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Shanshan Ai,1,&ast; Yue Wang,2 Pengli Niu,2 Wenjun Xiao,2 Guojun Xu,2 Chang Zhu3,&ast; 1Department of Nursing, Linping District Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Nursing, The First Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 3Department of Expanded Program on Immunisation, Linping District Centre for Disease Control and Prevention, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guojun Xu, Department of Nursing, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Xigang District, Dalian, Liaoning, 116011, People’s Republic of China, Email xgj1973@163.comPurpose: This study aimed to investigate the correlation between preoperative pain catastrophizing and social support, and acute post-surgical pain in patients who underwent knee arthroplasty. The study also aimed to determine whether social support moderates the role of pain catastrophizing psychologically in acute post-surgical pain after knee arthroplasty.Patients and Methods: This study recruited participants to survey a tertiary hospital in Dalian, China, between November 2022 and October 2023. Participants completed pain catastrophizing scales and social support reevaluated scales one day (T1) before they were confirmed to undergo knee arthroplasty, and finished the Numeric Rating Scale at 24h (T2), 48h (T3), and 72h (T4) postoperatively. Pearson correlation analyses were used to explore the relationship between social support, pain catastrophizing, and acute post-surgical pain, hierarchical regression analysis was used to test the moderating role of social support between pain catastrophizing and acute post-surgical pain.Results: This study recruited 178 knee arthroplasty patients. The results of the t-test or one-way ANOVA indicated that there were statistically significant differences in gender, age, education, occupation, disease duration, whether the knee replacement was performed for the first time, preoperative pain scores, and operation time in patients with knee arthroplasty (P < 0.05). The correlation analysis of social support, pain catastrophization, and acute post-surgical pain in knee arthroplasty patients showed that social support was negatively correlated with acute post-surgical pain (r=− 0.584, P< 0.01), and pain catastrophizing was positively correlated with postoperative acute pain (r=0.601, P< 0.01); The hierarchical regression analysis revealed that social support had a significant moderating effect on the relationship between pain catastrophizing and acute post-surgical pain (ΔR2=0.606, P< 0.05).Conclusion: The acute post-surgical pain of knee arthroplasty patients was affected by gender, age, education, occupation, disease duration, whether the knee arthroplasty was performed for the first time, preoperative pain scores, and operation time. Acute Post-surgical pain in patients with knee arthroplasty was affected by social support and pain catastrophizing, and social support had a moderating effect on the relationship between pain catastrophizing and acute post-surgical pain.Keywords: knee arthroplasty, pain, pain catastrophizing, social support

Mingyue Sun, Weiqiang Xiao, Qingxia Xu Department of Clinical Laboratory, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Qingxia Xu, Department of Clinical Laboratory, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Dongming Road No. 127, Zhengzhou, Henan Province, People’s Republic of China, Tel +860371-65587147, Email qxiaxu@126.comObjective: Klebsiella michiganensis is an emerging pathogen. In this context, we characterised a strain fxq isolated from a cerebrospinal fluid specimen of a patient with tentorial meningioma, and the K. michiganensis isolate produced carbapenemases of KPC and NDM types.Methods: The Phoenix 100 Automated Microbiology System, MALDI-TOF and whole-genome sequencing were used to identify the species. Anti-microbial susceptibility testing was also conducted with the Phoenix 100. The plasmid locations of the blaKPC-2 and blaNDM-1 genes were determined by S1-nuclease pulsed-field gel electrophoresis and Southern blot. The transfer capacity of plasmids carrying blaKPC-2 and blaNDM-1 was investigated by conjugation experiments, and the resistance plasmid stability was evaluated by culture and subculture. K. michiganensis subtypes were identified by multi-locus sequence typing. We performed whole-genome sequencing to confirm species, characterise plasmids and analyse core genes.Results: fxq was originally identified as Klebsiella oxytoca and showed resistance to imipenem and meropenem, but whole-genome sequencing identified it to be K. michiganensis. The strain fxq belonged to the novel sequence type 202 (ST202) and carried the blaKPC-2 and blaNDM-1 genes located on the pB_KPC InFIA and pE_NDM IncU plasmids, respectively. The blaKPC-2-carrying plasmid was successfully transferred to Escherichia coli EC600 by conjugation, whereas the blaNDM-1 gene on the pE_NDM plasmid was not. The pB_KPC and pE_NDM plasmids demonstrated high stability.Conclusion: This work is the first report on a carbapenem-resistant clinical isolate K. michiganensis ST202 harbouring the blaKPC-2 and blaNDM-1 genes encoded by the IncFIA and IncU plasmids, respectively.Keywords: Klebsiella michiganensis, IncU plasmid, carbapenemase gene, NDM, KPC

Wei Xiao,1 Yanqiong Liu,2 Hua Tang,3 Qin Xie,2 Yanlan Luo,2 Tao Mei1 1Department of Neurosurgical Care Unit, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, 415003, People’s Republic of China; 2Cardiovascular Medicine Department, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, 415003, People’s Republic of China; 3Neurosurgery Department, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, 415003, People’s Republic of ChinaCorrespondence: Tao Mei, Email yilan1008@sina.comBackground: Intracerebral hemorrhage (ICH) affects up to 1% of chronic oral anticoagulation (OAC) users per year. This study explored the knowledge, attitude and practice (KAP) towards ICH prevention among patients taking OACs.Methods: This multicenter cross-sectional survey was conducted at 4 hospitals from February to May 2023, and a self-administered questionnaire was developed to assess KAP toward ICH prevention among patients taking OACs. Structural equation modeling was used to assess the relationship between KAP.Results: A total of 536 valid questionnaires (67.25%) were analyzed, from 43.8% participants on Warfarin, 40.5% on Rivaroxaban and 15.7% on Dabigatran. The average knowledge, attitudes and practice scores were 9.22, 24.11, and 28.01 out of 16, 35 and 40, respectively. Participants who received Rivaroxaban had lower knowledge scores but higher attitude and practice store compared to those who received Warfarin or Dabigatran (all p < 0.001). According to Structure Equation Modeling, attitude had direct positive effect on practice (β = 0.694 [0.603– 0.804], p = 0.012), while knowledge had direct negative effect on attitude (β = − 2.077 [− 2.507– 1.651], p = 0.013), as well as negative effect on practice, both direct (β = − 0.450[− 0.689– 2.03], p=0.012), and indirect (β = − 1.441 [− 1.928– 1.192], p = 0.004).Conclusion: Patients taking OACs showed insufficient knowledge, negative attitude and proactive practice regarding ICH; practice scores were affected by age, type of anticoagulation medication, and attitude rather than knowledge.Keywords: cerebral hemorrhage, anticoagulants, warfarin, dabigatran, rivaroxaban, knowledge, attitude, practice

Yan Yu,1,&ast; Ti-wei Miao,1,&ast; Wei Xiao,1 Bing Mao,1 Long-yi Du,1 Yan Wang,2 Juan-juan Fu1 1Division of Pulmonary Medicine, Department of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China; 2Research Core Facility, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Juan-juan Fu, Division of Pulmonary Medicine, Department of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, 37 Guoxue Street, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86-18980606822, Email fu.juanjuan@scu.edu.cnPurpose: The aim of this study is to uncover the anti-inflammatory propertity of andrographolide (AGP) in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and the underlying mechanisms related to the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome pathway.Methods: An in vivo experiment was conducted on murine model of AECOPD through endotracheal atomization of elastase and lipopolysaccharide (LPS). Intraperitoneal AGP was administered four times. NLRP3 inflammasome pathway molecules were examined using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. By using enzyme-linked immunosorbent assay (ELISA), we tested interleukin (IL)-1β levels in bronchoalveolar lavage fluid. An in vitro study was conducted to determine how AGP impacts the NLRP3 inflammasome in THP-1 derived macrophages. The levels of molecules involved in the pathway were measured. Furthermore, molecular docking analyses were carried out to investigate the interactions between AGP and pathway targets.Results: In the in vivo study, NLRP3 inflammasome activation was observed in mice experiencing AECOPD. The administration of high-dose AGP demonstrated a mitigating effect on inflammatory cells infiltration in the lungs. Moreover, AGP administration effectively suppressed the expression of NLRP3, apoptosis associated speck-like protein that contains a CARD (PYCARD), cysteinyl aspartate-specific protease-1 (Caspase-1), IL-1β, and IL-18 at both the genetic and protein levels. In the in vitro experiment, IL-1β levels were significantly elevated in THP-1 derived macrophages with activated inflammasome compared to the control group. Furthermore, the downregulation of NLRP3, CASP1, and IL1B genes was observed upon the inhibition of NLRP3 expression through small interfering RNA (siRNA). AGP demonstrated inhibitory effects on the gene expression and protein levels of NLRP3, Caspase-1, and IL-1β. Additionally, molecular docking analysis confirmed that AGP exhibited a favorable binding affinity with all five targets of the pathway.Conclusion: AGP effectively inhibited NLRP3 inflammasome activation and mitigated the inflammatory reaction of AECOPD both in animal models and in vitro experiments, highlighting the potential of AGP as a treatment for AECOPD with anti-inflammatory properties.Keywords: andrographolide, NLRP3 inflammasome, IL-1β, chronic obstructive pulmonary disease

Shi-Hua Yan,1,2 Yong Chen,3 Zhi-Qian Huang,1 Wen-Xi Zhong,1 Xiao-Tian Wang,1 Yang-Can Tang,1 Xu-Yi Zhao,1 Yu-Shan Wu,1 Chun Zhou,4 Wei Zhu,5 Wei Xiao,1,6 Xuan Li,2 Dong-Shu Zhang1,2 1School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 2Department of Traditional Chinese Medicine, The Tenth affiliated Hospital, Southern Medical University (Dongguan People’s Hospital), Dongguan, Guangdong, 523058, People’s Republic of China; 3Department of Rheumatology and Immunology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, People’s Republic of China; 4School of Pharmaceutical Sciences; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 5Guangzhou Center for Disease Control and Prevention, Guangzhou, 510440, People’s Republic of China; 6Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, People’s Republic of ChinaCorrespondence: Dong-Shu Zhang, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China, Email nyzds@sina.com Wei Xiao, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, People’s Republic of China, Email xw7688@smu.edu.cnPurpose: Acupoint autohemotherapy (A-AHT) has been proposed as an alternative and complementary treatment for atopic dermatitis (AD), yet the exact role of its blood component in terms of therapeutic efficacy and mechanism of action is still largely unknown.Methods: This study aimed to evaluate the therapeutic efficacies and action mechanisms of intramuscular injections of autologous whole blood (AWB) and mouse immunoglobulin G (IgG) (autologous or heterologous) at acupoints on 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse models. Serum levels of total immunoglobulin E (IgE), IgG, interleukin-10 (IL-10), and interferon-gamma (IFN-γ) were measured, as well as mRNA expression levels of Forkhead box P3 (FoxP3), IL-10 and IFN-γ in dorsal skin lesions, and IL-10+, IFN-γ+ and FoxP3+CD4+T cells in murine spleen.Results: It showed that repeated acupoint injection of AWB, autologous total IgG (purified from autologous blood in AD mice) or heterologous total IgG (purified from healthy blood in normal mice) effectively reduced the severity of AD symptoms and decreased epidermal and dermal thickness as well as mast cells in skin lesions. Additionally, AWB acupoint injection was found to upregulate FoxP3+, IL-10+ and IFN-γ+ CD4+T cells in murine spleen, suppressing the production of IgE antibodies and increasing that of IgG antibodies in the serum. Furthermore, both AWB and autologous total IgG administrations significantly elevated FoxP3 expression, mRNA levels of IL-10 and IFN-γ in dorsal skin lesions. However, acupoint injection of heterologous total IgG had no effect on regulatory T (Treg) and Th1 cells modulation.Conclusion: These findings suggest that the therapeutic effects of A-AHT on AD are mediated by IgG-induced activation of Treg cells.Keywords: autologous whole blood, acupoint injection, atopic dermatitis, anti-idiotypic immunomodulation, Tregs

