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In the paper, we propose power weighted quantile regression(PWQR), which can reduce the effect of heterogeneous of the conditional densities of the response effectively and improve efficiency of quantile regression). In addition to PWQR, this article also proves that all the weighting of those that the actual value is less than the estimated value of PWQR and the proportion of all the weighting is very close to the corresponding quantile. At last, this article establishes the relationship between Geomagentic Indices and GIC. According to the problems of power system security operation, we make GIC risk value table. This table can have stronger practical operation ability, can provide power system security operation with important inferences.

Xiaojin Feng,1,2 Jialing Hu,1 Fenfang Zhan,1 Deqiang Luo,3 Fuzhou Hua,1,2 Guohai Xu1,2 1Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China; 2Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang, Jiangxi 330006, People’s Republic of China; 3Department of Intensive Care Unit, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of ChinaCorrespondence: Guohai Xu; Fuzhou HuaDepartment of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of ChinaTel +86-791-86299131Email xuguohai1@sina.com; 415134607@qq.comPurpose: Neuroinflammation is an essential causative factor in the pathogenesis and progression of cognitive impairment. The present study aims to evaluate the critical role of microRNA-138-5p (miR-138-5p) in hippocampal neuroinflammation and cognitive impairment through the NLRP3/caspase-1 signaling pathway in rats.Material and Methods: We established the cognitive impairment rat model and RM (Rat microglia) microglial cellular inflammation model by intracerebroventricular (icv) injection or stimulation of lipopolysaccharide (LPS). Morris water maze (MWM) and Y-maze tests were performed to assess the cognitive behaviors. Quantitative real-time polymerase chain reaction (qRT-PCR), Enzyme-linked immune-sorbent assay (ELISA) and Western blot analysis were utilized to evaluate mRNA or protein expression. Bioinformatic analysis and dual-luciferase reporter gene assay were performed to verify the targeting relationship between NLRP3 and miR-138-5p. Besides, Hematoxylin and eosin (H&E) staining and immunohistochemistry were applied to observe the neuronal morphology and detect the positive cells of the hippocampus, respectively.Results: Compared to the control groups, LPS-treated rats exhibited significantly impaired learning and memory in MWM and Y-maze tests. The expression of NLRP3, caspase-1 and pro-inflammation cytokines (IL-1β and IL-18) were upregulated, while miR-138-5p was downregulated both in rat hippocampus and RM cells treated with LPS. MiR-138-5p is downregulated in microarray data of cognitive impairment animals and could directly target the 3ʹ-UTR of NLRP3. Furthermore, upregulation of miR-138-5p improved impaired cognitive functions, while inhibited hippocampal neuroinflammation demonstrated by decreased expression of NLRP3/caspase-1 axis, pro-inflammation cytokines and microglial activation. This study demonstrates for the first time that miR-138-5p suppresses the hippocampal NLRP3/caspase-1 signaling pathway activation in cognition impaired rats.Conclusion: The low expression of miR-138-5p after LPS administration may contribute to the activation of the NLRP3/caspase-1 pathway, leading to hippocampal neuroinflammation and cognitive impairment in rat models. These findings indicate a promising therapeutic avenue for cognitive disorders.Keywords: microRNA-138-5p, NLRP3/caspase-1, neuroinflammation, cognitive impairment, microglial activation

Yu-fan Yang,1,* Hui Wang,1,2,* Nan Song,1,* Ya-hui Jiang,1 Jun Zhang,1 Xiao-wen Meng,1 Xiao-mei Feng,3,4 Hong Liu,5 Ke Peng,1 Fu-hai Ji1 1Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2Department of Anesthesiology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, People’s Republic of China; 3Department of Anesthesiology, University of Utah Health, Salt Lake City, UT, USA; 4Transitional Residency Program, Intermountain Medical Center, Murray, UT, USA; 5Department of Anesthesiology and Pain Medicine, University of California Davis Health, Sacramento, CA, USA*These authors contributed equally to this workCorrespondence: Ke Peng; Fu-hai JiDepartment of Anesthesiology, First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, People’s