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Yi Zheng,1 Pan-Pan Ye,2 Yue Zhou,1 Su-Ying Wu,3 Xi-Ting Liu,1 Bin Du,1 Bo-Hao Tang,1 Min Kan,1 Ai-Qing Nie,1 Rui Yin,1 Meng Wang,1 Guo-Xiang Hao,1 Lin-Lin Song,2 Xin-Mei Yang,2 Xin Huang,2 Le-Qun Su,2 Wen-Qi Wang,2 John van den Anker,4– 6 Wei Zhao1,2 1Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China; 2Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, 250014, People’s Republic of China; 3Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 4Division of Clinical Pharmacology, Children’s National Hospital, Washington, DC, USA; 5Departments of Pediatrics, Pharmacology & Physiology, Genomics & Precision Medicine, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA; 6Department of Paediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel, University of Basel, Basel, SwitzerlandCorrespondence: Wei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of ChinaEmail zhao4wei2@hotmail.comPurpose: Inflammation has a significant impact on CYP3A activity. We hypothesized that this effect might be age dependent. Our objective was to conduct a population pharmacokinetic study of midazolam in mice at different developmental stages with varying degrees of inflammation to verify our hypothesis.Methods: Different doses (2 and 5 mg/kg) of lipopolysaccharide (LPS) were used to induce different degrees of systemic inflammation in Swiss mice (postnatal age 9– 42 days, n = 220). The CYP3A substrate midazolam was selected as the pharmacological probe to study CYP3A activity. Postnatal age, current body weight, serum amyloid A protein 1 (SAA1) levels and LPS doses were collected as covariates to perform a population pharmacokinetic analysis using NONMEM 7.2.Results: A population pharmacokinetic model of midazolam in juvenile and adult mice was established. Postnatal age and current body weight were the most significant and positive covariates for clearance and volume of distribution. LPS dosage was the most significant and negative covariate for clearance. LPS dosage can significantly reduce the clearance of midazolam by 21.8% and 38.7% with 2 mg/kg and 5 mg/kg, respectively. Moreover, the magnitude of the reduction was higher in mice with advancing postnatal age.Conclusion: Both inflammation and ontogeny have an essential role in CYP3A activity in mice. The effect of LPS-induced systemic inflammation on midazolam clearance in mice is dependent on postnatal age.Keywords: CYP3A activity, ontogeny, inflammation, pharmacokinetic, mice

Wenjun Zhao,1 Gang Wang,2 Ping Xu,3 Tingting Wu,3 Binjuan Chen,3 Haijun Ren,2 Xingjie Li1 1Department of Ultrasound, Imaging, Healthy Management Centre, The Second Hospital of Lanzhou University, Lanzhou City, 730000, Gansu Province, People’s Republic of China; 2Department of Neurosurgeon, Neurology, Neurologist, The Second Hospital of Lanzhou University, Lanzhou City, 730000, Gansu Province, People’s Republic of China; 3Department of Ultrasound, Imaging, Ultrasound Centre, The Second Hospital of Lanzhou University, Lanzhou City, 730000, Gansu Province, People’s Republic of ChinaCorrespondence: Xingjie LiDepartment of Ultrasound, Imaging, Healthy Management Centre, The Second Hospital of Lanzhou University, Landa 2 Yard, No. 82, Cuiying Gate, Chengguan District, Lanzhou City, 730000, Gansu Province, People’s Republic of ChinaTel +86-9318942555; +86-13609337887Email LiXingjie723723@163.comObjective: To determine the risk factors associated with the progress of subaneurysmal aorta (SAA) to abdominal aortic aneurysm (AAA) and provide a reference for the prevention of AAA in rural areas.Methods: A total of 747 SAA patients screened by the Health Management Center of the Second Hospital of Lanzhou University from January 2015 to January 2016 were recruited. The ratio of SAA progressing to AAA was observed through 5 years of follow-up. Logistic stepwise regression analysis was performed to analyze the high-risk factors. The relevant clinical prediction model score table (Nom) was made and the C-index and calibration chart were used to verify the prediction ability of the model.Results: Of the 747 patients diagnosed with SAA, 260 developed to AAA, with an incidence of 34.8%. Univariate analysis showed that age (62– 65 years old), abdominal aorta diameter greater than 2.7 cm, smoking after 30 years old, moderate to severe hypertension, and blood pressure variability were the important high-risk factors of SAA progressing to AAA. Logistic regression analysis showed that these factors were statistically significant. The nomogram of clinical prediction model score showed that when 50– 60% of SAA developed to AAA, the score was 189– 201 and the C-index was 0.883, verifying the moderate predictive ability of this model.Conclusion: Age, smoking habit, degree of hypertension, and control situation were high-risk factors associated with the progression of SAA to AAA. The control of the above high-risk factors was imperative for the prevention of AAA in rural areas without sufficient medical resources.Keywords: abdominal aortic aneurysm, high-risk factors, abdominal aorta dilation, rural areas

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

Haibo Zhang, Wei Zhao Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital, Shijiazhuang, People’s Republic of ChinaCorrespondence: Haibo Zhang Email zhb840211@163.comObjective: Epithelial ovarian cancer (EOC) is one of the leading causes of death worldwide. The aim of this study was to explore the prognostic significance of prolyl-4-hydroxylase α subunit 2 (P4HA2) in patients with EOC.Patients and Methods: A total of 217 clinical samples (EOC tissues, 167 cases; normal ovarian, 50 cases) were collected and pathologically confirmed using hematoxylin and eosin (H&E) staining. P4HA2 expression in clinical samples was stained by immunohistochemistry (IHC). Relationship between P4HA2 expression and clinicopathological characteristics of EOC patients were analyzed using chi-square test. The differential expression of targets was analyzed in Oncomine database. The prognostic value of P4HA2 was investigated in clinical EOC patients and Kaplan–Meier (KM) Plotter database.Results: IHC staining showed that P4HA2 was significantly up-regulated in EOC tissues, compared to the normal tissues. Two databases retrieved from Oncomine database further confirmed the up-regulation P4HA2 in EOC. Chi-square test demonstrated that P4HA2 expression was associated with clinical stage (p=0.036), tumor grade (p< 0.001), and residual disease (p=0.022). Both in clinical samples and KM Plotter database, high P4HA2 expression was significantly associated with worse progression-free survival (PFS) and overall survival (OS). Cox’s proportional hazards regression analysis suggested that high P4HA2 expression were independent risk factors for the survival of EOC patients. Besides, we confirmed the positive correlation between P4HA2 and COL1A1 expression. Moreover, COL1A1 was found to be up-regulated in EOC and also associated with short PFS and OS.Conclusion: The present study preliminarily proved that P4HA2 expression was associated with clinical outcome in EOC patients. P4HA2 might be a prognostic factor for EOC progression, and has the potential to be a valuable therapeutic target for EOC.Keywords: P4HA2, prognosis, epithelial ovarian cancer, extracellular matrix, collagen

