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Qingcheng Song,1,2,* Yiran Zhang,3,* Hongzhi Hu,4,* Xuemei Yang,5 Xin Xing,1,2 Jianhua Wu,6 Yanbin Zhu,1,2 Yingze Zhang1,2 1Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Orthopaedic Institution of Hebei Province, Shijiazhuang, Hebei, People’s Republic of China; 3School of Medicine, Nankai University, Tianjin, People’s Republic of China; 4Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 5The Fourth Hospital of Shijiazhuang, Shijiazhuang, Hebei, People’s Republic of China; 6The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingze Zhang; Yanbin Zhu, Email yzling_liu@163.com; 38600312@hebmu.edu.cnIntroduction: Ferroptosis-driven tumor ablation strategies based on nanotechnology could be achieved by elevating intracellular iron levels or inhibiting glutathione peroxidase 4 (GPX4) activity. However, the intracellular antioxidative defense mechanisms endow tumor cells with ferroptosis resistance capacity. The purpose of this study was to develop a synergistic therapeutic platform to enhance the efficacy of ferroptosis-based tumor therapy.Methods: In this study, a multifunctional nano-catalytic therapeutic platform (mFeB@PDA-FA) based on chemodynamic therapy (CDT) and photothermal therapy (PTT) was developed to effectively trigger ferroptosis in tumor. In our work, iron-based mesoporous Fe3O4 nanoparticles (mFe3O4 NPs) were employed for the encapsulation of L-buthionine sulfoximine (BSO), followed by the modification of folic acid-functionalized polydopamine (PDA) coating on the periphery. Then, the antitumor effect of mFeB@PDA-FA NPs was evaluated using Human OS cells (MNNG/HOS) and a subcutaneous xenograft model of osteosarcoma.Results: mFe3O4 harboring multivalent elements (Fe2+/3+) could catalyze hydrogen peroxide (H2O2) into highly cytotoxic ˙OH, while the tumor microenvironment (TME)-responsive released BSO molecules inhibit the biosynthesis of GSH, thus achieving the deactivation of GPX4 and the enhancement of ferroptosis. Moreover, thanks to the remarkable photothermal conversion performance of mFe3O4 and PDA shell, PTT further synergistically enhanced the efficacy of CDT and facilitated ferroptosis. Both in vivo and in vitro experiments confirmed that this synergistic therapy could achieve excellent tumor inhibition effects.Conclusion: The nanotherapeutic platform mFeB@PDA-FA could effectively disrupted the redox homeostasis in tumor cells for boosting ferroptosis through the combination of CDT, PTT and GSH elimination, which provided a new perspective for the treatment of ferroptosis sensitive tumors. Keywords: ferroptosis, chemodynamic therapy, photothermal therapy, Fenton reaction, BSO

Man Huang,1,2,* Yudi Jin,3,* Mengyuan Wang,2 Qiang Song,4 Yanjia Fan,1 Yu Zhang,1 Cheng Tian,1 Chi Zhang,1 Shengchun Liu1 1Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Breast Center, Chongqing University Three Gorges Hospital, Chongqing, People’s Republic of China; 3Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Central Laboratory, Chongqing University Three Gorges Hospital, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shengchun Liu, Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China, Email liushengchun1968@163.comBackground: HER2-low breast cancer represents a distinct subgroup with unique clinical characteristics and treatment challenges. Nevertheless, it remains uncertain whether there exists a distinction in δKi67 between patients with HER2-low and HER2-zero statuses, and whether the prognosis varies among patients with differing HER2 statuses and δKi67.Methods: We conducted a multi-center retrospective study to investigate the correlation between alterations in Ki67 index following NAC and the prognosis among patients with HER2-low or HER2-zero breast cancer. 3 distinct cohorts comprising patients with HER2-negative breast cancer who underwent NAC were included. Comprehensive clinicopathological data were documented, with particular emphasis on evaluating changes in Ki67 index from baseline to post-NAC. These changes were then correlated with disease-free survival (DFS) through rigorous analysis.Results: Three cohorts, comprising 403, 315, and 72 patients respectively, were finally included. The study found that δKi67 did not show significant associations with other variables and were not identified as independent risk factors for survival. Nevertheless, across the three cohorts, following NAC, HER2-low breast cancer patients with δKi67 below the cut-off value demonstrated a better prognosis compared to those with δKi67 above the cut-off value. Additionally, their prognosis was also superior to that of HER2-zero breast cancer patients with δKi67 below the cut-off value.Conclusion: Our study demonstrates that HER2-low breast cancer patients with δKi67 values below the cut-off point after NAC are associated with improved prognosis. Monitoring δKi67 index and HER2 status may help identify patients who are likely to benefit from NAC and guide personalized treatment strategies.Keywords: HER2-low breast cancer, neoadjuvant chemotherapy, Ki67 index, prognosis, survival

Qian Song,1,2,* Kaili Zheng,1,2,* Zixia Ding,1,2 Zhengmiao Miao,1,2 Zhaoxia Liu,1,2 Ming Cheng,3 Jinyao Yi1,2,4 1Medical Psychological Center, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Medical Psychological Institute, Central South University, Changsha, People’s Republic of China; 3Department of Clinical Psychology, Hunan Brain Hospital, Changsha, People’s Republic of China; 4National Clinical Research Center for Mental Disorders, Changsha, 410011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinyao Yi, Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China, Email jinyaoyi@csu.edu.cnBackground: There exist four short forms of the Social Interaction Anxiety Scale (SIAS): 10-item version (SIAS-10), 6-item version by Peters et al (SIAS-6P), 6-item version by Fergus et al (SIAS-6F), and 5-item version (SIAS-5). This study aims to comprehensively examine the psychometric properties of the SIAS-10, SIAS-6P, SIAS-6F, and SIAS-5 and to determine which one performs relatively better in Chinese population.Methods: This study enrolled 733 Chinese college students. The unidimensionality of the SIAS-10, SIAS-6P, SIAS-6F, SIAS-5 was examined using Confirmatory Factor Analysis (CFA). Multi-Group CFA was further adopted to assess measurement equivalence across gender. Internal consistency reliability and criteria-related validity were also evaluated. Additionally, the measurement performance of the SIAS-10, SIAS-6P, SIAS-6F, and SIAS-5 was assessed with Item Response Theory (IRT), which estimated the discrimination parameter and the Item Characteristic Curve (ICC) for each item.Results: Except for the SIAS-5, the SIAS-10, SIAS-6P, and SIAS-6F displayed a good-fit to the one-factor model. Furthermore, the SIAS-10 achieved strict equivalence across gender while other versions did not. The SIAS-10, SIAS-6P, SIAS-6F and SIAS-5 all had acceptable internal consistency and significant correlations with criteria scales. The IRT results showed that the SIAS-10 included more items with higher discrimination and peaked ICCs (indicating more informative), whereas the SIAS-6P included more items with lower discrimination and flat ICCs (indicating less informative).Conclusion: For assessing social anxiety in Chinese under constrained conditions, the SIAS-10 is recommended to clinicians for it measuring equivalently across gender, reflecting the relevant criteria variables well, and discriminating various levels of social anxiety sensitively.Keywords: social anxiety, psychometric properties, measurement equivalence, item response theory, Chinese

Baoliang Liu,1,* Haotian Zheng,1,* Guoyuan Ma,1,2 Hongchang Shen,3 Zhaofei Pang,3 Gemu Huang,4 Qingtao Song,4 Guanghui Wang,1,2 Jiajun Du1,2 1Department of Thoracic Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 3Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 4Research and Development Department, Amoy Diagnostics Co., LTD., Xiamen, Fujian, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guanghui Wang; Jiajun Du, Email wangguanghui66@email.sdu.edu.cn; dujiajun@sdu.edu.cnBackground: Lung cancer is the most common type of cancer in the world. In lung adenocarcinoma (LUAD), studies on receptor tyrosine kinase ROS proto-oncogene 1 (ROS1) have mainly focused on the oncogenic effects of its fusion mutations, whereas ROS1 has been reported to be aberrantly expressed in a variety of cancers and can extensively regulate the growth, survival, and proliferation of tumor cells through multiple signaling pathways. The comprehensive analysis of ROS1 expression has not been fully investigated regarding its predictive value for LUAD patients.Methods: Gene expression profiles collected from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases were used to build and validate prognostic risk models. The association of ROS1 with overall survival and the immune landscape was obtained from the Tumor Immune Estimation Resource (TIMER) database. The following analyses were performed using the R package to determine the model’s validity: pathway dysregulation analysis, gene set enrichment analysis, Gene Oncology analysis, immune invasion analysis, chemotherapy, radiotherapy, and immunotherapy sensitivity analysis. Finally, we conducted a pan-cancer analysis and performed in vitro experiments to explore the regulatory role of intercellular adhesion molecule 5 (ICAM5) in the progression of LUAD.Results: We constructed a 17-gene model that categorized patients into two risk groups. The model had predictive accuracy for tumor prognosis and was specific for patients with high ROS1 expression. Comprehensive analysis showed that patients in the high-risk group were characterized by marked dysregulation of multiple pathways (eg, unfolded protein response), immune suppression of the tumor microenvironment, and poor benefit from immunotherapy and radiotherapy compared with patients in the low-risk group. PLX4720 may be a suitable treatment for the high-risk patient population. The ICAM5 gene has been demonstrated to inhibit the proliferation, cell cycle, invasion, and migration of LUAD cells.Conclusion: We constructed a 17-gene prognostic risk model and found differences in immune-related cells, biological processes, and prognosis among patients in different risk groups based on the correlation between ROS1 and immunity. Personalized therapy may play an essential role in treatment. We further investigated the role of ICAM5 in inhibiting the malignant bioactivity of LUAD cells.Keywords: ROS1, ICAM5, LUAD, immune, prognostic model

Junju Zou,1– 3,* Qianbo Song,2,* Pang Chui Shaw,4 Yongjun Wu,1,5 Zhong Zuo,2 Rong Yu1,3 1School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China; 2School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, People’s Republic of China; 3Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China; 4School of Life Sciences, The Chinese University of Hong Kong, Hong Kong SAR, People’s Republic of China; 5School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rong Yu, School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China, Email yurong8072@qq.com Zhong Zuo, School of Pharmacy, the Chinese University of Hong Kong, Hong Kong, SAR, 999077, People’s Republic of China, Email joanzuo@cuhk.edu.hkPurpose: Non-alcoholic fatty liver disease (NAFLD) represents a significant global health burden, exhibiting a strong correlation with insulin resistance, obesity, and type 2 diabetes (T2DM). Despite the severity of hepatic steatosis in T2DM patients, no specific drugs have been approved for clinical treatment of the disease. Tangerine peel is one kind of popular functional food and reported to possess hypoglycemic and lipid-lowering potential. In this study, we investigated the effects of Tangerine-peel-derived exosome-like nanovesicles (TNVs) on hepatic lipotoxicity associated with T2DM.Methods: The TNVs was prepared by differential centrifugation of the aqueous extract of Tangerine and chemical properties were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and LC-MS/MS. The hypoglycemic and lipid-lowering potential of TNVs were possessed by biochemical measurement, RT-PCR, 16S rRNA sequencing, GC/MS, UHPLC-MS/MS, in vivo small animal imaging assay and HE staining. Subsequently, effects of TNVs on lipid accumulation and glycolysis were investigated on 3T3-L1 and AML-12 cells.Results: TNVs significantly inhibited insulin resistance, reduced hepatic lipid accumulation, facilitate intestinal mucosal repair, rescued gut microbiota dysbiosis, regulated colonic SCFA and liver bile acid metabolism in db/db mice. Furthermore, TNVs restored the expression of key genes in glucose and lipid metabolism (ACC, AMPK, CD36, LXRα, PPAR-γ, SREBP-1) while activating the expression of genes related to glycolysis (G6Pase, GLUT2, PCK1, PEPCK) in db/db mice. Further cell-based mechanistic studies revealed that TNVs reduced lipid accumulation in 3T3-L1 and AML-12 cells via regulation of glucose and lipid metabolism-related genes (UCP1, FGFR4, PRDM16, PGC-1α, Tmem26, Cpt1, Cpt2 and PPAR-α).Conclusion: We for the first time demonstrated that TNVs could significantly improve glucose and lipid metabolism via activating the expression of genes related to fatty acid β-oxidation and glycolysis. Keywords: tangerine peel, plant-derived exosome-like nanoparticles, diabetes mellitus, metabolomics, gut microbiota, fat accumulation

