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Yuxia He,1,2,* Yuling Mao,1,2,* Yaoming Chen,3,* Ling Tang,1 Haiyu Hou,1 Chenyun Sun,1 Yaqi Shang,1 Na-Na Tan,4 Lei Li1,2 1Department of Obstetrics and Gynecology, Center for Reproductive Medicine; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 3Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 4Department of Health Management; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei Li; Na-Na Tan, Email lileigo@foxmail.com; tannana0212@126.comPurpose: This study investigated the incidence and microbial etiology of embryo contamination in assisted reproductive technology (ART), and its influence on embryo development, pregnancy and neonatal outcomes.Methods: A retrospective analysis was conducted on embryo contamination at the Reproductive Centre of the Third Affiliated Hospital of Guangzhou Medical University, between 2018 and 2021.Results: In the period from 2018 to 2021, the average incidence of embryo contamination was 0.12%. Bacterial growth was observed in 39 cases, with a preponderance of Escherichia coli (20, 51.28%), Streptococcus agalactiae (7, 17.95%). The fertilization rate of contaminated embryos was 18.18% (Klebsiella pneumoniae) to 94.79% (S. agalactiae), the cleavage rate was 9.09% (Enterobacter cloacae) to 98.90% (S. agalactiae), and the available embryo rate of Day 3 was 0 (Klebsiella pneumoniae, Enterobacter cloacae) to 63.33% (S. agalactiae). Blastocyst formation rate was 3.23% (Proteus mirabilis) to 64.29% (Streptococcus mitis). E. coli contamination occurred mostly on Day 1, and S. agalactiae on Days 3 and 5. After rinsing and rescuing treatment, six healthy male babies were born.Conclusion: E. coli and S. agalactiae were the most common bacterial embryo contaminants. Most microbial contamination can significantly decrease the fertilization rate. Embryo transfer after rinsing and continuing culture had no negative effect on neonatal outcomes, but there was an increased risk of early abortion due to E. coli contamination.Keywords: in vitro fertilization, microbial contamination, remedial treatment, pregnancy outcome, neonatal outcomes

Haisong Hou,1,2 Liu Liang,3 Lihong Deng,4 Wanping Ye,5 Yuanzhang Wen,6 Jun Liu1 1Laboratory of Pathogenic Biology, Guangdong Medical University, Zhanjiang, People’s Republic of China; 2Department of Blood Transfusion, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 3Department of Laboratory Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 4Department of Hepatology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 5Department of Gastroenterology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 6Department of Hepatobiliary Surgery, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of ChinaCorrespondence: Jun Liu, Laboratory of Pathogenic Biology, Guangdong Medical University, Zhanjiang, People’s Republic of China, Email liujungd6@163.comBackground: The aim of this study was to describe the demographic and clinical characteristics of hepatitis B virus (HBV) associated hepatocellular carcinoma (HCC), analyse the risk factors associated with HBV-associated HCC, and to provide some references to the diagnosis and treatment of HCC.Methods: This study retrospectively enrolled 730 patients, including 390 patients with chronic hepatitis B (CHB) as controls, and 340 patients with CHB complicated with HCC as patients. Relevant information and medical records of these participants were collected, including age, sex, cigarette smoking, alcoholism, diabetes mellitus (DM), hypertension, coronary heart disease (CHD), cirrhosis, occupation, ascites, HBV-DNA load, the qualitative analysis of HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb serological markers, and levels of alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), gamma-glutamyltransferase (GGT), TNM stage, tumor size and tumor number. The T test, Chi-square test, non-parametric rank-sum test, logistic regression analyses were used to explore the influencing factors and their degree of association with HCC in patients with HBV.Results: The proportion of smoking, alcoholism, married status, DM, hypertension, and the rate of HBV-DNA with a viral load of ≥ 500 copies/mL were significantly higher in the HCC group than in the controls (all p< 0.05). Cirrhosis was more common among patients with CHB+HCC than in controls (p=0.013). The proportion of patients with HBsAg, HBeAb, and HBcAb positive was greater in CHB+HCC group than that in CHB group. Logistic regression analysis indicated that age ≥ 60 years (OR: 1.835, 95% CI: 1.020– 3.302, p=0.043), HBeAb positive (OR: 9.105, 95% CI: 4.796– 17.288, p< 0.001), antiviral treatment with entecavir (OR: 2.209, 95% CI: 1.106– 4.409, p=0.025), and GGT (OR: 1.004, 95% CI: 1.001– 1.007, p=0.002) were risk factors for HCC in patients with CHB.Conclusion: Advanced age, HBeAb positive, antiviral treatment with entecavir, and GGT were independent risk factors for HCC in HBV patients.Keywords: chronic hepatitis B, hepatocellular carcinoma, cirrhosis, hepatitis B virus