Huixian Zhang,1– 3 Wencheng Zhao,1,2 Xingya Li,3 Yayi He1,2 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 2Tongji University, Shanghai, 200433, People’s Republic of China; 3Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, 450052, People’s Republic of ChinaCorrespondence: Yayi HeDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of ChinaTel +86-13818828623Email 2250601@qq.comXingya LiDepartment of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, 450052 Tel +86-13838253946Email fcclixy1@zzu.edu.cnAbstract: Checkpoint-based immunotherapies, such as programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors, have shown promising clinical outcomes in many types of cancers. Unfortunately, the response rate of immune checkpoint inhibitors is low. It is very important to discover novel therapeutic targets and prognostic biomarkers. Cholesterol metabolism has been demonstrated to be related to the occurrence and development of a variety of tumors and may provide a new breakthrough in the development of immunotherapy. First of all, cholesterol metabolism in the tumor microenvironment affects the function of tumor-infiltrating immune cells. In addition, intracellular cholesterol homeostasis is an important regulator of immune cell function. Furthermore, drugs that act on cholesterol metabolism affect the efficacy of immunotherapy. What is more, peripheral blood cholesterol level can be a biomarker to predict the efficacy of immunotherapy. In this review, we aimed to explore the potential role of cholesterol metabolism on immunotherapy. By summarizing the major findings of recent preclinical and clinical studies on cholesterol metabolism in immunotherapy, we suggested that cholesterol metabolism could be a potential therapeutic target and a prognostic biomarker for immunotherapy.Keywords: cholesterol metabolism, immunotherapy, immune cell, therapeutic target, biomarker

Hao Wang,1,2 Shanhao Chen,1 Die Meng,1,2 Chunyan Wu,3 Junjie Zhu,4 Minlin Jiang,1,2 Jing Ning,1,2 Shengyu Wu,1,2 Lijia Wu,5 Jingjie Li,5 Bin Chen,1 Sha Zhao,1 Wei Li,1 Jia Yu,1,2 Qiyu Fang,1,2 Jun Zhu,1,2 Wencheng Zhao,1,2 Yayi He,1 Caicun Zhou1 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 2Medical School, Tongji University, Shanghai, 200433, People’s Republic of China; 3Pathology Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 4Surgery Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 5Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, 214104, People’s Republic of ChinaCorrespondence: Yayi He; Caicun ZhouDepartment of Medical Oncology, Shanghai Pulmonary Hospital, No. 507 Zhengmin Road, Shanghai, People’s Republic of ChinaTel +86 13818828623; Tel +86 13818828623Email 2250601@qq.com; caicunzhoudr@126.comIntroduction: Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR-mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies.Methods: We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics.Results: The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (P=0.026), gender (P=0.041) and EGFR mutation status (P=0.015), and in EGFR-mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2. Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (P=0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes.Conclusion: Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR-mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.Keywords: lung adenocarcinoma, EGFR mutation, tumor mutation burden, immune phenotype, immune checkpoint blockade

Qingpeng Song,1,* Bin Zhu,2,* Wenkui Zhao,3,* Chen Liang,3 Bao Hai,1 Xiaoguang Liu1 1Department of Orthopaedics, Peking University Third Hospital, Beijing, People’s Republic of China; 2Department of Orthopaedics, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Pain Medicine Center, Peking University Third Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoguang LiuDepartment of Orthopedics, Peking University Third Hospital, Beijing, People’s Republic of ChinaEmail liuxgspine@126.comPurpose: Compare the efficacy of full-endoscopic lumbar decompression surgery (FELDS) and open decompression and fusion surgery (ODFS) for lumbar spinal stenosis (LSS).Patients and Methods: A retrospective analysis of 358 LSS patients treated by FELDS (“FELD” group) or ODFS (“open” group) was undertaken. There were 177 patients in the FELDS group with a mean age of 65.47± 9.26 years and 181 patients in the open group with a mean age of 64.18± 10.24 years. Duration of follow-up was 38.63± 11.88 months in the FELDS group and 38.56± 12.29 months in the open group. Visual analog scale (VAS) score, Oswestry Disability Index (ODI), and Modified MacNab criteria were used to access clinical outcomes. Surgical outcomes (duration of surgical procedure, blood loss, complications, duration of postoperative hospital stay (DOPHS), prevalence of revision procedures) were evaluated. Magnetic resonance imaging was used to evaluate the change in the Pfirrmann grade at adjacent segments.Results: VAS score (leg and back) and ODI improved significantly in both groups (P< 0.001). Success rate reached 86.55% and 90.60% in the FELDS group and open group (P> 0.05), respectively. Procedure duration (84.12 vs 112.08 min), blood loss (7.97 vs 279.67 mL), and DOPHS (2.68 vs 4.78 days) of the FELDS group were significantly better than those of the open group (P< 0.05). Total prevalence of complications and procedure revisions was 14.69% and 10.73% in the FELD group, respectively, but did not show a significant difference with that in the open group (12.15% and 9.39%, respectively). The Pfirrmann grade increased in 13.04% of adjacent segments in the FELDS group, significantly better than that in the open group (32.67%) (P< 0.05).Conclusion: FELDS had the same efficacy as ODFS for LSS treatment. FELDS had the advantages of minimal invasiveness, less surgical trauma, rapid recovery, and lower risk of degeneration of adjacent segments compared with that of ODFS.Keywords: lumbar spinal stenosis, full-endoscopic lumbar decompression, fusion, clinical outcome, adjacent segments degeneration

Xiangqian Guan, Yuyan Lu, Heping Zhu, Shuqi Yu, Wenxiu Zhao, Xiaoqin Chi, Chengrong Xie, Zhenyu Yin Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, People’s Republic of ChinaCorrespondence: Chengrong Xie; Zhenyu YinDepartment of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, 209 South Hubin Road, Xiamen, Fujian Province, 361004, People’s Republic of ChinaEmail eason_xiecr@126.com; yinzy@xmu.edu.cnBackground: Emerging evidences have highlighted the roles of neutrophils, as the major host microenvironment component, in the development of hepatocellular carcinoma (HCC). Neutrophils extracellular traps (NETs) produced in the infection can strengthen the behavior of cancer metastasis. Here, we investigated the roles of NETs in HCC metastasis and further explore the underlying mechanism of how NETs interact with cancer.Methods: The neutrophils were isolated from whole blood of HCC patients and used to evaluate the formation of NETs. NET markers were detected in tissue samples, plasma and cell climbing slice. Mouse models were used to evaluate the roles of NETs in HCC metastasis in vivo, and the corresponding mechanisms were explored using in vivo and in vitro assays.Results: An increase in the release of NETs in patients with HCC, particularly those with portal vein tumor thrombosis (PVTT). The presence of NETs in HCC tumor tissues closely correlated with a poor prognosis. Functionally, the invasion ability of HCC cells was enhanced by co-culture with HCC neutrophils, through NETs formation, while the neutrophils from a healthy donor (HD) exhibited the inhibition of the invasion ability. Furthermore, we observed an enhanced ability of forming NETs in neutrophils from HCC patients in vitro, especially patients with PVTT or extra-hepatic metastasis. An in-vivo animal study demonstrated that neutrophils of HCC facilitated the metastatic behavior towards the lung. The further mechanistic investigation unveiled that HCC cells-derived cytokine IL-8 triggered NETs formation in an NADPH oxidase-dependent manner, and NETs-associated cathepsin G (cG) promoted HCC metastasis in vitro as well as vivo. Clinically, the expression of the cG protein in tumor tissues displayed a close correlation with the disease prognosis of HCC patients.Conclusion: Our findings implicated that the induction of NETs by HCC cells is a critical metastasis-supporting cancer–host interaction and that NETs may serve as an immune-based potential therapeutic target against HCC progression.Keywords: hepatocellular carcinoma, neutrophils extracellular traps, cathepsin G, IL-8, E-cadherin, metastasis, NADPH