Republic of ChinaTel +86-159-6215-5989; +86-512-6797-2352Email pengke0422@163.com; jifuhaisuda@163.comBackground: Endoplasmic reticulum stress (ERS)-mediated myocardial inflammation and apoptosis plays an important role in myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine has been used clinically with sedative, analgesic, and anti-inflammatory properties. This study aimed to determine the effects of dexmedetomidine pretreatment on inflammation, apoptosis, and the expression of ERS signaling during myocardial I/R injury.Methods: Rats underwent myocardial ischemia for 30 min and reperfusion for 6 h, and H9c2 cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury (OGD for 12 h and reoxygenation for 3 h). Dexmedetomidine was administered prior to myocardial ischemia in rats or ODG in cardiomyocytes. In addition, the α 2-adrenergic receptor antagonist (yohimbine) or the PERK activator (CCT020312) was given prior to dexmedetomidine treatment.Results: Dexmedetomidine pretreatment decreased serum levels of cardiac troponin I, reduced myocardial infarct size, alleviated histological structure damage, and improved left ventricular function following myocardial I/R injury in rats. In addition, dexmedetomidine pretreatment increased cell viability and reduced cytotoxicity following OGD/R injury in cardiomyocytes. Mechanistically, the cardioprotection offered by dexmedetomidine was mediated via the inhibition of inflammation and apoptosis through downregulating the expression of the ERS signaling pathway, including glucose-regulated protein 78 (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), C/EBP homologous protein (CHOP), inositol-requiring protein 1 (IRE1), and activating transcription factor 6 (ATF6). Conversely, the protective effects of dexmedetomidine were diminished by blocking the α 2 adrenergic receptors with yohimbine or promoting PERK phosphorylation with CCT020312.Conclusion: Dexmedetomidine pretreatment protects the hearts against I/R injury via inhibiting inflammation and apoptosis through downregulation of the ERS signaling pathway. Future clinical studies are needed to confirm the cardioprotective effects of dexmedetomidine in patients at risk of myocardial I/R injury.Keywords: myocardial ischemia/reperfusion injury, dexmedetomidine, endoplasmic reticulum stress, inflammation, apoptosis, GRP78/PERK/CHOP

Jinjie Yuan,1,2 Ning Sun,1 Xinying Feng,3 Huan He,1 Dong Mei,1 Guanghua Zhu,4 Libo Zhao1 1Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, Beijing, People’s Republic of China; 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 3Phase I Clinical Trials Centre, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, People’s Republic of China; 4Hematology Oncology Center, Beijing Children’s Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Libo ZhaoClinical Research Center, Beijing Children’s Hospital, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing, 100045, People’s Republic of ChinaEmail libozhao2011@163.comGuanghua ZhuHematology Oncology Center, Beijing Children’s Hospital, 56 Nanlishi Road, Xicheng District, Beijing, 100045, People’s Republic of ChinaEmail guangh.zhu@gmail.comPurpose: The aim of this study was to develop a novel busulfan dosing regimen, based on a population pharmacokinetic (PPK) model in Chinese children, and to achieve better area under the concentration-time curve (AUC) targeting.Patients and Methods: We collected busulfan concentration-time samples from 69 children who received intravenous busulfan prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). A population pharmacokinetic model for busulfan was developed by nonlinear mixed effect modelling and was validated by an external dataset (n=14). A novel busulfan dosing regimen was developed through simulated patients, and has been verified on real patients. Limited sampling strategy (LSS) was established by Bayesian forecasting. Mean absolute prediction error (MAPE) and relative root mean Squared error (rRMSE) were calculated to evaluate predictive accuracy.Results: A one-compartment model with first-order elimination best described the data. GSTA1 genotypes, body surface area (BSA) and aspartate aminotransferase (AST) were found to be significant covariates of Bu clearance, and BSA had significant impact of the volume of distribution. Moreover, two equations were obtained for recommended dose regimens: dose (mg)=34.14×BSA (m2)+3.75 (for GSTA1 *A/*A), Dose (mg)=30.99×BSA (m2)+3.21 (for GSTA1 *A/*B). We also presented a piecewise dosage based on BSA categories for each GSTA1 mutation. A two-point LSS, two hours and four hours after dosing, behaved well with acceptable prediction precision (rRMSE=1.026%, MAPE=6.55%).Conclusion: We recommend a GSTA1-BSA and BSA-based dosing (Q6 h) based on a PPK model for personalizing busulfan therapy in pediatric population. Additionally, an optimal LSS (C2h and C4h) provides convenience for therapeutic drug monitoring (TDM) in the future.Keywords: busulfan, individualized therapy, population pharmacokinetics, HSCT, GST mutations

