (KPC), seven isolates had imipenemase (IMP), and four isolates had oxacillinase (OXA)-1. One strain of enterobacter cloacae carried both NDM-1 and IMP-8 genes. ESBL isolates included the genes CTX-M (72/149), SHV (64/149), and TEM (54/149). All ESBL-CRE isolates exhibited ertapenem resistance, and the rate of cephalosporin resistance was relatively high in general. Independent risk factors for infection with ESBL-CRE included previous exposure to β-lactam antibiotics, transfer from another hospital, and some underlying diseases. In addition, solid tumors, hypoalbuminemia, and central venous catheters were independent predictors of mortality in patients with ESBL-CRE infection. Conclusion: Physicians should understand the peculiar predictors for the identification of these organisms among high-risk patients. Keywords: risk factors, carbapenem, resistance, ESBL, mortality

Shuang Dou,1 Chunyan Zheng,1 Liwei Cui,1 Mengshuang Xie,1 Wei Wang,1 Hui Tian,1 Kang Li,1 Kaidi Liu,1 Xinyu Tian,1 Xin Wang,1 Qun Zhang,1 Xin Ai,1 Junchao Che,1 Qixiao Liu,1 Haijun Li,2 Wei Xiao1 1Department of Pulmonary Medicine, Qilu Hospital, Shandong University, Jinan, People’s Republic of China; 2Department of Cadre Health Care, Qilu Hospital, Shandong University, Jinan, People’s Republic of China Background: COPD has been identified as an etiology or related disease of bronchiectasis, and bronchiectasis has been classified as a comorbidity of COPD. In this study, we investigated the prevalence of bronchiectasis in different phenotypes of COPD subjects and the correlation between bronchiectasis and different phenotypes, especially emphysema. Methods: COPD patients were recruited from April 2012 to December 2015. The presence of bronchiectasis and related information were statistically analyzed. COPD subjects were separated into subgroups in two ways: COPD with and without bronchiectasis groups and emphysema-predominant (emphysema index, EI≥9.9%) and non-emphysema-predominant (EI

Lei Luo,1 Hong Zhong,1 Shuang Liu,1 Lidong Deng,1 Yonghuang Luo,1 Qiong Zhang,2 Yingzhong Zhu,2 Yupeng Tian,2 Yuan Sun,3 Xiaohe Tian4 1College of Pharmaceutical Sciences, Southwest University, Chongqing, People’s Republic of China; 2Department of Chemistry, Key Laboratory of Functional Inorganic Material Chemistry of Anhui Province, Anhui University, Hefei, People’s Republic of China; 3Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA; 4School of Life Science, Anhui University, Hefei, People’s Republic of China Abstract: The application of photodynamic therapy (PDT) for the diagnosis and treatment of cancer is hindered by the intrinsic defects of the currently available photosensitizers (PSs), such as poor water solubility and limited light-penetration depth. In this study, pH-responsive polymeric micelles that co-encapsulate therapeutic PSs and organooxotin two-photon compounds were applied for two-photon PDT (TP-PDT) against breast cancer. The TP-PDT effect of the drug-loaded micelles was “activated” when the micelles turned into aggregates at a triggering pH level. The in vitro therapeutic effect was evaluated on 4T1 murine breast cancer cells by viability assays, real-time morphology collapsing, and reactive oxygen species determination. Time-dependent ex vivo organ distribution and in vivo anticancer efficacy results suggested that the drug carriers could accumulate in tumors and suppress tumor growth by TP-PDT. The delivery system could enhance the solubility and distribution of PSs and, if administered along with a tissue-penetrating prolonged light source, could thus have good potential for cancer therapy. Keywords: photodynamic therapy, two-photon absorbance, drug delivery, pH responsiveness, cancer therapy

Mutian Lv,1 Yaming Li,1 Xin Tian,2 Shundong Dai,3,4 Jing Sun,5 Guojiang Jin,6 Shenyi Jiang7 1Department of Nuclear Medicine, 2Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated Hospital of China Medical University, 3Department of Pathology, The First Affiliated Hospital, College of Basic Medical Sciences of China Medical University, 4Department of Pathology, Institute of Pathology and Pathophysiology, 5Department of Immunology and Biotherapy, Liaoning Cancer Hospital and Institute, 6Department of Laboratory Medicine, 7Department of Rheumatology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China Abstract: Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, has been recognized as a critical regulator of various cancers. In this study, we investigated the role of NLK in human small-cell lung cancer (SCLC), which is the most aggressive form of lung cancer. NLK expression was evaluated by quantitative real-time polymerase chain reaction in 20 paired fresh SCLC tissue samples and found to be noticeably elevated in tumor tissues. Lentivirus-mediated RNAi efficiently suppressed NLK expression in NCI-H446 cells, resulting in a significant reduction in cell viability and proliferation in vitro. Moreover, knockdown of NLK led to cell cycle arrest at the S-phase via suppression of Cyclin A, CDK2, and CDC25A, which could contribute to cell growth inhibition. Furthermore, knockdown of NLK decreased the migration of NCI-H446 cells and downregulated matrix metalloproteinase 9. Treatment with NLK short hairpin RNA significantly reduced SCLC tumor growth in vivo. In conclusion, this study suggests that NLK plays an important role in the growth and metastasis of SCLC and may serve as a potential therapeutic target for the treatment of SCLC. Keywords: NLK, SCLC, RNAi, proliferation, migration