Tengfei Chen,1,&ast; Sihan Li,1,&ast; Dongyin Lian,1 Qin Hu,2 Hongping Hou,1 Delian Niu,1 Han Li,1 Ling Song,1 Yunhang Gao,1 Ying Chen,1 Xiaoru Hu,3 Jianrong Li,1 Zuguang Ye,1 Bo Peng,1 Guangping Zhang1 1Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2College of Life Sciences and Bio-Engineering, Beijing University of Technology, Beijing, People’s Republic of China; 3National Institute for Food and Drug Control, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Peng; Guangping Zhang, Tel +8610 64056575, Email bpeng@icmm.ac.cn; gpzhang@icmm.ac.cnPurpose: This study aimed to investigate the main pharmacological action and underlying mechanisms of Jin Gu Lian Capsule (JGL) against rheumatoid arthritis (RA) based on network pharmacology and experimental verification.Methods: Network pharmacology approaches were performed to explore the core active compounds of JGL, key therapeutic targets, and signaling pathways. Molecular docking was used to predict the binding affinity of compounds with targets. In vivo experiments were undertaken to validate the findings from network analysis.Results: A total of 52 targets were identified as candidate JGL targets for RA. Sixteen ingredients were identified as the core active compounds, including, quercetin, myricetin, salidroside, etc. Interleukin-1 beta (IL1B), transcription factor AP-1 (JUN), growth-regulated alpha protein (CXCL1), C-X-C motif chemokine (CXCL)3, CXCL2, signal transducer and activator of transcription 1 (STAT1), prostaglandin G/H synthase 2 (PTGS2), matrix metalloproteinase (MMP)1, inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB) and transcription factor p65 (RELA) were obtained as the key therapeutic targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the efficacy of JGL was functionally involved in regulating immune-mediated inflammation, in which IL-17/NF-κB signaling was recommended as one of the main pathways. Molecular docking suggested that the core active compounds bound strongly to their respective targets. Experimentally, JGL treatment mitigated inflammation, showed analgesic activity, and ameliorated collagen-induced arthritis. Enzyme-linked immunosorbent assay showed that JGL effectively reduced the serum levels of cytokines, chemokines, and MMPs. Immunohistochemistry staining showed that JGL markedly reduced the expression of the targets in IL-17/NF-κB pathway including IL-17A, IL-17RA, NF-κB p65, C-X-C motif ligand 2, MMP1 and MMP13.Conclusion: This investigation provided evidence that JGL may alleviate RA symptoms by partially inhibiting the immune-mediated inflammation via IL-17/NF-κB pathway. Keywords: rheumatoid arthritis, Jin Gu Lian capsules, network pharmacology, experimental validation, immune-mediated inflammation

Ling Zhou,1 Juanjuan Wang,1 Hui Hou,1 Jiao Li,1 Juan Li,1 Jiannan Liang,1 Junqin Li,1 Xuping Niu,1 Ruixia Hou,1 Kaiming Zhang2 1Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital, Taiyuan, People’s Republic of ChinaCorrespondence: Kaiming Zhang, Taiyuan Central Hospital, Taiyuan, People’s Republic of China, Tel/Fax +86-351-5656080, Email zhangkaiming@sina.com; tycchospital@sina.comObjective: Autophagy, an intracellular process of self-digestion, has been shown to modulate inflammatory responses. In the present study, we determined the effects of autophagy on inflammatory response induced by M5 cytokines.Methods: Human umbilical vein endothelial cells (HUVECs) were treated with M5 cytokines to induce inflammation. Expression levels of mRNA for inflammatory cytokines and BIRC2 were compared in HUVECs with vs without induction of autophagy with rapamycin (RAPA) by PCR, while cell apoptosis was assessed by flow cytometry and caspase-3 activity assay kit. Expression levels of LC3, p62, p-p38 MAPK (Thr180/Tyr182), p-mTOR (Ser2445) and p-ULK1 (Ser555) proteins were measured by Western blotting. The nitric oxide (NO) content, NO synthase (NOS) activity and cell angiogenesis were also evaluated.Results: Induction of autophagy with RAPA decreased expression levels of IL6, IL8 and CCL20, in addition to reduction in inflammation-induced apoptosis in HUVECs. Moreover, RAPA increased LC3II, while decreasing p62 expression. Likewise, expression levels of p-p38 MAPK and p-mTOR proteins were markedly decreased by the treatment with RAPA. Finally, RAPA treatment increased the NO content and the NOS activity, and inhibited angiogenesis.Conclusion: Induced autophagy can improve the function of endothelial cells in psoriasis, suggesting approaches to induce autophagy can be used to ameliorate psoriasis.Keywords: autophagy, inflammatory, HUVECs, p38 MAPK/mTOR

Zerong Wang,1 Yue Wu,1 Shude Chen,1 Heyang Hou,1 Yaowen Wang2 1The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 2Department of Clinical Laboratory, Weifang People’s Hospital, Weifang, Shandong, People’s Republic of ChinaCorrespondence: Yaowen Wang, Department of Clinical Laboratory, Weifang People’s Hospital, No. 151, Guangwen Street, Kuiwen District, Weifang, Shandong, People’s Republic of China, Tel +86 15864599659, Email 15864599659@163.comObjective: A strain of Proteus penneri with carbapenem resistance was found in a patient with a diabetic foot infection. We studied drug resistance, genome, and homology of P. penneri to support clinical prevention and treatment of infection caused by carbapenem-resistant P. penneri (CR-PPE).Methods: The strains were obtained through bacterial culture from purulence. VITEK 2 compact (GN13) and Kirby–Bauer (K-B) disk diffusion methods were used for antimicrobial susceptibility testing. Ceftriaxone, amikacin, gentamicin, ampicillin, aztreonam, ceftazidime, ciprofloxacin, levofloxacin, cefepime, trimethoprim-sulfamethoxazole, tobramycin, cefotetan, piperacillin-tazobactam, ampicillin-sulbactam, ertapenem, piperacillin, meropenem, cefuroxime, cefazolin, cefoperazone/sulbactam, cefoxitin, and imipenem were used for antimicrobial susceptibility testing. After bacterial genome extraction, sequencing, and sequence assembly, whole-genome sequencing (WGS) was performed to explore the CR-PPE genotype.Results: CR-PPE was resistant to two carbapenems (imipenem and ertapenem), ceftriaxone, and cefazolin, and was sensitive to aztreonam, piperacillin-tazobactam, and cefotetan. WGS results depict that the resistant phenotype of CR-PPE is consistent with the genotype, without common virulence genes of Enterobacteriaceae bacteria detected (virulence factor database). The carbapenem resistance gene blaNMD-1 is contained in a new plasmid, pWF127-NDM. The transposon Tn125 in pWF127-NDM carrying blaNMD-1 has almost the same structure as Tn125 in the reference plasmid pHFK418-NDM (Accession: MH491967). In addition, through phylogenetic analysis, CR-PPE depicts the closest evolutionary relationship with GCF 024129515.1, which was found in Gallus gallus in the Czech Republic in 2019 (downloaded from National Center for Biotechnology Information database). According to the evolutionary tree, CR-PPE has high homology with the two P. penneri strains found in China.Conclusion: CR-PPE exhibits strong drug resistance owing to the presence of multiple resistance genes. CR-PPE infection should receive more attention, especially in patients with underlying diseases, such as diabetes and weak immunity.Keywords: Proteus penneri, New Delhi metallo-β-lactamase, NDM, carbapenem resistance, diabetes, bacterial infection

