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Jianqun Yin,&ast; Jiawei Chen,&ast; Ting Wang, Huiming Sun, Yongdong Yan, Canhong Zhu, Li Huang, Zhengrong Chen Respiratory Department, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhengrong Chen; Li Huang, Respiratory Department, Children’s Hospital of Soochow University, No. 303 Jingde Road, Gusu District, Suzhou City, Jiangsu Province, People’s Republic of China, Tel +86-13771721180 ; +86-18962183510, Email chenzhengrong@suda.edu.cn; huanglilcy@163.comObjective: To investigate the significance of VISTA in bronchial asthma and its impact on the disease.Methods: Human peripheral blood of asthma children was gathered. The expression concentrations of VISTA, IL-4, IL-6, CD25, CD40L, and PD-L2 in peripheral blood plasma were detected by ELISA. We established the mouse model of asthma and intervened with agonistic anti-VISTA mAb (4C11) and VISTA fusion protein. ELISA, flow cytometry, and Western blotting were performed to detect the expression levels of Th1, Th2, and Th17 cell subsets and related characteristic cytokines, as well as the protein levels of MAPKs, NF-κB, and TRAF6 in lung tissues. In addition, the infiltration of eosinophils and inflammatory cells, airway mucus secretion, and VISTA protein expression in lung histopathological sections of different groups of mice were analyzed.Results: The concentration of VISTA in human asthma group decreased significantly (p < 0.05); A positive correlation was observed between VISTA and CD40L. The intervention of 4C11 mAb and fusion protein respectively during the induction period increase the differentiation of Th1 cells and the secretion of IFN-γ, and inhibit the differentiation of Th2 and Th17 cells, as well as the secretion of IL-4, IL-5, IL-13 and IL-17, partially reduce the pathological changes of asthma in mouse lungs and correct the progress of asthma. The MAPK, NF-κB, and TRAF6 protein levels were the middle range in the 4C11 mAb and fusion protein groups (p < 0.05).Conclusion: The findings suggest VISTA may play a negative regulatory role in the occurrence and development of bronchial asthma.Keywords: VISTA, bronchial asthma, Th2 cells, cytokines, anti-VISTA mAb, VISTA fusion protein

Jingxuan Zhang,1,&ast; Yun Yan,1,&ast; Feifei Jiang,2,&ast; Jingguo Chen,3,&ast; Yuhui Ouyang,1,4,5 Luo Zhang1,4,5 1Department of Allergy, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 3Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Xi ‘an Jiaotong University, Xi’an, People’s Republic of China; 4Beijing Laboratory of Allergic Diseases, Municipal Education Commission and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, People’s Republic of China; 5Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuhui Ouyang; Luo Zhang, Department of Allergy, Beijing Tongren Hospital, Capital Medical University, No. 1, Dongjiaominxiang, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +8610 58268375 ; +8610 65141136, Fax +8610 85115988, Email oyyuhui@sina.com; dr.luozhang@139.comBackground: Pollen allergies have a high prevalence in northern China, whereas, the types of pollen allergens and population characteristics among different regions remain unclear.Objective: To study the species and temporal distribution of the main allergenic pollen, as well as the characteristics of patients with pollen-related allergic rhinitis (AR) in different cities in northern China.Methods: Pollen data were obtained from pollen-monitoring stations in 13 cities of northern China between 2020 and 2021. Questionnaire surveys and allergen testing were conducted in 494 patients with pollen-related allergies from Beijing in Central, Shenyang in Northeast, and Xi’an in Northwest China.Results: In 13 cities of northern China, the main sources of pollen were cypress, poplar, elm, pine, birch and ash in spring, and mugwort, goosefoot, hop and ragweed in autumn. In Northwest China, the spring and autumn pollen periods started earlier and lasted longer than that in Central and Northeast China, and the pollen counts in autumn in was significantly higher than that in Central and Northeast China. Furthermore, the nasal, ocular and respiratory symptom and quality of life scores of AR patients in Northwest China were significantly higher than that in Central and Northeast China. 69.32– 73.28% of patients had annual cost of anti-allergic medication between 500– 5000 yuan. However, 40.93– 48.86% of patients reported minor control of symptoms.Conclusion: Our results can be used as a basis for developing effective prevention and management measures for patients with pollen-related allergy in these regions, including timely pollen monitoring, patient guidance on protective measures, early intervention, and specific immunotherapy, to improve pollen-related allergy management.Keywords: allergic rhinitis, pollen monitoring, Northern China, questionnaire survey, symptom scores

Jiawen Zhang,1,&ast; Duoduo Gu,2,&ast; Yang Yan,3,&ast; Ruoxin Pan,2 Hui Zhong,4,5 Chengfeng Zhang,1 Yang Xu2 1Department of Dermatology, Huashan Hospital of Fudan University, Shanghai, People’s Republic of China; 2Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 3Department of Cardiology, Ren Ji Hospital of Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, People’s Republic of China; 5School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chengfeng Zhang; Yang Xu, Email e3dangdang@hotmail.com; yangxu@njmu.edu.cnAbstract: Rosacea is a chronic inflammatory skin disease that affects a patient’s appearance and quality of life. It mainly affects the midface region and presents as erythema, flushing, telangiectasia, papules, pustules, and rhinophyma. Despite its prevalence, the precise pathophysiology of rosacea remains unknown, and novel pharmacological therapies are currently under investigation. Tranexamic acid (TA) is a synthetic, lysine-like compound that competitively inhibits fibrinogen production by synthesizing fibrinolytic enzymes. In addition to its popular application in hemorrhage treatment, TA has been used to manage a number of skin conditions, including melasma, chronic urticaria, and angioedema. TA is a better option for melasma treatment. However, the role of TA in treating rosacea has not yet been systematically elucidated. In this study, we reviewed all available literature on the use of TA for rosacea treatment. The included articles examined the therapeutic effects of TA in patients with rosacea, including traditional methods such as oral and topical administration and more novel approaches such as intradermal injections, microneedling, and laser-assisted delivery. Several recent clinical studies demonstrated that TA alleviates rosacea symptoms by restoring the permeability barrier, ameliorating the immune reaction, and inhibiting angiogenesis. In this review, we summarized the function and potential application of TA in rosacea treatment, aiming to facilitate the implementation of clinical applications.Keywords: rosacea, tranexamic acid, topical, oral, microinjection

Xiaoling Zhou,1,2 Jing Wu,3 Ying Liu,3 Yuzhong Yan,2 Geyao Zhou,1 Ming Li1,4 1School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, People’s Republic of China; 2Research Department, Shanghai University of Medicine&Health Sciences Affiliated Zhoupu Hospital, Shanghai, People’s Republic of China; 3School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Party Committee office, Tongji University Affiliated Shanghai East Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Ming Li; Geyao Zhou, Email liming1070202306@163.com; zhougeyao@163.comBackground: The health status of the occupational population is critical to the development of countries and regions as it is the main force of social and economic development. However, there is a dearth of comprehensive and systematic indicators to evaluate the health of occupational groups. This study aimed to construct a multi-dimensional evaluation index system for the general population.Methods: This study combined a literature review and initially established a multidimensional health system framework for the occupational population based on health ecology theory and then used two rounds of Delphi expert consultation to construct the final multidimensional health index system for the occupational population. Fifteen experts from related fields were selected for two rounds of Delphi expert consultation.Results: The recovery rates of the two rounds of expert questionnaires were 100.00% and 93.33% respectively, the expert authority coefficient were 0.90, and the Kendall’s coordination coefficients of the first and second level indexes were 0.32 and 0.42 (P ≥ 0. 001). The final index system includes four primary indicators (individual characteristics, health knowledge, health behavior, and health skills), 13 second-level indicators, and 41 third-level indicators; the weight coefficients of the four primary health dimensions are relatively close, and the “health knowledge” is slightly higher.Conclusion: The multi-dimensional health index system of the occupational population established in this study is comprehensive and reasonable from the perspective of health ecology, which can provide a solid foundation for the further development of a comprehensive health status prediction model for the occupational population.Keywords: health ecology, delphi method, multidimensional health, index system

Di-fei Duan,1,&ast; Yue Wen,1,&ast; Yu Yan,1 Ling Li,2 Xiang Xiao,3 Xing Li,1 Lin-Jia Yan,4 Deng-Yan Ma1 1Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University /West China School of Nursing, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 2Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 3West China School of Medicine, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 4The Nethersole School of Nursing Faculty of Medicine, The Chinese University of Hong Kong, Hongkong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Deng-Yan Ma, Department of Nephrology, West China Hospital of Sichuan University, No. 37 Guoxuexiang, Wuhou District, Chengdu, Sichuan, People’s Republic of China, Email mdy5104@wchscu.cnBackground: Given the importance of diabetic kidney disease (DKD) management, this study aims to explore the knowledge, attitudes, and practices in disease management demonstrated by healthcare workers from the nephrology department.Materials and Methods: This study is a multi-centered cross-sectional study, and adopts snowball sampling, with 530 healthcare workers being recruited to complete a questionnaire covering areas such as demographic characteristics, knowledge, attitude, and practices (KAP) of DKD management. This data was analyzed using descriptive statistics and binary logistics analysis.Results: In this study, 530 healthcare workers were studied, including 94 doctors and 436 nurses. The participants were mainly from general tertiary hospitals in 14 provinces. For Chinese nurse, the results indicate that both poor knowledge level (Odds Ratio (OR) =0.63, 95% Confidence Interval (CI): 0.42– 0.94) and having experience in further medical training in nephrology (OR=1.92, 95% CI: 1.20– 3.08) are associated with the practice levels. For Chinese doctors, having not experience in further medical training in nephrology (OR=0.36, 95% CI: 0.15– 0.83) are associated with their practice levels.Conclusion: In summary, Chinese doctors and nurses in this study showed positive attitudes towards DKD management, but their knowledge and practical skills were lacking. This underscores a notable gap in achieving optimal DKD care. Notably, nurses’ knowledge influenced their management practices, and additional nephrology training correlated with better engagement. To improve patient care, enhancing nephrology healthcare professional training and addressing knowledge-practice disparities are recommended.Keywords: knowledge, attitude, practice, diabetic kidney disease

Pengzhu Huang,1,2,&ast; Rongrong Wu,1,2,&ast; Xin Guo,1,2,&ast; Xiaoli Gao,1,2 Ye Yan,1,2 Cha Han,1,2 Fengxia Xue1,2 1Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fengxia Xue; Cha Han, Department of Gynecology and Obstetrics, Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China, Tel +86-22-60363769, Fax +86-22-27813550, Email xuefengxia@tmu.edu.cn; tjhancha@tmu.edu.cnObjective: This study aimed to evaluate the impact of twin pregnancies with antiphospholipid antibody (aPL) positivity, a rare and complex clinical condition that remains a huge challenge for management.Methods: This study enrolled twin-pregnant women at our hospital between January 2018 and August 2023. Women with and without aPL positivity were selected using propensity score matching (PSM). Clinical features and pregnancy outcomes were compared between the two groups in the PSM cohort. To analyze the effect of aPL positivity on pregnancy outcomes, multivariate logistic models were used to obtain adjusted odds ratios (aOR) with 95% confidence intervals (CI).Results: Among the 773 women with twin pregnancies, aPL positivity was found in 26 women (3.36%). In the PSM cohort, there were 24 twin-pregnant women with positive aPL, and 48 women without aPL were selected as controls. Twin-pregnant women with aPL positivity had a higher proportion of abortion (8.33% vs 0, P = 0.043), preterm birth < 34 weeks (33.33% vs 8.33%, P = 0.007) and very low birthweight (< 1500 g) (20.83% vs 4.17%, P = 0.016) than the control group. In addition, stillbirth of one fetus was observed in one twin-pregnant woman with positive aPL. Multivariate logistic regression analysis revealed that twin pregnancy with aPL positivity was associated with preterm birth < 34 weeks (aOR = 2.76, 95% CI: 0.83– 4.70, P = 0.005), very low birthweight (< 1500 g) (OR = 2.40, 95% CI: 0.18– 4.67, P = 0.034) and small for gestational age (SGA) (aOR = 1.66, 95% CI: 0.22– 3.10, P =0.024).Conclusion: Twin pregnancies with aPL positivity were correlated with obstetric complications, including abortion, preterm birth < 34 weeks and very low birthweight (< 1500 g). The detection of aPL may be of clinical significance for women with twin pregnancies and should be considered in future studies.Keywords: twin pregnancy, antiphospholipid antibody, pregnancy outcomes, propensity score matching

