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Zheng Wan,1 Tianyi Liu,1 Ning Xu,1 Wenhao Zhu,2 Xiaoyu Zhang,2 Qin Liu,1 Haifeng Wang,2 Honglei Wang1 1Department of Neurovascular Surgery, The First Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 2Department of Neurotrauma, The First Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of ChinaCorrespondence: Haifeng Wang; Honglei Wang, Email hfwang@jlu.edu.cn; wanghongl@jlu.edu.cnIntroduction: Extracellular vesicles (EVs) are nanosized membrane vesicles that are naturally secreted by almost all cells and have gained considerable attention. Many studies have applied EVs to the treatment of brain diseases and validated their effectiveness. Although only a few EVs can penetrate the blood‒brain barrier (BBB) into the brain after administration, it has been proven that EVs and their cargos exert their effects by interacting with brain cells. PKH dyes are commonly used to stain EVs for distribution studies. However, systematic investigations of imaging characteristics of the PKH-labeled EVs distributed in the brain are still scarce.Methods: We stained EVs derived from mesenchymal stem cells with PKH26 or PKH67. PKH26-labeled EVs and PKH67-labeled EVs were administered at the same time into each mouse while PKH26-labeled EVs were given through tail veins and PKH67-labeled EVs were given through intraperitoneal injection. Confocal microscopy was used to explore the distribution difference of two types of EVs given via different routes in the brain.Results: The fluorescence of PKH26 and PKH67 had nearly identical distributions in brain slices after 1 h, 6 h, 12 h and 1 day of EV administration. Under the same confocal parameters, brain slices without EVs administration demonstrated the same result. However, liver slices from mice administered with labeled EVs showed obviously different distributions of two types PKH fluorescence.Discussion: These findings raise questions about the ability of PKH dyes as labels for EVs when explore the EV brain distribution observed via confocal microscopy.Keywords: extracellular vesicles, PKH dyes, brain distribution

Qian Gui,1,* Jingcai Meng,2,* Mingqiang Shen,1 Hongxuan Feng,1 Xiaofeng Dong,1 Daqiang Xu,3 Wenxin Zhu,2 Qingzhang Cheng,1 Linhui Wang,2 Guanhui Wu,1 Yanli Lu3 1Department of Neurology, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Suzhou, Jiangsu, 215002, People’s Republic of China; 2Department of Physiology and Neurobiology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, People’s Republic of China; 3Department of Radiology, the Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Suzhou, Jiangsu, 215002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanli Lu, Department of Radiology, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), 26 Daoqian Street, Suzhou City, Jiangsu Province, People’s Republic of China, Tel +8618251135654, Email luyanli.2009@163.com Guanhui Wu, Department of Neurology, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), 26 Daoqian Street, Suzhou City, Jiangsu Province, People’s Republic of China, Email ghwusz26@njmu.edu.cnIntroduction: Previous studies have predominantly explored the relationship of the glymphatic system with motor symptoms in Parkinson’s disease (PD); however, research on non-motor symptoms remains limited. Therefore, this study investigated the association between glymphatic function and non-motor symptoms, including cognitive impairment and sleep disorders, in PD patients.Methods: This study recruited 49 PD patients and 38 healthy controls (HC). Glymphatic function was evaluated using enlarged perivascular spaces (EPVS) in the basal ganglia (BG) region and diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. Cognition, sleep, anxiety, and depression scales were assessed in all participants. According to the scale scores, PD patients were further divided into several groups to identify the presence of non-motor symptoms. Differences in EPVS numbers and ALPS index between PD subgroups and HC group were compared. Spearman correlation analysis was performed to investigate the association between the PD non-motor symptoms and ALPS index. Additionally, receiver operating characteristic (ROC) curves analysis was conducted for ALPS index to predict cognitive impairment and insomnia in PD patients.Results: PD patients with and without non-motor symptoms all showed more EPVS numbers than the controls, and the EPVS numbers in PD patients with cognitive impairment were also greater than those without. Notably, except for the depression subgroup, PD patients with non-motor symptoms showed significantly lower ALPS index than the controls. The Montreal Cognitive Assessment (MoCA) scores were positively correlated, whereas the Parkinson’s Disease Sleep Scale (PDSS)-2 and REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) scores were negatively correlated with the ALPS index in PD patients (r=0.3618, P=0.0053; r=− 0.4146, P=0.0015; r=− 0.2655, P=0.0326, respectively). The ALPS index proved to be predictive of cognitive impairment and insomnia in PD patients (AUC=0.7733, P=0.001; AUC=0.7993, P=0.0004, respectively).Conclusion: Glymphatic function is closely associated with cognition and sleep of PD patients.Keywords: glymphatic system, parkinson’s disease, non-motor symptoms, cognition, sleep

Yunxia Wu,1,* Yue Zhang,1,* Zishan Wang,1 Yun Lu,1 Yabei Wang,1 Jie Pan,1 Chenxi Liu,1 Wen Zhu,2,* Yue Wang2,* 1Academy of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 2Department of Rheumatology & Immunology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yue Wang; Wen Zhu, Department of Rheumatology & Immunology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China, Email wangyue@njucm.edu.cn; zhuwen@njucm.edu.cnBackground: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis and inflammatory cell infiltration. The traditional Chinese medicine prescription, Bitongqing (BTQ) exhibited significant efficacy in the clinical treatment of RA. However, the potential therapeutic mechanisms of BTQ in treating RA have not been fully investigated. This study aims to elucidate the effect of BTQ on collagen-induced arthritis (CIA) rat macrophage pyroptosis, providing a theoretical basis for treating RA.Methods: This research employed liquid chromatography-mass spectrometry (LC-MS) to identify the primary components of BTQ. The therapeutic effects of BTQ were evaluated in a rat model of CIA. In vivo experiments were conducted using pathohistological staining, immunofluorescence, micro-CT, and Western blotting. Next, Mouse leukemia cells of monocyte macrophage cells (RAW264.7) were induced to undergo pyroptosis using lipopolysaccharide (LPS) and adenosine triphosphate (ATP), and the impact of BTQ on RAW264.7 macrophages was assessed through cell viability, immunofluorescence analysis, lactate dehydrogenase (LDH) secretion measurement, and Western blotting.Results: BTQ had a therapeutic effect on CIA rats, which was mainly manifested as a reduction in joint inflammation, foot swelling, bone erosion, and amelioration of pathological changes in these rats. Further studies revealed that BTQ inhibited the levels of cytokine production interleukin-18 (IL-18) and interleukin-1β (IL-1β), and likewise, it inhibited the expression of key proteins in the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) mediated pyroptosis in the synovial tissues of CIA rats. The results of in vitro experiments demonstrated that BTQ attenuated LDH secretion, decreased IL-18 and IL-1β cytokine production, and downregulated expression of key proteins involved in the NLRP3-mediated pyroptosis on RAW264.7 macrophages.Conclusion: The therapeutic potential of BTQ in CIA lies in its ability to inhibit NLRP3-mediated macrophage pyroptosis, thereby suggesting a promising strategy for the treatment of RA. Keywords: rheumatoid arthritis, Bitongqing, pyroptosis, NLRP3 inflammasome, macrophage

