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Luyao Liu,1 Wang Xiao,2 Chaojie Zhang,1 Peizhi Fan,1 Jie Zeng,1 Jianing Yi1 1Department of Breast and Thyroid Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People’s Republic of China; 2Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Jianing Yi; Jie Zeng, Department of Breast and Thyroid Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, 61 Jiefang West Road, Changsha, Hunan, 410005, People’s Republic of China, Tel +8613007436234 ; +8613974837749, Email yijianing@hunnu.edu.cn; zengjie227@hunnu.edu.cnBackground: Breast cancer (BC) continues to pose a substantial challenge to global health, necessitating an enhanced understanding of its fundamental mechanisms. Among its various pathological classifications, breast invasive carcinoma (BRCA) is the most prevalent. The role of the transcription factor forkhead box P3 (FOXP3), associated with regulatory T cells, in BRCA’s diagnosis and prognosis remains insufficiently explored, despite its recognized importance.Methods: We examined the mRNA expression profile of FOXP3 in BRCA patients, assessing its correlation with disease detection, patient survival, immune checkpoint alterations, and response to anticancer drugs.Results: Our analysis revealed significantly elevated FOXP3 mRNA levels in BRCA patients, with a 95.7% accuracy for BRCA detection based on the area under the curve. High FOXP3 mRNA levels were positively correlated with overall survival and showed significant associations with CTLA4, CD274, PDCD1, TMB, and immune cell infiltration status. Furthermore, FOXP3 mRNA expression was linked to the efficacy of anticancer drugs and the tumor inflammation signature.Discussion: These findings suggest that FOXP3 serves as a promising biomarker for BRCA, offering valuable insights into its diagnosis and prognosis. The correlation between FOXP3 expression and immune checkpoint alterations, along with its predictive value for treatment response, underscores its potential in guiding therapeutic strategies.Conclusion: FOXP3 stands out as an influential factor in BRCA, highlighting its diagnostic accuracy and prognostic value. Its association with immune responses and treatment efficacy opens new avenues for research and clinical applications, positioning FOXP3 as a vital target for further investigation in BRCA management.Keywords: breast cancer, FOXP3, regulatory T cells, immune checkpoint alterations, anticancer drugs response, immune cell infiltration

Haibang Pan,1,&ast; Tianming Wang,1,2,&ast; Ying Che,3,4 Xiaoli Li,1,5 Yan Cui,1 Quanxin Chen,1 Zhihang Wu,1 Jianfeng Yi,1 Bo Wang3 1First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China; 2Gansu Provincial Key Laboratory of Traditional Chinese Medicine Recipe Mining and Innovation Transformation, Gansu Province New Production of Traditional Chinese Medicine Product Creation Engineering Laboratory, Lanzhou, People’s Republic of China; 3School of Nursing, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China; 4Research Ward, Gansu Provincial People’s Hospital, Lanzhou, People’s Republic of China; 5Gansu Provincial Maternity and Child-Care Hospital, Lanzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Wang; Jianfeng Yi, Email wbbphb@gszy.edu.cn; yijf02@163.comIntroduction: Skin and soft tissue infection (SSTI) is a frequently encountered clinical disease, and Sanhuang ointment, a traditional Chinese medicine, is used to treat it. However, the pharmacological effect of Sanhuang ointment on SSTI and its underlying mechanism remains unclear. Here, we investigate the protective effect of Sanhuang ointment on Methicillin-resistant Staphylococcus aureus (MRSA) infection in the skin and soft tissues and the underlying mechanism by network pharmacological analysis, followed by in vivo experimental validation.Methods: Via network pharmacology, the active components and disease targets of Sanhuang ointment were screened and intersected for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A rat model of skin and soft tissue infection was established, and pathological features were observed. Large, medium, and small-dose groups (1 g, 0.5 g, and 0.25 g/animal, with the total amount of Vaseline, dispensed 1 g/animal) of Sanhuang ointment were prepared and Mupirocin ointment was used as a positive control (0.5 g/animal, with the total amount of Vaseline, dispensed 1 g/animal). The expressions of key proteins of the IL-17/NF-κB signaling pathway and downstream inflammatory factors were analyzed by histomorphological analysis, enzyme-linked immunosorbent assay, polymerase chain reaction, and Western blotting.Results: In all, 119 active components and 275 target genes of Sanhuang ointment were identified and intersected with MRSA infection-related genes via network pharmacology analysis, and 34 target genes of Sanhuang ointment were found to be involved in skin and soft tissue infections with MRSA. Sanhuang ointment (1 g/mouse) could effectively ameliorate histopathological changes and significantly inhibit the expression of key proteins involved in the IL-17/NF-κB signaling pathway and downstream inflammatory factors (p < 0.05).Conclusion: Sanhuang ointment has a protective effect on MRSA infection and inhibits inflammation by inhibiting the IL-17/NF-κB signaling pathway. Our findings are important for the secondary development and new drug development of Sanhuang ointment.Plain Language Summary: Sanhuang ointment can significantly inhibit inflammatory response after skin and soft tissue infection with MRSA.Sanhuang ointment may inhibit the inflammatory response induced by MRSA in the skin and soft tissue infections by targeting the IL-17/NF-κB signaling pathway.We study the active components and mechanism of action of Sanhuang ointment on MRSA infection through network pharmacology.Keywords: Sanhuang ointment, MRSA, SSTI, network pharmacology, IL-17, NF-κB

Junlan Tan,1,2 Jian Yi,2,3 Xianya Cao,1,2 Feiying Wang,2,4 Silin Xie,2,4 Aiguo Dai2,4,5 1School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China; 2Hunan Provincial Key Laboratory of Vascular Biology and Translational Medicine, Changsha, Hunan, 410208, People’s Republic of China; 3The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, 410021, People’s Republic of China; 4Department of Respiratory Diseases, School of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China; 5Department of Respiratory Medicine, the First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, 410021, People’s Republic of ChinaCorrespondence: Aiguo Dai, Department of Respiratory Diseases, School of Medicine, Hunan University of Chinese Medicine, 300 Xueshi Road, Hanpu Science and Education District, Changsha, Hunan, 410208, People’s Republic of China, Tel +86-731-88458128, Fax +86-731-88458111, Email daiaiguo@hnucm.edu.cnAbstract: Respiratory diseases are an emerging public health concern, that pose a risk to the global community. There, it is essential to establish effective treatments to reduce the global burden of respiratory diseases. Astragaloside IV (AS-IV) is a natural saponin isolated from Radix astragali (Huangqi in Chinese) used for thousands of years in Chinese medicine. This compound has become increasingly popular due to its potential anti-inflammatory, antioxidant, and anticancer properties. In the last decade, accumulated evidence has indicated the AS-IV protective effect against respiratory diseases. This article presents a current understanding of AS-IV roles and mechanisms in combatting respiratory diseases. The ability of the agent to suppress oxidative stress, cell proliferation, and epithelial-mesenchymal transition (EMT), to attenuate inflammatory responses, and modulate programmed cell death (PCD) will be discussed. This review highlights the current challenges in respiratory diseases and recommendations to improve disease management.Keywords: astragaloside IV, Radix astragali, respiratory diseases, oxidative stress, inflammatory responses