Yufeng Yao,1,2 Qiyuan Song,3 Jingnan Zhang,2,4 Yingying Wen,2,4 Xiaoyan Dou2 1Shantou University Medical College, Shantou, Guangdong Province, People’s Republic of China; 2Department of Ophthalmology, Shenzhen Second People’s Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, People’s Republic of China; 3Department of Ophthalmology, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 4Shenzhen University Medical College, No.1066 Xueyuan Road, Shenzhen University, Shenzhen, Guangdong Province, People’s Republic of ChinaCorrespondence: Xiaoyan Dou, Email douxy08@163.comAbstract: The retina’s similar structure and function to the brain make it a unique visual “window” for studying cerebral disorders. Ophthalmic artery occlusion (OAO) or retinal artery occlusion (RAO) is a severe ophthalmic emergency that significantly affects visual acuity. Studies have demonstrated that patients with OAO or RAO face a notably higher risk of future acute ischemic stroke (AIS). However, ophthalmologists often overlook multidisciplinary approach involving the neurologist, to evaluate the risk of AIS and devise clinical treatment strategies for patients with OAO or RAO. Unlike the successful use of thrombolysis in AIS, the application of thrombolysis for OAO or RAO remains limited and controversial due to insufficient reliable evidence. In this review, we aim to summarize the anatomical and functional connections between the retina and the brain, and the clinical connection between OAO or RAO and AIS, compare and review recent advances in the effectiveness and safety of intravenous and intra-arterial thrombolysis therapy in patients with OAO or RAO, and discuss future research directions for OAO or RAO. Our goal is to advance the development of multidisciplinary diagnosis and treatment strategies for the disease, as well as to establish expedited pathways or thrombolysis guidelines for vascular intervention.Keywords: retina, brain, ophthalmic artery occlusion, retinal artery occlusion, stroke, thrombolysis

Wenjin Zhang,1 Qiang Song,1 Xiaofei Bi,1 Wei Cui,1 Chengmei Fang,1 Jianya Gao,1 Jinan Li,1 Xiang Wang,1 Kai Qu,1 Xian Qin,1 Xuan An,2,3 Cheng Zhang,1,3 Xianxiang Zhang,1,3 Fang Yan,4 Guicheng Wu1– 3 1Chongqing Municipality Clinical Research Center for Endocrinology and Metabolic Diseases, Chongqing University Three Gorges Hospital, Chongqing, People’s Republic of China; 2Department of Hepatology, Chongqing University Three Gorges Hospital, Chongqing, People’s Republic of China; 3School of Medicine, Chongqing University, Chongqing, People’s Republic of China; 4Geriatric Diseases Institute of Chengdu, Department of Geriatrics, Chengdu Fifth People’s Hospital, Chengdu, People’s Republic of ChinaCorrespondence: Guicheng Wu, Chongqing University Three Gorges Hospital, Xincheng Road 165#, Wanzhou District, Chongqing, 404000, People’s Republic of China, Tel +(86) 58103079, Fax +86 23 581045783, Email wuguicheng@cqu.edu.cn Fang Yan, Geriatric Diseases Institute of Chengdu, Department of Geriatrics, Chengdu Fifth People’s Hospital, Mashi Street 33#, Wenjiang District, Chengdu, 611130, People’s Republic of China, Tel/Fax +86 28 82661127, Email fangyan@cdutcm.edu.cnPurpose: Pueraria lobata (P. lobata), a dual-purpose food and medicine, displays limited efficacy in alcohol detoxification and liver protection, with previous research primarily focused on puerarin in its dried roots. In this study, we investigated the potential effects and mechanisms of fresh P. lobata root-derived exosome-like nanovesicles (P-ELNs) for mitigating alcoholic intoxication, promoting alcohol metabolism effects and protecting the liver in C57BL/6J mice.Methods: We isolated P-ELNs from fresh P. lobata root using differential centrifugation and characterized them via transmission electron microscopy, nanoscale particle sizing, ζ potential analysis, and biochemical assays. In Acute Alcoholism (AAI) mice pre-treated with P-ELNs, we evaluated their effects on the timing and duration of the loss of the righting reflex (LORR), liver alcohol metabolism enzymes activity, liver and serum alcohol content, and ferroptosis-related markers.Results: P-ELNs, enriched in proteins, lipids, and small RNAs, exhibited an ideal size (150.7 ± 82.8 nm) and negative surface charge (− 31 mV). Pre-treatment with 10 mg/(kg.bw) P-ELNs in both male and female mice significantly prolonged ebriety time, shortened sobriety time, enhanced acetaldehyde dehydrogenase (ALDH) activity while concurrently inhibited alcohol dehydrogenase (ADH) activity, and reduced alcohol content in the liver and serum. Notably, P-ELNs demonstrated more efficacy compared to P-ELNs supernatant fluid (abundant puerarin content), suggesting alternative active components beyond puerarin. Additionally, P-ELNs prevented ferroptosis by inhibiting the reduction of glutathione peroxidase 4 (GPX4) and reduced glutathione (GSH), and suppressing acyl-CoA synthetase long-chain family member 4 (ACSL4) elevation, thereby mitigating pathological liver lipid accumulation.Conclusion: P-ELNs exhibit distinct exosomal characteristics and effectively alleviate alcoholic intoxication, improve alcohol metabolism, suppress ferroptosis, and protect the liver from alcoholic injury. Consequently, P-ELNs hold promise as a therapeutic agent for detoxification, sobriety promotion, and prevention of alcoholic liver injury.Keywords: Pueraria lobata root-derived exosome-like nanovesicles, acute alcoholism, loss of the righting reflex, ethanol metabolism, ferroptosis

Shuqin Chen,1,* Xuepeng Wang,2,* Yong Jin,3 Xueqin Chen,4 Qifa Song,5 Gang Wei,6 Li Li1 1Department of Endocrinology and Metabolism, The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China; 2Department of Infectious Disease, The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China; 3Department of Internal Medicine, Ningbo Yinzhou No.2 Hospital, Ningbo, People’s Republic of China; 4Department of Traditional Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China; 5Medical Data Center, The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China; 6Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li Li, Department of Endocrinology and Metabolism, The First Affiliated Hospital of Ningbo University, Ningbo, 31500, People’s Republic of China, Email lilyningbo@163.com Gang Wei, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100000, People’s Republic of China, Email gangwei_2013@163.comBackground: Changes in body composition accompanied by glucagon-like peptide 1 receptor agonist (GLP-1RA) induced weight loss have drawn much attention. However, fewer studies have reported body composition changes in patients receiving dulaglutide therapy in Chinese population.Methods: A total of 70 overweight/obese type 2 diabetes mellitus (T2DM) patients who received dulaglutide therapy were included. Clinical data were collected. Visceral fat area (VFA) and body composition were also measured. Changes in clinical indicators and body composition of patients before and after intervention were also analyzed. Correlation analysis and multiple linear regression model were used to evaluate the association between hemoglobin A1C (HbA1c) and body composition.Results: The results showed that body weight (BW), VFA, body fat (BF), lean body mass (LBM), skeletal muscle mass (SMM) and water content were reduced after 3 months dulaglutide intervention. The lean body mass percentage (LBMP) and skeletal muscle mass percentage (SMMP) significantly increased. Moreover, there was no significant difference in bone mineral quality (BMQ) after the intervention. The multiple linear regression model revealed that the % change in BF was independently associated with % change in HbA1c (β = 0.449, t = 3.148, p=0.002).Conclusion: These results indicate that dulaglutide intervention does not cause muscle and bone mass loss while inducing weight loss, and % change in BF was independently associated with improved glucose control during dulaglutide therapy. This study offers some positive results to support the clinical application of dulaglutide.Keywords: dulaglutide, obesity, diabetes, body fat mass, visceral fat

Qing Song, Xi Wang,* Zhenhuan Cao,* Chun Xin,* Jingyuan Zhang,* Suwei Li Intensive Care Unit, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Suwei Li, Tel +86 180 9887 5867, Email lisuweicn@163.comAbstract: Apelin is the native ligand for the G protein-coupled receptor APJ. Numerous studies have demonstrated that the Apelin/APJ system has positive inotropic, anti-inflammatory, and anti-apoptotic effects and regulates fluid homeostasis. The Apelin/APJ system has been demonstrated to play a protective role in sepsis and may serve as a promising therapeutic target for the treatment of sepsis. Better understanding of the mechanisms of the effects of the Apelin/APJ system will aid in the development of novel drugs for the treatment of sepsis. In this review, we provide a brief overview of the physiological role of the Apelin/APJ system and its role in sepsis.Keywords: apelin, sepsis, organ dysfunction, hemodynamics, fluid homeostasis

Yiran Zhang,1– 4,* Qingcheng Song,2,3,* Yueyao Zhang,2,3,* Jiheng Xiao,5 Xiangtian Deng,6 Xin Xing,2,3 Hongzhi Hu,5 Yingze Zhang1– 3 1School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of China; 2Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China; 3NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 4HeBei Ex&Invivo Biotechnology Co. Ltd, Shijiazhuang, Hebei, 050051, People’s Republic of China; 5Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 6Orthopaedics Research Institute, Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingze Zhang; Hongzhi Hu, Email yzling_liu@163.com; 13720105746@163.comBackground: Although systemic chemotherapy is a standard approach for osteosarcoma (OS) treatment, its efficacy is limited by the inherent or acquired resistance to apoptosis of tumor cells. Ferroptosis is considered as an effective strategy capable of stimulating alternative pathways of cancer cell demise. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy.Methods and Results: A novel nanovehicle composed of arginine-glycine-aspartate (RGD) modified mesoporous silica-coated iron oxide loading Fin56 was rationally prepared (FSR-Fin56). With the RGD-mediated targeting affinity, FSR-Fin56 could achieve selective accumulation and accurate delivery of cargos into cancer cells. Upon exposure to NIR light, the nanovehicle could generate localized hyperthermia and disintegrate to liberate the therapeutic payload. The released Fin56 triggered the degradation of GPX4, while Fe3+ depleted the intracellular GSH pool, producing Fe2+ as a Fenton agent. The local rise in temperature, in conjunction with Fe2+-mediated Fenton reaction, led to a rapid and significant accumulation of ROS, culminating in LPOs and ferroptotic death. The outstanding therapeutic efficacy and safety of the nanovehicle were validated both in vitro and in vivo.Conclusion: The Fin56-loaded FSR nanovehicle could effectively disturb the redox balance in cancer cells. Coupled with NIR laser irradiation, the cooperative CDT and PTT achieved a boosted ferroptosis-inducing therapy. Taken together, this study offers a compelling strategy for cancer treatment, particularly for ferroptosis-sensitive tumors like osteosarcoma. Keywords: chemodynamic therapy, photothermal therapy, Fenton reaction, Fin56, ferroptosis

Qian Song,1,* Ying Chen,2,3,* JianQing Ma,1 Wei Zhou,4 JunYan Song,1 ChunFu Wu,5 Jie Liu2 1Department of Medical Laboratory, North China Medical & Health Group Xingtai General Hospital, Orthopedic Hospital of Xingtai, Xingtai, People’s Republic of China; 2BGI Genomics, BGI-Shenzhen, Shenzhen, People’s Republic of China; 3College of Life Sciences, University of Chinese Academy of Sciences, Beijing, People’s Republic of China; 4China National Genebank, BGI-Shenzhen, Shenzhen, People’s Republic of China; 5Yantai Harbor Hospital, Yantai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Liu, BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, People’s Republic of China, Email liujie8@genomics.cn ChunFu Wu, Yantai Harbor Hospital, Yantai, 264000, People’s Republic of China, Email tjnk2009@126.comPurpose: Psoriasis is a chronic, multi-system skin disease that can be influenced by immunological, environmental, and genetic factors. Plasma metabolomic analysis can provide a great deal of information on potential diagnostic biomarkers, pathogenesis and personalized treatment. However, the role of metabolites in psoriasis is unknown.Patients and Methods: We performed an untargeted metabolomic analysis of plasma based on high-resolution liquid chromatography mass spectrometry from 10 plaque psoriasis patients and 10 healthy controls.Results: A total of 301 differential metabolites were detected, of which 10 metabolites were possible potential biomarkers, including vitamins, amino acids, and lipids. At the same time, KEGG pathway enrichment analysis was performed for all detected differential metabolites, and it was found that protein digestion and absorption, amino acid metabolism and lipid metabolism may be jointly involved in regulating the pathogenesis of psoriasis. In addition, the proteins ESR1, OPRM1 and HSD11B1 were identified as possible potential topical therapeutic targets for psoriasis through analysis of the metabolite-protein interaction network.Conclusion: In this study, we identified 10 differential metabolites as possible potential combinatorial biomarkers for the diagnosis of psoriasis. 12 metabolic pathways were significantly enriched that may be closely related to the occurrence and development of psoriasis. Three proteins, ESR1, OPRM1, and HSD11B1, were identified as possible potential therapeutic targets for psoriasis.Keywords: psoriasis, metabolomics, biomarker, KEGG pathway, therapeutic target

