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Wenjuan Yi,1 Qionglin Bao,2 Dingkun Xu,3 Chenyu Long,1 Ruixin Fang,1 Wenlin Cheng,4 Jiquan Song,1 Huiting Feng1 1Department of Dermatology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Wound Repair Center, Chronic Wound and Diabetic Foot Clinical Medical Research Center, Liyuan Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, People’s Republic of China; 4Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan, People’s Republic of ChinaCorrespondence: Huiting Feng; Jiquan Song, Email feng_huiting@126.com; songjiq@126.comObjective: Diabetic foot ulcers (DFUs) are a serious complication of diabetes, characterized by impaired wound healing and high morbidity and mortality risks. While ETS1 is known to influence fibroblast pathological remodeling, its specific role in DFU and fibroblast wound healing remains unclear.Methods: Skin tissue samples from DFU patients were categorized by Wagner grades to analyze ETS1 expression. Primary fibroblasts derived from diabetes mellitus wound (DMFBs) were collected from wound margins to test migration ability and analyze cell phenotype by immunofluorescence; they were further treated with siETS1 and the ETS1 inhibitor YK-4-279. Techniques including Western blotting, quantitative Real-Time PCR (qRT-PCR), and immunofluorescence were used to assess the expressionof ETS1, Collagen I, and phenotype in DMFBs. Additionally, the binding sites between human ETS1 and the PP2A promoter were predicted by the UCSC and JASPAR databases. It intended to explore the negative transcriptional regulation of PP2A by ETS1 and its implications in fibroblast function and wound healing.Results: Fibroblasts derived from Wagner Grades II–IV exhibit differences in cell morphology, migratory ability, and phenotype. Our findings indicate a significant upregulation of ETS1 in Wagner III and IV. The downregulation of ETS1 was observed to enhance DMFB migration and increase the expression of Collagen I and α-SMA. These changes suggest a potential mechanism by which PP2A regulates the YAP/Hippo pathway in diabetic wound healing.Conclusion: ETS1 appears to impede the repair processes in DFUs, likely through the negative regulation of PP2A, affecting fibroblast function and wound healing.Keywords: diabetic wound, diabetic foot ulcer, ETS1, PP2A, YAP

Yangshuo Li,1,* Zhihao Zhou,1,2,* Xiaolan Liang,1,* Jie Ding,1 Yalun He,1 Shuai Sun,1 Wen Cheng,1 Zhexin Ni,1,3 Chaoqin Yu1 1Department of Traditional Chinese Gynecology, the First Affiliated Hospital of Naval Military Medical University (Changhai Hospital), Shanghai, People’s Republic of China; 2Traditional Chinese Medicine Department, No. 929 Hospital, Naval Medical University, Shanghai, People’s Republic of China; 3Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhexin Ni, Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, People’s Republic of China, Email nizxzg@163.com Chaoqin Yu, Department of Traditional Chinese Gynecology, the First Affiliated Hospital of Naval Military Medical University (Changhai Hospital), 168 Changhai Road, Shanghai, 200433, People’s Republic of China, Email cqyu@smmu.edu.cnIntroduction: Endometriosis (EM) is a chronic estrogen-dependent condition characterized by the growth of endometrial-like tissue outside the uterus, posing a significant burden on reproductive-aged women. Previous research has shown a correlation between gut microbiota dysbiosis and interleukin-17A (IL-17A) in EM patients. IL-17A, a promising immunomodulatory molecule, exerts dual roles in human physiology, driving inflammatory diseases. However, the functions and origins of IL-17A in EM remain poorly characterized.Methods: Single-cell data analysis was employed to characterize IL-17A activity in EM lesions. Fecal microbiota transplantation was conducted to explore the impact of gut microbiota on EM. Gut microbiota and bile acid metabolism were assessed via 16S rRNA sequencing and targeted metabolomics. Th17 cell proportions were measured using flow cytometry.Results: High expression of IL-17 receptor A (IL-17RA) was observed in myeloid cell subpopulations within EM lesions and may be involved in the migration and recruitment of inflammatory cells in lesions. Elevated IL-17A levels were further validated in peritoneal and follicular fluids of EM patients. Dysregulated bile acid levels, particularly elevated chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), were found in the gut and peritoneal fluid of EM mouse models. Additional CDCA administration reduced EM lesions and modulated Th17 cell proportions, while UDCA showed no significant effects.Discussion: Our findings shed light on the origins and functions of IL-17A in EM, implicating its involvement in lesion migration and recruitment. Dysregulated bile acid metabolism may contribute to EM pathogenesis, with CDCA exhibiting therapeutic potential. Keywords: endometriosis, single-cell sequencing, interleukin-17, gut microbiota, bile acids, myeloid cell

Xiuwen Chen,1,* Meiyan Zou,1,* Siquan Liu,1 Weilin Cheng,1 Weihong Guo,2 Xiaoli Feng1 1Stomatology Hospital, School of Stomatology, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of General Surgery, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weihong Guo; Xiaoli Feng, Email drguowh@163.com; dentistfxl226@163.comAbstract: Graphene family nanomaterials (GFNs) have attracted considerable attention in diverse fields from engineering and electronics to biomedical applications because of their distinctive physicochemical properties such as large specific surface area, high mechanical strength, and favorable hydrophilic nature. Moreover, GFNs have demonstrated the ability to create an anti-inflammatory environment and exhibit antibacterial effects. Consequently, these materials hold immense potential in facilitating cell adhesion, proliferation, and differentiation, further promoting the repair and regeneration of various tissues, including bone, nerve, oral, myocardial, and vascular tissues. Note that challenges still persist in current applications, including concerns regarding biosecurity risks, inadequate adhesion performance, and unsuitable degradability as matrix materials. This review provides a comprehensive overview of current advancements in the utilization of GFNs in regenerative medicine, as well as their molecular mechanism and signaling targets in facilitating tissue repair and regeneration. Future research prospects for GFNs, such as potential in promoting ocular tissue regeneration, are also discussed in details. We hope to offer a valuable reference for the clinical application of GFNs in the treatment of bone defects, nerve damage, periodontitis, and atherosclerosis. Keywords: graphene, graphene oxide, regenerative medicine, scaffold, anti-inflammatory, bone regeneration, nerve, angiogenesis, dental pulp stem cells

Youren Dai,1,* Huiyun Wu,1,* Jiahui Cao,1,* Yang Li,2 Wenjun Cheng,1 Chengyan Luo1 1Department of Gynecology, First Affiliated Hospital with Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Pathology, First Affiliated Hospital with Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chengyan Luo, Department of Gynecology, First Affiliated Hospital with Nanjing Medical University, 368 North Jiangdong Road, Nanjing, 210036, People’s Republic of China, Email betteryuan66@njmu.edu.cnPurpose: To investigate prognostic factors affecting cancer-specific survival (CSS) and to analyze the survival outcomes of patients with undifferentiated and dedifferentiated endometrial carcinoma (UDEC) who underwent various postoperative adjuvant therapies.Methods: The independent risk factors affecting CSS were studied using univariate and multivariate Cox regression analysis, and CSS in the presence of various postoperative treatments was evaluated using Kaplan-Meier method based on the cohort with pathologically confirmed UDEC from the Surveillance, Epidemiology, and End Results (SEER) database. Meanwhile, the study included 18 cases with UDEC in our center and explored their molecular characteristics and prognosis.Results: Between 2000 and 2019, a total of 443 patients were included from the SEER database. The median CSS duration was 14 months, with corresponding 3- and 5-year CSS rates of 45.9% and 44.0%, respectively. Factors such as pTNM stage, surgical resection of primary lesion, and chemoradiation independently influenced CSS. Postoperative chemotherapy alone improved CSS in patients with initial tumor spread beyond the uterus (pT3 and pT4), or lymph node (LN) invasion, or distant metastases. Additionally, postoperative radiotherapy enhanced CSS in patients who had undergone postoperative chemotherapy, those with primary tumors progressing to stage pT3, and those with LN involvement but without distant metastases. Of the 18 patients diagnosed at our center, with a median follow-up of 15.5 months, one experienced relapse and two succumbed to UDEC, who exhibited aberrant p53 expression in immunohistochemical staining.Conclusion: Postoperative chemotherapy and radiotherapy are beneficial for UDEC patients with tumors extending beyond the uterus or involving lymph nodes.Keywords: undifferentiated and dedifferentiated endometrial carcinoma, cancer-specific survival, prognostic factors, postoperative adjuvant therapy

Kai Guo,1,2 Yuqin Zhu,3 Qian Yu,4 Hong Chen,5 Wei Cheng,2 Xiaoyan Zhang,2 Xuelian Zhang,2 Biwen Liu,2 Zunhai Zhou,2 Xingya Kuang5 1School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China; 2Department of Endocrinology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, People’s Republic of China; 3Department of Emergency, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, People’s Republic of China; 4Department of Dermatology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, People’s Republic of China; 5Department of Occupational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, People’s Republic of ChinaCorrespondence: Xingya Kuang, Department of Occupational Medicine, Yangpu Hospital, School of Medicine, Tongji University, No. 1015, Hejian Road, Shanghai, 200090, People’s Republic of China, Tel +86-15021904362, Email kuangxingya@163.com Zunhai Zhou, Department of Endocrinology, Yangpu Hospital, School of Medicine, Tongji University, No. 450, Tengyue Road, Shanghai, 200090, People’s Republic of China, Tel +86-18001779479, Email zhouzunhai5008@163.comPurpose: Elevated urine albumin-to-creatinine ratio (UACR) is an established risk factor for microvascular disease in the general population. However, it is unclear whether UACR is associated with arterial stiffness in diabetes. We aimed to assess the relationship between UACR levels and the risk of arterial stiffness in patients with diabetes.Methods: From July 2021 to February 2023, a total of 1039 participants were assessed for the risk of arterial stiffness, which was evaluated by brachial-ankle pulse wave velocity (baPWV). The value of UACR≥ 30 mg/g was defined as high UACR. The UACR level had an abnormal distribution and was log2-transformed for analyses to reduce skewness and volatility. High baPWV was evaluated as categorical variables divided by the highest quartile of the values by sex. The relationship between UACR and arterial stiffness was analyzed by linear curve fitting analyses. Multiple logistic regression models were used to analyze the crude and adjusted odds ratio (OR) of UACR for high baPWV with 95% confidence interval (CI). In addition to applying non-adjusted and multivariate-adjusted models, interaction and stratified analyses were also carried out.Results: The baPWV level was significantly higher in the high UACR group compared with that in the normal UACR group (1861.84 ± 439.12 cm/s vs 1723.13 ± 399.63 cm/s, p< 0.001). Adjusted smoothed plots suggested that there are linear relationships between log2-transformed UACR and high baPWV, and Spearman correlation coefficient was 0.226 (0.176– 0.276, p< 0.001). The OR (95% CI) between log2-transformed UACR and high baPWV were 1.26 (1.19– 1.33, p< 0.001), and 1.16 (1.08– 1.25, p< 0.001) respectively in diabetic patients before and after adjusting for potential confounders.Conclusion: The elevated UACR was associated with arterial stiffness in Chinese patients with diabetes.Plain Language Summary: 1. The mean baPWV level was significantly higher in the high UACR group compared with that in the normal UACR group.2. The sex-specific hierarchical analysis revealed that baPWV levels and the incidence of high baPWV were significantly elevated with increased UACR.3. Curvilinear relationships between log2-transformed UACR and the risk of high baPWV.4. Positive association between UACR and high baPWV in patients with diabetes.Keywords: diabetic kidney disease, cardiovascular diseases, albuminuria, pulse wave velocity, biomarker, prognosis

Mai Zhang,1 Yan Li,1,2 Chunli Han,3 Shiying Chu,1 Peng Yu,1 Wenbo Cheng1,2 1Mass Spectrometry Application Center, Tianjin Guoke Medical Technology Development Co., Ltd, Tianjin, People’s Republic of China; 2Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences (CAS), Suzhou, People’s Republic of China; 3Mass Spectrometry Application Center, Shandong CAS Intelligent Manufacturing Medical Device Technology Co., Ltd, Zaozhuang, People’s Republic of ChinaCorrespondence: Wenbo Cheng, Email chengwb@sibet.ac.cnBackground: Inhibition of amyloid β protein fragment (Aβ) aggregation is considered to be one of the most effective strategies for the treatment of Alzheimer’s disease. (-)-Epigallocatechin-3-gallate (EGCG) has been found to be effective in this regard; however, owing to its low bioavailability, nanodelivery is recommended for practical applications. Compared to chemical reduction methods, biosynthesis avoids possible biotoxicity and cumbersome preparation processes.Materials and Methods: The interaction between EGCG and Aβ 42 was simulated by molecular docking, and green tea-conjugated gold nanoparticles (GT-Au NPs) and EGCG-Au NPs were synthesized using EGCG-enriched green tea and EGCG solutions, respectively. Surface active molecules of the particles were identified and analyzed using various liquid chromatography-tandem triple quadrupole mass spectrometry methods. ThT fluorescence assay, circular dichroism, and TEM were used to investigate the effect of synthesized particles on the inhibition of Aβ 42 aggregation.Results: EGCG as well as apigenin, quercetin, baicalin, and glutathione were identified as capping ligands stabilized on the surface of GT-Au NPs. They more or less inhibited Aβ 42 aggregation or promoted fibril disaggregation, with EGCG being the most effective, which bound to Aβ 42 through hydrogen bonding, hydrophobic interactions, etc. resulting in 39.86% and 88.50% inhibition of aggregation and disaggregation effects, respectively. EGCG-Au NPs were not as effective as free EGCG, whereas multiple thiols and polyphenols in green tea accelerated and optimized heavy metal detoxification. The synthesized GT-Au NPs conferred the efficacy of diverse ligands to the particles, with inhibition of aggregation and disaggregation effects of 54.69% and 88.75%, respectively, while increasing the yield, enhancing water solubility, and decreasing cost.Conclusion: Biosynthesis of nanoparticles using green tea is a promising simple and economical drug-carrying approach to confer multiple pharmacophore molecules to Au NPs. This could be used to design new drug candidates to treat Alzheimer’s disease.Keywords: gold nanoparticles, green synthesis, (-)-epigallocatechin-3-gallate, liquid chromatography tandem triple quadrupole mass spectrometry, amyloid β protein, green tea