Yan Guo,1,* Jing-Jing Pan,2,* Wen Zhu,1 Mu-Zi Wang,3 Tian-Yu Liu,4 Xiao-Xin Wang,5 Qian-Qian Wu,1 Yi-Xin Cheng,1 Yi-Sen Qian,1 Xiao-Guang Zhou,1 Yang Yang1 1Department of Neonatology, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Neonatology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Neonatology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, People’s Republic of China; 4Department of Neonatology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, People’s Republic of China; 5Department of Pediatrics, Shandong Tumor Hospital, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Guang Zhou; Yang Yang, Department of Neonatology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Email gzzhouxg@163.com; yy860507@126.comObjective: This prospective study is to explore the role of specific circRNAs in predicting the development of bronchopulmonary dysplasia (BPD).Methods: From July 1, 2021 to December 1, 2021, peripheral blood samples were collected from 62 premature infants with gestational age (GA) ≤ 32 weeks on the 7th, 14th, and 28th day after birth. Then, on the 28th day, the included infants were divided into the BPD group and the non-BPD group according to the definition of BPD. Serum exosomal circRNAs from peripheral blood were identified, sequenced, and compared between the BPD and non-BPD groups at different time points. Specific differentially expressed circRNAs were further verified from another 42 enrolled premature infants (GA ≤ 32 weeks). The classical lung biological markers in serum were also measured simultaneously.Results: Hsa_circ_0001359 in serum exosomes showed continuous differential expression between the BPD group and the non-BPD group on the 7th, 14th, and 28th day. Compared with that, classical lung biological markers like IL-6, IL-33, KL-6, and ET-1 did not exhibit continuous differences. Moreover, the expression of hsa_circ_0001359 on day 7 had a higher predictive value in predicting BPD (area under curve:0.853, 95% CI:0.738– 0.968; adjusted odds ratio:6.033, 95% CI:2.373– 13.326). The calibration curve further showed the mean absolute error = 0.033, mean squared error = 0.00231, and quantile of absolute error = 0.058.Conclusion: Hsa_circ_0001359 in serum exosomes is a promising marker for predicting BPD in preterm infants with gestational age ≤ 32 weeks.Keywords: bronchopulmonary dysplasia, circular RNAs, high-throughput sequencing, preterm infants

Yixin Li,1– 6,* Qi Sun,2,3,7,* Lingjia Hao,1,8 Han Shan,2,3,7 Zixi Jiang,1– 6 Ying Wang,1– 6 Zeyu Chen,2,3,7 Wu Zhu,1– 6 Shuang Zhao1– 6 1Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 2Furong Laboratory (Precision Medicine), Changsha, 410008, People’s Republic of China; 3National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 4Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 5Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 6National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 7School of Mechanical and Electrical Engineering, Central South University, Changsha, 410083, People’s Republic of China; 8Xiangya School of Medicine, Central South University, Changsha, 410083, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuang Zhao; Wu Zhu, Department of Dermatology, Xiangya Hospital of Central South University, 87 Xiangya Road, Kaifu District, Changsha, Hunan Province, People’s Republic of China, Email shuangxy@csu.edu.cn; zhuwuxy@csu.edu.cnIntroduction: Pathological scars, such as hypertrophic scars and keloids, are characterized by the proliferation of fibroblasts and the deposition of collagen that often cause pruritus, pain, and disfigurement. Due to their high incidence and deformity, pathological scars have resulted in severe physical and psychological trauma for patients. Intralesional injection of 5-fluorouracil (5-Fu) is a recommended option for treating pathological scars. However, the efficacy of 5-Fu injection was limited and unstable due to limited drug penetration and short retention time.Methods: Liposomes are promising carriers that have advantages, such as high biocompatibility, controlled release property, and enhanced clinical efficacy. Here, we constructed a transdermal 5-Fu-loaded liposome (5-Fu-Lip) to provide a more effective and safer modality to scar treatment.Results: Compared to 5-Fu, 5-Fu-Lip showed superior ability in inhibiting primary keloid fibroblasts proliferation, migration, and collagen deposition, and also significantly inhibited human umbilical vein endothelial cells (HUVECs) proliferation and microvessel construction. In vivo experiments demonstrated that 5-Fu-Lip can significantly reduce the severity of hypertrophic scars in a rabbit ear wounding model.Discussion: 5-Fu-Lip provides a promising strategy to improve drug efficacy, which has great potential in the treatment of pathological scars.Keywords: liposome, pathological scar, 5-fluorouracil, fibroblast

Keting Min,&ast; Yu Wang,&ast; Di Feng,&ast; Tian Jin, Wanli Zhu, Ruowang Duan, Xin Lv Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Lv; Ruowang Duan, Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 507 Zhengmin Road, Shanghai, 200032, People’s Republic of China, Tel +8613661869972 ; +8618019713255, Email xinlv@tongji.edu.cn; duanruowang@163.comBackground and Importance: Postoperative cough is a common complication of general anesthesia after bronchoscopy. The aim of the present study was to determine the safety profile and efficacy of piriform recess instillation with lidocaine in reducing the incidence of coughing.Objective: To what extent could piriform recess instillation with lidocaine decrease the incidence of cough at 10min after extubation?Outcome Measures and Analysis: Eighty-eight consecutive patients were equally randomized to a lidocaine group receiving piriform recess instillation with 2mL 2% lidocaine, and a normal saline group receiving piriform recess instillation with 2mL saline. The primary outcome was the incidence of cough after extubation, and the secondary outcomes were throat score at 10 min and 6 h after extubation assessed by the numerical rating scale, cough severity at 10 min and 6 h after extubation assessed by the Visual Analog Scale (VAS), 24 h 40-item Quality of Recovery Score (QoR-40), and subject-rated satisfaction score on a VAS.Main Results: Compared with saline group, the incidence of cough in lidocaine group was significantly lower (63.6% vs 86.4%, P=0.014). The sore throat score at 10 min after extubation was significantly lower (0[0,0] vs 1[0,2], P< 0.001). The subject-rated overall anesthesia satisfaction score was significantly higher (84.8[± 6.2] vs 76.6[± 8.6], P< 0.001). The severity of cough at 10 min after extubation was significantly lower (Mild: 36.4% vs 11.4%, P=0.006; Severe: 9.1% vs 43.2%, P< 0.001). There was no significant difference in the sore throat score at 6 h after extubation, severity of cough at 6 h after extubation, or QoR-40 at 24 h after extubation between the two groups.Conclusion: Piriform recess instillation with lidocaine before bronchoscopy is a simple and effective method for reducing early cough intensity and alleviating early sore throat. At 6 hours, there were no differences observed between the groups.Clinical Trial Registration: Chinese Clinical Trial Registry (identifier: ChiCTR2200067087).Keywords: piriform recess, lidocaine, general anesthesia, cough, bronchoscopy

Ying Hu,1,&ast; Wenhui Zhu,1,&ast; Xiaocong Wang,1 Yuefan Yu,1 Kangle Shi,2 Qinggang Meng1 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qinggang Meng; Kangle Shi, Email mqgangzy@126.com; bucmskl@sina.comBackground: This qualitative study, part of a prospective mixed-methods research, aimed to gain insights into the medical experiences and disease perceptions of Chinese patients living with rheumatoid arthritis (RA). Specifically, the study examined how RA patients’ perceptions of their disease were influenced by the diagnosis and treatment they receive.Methods: RA patients undergoing treatment were invited to participate in this qualitative study. Face-to-face semi-structured interviews were conducted among 18 patients, and the collected data were analyzed using thematic analysis.Results: The 18 participants in this study had a mean (SD) age of 58, a median disease duration of 6.5 years, and a predominance of female subjects (17 out of 18). The qualitative analysis identified two themes with six sub-themes: 1. Patients’ experiences of treatment: discovery of the disease, misdiagnosis and mistreatment, and patients’ treatment choices; 2. Feelings about the disease: psychological impact, reflections on the disease, and expectations of treatment.Conclusion: This study provides valuable perspectives and data to enhance the understanding of the relationship between patients’ illness perceptions and their healthcare choices.Keywords: rheumatoid arthritis, qualitative study, illness perception, patient choice