Yue Zhou,1 Ai-Qing Nie,1 Shang Chen,2 Meng-Meng Wang,1 Rui Yin,1 Bo-Hao Tang,1 Yue-E Wu,1 Fan Yang,1 Bin Du,1 Hai-Yan Shi,3 Xin-Mei Yang,3 Guo-Xiang Hao,1 Xiu-Li Guo,4 Qiu-Ju Han,5 Yi Zheng,1,* Wei Zhao1,3,* 1Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Institute of Biochemical and Biotechnological Drug, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China; 4Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 5Institute of Immunopharmaceutical Sciences, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Zheng; Wei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, No. 44, Wenhua West Road, Jinan, Shandong Province, People’s Republic of ChinaTel/Fax +86 531 8838 3308Email zhengyi@sdu.edu.cn; zhao4wei2@hotmail.comPurpose: Considering prior investigations on reductions of renal multidrug resistance-associated protein (MRP) 2 and 4 transporters in mice with acute lymphoblastic leukemia (ALL), we sought to characterize the underlying mechanisms responsible for IL-6/STAT3/PXR-mediated changes in the expression of MRP2 and MRP4 in ALL.Subjects and Methods: ALL xenograft models were established and intravenously injected with methotrexate (MTX) of MRPs substrate in NOD/SCID mice. Protein expression of MRPs and associated mechanisms were detected by Western blotting and immunocytochemistry. Plasma concentrations of MTX were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).Results: Plasma IL-6 levels in patients with newly diagnosed ALL were increased compared to children with pneumonia. Similarly, plasma IL-6 levels in ALL, ALL-tocilizumab (TCZ, an IL-6 receptor inhibitor) and ALL-S3I-201 (a selective inhibitor of STAT3) mice were increased compared to the control group. The MRP2, MRP4, and PXR expression in HK-2 cells treated with IL-6 were decreased, whereas the p-STAT3 expression was significantly increased compared to the control group results. These results are consistent with clearance of MRPs-mediated MTX in the ALL group. These effects were attenuated by blocking IL-6/STAT3/PXR signaling pathway.Conclusion: Inflammation-mediated changes in pharmacokinetics are thought to be executed through pathways IL-6-activated pathways, which can facilitate a better understanding of the potential for the use of IL-6 to predict the severity of adverse outcomes and the major implications on potential ALL treatments.Keywords: disease-induced pharmacokinetic change, renal transporters, inflammatory cytokines, clearance

Li Zhang,1,* Xin-Mei Yang,2,* Jing Chen,3 Lei Hu,4 Fan Yang,5 Yue Zhou,5 Bei-Bei Zhao,1 Wei Zhao,2,5,* Xiao-Fan Zhu1,* 1Department of Pediatric, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, People’s Republic of China; 2Department of Clinical Pharmacy, Clinical Trial Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People’s Republic of China; 3Pediatric Hematology & Oncology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Tianjin Institute of Pharmaceutical Research (TIPR), Tianjin, People’s Republic of China; 5Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Fan ZhuDepartment of Pediatric, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People’s Republic of ChinaTel/Fax +86 22 2390 9001Email xfzhu@ihcams.ac.cnWei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, No. 44, Wenhua West Road, Jinan, Shandong Province, People’s Republic of ChinaTel/Fax +86 531 8838 3308Email zhao4wei2@hotmail.comBackground: An oral tetra-arsenic tetra-sulfide (AS4S4) formula has been recommended as an outpatient post-remission treatment for Chinese adults with acute promyelocytic leukemia (APL) but limited data are available for children. In this exploratory study, we aimed to evaluate the pharmacokinetics and safety of the AS4S4 formula in children.Methods: Eleven newly diagnosed and one relapsed pediatric patient (4– 14 years of age) treated with the AS4S4 formula were included. Blood samples were collected from 12 children, and drug concentrations were quantified by ICP-MS. Population pharmacokinetic analysis and Monte-Carlo simulation were performed using NONMEM software. Toxic effects were graded according to the NCI-CTCAE, Version 3.Results: A total of 107 arsenic concentrations (0.1– 75.0 μg L− 1) were used for population pharmacokinetic analysis. The median (range) of estimated weight-normalized CL and volume distribution at steady-state were 45.26 (35.63– 82.18) L h− 1 kg− 1 and 230.37 (85.96– 495.68) L kg− 1, respectively. No patients discontinued AS4S4 treatment owing to adverse events, and there were no drug-related adverse events over grades 3– 4. All newly diagnosed APL patients were in MCR with a median follow-up of 28 months (range, 23 to 37 months). Both the estimated 3-year EFS and OS rates were 100%.Conclusion: The pharmacokinetics and safety oral AS4S4 formula was evaluated for the first time in pediatric APL. The pharmacokinetic assessment demonstrated that the dosing regimen of 60 mg/kg/d TID resulted in a higher steady-state through concentration in children than that which was achieved in adults. The results of this study indicate that the AS4S4 formula is safe in newly diagnosed pediatric APL patients.Keywords: acute promyelocytic leukemia, Realgar-Indigo Naturalis Formula, pediatric, safety, population pharmacokinetics