Yang Liu,1,2,&ast; Hui Yang,1,2,&ast; Xueshu Fu,1,2 Luting Zhong,1,2 Ping Xu,1,2 Fang Fang,1,2 Ying Liu,1,2 Qing Li,1,2 Ya’nan Yan,1,2 Shanchuang Wei,1,2 Junqing Wang,1,2 Chunhua Zhang1– 3 1Department of Gynaecology, Affiliated Hospital of YangZhou University Huai ‘an Maternal and Child Health Care Center, Huai’an, Jiangsu, People’s Republic of China; 2Department of Gynaecology, The Huai’an Maternity and Child Clinical College of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China; 3Department of Integrated Traditional Chinese & Western Clinical Medicine, Macau University of Science and Technology, Macau, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunhua Zhang, Department of Gynaecology, The Huai’an Maternity and Child Clinical College of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China, Tel +86-13952326117, Email hafyzch@126.comBackground: Multiple primary cancer (MPC) refers to the presence of more than one cancer in an individual. Triple primary malignancies are uncommon.Case: We report the case of a 50-year-old postmenopausal woman in our gynecology department, diagnosed with endometrial cancer, ovarian cancer, and unilateral breast cancer. She carried germline mutations in BRCA2, PALB2, and RECQL4, along with a somatic pathogenic variant in TP53. Endometrial cancer patients harboring germline pathogenic variants in BRCA2 exhibit a heightened risk of ovarian and breast cancer. BRCA2 is known to play a role in the development of ovarian and breast cancer, while PALB2 is identified as a gene associated with breast cancer susceptibility. RECQL4 has been linked to breast cancer, cervical cancer, and other tumors.Conclusion: Genetic testing may be imperative for identifying MPC in endometrial cancer patients. For individuals with BRCA2 and other gene pathogenic variants, routine examination and monitoring of the endometrium, ovaries, breasts, and other sites prone to polygenic cancer are recommended.Keywords: multiple primary cancer, endometrial cancer, ovarian cancer, breast cancer, genetic test

Wu Lin,1,&ast; Yuxiang Yan,2,&ast; Qingling Huang,1 Dali Zheng2 1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, People’s Republic of China; 2Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dali Zheng, Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, 88 Jiao Tong Road, Fuzhou, 350004, People’s Republic of China, Email dalizheng@fjmu.edu.cnAbstract: The p53 tumor suppressor protein plays an important role in physiological and pathological processes. MDM2 and its homolog MDMX are the most important negative regulators of p53. Many studies have shown that MDMX promotes the growth of cancer cells by influencing the regulation of the downstream target gene of tumor suppressor p53. Studies have found that inhibiting the MDMX-p53 interaction can effectively restore the tumor suppressor activity of p53. MDMX has growth-promoting activities without p53 or in the presence of mutant p53. Therefore, it is extremely important to study the function of MDMX in tumorigenesis, progression and prognosis. This article mainly reviews the current research progress and mechanism on MDMX function, summarizes known MDMX inhibitors and provides new ideas for the development of more specific and effective MDMX inhibitors for cancer treatment.Keywords: MDMX, P53, cancer, inhibitors

Jingwen Jiang,1– 3,&ast; Na Kong,1– 3,&ast; Qingqing Shi,1– 3,&ast; Yuan Yan,1– 3 Xiaoyue Shen,1– 3 Jie Mei,1– 3 Haixiang Sun,1– 3 Chenyang Huang1– 3 1Center for Reproductive Medicine and Obstetrics and Gynecology, Drum Tower Clinic Medical College of Nanjing Medical University, Nanjing, 210008, People’s Republic of China; 2Reproductive Medicine Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, People’s Republic of China; 3Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, 210008, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haixiang Sun; Chenyang Huang, Center for Reproductive Medicine and Obstetrics and Gynecology, Drum Tower Clinic Medical College of Nanjing Medical University, Nanjing, 210008, People’s Republic of China, Tel +8625-8310-6666-70261, Fax +8625-8310-7188, Email stevensunz@163.com; dianshui19901562@126.comBackground: Previous studies suggested higher serum progesterone (P) levels were strongly associated with a lower clinical pregnancy rate (CPR) for in vitro fertilization-embryo transfer (IVF-ET). However, the effect of increased serum P levels on the day of human chorionic gonadotropin (hCG) administration on clinical outcomes in short-acting gonadotropin-releasing hormone agonist (GnRHa) downregulated IVF-ET cycles remains unclear.Methods: We conducted a retrospective cohort study from January 2017 to December 2021, which included a total of 1664 patients receiving their first short-acting GnRHa IVF-ET cycles at our reproductive medicine centre of Nanjing Drum Tower Hospital. The smooth curve fitting and interaction analysis were employed to analyse the association between the CPR and the serum P levels with different embryo types (cleavage-stage embryo or blastocyst). In addition, total cycles were grouped according to different P levels on the trigger day of hCG administration for further analysis.Results: The CPR of patients with increased serum P level (higher than 1.5 ng/mL) on the hCG day did not decrease. A smoothing curve fitting showed that the CPR did not change obviously with the increase in serum P levels. Subgroup analysis of different types of embryos transferred showed that no correlation was observed between the CPR and serum P levels on the day of hCG administration in cleavage-stage embryo transfer cycles. However, the CPR of patients receiving blastocyst transfer showed a downward trend with the increase in serum P levels. At the same time, an interaction analysis also confirmed that the CPR of blastocyst transfer was more likely to be affected by elevated serum P levels on the hCG day.Conclusion: In the luteal phase short-acting GnRHa downregulated IVF-ET cycles, the elevated serum P levels on the hCG day did not affect the CPR of cleavage-stage embryo transfer but reduced the CPR of blastocyst transfer.Keywords: short-acting GnRHa, elevated progesterone level, hCG trigger day, clinical pregnancy rate, blastocyst transfer

Yunbo Yan,1 Linqian Yu,1 Binyang Chen,1 Chang’an Cao,1 Hairong Zhao,1,2 Qiang Wang,1 De Xie,1 Yuemei Xi,1 Chenggui Zhang,2 Jidong Cheng1,3 1Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 2Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, Dali University, Dali, People’s Republic of China; 3Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, People’s Republic of ChinaCorrespondence: Jidong Cheng; Chenggui Zhang, Email jidongcheng36@hotmail.com; chenggui_zcg@hotmail.comBackground: Gouty arthritis is characterized by the accumulation of monosodium urate crystals (MSU) in the synovial joints and surrounding tissues. Mastoparan M (Mast-M) is a biologically active peptide composed of 14 amino acids, extracted from wasp venom. This study aims to assess the impact of Mast-M on in vitro and in vivo gouty arthritis induced by lipolyaccharide (LPS) plus MSU crystal stimulation.Methods: PMA-differentiated THP-1 macrophages were pre-treated with Mast-M or left untreated, followed by stimulation with LPS and MSU crystals. Cell lysates were collected to assess the expression of the NLRP3 inflammasome, inflammatory signaling pathways, and oxidative stress. Furthermore, to evaluate the in vivo anti-inflammatory effect of Mast-M, an experimental acute gouty arthritis mouse model was established through intra-articular injection of MSU crystals.Results: Mast-M treatment demonstrated significant inhibition of the phosphorylation of MAPKs/NF-κB signaling pathways and reduction in oxidative stress expression in LPS and MSU-induced THP-1 macrophages. This resulted in the suppression of downstream NLRP3 inflammasome activation and IL-1β release. In vivo, Mast-M effectively attenuated the inflammation induced by MSU in mice with gouty arthritis. Specifically, Mast-M reduced swelling in the paws, inhibited the infiltration of neutrophils and macrophages into periarticular tissue, and decreased the activation of the NLRP3 inflammasome and IL-1β production.Conclusion: Mast-M significantly improves gouty arthritis, and its potential mechanism may be achieved by inhibiting the MAPK/NF-κB pathway and alleviating oxidative stress, thus suppressing the activation of NLRP3 inflammasomes.Keywords: Mastoparan M, NLRP3, MAPKs, NF-κB, oxidative stress, gout

Chenkai Yang,1,&ast; Xiangqian Cao,1,&ast; Lei He,2,3,&ast; Cong Wu,2,&ast; Mengxin Zhao,2 Fei Duan,2 Zhiwen Qiu,2 Xiaodong Zhu,2 Yilin Yan,1 Shengzhou Li,1 Wei Li,2 Bing Shen1 1Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Nanomedicine & Shanghai Key Laboratory of Cell Engineering, Naval Medical University, Shanghai, People’s Republic of China; 3School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Li, Department of Nanomedicine & Shanghai Key Laboratory of Cell Engineering, Naval Medical University, 800 Xiangyin Road, Yangpu District, Shanghai, 200433, People’s Republic of China, Tel +86 21 81871644, Fax +86 21 81870801, Email liwei_dds@163.com Bing Shen, Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 85 Wujin Road, Hongkou District, Shanghai, 200080, People’s Republic of China, Tel/Fax +86 18017181979, Email urodrshenbing@shsmu.edu.cnIntroduction: Insufficient tumor permeability and inadequate nanoparticle retention continue to be significant limitations in the efficacy of anti-tumor drug therapy. Numerous studies have focused on enhancing tumor perfusion by improvement of tumor-induced endothelial leakage, often known as the enhanced permeability and retention (EPR) effect. However, these approaches have produced suboptimal therapeutic outcomes and have been associated with significant side effects. Therefore, in this study, we prepared tumor cell membrane-coated gold nanorods (GNR@TM) to enhance drug delivery in tumors through homogeneous targeting of tumor cell membranes and in situ real-time photo-controlled therapy.Methods: Here, we fabricated GNR@TM, and characterized it using various techniques including Ultraviolet-Visible (UV-Vis) spectrophotometer, particle size analysis, potential measurement, and transmission electron microscopy (TEM). The cellular uptake and cytotoxicity of GNR@TM were analyzed by flow cytometry, confocal laser scanning microscopy (CLSM), TEM, CCK8 assay and live/dead staining. Tissue drug distribution was determined by inductively coupled plasma mass spectrometry (ICP-MS) and immunofluorescence staining. Furthermore, to evaluate the therapeutic effect, mice bearing MB49 tumors were intravenously administered with GNR@TM. Subsequently, near-infrared (NIR) laser therapy was performed, and the mice’s tumor growth and body weight were monitored.Results: The tumor cell membrane coating endowed GNR@TM with extended circulation time in vivo and homotypic targeting to tumor, thereby enhancing the accumulation of GNR@TM within tumors. Upon 780 nm laser, GNR@TM exhibited excellent photothermal conversion capability, leading to increased tumor vascular leakage. This magnification of the EPR effect induced by NIR laser further increased the accumulation of GNR@TM at the tumor site, demonstrating strong antitumor effects in vivo.Conclusion: In this study, we successfully developed a NIR-triggered nanomedicine that increased drug accumulation in tumor through photo-controlled therapy and homotypic targeting of the tumor cell membrane. GNR@TM has been demonstrated effective suppression of tumor growth, excellent biocompatibility, and significant potential for clinical applications. Keywords: intratumor drug accumulation, photo-controlled therapy, homotypic targeting, tumor cell membrane, gold nanorods

An Li,1 Huxiong Piao,1 Jiamin Zhang,2 Qingtao Cheng,1 Fangyu Piao,1 Chang Cao,1 Yuqi Yan,1 Jingxu Li,1 Bin Jin1 1Stomatology, Affiliated Hospital of Yanbian University, Yanji, People’s Republic of China; 2Department of Periodontal Mucosal Disease, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, People’s Republic of ChinaCorrespondence: Jingxu Li; Bin Jin, Email ljx0502@126.com; jinbin198629@sina.comPurpose: To compare the clinical repair effects of leaving the defect empty and using Platelet-Rich Fibrin (PRF) combined with BIO-GENE artificial bone powder in patients with bone defects 6 months after jaw cystectomy.Patients and Methods: From June 2021 to June 2022, 70 patients who were admitted to the Department of Stomatology, Affiliated Hospital of Yanbian University, and were diagnosed with jaw cysts postoperatively were selected. All of the patients were divided into two groups according to random method, among which 35 patients who underwent cystectomy alone were recorded as group A, which served as blank control; 35 patients who underwent cystectomy and PRF combined with BIO-GENE artificial bone meal repaired bone defects during the same period were recorded as group B. 3D Slicer 5.0.3 software was used to reconstruct Cone Beam Computed Tomography (CBCT) after operation. In this study, the preoperative and postoperative CBCT data of the patients were analyzed using 3D Slicer 5.0.3 software in DICOM format to calculate the cleft volume before surgery and the newly formed bone volume after surgery. The osteogenesis rate was measured based on these calculations.The bone formation percentage in the bone defect area was recorded at 6 months, and the clinical curative effects of the two groups were compared.Results: After 6 months of surgery, the patients showed varying degrees of restoration in the jaw cyst area.The osteogenesis rate at 6 months in group A was 76.06± 13.38%, while group B had a rate of 92.87± 5.72%.The CBCT values in group B were higher than those in group A at 6 months post-surgery (P< 0.05), t=− 6.84.Group A and Group B showed a statistically significant difference.Conclusion: Compared with simple cystectomy, PRF combined with BIO-GENE artificial bone powder has a better effect on the speed of bone repair after cystectomy within 6 months and provides more favorable effects for the repair of postoperative dentition defects, and provides support to repair teeth after defects such as dental implants.Keywords: PRF, bone transplantation, jaw cysts, bone regeneration