Jing Zhang,1,2 Ke Ma,3 Jun Yan,4 Pingsheng Pan,5 Jiangshan Yin,6 Fuqing Lin,7 Hui Chen,8 Weiwei Zhao,1,2 Menglei Chen,1,2 Zhe Zhang,1,2 Minghui Liu,1,2 Xiaoli Gu,1,2 Xinghe Liao,1,2 Chenyue Zhang,1,2 Wenwu Cheng1,2 1Department of Integrated Therapy, Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Department of Pain Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, People’s Republic of China; 5Department of Oncology, Fangta Hospital of Traditional Chinese Medicine in Songjiang District, Shanghai, People’s Republic of China; 6Department of Oncology, Fudan University Shanghai Cancer Center, Minhang Branch, Shanghai, People’s Republic of China; 7Department of Anaesthesiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 8Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Wenwu Cheng, Email cwwxxm@sina.comPurpose: This study aimed to assess the current status of clinical practice of refractory cancer pain (RCP) among a sample of physicians specializing in cancer pain management in Shanghai.Methods: From 2019 to 2021, a questionnaire survey was conducted among physicians engaged in diagnosis and treatment of cancer pain through the questionnaire WJX network platform in Shanghai, China.Results: A total of 238 responses participated in the survey. This survey reports physicians’ understanding and incidence rate of breakthrough cancer pain (BTCP). The choice of analgesics and satisfaction of analgesic effect were investigated. We also investigated doctors’ knowledge of the diagnostic criteria for RCP and their tendency to choose analgesics. Oral immediate-release morphine and intravenous or subcutaneous morphine injection have been the common treatment approach for transient cancer pain exacerbations. The main barriers to pain management are lack of standardized treatment methods for RCP, lack of knowledge related to RCP, and single drug dosage form. Doctors believe the most necessary measures to improve the current situation of poor cancer pain control include improving medical staff’s understanding and treatment techniques for RCP, updating treatment techniques and methods, and improving the configuration of drug types in medical institutions. Clinicians expect to improve understanding and treatment techniques through systematic training.Conclusion: Despite multiple available analgesic measures, the treatment of RCP remains challenging. Improving the understanding of medical staff towards RCP, improving treatment techniques, and increasing the accessibility of multiple drug types are important ways to improve the satisfaction of cancer pain management in the future.Keywords: refractory cancer pain, breakthrough cancer pain, pain management, opioid drugs

Lu-Yao Yang,1,&ast; Chao-Qing Li,1,2,&ast; Yu-Lin Zhang,1,2 Meng-Wen Ma,3 Wan Cheng,3 Guo-Jun Zhang1,2 1School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, People’s Republic of China; 2Hubei Shizhen Laboratory, Wuhan, 430065, People’s Republic of China; 3Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics - Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guo-Jun Zhang, School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, People’s Republic of China, Email zhanggj@hbtcm.edu.cnAbstract: Extracellular vesicles can transmit intercellular information and transport biomolecules to recipient cells during various pathophysiological processes in the organism. Animal cell exosomes have been identified as potential nanodrugs delivery vehicles, yet they have some shortcomings such as high immunogenicity, high cytotoxicity, and complicated preparation procedures. In addition to exosomes, plant-derived extracellular vesicles (PDVs), which carry a variety of active substances, are another promising nano-transport vehicles emerging in recent years due to their stable physicochemical properties, wide source, and low cost. This work briefly introduces the collection and characterization of PDVs, then focuses on the application of PDVs as natural or engineered drug carriers in biomedicine, and finally discusses the development and challenges of PDVs in future applications.Keywords: plant-derived vesicles, activated biomaterials, nanodrugs delivery systems, biomedicine applications

Weilu Cheng,1,* Lili Zhang,1,* Biwei Chen,1 Xin Tian,1 Yaqi Yao,1 Zezhou Zhang,1 Shaozong Chen2,3 1Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 2Institute of Acupuncture and Moxibustion and Massage, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 3Shaozong Chen, Cross-Regional Acupuncture Data Open Application Laboratory in the Yellow River Basin, Jinan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaozong Chen, Cross-regional Acupuncture Data Open Application Laboratory in the Yellow River Basin, Jinan, 250355, People’s Republic of China, Email ccsz1963@163.comObjective: This study aims to explore formula patterns and application rules for SP6 as the main acupoint in prescriptions, utilizing association rules.Methods: We conducted an extensive search in databases including China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform (CDDB), China Science and Technology Journal Database (CSTJ), PubMed and Web of Science databases for literature published between January 2013 and June 2023, focusing on acupuncture prescriptions with SP6 as the main acupoint for various diseases. Inclusion and exclusion criteria were applied for literature screening. Relevant data was extracted, creating a database. Acupoints in conjunction with SP6 were analyzed using SPSS Modeler 18.0 and Cytoscape 3.7.2 software for acupoints appearing ≥ 15 times. Gephi software constructed a complex network model. The frequency of acupuncture points was analyzed to summarize the composition rules and clinical application rules of acupuncture points.Results: A total of 902 articles met inclusion criteria, yielding 672 prescriptions with SP6 as the main acupoint, paired with 197 different acupoints including ST36, CV4, and LI4. Neurological, obstetric, and gynecologic, as well as urological diseases, were predominantly treated. Among them, the predominant diseases include insomnia, primary dysmenorrhea, sequelae of stroke, and others, totaling 42 types.Conclusion: SP6-based prescriptions exhibit diverse applications, effectively treating insomnia, post-stroke sequelae, and primary dysmenorrhea. Commonly paired acupoints belong to Conception Vessel, Stomach meridian of foot-yangming, and Governor Vessel, and there are certain rules in their composition.Keywords: Sanyinjiao, SP6, acupuncture prescriptions, acupoint combinations regularity, application regularity

Huimin Tian, Haitao Shang, Yichi Chen, Bolin Wu, Chunyue Wang, Xiaodong Wang, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Wen Cheng, Department of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of China, Tel +86 13313677182, Fax +86 451 85718392, Email hrbchengwen@163.comBackground: Apoptosis resistance of hepatocellular carcinoma (HCC) often leads to treatment failure. Nonetheless, overcoming the resistance of HCC to apoptosis by inducing necroptosis of tumor cells to bypass the apoptotic pathway may be a promising treatment strategy. Sonodynamic therapy (SDT) has broad prospects in disease treatment because of its noninvasive characteristic and spatiotemporal control. The combination of SDT and shikonin in the treatment of HCC is expected to be a new tumor treatment method that can overcome apoptosis resistance.Methods: In this study, the antitumor effect was evaluated using normal liver cell line WRL68, HCC cell line HepG2 and HepG2 xenograft mouse models. Indocyanine green (ICG) was loaded on nanobubbles (NBs) to construct ICG-loaded nanobubbles (ICG-NBs). Combined sonosensitizer nanoplatforms with ultrasound (US) to achieve efficient SDT, the combination of SDT and shikonin in treating HCC can activate shikonin-induced necroptosis. As a result, tumor cells that produced apoptosis resistance were destroyed by necroptosis.Results: The results indicated a successful preparation of ICG-NBs with a uniform particle size of 273.0 ± 118.9 nm spherical structures. ICG-NB-mediated SDT, in combination with shikonin treatment, inhibited the viability, invasion, and migration of tumor cells. SDT + shikonin treatment group caused a substantial increase in necroptotic cells. The increased degree of tumor necrosis and the upregulated expression of receptor-interacting protein 3 kinase were observed in vivo studies, which indicated that the antitumor effect was accompanied by enhanced necroptosis in the SDT + shikonin treatment group.Conclusion: ICG-NB-mediated SDT combined with shikonin inhibits the growth of HCC by increasing the necroptosis of tumor cells. Therefore, this combination therapy is a promising treatment strategy against the specific cancer.Keywords: sonodynamic therapy, hepatocellular carcinoma, necroptosis, shikonin, sonosensitizer

Wanchun Cheng,1 Mohammad Mofatteh,2 José Fidel Baizabal-Carvallo,3,4 Shaohuan Lu,1 Ping Su,1 Yimin Chen,5,6 Luoming Li,1 Lizhi Qin,1 Xingmei Zuo,1 Yifeng Lan,7 Yue Huang,8 Zhihui Yu,9 Zirui Luo,10,&ast; Gang Chen10,&ast; 1Department of Neurology and National Stroke Center, The 5th People’s Hospital of Foshan City, Foshan, People’s Republic of China; 2School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK; 3Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA; 4Department of Sciences and Engineering, University of Guanajuato, León, Mexico; 5Department of Neurology and Advanced National Stroke Center, Foshan Sanshui District People’s Hospital, Foshan, People’s Republic of China; 6Neuro International Collaboration (NIC), Foshan, People’s Republic of China; 7Department of Radiology, the 5th People’s Hospital of Foshan City, Foshan, People’s Republic of China; 8Department of Emergency, the 5th People’s Hospital of Foshan City, Foshan, People’s Republic of China; 9Department of Laboratory Medicine, the 5th People’s Hospital of Foshan City, Foshan, People’s Republic of China; 10Dean’s Office, the 5th People’s Hospital of Foshan City, Foshan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zirui Luo; Gang Chen, Dean’s Office, the 5th People’s Hospital of Foshan City, Foshan, Guangdong Province, 528211, People’s Republic of China, Email ziruiluo@126.com; vikingsaga@163.comPurpose: Intravenous thrombolysis has emerged as an effective approach to improve the long-term survival and functional status of patients with ischemic stroke. The aim of this study was to assess the impact of a national stroke project on the door-to-needle-time (DNT).Patients and Methods: The patients were divided into pre-construction and construction periods. Construction Measures were performed during the construction period. The DNT and onset-to-needle time (ONT) were compared in two period groups.Results: After participating in the National Stroke Center Project and effective measurements, the thrombolysis treatment metrics were improved significantly. The DNT (IQR) was shortened from 65.0 (54.5,85.0) minutes in the Pre-Construction period to 40.0 (33.0,53.0) minutes in the Construction period (p < 0.001). Similarly, the ONT was reduced from 157.0 (IQR) (115.0,184.0) minutes to 116.0 (87.8,170.0) minutes (p = 0.035).Conclusion: The DNT time and ONT time can be shortened by National Stroke Center Construction projects. More suitable hospitals should be encouraged to participate as the National Stroke Center.Keywords: acute ischemic stroke, intravenous thrombolysis, door-to-needle time, onset-to-needle time

Xiaodong Wang, Chunyue Wang, Huimin Tian, Yichi Chen, Bolin Wu, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Wen Cheng; Bolin Wu, Department of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, People’s Republic of China, Tel +86 13313677182 ; +86 15663615088, Email chengwen@hrbmu.edu.cn; wubolin@hrbmu.edu.cnPurpose: Sonodynamic therapy (SDT) is a promising and significant measure for the treatment of tumors. However, the internal situation of hepatocellular carcinoma (HCC) is complex, separate SDT treatment is difficult to play a good therapeutic effect. Here, we used SDT combined with MG-132 to mediate apoptosis and autophagy of HCC cells to achieve the purpose of treatment of cancer.Methods: To determine the generated reactive oxygen species (ROS) and the change of mitochondrial membrane potential (ΔΨm), HepG2 cells were stained by 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) and 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1) staining to determine the IR-820@NBs-mediated SDT to achieve HCC therapy through the mitochondrial pathway. Cell counting kit 8 (CCK-8) assay and flow cytometry were used to detect cell viability and apoptosis rate of HepG2 cells. Autophagy was detected by mCherry-GFP-LC3B fluorescence labeling. Chloroquine (Cq) pretreatment was used to explore the relationship between autophagy and apoptosis. To detect the ability of HepG2 cells migration and invasion, cell scratch assay and transwell assay were used.Results: The successfully prepared IR-820@NBs could effectively overcome the shortcomings of IR-820 and induce lethal levels of ROS by ultrasound irradiation. As a dual agonist of apoptosis and autophagy, MG-132 could effectively enhance the efficacy of SDT in the process of treating HCC. After pre-treatment with Cq, the cell activity increased and the level of apoptosis decreased, which proved that apoptosis and autophagy were induced by combined therapy, autophagy, and apoptosis have the synergistic anti-tumor effect, and part of apoptosis was autophagy-dependent. After combined therapy, the activity and invasive ability of HCC cells decreased significantly.Conclusion: SDT combined with MG-132 in the process of treating liver cancer could effectively induce apoptosis and autophagy anti-tumor therapy, which is helpful to the research of new methods to treat liver cancer.Keywords: sonodynamic therapy, MG-132, apoptosis, autophagy, hepatocellular carcinoma

