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Minna Han,1,2,* Zhikuan Xia,2,* Yuekun Zou,3 Ping Hu,4 Mingwang Zhang,5 Xin Yang,3 Ming-Guo Ma,6 Rongya Yang2 1Chinese PLA Medical School, Beijing, 100072, People’s Republic of China; 2Department of Dermatology, The Seventh Medical Center of PLA General Hospital, Beijing, 100072, People’s Republic of China; 3Department of Geriatrics, The Sixth Medical Center of PLA General Hospital, Beijing, 100072, People’s Republic of China; 4Department of Dermatology, Southern Medical Branch of PLA General Hospital, Beijing, 100072, People’s Republic of China; 5Department of Dermatology, Southwest Hospital, Army Medical University, Chongqing, People’s Republic of China; 6College of Materials Science and Technology, Beijing Forestry University, Beijing, 100083, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ming-Guo Ma; Rongya Yang, Email mg_ma@bjfu.edu.cn; yangrya@sina.comBackground: Silver nanomaterials have been widely proven to have antifungal effects against Trichosporon asahii. However, the antifungal mechanism of silver nanomaterials with different morphologies still needs to be explored.Methods: Herein, the antifungal effect of silver nanomaterials against fungus was comparative investigated via silver nanowires and silver nanoparticles with a similar size (30 nm).Results: The optimal antifungal concentration of silver nanowires is 6.24 μg/mL, meanwhile the antifungal concentration of silver nanoparticles is 100 μg/mL. The silver nanowires are significantly superior to the silver nanoparticles. SEM and TEM results indicated that both silver nanoparticles and silver nanowires showed significant morphological changes in the mycelium of the strain, compared with the control. The lower MFC value of silver nanowires indicates good sterilization effect and suitability for eradication treatment, which is slower than that of silver nanoparticles. Moreover, we also investigated the toxicological effects of silver nanoparticles and silver nanowires.Conclusion: We comparative studied and transcriptomic analyzed the antifungal mechanism of Ag nanoparticles and nanowires against Trichosporon asahii. The antifungal effects of silver nanowires were better than the silver nanoparticles, especially in the metabolic processes and oxidative phosphorylation. RNA sequencing results indicated that 15 key targets were selected for experimental verification to interpret the potential antifungal mechanism of Ag nanomaterials against fungus. This work proves that silver nanomaterials with different morphologies have potential applications in fungus therapy such as T. asahii.Keywords: Ag, nanoparticles, nanowires, fungus, antifungal mechanism, Trichosporon asahii, transcriptomics

Rong Yang,1,&ast; Qing Ma,1,2,&ast; Xiaolin Zhang,3 Qian Zhao,1,4,5 Suilan Zeng,6 Hechun Yan,7 Yi Lei,1,5 Shanye Yi,1 Xin Chen,8 Nianxi Wu9 1General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2West China School of Nursing, Sichuan University, Chengdu, People’s Republic of China; 3Preventive Health Section, Dayi County Shaqu Street Community Health Service Center, Chengdu, People’s Republic of China; 4Teaching & Research Section, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 5General Practice Medical Center and General Practice Research Institute, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 6Guan Ge Center Health Center, Guangan, People’s Republic of China; 7Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, People’s Republic of China; 8Big Buddha Street Community Health Service Center, Leshan, People’s Republic of China; 9Chongqing Magic MedTech Co., Ltd., Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qian Zhao, Email 27355151@qq.comPurpose: Osteoporosis is a major health concern among the elderly, underscoring the importance of investigating its prevalence across different geographical regions. There is a current research gap regarding the incidence of osteoporosis and its variation by altitude within Sichuan, China. This study aimed to assess the prevalence of osteoporosis among populations residing at different altitudes in western Sichuan Province.Basic Procedures: This study utilized data from a population-based cohort in Sichuan, China. Representative locations were selected, and cluster random sampling was employed to conduct cohort studies across multiple sites in southwestern China. T Baseline data were collected from populations in Mianzhu, Kangting, and Sertar between July 2020 and August 2021. To assess differences in osteoporosis incidence among populations at different altitudes and with varying characteristics, we applied Chi-square and rank-sum tests.Main Findings: The study involved 4074 participants, including 1404 males (34.46%) and 791 individuals diagnosed with osteoporosis (19.42%). The prevalence of osteopenia in mid-altitude and high-altitude regions was 20.05% and 16.28%, respectively, while the prevalence of osteoporosis was significantly different, at 25.85% in mid-altitude areas compared to 13.00% in high-altitude areas (P < 0.001). Further analysis identified statistically significant differences in the prevalence of osteopenia and osteoporosis among females (P< 0.001), middle-aged (P=0.015) and elderly populations (P=0.038), as well as among individuals who were underweight (P=0.011), normal weight (P< 0.001), overweight (P< 0.001), and obese (P=0.038). As altitude increased, the prevalence of osteoporosis decreased in all groups except the elderly, while the prevalence of osteopenia decreased among women and across various BMI categories, but increased among middle-aged and elderly individuals. Additionally, in high-altitude regions, Kangting recorded an 18.10% prevalence of osteopenia and a 14.26% prevalence of osteoporosis, compared to Sertar, which exhibited a 6.54% prevalence of osteopenia and a 6.23% prevalence of osteoporosis, indicating significant differences (P< 0.001).Conclusion: This study demonstrates that higher altitudes are associated with a decreased prevalence of osteopenia and osteoporosis, particularly among females and middle-aged individuals. These results emphasize the importance of developing region-specific osteoporosis prevention strategies.Keywords: osteoporosis, aging, prevalence, altitude, Sichuan province

Ru Yang,1,&ast; Wen Wang,1,2,&ast; Guomin Yin,1,2 Tingting Ma,1,2 Jia Tao1,2 1Center of Medical Laboratory, General Hospital of Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 2Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jia Tao, Email taojia880625@163.comObjective: During conditions accompanied by the disruption of normal mucosal barriers, anaerobic bacteria, which a part of normal human mucosal microflora, may cause various infections. In this study, clinical features of anaerobic bloodstream infections (BSI) in a general hospital in China were investigated.Methods: Patients with anaerobic BSI were retrospectively enrolled between 2012 and 2022. Demographic data, clinical manifestations, antibiotic treatments, and disease outcomes were analyzed.Results: In total, 391 anaerobic bacterial strains were isolated from 381 patients aged older than 11 years of age. Given that medical records of 47 patients were missing, 334 patients were included in the clinical investigation. Patients with anaerobic BSI included in the study were predominantly older than 50 years of age. Intra-abdominal infections were the most common source of anaerobic BSI (59%), followed by those of the female genital tract (10.2%) and lower respiratory tract (7.2%). Among the isolates, Bacteroides and Clostridium spp. were the most frequently isolated anaerobes. Most of the patients received antibiotic therapy. The crude mortality was 4.5%.Conclusion: The detection rate of anaerobic BSI in Ningxia, China, remained relatively stable from 2012 to 2022. These results provide a reference for the diagnosis and empirical treatment of anaerobic BSI in this region of China. Continuous mul-ticenter studies should be conducted to monitor the incidence of anaerobic BSI and drug resistance of anaerobic isolates to improve the treatment outcomes of patients.Keywords: anaerobes, bloodstream infections, blood cultures, clinical features

Qingbao Guo,1,2,&ast; Manli Xie,3,&ast; Qian-Nan Wang,4,&ast; Jingjie Li,1,2 Simeng Liu,1,2 Xiaopeng Wang,1,2 Dan Yu,5 Zhengxing Zou,5 Gan Gao,1,2 Qian Zhang,5 Fangbin Hao,1,2 Jie Feng,5 Rimiao Yang,5 Minjie Wang,1,2 Heguan Fu,5 Xiangyang Bao,5 Lian Duan2 1Medical School of Chinese PLA, Beijing, People’s Republic of China; 2Department of Neurosurgery, First Medical Centre, Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Department of Occupational Diseases, Xi’an Central Hospital, Xi’an, Shanxi, People’s Republic of China; 4Department of Neurosurgery, Eighth Medical Centre, Chinese PLA General Hospital, Beijing, People’s Republic of China; 5Department of Neurosurgery, Fifth Medical Centre, Chinese PLA General Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangyang Bao; Lian Duan, Email bzy123@163.com; duanlian307@sina.comBackground: Moyamoya disease (MMD) signifies a cerebrovascular disorder with obscure origin and a more rapid and severe progression in children than adults. This investigation aims to uncover age-associated distinctions through proteomic and metabolomic profiling to gain insights into the underlying mechanisms of MMD.Methods: Twelve MMD patients—six children and six adults—along with six healthy controls (HC), participated, each providing a 10 mL blood sample. Serum proteomic and metabolomic analyses were conducted using ultra-performance liquid chromatography and high-resolution mass spectrometry, complemented by bioinformatics to identify differential biomolecules and their interactions. Pathway implications were ascertained using GO and KEGG enrichment analysis.Results: Notable proteomic and metabolomic discrepancies were observed between pediatric and adult MMD subjects. A total of 235 and 216 proteins varied in adult and pediatric cases compared to HCs, with 73 proteins shared. In addition, 129 and 74 anionic, plus 96 and 104 cationic metabolites, were differentially expressed in the pediatric and adult groups, respectively, with 34 anionic and 28 cationic metabolites in common. Age-specific biomolecules further characterized these distinctions. Enrichment analysis pinpointed immunity and inflammation pathways, with vitamin digestion and absorption highlighted as pivotal in pediatric MMD.Conclusion: This study unveils distinct metabolic and proteomic patterns within pediatric and adult MMD patients. The critical role of the vitamin digestion and absorption pathway in the pathogenesis of pediatric MMD offers novel insight into disease mechanisms. Keywords: proteomics, metabolomics, pediatric patients, moyamoya disease, integration analysis

Qingqing Shen,1– 3,&ast; Qing Zhang,2,3,&ast; Yunxiao Liu,1– 3,&ast; Yingao Cui,1– 3 Jingwen Shang,1– 3 Xiaoping Yuan,2,3 Feng Geng,4 Liang Sun,5 Zhiwei Liu,5 Rongchun Yang,5 Kai Zhang,2,3 Huanzhong Liu2,3,6 1Department of Psychiatry, School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Anhui Psychiatric Center, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 4Department of Psychology and Sleep Medicine, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 5Department of Psychiatry, Fuyang Third People’s Hospital, Fuyang, Anhui, People’s Republic of China; 6Brain Bank Construction and Resource Utilization, Anhui Provincial Key Laboratory, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kai Zhang; Huanzhong Liu, Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China, Email zhangkai@ahmu.edu.cn; huanzhongliu@ahmu.edu.cnPurpose: The purpose of this study was to further explore the association of pain intensity and sensitivity with suicidal ideation in adolescents with depressive disorder by comparing the differences in pain intensity and sensitivity between adolescent patients with depressive disorders and healthy controls.Patients and Methods: A consecutive enrollment method was used to select 158 adolescent patients with depressive disorders from three hospitals in Anhui Province as the MDD group, and 47 healthy adolescents were recruited as the Control group. The subjects’ suicidal ideation was assessed using the Positive and Negative Suicide Ideation scale (PANSI), and the intensity of somatic pain was assessed using the Numerical Rating Scale-11 (NRS-11). Subjects were assessed for forearm and tibial pain sensitivity using a hand-held pressure pain instrument, and experimental pain sensitivity measures included pressure pain threshold (PPT) and pressure pain tolerance (PTO). Differences in pain intensity and sensitivity between the MDD group and the Control group were compared, and the association of pain intensity and sensitivity with suicidal ideation was analyzed.Results: The incidence of physical pain in adolescent depressive disorder was higher at 88.6%, which was significantly higher than the Control group (P< 0.001), and the pain intensity in the MDD group (3.77± 2.48) was significantly higher than the Control group (0.617± 0.99) (P < 0.001).The Pain tolerance was significantly higher in the MDD group (forearm 105.37 ± 41.46; tibia 121.29 ± 41.60) than in the Control group (forearm 91.92 ± 37.62; tibia 105.47 ± 35.52) (P < 0.05).Linear regression analysis showed that the greater the pain intensity and pain tolerance, the higher the total PANSI score.Binary logistic regression showed that pain intensity was an influencing factor for suicidal ideation.Conclusion: Adolescents with depressive disorders have higher pain intensity and lower pain sensitivity than healthy adolescents. Increased pain intensity and pain tolerance were positively correlated with suicidal ideation.Keywords: adolescents, depressive disorder, pain intensity, pain sensitivity, suicidal ideation

Jiajun Qiu,1– 3,&ast; Xin Huang,1– 3,&ast; Maobin Kuang,1– 3,&ast; Ruijuan Yang,1,4 Jiachong Li,1 Guotai Sheng,5,6 Yang Zou2,3 1Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China; 2Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People’s Hospital, Nanchang, Jiangxi Province, People’s Republic of China; 3Jiangxi Cardiovascular Research Institute, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, People’s Republic of China; 4Department of Endocrinology, Jiangxi Provincial People’s Hospital, Nanchang, Jiangxi Province, People’s Republic of China; 5Jiangxi Provincial Geriatric Hospital, Jiangxi Provincial People’s Hospital, Nanchang, Jiangxi Province, People’s Republic of China; 6Jiangxi Provincial Geriatric Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guotai Sheng, Jiangxi Provincial Geriatric Hospital, Jiangxi Provincial People’s Hospital, No. 92 Aiguo Road, Nanchang, Jiangxi, 330006, People’s Republic of China, Email tgs200509@163.com Yang Zou, Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People’s Hospital, No. 92 Aiguo Road, Nanchang, Jiangxi, 330006, People’s Republic of China, Email jxyxyzy@163.comPurpose: The association between traditional lipid parameters and non-alcoholic fatty liver disease (NAFLD) has been extensively discussed. This study aims to evaluate and compare the lipoprotein combine index (LCI) and traditional lipid parameters [total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)] to identify NAFLD.Patients and Methods: The analysis included 14,251 participants from the NAfld in the Gifu Area, Longitudinal Analysis (NAGALA). Logistic regression models were employed to calculate standardized odds ratios (ORs) and 95% confidence intervals (CIs) for assessing and comparing the association of LCI and traditional lipid parameters with NAFLD. Additionally, receiver operating characteristic (ROC) curves were used to calculate the area under the curve (AUC) for LCI and traditional lipid parameters in identifying NAFLD.Results: After adjusting for various confounders, we found that LCI was positively associated with NAFLD (OR=2.25, 95% CI 1.92– 2.63), and this association was stronger than that of traditional lipid parameters [OR: TC1.23, TG1.73 LDL-C1.10]. Further subgroup analyses revealed that the association of LCI with NAFLD was stronger than other traditional lipid parameters in all subgroups, including men and women, overweight/obese [body mass index (BMI)≥ 25 kg/m2] and non-obese (BMI< 25 kg/m2), and older (age≥ 45 years) and younger (age< 45 years) participants. Additionally, ROC analysis indicated that LCI (AUC=0.8118) had significantly higher accuracy (All DeLong P< 0.05) in identifying NAFLD compared to traditional lipid parameters (AUC: TC0.6309; TG0.7969; LDL-C0.6941); HDL-C0.7587). Sensitivity analysis further confirmed the robustness of the study findings.Conclusion: This study revealed for the first time a positive correlation between LCI and NAFLD. Compared to traditional lipid parameters, LCI has a higher correlation with NAFLD. Additionally, further ROC analysis demonstrated that LCI had higher accuracy in identifying NAFLD compared to traditional lipid parameters, suggesting that LCI may be a better marker for NAFLD identification than traditional lipid parameters.Keywords: non-alcoholic fatty liver disease, lipoprotein combine index, NAFLD, traditional lipid parameters, LCI