Yu Liu,1,&ast; Enyi Zhu,1,&ast; Yan Lei,1,&ast; Ailing Luo,2 Yaping Yan,2 Mansi Cai,2 Shanshan Liu,2 Yan Huang,3 Hui Guan,1 Ming Zhong,1 Weinian Li,4 Lian Lin,1 Michael Hultstöm,5,6 Enyin Lai,7 Zhihua Zheng,1 Xiaoping Liu,2 Chun Tang1 1Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, People’s Republic of China; 2Department of Hematology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, People’s Republic of China; 3The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China; 4Department of Rheumatology, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou, 510623, People’s Republic of China; 5Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden; 6Department of Medical Cell Biology, Unit for Integrative Physiology, Uppsala University, Uppsala, Sweden; 7Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chun Tang; Xiaoping Liu, Email tangch28@mail.sysu.edu.cn; liu_xiaoping@gwcmc.orgPurpose: Methyltransferase like 1 (METTL1) regulates epitranscriptomes via the m7G modification in mammalian mRNA and microRNA. Systemic lupus erythematosus (SLE) is caused by abnormal immune reactivity and has diverse clinical manifestations. RNA methylation as a mechanism to regulate gene expression is widely implicated in immune regulation. However, the role of m7G in immune response of SLE has not been extensively studied.Patients and Methods: Expression of METTL1 was identified in the public dataset GSE122459 and validated in an independent cohort of SLE patients. We investigated the association between METTL1-expression and clinical manifestations of SLE. Subsequently, differentially expressed genes (DEG) that were correlated with METTL1-expression in GSE122459 were used for functional enrichment analysis. The correlation between infiltrating immune cells and METTL1, as well as candidate biomarkers identified to be correlated with either METTL1 or immune cell infiltration were assessed by single-sample GSEA. Potential mechanisms were explored with Gene ontology and KEGG pathway enrichment. Diagnostic performances of candidate biomarkers in SLE were analyzed.Results: The mRNA and protein expression of METTL1 in SLE patients were significantly decreased in both datasets. METTL1-coexpressed DEGs were enriched in several key immune-related pathways. Activated CD8 T cells, activated CD4 T cells, memory B cells and type 2 helper T cells were different between patients with high and low METTL1 expression. Further, activated CD8 T-cells, activated CD4 T-cells, memory B-cells were correlated with METTL1. The genes of LAMP3, CD83, PDCD1LG2, IGKVD3D-20, IGKV5-2, IGKV2D-30, IGLV3-19 and IGLV4-60 were identified as candidate targets that were correlated with immune cell proportion. Moreover, LAMP3, CD83, and PDCD1LG2 expression were of diagnostic value in SLE as indicated by ROC analysis.Conclusion: Our findings suggested that METTL1 and its candidate targets LAMP3, CD83, PDCD1LG2 may be used for diagnosing SLE and could be explored for developing targeted molecular therapy for SLE.Keywords: methyltransferase like 1, systemic lupus erythematosus, immunity, single sample gene set enrichment analysis, biomarker

Abstract Activation of the NLRP3 inflammasome is a two-step process: the priming and the activating. The priming step involves the induction of NLRP3 and pro-IL-1β, while the activating step leads to the full inflammasome activation triggered by a NLRP3 activator. Although mechanisms underlying the NLRP3 inflammasome activation have been increasingly clear, the regulation of this process remains incompletely understood. In this study, we find that LPS and Pseudomonas aeruginosa cause a rapid downregulation in MafB transcription in macrophages, which leads to a quick decline in the level of MafB protein because MafB is short-lived and constantly degraded by the ubiquitin/proteasome system. We find that MafB knockdown or knockout markedly enhances the NLRP3, but not the NLRP1, NLRC4, or AIM2, inflammasome activation in macrophages. Conversely, pharmacological induction of MafB diminishes the NLRP3 inflammasome activation. Mechanistically, we find that MafB sustains the expression of p62, a key mediator of autophagy/mitophagy. We find that MafB inhibits mitochondrial damage, and mitochondrial ROS production and DNA cytoplasmic release. Furthermore, we find that myeloid MafB deficient mice demonstrate increased systemic and lung IL-1β production in response to LPS treatment and P. aeruginosa infection and deficient lung P. aeruginosa clearance in vivo. In conclusion, our study demonstrates that MafB is an important negative regulator of the NLRP3 inflammasome. Our findings suggest that strategies elevating MafB may be effective to treat immune disorders due to excessive activation of the NLRP3 inflammasome.

Xu X, Yan Y, Xun Q, et al. Onco Targets Ther. 2019;12:1215-1223. We, the Editor and Publisher of the journal OncoTargets and Therapy have retracted the published article. Following publication of the article, the authors raised concerns about the duplication of images from Figure 2. Specifically, The images for Figure 2D, siVEGF and siANG, have been duplicated. The corresponding author was cooperative and responded to our queries but was unable to provide a satisfactory explanation for how the images came to be duplicated or provide satisfactory original data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, the Publisher and Editor requested to retract the article and the corresponding author was notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Lu Zhang, Yan Yan, Ru Liao, Haiyan Dong Department of Pharmacy, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of ChinaCorrespondence: Haiyan Dong, Department of Pharmacy, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China, Tel/Fax +86-29-85323508, Email batistuta28@126.comBackground: Linezolid-induced thrombocytopenia incidence varies considerably. Linezolid-related thrombocytopenia in patients has received few studies which have investigated risk factors including platelet parameters except for platelet counts. The study aims to analyze the effect of platelet parameters, including mean platelet volume and platelet large cell ratio, on linezolid-related thrombocytopenia in patients.Methods: The effect of platelet parameters on linezolid-related thrombocytopenia was identified by univariate and multivariate logistic regressions. A Kaplan–Meier survival analysis was carried out to compare the survival of patients who developed linezolid-related thrombocytopenia with patients who did not.Results: Thrombocytopenia occurred at a rate of 41.5% (66/159) after linezolid therapy in hospitalized patients. Platelet parameters, including the difference in mean platelet volume (MPV/fL=0.08 (− 1.2– 0.9)vs-0.5 (− 1.5– 0.3), (OR, 0.459; P = 0.001), the difference in platelet large cell ratio (PLCR/fL=0.9 (− 5.1– 6.2)vs-3.8 (− 8.6– 2.4), (OR, 1.156; P = 0.001), baseline platelet counts (OR, 0.995; P = 0.006) and duration of linezolid therapy≥ 10d (OR, 1.346; P = 0.007), were significantly associated with linezolid-related thrombocytopenia in hospitalized patients. In addition, other risk factors which also are associated with linezolid-related thrombocytopenia include baseline red blood cells, co-medication with parecoxib and co-medication with caspofungin. Accumulated in-hospital mortality of patients with thrombocytopenia was significantly higher than that of patients without thrombocytopenia during linezolid treatment (19.7% vs 8.6%, P = 0.003).Conclusion: The difference in mean platelet volume, the difference in large platelet ratio, baseline platelet counts and duration of linezolid therapy≥ 10d significantly affected the development of linezolid-related thrombocytopenia in hospitalized patients.Keywords: linezolid, platelet parameters, thrombocytopenia, risk factors

Xiaohang Chen,1,2 Shuaiqi Ji,1,2 Yuxiang Yan,1 Shuoqi Lin,1,2 Lianghang He,1,2 Xiaoyu Huang,2 Lin Chang,2 Dali Zheng,1 Youguang Lu1,2 1Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, People’s Republic of China; 2Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, People’s Republic of ChinaCorrespondence: Youguang Lu; Dali Zheng, Email fjlyg63@fjmu.edu.cn; dalizheng@fjmu.edu.cnAbstract: Tumors are the second-most common disease in the world, killing people at an alarming rate. As issues with drug resistance, lack of targeting, and severe side effects are revealed, there is a growing demand for precision-targeted drug delivery systems. Plant-derived nanovesicles (PDNVs), which arecomposed of proteins, lipids, RNA, and metabolites, are widely distributed and readily accessible. The potential for anti-proliferative, pro-apoptotic, and drug-resistant-reversing effects on tumor cells, as well as the ability to alter the tumor microenvironment (TME) by modulating tumor-specific immune cells, make PDNVs promising anti-tumor therapeutics. With a lipid bilayer structure that allows drug loading and a transmembrane capacity readily endocytosed by cells, PDNVs are also expected to become a new drug delivery platform. Exogenous modifications of PDNVs enhance their circulating stability, tumor targeting ability, high cell endocytosis rate, and controlled-release capacity. In this review, we summarize PDNVs’ natural antitumor activity, as well as engineered PDNVs as efficient precision-targeted drug delivery tools that enhance therapeutic effects. Additionally, we discuss critical considerations related to the issues raised in this area, which will encourage researchers to improve PDNVs as better anti-tumor therapeutics for clinic applications.Graphical Abstract: Keywords: plant-derived nanovesicles, cancer therapy, natural bioactivity, drug delivery platform, engineered EVs, targeted precision therapy

Abstract The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota is causatively linked with the development of both metabolic dysfunctions and gastrointestinal disorders, thus gut dysbiosis in IBS may contribute to the development of metabolic syndrome. Here, we show that human gut bacterium Ruminococcus gnavus-derived tryptamine and phenethylamine play a pathogenic role in gut dysbiosis-induced insulin resistance in type 2 diabetes (T2D) and IBS. We show levels of R. gnavus, tryptamine, and phenethylamine are positively associated with insulin resistance in T2D patients and IBS patients. Monoassociation of R. gnavus impairs insulin sensitivity and glucose control in germ-free mice. Mechanistically, treatment of R. gnavus-derived metabolites tryptamine and phenethylamine directly impair insulin signaling in major metabolic tissues of healthy mice and monkeys and this effect is mediated by the trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. Our findings suggest a causal role for tryptamine/phenethylamine-producers in the development of insulin resistance, provide molecular mechanisms for the increased prevalence of metabolic syndrome in IBS, and highlight the TAAR1 signaling axis as a potential therapeutic target for the management of metabolic syndrome induced by gut dysbiosis.

Han Li,1,&ast; Ke Su,1,&ast; Lu Guo,2,&ast; Yi Jiang,1 Ke Xu,1 Tao Gu,1 Jiali Chen,1 Zhenying Wu,1 Pan Wang,3 Xi Zhang,4 Yushan Yan,1 Siyuan Li,1 Xue Wu,1 Lei Han,5 Kun He,6 Lianbin Wen,7 Bo Li,4 Yunwei Han1 1Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Department of Ophthalmology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3Clinical Research Institute, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 4Department of General Surgery (Hepatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 5Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, 272000, People’s Republic of China; 6Clinical Medical College, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 7Sichuan Provincial People’s Hospital, Chengdu, 610072, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunwei Han; Bo Li, The Affiliated Hospital of Southwest Medical University, 25 TAIPING Street, Luzhou City, Sichuan Province, People’s Republic of China, Tel +86-830-3165598 ; +86-830-3165613, Email lanpaoxiansheng@126.com; liboer2002@126.comBackground: At present, it is not known whether targeting plus immunotherapy combined with transarterial chemoembolization (TACE) can improve the efficacy of hepatocellular carcinoma (HCC). The aim of this retrospective experiment was to explore the difference in clinical efficacy between antiangiogenic drugs plus PD-1 inhibitors combined with and without TACE.Methods: Clinical data of 145 patients with HCC who received anti-angiogenesis therapy plus PD-1 inhibitor combined with TACE (TACE-P-T) (n = 62) or anti-angiogenesis therapy combined with PD-1 inhibitor (P-T) (n = 83) in China from October 2018 to December 2022 were collected and reviewed. We used propensity matching (PSM) to create two groups with comparable baseline scores, compared their median survival time (mOS) and median progression-free survival time (mPFS), and performed subgroup analysis.Results: Before PSM, the mOS and mPFS of patients were 20.3 and 5.0 months in the triple therapy group and 13.6 and 7.4 months in the control group, respectively. After PSM, the mOS and mPFS of patients were 19.7 and 6.6 months in the triple treatment group and 10.5 and 3.7 months in the control group, respectively. Therefore, the TACE-P-T group showed better survival outcomes than P-T. In the subgroup analysis, compared with the control group, the mOS was 10.7 vs 20.3 months in the alpha fetoprotein (AFP) (≥ 400ng/mL/< 400ng/mL) group, 29.3 vs 7.4 months in the alkaline phosphatase (ALP) (≥ 125u/L/< 125u/L) group and 10.5 vs 20.0 months in the Portal vein invasion (PVTT) group.Conclusion: Antiangiogenic therapy combined with PD-1 inhibitors combined with TACE has significant survival benefits for HCC patients.Keywords: HCC, PD-1 inhibitors, antiangiogenic therapy, TACE