Xin Jiang,1,* Wenqi Zhao,1,* Tiantian Zhao,2,* Mei Yang,1 Hongbin Yuan,1 Jun Qian,2 Zhenghua Xiang3 1Department of Anesthesiology, Changzheng Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of General Surgery, Affiliated Xinchang Hospital of Shaoxing University, Zhejiang, People’s Republic of China; 3Department of Neurobiology, Key Laboratory of Molecular Neurobiology, Ministry of Education, Naval Medical University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenghua XiangDepartment of Neurobiology, Key Laboratory of Molecular Neurobiology, Ministry of Education, Naval Medical University, No. 800 Xiangyin Road, Shanghai, 200433, People’s Republic of ChinaTel +86 21 81871044Fax +86 21 81885822Email xiang-zhenghua@163.comJun QianDepartment of General Surgery, Affiliated Xinchang Hospital of Shaoxing University, No. 117 Middle Gushan Road, Xinchang, Zhejiang, 312500, People’s Republic of ChinaTel +86 575 8638079Email qianj001@163.comPurpose: To detect the spatio-temporal expression of S100A4 in a spinal nerve ligation (SNL) rat model. Also to figure out which other molecules directly interact with S100A4 to explore the possible mechanisms which might be involved in neuropathic pain.Methods: Seven-week-old male SD rats were used for the SNL model construction. Immunofluorescence and Western blotting were used to detect the spatio-temporal expression of S100A4 in the model. S100A4 was co-labeled with a number of related molecules and marker molecules that can distinguish between cell types. After intrathecal injection of S100A4 neutralizing antibody, the behavioral changes of SNL rats were recorded, and molecular changes compared. The direct interaction between S100A4 and other related molecules was verified by co-immunoprecipitation (co-IP) to explore its possible mechanism.Results: After spinal nerve ligation, the content of S100A4 in the dorsal root ganglion (DRG) and spinal dorsal horn increased significantly. Intrathecal injection of S100A4 neutralizing antibody could effectively relieve the mechanical pain in rats. co-IP revealed a direct interaction between S100A4 and RAGE.Conclusion: The content of S100A4 in the DRG and spinal dorsal horn of SNL rats increased, compared with that of the control group. Intrathecal injection of S100A4 neutralizing antibody could effectively relieve the mechanical pain in SNL rats. S100A4 may be involved in the production of neuropathic pain through RAGE or other ways, but the specific mechanism needs to be further studied.Keywords: neuropathic pain, S100 calcium binding protein A4, receptor for advanced glycation end products, spinal nerve ligation model

Weizhu Zhao,1,2 Haiying Yang,3 Jie Chai,4 Ligang Xing1 1Department of Radiology, Cancer Hospital Affiliated to Shandong First Medical University, Shandong Cancer Hospital and Institute, Jinan, 250117, People’s Republic of China; 2Department of Oncology, Binzhou People’s Hospital, Binzhou, 256610, People’s Republic of China; 3Department of Nursing, Binzhou People’s Hospital, Binzhou, 256610, People’s Republic of China; 4Department of Gastrointestinal Surgery, Cancer Hospital Affiliated to Shandong First Medical University, Shandong Cancer Hospital and Institute, Jinan, 250117, People’s Republic of ChinaCorrespondence: Jie ChaiDepartment of Gastrointestinal Surgery, Cancer Hospital Affiliated to Shandong First Medical University, Shandong Cancer Hospital and Institute, No. 440, Jiyan Road, Jinan, 250117, People’s Republic of ChinaTel +86 18678867800Email gu421720jing@163.comLigang XingDepartment of Radiology, Cancer Hospital Affiliated to Shandong First Medical University, Shandong Cancer Hospital and Institute, No. 440 Jiyan Road, Jinan, 250117, People’s Republic of ChinaTel +86 15553181309Email xinglg@medmail.com.cnAbstract: The transcription factor runt-related protein 2 (RUNX2) has an important impact on the transformation of bone marrow mesenchymal stem cells to osteoblasts. Further studies have shown that RUNX2 plays a key role in the invasion and metastasis of cancers. RUNX2 is a “key” molecule in the regulatory network comprised of multiple signaling pathways upstream and its target downstream molecules. Due to the complex regulatory mechanisms of RUNX2, the specific mechanism underlying the occurrence, development and prognosis of malignant tumors has not been fully understood. Currently, RUNX2 as a promising therapeutic target for cancers has become a research hotspot. Herein, we reviewed the current literature on the modulatory functions and mechanisms of RUNX2 in the development of malignant tumors, aiming to explore its potential clinical application in the diagnosis, prognosis and treatment of tumors.Keywords: RUNX2, malignant tumor;, research progress

Hao Wang,1,2 Die Meng,1,2 Haoyue Guo,1,2 Chenglong Sun,1,2 Peixin Chen,1,2 Minlin Jiang,1,2 Yi Xu,1,2 Jia Yu,1,2 Qiyu Fang,1,2 Jun Zhu,1,2 Wencheng Zhao,1,2 Shengyu Wu,1,2 Sha Zhao,1 Wei Li,1 Bin Chen,1 Lei Wang,1 Yayi He1 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 2Tongji University, School of Medicine, Shanghai, 200433, People’s Republic of ChinaCorrespondence: Yayi HeDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai, 200433, People’s Republic of ChinaTel +86 13818828623Email 2250601@qq.comAbstract: Single-cell sequencing (SCS) which has an unprecedentedly high resolution is an advanced technique for cancer research. Lung cancer still has a high mortality and morbidity. For further understanding the lung cancer, SCS is also been applied to lung cancer research to investigate its heterogeneity, metastasis, drug resistance, tumor microenvironment and many other issues. In this review, we summarized lung cancer research using SCS and their research achievements.Keywords: single-cell sequencing, lung cancer, intratumoral heterogeneity, tumor microenvironment, lung cancer therapy

Yali Hu,1,2,* Kunpeng Zhang,1,* Xingyao Zhu,1,* Xiuyan Zheng,1 Chao Wang,1 Xiao Niu,1 Teng Jiang,1 Xinhua Ji,1 Weilin Zhao,1 Lijuan Pang,1 Yan Qi,1 Feng Li,1,3 Li Li,4 Zhiping Xu,4 Wenyi Gu,4 Hong Zou1 1Department of Pathology, The First Affiliated Hospital, School of Medicine, Shihezi University, Key Laboratory of Xinjiang Endemic and Ethnic Diseases of the Ministry of Education of China, Xinjiang, 832002, People’s Republic of China; 2Department of Oncology, Yongcheng People’s Hospital, Henan, 476600, People’s Republic of China; 3Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 10000, People’s Republic of China; 4Australian Institute of Bioengineering and Nanotechnology, University of Queensland, Queensland, 4072, Australia*These authors contributed equally to this workCorrespondence: Hong Zou; Wenyi Gu Tel +86 13899528366; +61733464168Email zouhong_patho@163.com; w.gu@uq.edu.auBackground: Colon cancer is a top lethal cancer in man and women worldwide and drug resistance is the major cause of cancer-related death. Combinational therapy and drug delivery with nanoparticles have been shown to effectively overcome drug resistance in many cancers. We previously reported that nanoemulsion (NE) loaded paclitaxel (PTX) and BEZ235 could synergistically inhibit colon cancer cell growth.Purpose: To investigate whether NE loaded PTX and BEZ235 can overcome drug resistance and synergistically inhibit drug-resistant colon cancer cell growth in vitro and in vivo.Methods: The in vitro treatment effect on cell viability was assayed using CCK8 kit, cell morphological change was detected by β-tubulin immunofluorescence staining, drug resistance-related proteins were analyzed by Western blotting, and in vivo tumor growth test was performed in nude mice xeno-transplanted with 2 drug-resistant colon cancer cell lines HCT116-LOHP and HT29-DDP.Results: Both cell lines were sensitive to PTX but relatively insensitive to BEZ235. PTX combined with BEZ235 synergistically inhibited the proliferation of both cell lines. Nanoemulsion loaded PTX (NE-PTX) reduced the IC50 of PTX to approximately 2/5 of free PTX, indicating a high inhibitory efficacy of NE-PTX. When NE-PTX combined with a low concentration of BEZ235 (50 nM), the IC50 was decreased to approximately 2/3 of free PTX. Moreover, NE-PTX+BEZ235 treatment increased apoptosis, decreased Pgp and ABCC1 expression, and reduced tumor weights compared to the single drug treatment and the control group. These results suggest that nanoemulsion loaded PTX+BEZ235 can overcome drug resistance and improve the inhibitory effect on cancer cell proliferation and tumor growth.Conclusion: Our study thus provides a possible new approach to treat colon cancer patients with drug resistance.Keywords: colon cancer, nanoemulsion, paclitaxel, BEZ235, drug-resistance