Yingxiu Liang,1 Xiaohong Hou,1 Haoying Chen,1 Ruqing Yang,1 Ruina Wang,1 Ruotong Mao,1 Junzhao Zhao,1 Hui Chen,2 Jing Cheng1 1Reproductive Center, Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325088, People’s Republic of China; 2School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, New South Wales, 2007, AustraliaCorrespondence: Jing Cheng, Reproductive Center, Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, No. 306 Hualongqiao Road, Lucheng District, Wenzhou, Zhejiang Province, 325088, People’s Republic of China, Tel +86 13780193700, Fax +86 57788002304, Email jingchengdoc_gyn@hotmail.com Hui Chen, Faculty of Science, University of Technology Sydney, No. 15 of Broadway, Ultimo, New South Wales, 2007, Australia, Tel/Fax +61 295141328, Email chenhuimind@sina.comObjective: Additive human menopausal gonadotropin (HMG)/recombinant luteinizing hormone (r-LH) to follicle-stimulating hormone (FSH) can improve pregnancy outcomes in patients with poor ovarian response during assisted reproductive procedures. However, their effects on patients with normal ovarian response during such procedures are unclear, which formed the aim of this study.Methods: This retrospective study enrolled 456 infertile women who underwent in vitro fertilization or intracytoplasmic sperm injection treatment. Group 1 received FSH; Group 2 received FSH+HMG/r-LH; Group 3 received FSH+HMG+r-LH.Results: The age and Body Mass Index were significantly greater in Group III. The endometrial thickness was greater in Groups II and III, suggesting better endometrial receptivity. Better pregnancy and birth outcomes were seen in Group 3. In sub-cohorts of women older than 32 years old or with overweight/obesity, pregnancy and birth outcomes were also much better in Group 3, albeit without statistical significance.Conclusion: The addition of both HMG and r-LH to FSH may improve the chance of infertile women with normal ovarian responses to have more success in having live birth babies, specifically in those over 32 years of age or with overweight/obese patients who typically face challenges in conceiving and sustaining a pregnancy.Keywords: in vitro fertilization, intracytoplasmic sperm injection, live birth rate, cumulative live birth rate

Yixuan Zhang,1,&ast; Min Wang,2,&ast; Ting Zhang,3 Honghua Wang,2 Ying Chen,1 Tao Zhou,1 Rui Yang1 1Research Institute for Reproductive Medicine and Genetic Diseases, Wuxi Maternity and Child Health Care Hospital, Wuxi, 214002, People’s Republic of China; 2Center for Reproductive Medicine, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, 214002, People’s Republic of China; 3Department of Laboratory Medicine, Wuxi Maternity and Child Health Care Hospital, Jiangnan University, Wuxi, 214002, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Zhou; Rui Yang, Email zhoutao@njmu.edu.cn; ruiyang826@163.comAbstract: Sperm quality is declining dramatically during the past decades. Male infertility has been a serious health and social problem. The sperm cell driven biohybrid nanorobot opens a new era for automated and precise assisted reproduction. Therefore, it is urgent and necessary to conduct an updated review and perspective from the viewpoints of the researchers and clinicians in the field of reproductive medicine. In the present review, we first update the current classification, design, control and applications of various spermbots. Then, by a comprehensive summary of the functional features of sperm cells, the journey of sperms to the oocyte, and sperm-related dysfunctions, we provide a systematic guidance to further improve the design of spermbots. Focusing on the translation of spermbots into clinical practice, we point out that the main challenges are biocompatibility, effectiveness, and ethical issues. Considering the special requirements of assisted reproduction, we also propose the three laws for the clinical usage of spermbots: good genetics, gentle operation and no contamination. Finally, a three-step roadmap is proposed to achieve the goal of clinical translation. We believe that spermbot-based treatments can be validated and approved for in vitro clinical usage in the near future. However, multi-center and multi-disciplinary collaborations are needed to further promote the translation of spermbots into in vivo clinical applications. Keywords: assisted reproduction, biohybrid nanorobot, clinical translation, male infertility, spermbot

Jiaman Yang,1,2,&ast; Yulin Xie,1,2,&ast; Zhikuan Xia,1,&ast; Shuaifei Ji,3,&ast; Xin Yang,1 Danxia Yue,1 Yuanyuan Liu,1,3 Rongya Yang,1– 3 Yunlong Fan1,3 1Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, People’s Republic of China; 2The Second School of Clinical Medicine, SouThern Medical University, Guangzhou, 510599, People’s Republic of China; 3Chinese PLA Medical School, Beijing, 100853, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rongya Yang, Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, No. 5, Nanmencang Alley, Dongsi Shitiao, Dongcheng District, Beijing, 100700, People’s Republic of China, Email YangRY301hospital@163.com Yunlong Fan, Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, No. 5, Nanmencang alley, Dongsi Shitiao, Dongcheng District, Beijing, 100700, People’s Republic of China, Email FanYL301hospital@163.comBackground: Neutrophils rapidly accumulate in large numbers at sites of tissue damage, exhibiting not only their well-known bactericidal capabilities but also playing crucial roles in angiogenesis and tissue repair. While exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exo) have emerged as a promising therapeutic tool, their exact mechanisms of action remain partly elusive. We hypothesize that HucMSC-Exo treatment may modulate neutrophil phenotypes, thereby significantly influencing wound healing outcomes.Methods: HucMSC-Exo were isolated via ultracentrifugation and subsequently administered through subcutaneous injection into full-thickness cutaneous wounds in mice. To determine the impact of host neutrophils on the healing effects of HucMSC-Exo in skin injuries, strategies including neutrophil depletion and adoptive transfer were employed. Flow cytometry was used to evaluate the proportion of N2 subtype neutrophils in both normal and diabetic wounds, and the effect of HucMSC-Exo on this proportion was assessed. Furthermore, the mitochondrial metabolic reprogramming driven by HucMSC-Exo during N2 polarization was investigated through JC1 staining, ATP quantification, fatty acid uptake assays, and assessment of FAO-related genes (Cpt1b, Acadm, and Acadl).Results: Depleting host neutrophils strikingly dampened prohealing effect of HucMSC-Exo on skin injury, while adoptive transfer of bone marrow neutrophils rescued this process. During normal healing process, some neutrophils expressed N2 markers, in contrast, diabetic wounds exhibited a reduced expression of N2 markers. After treatment with HucMSC-Exo, most neutrophils increased the phosphorylation of STAT6, leading to mitochondrial metabolic reprogramming and thus acquired an N2 phenotype. These N2 neutrophils, polarized by HucMSC-Exo, boosted the release of proangiogenic factors, particularly BV8, a myeloid cell-derived proangiogenic factor, and induced angiogenesis thereby favoring tissue restoration.Conclusion: This research uniquely demonstrates the identification of N2 neutrophils in skin injury and shows that HucMSC-Exo could skew neutrophils toward N2 phenotype, enhancing our insight into how cells react to HucMSC-Exo. Keywords: HucMSC-Exo, neutrophils, phenotype switching, cutaneous wound healing, tissue restoration

Yunxiang Hu,1,2,&ast; Rui Yang,1,2,&ast; Sanmao Liu,1,2,&ast; Zefeng Song,3 Hong Wang1,2 1Department of Orthopedics, Central Hospital of Dalian University of Technology, Dalian City, Liaoning Province, People’s Republic of China; 2School of Graduates, Dalian Medical University, Dalian City, Liaoning Province, People’s Republic of China; 3School of Graduates, Dalian University of Technology, Dalian City, Liaoning Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong WangDepartment of Orthopedics, Central Hospital of Dalian University of Technology, No. 826, Southwestern Road, Shahekou District, Dalian City, Liaoning Province, People’s Republic of China, Email wanghong@dmu.edu.cnAbstract: Low back pain (LBP) is a common condition that has substantial consequences on individuals and society, both socially and economically. The primary contributor to LBP is often identified as intervertebral disc degeneration (IVDD), which worsens and leads to significant spinal problems. The conventional treatment approach for IVDD involves physiotherapy, drug therapy for pain management, and, in severe cases, surgery. However, none of these treatments address the underlying cause of the condition, meaning that they cannot fundamentally reverse IVDD or restore the mechanical function of the spine. Nanotechnology and regenerative medicine have made significant advancements in the field of healthcare, particularly in the area of nanodrug delivery systems (NDDSs). These approaches have demonstrated significant potential in enhancing the efficacy of IVDD treatments by providing benefits such as high biocompatibility, biodegradability, precise drug delivery to targeted areas, prolonged drug release, and improved therapeutic results. The advancements in different NDDSs designed for delivering various genes, cells, proteins and therapeutic drugs have opened up new opportunities for effectively addressing IVDD. This comprehensive review provides a consolidated overview of the recent advancements in the use of NDDSs for the treatment of IVDD. It emphasizes the potential of these systems in overcoming the challenges associated with this condition. Meanwhile, the insights and ideas presented in this review aim to contribute to the advancement of precise IVDD treatment using NDDSs.Keywords: lumbar disc herniation, intervertebral disc degeneration, nanocarrier drug delivery system, targeted therapy, regenerative medicine

Dong Hu,1 Ruyue Yang,1 Guidan Wang,2 Hao Li,1 Xulong Fan,1 Gaofeng Liang1 1School of Basic Medicine and Forensic Medicine, Henan University of Science & Technology, Luoyang, 471023, People’s Republic of China; 2School of Medical Technology and Engineering, Henan University of Science & Technology, Luoyang, 471023, People’s Republic of ChinaCorrespondence: Gaofeng Liang, School of Basic Medicine and Forensic Medicine, Henan University of Science & Technology, Luoyang, 471023, People’s Republic of China, Email lgfeng990448@163.comAbstract: Adoptive T cells immunotherapy, specifically chimeric antigen receptor T cells (CAR-T), has shown promising therapeutic efficacy in the treatment of hematologic malignancies. As extensive research on CAR-T therapies has been conducted, various challenges have emerged that significantly hampered their clinical application, including tumor recurrence, CAR-T cell exhaustion, and cytokine release syndrome (CRS). To overcome the hurdles of CAR-T therapy in clinical treatment, cell-free emerging therapies based on exosomes derived from CAR-T cells have been developed as an effective and promising alternative approach. In this review, we present CAR-T cell-based therapies for the treatment of tumors, including the features and benefits of CAR-T therapies, the limitations that exist in this field, and the measures taken to overcome them. Furthermore, we discuss the notable benefits of utilizing exosomes released from CAR-T cells in tumor treatment and anticipate potential issues in clinical trials. Lastly, drawing from previous research on exosomes from CAR-T cells and the characteristics of exosomes, we propose strategies to overcome these restrictions. Additionally, the review discusses the plight in large-scale preparation of exosome and provides potential solutions for future clinical applications.Keywords: tumor, CAR-T cells, immune escape, exosome

Baojiang Liu,&ast; Song Gao,&ast; Jianhai Guo, Fuxin Kou, Shaoxing Liu, Xin Zhang, Aiwei Feng, Xiaodong Wang, Guang Cao, Hui Chen, Peng Liu, Haifeng Xu, Qinzong Gao, Renjie Yang, Liang Xu, Xu Zhu Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xu Zhu, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China, Tel + 86-10-8819-6059, Email drzhuxu@163.comPurpose: Recently, hepatic arterial infusion chemotherapy (HAIC) has also gained popularity for hepatocellular carcinoma (HCC). Several studies have compared HAIC and Transarterial chemoembolization (TACE). However, comparisons between TACE plus HAIC and HAIC are rarely reported. Here, we evaluated the performance of HepaSphere DEB-TACE combined with HAIC (Hepa-HAIC) compared to HAIC in patients with advanced HCC.Patients and Methods: In this retrospective study, we enrolled 167 patients diagnosed with advanced HCC and treated at Peking University Cancer Hospital from May 2018 to May 2022. The cohort comprised 74 patients who received HepaSphere DEB-TACE combined with HAIC-FOLFOX (Hepa-HAIC) and 93 patients who received HAIC-FOLFOX. Over 60% of patients received prior treatments. To avoid selection bias, propensity score matching was applied to the efficacy and safety analyses. The primary endpoints are progression-free survival (PFS) and overall survival (OS); the secondary endpoints include objective response rate (ORR), disease control rate (DCR), and safety.Results: Propensity-matching yielded 48 pairs, and group baselines were almost equal after matching. Median PFS and median OS were both higher in the matched Hepa-HAIC cohort (median PFS: 8.9 vs 5.8 months, p = 0.035; median OS: 22.4 vs 9.5 months, p = 0.027), which was consistent with pre-matching analysis. The ORR in the Hepa-HAIC and HAIC cohorts was 75.0% and 37.5%, respectively; the DCR was 93.8% after Hepa-HAIC and 81.3% after HAIC. There was no treatment-related death. Grade 3– 4 ALT elevation was more frequent in the Hepa-HAIC group (33.3% vs 8.3%, p = 0.003), while vomiting was more frequent in the HAIC group (29.2% vs 12.5%, p = 0.084).Conclusion: The Hepa-HAIC group is superior to the HAIC group in metrics of PFS, OS, ORR, and DCR, which indicates the combination of HepaSphere DEB-TACE and HAIC may lead to improved outcomes with a comparable safety profile in advanced HCC.Keywords: transarterial chemoembolization, advanced hepatocellular carcinoma, hepatic arterial infusion chemotherapy, propensity score matching