Xiaojuan Ji,1,&ast; Wenjie Zhu,1,&ast; Hongfei Lu,2 Zhiwei Wu,1 Huaqing Chen,1 Chunli Lin,1 Zhaolin Zeng,1 Cong You,1 Longnian Li1 1Department of Dermatology, First Affiliated Hospital of Gannan Medical University, Joint Organization of Jiangxi Clinical Medicine Research Center for Dermatology, Ganzhou, People’s Republic of China; 2Clinical Laboratory, First Affiliated Hospital of Gannan Medical University, Ganzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cong You; Longnian Li, Department of Dermatology, First Affiliated Hospital of Gannan Medical University, Ganzhou, People’s Republic of China, Email youcong1987@tmu.edu.cn; li_longnian@foxmail.comObjective: To analyze the antibiotic resistance profile, virulence genes, and molecular typing of Staphylococcus aureus (S. aureus) strains isolated in skin and soft tissue infections at the First Affiliated Hospital, Gannan Medical University, to better understand the molecular epidemiological characteristics of S. aureus.Methods: In 2023, 65 S. aureus strains were isolated from patients with skin and soft tissue infections. Strain identification and susceptibility tests were performed using VITEK 2 and gram-positive bacteria identification cards. DNA was extracted using a DNA extraction kit, and all genes were amplified using polymerase chain reaction. Multilocus sequence typing (MLST) was used for molecular typing.Results: In this study, of the 65 S. aureus strains were tested for their susceptibility to 16 antibiotics, the highest resistance rate to penicillin G was 95.4%. None of the staphylococcal isolates showed resistance to ceftaroline, daptomycin, linezolid, tigecycline, teicoplanin, or vancomycin. fnbA was the most prevalent virulence gene (100%) in S. aureus strains isolated in skin and soft tissue infections, followed by arcA (98.5%). Statistical analyses showed that the resistance rates of methicillin-resistant S. aureus isolates to various antibiotics were significantly higher than those of methicillin-susceptible S. aureus isolates. Fifty sequence types (STs), including 44 new ones, were identified by MLST.Conclusion: In this study, the high resistance rate to penicillin G and the high carrying rate of virulence gene fnbA and arcA of S.aureus were determine, and 44 new STs were identified, which may be associated with the geographical location of southern Jiangxi and local trends in antibiotic use. The study of the clonal lineage and evolutionary relationships of S. aureus in these regions may help in understanding the molecular epidemiology and provide the experimental basis for pathogenic bacteria prevention and treatment.Keywords: Staphylococcus aureus, skin and soft tissue infections, antibiotic resistance, multilocus sequence typing, virulence gene

Huiying Xu,1 Lizhen Wang,2 Wenchao Zhu,1 Chunguang Ren,1 Guoying Liu,1 Yanchao Liu1 1Department of Anaesthesiology, Liaocheng People’s Hospital, Liaocheng, People’s Republic of China; 2Department of Tuberculosis, Liaocheng Infectious Disease Hospital, Liaocheng, People’s Republic of ChinaCorrespondence: Yanchao Liu, Email lycxyl9@sina.comObjective: Remimazolam besylate is a novel ultra-short-acting benzodiazepine that is rapidly hydrolyzed to zolpidem propionic acid by tissue lipases. We designed this study to compare the safety and efficacy of remimazolam besylate alfentanil versus dexmedetomidine–alfentanil for fiberoptic bronchoscopy (FB).Methods: One hundred and twenty patients undergoing FB into this prospective randomized controlled trial were divided into two groups. The anesthesia induction consisted of 6 mg/kg/h of remimazolam besylate in the RA group and 0.5 μg/kg of dexmedetomidine in the DA group. 1– 2 mg/kg/h of remimazolam besylate or 0.2– 0.7 μg/kg/h of dexmedetomidine were administered to maintain during FB. The lowest oxygen saturation, success rate of FB, hemodynamics, time metrics, bronchoscopy feasibility, drug dose requirements, patient and bronchoscopist satisfaction scores, occurrence of intraoperative awareness, number of patients willing to repeat FB with the same sedation regimen, and occurrence and severity of adverse events.Results: The lowest oxygen saturation during the FB was significantly higher in the RA group (P = 0.001). Compared with the variables in the DA group, peripheral oxygen saturation, systolic blood pressure, and diastolic blood pressure were significantly lower at T2 and T3 in the RA group (P < 0.05). Heart rates were significantly higher from T2 to T4 in the DA group (P < 0.05). More patients experienced bradycardia in the DA group (P = 0.041). Compared with time metrics in the DA group, the induction time, fully-alert time, and recovery room-leaving time were all significantly shorter in the RA group (P < 0.05). The bronchoscopy feasibility scores in the RA group were significantly lower at T2, whereas they were lower at T3 in the DA group (P < 0.05).Conclusion: Remimazolam besylate is superior to dexmedetomidine when combined with alfentanil during FB, promoting faster patients’ recovery, better operative conditions and respiratory stability with similar rates of occurrence and severity of adverse events.Keywords: remimazolam besylate, dexmedetomidine, fiberoptic bronchoscopy, alfentanil, propofol

Kun Wang,1 Wei Zhu,2 Wei Huang,3 Kangkang Huang,1 Huidan Luo,1 Lu Long,1 Bin Yi1 1Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China; 2Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China; 3Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of ChinaCorrespondence: Bin Yi, Tel +86-13707495781, Email xyyibin@163.comObjective: Ubiquitination is an important post-translational modification. However, the significance of the TRIM family of E3 ubiquitin ligases in head and neck squamous cell carcinoma (HNSCC) has not been determined. In this study, the roles of TRIM E3 ubiquitin ligases in lymphovascular invasion in head and neck squamous cell carcinoma (HNSCC) were evaluated.Materials and Methods: TRIM expression and related parameters were obtained from UbiBrowser2.0, UALCAN, TIMER, TISIDB, LinkedOmics, STRING, and GeneMANIA databases. Immunohistochemistry was used to confirm their expression.Results: TRIM2, TRIM11, TRIM28, and TRIM56 were upregulated in HNSCC with lymphovascular invasion. TRIM expression was strongly associated with immune infiltration, including key treatment targets, like PD-1 and CTL4. Co-expressed genes and possible ubiquitination substrates included tumor-related factors. The TRIMs had predicted roles in ubiquitination-related pathways and vital signaling pathways, eg, MAPK, PI3K-Akt, and JAK-STAT signaling pathways.Conclusion: Ubiquitination mediated by four TRIMs might be involved in the regulation of tumor immunity, laying the foundation for future studies of the roles of the TRIM family on the prediction and personalized medicine in HNSCC. The four TRIMs might exert oncogenic effects by promoting lymphovascular invasion in HNSCC.Keywords: ubiquitination, TRIM, head and neck squamous cell carcinoma, bioinformatic analysis, lymphovascular invasion

Dawei Ren,1 Yan Zhang,1 Bo Du,1 Lina Wang,2 Meiheng Gong,1 Wei Zhu1 1Department of Otorhinolaryngology, the First Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Pediatric Respiration, the First Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Wei Zhu, Email zhuwei@jlu.edu.cnBackground: Electrical stimulation (ES) can effectively promote skin wound healing; however, single-electrode-based ES strategies are difficult to cover the entire wound area, and the effectiveness of ES is often limited by the inconsistent mechanical properties of the electrode and wound tissue. The above factors may lead to ES treatment is not ideal.Methods: A multifunctional conductive hydrogel dressing containing methacrylated gelatin (GelMA), Ti3C2 and collagen binding antimicrobial peptides (V-Os) was developed to improve wound management. Ti3C2 was selected as the electrode component due to its excellent electrical conductivity, the modified antimicrobial peptide V-Os could replace traditional antibiotics to suppress bacterial infections, and GelMA hydrogel was used due to its clinical applicability in wound healing.Results: The results showed that this new hydrogel dressing (GelMA@Ti3C2/V-Os) not only has excellent electrical conductivity and biocompatibility but also has a durable and efficient bactericidal effect. The modified antimicrobial peptides V-Os used were able to bind more closely to GelMA hydrogel to exert long-lasting antibacterial effects. The results of cell experiment showed that the GelMA@Ti3C2/V-Os hydrogel dressing could enhance the effect of current stimulation and significantly improve the migration, proliferation and tissue repair related genes expression of fibroblasts. In vitro experiments results showed that under ES, GelMA@Ti3C2/V-Os hydrogel dressing could promote re-epithelialization, enhance angiogenesis, mediate immune response and prevent wound infection.Conclusion: This multifunctional nanocomposite hydrogel could provide new strategies for promoting infectious wound healing. Keywords: MXene, GelMA, electrical stimulation, antimicrobial peptides, wound healing