Microemulsions, mixtures of oil, water, and surfactant, are thermodynamically stable. Unlike conventional emulsions, microemulsions form spontaneously, have a monodisperse droplet size that can be controlled by adjusting the surfactant concentration, and do not degrade with time. To make microemulsions, a judicious choice of surfactant molecules must be made, which significantly limits their potential use. Nanoparticle surfactants, on the other hand, are a promising alternative because the surface chemistry needed to make them bind to a liquid-liquid interface is both well flexible and understood. Here, we derive a thermodynamic model predicting the conditions in which nanoparticle surfactants drive spontaneous emulsification that agrees quantitatively with experiments using Noria nanoparticles. This new class of microemulsions inherits the mechanical, chemical, and optical properties of the nanoparticles used to form them, leading to novel applications.

Hui Hou, Jiao Li, Juanjuan Wang, Ling Zhou, Junqin Li, Jiannan Liang, Guohua Yin, Xinhua Li, Yueai Cheng, Kaiming Zhang Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Kaiming Zhang, Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, No. 5 Dong San Dao Xiang, Jiefang Road, Taiyuan, Shanxi Province, People’s Republic of China, Tel +86-351-5656080, Email zhangkaiming@sina.comBackground: Cell proliferation, migration, and angiogenesis are aberrant in psoriatic human dermal microvascular endothelial cells (HDMECs), resulting in abnormal endothelial function and microvascular dilation in psoriasis.Objective: To explore the role of Integrin subunit alpha 9 (ITGA9) in proliferation and migration of dermal microvascular endothelial cells.Methods: HDMECs were isolated from the skin of 6 psoriatic patients and 6 healthy controls. Expression levels of ITGA9 mRNA and protein were assessed with qRT-PCR and Western blot, respectively, while miqRT-PCR was used to determine expression levels of miR-146a-3p. Cell proliferation and migration were assessed in human microvascular endothelial cell line (HMEC-1), following overexpression of either ITGA9 or miR-146a-3p, or co-transfection with miR-146a-3p-mimic and pLVX - ITGA9. Cell viability was detected by Cell Counting Kit-8 assay and 5-ethynyl-2′-deoxyuridine (EdU) cell proliferation assay. Cell apoptosis was assessed, using annexin V-FITC/PI apoptosis detection kit, while cell migration was detected by wound healing and transwell assay.Results: Expression levels of ITGA9 were significantly decreased in psoriatic HDMECs compared to normal controls. Moreover, expression levels of miR-146a-3p were higher in psoriatic HDMECs than in normal controls. Overexpression of miR-146a-3p lowered expression levels of ITGA9, accompanied by increased proliferation and migration of HMEC-1 in vitro. In contrast, overexpression of ITGA9 inhibited proliferation and migration of HMEC-1, while increasing expression levels of cdc42, ki67, focal adhesion kinase (FAK), c-Src tyrosine kinase (Src), RAC1 and RhoA.Conclusion: ITGA9 can repress the proliferation and migration of HMEC-1, suggesting utility of ITGA9 as a potential therapeutic intervention for psoriasis.Keywords: ITGA9, miR-146a-3p, human dermal microvascular endothelial cells, psoriasis, proliferation, migration

Ruiqiong Liu, Wei Wei, Huaying Hou, Ping Cong, Yong Zhou, Xiaoming Yu Cancer Center, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, People’s Republic of ChinaCorrespondence: Xiaoming Yu, Cancer Center, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, People’s Republic of China, Tel +86-0531-85875541, Email yxm_sd@hotmail.comAbstract: Primary spinal cord glioblastoma (PSC GBM) is a rare disease with limited treatment options. Here, we describe a case of PSC GBM treated with anlotinib in this report. Molecular characterization confirmed the presence of the MGMT promoter unmethylated, IDH wild type, FGFR3 p.S249C and p53 p.V73fs mutations in the patient. Anlotinib is a multitarget tyrosine kinase inhibitor that target VEGFR2/3, FGFR1-4, PDGFRα/β, and c-kit. After a partial resection of the tumor at the extramedullary invasion site, the patient was administered anlotinib 12 mg p.o. once every day (days 1– 14, 21‐day cycle) in combination with irinotecan chemotherapy (days 1 and 8, 21‐day cycle). The patient exhibited significant symptom remission and partial response and was maintained for more than 10 months of follow-up. This case study showed that FGFR3 S249C may be a new marker for the treatment of PSC GBM with anlotinib. This case is also another strong support for molecular diagnosis and precision medicine.Keywords: spinal cord glioblastoma, FGFR3 mutation, anlotinib, targeted therapy, precision medicine

Hao Hou,1,&ast; Yifei Pei,1,&ast; Yinmei Yang,2 Lili Lu,3 Wenjun Yan,1 Xiuyin Gao,1 Wei Wang1 1Department of Community and Health Education, School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 2Department of Social Medicine, School of Health Sciences, Wuhan University, Wuhan, People’s Republic of China; 3Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Wang; Xiuyin GaoDepartment of Community and Health Education, School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of ChinaTel +86 516-83262655; +86 13813287473Email weiwang90@163.com; 460629860@qq.comPurpose: This study assessed the prevalence of turnover intention and explored associated factors on turnover intention among healthcare workers during the COVID-19 pandemic in China.Methods: An institutional-based cross-sectional study was conducted from July to February 13th to 20th, 2020, in 31 provinces of mainland China. A total of 1403 healthcare workers were recruited. Hierarchical logistic regressions were used to identify potential factors associated with turnover intention among Chinese health care workers.Results: The prevalence of turnover intention among healthcare workers was 10.1% during the COVID-19 pandemic in China. Results of hierarchical regression revealed that working in Grade II hospital (OR = 1.78), technician (OR = 0.30), daily working hours over 12 h (OR = 2.92), frequency of mask replacement between 4 and 8 h (OR = 3.51), refuse volunteer to frontline (OR = 1.68), patient–physician relation unchanged (OR = 1.73), depression (OR = 2.21) and lower social support (OR = 1.75) were significantly associated with the risk of turnover intention. Additionally, healthcare worker’s psychosocial syndemic (OR = 6.13) was positively associated with turnover intention.Conclusion: Turnover intention is relatively prevalent among healthcare workers during the COVID-19 pandemic in China, and the factors contributing to turnover intention were complex and varied. Early screening of high-risk groups for turnover intention among healthcare workers and more psychosocial health care and physical protection are needed during the COVID-19 pandemic in China.Keywords: COVID-19, healthcare workers, turnover intention, China