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

Yubin Zhu,1 Yilu Zhuang,2 Yawen Yu,2 Jinyue Wang,2 Yongtai Liu,3 Zhi Ruan,2,4 Wei Xiao,5 Yingying Kong2,4 1Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3The First Division Hospital of XinJiang Production and Construction Group, XinJiang, People’s Republic of China; 4Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, People’s Republic of China; 5Department of Emergency Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Yingying Kong; Wei Xiao, Email kongyy@zju.edu.cn; Xiaowei 2022@zju.edu.cnAbstract: Raoultella planticola is an emerging bacterial pathogen responsible for causing infections in both humans and animals. Unfortunately, sporadic reports of carbapenem-resistant R. planticola (CRRP) have been documented worldwide. Here we first reported the complete genome sequence of a CRRP isolate RP_3045 co-carrying blaIMP-4 and blaSHV-12, recovered from a patient in China, and its genetic relatedness to 82 R. planticola strains deposited in the NCBI GenBank database, sourced from humans, animals, and the environment. Whole-genome sequencing was performed using the Illumina NovaSeq 6000 and Oxford Nanopore MinION platforms. Phylogenetic analysis was also performed and visualized using a single nucleotide polymorphism (SNP)-based strategy. The complete genome of R. planticola strain RP_3045 was determined to be 6,312,961 bp in length, comprising five contigs that included one chromosome and four plasmids. RP_3045 was found to be multidrug-resistant and harbored several antimicrobial resistance genes, including both blaIMP-4 and blaSHV-12 genes located on a single plasmid. The most closely related strain was hkcpe63, recovered from humans in Hong Kong, China, in 2014, with 506 SNP differences. R. planticola strains were distributed globally and exhibited strong associations among isolates obtained from different sectors. This study provides evidence for the potential of R. planticola to disseminate carbapenem resistance across different sectors, highlighting the critical need for active and continuous surveillance of CRRP.Keywords: Raoultella planticola, blaIMP-4, blaSHV-12, antimicrobial resistance

Jiaxing Zhang,1,2,&ast; Liwei Gu,3,&ast; Yumao Jiang,4,&ast; Yun Ma,5,&ast; Ziyue Zhang,3 Shengnan Shen,3 Shuo Shen,3 Qing Peng,6 Wei Xiao2,7 1Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guang Dong, People’s Republic of China; 2School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guang Dong, People’s Republic of China; 3Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 4Gannan Medical University, Ganzhou, Jiang Xi, People’s Republic of China; 5Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, Guang Dong, People’s Republic of China; 6Institute of Basic Medical Sciences, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 7Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qing Peng; Wei Xiao, Email pengqing85@163.com; xw7688@smu.edu.cnBackground: Acute kidney injury (AKI) is a syndrome, posing a substantial healthcare burden. The pathological basis of AKI is associated with inflammation and oxidative stress which cause additional damage to mitochondria. Artesunate (ATS) is a derivative of artemisinin isolated from Artemisia annua L. that is an effective treatment for malaria and favored for the prevention and treatment of kidney diseases. However, there are still challenges related to its efficacy, including poor water solubility, limited oral bioavailability and short half-life. Liposome-based nanoparticles are used for drug delivery due to their ideal biocompatibility and their ability to improve the bioavailability of specific drugs and enhance drug efficacy.Methods: In this study, a novel TPP-based natural ATS-nanoliposome, namely T-A-Ls, was applied for the treatment of AKI. ATS was encapsulated with or without triphenylphosphonium (TPP)-modified nanoliposomes. AKI was induced by cisplatin in C57BL/6J mice and a cisplatin-induced injury model was generated in HK-2 cells in vitro. Blood urea nitrogen (BUN), serum creatinine (Scr) measurements and section staining were utilized to assess renal protective effect of T-A-Ls. Inflammatory-related factors and proteins were quantified via Elisa, Immunofluorescence and Western Blot (WB). The anti-mitochondrial oxidative stress effect of T-A-Ls was determined by ROS, JC-1 and oxygen consumption rate (OCR) kits. Immunohistochemistry and WB were conducted to measure associated protein expressions. In vivo biodistribution and the concentration of T-A-Ls in kidney were also explored.Results: T-A-Ls exhibited good oxidative resistance, preferential renal uptake, mitochondrial targeting, and it ameliorated kidney injury in cisplatin-induced AKI mice. Mitochondrial dysfunction, ATP production and respiratory capacity were improved in damaged HK-2 cells; ROS content decreased while mitochondrial membrane potential recovered. T-A-Ls exerted renal protection by inhibiting inflammation and reducing oxidative stress; these effects were mediated by a downregulation in the expression of RAGE and iNOS and an upregulation in both Nrf2 and HO-1.Conclusion: T-A-Ls could improve the delivery of ATS to the kidney, offering a promising avenue to treat AKI. Keywords: artesunate, liposomes, AKI, cisplatin, oxidative stress, inflammation

Na Li,1 Xiaochun Jiang,2 Wanju Zhang,1 Wenping Xiao,1 Zhaona Wu,1 Huirong Wang,1 Feng He1 1Li Shizhen College of Traditional Chinese Medicine, Huanggang Normal University, Huanggang, 438000, People’s Republic of China; 2Hubei Key Laboratory for Processing and Application of Catalytic Materials, College of Chemistry and Chemical Engineering, Huanggang Normal University, Huanggang, 438000, People’s Republic of ChinaCorrespondence: Na Li; Feng He, Email ln19860622@126.com; hfeng@hust.edu.cnIntroduction: Combined multimodal therapy for breast cancer is a promising therapeutic approach to increase treatment efficacy and reduce systemic toxicity. The present study aimed to develop a novel multifunctional drug release nanoplatform based on RGD-conjugated hyaluronic acid (HA)-functionalized copper sulfide (CuS) for activatable dual-targeted synergetic therapy against cancer.Methods: The pH and NIR-responsive dual-targeting nanoplatform CuS:Ce6@HA:DOX@RGD was prepared, characterized, and evaluated for its stability and photodynamic and photothermal properties. The loading and release of the drug were measured at different pH values with or without laser radiation using the dialysis method. The cellular uptake of the platform specifically by the tumor cells treated with different formulations was investigated through fluorescence imaging. The in vitro and in vivo biosafety levels were assessed systematically. Finally, the antitumor efficiencies against breast cancer were assessed via in vitro and in vivo experiments.Results: The spheroid CuS:Ce6@HA:DOX@RGD exhibited remarkable stability and monodispersity in solution. The photosensitive CuS and Ce6 could simultaneously absorb the near-infrared light efficiently to convert NIR light to fatal heat and to generate reactive oxygen species. The CuS:Ce6@HA:DOX@RGD dissociated under an acid environment, causing the release of DOX into the tumor to accelerate upon laser irradiation. The CuS:Ce6@HA:DOX@RGD exhibited target-specific and strong binding ability via a synergic CD44/αvβ3 receptor-mediated bimodal targeting, which led to improved therapeutic efficacy. The tumor growth was effectively inhibited using synergetic photodynamic/photothermal/chemo therapy. No evident systemic toxicity was noted during treatment.Conclusion: The newly prepared CuS:Ce6@HA:DOX@RGD has great potential as an activatable theranostic nanoplatform for efficient dual-targeted synergistic therapy against breast cancer. Keywords: responsive nanoplatform, targeting, drug delivery, synergistic therapy, breast cancer

Danni Xue,1,&ast; Binghai Sun,1,&ast; Weijian Li,1 Hui Zhou,2 Fujun Ding,1 Weilong Xiao1,3 1School of Psychology, Zhejiang Normal University, Jinhua, 321004, People’s Republic of China; 2Jinhua Advanced Research Institute, Jinhua, Zhejiang, 321004, People’s Republic of China; 3Research Unit Occupational & Organizational Psychology and Professional Learning, KU Leuven, Leuven, 3000, Belgium&ast;These authors contributed equally to this workCorrespondence: Fujun Ding, School of Psychology, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, People’s Republic of China, Email dfj201810100017@163.comBackground: Teacher burnout is characterized by emotional and physical exhaustion resulting from excessive work-related stress. Previous research based on traditional latent variable theory has revealed a significant negative relationship between TB and psychological capital (PsyCap). This study explored the complex symptoms of TB and the contact points of PsyCap in reducing TB using psychometric network analysis.Methods: A total of 3991 teachers completed the burnout subscale of the Professional Quality of Life and Psychological Capital Scale.Results: The results showed that: (a) In the TB network, the core symptoms displayed by teachers due to burnout are difficulty feeling “I am a very caring person”, “I am happy”, and “I am the person I always wanted to be”; (b) The TB-PsyCap network was closely connected, and the symptoms affected each other. PsyCap affected the TB network through “I feel optimistic and happy almost every day” and “I often feel that there is a future as a teacher”; (c) PsyCap’s bridge symptoms had a negative impact on TB, and PsyCap may reduce TB primarily through optimistic, hopeful dimensions.Conclusion and Implications: Psychometric network analysis helps us understand the complex symptoms of TB and the contact points of PsyCap in reducing TB. This study offers valuable insights into the prevention of, and intervention in, burnout within the teaching community.Keywords: teacher burnout, psychological capital, network analysis, network comparison

Fangfang Yuan,1 Weiqiang Xiao,2 Xiaokun Wang,2 Yuewen Fu,1 Xudong Wei1 1Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University& Henan Cancer Hospital, Zhengzhou, People’s Republic of China; 2Department of Laboratory Science, The Affiliated Cancer Hospital of Zhengzhou University& Henan Cancer Hospital, Zhengzhou, People’s Republic of China;Correspondence: Xudong Wei; Yuewen Fu, Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, People’s Republic of China, Tel +86-371-65587218 ; +86-371-65587027, Email xudongwei@zzu.edu.cn; zlyyfuyuewen1480@zzu.edu.cnObjective: To analyze the clinical characteristics and prognostic risk factors of carbapenem-resistant Pseudomonas aeruginosa (CRPA) bloodstream infections in patients with hematologic malignancies.Methods: Medical records and drug susceptibility data of patients with hematologic malignancies complicated by CRPA bloodstream infections admitted to the Cancer Hospital of Zhengzhou University between January 1, 2018, and December 31, 2022, were retrospectively analyzed.Results: A total of 64 patients were included in the study, with a mortality rate of 37.5% (24/64) at 28 days after the occurrence of CRPA bloodstream infection. In Cox regression analysis, an absolute neutrophil count < 0.5× 109/L at discharge (HR 0.039, 95% CI 0.006 ~ 0.258, p=0.001), admission to the intensive care unit (HR 7.546, 95% CI 1.345 ~ 42.338, p= 0.022), and a higher Pitt bacteremia score (HR 0.207, 95% CI 0.046 ~ 0.939, p = 0.041) were independent risk factors associated with 28-day mortality. Survival analysis showed that patients receiving ceftazidime-avibactam-based (HR 0.368, 95% CI 0.107~ 1.268, p = 0.023) or polymyxin B (HR 2.561, 95% CI 0.721 ~ 9.101, p = 0.015) therapy had a higher survival rate.Conclusion: Patients with hematologic neoplasms had high mortality from CRPA bloodstream infections, and admission to the intensive care unit, higher Pitt bacteremia score (PBS) scores, granulocyte deficiency, and granulocyte deficiency at discharge were independently associated with higher mortality. Early anti-infective treatment with ceftazidime-avibactam or polymyxin B may improve the clinical prognosis of patients.Keywords: Pseudomonas aeruginosa, carbapenem resistance, bloodstream infection, hematologic neoplasm, risk factors

Yubo Li,1,2,&ast; Chengming Li,1,2,&ast; Tao Luo,3,&ast; Tian Yue,4 Wenjing Xiao,5 Ling Yang,1,2 Zaiyuan Zhang,6 Fei Han,3,&ast; Pan Long,3 Yonghe Hu6 1School of Clinical Medicine, Chengdu University of TCM, Chengdu, People’s Republic of China; 2Basic Medical Laboratory, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 3Department of Ophthalmology, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 4School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, People’s Republic of China; 5Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 6College of Medicine, Southwest Jiaotong University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pan Long, Department of Ophthalmology, The General Hospital of Western Theater Command, Rongdu Avenue &num;270, Chengdu, People’s Republic of China, Tel +86-181-9125-6132, Email longpan1005@qq.com Yonghe Hu, College of Medicine, Southwest Jiaotong University, No. 111, North First section of the Second Ring Road, Chengdu, People’s Republic of China, Tel +86-138-8059-6789, Email huyonghezyy@163.comAbstract: With the increasing of altitude activities from low-altitude people, the study of high altitude cerebral edema (HACE) has been revived. HACE is a severe acute mountain sickness associated with exposure to hypobaric hypoxia at high altitude, often characterized by disturbance of consciousness and ataxia. As for the pathogenesis of HACE, previous studies suggested that it might be related to the disorder of cerebral blood flow, the destruction of blood-brain barrier and the injury of brain parenchyma cells caused by inflammatory factors. In recent years, studies have confirmed that the imbalance of REDOX homeostasis is also involved in the pathogenesis of HACE, which mainly leads to abnormal activation of microglia and destruction of tight junction of vascular endothelial cells through the excessive production of mitochondrial-related reactive oxygen species. Therefore, this review summarizes the role of REDOX homeostasis and the potential of the treatment of REDOX homeostasis in HACE, which is of great significance to expand the understanding of the pathogenesis of HACE. Moreover, it will also be helpful to further study the possible therapy of HACE related to the key link of REDOX homeostasis.Keywords: high altitude cerebral edema, hypobaric hypoxia, REDOX homeostasis, mitochondria dysfunction, microglia