Peng Wu,1,&ast; Xiaoyong Wang,2,&ast; Min Yin,1,&ast; Wenjie Zhu,3,&ast; Zheng Chen,1 Yang Zhang,1 Ziyu Jiang,4 Longqing Shi,5 Qiang Zhu1 1Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2The People’s Hospital of Rugao, Nantong, People’s Republic of China; 3Kangda College of Nanjing Medical University, Nanjing, People’s Republic of China; 4Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China; 5Department of Hepatobiliary and Pancreatic Surgery, Third Affiliated Hospital of Soochow University, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Longqing Shi, Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Jiangsu, People’s Republic of China, Email 20204135017@stu.suda.edu.cn Qiang Zhu, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China, Email zhu20081023@yeah.netBackground: Liver cancer remains to be one of the leading causes of cancer worldwide. The treatment options face several challenges and nanomaterials have proven to improve the bioavailability of several drug candidates and their applications in nanomedicine. Specifically, chitosan nanoparticles (CNPs) are extremely biodegradable, pose enhanced biocompatibility and are considered safe for use in medicine.Methods: CNPs were synthesized by ionic gelation, loaded with rutin (rCNPs) and characterized by ultraviolet–visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS) and transmission electron microscopy (TEM). The rCNPs were tested for their cytotoxic effects on human hepatoma Hep3B cells, and experiments were conducted to determine the mechanism of such effects. Further, the biocompatibility of the rCNPs was tested on L929 fibroblasts, and their hemocompatibility was determined.Results: Initially, UV–vis and FTIR analyses indicated the possible loading of rutin on rCNPs. Further, the rutin load was quantitatively measured using Ultra-Performance Liquid Chromatography (UPLC) and the concentration was 88 μg/mL for 0.22 micron filtered rCNPs. The drug loading capacity (LC%) of the rCNPs was observed to be 13.29 ± 0.68%, and encapsulation efficiency (EE%) was 19.55 ± 1.01%. The drug release was pH-responsive as 88.58% of the drug was released after 24 hrs at the lysosomal pH 5.5, whereas 91.44% of the drug was released at physiological pH 7.4 after 102 hrs. The cytotoxic effects were prominent in 0.22 micron filtered samples of 5 mg/mL rutin precursor. The particle size for the rCNPs at this concentration was 144.1 nm and the polydispersity index (PDI) was 0.244, which is deemed to be ideal for tumor targeting. A zeta potential (ζ-potential) value of 16.4 mV indicated rCNPs with good stability. The IC50 value for the cytotoxic effects of rCNPs on human hepatoma Hep3B cells was 9.7 ± 0.19 μg/mL of rutin load. In addition, the increased production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential (MMP) were observed. Gene expression studies indicated that the mechanism for cytotoxic effects of rCNPs on Hep3B cells was due to the activation of Unc-51-like autophagy-activating kinase (ULK1) mediated autophagy and nuclear factor kappa B (NF-κB) signaling besides inhibiting the epithelial–mesenchymal Transition (EMT). In addition, the rCNPs were less toxic on NCTC clone 929 (L929) fibroblasts in comparison to the Hep3B cells and possessed excellent hemocompatibility (less than 2% of hemolysis).Conclusion: The synthesized rCNPs were pH-responsive and possessed the physicochemical properties suitable for tumor targeting. The particles were effectively cytotoxic on Hep3B cells in comparison to normal cells and possessed excellent hemocompatibility. The very low hemolytic profile of rCNPs indicates that the drug could be administered intravenously for cancer therapy.Keywords: rCNPs, Hep3B, ROS, qPCR, mechanism

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

Yan Ma,1,2,&ast; Qian Cui,3,&ast; Wenjing Zhu,1,4,&ast; Mei Wang,1,2 Li Zhai,5 Wenmin Hu,1,2 Dongdong Liu,6 Min Liu,5 Yongchun Li,2 Meng Li,2 Wei Han1,2 1Qingdao Key Laboratory of Common Diseases, Qingdao Municipal Hospital, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong, 260071, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, 266071, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Shenzhen Luohu People’s Hospital, Shenzhen, 518000, People’s Republic of China; 4NMPA Key Laboratory for Quality Research and Evaluation of Traditional Marine Chinese Medicine, Qingdao, 266071, People’s Republic of China; 5Department of Pharmacy, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, 266071, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Shanting District People’s Hospital, Zaozhuang, 277200, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Han; Meng Li, Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, 266071, People’s Republic of China, Email hanw@uor.edu.cn; cqdpd@126.comPurpose: Lung adenocarcinoma currently ranks the leading causes of cancer-related mortality worldwide. Many anti-inflammation herbs, like tetramethylpyrazine, have shown their anti-tumor potentials. Here, we evaluated the role of a novel chalcone derivative of tetramethylpyrazine ((E) -1- (E) -1- (2-hydroxy-5-chlorophenyl) -3- (3,5,6-trimethylpyrazin-2-yl) -2-propen-1, HCTMPPK) in lung adenocarcinoma.Methods: The effects of HCTMPPK on cell proliferation, apoptosis, and invasion were investigated by in-vitro assays, including CCK-8, colony formation assay, flow cytometry, transwell assay, and wound-healing assay. The therapeutic potential of HCTMPPK in vivo was evaluated in xenograft mice. To figure out the target molecules of HCTMPPK, a network pharmacology approach and molecular docking studies were employed, and subsequent experiments were conducted to confirm these candidate molecules.Results: HCTMPPK effectively suppressed the proliferative activity and migration, as well as enhanced the apoptosis of A549 cells in a concentration-dependent manner. Consistent with this, tumor growth was inhibited by HCTMPPK significantly in vivo. Regarding the mechanisms, HCTMPPK down-regulated Bcl-2 and MMP-9 and up-regulating Bax and cleaved-caspase-3. Subsequently, we identified 601 overlapping DEGs from LUAD patients in TCGA and GEO database. Then, 15 hub genes were identified by PPI network and CytoHubba. Finally, MELK was verified to be the HCTMPPK targeted site, through the molecular docking studies and validation experiments.Conclusion: Overall, our study indicates HCTMPPK as a potential MELK inhibitor and may be a promising candidate for the therapy of lung cancer.Keywords: HCTMPPK((E) -1- (E) -1- (2-hydroxy-5-chlorophenyl) -3- (3,5,6-trimethylpyrazin-2-yl) -2-propen-1), chalcone, TMP, lung adenocarcinoma, network pharmacology, AutoDock