Yaqi Xu,1– 3 Xiaoli Feng,4 Qian Zhou,1,2,5 Wen Jiang,1,2,6 Yibo Dai,1– 3 Yang Jiang,1– 3 Xiaoli Liu,1– 3 Shuo Li,1,2,7 Yongjing Wang,1– 3 Fang Wang,6 Ai Li,1– 3 Chengyun Zheng1– 3 1Department of Hematology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong, People’s Republic of China; 3Shandong University-Karolinska Institute Collaboration Laboratory for Stem Cell Research, Jinan, Shandong, People’s Republic of China; 4Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 5Department of Hematology, Linyi Central Hospital, Linyi, Shandong, People’s Republic of China; 6Institute of Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 7Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of ChinaCorrespondence: Chengyun Zheng; Ai LiHematology Department of the Second Hospital of Shandong University, 247th of Beiyuan Road, Jinan, Shandong, People’s Republic of ChinaTel +86 13675319282; +86 176 6008 0688Email zhengchengyun186@126.com; aili1976@126.comBackground: We aimed to investigate the anti-multiple myeloma (MM) activity of the new small molecular compound AE-848 (5-bromo-2-hydroxyisophthalaldehyde bis[(1-methyl-1H-benzimidazol-2-yl)hydrazone]) and its underlying anti-MM mechanism.Methods: Cell viability and apoptosis were detected and quantified by using MTT and flow cytometry, respectively. JC-1 dye-related techniques were used to assess mitochondrial membrane potential (MMP). Western blotting was applied to detect the expression of NF-κB and PI3K/Akt/mTOR pathway-associated proteins. The in vivo activity of AE-848 against MM was evaluated in a MM mouse model.Results: Application of AE-848 into the in vitro cell culture system significantly reduced the viability and induced apoptosis of the MM cell lines, RPMI-8226 and U266, in a dose- and time-dependent manner, respectively. JC-1 dye and Western blotting analysis revealed that AE-848 induced the cleavage of caspase-8, caspase-3, and poly ADP-ribose polymerase (PARP), resulting in loss of mitochondrial membrane potential (MMP). Both the NF-κB and PI3K/AKT/mTOR signaling pathways were involved in AE-848-induced apoptosis of U266 and RPMI8226 cells. Moreover, AE-848 leads to cell cycle arrest of MM cells. Its anti-MM efficacy was further confirmed in a xenograft model of MM. AE-848 administration significantly inhibited MM tumor progression and prolonged the survival of MM-bearing mice. More importantly, our results demonstrated that AE-848 markedly induced primary MM cell apoptosis.Conclusion: Our results for the first time showed that the small compound AE-848 had potent in vitro and in vivo anti-myeloma activity, indicating that AE-848 may have great potential to be developed as a drug for MM treatment.Keywords: small molecular compound, AE-848, multiple myeloma, apoptosis, NF-κB and PI3K/Akt/mTOR pathway

Chengbin Zheng,1,* Xingyu Feng,2,* Jiabin Zheng,2 Qian Yan,2 Xu Hu,2 Huolun Feng,2 Zhenru Deng,2 Qianchao Liao,2 Junjiang Wang,2 Yong Li1,2 1Department of General Surgery, Guangdong Provincial People’s Hospital; Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510080, People’s Republic of China; 2Department of General Surgery, Guangdong Provincial People’s Hospital; Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yong LiDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, 106 Zhongshan Road 2, Guangzhou, Guangzhou 510080, People’s Republic of ChinaTel +86-13822177479Fax +86-020-83827812Email liyong@gdph.org.cnPurpose: Tumors with lymphovascular invasion (LVI) are thought to be associated with lymph node metastasis and to lead to a worse prognosis. However, the effect of LVI on the prognosis of adenocarcinoma of esophagogastric junction (AEG) is still unclear.Patients and Methods: We retrospectively analyzed 224 consecutive patients with non-metastatic AEG who underwent radical surgery in our hospital from 2004 to 2018. Inverse probability