Ling Zhou,1 Juanjuan Wang,1 Hui Hou,1 Jiao Li,1 Juan Li,1 Jiannan Liang,1 Junqin Li,1 Xuping Niu,1 Ruixia Hou,1 Kaiming Zhang2 1Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital, Taiyuan, People’s Republic of ChinaCorrespondence: Kaiming Zhang, Email zhangkaiming@sina.com

Dan Lv,1 Zepu Wang,2 Shuai Ji,1 Xiaoxi Wang,1 Huiqing Hou1 1Physical Examination Center, Hebei General Hospital, Shijiazhuang City, Hebei Province, People’s Republic of China; 2Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang City, Hebei Province, People’s Republic of ChinaCorrespondence: Dan LvPhysical Examination Center, Hebei General Hospital, Shijiazhuang City, Hebei Province, People’s Republic of ChinaEmail ld2449@163.comObject: Studies have shown a link between homocysteine (Hcy) and heart diseases, kidney diseases, cerebrovascular diseases, liver diseases, and other pathological conditions. However, the relationship between Hcy and liver fibrosis (LF) is unclear. Here, we studied the link between plasma Hcy concentration and LF.Methods: We determined and recorded the plasma Hcy concentration, general biochemical parameters, and liver stiffness measurement (LSM) in 1582 subjects, followed by statistical data analyses.Results: During different stages of LF, we found a considerable difference (p < 0.001 unless specified) in body mass index (BMI), sex, age, Hcy, the levels of alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT; P = 0.012), triglycerides (TG; P = 0.006), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBS), and platelet count (PLT). There was a strong association between the plasma Hcy concentration and the serum biomarkers of LF (P < 0.001) and the values of LSM (P < 0.001).Conclusion: The plasma Hcy concentration was substantially different among different stages of LF. The higher the plasma Hcy concentration, the more evident was the degree of LF.Keywords: liver fibrosis, homocysteine, FibroScan

Al-substituted Li7La3Zr2O12 samples processed under argon show enhanced Li-ion transport and interfacial properties in symmetrical cells with lithium electrodes, compared to those prepared in air. In particular, the samples prepared under argon have higher ionic conductivities and lower interfacial impedances in symmetrical lithium cells, and show better DC cycling characteristics. The electronic conductivities are also somewhat higher. Pellets subjected to thermal treatment under the two types of atmospheres have different colors but exhibit similar microstructures. X-ray diffraction experiments suggest that there are slight structural differences between the two types of samples, but few dissimilarities were observed in elemental composition, distribution of ions, oxidation states, or bond lengths using laser-induced breakdown spectroscopy (LIBS), x-ray photoelectron spectroscopy (XPS), and extended x-ray absorption fine structure spectroscopy (EXAFS) to analyze the materials. Additionally, there was no evidence that La or Zr were reduced during the processing under Ar. Possible explanations for the improved electrochemical properties of the sample prepared under Ar compared to the one prepared in air include differences in grain boundary chemistries and conductivities and/or a small concentration of oxygen vacancies in the former.

Partial tandem duplication of MLL (MLL-PTD) characterizes acute myeloid leukemia (AML) patients often with a poor prognosis. To understand the order of occurrence of MLL-PTD in relation to other major AML mutations and to identify novel mutations that may be present in this unique AML molecular subtype, exome and targeted sequencing was performed on 85 MLL-PTD AML samples using HiSeq-2000. Genes involved in the cohesin complex (STAG2), a splicing factor (U2AF1) and a poorly studied gene, MGA were recurrently mutated, whereas NPM1, one of the most frequently mutated AML gene, was not mutated in MLL-PTD patients. Interestingly, clonality analysis suggests that IDH2/1, DNMT3A, U2AF1 and TET2 mutations are clonal and occur early, and MLL-PTD likely arises after these initial mutations. Conversely, proliferative mutations (FLT3, RAS), typically appear later, are largely subclonal and tend to be unstable. This study provides important insights for understanding the relative importance of different mutations for defining a targeted therapeutic strategy for MLL-PTD AML patients.