Weijian Zhu,1 Ying He,1 Mufang Huang,1 Shezhu Fu,1 Ziyi Liu,1 Xiaoqi Wang,1 Zhixin Li,1 Xiaoliang Li,1 Jiangming Chen,2 Yangqiu Li3 1Department of Hematology, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), Zhuahai, 519050, People’s Republic of China; 2Department of Haematology, Wuzhou Gongren Hospital, Wuzhou, 543001, People’s Republic of China; 3Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 10632, People’s Republic of ChinaCorrespondence: Yangqiu Li, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, People’s Republic of China, Email yangqiuli@hotmail.comObjective: We evaluated the long-term safety and efficacy of thalidomide in the treatment of transfusion-dependent β-thalassemia (TDT).Methods: Fifty patients with TDT were treated with thalidomide and followed-up for 5 years. Thalidomide at a 50 mg dose was administered once a day after dinner. The dose was increased to 150 mg/d after 3 d if well tolerated. After 1 year of treatment, the hemoglobin (Hb) level was stabilized at its maximum, and thalidomide was gradually reduced and maintained at the minimum dose. The hematological response, transfusion dependence, and haemolytic indicators were assessed.Results: At 9 month of follow-up, 38 (76%) patients achieved an excellent response, 1 (2%) a good response, 4(8%) a minor response, and 7(14%) did not show a response. The overall response rate was 86%. At 9 months, the Hb level increased from 79.0 ± 13.2 g/L at baseline to 99.0 ± 13.7g/L (P< 0.001). Patients who achieved excellent response continued to show an increase in Hb levels during follow-up. At 48 months, the mean Hb level was 98.99 ± 10.3g/L; 21 patients (84.0%) became transfusion independent. Thalidomide was reduced and maintained to 25 mg/d in three of these patients. Moreover, five patients completed 60 months of follow-up, and with a mean Hb level of 99.8 ± 6.7g/L. During follow-up, grade 1– 2 adverse drug reactions were noted; however, no grade 3 or higher adverse event was reported. However, no decrease in hemolytic indicators was observed.Conclusion: Thalidomide was well tolerated in the long term, while it significantly improved Hb levels and reduced the transfusion burden.Keywords: β-thalassemia, transfusion-dependent, thalassemia, thalidomide, foetal hemoglobin

Guiyuan He,1,&ast; Xi Wang,1,&ast; Beiqing Li,1 Lei Wang,1 Jing Zhang,2 Yang Shi,1 Wenxiu Zhu,1 Ming Shi1,3 1Centre for Reproductive and Genetic Medicine, Dalian Women and Children’s Medical Group, Dalian, People’s Republic of China; 2Department of Clinical Laboratory, Central Hospital of Dalian University of Technology, Dalian Municipal Central Hospital, Dalian, People’s Republic of China; 3Department of Clinical Laboratory, Dalian Women and Children’s Medical Group, Dalian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Shi, Centre for Reproductive and Genetic Medicine & Department of Clinical Laboratory, Dalian Women and Children’s Medical Group, Dalian, 116037, People’s Republic of China, Email zhsh6655@sohu.comPurpose: Fragile sites are specific chromosomal regions showing gaps, poor staining, contractions, or even breaks in the chromosomes. These spontaneous and heritable fragile sites are prone to structural variations which can lead to adverse reproductive outcomes. This paper aims to present a specific case study of a female patient, with a mosaic karyotype involving chromosome 16q22 fragile site which is very rare in clinic and her experience of infertility.Case Presentation: A 37-year-old woman is diagnosed with ten-year primary infertility. She worked in a factory, and she was occasionally exposed to paint. She underwent two cycles of follicular monitoring with intrauterine insemination (IUI) using her husband’s sperm six years ago but failed. Most of her prepregnancy tests were normal, except a not smooth right fallopian tube. Her G-band karyotype of peripheral blood lymphocytes was mos 46, XX, del(16)(q22)[40]/46, XX, fra(16)(q22)[29]/46, XX, fra(16)tr(16)(q22)[3]/46, XX[28] which inherited from her mother. The SCE assay detected a significantly higher frequency of SCEs in the 16q region of the patient’s chromosomes compared to her mother and a healthy control. However, the average SCEs per chromosome were quite close. Moreover, copy number variation (CNV) sequencing showed no deletion nor duplication at 16q22.Conclusion: Infertility cannot be completely attributed to the fragile site on chromosome 16q22. Assisted reproductive technology combined with preimplantation genetic testing may help in achieving a healthy live birth.Keywords: fragile sites, infertility, fra(16)(q22), del(16)(q22), SCE, CNV

Haopeng Wang,1,&ast; Hua Zhao,1,&ast; Zheng Chen,1,&ast; Xiaomin Cai,1 Xuhui Wang,1 Ping Zhou,1 Yinda Tang,1 Tingting Ying,1 Xin Zhang,1 Yiman Shen,1 Baimiao Wang,1 Wanchun Zhu,1 Jin Zhu,1 Xinjun Wang,2 Shiting Li1 1Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, People’s Republic of China; 2Department of Neurosurgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shiting Li, Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, People’s Republic of China, Email lishiting@xinhuamed.com.cn Xinjun Wang, Department of Neurosurgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China, Email wangxj@zzu.edu.cnBackground: Facial nerves have the potential for regeneration following injury, but this process is often challenging and slow. Schwann cells (SCs) are pivotal in this process. Bone mesenchymal stem cells (BMSC)-derived exosomes promote tissue repair through paracrine action, with hypoxic preconditioning enhancing their effects. The main purpose of this study was to determine whether hypoxia-preconditioned BMSC-derived exosomes (Hypo-Exos) exhibit a greater therapeutic effect on facial nerve repair/regeneration and reveal the mechanism.Methods: CCK-8, EdU, Transwell, and ELISA assays were used to evaluate the functions of Hypo-Exos in SCs. Histological analysis and Vibrissae Movements (VMs) recovery were used to evaluate the therapeutic effects of Hypo-Exos in rat model. circRNA array was used to identify the significantly differentially expressed exosomal circRNAs between normoxia-preconditioned BMSC-derived exosomes (Nor-Exos) and Hypo-Exos. miRDB, TargetScan, double luciferase assay, qRT-PCR and WB were used to predict and identify potential exosomal cirRNA_Nkd2-complementary miRNAs and its target gene. The function of exosomal circRNA_Nkd2 in facial nerve repair/regeneration was evaluated by cell and animal experiments.Results: This study confirmed that Hypo-Exos more effectively promote SCs proliferation, migration, and paracrine function, accelerating facial nerve repair following facial nerve injury (FNI) compared with Nor-Exos. Furthermore, circRNA analysis identified significant enrichment of circRNA_Nkd2 in Hypo-Exos compared with Nor-Exos. Exosomal circRNA_Nkd2 positively regulates mediator complex subunit 19 (MED19) expression by sponging rno-miR-214-3p.Conclusion: Our results demonstrated a mechanism by which Hypo-Exos enhanced SCs proliferation, migration, and paracrine function and facial nerve repair and regeneration following FNI through the circRNA_Nkd2/miR-214-3p/Med19 axis. Hypoxic preconditioning is an effective and promising method for optimizing the therapeutic action of BMSC-derived exosomes in FNI. Keywords: hypoxic, BMSCs, exosomes, Schwann cells, facial nerve injury

Jie Huang,1,&ast; Wenqiang Zhu,1,&ast; Qiangzhi Duan,2,&ast; Chaomang Zhu,1 Xueling Shi,1 Hongyu Zhao,1 Peng Cai,1 Duojie Li1 1Department of Radiotherapy, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233000, People’s Republic of China; 2Department of Radiotherapy, The 2nd Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Duojie Li, Department of Radiotherapy, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233000, People’s Republic of China, Tel/Fax +86-139-5633-2626, Email liduojie@163.comPurpose: To explore the efficacy and safety of pyrotinib combined with different radiotherapy modes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastasis (BM).Patients and Methods: This study is a retrospective analysis of patients diagnosed with BM who underwent treatment with pyrotinib between November 2018 and April 2023. A total of 66 patients were administered radiotherapy in conjunction with pyrotinib (Group A), while 26 patients received pyrotinib as a standalone treatment (Group B). Within Group A, 18 patients underwent conventional fractionated radiotherapy (2Gy/F), while 48 patients received hyperfractionated radiotherapy (HFRT) (≥ 3Gy/F). The primary endpoints were intracranial progression-free survival (IC-PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR) and clinical benefit rate (CBR).Results: The ORR of Group A was 54.5% (36/66), while the ORR of Group B was 34.6% (9/26) (P= 0.047). The CBR of Group A was 89.4% (59/66) and that of Group B was 69.2% (18/26) (P= 0.041). The IC-PFS between Group A and Group B were 12 months and 8 months, respectively (P< 0.001), and the OS were 20 months and 16 months, respectively (P= 0.065). In Group A, the IC-PFS and OS between the conventional fractionation radiotherapy group and the HFRT group were 10 months and 12 months, respectively (P= 0.001) and 16 months and 24 months, respectively (P< 0.001). No serious adverse reactions were observed in Group A and Group B.Conclusion: For HER2-positive BC patients with BM, it is recommended to adopt the treatment mode of HFRT combined with pyrotinib, which can improve the local control and survival of patients.Keywords: breast cancer, human epidermal growth factor receptor type 2, brain metastasis, pyrotinib, radiation therapy, hyperfractionated radiotherapy