Meng Tao,1,2 Jing Han,3 Juanyi Shi,1,2 Hao Liao,1,2 Kai Wen,1,2 Weidong Wang,1,2 Sintim Mui,1,2 Huoming Li,1,2 Yongcong Yan,1,2 Zhiyu Xiao1,2 1Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 3Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, People’s Republic of ChinaCorrespondence: Yongcong Yan; Zhiyu Xiao, Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road &num;107, Guangzhou, 510120, People’s Republic of China, Tel +86-15800039176 ; +86-13682283695, Fax +86 20 34071073, Email yanyc3@mail.sysu.edu.cn; xiaozhiy@mail.sysu.edu.cnAbstract: Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), is one of the preferred targeted drugs for the treatment of advanced hepatocellular carcinoma (aHCC). Since the REFLECT study showed that lenvatinib was noninferior to sorafenib in overall survival (OS), lenvatinib monotherapy has been widely used for aHCC. Moreover, lenvatinib combination therapy, especially lenvatinib combined with immune checkpoint inhibitors (ICIs), has shown more encouraging clinical results. However, drug development and comprehensive treatment have not significantly improved the prognosis, and lenvatinib resistance is often encountered in treatment. The underlying molecular mechanism of lenvatinib resistance is still unclear, and studies to solve drug resistance are ongoing. The molecular mechanisms of lenvatinib resistance in patients with aHCC include the regulation of signaling pathways, the regulation of noncoding RNAs, the impact of the immune microenvironment, tumor stem cell activation and other mechanisms. This review aims to (1) summarize the progress of lenvatinib in treating aHCC, (2) delineate the known lenvatinib resistance mechanisms of current therapy, and (3) describe the development of therapeutic methods intended to overcome these resistance mechanisms.Keywords: lenvatinib, application, drug resistance, hepatocellular carcinoma

Chen Y, Deng Y, Chen L, Huang Z, Yan Y, Huang Z. J Inflamm Res. 2023;16:1077–1089. We, the Editors and Publisher of Journal of Inflammation Research, have retracted the following article. Following publication of the article, concerns were raised about the duplication of images from Figure 5D with images from another unrelated article. Specifically, The images for Figure 5D, have been duplicated with the images for Figure 4G from Wang M, Li Q, Yu S, et al. Coronin 3 Promotes the Development of Oncogenic Properties in Glioma Through the Wnt/β-Catenin Signaling Pathway. Onco Targets Ther. 2020;13:6661–6673. https://doi.org/10.2147/OTT.S257001. The authors did not respond to our queries and were unable to provide an explanation for the duplicated images or provide data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors were notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Anam Herekar, Dhanush Shimoga, Asad Jehangir, Dariush Shahsavari, Yun Yan, Tennekoon Buddhika Karunaratne, Amol Sharma Department of Medicine, Augusta University, Augusta, GA, USACorrespondence: Amol Sharma, Medical College of Georgia, Augusta University, 1120 15th Street, AD 2226, Augusta, GA, 30912, USA, Email amosharma@augusta.eduAbstract: Irritable bowel syndrome (IBS) is a common disorder of gut–brain interaction (DGBI). IBS significantly impacts the quality of life of patients. Since its pathogenesis is unclear and can be multifactorial, it highlights the need for new and improved pharmaceutical drugs that not only improve bowel symptoms, but also address global IBS symptoms, such as abdominal pain. Tenapanor, a recently Food & Drug Administration (FDA)-approved medication for IBS with constipation (IBS-C), is a small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3) that inhibits the absorption of sodium and phosphate in the gastrointestinal tract, resulting in fluid retention and softer stool. Furthermore, tenapanor reduces intestinal permeability to improve visceral hypersensitivity and abdominal pain. Due to its recent approval, tenapanor was not included in the recent IBS guidelines, however, it may be considered for IBS-C patients failing first-line treatment of soluble fiber. In this review article, we aim to provide in-depth information to the reader regarding the design of tenapanor, its development through Phase I, II and III randomized clinical trials, and its role in the treatment of IBS-C.Keywords: irritable bowel syndrome, irritable bowel syndrome with constipation, IBS, IBS-C, constipation, tenapanor

Jing Li,1,2,&ast; Liang Huang,1,&ast; Chao Ge,3,&ast; Xingwu Zhu,1 Maixuan Qiu,1 Chaopan Chen,3 Shaohua Wei,2 Yiqun Yan1 1Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China; 2Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 3Department of General Surgery, Ningbo Development Zone Hospital, Ningbo, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yiqun Yan, Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, No. 700 North Moyu Road, Shanghai, 201805, People’s Republic of China, Email ehbhyyq@163.com Shaohua Wei, Department of General Surgery, The Second Affiliated Hospital of Soochow University, No. 1055 Shanxiang Road, Suzhou, 215004, People’s Republic of China, Email shaohuawei2010@sina.comPurpose: Molecular targeted agents (MTAs) plus immune checkpoint inhibitors (ICIs) treatment for advanced hepatocellular carcinoma (HCC) has shown an exciting prospect. This study aimed to report the efficacy of the Simultaneous and Sequential use of them in a real-world practice.Patients and Methods: From April 2019 to December 2020, patients with advanced HCC in three Chinese medical centers receiving MTAs and ICIs as their initial systemic therapy were enrolled. Participants were classified into the Simultaneous group (treated with them simultaneously) and the Sequential group (treated with MTAs initially and added ICIs after tumor progression). Toxicity, tumor response, survival outcomes and prognostic factors were investigated.Results: One hundred and ten consecutive patients participated in the study (64 in the Simultaneous group and 46 in the Sequential group). A total of 93 (84.5%) patients experienced treatment-related adverse events (AEs), of which 55 (85.9%) in the Simultaneous group and 38 (82.6%) in the Sequential group (P=0.19). Grade 3/4 AEs were observed in 9 (8.2%) patients. Patients in the Simultaneous group achieved a higher objective response rate than those in the Sequential group (25.0% vs 4.3%, p=0.04). The median overall survival (OS) of the entire cohort was 14.8 [95% confidence interval (CI): 4.6– 25.5] months and the OS rates at 6 and 12 months were 80.6% and 60.9%, respectively. Patients in the Simultaneous group achieved better survival outcomes than those in the Sequential group, but without statistically significant differences. Child-Pugh 6 scores (HR: 2.97, 95% CI: 1.33– 6.61, P=0.008), tumor number ≤ 3 (HR: 0.18, 95% CI: 0.04– 0.78, P=0.022), extrahepatic metastasis (HR: 3.05, 95% CI: 1.35– 6.87, P=0.007) were independent prognostic factors for survival.Conclusion: The combined treatment of MTAs and ICIs shows good tumor response and survival outcomes with acceptable toxicity for advanced HCC in the real-world practice, in particular when they are applied simultaneously.Keywords: hepatocellular carcinoma, systemic therapy, molecular targeted agents, immune checkpoint inhibitors

Gaofei Ren,1 Pengfei Jiao,2 Yushan Yan,1 Xiaojun Ma,1 Guijun Qin1 1Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Xiaojun Ma; Guijun Qin, Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, People’s Republic of China, Tel +86-0371-66295052, Email fccmaxj1@zzu.edu.cn; hyqingj@zzu.edu.cnBackground: Inflammation and oxidative stress contribute to the development of diabetic nephropathy (DN). Baicalin (BA) shows renal protection against DN through its anti-inflammatory and anti-oxidant properties. However, the molecular mechanism by which BA exerts the therapeutic effects on DN remains to be investigated.Methods: The db/db mice and high glucose (HG)-induced HK-2 cells were used as the in vivo and in vitro model of DN, respectively. The effects of BA were assessed by detecting the related blood and urine biochemical parameters, kidney histopathology, inflammatory cytokine production, oxidative stress indicators, and apoptosis. Cell viability and apoptosis were detected by CCK-8 assay and TUNEL assay, respectively. Related protein levels were measured by an immunoblotting method.Results: In db/db model mice, BA reduced serum glucose concentration, decreased blood lipid levels, ameliorated kidney functions, and decreased histopathological changes in kidney tissues. BA also alleviated oxidative stress and inflammation in db/db mice. In addition, BA blocked the activation of sphingosine kinases type 1/sphingosine 1-phosphate (SphK1/S1P)/NF-κB pathway in db/db mice. In HK-2 cells, BA hindered HG-induced apoptosis, oxidative stress and inflammation, while overexpression of SphK1 or S1P could reverse these effects. BA alleviated HG-induced apoptosis, oxidative stress and inflammation in HK-2 cells through the S1P/NF-κB pathway. Furthermore, BA blocked the NF-κB signaling by diminishing p65 nuclear translocation via the SphK1/S1P pathway.Conclusion: Our study strongly suggests that BA protects against DN via ameliorating inflammation, oxidative stress and apoptosis through the SphK1/S1P/NF-κB pathway. This study provides a novel insight into the therapeutic effects of BA in DN.Keywords: diabetic nephropathy, baicalin, SphK1/S1P/NF-κB pathway, inflammation, oxidative stress

Fei Guo,1,&ast; Yuting Yan,1,&ast; Li Sun,1 Ruili Han,1 Lanlan Zheng,1 Yuan Qin,1 Shuang Wang,1 Xude Sun,1 Zhaohua Ji,2 Changjun Gao1 1Department of Anesthesiology, Second Affiliated Hospital of Air Force Medical University, Xi’an, 710038, People’s Republic of China; 2Department of Epidemiology, School of Public Health, Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environment, Air Force Medical University, Xi’an, 710032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changjun Gao, Department of Anesthesiology, Second Affiliated Hospital of Air Force Medical University, Xin Si Road & 569, Xi’an City, Shaanxi, 710038, People’s Republic of China, Tel/Fax +86 2984777439, Email gaocj74@163.com Zhaohua Ji, Department of Epidemiology, School of Public Health, Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environment, Air Force Medical University, ChangLe Road & 169, Xi’an City, Shaanxi, 710032, People’s Republic of China, Tel/Fax +86 2884711316, Email hellojzh@msn.comObjective: This meta-analysis of randomized controlled trials (RCTs) aims to evaluate the efficacy and safety of transcutaneous electrical acupoint stimulation (TEAS) for postoperative delirium (POD) in surgical patients.Methods: Based on database searches of the Wanfang, China National Knowledge Infrastructure (CNKI), VIP, Chinese Biology Medicine (CBM), PubMed, Cochrane Library, and Web of Science, relevant RCTs published before December 30, 2022, were extracted. Outcome indicators included the incidence of POD, changes in Confusion Assessment Method (CAM) scores, Visual Analogue Scale (VAS) scores, and the intraoperative consumption of anesthetics. Data were pooled and analyzed by Review Manager 5.3, and publication bias detection was conducted using Stata 17.0.Results: A meta-analysis containing 715 experimental and 717 control participants from 12 RCTs was performed. The overall results showed that TEAS had obvious superiority with a lower incidence of POD on any day during the postoperative 1 week. In subgroup analyses, the CAM scores on the third postoperative day were significantly lower in the TEAS group than in the control group (MD = − 0.52, 95% CI: − 1.02 to − 0.03, P = 0.04), the VAS scores on the first postoperative day were significantly lower in the TEAS group than in the control group (MD = − 0.19, 95% CI: − 0.36 to − 0.02, P = 0.03), the consumption of propofol and remifentanil were both significantly lower in the TEAS group compared with the control group (MD = − 23.1, 95% CI: − 37.27 to − 8.94, P = 0.001; MD = − 105.69, 95% CI: − 174.20 to − 37.19, P = 0.002). No serious adverse events of TEAS were reported in any of the referenced studies.Conclusion: TEAS has an obvious curative effect in preventing POD and pain in the earlier stage of surgical patients. It could be a promising assisted anesthesia technique in the future.Keywords: transcutaneous electrical acupoint stimulation, TEAS, postoperative delirium, POD, meta-analysis