Wei Cheng,1 Aiyuan Zhou,2 Yuqin Zeng,1 Ling Lin,1 Qing Song,1 Cong Liu,1 Zijing Zhou,1 Yating Peng,1 Min Yang,1 Lizhen Yang,1 Yan Chen,1 Shan Cai,1 Ping Chen1 1Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital; Research Unit of Respiratory Disease; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of ChinaCorrespondence: Ping Chen, Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital; Research Unit of Respiratory Disease; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan, 410011, People’s Republic of China, Tel +86-13873115563, Fax +86 731-85295848, Email pingchen0731@csu.edu.cnBackground: The revised Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 group ABE classification has undergone major modifications, which can simplify clinical assessment and optimize treatment recommendations for Chronic Obstructive Pulmonary Disease (COPD). However, the predictive value of the new grouping classification for prognosis is worth further exploration. We aimed to compare the prediction of hospitalization and mortality between this new GOLD group 2023 ABE classification and the earlier 2017 ABCD classification in a Chinese COPD cohort.Methods: Data from 2,499 outpatients with COPD, who first registered in the RealDTC study of Second Xiangya Hospital from December 2016 to December 2019, were collected prospectively and assessed retrospectively. Patients were followed up on all-cause mortality until October 2022 or death.Results: : Of the 2,499 patients with COPD, the risk of hospitalization during the first-year follow-up was higher in group E than in groups A and B. The mortality was higher in group E than in groups A and B, and group B was higher than group A. No differences were seen in the area under the curve (AUC) of 2017 vs 2023 GOLD grouping to predict hospitalization. The time-dependent AUC and concordance index for predicting mortality is slightly higher in the GOLD 2017 ABCD than in the 2023 ABE groups. The new GOLD 12-subgroup (1A– 4E) classification combining the GOLD 1– 4 staging and grouping performed similarly discriminate predictive power for mortality to the GOLD 2017 16-subgroup (A1– 4D) classification.Conclusion: The risk of hospitalization during the first-year follow-up was higher in group E than in groups A and B. The all-cause mortality increased gradually from GOLD group A to E. The GOLD 2023 classification based on ABE groups did not predict mortality better than the earlier 2017 ABCD classifications.Keywords: COPD, mortality, hospitalization, GOLD 2023

Yichi Chen,1– 3 Bolin Wu,1– 3 Haitao Shang,1– 3 Yucao Sun,1– 3 Huimin Tian,1– 3 Huajing Yang,1– 3 Chunyue Wang,1– 3 Xiaodong Wang,1– 3 Wen Cheng1– 3 1Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China; 2Department of Interventional Ultrasound, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China; 3Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin, 150081, People’s Republic of ChinaCorrespondence: Wen Cheng, Department of Ultrasound, Department of Interventional Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of China, Tel +86 13313677182, Fax +86 451 85718392, Email chengwen@hrbmu.edu.cnBackground: Despite the clinical efficacy of immunotherapy in treating malignant tumors, its effectiveness is often hampered by the immunosuppressive nature of the tumor microenvironment (TME). In this study, we propose the design of a nanoscale ultrasound contrast agent capable of triggering macrophage polarization and immunogenic cell death (ICD) for the treatment of hepatocellular carcinoma (HCC) through sonodynamic treatment (SDT) and immunotherapy.Methods: The re-educator (designated as ICG@C3F8-R848 NBs) is composed of the Toll-like receptor agonist resiquimod (R848) and the sonosensitizer Indocyanine green (ICG), utilizing nanobubbles (NBs) as carriers. The technique known as ultrasound-targeted nanobubble destruction (UTND) employs nanosized microbubbles and low-frequency ultrasound (LFUS) to ensure accurate drug delivery and enhance safety.Results: Following intravenous delivery, ICG@C3F8-R848 NBs have the potential to selectively target and treat primary tumors using SDT in conjunction with ultrasonography. Importantly, R848 can enhance antitumor immunity by inducing the polarization of macrophages from an M2 to an M1 phenotype.Conclusion: The SDT-initiated immunotherapy utilizing ICG@C3F8-R848 NBs demonstrates significant tumor suppression effects with minimal risk of systemic toxicity. The utilization of this self-delivery re-education technique would contribute to advancing the development of nanomedicine for the treatment of hepatocellular carcinoma.Keywords: hepatocellular carcinoma, synergistic sono-immunotherapy strategy, tumor-associated-macrophage

Ruan Z, Yang X, Cheng W. Cancer Manag Res. 2019;11:389–399. We, the Editors and Publisher of Cancer Management and Research, have retracted the following article. Following publication of the article, concerns were raised about the duplication of images from Figures 2, 4 and 5 with images from other unrelated articles. Specifically, Images for Figure 2I have been duplicated with images for Figure 3b from Qin S, Zhao Y, Lim G, et al. Circular RNA PVT1 acts as a competing endogenous RNA for miR-497 in promoting non-small cell lung cancer progression. Biomedicine & Pharmacotherapy. 2019;111:244-250. https://doi.org/10.1016/j.biopha.2018.12.007 and Figure 5 from Wang D, Gao Y, Zhang Y, Wang L, Chen G; Glypican-3 promotes cell proliferation and tumorigenesis through up-regulation of β-catenin expression in lung squamous cell carcinoma. Biosci Rep. 2019;39(6):BSR20181147. https://doi.org/10.1042/BSR20181147. Images for Figure 4G have been duplicated with images for Figure 3C from Xu X, Chen Y, Wang X, Mu X. Role of Hippo/YAP signaling in irradiation-induced glioma cell apoptosis. Cancer Manag Res. 2019;11:7577-7585. https://doi.org/10.2147/CMAR.S210825. Images for Figure 4H have been duplicated with images for Figures 2G and 4C from Xu, M, Gu M, Zhou J, Da J, Wang Z. Interaction of YAP1 and mTOR promotes bladder cancer progression. International Journal of Oncology. 2020;56:232-242. RETRACTED https://doi.org/10.3892/ijo.2019.4922 and Gao Y, Zhang G, Liu J, Li H. Tissue-specific transplantation antigen P35B functions as an oncogene and is regulated by microRNA-125a-5p in lung cancer. Oncology Reports. 2021;45:72. https://doi.org/10.3892/or.2021.8023, respectively. Images for Figure 5F have been duplicated with images for Figure 2C from Li Y, Tao C, Dai L, et al. MicroRNA-625 inhibits cell invasion and epithelial–mesenchymal transition by targeting SOX4 in laryngeal squamous cell carcinoma. Biosci Rep. 2019;39(1):BSR20181882. https://doi.org/10.1042/BSR20181882; Figure 2C from Gao Y, Zhang G, Liu J, Li H. Tissue-specific transplantation antigen P35B functions as an oncogene and is regulated by microRNA-125a-5p in lung cancer. Oncology Reports. 2021;45:72. https://doi.org/10.3892/or.2021.8023; Figure 2E from Wang L, Kong W, Liu B, Zhang X. Proliferating cell nuclear antigen promotes cell proliferation and tumorigenesis by up-regulating STAT3 in non-small cell lung cancer. Biomedicine & Pharmacotherapy. 2018;104:595-602. https://doi.org/10.1016/j.biopha.2018.05.071 and Figure 3D and 5D from Yuan L, Tian J. LIN28B promotes the progression of colon cancer by increasing B-cell lymphoma 2 expression. Biomedicine & Pharmacotherapy. 2018;103:355-361. https://doi.org/10.1016/j.biopha.2018.04.002. Images for Figure 5G have been duplicated with images for Figure 3I from Yang J, Yu L, Yan J, et al. Circular RNA DGKB Promotes the Progression of Neuroblastoma by Targeting miR-873/GLI1 Axis. Front. Oncol. 2020;10:1104. https://doi.org/10.3389/fonc.2020.01104 and Figure 5J from Du M, Shen P, Tan R, Wu D, Tu S. Aloe-emodin inhibits the proliferation, migration, and invasion of melanoma cells via inactivation of the Wnt/beta-catenin signaling pathway. Ann Transl Med. 2021;9(23):1722. https://doi.org/10.21037/atm-21-5437. The authors responded to our queries but were unable to provide a satisfactory explanation for the duplicated images or provide satisfactory 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”.

Xiao-kun Liu,1,&ast; Dan-ling Huang,1,2,&ast; Li-ping Meng,1 Wei Cheng,1 Yi-yi Li,1 Lu-lu Qin,3 Ao Yang,4 Fan Zeng,5 Qin Zou,1 Qi-fu Li6 1Clinical Psychology Department, The First Affiliated Hospital of Hainan Medical University, Haikou City, Hainan Province, People’s Republic of China; 2Neurology Department, Graduate School of Tianjin Medical University, Tianjin City, People’s Republic of China; 3Department of Social Medicine and Health Management, School of Medicine, Hunan Normal University, Changsha City, Hunan Province, People’s Republic of China; 4Health Management Department, School of Management of Hainan Medical University, Haikou City, Hainan Province, People’s Republic of China; 5Graduate School of Hainan Medical University, Haikou City, Hainan Province, People’s Republic of China; 6Neurology Department, The First Affiliated Hospital of Hainan Medical University, Haikou City, Hainan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiao-kun Liu; Qi-fu Li, Email lacyfairy@qq.com; lee-chief@163.comAim: This study was designed to develop an effective measurement tool for occupational stress among medical staff and to identify the underlying risk factors among clinical nurses in China under depression during and after COVID-19.Methods: In the first stage, an occupational stress scale was developed for medical staff based on qualitative and quantitative methods. The dimensions of the scale were based on childhood stress and seven other parameters of working stress. In the second stage, a provincial survey was conducted among clinical nurses in Hainan. The structure of Medical Staff Occupational Stress Scale was tested in secondary and tertiary hospitals. The socio-demographic information, occupational stress (measured using the developed scale), and current depression symptoms (assessed with the nine‐item Patient Health Questionnaire) were evaluated. The risk factors for occupational stress-induced depression were tested using multivariate logistic regression.Results: The Medical Staff Occupational Stress Scale consisted of 42 items under eight dimensions with strong reliability and validity. Almost 80% of the clinical nurses reported obvious symptoms of depression. Based on multivariate logistical regression analysis, the significant risk factors for depression in nurses at secondary hospitals and tertiary hospitals were childhood stress, teaching stress, relationship with patient stress, and administration stress.Conclusion: The Medical Staff Occupational Stress Scale utilized in nursing population is based on strong psychometric features. Childhood stress contributes to occupational stress in nurses. The selection of nurses for clinical work may require evaluation of past history for childhood stress to prevent occupational depression. Teaching stress, relationship with patient stress and administration stress play significant roles in the prevention of depression among clinical nurses.Keywords: occupational stress, depression, teaching stress, relationship with patient stress, nurses

Weiqin Cheng,1 Ling He,1 Hechuan Luo,1 Yan Jiang,2 Chengbing Tan,2 Xiao Fan1 1Department of Radiology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, People’s Republic of China; 2Department of Neurology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, People’s Republic of ChinaCorrespondence: Xiao Fan, Department of Radiology, Children’s Hospital of Chongqing Medical University, No. 136 Zhongshan Er Road, Yuzhong District, Chongqing, 400014, People’s Republic of China, Tel +86 13637907710, Email fanxiao@cqmu.edu.cnObjective: To investigate and summarize the magnetic resonance imaging (MRI) manifestations of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy in children.Methods: We retrospectively analyzed data from 17 pediatric patients with autoimmune GFAP astrocytopathy confirmed by the detection of GFAP autoantibodies in cerebrospinal fluid in our single-center. Furthermore, we reviewed current literature and summarized previous findings on the MRI characteristics of this disease in children.Results: In these 17 patients, the clinical manifestations and results of CSF analysis were suggestive of autoimmune disorder, with a good improvement. The lesions on MRI were most commonly located in the bilateral basal ganglia (70.6%), thalamus (64.7%), cerebral white matter (29.4%). 93.3% of the cerebral lesions were relatively scattered and small, 80% of the spinal lesions presented as longitudinally extensive ones. Both periventricular radial linear (PVRL) (53.8%) and punctate or linear enhancement in basal ganglia and thalamus (53.8%) were commonly observed, followed by the leptomeningeal enhancement (46.2% in the brain and 62.5% in the spinal cord). We then included 55 pediatric patients with MRI data from current literature in our analysis (n = 72, 44 males). Our results revealed similar MRI findings but the enhancement pattern between our series and previously published cases, that is, leptomeningeal enhancement in the brain 46.2% vs 31.4%, in spinal cord 62.5% vs 18.4%, and PVRL enhancement 53.8% vs 11.2%. There were no detailed reports on punctate or linear enhancement.Conclusion: The MRI characteristics of autoimmune GFAP astrocytopathy in children could be suggestive. Scattered and small lesions (especially punctate or linear) in the bilateral thalamus, basal ganglia, and white matter, as well as longitudinally extensive spinal cord lesions (if present), with punctate, PVRL and leptomeningeal enhancement might be a distinct indication for the early diagnosis of this disorder.Keywords: glial fibrillary acidic protein, GFAP, astrocytopathy, autoimmune, magnetic resonance imaging, children

Ruye Wang,1,&ast; Ying Zhao,2,&ast; Chenyun Miao,3 Yun Chen,1 Ning Ren,1 Liuqin Yang,1 Wei Cheng,4 Qin Zhang,1,5 Xiaohong Fang1 1Department of TCM Gynecology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2School of Public Health, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 4Department of Orthopedics, Hangzhou TCM Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 5Research Institute of Women’s Reproductive Health, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qin Zhang; Xiaohong Fang, Department of Medical TCM Gynecology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310007, People’s Republic of China, Email zhaqin01@163.com; fxh13527806@163.comPurpose: The aim of this study is to examine, using network pharmacology analysis and experimental validation, the pharmacological processes by which Yulin Formula (YLF) reduces cyclophosphamide-induced diminished ovarian reserve (DOR).Methods: First, information about the active components, associated targets, and related genes of YLF and DOR was gathered from open-access databases. The primary targets and pathways of YLF to reduce DOR were predicted using studies of functional enrichment from the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Protein-Protein Interaction (PPI) networks. Second, we built a cyclophosphamide-induced diminished ovarian reserve (DOR) rat model to verify the primary target proteins implicated in the predicted signaling pathway to explore the mechanism of improve ovarian function of YLF.Results: 98 targets met the targets of the 82 active ingredients in YLF and DOR after searching the intersection of the active ingredient targets and DOR targets. Fourteen targets, including AKT and Caspase-3 among others, were hub targets, according to the PPI network study. The PI3K/AKT pathway was revealed to be enriched by numerous targets by the GO and KEGG enrichment studies, and it was used as a target for in vivo validation. Animal studies showed that YLF administration not only reduced the number of atretic follicles, the proportion of TUNEL-positive ovarian cells, the rate of apoptosis of granulosa cells (GCs) and the proportion of abnormal mitochondria in DOR rats, but also reversed the high expression of Caspase-3, Caspase-9, BAX, cytochrome C, PI3K and P-AKT, improving the ovarian reserve in cyclophosphamide (CTX)-induced DOR rats.Conclusion: Our research results predicted the active ingredients and potential targets of YLF-interfering DOR by an integrated network pharmacology approach, and experimentally validated some key target proteins participated in the predicted signaling pathway. A more comprehensive understanding of the pharmacological mechanism of YLF for DOR treatment was obtained.Keywords: diminished ovarian reserve, Yulin Formula, network pharmacology, pharmacological mechanisms, apoptosis, PI3K/AKT