Wenyan Zhu,1 Tiange Xie,2 Mengru Xu,1 Ruxuan Chen,1 Ting Zhang1 1Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of General Practice, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Ting Zhang; Ruxuan Chen, Email tintin-03@163.com; nandao2006@126.comBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still rampant around the world. Immunocompromised patients are prone to have long-term infection with coronavirus disease 2019 (COVID-19). However, it is difficult to decide on an appropriate treatment for persistent SARS-CoV-2 infection.Case Presentation: We present a case of prolonged SARS-CoV-2 infection in a patient who had undergone B-cell depletion therapy. Chest computed tomography (CT) revealed notable migratory pulmonary infiltrates, and bronchoalveolar lavage fluid was positive for SARS-CoV-2 (day-120). The patient responded well to the combination treatment of antiviral medication, convalescent plasma, and corticosteroid.Conclusion: When chest CT shows migratory pulmonary infiltrates in patients with recent COVID-19, it is necessary to be alert to the possibility of persistent SARS-CoV-2 infection, especially in B-cell-depleted immunocompromised patients. Once the diagnosis is confirmed, repeated antiviral therapy and intravenous convalescent plasma should be considered.Keywords: SARS-CoV-2, migratory pulmonary infiltrates, B-cell depletion, antiviral therapy, convalescent plasma

Lijuan Zhang,1,2 Weiyi Zhu,1 Beiwen Wu1 1Department of Nursing, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2School of Nursing, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Beiwen Wu, Department of Nursing, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Ruijin Er Road, Shanghai, 200025, People’s Republic of China, Tel +86 18917762079, Fax +86 54314096, Email Gaoan2005new@163.comBackground: This study aimed to examine how personality traits, social support and clinical features including pain, disease activity, functional status, sleep quality, and fatigue influence on depressive symptoms in Chinese rheumatoid arthritis (RA) patients.Methods: This study was conducted from November, 2022 to June, 2023 among Chinese RA patients. Pain, disease activity, functional status, sleep quality, fatigue, social support, personality traits, and depressive symptoms were assessed. The following relationships among three hypotheses were analyzed by structural equation model (SEM): H1: clinical features have a direct effect on depressive symptoms; H2: personality traits might work as a mediator between clinical features and depression; H3: social support is related to depressive symptoms, being a direct effect or an indirect effect through clinical features or personality traits.Results: The final model including 326 RA patients presented a good fit (χ2=103, χ2/df=1.69; GFI=0.96; AGFI=0.93; CFI=0.97; TLI=0.96; RMSEA=0.046). Clinical features had a total effect of 0.59 on depressive symptoms, of which β=0.33 (P=0.013) was an indirect effect through personality traits, indicating a mediating influence between this relationship; moreover, there was a significant direct association between clinical features and depressive symptoms (β=0.26; P=0.022). Personality traits (β=− 0.65; P< 0.001) had a much stronger relation with depressive symptoms than with clinical features. Social support had a total effect of 0.81 on personality traits, being a direct effect of β=0.52 (P< 0.001) and an indirect effect of β=0.29 (P< 0.001) through clinical features. The final proposed model explained 77% of the variance of depressive symptoms.Conclusion: Personality traits had a considerable influence upon depressive symptoms, while social support seemed to have a major effect on personality traits. It is necessary to apply comprehensive assessment and interventions of patients’ personality traits, clinical features, as well as social support, which could optimize their mental health.Keywords: rheumatoid arthritis, depressive symptoms, structural equation model, personality traits

Wanshan Zhu, Lexia Wu, Jiaming Wu, Sihong Lin, Cantu Fang, Huatang Zhang Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan, Guangdong Province, People’s Republic of ChinaCorrespondence: Huatang Zhang, Email paul201503@163.comAbstract: Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers and is on the rise annually. It is characterized by low differentiation, high malignancy, and rapid growth. Consequently, treatment options are limited, and the patient’s prognosis is poor. The emergence of immunotherapy has partially improved the survival and prognosis of SCLC patients. However, a unique response known as “pseudoprogression” during immunotherapy has raised concerns. The occurrence of tumor enlargement despite a positive response to immune checkpoint inhibitor therapy undoubtedly affects the assessment of clinical drug efficacy and the selection of subsequent treatment strategies. In this article, we analyze a clinical case of pseudoprogression in a patient with SCLC who received immune therapy (Durvalumab). Currently, there is insufficient evidence-based medicine to guide the diagnosis, differentiation and subsequent treatment strategies for pseudoprogression in SCLC following immunotherapy. Through this case report and literature review, we aim to provide diagnostic and therapeutic insights for the clinical use of immunotherapy in advanced SCLC. Additionally, we hope that fellow readers of this article can engage in further collaborative discussions through more clinical research.Keywords: small cell lung cancer, immunotherapy, pseudoprogression

Longfei Xing,1,&ast; Xilin Chen,2,3,&ast; Changqing Guo,1 Wenting Zhu,4 Tingyao Hu,1 Weiwei Ma,1 Mei Du,1 Yue Xu,1 Changqing Guo5 1School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, People’s of Republic of China; 2Department of Acupuncture and Rehabilitation, The Fifth College of Clinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, People’s Republic of China; 3Department of Acupuncture and Rehabilitation, Guangdong Second Hospital of Traditional Chinese Medicine, Guangzhou, People’s Republic of China; 4The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 5Department of Medical Technology, Shijiazhuang Medical College, Shijiazhuang, Hebei Province, People’s of Republic of China&ast;These authors contributed equally to this workCorrespondence: Changqing Guo, Shijiazhuang Medical College, Shijiazhuang, Hebei Province, 050599, People’s of Republic of China, Tel +86-13081033381, Fax +86-82517626, Email 925499172@qq.comPurpose: Mitochondrial dysfunction of chondrocytes has become an area of focus in Knee Osteoarthritis (KOA) in recent years. Activation of mitophagy could promote the survival of chondrocytes and alleviate cartilage degeneration. The aim of this study was to explore whether mitophagy was involved in the cartilage protection of KOA rabbits after electroacupuncture (EA) intervention.Methods: The rabbits were divided into 3 groups, Control group, KOA group, EA group, with 6 rabbits in each group. KOA model rabbits were established by modified Videman’s extended immobilization method for 6 weeks and randomly divided into KOA group and EA group. The rabbits in EA group were treated every other day for 3 weeks. The degree of cartilage degeneration was detected by Safranine O-Fast Green staining and immunofluorescence. The morphological changes of chondrocytes mitochondria were detected by transmission electron microscope. ATP concentration in cartilage was measured by ATP Assay Kit. The changes of Pink1-Parkin signal pathway were detected by immunofluorescence, Western blot, and Real-time PCR.Results: The morphology showed that EA could reduce the degeneration of KOA cartilage and increase the distribution of collagen II. We also found that EA could activate mitophagy in KOA rabbit chondrocytes to remove damaged mitochondria and restore mitochondrial homeostasis, which was manifested as increasing the expression of LC3 II/I, promoting the colocalization of TOM20 and LC3B, reducing the accumulation of mitochondrial markers outer mitochondrial membrane 20 (TOM20) and inner mitochondrial membrane 23 (TIM23), and increasing ATP production in chondrocytes. This regulation might be achieved by upregulating the Pink1-Parkin signal pathway.Conclusion: EA may play a role in protecting KOA cartilage by activating mitophagy mediated through Pink1-Parkin pathway.Keywords: osteoarthritis, electroacupuncture, mitophagy, mitochondria, Pink1-Parkin

Recent studies have addressed the association between lung development and long-noncoding RNAs (lncRNAs). But few studies have investigated the role of lncRNAs in neonatal respiratory distress syndrome (RDS). Thus, this study aimed to compare the expression profile of circulating lncRNAs between RDS infants and controls.