Yongquan Chen, Yecheng Deng, Linghua Chen, Ziyao Huang, Yi Yan, Zhaoqi Huang Department of Cardiology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Zhaoqi Huang, Department of Cardiology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510150, People’s Republic of China, Email zhaoqihuang2007@163.comIntroduction: Adriamycin (ADR) is commonly used in tumor chemotherapy, but its nonreversible cardiotoxicity severely hampers its clinical application. Ferroptosis is an implicated cause of ADR-induced injury. However, the underlying molecular mechanisms remain poorly understood. This study explored whether ferroptosis is a pivotal pathogenic pathway underlying ADR-induced cardiotoxicity and the possible molecular mechanisms involved.Methods: In vivo and in vitro experimental models were used to study the mechanism of ADR-mediated ferroptosis. Ferroptosis levels were examined in mice and human/rat cardiomyocytes. Mechanistically, the expression levels of SLC7A11 and related miRNAs were examined. Bioinformatics prediction and luciferase reporter assays were used to verify the potential interaction between miR-16-5p and SLC7A11. The biological functions and interaction of SLC7A11 and miR-16-5p were investigated in vivo and in vitro.Results: Our study observed that ADR treatment significantly increased ferroptosis levels in vivo and in vitro. Ferroptosis-related pharmacological interventions further confirmed these results. Our data displayed that the SLC7A11 level was significantly decreased in cardiac tissues and cells, while an increased expression level of miR-16-5p was observed. Moreover, upregulation of SLC7A1 and inhibition of miR-16-5p attenuated ADR-induced cardiomyocyte ferroptosis injury. Interactive rescue experiments showed that the protective effects of miR-16-5p inhibition on ADR-induced cardiomyocyte injury were blocked by SLC7A11 knockdown.Discussion: Based on these findings, targeting miR-16-5p could partially reverse the ADR-induced cardiotoxicity by rescuing the SLC7A11 to attenuate ferroptosis. This study presents a pre-clinical basis to identify miR-16-5p/SLC7A11 as a potential treatment target for ADR-induced cardiotoxicity.Keywords: adriamycin, cardiomyocytes, ferroptosis, SLC7A11, miR-16-5p

Yanhong Yan,1 Jiao Geng,2 Xu Cui,1 Guiyu Lei,1 Lili Wu,1 Guyan Wang1 1Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Guyan Wang, Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, No. 1 Dongjiaomingxiang, Beijing, 100730, People’s Republic of China, Tel +86-13910985139, Fax +86-10-58268017, Email guyanwang2006@163.comPurpose: Thoracic paravertebral block (TPVB) may be highly beneficial for thoracoscopic lobectomy patients, but it may increase the risk of hypothermia. Apart from its anesthetic-reducing effects, this randomized controlled trial aimed to investigate the hypothermic effect of TPVB, and thus optimize its clinical use.Patients and methods: Adult patients were randomly allocated to two groups: TPVB + general anesthesia (GA) group or GA group. In the TPVB+GA group, the block was performed after GA induction by an experienced but unrelated anesthesiologist. Both the lower esophageal and axillary temperature were recorded at the beginning of surgery (T0) and every 15 min thereafter (T1-T8), and the end of surgery (Tp). The primary outcome was the lower esophageal temperature at Tp. The secondary outcomes included lower esophageal temperature from T0-T8 and axillary temperature from T0-Tp. The total propofol, analgesics, and norepinephrine consumption and the incidence of adverse events were also recorded.Results: Forty-eight patients were randomly allocated to the TPVB+GA (n=24) and GA (n=24) groups. The core temperature at the end of the surgery was lower in the TPVB+GA group than the GA group (35.90± 0.30°C vs 36.35± 0.33°C, P< 0.001), with a significant difference from 45 min after the surgery began until the end of the surgery (P< 0.05). In contrast, the peripheral temperature showed a significant difference at 60 min after the surgery began till the end (P< 0.05). TPVB+GA exhibited excellent analgesic and sedative-sparing effects compared to GA alone (P< 0.001), though it increased norepinephrine consumption due to hypotension (P< 0.001).Conclusion: Although thorough warming strategies were used, TPVB combined with GA remarkably reduced the body temperature, which is an easily neglected side effect. Further studies on the most effective precautions are needed to optimize the clinical use of TPVB.Keywords: core temperature, peripheral temperature, general anesthesia, warming strategy

Lingling Li,1 Gui Huang,2 Yanling Yan3 1School of Management, Zhengzhou Shengda University, Zhengzhou, People’s Republic of China; 2School of Business, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 3College of Economics and Management, Zhengzhou University of Light Industry, Zhengzhou, People’s Republic of ChinaCorrespondence: Gui Huang, 510275, Tel +86 186 6608 0293, Fax +86 020 8411 2624, Email mnshg@mail.sysu.edu.cnPurpose: Previous studies are based on social exchange theory to explore the influence of leadership style on employees’ deviant innovation behavior. However, deviant innovation is risky, not supported by the organization, and is expected to benefit the long-term development of the organization. The key to the problem lies in how to guide employees to think and solve problems from the perspective of the organization, instead of just relying on material or spiritual exchange and return. Therefore, the purpose of this study was to analyze the relationship between coaching leadership, interactional justice, organizational identification and employees’ deviant innovation from the perspective of changing cognition.Methods: This work surveyed employees in 26 Chinese enterprises in more than 10 regions. Questionnaires were distributed to 450 employees, the first round of survey mainly investigated demographic information of employees and coaching leadership style of supervisors, and the second round of survey mainly investigated employees’ organizational identification, interactional justice, and deviant innovation behavior. By tracking and matching, 340 valid questionnaires were finally obtained. Spss 22.0 was used to describe all the study variables; Mplus 7.0 is used to carry out a confirmatory factor analysis and a multi-path regression model.Results: According to self-categorization theory, the results demonstrated that coaching leadership can directly or indirectly promote employees’ deviant innovation behavior through the dual-path intermediary and chain intermediary of interactional fairness and organizational identification.Conclusion: Under the open situation created by coaching leadership, coaching leaders will interact and communicate sincerely with employees, and employees’ cognition will change. The original “I” of employees will be transformed into “big self” with organizational membership, which will guide employees to show behaviors beneficial to the organization. Therefore, interactional justice and organizational identification can play a key role of the influence of coaching leadership on employees’ deviant innovation behavior.Keywords: coaching leadership, deviant innovation behavior, interactional justice, organizational identification

Ling-Ling Xu,1– 4,&ast; Yao Yan,1– 3,&ast; Yu-Min Yuan,1– 3 Ying Li,1– 3 Jun Jiang,1– 3 Li-Cai Zhang1– 3 1Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, People’s Republic of China; 2Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, People’s Republic of China; 3NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou, People’s Republic of China; 4Department of Anesthesiology, Nanjing Gaochun People’s Hospital, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li-Cai Zhang, Email licaizhang001@163.comObjective: To assess the receptors of TRPV1 and GABAB1 receptors that were colocalized in cerebrospinal fluid contacting nucleus (CSF-contact nucleus) of chronic inflammatory pain (CIP) rats bringing inspiration for reducing chronic pain.Methods: A rat model of CIP was constructed by plantar injection of complete Freund’s adjuvant (CFA), and the paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured 1, 3, 5, 7, 10, and 14 days after plantar injection. In the first part of the experiment, rats with CIP were divided into the immunofluorescence group and the coimmunoprecipitation (Co-IP) group (n = 6). Rats in the immunofluorescence group were injected with the retrograde tracer CB conjugated with Alexa Fluor 594 into the lateral ventricle two days before the injection of CFA into the plantar surface of the left paw. Three days later, rats that exhibited hyperalgesia were perfused, and their brains were extracted and used for double immunofluorescence staining of the CSF-contacting nucleus. Rats in the Co-IP group were anesthetized and dissected 3 days after CFA injection, and fresh brain segments containing the CSF-contacting nucleus were collected for Co-IP to assess the colocalization of TRPV1 and GABAB1 in the CSF-contacting nucleus (n = 6). In the second part of the experiment, SD rats were divided into the normal saline group (control group) and the CFA group. Fresh CSF-contacting nucleus-containing tissues were collected for Western blot analysis 3 days after plantar injection to observe the changes in TRPV1 and GABAB1 expression in the CSF-contacting nucleus.Results: TRPV1 and GABAB1 were co-expressed in the CSF-contacting nucleus in rats with CIP, and their expression was upregulated.Conclusion: TRPV1 and GABAB1 in the CSF-contacting nucleus are jointly involved in CIP in rats, and there is a direct or indirect link between TRPV1 and GABAB1.Keywords: cerebrospinal fluid-contacting nucleus, TRPV1 receptor, GABAB1 receptor, chronic inflammatory pain

Lijun Fan,1,2 Hui Xue,1 Qian Wang,3 Yuhan Yan,4 Wei Du1 1School of Public Health, Southeast University, Nanjing, People’s Republic of China; 2School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 4General Hospital of Eastern Theater Command, Nanjing, People’s Republic of ChinaCorrespondence: Wei Du, School of Public Health, Southeast University, Nanjing, 210009, People’s Republic of China, Email duwei@seu.edu.cn Yuhan Yan, General Hospital of Eastern Theater Command, Nanjing, 210009, People’s Republic of China, Email yanyuhan0215@163.comObjective: The identification of older patients at risk of repeated emergency department (ED) visits is crucial for managing preventable adverse outcomes. This study aims to identify risk factors associated with ED revisits and to develop and validate a nomogram for predicting risk of geriatric ED revisits.Methods: This was a cohort study comprising 553 older patients, who attended the two tertiary hospitals EDs in China from August 2018 to February 2019 and were prospectively followed for any unplanned revisit within 1 year after discharge. Patients were randomly assigned to a training or validation set at a ratio of 2:1. Stepwise selection procedure was applied to select factors associated with ED revisits for inclusion in a multivariable logistic model from which a nomogram was elaborated. Discrimination, calibration and clinical utility of the nomogram were assessed using C-statistic, calibration plot, Hosmer-Lemeshow test, and decision curve analysis (DCA).Results: The final nomogram included four predictors for ED revisits: age, BMI, frailty and polypharmacy. Older patients having revisits were more likely to be frail (OR = 1.17, p = 0.031), have polypharmacy (OR = 1.69, p = 0.049) or BMI < 18.5 kg/m2 (OR = 2.45, p = 0.025), and were less likely to be older than 90 years (OR = 0.21, p = 0.002). The nomogram demonstrated acceptable discrimination ability in the training (C-index = 0.661) and validation sets (C-index = 0.651), satisfactory calibration (p > 0.05), and good clinical applicability.Conclusion: A nomogram incorporating four obtainable variables was constructed to individualize ED readmission risk in older patients. These patients may benefit from early triage and better-targeted care if considering the nomogram as a clinical decision aid.Keywords: nomogram, risk prediction, emergency department revisit, acute care, older adults

Fan Zhang,1 Yi-Nuo Yang,2 Jin-Di Feng,2 Jing-Hui Zhao,1 Li Wan,1 Jing Che,1 Ying Yan,1 Ning-Ning Guo,1 Jia-Yu Zhang1 1Hair Medical Research Center, Department of Dermatology and Venereology, Beijing Jishuitan Hospital, Beijing, People’s Republic of China; 2School of Clinical Medicine, Peking University School of Medicine, Beijing, People’s Republic of ChinaCorrespondence: Fan Zhang, Hair Medical Research Center, Department of Dermatology and Venereology, Beijing Jishuitan Hospital, No. 31 of Xinjiekou East Street, Xicheng District, Beijing, 100035, People’s Republic of China, Tel +86 10 58516688, Email zhangfanzf63z@126.comObjective: To evaluate the effectiveness and safety of a combined treatment for moderate and severe androgenetic alopecia (AGA) involving the use of electric microneedles.Methods: A total of 83 patients with moderate to severe AGA in the Department of Dermatology at Beijing Jishuitan Hospital were included in this study. The male patients were administered finasteride orally and 5% minoxidil for external use, while the female patients were given spironolactone orally or Diane-35 and 2% minoxidil for external use. All the patients were then treated via electric microneedle therapy alongside the YUFA ®medical care package (Foshan, China) once a week for 1– 28 weeks. The seven-point method and root hair measurement using a hair mirror were adopted to evaluate the efficacy and any adverse reactions of the combined treatment.Results: Eleven patients were treated for 1– 3 weeks, 60 for 4– 12 weeks, and 12 for more than 12 weeks. The efficacy evaluation using the seven-point method for 12 weeks of treatment indicated a 100% response rate, specifically, a 42.1% mild improvement rate, a 38.6% moderate improvement rate, and a 19.3% marked improvement rate. Besides, the efficacy assessment was also completed with root hair count method and the number of hair roots measured at fixed points were 148.67± 11.15, 158.13± 5.11 and 169.75± 2.06 after treatment time at 16, 20 and 24 weeks, respectively. Of note, a statistical difference in the number of hair roots could be observed during the period of week 20–week 24 (P < 0.01).Conclusion: The combined treatment of moderate to severe AGA using the electric microneedle technique has a clear effect and can effectively increase the hair density. With a simple operation and mild side effects, the technique has wide application prospects.Keywords: electric microneedles, androgenic alopecia, combined therapy, efficacy observation