Yanyan Ma,1,&ast; Ying Cao,2,&ast; Hong Gao,3 Rui Tong,1 Jing Yi,3 Zhongwei Zhang,1 Rui Chen,1 Zhijun Pan1 1School of Anesthesia, Guizhou Medical University, Guiyang, People’s Republic of China; 2Department of Anesthesiology, The Second People’s Hospital of Guiyang, Guiyang, People’s Republic of China; 3Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Gao, Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, No. 9 Beijing Road, Guiyang, People’s Republic of China, Email 2169617@qq.com; anesth@qq.comPurpose: This study investigated the effect of exosomes derived from sevoflurane-treated cardiac fibroblasts (Sev-CFs-Exo) on reperfusion arrhythmias (RA), ventricular conduction, and myocardial ischemia-reperfusion injury (MIRI).Methods: Primary cardiac fibroblasts (CFs) were isolated from the hearts of neonatal rats and identified by morphology and immunofluorescence. Exosomes were isolated from CFs at passages 2– 3 after they had been treated with 2.5% sevoflurane for an hour and cultivated for 24– 48 hours. The control group was CFs that did not receive any treatment. The hypothermic global ischemia-reperfusion injury model was established using the Langendorff perfusion technique following injection with exosomes through the caudal vein. Multi-electrode array (MEA) mapping was used to investigate the changes in RA and ventricular conduction in isolated hearts. Western blots and immunofluorescence were used to examine the relative expression and location of connexin 43 (Cx43). In addition, the MIRI was evaluated with triphenyl tetrazolium chloride and Hematoxylin-Eosin staining.Results: The primary CFs had a variety of morphologies, no spontaneous pulsation, and were vimentin-positive, which confirmed their successful isolation. Sev-CFs-Exo increased the heart rate (HR) at reperfusion for 15 minutes (T2) and 30 minutes (T3) and lowered the score and duration of RA and the time for restoration of heartbeat in reperfusion. Meanwhile, Sev-CFs-Exo increased conduction velocity (CV), decreased absolute inhomogeneity (P5-95) and inhomogeneity index (P5-95/P50) at T2 and T3, as well as promoted the recovery of HR, CV, P5-95 and P5-95/P50 after hypothermic global ischemia-reperfusion injury. Furthermore, Sev-CFs-Exo raised expression and reduced lateralization of Cx43, and improved myocardial infarct sizes and cellular necrosis. However, while cardiac fibroblast-derived exosomes (CFs-Exo) showed similar cardioprotective effects, the outcomes were not as significant.Conclusion: Sevoflurane reduces the risk of RA and improves ventricular conduction and MIRI by CFs-Exo, and this may be driven by the expression and location of Cx43.Keywords: anesthetic, extracellular vesicles, arrhythmia, electrophysiology, electrical mapping, connexin 43, Cx43

Sofia V Krylova, Sara Glickman, Ali Kalam, Katherine Chemakin, Joseph Yi, Linda Forrester, Priti Mishall, Adi Pinkas Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USACorrespondence: Adi Pinkas, Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, F620S, Bronx, NY, 10461, USA, Email adi.pinkas@einsteinmed.eduAbstract: The thoracic cavity contains vital cardiovascular and pulmonary structures. Few congenital anatomical variations in the bronchial tree and pulmonary vasculature have been reported. Understanding such variants is crucial during surgical procedures that involve the thorax. During routine dissection of an 89-year-old male cadaver as part of a first-year anatomy course, an anomaly of the bronchial tree was discovered. The left lung hilum was notable for the pulmonary artery being posterior to the mainstem bronchus. The case report describes normal lung development and anatomy and the significance of this novel variation in which has not been previously described in the literature.Keywords: pulmonary artery, bronchus, lung, pulmonary vein, thoracic region

Zixia Ding,1,2,&ast; Qian Song,1,2,&ast; Jun Chu,1,2 Tao Zou,3 Kaili Zheng,1,2 Zhaoxia Liu,1,2 Wanrong Peng,1,2 Jinyao Yi1,2,4 1Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Medical Psychology Institution, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Department of Psychiatry, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, People’s Republic of China; 4National Clinical Research Center for Mental Disorders, Changsha, Hunan, 410011, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinyao Yi, Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China, Email jinyaoyi@csu.edu.cnBackground: The present study investigated the applicability of the Cognitive Emotion Regulation Questionnaire (CERQ) in the Chinese community elderly and explored the influence of cognitive emotion regulation strategies on late-life depression.Methods: A total of 367 community elderly aged 60– 94 were deemed eligible and completed CERQ, the Perceived Stress Scale-10, the Geriatric Depression Questionnaire-15, and the State Anxiety Inventory. Confirmatory factor analysis was adopted to verify the 9-factor structure of CERQ. Cronbach’s α coefficient, Ω coefficient and split-half reliability were used to test the internal consistency of CERQ. Pearson correlations among scores of CERQ and other scales were calculated to examine its convergent validity. In addition, a structural equation model was used to further examine the effect of cognitive emotion regulation strategies on the association between perceived stress and late-life depression.Results: All the fitting indexes of CERQ’s 9-factor model met the criterion (χ2/df= 2.26, CFI= 0.916, TLI= 0.904, RMSEA= 0.052). For the total score of CERQ, the Cronbach’s α coefficient and Ω coefficient were both 0.90, and the split-half reliability was 0.74. For the nine subscales, the α coefficients ranged from 0.66 to 0.88, and the Ω coefficients ranged from 0.69 to 0.88. Significant positive correlations were found between the maladaptive dimension of CERQ and other scales (all p < 0.001). The maladaptive emotion regulation strategies indirectly affected the effect of perceived stress on late-life depression (effect size was 21.57%).Conclusion: With good reliability and factor validity, the CERQ showed good applicability in the Chinese elderly population. The influence of perceived stress on depression in the elderly was mediated by maladaptive emotion regulation strategies.Keywords: cognitive emotion regulation, late-life depression, perceived stress, psychometric properties, mediating effect

Pan Su,1 Jindong Yi,1 Xiuwen Chen,2 Yao Xiao3– 5 1Teaching and Research Section of Clinical Nursing, Emergency Department, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Teaching and Research Section of Clinical Nursing, Department of Operating Room, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of General Surgery, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standards, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 5National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Yao Xiao; Xiuwen Chen, Email yaoxiao@csu.edu.cn; chenxiuwen2020@163.comBackground: The importance of psychological resilience that people show in coping with stress and adversity is prominent, but few studies have used rigorous bibliometric tools to analyze the knowledge structure and distribution of psychological resilience research.Objective: The purpose of this study was to sort out and summarize the previous studies on psychological resilience by using bibliometrics. Specifically, the time distribution of psychological resilience research was determined by publication trend, the power distribution was determined by the distribution of countries, authors, institutions and journals, the hot research spots were analyzed according to the results of keyword cluster analysis, and the research frontier was explored according to the results of burst keywords.Methods: CiteSpace5.8.R3 was used to analyze the literatures on psychological resilience collected in Web of Science core Collection database from January 1, 2010, to June 16, 2022.Results: A total of 8462 literatures were included after screening. Research on psychological resilience has been on the rise in recent years. The United States had made a high contribution in this field. Robert H Pietrzak, George A Bonanno, Connor KM and others were highly influential. J Pers Soc Psychol has the highest citation frequency and centrality. The research hot spots focus on five aspects: study on psychological resilience related to COVID-19 pandemic, influencing factors of psychological resilience, psychological resilience related to PTSD, study on psychological resilience of special population, and the molecular biology and genetic basis of psychological resilience. Psychological resilience related to COVID-19 pandemic was the most cutting-edge research aspect.Conclusion: The current situation and trend of psychological resilience research were found in this study, which may be used to identify more hot issues and explore new research directions in this field.Keywords: psychological resilience, CiteSpace, hot spots, visualization

Lei Yang,1,2 Weimin Dang,2,3 Xin Yu,1,2 Yi He,4,5 Chuan Shi,1,2 Jialong Yi,1,2 Lu Gao,6 Siheng Li,7 Tianhang Zhou,1,2 Yantao Ma1,2 1Department of Clinical Research, Peking University Sixth Hospital (Institute of Mental Health), Beijing, People’s Republic of China; 2NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, People’s Republic of China; 3The Division of Medical Affairs, Peking University Sixth Hospital (Institute of Mental Health), Beijing, People’s Republic of China; 4Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, People’s Republic of China; 5Department of Psycho-Oncology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 6Department of Stomatology, Beijing Children’s Hospital, Capital Medical University, Beijing, People’s Republic of China; 7Department of Neurology, Peking University First Hospital, Beijing, People’s Republic of ChinaCorrespondence: Xin Yu, Peking University Sixth Hospital, No. 51 Hua Yuan Bei Road, Haidian District, Beijing, 100191, People’s Republic of China, Tel +86 13718747842, Fax +86-10-62026310, Email yuxin@bjmu.edu.cnIntroduction: Processed betel quid product chewing is a public health problem in areca non-plant areas in China. However, there is no valid instrument to screen for betel quid use disorder (BQUD) in mainland China. We developed a self-administered screening test for betel quid use disorders (SST-BQUD) and tested its reliability and validity in a sample of betel quid chewers (BQCers) in Hunan, China.Methods: Items of SST-BQUD were selected from the test results of an item pool, which includes 52 questions related to the psycho-social and behavioral presentations of BQUD. All participants, in a self-administered manner, completed the item pool. A subsample completed the re-test one week later. Two psychiatrists interviewed all participants to ascertain the presence of BQUD. The receiver Operating Characteristic curve was used to determine the best cut-off value to discriminate BQUD.Results: One hundred and twelve BQCers were recruited. Based on the statistical analysis of receiver operating characteristic (ROC) curves, 14 yes/no questions were selected for SST-BQUD. As indicated by Cronbach’s α coefficient, the internal consistency was 0.876. The area under the curve of SST-BQUD was 0.881, representing a satisfactory diagnostic value. The one-week re-test reliability test was 0.771 (P< 0.001), suggesting good stability over time. The optimal cut-off score for BQUD screening was six, with a sensitivity of 0.921 and a specificity of 0.716, implying the satisfactory accuracy of SST-BQUD to screen for BQUD.Conclusion: The standard version of SST-BQUD consists of 14 items. The total score of SST-BQUD was the sum of affirmative answers, with higher scores denoting a more severe BQUD symptom. If one answered six or more times “yes” to these 14 questions, they can be classified with BQUD. The SST-BQUD is a valid screening method for BQUD among BQCers in betel quid processed area.Keywords: betel quid use disorders, screener, development, validity, diagnostic test