weighting (IPW) analysis was used to eliminate the selection bias. IPW-adjusted Kaplan–Meier curves and Cox proportional hazards models were used to compare disease-specific survival (DSS) and overall survival (OS) between patients with and without LVI.Results: A total of 224 patients with non-metastatic AEG who underwent radical resection were included in the study and 96 (42.9%) patients developed LVI. Survival analysis showed that LVI were associated with worse DSS (hazard ratio (HR) = 3.12; 95% CI: 1.93– 5.03) and worse OS (HR = 2.33; 95% CI: 1.61– 3.38). The results were consistent across subgroups stratified by pathologic N stage. Subgroup analysis demonstrated that Siewert type III (HR= 3.20, 95% CI: 1.45– 7.06) was associated with worse DSS, but not Siewert type I/II (HR= 1.46, 95% CI: 0.94– 2.31, P-interaction=0.047).Conclusion: LVI are associated with worse prognosis in AEG. LVI had a worse effect on DSS in Siewert type III AEG than Siewert type I/II AEG.Keywords: lymphovascular invasion, adenocarcinoma of esophagogastric junction, risk factor, overall survival, disease-specific survival

Wanru Guo,1 Xuewen Feng,1 Meifang Yang,1 Yanwan Shangguan,1 Pei Shi,1 Shuting Wang,1 Ming Hu,1 Mohamed S Draz,2 Kaijin Xu1 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USACorrespondence: Kaijin Xu Email zdyxyxkj@zju.edu.cnAbstract: Individuals with genetic defects show an increased susceptibility to poorly pathogenic mycobacteria including nontuberculous mycobacteria and Bacillus Calmette-Guerin (BCG). In previous studies, defects in multiple genes were identified to be associated with mycobacterium infection including tyrosine kinase 2 (TYK2). The mutations lead to insufficient production of interferon (IFN)-γ or an insufficient response to IFN-α/β, interleukin (IL)-6, IL-10, IL-12 and IL-23. Herein, we describe a case of Mycobacterium intracellulare infection in a male with abdominal pain and diarrhea. Whole exome sequencing of the genomes revealed a compound heterozygous mutation (c.3083A>G/c.2590C>T, p.N1028S/p.R864C) in the TYK2 gene. The patient recovered after two years of anti-mycobacterial treatment and no relapse was observed so far. We also reviewed 24 cases of mycobacterial infection associated with TYK2 deficiency which provides evidence of how personalised genomics can improve outcomes.Keywords: TYK2 deficiency, Mycobacterium intracellulare infection, case report, genetic testing, treatment

Hanxi Yu,1,* Weichen Zhang,2,* Peilin Han,1 Beng Yang,2 Xiaode Feng,2 Ping Zhou,1 Xiaoxu Zhu,1 Bingqian Zhou,3 Wei Chen,4 Jianhua Qian,1 Jun Yu2 1Department of Gynecology, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou 310006, People’s Republic of China; 2Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou 310006, People’s Republic of China; 3Department of Gynecology, The First Affiliated Hospital of Zhejiang University, School of Medicine, Pujiang 322200, People’s Republic of China; 4Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianhua Qian; Jun Yu Tel +86-0571-87236114Email qianjianhua@zju.edu.cn; dryujun@zju.edu.cnBackground: Mammalian Ste20-like kinase 4 (MST4), also known as serine/threonine kinase 26 (STK26), promotes development of several cancers and is found to be highly expressed in the placenta. However, in choriocarcinoma that originated from the placenta, the expression of MST4 was undetermined and its mechanism was unknown. In this study, the expression of MST4 in choriocarcinoma as well as the underlying mechanism was explored.Purpose: To detect the expression of MST4 in patient samples and mechanism of mediating EMT by MST4 in choriocarcinoma.Patients and Methods: The metastatic lesions of choriocarcinoma (n=17) and volunteer villus (n=17) were collected to determine MST4 expression using immunohistochemistry and H&E staining. We use siRNA and lentiviral vector to knockdown MST4 and use plasmid to overexpress MST4 in choriocarcinoma. Then, we apply real-time polymerase chain reaction (RT-PCR), Western blot assay and immunofluorescence assay to detect target protein expressions. Cell invasion and migration and cell proliferation were detected by transwell assay and wound healing assay and CCK-8 and cell colony formation.Results: MST4 is lowly expressed in the metastatic lesions of choriocarcinoma patients when compared with normal villus. Knockdown of MST4 activated epithelial–mesenchymal transition (EMT) process, significantly increasing the ability of invasion