Rong Dong,1 Youyou Yan,2 Xiaokang Zeng,3 Nengming Lin,1,2 Biqin Tan1 1Department of Clinical Pharmacy, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China; 2Translational Medicine Research Center, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 31006, People’s Republic of China; 3Department of Critical Care Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 31006, People’s Republic of ChinaCorrespondence: Biqin Tan, Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Room 207, No. 5 Building, Hangzhou, People’s Republic of China, Tel +86-571-56007824, Fax +86-571-56005600, Email biqintan@zju.edu.cn Nengming Lin, Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Room 903, No. 7 Building, Hangzhou, People’s Republic of China, Tel/Fax +86-571-56005600, Email lnm1013@zju.edu.cnAbstract: Ibrutinib is the first-in-class Bruton tyrosine kinase (BTK) inhibitor that has revolutionized the treatment of B cell malignancies. Unfortunately, increased incidences of cardiotoxicity have limited its use. Despite over a decade of research, the biological mechanisms underlying ibrutinib cardiotoxicity remain unclear. In this review, we discuss the pharmacological properties of ibrutinib, the incidence and mechanisms of ibrutinib-induced cardiotoxicity, and practical management to prevent and treat this condition. We also synopsize and discuss the cardiovascular adverse effects related to other more selective BTK inhibitors, which may guide the selection of appropriate BTK inhibitors.Keywords: ibrutinib, cardiotoxicity, BTK inhibitors, atrial fibrillation, cardio-oncology

Yao Yao,1,&ast; Chunlai Shao,2,&ast; Xiaoye Li,1 Zi Wang,1 Chengchun Zuo,1 Yan Yan,3 Qianzhou Lv1 1Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 3Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Yan; Qianzhou Lv, Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032, People’s Republic of China, Tel +86 13916088938, Fax +86 021-64041990, Email yan.yan@zs-hospital.sh.cn; 13916088938@163.comPurpose: The Global Registry of Acute Coronary Events (GRACE) score has proven value in predicting short-term prognosis in non-ST-elevation myocardial infarction (NSTEMI), but it has only moderate discrimination for long-term outcomes. The purpose of this study is to develop and test a multi-biomarker score for better risk stratification and indication of 2-year risk in patients with NSTEMI.Patients and Methods: A total of 6076 consecutive patients with NSTEMI (66 [59– 73] years, 73.1% males) admitted at Zhongshan Hospital, Fudan University were collected in this observational, prospective study between 2012 and 2018 with a 24-month follow-up. The primary endpoint was all-cause death and non-fatal major adverse cardiac events (MACE). A biomarker score ranged from 0 to 12 was constructed. The predictive power of the biomarker score was evaluated alone or combined with the GRACE score by C-statistic, net reclassification index (NRI) and integrated discrimination index (IDI).Results: During a 2-year follow-up, all-cause death occurred in 159 patients (2.6%), and non-fatal MACEs were presented in 709 patients (11.7%). When added to the GRACE score, the biomarker score demonstrated better prognostic accuracy, patient reclassification and risk discrimination for both mortality and non-fatal MACEs at 2 years by improving the C-statistic from 0.714 (0.671– 0.756) and 0.623 (0.600– 0.646) to 0.851 (0.820– 0.882) and 0.721 (0.702– 0.741) with NRI > 25% (P< 0.001) and IDI > 0.30 (P< 0.001).Conclusion: The single use of biomarker score could markedly enhance the prognostic value of concurrent risk stratification tools for 2-year mortality and non-fatal MACEs in NSTEMI. The GRACE score with incorporation of the biomarker score led to more accurate risk reclassification and warrants more consideration in further NSTEMI management.Keywords: risk stratification, prognosis, net reclassification improvement, integrated discrimination improvement

Jin Ke, Jie Wang, Xing Wu, Yuehua Yan Department of Dermatology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, People’s Republic of ChinaCorrespondence: Yuehua Yan, Department of Dermatology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800 Gongwei Road, Pudong New District, Shanghai, 201399, People’s Republic of China, Tel +86-18918181952, Email yanyuehuash@163.comIntroduction: Autophagy is an important process for maintaining intracellular homeostasis and is deregulated in ultraviolet B (UVB)-induced skin injury. Salidroside (SAL) is an active ingredient extracted from Rhodiola rosea, which is a herbal medicine that has shown protection against ultraviolet (UV) radiation. Here, we investigated the functions and mechanisms of SAL on UVB-induced skin cell oxidative damage and autophagy.Methods: Human immortalized keratinocyte cell line HaCaT was used as a cell model of UV injury. HaCaT cells were exposed to UVB irradiation and then incubated with SAL to investigate cell viability, lactate dehydrogenase (LSD) in culture media, intracellular reactive oxygen species (ROS) level, oxidative stress, autophagy, and regulatory effects on SIRT1 protein.Results: SAL pretreatment (25, 50 and 100 μM) increased cell viability and inhibited LDH release in UVB-challenged HaCaT cells. SAL (100 μM) significantly reduced intracellular ROS level and suppressed oxidative stress, with increased MDA content and increased SOD activity. In addition, SAL pretreatment enhanced autophagy in UVB-irradiated HaCaT cells, increased protein expressions of Beclin-1 and ATG7, and decreased protein expression of P62. We also found that pretreatment with SAL increased the SIRT1 protein in irradiated HaCaT cells. SAL protected UVB-induced damage in a dependent manner on autophagy and SIRT1, as SAL-induced increase in viability was significantly attenuated by specific autophagy inhibitor Wortmannin (1 μM) or SIRT1 inhibitor EX-527 (100 nM).Discussion: The present study results speculate that SAL suppresses UVB-induced injury and autophagy by enhancing SIRT1 expression.Keywords: keratinocytes, salidroside, ultraviolet radiation, oxidative stress, autophagy, SIRT1

Tao Liu,&ast; Chaofan Wang,&ast; Jie Yin, Lili Wang, Haochen Xuan, Yan Yan, Junhong Chen, Jieli Bao, Dongye Li, Tongda Xu Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tongda Xu; Dongye Li, Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China, Email xutongda3004@163.com; dongyeli@xzhmu.edu.cnBackground: Coronary microvascular obstruction (CMVO) is closely associated with poor prognosis of ST-segment elevation myocardial infarction (STEMI) patients. However, data showing the comparison between cardiac magnetic resonance feature tracking (CMR-FT) and speckle tracking echocardiography (STE) combined with low-dose dobutamine stress echocardiography (LDDSE) in evaluating CMVO was scarcely available. We aimed to explore and compare the predictive value between CMR-FT and STE+LDDSE in detecting CMVO.Methods: Sixty-one STEMI patients were executed cardiac magnetic resonance and echocardiography within the first 5– 7 days after primary percutaneous coronary intervention (PCI). The myocardial strain analysis was performed in STE, STE+LDDSE, and CMR-FT, and strain parameters included radial strain (RS), circumferential strain (CS), and longitudinal strain (LS). ROC curves were performed to predict infarcted myocardium segments with CMVO.Results: Finally, 324 infarcted myocardium segments were analyzed, including 100 infarcted segments with CMVO and 224 segments without CMVO by the gold standard assessment of late gadolinium-enhancement cardiac magnetic resonance imaging (LGE-CMR). The results showed that CS was generally superior to RS and LS in identifying CMVO. CS in CMR-FT facilitated the detection of CMVO, with a sensitivity, specificity, and accuracy of 78.00%, 81.25%, and 80.25%, respectively. The sensitivity, specificity, and accuracy of CS in STE combined with LDDSE were better than STE alone (76.00% vs 60.00%, 79.91% vs 64.29%, and 78.70% vs 62.96%, P < 0.05). In addition, CMR-FT is not superior to STE+LDDSE for detection of CMVO (P > 0.05).Conclusion: Low-dose dobutamine can improve the clinical value of STE for evaluating CMVO in STEMI patients. Compared with CMR-FT, STE+LDDSE might be a better choice for STEMI patients because of its safety, convenience, and low-cost.Keywords: ST-segment elevation myocardial infarction, magnetic resonance feature tracking, speckle tracking echocardiography, low-dose dobutamine, coronary microvascular obstruction

Dan Yang,1 Yongjie Yan,1 Kexue Pu1,2 1School of Medical Information, Chongqing Medical University, Chongqing, People’s Republic of China; 2Medical Data Research Institute of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Kexue Pu, Chongqing Medical University, Yuanjiagang Campus of Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, People’s Republic of China, Tel +86 15683896497, Email pukexue@cqmu.edu.cnBackground: Allergic rhinitis (AR) is a severe and the most common chronic allergic disease, affecting 10– 40% of the world population. The effect of air pollutants on AR has been confirmed in clinical experiments.Purpose: This study aimed to quantify the association between air pollutants and daily outpatient visits for AR in Chongqing, China.Methods: Based on the data of AR outpatients in the primary urban area of Chongqing from 2016 to 2017, along with the atmospheric pollutants and meteorological data in the same period, the distributed lag nonlinear model (DLNM) and generalized additive model (GAM) were used to analyze the time-series. We examined the effects of the single and double pollutant models with a maximum lag day of 30 days. Effect estimates were described as relative risk (RR) and 95% confidence intervals (CIs) in daily outpatient visits for AR per 10 μg/m3 increases in PM2.5, PM10, SO2, NO2, O3, and per 1 mg/m3 increase in CO.Results: A single pollutant’s O3 level had an immediate positive effect on AR within two days, the relative risks (RR, 95% CI) were 1.066 (1.008– 1.127), 1.057 (1.005– 1.112) and 1.048 (1.002– 1.097). PM2.5 had a lag effect within 11– 18 days, the max relative risks (RR, 95% CI) were 1.083 (1.010– 1.160). Moreover, O3, PM2.5, PM10, SO2 and NO2 had significant effects on AR in the two-pollutant model. The RR cumulative effect of PM2.5 became more pronounced as the concentration increased. The cumulative effect of NO2 was lesser than PM2.5.Conclusion: Air pollutants were associated with the daily outpatient visits for AR, which may have considerable implications for developing tailored health policies and services to prevent AR in Chongqing and even all over the world.Keywords: allergic rhinitis, air pollution, time-series analysis, generalized additive model, distributed lag nonlinear model

Yaowen Li,1,2 Yu Peng,1,2 Na Zhang,1,2 Huiping Liu,1,2 Jun Mao,1,2 Yisong Yan,3 Shuaishuai Wang,1,2 Guang Yang,4 Yanyan Liu,5 Jiabin Li,5 Xiaohui Huang1,2 1Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, People’s Republic of China; 2Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, People’s Republic of China; 3Department of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, Anhui, People’s Republic of China; 4Department of Pharmacy, The Third People’s Hospital of Tongling, Tongling, Anhui, People’s Republic of China; 5Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Xiaohui Huang, Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Meishan Road 81#, Hefei, Anhui, 230032, People’s Republic of China, Tel +86 138 5518 3138, Email math2088@163.comPurpose: We aimed to evaluate the synergistic effect of linezolid and fosfomycin on fosfomycin-sensitive and -resistant Enterococcus clinical isolates in vitro and in vivo and whether the emergence of fosfomycin resistance in Enterococcus is associated with changes in strain virulence, from the perspective of fitness cost.Methods: The synergistic effect of linezolid and fosfomycin was studied via in vitro checkerboard and static time-kill assays, as well as based on the in vivo survival rate and hemolymph load of a Galleria mellonella infection model. Fosfomycin resistance was induced via a stepwise increase in concentration. Changes in the virulence of the strains after drug resistance were investigated using the G. mellonella infection model and reverse transcription quantitative polymerase chain reaction (RT-qPCR). In vitro and in vivo growth curves and competitive experiments were used to study the fitness cost of the strain. Finally, a static time-kill assay was performed to explore the effect of the combined medication.Results: In vitro and in vivo data showed that linezolid combined with fosfomycin had a good synergistic effect on Enterococcus treatment. The G. mellonella infection model and RT-qPCR data showed that the virulence of the resistant strains was weakened to varying degrees. A survival curve and competition experimental data showed that this was related to the fitness cost of strains while acquiring resistance and negatively impacted linezolid treatment; however, the combination still showed a good synergistic effect in drug-resistant strains.Conclusion: Linezolid combined with fosfomycin had a synergistic effect on both fosfomycin-sensitive and -resistant Enterococcus strains. Strains incur fitness costs as they develop drug resistance, which leads to a decrease in virulence. There is an interaction between fitness cost, virulence, and drug resistance, which indirectly affects drug treatment.Keywords: linezolid, fosfomycin, resistance, fitness cost, virulence