Ping Yang,1,2 Chao Liu,3 Zhenchao Wu,2 Jiajia Zheng,4 Juan Yi,1 Nan Wu,2 Zhangli Wu,1,2 Ming Lu,2,3 Liyan Cui,4,&ast; Ning Shen1– 3,&ast; 1Institute of Medical Technology, Peking University Health Science Center, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 3Department of Infectious Diseases, Peking University Third Hospital, Beijing, People’s Republic of China; 4Department of Laboratory Medicine, Peking University Third Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liyan Cui; Ning Shen, Email cliyan@163.com; shenningputh@163.comPurpose: This study aimed to identify the clinical outcomes, microbiological features and risk factors for difficult-to-treat resistance (DTR) Klebsiella pneumoniae (Kp) infection.Materials and Methods: A retrospective study was conducted at Peking University Third Hospital from January 2020 to March 2021. DTR was defined as resistance to ≥ 1 carbapenem, ≥ 1 extended-spectrum cephalosporin, and ≥ 1 fluoroquinolone. Hypervirulent Kp (HvKp) was defined as peg-344-, iroB-, iucA-, rmpA-, or rmpA2-positive. Clinical data were collected. Antimicrobial susceptibility testing and string tests were performed to determine resistance and hypermucoviscosity phenotype. Whole genome sequencing was performed to analyze the sequence type (ST), capsular serotypes, resistance and virulence genes. Risk factors for 30-day mortality were analyzed.Results: Fifty DTR-Kp (50.0%) strains were identified among 100 patients. Compared to non-DTR-Kp group, a significant number of patients with DTR-Kp infection experienced ICU admission (44.0% versus 10.0%, P< 0.001) and mechanical ventilation after Kp detection (26.0% versus 10.0%, P=0.037). Notably, the percentage of hvKp among the DTR-Kp isolates increased consistently over the 15 months evaluated. Most DTR-Kp strains belonged to ST11 (82.0%), followed by ST15 (12.0%), ST86 (2.0%), ST996 (2.0%), and ST3157 (2.0%). DTR-Kp isolates possessed various resistance genes, such as blaKPC-2, blaTEM-1D and fosA3 (90.0%, 80.0% and 72.0%, respectively). Importantly, the yersiniabactin genes were significantly clustered in DTR group (48/50, 96.0%). The 30-day mortality was significantly higher in patients with DTR-Kp infection than non-DTR-Kp group (38.0% versus 8.2%, P=0.001). DTR-Kp infection (odds ratio [OR] = 4.196) was an independent risk factor for the 30-day mortality of Kp-infected patients. Additionally, cerebrovascular disease (OR = 2.780) and Charlson comorbidity index (OR= 1.584) were independent risk factors for DTR-Kp infections.Conclusion: DTR-hvKp is rapidly emerging. The DTR-Kp strains harbored various resistance genes and high rates of yersiniabactin siderophore genes. DTR-Kp infection was an independent risk factor for mortality, suggesting that enhanced awareness essential.Keywords: Klebsiella pneumoniae, difficult-to-treat resistance, mortality, risk factor

Donghui Cao,1,&ast; Tongrong Su,2,&ast; Yanhua Wu,1 Zhifang Jia,1 Yingli Fu,1 Yuanlin Sun,2 Meishan Jin,3 Yueqi Wang,1 Jiaxin Yi,1 Yingnan Cui,2 Yuzheng Zhang,1 Haiyong Lv,1 Limei Qu,3 Jing Jiang,1 Xueyuan Cao2 1Division of Clinical Epidemiology, The First Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, People’s Republic of China; 3Division of Pathology, First Hospital of Jilin University, Changchun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xueyuan Cao, Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China, Email jd3d2ub@jlu.edu.cnPurpose: Gastric cancer (GC) remains a prevalent aggressive tumor with high morbidity and mortality globally. The identification of GC subtypes based on molecular features improved the prediction of prognosis and the selection of targeted therapies. PTEN is a characteristic tumor suppressor, while its association with different GC subtypes was unknown.Patients and Methods: The cohort consisted of 248 patients diagnosed with gastric cancer who were hospitalized and received radical gastrectomy. In addition, PTEN gene expression matrix of STAD was retrieved from TCGA. The mRNA and protein levels of PTEN and PD-L1 were detected using qRT-PCR and IHC staining. Multivariate logistic regression and Kaplan–Meier analysis were used to examine the relationship between PTEN expression and clinical characteristics.Results: In our study, PTEN was downregulated in gastric tumors both in mRNA and protein levels. Its inactivation was closely linked to higher histological grade (P = 0.005), neural invasion (P = 0.012), depth of invasion (P = 0.021), lymph metastasis (P = 0.026), and TNM stage (P = 0.001) of GC in the present study. Moreover, according to the molecular subtypes, high PTEN expression was related to high TPS score of PD-L1 positively (P = 0.010) but was not associated with MSI and EBV infection. Further, TCGA data validated that PTEN was indeed correlated with histological grade and invasion depth and positively related to PD-L1 expression (R = 0.29, adjusted P < 0.001).Conclusion: The above results suggested that PTEN expression was a useful marker in gastric carcinogenesis and progression and in the selection of immunotherapy-based treatments for GC patients.Keywords: gastric cancer, PTEN, molecular subtype, PD-L1, biomarker

Hao Yu,1,2 Jie Yi,1 Ya-ling Dou,1 Yu Chen,1 Ling-jun Kong,1 Jie Wu1 1Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Laboratory Medicine, Beijing Hepingli Hospital, Beijing, People’s Republic of ChinaCorrespondence: Jie WuDepartment of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing, 100730, People’s Republic of ChinaTel +86 106 915 9701Email wujie_pumch@163.comObjective: Human papillomavirus (HPV) infection, especially with high-risk HPV (HR-HPV) genotypes, is closely associated with cervical cancer. This study aimed to observe the epidemiological characteristics of HPV infection among healthy women in Beijing, China.Materials and Methods: Cervical specimens were collected from 29,436 healthy women, who underwent health check-ups in Peking Union Medical College Hospital between 2016 and 2019. A commercial kit was used for the detection of 15 HR-HPV and two low-risk HPV (LR-HPV) genotypes.Results: A total of 3586 (12.18%) participants tested positive for HPV, 3467 of which were infected with HR-HPVs. The most prevalent genotypes were HPV52, 58, 16, 51, and 56. Moreover, while infection with a single genotype (9.84%) was more prevalent, HPV16+52 was the most common combination in those infected with multiple HPVs. Furthermore, the highest infection rate among age groups was in women aged < 25 years (20.92%). No significant difference in the prevalence was observed from 2016 to 2019. However, HPV incidence in Beijing was significantly different than that in all other areas in China, except for Zhengzhou (p < 0.05).Conclusion: Our findings could serve as potential reference for better understanding of the epidemiological characteristics of HPV infection in Beijing.Keywords: human papillomavirus, cervical cancer, prevalence, genotype