and migration in choriocarcinoma cell lines (JAR and JEG-3). In contrast, the EMT process was restrained in choriocarcinoma cell lines with overexpressed MST4. Meanwhile, genome-wide gene expression array, Western blot and ELISA revealed that tumor growth factor-beta 1 (TGF-β 1) has significantly increased. The EMT process and metastatic prompting biofunction were reversed after using TGF-β 1 inhibitor (LY364947) in the choriocarcinoma cell lines with MST4 knockdown.Conclusion: Our studies demonstrated that MST4 was lowly expressed in patient samples. Additionally, JAR and JEG-3 increase cell invasion and migration ability while there is no influence on cell proliferation with MST4 knockdown. Conversely, the metastatic ability of JAR and JEG-3 was decreased with overexpressed MST4. Moreover, TGF-β 1 was a key factor after MST4 knockdown. In conclusion, MST4 affects choriocarcinoma EMT by mediating TGF-β 1 expression.Keywords: choriocarcinoma, TGF-β 1, EMT, MST4

Qianqian Cheng,1 Xiaodi Feng,1 Qi Meng,1,2 Yaqi Li,1 Siqi Chen,1 Guoen Wang,1 Ke Nie1 1School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province 510006, People’s Republic of China; 2School of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, People’s Republic of ChinaCorrespondence: Ke NieSchool of Chinese Materia Medica, Guangdong Pharmaceutical University, 280 Waihuan East Road, Panyu District, Guangzhou, Guangdong Province 510006, People’s Republic of ChinaTel +86 203 935 2557Email nicknk@hotmail.comPurpose: [6]-gingerol is a bioactive compound extracted from ginger, a traditional anti-emetic herb in Chinese medicine. Previous studies have demonstrated that [6]-gingerol can ameliorate chemotherapy-induced pica in rats, although the underlying mechanism has not been elucidated. This study is designed to investigate [6]-gingerol’s antiemetic mechanism focusing on the 5-hydroxytryptamine (serotonin, 5-HT) system by evaluating the synthesis, metabolism and reuptake of 5-HT, as well as the mechanism of 5-hydroxytryptamine type 3 receptor (5-HT3 receptor), in a cisplatin-induced pica model of rats.Methods: Rats were randomly divided into control group (vehicle + saline, Con), [6]-gingerol control group (50 mg/kg [6]-gingerol + saline, G-con), ondansetron control group (2.6 mg/kg ondansetron + saline, O-con), cisplatin model group (vehicle + cisplatin, Model), ondansetron-treated group (2.6 mg/kg ondansetron + cisplatin, O-treated), high dosage of [6]-gingerol-treated group (100 mg/kg [6]-gingerol + cisplatin, GH-treated), and low dosage of [6]-gingerol-treated group (50 mg/kg [6]-gingerol + cisplatin, GL-treated). The rats were administered with [6]-gingerol, ondansetron, and vehicle (3% Tween-80) by gavage twice (7:00 AM and 7:00 PM). One hour after the first treatment (8:00 AM), rats in groups Model, O-treated, GH-treated and GL-treated were injected intraperitoneally (i.p.) with 6 mg/kg cisplatin, and the other groups were injected i.p. with saline of equal volume. The consumption of kaolin of the rats were measured. All the rats were anesthetized by i.p. injection of pentobarbital sodium at 24 h post-cisplatin. After blood samples were taken, medulla oblongata and ileum were removed. The levels of 5-HT and its metabolite 5-HIAA in ileum, medulla oblongata and serum were determined using high-performance liquid chromatography with electrochemical detection (HPLC-ECD). The mRNA expression levels of 5-HT3 receptor, tryptophan hydroxylase (TPH), monoamine oxidase A (MAO-A) and serotonin reuptake transporter (SERT) were detected by real-time PCR. The protein expression levels and distribution of 5-HT3 receptor, TPH and MAO-A in the medulla oblongata and ileum were measured by Western blotting and immunohistochemistry, respectively.Results: [6]-gingerol treatment significantly reduced the kaolin ingestion and the increase in 5-HT concentration in rats induced by cisplatin. TPH, MAO-A, SERT, and 5-HT3 receptor are important in 5-HT metabolism, and cisplatin-induced alterations in the associated protein/mRNA levels were restored when treated with [6]-gingerol.Conclusion: This suggests that the antiemetic effect of [6]-gingerol against cisplatin-induced emesis may be due to 5-HT attenuation via modulating the TPH/MAO-A/SERT/5-HT/5-HT3 receptor system.Keywords: [6]-gingerol, serotonin, cisplatin, pica, rats