Jia-run Yang, Dong Han, Zheng-xue Qiao, Xue Tian, Dong Qi, Xiao-hui QiuDepartment of Medical Psychology, Public Health Institute of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of ChinaObjectives: Previous randomized controlled trials (RCTs) suggest that depression can be effectively treated by omega-3 polyunsaturated fatty acids (PUFAs). Therefore, we conducted this meta-analysis to systematically evaluate the clinical applicability of the combination of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are the two major bioactive types of PUFAs, in depressed women.Methods: RCTs that compared the combination of DHA and EPA to placebo for short-course treatment of depression in women were systematically reviewed up to March 2015. Outcome measurement was the standardized difference in means in clinical measure of depression severity. Random effect model was performed. Meta-regression analysis was performed to assess the effects of baseline depression scores.Results: Data were obtained from eight RCTs. In these RCTs, 182 patients received placebo and 185 patients received DHA and EPA. The pooled standardized difference in mean was 0.65 with 95% CI = [0.18, 1.12]. There was no relation between the efficacy and the baseline depression scores. The sensitivity analysis found that the combination of EPA and DHA as monotherapy yielded a standardized difference in means of 0.65 (95% CI =0.41, 0.90) without heterogeneity.Discussion: These results indicate a beneficial effect of the combination of EPA and DHA on depressed mood in women compared with placebo. The clinical applicability of EPA and DHA showed greater promise and should be further explored.Keywords: depression, omega-3 polyunsaturated fatty acids, PUFAs, docosahexaenoic acid, DHA, eicosapentaenoic acid, EPA

Xin Tian,1 Ying Dai,1 Da-qing Wang,2 Li Zhang,1 Cheng-guang Sui,1 Fan-dong Meng,1 Shen-yi Jiang,1 Yun-peng Liu,1 You-hong Jiang1 1Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang, 2Health and Family Planning Commission of Liaoning Province, People’s Republic of China Background: A number of cohort studies have compared the outcomes of transarterial chemoembolization (TACE) and hepatic resection (HR) in the treatment of hepatocellular carcinoma (HCC). However, the effect of TACE versus HR remains controversial. Therefore, we conducted a meta-analysis to assess the effectiveness of TACE and HR in HCC treatment.Materials and methods: PubMed, Embase, Web of Science, Scopus, ClinicalTrials.gov, and Cochrane library were searched from their inception until February 27, 2015 for relevant studies. The literature search was updated on May 25, 2015. Eligible studies were cohort studies comparing the survival outcomes between HCC patients undergoing TACE and HR. The primary outcome was overall survival (OS). Secondary outcomes were the recurrence rate and prognostic factors for OS. The risk ratio (RR) was used for the meta-analysis and was expressed with 95% confidence intervals (CIs).Results: This meta-analysis included eleven cohort studies with 6,297 patients, all treated with TACE or HR. Pooled estimates showed that, compared with TACE, HR significantly improved the 3-year OS (RR =0.77; 95% CI, 0.63–0.93; P=0.009). TACE and HR had similar effects on OS after 1 year (RR =0.94; 95% CI, 0.86–1.01; P=0.103), 2 years (RR =0.50; 95% CI, 0.21–1.19; P=0.114), 4 years (RR =0.61; 95% CI, 0.58–1.10; P=0.174), and 5 years (RR =0.77; 95% CI, 0.59–1.01; P=0.06). There was no significant difference between the 3-year (RR =1.31; 95% CI, 0.65–2.64; P=0.457) and 5-year recurrence rates (RR =1.14; 95% CI, 0.69–1.89; P=0.597) in the TACE and HR groups. Age (>65 vs ≤65 years; hazard ratio =0.99; 95% CI, 0.98–1.00; P=0.000), sex (male vs female; hazard ratio =0.79; 95% CI, 0.65–0.96; P=0.02), treatment method (TACE vs HR; hazard ratio =1.90; 95% CI, 1.46–2.46; P=0.000), and Eastern Cooperative Oncology Group performance score (≥1 vs 0; hazard ratio =1.69; 95% CI, 1.22–2.33; P=0.002) were independent predictors for OS.Conclusion: This meta-analysis suggests that the TACE and HR likely have similar effects in the treatment of HCC patients in terms of OS and recurrence rate. However, this conclusion should be interpreted cautiously due to the presence of further subgroup analyses with respect to outcomes in patients with different liver statuses (Barcelona Clinic Liver Cancer stage A or stage B). Keywords: transarterial chemoembolization, hepatic resection, hepatocellular carcinoma, meta-analysis