Miao Chen,1,2 Weimin Lin,1 Jianru Yi,1,2 Zhihe Zhao1,2 1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China; 2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Jianru Yi; Zhihe Zhao Tel +86-28-85503040; +86-28-85503645Email jianruyi@scu.edu.cn; zhzhao@scu.edu.cnPurpose: Genetic factors in type 2 diabetes (T2D) pathogenesis have been widely explored by the genome-wide association studies (GWAS), identifying a great amount of susceptibility loci. With the development of high-resolution sequencing, the N(6)-methyladenosine (m6A) RNA modification has been proved to be affected by genetic variation. In this study, we identified the T2D-associated m6A-SNPs from T2D GWAS data and explored the underlying mechanism of the pathogenesis of T2D.Methods: We examined the association of m6A-SNPs with T2D among large-scale T2D GWAS summary statistics and further performed multi-omics integrated analysis to explore the potential role of the identified m6A-SNPs in T2D pathogenesis.Results: Among the 15,124 T2D-associated m6A-SNPs, 71 of them reach the genome-wide significant threshold (5.0e-05). The leading SNP rs4993986 (C>G), which is located near the m6A modification site at the 3ʹ end of the HLA-DQB1 transcript, is expected to participate in the pathogenesis of T2D by influencing m6A modification to regulate the HLA-DQB1 expression.Conclusion: The current study has suggested a potential correlation between m6A-SNPs and T2D pathogenesis and also provided new insights into the pathogenic mechanism of the T2D susceptibility loci identified by GWAS.Keywords: type 2 diabetes, single nucleotide polymorphism, epigenetics, m6A, genome-wide association study

Jie Yi, Xiao Han, Ziyi Wang, Yu Chen, Yingchun Xu, Jie Wu Department of Laboratory Medicine, and Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Jie WuDepartment of Laboratory Medicine, and Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaTel/Fax +86-10-69152330Email wuj8289@163.comPurpose: To cope with the SARS-CoV-2 epidemic, several rapid nucleic acid assays have been approved for use, but the analytical performance has not been well evaluated. In this report, two key performance parameters, analytical sensitivity (limit of detection) and reproducibility, of three approved rapid nucleic acid assays were assessed using heat-inactivated SARS-CoV-2 culture supernatants quantified by digital PCR.Methods: The LOD (limit of detection) and reproducibility of three approved rapid nucleic acid assays using their own instruments were assessed, while the LOD and reproducibility of two assays on a 7500 Real-Time instrument were assessed at the same time.Results: Using their own instruments, 100% of samples with 1150 copies/mL viral RNA could be detected by the Da An and Coyote assays, while 90% of samples could be detected by the Ustar assay; yet, for 525 copies/mL and 287.5 copies/mL viral RNA, the detection rate of the Ustar assay was higher than that of either the Da An or Coyote assays. However, the three assays did not produce statistically significant results with the three different concentrations of viral RNA (P=0.46, 0.46 and 0.46). Using a 7500 Real-Time instrument, Da An and Coyote assays did not produce statistically significant results with the 1150, 525 and 287.5 copies/mL viral RNA (P> 0.99, > 0.99 and > 0.99). The positive and negative detection rates of the three assays in the intra- and inter-assay stages were 100% on both their own instruments and the 7500 real-time PCR instrument.Conclusion: Positive or strongly positive samples can be detected by the rapid nucleic acid assay, but the analytical performance should be optimized, and comprehensive evaluations are also required.Keywords: COVID-19, rapid molecular-based tests, limit of detection, reproducibility

Soyeon Jang,1 Soyoung Jang,1 Si-Yong Kim,1 Jiwon Ko,1 Eungyung Kim,2 Ji Yeong Park,1 Hyejin Hyung,1 Jin Hong Lee,1 Su-Geun Lim,3 Sijun Park,3 Junkoo Yi,4 Heon-Jin Lee,5 Myoung Ok Kim,2 Hyun-Shik Lee,1 Zae Young Ryoo1 1School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, Korea; 2Department of Animal Science and Biotechnology, Kyungpook National University, Daegu, Korea; 3School of Life Science, Kyungpook National University, Daegu, Korea; 4Gyeongsangbukdo Livestock Research Institute, Yeongju, Korea; 5Department of Microbiology and Immunology, School of Dentistry, Kyungpook National University, Daegu, 41940, KoreaCorrespondence: Zae Young Ryoo; Hyun-Shik LeeSchool of Life Science, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, KoreaTel +82-53-950-7361; +82-53-950-7367Fax +82-53-943-6925; +82-53-943-2762Email jaewoong64@knu.ac.kr; leeh@knu.ac.krPurpose: Psoriasis is a common and well-studied autoimmune skin disease, which is characterized by plaques. The formation of psoriasis plaques occurs through the hyperproliferation and abnormal differentiation of keratinocytes, infiltration of numerous immune cells into the dermis, increased subepidermal angiogenesis, and various autoimmune-associated cytokines and chemokines. According to previous research, Lin28 regulates the let-7 family, and let-7b is associated with psoriasis. However, the link between Lin28 and psoriasis is unclear. In this study, an association was identified between Lin28a and psoriasis progression, which promoted the pathological characteristic of psoriasis in epidermal keratinocytes.Patients and Methods: This study aims to investigate the role of Lin28a and its underlying mechanism in psoriasis through in vivo and in vitro models, which include the Lin28a-overexpressing transgenic (TG) mice and Lin28a-overexpressing human keratinocyte (HaCaT) cell lines, respectively.Results: In vivo and in vitro results revealed that overexpression of Lin28a downregulated microRNA let-7 expression levels and caused hyperproliferation and abnormal differentiation in keratinocytes. In imiquimod (IMQ)-induced psoriasis-like inflammation, Lin28a overexpressing transgenic (TG) mice exhibited more severe symptoms of psoriasis.Conclusion: Mechanistically, Lin28a exacerbated psoriasis-like inflammation through the activation of the extracellular-signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 signaling (STAT 3) by targeting proinflammatory cytokine interleukin-6 (IL-6).Keywords: psoriasis, keratinocyte, Lin28a, let-7

Lixia Yang, Liangyan Pei, Jilong Yi Department of Neurology, The First People’s Hospital of Jingmen Affiliated to Hubei Minzu University, Jingmen, 434000, People’s Republic of ChinaCorrespondence: Jilong YiDepartment of Neurology, The First People’s Hospital of Jingmen Affiliated to Hubei Minzu University, No.168 Xiangshan Avenue, Jingmen, 434000, People’s Republic of ChinaEmail gxhkah@163.comBackground: Long noncoding RNAs (lncRNAs) are related to the development and treatment of neuroblastoma. The lncRNA LINC00839 is dysregulated in neuroblastoma, while its function and mechanism in neuroblastoma development remain largely unclear.Methods: The tumor and adjacent noncancerous tissues were collected from 48 neuroblastoma patients. LINC00839, glucose transporter 1 (GLUT1) and microRNA-338-3p (miR-338-3p) abundances were examined via quantitative reverse transcription polymerase chain reaction or Western blot. Cell proliferation, apoptosis, migration, invasion and glycolysis were assessed via Cell Counting Kit-8, colony formation, flow cytometry, wound healing, transwell, glucose uptake and lactate production. The target relationship of miR-338-3p and LINC00839 or GLUT1 was tested via dual-luciferase reporter analysis and RNA immunoprecipitation. The function of LINC00839 on neuroblastoma cell growth in vivo was tested via a xenograft model.Results: LINC00839 and GLUT1 abundances were increased in neuroblastoma tissues and cell lines. The high expression of LINC00839 and GLUT1 indicated the lower overall survival. LINC00839 interference constrained neuroblastoma cell proliferation, migration, invasion and glycolysis, and facilitated apoptosis. GLUT1 overexpression or miR-338-3p knockdown could mitigate the influence of LINC00839 silence on neuroblastoma cell processes. LINC00839 could regulate GLUT1 expression via miR-338-3p. LINC00839 knockdown reduced neuroblastoma cell growth in xenograft model.Conclusion: LINC00839 silence repressed neuroblastoma cell proliferation, migration, invasion and glycolysis and promoted apoptosis via regulating miR-338-3p/GLUT1 axis.Keywords: neuroblastoma, LINC00839, GLUT1, miR-338-3p