Weiqiang Xiao,1,&ast; Xiaokun Wang,1,&ast; Yuanye Qu,1 Mingyue Sun,1 Yanmin Chang,1 Wenjiao Li,1 Yong Shen,1,2 Xiufang Shi,3 Min Jing,1 Qingxia Xu1,4 1Department of Clinical Laboratory, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Institute of Biophysics, Chinese Academy of Sciences, Foshan, People’s Republic of China; 3School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China; 4Zhengzhou Key Laboratory for Diagnosis of Digestive System Tumor Markers, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingxia Xu; Xiufang Shi, Email zlyyxuqingxia0575@zzu.edu.cn; xfshi@zzu.edu.cnBackground: Emergence of blaKPC and blaNDM co-harboring Klebsiella pneumoniae has escalated the threat of Carbapenem-resistant Klebsiella pneumoniae (CRKP) to healthcare. It remains unknown the prevalence and molecular characteristics of CRKP co-producing KPC and NDMs carbapenemases in Henan.Methods and Results: Twenty-seven CRKP strains isolated from different times were selected randomly in affiliated cancer hospital of Zhengzhou University from January 2019 to January 2021, among which one KPC-2 and NDM-5 positive CRKP named K9 was isolated from an abdominal pus sample of a 63-year-old male patient with leukemia. Sequencing of K9 determined that K9 belonged to ST11-KL47, which is resistant to antibiotics such as meropenem, ceftazidime-avibactam and tetracycline. K9 carried two different plasmids that contained blaNDM− 5 and blaKPC− 2. Both plasmids were shown to be novel hybrid plasmids and IS 26 played an important role in generation of two plasmids. Gene blaKPC-2 was flanked by the NTEKPC-Ib-like genetic structure (IS 26-ΔTn 3-ISKpn8-blaKPC-2-ISKpn6-IS 26) and was located on a conjugative IncFII/R/N type hybrid plasmid.Conclusion: The resistance gene blaNDM− 5 located on a region organized as IS 26-blaNDM– 5-ble-trpF-dsbD-ISCR1-sul1-aadA2-dfrA12-IntI1-IS 26 was carried by a phage-plasmid. We described a clinical CRKP co-producing KPC-2 and NDM-5 and emphasized an urgent need to control their further spread.Keywords: carbapenem-resistant Klebsiella pneumoniae, KPC-2, NDM-5, beta-lactamases, hybrid plasmid, IS 26

Jin Chen,1,&ast; Guoping Zhu,2,&ast; Wenbo Xiao,3 Xiaosong Huang,4 Kewu Wang,2 Yi Zong2 1Department of Hematology, Yiwu Central Hospital, Yiwu, People’s Republic of China; 2Department of Radiology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, People’s Republic of China; 3Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Department of Pharmacy, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kewu Wang; Yi Zong, Department of Radiology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, No. N1, Shangcheng Avenue, Yiwu, Zhejiang, People’s Republic of China, Email 8016070@zju.edu.cn; zong@zju.edu.cnBackground: The main propanaxatriol-type saponin found in ginseng (Panax ginseng C. A. Mey), ginsenoside Rg1 (G-Rg1), has bioactivities that include anti-inflammatory, antioxidant, and anti-diabetic properties. This study aimed to investigate the effects of G-Rg1 on streptozotocin (STZ)-induced Type 1 Diabetes mellitus (T1DM) mice and the insulin-secreting cell line in RIN-m5F cells with high-glucose (HG) treatment.Methods: The STZ-induced DM mice model was treated with G-Rg1 alone or combined with 3-Methyladenine (3-MA, an autophagy inhibitor)/rapamycin (RAPA, an autophagy activator) for 8 weeks, and levels of glucose and lipid metabolism, histopathological changes, as well as autophagy and apoptosis of relevant markers were estimated. In vitro, the HG-induced RIN-m5F cells were treated with G-Rg1, 3-MA, and Compound C (CC), an AMPK inhibitor, or their combinations to estimate the influences on cell apoptosis, autophagy, and AMPK/mTOR pathway-associated target gene levels.Results: G-Rg1 treatment attenuated glucose and lipid metabolism disorder and pancreatic fibrosis in diabetic mice. In addition, subdued autophagy and p-AMPK protein expression, and enhanced p-mTOR protein expression and apoptosis levels in TIDM mice and HG-induced RIN-m5F cells were ameliorated by G-Rg1 treatment. Furthermore, these anti-apoptosis effects of G-Rg1 were partially abolished by 3-MA and CC.Conclusion: Our findings revealed that G-Rg1 exhibits strong anti-apoptosis ability in pancreatic tissues of type 1 diabetic mice and HG-induced RIN-m5F cells, and the mechanisms involved in activating AMPK and inhibiting mTOR-mediated autophagy, indicating that G-Rg1 may have the therapeutic and preventive potential for treating pancreatic injury in diabetic patients.Keywords: diabetes mellitus, ginsenoside Rg1, autophagy, apoptosis, AMPK

Xiachuan Qin,1,2 Xiaomin Hu,2 Weihan Xiao,2 Chao Zhu,3 Qianqin Ma,1 Chaoxue Zhang1 1Department of Ultrasound, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Ultrasound, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College (University), Nan Chong, People’s Republic of China; 3Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Chaoxue Zhang, Department of Ultrasound, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China, Tel +86-13955158023, Email zcxay@163.comObjective: Distinguishing the degree of differentiation, hepatocellular carcinoma (HCC) has important clinical significance in the therapeutic decision-making and patient prognosis evaluation.Methods: We developed a deep-learning radiomics (DLR) model based on contrast-enhanced ultrasound (CEUS) to evaluate the differentiation of HCC noninvasive. We retrospectively analyzed HCC patients who had undergone resection and CEUS one week preoperatively between November 2015 and August 2022. Enrolled patients were randomly divided into training (n=190) and testing (n=82) cohorts in a 7:3 ratio. The depth of learning and radiological characteristics reflecting the differentiation degree of HCC were extracted, and the least absolute shrinkage and selection operator(LASSO) was used for feature selection to obtain the most valuable features and then build a DLR model based on the useful features.Results: The deep-learning Radiomics model could accurately predict the degree of differentiation of HCC; the area under the curve of the DLR model in the training and testing cohorts was 0.969 and 0.932, respectively. The accuracy, sensitivity, and specificity of the CEUS-based DLR model for predicting the differentiation of HCC were 0.915, 0.938, and 0.900, respectively, in the testing cohort. The decision curve analysis confirmed that the combined model predicted good overall net income for differentiation.Conclusion: The CEUS-based DLR model provides an easy-to-use, visual, and personalized tool for predicting the differentiation of HCC and can help doctors formulate more favorable treatment plans for patients.Keywords: hepatocellular carcinoma, differentiated, contrast-enhanced ultrasound, deep-learning, radiomics

Xiachuan Qin,1,2,&ast; Linlin Xia,1,&ast; Chao Zhu,3 Xiaomin Hu,2 Weihan Xiao,2 Xisheng Xie,4 Chaoxue Zhang1 1Department of Ultrasound, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Ultrasound, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College (University), Nan Chong, Sichuan, People’s Republic of China; 3Department of Radiology, The First Affiliated Hospital of Anhui Medical university, Hefei, Anhui, People’s Republic of China; 4Department of Nephrology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College (University), Nan Chong, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chaoxue Zhang, Department of Ultrasound, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China, Email zcxay@163.com Xisheng Xie, Department of Nephrology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College (University), Nan Chong, Sichuan, People’s Republic of China, Email xishengx@163.comIntroduction: To explore whether ultrasonic radiomics extracted by machine learning method can noninvasively evaluate lupus nephritis (LN) activity.Materials and Methods: This retrospective study included 149 patients with LN diagnosed by renal biopsy. They were divided into a training cohort (n=104) and a test cohort (n=45). Ultrasonic radiomics features were extracted from the ultrasound images, and the radiomics features were constructed. Furthermore, five machine learning algorithms were compared to evaluate LN activity. The performance of the binary classification model was evaluated by the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).Results: The average AUC of the five machine learning models was 79.4, of which the MLP model was the best. The AUC of the training group was 89.1, with an accuracy of 81.7%, a sensitivity of 83%, a specificity of 80.7%, a negative predictive value of 85.2%, and a positive predictive value of 78%. The AUC of the test group was 82.2, the accuracy was 73.3%, the sensitivity was 78.9%, the specificity was 69.2%, the negative predictive value was 81.8%, and the positive predictive value was 65.2%.Conclusion: Machine learning classifier based on ultrasonic radiomics has high accuracy for LN activity. The model can be used to noninvasively detect the activity of LN and can be an effective tool to assist the clinical decision-making process.Keywords: systemic lupus erythematosus, lupus nephritis, activity, ultrasound, machine learning

Wenwu Xiao,1 Huaichun Yang,1 Zhuangfu Wang,2 Haian Mao,1 Hongjiang Wang,1 Zengming Hao,1 Yao Zu,1 Chuhuai Wang1 1Department of Rehabilitation Medicine, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Faculty of Population Health Sciences, Institute of Child Health I, University College London, London, UKCorrespondence: Chuhuai Wang, Department of Rehabilitation Medicine, the First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, People’s Republic of China, Tel +86 13316191023, Email wangchuh@mail.sysu.edu.cnAbstract: Low back pain is a major global public health problem, but the current intervention effect is not ideal. A large body of previous literature suggests that patients with chronic low back pain may have abnormal postural control, which is more evident in the dual task situation. In recent years, research on postural control in patients with low back pain under dual-task conditions has gradually become a hot topic. However, the results obtained from these studies were not entirely consistent. In this review, we summarized relevant studies on the performance of postural control in patients with low back pain under dual-task conditions, analyze it from the perspective of the theoretical model of dual-task interaction, the specific research paradigm of dual task, the performance of postural control, and the related factors affecting postural control performance, etc. It was reasonable to assume that patients with low back pain might have a certain degree of abnormal postural control, and this abnormality was affected by comprehensive factors such as age, cognitive resource capacity, attention needs, complex sensorimotor integration, external environment, etc. Furthermore, postural control performance in low back pain patients under dual-task conditions was further influenced by the nature and complexity of the different tasks. In general, the more attention resources were needed, the external environmental conditions were worse, and the age-related functions were degenerate, etc., the weaker posture control ability was. In short, a deeper understanding of postural control in patients with low back pain under dual-task conditions may shed light on more references for the rehabilitation and management of low back pain, as well as some new ideas for scientific research on cognition and postural control.Keywords: postural control, low back pain, dual-task, cognitive, motor

Xuegang Wang,1,&ast; Weiquan Li,2,&ast; Ning Lou,3,&ast; Weiwei Han,3 Bo Hai,2 Wen Xiao,2 Xiaoping Zhang2 1Department of Urology, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, People’s Republic of China; 2Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 3Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen Xiao; Bo, Hai, Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province, 430022, People’s Republic of China, Tel +86-17088353610, Fax +86 85776343, Email xiaowenx11@163.com; Haibo2022@hust.edu.cnBackground: Invasion and metastasis led to poor prognosis and death of clear cell renal cell carcinoma (ccRCC) patients. The deoxynucleotidyl transferase terminal interacting protein 1 (DNTTIP1) was reported to promote multiple tumor progression. However, there is no research about DNTTIP1 in ccRCC.Methods: Kaplan–Meier survival analysis, multivariate analysis demonstrated the prognostic indicator in overall survival (OS) and disease-free survival (DFS) of ccRCC with DNTTIP1 expression in the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC). Receiver operator characteristic (ROC) curve analyzed diagnostic ability of DNTTIP1 in TCGA-KIRC and validation dataset. The quantitative real-time polymerase chain reaction (qRT-PCR) detected the DNTTIP1 expression in renal cancer tissues, and the Office of Cancer Clinical Proteomics Research (CPTAC) verified the protein expression of DNTTIP1. Moreover, nomogram predicted the role of DNTTIP1 in ccRCC patient. Single-sample Gene Set Enrichment Analysis (SsGSEA) and GSEA evaluated the pathogenesis role of DNTTIP1 in TCGA-KIRC.Results: DNTTIP1 expression was higher in ccRCC tumor tissues. High expression of DNTTIP1 was associated with poor OS (HR = 1.618, P < 0.0001), and poor DFS (HR = 1.789, P < 0.0001). SsGSEA and GSEA showed DNTTIP1 was associated with hypoxia, epithelial-mesenchymal transition (EMT), angiogenesis, G2M checkpoint. DNTTIP1 had a positive correlation with EMT biomarkers in ccRCC, and might be an effective target for ccRCC.Conclusion: This study provided that higher expression of DNTTIP1 predicted poor prognosis in ccRCC, and DNTTIP1 might be a novel detection biomarker and therapeutic target of tumor malignant in the future.Keywords: DNTTIP1, ccRCC, gene therapy, prognostic indicator

Abstract The space environment includes unique hazards like radiation and microgravity which can adversely affect biological systems. We assessed a multi-omics NASA GeneLab dataset where mice were hindlimb unloaded and/or gamma irradiated for 21 days followed by retinal analysis at 7 days, 1 month or 4 months post-exposure. We compared time-matched epigenomic and transcriptomic retinal profiles resulting in a total of 4178 differentially methylated loci or regions, and 457 differentially expressed genes. Highest correlation in methylation difference was seen across different conditions at the same time point. Nucleotide metabolism biological processes were enriched in all groups with activation at 1 month and suppression at 7 days and 4 months. Genes and processes related to Notch and Wnt signaling showed alterations 4 months post-exposure. A total of 23 genes showed significant changes in methylation and expression compared to unexposed controls, including genes involved in retinal function and inflammatory response. This multi-omics analysis interrogates the epigenomic and transcriptomic impacts of radiation and hindlimb unloading on the retina in isolation and in combination and highlights important molecular mechanisms at different post-exposure stages.