Hong Peng,1 Jie Zheng,2 Qiang Su,3 Xueya Feng,1 Mingsha Peng,1 Lei Gong,4 Hong Wu,1 Xue Pan5 1Department of Anorectal Surgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 2Department of Anesthesiology, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan 646000, People’s Republic of China; 3Department of Pharmacy, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong Key Laboratory of Individualized Drug Therapy, Nanchong, Sichuan, 637000, People’s Republic of China; 4Department of Gastrointestinal Surgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 5Scientific Research Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Xue PanScientific Research Department, The First Affiliated Hospital of Chongqing Medical University, No. 1 of Youyi Road, Yuanjiagang, Yuzhong District, Chongqing 400016, People’s Republic of ChinaTel +86 13594002025Email panxue89012705@163.comBackground: Many studies found that VPS53, one of the subunits of the golgi-associated retrograde protein (GARP) complexes, was aberrantly expressed in human diseases.Aim: This study investigated the functions and molecular mechanisms of VPS53 in colorectal cancer (CRC).Methods: Expression and correlation of Beclin 1 and VPS53 were analyzed by RT-qPCR and Pearson’s correlation in CRC tissues, and VPS53 expression was also determined in CRC cells. The changes of proliferation, migration, invasion, apoptosis, and autophagy of CRC cells were examined by a succession of functional experiments including CCK-8, flow cytometry, transwell assay, and electron microscopy. The levels of autophagy related proteins were evaluated by Western blotting analysis.Results: RT-qPCR results found that VPS53 was downregulated in CRC tissues and cells, and Beclin 1 expression was also decreased in CRC tissues. There was a positive correlation between VPS53 and Beclin 1. Functional results showed that overexpression of VPS53 could suppress proliferation, migration, and invasion, and accelerate apoptosis and autophagy of CRC cells. Also, VPS53 could upregulate Beclin 1 and LC3BII, suggesting the inductive effect of VPS53 on CRC cell autophagy. Furthermore, it was found that the autophagy inhibitor (Inhb) could attenuate the inhibition of VPS53 on CRC progression.Conclusion: VPS53 repressed CRC progression by regulating the autophagy signaling pathway, suggesting that VPS53 might be a promising therapeutic target for CRC.Keywords: colorectal cancer, VPS53, autophagy, cell migration, cell invasion

Shulan Lv,1,* Qing Wang,1,* Yan Li,1,2,* Lanbo Zhao,3 Yiran Wang,1 Xue Feng,1 Lu Han,1 Kailu Zhang,1 Panyue Yin,1 Huilian Hou,4 Guizhi Shi,5 Qiling Li1 1Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China; 2Department of Obstetrics and Gynecology, Yan’an People’s Hospital, Yan’an, Shaanxi, China; 3Health Science Center, Xi’an Jiaotong University, Xi’an, Shaanxi, China; 4Department of Pathology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China; 5Aviation General Hospital of Beijing, Medical, Pathology Department of Aviation General Hospital of Beijing, Beijing, China*These authors contributed equally to this workCorrespondence: Qiling LiDepartment of Obstetrics and Gynecology, First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, Shaanxi, ChinaTel +86-29-85323849Fax +86-29-88214667Email liqiling@mail.xjtu.edu.cnPurpose: Cytopathology detecting for endometrial cancer is becoming accepted, and Tao Brush is the most widely used sampler for endometrial cells. This study aims to compare the effectiveness between Li brushes and Tao brushes for the diagnosis of endometrial lesions and to evaluate the diagnostic accuracy of endometrial cytology compared with histology.Methods: There were 109 patients needing dilation and curettage (D&C) and 21 patients needing hysterectomies included from November 2017 to April 2018. Every patient was sampled by Tao brush and Li brush before D&C or hysterectomy performed. The cytological results were compared based on the gold standard histological results of D&C or hysterectomy.Results: The sensitivity of Li brush cytology for detecting endometrial cancer and atypical hyperplasia was estimated at 83.33%, specificity at 100%, positive predictive value (PPV) at 100%, and negative predictive value (NPV) at 98.02%, respectively. While for the Tao brush, it was 91.67% of sensitivity, 96.04% of specificity, 73.33% of PPV, and 98.98% of NPV, respectively. The kappa value was 0.767, which indicated a substantial agreement. Cytology by both two brushes had a lower insufficient sample rate (2.75% of Tao brush, 4.59% of Li brush) than did D&C (11.93%).Discussion: Endometrial cytology is a reliable approach for evaluating endometrium with a lower insufficient sample rate. Cytology sampled by both Li brushes and Tao brushes has a high accuracy with histological diagnosis in detecting endometrial cancer and atypical hyperplasia. Combining social and economic benefits, the Li brush may be a better endometrial cell collector.Keywords: Li brush, Tao brush, cytology, dilation and curettage, endometrial cancer