Yingying Shen,1,2,* Yuanzhi Shao,3,* Haoqiang He,1 Yunpu Tan,4 Xiumei Tian,2 Fukang Xie,2 Li Li11Imaging Diagnostic and Interventional Center, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; 2Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China; 3Key Laboratory of Optoelectronic Materials and Technologies, School of Physics and Engineering, Sun Yat-sen University, Guangzhou, Guangdong, China; 4Department of Gastrointestinal Surgery, Sun Yat-sen University, Guangzhou, Guangdong, China *These authors contributed equally to this workAbstract: We investigated the tracking potential of a magnetic resonance imaging (MRI) probe made of gadolinium-doped mesoporous silica MCM-41 (Gd2O3@MCM-41) nanoparticles for transplanted bone mesenchymal stem cells (MSCs) and neural stem cells (NSCs) in vivo. The nanoparticles, synthesized using a one-step synthetic method, possess hexagonal mesoporous structures with appropriate assembly of nanoscale Gd2O3 clusters. They show little cytotoxicity against proliferation and have a lower effect on the inherent differentiation potential of these labeled stem cells. The tracking of labeled NSCs in murine brains was dynamically determined with a clinical 3T MRI system for at least 14 days. The migration of labeled NSCs identified by MRI corresponded to the results of immunofluorescence imaging. Our study confirms that Gd2O3@MCM-41 particles can serve as an ideal vector for long-term MRI tracking of MSCs and NSCs in vivo.Keywords: nanoparticles, gadolinium, magnetic resonance imaging, stem cells

Xiang Li1, Xin Tian2, Jing Zhang3, Xu Zhao1, Xiaohui Chen1, Youhong Jiang2, Dongkai Wang1, Weisan Pan11Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang; 2The Second Laboratory of Cancer Research Institution, The First Hospital of China Medical University, Shenyang; 3Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, ChinaBackground: The purpose of this study was to develop folate-poly (PEG-cyanoacrylate-co-cholesteryl cyanoacrylate) (FA-PEG-PCHL)-modified freeze-dried liposomes for targeted chemotherapy using docetaxel as a model drug.Methods: FA-PEG-PCHL was synthesized and its cytotoxicity was evaluated by CCK-8 assay in L929. Docetaxel-loaded liposomes modified by FA-PEG-PCHL were prepared by an organic solvent injection method and lyophilized to obtain freeze-dried FA-PEG-PCHL-docetaxel liposomes (FA-PDCT-L). Two carcinoma cell lines (MCF-7 and A-549 cells) were cultured with docetaxel solution, conventional docetaxel-loaded liposomes, or FA-PDCT-L, and the cytotoxicity and apoptosis was evaluated for each preparation. The uptake of the docetaxel preparations into MCF-7 cells was studied by confocal laser scanning microscopy. Liquid chromatography-mass spectrometry was used to study the pharmacokinetics and tissue distribution characteristics of the preparations.Results: The existence of an enlarged fixed aqueous layer on the surface of the liposomes was affirmed by zeta potential analysis. The entrapment efficiency and particle size distribution were almost the same as those of docetaxel-loaded liposomes. The drug release profile showed that the release rate was faster at higher molecular weight of the polymer. Compared with docetaxel solution and docetaxel-loaded liposomes, FA-PDCT-L demonstrated the strongest cytotoxicity against two carcinoma cell lines, the greatest intracellular uptake especially in the nucleus, as well as the most powerful apoptotic efficacy. In pharmacokinetic studies, the area under the plasma concentration-time curve of FA-PDCT-L was increased 3.82 and 6.23 times in comparison with the values for the docetaxel-loaded liposomes and docetaxel solution, respectively. Meanwhile, a lower concentration of docetaxel was observed for FA-PDCT-L in the liver and spleen, and a significantly higher concentration of FA-PDCT-L in tumors suggested that the presence of FA-PEG-PCHL on the liposomes resulted in greater accumulation of the drug in tumor tissue.Conclusion: Liposomes modified by FA-PEG-PCHL could be one of the promising suspensions for the delivery of antitumor drugs in cancer.Keywords: folate-poly (PEG-cyanoacrylate-co-cholesteryl cyanoacrylate), docetaxel, freeze-dried liposomes, tumor targeting

Tahirou Talba1, Xia Wen Shui1, Qinyuan Cheng1,2, Xin Tian21Key Laboratory of Food Processing Technology, 2School of Medicine and Pharmaceutics, Jiangnan University, Wuxi, Jiangsu, People's Republic of ChinaBackground: The purpose of this study was to assess the in vivo ability of glucosaminic acid-cobalt (II) chelate to reduce glycemia.Methods: Different concentrations of chelate solution were administrated to mice with diabetes induced by streptozotocin. Daily oral administration of chelate solution 0.4 mL at various concentrations (0.32–0.4 g/mL) led to reduction in water intake by the diabetic mice after 5 days of treatment, with a subsequent reduction in glucose levels observed 2 weeks later. Daily food intake was related to both chelate concentration as well as glycemia reduction. The food intake of mice treated with glucosaminic acid-cobalt (II) chelate solution was 1.5-fold that of untreated mice.Keywords: glucosaminic acid, cobalt, chelate, streptozotocin, glycemia reduction