Debiao Xiang,1– 3 Lili Zhou,4 Rui Yang,1,4 Fang Yuan,1– 3 Yilin Xu,4 Yuan Yang,1,4 Yong Qiao,1– 3 Xin Li1– 3 1Department of Pharmacy, The Third Hospital of Changsha, Changsha, Hunan Province, People’s Republic of China; 2Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs, Changsha, Hunan Province, People’s Republic of China; 3The Clinical Application Research Institute of Antibiotics in Changsha, Changsha, Hunan Province, People’s Republic of China; 4College of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan Province, People’s Republic of ChinaCorrespondence: Xin Li, 176 Laodong West Road, Tianxin District, Changsha, Hunan Province, People’s Republic of China, Tel +86 0731-85171320, Email xin-li@cssdsyy.comAbstract: Currently, cancer remains one of the most significant threats to human health. Treatment of most cancers remains challenging, despite the implementation of diverse therapies in clinical practice. In recent years, research on the mechanism of ferroptosis has presented novel perspectives for cancer treatment. Ferroptosis is a regulated cell death process caused by lipid peroxidation of membrane unsaturated fatty acids catalyzed by iron ions. The rapid development of bio-nanotechnology has generated considerable interest in exploiting iron-induced cell death as a new therapeutic target against cancer. This article provides a comprehensive overview of recent advancements at the intersection of iron-induced cell death and bionanotechnology. In this respect, the mechanism of iron-induced cell death and its relation to cancer are summarized. Furthermore, the feasibility of a nano-drug delivery system based on iron-induced cell death for cancer treatment is introduced and analyzed. Secondly, strategies for inducing iron-induced cell death using nanodrug delivery technology are discussed, including promoting Fenton reactions, inhibiting glutathione peroxidase 4, reducing low glutathione levels, and inhibiting system Xc−. Additionally, the article explores the potential of combined treatment strategies involving iron-induced cell death and bionanotechnology. Finally, the application prospects and challenges of iron-induced nanoagents for cancer treatment are discussed.Keywords: cancers, ferroptosis, nano-drug delivery system, target

Chunhui Zhang,1,&ast; Yuqing Tao,1,&ast; Rui Yang,1 Yueqi Wang,1 Yanyan Yu,2 Yang Zhou2 1Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150010, People’s Republic of China; 2Department of Radiology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150010, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Zhou, Department of Radiology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang, 150010, People’s Republic of China, Email zhouyang094@126.comPurpose: Using a combination model of preoperative imaging and clinical factors to predict non-transplantable recurrence (NTR) after liver resection and assist solitary hepatocellular carcinoma (HCC) patients in the selection of early treatment options.Patients and Methods: A retrospective analysis was conducted on 253 solitary HCC patients who underwent radical resection and had preoperative MRI. NTR patients were defined as those exceeding the University of California, San Francisco (UCSF) criteria at the time of recurrence. Cox regression analysis was employed to identify preoperative factors associated with NTR based on clinical and tumor imaging characteristics. A risk scoring model (NTRScore) was developed and validated.Results: Among the 253 patients, 86 (33.9%) experienced recurrence, and among those with recurrence, 34 patients (39.5%) developed NTR. In multivariate analysis, factors associated with NTR included alpha-fetoprotein (AFP) [> 10 ng/mL] [HR: 3.42, 95% confidence interval (CI): 1.54– 7.63, P: 0.003], arterial phase hyperenhancement (APHE) [HR: 2.23, 95% CI: 1.03– 4.81, P: 0.041], washout[HR: 0.35, 95% CI: 0.15– 0.84, P: 0.019], and capsule [HR: 0.44, 95% CI: 0.22– 0.88, P: 0.021]. The β-coefficients of these variables were utilized to develop the weighted NTRScore(c-index 0.72, 95% CI: 0.65– 0.79). The NTR occurrence increased across the three categories (low: 5.6%, medium: 13.6%, high: 35.1%, p < 0.001), and the Kaplan-Meier curves of recurrence-free survival(RFS) and overall survival(OS) show significant differences (p = 0.004 and p< 0.001). Furthermore, the higher NTR categories may be associated with an increased risk of extrahepatic recurrence.Conclusion: The NTRScore demonstrated strong discriminatory ability and may serve as a clinically useful tool to assist in risk stratification and potential to guide treatment and optimal surveillance for patients of solitary hepatocellular carcinoma within UCSF criteria.Keywords: hepatocellular carcinoma, salvage liver transplantation, non-transplantable recurrence, treatment, prognosis

Jingrui Zhang,1,&ast; Zengbin Liu,2,&ast; Zhirong Li,2 Caihong Xu,1 Hongbin Wang,3 Rugang Yang,1 Li Liu1 1Department of Clinical Laboratory, The Fourth Hospital of Shijiazhuang, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 3Department of Gynecology and Obstetrics, The Fourth Hospital of Shijiazhuang, Shijiazhuang, Hebei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jingrui Zhang; Li Liu, The Fourth Hospital of Shijiazhuang, Shijiazhuang, 050000, People’s Republic of China, Email jingrui20005@163.com; liuliok2012@163.comBackground: Maternal–fetal listeriosis, caused by Listeria monocytogenes, is a rare but serious infection. Herein, we report the clinical and genomic characteristics of a clinical L. monocytogenes ST120 isolate recovered from a pregnant woman.Methods: The clinical symptoms and treatment in pregnant woman were described in detail. Whole genome sequencing (WGS) was performed on the L. monocytogenes isolate SJZ_LM001, and the genomic characterization of the isolate was deeply analyzed.Results: The clinical symptoms in pregnant women were mainly fever, and the placenta experienced severe inflammation. The pregnant woman was treated with ampicillin for effective anti-infective therapy. Genomic analysis showed that isolate SJZ_LM001 is sequence type (ST) 120, belong to clonal complex (CC)8 and lineage II of L. monocytogenes. Additionally, the isolates SJZ_LM001 harbored a novel plasmid pSJZ_LM001, which carried arsenical resistance genes (arsACD and acr3), and cadmium resistance genes (cadAC). Drug susceptibility testing showed that the isolate SJZ-LM001 was susceptible to ampicillin, meropenem, penicillin, and cotrimoxazole.Conclusion: This is the first to identify a clinical case of infection in a pregnant woman caused by ST120 L. monocytogenes in China. These findings could benefit our understanding of the genomic characteristics of L. monocytogenes, and the pregnancy-related listeriosis and providing early diagnosis and effective targeted treatment.Keywords: Listeria monocytogenes, whole genome sequence, ST120, plasmid

Xin Yang,1,2,&ast; Zhikuan Xia,1,&ast; Yunlong Fan,1 Yitong Xie,1 Ge Ge,1 Dexiu Lang,3 Junhong Ao,1 Danxia Yue,1 Jiamin Wu,1 Tong Chen,1 Yuekun Zou,1 Mingwang Zhang,4 Rongya Yang1,2 1Department of Dermatology, The Seventh Medical Center of PLA General Hospital, Beijing, People’s Republic of China; 2Department of Dermatology, Yanbian University Hospital, Yanji, People’s Republic of China; 3Department of Dermatology, XingYi People’s Hospital, Xingyi, People’s Republic of China; 4Department of Dermatology, Southwest Hospital, Army Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingwang Zhang; Rongya Yang, Email mingwangzhang2@163.com; yangrya@sina.comBackground: Solar lentigines (SLs), serving as a prevalent characteristic of skin photoaging, present as cutaneous aberrant pigmentation. However, the underlying pathogenesis remains unclear and there is a dearth of reliable diagnostic biomarkers.Objective: The aim of this study was to identify diagnostic biomarkers for SLs and reveal its immunological features.Methods: In this study, gene expression profiling datasets (GSE192564 and GSE192565) of SLs were obtained from the GEO database. The GSE192564 was used as the training group for screening of differentially expressed genes (DEGs) and subsequent depth analysis. Gene set enrichment analysis (GSEA) was employed to explore the biological states associated with SLs. The weighted gene co-expression network analysis (WGCNA) was employed to identify the significant modules and hub genes. Then, the feature genes were further screened by the overlapping of hub genes and up-regulated differential genes. Subsequently, an artificial neural network was constructed for identifying SLs samples. The GSE192565 was used as the test group for validation of feature genes expression level and the model’s classification performance. Furthermore, we conducted immune cell infiltration analysis to reveal the immune infiltration landscape of SLs.Results: The 9 feature genes were identified as diagnostic biomarkers for SLs in this study. And an artificial neural network based on diagnostic biomarkers was successfully constructed for identification of SLs. GSEA highlighted potential role of immune system in pathogenesis of SLs. SLs samples had a higher proportion of several immune cells, including activated CD8 T cell, dendritic cell, myeloid-derived suppressor cell and so on. And diagnostic biomarkers exhibited a strong relationship with the infiltration of most immune cells.Conclusion: Our study identified diagnostic biomarkers for SLs and explored its immunological features, enhancing the comprehension of its pathogenesis.Keywords: solar lentigines, photoaging, diagnostic biomarkers, immune infiltration, artificial neural network

Qinglin Ye,1,&ast; Guiling Xu,1,&ast; Hao Yuan,2,3 Junhao Mi,2,3 Yuli Xie,2,3 Haoyu Li,1 Zhejun Li,1 Guanwen Huang,1 Xuesong Chen,1 Wei Li,1 Rirong Yang2,3 1Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530005, People’s Republic of China; 2Centre for Genomic and Personalized Medicine, Guangxi key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, 530021, People’s Republic of China; 3Department of Immunology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rirong Yang, Centre for Genomic and Personalized Medicine, Guangxi key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Department of Immunology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China, Fax +86 0771 5317061, Email yangrirong@sr.gxmu.edu.cn; 520yrr@163.com Wei Li, Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530005, People’s Republic of China, Email liwei030514@126.comBackground: Diabetic kidney disease (DKD) is a chronic renal disease which could eventually develop into renal failure. Though albuminuria and estimated glomerular filtration rate (eGFR) are helpful for the diagnosis of DKD, the lack of specific biomarkers reduces the efficiency of therapeutic interventions.Methods: Based on bulk-seq of 56 urine samples collected at different time points (including 11 acquired from DKD patients and 11 from healthy controls), in corporation of scRNA-seq data of urine samples and snRNA-seq data of renal punctures from DKD patients (retrieved from NCBI GEO Omnibus), urine-kidney specific genes were identified by Multiple Biological Information methods.Results: Forty urine-kidney specific genes/differentially expressed genes (DEGs) were identified to be highly related to kidney injury and proteinuria for the DKD patients. Most of these genes participate in regulating glucagon and apoptosis, among which, urinary PART1 (mainly derived from distal tubular cells) and PLA2R1 (podocyte cell surface marker) could be used together for the early diagnosis of DKD. Moreover, urinary PART1 was significantly associated with multiple clinical indicators, and remained stable over time in urine.Conclusion: Urinary PART1 and PLA2R1 could be shed lights on the discovery and development of non-invasive diagnostic method for DKD, especially in early stages. Keywords: diabetic kidney disease, urine, non-invasive, diagnosis, biomarker

Ronghui Yang, Sirui Sun Department of Public Administration, College of Humanities, Donghua University, Shanghai, 200051, People’s Republic of ChinaCorrespondence: Sirui Sun, Department of Public Administration, College of Humanities, Donghua University, 1882 West Yan’an Road, Shanghai, 200051, People’s Republic of China, Tel +8618521057816, Email sirui_sun@dhu.edu.cnBackground: COVID-19 vaccine promotion helps counter vaccine hesitancy and raise vaccine acceptance. Therefore, the Chinese state created collaborative infrastructures of COVID-19 vaccine promotion programs to promote stakeholder engagement and unload the burden of policy practitioners. However, partnerships in COVID-19 vaccine promotion programs have been underrepresented.Methods: To address this lacuna, we qualitatively explored how partnerships in the COVID-19 vaccine promotion campaign (CVPC) were organized in China’s neighborhoods. Specifically, we recruited participants via personal networks, referrals from acquaintances, and snowballing approaches, and conducted the qualitative thematic analysis following interviews with 62 Chinese stakeholders.Results: This study indicates that to promote partnerships in CVPCs, neighborhood managers formed leadership in CVPCs, expanded the collaborative network, trained Health Promotion Practitioners (HPPs), and coordinated with HPPs to shape partnership agreements, produced COVID-19 vaccine promotional materials and advertised COVID-19 vaccines via diverse media tools. Although coproduction of CVPCs to a certain extent promoted state-society interaction in neighborhoods and state responsiveness to public demands, partners’ disagreements on strategies applied by states for promoting COVID-19 vaccines eroded partnerships in CVPCs.Conclusion: To construct a robust partnership in CVPCs, depoliticizing CVPCs and creating shared values among stakeholders in CVPCs are expected. Our study will not only deepen global audiences’ understanding of CVCPs in China but also offer potential neighborhood-level solutions for implementing local and global health promotion efforts.Keywords: campaign governance, partnerships, COVID-19 vaccine promotion, neighborhood, China

Lan Gao,1 Lei-Lei Wang,1 Rui Yang,2 Xing-Jie Yang,1 Shuang-Jiang Zhou1 1Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, People’s Republic of China; 2Beijing Anding Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Shuang-Jiang Zhou, Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, 10096, People’s Republic of China, Tel +86-10-83024136, Email zhoushuangjiang@126.comPurpose: Depression and anxiety have a significant impact on an individuals’ work and personal life alike. The mental health of researchers is a significant concern worldwide. This study investigated the mental health status of Chinese researchers specifically and explored the moderating effects of perceived stress on the influence of low self-accomplishment on anxiety and depression.Methods: The online survey platform “Survey Star” was used to create a questionnaire to be distributed to researchers, with 949 questionnaires retrieved. The general information questionnaire, 10-item Perceived Stress Scale (PSS-10), Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Maslach Burnout Inventory General Survey (MBI-GS) were used for this investigation. Pearson’s correlation analysis was performed to investigate correlations among the relevant variables. Model 8 of PROCESS 3.3 program was used to analyze the moderating effects of perceived stress.Results: Among the 949 participants, 570 (60.1%) reported symptoms of depression and 431 (45.4%) had symptoms of anxiety, with about one in six reporting symptoms of self-harm or suicidal ideation. Perceived stress was found to moderate the effect of low self-accomplishment on depression and anxiety.Conclusion: Here we show that researchers exhibit a high rate of depression and anxiety symptoms. Perceived stress is also shown to play a moderating role on the influence of low self-accomplishment on anxiety and depression. Thus, reducing perceived stress levels can help to improve the mental health of researchers.Keywords: research personnel, mental health, burnout, accomplishment, stress, suicidal ideation