Yu Cao,1 Ying Han,2 Jiangping Wu,1 Jianping Sun,3 Yanchao Dai,3 Guifang Qiao,3 Kang Li,3 Ang Li,3 Yonghong Zhang,4 Yingmin Ma,5,* Qingkun Song1,3,* 1Department of Clinical Epidemiology, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Center of Liver Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Center of Biobank, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Hepatic Intervention, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 5Department of Respiratory and Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingmin Ma, Department of Respiratory and Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Youanmen Wai 8, Fengtai District, Beijing, 100069, People’s Republic of China, Tel/Fax +86-10-83997022, Email ma.yingmin@163.com Qingkun Song, Department of Clinical Epidemiology, Beijing Youan Hospital, Capital Medical University, Youanmen Wai 8, Fengtai District, Beijing, 100069, People’s Republic of China, Tel/Fax +86-10-83997022, Email songqingkun@ccmu.edu.cnBackground: For the distinct immune/inflammatory responses from Omicron variant infection, this study aimed to investigate the diagnostic efficacy of systemic inflammatory indicators and the clinical efficacy of corticosteroids on the in-hospital mortality among COVID-19 patients.Methods: Under a retrospective cohort study, 1081 COVID-19 patients were recruited from Beijing Youan Hospital, Capital Medical University between November 16, 2022 and January 30, 2023. We chose neutrophil-to-lymphocyte ratio (NLR), CRP-to-lymphocyte ratio (CLR), and CRP-to-albumin ratio (CAR) as the systemic inflammatory indicators. Receiver operating curve (ROC) and multivariate logistic regression analysis were used to determine the diagnostic efficacy of systemic inflammatory indicators and the association between systemic inflammatory indicators and in-hospital mortality.Results: Among 684 patients included in analysis, 96 died during hospitalization. NLR, CLR and CAR performed well (with an area under the curve (AUC) greater than 0.75) in discriminating in-hospital mortality among COVID-19 patients. The severe status of systemic inflammation, with optimal cut-off value derived from ROC analysis, significantly associated higher risk of in-hospital mortality (OR = 3.81 for NLR ≥ 6.131; OR = 3.76 for CLR ≥ 45.455; OR = 5.10 for CAR ≥ 1.436). Corticosteroids use within 72 hours of admission increased the in-hospital mortality 2.88-fold for COVID-19 patients. In the subgroup of patients with severe systemic inflammation, corticosteroids increased the risk of in-hospital mortality (OR = 2.11 for NLR, p = 0.055; OR = 2.94 for CLR, p = 0.005; OR = 2.31 for CAR, p = 0.036).Conclusion: Systemic inflammatory indicators had good diagnostic performance for in-hospital mortality. Patients with severe systemic inflammatory status should not receive corticosteroid treatment and further studies are warranted for confirmation.Keywords: COVID-19, systemic inflammatory indicators, in-hospital mortality, anti-inflammatory treatment

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

Dan Liu,1,&ast; Qing Song,2– 4,&ast; Yuqin Zeng,2– 4 Rong Yi,5 Yi Liu,5 Xin Li,6 Yan Chen,2– 4 Shan Cai,2– 4 Ping Chen2– 4 1Department of Respiratory and Critical Care Medicine, Changsha Hospital of Traditional Chinese Medicine (Changsha Eighth Hospital), Changsha, Hunan, 410000, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 4Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 5Department of Pulmonary and Critical Care Medicine, Zhuzhou Central Hospital, Zhuzhou, Hunan, 412000, People’s Republic of China; 6Division 4 of Occupational Diseases, Hunan Prevention and Treatment Institute for Occupational Diseases, Changsha, Hunan, 412000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ping Chen, Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, Hunan, 410011, People’s Republic of China, Tel +86 731 8529 5248, Email pingchen0731@csu.edu.cnBackground: We analyzed the clinical characteristics and outcomes in non-frequent exacerbation patients with chronic obstructive pulmonary disease (COPD).Methods: In this retrospective cohort study, we enrolled patients with stable COPD from 12 hospitals. Non-frequent exacerbation was defined as less than two times of exacerbations in the past year. The non-frequent exacerbation patients were classified into less and more symptomatic groups based on the COPD Assessment Test (CAT) and modified Medical Research Council (mMRC). Finally, the non-frequent exacerbation patients with less and more symptomatic were classified into the long-acting muscarinic antagonist (LAMA), long-acting β 2-agonist (LABA)+inhaled corticosteroids (ICS), LABA+LAMA, and LABA+LAMA+ICS groups. Minimum clinically important difference (MCID) was defined as a CAT score decrease of ≥ 2 during six months of follow-up. We recorded the number of exacerbations and mortality during one year of follow-up.Results: A total of 834 (67.5%) non-frequent exacerbation patients with COPD were included in this study. The non-frequent exacerbation patients had a higher education level and body mass index (BMI), and lower CAT and mMRC scores (P< 0.05). In addition, the non-frequent exacerbation patients had lower mortality and risk of future exacerbation, and were more likely to attain MCID (P< 0.05). Furthermore, the non-frequent exacerbation patients with more symptomatic COPD treated with LABA+LAMA or LABA+LAMA+ICS were more likely to attain MCID and had a lower risk of future exacerbation (P< 0.05). However, there were no significant differences among the different inhalation therapies in non-frequent exacerbation patients with less symptomatic COPD.Conclusion: The non-frequent exacerbation patients with COPD had a higher education level and BMI, a lower symptom burden, and better outcomes. In addition, LABA+LAMA should be recommended to non-frequent exacerbation patients with more symptomatic COPD, while mono-LAMA should be recommended to non-frequent exacerbation patients with less symptomatic COPD as the initial inhalation therapy.Keywords: chronic obstructive pulmonary disease, non-frequent exacerbation, minimum clinically important difference, mortality, inhalation therapy

Wei Liu,1,&ast; Qingkun Song,2,&ast; Fang Li,1 Yu Cao,2 Ying Han,3 Jiangping Wu,2 Zhongjie Hu,4 Yonghong Zhang,5 Yingmin Ma6 1Department of Pharmacy, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Clinical Epidemiology, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Center of Liver Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Gastroenterology, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 5Department of Hepatic Intervention, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 6Department of Respiratory and Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingmin Ma, Beijing Youan Hospital, Capital Medical University, Youanmen Wai 8, Fengtai District, Beijing, 100069, People’s Republic of China, Tel/Fax +86-10-83997022, Email ma.yingmin@163.comPurpose: Anti-viral and anti-inflammatory therapies were effective in altering virus repletion and immune dysregulation in Coronavirus Disease 2019 (COVID-19) patients. This study aimed to explore the effect of combination therapy on disease progression in a real-world setting.Patients and Methods: A total of 836 patients confirmed with SARS-CoV-2 infection participated in the study from 15 November to 25 December 2022 at Beijing Youan Hospital, Capital Medical University. A prospective cohort study was implemented to investigate the prognostic effect of the combination therapy on virus shedding and clinical recovery.Results: About 78% of patients used nirmatrelvir/ritonavir (N/R, Paxlovid®, Pfizer) negatively, 16% of patients were prescribed nirmatrelvir/ritonavir beyond five days of symptom onset, 4% of patients received N/R monotherapy within five days of symptom onset and 2% of patients received N/R combined with dexamethasone. Compared with untreated patients, N/R monotherapy reduced the median time to 10.0 days from 12.0 days according to the negative conversion of nucleic acid amplification test (NAAT), and combination therapy reduced the time to 7.0 days, and increased to a 1.99 (95% CI 0.92, 4.32) and 14.23-fold (95% CI 4.50, 44.95) probability of negative NAAT, respectively. N/R monotherapy reduced the clinical recovery time to 10.0 days from 13.0 days. Single-use and combined-use non-significantly increased the recovery probability by 61% and 69%, respectively. In mild and moderate patients, the HRs for clinical recovery increased to 1.69 (95% CI 0.73, 3.94) and 2.18 (95% CI 0.29, 16.62), respectively.Conclusion: Combination therapy of N/R and dexamethasone increased negative conversion of NAAT and was associated with a non-significant improvement in clinical recovery. Further studies are warranted to confirm this efficacy.Keywords: N/R, dexamethasone, negative conversion of NAAT, clinical recovery

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

Ruibin Wang,1 Yuchen Li,2 Yanjie Zhao,3 Feng Shi,4 Quan Zhou,5 Jiangping Wu,6 Shuzhen Lyu,7 Qingkun Song8,9 1Department of Emergency, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; 3Department of Medical Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 5Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China; 6Department of Cancer Research, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 7Department of Breast Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 8Department of Clinical Epidemiology, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 9Department of Clinical Epidemiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Qingkun Song, Department of Clinical Epidemiology, Beijing Youan Hospital, Capital Medical University, Xitoutiao 8, Fengtai Dist, Beijing, People’s Republic of China, Email songqingkun@aliyun.comBackground: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Metformin has been shown to have the potential to inhibit the proliferation of malignant cells. This study aimed to investigate the regulatory effect of metformin on phenotypic tumor-infiltrated lymphocytes (TILs) and mechanisms in TNBC.Methods: Microarray analysis was performed on 4T1 cells post metformin treatment. BALB/c mice were inoculated with 4T1 cells with knockdown/overexpression of C-Jun N-terminal kinase (JNK), and administered with metformin. Phenotypic TILs in the tumor microenvironment (TME) were visualized by immunofluorescence staining.Results: Metformin inhibited 4T1 cell proliferation and increased expression of JNK by 21% in vitro. In vivo, Metformin increased cell counts of CD4+ and CD8+TILs by 100% and 85%, respectively, and the increase of TILs was associated with JNK pathway. Cell counts of CD4+/PD-1+ and CD8+/PD-1+TILs were reduced by 64% and 58%, respectively, post metformin treatment, but the reduction of exhausted TILs was not associated with JNK pathway. Metformin induced a 11% and 20% reduction of IL-6 and TNF-α level in the TNBC model.Conclusion: Our study demonstrated that metformin increased the functional phenotype of TILs and associated with JNK pathway, and suppressed the exhausted phenotype of TILs independently to JNK pathway in TNBC microenvironment. Further studies are needed to explore the basic mechanism of action of the drug. Metformin has potentially enhanced efficacy when used in combination with immunotherapy against TNBC.Keywords: triple-negative breast cancer, metformin, phenotypic tumor-infiltrated lymphocytes, C-Jun N-terminal kinase

Yiran Zhang,1– 4,&ast; Hongzhi Hu,5,&ast; Xiangtian Deng,6,&ast; Qingcheng Song,2 Xin Xing,2,3 Weijian Liu,5 Yingze Zhang1– 3 1School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of China; 2Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China; 3NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 4HeBei Ex&Invivo Biotechnology Co. Ltd, Shijiazhuang, Hebei, 050051, People’s Republic of China; 5Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 6Orthopaedics Research Institute, Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingze Zhang; Weijian Liu, Email yzling_liu@163.com; xh_liuweijian@hust.edu.cnBackground: Although chemodynamic therapy (CDT) has attracted enormous attention in anti-tumor studies for converting endogenous hydrogen peroxide (H2O2) into toxic hydroxyl radicals (•OH) by Fenton-type reaction, the treating effects of using CDT alone is still unsatisfying. Recently, glucose oxidase (GOx) was reported to be co-delivered with Fenton agent for synergistic starvation therapy (ST) and CDT. However, the overexpressed glutathione (GSH) and hypoxia in tumor microenvironment (TME) restrict the therapeutic efficacy of ST/CDT.Methods and Results: In this work, a novel nanoplatform composed of GOx plus Fenton agent (Cu2+) encapsulated core and metformin (MET)-loaded manganese dioxide nanosheets (MNSs) shell was prepared and further functionalized by arginine-glycine-aspartate (RGD). With the RGD-mediated affinity with cancer cells, the nanocomposite (GOx-CuCaP@MNSs-MET@PEG-RGD, GCMMR) could accomplish targeting delivery and TME-activated release of cargos. The intracellular GSH was depleted by MnO2/Cu2+ and abundant H2O2 was generated along with the GOx-induced glucose deprivation, which process was further enhanced by MET-mediated hypoxia relief via inhibiting mitochondria-associated respiration. Subsequently generated •OH from Cu+-mediated Fenton-like reaction exerts severe intracellular oxidative stress and cause apoptosis. Moreover, significant inhibition of tumor growth was detected in a subcutaneous xenograft model of osteosarcoma (OS) after GCMMR treatment.Conclusion: The excellent therapeutic efficacy and biosafety of the nanoplatform were confirmed both in vitro and in vivo. Collectively, this study provides an appealing strategy with catalytic cascade enhancement on targeted ST/CDT for cancer treatment, especially for hypoxic solid tumors.Graphical Abstract: Keywords: chemodynamic therapy, starvation therapy, glucose oxidase, Fenton reaction, biomineralization, metformin