Bisheng Shen,1 Baoxin Chen,2 Kuangyi Li,1 Weiyin Cheng,3 Mohammad Mofatteh,4 Robert W Regenhardt,5 Jack Wellington,6 Zhangrong Liang,1 Qi Tang,1 Jingli Chen,1 Yimin Chen7 1Department of Emergency Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan City, Guangdong Province, People’s Republic of China; 2Faculty of Humanities and Social Sciences, Macao Polytechnic University, Macao, People’s Republic of China; 3Department of Clinical Nutrition, Foshan Hospital of Traditional Chinese Medicine, Foshan City, People’s Republic of China; 4School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK; 5Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 6School of Medicine, Cardiff University, Cardiff, Wales, UK; 7Department of Neurology and Advanced National Stroke Center, Foshan Sanshui District People’s Hospital, Foshan, People’s Republic of ChinaCorrespondence: Baoxin Chen, Faculty of Humanities and Social Sciences, Macao Polytechnic University, Macao, People’s Republic of China, Email P2009495@ipm.edu.mo Kuangyi Li, Department of Emergency Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan City, Guangdong Province, People’s Republic of China, Email 13809211066@163.comPurpose: This study aimed to highlight the impact of the COVID-19 pandemic lockdown on emergency department (ED) visits of non-COVID-19 patients in a tertiary hospital and evaluate protocol development during this period.Patients and Methods: Clinical data of patients who visited the ED of Foshan Hospital of Traditional Chinese Medicine during the first-level response in Foshan, Guangdong province in 2020 (from January 23 to February 24) and the same period in 2019 and 2021 were collected. A retrospective cross-sectional analysis was performed to understand the characteristics of critically ill patients and compare the proportion of hospitalizations, deaths, and emergency ambulance calls (EACs).Results: The number of patients presenting to the ED was significantly decreased, with a 37.75% reduction in 2020 (6196) compared to the same period in 2019 (9954). A rise in patient ED presentations was observed in the same period in 2021 (10,503). This decline was mostly in the 15– 45 age group. In 2019, 2020, and 2021, critically ill patients treated by the ED totaled 568 (5.706%), 339 (5.495%), and 590 (5.617%), respectively. Compared to the same period in 2019 and 2021, the proportion of critically ill patients with respiratory system involvement, severe trauma, and poisoning decreased most significantly in 2020 (P< 0.05). In contrast, the rates of EACs, hospitalizations, and deaths increased significantly (P< 0.05).Conclusion: The number of ED visits to hospitals was decreased during the 2020 lockdown, while the rates of EACs, hospitalizations, and deaths increased significantly though there were no documented COVID-19 cases. Optimizing emergency medical resources and ensuring the safety of healthcare providers and patients were essential to provide efficient emergency diagnosis and treatment during the lockdown.Keywords: COVID-19 pandemic, emergency medicine, coping strategies, emergency visit, non-COVID-19 patients

Sheng Liu,1,&ast; Guanyun Shi,1 Zhengbo Pan,1 Weisong Cheng,1 Linfei Xu,1 Xingzhang Lin,1 Yongfeng Lin,1 Liming Zhang,1 Guanghua Ji,1 Xin Lv,1 Dongguo Wang2,&ast; 1Department of Urinary Surgery, Taizhou Municipal Hospital Affiliated with Taizhou University, Taizhou, Zhejiang Province, People’s Republic of China; 2Department of Central Laboratory, Taizhou Municipal Hospital Affiliated with Taizhou University, Taizhou, Zhejiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongguo Wang, Department of Central Laboratory, Taizhou Municipal Hospital Affiliated with Taizhou University, 381-1 Eastern Road of Zhongshan, Taizhou, Zhejiang Province, 318000, People’s Republic of China, Tel +86-13566871738, Email wdgtzs@163.comPurpose: The overall survival of clear cell renal cell carcinoma (ccRCC) is poor. Markers for early detection and progression could improve disease outcomes. This study aims to reveal the potential pathogenesis of ccRCC by integrative bioinformatics analysis and to further develop new therapeutic strategies.Patients and Methods: RNA-seq data of 530 ccRCC cases in TCGA were downloaded, and a comprehensive analysis was carried out using bioinformatics tools. Another 14 tissue samples were included to verify the expression of selected lncRNAs by qRT-PCR. DGIdb database was used to screen out potential drugs, and molecular docking was used to explore the interaction and mechanism between candidate drugs and targets.Results: A total of 58 differentially expressed lncRNAs (DElncRNAs) and 660 differentially expressed mRNAs (DEmRNAs) were identified in ccRCC. LINC02038, FAM242C, LINC01762, and PVT1 were identified as the optimal diagnostic lncRNAs, of which PVT1 was significantly correlated with the survival rate of ccRCC. GO analysis of cell components showed that DEmRNAs co-expressed with 4 DElncRNAs were mainly distributed in the extracellular area and the plasma membrane, involved in the transport of metal ions, the transport of proteins across membranes, and the binding of immunoglobulins. Immune infiltration analysis showed that MDSC was the most correlated immune cells with PVT1 and key mRNA SIGLEC8. Validation analysis showed that GABRD, SIGLEC8 and CDKN2A were significantly overexpressed, while ESRRB, ELF5 and UMOD were significantly down-regulated, which was consistent with the expression in our analysis. Furthermore, 84 potential drugs were screened by 6 key mRNAs, of which ABEMACICLIB and RIBOCICLIB were selected for molecular docking with CDKN2A, with stable binding affinity.Conclusion: In summary, 4 key lncRNAs and key mRNAs of ccRCC were identified by integrative bioinformatics analysis. Potential drugs were screened for the treatment of ccRCC, providing a new perspective for disease diagnosis and treatment.Keywords: clear cell renal cell carcinoma, bioinformatics analysis, lncRNA, mRNA, drugs prediction, molecular docking

Xiang He, Shentao Zhang, Yuhang Tian, Wen Cheng, Hui Jing Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Hui Jing; Wen Cheng, Department of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, People’s Republic of China, Tel +86 13304504935 ; +86 13313677182, Email jinghuihrb@163.com; chengwen@hrbmu.edu.cnAbstract: With the booming development of nanomedicine, mild photothermal therapy (mPTT, 42– 45°C) has exhibited promising potential in tumor therapy. Compared with traditional PTT (> 50°C), mPTT has less side effects and better biological effects conducive to tumor treatment, such as loosening the dense structure in tumor tissues, enhancing blood perfusion, and improving the immunosuppressive microenvironment. However, such a relatively low temperature cannot allow mPTT to completely eradicate tumors, and therefore, substantial efforts have been conducted to optimize the application of mPTT in tumor therapy. This review extensively summarizes the latest advances of mPTT, including two sections: (1) taking mPTT as a leading role to maximize its effect by blocking the cell defense mechanisms, and (2) regarding mPTT as a supporting role to assist other therapies to achieve synergistic antitumor curative effect. Meanwhile, the special characteristics and imaging capabilities of nanoplatforms applied in various therapies are discussed. At last, this paper puts forward the bottlenecks and challenges in the current research path of mPTT, and possible solutions and research directions in future are proposed correspondingly.Keywords: nanomedicine, nanotechnology, mild photothermal therapy, tumor therapy

Ziwen Mao,1,2 Weyland Cheng,1,2 Zhenwei Li,2 Manye Yao,2 Keming Sun2 1Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of China; 2Department of Orthopaedic Surgery, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Weyland Cheng, Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, 33 Longhu Waihuan East Road, Zhengzhou, Henan, People’s Republic of China, Tel +86 18502758200, Email wey_c@hotmail.comAbstract: Bitter taste receptors (T2Rs) consist of 25 functional receptors that can be found in various types of cells throughout the human body with responses ranging from detecting bitter taste to suppressing pathogen-induced inflammation upon activation. Numerous studies have observed clinical associations with genetic or phenotypic variants in bitter taste receptors, most notably that of the receptor isoform T2R38. With genetic variants playing a role in the response of the body to bacterial quorum-sensing molecules, bacterial metabolites, medicinal agonists and nutrients, we examine how T2R polymorphisms, expression levels and bitter taste perception can lead to varying clinical associations. From these genetic and phenotypic differences, healthcare management can potentially be individualized through appropriately administering drugs with bitter masking to increase compliance; optimizing nutritional strategies and diets; avoiding the use of T2R agonists if this pathway is already activated from bacterial infections; adjusting drug regimens based on differing prognoses; or adjusting drug regimens based on T2R expression levels in the target cell type and bodily region.Keywords: bitter taste receptors, TAS2R38, chronic rhinosinusitis, obesity, oral health, cancer

Yingyi Zhu,1,&ast; Kangyao Cheng,1,&ast; Hui Wang,1 Ziwei Xu,1 Ruiyu Zhang,1 Wenjie Cheng,1 Yan Wang,2 Weibo Lyu1 1School of Nursing, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Nursing Department, Tangzhen Community Healthcare Center, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Wang, Tangzhen Community Healthcare Center, 75 Middle Chuangxin Road, Shanghai, 201203, People’s Republic of China, Tel +86 13816514677, Email guwangxin@aliyun.com Weibo Lyu, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201210, People’s Republic of China, Tel +86 13661498053, Email Lyu_weibo@shutcm.edu.cnPurpose: To explore exercise adherence and compliance as well as its related factors among elderly patients with type 2 diabetes mellitus (T2DM) to provide a basis for clinical intervention strategies.Patients and Methods: The present study was a cross-sectional study of 205 elderly patients with T2DM who regularly visited a Shanghai community health center from August 2020 to July 2021. Exercise adherence and compliance was measured using an exercise adherence and compliance questionnaire, and potential correlates were explored using multiple linear regression analysis.Results: The mean total score of the exercise adherence and compliance questionnaire was 16.72± 5.08. The stepwise regression results revealed that exercise adherence and compliance was positively correlated with self-monitoring (F=3.510, P=0.005), exercise knowledge (r=0.784, P< 0.001), exercise willingness (r=0.556, P< 0.001), professional support (r=0.426, P< 0.001), and self-efficiency (r=0.5, P< 0.001). There was a negative correlation between hypoglycemia and exercise adherence and compliance (F=− 3.672, P< 0.001).Conclusion: Low exercise adherence and compliance was related to low glucose self-monitoring frequency, increased hypoglycemia, less exercise knowledge, less exercise willingness, less professional support, and less self-efficiency. When developing exercise instructions adapted to the cognitive and volitional needs of diabetic patients, it is essential to focus on their daily self-management habits and extrinsic motivation to improve exercise adherence and compliance.Keywords: aged, type 2 diabetes mellitus, T2DM, exercise, adherence and compliance

Chunyue Wang, Yuhang Tian, Bolin Wu, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Wen Cheng; Bolin Wu, Department of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, People’s Republic of China, Tel +86 13313677182 ; +86 15663615088, Fax +86 451 85718392 ; +86 451 86298651, Email chengwen@hrbmu.edu.cn; wubolin@hrbmu.edu.cnAbstract: Sonodynamic therapy (SDT) is a rapidly developing non-surgical therapy that initiates sensitizers’ catalytic reaction using ultrasound, showing great potential for cancer treatment due to its high safety and non-invasive nature. In addition, recent research has found that using different diagnostic and therapeutic methods in tandem can lead to better anticancer outcomes. Therefore, as essential components of SDT, sonosensitizers have been extensively explored to optimize their functions and integrate multiple medical fields. The review is based on five years of articles evaluating the combined use of SDT and imaging in treating cancer. By developing multifunctional sonosensitive particles that combine imaging and sonodynamic therapy, we have integrated diagnosis into the treatment of precision medicine applications, improving SDT cell uptake and antitumor efficacy utilizing different tumour models. This paper describes the imaging principle and the results of cellular and animal imaging of the multifunctional sonosensitizers. Efforts are made in this paper to provide data and design references for future SDT combined imaging research and clinical application development and to provide offer suggestions.Keywords: sonodynamic therapy, multifunctional sonosensitizers, imaging, ultrasound

Wei Cheng, Fen Li, Jing Tian, Xi Xie, Jin-Wei Chen, Xiao-Fei Peng, Qi Tang, Yan Ge Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People’s Republic of ChinaCorrespondence: Yan Ge, Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People’s Republic of China, Email geyan2003@csu.edu.cnAbstract: Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a rare autoinflammatory disease characterized by dermatological disorders and osteoarticular inflammatory lesions. This article reviews the application of biologics and other treatments based on the therapeutic target and the size of molecules in SAPHO syndrome. We found that drugs, especially biologics, have different effects on bone, joint, and skin damage. This may relate to the different inflammatory pathways involved in the osteoarticular and cutaneous symptoms in SAPHO patients. In this study, we provide stratified medication recommendations for SAPHO syndrome. Patients with osteoarticular symptoms can consider tumor necrosis factor blockers, JAK inhibitor, interleukin (IL)-1 inhibitor, and IL-17 inhibitor. Patients with cutaneous symptoms should consider IL-17 and JAK inhibitors. Apremilast, Tripterygium wilfordii Hook F, and bisphosphonates are other effective treatments.Keywords: SAPHO, osteoarticular symptoms, cutaneous symptoms, immune pathway pathways, biologics, targeted small molecule compounds