Hao Qin,1,&ast; Wenjun Wang,2,&ast; Longlong Hu,1 Zuozhong Yu,1 Yang Chen,1 Yuanbin Zhao,1 Yanhui Liao,1 Renqiang Yang1 1Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China; 2Department of Respiratory Diseases, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Renqiang Yang, Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel +86-13979117790, Fax +86-0791-87357375, Email yangrenqiangcn@163.comBackground: Ischemic heart disease is one of the leading causes of death in the world, of which ST-segment elevation myocardial infarction (STEMI) is an important type. Inappropriate activation and accumulation of platelets typically induced thrombosis, which may result in acute vessel occlusion and STEMI. Multiple cytokines have been shown to regulate platelet activation, but the relationship between HMGB2 and platelet activation has not been elucidated.Methods: We collected peripheral blood of STEMI patients and healthy adults, and mass spectrometry analysis of platelet proteins was conducted. The “edgeR” package was used to identify the differentially expressed proteins (DEPs). The Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO) and Gene Set Enrichment Analysis (GSEA) were used to identify the significantly changed pathways. Western blot and ELISA were used to detect the expression of a high mobility group box 2 (HMGB2). Flow cytometric analysis and platelet aggregation rate were performed to evaluate the activation of platelets.Results: We identified ALOX5, HIST1H1B, S100A11, HMGB2, and RPS15A were the top five up-regulated proteins by differential expression analysis. Western blot verified that the relative protein expression of HMGB2 in platelet was significantly higher in STEMI patients compared with control adults, and the results of ELISA indicated that the serum HMGB2 level increased and significantly correlated with neutrophil count in STEMI patients. Further investigation showed that the platelet aggregation induced by ADP, the activation of integrin αIIbβ 3 and CD62P expression on platelet surface were all enhanced by the recombinant HMGB2 (rHMGB2).Conclusion: In conclusion, HMGB2 may be the key molecule to regulate platelet activation in patients with STEMI, which may serve as a potential therapeutic target for STEMI.Keywords: ST-segment elevation myocardial infarction, STEMI, proteomics analysis, platelet, HMGB2

Dan He,1,&ast; Qiao Yu,2,&ast; Xiaona Zeng,2,&ast; Jihua Feng,2 Ruiqi Yang,2 Huan Wan,2 Ying Zhong,2 Yanli Yang,2 Ruzhi Zhao,2 Junyu Lu,3,4 Jianfeng Zhang1,2,4 1Department of General Practice, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, People’s Republic of China; 2Department of Emergency Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, People’s Republic of China; 3Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, People’s Republic of China; 4Guangxi Health Commission Key Laboratory of Emergency and Critical Medicine, Nanning, 530007, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianfeng Zhang, Junyu Lu, The Second Affiliated Hospital of Guangxi Medical University, No. 166 Daxuedong Road, Nanning, Guangxi, 530007, People’s Republic of China, Tel +86 7713277166, Fax +86 7713277285, Email zhangjianfeng@gxmu.edu.cn; junyulu@gxmu.edu.cnBackground: Acute respiratory distress syndrome (ARDS) is caused by severe pulmonary inflammation and the leading cause of death in the intensive care unit.Methods: We used single-cell RNA sequencing to compare peripheral blood mononuclear cells from sepsis-induced ARDS (SEP-ARDS) and pneumonic ARDS (PNE-ARDS) patient. Then, we used the GSE152978 and GSE152979 datasets to identify molecular dysregulation mechanisms at the transcriptional level in ARDS.Results: Markedly increased CD14 cells were the predominant immune cell type observed in SEP-ARDS and PNE-ARDS patients. Cytotoxic cells and natural killer (NK) T cells were exclusively identified in patients with PNE-ARDS. An enrichment analysis of differentially expressed genes (DEGs) suggested that Th1 cell differentiation and Th2 cell differentiation were enriched in cytotoxic cells, and that the IL-17 signaling pathway, NOD receptor signaling pathway, and complement and coagulation cascades were enriched in CD14 cells. Furthermore, according to GSE152978 and GSE152979, 1939 DEGs were identified in patients with ARDS and controls; they were mainly enriched in the Kyoto Encyclopedia of Genes and Genomes pathways. RBP7 had the highest area under the curve values among the 12 hub genes and was mainly expressed in CD14 cells. Additionally, hub genes were negatively correlated with NK cells and positively correlated with neutrophils, cytotoxic cells, B cells, and macrophages.Conclusion: A severe imbalance in the proportion of immune cells and immune dysfunction were observed in SEP-ARDS and PNE-ARDS patients. RBP7 may be immunologically associated with CD14 cells and serve as a potential marker of ARDS.Keywords: acute respiratory distress syndrome, single-cell RNA sequencing, biomarker, immune disorders, differentially expressed genes

Tong Zhang,&ast; Rui Yang,&ast; Juhua Pan, Shijing Huang Research and Development Center of Traditional Chinese Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shijing Huang; Juhua Pan, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China, Email gamhsj@126.com; panjuhua@126.comBackground: Parkinson’s disease (PD) is one of the common neurodegenerative diseases. Depression and anxiety are the most common psychiatric symptoms of PD. It is important to study the potential relationship between PD and depression or anxiety.Aim: This study aimed to use bibliometrics to analyze the papers about parkinson’s disease related depression and anxiety over the last 22 years, and to characterize the current status of research and predict future hotspots.Methods: In the Web of Science Core Collection (WoSCC) from 2000 to 2022, documents are searched according to specific subject words. The selected literature was retrospectively analyzed and mapped using CiteSpace and Vosviewer software. We analyzed countries, institutions, journals, authors, references and keywords.Results: A total of 7368 papers were included from 2000 to 2022, and the number of publications has shown an upward trend year by year. Movement Disorder is the journal with the highest number of publications (391 publications, 5.31%) and citations (30,549 times), with the United States (2055 publications, 27.9%) and the University of Toronto (158 publications) being the countries and institutions with the highest number of publications. The high-frequency keywords focused on “quality of life”, “deep brain stimulation” and “non-motor symptoms”. “Functional connectivity”, “gut microbiota” and “inflammation” may be at the forefront of future research.Conclusion: Parkinson’s disease related depression and anxiety have been increasingly studied over the past 22 years. Functional connectivity, gut microbiota, and inflammation will be the subject of active research hotspots in the future, and these findings may provide new research ideas for researchers.Keywords: Parkinson’s disease, depression, anxiety, bibliometric analysis, Citespace, VOSviewer

Shuang-Jiang Zhou,1,&ast; Rui Yang,2,&ast; Lei-Lei Wang,1 Meng Qi,1 Xiao-Fei Yuan,2 Ting-Ting Wang,3 Tian-He Song,4 Yun-Yue Zhuang,4 Hong-Juan Li,1 Yun-Long Tan,1 Xue Wang,2 Jing-Xu Chen1 1Sleep Medicine Center, Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, People’s Republic of China; 2Beijing Anding Hospital, Capital Medical University, Beijing, People’s Republic of China; 3School of Mental Health, Bengbu Medical College, Bengbu, People’s Republic of China; 4Department of Psychology, Chengde Medical University, Chengde, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xue Wang, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, People’s Republic of China, Tel +86-10-58303034, Email xuew37@ccmu.edu.cn Jing-Xu Chen, Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, 100096, People’s Republic of China, Tel +86-10-83024278, Email chenjx1110@163.comObjective: To assess the performance of a wearable multi-sensor system (SensEcho) in comparison to polysomnography (PSG) in measuring sleep stages and searching for obstructive sleep apnea (OSA).Methods: Participants underwent overnight simultaneous monitoring using SensEcho and PSG in a sleep laboratory. SensEcho analyzed the recordings spontaneously, and PSG was assessed as per standard guidelines. The degree of snoring was evaluated according to the guidelines for the diagnosis and treatment of OSA hypopnea syndrome (2011 revision). The Epworth Sleepiness Scale (ESS) was used to assess general daytime sleepiness.Results: This study included 103 Han Chinese, 91 of whom (age 39.02 ± 13.84 years, body mass index 27.28 ± 5.12 kg/m2, 61.54% male) completed the assessments. The measures of total sleep time (P = 0.198); total wake time (P = 0.182); shallow sleep (P = 0.297), deep sleep (P = 0.422), rapid eye movement sleep (P = 0.570), and awake (P = 0.336) proportions were similar between SensEcho and PSG. Using an apnea-hypopnea index (AHI) cutoff of ≥ 5 events/h, the SensEcho had 82.69% sensitivity and 89.74% specificity. Almost the same results were obtained at an AHI threshold of ≥ 15 events/h. Although the specificity increased to 94.67%, it decreased to 43.75% at an AHI cutoff of ≥ 30 events/h.Conclusion: This study demonstrated that SensEcho can be used to evaluate sleep status and screen for OSA. Nevertheless, improving the accuracy of its assessment of severe OSA and further testing its effectiveness in community and home environments is necessary.Keywords: wearable multi-sensor system, polysomnography, sleep stages, obstructive sleep apnea

Lan Gao,1,&ast; Rui Yang,2,&ast; Hong-Zhen Fan,1 Lei-Lei Wang,1 Yan-Li Zhao,1 Shu-Ping Tan,1 Chun-Ling Xiao,1 Shuang-Jiang Zhou1 1Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, People’s Republic of China; 2Beijing Anding Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chun-Ling Xiao; Shuang-Jiang Zhou, Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, 10096, People’s Republic of China, Email xiaocl2002@163.com; zhoushuangjiang@126.comPurpose: To explore the correlation between aggressive behavior and impulsive and aggressive personality traits in inpatients with schizophrenia.Methods: In total, 367 inpatients with schizophrenia were divided into two groups: the aggressive group and the non-aggressive group. We assessed inpatients’ psychotic symptoms as well as their aggressive and impulsive personality traits using the Positive and Negative Symptom Scale, the Barratt Impulsiveness Scale, and the Buss-Perry Aggression Questionnaire.Results: Compared with the scores of inpatients in the non-aggressive group, the total Buss-Perry Aggression Questionnaire, subscale, and Barratt Impulsiveness Scale behavioral factor scores in those in the aggressive group were higher (p < 0.05). The results of logistic regression analysis suggested that a high Positive and Negative Symptom Scale positive factor score (odds ratio = 1.07) and a high Buss-Perry Aggression Questionnaire physical aggression score (odds ratio = 1.02) were risk factors for aggressive behavior.Conclusion: Hospitalized patients with schizophrenia with more severe positive symptoms and aggressive traits may be more prone to aggressive behavior.Keywords: schizophrenia, aggressive behavior, impulsivity trait, aggressive trait, stable patients

Jie Zhou,1,2 Hongjin Xiang,1,2 Jianbo Huang,1,2 Yi Zhong,3 Xiaoxia Zhu,1,2 Jinshun Xu,1,2 Qiang Lu,1,2 Binyang Gao,1,2 Huan Zhang,1,2 Rui Yang,1,2 Yan Luo,1,2 Feng Yan1,2 1Ultrasound Department, West China Hospital of Sichuan University, Chengdu, People’s Republic of China; 2Laboratory of Ultrasound Imaging, West China Hospital of Sichuan University, Chengdu, People’s Republic of China; 3Laboratory of Mitochondria and Metabolism, West China Hospital of Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Feng Yan, Laboratory of Ultrasound Imaging, West China Hospital of Sichuan University, Chengdu, People’s Republic of China, Tel/Fax +86 028 8516 4146, Email yan_feng@scu.edu.cn Yan Luo, Ultrasound Department, West China Hospital of Sichuan University, Chengdu, People’s Republic of China, Tel/Fax +86 028 8542 3192, Email yanluo@scu.edu.cnPurpose: To prepare nanoscale ultrasound contrast agents (Nano-UCAs) and examine the role of their surface charge in complement activation and phagocytosis.Materials and Methods: We analyzed serum proteins present in the corona formed on Nano-UCAs and evaluated two important protein markers of complement activation (C3 and SC5b-9). The effect of surface charge on phagocytosis was further assessed using THP-1 macrophages.Results: When Nano-UCAs were incubated with human serum, they were opsonized by various blood proteins, especially C3. Highly charged Nano-UCAs, whether positive or negative, were favorably opsonized by complement proteins and phagocytized by macrophages.Conclusion: Charged Nano-UCAs show a higher tendency to activated complement system, and are efficiently engulfed by macrophages. The present results provide meaningful insights into the role of the surface charge of nanoparticles in the activation of the innate immune system, which is important not only for the design of targeted Nano-UCAs, but also for the effectiveness and safety of other theranostic agents.Graphical Abstract: Keywords: nanoscale ultrasound contrast agents, surface charge, protein corona, complement activation, opsonization, phagocytosis

Rui Yang,1 Jiayan Huang,1 Min Liao,1 Jianbo Huang,1 Binyang Gao,1 Huan Zhang,1 Jie Zhou,1 Jinshun Xu,2 Qiang Lu1 1Department of Ultrasound, Laboratory of Ultrasound Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China; 2Ultrasound Medical Center, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610041, People’s Republic of ChinaCorrespondence: Qiang Lu, Department of Ultrasound, Laboratory of Ultrasound Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China, Tel/Fax +86 13882175090, Email luqiang@scu.edu.cn Jinshun Xu, Ultrasound Medical Center, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610041, People’s Republic of China, Tel/Fax +86 18708491127, Email jsxu86@163.comBackground: Microwave dynamic therapy (MDT) as a novel reactive oxygen species (ROS)-based therapeutic modality has been explored as a promising modality for cancer treatment. However, the intrinsic hypoxic tumor microenvironment (TME) restricted the effectiveness of the MDT. The aim of this study is to develop an oxygen-sufficient nanoplatform with multi-modal imaging capability for enhanced MDT against hypoxic tumors.Methods and Materials: The liquid perfluorocarbon-based nanoplatform PFP@IR780@O2 was constructed by the phospholipid hydration and sonication method. Then, the characteristics, intracellular uptake process, and subcellular localization of PFP@IR780@O2 were verified. Additionally, the abilities of ROS generation, the anti-hypoxia capability, multi-mode imaging capabilities, and MDT efficacy of the nanoplatform were evaluated via in vitro and in vivo experiments. Finally, the in vivo biocompatibility and toxicity were also evaluated.Results: The prepared nanoparticles PFP@IR780@O2 exhibited suitable size, improved stability, elevated dissolved oxygen level, enhanced cellular uptake, and mitochondria targeting capacity. Additionally, PFP@IR780@O2 demonstrated in vitro and in vivo multimodal imaging capabilities involving ultrasound, fluorescence, and photoacoustic imaging. In vivo studies also indicated that nanoparticles were safe and capable of accumulating in the tumor site after intravenous injection. Furthermore, the PFP@IR780@O2 nanoplatform mediated MDT could effectively alleviate the hypoxic TME, and elevate ROS concentration, thereby resulting in significant tumor growth inhibition.Conclusion: Overall, the oxygen-sufficient nanoplatform with multi-bimodal imaging capability demonstrated improved MDT efficiency, indicating a promising strategy for treating hypoxic tumors.Keywords: nanomedicine, perfluorocarbon, reactive oxygen species, tumor hypoxia relief