Yue Wang,1 Qun Lin,1 Zhongju Chen,1 Hongyan Hou,1 Na Shen,1 Zhen Wang,2 Feng Wang,1 Ziyong Sun1 1Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China; 2Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of ChinaCorrespondence: Ziyong SunDepartment of Laboratory Medicine, Tongji Hospital, No. 1095 Jiefang Avenue, Wuhan, Hubei Province, 430030, People’s Republic of ChinaEmail zysun@tjh.tjmu.edu.cnBackground: To establish a risk prediction model for carbapenem-resistant Enterobacteriaceae (CRE) bloodstream infection (BSI) in intestinal carriers.Methods: CRE screenings were performed every two weeks in hematology department and intensive care unit (ICU). Patients with positive CRE rectal swab screening were identified using electronic medical records from 15 May 2018 to 31 December 2019. Intestinal carriers who developed CRE BSI were compared with those who did not develop CRE infection. A 1:1 matched case-control study was conducted. The control group was selected by stratified random sampling based on the department to ensure that all the departments were represented. Univariate logistic analysis, multivariate logistic analysis and stepwise regression analysis were carried on a variety of patient factors and microbial factors.Results: A total of 42 cases were included. Multivariate analysis showed that gastrointestinal injury (OR 86.819, 95% CI 2.584– 2916.592, P=0.013), tigecycline exposure (OR 14.991, 95% CI 1.816– 123.737, P=0.012) and carbapenem resistance score (OR 11.236, 95% CI 1.811– 69.700, P=0.009) were independent risk factors for CRE BSI in intestinal carriers (P< 0.050). They were included in the Logistic regression model to predict BSI. According to receiver operating characteristic (ROC) curve analysis, the cut-off value of the model was 0.722, and the sensitivity, specificity and area under the curve (AUC) were 90.5%, 85.7% and 0.921, respectively.Conclusion: The risk prediction model based on gastrointestinal injury, tigecycline exposure and carbapenem resistance score of colonizing strain can effectively predict CRE BSI in patients with CRE colonization. Early CRE screening and detection for inpatients in key departments may promote early warning and reduce the risk of nosocomial infection of CRE.Keywords: carbapenem-resistant Enterobacteriaceae, colonization, bloodstream infection, risk factor, risk prediction model

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

A new remote sensing technology for real-time isotopic analysis is introduced: Femtosecond Filament-Induced Laser Ablation Molecular Isotopic Spectrometry (F2-LAMIS). The technique combines femtosecond (fs) laser filamentation and ablation-based molecular isotopic spectroscopy, thereby enabling isotopic analysis of samples at a distance, in ambient air and at ambient pressure conditions. Isotopic analysis of zirconium (Zr) samples by F2-LAMIS is demonstrated, and the molecular and atomic emission intensity, and properties of the filament-induced plasma generated at different filament propagation distances were investigated. Spectral fitting of F2-LAMIS spectra enabled semi-quantitative isotopic analysis without the use of calibration standards, which was independent of the filament propagation distance for the studied range. This technology provides new capabilities for direct isotopic ratio measurements at remote distances.

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

Zaibing Li,1,2,* Jingyu Li,1,* Liyan Liu,1 Wenyi Deng,3 Qingrong Liu,4 Ruofan Liu,4 Wen Zhang,3 Zaiqing He,5 Lei Fan,6 Yingzhuo Yang,7 Yun Duan,7 Huifang Hou,1 Xinyuan Wang,1 Zhimei Yang,1 Xiaoying Wang,1 Shanze Chen,1 Yi Wang,1 Ning Huang,1 Junli Chen1 1Department of Pathophysiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, People’s Republic of China; 2Department of Pathophysiology, School of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan 646000, People’s Republic of China; 3West China Medical School, Sichuan University, Chengdu 610041, People’s Republic of China; 4West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, People’s Republic of China; 5Department of Pathology, Nuclear of Industry 416 Hospital, Chengdu, Sichuan 610051, People’s Republic of China; 6Department of Occupational Medicine, Nuclear of Industry 416 Hospital, Chengdu, Sichuan 610051, People’s Republic of China; 7Department of Nuclear Medicine, Sichuan Cancer Hospital, Chengdu 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junli Chen; Ning Huang Email chenjunlinsf@163.com; ninghuangcjl@163.comBackground: α2A-adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α2A-AR agonists are effective drugs for this condition. However, the lack of high selectivity for α2A-AR subtype of traditional drugs greatly limits their clinic usage.Methods: A series of homobivalent 4-aminoquinolines conjugated by two 4-aminoquinoline moieties via varying alkane linker length (C2-C12) were characterized for their affinities for each α2-AR subtype. Subsequently, docking, molecular dynamics and mutagenesis were applied to uncover the molecular mechanism.Results: Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for α2A-AR over α2B- and α2C-ARs. Besides, the affinities are of similar linker length-dependence for each α2-AR subtype. Among all the compounds tested, C10 has the highest affinity for α2A-AR (pKi=− 7.45± 0.62), which is 12-fold and 60-fold selective over α2B-AR and α2C-AR, respectively. Docking and molecular dynamics suggest that C10 simultaneously interacts with orthosteric and “allosteric” sites of the α2A-AR. The mutation of F205 decreases the affinity by 2-fold. The potential allosteric residues include S90, N93, E94 and W99.Conclusion: The specificity of C10 for the α2A-AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α2A-AR subtype selective compounds.Keywords: alpha2-adrenoceptor, selectivity, linker length, allosteric modulation

Neha Maharao,* Victor Antontsev,* Hypatia Hou, Jason Walsh, Jyotika Varshney VeriSIM Life Inc., San Francisco, CA, USA*These authors contributed equally to this workCorrespondence: Jyotika VarshneyVeriSIM Life Inc, 315 Montgomery St,10th Floor, San Francisco, CA 94104 USAEmail jo.varshney@verisimlife.comIntroduction: Transdermal drug delivery is gaining popularity as an alternative to traditional routes of administration. It can increase patient compliance because of its painless and noninvasive nature, aid compounds in bypassing presystemic metabolic effects, and reduce the likelihood of adverse effects through decreased systemic exposure. In silico physiological modeling is critical to predicting dermal exposure for a therapeutic and assessing the impact of different formulations on transdermal disposition.Methods: The present study aimed at developing a physiologically based transdermal platform, “BIOiSIM”, that could be globally applied to a wide variety of compounds to predict their transdermal disposition. The platform integrates a 16-compartment model of compound pharmacokinetics and was used to simulate and predict drug exposure of three chemically and biologically distinct drug-like compounds. Machine learning optimization was composed of two components: exhaustive search algorithm (coarse-tuning) and descent (fine-tuning) integrated with the platform used to quantitatively determine parameters influencing pharmacokinetics (eg permeability, kperm) of test compounds.Results: The model successfully predicted drug exposure (AUC, Cmax and Tmax) following transdermal application of morphine, buprenorphine and nicotine in human subjects, mostly with less than two-fold absolute average fold error (AAFE). The model was further able to successfully characterize the relationship between observed systemic exposure and intended pharmacological effect. The predicted systemic concentration of morphine and plasma levels of endogenous pain biomarkers were used to estimate the effectiveness of a given therapeutic regimen.Conclusion: BIOiSIM marks a novel approach to in silico prediction that will enable leveraging of machine learning technology in the pharmaceutical space. The approach to model development outlined results in scalable, accurate models and enables the generation of large parameter/coefficient datasets from in vivo clinical data that can be used in future work to train quantitative structure activity relationship (QSAR) models for predicting likelihood of compound utility as a transdermally administered therapeutic.Keywords: transdermal absorption, computational modeling, machine learning, BIOiSIM