Suhua Wang,1,2 Siyuan Han,1,2 Weiyan Cheng,1,2 Ruoyang Miao,1,2 Shasha Li,1,2 Xin Tian,1,2 Quancheng Kan1,2 1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China; 2Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of ChinaCorrespondence: Xin Tian; Quancheng Kan, Email tianx@zzu.edu.cn; kanqc@zzu.edu.cnPurpose: To enhance the cytotoxicities of our obtained CDK4 inhibitors and get CDK4/HDACs inhibitors with potent enzymatic inhibitory and anti-proliferative activities.Methods: A series of novel CDK4/HDACs inhibitors were designed and synthesized by incorporating the HDAC pharmacophores (hydroxylamine or o-diaminoaniline) into the basic structure of our newly obtained 2-anilino-4-triazolpyrimidine based CDK4 inhibitors. The enzymatic inhibitory (HDAC1, CDK2, CDK4, and CDK6) activities and cytotoxicities of these compounds were evaluated. Moreover, HDAC isoforms inhibitory activity, cell cycle arrest assay, cell apoptosis analysis, cell migration, and cell colony formation assay were performed for the representative compound 11k.Results: Most of these compounds showed excellent HDAC1 inhibitory activities (IC50s: 0.68∼ 244.5 nM) and anti-proliferative activities against cancer cell lines. Some compounds displayed potent CDK4 inhibitory activities and a certain selectivity towards CDK2 and CDK6. Compound 11k exhibited potent enzymatic (CDK4: IC50=23.59 nM; HDAC1: IC50=61.11 nM; HDAC2: IC50=80.62 nM; HDAC6: IC50=45.33 nM) and anti-proliferative activities against H460, MDA-MB-468, HCT116, and HepG2 cell lines with IC50 values 1.20, 1.34, 2.07, and 2.66 μM, respectively. Further mechanistic studies revealed that compound 11k could arrest the cell cycle in G0/G1 phase and induce apoptosis in HCT116 and MDA-MB-468 cells. In addition, compound 11k significantly inhibited the migration and cell colony formation of H460 and HCT116 cells.Conclusion: This study suggested that the incorporation of the HDAC pharmacophore into CDK4 inhibitor scaffold to design CDK/HDAC inhibitors might be a tractable strategy to enhance the antitumor potency of compounds.Keywords: CDK4, HDAC, inhibitor, 2-anilino-4-triazolpyrimidine, cancer

Xianhong Yang,1 Rui Qiao,1 Nana Ni,1 Qian Zhang,2 Ke Zhang,2 Xuebao Shao,1 Wei Cheng,1 Jianfang Sun,1 Yiqun Jiang1 1Department of Dermatopathology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, People’s Republic of China; 2Department of Surgery, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, People’s Republic of ChinaCorrespondence: Yiqun Jiang; Jianfang Sun, Email yiqunjiang@qq.com; sunjf57@163.comBackground: Nevus sebaceous (NS) is a benign hamartoma of the skin, characterized by hyperplasia of the epidermis, in addition to immature hair follicles. The exact mechanisms of folliculo-sebaceous-apocrine defects and adnexal tumorigenesis are unknown in NS, but benign and malignant neoplasms are often due to a complex etiology in NS. Long noncoding RNAs (lncRNAs) have been implicated in various important biological processes and regulate inflammatory diseases and tumors. However, the role of lncRNAs in nevus sebaceous is unclear.Objective: To identify NS-associated mRNA and lncRNA profiles and predict their potential roles in the development of the folliculo-sebaceous-apocrine unit and adnexal tumorigenesis.Methods: RNA-seq was used to identify NS-associated genes and lncRNAs. Analysis software Illumina NovaSeq 6000 was used to analyze the sequences, and real-time PCR and Western blot were used to validate the differentially expressed genes. Competing endogenous RNAs (ceRNA) networks were constructed by prediction software TargetScan & miRanda.Results: Many mRNAs were significantly differentially expressed between nevus sebaceous and adjacent normal scalp tissues. Among them, 72 were upregulated and 18 were downregulated. KEGG pathway analysis further revealed that 32 functional pathways were associated with the upregulated mRNAs, while only 1 pathway was associated with the downregulated mRNAs. Verification by real-time PCR and Western blot indicated that CDKN2AIP gene was downregulated consistently in NS tissue compared to normal scalp skin. Additionally, 7 upregulated and 10 downregulated significantly differentially expressed lncRNAs were detected between NS and adjacent normal scalp tissues. Three downregulated lncRNAs including AL355607.2, RP5-1024G6.8 and AC007780.1 were predicted to consistently associate with CDKN2AIP expression by competing endogenous RNAs(ceRNA) construction.Conclusion: Both mRNA and lncRNA profiles were altered in NS scalp tissues. We identified a downregulated gene, CDKN2AIP, as a target of differentially expressed mRNA and predicted a ceRNA network of CDKN2AIP with differentially expressed lncRNA.Keywords: nevus sebaceous, long noncoding RNA, ceRNA network, CDKN2AIP, wnt/β-catenin pathway

Yating Peng,1– 3 Wei Cheng,1– 3 Jiaxi Duan,1– 3 Yiyang Zhao,1– 3 Zijing Zhou,1– 3 Aiyuan Zhou,1– 3 Minhua Deng,1– 4 Hong Peng,1– 3 Ruoyun Ouyang,1– 3 Yan Chen,1– 3 Ping Chen1– 3 1Department of Pulmonary and Critical Care Medicine, Second Xiang Ya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Institute of Respiratory Disease, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Hunan Centre for Diagnosis and Treatment of Respiratory Disease, Changsha, Hunan, 410011, People’s Republic of China; 4Department of Respiratory, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, People’s Republic of ChinaCorrespondence: Ping Chen, Email pingchen0731@csu.edu.cnBackground: Prohibitin has been identified to play roles in cell survival and apoptosis. Here, this study aimed to clarify the role of prohibitin in cigarette smoke extract (CSE)-induced endothelial cell apoptosis.Methods: The protein level of prohibitin was assessed by Western blot in lung tissues from emphysema and control mice. CSE-induced human pulmonary microvascular endothelial cells (hPMECs) were applied to mimic smoke-related cell apoptosis in vitro. Prohibitin was overexpressed in hPMECs with or without CSE. Mitochondrial function was analyzed by JC-1 staining and ATP assay kits. Oxidative stress was assessed by flow cytometry, fluorescence staining and immunocytochemistry. Apoptosis was analyzed by flow cytometry, Western blot and caspase-3 activity assays. In addition, the expression of inflammatory markers was assessed by Western blot and real-time polymerase chain reaction (PCR). The secretion of inflammatory cytokines was measured by ELISA.Results: Prohibitin was downregulated in emphysema mouse tissues compared with control experiments. Consistently, CSE inhibited both the protein and RNA levels of prohibitin in hPMECs in a dose-dependent manner. Gain-of-function experiments indicated that CSE induced collapse of mitochondrial membrane potential (MMP) and loss of ATP, while prohibitin improved mitochondrial function. CSE induced robust ROS production and oxidative DNA damage, while prohibitin decreased this damage. Upregulation of prohibitin protected the apoptosis of hPMECs from CSE. Overexpression of prohibitin significantly reduced the levels of the main proinflammatory cytokines. Finally, prohibitin inhibited nuclear factor-kappa B (NF-κB) p65 accumulation and IκBα degradation induced by CSE.Conclusion: The current findings suggest that CSE-mediated mitochondrial dysfunction, oxidative stress, cell apoptosis and inflammation in hPMECs were reduced by overexpression of prohibitin. We identified prohibitin as a novel regulator of endothelial cell apoptosis and survival in the context of CSE exposure.Keywords: prohibitin, hPMECs, CSE, apoptosis, mitochondrial, inflammation

Song Liu,1,&ast; Xiaojun Cai,1,&ast; Tao Wang,1 Jiwen Xu,2 Weilun Cheng,3 Xuling Wang,1 Gangjie Wei,4 Shuang Yan5 1Endocrinology Department, Traditional Chinese Medicine Academy of Heilongjiang, Harbin, Heilongjiang Province, People’s Republic of China; 2Anatomy, Histology and Embryology Teaching and Research Section, School of Basic Medicine, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, People’s Republic of China; 3Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China; 4Medical Department, Traditional Chinese Medicine Academy of Heilongjiang, Harbin, Heilongjiang Province, People’s Republic of China; 5Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuang Yan, Email yan8028397483@126.comPurpose: Skeletal muscle insulin resistance (IR) is an important etiology of type 2 diabetes mellitus (T2DM); however, its molecular mechanism is yet to be fully defined. This study attempted to identify the gene expression patterns and molecular disorders in T2DM patients’ skeletal muscle samples.Methods: First, the difference in genetic expression among GSE25462 data was analyzed. Next, PPI network analysis of differential genes was carried out, after which the maladjustment module was identified. Then, an enrichment analysis and gene set enrichment analysis (GSEA) were carried out. Finally, the transcription factors that regulate the modular genes by raid were predicted.Results: Most differentially expressed genes were found to be able to form an interaction network and cluster into 9 modules. These modular genes were shown to possess a significant correlation with immune inflammation and metabolic response. Importantly, the top 15 genes of area under receiver operating characteristic curve (AUC) were identified, and the expression of 10 genes by GSE12643, GSE18732 and GSE29221 was confirmed. The expression and AUC value of ALDH6A1 were then verified according to three sets of data, where ALDH6A1 was found to be negatively correlated with follicular helper T cells. However, among the predicted transcription regulators, HDAC was shown to have a better regulatory effect.Conclusion: The findings highlight that the dysregulation of ALDH6A1 expression in IR of T2DM may serve as a potential therapeutic target. ALDH6A1 is involved in the immune inflammation and metabolic pathways.Keywords: type 2 diabetes mellitus, ALDH6A1, immune inflammatory response, metabolic pathway, HDAC

Yichi Chen,1 Haitao Shang,1 Chunyue Wang,1 Jiaqi Zeng,2 Shentao Zhang,1 Bolin Wu,1,3 Wen Cheng1,3 1Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 2School of Life Science and Technology, Computational Biology Research Center, Harbin Institute of Technology, Harbin, People’s Republic of China; 3Department of Interventional Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Wen Cheng; Bolin WuDepartment of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of ChinaTel +86 13313677182; +86 15663615088Fax +86 451 85718392; +86 451 86298651Email chengwen@hrbmu.edu.cn; wubolin@hrbmu.edu.cnBackground: The combination of sonodynamic therapy and oxygenation strategy is widely used in cancer treatment. However, due to the complexity, heterogeneity and irreversible hypoxic environment produced by hepatocellular carcinoma (HCC) tissues, oxygen-enhancing sonodynamic therapy (SDT) has failed to achieve the desired results. With the emergence of ferroptosis with reactive oxygen species (ROS) cytotoxicity, this novel cell death method has attracted widespread attention.Methods: In this study, nanobubbles (NBs) were connected with the sonosensitizer Indocyanine green (ICG) to construct a 2-in-1 nanoplatform loaded with RAS-selective lethal (RSL3, ferroptosis promoter) (RSL3@O2-ICG NBs), combined with oxygen-enhanced SDT and potent ferroptosis. In addition, nanobubbles (NBs) combined with low-frequency ultrasound (LFUS) are called ultrasound-targeted nanobubble destruction (UTND) to ensure specific drug release and improve safety.Results: MDA/GSH and other related experimental results show that RSL3@O2-ICG NBs can enhance SDT and ferroptosis. Through RNA sequencing (RNA-seq), the differential expression of LncRNA and mRNA before and after synergistic treatment was identified, and then GO and KEGG pathways were used to enrich and analyze target genes and pathways related ferroptosis sensitivity. We found that they were significantly enriched in the ferroptosis-related pathway MAPK cascade and cell proliferation. Then, we searched for the expression of differentially expressed genes in the TCGA Hepatocellular carcinoma cohort. At the same time, we evaluated the proportion of immune cell infiltration and the identification of co-expression network modules and related prognostic analysis. We found that it was significantly related to the tumor microenvironment of hepatocellular carcinoma. The prognostic risk genes “SLC37A2” and “ITGB7” may represent new hepatocellular carcinoma ferroptosis-inducing markers and have guiding significance for treating hepatocellular carcinoma.Conclusion: The therapeutic effect of the in vitro synergistic treatment has been proven to be significant, revealing the prospect of 2-in-1 nanobubbles combined with SDT and ferroptosis in treating HCC.Keywords: ferroptosis, sonodynamic therapy, HCC, RSL3, synergistic therapy