Jian Liu, Ying Jiang, Zhe Liu, Qun Song, Zhuo Li Department of Urology, The First Affiliated Hospital of Hunan Normal University Hunan Provincial People’s Hospital, Changsha, People’s Republic of ChinaCorrespondence: Zhuo Li, Tel +8615197591937, Email 376941577@qq.comAbstract: Upper urinary tract obstruction caused by fungal balls is a rare urinary system disease. We admitted an elderly man with symptoms of urinary tract infection and diabetes mellitus. When the patient was transported into the hospital, a CT scan revealed right renal pelvis dilatation and gas buildup, routine urinalysis showing full field of view of white blood cells and middle urinary bacteria and fungi cultures came back negative, leading to the incorrect diagnosis of emphysematous pyelonephritis with Aerogenes infection. When the diagnosis is confirmed, surgery and antifungal therapy are used to deal with both the obstruction and the fungal ball.Keywords: fungal ball, urinary tract obstruction, misdiagnosed, emphysematous pyelonephritis, infection

Qingxiang Liu,1 Ming Xue,1 Qianwen Song,1 Jianfeng Xie,1 Yi Yang,1 Songqiao Liu1,2 1Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China; 2Department of Critical Care Medicine, Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Nanjing, People’s Republic of ChinaCorrespondence: Yi Yang; Songqiao Liu, Email yiyiyang2004@163.com; liusongqiao@ymail.comBackground: PD-1 is an important immune checkpoint expressed on T lymphocytes and is associated with T-cell function in sepsis. However, the role of PD-1 in naive and memory T-cell responses in sepsis is not well understood. We aimed to determine the expression of PD-1 induced on naive and memory T lymphocytes in patients with sepsis and its association with clinical outcome.Methods: A prospective observational study was conducted at a general intensive care unit (ICU). Whole blood samples were collected from patients within 48 h after sepsis diagnosis. PD-1 expression on naive and memory T cells was measured by flow cytometry. The levels of IFN-γ, IL-2 and TNF-α released by memory T cells were also determined. All patients were followed up to 28 days, and 28-day mortality was recorded.Results: PD-1 expression showed no difference in naive CD4+ T cells (P=0.617) or naive CD8+ T cells (P=0.079) between survivors (n = 21) and nonsurvivors (n = 9). Increased PD-1 expression on memory CD4+ T cells was found in nonsurvivors (P=0.030) and memory CD8+ T cells (P=0.006) in comparison with survivors. According to the cutoff value of the percentage of PD-1 on memory CD8+ T cells in predicting 28-day mortality of patients with sepsis, patients were divided into two groups. The 28-day mortality rates between the two groups were significantly different (P=0.009). A Kaplan Meier curve was constructed to derive a hazard ratio of 9.33 (95% CI: 2.52– 34.60) for the percentage of PD-1 on memory CD8+ T cells regarding 28-day mortality. In addition, the IFN-γ secretion of memory CD4+ T cells (P=0.046) and IL-2 secretion of memory CD8+ T cells (P=0.014) were significantly greater in survivors than nonsurvivors.Conclusion: Flow cytometric assessment of PD-1 expression on memory CD8+ T cells identifies patients with poor outcomes during sepsis.Keywords: PD-1, memory T cells, sepsis, outcome

Chunyan Shao,1– 5,&ast; Ziwei Yu,1– 5,&ast; Tongwang Luo,1– 5,&ast; Bin Zhou,1– 5 Quanjiang Song,1– 5 Zhuoyue Li,1– 5 Xiaoqiang Yu,1– 5 Sheng Jiang,1– 5 Yingshan Zhou,1– 5 Wanyu Dong,1– 5 Xingdong Zhou,1– 5 Xiaodu Wang,1– 5 Houhui Song1– 5 1Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Hangzhou, Zhejiang, 311300, People’s Republic of China; 2Zhejiang Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Hangzhou, Zhejiang, 311300, People’s Republic of China; 3Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, Hangzhou, Zhejiang, 311300, People’s Republic of China; 4China-Australia Joint Laboratory for Animal Health Big Data Analytics, Hangzhou, Zhejiang, 311300, People’s Republic of China; 5College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, 311300, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Houhui Song; Xiaodu Wang, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, 311300, People’s Republic of China, Tel +86 15064890670 ; +86 18806537583, Email songhh@zafu.edu.cn; xdwang@zafu.edu.cnIntroduction: Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly prevalent and endemic swine pathogen that causes significant economic losses to the global swine industry. Selenium nanoparticles (SeNPs) have attracted increasing attention in the biomedical field, given their antiviral effects. This study aimed to investigate the inhibitory effect of chitosan-coated SeNPs (CS-SeNPs) on PRRSV replication.Methods: In this study, CS-SeNPs were synthesized by chemical reduction and characterized by assessing the morphology, size distribution, zeta potential, and element composition. Marc-145 cells were infected with r-PRRSV-EGFP (0.1 MOI) and inoculated with CS-SeNPs (10 μM). Subsequently, the concentrations of hydrogen peroxide (H2O2) and glutathione (GSH), and glutathione peroxidase (GSH-Px) activity were measured using specific commercial assay kits. ORF5 RNA expression, viral titer, and nucleocapsid (N) protein expression were assessed using qRT-PCR, TCID50, and Western blot. ROS generation, apoptosis rates, and JNK /caspase-3/PARP protein expression were evaluated using dihydroethidium staining, flow cytometry, and Western blot.Results: The results showed that CS-SeNPs treatment significantly suppressed oxidative stress induced by r-PRRSV-EGFP infection by increasing GSH-Px activity, promoting GSH production, and inhibiting H2O2 synthesis. CS-SeNPs treatment significantly inhibited ORF5 gene expression, viral titers, and N protein of r-PRRSV-EGFP at 24 and 48 hours post-infection (hpi) in Marc-145 cells. The increase in apoptosis rates induced by r-PRRSV-EGFP infection was significantly decreased by CS-SeNPs inoculation through inhibiting ROS generation, JNK phosphorylation levels, and cleavage of caspase-3 and PARP mainly at 48 hpi.Conclusion: These results demonstrated that CS-SeNPs suppress PRRSV-induced apoptosis in Marc-145 cells via the ROS/JNK signaling pathway, thereby inhibiting PRRSV replication, which suggested the potential antiviral activity of CS-SeNPs that deserves further investigation for clinical applications.Keywords: chitosan-coated selenium nanoparticles, PRRSV, apoptosis, ROS, JNK signaling pathways

Shuqin Chen,1,&ast; Yong Jin,2,&ast; Miao Xu,1 Pingping Zhang,3 Ye Zhou,1 Xingjun Qian,4 Qifa Song,5 Shizhong Bu,6 Jing Sun,7 Li Li1 1Department of Endocrinology and Metabolism, Ningbo First Hospital, Ningbo, Zhejiang Province, People’s Republic of China; 2Department of Internal Medicine, Ningbo Yinzhou Second Hospital, Ningbo, Zhejiang Province, People’s Republic of China; 3School of Public Health, Peking University, Beijing, People’s Republic of China; 4Health Management Center, Ningbo First Hospital, Ningbo, Zhejiang Province, People’s Republic of China; 5Medical Research Center, Ningbo First Hospital, Ningbo, Zhejiang Province, People’s Republic of China; 6Diabetes Research Center, School of Medicine, Ningbo University, Ningbo, Zhejiang Province, People’s Republic of China; 7School of Medicine and Dentistry, Griffith University, Gold Coast, Queensland, Australia&ast;These authors contributed equally to this workCorrespondence: Li Li, Department of Endocrinology and Metabolism, Ningbo First Hospital, Ningbo, Zhejiang Province, People’s Republic of China, Tel +8613757426626, Email lilyningbo@163.com Jing Sun, School of Medicine and Dentistry, Griffith University, Gold Coast, Queensland, Australia, Tel +61756780924, Email j.sun@griffith.edu.auObjective: The thyroid hormone has been demonstrated to be associated with nonalcoholic fatty liver disease (NAFLD) in different populations. However, the relationship between thyroid hormone and the degree of liver steatosis in overweight/obese subjects is still unclear. Liver ultra-sound attenuation (LiSA) is a newly developed ultrasound attenuation parameter for the analysis of hepatic steatosis. The study aimed to characterize the relationship between thyroid hormone and LiSA in overweight/obese participants.Methods: This case-control study was performed in Ningbo First Hospital, China. A total of 24 lean, 66 overweight and 49 obese participants were consecutively recruited from January 2021 to May 2021. Thyroid hormone and other clinical features were measured. LiSA was acquired by using a Hepatus ultrasound machine. Multiple linear regression analyses were performed to examine associations of LiSA and clinic indices.Results: Obese subjects had higher LiSA, fT3 and TSH levels than lean participants of similar age and sex (P < 0.05). LiSA was positively associated with the fT3 level. The multiple linear regression analyses showed that fT3 (ß = 0.353, P < 0.001) was independently associated with LiSA in overweight/obese participants.Conclusion: The fT3 level was independently associated with the degree of liver steatosis among the overweight/obese participants.Keywords: LiSA, obesity, NAFLD, thyroid hormone

The phase equilibria of Bi-Te-RE (Yb, Nd, Sm, Er, Tb) at 673 K were established through equilibrated alloys. The isothermal sections of Bi-Te-RE (Yb, Nd, Sm, Er, Tb) at 673 K were established according to the result of Scanning Electron Microscopy (SEM), Electron probe micro-analysis (EPMA), and Powder X-ray diffractometry (XRD). In the Bi-Te-Yb system at 673 K, the existence of 4 three-phase equilibria (YbTe+Bi2Te3+Te, YbTe+Bi2Te3+β, YbTe+Bi+β, YbTe+Yb5Bi3+Yb4Bi3) was established, while 3 three-phase regions (NdTe2+β+Bi2Te3, NdTe2+β+Bi, Nd2Te3+Bi+BiTeNd) in Bi-Te-Nd system, 3 threephase regions (SmTe3+Te+Bi2Te3, SmTe1.8+Bi2Te3+β, SmTe1.8+β+Bi) in Bi-Te-Nd system, 3 three-phase regions (TbTe3+Te+Bi2Te3, Tb4Te7+Bi2Te3+β, TbTe+Bi+β) in Bi-Te-Nd system, and 4 three-phase regions (ErTe3+Te+Bi2Te3, ErTe3+Bi2Te3+Er2Te3, Bi2Te3+Er2Te3+β, Er2Te3+β+ErTe, β+ErTe+Bi) in Bi-Te-Nd system were also identified, respectively. Among the Bi-Te-RE (Nd, Sm, Er, Tb, Yb) systems, the solubilities of RE in Bi2Te3 were 0.19 at % Nd, 0.22 at % Sm, 0.28 at % Tb, 0.35 at %Er, and 0.37 at % Yb. In general, the maximum solubility of elements in Bi2Te3 phase alloy became larger with the increase in RE atomic number. A ternary compound BiTeNd in the Bi-Te-Nd ternary system was confirmed in this work.