Yun Yan,1,&ast; Lei Yang,2,&ast; Xiaoli Li,3,&ast; Jian Hao,4,&ast; Bijue Wang,4 Dan Wang,5 Junning Wang3 1Department of Orthopedics and Traumatology, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, 710054, People’s Republic of China; 2Department of Osteoporosis, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, 710054, People’s Republic of China; 3Department of Respiratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, 710054, People’s Republic of China; 4Xi’an Public Health Center, Xi’an, Shaanxi, 710200, People’s Republic of China; 5Department of Pathology, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, 710054, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Junning Wang, Department of Respiratory, Honghui Hospital, Xi’an Jiaotong University, No. 555, Youyi East Road, Nanshaomen, Xi’an, Shaanxi, 710054, People’s Republic of China, Tel/Fax +86 02962818354, Email wangjunningde@163.comPurpose: At present, it has been found that managing patients with a redetected positive RNA test after recovery from foreign-imported coronavirus disease 2019 (COVID-19) cases in China is challenging. The purpose of the current study was to describe the clinical characteristics of these patients.Methods: This retrospective cohort study included 137 COVID-19 patients who were discharged from the Xi’an Public Health Center from 28 July 2020 to 31 December 2021. We compared the clinical characteristics between positive retest patients and non-positive retest patients.Results: 137 COVID-19 patients entered our study, 27 (19.7%) cases of COVID-19 with a redetected positive RNA test by the end of the follow-up period. Fever [(n = 31 (22.6%)], cough [n = 26 (18.9%)] and sore throat [n = 20 (14.5%)] were the most common initial symptoms among the foreign-imported COVID-19 patients, and there were almost no significant differences in initial symptoms between positive retest patients and non-positive retest patients. The positive retest patients had a higher lymphocyte count (p = 0.031) and lymphocyte percentage (p = 0.007) during readmission. There were generally no significant differences in other routine blood test findings, IgG and IgM antibody responses, between positive retest patients and non-positive retest patients, or in positive retest patients over time (before, during, or after positive patient detection). After readmission, positive retest patients displayed fewer symptoms or no obvious disease progression and more sustained remission by CT imaging.Conclusion: Our findings revealed that the clinical characteristics at the time of initial diagnosis were not closely related to redetected positive RNA tests after recovery from foreign-imported COVID-19 cases. Positive retest patients had virtually no symptoms and displayed no obvious disease progression during readmission. These findings provide important information and clinical evidence for the effective management of foreign-imported COVID-19 patients during their convalescent phase.Keywords: SARS-CoV-2, COVID-19, clinical characteristics, foreign-imported cases, redetected positive RNA test

Linzhi Yu,1,&ast; Yu Li,1,&ast; Rulin Ma,1 Heng Guo,1 Xianghui Zhang,1 Yizhong Yan,1 Jia He,1 Xinping Wang,1 Qiang Niu,1 Shuxia Guo1,2 1Department of Public Health, Shihezi University School of Medicine, Shihezi, Xinjiang, People’s Republic of China; 2Department of NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, The First Affiliated Hospital of Shihezi University Medical College, Shihezi, Xinjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuxia Guo; Qiang Niu, Tel +86-1800-9932-625; 86-993-2057153, Fax +86-993-2057-153, Email gsxshzu@sina.com; niuqiang@shzu.edu.cnPurpose: This study aimed to explore the relationship between obesity- and lipid-related indices and insulin resistance (IR) and construct a personalized IR risk model for Xinjiang Kazakhs based on representative indices.Methods: This cross-sectional study was performed from 2010 to 2012. A total of 2170 Kazakhs from Xinyuan County were selected as research subjects. IR was estimated using the homeostasis model assessment of insulin resistance. Multivariable logistic regression analysis, least absolute shrinkage and selection operator penalized regression analysis, and restricted cubic spline were applied to evaluate the association between lipid- and obesity-related indices and IR. The risk model was developed based on selected representative variables and presented using a nomogram. The model performance was assessed using the area under the ROC curve (AUC), the Hosmer–Lemeshow goodness-of-fit test, and decision curve analysis (DCA).Results: After screening out 25 of the variables, the final risk model included four independent risk factors: smoking, sex, triglyceride-glucose (TyG) index, and body mass index (BMI). A linear dose–response relationship was observed for the BMI and TyG indices against IR risk. The AUC of the risk model was 0.720 based on an independent test and 0.716 based on a 10-fold cross-validation. Calibration curves showed good consistency between actual and predicted IR risks. The DCA demonstrated that the risk model was clinically effective.Conclusion: The TyG index and BMI had the strongest association with IR among all obesity- and lipid-related indices, and the developed model was useful for predicting IR risk among Kazakh individuals.Keywords: lipid-related indices, obesity-related indices, insulin resistance, Xinjiang Kazakhs

Yun Yan, Xin Chai, Yu Chen, Xijing Zhang Department of Critical Care Medicine, Xijing Hospital, The Fourth Military Medical University, Xi’an, People’s Republic of ChinaCorrespondence: Yu Chen; Xijing Zhang, Department of Critical Care Medicine, Xijing Hospital, The Fourth Military Medical University, Xi’an, People’s Republic of China, Tel +862984775344, Fax +862983244986, Email chenyu007@gmail.com; xjzhang0806@163.comAbstract: Shewanella algae, a Gram-negative bacillus found in warm saltwater environments, has been increasingly recognized as a human pathogen that can cause infection of the skin and soft tissue, ear, blood, and intra-abdominal. In this case, we report a Shewanella algae infection that caused sepsis, renal insufficiency, cardiac dysfunction, fistula and massive pleural effusion after surgery in a 73-year-old man with cancer of the esophagus and cardia.Keywords: Shewanella species, Shewanella algae, fulminating course, malignancy, sepsis

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease with limited therapeutic options. Aspirin can alleviate liver, kidney, and cardiac fibrosis. However, its role in lung fibrosis is unclear. This study aims to investigate the effects of aspirin on lung fibroblast differentiation and pulmonary fibrosis. TGF-β1-induced human embryonic lung fibroblasts, IPF lung fibroblasts, and bleomycin-induced lung fibrosis mouse model were used in this study. The results showed that aspirin significantly decreased the expression of Collagen 1A1, Fibronectin, Alpha-smooth muscle actin, and equestosome1, and increased the ratio of light chain 3 beta II/I and the number of autophagosome in vivo and in vitro; reduced bleomycin-induced lung fibrosis. Aspirin also decreased the ratios of phosphorylated phosphatidylinositol 3 kinase (p-PI3K)/PI3K, protein kinase B (p-AKT)/AKT, and mechanistic target of rapamycin (p-mTOR)/mTOR in vitro. Autophagy inhibitor 3-methyladenine, bafilomycin-A1, and AKT activator SC-79 abrogated the effects of aspirin. These findings indicate that aspirin ameliorates pulmonary fibrosis through a PI3K/AKT/mTOR-dependent autophagy pathway.

Objective: Excessive extra-cellular-matrix production and uncontrolled proliferation of the fibroblasts are characteristics of many fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). The fibroblasts have enhanced glutaminolysis with up-regulated glutaminase, GLS1, which converts glutamine to glutamate. Here, we investigated the role of glutaminolysis and glutaminolysis-derived metabolite α-ketoglutarate (α-KG) on IPF fibroblast phenotype and gene expression. Methods: Reduced glutamine conditions were carried out either using glutamine-free culture medium or silencing the expression of GLS1 with siRNA, with or without α-KG compensation. Cell phenotype has been characterized under these different conditions, and gene expression profile was examined by RNA-Seq. Specific profibrotic genes (Col3A1 and PLK1) expression were examined by real-time PCR and western blots. The levels of repressive histone H3K27me3, which demethylase activity is affected by glutaminolysis, were examined and H3K27me3 association with promoter region of Col3A1 and PLK1 were checked by ChIP assays. Effects of reduced glutaminolysis on fibrosis markers were checked in an animal model of lung fibrosis. Results: The lack of glutamine in the culture medium alters the profibrotic phenotype of activated fibroblasts. The addition of exogenous and glutaminolysis-derived metabolite α-KG to glutamine-free media barely restores the pro-fibrotic phenotype of activated fibroblasts. Many genes are down-regulated in glutamine-free medium, α-KG supplementation only rescues a limited number of genes. As α-KG is a cofactor for histone demethylases of H3K27me3, the reduced glutaminolysis alters H3K27me3 levels, and enriches H3K27me3 association with Col3A1 and PLK1 promoter region. Adding α-KG in glutamine-free medium depleted H3K27me3 association with Col3A1 promoter region but not that of PLK1. In a murine model of lung fibrosis, mice with reduced glutaminolysis showed markedly reduced fibrotic markers. Conclusions: This study indicates that glutamine is critical for supporting pro-fibrotic fibroblast phenotype in lung fibrosis, partially through α-KG-dependent and –independent mechanisms, and supports targeting fibroblast metabolism as a therapeutic method for fibrotic diseases.

Dan Jin,&ast; Yuanyuan pan,&ast; Wenjun Jin, Yixiu Yan, Luping Huang, Junlu Wang Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Junlu Wang, Departments of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China, Tel +86 13806689854, Fax +86 577-55578999-689854, Email wangjunlu973@163.comPurpose: Propofol is a widely used intravenous anesthetic in clinical practice. Lidocaine pretreatment is currently the most commonly used method to reduce the pain of propofol injection. However, propofol injection pain has not been eliminated and its incidence remains high. Transcutaneous electrical acupoint stimulation is a green therapy that combines transcutaneous electrical nerve stimulation therapy with the traditional acupuncture therapy of our motherland. This study investigated the effectiveness of transcutaneous electrical acupoint stimulation (TEAS) combined with lidocaine in preventing propofol injection pain and determined whether it can reduce postoperative complications and promote rapid postoperative recovery of patients.Patients and Methods: A total of 220 women scheduled to undergo hysteroscopic surgery were enrolled in the study. The included patients were randomly divided into four groups of 55 patients each: normal saline group (group K), lidocaine group (group L), TEAS group (group T), and lidocaine + TEAS group (group L + T). Patients in group K received 2 mL saline (0.9% NaCl) pre-injection before anesthesia induction. Group L received 40 mg lidocaine pre-injection (2 mL of 2% lidocaine) before anesthesia induction. Group T received 30 min of transcutaneous electrical stimulation at bilateral election Hegu, Neiguan, and 2 mL saline pre-injections before anesthesia induction. Group L + T received TEAS and lidocaine pre-injection.Results: The VAS scores and the four-point verbal rating scale of propofol injection were significantly different among the four groups. The prevalence of nausea, vomiting, abdominal pain, and abdominal distension after surgery among the four groups were statistically different. The bleeding days after surgery were significantly different among the four groups.Conclusion: TEAS combined with lidocaine pre-injection reduced the incidence of propofol injection pain and significantly reduced patients’ pain levels compared with single lidocaine pre-injection. TEAS can also reduce the incidence of postoperative nausea and vomiting, abdominal pain, and abdominal distension, shorten postoperative bleeding days, and accelerate the postoperative recovery of patients.Keywords: transcutaneous electrical acupoint stimulation, propofol, lidocaine, injection pain

Fei Guo,1,&ast; Ruili Han,1,&ast; Ting Luo,2,&ast; Shengyang Jin,3 Yuting Yan,1 Jun Wang,4 Xude Sun,1 Changjun Gao1 1Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, People’s Republic of China; 2Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 3Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 4Department of Anesthesiology, Shaanxi Provincial Armed Police Hospital, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changjun Gao; Xude Sun, Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, 710038, People’s Republic of China, Tel +86-13379227869 ; +86-13891905550, Fax +86-029-84777439, Email gaocj74@163.com; sunxude@fmmu.edu.cnPurpose: This study aims to evaluate the psychological status and the attitudes toward the novel coronavirus disease 2019 (COVID-19) vaccine among anesthesiologists. We expected to analyze related factors and offer them some strategies to prevent and manage psychological issues under the post COVID-19 era.Methods: Based on the Checklist for Reporting Results of Internet E-Surveys (CHERRIES), an online survey was designed and conducted among anesthesiologists in Shaanxi, China. Participants were asked to complete a validated questionnaire voluntarily. The following tests were performed: Depression, Anxiety and Stress Scale (DASS-21), Primary Care Post-traumatic Stress Disorder Screen (PC-PTSD), and the attitudes toward COVID-19 vaccine.Results: A total of 795 anesthesiologists completed the survey, the majority of them were female, young and middle-aged, well educated, and married. The prevalence of depression, anxiety, and stress in this sample were 26.5%, 35.5%, and 19.9%, respectively. Longer daily working time, concomitant basic chronic disease, and COVID-19 exposure were extracted as risk factors for the psychological symptoms, while vaccination, elder age, and married status were negatively associated with them. An unsatisfied vaccination rate (71.9%) which might be linked with inadequate awareness and perception of the COVID-19 vaccine was also detected in this study.Conclusion: Anesthesiologists are still under rising pressure of psychological symptoms in the post COVID-19 era. It is imperative to afford continuous psychological support to them and ensure their mental health and professional performance.Keywords: COVID-19, anesthesiologist, depression, anxiety, stress