Qiaochu Zhou,1 Wei Wang,2 Qi Yu,1 Jinhui Wang,1 Wenzheng Zhu1 1Department of Dermatology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai University, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Gynecology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Wei Wang, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai University, 75Jinxiu, Wenzhou, 325000, People’s Republic of China, Tel +8613968900070, Fax +8657788980818, Email w2wangwei@126.comObjective: Hairline vitiligo is a special area. Hairy areas within the hairline often require repigmentation and regrowing hair shafts. The face and forehead outside the hairline do not require regrowing hair shafts, only repigmentation. To tackle this issue, we modified the conventional mini-punch grafting with a combined application of mini-punch grafting and follicular hair transplant.Methods: Five patients with localized hairline stable vitiligo aged 26– 32 years old had a history of nonsurgical treatments for at least 3 months and without progress. The grafts were transversely sectioned. The intact half follicles were preserved below the cross-section. Sectioned grafts were placed into the chambers for transplanting with forceps.Results: The treatment using transversely sectioned mini-punch grafting with the patient was performed for all five patients, and the results were satisfactory. In the area of the forehead outside the hairline with the sectioned mini-punch grafting above the cross-section, hair loss and repigmentation were observed. In the area of the hairy areas within the hairline, growing hair shafts and repigmentation were observed, without hair loss.Conclusion: Our report can help to manage hairline vitiligo or hairy areas vitiligo. This method can be considered a potential method for the treatment of hairline vitiligo, thus providing a simple solution to complex problems.Keywords: vitiligo, punch grafting, mini-punch grafting, skin punch

Yunbo Chen,1,2 Yuanyuan Dai,3 Yizheng Zhou,4 Ying Huang,5 Yan Jin,6 Yan Geng,7 Bing Ji,8 Rong Xu,9 Wencheng Zhu,10 Shuyan Hu,11 Zhuo Li,12 Jinhua Liang,13 Yonghong Xiao1,2 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People’s Republic of China; 3Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China; 4Clinical Laboratory, Jingzhou Central Hospital, Jingzhou, People’s Republic of China; 5Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 6Clinical Laboratory, Shandong Provincial Hospital, Jinan, People’s Republic of China; 7Clinical Laboratory, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 8Clinical Laboratory, Affiliated Hospital of Binzhou Medical College, Binzhou, People’s Republic of China; 9Clinical Laboratory, People’s Hospital of Yichun City, Yichun, People’s Republic of China; 10Clinical Laboratory, Lu’an Civil Hospital, Lu’an, People’s Republic of China; 11Clinical Laboratory, People’s Hospital of Qingyang, Qingyang, People’s Republic of China; 12Clinical Laboratory, The First Affiliated Hospital of Xi’an Medical University, Xi’an, People’s Republic of China; 13Clinical Laboratory, The Affiliated Hongqi Hospital of Mudanjiang Medicine College, Mudanjiang, People’s Republic of ChinaCorrespondence: Yonghong Xiao, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang, 310003, People’s Republic of China, Tel/Fax +86 571 87236421, Email xiao-yonghong@163.comPurpose: Blood cultures (BCs) are essential laboratory tests for diagnosing blood stream infections. BC diagnostic improvement depends on several factors during the preanalytical phase outside of innovative technologies. In order to evaluate the impact of an educational program on BC quality improvement, a total of 11 hospitals across China were included from June 1st 2020 to January 31st 2021.Methods: Each hospital recruited 3 to 4 wards to participate. The project was divided into three different periods, pre-implementation (baseline), implementation (educational activities administered to the medical staff) and post-implementation (experimental group). The educational program was led by hospital microbiologists and included professional presentations, morning meetings, academic salons, seminars, posters and procedural feedback.Results: The total number of valid BC case report forms was 6299, including 2739 sets during the pre-implementation period and 3560 sets during the post-implementation period. Compared with the pre-implementation period, some indicators, such as the proportion of patients who had 2 sets or more, volume of blood cultured, and BC sets per 1000 patient days, were improved in the post-implementation period (61.2% vs 49.8%, 18.56 vs 16.09 sets, and 8.0 vs 9.0mL). While BC positivity and contamination rates did not change following the educational intervention (10.44% vs 11.97%, 1.86% vs 1.94%, respectively), the proportion of coagulase negative staphylococci-positive samples decreased in BSI patients (6.87% vs 4.28%).Conclusion: Therefore, medical staff education can improve BC quality, especially increasing volume of blood cultured as the most important variable to determine BC positivity, which may lead to improved BSI diagnosis.Keywords: blood culture, bloodstream infection, medical education, medical staff, quality improvement

Wenjun Zhu,&ast; Yaping Tian,&ast; Lin Xiang, Linna Cao, Lirong He Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lirong He, Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel +86 18170905103, Fax +86 0791 86311242, Email hlr_ndefy@163.comAbstract: One of the most pressing emerging issues in bacterial resistance is multidrug-resistant Klebsiella pneumoniae. The treatment of K. pneumoniae infections is often problematic because of the lack of available therapeutic options, leading to negative effects on morbidity, mortality, and healthcare-associated costs. Carrimycin is a macrolide antibiotic with good antibacterial effects. In this study, we report a patient diagnosed with multidrug-resistant K. pneumoniae infection who was treated with carrimycin. The patient presented with cough, expectoration, dyspnea, and severe hypoxemia requiring noninvasive ventilation. We successively used a variety of antibiotics, including meropenem, tigecycline, and polymyxin, with unsatisfactory results. Finally, we used carrimycin, and the patient’s condition improved, resulting in hospital discharge. Therefore, for patients with multidrug-resistant K. pneumoniae infection that does not respond to conventional anti-infective treatments, carrimycin can be considered a treatment option.Keywords: carrimycin, Klebsiella pneumoniae, multidrug-resistant