Weixian Hu,1,* Chengbin Zheng,1,* Renjie Li,2 Xingyu Feng,1 Guoliang Zheng,3 Zhichao Zheng,3 Wenjun Xiong,4 Guosheng Lin,5 Yongjian Zhou,5 Wei Wang,4 Yan Zhao,3 Yong Li1 1Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, People’s Republic of China; 2Department of Bariatric and Metabolic Surgery, Klinikum Ernst von Bergmann, Potsdam 14467, Germany; 3Department of Gastric Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, People’s Republic of China; 4Department of Gastrointestinal Surgery, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, People’s Republic of China; 5Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People’s Republic of China*These authors contributed equally to this work.Correspondence: Yong LiDepartment of General Surgery, Guangdong Provincial People’s Hospital; Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, Guangzhou, Guangdong 510080, People’s Republic of ChinaTel +86-13822177479Fax +86-83827812Email liyong@gdph.org.cnYan ZhaoDepartment of Gastric Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, People’s Republic of ChinaTel +86-18900918909Email zhaoyan@CancerHosp-LN-CMU.comPurpose: Gastrointestinal stromal tumors (GISTs) are commonly known to be derived from the gastrointestinal (GI) tract, but recently there have been more and more literature describing lesions with similar pathological and immunohistochemical resembling GISTs but located outside the GI tract, and they have been termed as extra-GISTs (eGISTs). However, due to the rare incidence of eGISTs, its association with survival outcomes is poorly understood, especially in the Chinese population. Here, we aimed to identify the risk factors of eGISTs and to assess their association with overall survival (OS) and disease-free survival (DFS).Patients and Methods: Data of pathologically confirmed eGISTs cases, without radiological and perioperative evidence of other primary lesions, and with no microscopically identified adhesion between the tumor and the gastrointestinal serosa, which were surgically treated between January 2006 and September 2017 were retrieved from the database of four high-volume hospitals. Immunohistochemical and genetic testing were performed on the postoperative lesions and were staged using the National Institutes of Health (NIH) criteria.Results: A total of 55 cases were retrieved. eGISTs were identified from the retroperitoneum (36.4%), mesocolon (25.5%), small bowel mesentery (12.7%), abdominopelvic cavity (12.7%), lesser omental sac (5.5%), ovary (3.6%), pancreatic capsule (1.8%), or urinary bladder (1.8%). Based on the NIH risk classification, majority of the lesion were classified as high risk (85.5%). KIT 11 was the most common mutation site (76.5%) and 25.0% of the cases were wild-type eGISTs. Multivariate analyses showed that tumor location and size were independent factors affecting prognoses. Patients with tumors in the retroperitoneum had significantly poorer OS and DFS as compared to those in the non-retroperitoneum (HR [95% CI] for OS and DFS: 2.546 [1.023– 6.337] [P = 0.037] and 2.475 [0.975– 6.273] [P = 0.049], respectively). Similar findings were found for tumors of size > 15 cm, compared to ≤ 15 cm (HR [95% CI] for OS and DFS: 5.350 [2.022– 14.156] [P < 0.001] and 3.861 [1.493– 9.988] [P = 0.003], respectively).Conclusion: eGISTs were predominantly found from the retroperitoneum and mostly classified as high risk. Those located in the retroperitoneum and of size > 15 cm had the poorer OS and DFS as compared to those in the non-retroperitoneum and of size < 15 cm.Keywords: extra gastrointestinal stromal tumors, multicenter, immunohistopathology, gene mutation, National Institutes of Health criteria, risk factor, retroperitoneum, overall survival, disease-free survival, recurrence