Yanping Su,1 Meirong Huo,1 Lin Hua,2 Yuan Zhang,1 Jiawen Yi,1 Shu Zhang,1 Jie Li,1 Yuhui Zhang1 1Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, Beijing, People’s Republic of China; 2School of Biomedical Engineering, Capital Medical University, Beijing, 100069, People’s Republic of ChinaCorrespondence: Yuhui ZhangDepartment of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, 8 Gongtinan Road, Chaoyang District, Beijing, People’s Republic of ChinaTel +86 13520208369Email zhangyhcy@163.comPurpose: To explore the relationship between venous thromboembolism (VTE) and early mortality (within six months) in Chinese patients with newly diagnosed metastatic non-small cell lung cancer (NSCLC) after entering the era of precision treatment.Methods: A cohort of 706 consecutive subjects with newly diagnosed metastatic NSCLC were prospectively observed. Clinical and survival data were recorded over a six-month follow-up period. The predictive factors for the occurrence of VTE and the relationship with early mortality were evaluated through univariate and multivariate analyses.Results: During the six-month follow-up period, VTE events occurred in 12.2% (86/706) of the enrolled patients. In the multivariate analyses for VTE, an age older than 70 years (vs < 70: sub-distribution hazard radio [SHR], 1.678; 95% confidence interval (CI), 1.073– 2.600; P=0.022), an Eastern Cooperative Oncology Group performance status ≥ 2 (vs 0/1: SHR, 1.946; 95% CI, 1.277– 2.970; P=0.002), and having an ALK rearrangement (vs non-rearrangement: SHR, 2.377; 95% CI, 1.186– 4.760; P=0.015) were significantly associated with the occurrence of VTE. Within six months, 116 subjects (16.4%) died, and the occurrence of VTE (vs no VTE: adjusted HR: 1.863; 95% CI: 1.178– 2.947, P=0.008) was remarkably associated with early mortality. Further analysis showed 98 patients (13.9%) with early mortality had EGFR/ALK wild-type genes, with a risk of early mortality 5.935-fold higher than that of patients with an EGFR mutation/ALK rearrangement. Finally, subgroup analyses showed that VTE occurrence was a significant factor for predicting early mortality in patients with EGFR/ALK wild-type genes (adjusted HR: 1.682; 95% CI: 1.023– 2.768, P=0.041).Conclusion: Patients with an EGFR mutation/ALK rearrangement had a significantly decreased risk of early mortality in the era of targeted therapy; however, VTE occurrence remained an important predictor for early mortality in metastatic NSCLC patients, especially in patients with EGFR/ALK wild-type genes.Keywords: venous thromboembolism, non-small cell lung cancer, early mortality

Abstract For the global telecom operators, mobile data services have gradually taken the part of traditional voice services to become the main revenue growth point. However, during the upgrading period of new generation networks (such as 5G), new mobile data services are still at the stage of exploration; the network capabilities and the application scenarios are unmatured. In this phase, it is incomplete and misleading to simply measure the performance of new services from one dimension, such as data traffic or revenue, and the measurement should be dynamically changed according to the development of the new services. Therefore, telecom operators want to improve the existing performance measurement from the aspect of integrity and dynamics. In this paper, we propose mobile-data-service development index (MDDI) and build a quantitative model to dynamic measure the overall performance of mobile data services. To approach a fuller understanding, we creatively bring investment indicators and networks reliability indicators into performance indicators system and discuss the relationships among subindices and the selection of outcome criteria in MDDI. In the part of empirical research, we use the model to analyze the dynamic characteristics of a new mobile data service in China and summarize the development strategies of every stage. The findings can also give guidelines for new services of 5G and other new generation networks in the future.

Yangliang Yang, Jing Yi, Mengzhi Pan, Baoji Hu, Hongwei Duan Department of Anesthesiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of ChinaCorrespondence: Hongwei DuanDepartment of Anesthesiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800 Gongwei Road, Shanghai, 201399, People’s Republic of ChinaEmail duanhongwei120@126.comBackground: To investigate the neuroprotective effect of edaravone on excessive-dose propofol-induced neurotoxicity in the hippocampus of newborn rats and HT22 cells.Methods: Cell proliferation was investigated by assessing ki67 expression in the neural stem of the hippocampus of newborn rats and by cell counting kit-8 (CCK8) assay in HT22 cells. Cell apoptosis was assessed in vivo by caspase 3 detection in Western blots and measurement of apoptosis in neurons and glial cells by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Apoptosis was analyzed by flow cytometry in HT22 cells. The Morris water maze was used to evaluate the long-term learning and memory ability of rats. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). The expression of mBDNF/TrkB/PI3K pathway-related proteins was detected by Western blot and quantitative reverse transcription-polymerase chain reaction (q-RT PCR).Results: In neonatal rat hippocampus and HT22 cells, edaravone increased cell proliferation and decreased cell apoptosis after excessive propofol-induced neurotoxicity. In addition, the levels of proinflammatory factors interleukin (IL)-6 and tumor necrosis factor (TNF)-α were reduced by edaravone pretreatment. The use of the tropomyosin receptor kinase B (TrkB) antagonist ANA-12 and TrkB agonist 7,8DHF with propofol groups showed that edaravone mitigated excessive propofol-induced neurotoxicity through the mature brain-derived neurotrophic factor (mBDNF)/TrkB/phosphoinositide 3-kinase (PI3K) pathway. However, the current dose of propofol did not significantly affect long-term learning and memory in rats.Conclusion: Edaravone pretreatment ameliorated propofol-induced proliferation inhibition, neuroapoptosis, and neural inflammation by activating the mBDNF/TrkB/PI3K pathway.Keywords: edaravone, propofol, hippocampus, the brain-derived neurotrophic factor, BDNF, the tyrosine kinase receptor B, TrkB, 7,8-dihydroxyflavone, 7,8-DHF, ANA-12

Ruizhi Zhao,1 Yuchao Ma,1 Siran Yang,1 Qingfeng Liu,1 Yuan Tang,1 Kai Wang,1 Ye Zhang,1 Nan Bi,1 Hongmei Zhang,2 Junlin Yi,1 Yexiong Li,1 Jingwei Luo,1 Jianping Xiao1 1Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People’s Republic of China; 2Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People’s Republic of ChinaCorrespondence: Jianping Xiao; Jingwei LuoNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academic of Medical Sciences, Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, People’s Republic of ChinaTel +86-10-87788281; Tel +86-10-87788288Fax +86-10-67706153Email jpxiao8@163.com; jingwei-luo@outlook.comObjective: To investigate the clinical outcomes of hypofractionated radiotherapy for adrenal metastases.Materials and Methods: We retrospectively reviewed patients diagnosed with adrenal metastases and treated with hypofractionated radiotherapy, who did not receive adrenalectomy or have disease progression after chemotherapy, from 2007 to 2019. The Kaplan–Meier method was used to estimate local control rate (LCR), progression-free survival (PFS), and overall survival (OS). Univariate analysis was performed using Log rank test.Results: Thirty-five patients with 42 lesions were enrolled, and the lung was the most common primary site (80.0%). The median follow-up time was 46.4 months. The median volume of GTV and PTV was 23.2 cm3 (range: 3.5– 97.8 cm3) and 38.3 cm3 (range: 10.2– 135.6 cm3), respectively. The main dose regimens were 60 Gy delivered in 4– 15 fractions, with the median dose of PTV being 60 Gy (range: 40– 66.3 Gy) and the biologically effective dose (BED) being 84 Gy (range: 56– 110 Gy). The 1-year and 2-year LCR, OS, and PFS were 92.7% and 88.1%, 76.9% and 45.4%, and 25.1% and 14.4%, respectively. Univariate analysis showed that chemotherapy, disease-free interval from primary disease diagnosis to adrenal metastases diagnosis, and age were significant factors for LCR, OS, and PFS, respectively (p=0.017, 0.049, and 0.004, respectively). No more than grade III toxicities were observed.Conclusion: As a non-invasive approach, hypofractionated radiotherapy is safe and effective for metastatic adrenal lesions, without serious complications.Keywords: adrenal metastases, hypofractionated radiotherapy, prognosis, toxicities