He Chen,1 Ming Han,2 Hui Jing,1 Zhao Liu,1 Haitao Shang,1 Qiucheng Wang,1 Wen Cheng1 1Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin City, Heilongjiang Province, People’s Republic of China; 2Department of General Surgery, Heji Hospital of Changzhi Medical College, Changzhi City, Shanxi Province, People’s Republic of ChinaCorrespondence: Wen Cheng; Qiucheng WangDepartment of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin City, 150081, Heilongjiang Province, People’s Republic of ChinaTel +86 13313677182; +86 13836134350Fax +86 45185718392Email hrbchengwen@163.com; haerbincss@126.comPurpose: This study aimed to evaluate the dependability of automated breast ultrasound (ABUS) compared with handheld ultrasound (HHUS) and mammography (MG) on the Breast Imaging Reporting and Data System (BI-RADS) category and size assessment of malignant breast lesions.Patients and Methods: A total of 344 confirmed malignant lesions were recruited. All participants underwent MG, HHUS, and ABUS examinations. Agreements on the BI-RADS category were evaluated. Lesion size assessed using the three methods was compared with the size of the pathological result as the control. Regarding the four major molecular subtypes, correlation coefficients between size on imaging and pathology were also evaluated.Results: The agreement between ABUS and HHUS on the BI-RADS category was 86.63% (kappa = 0.77), whereas it was 32.22% (kappa = 0.10) between ABUS and MG. Imaging lesion size compared to pathologic lesion size was assessed correctly in 36.92%/52.91% (ABUS), 33.14%/48.84% (HHUS) and 33.44%/43.87% (MG), with the threshold of 3 mm/5 mm, respectively. The correlation coefficient of size of ABUS-Pathology (0.75, Spearman) was statistically higher than that of the MG-Pathology (0.58, Spearman) with P < 0.01, but not different from that of the HHUS-Pathology (0.74, Spearman) with P > 0.05. The correlation coefficient of ABUS-Pathology was statistically higher than that of MG-Pathology in the triple-negative subtype, luminal B subtype, and luminal A subtype (P< 0.01).Conclusion: The agreement between ABUS and HHUS in the BI-RADS category was good, whereas that between ABUS and MG was poor. ABUS and HHUS allowed a more accurate assessment of malignant tumor size compared to MG.Keywords: automated breast ultrasound, hand-held ultrasound, mammography, breast imaging reporting and data system category, size assessment

Xiuqin Shi,1,2 Wenjing Cheng,1,3,4 Qian Wang,1 Jiachan Zhang,1,3,4 Changtao Wang,1,3,4 Meng Li,1,3,4 Dan Zhao,1,3,4 Dongdong Wang,1,3,4 Quan An2 1Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, 100048, People’s Republic of China; 2Yunnan Baiyao Group Co., Ltd, Kunming, 650000, People’s Republic of China; 3Beijing Key Lab of Plant Resource Research and Development, Beijing Technology and Business University, Beijing, 100048, People’s Republic of China; 4Institute of Cosmetic Regulatory Science, Beijing Technology and Business University, Beijing, 100048, People’s Republic of ChinaCorrespondence: Jiachan Zhang; Changtao WangCollege of Chemistry and Materials Engineering, Beijing Technology and Business University, 11 Fucheng Road, Haidian District, Beijing, 100048, People’s Republic of ChinaTel +86-13426258535; +86-18910839617Email xiaochan8787@163.com; wangct@th.btbu.edu.cnBackground: Ganoderma lucidum (G. lucidum) is one of China’s traditional medicinal materials. G. lucidum polysaccharide has a wide range of promising pharmacological applications. However, there are many kinds of G. lucidum and they contain different kinds of polysaccharides. The biological mechanism through which Ganoderma lucidum polysaccharides (GLP) is able to protect human skin fibroblasts (HSFs) from H2O2-induced oxidative damage is still unclear.Methods: Six polysaccharides were obtained from G. lucidum to evaluate their free radical scavenging ability (DPPH free radical, ABTS free radical, hydroxyl-free radical, superoxide anion-free radical) in vitro, and their protective and reparative effects on oxidative damage induced by H2O2 in human skin fibroblasts. One polysaccharide was selected to detect oxidative damage markers and gene expression in the Keap1-Nrf2/ARE signaling pathway in HSFs.Results: All six polysaccharides showed the ability to scavenge free radicals and enhance the tolerance of human skin fibroblasts to H2O2 damage. Among them, GLP1 was selected and separated into two components (GLP1I and GLP1II). The results showed that GLP1, GLP1I and GLPII could significantly reduce the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). The protective effect of GLP1II was stronger than that of positive control vitamin C. In addition, GLP1, GLP1I and GLP1II could significantly increase the levels of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). And GLP1I works best in both ways. Meanwhile, Nrf2, a key regulator of keAP1-NRF2/ARE signaling pathway, was activated, while Keap1, a negative regulator, was inhibited, thus promoting the expression of downstream antioxidant enzyme genes (GSTs, GCLs, Nqo1, and Ho-1).Conclusion: The results showed that GLP could protect human skin fibroblasts from oxidative damage caused by H2O2 peroxide by enhancing enzyme activity and activating Keap1-Nrf2/ARE signaling pathway. GLP will act as a natural antioxidant to protect the skin from oxidative stress damage.Keywords: Ganoderma lucidum, polysaccharide, oxidative stress, Keap1-Nrf2/ARE signaling pathway

Wenshu Cheng,1,&ast; Xinyue Xu,1,&ast; Yuanyuan Lang,2,&ast; Zugen Cheng,1 Mohammad Rizwan,1 Xiaomin Tang,1 Lixin Xie,1 Yanling Liu,1 Hengyi Xu,3 Yang Liu1 1Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China; 2Medical Imaging Center, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China; 3State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi Province, 330047, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang LiuDepartment of Pediatrics, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, Jiangxi Province, People’s Republic of ChinaTel +0086-791-8631-1209Email ocean3166@yeah.netPurpose: To evaluate the effects of anatase and rutile TiO2 nanoparticles (NPs) on the growth and development of bones in young rats and explore their possible mechanisms.Methods: Three-week-old male rats were orally administered anatase TiO2 NPs and rutile TiO2 NPs for 28 days. The indicators of rat growth and development, liver function, bone metabolism, and insulin-like growth factor-1 (IGF-1) levels were evaluated. Micro-computed tomography (micro-CT) and immunohistochemistry were used to evaluate the tibia.Results: No significant differences were observed among growth and development indicators in young rats. Significant differences were found in IGF-1 levels, phosphorus levels, and liver function. Micro-CT revealed osteoporosis in the bones. The micro-CT data supported the same result. Bone immunohistochemistry results showed that the expression of osteoprotegerin (OPG) was decreased and the expression of receptor activator of nuclear factor-κB ligand (RANKL) and cathepsin K (CTSK) was increased.Conclusion: This study demonstrated that TiO2 NPs can damage bones via the IGF-1/OPG/RANKL/CTSK pathway in young rats. Furthermore, rutile TiO2 NPs damaged the bones more seriously than anatase TiO2 NPs.Keywords: TiO2 NPs, different crystal forms, IGF-1/OPG/RANKL/CTSK pathway, young rats, bone growth

Zejuan Ji,1 Keming Sun,1 Zhenwei Li,1 Weyland Cheng,1,2 Junwen Yang3 1Department of Orthopaedic Surgery, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of China; 2Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of China; 3Microbiology Laboratory, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Zejuan Ji; Weyland Cheng Tel +86 18538557605; +86 18502758200Email Jizejuan_Cristina@126.com; wey_c@hotmail.comAbstract: Increasing cases of carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections have been observed globally where multi-drug resistance to CR-KP can make the infection difficult to treat. In recent years, the β-lactam/β-lactamase inhibitor, ceftazidime-avibactam (CAZ-AVI), has been developed to treat complicated urinary tract infections and complicated intra-abdominal infections. CAZ-AVI is approved for children over 3-month old but has yet to be investigated for cases of osteomyelitis. Only three case reports exist in literature on the use of CAZ-AVI for CR-KP osteomyelitis in adults. In this report, we present an infant with primary hematogenous osteomyelitis and septic arthritis in the right shoulder following surgical treatment for a heart murmur. Bacterial isolation revealed a strain of CR-KP, which was successfully treated with CAZ-AVI after initial administration of imipenem-based treatments.Keywords: carbapenem-resistant Enterobacteriaceae, multi-drug resistant, β-lactam/β-lactamase inhibitor, antibiotic, susceptibility test

Hui Ma,1,2 Ping Kuen Lam,3 Wing Sum Siu,1,2 Cindy See Wai Tong,3 Kin Ki Yan Lo,3 Chi Man Koon,1,2 Xiao Xiao Wu,1,2 Xiang Li,1,2 Wen Cheng,1,2 Wai Ting Shum,1,2 Ping Chung Leung1,2 1Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China; 2State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China; 3Chow Tai Fook-Cheng Yu Tung Surgical Stem Cell Research Center, Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of ChinaCorrespondence: Ping Chung LeungInstitute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of ChinaTel +85222528868Email pingcleung@cuhk.edu.hkIntroduction: The biological role of mesenchymal stem cells (MSCs) in wound healing has been demonstrated. However, there were limited studies on the healing effect of secretome which consists of many biological factors secreted by MSCs. In this study, we aimed to compare the therapeutic effects of secretome with MSCs on facilitating wound healing.Methods: Green fluorescent protein labelled adipose-derived MSCs (GFP-ADMSCs) or secretome was injected in the full-thickness skin excision model on SD rats. The wound healing process was evaluated by calculating the healing rate and the histological examinations on skin biopsy. The cell viability, proliferation and mobility of the rat dermal fibroblasts were compared after different treatments. The inflammatory response in macrophages was indicated by the level of nitric oxide (NO) and inflammatory cytokines through NO assay and ELISA.Results: On day 5 and day 14, both MSCs and secretome accelerated the wound healing, secretome further enhanced the process. GFP-MSCs were detected 10 days after transplantation. The level of IL-6 and TNF-α in blood was reduced after MSCs and secretome treatments. The expressions of VEGF and PCNA were increased after treatment, higher intensity of VEGF was observed in secretome-injected tissue. The concentrations of total protein and VEGF in secretome were 2.2 ± 0.5 mg/mL and 882.0 ± 72.7 pg/mL, respectively. The cell viability and proliferation of FR were promoted significantly after the treatment. The scratch test showed that secretome accelerated the wound healing speed. Secretome reduced the metabolism of macrophages remarkably, but it did not decrease the level of macrophage-secreted NO. The expression of the pro-inflammatory cytokines (IL-6, MCP-1 and TNF-α) was downregulated significantly.Conclusion: Our study indicated both MSCs and MSCs-derived secretome enhanced the wound healing process in early phase. Secretome further promoted the healing effects through promoting the fibroblast proliferation and migration and suppressing the inflammatory response.Keywords: MSCs, secretome, wound healing, local injection, skin

Qing Song,1– 3 Yi-Yang Zhao,1– 3 Yu-Qin Zeng,1– 3 Cong Liu,1– 3 Wei Cheng,1– 3 Min-Hua Deng,4 Xin Li,5 Li-Bing Ma,6 Yan Chen,1– 3 Shan Cai,1– 3 Ping Chen1– 3 1Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 4Department of Respiratory, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, People’s Republic of China; 5Division 4 of Occupational Disease, Hunan Occupational Disease Prevention and Treatment Hospital, Changsha, Hunan, 410000, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541000, People’s Republic of ChinaCorrespondence: Ping ChenDepartment of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, Hunan, 410011, People’s Republic of ChinaTel +86 731 8529 5248Fax +86 731 8529 5848Email pingchen0731@csu.edu.cnBackground: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 separated pulmonary function from combined assessment. We aimed to analyze the characteristics of airflow limitation and future exacerbations in different GOLD groups of chronic obstructive pulmonary disease (COPD) patients.Methods: For this prospective observational study, stable COPD outpatients were enrolled and divided into Groups A, B, C and D based on GOLD 2017, and followed-up for 18 months. Data on demographics, pulmonary function, COPD assessment test (CAT), Clinical COPD Questionnaire (CCQ), modified Medical Research Council (mMRC), exacerbations, mortality and treatments were collected. A post-bronchodilator ratio of forced expiratory volume in one second to forced vital capacity < 0.70 confirms the presence of airflow limitation.Results: A total of 993 subjects were classified into Groups A (n = 170, 17.1%), B (n = 360, 36.3%), C (n = 122, 12.3%), and D (n = 341, 34.3%). There were significant differences in mMRC, CAT, CCQ, exacerbations and hospitalizations rates among the different groups (P < 0.001). Groups B and D had more severe airflow limitation than Groups A and C (P < 0.05). In the same groups with different severity of airflow limitation, the differences were mainly observed in body mass index, CAT, CCQ and treatment with long-acting muscarinic antagonist (LAMA) and LAMA + long-acting β 2-agonist + inhaled corticosteroid (P < 0.05). After 18 months of follow-up, the exacerbations and hospitalizations rates were significantly different among different groups (P < 0.05). However, in the same groups with different airflow limitation severity, the mortality rates and number of exacerbations, hospitalizations and frequent exacerbators showed no differences.Conclusion: In the GOLD groups, different severity of airflow limitation had no impact on future exacerbations and mortality rate. It implies that pulmonary function is not a good indicator for predicting exacerbation.Keywords: chronic obstructive pulmonary disease, Global Initiative for Chronic Obstructive Lung Disease, pulmonary function, exacerbation