Yuejie Xu,1,* Lei Xu,1,* Weijing Zhao,1 Qing Li,1 Ming Li,1 Wei Lu,1 Hui Zeng,1 Jinhua Yan,2 Daizhi Yang,2 Wei Wu,3 Jianping Weng,2 Jiemin Pan,1 Fang Liu1 1Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, 200233, People’s Republic of China; 2Department of Endocrinology and Metabolic Disease, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People’s Republic of China; 3Department of Pediatrics, Tongji Hospital, Wuhan Tongji Medical University, Wuhan, Hubei, 430030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiemin Pan; Fang LiuDepartment of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, 600 Yishan Road, Xuhui District, Shanghai, 200233, People’s Republic of ChinaTel +86-18930173803Email lilypjm@hotmail.com; f-liu@sjtu.edu.cnPurpose: Smartphones have received increasing attention and achieved positive outcomes in diabetes intervention. The widespread use of WeChat in China provides an opportunity for self-management practices in patients with diabetes. Nevertheless, how to combine the strengths of the WeChat platform with traditional medical strategy remains to be explored. This study aimed to evaluate the efficacy of a novel flash glucose monitoring device combined with the WeChat platform in juvenile type 1 diabetes management.Patients and Methods: A total of 60 juvenile patients with type 1 diabetes were randomly assigned into three groups: a blood glucose self-monitoring group (group A), a flash glucose monitoring (group B), and a flash glucose monitoring combined WeChat-interactive management group (group C). The intergroup differences in demographics, biochemical indicators, and questionnaire scores of the Diabetes Monitoring and Treatment Satisfaction Questionnaire and Diabetes Specific Quality of Life assessment were compared at the baseline and after 6 months.Results: After the 6-month intervention, groups B and C showed significantly lower glycated hemoglobin A1c (HbA1c) levels compared to those observed at baseline (both P < 0.05), with the largest decrease observed in group C (group B vs group C, P =0.04). Hypoglycemic episodes per month decreased from baseline in groups B and C (both P < 0.05) and were more significant in group C (P < 0.001). In addition, the DMTSQ scores increased in the 6th month in all groups (all P < 0.05), and the largest rise in scores was found in group C, followed by groups B and A. The DQOL scores in groups B and C decreased significantly from the baseline (both P < 0.05), with no change in group A.Conclusion: Flash glucose monitoring combined with the WeChat-interactive system may help achieve sustained glycemic control and higher satisfaction in patients with juvenile type 1 diabetes.Trial Registration: This study was registered at chictr.org.cn, number ChiCTR1900025495. Registered 29 August 2019.Keywords: WeChat, type 1 diabetes, self-management, glycated hemoglobin A1c

Wancheng Zhao, Qing Yang Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Qing Yang Email Yangqing_sj@126.comObjective: To explore the relationship between laparoscopic radical hysterectomy (LRH) and cervical cancer lymph-vascular space invasion (LVSI) by comparing the prevalence of LVSI in cervical cancer patients who underwent LRH versus open radical hysterectomy (ORH).Methods: The study participants were 1087 cervical cancer patients (FIGO 2009 stages IA2-IIA2) with pathologically confirmed with or without LVSI who underwent radical hysterectomy at Shengjing Hospital of China Medical University from 2013 through 2018. The patients were divided according to the type of surgical procedure into an LRH group (n=148) and an ORH group (n=939).Results: In the LRH group, 31.76% of patients (47/148) had LVSI-positive tumors compared to 33.23% of patients (312/939) in the ORH group; the difference was not significant (p=0.724). No between-group differences in LVSI prevalence according to lymph node metastasis, interstitial infiltration depth, differentiation degree, and parametrial infiltration were found. However, the number of LVSI-positive patients whose cervical cancer lesions > 4 cm (stage I B2 and II A2) was significantly higher in the LRH group than in the ORH group (Odds Ratio [OR] 0.333, 95% confidence interval [CI] 0.157– 0.706, p=0.005). The 3-Year disease-free survival (DFS) in the LRH group is lower than that in the ORH group (94.75% vs 97.27%), but there was no significance (P=0.187). Furthermore, the percentage of LVSI-positive tumors in patients with lymph node metastases was significantly higher than those without lymph node metastases (OR 2.897, 95% CI 2.129– 3.942, p=0.000). The 3-Year DFS were 98.22% in the LVSI negative patients and 93.78% in the LVSI positive patients, the difference was significant (P=0.002).Conclusion: A higher risk of lymph node metastasis and a lower 3-Year DFS was found in the LVSI-positive patients. In case of LVSI, it would be dangerous to treat patient in laparoscopy, especially in case of cervical cancer lesions > 4cm.Keywords: laparoscopic, cervical cancer, lymph-vascular space invasion, LVSI, radical hysterectomy

Zhen Wu,1 Wei Zhao,1 Zhen Yang,1 Yue Ming Wang,2 Yu Dai,1 Liang-An Chen1,2 1Respiratory Department of Chinese PLA General Hospital, Beijing, People’s Republic of China; 2School of Medicine, Nankai University, Tianjin, People’s Republic of ChinaCorrespondence: Liang-An Chen IMB 16th Floor, Room 16-104, 28 Fuxing Road, Haidian District, Beijing, 100853, People’s Republic of ChinaTel +86 10-66936184Email chenliangan301@163.comPurpose: Molecular-based targeted therapy has improved life expectancy for advanced non-small cell lung cancer (NSCLC). However, it does not have to be inevitable that patients receiving third-generation EGFR-TKIs become drug resistant. EGFR C797S and MET amplification are common mechanisms of osimertinib. However, a large part of these potential drug mechanisms remains unknown, and further research is needed.Methods: Tumour and blood samples from forty advanced NSCLC patients were identified as acquired drug resistant to osimertinib. The NGS panel was applied to detect EGFR C797S and MET amplification in tumour tissues or plasma samples. Whole-exome sequencing was conducted in five pairs of tumour tissues obtained before osimertinib administration and after osimertinib resistance in patients without C797S/cMET amplification.Results: The overall C797S mutation rate was 20%, and MET amplification was detected in six out of sixteen C797S-negative samples. PDGFRA in the PI3K-AKT-mTOR signalling pathway, RASAL2, RIN3 and SOS2 in the RAS-Raf-ERK signalling pathway, PTK2 in the ERBB signalling pathway and ABCC1 and ABCB5 in the ABC membrane pump system were identified as candidate crucial genes of drug resistance to osimertinib.Conclusion: EGFR C797S mutation and MET amplification are leading mechanisms for osimertinib resistance in lung cancer. The crucial potential mutated genes defined in our present study may need further validation in a considerable number of lung cancer patients.Keywords: osimertinib, drug resistance, whole-exome sequencing, lung cancer, targeted therapy