Junwei Gao,1 Ziyun Li,1 Jing Li,2 Ping Song,3 Jinsheng Yang,1 Wei Xiao,4 Ning Li,1 Ruodan Xu1 1Department of Biomedical Engineering and Technology, Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Department of Nephropathy, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Department of Dermatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 4Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical Co. Ltd., Lianyungang, People’s Republic of ChinaCorrespondence: Ruodan Xu; Ning Li, Email ruodanxu@gmail.com; lili.li.ning@gmail.comPurpose: Peptide-based high-density lipoprotein (pHDL) structurally and functionally resembles the natural HDL as anti-atherosclerosis (AS) therapies. Since pHDL contains a large hydrophobic core, this study aims to evaluate the potentials of pHDL as a hydrophobic drug carrier and the efficiency of drug-loaded pHDL in the control of AS.Methods: The pHDL encapsulation of hydrophobic components from natural plants, including curcumin (Cur) and tanshinone IIA (TanIIA), was achieved using one-step microfluidics. Then, morphological features and loading efficiencies of pHDL-Cur and pHDL-TanIIA were determined by TEM and high-performance liquid chromatography (HPLC), respectively. Taking the fluorescence advantage of Cur, localizations of loaded Cur in pHDL were investigated by fluorescence quenchers, and recruitments of Cur to AS plaques were assessed with ex vivo imaging. Based on anti-inflammatory properties of TanIIA, pHDL-TanIIA was accordingly developed to evaluate the anti-AS effects through examinations of plasma lipid parameters and pathological alterations of plaque-associated regions.Results: Both lipophilic Cur and TanIIA can be efficiently loaded into pHDL carriers. The resultant pHDL-Cur and pHDL-TanIIA inherit the homogeneous nano-disk structure of pHDL. By using pHDL-Cur, the encapsulated hydrophobics are tracked in the core of pHDL, and incorporations of Cur with pHDL vehicles greatly improve the bioavailability and association of Cur with AS plaques. Moreover, when loaded with TanIIA, which has established its role in anti-AS as an anti-inflammatory candidate, synergistic effects in reducing AS lesions and improving pathological alterations of main organs related to AS were achieved.Conclusion: The pHDL system could potentially be applied for both imaging and therapy in animal models of AS. Benefits of pHDL-based drug delivery will potentially extend the application scenarios of bioactive chemicals from natural plants which are underutilized due to features like low bioavailability and facilitate the clinical translation of synthetic HDL therapies in HDL-associated disorders, including but not limited to AS.Graphical Abstract: Keywords: HDL, peptide-based HDL, atherosclerosis, drug delivery, natural plants, antiatherogenic therapy

Xiaoning Zhao, Xiaoqian Li, Ying Wang, Weijie Xiao, Baihui Zhang, Xin Meng, Xijia Sun The Department of Anesthesiology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Xijia Sun, The Department of Anesthesiology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China, Tel +86 15840015620, Email xijia0822@163.comBackground: Patients undergoing video-assisted thoracoscopic surgery (VATS) frequently suffered postoperative acute and chronic pains. In recent years, intrathoracic intercostal nerve block (INB) is regularly used thanks to its safety and accuracy, especially under the circumstance of lacking ultrasound or in face of the contraindications of the thoracic paravertebral block (TPVB). However, clinical evidence of comparing TPVB and INB for pain management after VATS has been limited and the observation of the chronic pain has been less than clear.Methods: A total of 180 patients undergoing VATS were randomly divided into three groups: A single multi-point paravertebral nerve block (Group P), intrathoracic intercostal nerve block (Group I), and general anesthesia without any regional block (Group C). Postoperative acute pain was scored at rest and coughing by the Visual Analog Scale (VAS) for recording 24h, 48h and 72h after VATS. All patients were interviewed 1, 3 and 6 months after the surgery to investigate both the incidence and intensity of chronic pains.Results: There were significantly less incidence and intensity of acute pain in Group P and Group I, compared to those in Group C. The patients in Group I showed the least incidence and intensity of chronic pain after 3 months compared with those in Group P and Group C. There are 89 of 98 patients suffering pains after 1 month, which grew into chronic pains after 3 months and 78 of them still suffered chronic pains even after 6 months.Conclusion: The intrathoracic INB offers excellent relief from acute and chronic pains, which does as effectively as TPVB. Besides, one-month postoperative pain could increase the risk of a chronic one.Keywords: video-assisted thoracoscopic surgery, acute pain, chronic pain, intrathoracic intercostal nerve block, paravertebral nerve block

Luo Jindan,&ast; Wang Xiao,&ast; Xie Liping Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xie Liping, Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China, Email xielp@zju.edu.cnAbstract: Use of α-androgenic receptor blockers remains a mainstay therapeutic approach for the treatment of urological diseases. Silodosin is recommended over other α-blockers for the treatment of lower urinary tract symptoms (LUTS) and benign prostate hyperplasia (BPH), due to its high α1A uroselectivity. Current research data suggest that silodosin is efficacious in the management of various urological diseases. Thus, we herein review the current evidence of silodosin related to its efficacy and tolerability and appraise the available literature that might ultimately aid in management of various urological conditions at routine clinical practice. Literature reveals that silodosin is beneficial in improving nocturia events related to LUTS/BPH. Silodosin exerts effect on relaxing muscles involved in detrusor obstruction, therefore prolonging the need for patients undergoing invasive surgery. Silodosin treatment, either as a monotherapy or combination, significantly improves International Prostate Symptom Score (IPSS) including both storage and voiding symptoms in patients with BPH/LUTS. Patients on other treatment therapies such as phosphodiesterase 5 inhibitors or other α-blockers are well managed with this drug. Steadily, silodosin has proved beneficial in the treatment of other urological disorders such as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), overactive bladder/acute urinary retention (AUR), premature ejaculation (PE), and prostate cancer post brachytherapy-induced progression. In patients with distal ureteral stones, silodosin treatment is beneficial in decreasing stone expulsion time without affecting stone expulsion rate or analgesic need. Moreover, there were significant improvements in intravaginal ejaculation latency time, quality of life scores, and decrease in PE profile among patients with PE. Silodosin has also demonstrated promising results in increasing the likelihood of successful trial without catheter in patients with AUR and those taking antihypertensive drugs. Reports from Phase II studies have shown promising role of silodosin in the treatment of CP/CPPS as well as facilitating ureteral stone passage. From the robust data in this review, further silodosin treatment strategies in the management of different urological conditions need to be focused on.Keywords: efficacy, benign prostate hyperplasia, ureteral calculi, prostatitis, silodosin, urological

Jun Hou,1,&ast; Dezhi Zheng,2,&ast; Xudong Wen,3,&ast; Wenjing Xiao,4 Fei Han,5 Hongmei Lang,6 Shiqiang Xiong,1 Wei Jiang,5 Yonghe Hu,4 Mengshan He,7 Pan Long4,5 1Department of Cardiology, Chengdu Third People’s Hospital/Affiliated Hospital of Southwest Jiaotong University, Chengdu, People’s Republic of China; 2Department of Cardiovascular Surgery, the 960th Hospital of the PLA Joint Logistic Support Force, Jinan, People’s Republic of China; 3Department of Gastroenterology and Hepatology, Chengdu First People’s Hospital, Chengdu, People’s Republic of China; 4School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, People’s Republic of China; 5Department of Ophthalmology, the General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 6The Center of Obesity and Metabolic Diseases, Department of General Surgery, Chengdu Third People’s Hospital & the Affiliated Hospital of Southwest Jiaotong University, Chengdu, People’s Republic of China; 7Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pan Long, Department of Ophthalmology, the General Hospital of Western Theater Command, Rongdu Avenue #270, Chengdu, People’s Republic of China, Tel +86-181-9125-6132, Email longpan1005@qq.com Yonghe Hu, School of Materials Science and Engineering, Southwest Jiaotong University, No. 111, North First Section of the Second Ring Road, Chengdu, People’s Republic of China, Tel +86-138-8059-6789, Email huyonghe789@sina.comPurpose: High-altitude environment mainly with hypobaric hypoxia could induce pathological alterations in ocular tissue. Previous studies have mostly focused on sporadic case reports and simulated high-altitude hypoxia experiments. This aim of this study was to explore the proteomic and morphological changes of ocular tissue in mice at real altitude environment.Methods: In this study, mice were flown from Chengdu (elevation: 500 m) to Lhasa (elevation: 3600 m). After exposure for 1day, 3, 6, 10, 20, 30, and 40days, the mice were euthanatized to obtain blood and ocular tissue. Serological tests, ocular pathological examinations, integral ocular proteomics analysis, and Western blot were conducted.Results: We focused on acute phase (1– 3 days) and chronic phase (> 30 days) during high-altitude acclimatization. Serum interleukin-1 was increased at 3 days, while superoxide dismutase, interleukin-6, and tumor necrosis factor-α showed no statistical changes. H&E staining demonstrated that the cornea was edematous at 3 days and exhibited slower proliferation at 30 days. The choroid showed a consistently significant thickening, while there existed no noticeable changes in retinal thickness. Overall, 4073 proteins were identified, among which 71 and 119 proteins were detected to have significant difference at 3 days and 40 days when compared with the control group. Functional enrichment analysis found the differentiated proteins at 3 days exposure functionally related with response to radiation, dephosphorylation, negative regulation of cell adhesion, and erythrocyte homeostasis. Moreover, the differential profiles of the proteins at 40 days exposure exhibited changes of regulation of complement activation, regulation of protein activation cascade, regulation of humoral immune response, second-messenger-mediated signaling, regulation of leukocyte activation, and cellular iron homeostasis. Interestingly, we found the ocular proteins with lactylation modification were increased along high-altitude adaptation.Conclusion: This is the first work reporting the ocular proteomic and morphological changes at real high-altitude environment. We expect it would deep the understanding of ocular response during altitude acclimatization.Keywords: altitude response, ocular proteomics analysis, cornea edema, choroid thickening, post-translational modification

Yi Yang,1 Wei Xiao,2 Xingtai Liu,1 Yan Zhang,1 Xin Jin,1 Xiao Li1 1Department of Clinical Laboratory, The Third Clinical Medical College of the Three Gorges University, Gezhouba Central Hospital of Sinopharm, Yichang, People’s Republic of China; 2Department of Gastroenterology, Xianning central Hospital, The First Affiliated Hospital of Hubby University of Science and Technology, Xianning, People’s Republic of ChinaCorrespondence: Xiao Li, Department of Clinical Laboratory, The Third Clinical Medical College of the Three Gorges University, Gezhouba Central Hospital of Sinopharm, Yichang, 443002, People’s Republic of China, Tel +86 717-672020, Email yi8847307962629@126.comPurpose: Acute kidney injury (AKI) is a frequent complication of severe acute pancreatitis (AP) and carries a very poor prognosis. The present study aimed to construct a model capable of accurately identifying those patients at high risk of harboring occult acute kidney injury (AKI) characteristics.Patients and Methods: We retrospectively recruited a total of 424 consecutive patients at the Gezhouba central hospital of Sinopharm and Xianning central hospital between January 1, 2016, and October 30, 2021. ML-assisted models were developed from candidate clinical features using two-step estimation methods. The receiver operating characteristic curve (ROC), decision curve analysis (DCA), and clinical impact curve (CIC) were performed to evaluate the robustness and clinical practicability of each model.Results: Finally, a total of 30 candidate variables were included, and the AKI prediction model was established by an ML-based algorithm. The areas under the ROC curve (AUCs) of the random forest classifier (RFC) model, support vector machine (SVM), eXtreme gradient boosting (XGBoost), artificial neural network (ANN), and decision tree (DT) ranged from 0.725 (95% CI 0.223– 1.227) to 0.902 (95% CI 0.400– 1.403). Among them, RFC obtained the optimal prediction efficiency via adding inflammatory factors, which are serum creatinine (Scr), C-reactive protein (CRP), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-albumin ratio (NAR), and CysC, respectively.Conclusion: We successfully developed ML-based prediction models for AKI, particularly the RFC, which can improve the prediction of AKI in patients with AP. The practicality of prediction and early detection may be greatly beneficial to risk stratification and management decisions.Keywords: acute pancreatitis, acute kidney injury, serum cytokines, cystatin-C, machine learning algorithms, prediction

Simin Wu,1 Weihua Hu,1 Wei Xiao,1 Yongxia Li,2 Yan Huang,1 Xu Zhang1 1Department of Respiratory Medicine, The First Affiliated Hospital of Yangtze University, Jingzhou, 434000, Hubei, People’s Republic of China; 2Department of Respiratory Medicine, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650000, Yunnan, People’s Republic of ChinaCorrespondence: Weihua Hu; Wei Xiao Tel +86-18163137571; +86-18972161798Email huweihua@yangtzeu.edu.cn; 99xw@sina.comAbstract: Gardnerella vaginalis is a pathogen responsible for bacterial vaginosis, which is commonly found in female vaginas and rarely causes infections outside the female genitalia. Here, we report the use of metagenomic next-generation sequencing (mNGS) to detect and confirm pulmonary infection and pleural effusion caused by G. vaginalis in a 47-year-old man. The patient’s symptoms and imaging improved after 2 weeks of oral ornidazole, and he was cured after 3 months. Overall, the findings of this case demonstrate that mNGS is a useful tool for diagnosis of unexplained lung infections and pleural effusions. Its effectiveness in rapid and accurate etiological diagnosis and monitoring of diseases can allow detection of the etiology of difficult cases that return negative results after traditional cultures.Keywords: Gardnerella vaginalis, lung infection, metagenomic next-generation sequencing

Abstract Alpha(α)Klotho, a soluble transmembrane protein, facilitates calcium-phosphorus homeostasis through feedback between bone and kidney and is a potential systemic biomarker for bone-kidney health during spaceflight. We determined if: (1) plasma αKlotho was reduced after both spaceflight aboard the ISS and hindlimb unloading (HU); and (2) deficiency could be reversed with exercise. Both spaceflight and HU lowered circulating plasma αKlotho: plasma αKlotho recovered with exercise after HU.