Jingru Pan,1,* Ziqing Hei,1,* Liping Li,1 Dan Zhu,1 Hongying Hou,2 Huizhen Wu,1 Chulian Gong,1 Shaoli Zhou1 1Department of Anesthesiology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Obstetrics, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaoli Zhou; Chulian GongDepartment of Anesthesiology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, People’s Republic of ChinaTel +86-20-85252297Fax +86-20-87580876Email shaolizhou@139.com; gongchulian@163.comObjective: The aim of this study was to test whether the implementation of an enhanced recovery after surgery (ERAS) protocol for patients undergoing elective cesarean delivery has a positive impact on the postoperative status of the patients in terms of pain management, hospital stay, hospitalization costs, and adverse reactions.Methods: Patients who underwent elective cesarean delivery were randomized into two groups – ERAS group and control group – and the groups were managed with the ERAS protocol and traditional protocol, respectively.Results: Compared to the control group, the ERAS group had significantly fewer patients with intraoperative nausea, pain of visual analog scale (VAS) scores, and VAS grade > 3 during rest in the first 24 h and during motion in the first 24 and 48 h after surgery. There were no intergroup differences in the requirement of extra analgesics, the incidence of vomiting, shivering, hypotension, postoperative nausea, and pruritus. None of the patients in either group had postoperative vomiting. Patient satisfaction rated as per the VAS was significantly higher in the ERAS group than in the control group. The total length of stay, postoperative length of stay, and the cost of anesthesia in both groups were comparable. Further, the average daily hospitalization cost was significantly lower in the ERAS group than in the control group.Conclusion: The ERAS protocol shows promise and appears to be worthwhile for widespread implementation among patients undergoing elective cesarean delivery; it was found to be beneficial in reducing the postoperative pain, incidence of intraoperative nausea, and average cost of hospitalization and also improved patient satisfaction.Keywords: enhanced recovery after surgery, ERAS, cesarean delivery, pain

Di Liu,1,* Qihuan Li,1,2,* Jing Dong,3 Dong Li,4 Xizhu Xu,4 Weijia Xing,4 Xiaoyu Zhang,1 Weijie Cao,1 Haifeng Hou,4 Hao Wang,1,5 Manshu Song,1 Lixin Tao,1 Xiaoping Kang,6 Qun Meng,1 Wei Wang,1,4,5 Xiuhua Guo,1 Youxin Wang1 1Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing 100069, People’s Republic of China; 2Meinian Institute of Health, Beijing 100191, People’s Republic of China; 3Center for Physical Examination, Xuanwu Hospital, Capital Medical University, Beijing 100050, People’s Republic of China; 4School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong Province, People’s Republic of China; 5School of Medical and Health Sciences, Edith Cowan University, Perth 6027, Australia; 6The Rehabilitation Center, Beijing Xiaotangshan Hospital, Beijing 102211, People’s Republic of China*These authors contributed equally to this workCorrespondence: Youxin WangSchool of Public Health, Capital Medical University, 10 Youanmen Xitoutiao, Beijing 100069, People’s Republic of ChinaTel +86 10 83911779Email wangy@ccmu.edu.cn Xiuhua GuoSchool of Public Health, Capital Medical University, 10 Youanmen Xitoutiao, Beijing 100069, People’s Republic of ChinaTel +86 10 83911504Email guoxiuh@ccmu.edu.cnBackground: The mechanism by which normal body mass index (BMI) with central adiposity (NWCA) increases the risk of the diseases has not been completely elucidated. The inflammatory role of immunoglobulin G (IgG) N-glycosylation in obesity defined by BMI or central adiposity defined by waist-to-hip ratio (WHR) was reported, respectively. We undertook this three-center cross-sectional study to determine the association between the IgG N-glycans and NWCA.Methods: The participants were categorized into four different phenotypes: normal BMI with normal WHR (NW), normal BMI with central adiposity (NWCA), obesity with normal WHR (ONCA) and obesity with central adiposity (OCA). The IgG N-glycans were analyzed using ultra-performance liquid chromatography analysis of released glycans, and differences among groups were compared.Results: In total, 17 out of 24 initial IgG N-glycans were significantly different among the four groups (NW, ONCA, NWCA and OCA) (P

Since Huanglongbing (HLB) was first found in Florida, growers have recognized the importance of controlling the Asian citrus psyllid (ACP) that vectors the disease.   ACP management programs have been developed and applied over large acreages, yet in many instances, the incidence of the disease continues to increase.   When asked, the growers invariably report that they are controlling ACP and it is obvious that the control programs are reducing the level of ACP in the groves.  However there is an outstanding question as to whether the levels of ACP are being reduced enough to limit the spread of HLB.  In most cases, growers have not implemented ACP scouting programs so the level of infestation is based on rough grove surveys and feelings.  Even if scouting programs are in place, there are no established data-based thresholds to trigger additional applications of pesticides resulting in a “chasing” approach where applications are made after an infestation is found.  Southern Gardens has had an ACP and HLB scouting program in place for many years.  By comparing the annual ACP levels to resulting HLB infection succeeding years, it may be possible to elucidate thresholds and then design ACP control programs that effectively limit the spread of HLB.  Data will be presented for three years of ACP scouting and four years of HLB scouting in an attempt to show the level of control that must be achieved in order to limit the spread of HLB.  The bottom line is that control thresholds are very low and the level of ACP control that must be achieved in order to limit spread HLB is much lower than most growers realize.