Na Li, Yuxin Chu, Qibin Song Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of ChinaCorrespondence: Qibin Song Email qibinsong@whu.edu.cnPurpose: To characterize the risk factors for brain metastasis (BM) at presentation and analyze the prognostic factors for patients with small cell lung cancer (SCLC).Patients and Methods: Patients were recruited from the SEER database between 2010 and 2016. They were divided into two groups according to BM status. The incidence trends of SCLC and its BM were analyzed by joinpoint software. The risk factors for BM in SCLC were identified by binary logistic regression models. The prognostic factors for SCLC patients with BM were identified by Cox proportional hazard models.Results: The incidence of SCLC and its BM significantly decreased after 2010. Totally 11,093 patients were collected, including 1717 (15.5%) patients with BM and 9376 (84.5%) patients without BM. In multivariate logistic regression analysis, age, male and higher T stage were independent risk factors for BM in SCLC patients at presentation. SCLC patients with BM showed inferior survival to those without BM. In multivariate Cox regression analysis, increasing age, large tumor size, and higher N stage were risk factors for poor prognosis, while other race, surgery, adjuvant radiotherapy, and chemotherapy were protective factors for SCLC patients with BM. A nomogram was developed for prognosis evaluation of such patients.Conclusion: Age, male and higher T stage were risk factors for BM in SCLC patients at presentation. Increasing age, large tumor size, and advanced N stage may predict poor survival for SCLC patients with BM. Multidisciplinary therapies may provide clinical benefits. This study will help identify patients with higher BM risk and hopefully improve their clinical outcome.Keywords: small cell lung cancer, SCLC, brain metastasis, BM, survival, risk factor

Qingqing Qi,1 Qingxu Song,2 Yufeng Cheng,2 Nana Wang2 1Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 2Department of Radiation Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of ChinaCorrespondence: Nana WangDepartment of Radiation Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of ChinaEmail wangna03@163.comBackground: Prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) are the most common factors to estimate nutritional and inflammatory status. The aim of this study is to systematically evaluate the prognostic significance of above nutritional and inflammatory indexes for overall survival (OS) and surgical complications in esophageal cancer patients.Methods: Esophageal cancer patients who underwent esophagectomy were retrospectively collected. PNI, NLR, PLR, and SII were introduced to evaluate the baseline nutritional and inflammatory status.Results: A total of 407 patients were included in the present study. Kaplan–Meier survival analysis revealed that PNI-low group, NLR-high group and PLR-high group, all showed a significantly shorter OS (34.38% vs 49.46%, P < 0.001; 36.13% vs 48.26%, P = 0.026 and 33.33% vs 48.52%, P = 0.001 respectively), while no significant difference was found in SII groups (42.33% vs 46.31%, P = 0.067). Multivariable analyses identified PNI (P = 0.002) was an independent prognostic factor for OS, but NLR (P = 0.672) and PLR (P = 0.186) were not. Postoperative complications occurred significantly more frequently in the low-PNI group (29.69% vs 13.26%, P < 0.001). However, no significant differences were found in the postoperative complication rates between different NLR (16.67% vs 22.69%, P = 0.124), PLR (18.03% vs 19.61%, P = 0.867) and SII (15.34% vs 20.49%, P = 0.326) groups. Multivariate logistic regression analysis showed only PNI (P = 0.008) was an independent prognostic factor for postoperative complications.Conclusion: Preoperative low PNI was not only an independent prognostic factor for worse survival in esophageal cancer patients but also associated with high incidence of postoperative complications.Keywords: esophageal cancer, prognostic nutritional index, prognosis, postoperative complications

Aiyuan Zhou, 1,* Qing Song, 1,* Yating Peng, 1 Dingding Deng, 2 Xin Liao, 3 Peng Huang, 4 Wenlong Liu, 5 Zhi Xiang, 6 Qimi Liu, 7 Mingyan Jiang, 8 Xiaoying Huang, 9 Xudong Xiang, 10 Hong Peng, 1 Ping Chen 1 1Department of Respiratory and Critical Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Department of Respiratory Medicine, The First Attached Hospital of Shaoyang University, Shaoyang, Hunan, 422001, People’s Republic of China; 3Department of Respiratory Medicine, Affiliated Shaoyang Central Hospital of University of South China, Shaoyang, Hunan, 422001, People’s Republic of China; 4Department of Respiratory Medicine, Zhuzhou Central Hospital, Zhuzhou, Hunan, 412000, People’s Republic of China; 5Department of Respiratory Medicine, Yueyang Second People’s Hospital, Designated Hospital of Junshan District, Yueyang, Hunan, 414005, People’s Republic of China; 6Department of Respiratory Medicine, The First People’s Hospital of Huaihua Affiliated to University of South China, Huaihua, Hunan, 418000, People’s Republic of China; 7Department of Respiratory Medicine, The Second People’s Hospital of Guilin, Guilin, Guangxi, 541001, People’s Republic of China; 8Department of Respiratory and Critical Medicine, Xiangtan Central Hospital, Xiangtan, Hunan, 411100, People’s Republic of China; 9Department of Respiratory and Critical Medicine, Loudi Central Hospital, Loudi, Hunan, 411100, People’s Republic of China; 10Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ping Chen; Hong PengDepartment of Respiratory and Critical Care Medicine, Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, Hunan, 410011, People’s Republic of ChinaEmail pingchen0731@csu.edu.cn; penghong66@csu.edu.cnBackground: Oxygen therapy (OT) is the most widely used supportive regime in patients with hypoxemic acute respiratory failure (ARF) due to severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. The aim of this study was to identify the effect of noninvasive ventilation support on coronavirus disease 2019 (COVID-19) patients and risk factors for invasive mechanical ventilation (IMV).Methods: We retrospectively analyzed confirmed COVID-19 subjects from nine hospitals outside Wuhan. All hospitalized patients who tested positive for COVID-19 by real-time polymerase chain reaction between January 1st and March 31st, 2020, were recruited. The patients were divided into four groups based on the most advanced OT regime, including no OT, nasal oxygen therapy, high-flow nasal oxygen therapy (HFNOT) or noninvasive ventilation (NIV), and IMV. Multiple logistic regression models were performed to determine risk factors for IMV.Results: Of the 683 recruited subjects, 315 (46.1%) subjects did not need OT, 300 (43.9%) received nasal oxygen therapy, 51 (7.5%) received HFNOT or NIV, while 17 (2.5%) subjects had to be intubated. The lactate in the OT group was higher than in the no OT group (2.7 vs 1.6, P = 0.02). In addition, HFNOT or NIV patients had a higher respiratory rate, but a lower PaO2 (P < 0.001). HFNOT and NIV had an obvious beneficial effect on ARF with 75% of COVID-19 patients recovering from respiratory failure. Patients with IMV were older (P < 0.001), had a higher rate of hypertension (P < 0.001) and more secondary bacterial infections (P < 0.001) compared to those without intubation. The multivariate model showed that secondary bacterial infection (OR = 6.87, P = 0.009) was independently associated with IMV failure among COVID-19 patients.Conclusion: We identified that HFNOT and NIV had an obvious beneficial effect on ARF among COVID-19 patients. We also demonstrated that secondary bacterial infection was an independent risk factor for NIV failure in patients infected by SARS-COV2.Keywords: COVID-19, SARS-CoV-2, oxygen therapy, invasive mechanical ventilation

Shuyuan Liu,1,2,&ast; Ling Xing,1,3,&ast; Qian Wang,4 Tianyu Xin,2 Handing Mao,1 Ye Tao,5 Jinbao Zhao,2 Xin Li,4 Cong Li,1 Qinghua Li,6 Yan Dou,7 Yixin Li,8 Wei Zhang,9 Bo Ning,10 Qing Song1 1Medical School of Chinese PLA, Beijing, People’s Republic of China; 2Emergency Department, Sixth Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Department of Emergency, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Emergency Department, Third Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China; 5Health Care Department, Beijing Huangsi Aesthetic Surgery Hospital, Beijing, People’s Republic of China; 6Department of Intensive Care Unit, The 990th Hospital of Chinese PLA, Zhumadian, People’s Republic of China; 7Department of Intensive Care Unit, The 909th Hospital of Chinese PLA, Zhangzhou, People’s Republic of China; 8Department of Intensive Care Unit, The 910th Hospital of Chinese PLA, Quanzhou, People’s Republic of China; 9Emergency Department, The 900th Hospital of Chinese PLA, Fuzhou, People’s Republic of China; 10Department of Intensive Care Unit, Air Force Medical Center of China, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo NingDepartment of Intensive Care Unit, Air Force Medical Center of China, Beijing, 100142, People’s Republic of ChinaTel +86 15611161110Fax +86 1068410099Email boningbn@163.comQing SongMedical School of Chinese PLA, Beijing, 100853, People’s Republic of ChinaTel +86 13911374534Fax +86 1068182255Email songqing_sq87@163.comObjective: The purpose of this study is to evaluate the factors involved in the early stage of exertional heat stroke (EHS) that are associated with mortality.Methods: In this retrospective, case-control study, patients from 11 tertiary medical centers in China were enrolled from January 1, 2012, to December 31, 2019. Demographic information, underlying diseases, ambient temperature, and relative humidity, clinical manifestations, initial body temperature, time from onset to diagnosis of EHS (including suspected), and the duration of body temperature > 38°C of all enrolled patients were recorded. The occurrence of organ dysfunction within 72 h was evaluated, and in-hospital deaths were recorded. The patients were subsequently divided into a survival group and a non-survival group. The “case” refers to patients in the non-survival group, while the “control” refers to patients without death.Results: Of the 214 hospitalized patients with EHS, 183 survived and 31 died, and the overall mortality was 14.49% (31/214). A binary logistic regression showed that only the duration of body temperature > 38°C (OR 1.80, 95% CI 1.34– 2.42) and the number of organs damaged within 72 h of onset (OR 6.54, 95% CI 2.31– 18.56) were statistically significant in terms of risk of death in hospital (p < 0.05). A goodness of fit test produced a p-value of 0.76. According to receiver operating characteristic curve (ROC) analysis, the areas under the curve (AUC) were 0.989 (95% CI 0.978– 1.000; p < 0.05) and 0.936 (95% CI 0.896– 0.976; p < 0.05).Conclusion: Of the various factors involved in the early stage of the disease, the duration of high body temperature and the number of organs damaged within 72 h of onset were independent risk factors and predictors associated with death.Keywords: heat stroke, exertional, cooling, mortality

Wen Li,1,2 Qing Song,2 Yu Lan,2 Jie Li,3 Ying Zhang,2 Lin Yan,2 Yingying Li,2 Yan Zhang,2 Yukun Luo2 1Department of Ultrasound, Medical School of Chinese PLA, Beijing, People’s Republic of China; 2Department of Ultrasound, The First Medical Center Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Department of Pathology, The First Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Yukun Luo; Yan Zhang No. 28 Fuxing Road, Haidian District, Beijing, 100853, People’s Republic of ChinaTel +8613311373556; +8613581937501Fax +8601055499255Email luoyk301@126.com; zhangyaner301@126.comPurpose: Differentiation between follicular thyroid carcinomas (FTCs) and follicular thyroid adenomas (FTAs) is difficult and the sonographic features of FTC are not yet fully established. The purpose of this study is to explore the sonographic features of FTC and the value of sonography in differentiating FTCs from FTAs.Patients and Methods: A total of 28 pathologically proven FTCs and 53 FTAs in 78 patients who were performed thyroid surgery were included in this retrospective study. The sonographic features of each tumor including an interrupted halo, satellite nodule(s) with or without halo ring, local irregularity of margin and cluster of grapes sign were evaluated. A mode image of FTC halo was built up in our study. The frequencies of the sonographic features were compared by chi-square test or Fisher exact test between FTCs and FTAs. The relative risk of malignancy was assessed by logistic regression analysis.Results: Logistic regression analysis showed that a thick, irregular and/or interrupted halo with or without satellite nodule(s), hypoechoic or marked hypoechoic echogenicity, a predominantly solid pattern, cluster of grapes sign, micro-or macro-calcifications, rim calcifications correlated with significant increases in relative risk for FTCs (odds ratio 11.48 (1.37– 96.56), 6.74 (1.05– 43.30), 17.51 (1.78– 172.53), 9.55 (1.44– 63.46), 9.36 (1.25– 70.15) and 17.45 (1.04– 292.65), respectively, p< 0.05). Two new sonographic features, an interrupted halo and satellite nodule(s) with or without halo ring, can only be found in FTCs.Conclusion: An interrupted halo and satellite nodule(s) with or without halo ring are specific sonographic features for FTCs. Sonography could play a role in differentiating follicular thyroid carcinoma from adenoma.Keywords: follicular thyroid carcinoma, follicular thyroid adenoma, ultrasonography