Weilong Xiao1,2 &ast;, Binghai Sun1 &ast;, Hui Zhou,3 Liting Fan,1,2 Changkang Sun,1 Yanhong Shao4 1College of Teacher Education, Zhejiang Normal University, Jinhua, Zhejiang, People’s Republic of China; 2Key Laboratory of Intelligent Education Technology and Application of Zhejiang Province, Zhejiang Normal University, Jinhua, Zhejiang, People’s Republic of China; 3Jinhua Advanced Research Institute, Jinhua, Zhejiang, People’s Republic of China; 4Zhejiang International Studies University, Hangzhou, Zhejiang, People’s Republic of China&ast; These authors contributed equally to this workCorrespondence: Changkang SunCollege of Teacher Education, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, Zhejiang, People’s Republic of ChinaEmail 1158067980@qq.comYanhong ShaoZhejiang International Studies University, 299 Liuhe Road, Xihu District, Hangzhou, 310013, Zhejiang Province, People’s Republic of ChinaEmail yhshao2003@126.comPurpose: People choose actions that maintain their moral self-regard. This paper explains how one’s moral actions influence moral self-regard. The moral threshold model (MTM) has been proposed by scholars and tested using a limited sample. However, whether the MTM is universally applicable among people is still unknown.Participants and Methods: Our sample comprised 1761 individuals living in China, a collectivist culture, who were recruited to test the two main hypotheses of the MTM. Participants engaged in a hypothetical investment task.Results: 1) When the beneficiary was a prosocial cause, participants showed stronger preferences for smaller guaranteed positive payouts over larger uncertain ones; 2) as compared to making decisions for charities, when a participant made decisions exclusively for themselves, the maximum potential benefit was more likely to influence participant behavior.Conclusion: The current study provides initial evidence for the validity of using the worst outcome avoidance (WOA) hypothesis of MTM among members of China’s collectivist culture, indicating that the WOA hypothesis of MTM may have universal application.Keywords: collectivist culture, morality, moral self-regard, prosocial behavior, egoistic behavior

Weilong Xiao,1,2,&ast; Hui Zhou,3,&ast; Xinwei Li,1 Xue Lin4 1School of Teacher Education, Zhejiang Normal University, Jinhua, People’s Republic of China; 2School of Education, Fujian Polytechnic Normal University, Fuzhou, People’s Republic of China; 3Jinhua Advanced Research Institute, Jinhua, People’s Republic of China; 4Psychological Counseling Center of Student Affairs Office, Zhangzhou City College, Zhangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinwei Li; Xue Lin Email Lixinwei0417@126.com; 564056074@qq.comPurpose: Previous studies have investigated the relationship between alexithymia and problematic mobile phone use (PMPU). However, yet gaps in identifying the internal mechanisms of this relationship remain. Hence, based on the Interaction of Person–Affect–Cognition–Execution model, the current research examined the mediating roles of college students’ social interaction anxiousness (SIA) and boredom proneness (BPS) in the relationship between alexithymia and PMPU.Methods: A total of 1300 college students (Mage = 20.36 years, SD = 0.97) were recruited from two universities in the southeast of China to complete a series of questionnaires, including the Toronto alexithymia scale, SIA scale, BPS scale, and mobile phone addiction index questionnaire. In order to conduct conservative predictions, the demographic variables (ie, gender) were controlled as covariates.Results: The results of multiple mediation analysis showed that (1) alexithymia was positively linked with PMPU; (2) both SIA and BPS mediated the link between alexithymia and PMPU; and (3) a serial indirect pathway emerged (ie, alexithymia → SIA → BPS → PMPU).Conclusion: These findings indicated that alexithymia could influence PMPU in a simple indirect way (parallel mediation) and in a complex indirect way (serial mediation). Besides, these findings provide some insights into the prevention and intervention of PMPU.Keywords: alexithymia, social interaction anxiousness, boredom proneness, problematic mobile phone use, college students

Junwei Tong,1– 3,&ast; Xiangui Meng,1– 3,&ast; Qingyang Lv,1– 3,&ast; Hongwei Yuan,1– 3 Weiquan Li,1– 3 Wen Xiao,1– 3 Xiaoping Zhang1– 3 1Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, People’s Republic of China; 3Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoping Zhang; Wen XiaoDepartment of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province, 430022, People’s Republic of ChinaFax +86 85776343Email xzhang@hust.edu.cn; xiaowenx11@163.comBackground: Increasing evidence indicated that the aberrant expression of the cytoplasmic FMR1-interacting protein (CYFIP) family might possess critical role and potential functions in cancer. But the role of CYFIP2 in clear cell renal cell carcinoma (ccRCC) is still uncharacteristic.Methods: We investigated the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) database for the expression profile, clinicopathological variables, clinical prognosis information, and promoter methylation levels of CYFIPs in ccRCC. The aberrant CYFIP2 protein expression was validated by the Human Protein Atlas (HPA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to uncover CYFIP2 mRNA levels in 28 pairs of ccRCC cancer tissues. Kaplan–Meier analysis, univariate and multivariate Cox proportional hazard regression were performed to assess CYFIPs’ prognosis value. Gene set enrichment analysis (GSEA) was used to determined hallmark functions, gene ontology of CYFIP2. TIMER database was utilized to assess the correlation with immune infiltration in ccRCC.Results: Results showed CYFIP2 was downregulated in ccRCC, relative to paired normal tissues in TCGA-KIRC database and 28 pairs of clinical samples (P < 0.0001). Similarly, a decreased CYFIP2 protein expression was confirmed by ccRCC tissues. The results showed CYFIP2 was negatively regulated by promoter DNA methylation. Survival analysis results showed CYFIP2 could be an independent biomarker for ccRCC and its reduction predicted a poor overall survival (OS) and disease-free survival (DFS). GSEA showed CYFIP2 was involved in metabolic pathways and epithelial–mesenchymal transition (EMT). Immune infiltration analysis revealed that a list of immune markers was significantly correlated with CYFIP2 expression especially with CD4+ cells and CD8+ cells in ccRCC.Conclusion: These results show that CYFIP2 was downregulated in ccRCC patients and predicted an unfavorable prognosis. CYFIP2 might be a potential novel prognostic molecule, and related to immune infiltration, the metabolism, as well as EMT process in ccRCC. CYFIP2 could act as tumor suppressor gene in ccRCC and positive modulation of CYFIP2 might lead to development of a novel strategy for ccRCC treatment.Keywords: CYFIP2, ccRCC, methylation, prognosis, immune infiltration

Wei-xiong Xiao,&ast; Yu-ting Zhu,&ast; Zhi-chao Zhang, Min Luo, Ming-ping Ma Department of Radiology, Fujian Provincial Hospital, Provincial Clinical College of Fujian Medical University, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Luo; Ming-ping MaDepartment of Radiology, Fujian Provincial Hospital, Provincial Clinical College of Fujian Medical University, No. 134 East Street, Gulou District, Fuzhou, 350001, People’s Republic of ChinaTel +86 59187557768Email radiodrluo@163.comObjective: To investigate the value of dual energy CT enterography (DECTE) in evaluating the activity of Crohn’s disease (CD).Methods: The endoscopy and imaging data of 29 patients with CD confirmed by clinic and pathology were analyzed retrospectively. The clinical CD activity index (CDAI) was used as the disease activity grouping standard, 29 patients with CD were grouped into activity groups, 18 patients in the active group (CDAI ≥ 150) with 36 intestinal segments, and 11 patients in the remission group (CDAI < 150) with 20 intestinal segments.The virtual single energy CT value, slope of energy spectrum curve and iodine content were analyzed to evaluate the evaluation of intestinal CD activity by DECTE.Results: There were statistically significant differences in virtual single energy CT value (except 90 keV and 100 keV virtual single energy CT value), curve slope and iodine content between remission group and active group (P < 0.05), and has more diagnostic value for active phase (AUC > 0.5). ① Virtual single energy CT value: the AUC of 60 keV in arterial phase was the highest (0.924). The specificity of diagnosing CD in active stage was high (95%). ② Curve slope: the AUC of portal vein phase was the largest (0.731). The specificity of diagnosing CD in active stage was higher (85%). ③ Iodine content: the AUC of arterial phase was the highest (0.885). The specificity of diagnosing CD lesions in the active stage was 100%.Conclusion: The virtual single energy CT value, energy spectrum curve slope and iodine content can provide reference for clinical accurate diagnosis of CD activity.Keywords: Crohn’s disease, computed tomography, dual energy CT, virtual single

Xiangui Meng,1– 3,&ast; Hongwei Yuan,1– 3,&ast; Weiquan Li,1– 3,&ast; Wen Xiao,1– 3 Xiaoping Zhang1– 3 1Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, People’s Republic of China; 3Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoping Zhang; Wen XiaoDepartment of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province, 430022, People’s Republic of ChinaTel +86-18602752025Fax +86 2785776343Email xzhang@hust.edu.cn; xiaowenx11@163.comBackground: Studies report that conventional treatment of clear cell renal cell carcinoma (ccRCC) is effective, but several advanced patients present with poor prognosis. The current study explored potential new tumor markers and therapeutic targets in advanced ccRCC.Methods: Biomarker gene expression of ccRCC was retrieved from GEO database and the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) database. Gene ontology (GO) analysis and protein–protein interaction (PPI) networks of biomarker genes were constructed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool. Kaplan–Meier analysis and receiver operating characteristic curve (ROC) analysis were performed to explore the prognostic and diagnostic roles of these genes. Gene set enrichment analysis (GSEA) analysis was used to determine hallmark functions of the biomarker genes. qRT-PCR was used to verify the reliability of the analysis results in tumor tissues.Results: A total of 21 upregulated genes were identified between advanced ccRCC and early ccRCC (grade III+IV vs grade I+II). Gene ontology analysis showed that the 21 upregulated genes were mainly implicated in biological processes including metabolic and lipid transport. The findings showed that 7 out of the 21 genes were significantly upregulated in 72-paired samples retrieved from the TCGA-KIRC. High expression of 5 genes indicated a poor prognosis of overall survival and disease-free survival in KIRC. Three genes effectively distinguished renal cancer tissue and adjacent renal tissues in a total of 533 ccRCC samples. GSEA showed that the 3 biomarkers were significantly enriched in epithelial–mesenchymal transition, G2M checkpoint, and angiogenesis. The results of qRT-PCR showed that STEAP3, IBSP, and AQP9 had a significant identification effect in ccRCC.Conclusion: The findings showed that 3 biomarkers were significantly upregulated in advanced ccRCC and could be used for diagnosis, prediction, and potential novel therapeutic targets for progression of ccRCC.Keywords: advanced ccRCC, biomarker, progression, differentially expressed genes