Danlei Yu,1,2,* Wen Zhao,2,3,* Karin A Vallega,2 Shi-Yong Sun2 1Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA; 3Department of Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shi-Yong SunDepartment of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, 1365-C Clifton Road, C3088, Atlanta, GA, 30322, USATel +1 (404) 778-2170Fax +1 (404) 778-5520Email ssun@emory.eduAbstract: Although epidermal growth factor receptor (EGFR)-targeted therapy has improved clinical outcomes of patients with advanced non-small-cell lung cancer (NSCLC) carrying activating EGFR mutations, the development of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), including the promising third-generation ones, results in disease progression and has become an unavoidable problem that limits patient long-term benefit. The third-generation EGFR-TKIs, osimertinib and almonertinib, are now approved for the treatment of advanced NSCLC patients harboring activating EGFR mutations (first-line) and/or the resistant T790M mutation (second-line). Clinically, appropriate management of acquired resistance to third-generation EGFR-TKIs will substantially improve their long-term efficacy against EGFR-mutant NSCLC. Recent preclinical and clinical studies suggest that activation of the Ras/Raf/MEK/ERK signaling pathway may be an important resistance mechanism and accordingly co-targeting this pathway effectively overcomes and abrogates acquired resistance to third-generation EGFR-TKIs. This review focuses on discussing the scientific rationale for and potential of co-targeting MEK/ERK signaling in delaying and overcoming acquired resistance to third-generation EGFR-TKIs, particularly osimertinib.Keywords: acquired resistance, EGFR inhibitors, osimertinib, MEK/ERK, lung cancer

Jincai Wang,1 Xufeng Zhang,1 Fang Yang,2 Yuguang Yang,1 Tianjiao Wang,1 Wenming Liu,1 Hongfeng Zhou,1 Wei Zhao3 1Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150086, People’s Republic of China; 2Department of Medical Oncology, Boao Evergrande International Hospital, Qionghai, Hainan 571400, People’s Republic of China; 3Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang, 150086, People’s Republic of ChinaCorrespondence: Wei ZhaoDepartment of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, No. 194, Harbin, Heilongjiang 150086, People’s Republic of ChinaTel +86-13796666580Email Zhaowei7700@126.comObjective: Cisplatin (DDP) is an effective first-line therapy for non-small cell lung cancer (NSCLC) treatment; however, it can cause resistance and thus pose an obstacle to the efficacy of chemotherapy in NSCLC. This study aims to detect the effect of RASSF1A on DDP resistance of NSCLC and the underlying mechanism.Methods: The expression levels of RASSF1A and microtubule-associated protein 1S (MAP1S) were investigated by qRT-PCR and Western blot and their interaction was testified by co-immunoprecipitation (Co-IP) analysis. The IC50 value of DDP on A549 and A549/DDP cells (DDP-resistant cells) was measured. A549/DDP cells were transfected with pCDNA3.1-RASSF1A, pCDNA3.1-MAP1S, or si-RASSF1A, followed by treated with DDP. Cell counting kit-8 (CCK-8) and 5-ethynyl-2ʹ-deoxyuridine (EDU) were employed to measure cell survival rate. Western blot was applied to test the levels of autophagy-associated proteins p62, LC3II, and LC3I. Immunofluorescence staining was used to detect the green fluorescent protein (GFP)-LC3 puncta to evaluate the level of autophagy. Finally, a xenograft model in nude mice using A549/DDP cells was developed.Results: RASSF1A and MAP1S were lowly expressed and positively correlated in NSCLC tissues. We observed that RASSF1A and MAP1S overexpression significantly enhanced DDP-induced effects in A549 and A549/DDP cells, including decreased cell viability, as well as increased autophagy levels. Besides, investigations into the mechanism between RASSF1A and MAP1S disclosed that RASSF1A could regulate MAP1S to inactivate the Keap1-Nrf2 pathway, thus activating autophagy to enhance chemosensitivity. Moreover, consistent results were confirmed in vivo experiments.Conclusion: RASSF1A increases chemosensitivity in NSCLC by facilitating autophagy via MAP1S-mediated Keap1-Nrf2 pathway.Keywords: RASSF1A, MAP1S, chemosensitivity, autophagy, Keap1-Nrf2, A549/DDP

In this study, LVE (liquid-vapor equilibrium) data of cadmium-zinc system were determined at a pressure of 7.5 Pa. We compare the use of the Redlich-Kister polynomials with the Wilson equation in fitting activities. The LVE for Cd-Zn system in vacuum distillation was modeled using the two models. The results of the two models are reliable, the Redlich-Kister polynomials are better than the Wilson equation. The LVE phase diagram is reliable for predicting the process of vacuum distillation for Cd-Zn system. The evaporation rates of the elements in Cd-Zn alloy were experimentally measured and calculated by the Langmuir equation. The experimental data on the evaporation of pure metals Cd and Zn are included. The evaporation coefficients of zinc and cadmium under vacuum conditions were calculated. The deviations were discussed. Comparing the calculations with the experimental results, it can be found that the trend is consistent. The activation energies of Cd and Zn in the Cd-Zn alloy under experimental conditions were also calculated.