The European physical journal / C 82(10), 869 (2022). doi:10.1140/epjc/s10052-022-10536-1, We review lattice results related to pion, kaon, D-meson, B-meson, and nucleon physics with the aim of making them easily accessible to the nuclear and particle physics communities. More specifically, we report on the determination of the light-quark masses, the form factor $f_+(0)$ arising in the semileptonic $K \rightarrow \pi $ transition at zero momentum transfer, as well as the decay constant ratio $f_K/f_\pi $ and its consequences for the CKM matrix elements $V_{us}$ and $V_{ud}$. Furthermore, we describe the results obtained on the lattice for some of the low-energy constants of $SU(2)_L\times SU(2)_R$ and $SU(3)_L\times SU(3)_R$ Chiral Perturbation Theory. We review the determination of the $B_K$ parameter of neutral kaon mixing as well as the additional four B parameters that arise in theories of physics beyond the Standard Model. For the heavy-quark sector, we provide results for $m_c$ and $m_b$ as well as those for the decay constants, form factors, and mixing parameters of charmed and bottom mesons and baryons. These are the heavy-quark quantities most relevant for the determination of CKM matrix elements and the global CKM unitarity-triangle fit. We review the status of lattice determinations of the strong coupling constant $\alpha _s$. We consider nucleon matrix elements, and review the determinations of the axial, scalar and tensor bilinears, both isovector and flavor diagonal. Finally, in this review we have added a new section reviewing determinations of scale-setting quantities., Published by Springer, Heidelberg

Single iron atom and nitrogen-codoped carbon (Fe–N–C) electrocatalysts, which have great potential to catalyze the kinetically sluggish oxygen reduction reaction (ORR), have been recognized as the most promising alternatives to the precious metal platinum. Unfortunately, the ORR properties of the existing Fe–N–C catalysts are significantly hampered by the inferior accessibility and intrinsic activity of FeN4 moieties. Here, we constructed densely exposed surface FeN4 moieties on a hierarchically porous carbon (sur-FeN4-HPC) by Fe ion anchoring and a subsequent pyrolysis strategy using the nitrogen- doped hierarchically porous carbon (NHPC) as the scaffold. The high surface area of the NHPC with abundant surface Fe anchoring sites enabled the successful fabrication of densely accessible FeN4 active moieties (34.7 􏰁x 10^19 sites g^-􏰂1) on sur-FeN4-HPC. First-principles calculations further suggested that the edge effect could regulate the electronic structure of the single Fe site, hence promoting the intrinsic ORR activity of the FeN4 moiety. As a result, the sur-FeN4-HPC electrocatalyst exhibited excellent ORR activity in acidic media with a high half-wave potential of 0.83 V (vs. the reversible hydrogen electrode). We further examined sur-FeN4-HPC as a cathode catalyst in proton exchange membrane fuel cells (PEMFCs). The membrane electrode assembly delivered a high current density of 24.2 mA cm􏰂2 at 0.9 ViR-free (internal resistance-compensated voltage) under 1.0 bar O2 and a maximum peak power den- sity of 0.412 W cm􏰂2 under 1.0 bar air. Importantly, the catalyst demonstrated promising durability during 30000 voltage cycles under harsh H2 and air conditions. The PEMFC performance of sur-FeN4-HPC outperforms those of the previously reported Fe–N–C electrocatalysts. The engineering of highly acces- sible and dense surface FeN4 sites on sur-FeN4-HPC offers a fruitful pathway for designing high- performance electrocatalysts for different electrochemical processes.

Understanding and potentially predicting or even controlling urban labour markets represents a great challenge for workers and policy makers alike. Cities are effective engines of economic growth and prosperity and incubate complex dynamics within their labour market, and the labour markets they support demonstrate considerable diversity. This presents a challenge to policy makers who would like to optimise labour markets to benefit workers, promote economic growth and manage the impact of technological change. While much previous work has studied the economic characteristics of cities as a function of size and examined the exposure of urban economies to automation, this has often been from a static perspective. In this work we examine the structure of city job networks to uncover the diffusive properties. More specifically, we identify the occupations which are most important in promoting the diffusion of beneficial or deleterious properties. We find that these properties vary considerably with city size., Comment: 27pages, 5 figures