Qingpeng Song,1,* Bin Zhu,2,* Wenkui Zhao,3,* Chen Liang,3 Bao Hai,1 Xiaoguang Liu1 1Department of Orthopaedics, Peking University Third Hospital, Beijing, People’s Republic of China; 2Department of Orthopaedics, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Pain Medicine Center, Peking University Third Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoguang LiuDepartment of Orthopedics, Peking University Third Hospital, Beijing, People’s Republic of ChinaEmail liuxgspine@126.comPurpose: Compare the efficacy of full-endoscopic lumbar decompression surgery (FELDS) and open decompression and fusion surgery (ODFS) for lumbar spinal stenosis (LSS).Patients and Methods: A retrospective analysis of 358 LSS patients treated by FELDS (“FELD” group) or ODFS (“open” group) was undertaken. There were 177 patients in the FELDS group with a mean age of 65.47± 9.26 years and 181 patients in the open group with a mean age of 64.18± 10.24 years. Duration of follow-up was 38.63± 11.88 months in the FELDS group and 38.56± 12.29 months in the open group. Visual analog scale (VAS) score, Oswestry Disability Index (ODI), and Modified MacNab criteria were used to access clinical outcomes. Surgical outcomes (duration of surgical procedure, blood loss, complications, duration of postoperative hospital stay (DOPHS), prevalence of revision procedures) were evaluated. Magnetic resonance imaging was used to evaluate the change in the Pfirrmann grade at adjacent segments.Results: VAS score (leg and back) and ODI improved significantly in both groups (P< 0.001). Success rate reached 86.55% and 90.60% in the FELDS group and open group (P> 0.05), respectively. Procedure duration (84.12 vs 112.08 min), blood loss (7.97 vs 279.67 mL), and DOPHS (2.68 vs 4.78 days) of the FELDS group were significantly better than those of the open group (P< 0.05). Total prevalence of complications and procedure revisions was 14.69% and 10.73% in the FELD group, respectively, but did not show a significant difference with that in the open group (12.15% and 9.39%, respectively). The Pfirrmann grade increased in 13.04% of adjacent segments in the FELDS group, significantly better than that in the open group (32.67%) (P< 0.05).Conclusion: FELDS had the same efficacy as ODFS for LSS treatment. FELDS had the advantages of minimal invasiveness, less surgical trauma, rapid recovery, and lower risk of degeneration of adjacent segments compared with that of ODFS.Keywords: lumbar spinal stenosis, full-endoscopic lumbar decompression, fusion, clinical outcome, adjacent segments degeneration

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

Luna Liu,1,2 Shuang Liu,1,2 Qianmei Song,1,2 Dandan Luo,1,2 Yu Su,1,2 Xiangyu Qi,1,2 Qian Wang,3 Jing Ning,1,2 Youyuan Lv,1,2 Qingbo Guan1,2,4 1Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, People’s Republic of China; 2Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, People’s Republic of China; 3Department of Ultrasound, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, People’s Republic of China; 4Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, People’s Republic of ChinaCorrespondence: Qingbo Guan Tel +86-531-68776375Fax +86-531-87068707Email doctorguanqingbo@163.comObjective: Obesity and metabolic syndrome have been reported to exert an impact on the male reproductive system with decreasing levels of serum total testosterone (TT); however, the effect of different metabolic obesity phenotypes on testosterone has been poorly studied. We aimed to evaluate the association of metabolic obesity phenotypes and total testosterone levels in a Chinese male population.Methods: We performed a retrospective study based on an epidemiological investigation, a total of 4,081 male individuals aged from 40– 75 years old were recruited. The population was classified as metabolically healthy normal weight (MHNW), metabolically healthy overweight/obese (MHO), metabolically unhealthy normal weight (MUNW), and metabolically unhealthy overweight/obese (MUO) according to normal weight (BMI< 25.0) and overweight/obesity (BMI≥ 25.0) with or without metabolic syndrome.Results: We collected 563 hypotestosteronemia among 4,081 male individuals. The odds ratios (ORs) (95% CIs) of hypotestosteronemia in obesity and metabolic syndrome were 3.072 (2.414– 3.911) and 3.294 (2.631– 4.125), respectively, after adjusting for age, luteinizing hormone, smoking status, and alcohol consumption. Compared to the MHNW group, male subjects in MHO, MUNW, and MUO groups had decreased serum TT levels. Additionally, the MUO group had a lowest concentration of serum TT and a highest proportion of hypotestosteronemia. There was no significant difference of TT levels between the MHO and MUNW groups.Conclusion: Obesity and metabolic syndrome are independent risk factors of hypotestosteronemia in Chinese male populations. Our study also suggested that individuals with MHO, MUNW, and MUO have a higher risk of developing hypotestosteronemia.Keywords: metabolic obesity phenotypes, testosterone, metabolically healthy overweight/obese, metabolically unhealthy normal weight, hypotestosteronemia

Xuxia Yu,1 Danyang Zhang,2 Qifa Song3 1Department of Hospital Infection, Ningbo City First Hospital, Ningbo, Zhejiang Province, People’s Republic of China; 2Department of Microbiology, Ningbo Municipal Centre for Disease Control and Prevention, Ningbo, Zhejiang Province, People’s Republic of China; 3Central Laboratory, Ningbo City First Hospital, Ningbo, Zhejiang Province, People’s Republic of ChinaCorrespondence: Qifa Song Email qifasong@126.comPurpose: Fluoroquinolone-resistant Shigella is considered a serious public health problem and has been put on the WHO global priority list of antibiotic-resistant bacteria. This study was aimed to investigate the fluoroquinolone resistance in Shigella and its relevant genetic mechanisms.Materials and Methods: Shigella isolates that were isolated from diarrheal patient’s feces in Ningbo China from 2011 to 2018 were tested for susceptibility to ampicillin, gentamicin, tetracycline, nalidixic acid, ciprofloxacin, and cefotaxime. Genes related to quinolone resistance were amplified by PCR.Results: A total of 118 Shigella isolates were collected, including 76 S. flexneri isolates, 40 S. sonnei isolates, and 2 S. boydii isolates. Ciprofloxacin susceptibility test identified 10 (9%) susceptible, 65 (55%) intermediate, and 43 (36%) resistant isolates. Of 76 S. flexneri isolates, 37 were ciprofloxacin resistant, a prevalence significantly higher than 6 of 40 S. sonnei isolates (P=0.01). The isolates collected during 2014– 2018 displayed a significant increase in the prevalence of ciprofloxacin resistance (P=0.05) than those collected during 2011– 2013. All the ciprofloxacin-intermediate and resistant isolates had mutations of gyrA(S83L) and parC (S80I), whereas only the ciprofloxacin-resistant isolates had gyrA (D87N) mutation and qnrB gene. Additionally, 30% of the ciprofloxacin-resistant isolates were positive for aac(6´)-Ib-cr gene.Conclusion: This study shows the currently increasing prevalence of ciprofloxacin resistance. The reduced fluoroquinolone susceptibility is highly associated with gyrA (S83L) and parC (S80I) mutations, while the fluoroquinolone resistance is highly associated with gyrA (D87N) mutation, qnrB gene and perhaps aac(6´)-Ib-cr gene.Keywords: Shigella, ciprofloxacin resistance, gyrA mutations, plasmid-mediated quinolone resistance, PMQR, quinolone resistance-determining region, QRDR

Tianyu Xie,1,2 Di Wu,2 Shuo Li,1,2 Xiongguang Li,1,2 Lipeng Wang,2 Yixun Lu,2 Qiying Song,2 Xuehong Sun,2 Xinxin Wang1,2 1School of Medicine, Nankai University, Tianjin 300071, People’s Republic of China; 2Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, People’s Republic of ChinaCorrespondence: Xinxin Wang Tel/ Fax +86-10-66938328Email xinxinwang1111@163.comBackground: The dysregulation of microRNA (miRNAs) is broadly participated in cancer progression, resulting in sustained cell proliferation by directly targeting various targets. This study investigated the expression of miR-582 in GC and its association with liver metastasis.Methods: Firstly, differentially expressed miRNAs in gastric cancer (GC) tissues were predicted by microarray. Then, the relationship between miR-582 and clinical characteristics of GC patients was analyzed. By silencing of miR-582 in GC cells, the change in malignant biological behaviors of GC cells was detected. The upstream lncRNA, downstream targeting genes of miR-582 and the corresponding signaling pathway were predicted by online databases and verified by luciferase reporter assays, RT-qPCR and Western blot analysis. Finally, the effects of miR-582 on the growth and metastasis of GC cells were detected by in vivo tumorigenesis and metastasis tests.Results: MiR-582 was highly expressed in GC tissues and related to the metastasis of patients with GC. Silencing of miR-582 expression blocked malignant biological behaviors of GC cells in vitro and in vivo. MiR-582 inhibited forkhead box protein O3 (FOXO3) to upregulate the PI3K/AKT/Snail signaling pathway in GC cells. Besides, GATA6-AS1 was found as an upstream lncRNA to modulate the expression of miR-582.Conclusion: MiR-582 induced by GATA6-AS1 silencing promotes the growth and metastasis of GC cells by targeting FOXO3 to induce the activation of the PI3K/AKT/Snail signaling pathway. MiR-582 could be a potential molecular therapy target for patients with GC.Keywords: gastric cancer, miR-582, PI3K/AKT/Snail signaling pathway, proliferation, metastasis, tumorigenesis

Na Li,1 Hao Zuo,1 Luojun Chen,1 Huali Liu,1 Jin Zhou,1 Yi Yao,1 Bin Xu,1 Hongyun Gong,1 Yiming Weng,1 Qinyong Hu,1 Qibin Song,1 Min Peng,1 Yanxiang Cheng2 1Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Min PengDepartment of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, People’s Republic of ChinaTel +86 133 1713 3140Email mpeng320@whu.edu.cnYanxiang ChengDepartment of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, People’s Republic of ChinaTel +86 27 8804 1911Email doctornancy@qq.comPurpose: Circulating tumor cell (CTC) detection methods based on epithelial cell adhesion molecule (EpCAM) have low detection rates in epithelial ovarian cancer (EOC). Meanwhile, folate receptor alpha (FRα) has high expression in EOC cells. We explored the feasibility of combining FRα and EpCAM as CTC capture targets in EOC.Patients and methods: EpCAM and FRα antibodies were linked to magnetic nanospheres (MNs) using the principle of carbodiimide chemistry. Blood samples from healthy donor spiked with A2780 ovarian cancer cells were used for detecting the capture rate. Ninety-five blood samples from 30 patients with EOC were used for comparing the positive rate of detection when using anti-EpCAM-MNs alone with that when using combination of anti-EpCAM-MNs and anti-FRα-MNs. Samples from 28 patients initially diagnosed with EOC and 20 patients with ovarian benign disease were used for evaluating the sensitivity and specificity of combination of anti-EpCAM-MNs and anti-FRα-MNs.Results: Regression analysis between the number of recovered and that of spiked A2780 cells revealed yEpCAM = 0.535x (R2 = 0.99), yFRα = 0.901x (R2 = 0.99), and yEpCAM+FRα = 0.928x (R2 = 0.99). In mixtures of A2780 and MCF7 cells, the capture rate was 92% using the combination of anti-EpCAM-MNs and anti-FRα-MNs, exceeding the rate when using anti-EpCAM-MNs or anti-FRα-MNs alone by approximately 20% (P < 0.01). The combination of anti-EpCAM-MNs and anti-FRα-MNs showed a significantly increased positive rate of CTC detection in EOC patients compared with anti-EpCAM-MNs alone (χ2 = 14.45, P < 0.001). Sensitivity values were 0.536 and 0.75 and specificity values were 0.9 and 0.85 when using anti-EpCAM-MNs alone and when using the combination of anti-EpCAM-MNs and anti-FRα-MNs, respectively.Conclusion: The combination of FRα and EpCAM is feasible as a CTC capture target of CTC detection in patients with EOC.Keywords: circulating tumor cells, ovarian cancer, epithelial cell adhesion molecule, folate receptor alpha

Li Li,1 Qifa Song,2 Xi Yang11Department of Endocrinology and Metabolism, Ningbo First Hospital, Ningbo, People’s Republic of China; 2Department of Microbiology, Ningbo Municipal Centre for Disease Control and Prevention, Ningbo, People’s Republic of ChinaCorrespondence: Qifa SongDepartment of Microbiology, Ningbo Municipal Centre for Disease Control and Prevention, No. 237, Yongfeng Road, Ningbo, Zhejiang Province 315010, People’s Republic of ChinaTel +86 05 748 727 4563Email qifasong@126.comObjective: Use of K-means clustering for big data technology to cluster an overweight and obese population metabolically.Methods: K-means clustering with the help of quantile transformation of attribute values was applied to overcome the impact of the considerable variation in the values of obesity attributes involving outliers and skewed distribution.Results: Overall, 447 subjects were categorized into six clusters; metabolically normal, mild, and severe categories. There were clearly separated metabolically normal Cluster 1 and severe Cluster 2, as well as intermediate Cluster 3, 4, and 5 that had profiles of fewer attributes with abnormal values. Cluster 3 was characteristic of sole hypertension. Cluster 3 and 4 exhibited contrasting HDL-C and LDL-C levels despite similarly elevated total cholesterol. Cluster 6 with slightly elevated triglyceride was closest to the normal group. Four- and 10-quantile-transformations yielded consistent clustering results. Compared with the original data, the quantile-transformed data produced more regular and spherical clusters and evenly distributed clusters in terms of object numbers.Conclusions: This big data analysis strategy makes use of quantile-transformation of data to overcome the issue of outliers and the irregular distribution and applies to the analysis of other non-communicable diseases.Keywords: overweight and obesity, big data technology, quantile-transformation, K-means clustering