Rui Yang,&ast; Xiao-Xia Xu,&ast; Hu Liu, Wei Dai, Zheng-Qin Zhang, Ting-Ting Wang, Shi-Shou Chen, Er-Wei Gu, Xue-Sheng Liu, Bin Mei Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xue-Sheng Liu; Bin Mei, Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, Anhui, 230022, People’s Republic of China, Tel +86 551-62922344, Fax +86 551 62923704, Email liuxuesheng@ahmu.edu.cn; binmei@ahmu.edu.cnObjective: Postoperative sleep disturbance after surgery is not conducive to the recovery of patients. The purpose of this study was to determine the influence of the timing of surgery (morning vs afternoon) on the postoperative sleep quality of elderly patients and to analyze the relationship between the timing of surgery and the change in the melatonin level.Methods: Sixty patients who received hip surgery were randomly assigned to the Morning Group (Group M) or the Afternoon Group (Group A). The sleep quality was assessed by the Richards–Campbell Sleep Questionnaire. Before and after surgery, the nocturnal urine was collected over a 12-h period, and the 6-sulfatoxymelatonin concentration was measured. Also, the incidence of postoperative delirium (POD) was observed.Results: On the first and second nights after surgery, the sleep quality scores of the patients in Group A were greater than those in Group M, and there was no difference in the sleep quality scores between the two groups on the third night after surgery (P=0.000, P=0.002, P> 0.05, respectively). In addition, the urine 6-sulphatoxymelatonin concentration was found to be greater in Group A than in Group M on the first night of surgery (P=0.00). Both the postoperative sleep quality scores and urine 6-sulphatoxymelatonin concentration were significantly less than those before surgery (P=0.00, P=0.00).Conclusion: The postoperative sleep quality scores and melatonin levels of elderly patients who received hip surgery under general anesthesia were significantly less than those of the patients before surgery. Furthermore, the short-term sleep quality of the patients who received surgery in the afternoon was better than that of the patients who received surgery in the morning. This difference may be related to the short-term change of the melatonin level after surgery.Keywords: sleep quality, melatonin, timing of surgery

Mei Ma,1,&ast; Yijia Liu,1,&ast; Lichun Wang,2,&ast; Rongrong Yang,1 Zhu Li,1 Sheng Gao,3 Lin Li,1 Chunquan Yu1 1Department of Graduate Schools, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 2Department of Information Center, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 3Department of Endocrine Metabolic Diseases, Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western Medicine, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lin Li, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China, Email llbianji@163.com Sheng Gao, Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western Medicine, Tianjin, People’s Republic of China, Email gaosheng6747@163.comPurpose: This study explored the relationship between monocyte-to-lymphocyte ratio (MLR) as well as other leukocyte-derived ratios and carotid plaques in patients with coronary heart disease (CHD).Patients and Methods: A total of 12,093 patients with CHD were selected as research participants. Leukocyte-derived ratios assessed in this study included neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), MLR, platelet-to-lymphocyte ratio (PLR), white blood cell-to-mean platelet volume ratio (WMR), lymphocyte×neutrophil/104 ratio (MNM), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI). Leukocyte-derived ratios were divided into four groups according to quarters. Logistic regression analysis was performed to evaluate the relationship between leukocyte-derived ratios and the incidence, number, and echo characteristics of carotid plaques in patients with CHD. Further analysis was performed after adjusting for confounding factors.Results: Among the 12,093 participants, 71.7% had carotid plaques. After adjusting for confounding factors, MLR, NLR, dNLR, PLR, SII, SIRI, and WMR were found to be associated with carotid plaque formation. Among them, MLR had the strongest association with the incidence of carotid plaques (odd ratio[OR]:1.889; 95% confidence interval[CI]:1.406– 2.539) and hyperechoic plaques (OR:2.024; 95% CI:1.481– 2.767). When MLR was viewed as a categorical variable, the risk of carotid plaque formation in Q4 was 1.4 times higher than that in Q1. The relationship between MLR and carotid plaques in females (OR:2.250; 95% CI:1.458– 3.473) was stronger than that in males (OR: 1.638; 95% CI:1.102–-2.436). The relationship between MLR and carotid plaques in patients younger than 65 years (OR:3.597; 95% CI:2.379– 5.439) was stronger than that in those older than 65 years (OR:1.577; 95% CI:1.046– 2.378).Conclusion: Leukocyte-derived ratios were related to the incidence, number, and echo characteristics of carotid plaques. In particular, MLR, an inflammatory biomarker that encompasses innate and adaptive immunity, may be of great value in revealing the incidence and echo characteristics of plaques.Graphical Abstract: Keywords: coronary heart disease, leukocyte-derived ratios, monocyte-to-lymphocyte ratio, carotid plaque

Yimin Chen,1 Thanh N Nguyen,2 James E Siegler,3 Mohammad Mofatteh,4 Jack Wellington,5 Rongshen Yang,6,7 Lihong Zeng,1 Jiale Wu,6,7 Xi Sun,6,7 Daiyu Liang,6,7 Qiubi Tang,8 Sijie Chen,6,7 Xisheng Huang,6,7 Shuiquan Yang,1 Xuxing Liao9,10 1Department of Neurology and Advanced National Stroke Center, Foshan Sanshui District People’s Hospital, Foshan, People’s Republic of China; 2Department of Neurology, Radiology, Boston University School of Medicine, Boston, MA, USA; 3Cooper Neurological Institute, Cooper University Hospital, Camden, NJ, USA; 4School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK; 5School of Medicine, Cardiff University, Cardiff, UK; 6Medical Intern of Neurology Department, Foshan Sanshui District People’s Hospital, Foshan, People’s Republic of China; 7School of Medicine, Shaoguan University, Shaoguan, People’s Republic of China; 8Chronic Disease Department, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 9Dean Office and Advanced National Stroke Center, Foshan Sanshui District People’s Hospital, Foshan, People’s Republic of China; 10Department of Neurosurgery, First People’s Hospital of Foshan, Foshan, People’s Republic of ChinaCorrespondence: Shuiquan Yang, Department of Neurology and Advanced National Stroke Center, Foshan Sanshui District People’s Hospital, No. 16, Guanghaidadaoxi, Sanshui District, Foshan, People’s Republic of China, Email yangshuiquan1969@126.com Xuxing Liao, Dean Office and Advanced National Stroke Center, Foshan Sanshui District People’s Hospital, Foshan, People’s Republic of China, Email drliao210409@163.comPurpose: This study aimed to investigate the impact of characteristic ischemic stroke and outcomes during the first COVID-19 pandemic lockdown.Patients and Methods: A retrospective, observational cohort study of a comprehensive tertiary stroke center was conducted. Patients with ischemic stroke were divided into pre-COVID-19 lockdown (11/1/2019 to 1/30/2020) and COVID-19 lockdown (1/31/2020 to 4/30/2020) period groups. Patient data on stroke admission, thrombolysis, endovascular treatment, and 3-month routine follow-up were recorded. Data analysis was performed using SPSS according to values following a Gaussian distribution.Results: The pre-COVID-19 lockdown period group comprised 230 patients compared to 215 patients in the COVID-19 lockdown period group. Atrial fibrillation was more predominant in the COVID-19 lockdown period group (11.68% vs 5.65%, p=0.02) alongside patients who were currently smoking (38.8% vs 28.7%, p=0.02) and drinking alcohol (30.37% vs 20.00%, p=0.012) compared with that of the pre-COVID-19 lockdown period group. For patients receiving thrombolysis, the median door-to-CT time was longer in the COVID-19 lockdown period group (17.0 min (13.0, 24.0) vs 12.0 min (8.0, 17.3), p=0.012), median door to needle time was 48.0 minutes (35.5, 73.0) vs 43.5 minutes (38.0, 53.3), p=0.50, compared with that of the pre-COVID-19 lockdown period group. There were no differences for patients receiving mechanical thrombectomy. The median length of hospitalization (IQR) was no different. Discharge mRS scores (IQR) were higher in the COVID-19 lockdown period group (1.0 (1.0, 3.0) vs 1.0 (1.0, 2.0), p=0.022). Compared with the pre-COVID-19 lockdown period, hospitalization cost (Chinese Yuan) in the COVID-19 period group was higher (13,445.7 (11,009.7, 20,030.5) vs 10,799.2 (8692.4, 16,381.7), p=0.000). There was no difference observed in 3-month mRS scores.Conclusion: Patients presenting with ischemic stroke during the COVID-19 pandemic lockdown period had longer median door-to-CT time and higher hospitalization costs. There were no significant differences in 3-month outcomes. Multidisciplinary collaboration and continuous workflow optimization may maintain stroke care during the COVID-19 pandemic lockdown.Keywords: ischemic stroke, COVID-19 pandemic, thrombolysis, thrombectomy, hospitalization cost

Mei Ma,1,&ast; Yijia Liu,1,&ast; Fanfan Liu,1 Zhu Li,1 Qi Cheng,1 Zhao Liu,2,&ast; Rongrong Yang,1 Chunquan Yu1 1Department of Graduate Schools, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 2Department of Information Center, Second Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rongrong Yang; Chunquan Yu, Department of Graduate Schools, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China, Email rongrong0423@hotmail.com; ycqtjutcm@foxmail.comAim: This study aimed to elucidate the relationship between the prognostic nutrition index (PNI) of patients with coronary heart disease (CHD) and the New York Heart Association (NYHA) classification and the complex relationship between PNI combined body mass index (BMI) and NYHA classification.Methods: The PNI was applied to 17,413 consecutive patients with CHD. Patients were divided into three groups according to PNI: normal nutrition (PNI ≥ 38), moderate malnutrition (35 < PNI < 38), and severe malnutrition (PNI ≤ 35). A total of 2,052 CHD patients with BMI were selected and stratified by combined subgroups of nutritional status and BMI. Logistic regression analysis was used to evaluate the relationship between the PNI and NYHA classification and to adjust for confounding factors.Results: The prevalence of malnutrition among the 17,413participants with CHD was 4.2%. Moderate and severe malnutrition were significantly related to NYHA class III and V, and the strongest relationship was observed in NYHA class V (odd ratio [OR]: 6.564; 95% confidence interval [CI]: 4.043– 10.658). Malnourished-underweight patients and malnourished-overweight patients were significantly associated with higher NYHA classification, and malnourished-underweight patients (OR: 8.038; 95% CI: 2.091– 30.892) were significantly more than malnourished-overweight patients (OR: 3.580; 95% CI: 1.286– 9.966).Conclusion: There were differences in the NYHA classification of CHD patients with different nutritional statuses. The lower the PNI, the worse the NYHA classification of CHD patients. Malnourished-underweight patients had a worse NYHA classification than malnourished-overweight patients.Graphical Abstract: Keywords: coronary heart disease, prognostic nutrition index, malnourished-underweight, malnourished-overweight, New York Heart Association classification

Zhengquan Dong,1 Zhou Ma,1 Meiju Yang,2 Linlin Cong,2 Ruipeng Zhao,1 Liyun Cheng,3 Jian Sun,1 Yunfei Wang,1 Ruijia Yang,2 Xiaochun Wei,1 Pengcui Li1 1Department of Orthopaedic, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 2Department of Biochemistry and Molecular Biology, the Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 3Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of ChinaCorrespondence: Pengcui Li, Department of Orthopedic, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, Shanxi, People’s Republic of China, Tel +86-13546114630, Email lpc1977@163.comPurpose: To determine the role of histone deacetylase 4 (HDAC4)-controlled chondrocyte hypertrophy in the onset and development of age-related osteoarthritis (OA).Methods: Morphological analysis of human knee cartilages was performed to observe structural changes during cartilage degeneration. HDAC4 expression was deleted in adult aggrecan (Acan)-CreERT2; HDAC4fl/fl transgenic mice. The onset and development of age-related OA were investigated in transgenic and control mice using hematoxylin and eosin (H&E) and Safranin O staining. Furthermore, the progression of ACLT-induced OA following adenovirus-mediated HDAC4 overexpression was explored in rats. The expression levels of genes related to hypertrophy, cartilage matrix and its digestion, and chondrocyte proliferation were investigated using qPCR. Immunohistochemistry (IHC) was used to explore the mechanisms underlying HDAC4-controlled age-related changes in OA progression.Results: In human cartilage, we performed morphological analysis and IHC, the results showed that hypertrophy-related structural changes are related to HDAC4 expression. Age-related OA was detected early (OARSI scores 2.7 at 8-month-old) following HDAC4 deletion in 2-month-old mice. Furthermore, qPCR and IHC results showed changes in hypertrophy-related genes Col10a1, Runx2 and Sox9 in chondrocytes, particularly in the expression of Runt-related transcription factor 2 (Runx2, 13.29± 0.99 fold). The expression of the main cartilage matrix-related genes Col2a1 and Acan decreased, that of cartilage matrix digestion-related gene MMP-13 increased, while that of chondrocyte proliferation-related genes PTHrP, Ihh and Gli1 changed. In contrast, rat cartilage’s qPCR and IHC results showed opposite outcomes after HDAC4 overexpression.Conclusion: Based on the results above, we concluded that HDAC4 expression regulates the onset and development of age-related OA by controlling chondrocyte hypertrophy. These results may help in the development of early diagnosis and treatment of age-related OA.Keywords: osteoarthritis, HDAC4, cartilage, chondrocytes, degeneration