Huili Wang, Runye Wu, Xiaodong Huang, Yuan Qu, Kai Wang, Qingfeng Liu, Xuesong Chen, Ye Zhang, Shiping Zhang, Jianping Xiao, Junlin Yi, Guozhen Xu, Li Gao, Jingwei Luo National Cancer Center/National Cancer Clinical Medical Research Center/Chinese Academy of Medical Sciences, Peking Union Medical College, Cancer Hospital, Beijing, People’s Republic of ChinaCorrespondence: Jingwei LuoNational Cancer Center/National Cancer Clinical Medical Research Center/Chinese Academy of Medical Sciences, Peking Union Medical College, Cancer Hospital, Beijing, People’s Republic of ChinaTel +86 13601181202Email jingwei-luo@outlook.comBackground: This study was to determine the patterns of regional lymph node (LN) spread and the risk factors of retropharyngeal lymph node (RPLN) metastasis based on magnetic resonance imaging (MRI) in hypopharyngeal squamous carcinoma (HPC) to improve clinical target volume (CTV) delineation.Methods: A cohort of 326 consecutive patients of HPC in a single institute were retrospectively reviewed. All patients underwent MRI prior to initial treatment, and the diagnosis based on MRI of the LN metastasis was confirmed by all radiation oncologists in the head and neck group during twice weekly chat rounds. Statistical analysis of data was using chi-square test and multivariant logistic regression model in SPSS 22.0 software.Results: The LN metastasis rate of all patients in this cohort was 90.5% (295/326). Level IIa/b and level III were the most frequently involved regions followed by level IV and retropharyngeal region. Skip metastasis only occurred in 6.4% (19/295). Univariate and multivariate analysis demonstrated that primary tumor subsites were located in the posterior pharyngeal wall (P=0.002), bilateral cervical LN metastasis (P=0.020), larger volume of primary gross target (GTVp, P=0.003), and larger volume of LN gross target (GTVnd, P=0.023) were significantly associated with RPLN metastasis.Conclusion: The regional LN spread of HPC follows an ordered pattern as level II is the most frequently involved area followed by level III, level IV, and RPLN. RPLN metastasis is more likely to occur in patients with primary site of posterior pharyngeal wall, large tumor burden, or bilateral neck LN metastasis. Therefore, it is highly recommended that the RPLN should be included into CTV for patients who have these risk factors.Keywords: hypopharyngeal carcinoma, lymph node metastasis, risk factors, retropharyngeal lymph node, metastasis

Shuqi Li, 1–3 Jie Zhang, 1–3 Yuqi Fang, 1–3 Jun Yi, 1 Zhufen Lu, 2, 3 Yanzhong Chen, 2, 3 Bohong Guo 1–3 1Department of Pharmaceutics, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 3R&D Team for Formulation Innovation, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of ChinaCorrespondence: Yanzhong ChenGuangdong Provincial Key Laboratory of Advanced Drug Delivery Systems, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of ChinaTel +86 20 3935 2678Fax +86 20 3935 2501Email doctor.c@163.comBohong GuoDepartment of Pharmaceutics, School of Pharmacy, Guangdong Pharmaceutical University, 280 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, People’s Republic of ChinaTel +86 20 3935 2117Fax +86 20 3935 2129Email guobohong@gdpu.edu.cnPurpose: The aim of this study was to prepare and evaluate betulinic acid nanosuspension (BA-NS) for new drug delivery to enhance its solubility and in vitro anti-tumor activity.Methods: BA-NS was formulated by an anti-solvent precipitation method using the Box-Behnken design (BBD). Particle size (PS) and Zeta potential were measured by laser particle size analysis. The drug solid state after freeze drying was characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FTIR) after freeze drying. The saturation solubility and dissolution rate were determined by solubility assay and in vitro dissolution studies, respectively. The in vitro cytotoxicity assay was performed using 3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide (MTT) method.Results: The PS was 129.7± 12.2 nm having a Zeta potential of − 28.1± 4.5 mV and the polydispersity index (PDI) was 0.231± 0.013, which confirmed that the nanosuspension was in the stable amorphous state. A series of characterization experiments demonstrated that nanoparticles retained original effective structure and existed as spherical or near-spherical nanoparticles in the nanosuspension, but the drug transferred from the crystal state to the amorphous state. The form of lyophilized BA-NS was very successful in enhancing the dissolution rate in PH-dependent way. The cytotoxicity assay revealed that BA-NS could significantly enhance the in vitro anti-proliferation against tumor cells compared to the BA suspension (BA-S).Conclusion: The BA-NS can remarkably improve solubility and in vitro antitumor activity, which seems very promising for the treatment of cancers in practical application.Keywords: betulinic acid, nanosuspension, anti-solvent precipitation, Box-Behnken design, cytotoxicity

Seung Youn Kang, 1 Osama Nezar Kashlan, 2 Ravindra Singh, 2 Rahul Rane, 2 Nitin Maruti Adsul, 3 Sung Chan Jung, 1 Jihwan Yi, 1 Hae Sun Cho, 1 Hyeun Sung Kim, 2 Il-Tae Jang, 2 Seong-Hoon Oh 4 1Department of Anesthesiology, Nanoori Hospital Gangnam, Seoul, Republic of Korea; 2Department of Neurosurgery, Nanoori Hospital Gangnam, Seoul, Republic of Korea; 3Department of Orthopedics, Ganga Ram Hospital, Delhi, India; 4Department of Neurosurgery, Nanoori Hospital Bupyeong, Incheon, Republic of KoreaCorrespondence: Hyeun Sung KimDepartment of Neurosurgery, Nanoori Hospital Gangnam, #06048 731 Eonju Street, Gangnam-Gu, Seoul, Republic of KoreaTel +82 2 6003 9767Fax +82 2 3445 9755Email neurospinekim@gmail.comBackground: With the increase in life expectancy seen throughout the world, the prevalence of degenerative spinal pathology and surgery to treat it has increased. Spinal surgery under general anesthesia leads to various problems and complications, especially in patients with numerous medical comorbidities or elderly patients. For this reason, there is a need for safer anesthetic methods applicable to unhealthy, elderly patients undergoing spinal surgery.Purpose: To report our experience with utilizing fluoroscopy-guided epidural anesthesia in conjunction with conscious sedation in spinal surgery.Patients and Methods: We performed a retrospective review of 111 patients at our institution that received fluoroscopy-guided epidural anesthesia for lumbar surgery from February to September 2018. Patients’ records were evaluated to evaluate patient demographics, American Society of Anesthesiology Physical Classification System (ASA) class, and pain numerical rating scores (NRS) preoperatively and throughout their recovery postoperatively. Intraoperative data including volume of epidural anesthetic used, extent of epidural spread, and inadvertent subdural injection was collected. Postoperative recovery time was also collected.Results: The mean age of our patients was 60 years old with a range between 31 and 83 years old. All patients experienced decreases in postoperative pain with no significant differences based on age or ASA class. There was no association between ASA class and time to recovery postoperatively. Older patients (age 70 years or greater) had a significantly longer recovery time when compared to younger patients. Recovery also was longer for patients who received higher volumes of epidural anesthesia. For every 1 mL increase of epidural anesthetic given, there was an increase in the extent of spread of 1.8 spinal levels.Conclusion: We demonstrate the safety and feasibility of utilizing conscious sedation in conjunction with fluoroscopy-guided epidural anesthesia in the lumbar spinal surgery.Keywords: fluoroscopy-guided epidural anesthesia, conscious sedation, endoscopic decompressive lumbar spine surgery, capnogram monitoring

Langlang Liu, Honglian Dai, Yanzeng Wu, Binbin Li, Jiling Yi, Chao Xu, Xiaopei WuState Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan, People’s Republic of ChinaBackground: Studies have showed that nanoparticles have a certain anti-cancer activity and can inhibit many kinds of cancer cells. β-tricalcium phosphate nanoparticles (nano-β-TCP) displays better biodegradation, but the application and mechanism of nano-β-TCP in anti-cancer activity are still not clear.Purpose: The objective of this study was to synthesize nano-β-TCP and investigate its inhibitory properties and mechanism on hepatocellular carcinoma (HepG2) cells in vitro and in vivo.Methods: Nano-β-TCP was synthesized using ethanol-water system and characterized. The effects of nano-β-TCP on cell viability, cell uptake, intracellular oxidative stress (ROS), cell cycle and apoptosis were also investigated with HepG2 cells and human hepatocyte cells (L-02). Intratumoral injection of nano-β-TCP was performed on the xenograft liver cancer model to explore the inhibitory effect and mechanism of nano-β-TCP on liver tumors.Results: In vitro results revealed that nano-β-TCP caused reduced cell viability of HepG2 cells in a time-and dose-dependent manner. Nano-β-TCP was internalized through endocytosis and degraded in cells, resulting in obvious increase of the intracellular Ca2+, and PO43-, ions. Nano-β-TCP induced cancer cells to produce ROS and induced apoptosis of tumor cells by an apoptotic signaling pathways both in extrinsic and intrinsic pathway. In addition, nano-β-TCP blocked cell cycle of HepG2 cells in G0/G1 phase and disturbed expression of some related cyclins. In vivo results showed that 40 mg/kg of nano-β-TCP had no significant toxic side effects, but could effectively suppress hepatocellular carcinoma growth.Conclusion: These findings revealed the anticancer effect of nano-β-TCP and also clarified the mechanism of its inhibitory effect on hepatocellular carcinoma.Keywords: nano-β-TCP, HepG2 cells, ROS, cell cycle, apoptosis, inhibition