Wei Cheng,1,* Lichang Chen,1,* Huapeng Yu,1 Dongzhu Lu,1 Rong Yu,1 Jian Chen2 1Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian ChenDepartment of Neurology, Zhujiang Hospital of Southern Medical University, No. 253, Industrial Avenue, Guangzhou, Guangdong, 510280, People’s Republic of ChinaTel +86 18665000975Fax +86 02062783083Email smuchenjian@163.comPurpose: To evaluate the value of the NLR (neutrophil-to-lymphocyte ratio) and the fibrinogen level in predicting stroke-associated pneumonia (SAP) in acute ischemic stroke (AIS) patients.Patients and Methods: In total, we enrolled 734 medical-ward patients with AIS in this retrospective study. Patients were divided into SAP (n=52) and non-SAP (n=682) groups according to the diagnostic criteria of SAP. Binary logistic regression analysis was used to analyze the relationship between the NLR, serum fibrinogen concentration and SAP. Receiver operating characteristic (ROC) curves were generated to identify the optimal cutoff points and assess the diagnostic value of the NLR, serum fibrinogen and the combination of NLR and fibrinogen in predicting SAP.Results: SAP occurred in 52 (7.08%) patients among the enrolled AIS patients. Binary logistic regression analysis showed that the NLR (odds ratio [OR]: 2.802, 95% confidence interval [CI]: 1.302– 6.032, P=0.008) and serum fibrinogen concentration (OR: 7.850, 95% CI: 3.636– 16.949, P=0.000) were independently associated with a higher risk of SAP incidence after adjusting for age, sex, ASPECT score, atrial fibrillation, nasogastric tube feeding, LDL-C and TC, temperature at admission and mechanical ventilation. The optimal cutoff points of the NLR and serum fibrinogen to distinguish SAP among AIS patients were 3.603 (AUC, 0.690; NPV, 95.78; PPV, 19.01) and 4.595 (AUC, 0.727; NPV, 95.60; PPV, 24.49), respectively. When the combination of NLR and fibrinogen was used to predict SAP, the optimal cutoff points were > 2.436 for NLR and > 3.24 for fibrinogen (AUC, 0.758; NPV, 98.50; PPV, 11.80).Conclusion: The NLR and serum fibrinogen might have greater negative diagnostic value in predicting SAP among AIS patients. Combining the NLR and serum fibrinogen showed an increased AUC for predicting SAP among AIS patients.Keywords: stroke-associated pneumonia, neutrophil-to-lymphocyte ratio, fibrinogen, receiver operating characteristic curve

Fengguang Li,1,* Yan Xu,2,* Xing Li,1 Xinghua Wang,1 Zhigang Yang,1 Wanli Li,1 Wei Cheng,1 Gangli Yan1 1Department of Neurology, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, 430081, People’s Republic of China; 2Department of Pharmacy, General Hospital of Central Theater Command, Wuhan, 430010, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gangli Yan No. 1 Benxi Street, Qingshan District, Wuhan, 430081, Hubei Province, People’s Republic of ChinaEmail gangli_yan@126.comAim: Cerebral ischemic injury is one of the debilitating diseases showing that inflammation plays an important role in worsening ischemic damage. Therefore, studying the effects of some potential anti-inflammatory compounds can be very important in the treatment of cerebral ischemic injury.Methods: This study investigated anti-inflammatory effects of triblock copolymer nanomicelles loaded with curcumin (abbreviated as NC) in the brain of rats following transient cerebral ischemia/reperfusion (I/R) injury in stroke. After preparation of NC, their protective effects against bilateral common carotid artery occlusion (BCCAO) were explored by different techniques. Concentrations of free curcumin (C) and NC in liver, kidney, brain, and heart organs, as well as in plasma, were measured using a spectrofluorometer. Western blot analysis was then used to measure NF-κB-p65 protein expression levels. Also, ELISA assay was used to examine the level of cytokines IL-1β, IL-6, and TNF-α. Lipid peroxidation levels were assessed using MDA assay and H&E staining was used for histopathological examination of the hippocampus tissue sections.Results: The results showed a higher level of NC compared to C in plasma and organs including the brain, heart, and kidneys. Significant upregulation of NF-κB, IL-1β, IL-6, and TNF-α expressions compared to control was observed in rats after induction of I/R, which leads to an increase in inflammation. However, NC was able to downregulate significantly the level of these inflammatory cytokines compared to C. Also, the level of lipid peroxidation in pre-treated rats with 80mg/kg NC was significantly reduced.Conclusion: Our findings in the current study demonstrate a therapeutic effect of NC in an animal model of cerebral ischemia/reperfusion (I/R) injury in stroke through the downregulation of NF-κB-p65 protein and inflammatory cytokines.Keywords: ischemia-reperfusion injury, stroke, NF-ĸB, inflammation, curcumin, nanomicelle, rat

Huajing Yang, Hui Jing, Xue Han, Haoyan Tan, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, 150081, People’s Republic of ChinaCorrespondence: Wen ChengDepartment of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of ChinaTel +86 13313677182Fax +86 451 85718392Email hrbchengwen@163.comPurpose: Sonodynamic therapy (SDT) is considered a promising therapeutic strategy for the effective elimination of cancer cells. However, developing novel sonosensitizers with potentially high SDT efficacy remains a considerable challenge. Herein, we utilized near-infrared dye IR820 nanobubbles (NBs) combined with a dual PI3K/mTOR inhibitor PI-103 for the SDT treatment of hepatocellular carcinoma (HCC) in vitro.Methods: The generated reactive oxygen species (ROS) were quantified using 2,7-dichlorodihydrofluorescein diacetate to determine the feasibility of using IR820 NBs as a potential sonosensitizer. The inhibition effects of the synergistic therapy was examined using the cell counting Kit 8 assay and apoptosis assay. JC-1 staining was performed to study mitochondrial membrane depolarization, and the transwell assay was used for cell migration analysis.Results: The particle size and zeta potential of IR820 NBs were 545.5± 93.1 nm and − 5.19± 1.73 mV, respectively. ROS accumulation was observed after HepG2 cells were treated with IR820 NBs under ultrasound irradiation. The SDT combined with PI-103 group inhibited cell viability and migration more strongly than the other groups (P < 0.01). The apoptosis assay also demonstrated a relatively high anti-HCC efficacy with the synergistic therapy, while JC-1 staining showed a decrease in the mitochondrial membrane potential after the combined treatment.Conclusion: The combination of SDT and PI-103 was very effective in suppressing HCC proliferation, which might help develop new minimally invasive cancer treatment strategies.Keywords: minimally invasive cancer treatment strategy, sonosensitizer, PI3K/mTOR inhibitor, IR820 nanobubbles

Weyland Cheng,1,2 Manye Yao,1 Fangna Liu1 1Department of Orthopaedic Surgery, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of China; 2Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Weyland Cheng Tel +86 18502758200Email wey_c@hotmail.comAbstract: Non-gustatory, extraoral bitter taste receptors (T2Rs) are G-protein coupled receptors that are expressed throughout the body and have various functional responses when stimulated by bitter agonists. Presently, T2Rs have been found to be expressed in osteoclasts and osteocytes where osteoclasts were capable of detecting bacterial quorum-sensing molecules through the T2R38 isoform. In the innate immune system, stimulating T2Rs induces anti-inflammatory and anti-pathogenic effects through the phospholipase C/inositol triphosphate pathway, which leads to intracellular calcium release from the endoplasmic reticulum. The immune cells with functional responses to T2R activation also play a role in bone inflammation and orthopaedic disorders. Furthermore, increasing intracellular calcium levels in bone cells through T2R activation can potentially influence bone formation and resorption. With recent studies finding T2R expression in bone cells, we examine the potential of targeting this receptor to treat bone inflammation and to promote bone anabolism.Keywords: TAS2R, calcium signaling, osteoblasts, drug target, bone inflammation

Xinyue Xu,1,* Yizhou Tang,2,* Yuanyuan Lang,3,* Yanling Liu,1 Wenshu Cheng,1 Hengyi Xu,2 Yang Liu1 1Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of China; 2State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, People’s Republic of China; 3Medical Imaging Center, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yang LiuDepartment of Pediatrics, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang 330006 Jiangxi Province, People’s Republic of ChinaTel +86-791-8631-1209Email ocean3166@yeah.netHengyi XuState Key Laboratory of Food Science and Technology, Nanchang University, 235 Nanjing East Road, Nanchang 330047, People’s Republic of ChinaTel +86-791-8830-4447-ext-9520Fax +86-791-8830-4400Email kidyxu@163.comPurpose: To evaluate the effects of ZnO NPs on bone growth in rats and explore the possible mechanisms of action.Materials and Methods: Three-week-old male rats received ultrapure water or 68, 203, and 610 mg/kg zinc oxide nanoparticles (ZnO NPs) for 28 days, orally.Results: The high-dosage groups caused significant differences in weight growth rate, body length, and tibia length (P< 0.05), all decreasing with increased ZnO NP dosage. There were no significant differences in body mass index (BMI) (P> 0.05). The zinc concentration in liver and bone tissue increased significantly with increased ZnO NP dosage (P< 0.05). Clearly increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were observed in the 610 mg/kg ZnO NP group (P> 0.05), whereas alkaline phosphatase (ALP) increased in the 610 mg/kg ZnO NP group (P< 0.05). Significant differences in insulin-like growth factor type 1 (IGF-1) levels and a decrease in calcium (Ca) levels were observed in 203 and 610 mg/kg ZnO NP groups (P< 0.05). Phosphorus (P) levels increased and the Ca/P ratio decreased in the 610 mg/kg ZnO NP group (P< 0.05). Micro-computed tomography (micro-CT) of the tibia demonstrated signs of osteoporosis, such as decreased bone density, little trabecular bone structure and reduced cortical bone thickness. Micro-CT data further demonstrated significantly decreased bone mineral density (BMD), trabecular number (Tb.N), and relative bone volume (BV/TV) with increasing dosage of ZnO NPs. Osteoprotegerin (OPG) expression and the ratio of OPG to receptor activator of nuclear factor-κB ligand (RANKL) were statistically lower in the 610 mg/kg ZnO NP group (P< 0.05), whereas RANKL expression did not change significantly (P> 0.05).Conclusion: We infer that ZnO NPs affect bone growth in young rats directly or indirectly by altering IGF-1 levels. Overall, the results indicate that ZnO NPs promote osteoclast activity and increase bone loss through the OPG/RANK/RANKL/IGF-1 pathway.Keywords: ZnO NPs, young rats, bone growth, OPG/RANK/RANKL/IGF-1 pathway

Jia-xi Duan,1,2 Wei Cheng,1,2 Yu-qin Zeng,1,2 Yan Chen,1,2 Shan Cai,1,2 Xin Li,3 Ying-qun Zhu,4 Ming Chen,5 Mei-ling Zhou,6 Li-bing Ma,7 Qi-mi Liu,8 Ping Chen1,2 1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People’s Republic of China; 2Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, People’s Republic of China; 3Division 4 of Occupational Diseases, Hunan Prevention and Treatment Institute for Occupational Diseases, Changsha, Hunan 410000, People’s Republic of China; 4Department of Respiratory Medicine, The Third Hospital of Changsha, Changsha, Hunan 410011, People’s Republic of China; 5Department of Respiratory Medicine, The No.1 Traditional Chinese Medicine Hospital in Changde, Changde, Hunan 415000, People’s Republic of China; 6Department of Respiratory Medicine, The First People’s Hospital of Huaihua, Huaihua, Hunan 418000, People’s Republic of China; 7Department of Respiratory Medicine, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541000, People’s Republic of China; 8Department of Respiratory and Critical Care Medicine, The Second People’s Hospital of Guilin, Guilin, Guangxi 541000, People’s Republic of ChinaCorrespondence: Ping ChenDepartment of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, People’s Republic of ChinaTel +86 731 8529 5248Email pingchen0731@csu.edu.cnPurpose: Tobacco smoking, biomass smoke, and occupational exposure are the main risk factors for chronic obstructive pulmonary disease (COPD). The present study analyzes data on exposure to these factors in a cohort of patients with COPD and assesses their differences in demographic and clinical characteristics.Patients and Methods: The cross-sectional observational study was conducted from November 2016 to December 2019. Inclusion criteria were patients aged over 40 years old with post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < 0.7. At baseline, demographic features and exposure history were recorded. Moreover, respiratory symptoms were assessed by the COPD Assessment Test (CAT) and modified Medical Research Council scale (mMRC). A generalized linear mixed model was used to adjust for potential confounders.Results: A total of 5183 patients with COPD were included in the final analysis. The results demonstrate that exposure to tobacco combined with other risk factors resulted in significantly higher CAT scores (16.0 ± 6.7 vs 15.3 ± 6.3, P = 0.003) and more severe dyspnea (patients with mMRC ≥ 2, 71.5% vs 61.6%, P < 0.001) than exposure to tobacco alone. In addition, COPD patients with biomass smoke exposure alone had higher CAT scores than patients with only tobacco or occupational exposure (17.5 ± 6.3 vs 15.3 ± 6.3, and 15.2 ± 6.3, respectively, P < 0.05 for each comparison) and were more likely to be female and older. In addition, COPD patients who suffered from occupational exposure developed more severe dyspnea than those exposed to tobacco alone (70.8% vs 61.6%, P < 0.05), as did those exposed to biomass smoke alone (74.2% vs 61.6%, P < 0.05). This difference remained strong even after adjustment for potential confounders.Conclusion: There are significant demographic and clinical differences among COPD patients with tobacco smoking, biomass smoke, and occupational exposures.Keywords: chronic obstructive pulmonary disease, tobacco, biomass smoke, occupational exposure