Mingyue Sun, Weiqiang Xiao, Qingxia Xu Department of Clinical Laboratory, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Qingxia XuDepartment of Clinical Laboratory, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Dongming Road No.127, Zhengzhou, Henan Province, People’s Republic of ChinaTel +860371-65587147Email qxiaxu@126.comPurpose: Klebsiella oxytoca is an opportunistic pathogen causing nosocomial infections. This study was designed to characterize the genomic features of a carbapenem-resistant K. oxytoca strain and analyze its molecular characteristics.Materials and Methods: The strain wzx-IMP was isolated from the blood of a 2-year-old girl diagnosed with acute myeloid leukemia-M7. Species identification was performed, and the minimal inhibitory concentration of the strain was measured. Multilocus sequence typing was performed to identify the subtypes of K. oxytoca. The transfer capacity of the blaIMP-4-harboring plasmid was investigated by conjugation experiments, and the genome characteristics of the strain were examined using whole-genome sequencing.Results: wzx-IMP belongs to the ST85 type and is resistant to imipenem and meropenem, which harbored the blaIMP-4 gene. The blaIMP-4 gene was located in an IS26-associated class 1 integron of pwzx_IMP, which contains conserved IncN1-type backbone regions with a replication gene and its accessory structure for plasmid replication. The blaIMP-4-carrying plasmid in wzx-IMP was successfully transferred to Escherichia coli EC600 by conjugation. Whole-genome sequencing showed that the wzx-IMP isolate included the blaOXY-1-1 gene, accompanied by OmpK36 absence.Conclusion: We report an ST85-type carbapenem-resistant K. oxytoca strain, which produces blaIMP-4 located in an IncN1-type plasmid and accompanied by OmpK36 porin deficiency.Keywords: Klebsiella oxytoca, blaIMP-4, ST85, IncN1, OmpK36

Dong Zhang, Ying Yuan, Hao Zhang, Xinzeyu Yi, Weidong Xiao, Aixi Yu Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of ChinaCorrespondence: Aixi Yu; Weidong XiaoDepartment of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of ChinaTel +86-027-67813120; +86-18707182868Email yuaixi@whu.edu.cn; xiaoweidong@whu.edu.cnBackground: Skin avulsion injuries caused by high-energy traffic and machinery accidents are important topics in the field of repair and reconstruction. The injury generates a skin flap with uncertain vascular basis resulting in ischemic necrosis of the distal portion of the flap. Yet there is lack of reliable way for estimating the extent of blood supply in damaged tissue, which has limited the possibility of prompt surgical intervention. Recent studies have confirmed that photoacoustic microscopy imaging has a wide range of applications in the biomedical field owing to its good performance in angiography.Methods: In our study, we successfully surgically induced skin avulsion injury on mice hindlimbs. Then, we used this novel approach to image skin microcirculation and predict skin necrosis with impaired blood supply after injury in live mice.Results and Conclusion: All skin tissues in the avulsed hindlimb flap group show different levels of necrosis at the end of the observation period. The “dark zone” with impaired microcirculation in PAM images, which continuously extends over time, was seen as a prediction of necrosis of skin tissue and at 60 min after surgery was similar to the area of clinical necrosis on postoperative day 7. All these indicate that photoacoustic microscopy imaging is a feasible, precise, high-resolution, non-invasive technique for early prediction of necrosis in skin avulsion injury, providing a promising tool for surgeons to manage the injury.Keywords: skin avulsion injuries, photoacoustic microscope, monitoring microcirculation

Chenye Feng,1 Mingtao Xu,1 Jian Kang,1 Fuqiang Wen,2 Yahong Chen,3 Jing Zhang,4 Wei Xiao,5 Zhonghe Zhang,6 Lan Yang,7 Jianmin Huo,8 Jie Cao,9 Li Zhao,10 Shuyue Xia,11 Yan Yin,1 Wei Wang1 1Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Disease, State Key Laboratory of Biotherapy of China, Chengdu, Sichuan, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Peking University, Third Hospital, Beijing, People’s Republic of China; 4Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 5Department of Pulmonary Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, People’s Republic of China; 6Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaonign, People’s Republic of China; 7Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shanxi, People’s Republic of China; 8Department of Respiratory, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; 9Respiratory Department, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 10Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China; 11Department of Pulmonary Medicine, Central Hospital Affiliated with Shenyang Medical College, Shenyang, People’s Republic of ChinaCorrespondence: Jian KangDepartment of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of ChinaTel +86-024-83282530Fax +86-024-83282002Email kangjian58@163.comPurpose: The proportion of atypical pathogens in patient with AECOPD within mainland China is unknown. The objectives of this study were to determine the distribution of atypical pathogens among Chinese patients with AECOPD, to evaluate the clinical characteristics of different atypical pathogen infections, and to compare different detection methods for atypical pathogens.Patients and Methods: Specimens were collected from patients with AECOPD from March 2016 to November 2018 at eleven medical institutions in eight cities in China. Double serum, sputum, and urine samples were obtained from 145 patients. Serological and nucleic acid tests were used to assess for Mycoplasma pneumonia and Chlamydia pneumoniae; serological, urinary antigen, and nucleic acid tests were applied to detect Legionella pneumophila. The clinical characteristics of atypical pathogen-positive and -negative groups were also compared.Results: The overall positivity rate for Mycoplasma pneumoniae was 20.69% (30/145), with the highest rate being 20.00% (29/145) when determined by passive agglutination.The overall positive rates for Chlamydia pneumoniae and Legionella pneumophila were 29.66% (43/145) and 10.34% (15/145), respectively. The most common serotype of Legionella pneumophila was type 6. The maximum hospitalized body temperature, ratio of eosinophils, C-reactive protein (CRP) level, and procalcitonin (PCT) level of the Mycoplasma pneumoniae-positive group were significantly higher than those of the Mycoplasma pneumoniae-negative group. Patients in the Chlamydia pneumoniae-positive group smoked more, had higher proportions of comorbidities and frequent aggravations in the previous two years than those in the Chlamydia pneumoniae-negative group. Furthermore, the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) ratio assessment of lung function was higher, and the concentration of arterial blood bicarbonate (HCO3−) was lower in the Legionella pneumophila-positive group than in the Legionella pneumophila-negative group.Conclusion: Overall, atypical pathogens play an important role in AECOPD. Regarding the testing method, serological testing is a superior method to nucleic acid testing.Keywords: COPD, exacerbations, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila

Xinwei Li,1,* Xuechao Feng,2,* Weilong Xiao,1 Hui Zhou3 1College of Education and Human Development, Zhejiang Normal University, Jinhua, 321004, People’s Republic of China; 2Yuxiu Secondary School, Changyi, 261300, People’s Republic of China; 3Jinhua Advanced Research Institute, Jinhua, 321004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weilong XiaoCollege of Education and Human Development, Zhejiang Normal University, Jinhua, 321004, People’s Republic of ChinaEmail xwl743@163.comHui ZhouJinhua Advanced Research Institute, Jinhua, 321004, People’s Republic of ChinaEmail zhouhui102@163.comIntroduction: Mobile phones bring convenience to people’s lives, but also affect their physical and mental health (especially in college students). Previous studies have revealed that mobile phone addiction is positively related to loneliness. This study further explored the mediating effects of boredom proneness and self-control on the relationship between loneliness and mobile phone addiction.Methods: A cross-sectional design was conducted in the present study. The investigation employed the Chinese version of the UCLA Loneliness Self-report Scale, Boredom Proneness Scale-Short Form, the Chinese version of the Self-control scale, and the Mobile Phone Addiction Index. Out of 1122 college students, 1078 completed the questionnaire survey and became our final subjects. PROCESS macro of SPSS 21 was used to conduct explore the mediating roles of boredom proneness and self-control in the relationship between loneliness and mobile phone addiction.Results: Loneliness, boredom proneness, and mobile phone addiction were significantly and positively correlated with each other, as well as significantly negatively correlated with self-control. Boredom proneness and self-control, when operating in parallel, partially mediated the relationship between loneliness and mobile phone addiction. By contrast, when occurring sequentially, they fully mediated the relationship between loneliness and mobile phone addiction.Conclusion: Mobile phone addiction among lonely college students can be eliminated by exercising self-control and alleviating boredom proneness.Keywords: loneliness, boredom proneness, self-control, mobile phone addiction, college students

Ting Jiang,1,* Shuang Liu,1,* Xiaojun Wu,2,* Xiaoqing Liu,3 Weizhan Li,4 Shanfei Yang,1 Peiqiang Cai,5 Shaoyan Xi,6 Zhifan Zeng,1 Yuanhong Gao,1 Gong Chen,2 Weiwei Xiao1 1Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 3Department of Radiation Oncology, Guangzhou Concord Cancer Center, Guangzhou, People’s Republic of China; 4Department of Radiation Oncology, Panyu Center Hospital, Guangzhou, People’s Republic of China; 5Department of Radiology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 6Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gong Chen; Weiwei Xiao Email chengong@sysucc.org.cn; xiaoww@sysucc.org.cnPurpose: This study aimed to predict the risks of distant metastasis (DM) of locally advanced rectal cancer (LARC) patients with pathological complete response (pCR) after neoadjuvant chemoradiotherapy (NACRT) and total mesorectal excision (TME), and to find the association between adjuvant chemotherapy (ACT) and their survival outcomes.Methods and Materials: A total of 242 patients with LARC achieving pCR after NACRT were enrolled in this retrospective study. We developed a nomogram model using logistic regression analyses for predicting risk of DM. The model performance was evaluated by the concordance index and calibration curve. Survival was determined using Kaplan–Meier survival curve.Results: Age, pre-operative CEA, pre-treatment CEA and distance of tumor to anal verge were identified as significantly associated variables that could be enrolled in the model to predict the risk of DM for pCR patients. The nomogram we created had a bootstrapped-concordance index of 0.731 (95% CI = 0.627 to 0.834) and was well calibrated. The high risk group was more likely to develop DM than low risk group (total score) (95% CI = 1.439 to 6.493, P = 0.0036). The 1-year, 3-year, and 5-year distant metastasis-free survival (DMFS) for the low and high risk groups (total score ≤ 90 vs > 90) was 97.8%, 94.2%, 94.2% and 91.3%, 83.4%, 81.8%, respectively (P = 0.0036). DM occurred within 1 and 2 years after TME surgery was 33.3% and 55.6% for the low risk group, and 47.3% and 84.2% for the high risk group. The value of ACT was assessed among the whole cohort, patients with cT3-4, with cN+ or with either DM risk group, but no significant difference was observed concerning DMFS whether ACT was given or not (all P > 0.05). Active treatment after DM was more beneficial than palliative treatment (P < 0.001).Conclusion: The nomogram model, including age, pre-operative CEA, pre-treatment CEA and distance to anal verge, predicted the probability of DM among LARC patients achieving pCR after NACRT. The effects of ACT were not seen in different subgroups, while closer clinical follow-up may have greater contribution to pCR patients in the first 2 years, especially for patients with relatively higher risk to develop DM. It is suggested that timely active treatment can bring survival benefit for pCR patients developing DM after NACRT.Keywords: locally advanced rectal cancer; LARC, pathological complete response; pCR, adjuvant chemotherapy; ACT, distant metastasis; DM

Abstract Reduced knee weight-bearing from prescription or sedentary lifestyles are associated with cartilage degradation; effects on the meniscus are unclear. Rodents exposed to spaceflight or hind limb unloading (HLU) represent unique opportunities to evaluate this question. This study evaluated arthritic changes in the medial knee compartment that bears the highest loads across the knee after actual and simulated spaceflight, and recovery with subsequent full weight-bearing. Cartilage and meniscal degradation in mice were measured via microCT, histology, and proteomics and/or biochemically after: (1) ~ 35 days on the International Space Station (ISS); (2) 13-days aboard the Space Shuttle Atlantis; or (3) 30 days of HLU, followed by a 49-day weight-bearing readaptation with/without exercise. Cartilage degradation post-ISS and HLU occurred at similar spatial locations, the tibial-femoral cartilage-cartilage contact point, with meniscal volume decline. Cartilage and meniscal glycosaminoglycan content were decreased in unloaded mice, with elevated catabolic enzymes (e.g., matrix metalloproteinases), and elevated oxidative stress and catabolic molecular pathway responses in menisci. After the 13-day Shuttle flight, meniscal degradation was observed. During readaptation, recovery of cartilage volume and thickness occurred with exercise. Reduced weight-bearing from either spaceflight or HLU induced an arthritic phenotype in cartilage and menisci, and exercise promoted recovery.