Bohong Guo, Cancheng Liao, Xiaohong Liu, Jun Yi Department of Pharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China Background: The present work was conducted to prepare and evaluate multiwalled carbon nanotube–formononetin (MWCNT-FMN) composite for sustained delivery and inducing apoptosis via reactive oxygen species (ROS) production in HeLa cells.Methods: The composite was prepared by solution mixing with short carboxylic group-functionalized multiwalled carbon nanotubes (MWCNT-COOH). Then the composite was characterized by laser particle size analysis, Fourier transform infrared spectrometry, X-ray diffractometry, differential scanning calorimetry, and scanning electron microscopy. Drug release rates in vitro were determined by dialysis method. The in vitro cytotoxicity study was performed using water soluble tetrazolium assay. The cellular apoptosis assay, ROS, and mitochondrial membrane potential (MMP) of HeLa cells were investigated by acridine orange and ethidium bromide double dye, 2',7'-dichlorodihydrofluorescein diacetate, and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide probe, respectively.Results: The entrapment efficiency was 28.77%±0.15%, and the loading capacity was 12.05%±0.20%. The release of MWCNT-FMN was sustained, and the cumulative release rate of formononetin (FMN) from MWCNT-COOH was higher at pH 7.4 than at pH 5.3. The in vitro cytotoxicity assay demonstrated that FMN, MWCNT-COOH, and MWCNT-FMN had no significant effects on the proliferation and viability of mouse fibroblast 3T3 cells over 48 hours, while the cell growth inhibition of the three samples showed concentration-dependent for HeLa cells. Biological assay suggested FMN and MWCNT-FMN could induce apoptosis in HeLa cells, meanwhile the cells exhibited stronger ROS signal and more depolarized MMP than that of the control group.Conclusion: These results preliminarily demonstrated that MWCNT-FMN exerted anticancer efficacy through cellular apoptosis induced by ROS-mediated mitochondrial dysfunctions in HeLa cells. Keywords: multiwalled carbon nanotube, characterization, cytotoxicity, formononetin, apoptosis

Summary: Dysregulation of mitophagy, whereby damaged mitochondria are labeled for degradation by the mitochondrial kinase PINK1 and E3 ubiquitin ligase Parkin with phosphorylated ubiquitin chains (p-S65 ubiquitin), may contribute to neurodegeneration in Parkinson’s disease. Here, we identify a phosphatase antagonistic to PINK1, protein phosphatase with EF-hand domain 2 (PPEF2), that can dephosphorylate ubiquitin and suppress PINK1-dependent mitophagy. Knockdown of PPEF2 amplifies the accumulation of p-S65 ubiquitin in cells and enhances baseline mitophagy in dissociated cortical cultures. Overexpressing enzymatically active PPEF2 reduces the p-S65 ubiquitin signal in cells, and partially purified PPEF2 can dephosphorylate recombinant p-S65 ubiquitin chains in vitro. Using a mass spectrometry approach, we have identified several p-S65-ubiquitinated proteins following mitochondrial damage that are inversely regulated by PPEF2 and PINK1. Interestingly, many of these proteins are involved in nuclear processes such as DNA repair. Collectively, PPEF2 functions to suppress mitochondrial quality control on a cellular level through dephosphorylation of p-S65 ubiquitin. : Wall et al. identify PPEF2 as a phosphatase that can dephosphorylate p-S65 ubiquitin and suppress mitophagy. PPEF2 regulates mitophagy at baseline, which has pronounced activity in astrocytes. They also identify proteins that are p-S65-ubiquitinated in response to mitochondrial damage, several of which are involved in DNA repair inside the nucleus. Keywords: Parkinson’s disease, mitochondria, mitophagy, PINK1, Parkin, PPEF2, ubiquitin

Cancheng Liao,* Danqiao Xu,* Xiaohong Liu, Yuqi Fang, Jun Yi, Xiaofang Li, Bohong Guo Department of Pharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China *These authors contributed equally to this work Background and aim: Iridium (Ir)-based complex is a potential antitumor ingredient, but its poor physicochemical properties such as hydrophobicity and low biocompatibility hamper further application. Liposome provides a potential delivery approach for improving the poor physicochemical property and reducing the side effects of antitumor drug. In this study, we aimed at incorporating Ir ([Ir(ppy)2(BTCP)]PF6) into liposomes to enhance the biocompatibility and sustained release of Ir for intravenous administration and to elucidate the mechanism in A549 cells. Materials and methods: Ir-loaded PEGylated liposomes (Lipo-Ir) were formulated by thin-film dispersion and ultrasonic method. Morphology, size distribution, and zeta potential of Lipo-Ir were examined by transmission electron microscopy (TEM) and Zetasizer. The released profile and biocompatibility were investigated by dialysis method and hemolysis test, respectively. Additionally, the cytotoxic activity and mechanism of Lipo-Ir and Ir inducing apoptosis in A549 cells were evaluated. Results: Lipo-Ir can keep sustained release, excellent biocompatibility, and physical stability. The average particle size, polydispersity index, zeta potential, encapsulation efficiency, and drug loading are 112.57±1.15 nm, 0.19±0.02, -10.66±0.61 mV, 94.71%±3.21%, and 4.71%±0.41%, respectively. 3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide (MTT) assay show that Lipo-Ir and Ir display high cytotoxicity against selected cancer cells. Furthermore, the apoptotic features of morphology, depolarization of mitochondrial membrane potential, increase in the reactive oxygen species (ROS) levels, and disorder of Ca2+ homeostasis are observed after treating A549 cells with Ir and Lipo-Ir. Besides, Lipo-Ir can arrest the cell growth in G0/G1 phase. Conclusion: The studies demonstrate that Lipo-Ir can trigger apoptosis in A549 cells via ROS-mediated mitochondrial dysfunctions, and the biocompatible and sustained Lipo-Ir will be a promising drug delivery system. Keywords: iridium complex, liposome, apoptosis, reactive oxygen species, mitochondria

This study presents a low-altitude wind shear speed estimation method based on combined space–time main channel adaptive processing. The method first reduces the dimension of the radar echo data of the measured range unit by constructing a dimension-reduced joint space–time transform matrix, and then constructs the optimal weight vector of the dimension-reducing processor to adaptively filter the reduced-dimensional data. Furthermore, accurate estimation of the speed of the wind field is achieved in the presence of the amplitude–phase error. Simulation results demonstrate the effectiveness of the proposed method.

Abstract Seed predation by insects is common in seeds of Fabaceae (legume) species with physical dormancy (PY). However, the consequences of insect seed predation on the life history of legumes with PY have been little studied. In the largest genus of seed plants, Astragalus (Fabaceae), only one study has tested the effects of insect predation on germination, and none has tested it directly on seedling survival. Thus, we tested the effects of insect predation on seed germination and seedling growth and survival of Astragalus lehmannianus, a central Asian sand-desert endemic. Under laboratory conditions, seeds lightly predated in the natural habitat of this perennial legume germinated to a much higher percentage than intact seeds, and seedlings from predated and nonpredated seeds survived and grew about equally well. Further, in contrast to our prediction seedlings from predated seeds that germinated “out-of-season” under near-natural conditions in NW China survived over winter. The implication of our results is that individual plants from predated seeds that germinate early (in our case autumn) potentially have a fitness advantage over those from nonpredated seeds, which delay germination until spring of a subsequent year.