Aiyuan Zhou,1,2 Zijing Zhou,1,2 Dingding Deng,3 Yiyang Zhao,1,2 Jiaxi Duan,1,2 Wei Cheng,1,2 Cong Liu,1,2 Ping Chen1,2 1Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People’s Republic of China; 2Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, People’s Republic of China; 3Department of Respiratory Medicine, The First Affiliated People’s Hospital, Shaoyang College, Shaoyang, Hunan 422000, People’s Republic of ChinaCorrespondence: Ping ChenDepartment of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People’s Republic of ChinaEmail pingchen0731@csu.edu.cnBackground: Fractional exhaled nitric oxide (FENO) has been shown to be a marker of airway inflammation in various pulmonary diseases, including chronic obstructive pulmonary disease (COPD). In this study, we assessed the FENO level in patients with acute exacerbations of COPD (AECOPD) and analyzed the predictive value of the FENO level for treatment response.Methods: Demographic data were collected at admission. FENO, lung function, blood gases, COPD Assessment Test (CAT), and modified Medical Research Council (mMRC) scores were measured at admission and on day 7. At the second visit, the patients were asked to report their health status; scores ranged from 1 to 5, representing “much better”, “slightly better”, “no change”, “slightly worse”, and “much worse”, respectively. The treatment response was evaluated based on the patient’s reported health status (responders were those who reported much better and slightly better) and lung function (responders were those who presented an increase in FEV1 over 200 mL).Results: A total of 182 patients were recruited into the analysis. The FENO level positively correlated with an increase in FEV1 and FEV1% (r = 0.291, p < 0.001 and r = 0.205, p = 0.005, respectively), but negatively correlated with a decrease in the COPD Assessment Test (CAT) score (r = − 0.197, p = 0.008) and patient-reported health status (rho = − 0.408, p< 0.001). An inverse correlation was observed between FENO concentrations at admission and the length of hospital stay. The cut-off point for differentiating responders, identified by health status, was 18 ppb, with the sensitivity being 89.7% and specificity 88.9%.Conclusion: FENO levels, determined at hospital admission, are potential to predict the overall treatment response in AECOPD patients, including remission in subjective patient-reported health statuses and, also, improvements in lung function.Registry Number: ChiCTR-ROC-16,009,087 (http://www.chictr.org.cn/).Keywords: COPD, exacerbation, FENO, lung function, treatment response

Tian Sun,1,2 Xiaoyun Li,3 Wei Cheng,1,2 Yating Peng,1,2 Yiyang Zhao,1,2 Cong Liu,1,2 Yuqin Zeng,1,2 Yan Chen,1,2 Shan Cai,1,2 Ping Chen1,2 1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People’s Republic of China; 2Research Unit of Respiratory Disease, Central South University, Central South University, Changsha, Hunan 410011, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510000, People’s Republic of ChinaCorrespondence: Ping ChenDepartment of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital 139 Renmin Middle Road, Changsha, Hunan 410011, People’s Republic of ChinaTel +86-13873115563Fax +86 731-85295848Email pingchen0731@csu.edu.cnBackground: The morning is the most troublesome time of day for patients with chronic obstructive pulmonary disease (COPD). However, the association of morning symptoms and COPD exacerbations in longitudinal follow-up has not been studied. In this study, we mainly aimed to investigate the relationship between morning symptoms and exacerbations over a one-year follow-up period. And the secondary aim was an investigation of the association between morning symptoms and baseline clinical features.Patients and Methods: Ninety-two patients with stable COPD provided the baseline information. Morning symptoms were assessed with the Chinese version of Chronic Obstructive Pulmonary Disease Morning Symptom Diary (Ch-COPD-MSD); the median morning symptoms score was used as a cut-off to separate the study cohort in two groups. Modified Medical Research Council (mMRC), COPD assessment test (CAT), and Clinical COPD Questionnaire (CCQ) were used and exacerbation history of the previous year was recorded. Seventy-eight patients (84.8%) completed the longitudinal follow-up of exacerbations.Results: The median morning symptoms score was 30 in stable COPD patients. Morning symptoms severity was different between COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups (p< 0.001). Patients with high morning symptoms (score > 30) had higher scores of mMRC, CAT, and CCQ (p< 0.05). CAT score was an independent risk factor of morning symptoms. During follow-up, 41% of patients experienced ≥ 1 exacerbation. The frequency of severe exacerbations was higher in patients with high morning symptoms compared to patients with low morning symptoms (p< 0.005). The Ch-COPD-MSD score could predict future severe exacerbations; the area under the ROC curve was 0.751 (95% CI: 0.633– 0.868, p=0.002).Conclusion: Worse health status and more dyspnea symptom were associated with increased severity of morning symptoms. Morning symptoms were most strongly related to future severe exacerbations and could predict future exacerbations in patients with COPD.Keywords: chronic obstructive pulmonary disease, morning symptoms, future exacerbations

Cong Liu,1 Wei Cheng,1 Yuqin Zeng,1 Zijing Zhou,1 Yiyang Zhao,1 Jiaxi Duan,1 Ran Wang,1 Tian Sun,1 Xin Li,2 Zhi Xiang,3 Ping Chen,1 Si Lei1 1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University; Research Unit of Respiratory Disease, Central South University; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha 410011, Hunan, People’s Republic of China; 2Department of Respiratory Diseases, Hunan Prevention and Treatment Institute for Occupational Diseases, Changsha 410007, Hunan, People’s Republic of China; 3Department of Respiratory Diseases, The First People’s Hospital of Huaihua, Affiliated to University of South China, Huaihua 418000, Hunan, People’s Republic of ChinaCorrespondence: Ping Chen; Si Lei Email pingchen0731@csu.edu.cn; leisi0831@csu.edu.cnPurpose: Chronic obstructive pulmonary disease (COPD), usually caused by tobacco smoking, is increased in China. Smoking cessation is the first step in COPD management. Data on predictors of smoking cessation are sparse in COPD patients in China. We aim to find the differences in the clinical characteristics between ex-smokers and current smokers with COPD to determine the factors related to smoking cessation.Patients and Methods: From outpatient departments of 12 hospitals in Hunan and Guangxi provinces, a total of 4331 patients were included. Information on demographic and sociological data, lung function, and modified Medical Research Council (mMRC) dyspnea scale scores were recorded. Patients were divided into an ex-smokers group and a current smokers group based on whether they gave up smoking. A logistic regression analysis was performed to analyze the factors associated with smoking cessation.Results: Of the total, the mean age was 62.9± 8.5 years, and 47.3% were ex-smokers. Compared with the current smokers, the ex-smokers were older, and had heavier dyspnea, more severe airflow limitation, fewer pack-years, shorter smoking duration, and a higher proportion of Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups C and D. The logistic regression model showed that smoking cessation was negatively correlated with widowhood, years of smoking, and forced expiratory volume in 1 second (FEV1), but was positively correlated with age, education level, amount smoked, mMRC score, GOLD grades, and GOLD groups.Conclusion: Among patients with COPD, more than half still smoked. In the group of patients who quit smoking, many of them quit rather late in age after they had significant symptoms. Several predictors of smoking cessation were identified, indicating that ex-smokers differ substantially from continuing smokers. This should be taken into account in smoking-cessation interventions.Keywords: COPD, cross-sectional study, ex-smokers and current smokers, smoking cessation

Huili Bai,1,* Rong Wang,1,2,* Wei Cheng,1 Yifan Shen,1 Haijun Li,2 Wei Xia,1 Zhenglin Ding,3,* Yuhong Zhang1,* 1The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Laboratory Medicine, Guangyuan Central Hospital, Guangyuan, Sichuan, People’s Republic of China; 3Department of Laboratory Medicine, The People’s Hospital of Nanchuan, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuhong Zhang; Zhenglin Ding Email zhangyuhong0730@126.com; 782829997@qq.comBackground: Microsatellite instability (MSI) is one of the most important molecular characteristics of colorectal cancer (CRC), which mainly results from defective DNA mismatch repair (MMR). This study was performed to investigate the concordance between deficient MMR and MSI testing, and to evaluate the association of these two results with clinicopathological characteristics in Chinese CRC patients.Methods: A total of 738 CRC patients were included. Tumor tissues and paired peripheral blood specimens were obtained. Screening for MMR was investigated using immunohistochemical (IHC) technique, and multiple polymerase chain reaction-capillary electrophoresis (PCR-CE) method was performed to detect the MSI status. All clinicopathological data, immunohistochemistry and microsatellite instability analyses were then statistically analyzed.Results: Of the 738 (17.75%) CRC patients, 131 expressed as deficient mismatch repair (dMMR) status, and postmeiotic segregation increased 2 (PMS2) deficiency was the most frequent deficiency among these four MMR proteins. MSI-high (MSI-H) status occurred in 74 of the 738 (10.03%) CRC patients, 55 of whom showed instability at all six mononucleotides repeat markers. dMMR was significantly associated with MSI-H and moderate concordance was observed between IHC and PCR-CE in evaluating deficient MMR/MSI through Kappa test. Statistically, dMMR was significantly associated with younger age, right-sided colon and poor differentiation. MSI-H was associated with younger age, right-sided colon, poor differentiation, mucinous type and tumor, node, metastasis (TNM) stage II.Conclusion: A moderate concordance between deficient MMR and MSI testing indicates that both IHC and PCR-CE methods should be routinely tested to provide reliable data for clinical treatment decisions.Keywords: deficient mismatch repair, microsatellite instability, clinicopathological features, colorectal cancer

Yuhang Tian,* Zhao Liu,* Haoyan Tan, Jiahui Hou, Xin Wen, Fan Yang, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin 150080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen ChengDepartment of Ultrasound, Harbin Medical University Cancer Hospital, 150 Haping Road, Nangang District, Harbin 150080, People’s Republic of ChinaTel +86 13313677182Email chengwen69@yahoo.comAbstract: Ultrasound-mediated targeted delivery (UMTD), a novel delivery modality of therapeutic materials based on ultrasound, shows great potential in biomedical applications. By coupling ultrasound contrast agents with therapeutic materials, UMTD combines the advantages of ultrasound imaging and carrier, which benefit deep tissue penetration and high concentration aggregation. In this paper we introduced recent advances in ultrasound contrast agents and applications in tumor therapy. Ultrasound contrast agents were categorized by their functions, mainly including thermosensitive, pH-sensitive and photosensitive ultrasound contrast agents. The various applications of UMTD in tumor treatment were summarized as follows: drug therapy, transfection of anti-oncogene, RNA interference, vaccine immunotherapy, monoclonal antibody immunotherapy, adoptive cellular immunotherapy, cytokine immunotherapy, and so on. In the end, we elaborated on the current challenges and provided perspectives of UMTD for clinical applications.Keywords: ultrasound, targeted delivery, immunotherapy, gene therapy

Chuanhui Song, 1, 2,* Chuanchao Tang, 1, 2,* Wenguang Xu, 2 Jianchuan Ran, 1, 2 Zheng Wei, 1, 3 Yufeng Wang, 1, 2 Huihui Zou, 1, 2 Wei Cheng, 4 Yu Cai, 1 Wei Han 1, 2 1Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, People’s Republic of China; 3Pediatric Dentistry, Nanjing Stomatology Hospital, Medical School of Nanjing University, Nanjing 210008, People’s Republic of China; 4Department of Oral Implantology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei ChengDepartment of Oral Implantology, Nanjing Stomatological Hospital, Medical School of Nanjing University, No. 30 Zhongyang Road, Nanjing 210008, People’s Republic of ChinaTel +86-025-83620238Email dentist_nj@163.com Wei HanDepartment of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, No 30 Zhongyang Road, Nanjing 210008, People’s Republic of ChinaTel +86-025-83620349Email doctorhanwei@hotmail.comPurpose: Chemotherapy in head and neck squamous cell carcinoma (HNSCC) has many systemic side effects, as well as hypoxia-induced chemoresistance. To reduce side effects and enhance chemosensitivity are urgently needed.Methods: We synthesized a drug delivery system (named CECMa NPs) based on cisplatin (CDDP) and metformin (chemotherapeutic sensitizer), of which chlorin e6 (Ce6) and polyethylene glycol diamine (PEG) were synthesized as the shell, an anti-LDLR antibody (which can target to hypoxic tumor cells) was modified on the surface to achieve tumor targeting.Results: The NPs possessed a great synergistic effect of chemotherapy and phototherapy. After laser stimulation, both CDDP and metformin can be released in situ to achieve anti-tumor effects. Meanwhile, PDT and PTT triggered by a laser have anticancer effects. Furthermore, compared with free cisplatin, CECMa exhibits less systemic toxicity with laser irradiation in the xenograft mouse tumor model.Conclusion: CECMa effectively destroyed the tumors via hypoxia targeting multimodal therapy both in vitro and in vivo, thereby providing a novel strategy for targeting head and neck squamous cell carcinoma.Keywords: cisplatin, metformin, chlorin e6, head and neck squamous cell carcinoma, nano-delivery

Weiyan Cheng,1,2,* Suhua Wang,1,2,* Zhiheng Yang,1,2 Xin Tian,1,2 Yongzhou Hu31Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of China; 2Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; 3Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People’s Republic of ChinaCorrespondence: Xin TianDepartment of Pharmacy, The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Road, Zhengzhou 450052, People’s Republic of ChinaEmail tianx@zzu.edu.cnYongzhou HuZhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, People’s Republic of ChinaEmail huyz@zju.edu.cn*These authors contributed equally to this workPurpose: In order to get novel EGFR inhibitors exerting more potency in tumor hypoxia than in normoxia.Methods: A series of 4-[(2-nitroimidazole-1H-alkyloxyl)aniline]-quinazolines were designed and synthesized, and their in vitro cytotoxicity and EGFR inhibitory activity were evaluated. Molecule docking study was performed for the representative compound.Results: The structure-activity relationship (SAR) studies revealed that compounds bearing both meta-chloride and para-(2-nitroimidazole-1H-alkyloxy) groups on the aniline displayed potent inhibitory activities both in enzymatic and cellular levels. The most promising compound 16i potently inhibited EGFR with an IC50 value of 0.12 μM. Meanwhile, it manifested more potent cytotoxicity than the positive control lapatinib under tumor normoxia and hypoxia conditions (IC50 values of 1.59 and 1.09 μM against A549 cells, 2.46 and 1.35 μM against HT-29 cells, respectively). The proposed binding model of 16i in complex with EGFR was displayed by the docking results.Conclusion: This study provides insights for developing hypoxia-activated kinase inhibitors.Keywords: EGFR inhibitor, hypoxia, tumor, 4-anilinoquinazoline, 2-nitroimidazole