Dingfeng Lv,1 Danyang Zhang,2 Qifa Song21Department of Clinical Laboratory, Ningbo First Hospital, Ningbo, Zhejiang Province, People’s Republic of China; 2Department of Microbiology, Ningbo Municipal Centre for Disease Control and Prevention, Ningbo, Zhejiang Province, People’s Republic of ChinaPurpose: This study was aimed to investigate the dynamics of antimicrobial resistance expansion among different lineages and isolates of S. Typhi.Materials and methods: The S. Typhi isolates were collected from the patients clinically suspected of typhoid fever in Eastern China during 2005–2017. All isolates were tested retrospectively for susceptibility to eight antimicrobials and the genes related to quinolone and ampicillin resistance, including gyrA, ParC, qnrA, qnrB, qnrS, aac(6´)-Ib-cr, qepA and blaTEM. The isolates were subtyped by PFGE.Results: Of 140 isolates, all were susceptible to ciprofloxacin, cefotaxime, chloramphenicol, and trimethoprim-sulfamethoxazole, 95 (68%) were nalidixic acid resistant, and 74 (53%) were ampicillin resistant. The resistance to ampicillin and nalidixic acid was first observed in 2006. Among the 95 nalidixic acid-resistant S. Typhi isolates, 62 possessed S83F mutation in gyrA and 25 possessed D87Y mutation. All ampicillin-resistant isolates harbored gene blaTEM-1. PFGE generated 47 distinguishable clonal lineages. Overall, 64% (89/140) belonged to seven prevalent lineages of clustering isolates. PFGE results illustrated the prevalence of nalidixic acid-resistant lineages increased steadily from 19% during 2005–2012 to 50% during 2013–2014, and thereafter to 74% during 2015–2017 and similar development of ampicillin-resistant lineages increased from 6% to 38%, and also to 39%.Conclusion: The present study indicated the clonal expansion of S. Typhi with ampicillin resistance and reduced ciprofloxacin susceptibility. The findings also suggested that the differential development of antimicrobial resistance to various antimicrobial agents in S. Typhi, showing the rapid increase in ampicillin resistance and reduced ciprofloxacin susceptibility, and the high susceptibility to other traditional antimicrobial agents.Keywords: ampicillin resistance, reduced ciprofloxacin susceptibility, Salmonella Typhi, clonal expansion

Chenhao Zhang,1 Yanjing Zang,2 Qin Song,3 Hongxuan Li,1 Lei Hu,1 Weidong Zhao,3 Shanshan Feng,1 Fang Gu,4 FengLi Zhao,1 Chunliang Zhang11Department of Neurology, The Second Hospital of Baoding City, Baoding, Hebei 071051, People’s Republic of China; 2Department of Geriatric, The Second Hospital of Baoding City, Baoding, Hebei 071051, People’s Republic of China; 3Second Neurology Department, The Second Hospital of Baoding City, Baoding, Hebei, 071051, People’s Republic of China; 4Fifth Department of Internal Medicine, Baoding Children’s Hospital, Baoding, Hebei 071051, People’s Republic of ChinaObjective: To explore the efficacy and safety of “cocktail therapy” in Parkinson’s disease with dementia (PDD).Patients and methods: Sixty patients with PDD were randomly assigned to the test group (n=30) and a control group (n=30). The control group received 10 mg of donepezil hydrochloride tablets orally, once a day. The test group was treated with a “cocktail therapy”, which consisted of 10 mg of donepezil hydrochloride tablets taken orally, once a day; 200 mg of dl-3n-butylphthalide soft capsules taken orally, 15 mins before each meal, three times daily; 800 mg of oxiracetam capsules taken orally, three times daily; and 80 mg of Ginkgo biloba extract tablets taken orally, three times daily. Treatment was administered for six months. The Montreal cognitive assessment scale (MoCA), Blessed-Roth dementia scale, and Clinical Dementia Rating Scale sum of boxes (CDR-SB) were used before treatment and on the third and sixth month after treatment. Adverse events were also monitored.Results: There were no statistical differences in MoCA, CDR-SB, or Blessed-Roth dementia scale scores between the two groups before treatment. MoCA scores of the test group at six months were significantly higher than those before the treatment and at three months, while both the Blessed-Roth and CDR-SB scores were significantly lower than those before treatment and at three months (p0.05) between the test group (16.67%) and the control group (13.33%) in the rate of abnormal liver function after treatment.Conclusion: Treatment with “cocktail therapy” was safe and improved the conditions of patients with PDD, as well as the quality of life of the patients.Keywords: cocktail therapy, Parkinson’s disease with dementia, efficacy, donepezil hydrochloride, cocktail therapy

Xinxin Yu, Renshu Zhang, Lei Lei, Qianqian Song, Xingyi Li Institute of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, People’s Republic of China Purpose: To develop and demonstrate the effectiveness of a novel dexamethasone (Dex) nanoformulation for treating uveitis. Materials and methods: We designed and screened a dexamethasone-peptide conjugate (Dex-SA-FFFE), formed via a biodegradable ester bond linkage, that could spontaneously form high drug payload nanoparticles in aqueous solution for treating uveitis. Results: An in vitro release study indicated that Dex and Dex-SA-FFFE sustainably released from Dex-SA-FFFE nanoparticles over a 48 h study period. Meanwhile, the formed Dex-SA-FFFE nanoparticles hardly caused cytotoxicity in human corneal epithelial cell at drug concentrations up to 1 mM after 24 h of incubation but reduced cell viability after 48 h and 72 h of incubation. An in vitro anti-inflammatory efficacy assay showed that the Dex-SA-FFFE nanoparticles exhibited a comparable anti-inflammatory efficacy to that of Dex in lipopolysaccharide (LPS)-activated RAW264.7 macrophages via significant decreases in the secretion of various pro-inflammatory cytokines (e.g., nitric oxide, tumor necrosis factor-α, interleukin-6). Topical instillation of Dex-SA-FFFE nanoparticles showed good ocular tolerance without causing changes in corneal thickness and intraocular pressure during the entire study period. Furthermore, topical instillation of Dex-SA-FFFE nanoparticles displayed a comparable in vivo therapeutic efficacy to that of dexamethasone sodium phosphate (Dexp) aqueous solutions in an endotoxin-induced uveitis (EIU) rabbit model. Conclusion: Based on these results, it is reasonable to believe that the proposed Dex-SA-FFFE nanoparticles might have great application for the treatment of anterior uveitis. Keywords: drug-peptide conjugate, self-assembly, ocular inflammation, in vivo, nanoparticle

Ruibin Wang,1 Minjia Sheng,2 Feng Shi,3 Yanjie Zhao,4 Lin Zhao,5 Jiangping Wu,4 Guangjiang Wu,6 Qingkun Song7–9 1Department of Emergency, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China; 2Department of Gynaecology and Obstetrics, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China; 3Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China; 4Department of Medical Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China; 5Department of Medical Records and Statistics, Xuanwu Hospital, Capital Medical University, Beijing 100045, China; 6Department of Infection Control, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China; 7Department of Gynaecology and Obstetrics, Beijing Key Laboratory of Cancer Therapeutic Vaccine, Beijing 100038, China; 8Department of Evidence-based Medicine, Oncology School of Capital Medical University, Beijing 100038, China; 9Department of Science and Technology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China Purpose: Kupffer cells (KCs) present dysfunctional immunity capacity among the diabetes mellitus patients. This study aims to investigate whether Lidocaine could reverse dysfunctions of KCs, in terms of phagocytosis, granulocyte recruitment and inflammatory mediator secretion.Methods: db/db and C57BL/6 mice were employed to establish diabetic and nondiabetic models. Upon intravenous injection of Lidocaine, KCs were isolated and cultured ex vivo. The functions of phagocytosis, recruiting granulocytes and inflammatory mediator secretion in KCs were compared between Lidocaine-treated and untreated (control) groups.Results: Comparing with nondiabetic mice, KCs in diabetic mice presented reduced phagocytosis, activated granulocyte recruitment, increased expression of intercellular cell adhesion molecule-1 (ICAM-1) and activated levels of inflammatory mediators. With Lidocaine injection, phagocytic functions of KCs in diabetic mice were improved significantly; in contrast, recruitment of granulocytes, expression of ICAM-1 and secretion of inflammatory mediators were reduced markedly. However, Lidocaine intervention did not alter KC functions in phagocytosis, granulocyte recruitment, ICAM-1 expression or inflammatory mediator secretion among nondiabetic mice.Conclusion: Lidocaine reversed diabetes-related dysfunctions of KCs in terms of phagocytosis, granulocyte recruitment, ICAM-1 expression or inflammatory mediator secretion. Keywords: macrophages, diabetes, phagocytosis, granulocyte recruitment, inflammatory mediator, Lidocaine

Rui Zhang,* Ping Li,* Qin Li, Yunfeng Qiao, Tangpeng Xu, Peng Ruan, Qibin Song, Zhenming Fu Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China *These authors contributed equally to this work Background: The survival advantage of radiotherapy for patients with extensive-disease small-cell lung cancer (ED-SCLC) has not been adequately evaluated.Methods: We analyzed stage IV SCLC patients enrolled from the Surveillance, Epidemiology, and End Results (SEER) registry through January 2010 and December 2012. Propensity score analysis with 1:1 matching was performed to ensure well-balanced characteristics of all comparison groups. Kaplan–Meier and Cox proportional hazardous model were used to evaluate the overall survival (OS), cancer-specific survival (CSS), and corresponding 95% CI.Results: Overall, for all metastatic ED-SCLC, receiving radiotherapy was associated with both improved OS and CSS. Radiotherapy for thoracic lesion and any metastatic sites could significantly improve the OS and CSS, except for brain metastasis. For M1a-SCLC patient, radiotherapy, most likely to the primary site, significantly improved the survival (P

Chao Liu,1,2 Bing Sun,2 Bin Xu,1 Xiangying Meng,2 Lan Li,1 Yang Cong,2 Jiannan Liu,2 Qian Wang,2 Liang Xuan,2 Qibin Song,1 Shikai Wu2 1Cancer Center, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People’s Republic of China Introduction: Programmed cell death protein 1 (PD-1), an immune checkpoint molecule, has recently been recognized as a predictive and prognostic biomarker in several malignant tumors, but its diagnostic value remains largely unknown. We aimed to investigate the differential diagnostic efficiency of PD-1 and other immune molecules and propose a panel of immune molecules combined with cancer antigen 15-3 (CA15-3) to distinguish breast cancer (BC) from benign breast disease (BBD).Patients and methods: Ninety-one eligible BC patients and 31 BBD patients were enrolled. Pretreatment peripheral blood was collected and tested for mRNA expression of PD-1, cytotoxic T lymphocyte antigen 4, forkhead box P3, transforming growth factor beta, interleukin-10 (IL-10), IL-2 receptor alpha (IL-2Rα), and cluster of differentiation 28 by quantitative reverse transcription PCR.Results: The diagnostic areas under curve (AUCs) of PD-1, IL-2Rα, and IL-10 for BC–BBD discrimination were 0.764, 0.758, and 0.743, respectively. The diagnostic efficiencies of these three parameters in distinguishing early-stage or advanced BC from BBD were consistent with a role in BC–BBD discrimination. A panel of PD-1 + IL-10 + IL-2Rα + CA15-3 showed the highest AUC (0.862), with a sensitivity of 0.933 and a specificity of 0.724, for BC–BBD discrimination. In addition, for early-stage BC discrimination, this panel also had the highest AUC (0.811), with a sensitivity of 0.933 and a specificity of 0.614, while for advanced BC discrimination, a panel of PD-1 + IL-10 + CA15-3 exhibited the highest AUC (0.896), with a sensitivity of 0.933 and a specificity of 0.783.Conclusion: These data indicate that the panel containing PD-1, IL-2Rα, IL-10, and CA15-3 can effectively discriminate BC from BBD with a high efficiency. After further confirmation, it could be used to complement conventional imaging modalities, especially in discriminating early-stage BC from BBD. Keywords: breast cancer, immune checkpoint, PD-1, CTLA-4, IL-2Rα, diagnosis, biomarker