Fulai Tu,1,&ast; Ruizhe Yang,2,&ast; Weixiang Wang,3,&ast; Rui Li,1,&ast; Guoping Du,4 Yangyang Liu,1 Wei Li,5 Pingmin Wei1 1Key Laboratory of Environmental Medicine Engineering, Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, 210009, People’s Republic of China; 2Department of Prevention and Health Care, Children’s Hospital of Nanjing Medical University, Nanjing, 210008, People’s Republic of China; 3Department of Acute Infectious Disease Control, Nanjing Municipal Center for Disease Control and Prevention, Nanjing, 210003, People’s Republic of China; 4Department of General Practice, Southeast University Hospital, Nanjing, 210018, People’s Republic of China; 5Department of Quality Management, Children’s Hospital of Nanjing Medical University, Nanjing, 210009, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pingmin Wei, Key Laboratory of Environmental Medicine Engineering, Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, 210009, People’s Republic of China, Tel/Fax +86 025 87232481, Email mpw1963@126.com Wei Li, Department of Quality Management, Children’s Hospital of Nanjing Medical University, Nanjing, 210009, People’s Republic of China, Tel/Fax +86 025 52862911, Email weili126@126.comObjective: We aimed to describe the knowledge, attitude and practice (KAP) status of hepatitis B virus (HBV) among freshmen who were in the class of 2020 and from Jiangsu Province.Methods: A random multistage sampling had been used to screen freshmen to conduct online questionnaire. The chi-square test was applied for pairwise comparison between sub-groups. Lasso regression and logistic regression were used to analyze the influencing factors of KAP about HBV. A structural equation model was established to explore the relationships among KAP of HBV.Results: The total awareness rate of HBV among freshmen was 63.1%. More than 50% of freshmen reported that they were not willing to live with hepatitis B carriers. Only 51.0% of students had been immunized against HBV. The knowledge of HBV among students whose fathers had college/bachelor degree or above was 1.464 times higher than those whose fathers’ education level was junior high school or below (95% CI = 1.277∼ 1.677). Both of positive attitude and behavior among female students were 1.424 times (95% CI = 1.329∼ 1.525) and 1.468 times (95% CI = 1.291∼ 1.669) than that within male students, respectively. The positive behaviors of students whose mothers had college education or above were 1.347 times higher than those whose mothers had the degree of junior high or below (95% CI = 1.147∼ 1.582). Students who living with their parents were 1.167 times likely to have positive behaviors than those who living in other methods (95% CI = 1.020∼ 1.334). The structural equation model had shown that the direct effect of knowledge on preventive motivation, attitude and behavior was 0.28, 0.53 and 0.10, respectively.Conclusion: The population of freshmen still was far from a comprehensive understanding of HBV prevention and treatment. It is suggested that administrators of colleges and universities should pay more attentions to education of HBV knowledge as well as take multi-channel measures for prevention and management.Keywords: hepatitis B virus, knowledge attitude and practice, freshmen, Lasso-logistic regression, structural equation model

Rui Yang,1,&ast; Leilei Wang,2,&ast; Zhifeng Wu,3 Yongxiang Yin,4 Shi-Wen Jiang1 1Center of Reproductive Medicine, State Key Laboratory of Reproductive Medicine, Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, 214002, Jiangsu, People’s Republic of China; 2Department of Medical Genetics, Lianyungang Maternal and Child Health Hospital Affiliated to Yangzhou University, Lianyungang, 222000, Jiangsu, People’s Republic of China; 3Department of Ophthalmology, The Affiliated Wuxi Clinical College of Nantong University, Wuxi, 214002, Jiangsu, People’s Republic of China; 4Department of Pathology, The Affiliated Maternity and Child Health Hospital of Nanjing Medical University, Wuxi, 214002, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shi-Wen Jiang, Center of Reproductive Medicine, State Key Laboratory of Reproductive Medicine, Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, 214002, Jiangsu, People’s Republic of China, Tel +86-13730975986, Fax +86-510-82725094, Email jiangsw137@163.comAbstract: Accumulated data indicated that many types of cancers have increased protein O-GlcNAcylation at cell surface and inside cells. The aberrant O-GlcNAcylation is considered a potential therapeutic target. Although several types of compounds capable of inhibiting O-GlcNAcylation have been developed, their low solubility, poor permeability and delivery efficiency have impeded the application for in vivo and pre-clinical studies. Nanocarriers have the advantages of controllable drug release and active cancer-targeting capability. Moreover, nanoparticles can improve drug delivery efficiency and reduce the non-specific distribution in normal tissues by the enhanced permeability and retention (EPR) effect in cancer. Taking the advantage of O-GlcNAc-specific antibodies or lectins, nanoparticles could further improve their cancer-targeting capability. Although nanocarriers targeting the canonical N- and O-linked glycosylation have been extensively investigated for cancer detection and therapy, application of nanotechniques for the specific targeting of O-GlcNAcylation has not been actively pursued. This review summarizes the general features of GlcNAcylation and its alterations in cancers. Analyses are focused on the following areas: How the nanocarriers may improve the solubility and/or cell permeability of O-GlcNAc transferase (OGT) inhibitors; The modification of nanocarriers with lectins or antibodies for active targeting of O-GlcNAc; The nanocarriers-mediated co-delivery of OGT inhibitors and conventional drugs, which may lead to synergistic effects. Unsolved issues impeding the research progression on O-GlcNAcylation-targeting scheme are also discussed.Graphical Abstract: Keywords: O-GlcNAcylation, nanocarriers, OGT inhibitor, targeted therapy, lectin, combined therapy

Hongyan Chen,1,&ast; Yang He,2,&ast; Xiaoling Zeng,3,&ast; Qing Chen,3 Niya Zhou,3 Huan Yang,3 Wenzheng Zhou,1 Liwen Zhang,3 Rong Yang,4 Qiao Huang,4 Hua Zhang5 1Quality Management Department, Chongqing Health Center for Women and Children, Chongqing, People’s Republic of China; 2Operating Room, Chongqing Health Center for Women and Children, Chongqing, People’s Republic of China; 3Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China; 4Obstetric Outpatient Department, Chongqing Health Center for Women and Children, Chongqing, People’s Republic of China; 5Administration Office, Chongqing Health Center for Women and Children, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hua Zhang, Administration Office, Chongqing Health Center for Women and Children, No. 120, Longshan Road, Yubei District, Chongqing, People’s Republic of China, Email cqfyzhanghua@163.com Qiao Huang, Obstetric Outpatient Department, Chongqing Health Center for Women and Children, No. 120, Longshan Road, Yubei District, Chongqing, People’s Republic of China, Email 1013658406@qq.comPurpose: To investigate whether pregnant women’s subjective sleep quality during the first trimester independently predicted blood glucose and gestational diabetes mellitus (GDM).Methods: A total of 4550 pregnant women in the first trimester were enrolled in Chongqing Health Center for Women and Children, China, from January to October 2020.The Pittsburgh Sleep Quality Index (PSQI) was used to measure subjective sleep quality. Depression symptoms and anxiety were measured with the Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7). Oral glucose tolerance tests (OGTT) and blood glucose area under the curve (AUC) were used for estimation of blood glucose and diagnosis of GDM during the second trimester. Linear, mixed model, and logistic regression were used to analyze the association between PSQI and blood glucose as well as GDM.Results: 946/4550 were diagnosed with GDM (20.8%). In the mixed model analysis, the blood glucose level of the highest-scoring group (PSQI score = 18) was 1.94 (95% CI: 0.45∼ 3.43, P = 0.011) mmol/L higher than that of the lowest-scoring group (PSQI score = 0). After adjusting for potential confounders, a one-point PSQI score increase was associated with a 0.014 (95% CI: 0.001∼ 0.027, P = 0.039) mmol/L increase in blood glucose level. Blood glucose AUC was also positively associated with PSQI scores (β = 0.034, 95% CI: 0.003∼ 0.064, P = 0.030). The results for the logistic regression model showed that PSQI was marginal positively correlated with GDM (OR = 1.146, 95% CI: 0.995∼ 1.321, P = 0.059) when age and BMI were not controlled for. When investigating the association between PSQI and the GDM-diagnosed time window, the 1-h diagnosed GDM had a borderline positive correlation with PSQI (OR = 1.182, 95% CI: 0.993∼ 1.405, P = 0.060).Conclusion: Sleep quality during the first trimester may be a risk factor for elevated blood glucose and GDM later in gestation.Keywords: gestational diabetes mellitus, PSQI, blood glucose AUC, sleep disturbance

Guoping Du,1,&ast; Chao Li,2,&ast; Yangyang Liu,3,&ast; Fulai Tu,3 Ruizhe Yang,4 Rui Li,3 Hongbing Shen,2 Wei Li5 1Department of General Practice, Southeast University Hospital, Nanjing, Jiangsu, People’s Republic of China; 2Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 3Key Laboratory of Environmental Medicine Engineering, Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, Jiangsu, People’s Republic of China; 4Department of Prevention and Health Care, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 5Department of Quality Management, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Li, Department of Quality Management, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China, Tel/Fax +86 025 52862911, Email weili126@126.com Hongbing Shen, Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China, Tel/Fax +86 025 86868409, Email hbshen@njmu.edu.cnBackground: Adolescents aged from 19 to 22 are the main high-risk population of pulmonary tuberculosis (PTB). This study aimed to understand the current status of knowledge, attitudes and practices (KAP) about TB among freshmen from Jiangsu colleges and universities. Analyze its influencing factors and explore the interrelationships of KAP. This provides a basis for building a reversing mechanism for health education on tuberculosis prevention and treatment in middle and high schools.Methods: A multistage randomly was used to select freshmen to conduct this online survey. The χ2 test was used to compare the rates. Construct linear regression model, logistic regression model, decision tree model and random forest model, use grid search to adjust the parameters of the model, and use multiple models to explore the influencing factors of the overall awareness rate of students’ core knowledge of tuberculosis.Results: A total of 6980 freshmen in colleges and universities were investigated. The total awareness rate was 89.02%, and the awareness rate of all core knowledge about TB was 58.94%. It is characterized by general demographic data, and all core knowledge is known as a label to establish a model, based on the f1- of the four models The score believes that the random forest model has the best fitting effect, and the ranking of the influencing factors included in the model is school type (0.72) >father’s education (0.15) >family monthly income (0.03) >mother’s education, gender, region (0.02); a structural equation model is established, and the modified knowledge and attitude path coefficient is 0.29 (P< 0.05); the attitude and behavior path coefficient is 0.64 (P< 0.05).Conclusion: The total awareness rate of core knowledge of Jiangsu college freshmen reaches the national requirements, but the overall awareness rate is low. It is necessary to strengthen the health education of tuberculosis for those with identified risk factors.Keywords: knowledge, attitudes and practices, tuberculosis, freshmen

Kaidian Chen,1,&ast; Yao Lin,1,&ast; Yuchun Liu,1,&ast; Shuanglin Liao,2 Ruoxuan Yang,1 Jiefeng Huang,1 Mingwei Xu,1 Junbing He1 1The Intensive Care Unit, Jieyang Affiliated Hospital, Sun Yat-sen University, Jieyang, Guangdong, People’s Republic of China; 2The Intensive Care Unit, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Junbing He; Mingwei XuThe Intensive Care Unit, Jieyang Affiliated Hospital, Sun Yat-sen University, Tianfu Road 107, Rongcheng district, Jieyang, 522000, Guangdong Province, People’s Republic of ChinaEmail junbinghe_gmc@163.com; mingweixu_gmc@126.comBackground: Complement 5 (C5) and C5a production play a pivotal role in the pathophysiology of sepsis. Strong evidence demonstrates an association of C5 gene polymorphisms with various inflammatory diseases. However, no current studies have explored the clinical relevance of C5 polymorphisms in sepsis.Methods: Two C5 gene polymorphisms, rs17611 and rs2269067, were identified by genotyping in 636 sepsis patients and 753 controls in a Han Chinese population. C5 gene expression was detected via quantitative real-time PCR. C5a and proinflammatory cytokine production was measured by enzyme-linked immunosorbent assay. An Annexin V apoptosis assay was performed to assess cell apoptosis.Results: Our results showed significantly lower frequencies of rs2269067 GC/CC genotypes or C allele in sepsis patients than healthy controls. The frequencies of rs17611 CC/CT genotypes or C allele were significantly overrepresented in both the septic shock and non-survivor subgroups. Patients with this sepsis-associated high-risk rs17611 C allele exhibited a significant increase in C5a, TNF-α and IL-6 production. However, no significant difference in C5a and downstream proinflammatory cytokine production was observed among patients with different rs2269067 genotypes. In addition, in vitro experiments showed an effect of recombinant C5a on enhancing LPS-stimulated IL-1β, IL-6 and TNF-α production and cell apoptosis in THP-1 monocytes.Conclusion: The rs2269067 polymorphism conferred protection against sepsis susceptibility. The rs17611 polymorphism was associated with increased C5a production, which ultimately potentiated the secretion of downstream proinflammatory cytokines and conferred susceptibility to sepsis progression and poor prognosis.Keywords: C5, C5a, polymorphism, sepsis, inflammation

Rong Qiao,1,&ast; Mengxia Li,2,&ast; Runbo Zhong,1 Yujie Wei,3 Jun Wang,3 Zheng Zhang,3 Ling Wang,3 Tian Xu,4 Yue Wang,1 Liping Dai,5 Wanjian Gu,4 Baohui Han,1 Rongxi Yang2,3 1Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 200030, People’s Republic of China; 2Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 210000, People’s Republic of China; 3Nanjing TANTICA Biotechnology Co. Ltd, Nanjing, 210000, People’s Republic of China; 4Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210000, People’s Republic of China; 5Henan Institute of Medical and Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rongxi Yang; Baohui Han Fax +86 25 86527613Email rongxiyang@njmu.edu.cn; 18930858216@163.comPurpose: Lung cancer (LC) brings great burden to the society worldwide. Exploring novel biomarkers in vitro for the early detection of LC would be of great importance.Patients and Methods: We measured DNA methylation levels of 21 CpG sites within Patatin-like phospholipase domain containing 2 (PNPLA2) gene in the peripheral blood of 168 early-stage LC cases (94.0% LC at stage I) and 187 age- and gender-matched cancer-free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression adjusted for covariates. Non-parametric tests were applied for the comparisons of stratified groups.Results: Hypomethylation of PNPLA2_CpG_8,10 and hypermethylation of PNPLA2_CpG_9 were correlated to the early-stage LC with the ORs of 1.44 (95% CI: 1.06– 1.96, P = 0.018) and 0.82 (95% CI: 0.69– 0.98, P = 0.029), respectively. The associations were still significant for the very early-stage LC patients (stage I). Further gender- and age-stratified analyses indicated that the association between hypomethylation of PNPLA2_CpG_8,10 and LC existed only in females and in subjects younger than 55 years. In addition, the association between LC and hypermethylation of PNPLA2_CpG_6 and PNPLA2_CpG_9 was also observed in the younger population.Conclusion: Taken together, our study has proved the hypothesis that the altered methylation in the peripheral blood may be correlated with the burden of cancer at an early stage. Here, we find a novel association between blood-based aberrant PNPLA2 methylation and LC at a very early stage and particularly for women at a younger age.Keywords: lung cancer, DNA methylation, peripheral blood, biomarker