Jianping Liu,1 Weihua Zhao,2 Qinghong Gui,1 Ying Zhang,1 Zaiyu Guo,2 Wei Liu3 1Department of Neurology, Tianjin TEDA Hospital, Tianjin 300457, People’s Republic of China; 2Department of Neurosurgery, Tianjin TEDA Hospital, Tianjin 300457, People’s Republic of China; 3Department of Neurology, Tianjin Medical University General Hospital, Tianjin 300052, People’s Republic of ChinaCorrespondence: Zaiyu GuoDepartment of Neurosurgery, Tianjin TEDA Hospital, No. 65, The Third Avenue, Tianjin Economy Development Area, Tianjin 300457, People’s Republic of ChinaTel +86-15302100230Email guozaiyu_teda@163.comWei LiuDepartment of Neurology, Tianjin Medical University General Hospital, No. 154, An Shan Road, Heping District, Tianjin 300052, People’s Republic of ChinaTel +86-2260362255Email liuweithird@126.comPurpose: To investigate the associations between concentrations of Aβ40 and Aβ42 and vascular cognitive impairment (VCI) in cerebral small vessel disease (CSVD) patients and evaluate the value of combination of levels of Aβ40 or Aβ42 and the total CSVD score in predicting VCI.Patients and Methods: A total of 199 CSVD patients were divided into VCI group and non-VCI group according to the criteria of VCI. Demographic data, MRI markers of CSVD, blood pressure, vascular risk factors, laboratory markers, and serum Aβ40 and Aβ42 concentration were collected. Univariate analysis was performed with the Student’s t-test, Mann–Whitney U-test or Chi-square test. Variables with P< 0.10 in univariate analysis were then included in multivariate analysis that used a backward stepwise logistic regression model. The predictive values were assessed with receiver operating characteristic (ROC) curve.Results: VCI was determined in 112 CSVD patients (56.3%). Hyperlipidemia (OR: 1.618, 95% CI: 1.265– 3.049), the total CSVD score (OR: 1.414, 95% CI: 1.213– 2.278) and serum Aβ42 concentration (OR: 1.401, 95% CI: 1.212– 1.946) were independent risk factors for VCI in CSVD patients with adjustment for age, education years, diabetes and fasting blood-glucose (FBG). The area under curves (AUCs) were 0.640 (SE: 0.040, 95% CI: 0.563– 0.718), 0.733 (SE: 0.035, 95% CI: 0.664– 0.802) and 0.827 (SE: 0.030, 95% CI: 0.768– 0.887), respectively, for the total CSVD score, serum Aβ42 concentration and their combination applied in predicting VCI in CSVD patients. Z test demonstrated that the AUC of combination prediction was significantly higher than individual prediction (0.827 vs 0.640, Z=3.740, P< 0.001; 0.827 vs 0.733, Z=2.039, P=0.021).Conclusion: Combination of Aβ42 and total CSVD score could significantly elevate the predictive value of cognitive impairment in CSVD patients.Keywords: Aβ40, Aβ42, vascular cognitive impairment, cerebral small vessel disease, total cerebral small vessel disease score

Yonghui Liu,1 Zhaoyu Wang,1 Fan Yu,2 Mingjing Li,1 Haomiao Zhu,1 Kun Wang,1 Meng Meng,1 Wei Zhao1 1State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and KLMDASR of Tianjin, Nankai University, Tianjin 300353, People’s Republic of China; 2College of Life Sciences, Nankai University, Tianjin 300071, People’s Republic of ChinaCorrespondence: Meng Meng; Wei ZhaoState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and KLMDASR of Tianjin, Nankai University, No. 38 Tongyan Road, Haihe Education Park, Tianjin 300353, People’s Republic of ChinaTel/Fax +86 22-23507760Email mengmeng@nankai.edu.cn; wzhao@nankai.edu.cnBackground: Therapeutic tumor vaccines are one of the most promising strategies and have attracted great attention in cancer treatment. However, most of them have shown unsatisfactory immunogenicity, there are still few available vaccines for clinical use. Therefore, there is an urgent demand to develop novel strategies to improve the immune efficacy of antitumor vaccines.Purpose: This study aimed to develop novel adjuvants and carriers to enhance the immune effect of MUC1 glycopeptide antigen-based antitumor vaccines.Methods: An antitumor vaccine was developed, in which MUC1 glycopeptide was used as tumor-associated antigen, α-GalCer served as an immune adjuvant and AuNPs was a multivalent carrier.Results: Immunological evaluation results indicated that the constructed vaccines enabled a significant antibody response. FACS analysis and immunofluorescence assay showed that the induced antisera exhibited a specific binding with MUC1 positive MCF-7 cells. Moreover, the induced antibody can mediate CDC to kill MCF-7 cells. Besides stimulating B cells to produce MUC1-specific antibodies, the prepared vaccines also induced MUC1-specific CTLs in vitro. Furthermore, the vaccines significantly delayed tumor development in tumor-bearing mice model.Conclusion: These results showed that the construction of vaccines by presenting α-GalCer adjuvant and an antigen on gold nanoparticles offers a potential strategy to improve the antitumor response in cancer immunotherapy.Keywords: MUC1 glycopeptide, α-galactosylceramide, gold nanoparticle, antitumor vaccine

Candida is a polyphyletic genus of asexually reproducing yeasts in the Saccharomycotina with more than 400 species that occur in almost all families of the subclass and its name is strongly connected with the infectious disease candidiasis. During the last two decades, approximately half of the Candida species have been reassigned into more than 36 already existing genera and 14 newly proposed genera, but the polyphyletic feature of the genus largely remained. Candida auris is an important, globally emerging opportunistic pathogen that has caused life-threatening outbreaks in healthcare facilities worldwide. This species belongs to the Candida auris-Candida haemuli (CAH) clade in the Metschnikowiaceae, a clade that contains multidrug-resistant clinically relevant species, but also species isolated from natural environments. The clade is phylogenetically positioned remotely from the type species of the genus Candida that is Candida vulgaris (currently interpreted as a synonym of Candida tropicalis) and belongs to the family Debaryomycetaceae. Although previous phylogenetic and phylogenomic studies confirmed the position of C. auris in the Metschnikowiaceae, these analyses failed to resolve the position of the CAH clade within the family and its delimitation from the genera Clavispora and Metschnikowia. To resolve the position of the CAH clade, phylogenomic and comparative genomics analyses were carried out to address the phylogenetic position of C. auris and related species in the Metschnikowiaceae using several metrics, such as the average amino acid identity (AAI) values, the percentage of conserved proteins (POCP) and the presence-absence patterns of orthologs (PAPO). Based on those approaches, 13 new genera are proposed for various Candida and Hyphopichia species, including members of the CAH clade in the Metschnikowiaceae. As a result, C. auris and related species are reassigned to the genus Candidozyma. Fifty-five new combinations and nine new species are introduced and this will reduce the polyphyly of the genus Candida. [ABSTRACT FROM AUTHOR]