Dong Chen,1,* Qifa Song,2,* Zhaojun Xu,3 Dandan Zhang2 1Department of Clinical Laboratory, Sixth People’s Hospital of Wenzhou, Wenzhou, Zhejiang Province, People’s Republic of China; 2Department of Microbiology, Ningbo Municipal Center for Disease Control and Prevention, Ningbo, Zhejiang Province, People’s Republic of China; 3Intensive Care Unit, Ningbo No. 2 Hospital, Zhejiang, People’s Republic of China *These authors contributed equally to this work Purpose: This study aims to characterize the wild-type staphylococcal enterotoxin A (SEA)-producing Staphylococcus aureus.Materials and methods: We identified 29 wild-type sea-positive S. aureus isolates from dairy and meat samples, as well as from patients, measured the amount of SEA produced under favorable cultivation conditions using enzyme-linked immunosorbent assay and sea mRNA transcriptional level and investigated the phage type as well as genetic diversity by means of pulsed-field gel electrophoresis and multilocus sequence typing.Results: Among 29 sea-positive isolates, 22 were from food sources (including one outbreak case) and seven from clinical patients. Five enterotoxin gene profiles, namely, sea (14 isolates), sea+sec (9 isolates), sea+seb (4 isolates), sea+seb+sec (1 isolate) and sea+seb+sed (1 isolate), were identified. Multilocus sequence typing generated sequence type (ST)1 (13 isolates), ST6 (5 isolates), ST59 (3 isolates), ST239 (3 isolates), ST5 (2 isolates), ST188 (2 isolate) and ST15 (1 isolate). The amount of SEA per 108 colony-forming unit (CFU) after 24 h of incubation was 1.1–33.5 (mean, 8.74; SD, 7.7) ng/108 CFU. The amount of SEA per hour incubation in the log growth phase was 0.1–12.0 (mean, 2.37; SD, 3.06) ng/108 CFU. Overall, 54.2% of SEA was produced in the log growth phase. Both the transcriptional level of sea mRNA and the amount of SEA in the log growth phase correlated well with the amount of SEA after 24 h of cultivation. Four isolates, namely, SA-212, SA-217, SA-340 and SA-341, were categorized to be of high SEA production (877–1,109 ng/mL, 24 h). The total amount of SEA was mainly based on the amount of SEA in 108 CFU, not the relatively fixed bacterial cell counts (21.1–43×108 CFU/mL). Seven isolates from patients all carried the ФMu3A phage, whereas 21 of the 22 isolates from the environmental sources all carried the ФSa3ms phage.Conclusion: The present study exhibits varied SEA production capacity of the wild sea-positive S. aureus strains. An apparent boundary in phage types between strains from the clinical samples and strains from the environment was also identified. Keywords: Staphylococcus aureus, staphylococcal enterotoxin A, multilocus sequence typing, phage, SEA production capacity

Qifa Song,1 Zhaojun Xu,2 Hong Gao,1 Danyang Zhang1 1Department of Microbiology, Ningbo Municipal Centre for Disease Control and Prevention, Ningbo, Zhejiang, China; 2Intensive Care Unit, Ningbo No. 2 Hospital, Zhejiang, China Purpose: Several factors contribute to the complexity of quinolone resistance in Salmonella, including >2000 different Salmonella serotypes, a variety of hosts for Salmonella, and wide use of quinolones in human beings and animals. We thus aimed to obtain an overview of the development of quinolone resistance and relevant molecular mechanisms of such a resistance in Salmonella species.Materials and methods: A total of 1,776 Salmonella isolates were collected in Ningbo, China, between 2005 and 2016. Antimicrobial susceptibility to quinolone and relevant genetic mechanisms in these isolates were retrospectively analyzed.Results: The ratio for ciprofloxacin (CIP) resistant:reduced CIP susceptible:CIP susceptible was 26:522:1,228. CIP resistance was found in nine of 51 serotypes: Derby, London, Kentucky, Indiana, Corvallis, Rissen, Hadar, Typhimurium, and Agona. Of 26 CIP-resistant isolates, all were concurrently resistant to ampicillin and 21 were also concurrently resistant to cefotaxime and produced extended-spectrum β-lactamase (ESBL). The minimal inhibitory concentration values were at three levels: 2–4 μg/mL (serotypes except for Kentucky and Indiana), 16 μg/mL (one Kentucky isolate), and >32 μg/mL (Indiana isolates). As with the three most common serotypes, Salmonella Typhi showed quickly increased prevalence of reduced CIP susceptibility in recent years, Salmonella Enteritidis remained at a high prevalence of reduced CIP susceptibility throughout the study period, and several isolates of Salmonella Typhimurium were resistant to CIP. Transferable plasmid-mediated quinolone resistance gene qnrB was only found in all CIP-resistant isolates. In contrast, gyrA mutations were often found in reduced CIP-susceptible isolates and were not necessarily found in all CIP-resistant isolates.Conclusion: We conclude that in Salmonella, there exists a high prevalence of reduced CIP susceptibility and a low prevalence of CIP resistance, which focuses on several serotypes. Our study also demonstrates that, rather than gyrA mutations, qnrB is the most common indicator for CIP resistance. Keywords: quinolone resistance, Salmonella species, ciprofloxacin-resistant Salmonella isolates, genetic determinant of quinolone resistance

Canopy temperature (Tc) measurements with infrared thermometry have been widely used to assess plant water status. Here, we evaluated Tc and its controlling factors in a primary tropical rainforest (TRF), subtropical evergreen broad-leaved forest (STF) and valley savanna forest (SAF) in southwestern China. We found differences between Tc and air temperature (Ta) of as much as 2.2 °C between the dry and wet seasons in the TRF. However, the canopy-to-air temperature difference (Tc-Ta) was only 0.3 °C between the dry and wet seasons in the STF. Solar radiation (SR) was the dominant factor in Tc-Ta variations during the dry and wet seasons at the three sites. The increased heating in the canopy leaves was likely the result of low stomatal conductance leading to low transpiration cooling. Changes in Tc-Ta in the TRF were highly sensitive to the degree of stomatal closure. The change in Tc-Ta was controlled by the climate, but inherent plant traits, such as stomatal conductance, also played an important controlling role.

Species diversity is the most important component of biodiversity and plays an important role in maintaining forest ecosystem processes and stability. The assessment of the forest conservation value of species diversity is commonly carried out based on the Shannon-Wiener index. However, endangered and endemic species were always ignored in previous studies aimed at assessing the conservation value of forest species diversity. In this study, the conservation value of forest species diversity was assessed in two representative provinces of southern and northern China (Yunnan and Jilin provinces, respectively). The conservation values of species diversity for different forest types was calculated based on the standard Shannon-Wiener index, and on two different indexes derived from it by including: (i) an endangered species index (Ei) based on the China Species Red List; (ii) an endemic species index (Bx) based on the geographic distribution of the species considered. The results showed that the inclusion of the endangered and endemic species indexes dramatically increased the forest conservation values in these two provinces. The total conservation value in the Yunnan province was 268.65 billion yuan yr-1 based on the Shannon-Wiener index, 269.78 billion yuan yr-1 after including Ei in the assessment, and 324.44 billion yuan yr-1 after the inclusion of both Ei and Bx. In Jilin province, the total conservation value was 123.94 billion yuan yr-1 based on the standard Shannon-Wiener index, 124.60 billion yuan yr-1 after including Ei, and 125.74 billion yuan yr-1 after including both Ei and Bx in the assessment. Therefore, the inclusion of endangered and endemic species in the assessment of forest conservation values, as well as other aspects related to biodiversity like the presence of ancient trees, can contribute to the protection of endangered and endemic species in these two provinces of China.

Hongjun Kang,1 Zhi Mao,1 Yan Zhao,1 Ting Yin,2 Qing Song,1 Liang Pan,1 Xin Hu,1 Jie Hu,1 Feihu Zhou1 1Department of Critical Care Medicine, Chinese PLA General Hospital, Beijing, 2Department of Critical Care Medicine, The Centre Hospital of BaoTou, BaoTou, People’s Republic of China Background: Ethyl pyruvate (EP) is a derivative of pyruvic acid that has been demonstrated to be a potential scavenger of reactive oxygen species as well as an anti-inflammatory agent. In this study, we investigated the protective effects of EP and its role in regulating the energy metabolism in the livers of cecal-ligation-and-puncture-induced septic mice. Methods: The animals were treated intraperitoneally with 0.2 mL of Ringer’s lactate solution or an equivalent volume of Ringer’s lactate solution containing EP immediately after cecal ligation and puncture. Each mouse in the Sham group was only subjected to a laparotomy. At 30-, 60-, 180-, and 360-minute time points, we measured the histopathological alterations of the intestines, and the plasma levels of interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor-α, and the total antioxidative capacity, malondialdehyde content, and lactate and lactate/pyruvate levels in livers. Furthermore, we detected the levels of adenosine triphosphate, total adenylate, and energy charge in the livers. Results: Our results demonstrated that the administration of EP significantly improved the survival rate and reduced intestinal histological alterations. EP inhibited the plasma levels of IL-1β, IL-6, and tumor necrosis factor-α and increased the IL-10 level. EP significantly inhibited the elevation of the malondialdehyde, lactate, and lactate/pyruvate levels and enhanced the total antioxidative capacity levels in the liver tissues. The downregulation of the adenosine triphosphate, total adenylate, and energy charge levels in the liver tissues was reversed in the septic mice treated with EP. Conclusion: The results suggest that EP administration effectively modulates the energy metabolism, which may be an important component in treatment of sepsis. Keywords: sepsis, ethyl pyruvate, energy metabolism, inflammation, reactive oxygen species

Shane D Scholten,1 Igor N Sergeev,2 Qingming Song,3 Chad B Birger41Exercise and Sport Sciences, Augustana College, Sioux Falls, 2Department of Health and Nutritional Sciences, South Dakota State University, Brookings, SD, 3Gold Green Farm Corporation, Hammonton, NJ, 4Center for Health Outcomes and Prevention Research, Sanford Research, Sioux Falls, SD, USAIntroduction: Vitamin D and the antioxidant quercetin, are promising agents for improving physical performance because of their possible beneficial effects on muscular strength and cardiorespiratory fitness.Purpose: The purpose of this study was to determine the effects of increased intakes of vitamin D, quercetin, and their combination on antioxidant status, the steroid hormone regulators of muscle function, and measures of physical performance in apparently healthy male adults engaged in moderate-to-vigorous-intensity exercise training.Methods: A total of 40 adult male participants were randomized to either 4,000 IU vitamin D/d, 1,000 mg/d quercetin, vitamin D plus quercetin, or placebo for 8 weeks. Measures of cardiorespiratory fitness and muscle function, blood markers for antioxidant and vitamin D status, and hormones 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and testosterone were measured pre- and postsupplementation.Results: At enrollment, 88.6% of participants were vitamin D sufficient (serum 25-hydroxyvitamin D >50 nmol/L) and had normal serum testosterone levels. Supplementation with vitamin D significantly increased serum 25(OH)D concentration (by 87.3% in the vitamin D group, P

Qinxin Song,1–3 Danhui Li,3 Yongzhi Zhou,3 Jie Yang,1 Wanqi Yang,1 Guohua Zhou,2 Jingyuan Wen31Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, School of Pharmacy, China Pharmaceutical University, 2Department of Pharmacology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, People’s Republic of China; 3School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New ZealandAbstract: The aim of this study was to evaluate (+)-catechin and (−)-epigallocatechin gallate (EGCG) cellular uptake and transport across human intestinal Caco-2 cell monolayer in both the absence and presence of niosomal carrier in variable conditions. The effect of free drugs and drug-loaded niosomes on the growth of Caco-2 cells was studied. The effects of time, temperature, and concentration on drug cellular uptake in the absence or presence of its niosomal delivery systems were investigated. The intestinal epithelial membrane transport of the drug-loaded niosomes was examined using the monolayer of the human Caco-2 cells. The kinetics of transport, and the effect of temperature, adenosine triphosphate inhibitor, permeability glycoprotein inhibitor, multidrug resistance-associated protein 2 inhibitor, and the absorption enhancer on transport mechanism were investigated. It was found that the uptake of catechin, EGCG, and their niosomes by Caco-2 cells was 1.22±0.16, 0.90±0.14, 3.25±0.37, and 1.92±0.22 µg/mg protein, respectively (n=3). The apparent permeability coefficient values of catechin, EGCG, and their niosomes were 1.68±0.16, 0.88±0.09, 2.39±0.31, and 1.42±0.24 cm/second (n=3) at 37°C, respectively. The transport was temperature- and energy-dependent. The inhibitors of permeability glycoprotein and multidrug resistance-associated protein 2 and the absorption enhancer significantly enhanced the uptake amount. Compared with the free drugs, niosomal formulation significantly enhanced drug absorption. Additionally, drug-loaded niosomes exhibited stronger stability and lower toxicity. These findings showed that the oral absorption of tea flavonoids could be improved by using the novel drug delivery systems.Keywords: niosomes, formulation, bioavailability, stability