The electronic structure, elastic and thermodynamic properties of Cu2MgSnS4 was studied based on density functional theory (DFT). The results show that Cu2MgSnS4 is a direct bandgap semiconductor. The B/G of Cu2MgSnS4 is greater than 1.75, indicating that Cu2MgSnS4 is a ductile material. Through the study of thermodynamic properties, it is found that the temperature increases, the bulk modulus B and Debye temperature Θ decrease, while the heat capacity CV, entropy S, Grüneisen constant γ and thermal expansion coefficient α increase, and the heat capacity is close to the Dulong-Petit limit. As the pressure increases, the bulk modulus B, Debye temperature Θ increases, while the entropy S, Grüneisen constant γ and heat capacity CV decrease. [ABSTRACT FROM AUTHOR]

Yue Xu,1 Chunyun Lai,2 Guogang Xu,3 Wenwen Meng,3 Jie Zhang,1 Huiru Hou,4,* Hongying Pi1,*1Department of Nursing, Chinese People’s Liberation Army (PLA) General Hospital, Chinese PLA Medical Academy, Beijing, People’s Republic of China; 2Department of Respiratory, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, People’s Republic of China; 3The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, People’s Republic of China; 4Department of Nursing, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this work Purpose: The aim of this study was to verify the potential risk factors of ventilator-associated pneumonia (VAP) in elderly Chinese patients receiving mechanical ventilation (MV). The secondary aim of this study was to present logistical regression prediction models of VAP occurrence in elderly Chinese patients receiving MV.Methods: Patients (aged 80 years or above) receiving MV for ≥48 h were enrolled from the Chinese People’s Liberation Army (PLA) General Hospital from January 2011 to December 2015. A chi-squared test and Mann–Whitney U-test were used to compare the data between participants with VAP and without VAP. Univariate logistic regression models were performed to explore the relationship between risk factors and VAP.Results: A total of 901 patients were included in the study, of which 156 were diagnosed as VAP (17.3%). The incidence density of VAP was 4.25/1,000 ventilator days. Logistic regression analysis showed that the independent risk factors for elderly patients with VAP were COPD (OR =1.526, P

Luwei Cui,1,2 Ming Liu,2 Shicong Lai,2,3 Huimin Hou,2,3 Tongxiang Diao,1,2 Dalei Zhang,2 Miao Wang,2,3 Yaoguang Zhang,1,2 Jianye Wang1,21Peking University Fifth School of Clinical Medicine, Beijing, People’s Republic of China; 2Department of Urology, Beijing Hospital, National Center of Gerontology, Beijing, People’s Republic of China; 3Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaBackground: Prostate cancer is the second leading cause of cancer-related deaths in Western countries. Most patients diagnosed with advanced prostate cancer can be treated with the main treatment: androgen deprivation therapy (ADT). The androgen receptor (AR) signaling axis plays a pivotal role in the progression of prostate cancer. However, most patients can ultimately progress to the castration-resistant prostate cancer (CRPC) stage within 2 years. At this stage, drugs targeting the AR signaling axis, including enzalutamide and abiraterone acetate, cannot prevent the progression of prostate cancer, thus predicting a poor prognosis. The molecular mechanism lies in the aberrant AR reactivation, which exhibits an adaptive response to ADT, such as the presence of AR splice variants. Thus, CRPC treatment remains a challenge.Purpose: In addition to the AR axis, a mechanism leading to this progression should be determined. The present study mainly compared palmitoylated proteins between androgen-treated LNCaP cells and non-treated LNCaP cells by palmitoylome profiling, to illustrate the changes at proteomic levels.Materials and methods: To screen the androgen-induced palmitoylated proteins, we conducted proteomic experiments using clickable palmitate probe (Alk-C16) between three individual pairs of androgen-treated and non-treated LNCaP cells.Results: We identified 4351 unique peptides corresponding to 835 proteins, among them a number of these identified proteins were palmitoylated proteins, particularly eIF3L. Androgen treatment significantly increased the palmitoylation level of eIF3L, an individual subunit of eIF3. As an initiation factor, eIF3L plays a pivotal role in the translation of mRNAs encoding growth-promoting proteins by enhancing translation rates, thus controlling cell proliferation.Conclusion: In this study, we demonstrated that the regulation of eIF3L palmitoylation may provide new directions for the therapy of prostate cancer. Moreover, the increased level of androgen-induced eIF3L may be used as a biomarker for the diagnosis of early-stage prostate cancer.Keywords: androgen, palmitoylation, eIF3L, prostate cancer, biomarker

Helei Hou,* Kang Qin,* Yu Liang, Chuantao Zhang, Dong Liu, Haiping Jiang, Kewei Liu, Jingjuan Zhu, Hongying Lv, Tianjun Li, Xiaochun ZhangDepartment of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of China*These authors contributed equally to this work Purpose: The study investigated the impact of TP53 mutations on the clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors (TKIs) in Chinese patients with advanced or recurrent non-small-cell lung cancer (NSCLC).Patients and methods: Tissues from 163 NSCLC patients at the Affiliated Hospital of Qingdao University were analyzed by next-generation sequencing (NGS) to determine the mutational status of EGFR and concurrent genetic alterations. TP53 mutations were evaluated in relation to baseline patient characteristics and treatment outcomes (progression-free survival [PFS], overall survival [OS], objective response rate [ORR] and disease control rate [DCR]).Results: Among 163 patients with advanced NSCLC, 77 were identified as EGFR-mutant (47.2%). Six patients who did not receive TKI treatment were excluded. Among the remaining 71 patients with EGFR genetic alterations, the frequency of pathogenic TP53 mutations was 60.6% (43/71), while other concurrent mutations were rare events. Markedly shorter median PFS (mPFS) (6.5 versus 14.0 months, P=0.025) and median OS (mOS) (28.0 versus 52.0 months, P=0.023) were observed in TP53-mut patients than in TP53-wt controls. The overall DCR and ORR of TP53-mutant patients were both lower than those of the TP53-wt cases (DCR: 76.7% versus 89.3%, P=0.160; ORR: 25% versus 28%, P=0.374). Differences in prognosis were significant, especially in the subgroup of patients with TP53 non-missense mutations, non-disruptive mutations, mutations in exon 6, mutations in exon 7 and mutations in the non-DBD region among all TP53 mutations.Conclusion: TP53 mutations reduce responsiveness to TKIs and worsen the prognosis of EGFR-mutant NSCLC patients, especially for those with non-missense mutations and non-disruptive mutations, as well as mutations in exon 6, exon 7 and non-DBD region, thus acting as an independent predictor of poor outcome in advanced NSCLC patients treated with first-generation TKI therapy. Our study also suggests that TP53 mutation might be involved in primary resistance to EGFR-TKIs in Chinese NSCLC patients.Keywords: TP53, epidermal growth factor receptor, tyrosine kinase inhibitors, non-small-cell lung cancer, mutation, exon