Acorrect classification of fungi, including yeasts, is of prime importance to understand fungal biodiversity and to communicate about this diversity. Fungal genera are mainly defined based on phenotypic characteristics and the results of single or multigene-based phylogenetic analyses. However, because yeasts often have less phenotypic characters, their classification experienced a strong move towards DNA-based data, from short riboso)mal sequences to multigene phylogenies and more recently to phylogenomics. Here, we explore the usefulness of various genomics-based parameters to circumscribe fungal genera more correctly taking the yeast domain as an example. Therefore, we compared the results of a phylogenomic analysis, average amino acid identity (AAI) values, the presence of conserved signature indels (CSIs), the percentage of conserved proteins (POCP) and the presence-absence patterns of orthologs (PAPO). These genome-based metrics were used to investigate their usefulness in demarcating 13 hitherto relatively well accepted genera in Saccharomycetaceae, namely Eremothecium, Grigorovia, Kazachstania, Kluyveromyces, Lachancea, Nakaseomyces, Naumovozyma, Saccharomyces, Tetrapisispora, Torulaspora, Vanderwaltozyma, Zygosaccharomyces and Zygotorulaspora. As a result, most of these genera are supported by the genomics-based metrics, but the genera Kazachstania, Nakaseomyces and Tetrapisispora were shown to be genetically highly diverse based on the above listed analyses. Considering the results obtained for the presently recognized genera, a range of 80–92 % POCP values and a range of 60–70 % AAI values might be valuable thresholds to discriminate genera in Saccharomycetaceae. Furthermore, the genus-specific genes identified in the PAPO analysis and the CSIs were found to be useful as synapomorphies to characterize and define genera in Saccharomycetaceae. Our results indicate that the combined monophyly-based phylogenomic analysis together with genomic relatedness indices and synapomorphies provide promising approaches to delineating yeast genera and likely those of filamentous fungi as well. The genera Kazachstania, Nakaseomyces and Tetrapisispora are revised and we propose eight new genera and 41 new combinations. [ABSTRACT FROM AUTHOR]

In this study, we conducted field campaigns at two mountain‐top observatories on the Qilian Mountains (QLM) in the northeastern Tibetan Plateau of China, which plays a vital role in sustaining water resources for the downstream arid and semi‐arid regions. The two observatories, Waliguan Baseline Observatory (WLG) and Laohugou station (LHG), are situated on the eastern and western edge of the QLM, respectively. The objectives of this study were to examine the properties of atmospheric aerosols, CCN concentrations (NCCN) at varying supersaturation levels (SS = 0.2%–1.0%), and the hygroscopic nature of aerosols in the QLM, especially during the formation of orographic cloud. Notably, the average aerosol concentration and NCCN was approximately 2–3 factors higher at WLG compared to LHG. The chemical compositions of aerosols were primarily dominated by sulfate and organic aerosol (OA) at these two sites. A very high hygroscopicity parameter of aerosol calculated using chemical composition was observed at these two sites (0.37 ± 0.03 at LHG vs. 0.30 ± 0.04 at WLG). Enhanced aerosol loading episodes impacted by anthropogenic emission were observed at these two sites. Exploration on high‐loading cases at each site, we found that the CCN activity was dominated by aerosol size, but the chemical processes of aerosol during the formation of orographic cloud could also be important in CCN activity, especially for low SS conditions. These findings collectively underscore the significant impact of anthropogenic air plumes on CCN concentrations in the QLM and their potential influence on precipitation patterns. Plain Language Summary: The Qilian Mountains (QLM), situated in the northeastern Tibetan Plateau of China, have been constructed as a national park, dedicated to protecting its fragile ecological environment. Renowned for its "wet island" effect, the mountains serve as a crucial water resource for the downstream residents in northwest China. Orographic clouds, a primary source of precipitation in these mountains, heavily rely on the presence of cloud condensation nuclei (CCN), typically dominated by natural mineral dust due to its arid and semi‐arid regions around. In recent years, rapid urbanization and heavy human activities around has introduced a significant influx of anthropogenic aerosols. However, the impact of anthropogenic aerosol on the orographic cloud is unclear, especially during summer season when natural mineral dust emissions are limited. To unravel this mystery, we conducted campaigns at two mountain‐top observatories to explore the impact of anthropogenic aerosol transport from low elevation regions during summer season to mountain areas. Our findings highlight the substantial impact of anthropogenic aerosols on CCN concentrations, which offer valuable insights into the understanding the interaction of aerosol and cloud, and potential impact on precipitation in this mountain region. Key Points: Two mountain‐top studies were explored to characterize aerosol and CCN on the QLM in the northeastern TP of ChinaAn overall low NCCN values were observed in these mountain areas, but the concentration at the east was 2–3 times higher than the westElevated NCCN occurred at these two sites when anthropogenic pollutants were transported upslope [ABSTRACT FROM AUTHOR]

Background: Although it is a key soybean-producing region, northeast China frequently faces drought. Drought severely affects soybean growth, development and even leads to yield reduction. Methods: Sand cultivation method was employed to investigate the changes in malondialdehyde (MDA) content, nitric oxide (NO) content and individual leaf area of drought-tolerant soybean variety Heinong 44 (HN44) and drought-sensitive soybean variety Heinong 65 (HN65) under drought stress during the flowering stage, with different concentrations of sodium nitroprusside (SNP) used for irrigation. Result: The NO and MDA contents of HN44 and HN65 leaves rose in response to drought stress, MDA content in HN44 and HN65 leaves was noticeably elevated, the individual leaf area showed a downward trend. Irrigation with SNP further increased NO accumulation and reduced membrane lipid peroxidation in the leaves, with the best effect observed at a concentration of 1000 μmol·g-1. In practical production, SNP can be used to alleviate membrane lipid peroxidation damage in soybean leaves and improve soybean drought resistance when encountering drought. [ABSTRACT FROM AUTHOR]

The Gregg‐Henyey‐Polzin (GHP) finescale parameterization is widely employed to infer turbulent mixing when microstructure measurements are unavailable. However, the strain‐only GHP scaling is the only option when shear information is lacking, in which case the shear‐to‐strain ratio (Rω) is commonly treated as a constant. Since Rω has been reported to vary spatiotemporally, using a fixed value of Rω might result in a significant bias in inferring turbulent mixing. In this study, we present a global map of Rω, based on the microstructure database contributed by the Climate Process Team on internal wave‐driven ocean mixing, which covers the Indian, Pacific, and Atlantic oceans across both high and low latitudes. Then, we propose a parameterization of Rω by considering buoyancy frequency, Coriolis frequency, and topographic features. Compared to the GHP scaling with constant Rω, the turbulent dissipation rate values inferred from the GHP scaling with parameterized Rω are more accurate. In this manner, this study provides a reference for choosing optimal Rω when using the strain‐only GHP scaling to explore turbulent mixing in the open ocean. Plain Language Summary: Although diapycnal mixing is the smallest‐scale motion in the ocean, understanding its global distribution is crucial because it can modulate large‐scale circulation and hence influence climate change. However, field observations of ocean mixing are costly and therefore limited in a global sense. Given that internal wave breaking is the dominant energy source for ocean mixing, estimating internal wave‐driven mixing using easily available temperature and salinity data becomes an effective way to understand its spatiotemporal variability. Here, we modify an essential parameter in such an estimation method by changing the constant to a variable that depends on stratification, latitude, and topography. This modification significantly improves the accuracy of the method for estimating internal wave‐driven mixing, making it more consistent with observations compared to using a constant. Key Points: Shear‐to‐strain ratio varies significantly with spaceA parameterization of shear‐to‐strain ratio is proposed based on buoyancy frequency, Coriolis frequency, and topographic featuresBy using a parameterized shear‐to‐strain ratio, instead of a fixed value, we show the finescale parameterization performs better [ABSTRACT FROM AUTHOR]