Luting Yang, Yaping Yan Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, People’s Republic of ChinaCorrespondence: Luting Yang; Yaping Yan, Email yangluting@snnu.edu.cn; yaping.yan@snnu.edu.cnAbstract: Post-translational modifications (PTMs) of proteins represent as a key step in regulating their biological functions and dynamic interaction with other players. This process is fine-tuned by a myriad of enzymes named “writers, readers and erasers” whose actions are precisely controlled. Either the mutation, aberration in the expression of the aforementioned enzymes or their substrates have shown to participate in the pathogenesis of various skin diseases such as melanoma, vitiligo, psoriasis, eczema, atopic dermatitis and inherited dermatological diseases. It is becoming increasingly clear that key transcriptional factors, inflammation-related molecules are prone to PTMs. Despite their importance in regulating key processes including inflammation, keratinocyte apoptosis, proliferation and differentiation, PTMs have received less attention due to the challenges involved. Here in this review we summarize the role of the most common types and the newly discovered PTMs, including acetylation, glycosylation, citrullination, PARylation and sumoylation in dermatoses and surveys the recent progress in PTM-based therapeutic approaches in skin diseases.Keywords: post-translational modification, skin diseases, molecular mechanism, therapeutics

Yugang Yan,1,2 Ronghua Gao,3 Shaohui Zhang,3 Zhencai Gao,3 Anyong Chen,3 Jianjun Wang,3 Shufang Zhang,3 Wen Dai,3 Fen Li,4 Xiangting Li,3 Guoliang Yang,3 Lixin Liu,3 Xueying Chen2,3 1School of Medical Engineering, Jining Medical University, Jining, Shandong, People’s Republic of China; 2The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 3Department of Cardiology, Affiliated Hospital of Jining Medical University, Jining, Shandong, People’s Republic of China; 4Electrocardiogram Room, Jining First People’s Hospital, Jining, Shandong, People’s Republic of ChinaCorrespondence: Xueying Chen, Department of Cardiology, Affiliated Hospital of Jining Medical University, No. 89 Guhuai Road, Jining, 272029, Shandong, People’s Republic of China, Tel +86- 537- 2903508, Fax +86 537-2213030, Email chxy221@163.comBackground: Many studies have shown that glycated hemoglobin (HbA1c) is associated with coronary artery disease (CAD). HbA1c was independently related to angiographic severity in Chinese patients with CAD after adjusting for other covariates. Some traditional cardiovascular drugs may have an impact on this relationship.Methods: This retrospective study enrolled a total of 572 CAD patients who underwent their coronary angiography and had their HbA1c levels measured at the Chinese Hospital. The complexity of the coronary artery lesions was evaluated using the Syntax score, and the subjects were divided into 4 inter quartiles according to HbA1c levels. Covariates included history of traditional cardiovascular drugs.Results: The average age of selected participants was 61.00 ± 9.15 years old, and about 54.72% of them were male. Result of fully adjusted linear regression showed that HbA1c was positively associated with Syntax score after adjusting confounders (β = 1.09, 95% CI: 0.27, 1.91, P = 0.0096). By interaction and stratified analyses, the interactions were observed based on our specification including with the medication history of statins and angiotensin receptor blockers (ARBs) (P values for interaction < 0.05).Conclusion: In this study, we found a positive correlation between the HbA1c levels and the SYNTAX score among CAD individuals, and oral statins and ARBs medication could affect the correlation. Thus, HbA1c measurement could be used for the evaluation of the severity and complexity of coronary lesions among CAD patients.Keywords: HbA1c, SYNTAX score, coronary artery disease, statins, ARBs

Chongrong Huang,1 Liuqi Sun,1 Qingchen Liu,1 Yuzhou Yan,2 Chengyan Li2 1Faculty of Education, Shanghai Normal University, Shanghai, People’s Republic of China; 2College of Philosophy, Law & Political Science, Shanghai Normal University, Shanghai, People’s Republic of ChinaCorrespondence: Chengyan LiCollege of Philosophy, Law & Political Science, Shanghai Normal University, 81 Guilin Road, Shanghai, 200000, People’s Republic of ChinaTel +86 13501842154Email licylicy2@163.comPurpose: Due to the low success rate of entrepreneurship, the correct identification of entrepreneurial opportunities is one of the important concerns in the field of entrepreneurship research. Therefore, this study focuses on the influence mechanism of entrepreneurial opportunity identification, so as to enrich the influence path of entrepreneurial opportunity identification and provide suggestions for improving the success rate of entrepreneurship.Methods: After screening and judging the quality of the questionnaires, the valid questionnaires were numbered and matched with 106 team samples. The researchers carried out telephone communication with participants to ask for their attendance, and then took samples on-site at the appointed time and place.Results: The results show that: (1) team knowledge heterogeneity has a significant positive impact on entrepreneurial opportunity identification. (2) Social capital plays a mediating role between team knowledge heterogeneity and entrepreneurial opportunity identification. (3) Promotional regulatory focus, a type of regulation that tends to adopt a radical approach to achieve goals, positively moderates the mediating effect of team knowledge heterogeneity on entrepreneurial opportunity identification through social capital. However, preventive regulatory focus, a type of regulation that tends to adopt a cautious and vigilant way to achieve goals, has no moderating effect.Discussion: In order to improve the correct identification of entrepreneurial opportunities, it is necessary to establish team with knowledge heterogeneity rationally and excavate different levels of social capital behind heterogeneous members. In addition, it also reveals that team style can retain certain promotive in the process of entrepreneurship, which is conducive to the feasibility and profitability of entrepreneurial opportunity identification.Keywords: team knowledge heterogeneity, social capital, regulatory focus theory, entrepreneurial opportunity identification

Xiangyuan Qiu,1 Xinying Li,1 Yuanliang Yan,2 Yuan Cai,3 Qiuju Liang,2 Bi Peng,3 Zhijie Xu,3– 5 Muzhang Xiao,6 Fada Xia,1 Jinwu Peng3,4 1Department of Thyroid Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 2Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 3Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 4Department of Pathology, Xiangya Changde Hospital, Changde, 415000, Hunan, People’s Republic of China; 5National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 6Department of Burn and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of ChinaCorrespondence: Muzhang XiaoDepartment of Burn and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of ChinaEmail xmzsir@sina.comFada XiaDepartment of Thyroid Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of ChinaEmail xiafada@csu.edu.cnBackground: N6-methyladenosine (m6A) is most common internal RNA modification in eukaryotic cells. Existing evidence shows that m6A is closely related to pathogenesis and progression in breast cancer (BRCA). Therefore, it is critical to investigate the key role of m6A target genes in BRCA.Methods: M6A target genes in BRCA are acquired using RMVar online database. The differentially expressed genes (DEGs) from three microarray datasets (GSE5764, GSE22358, GSE9014) is processed by GEO2R. Oncomine, GEPIA, UALCAN and TNMplot were applied to validate the expression of DST. Survival analyses were performed via DRUGSURV and Kaplan–Meier Plotter database. Univariable survival and multivariate Cox analysis were completed to assess the prognostic value of DST and receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic value of DST. We also investigated the correlation between DST and cancer immune infiltration via using CIBERSORT, TIMER and TISIDB.Results: DST and COL11A1 were significantly expressed in both DEGs and m6A target genes set. COL11A1 show no significance on the patients’ survival. However, high expression of DST was related to the favorable prognosis. Multivariate analysis revealed that the DST dysregulation is an independent prognostic factor and ROC indicated that the great diagnostic value of DST with AUC of 0.948. Subsequently, immunological analyses showed that DST was significantly associated with various immune infiltration cells, including NK cells, T helper cells and Mast cells. Furthermore, DST was also related with multiple immune checkpoints and chemokines, including LAG3, LMTK3 CD24, CXCL12, KDR and CX3CR1. These results indicated the potential roles of DST in the development of BRCA via altering the immune response.Conclusion: DST can influence the development and progression of BRCA by altering the immune microenvironment.Keywords: breast cancer, DST, N6-methyladenosine, immune microenvironment, immune infiltration

Yingmei Wu,1,2,&ast; Junhui Zheng,1,2,&ast; Yanhua Yan,1,2 Jiduo Liu,3 Yingchun Zhou3 1Guangzhou University of Chinese Medicine, Guangzhou, 510000, People’s Republic of China; 2Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510000, People’s Republic of China; 3Department of Clinical Laboratory, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingchun Zhou; Jiduo LiuDepartment of Clinical Laboratory, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510000, People’s Republic of ChinaEmail yingchunbaby@126.com; 13668996592@163.comBackground: Gelsolin (GSN) is the most widely expressed actin-severing protein in humans, which could regulate cell morphology, differentiation, movement and apoptosis. This study aims to explore the GSN as a prognostic biomarker of stomach adenocarcinoma (STAD).Methods: In this study, we used several online databases to comprehensively analyze the role of GSN in STAD. Oncomine and HPA databases were used to explore the GSN expression in various cancer, especially in gastric cancer. Then, UALCAN database was used to evaluate the relationship between GSN expression and promoter methylation in clinical characteristics. Finally, we used TIMER to analyze the correlation between GSN expression and immune infiltrates in gastric cancer.Results: GSN was down-regulated in gastric cancer, and decreased expression of GSN was related to worse survival. The GSN expression was significantly related to tumor purity in STAD and significantly correlated with infiltrating level of various immune cells, especially the dendritic cells.Conclusion: Our study proposes that GSN can be served as the biomarker of disease and neoantigen for STAD treatment, which can improve the deficiency of disease-specific targeted therapies currently exist.Keywords: gelsolin, gastric cancer, prognosis, immune cell infiltration

Guang Yang,1,2 Yisong Yan,1,3 Jun Mao,1 Huiping Liu,1 Mingtao Chen,1 Na Zhang,1 Yaowen Li,1 Jiangjun Gu,2 Xiaohui Huang1 1Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Pharmacy, The Third People’s Hospital of Tongling, Tongling, Anhui, People’s Republic of China; 3Department of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, Anhui, People’s Republic of ChinaCorrespondence: Xiaohui HuangDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Meishan Road 81#, Hefei, Anhui, 230032, People’s Republic of ChinaTel +86 138 5518 3138Email math2088@163.comBackground: Linezolid (LNZ), an oxazolidinone antibiotic, has 100% oral bioavailability and favorable activities against gram-positive pathogens. The in vitro PK/PD model was developed based on concentrations obtained with routine doses in humans can be used to guide dose optimization in the clinic.Methods: In this study, we employed an in vitro PK/PD model to simulate the changes in the plasma concentration of linezolid in the human body against a clinical isolate of MRSA in vitro. A high-performance liquid chromatography (HPLC)-UV method was applied to measure the concentration of linezolid. Bacterial samples were collected at different times from the central compartment for count.Results: The chromatographic separation was carried out with an AichromBond-AQC18 column(250mm× 4.6mm, 5μm), using a mobile phase of water with 0.1% formic acid:acetonitrile 70:30 (v/v), followed by detection at 254 nm, and a single detection run was completed within 10 min. The method was validated by estimating the precision and accuracy for the inter- and intra-day analyses in the concentration range of 0.25– 32 mg/L. The method was linear over the investigated range of 0.125– 32 mg/L, with all correlation coef&filig;cients R2 = 0.9999. The intra-day and inter-day precisions were within 7.598%, and the method recovery ranged from 90.912% to 106.459%. In vitro PK/PD model, both the absorption and elimination of linezolid being simulated can be precisely controlled by computer. In the control group, the bacterial reached 7.9 Log10CFU/mL in the &filig;rst 48h and maintained until the end, indicating that the colonies grew well in vitro PK/PD model. In the linezolid 600 mg q12h administration group, the colony decreased to 2.39 Log10CFU/mL at 24h, showing a good bactericidal effect; however, the colonies resumed growth to the initial level in 48h, indicating an emergence of resistance.Conclusion: We successfully established an in vitro infection PK/PD model and developed an HPLC-UV method to determine linezolid concentration for resistance investigation. The results suggest that the 600 mg q12h dosing regimen may no longer be applicable and requires optimization.Keywords: linezolid, HPLC-UV, PK/PD model, resistance