Chen He,1 Huiyan Ding,1 Jing Chen,1 Yinan Ding,1 Rui Yang,2 Chunmei Hu,3 Yanli An,1 Dongfang Liu,1 Peidang Liu,1 Qiusha Tang,1 Zhiyuan Zhang4 1Medical School of Southeast University, Nanjing, People’s Republic of China; 2Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, People’s Republic of China; 3Department of Tuberculosis, The Second Affiliated Hospital of Southeast University (The Second Hospital of Nanjing), Nanjing, People’s Republic of China; 4Department of Neurosurgery, Nanjing Jinling Hospital, Nanjing University, Nanjing, People’s Republic of ChinaCorrespondence: Qiusha TangMedical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, People’s Republic of ChinaEmail panyixi-tqs@163.comZhiyuan ZhangDepartment of Neurosurgery, Nanjing Jinling Hospital, Nanjing University, Nanjing, People’s Republic of ChinaEmail zzy8896@163.comBackground: Inducing the immunogenic cell death of tumour cells can mediate the occurrence of antitumour immune responses and make the therapeutic effect more significant. Therefore, the development of treatments that can induce ICD to destroy tumour cells most effectively is promising. Previously, a new type of pH-sensitive polymersome was designed for the treatment of glioblastoma which represents a promising nanoplatform for future translational research in glioblastoma therapy. In this study, the aim of this work was to analyse whether chemoradiotherapy of the novel pH-sensitive cargo-loaded polymersomes can induce ICD.Methods: Cell death in U87-MG and G422 cells was induced by Au-DOX@PO-ANG, and cell death was analysed by CCK-8 and flow cytometry. The release of CRT was determined by using laser scanning confocal microscopy and flow cytometry. ELISA kits were used to detect the release of HMGB1 and ATP. The dying cancer cells treated with different treatments were cocultured with bone-marrow-derived dendritic cells (BMDCs), and then flow cytometry was used to determine the maturation rate of BMDCs (CD11c+CD86+CD80+) to analyse the in vitro immunogenicity. Tumour vaccination experiments were used to evaluate the ability of Au-DOX@PO-ANG to induce ICD in vivo.Results: We determined the optimal treatment strategy to evaluate the ability of chemotherapy combined with radiotherapy to induce ICD and dying cancer cells induced by Au-DOX@PO-ANG+RT could induce calreticulin eversion to the cell membrane, promote the release of HMGB1 and ATP, and induce the maturation of BMDCs. Using dying cancer cells induced by Au-DOX@PO-ANG+RT, we demonstrate the efficient vaccination potential of ICD in vivo.Conclusion: These results identify Au-DOX@PO-ANG as a novel immunogenic cell death inducer in vitro and in vivo that could be effectively combined with RT in cancer therapy.Keywords: immunogenic cell death, ICD, glioblastoma, radiotherapy, polymersomes, nanodrug delivery system

Han Ren, Rui Yang Business School, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Han RenBusiness School, Sichuan University, No. 24 South Section 1, Yihuan Road, Chengdu, 610064, People’s Republic of ChinaEmail renhan_90_12@126.comPurpose: Drawing on the uncertainty management theory, this study explores the relationships between paradoxical leader behaviors (PLB) and followers perceptions of overall justice and organizational citizenship behaviors (OCB), as well as the mediating role of two components of followers perceptions of renqing (affective interaction and discretionary consideration) and the moderating role of trait agreeableness.Methods: This study employed two-wave surveys with the aim of reducing the potential risk of common method bias. Participants were 325 employees from seven enterprises located in Northern and Southwest China. A moderated-mediation path analysis based on Hayes’ Process Model was performed in AMOS to examine the hypotheses.Results: Results from two-wave surveys of 325 Chinese employees indicated that PLB is positively related to followers perceptions of overall justice. Two components of followers perceptions of renqing significantly mediate the relationship between PLB and overall justice. Moreover, two components of perceptions of renqing and overall justice exert a serial mediation effect in the relationship of PLB and OCB. More importantly, followers trait agreeableness strengthens the effects of affective interaction on overall justice.Conclusion: This study advances the current understandings of the influencing mechanisms between PLB and followers overall justice perceptions and OCB. It is suggested that leaders PLB will facilitate two components of followers perceptions of renqing first, then boost their perceptions of overall justice, which in turn leading to more OCB, especially for those followers who endorse more agreeableness.Keywords: paradoxical leader behaviors, perception of renqing, overall justice, organizational citizenship behaviors, trait agreeableness

Rui Yang,1,2 Qiang Lu,1 Jinshun Xu,1,2 Jiayan Huang,1 Binyang Gao,1,2 Huan Zhang,1,2 Jie Zhou,1,2 Lanxin Du,1 Feng Yan2 1Ultrasound Department, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Laboratory of Ultrasound Imaging, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Feng YanLaboratory of Ultrasound Imaging, West China Hospital of Sichuan University, No. 88 Keyuan Road South, Chengdu, Sichuan, 610041, People’s Republic of ChinaTel +86 18980606323Email yan_feng@scu.edu.cnPurpose: To identify and validate contrast-enhanced ultrasound (CEUS) features for differentiating malignant from benign splenic lesions.Patients and Methods: Splenic lesions in 123 patients who underwent conventional ultrasound (B-mode US) and CEUS were included in this study. Two radiologists evaluated the sonograms of B-mode and CEUS. Statistical analysis was performed to identify significant imaging predictors for splenic malignant lesions. Two other radiologists independently reviewed B-mode and CEUS sonograms and diagnosed the lesions based on proposed criteria as 1) benign, 2) probably benign, 3) probably malignant or 4) malignant. The diagnostic efficiency between B-mode US and CEUS was compared.Results: Common imaging findings of malignant lesions included hypoechoic, ill-defined margin, absence of cystic/necrotic portion, presence of splenomegaly on B-mode US, and hypoenhancement, rapid washout and presence of intralesional vessels on CEUS (P < 0.05). Among them, three independent features were identified using multivariate logistic regression analysis: hypoechoic pattern, hypoenhancement pattern and intralesional vessels. When three of these findings were combined as a predictor for splenic malignant lesions, 22 (55.0%) of 40 malignant splenic lesions were identified with a specificity of 100%. The diagnostic performance of two readers using receiver operating characteristic curve analysis was 0.622 and 0.533, respectively, for B-mode US, which was significantly improved to 0.908 and 0.906 for CEUS (P < 0.001). The degree of other diagnostic efficiency and inter-reader agreement also increased with CEUS compared to B-mode US.Conclusion: CEUS may provide more useful information than B-mode US and improve the diagnosis efficiency for distinguishing malignant from benign splenic lesions.Keywords: spleen, splenic diseases, contrast-enhanced ultrasound, conventional ultrasound

Hongchun Chen,1,2 Yuchen Huang,1,2 Ningning Yang,1,2 Wentian Yan,1,2 Ruxue Yang,3 Shan Zhang,4 Panpan Yang,5 Nan Li,1,2 Zhenzhong Feng1,2 1Department of Pathology, Bengbu Medical College, Bengbu, Anhui Province, 233000, People’s Republic of China; 2Department of Pathology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, 233000, People’s Republic of China; 3Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230000, People’s Republic of China; 4Department of Pathology, Second People’s Hospital of Hefei, Hefei, Anhui Province, 230000, People’s Republic of China; 5Department of Pathology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230000, People’s Republic of ChinaCorrespondence: Zhenzhong FengDepartment of Pathology, First Affiliated Hospital of Bengbu Medical College, No. 287 Changhuai Road, Longzihu District, Bengbu, Anhui, 233000, People’s Republic of ChinaTel +86 1 505 528 9508Email fzz18297301626@163.comPurpose: Solid-pseudopapillary neoplasm (SPN) of the pancreas, a rare tumor, has low malignant potential. However, some patients develop metastasis and recurrence after resection, with aggressive biological behaviors. This study aimed to explore the features and risk factors associated with the aggressive biological behaviors of SPNs.Patients and Methods: We retrospectively analyzed the clinicopathological and long-term follow-up data of 63 patients diagnosed with SPN at the First Affiliated Hospital of Bengbu Medical College between January 2007 and February 2019.Results: Sixty-three patients presented atypical clinical symptoms. The median tumor size was 7.0 cm (range, 2.4– 17 cm), and imaging features were solid and cystic or solid tumors with uneven density. Frequent and diffuse nuclear LEF1 protein expression (94.2%) was observed with LEF1 having a higher sensitivity and specificity. Overall survival significantly correlated with tumor size, Ki-67 index, and lymph node metastasis (P < 0.05).Conclusion: SPN is a rare low-grade malignancy with a specific pseudopapillary structure. LEF1 is an effective biomarker of SPNs. Although SPNs generally display indolent biological behavior, a large tumor size, high proliferation index, and lymph node metastasis may be risk factors for the aggressive behavior and poor prognosis of SPN.Keywords: pancreatic tumor, LEF1, retrospective study, overall survival, metastasis

Shengsheng Lai,1,* Lei Sun,2,* Jialiang Wu,3 Ruili Wei,4 Shiwei Luo,4 Wenshuang Ding,5 Xilong Liu,6 Ruimeng Yang,4 Xin Zhen2 1School of Medical Equipment, Guangdong Food and Drug Vocational College, Guangzhou, Guangdong, 510520, People’s Republic of China; 2School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 3Department of Radiology, The University of Hong Kong Shenzhen Hospital, Shenzhen, Guangdong, 518000, People’s Republic of China; 4Department of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People’s Republic of China; 5Department of Pathology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People’s Republic of China; 6Department of Radiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ruimeng YangDepartment of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People’s Republic of ChinaTel +86-20-81048873Email eyruimengyang@scut.edu.cnXin ZhenSchool of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of ChinaTel +86-20-62789323Email xinzhen@smu.edu.cnObjective: To investigate the predictive performance of different machine learning models for the discrimination of low and high nuclear grade clear cell renal cell carcinoma (ccRCC) by using multiphase computed tomography (CT)-based radiomic features.Materials and Methods: A total of 137 consecutive patients with pathologically proven ccRCC (including 96 low-grade [grade 1 or 2] and 41 high-grade [grade 3 or 4] ccRCC) from January 2011 to January 2019 were enrolled in this retrospective study. Target region of interest (ROI) delineation followed by texture extraction was performed on a representative slice with the largest section of the tumor on the four-phase (unenhanced phase [UP], corticomedullary phase [CMP], nephrographic phase [NP] and excretory phase [EP]) CT images. Fifteen concatenations of the four-phase features were fed into 176 classification models (built with 8 classifiers and 22 feature selection methods), the classification performances of the 2640 resultant discriminative models were compared, and the top-ranked features were analyzed.Results: Image features extracted from the unenhanced phase (UP) CT images demonstrated a dominant classification performance over features from the other three phases. The discriminative model “Bagging + CMIM” achieved the highest classification AUC of 0.75. The top-ranked features from the UP included one shape-based feature and five first-order statistical features.Conclusion: Image features extracted from the UP are more effective than other CT phases in differentiating low and high nuclear grade ccRCC based on machine learning–based classification modeling.Keywords: clear cell renal cell carcinoma, Fuhrman nuclear grade, computed tomography, machine learning, classification

Rui Yang,1 Rui-hong Liu,1 Jia-nan Xu,1 Guang-hong Xu,1,2 Xiao-bin Jin,1 Rui Xiao,1 Bin Mei1 1Department of Anesthesiology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China; 2Department of Neurology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of ChinaCorrespondence: Guang-hong XuDepartment of Anesthesiology, First Affiliated Hospital, Anhui Medical University, 218 Jixi Road, Hefei, Anhui, 230022, People’s Republic of ChinaTel +86-551-62922344Fax +86 551 62923704Email xuguanghong2004@163.comBackground: Both lumbosacral plexus block (LSPB) and local infiltration analgesia (LIA) can provide postoperative analgesia for patients undergoing total hip arthroplasty (THA). The current study aimed to compare the differences between LSPB and LIA on postoperative pain and quality of life (QoL) in THA patients.Methods: A total of 117 patients aged 40– 80 years, ASA I-III, were prospectively randomized into two groups: a general anesthesia plus LSPB (Group LSPB) and a general anesthesia plus LIA (Group LIA). Pain intensity and opioid consumption were recorded Within 72 hours after surgery. QoL was measured by EQ-5D and EQ-VAS questionnaires, and the incidence of postoperative pain was measured as part of the EQ-5D on day 1, day 3, day 7, and month 1, month 3, and month 6 after surgery.Results: EQ-5D scores: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression were higher in Group LSPB versus Group LIA throughout six-month follow-ups (p = 0.039). The pain intensity was lower in Group LSPB than in Group LIA 0– 12 h after surgery (2.41 vs 2.79, p = 0.01), but was higher in Group LSPB than in Group LIA 12– 24 h (2.59 vs 2.05, p = 0.02) and 24– 48 h (2.18 vs 1.73, p = 0.02) after surgery. There were no differences in opioid consumption between the groups during the first 72 postoperative hours. In the first month after surgery, more patients in Group LSPB than in Group LIA had no pain (52 vs 40, p = 0.04).Conclusion: Both LSPB and LIA can provide satisfactory postoperative analgesia. The LSPB is better than LIA for long-term QoL in THA patients undergoing general anesthesia.Clinical Trial Registration Number: The Chinese Clinical Trial Registry (ChiCTR-INR-17012545).Keywords: total hip arthroplasty, lumbosacral plexus block, local infiltration analgesia, postoperative pain, quality of life

Renchi Yang,1 Yongqiang Zhao,2 Xuefeng Wang,3 Jing Sun,4 Runhui Wu,5 Chenghao Jin,6 Jie Jin,7 Depei Wu,8 Pablo Rendo,9 Feifei Sun,10 Jeremy Rupon,9 Francois Huard11,†, Joan M Korth-Bradley,12 Lihong Xu,10 Binyu Luo,10 Yingxue Cathy Liu13 1Thrombosis and Hemostasis Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, People’s Republic of China; 2Department of Hematology, Peking Union Medical College Hospital, Beijing, People’s Republic of China; 3Department of Clinical Blood Transfusion, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 5Department of Hematology, Beijing Children’s Hospital and Capital Medical University, Beijing, People’s Republic of China; 6Department of Hematology, Jiangxi Provincial People’s Hospital, Jiangxi, People’s Republic of China; 7Department of Hematology, The First Affiliated Hospital – Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 8Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 9Rare Disease, Pfizer Inc, Collegeville, PA, USA; 10 Pfizer (China) Research & Development Co, Ltd, Shanghai, People’s Republic of China; 11Clinical Pharmacology, Pfizer PIO, Paris, France; 12Pfizer Inc, Collegeville, PA, USA; 13Statistics, Pfizer (China) Research & Development Co, Ltd, Shanghai, People’s Republic of China†Dr. Francois Huard passed away on July 20, 2017.Correspondence: Renchi Yang Email rcyang65@163.comIntroduction: Moroctocog alfa albumin-free cell culture (AF-CC) increases plasma levels of factor VIII (FVIII) activity and, in China, is indicated for the control and prevention of bleeding episodes in patients with hemophilia A. This study aimed to evaluate the efficacy, safety, and recovery data of moroctocog alfa (AF-CC) in patients with hemophilia participating in two open-label studies, both conducted in China.Methods: The authorization study (clinicaltrials.gov identifier NCT00868530) enrolled patients aged ≥ 6 years, previously treated with ≥ 1 exposure day of FVIII replacement therapy. The real-world study (clinicaltrials.gov identifier NCT02492984) enrolled patients of any age who were previously untreated or requiring surgical prophylaxis. In both studies, on-demand treatment was administered over 6 months. Key assessments included response to treatment, FVIII inhibitor development, and recovery.Results: In the authorization study (N = 53; mean age, 23.2 years; severe hemophilia, 23%), response was excellent/good for 90% of infusions at 24 hours. Seven patients developed inhibitors. Mean (SD) FVIII recovery at the initial and final visits was 1.77 (0.50) and 1.67 (0.45) (IU/dL)/(IU/kg), respectively. In the real-world study (N = 85; mean age, 9.5 years; severe hemophilia, 58%), response was rated as excellent or good for most (87%) on-demand infusions and for all surgical prophylaxis patients (n = 14). Seven patients developed FVIII inhibitors. Mean (SD) FVIII recovery at the initial and final visits was 1.71 (0.50) and 1.68 (0.31) (IU/dL)/(IU/kg), respectively. No new safety signals were observed in either study.Conclusion: On-demand treatment and surgical prophylaxis with moroctocog alfa (AF-CC) is safe and effective for both previously treated and previously untreated Chinese patients with hemophilia A.Keywords: Asian, blood coagulation factor VIII, deficiency, factor VIII, ReFacto, Xyntha