Bohong Guo, Danqiao Xu, Xiaohong Liu, Jun Yi Department of Pharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China Abstract: In this study, folate–poly(ethylene glycol)3400–cholesterol conjugates (FA–PEG–Chol) were enzymatically synthesized in one step and incorporated into liposomes to prepare folate (FA)-functionalized liposomes for targeted drug delivery. The FA-functionalized liposomes loaded with betulinic acid (BA) (FA-L-BA) were prepared by thin lipid film method. The FA-L-BA was characterized by their morphology, particle size, zeta potential, encapsulation efficiency (EE), stability, cell cytotoxicity and cellular uptake. The average size of FA-L-BA was 222±8 nm. The spherical particles exhibited a negative electrical charge of -20.12±1.45 mV and high EE of 91.61%±1.16%. The liposomes were taken up selectively by HepG2 cells. FA-L-BA showed enhanced cytotoxicity (50% inhibitory concentration [IC50] =63.07±2.22 µg/mL) compared to nontargeted control normal liposomes loaded with BA (L-BA; IC50 =93.14±2.19 µg/mL) in HepG2 cells in vitro. In addition, FA-functionalized liposomes loaded with Ir-1 (FA-L-Ir-1) showed significantly higher cellular uptake in HepG2 cells compared to nontargeted control normal liposomes loaded with Ir-1 (L-Ir-1). This novel approach for the liposomes surface modified with FA by a one-step enzymatic amidation was expected to provide potential application as a drug carrier for active targeted delivery to tumor cells. Keywords: enzymatic synthesis, liposomes, folate, surface modification, betulinic acid

Weiguang Yu,1,* Jun Hu,1,* Xinchao Zhang,2 Xingfei Zhu,2 Yinfeng Xu,1 Jianhua Yi,1 Yunjiang Liu1 1Department of Orthopedics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 2Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Acute unstable complex radial head and neck fractures in adults are seldom reported in the literature. Early recognition and appropriate management are essential to prevent long-term consequences of the loss of elbow function, forearm rotation, and chronic pain. Here, we describe an unusual case of a 20-year-old man who exhibited acute unstable complex fractures of the head and neck of the right radius without other injuries or comorbidity. An open reduction and mini T-shaped plate fixation were performed within 3 hours after injury, and the results were satisfactory. A long plaster fixation was continued for 3 weeks. A gradual mobilization was started after the removal of the plaster under the supervision of a physiotherapist. At the 12-month follow-up, no complications associated with the use of the mini T-shaped plate were noted, and the Mayo Elbow Performance Score was 97 (excellent). To our knowledge, acute unstable complex radial head and neck fractures in adults can be successfully treated with a mini T-shaped plate reconstruction technique. Keywords: unstable complex fractures, mini T-shaped plate, radial head, internal fixation, radial head replacement

The post-installation consolidation settlement of spudcan foundations is an issue of concern for the offshore jack-up industry, especially when jack-up rigs operate for a long period such as those serving as production units. Although many centrifuge tests or numerical calculations have been conducted for spudcan behaviour after consolidation, there are no guidelines available to predict the consolidation settlement development. This paper reports a study dedicated to this subject. The spudcan installation and consolidation under operational load was continually simulated through the dual-stage Eulerian-Lagrangian analyses incorporating the modified Cam-clay model. Its feasibility and reliability were verified by comparison with other experimental results in literature. Parametric studies were carried out for spudcans under various soil parameters and geometrical conditions. A suitable method, Hyperbolic method, is proposed to predict spudcan settlement during consolidation with observed data.

Oncogenic osteomalacia (OO) is an uncommon but treatable cause of osteomalacia related to tumor production of FGF23, usually caused by benign mesenchymal neoplasms. Paranasal sinus glomangiomas are a rare cause of OO, with only one previously reported case. Here we describe a second case (first reported in English) of paranasal sinus glomangioma-induced osteomalacia in a 42-year-old man. He presented with weakness and multiple spontaneous fractures, and was found to have an ethmoid sinus glomangioma with intracranial extension. The tumor was removed via endoscopic endonasal approach to the anterior skull base, which resulted in complete resolution of symptoms and no further evidence of disease 1 year postoperatively.

The performance of an oxygen carrier for Chemical Looping Combustion varies with the support material used. NiO oxygen carriers were prepared using 60 or 70 wt% NiO and different raw support materials (γ-Al2O3, pseudoboehmite, α-Al2O3, γ-Al2O3 mixed with MgO, hydrotalcite, MgAl2O4, and γ-Al2O3 with added graphite) by the mechanical mixing method. Reactivity tests were conducted using a thermogravimetric analyzer (TGA) at 950˚C. The oxygen carriers prepared using γ-Al2O3, γ-Al2O3 mixed with a small amount of MgO, hydrotalcite, and MgAl2O4 showed high oxygen transfer capacity, high oxygen utilization, and a high oxygen transfer rate. Graphite addition to γ-Al2O3 did not increase the surface area or reactivity. The use of pseudoboehmite as a support led to a significant decrease in oxygen transfer capacity and severe agglomeration of the oxygen carriers during the redox reaction. The increase in MgO content in the raw support materials decreased the reduction reactivity. The oxygen carriers prepared with α-Al2O3 showed less oxygen transfer capacity than the other oxygen carriers. The differences in the reactivity according to the support type were explained by the relative strength of NiO-support interaction obtained from the temperature-programmed reduction analysis. The reactivity test results in this work indicate that γ-Al2O3 and hydrotalcite could be desirable raw support materials to prepare highly reactive NiO oxygen carriers with high NiO content. Les performances des materiaux transporteurs d’oxygene varient en fonction du support utilise dans le procede de combustion en boucle chimique. Differents materiaux a base d’oxyde de Nickel ont ete synthetises avec des concentrations elevees en NiO, comprises entre 60 et 70 %, sur differents supports (γ-Al2O3, pseudobohemite, α-Al2O3, γ-Al2O3 melangee avec MgO, hydrotalcite, MgAl2O4 et γ-Al2O3 additivees avec du graphite) par melange mecanique. Des tests de reactivite ont ete conduits dans une thermobalance (ATG) a 950˚C. Les materiaux supportes avec γ-Al2O3, γ-Al2O3 melangee avec MgO, l’hydrotalcite et MgAl2O4 ont une capacite de transfert d’oxygene elevee et une reactivite elevee. L’addition de graphite dans l’alumine γ n’ameliore ni la surface specifique ni la reactivite. Avec la pseudo-bohemite, on observe une decroissance de la capacite de transfert d’oxygene et l’agglomeration du materiau pendant la phase de reduction. L’ajout de MgO conduit a une baisse de la reactivite en reduction. Avec l’alumine α, la capacite de transfert est reduite. Les differences de reactivite peuvent etre expliquees par les interactions entre NiO et le support, a partir d’analyses en reduction par temperature programmee. Les tests de reactivite conduits dans cette etude suggerent que les supports a base de γ-Al2O3 et d’hydrotalcite sont les plus appropries pour preparer les transporteurs d’oxygene contenant de l’oxyde de Nickel a haute concentration pour la combustion en boucle chimique.

This article presents the basic idea of VHMPID, an upgrade detector for the ALICE experiment at LHC, CERN. The main goal of this detector is to extend the particle identification capabilities of ALICE to give more insight into the evolution of the hot and dense matter created in Pb-Pb collisions. Starting from the physics motivations and working principles the challenges and current status of development is detailed.

The Stimulator of Interferon Genes (STING) pathway initiates potent immune responses upon recognition of DNA. To initiate signaling, serine 365 (S365) in the C-terminal tail (CTT) of STING is phosphorylated, leading to induction of type I interferons (IFNs). Additionally, evolutionary conserved responses such as autophagy also occur downstream of STING, but their relative importance during in vivo infections remains unclear. Here we report that mice harboring a serine 365-to-alanine (S365A) mutation in STING are unexpectedly resistant to Herpes Simplex Virus (HSV)-1, despite lacking STING-induced type I IFN responses. By contrast, resistance to HSV-1 is abolished in mice lacking the STING CTT, suggesting that the STING CTT initiates protective responses against HSV-1, independently of type I IFNs. Interestingly, we find that STING-induced autophagy is a CTT- and TBK1-dependent but IRF3-independent process that is conserved in the STING S365A mice. Thus, interferon-independent functions of STING mediate STING-dependent antiviral responses in vivo.