Lingzhu Wen,1,* Guochun Zhang,1,* Chongyang Ren,1,* Xuerui Li,1 Hsiaopei Mok,1 Minghan Jia,1 Yulei Wang,1 Bo Chen,1 Kai Li,1 Li Cao,1 Cheukfai Li,1 Weikai Xiao,1 Jianguo Lai,1 Jiali Lin,1 Guangnan Wei,1 Yingzi Li,1 Yuchen Zhang,1 Xiaoqing Chen,2 Ning Liao1 1Department of Breast Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Guangzhou, Guangdong, People’s Republic of China; 2Department of Breast Surgical Oncology, Foshan Maternity and Children’s Healthcare Hospital Affiliated to Southern Medical University, Foshan, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ning LiaoDepartment of Breast Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), No. 106, Zhongshan 2nd Road, Yuexiu District, Guangzhou, Guangdong, People’s Republic of ChinaTel/Fax +86 20-83827812Email syliaoning@scut.edu.cnPurpose: This study aimed to investigate AKT gene mutation status in Chinese breast cancer patients.Methods: The study included 411 breast cancer patients hospitalized in Guangdong Provincial People’s Hospital (GDPH) from June 1, 2017 to September 27, 2018. Mastectomy or breast conserving surgery was performed, and tissue samples were subjected to next-generation sequencing (NGS) to determine AKT gene mutation status. Meanwhile, the expression of human epidermal growth factor receptor 2 (Her2), progesterone receptor (PR), and estrogen receptor (ER) was analyzed by immunohistochemistry staining. The Cancer Genome Atlas (TCGA) database was used for comparative studies.Results: Patients in the GDPH cohort had an older age (P < 0.001), higher postmenopausal rate (P < 0.001), larger tumor size (P < 0.001), higher histologic type of infiltrating duct cancer (P < 0.001), higher metastatic rate (P < 0.001), higher expression of ER (P = 0.015) and HER2 (P < 0.001), and higher percentage of the HR/HER2 subtype (P < 0.001) than those in the TCGA cohort. The GDPH cohort displayed lower rates of overall AKT and AKT3 mutation (P < 0.001), but a higher AKT1 mutation rate (P < 0.0001) compared with the TCGA cohort. Notably, the NGS studies identified missense mutation and copy number amplification as the most common AKT variation type in the GDPH and TCGA cohorts, respectively. Specifically, E17K mutation in AKT1 was predominantly detected in GDPH cohort, while being absent in TCGA cohort. Moreover, in the GDPH cohort, AKT variation was correlated with a number of clinicopathological variables, including age over 50, HER2-, HR+/HER2-, and PR+.Conclusion: Patients in the GDPH cohort had lower rates of AKT and AKT3 mutation and higher AKT1 mutation rate than those in the TCGA cohort, while harboring missense mutations detected predominantly as E17K mutation in AKT1. In GDPH cohort, there were correlations between AKT mutation and the clinicopathological characteristics of patients.Keywords: AKT, next-generation sequencing, breast cancer, somatic mutations, population study

Liwei Cui,1 Haijun Li,2 Mengshuang Xie,1 Xia Xu,2 Yingmei Zhang,3 Wei Wang,1 Shuang Dou,1 Wei Xiao1 1Department of Pulmonary Medicine, Qilu Hospital, Shandong University, Jinan, People’s Republic of China; 2Department of Cadre Health Care, Qilu Hospital, Shandong University, Jinan, People’s Republic of China; 3Department of Pulmonary Medicine, Linyi People’s Hospital, Linyi, People’s Republic of ChinaCorrespondence: Wei XiaoDepartment of Pulmonary Medicine, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan 250012, People’s Republic of ChinaEmail xiaowei4226@163.comBackground and Objective: The link between ADAM9 and airway remodeling and emphysema severity in COPD patients has not been elucidated. Here, we investigated the relationship between ADAM9 levels in sputum and airway epithelium and the clinical characteristics of COPD patients.Methods: A sputum cohort and a lung tissue cohort were included in the study. Pulmonary function and computed tomography data were analyzed in COPD patients, non-COPD smokers, and non-smokers. Soluble ADAM9 and interleukin 8 (IL-8) levels in sputum supernatants as well as surface ADAM9 expression in airway epithelium were detected. Emphysema scores were calculated by the percentage of low attenuation area (%LAA-950), and airway remodeling was measured via airway thickening and loss of airway counts.Results: Both soluble ADAM9 levels in sputum and relative surface ADAM9 expression in airway epithelium were increased in COPD patients. Sputum ADAM9 levels were negatively correlated with forced expiratory volume in 1 s of predicted (FEV1% of predicted) and positively correlated with sputum IL-8 levels, but not with CT measured emphysema nor airway remodeling. The ADAM9 expression in airway epithelia was positively correlated with %LAA-950 and airway wall thickening parameters (wall area percentage, WA%; the square root of the wall area in a standard airway with a 10 mm internal perimeter, Pi-10), while negatively correlated with airway counts derived from the 4th to 9th bronchial generations.Conclusion: Airway ADAM9 levels in sputum and airway epithelium were both elevated in COPD patients compared to non-COPD controls. Sputum ADAM9 seemed to be associated with inflammatory responses in COPD, while epithelial ADAM9 was more correlated with emphysema and airway remodeling.Keywords: chronic obstructive pulmonary disease, proteinase with a disintegrin and a metalloproteinase domain-9, computed tomography, emphysema, airway remodeling

Langzi Tan, Yayu Chen, Wenyue Wu, Chaorong Liu, Yujiao Fu, Jialinzi He, Min Zhang, Ge Wang, Kangrun Wang, Hongyu Long, Wenbiao Xiao, Bo Xiao, Lili Long Department of Neurology, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Lili LongDepartment of Neurology, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaTel +86 0731 84328888Fax +86 0731 84327332Email longlili1982@126.comPurpose: Patients with temporal lobe epilepsy (TLE) are at high risk of cognitive impairment. In addition to persistent seizures and antiepileptic drugs (AEDs), genetic factors also play an important role in the progression of cognitive deficits in TLE patients. Defining a cognitive endophenotype for TLE can provide information on the risk of cognitive impairment in patients. This study investigated the cognitive endophenotype of TLE by comparing neuropsychological function between patients with TLE, their unaffected siblings, and healthy control subjects.Patients and Methods: A total of 46 patients with TLE, 26 siblings, and 33 control subjects were recruited. Cognitive function (ie, general cognition, short- and long-term memory, attention, visuospatial and executive functions, and working memory) was assessed with a battery of neuropsychological tests. Differences between groups were evaluated by analysis of covariance, with age and years of education as covariates. The Kruskal–Wallis test was used to evaluate data that did not satisfy the homogeneity of variance assumption. Pairwise comparisons were adjusted by Bonferroni correction, with a significance threshold of P< 0.05.Results: Patients with TLE showed deficits in the information test (P< 0.001), arithmetic test (P=0.003), digit symbol substitution test (P=0.001), block design test (BDT; P=0.005), and backward digit span test (P=0.001) and took a longer time to complete the Hayling test Part A (P=0.011) compared to controls. Left TLE patients tended to have worse executive function test scores than right TLE patients. The siblings of TLE patients showed deficits in the BDT (P=0.006, Bonferroni-corrected) relative to controls.Conclusion: Patients with TLE exhibit cognitive impairment. Executive function is worse in patients with left TLE than in those with right TLE. Siblings show impaired visuospatial function relative to controls. Thus, cognitive deficits in TLE patients have a genetic component and are independent of seizures or AED use.Keywords: temporal lobe epilepsy, cognitive impairment, endophenotype

Xiaozhou Liang,1 Xuchao Miao,1 Weijin Xiao,2 Qin Ye,3 Sisi Wang,4 Juqiang Lin,1 Chao Li,2,5,6 Zufang Huang1 1Fujian Normal University, Ministry of Education, Key Laboratory of Optoelectronic Science and Technology for Medicine, Fujian Provincial Key Laboratory for Photonics Technology, Fuzhou, People’s Republic of China; 2Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, People’s Republic of China; 3Department of Head and Neck Surgery, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, People’s Republic of China; 4Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China; 5Department of Pathology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, People’s Republic of China; 6Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, People’s Republic of ChinaCorrespondence: Zufang Huang Tel +86 591 834 65373Email zfhuang@fjnu.edu.cnObjective: The objective of this study is to evaluate the performance and feasibility of surface-enhanced Raman spectroscopy coupled with a filter membrane and advanced multivariate data analysis on identifying and differentiating benign and malignant thyroid tumors from blood plasma.Patients and Methods: We proposed a membrane filter SERS technology for the differentiation between benign thyroid tumor and thyroid cancer. That is to say, by using filter membranes with optimal pore size, the blood plasma samples from thyroid tumor patients were pretreated with the macromolecular proteins being filtered out prior to SERS measurement. The SERS spectra of blood plasma ultrafiltrate obtained using filter membranes from 102 patients with thyroid tumors (70 thyroid cancers and 32 benign thyroid tumors) were then analyzed and compared. Two multivariate statistical analyses, principal component analysis-linear discriminate analysis (PCA-LDA) and Lasso-partial least squares-discriminant analysis (Lasso-PLS-DA), were performed on the SERS spectral data after background subtraction and normalization, as well as the first derivative processing, to analyze and compare the differential diagnosis of benign thyroid tumors and thyroid cancer.Results: SERS measurements were performed in blood plasma acquired from a total of 102 thyroid tumor patients (benign thyroid tumor N=32; thyroid cancer N=70). By using filter membranes, the macromolecular proteins in blood plasma were effectively filtered out to yield high-quality SERS spectra. 84.3% discrimination accuracy between benign and malignant thyroid tumor was achieved using PCA-LDA method, while Lasso-PLS-DA yields a discrimination accuracy of 90.2%.Conclusion: Our results demonstrate that SERS spectroscopy, coupled with ultrafiltration and multivariate analysis has the potential of providing a non-invasive, rapid, and objective detection and differentiation of benign and malignant thyroid tumors.Keywords: surface-enhanced Raman spectroscopy, thyroid tumor, filter membrane, silver nanoparticles, blood plasma

Peide Bai,1 Wei Li,1 Zhenghua Wan,2 Yujuan Xiao,3 Wen Xiao,1 Xuegang Wang,1 Zhun Wu,1 Kaiyan Zhang,1 Yongfeng Wang,1 Bin Chen,1 Jinchun Xing,1 Tao Wang1 1The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen 361003, People’s Republic of China; 2Xiang’an Branch, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen 361101, People’s Republic of China; 3Department of Pediatrics, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen 361003, People’s Republic of ChinaCorrespondence: Jinchun Xing; Tao WangThe First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People’s Republic of ChinaTel/Fax +86-592-2139814; +86-592-2137125Email xmcua2007@sina.com; taowang@xmu.edu.cnPurpose: Prostate cancer (PCa) is the third most common cancer in men and the second leading cause of cancer-related death in men. DLX1 belongs to the DLX homeobox family and exhibits antitumor activity in many kinds of tumors. MicroRNAs (miRNAs) play important roles in the progression of cancer. However, whether miRNAs affect the development of PCa by targeting DLX1 has not been determined. In this study, we aimed to investigate the role of miR-489-3p in the regulation of DLX1 expression and PCa progression and to provide a potential therapeutic target for PCa treatment.Methods and Materials: The Cancer Genome Atlas database was used to analyze the divergent expression of DLX1 in carcinomas and adjacent normal tissues. The expression level of DLX1 in malignant and normal prostate cells was also measured using RT-qPCR and Western blotting. A dual-luciferase reporter assay was performed to determine whether miR-489-3p directly targets DLX1. We transfected 22Rv1 and DU145 cells with miR-489-3p mimics to overexpress miR-489-3p and then evaluated its effect on cellular function. MTT, EdU, colony formation and cell cycle assays were used to evaluate cell growth. JC-1 and ROS assays with flow cytometry were performed to indirectly analyze apoptosis. Transwell assays were conducted to investigate metastasis.Results: The expression level of DLX1 was upregulated in both PCa tissues and cell lines. MiR-489-3p directly targeted DLX1 and downregulated its expression. Overexpression of miR-489-3p significantly suppressed cell growth. MiR-489-3p induced apoptosis through mitochondrial function impairment. Overexpression of miR-489-3p also inhibited cell migration and invasion. DLX1 overexpression reversed the above effects induced by miR-489-3p.Conclusion: We identified the involvement of the miR-489-3p/DLX1 pathway in PCa for the first time. In this pathway, miR-489-3p acts as a tumor suppressor by negatively regulating the expression of DLX1. MiR-489-3p may be a potential therapeutic target for PCa treatment.Keywords: prostate cancer, DLX1, miR-489-3p, growth, apoptosis, migration, invasion

Mengshuang Xie, Liwei Cui, Jinhuan Liu, Wei Wang, Jun Li, Wei Xiao Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Wei XiaoDepartment of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, People’s Republic of ChinaTel/ Fax +86 53182166294Email xiaowei4226@163.comBackground and Objective: The reference equations and diagnostic criteria play a critical role in the interpretation of pulmonary function tests (PFTs). The aim was to investigate the impacts of different reference equations and diagnostic criteria on the frequency of airway obstruction in adult people of a large teaching hospital of North China.Methods: The spirometry data of all adult people who underwent PFTs in Qilu hospital from April 2012 to November 2015 were collected. Two spirometry reference equations, namely, Zhongshan-2011 and Global Lung Function Initiative 2012 (GLI-2012) were compared. The frequency of airway obstruction using different spirometry prediction equations and diagnostic criteria including forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 92% of predicted value and FEV1/FVC