Rui Yang,1,* Mudan Lu,2,* Lan Ming,1,* Yu Chen,1 Kai Cheng,1 Jie Zhou,1 Shiwen Jiang,1 Zhenyu Lin,3 Daozhen Chen1 1Research Institute for Reproductive Health and Genetic Diseases, Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, People’s Republic of China; 2Internal Medicine, Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, People’s Republic of China; 3Ministry of Education Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection for Food Safety, College of Chemistry, Fuzhou University, Fuzhou 350116, People’s Republic of China*These authors contributed equally to this workCorrespondence: Daozhen ChenResearch Institute for Reproductive Health and Genetic Diseases, Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, People’s Republic of ChinaTel +86-13584189188Fax +86-510-82725094Email chendaozhen@163.comPurpose: Therapy for triple-negative breast cancer (TNBC) is a global problem due to lack of specific targets for treatment selection. Cancer stem cells (CSCs) are responsible for tumor formation and recurrence but also offer a promising target for TNBC-targeted therapy. Here, zirconium-89 (89Zr)-labelled multifunctional liposomes (MLPs) surface-decorated with chitosan (CS) were fabricated to specifically target and trace cluster of differentiation 44+ (CD44+) TNBC CSCs specifically.Patients and Methods: The biological basis of CS targeting CD44 for cancer therapy was investigated by detecting the expression of CD44 in TNBC CSCs and TNBC tissues. Molecular docking and dynamics simulations were performed to investigate the molecular basis of CS targeting CD44 for cancer therapy. Gambogic acid (GA)-loaded, 89Zr@CS-MLPs (89Zr-CS-GA-MLPs) were prepared, and their uptake and biodistribution were observed. The anti-tumor efficacy of 89Zr@CS-GA-MLPs was investigated in vivo.Results: CD44 is overexpressed in TNBC CSCs and tissues. Molecular docking and dynamics simulations showed that CS could be stably docked into the active site of CD44 in a reasonable conformation. Furthermore, 89Zr@CS-GA-MLPs were able to bind specifically to CD44+ TNBC stem-like cells and accumulated in tumors of xenograft-bearing mice with excellent radiochemical stability. 89Zr@CS-GA-MLPs loaded with GA showed remarkable anti-tumor efficacy in vivo.Conclusion: The GA-loaded, 89Zr-labelled, CS-decorated MLPs developed in this study represent a novel strategy for TNBC imaging and therapy.Keywords: radionuclide, PET, CS, CD44, molecular docking, molecular dynamics simulation

Rong Qiao,1,* Feifei Di,2,* Jun Wang,2 Yujie Wei,2 Yanman Zhang,2 Tian Xu,3 Yue Wang,1 Wanjian Gu,3 Baohui Han,1 Rongxi Yang2,4 1Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, People’s Republic of China; 2Department of Research and Academic, Nanjing TANTICA Biotechnology Co. Ltd, Nanjing 210000, People’s Republic of China; 3Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210000, People’s Republic of China; 4Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 210000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rongxi Yang; Baohui Han Email rongxiyang@njmu.edu.cn; 18930858216@163.comBackground: Early detection is essential to improve the survival and life quality of lung cancer (LC) patients. Changes of peripheral blood DNA methylation could be associated with malignancy but were mostly studied in Caucasians.Methods: Here, in a Chinese population, we performed mass spectrometry assays to investigate the association between very early stage LC and methylation levels of RAPSN in the peripheral blood by a case–control cohort using of 221 LC patients (93.2% LC at stage I) and 285 unrelated cancer free control individuals.Results: The odds ratios (ORs) of all CpG sites were evaluated for their risk to LC using inter-quartile analyses by logistic regression. In general, we observed an association between very early LC and decreased methylation of RAPSN_CpG_1.15 and RAPSN_CpG_3.4 (referring to Q4, OR range from 1.64 to 1.81, p< 0.05). Stratified by gender, while hypomethylation of RAPSN_CpG_1.15, RAPSN_CpG_3.4 and RAPSN_CpG_7.14 were associated with LC in males (referring to Q4, ORs range from 1.94 to 2.31, p< 0.05), RAPSN_CpG_2 and RAPSN_CpG_5 showed significantly lower methylation in female LC patients comparing to controls (referring to Q4, ORs range from 2.49 to 3.60, p< 0.05). The risk of RAPSN hypomethylation to LC was enhanced by aging, and typically for people older than 55 years (referring to Q4, ORs range from 2.17 to 3.61 in six out of all 10 analyzed CpG groups, p< 0.05).Conclusion: Our study reveals an association between RAPSN hypomethylation in peripheral blood and LC and suggests the occurrence of altered blood-based methylation at the early stage of cancer.Keywords: LC, early detection, DNA methylation, RAPSN, peripheral blood

Xuguang Li,1,2 Weirun Chen,2 Kaihang Liu,3 Sheng Zhang,2 Ru Yang,4 Kairui Liu,2 Dateng Li,5 Youxing Huang2 1Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, People’s Republic of China; 2Department of Abdominal Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People’s Republic of China; 3Department of General Practice, The People’s Hospital of Longhua, Shenzhen, Guangdong Province, People’s Republic of China; 4Department of General Practice, Women & Children Health Institute Futian Shenzhen, Shenzhen, Guangdong Province, People’s Republic of China; 5Department of Statistical Science, Southern Methodist University, Dallas, TX 75275, USACorrespondence: Youxing HuangDepartment of Abdominal Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 111 Dade Road, Guangzhou, Guangdong Province, People’s Republic of ChinaTel +86-13632255441Fax +86-20-39318790Email waiqike7@163.comBackground: Oridonin is the core bioactive component of Rabdosia rubescens, a traditional Chinese herbal medicine used in the treatment of hepatoma. Sorafenib, a targeted therapeutic agent for advanced hepatocellular carcinoma (HCC), has recently been shown to exert limited clinical effects. However, few studies have focused on the synergistic effect of these two drugs on hepatocellular carcinoma.Methods: We treated different HCC cell lines with different concentrations of oridonin and sorafenib and assessed the viability by using MTT assays and examined proliferation, migration, invasion and apoptosis after cotreatment of HepG2 cells with 20 μM oridonin and 5 μM sorafenib via colony formation assays, Transwell assays and flow cytometry. Regulatory effects were measured by Western blotting. The in vivo synergistic effect was confirmed through xenograft tumor models, and tumor tissues were analyzed by immunohistochemistry.Results: The inhibitory effects of oridonin and sorafenib cotreatment on HCC cells were stronger than those of either drug alone. In addition, combined treatment with the two drugs synergistically inhibited epithelial–mesenchymal transition and the Akt pathway but not NF-κB or MAPK signaling. Akt phosphorylation by SC79 reversed the inhibitory effects of the combined treatment. Synergistic inhibition was equally observed in vivo.Conclusion: Oridonin combined with sorafenib synergistically inhibited proliferation, migration, invasion, and epithelial–mesenchymal transition and induced apoptosis by targeting the Akt pathway but not NF-κB or MAPK signaling.Keywords: oridonin, sorafenib, HCC, Akt pathway

Zihan Zhao ,* Shangxun Xie ,* Baofu Feng, Shiwei Zhang, Yifan Sun, Hongqian Guo, Rong Yang Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongqian Guo; Rong YangDepartment of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, 321 Zhongshan Road, Nanjing, Jiangsu 210008, People’s Republic of ChinaTel +86-25-83106666Email doctorghq@gmail.com; doctoryr@gmail.comPurpose: To improve the preoperative prediction of the outcomes of patients diagnosed with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU), we explored various preoperative laboratory factors and established a prognostic risk stratification method.Patients and Methods: We retrospectively reviewed 232 UTUC patients who underwent RNU from September 2010 to October 2019 and analyzed their comprehensive clinicopathologic data and preoperative blood-based biomarkers. Kaplan–Meier analysis, receiver-operating characteristic (ROC) curves analysis and Cox regression analysis were performed to assess the relationship between these factors and the prognosis.Results: The median follow-up and age were 24 months and 68.5 years, respectively. Preoperative elevated neutrophil-to-lymphocyte ratio (NLR > 3.44) and decreased albumin (ALB < 39.8 g/L) were negatively correlated with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS) in both univariate and multivariate analyses. Patients were sorted into three groups based on their NLR and ALB: the low-risk group (neither elevated NLR nor decreased ALB), intermediate-risk group (either elevated NLR or decreased ALB) and high-risk group (elevated NLR and decreased ALB). Their 5-year PFS rates were 77.8%, 52.6% and 32.3%; their 5-year CSS rates were 97.7%, 71.4% and 32.9%; and their 5-year OS rates were 92.7%, 70.4% and 29.2%, respectively (all P < 0.0001). ROC curves analysis showed that NLR plus ALB had a more accurate prognostic value (P < 0.05).Conclusion: Preoperative risk classification using NLR and ALB was identified as an independent prognostic factor for patients with UTUC. The combination of NLR and ALB may help to determine the most appropriate treatment options before RNU.Keywords: neutrophil-to-lymphocyte ratio, albumin, upper tract urothelial carcinoma, radical nephroureterectomy, risk classification

Ting Huyan,1,2 Hongduo Li,3 Hourong Peng,1 Jinzhao Chen,4 Ruixin Yang,3 Wei Zhang,5 Qi Li1 1Key Laboratory for Space Biosciences and Biotechnology, Institute of Special Environment Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, People’s Republic of China; 2Institute of Flexible Electronics (IFE), Northwestern Polytechnical University, Xi’an 710072, People’s Republic of China; 3Xi’an Institute for Food and Drug Control, Xi’an 710054, People’s Republic of China; 4Shanxi Weiqidaguangming Pharmaceutical Co., Ltd, Datong, Shanxi Province 037301, People’s Republic of China; 5Department of Anesthesiology, Henan Provincial People’s Hospital (People’s Hospital of Zhengzhou University), Zhengzhou 450003, People’s Republic of ChinaCorrespondence: Qi Li KeyLaboratory for Space Biosciences and Biotechnology, Institute of Special Environment Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, People’s Republic of ChinaTel/ Fax +86 29 8846 0332Email liqi_1111@nwpu.edu.cnWei ZhangDepartment of Anesthesiology, Henan Provincial People’s Hospital (People’s Hospital of Zhengzhou University), Zhengzhou 450003, People’s Republic of ChinaTel +86 371 6558 0014Fax +86 371 6596 4376Email myhope2005@163.comAbstract: Extracellular vesicles (EVs) are a class of cell-derived, lipid bilayer membrane composed vesicles, and some of them such as exosomes and ectosomes have been proven, playing remarkable roles in transmitting intercellular information, and being involved in each property of cell physiological activities. Nowadays, EVs are considered as potential nanocarriers which could partially resolve the problems of current chemotherapy because of their distinctive advantages. As endogenous membrane encompassed vesicles with nanosize, EVs are able to pass through the natural barriers with prolonged circulation time in vivo and have intrinsic cell targeting properties, they are less toxic, and less immunogenic. Recently, studies focusing on EV-based drug delivery system for cancer therapy have exploded dramatically. This review aims to outline the current applications of EVs as potential nanosized drug carriers in cancer therapy. Firstly, the characteristics and biofunctions of each EV subtype are described. Then the variety of therapeutic cargoes, the loading methods, and the targeting strategy of engineered EVs are emphatically introduced. Thereafter the pros and cons of EVs applied as therapeutic carriers, as well as the future prospects in this field, are discussed.Keywords: Extracellular vesicles, exosomes, nano-sized carriers, tumor, drug delivery system

Ran Yang,1 Yusen Shui,2 Shoushan Hu,2 Kun Zhang,2 Yuru Wang,2 Yiran Peng1 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, Sichuan, People’s Republic of China; 2Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, People’s Republic of ChinaCorrespondence: Yiran PengDepartment of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, 14 Renmin South Road Third Section, Chengdu 610041, Sichuan, People’s Republic of ChinaTel/ Fax +86-28-85503527Email Drpeng1021@163.comBackground: Oral tongue squamous cell carcinoma (OTSCC) represents oral epithelial cell damage. Myeloblastosis (MYB) is involved in OTSCC. This study tried to probe roles of MYB in OSCC with potential axis.Methods: Expression of MYB and miR-130a in OTSCC was detected. Western blot analysis was utilized to determine epithelial–mesenchymal transition-related protein levels. Dual-luciferase reporter gene assay certified the target relation between miR-130a and CYLD. Moreover, xenograft tumors in nude mice were applied to confirm the in vitro experiments.Results: Both MYB and miR-130a were highly expressed in OTSCC, which promoted cell growth. Meanwhile, silenced miR-130a discouraged cell development enhanced by overexpressed MYB. CYLD was poorly expressed in OTSCC and targeted by miR-130a. Additionally, MYB knockdown activated CYLD to suppress OTSCC by downregulating miR-130a.Conclusion: Our experiment supported that silenced MYB suppressed OTSCC malignancy by inhibiting miR-130a and activating CYLD. This investigation may provide novel insights for OTSCC treatment.Keywords: oral tongue squamous cell carcinoma, MYB, microRNA-130a, CYLD, epithelial–mesenchymal transition, proliferation