Helei Hou,* Dantong Sun,* Kewei Liu, Man Jiang, Dong Liu, Jingjuan Zhu, Na Zhou, Jing Cong, Xiaochun ZhangDepartment of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, People’s Republic of China*These authors contributed equally to this workBackground: A total of 2%–7% of non-small cell lung cancer (NSCLC) patients have anaplastic lymphoma kinase (ALK) mutations. At present, three or more generations of ALK inhibitors have been used for ALK-positive NSCLC treatment, including crizotinib, alectinib, ceritinib, and brigatinib. Although most adverse events (AEs) of ALK inhibitors are grades 1 to 2 and generally can be well tolerated, serious adverse events (SAEs) of ALK inhibitors lack data analysis, and the lung toxicity of ALK inhibitors needs attention. Thus, we performed this meta-analysis to evaluate the safety of ALK inhibitors, especially in terms of drug-related SAEs.Methods: A total of 19 studies from 4 databases (PubMed, Science Direct, ClinicalTrials.gov and Cochrane Library) were included in this meta-analysis. All statistical analyses in this meta-analysis were performed with the STATA 14.0 software. We analyzed the incidences of total AEs, total SAEs and SAEs for different ALK inhibitors.Results: AEs of the ALK inhibitors occurred in almost all participants, and SAEs occurred in more than 20% of the participants. For ceritinib and brigatinib, SAEs occurred in more than 40% of the participants. Alectinib is most likely the safest of the two generations of ALK inhibitors. Generally, the ALK inhibitors showed significant lung toxicity.Conclusion: In conclusion, attention should be focused on ALK inhibitor-related SAEs, especially lung toxicity. According to this meta-analysis, alxectinib seems to be the safest ALK inhibitor. Physicians should focus on the related SAEs when prescribing ALK inhibitors.Keywords: ALK inhibitors, safety, serious adverse events, lung toxicity

Dantong Sun, Helei Hou, Chuantao Zhang, Xiaochun Zhang Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China Background and purpose: Apatinib is a novel, oral, small-molecule tyrosine kinase inhibitor that targets VEGFR-2. Recent clinical trials have revealed its broad-spectrum anticancer effect. However, most recent studies of apatinib have involved single-arm studies with insufficient cases, different doses of drugs, and different incidences of adverse events (AEs), which has resulted in a lack of accurate measurement of the efficacy and safety of apatinib. Thus, we performed this meta-analysis to evaluate the efficacy and safety of apatinib.Methods: In total, 21 studies from five databases (PubMed, ScienceDirect, ClinicalTrials.gov, China National Knowledge Infrastructure [CNKI], and Cochrane Library) were included in this meta-analysis. All statistical analyses in this meta-analysis were performed using Stata 14.0 software. We used objective response rate (ORR) and disease control rate (DCR) to evaluate the efficacy of apatinib for five major types of solid tumors. Additionally, we used the total incidence of AEs and the incidence of the three most common grade 3–4 AEs to evaluate the safety of apatinib.Results: The pooled results for the efficacy of apatinib in the treatment of different types of solid tumors revealed that patients treated with apatinib exhibited good disease control. In addition, it was likely that an increased dose of apatinib resulted in an increased ORR in lung and breast cancer and an increased DCR in liver and gastric cancer. Although AEs appeared in 84% of patients included in this meta-analysis, most of these AEs were of grades 1–2 and were well tolerated and controlled. The most common grade 3–4 AEs included hypertension, hand-foot syndrome, and proteinuria. Importantly, there were no significant differences in these grade 3–4 AEs with higher doses of apatinib.Conclusion: Apatinib is a novel VEGFR-2 inhibitor with proven efficacy and safety for solid tumors. The meta-analysis reveals the broad-spectrum anticancer effect of apatinib. Keywords: apatinib, solid tumors, objective response rate, disease control rate, adverse events

Deze Zhao, Helei Hou, Xiaochun Zhang Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China Abstract: With the investigation of molecular targets, many agents, such as trastuzumab and ramucirumab, have attained a positive outcome in oncotherapy. Vascular endothelial growth factor (VEGF) is considered a potent factor in angiogenesis and plays an important role in the growth of tumors. Moreover, both VEGF and its receptor are usually excessively expressed in solid tumors and could be hopeful targets for the treatment of neoplasms. Apatinib (YN968D1) is an oral small-molecule tyrosine kinase inhibitor of VEGFR-2. By inhibiting several signaling transduction pathways, it restrains angiogenesis and subsequently controls tumorigenesis. According to current studies, apatinib shows promising application in various solid tumors as a post-second- and post-third-line treatment. It could significantly improve the median overall survival and progression-free survival of patients with tolerated adverse reactions. This paper aims to summarize the recent research on apatinib including the mechanism, pharmacokinetics, trials, adverse reactions, and prospect as a treatment. Keywords: VEGF, VEGFR-2, apatinib, angiogenesis, solid tumors, gastric cancer