Wenxiu He,1,* Wenze Xiao,2,* Xiulei Zhang,1 Yali Sun,1 Yiting Chen,1 Qinyue Chen,1 Xiaoling Fang,1 Shilin Du,3 Xianyi Sha1,4 1Key Laboratory of Smart Drug Delivery, Ministry of Education, Center for Medical Research and Innovation, Shanghai Pudong Hospital, School of Pharmacy, Fudan University, Shanghai 201203, People’s Republic of China; 2Department of Rheumatology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, People’s Republic of China; 3Department of Emergency Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China; 4The Institutes of Integrative Medicine of Fudan University, Shanghai 200040, People’s Republic of China *These authors contributed equally to this workCorrespondence: Xianyi Sha; Shilin Du Tel +86-21-51980072Email shaxy@fudan.edu.cn; du.shilin@zs-hospital.sh.cnPurpose: Cancer chemotherapy effect has been largely limited by cell autophagy and little drug accumulation at the action sites. Herein, we designed an intelligent strategy involving paclitaxel (PTX) polymer micelles in response to biological functions of ambroxol (Ax). The amphiphilic polymers polyethyleneglycol-polylactic acid (PEG-PLA) and Pluronic P105 were selected as nanocarriers to encapsulate PTX to form into lung affinity PEG-PLA/P105/PTX micelles. Ax which can up-regulate the secretion of pulmonary surfactant (PS) and inhibit autophagy was hired to change the microenvironment of the lung, thereby promoting the lung accumulation and increasing cell-killing sensitivity of the micelles.Methods: The physical and chemical properties of the micelles were characterized including size, morphology, critical micellar concentration (CMC) and in vitro drug release behavior. The therapeutic effects of the combination regimen were characterized both in vitro and in vivo including study on Ax in promoting the secretion of pulmonary surfactant, in vitro cytotoxicity, cellular uptake, Western blotting, in vivo biodistribution, in vivo pharmacokinetics and in vivo antitumor efficacy.Results: The PEG-PLA/P105/PTX micelles showed a particle size of 16.7 ± 0.5 nm, a nearly round shape, small CMC and sustained drug release property. Moreover, the in vitro results indicated that Ax could increase PS and LC3 protein secretion and enhance the cytotoxicity of PEG-PLA/P105/PTX micelles toward A549 cells. The in vivo results indicated that the combination therapeutic regimen could promote the micelles to distribute in lung and enhance the therapeutic effect on lung cancer.Conclusion: This multifunctional approach of modulating the tumor microenvironment to enhance drug transportation and cell-killing sensitivity in the action sites might offer a new avenue for effective lung cancer treatment.Keywords: lung cancer, pulmonary-affinity micelles, ambroxol, pulmonary microenvironment, combination therapy

Li Du,1 De-Hui Du,2 Biao Chen,2 Yue Ding,3 Tong Zhang,3 Wei Xiao1,4 1Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Trustworthy Computing and Software Engineering Institute, East China Normal University, Shanghai, People’s Republic of China; 3Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Jiangsu Kanion Pharmaceutical Co., Ltd, Jiangsu, People’s Republic of ChinaCorrespondence: Tong ZhangExperiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, People’s Republic of ChinaTel +86 021-5132-3175Email zhangtdmj@hotmail.comWei XiaoJiangsu Kanion Pharmaceutical Co., Ltd, Jiangning Industrial City, Economic and Technological Development Zone, Jiangsu, Lianyungang 222001, People’s Republic of ChinaTel +86 0518-85521956Email xw-kanion@163.comBackground: Sanjie Zhentong capsule (SZC) offers excellent effect in treating adenomyosis (AM), which is a common and difficult gynecological disease in the clinic. However, the systematic analysis of its mechanism has not been carried out yet and further studies are needed to reveal the role of SZC.Methods: A systematic network pharmacology analysis was conducted by integrating construction of SZC compound database and AM target database, prediction of potential active compounds and targets by molecular docking combined with compound-target prediction graph (CTPG), protein-protein interaction (PPI) analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Then, the anti–inflammation experiments in vitro were performed by investigating SZC and the representative compounds regulating nitric oxide (NO), interleukin-6 (IL-6), and interleukin-10 (IL-10).Results: Our findings show that SZC mainly treated AM by stimulating 28 core targets through 30 key potential active compounds, and affecting 4 crucial pathways. The treatment was associated with inflammation reaction, hormone regulation, cell adhesion, proliferation, and angiogenesis. Additionally, SZC achieved the anti–inflammatory activity by the cooperation of the compounds through inhibiting NO and IL-6, both promoting and inhibiting IL-10.Conclusion: This study investigated the anti–inflammatory activity of SZC based on a systematic analysis of SZC remedying AM, which was revealed to be one of the essential mechanisms. These findings will provide valuable guidance for further research of the SZC treatment of AM, and help improve the comprehension of SZC pharmacological basis as well as AM pathogenesis.Keywords: Sanjie Zhentong capsule, adenomyosis, network pharmacology, molecular docking, compound-target prediction graph, anti-inflammation

Haoyue Zhu, Mengqi Zhang, Yujiao Fu, Hongyu Long, Wenbiao Xiao, Li Feng, Bo Xiao, Luo Zhou Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of ChinaCorrespondence: Luo ZhouDepartment of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of ChinaTel +86 731 8432 8888Fax +86 731 8432 7332Email zhouluo33@163.comBackground and Purpose: Epilepsy is a common chronic neurological disorder. About one third of epilepsy patients will suffer from drug resistance after rational selection of antiepileptic drug treatment. The formation of drug-resistant epilepsy has quite a few causes of which genetic factors are considered to be the most important. Previous studies have suggested that the aquaporin 4(AQP4) and inward rectifier potassium ion channel Kir4.1 (encoded by gene KCNJ10) may act in concert to adjust water homeostasis and concentration of potassium ions in extracellular spaces of the central nervous system. Therefore, these two molecules would play a major role in the regulation of the excitability of neurons. In order to explore the potential mechanism of genetic factors related to AQP4 and Kir4.1, we conducted a study to analyze the effects of the AQP4 and KCNJ10 genes’ single nucleotide polymorphisms (SNPs) on epileptic drug resistance and seizure susceptibility in a group of Chinese Han patients with focal epilepsy.Materials and Methods: In total, 510 patients with focal-onset seizures and 206 healthy controls were recruited. Among the patients, 222 were drug resistant and 288 were responsive. The selection of tag SNPs was based on the Hapmap database and Haploview software. Genotyping of three loci of the AQP4 gene (rs1058424, rs3763043 and rs35931) and nine loci of the KCNJ10 gene (rs12122979, rs1186685, rs6690889, rs2486253, rs1186675, rs12402969, rs12729701, rs1890532 and rs3795339) was conducted on the Sequenom MassARRAY iPLEX platform.Results: The distribution of genotype and allele frequencies of selected SNP loci of AQP4 and KCNJ10 genes showed no significant difference between the drug-resistant and drug-responsive groups (p>0.05), and no significant difference between all the idiopathic focal epilepsy patients and healthy controls either.Conclusion: AQP4 and KCNJ10 genetic polymorphisms may not be associated with drug resistance or seizure susceptibility of focal epilepsy in the Chinese Han population.Keywords: AQP4, KCNJ10, focal epilepsy, polymorphism, Chinese Han population

Rongxin Chen,1,* Huijing Ye,1,* Shu Liu,2,* Yueyan Lin,1 Wei Xiao,1 Shaowei Bi,1 Guo Chen,1 Te Zhang,1 Jingqiao Chen,1 Huasheng Yang1 1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huasheng YangState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou 510060, People’s Republic of ChinaTel +86 20 8733 1539Fax +86 20 8733 3271Email yanghs64@126.comPurpose: To improve public and medical awareness of the possibility of retinoblastoma (RB) in children who experienced inadvertent trauma with or without trauma-related symptoms and signs.Patients and methods: Retrospective study of the clinical characteristics of children with a trauma history preceding a diagnosis of RB at the Zhongshan Ophthalmic Center, Sun Yat-sen University, between January 2013 and August 2018, and the number of children hospitalized with eye trauma during the same period.Results: Among 793 consecutive patients with RB, 10 (1.3%) had a history of trauma. Two of these 10 patients (20%, accounting for nearly 0.2% of the 1103 eye trauma patients who were treated at our center) had undergone vitrectomy in an eye with unsuspected tumors. Of the 10 cases (12 eyes), only 5 (7 eyes) were initially diagnosed with RB or an intraocular space-occupying mass before referral to the oncology clinic, and 8 patients (80%) with 8 eyes that were ultimately staged as cT2b or higher underwent enucleation on referral to the oncology clinic. Although additional treatment was performed, two of these patients experienced intracranial metastasis and death during a mean follow-up time of 25.9 months from treatment.Conclusion: More attention should be paid to the possibility of underlying RB in children of preschool age who have experienced trauma with or without eye signs.Keywords: unsuspected retinoblastoma, injury, awareness

Jiang T, Liu S, Wu X, et al. Cancer Manag Res. 2021;13:4751–4761. Table 2 Distant metastasis events in 28 patients The authors have advised Table 2 on page 4755 is incorrect. The correct table is as follows. Furthermore, page 4755, left column, second paragraph, the text “The median DMFS of these 28 patients was 13.4 months (0.93–62.57 months) (Table 2). The 1-year, 3-year, 5-year DMFS was 95.0%, 89.6%, 88.9%, respectively. Metastatic organs included 1 with bone, 1 with liver, 10 with lung and 16 with multiple metastases to lymph nodes, as we shown in Table 2” should read “The median DMFS of these 28 patients was 13.4 months (0.93–62.57 months). The 1-year, 3-year, 5-year DMFS was 95.0%, 89.6%, 88.9%, respectively. Metastatic organs included 2 with bone, 2 with liver, 12 with lung and 15 with multiple metastases to lymph nodes, as shown in Table 2”. The authors advise these errors do not affect the previously shown results and conclusion of the paper and apologize for any confusion this may have caused.

Dong Zhang, Zonghuan Li, Zheng Wang, Fanwei Zeng, Weidong Xiao, Aixi YuDepartment of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, People’s Republic of ChinaCorrespondence: Weidong Xiao; Aixi YuDepartment of Orthopedics, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang district, Wuhan, Hubei 430071, People’s Republic of ChinaTel +86 1 870 718 2868; +86 1 350 718 7489Email 1539562641@qq.com yuaixi@whu.edu.cnBackground: Negative pressure wound therapy represents an effective therapy to treat nonhealing diabetic wounds by promoting angiogenesis, of which the mechanism hasn’t been investigated thoroughly. Growing evidence suggests that miRNAs hold great potential to be clinical biomarkers, and miR-126 is an essential angiogenesis regulator in diabetic wound repair.Purpose: Our study aims to explore the effect of NPWT on the expression of miR-126 in the wound tissue and plasma of diabetic rat models and the association between circulating miR-126 and two quantitative indexes of angiogenesis.Methods: Full-thickness excisional wounds were created on the back of diabetic rats. Measure the wound closure and collect the wound tissue and blood for H&E, immunohistochemistry, Western blot and RT-PCR. Here we demonstrated that significantly increased capillary density and arteriolar density in the NPWT group at each specified time-point.Results: In the NPWT group, miR-126 expression was significantly increased on days 3, 5, 7, and 9 (P

Yilun Pei,1,* Fuai Cui,1,2,* Xuejun Du,1 Guowei Shang,1 Wanan Xiao,1 Xinlin Yang,1 Quanjun Cui11Orthopaedic Research Lab, University of Virginia, Charlottesville, VA, USA; 2Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China*These authors contributed equally to this work Background: There is emerging evidence which suggests that cellular ROS including nitric oxide (NO) are important mediators for inflammation and osteoarthritis (OA). Water-soluble polyhydroxylated fullerene C60 (fullerol) nanoparticle has been demonstrated to have an outstanding ability to scavenge ROS. Purpose: The objective of this study is to assess the effects of fullerol on inflammation and OA by in vitro and in vivo studies.Methods: For in vitro experiments, primary mouse peritoneal macrophages and a macrophage cell line RAW264.7 were stimulated to inflammatory phenotypes by lipopolysaccharide (LPS) in the presence of fullerol. For the animal study, OA model was created by intra-articular injection of monoiodoacetate into the knee joints of rats and fullerol was intravenously injected immediately after OA induction.Results: NO production and pro-inflammatory gene expression induced by LPS was significantly diminished by fullerol in both macrophage cell types. Meanwhile, fullerol could remarkably reduce phosphorylation of p38 mitogen-activated protein kinase, and protein level of transcription factors nuclear factor-kappaB and forkhead box transcription factor 1 within the nucleus. The animal study delineated that systematic administration of fullerol prevented OA, inhibiting inflammation of synovial membranes and the damage toward the cartilage chondrocytes in the OA joints.Conclusion: Antioxidative fullerol may have a potential therapeutic application for OA.Keywords: macrophages, inflammation, osteoarthritis, antioxidant, polyhydroxylated fullerene C60