Ling Sun,1,&ast; Bing Han,2,&ast; Yu Wang,1,&ast; Wenwu Zhu,2 Jianguang Jiang,1 Ailin Zou,1 Boyu Chi,1,3 Lipeng Mao,1,3 Yuan Ji,1 Qingjie Wang,1 Liming Tang4 1Department of Cardiology, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213003, People’s Republic of China; 2Department of Cardiology, Xuzhou Central Hospital, Xuzhou Clinical School of Nanjing Medical University, Xuzhou, Jiangsu, 221009, People’s Republic of China; 3Dalian Medical University, Dalian, Liaoning, 116000, People’s Republic of China; 4Department of Gastrointestinal Disease, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liming Tang, Center of Gastrointestinal Disease, Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, 29 Xinglong Alley, Changzhou, Jiangsu, 213003, People’s Republic of China, Email drtangliming@163.com Yuan Ji, Department of Cardiology, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213003, People’s Republic of China, Email jiyuan1213@aliyun.comObjective: In this study, a risk score for ventricular arrhythmias (VA) were evaluated for predicting the risk of ventricular arrhythmia (VA) of acute myocardial infarction (AMI) patients.Methods: Patients with AMI were divided into two sets according to whether VA occurred during hospitalization. Another cohort was enrolled for external validation. The area under the curve (AUC) of receiver operating characteristic (ROC) was calculated to evaluate the accuracy of the model.Results: A total of 1493 eligible patients with AMI were enrolled as the training set, of whom 70 (4.7%) developed VA during hospitalization. In-hospital mortality was significantly higher in the VA set than in the non-VA set (31.4% vs 2.7%, P=0.001). The independent predictors of VA in patients with AMI including Killip grade ≥ 3, STEMI patients, LVEF < 50%, frequent premature ventricular beats, serum potassium < 3.5 mmol/L, type 2 diabetes, and creatinine level. The AUC of the model for predicting VT/VF in the training set was 0.815 (95% CI: 0.763– 0.866). A total of 1149 cases were enrolled from Xuzhou Center Hospital as the external validation set. The AUC of the model in the external validation set for predicting VT/VF was 0.755 (95% CI: 0.687– 0.823). Calibration curves indicated a good consistency between the predicted and the observed probabilities of VA in both sets.Conclusion: We have established a clinical prediction risk score for predicting the occurrence of VA in AMI patients. The prediction score is easy to use, performs well and can be used to guide clinical practice.Keywords: ventricular tachycardia, ventricular flutter and fibrillation, risk stratification, scoring system, acute myocardial infarction

Minjia Tan,1– 3,&ast; Yan Luo,4,&ast; Jingjin Hu,1– 3 Kun Hu,1– 3 Xingyu Li,1– 3 Jing Yang,1– 3 Junchen Chen,1– 3 Wu Zhu,1– 3 Yehong Kuang1– 3 1The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, People’s Republic of China; 3Hunan Engineering Research Center of Skin Health and Disease; Hunan Key Laboratory of Skin Cancer and Psoriasis (Xiangya Hospital), Changsha, People’s Republic of China; 4Department of Dermatology, Jiangxi Provincial People’s Hospital, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yehong Kuang; Wu Zhu, Email yh_927@126.com; zhuwu70@hotmail.comPurpose: Psoriasis patients often suffers from anxiety and depression. Inflammation, anxiety, and depression have been associated with each other, but the relationship has not been examined in subjects with psoriasis. The primary objective was to investigate the relationship between the C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) and depression among patients with psoriasis.Methods: In this case-control, cross-sectional study, 239 individuals with psoriasis and 142 with healthy controls (HCs) were recruited. Psychological as well as clinical, and laboratory data were collected.Results: 50.2% of subjects with psoriasis reported depressive symptoms, compared with 26.8% of HCs. 39.7% and 17.6% observed anxiety symptoms in psoriasis patients and HCs. The odds of anxiety (AOR= 3.123; 95% CI = 1.851– 5.269) and depression (AOR= 2.698; 95% CI = 1.690– 4.306) were higher in psoriasis patients relative to HCs. Furthermore, the elevated CRP (AOR =2.139; 95% CI = 1.249– 3.663) and ESR (AOR =1.827; 95% CI = 1.078– 3.096) were the risk factors of depression in patients with psoriasis. The threshold for distinguish psoriasis patients in depression was 3.24 (area under the curve [AUC], 0.605; sensitivity, 0.57; specificity, 0.64) for CRP and 26.5 (AUC, 0.632; sensitivity, 0.52; specificity, 0.73) for ESR.Conclusion: A substantial prevalence of anxiety and depression symptoms was observed in Chinese psoriasis subjects, and the odds were much higher in psoriasis patients relative to HCs. The elevated CRP and ESR level was significantly associated with depression in psoriasis patients. Besides, the discrimination capability of CPR and ESR on depression further indicates the extra value of inflammatory biomarkers in the management of psoriasis patients.Keywords: psoriasis, depression, anxiety, C-reactive protein, erythrocyte sedimentation rate

Jingmou Yu,1– 3 Liangliang Wang,4 Xin Xie,2 Wenjing Zhu,3 Zhineng Lei,3 Linghui Lv,3 Hongling Yu,3 Jing Xu,4 Jin Ren2,3 1Huzhou Key Laboratory of Medical and Environmental Applications Technologies, School of Life Sciences, Huzhou University, Huzhou, People’s Republic of China; 2Jiangxi Provincial Laboratory Laboratory of System Biomedicine, Jiujiang University, Jiujiang, People’s Republic of China; 3School of Pharmacy and Life Sciences, Jiujiang University, Jiujiang, People’s Republic of China; 4Affiliated Hospital of Jiujiang University, Jiujiang, People’s Republic of ChinaCorrespondence: Jingmou Yu; Jin Ren, Email yjm1016@hotmail.com; yanjiushengrj@126.comBackground: Multifunctional stimuli-responsive nanoparticles with photothermal-chemotherapy provided a powerful tool for improving the accuracy and efficiency in the treatment of malignant tumors.Methods: Herein, photosensitizer indocyanine green (ICG)-loaded amorphous calcium-carbonate (ICG@) nanoparticle was prepared by a gas diffusion reaction. Doxorubicin (DOX) and ICG@ were simultaneously encapsulated into poly(lactic-co-glycolic acid)-ss-chondroitin sulfate A (PSC) nanoparticles by a film hydration method. The obtained PSC/ICG@+DOX hybrid nanoparticles were characterized and evaluated by Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), transmission electron microscopy (TEM), and differential scanning calorimetry (DSC). The cellular uptake and cytotoxicity of PSC/ICG@+DOX nanoparticles were analyzed by confocal laser scanning microscopy (CLSM) and MTT assay in 4T1 cells. In vivo antitumor activity of the nanoparticles was evaluated in 4T1-bearing Balb/c mice.Results: PSC/ICG@+DOX nanoparticles were nearly spherical in shape by TEM observation, and the diameter was 407 nm determined by DLS. Owing to calcium carbonate and disulfide bond linked copolymer, PSC/ICG@+DOX nanoparticles exhibited pH and reduction-sensitive drug release. Further, PSC/ICG@+DOX nanoparticles showed an effective photothermal effect under near-infrared (NIR) laser irradiation, and improved cellular uptake and cytotoxicity in breast cancer 4T1 cells. Importantly, PSC/ICG@+DOX nanoparticles demonstrated the most effective suppression of tumor growth in orthotopic 4T1-bearing mice among the treatment groups. In contrast with single chemotherapy or photothermal therapy, chemo-photothermal treatment by PSC/ICG@+DOX nanoparticles synergistically inhibited the growth of 4T1 cells.Conclusion: This study demonstrated that PSC/ICG@+DOX nanoparticles with active targeting and stimuli-sensitivity would be a promising strategy to enhance chemo-photothermal cancer therapy.Graphical Abstract: Keywords: chemo-photothermal treatment, amorphous calcium carbonate, nanoparticles, stimuli-sensitivity, drug delivery, cancer therapy

Jing He,1,&ast; Xin Zhou,1,&ast; Xiaping Wang,2,&ast; Qing Zhang,3 Lan Zhang,4,5 Tongshan Wang,1 Wei Zhu,1 Ping Liu,1 Mingxia Zhu6 1Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China; 2Department of Pathology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, People’s Republic of China; 3Department of Neurosurgery, Xinghua People’s Hospital, Xinghua, Jiangsu, 225700, People’s Republic of China; 4Department of Radiotherapy & Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, People’s Republic of China; 5Department of Radiation Oncology, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, People’s Republic of China; 6Department of Radiation Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingxia Zhu; Ping Liu, Email zhumingxia@suda.edu.cn; liupinga28@163.comBackground: There have been several studies evaluating the prognostic significance of cell division cycle associated 5 (CDCA5). However, few reports analyzed the correlation between CDCA5 and prognosis of diverse cancers based on large clinical data. We thus comprehensively analyzed CDCA5 expression and clinical significance using The Cancer Genome Atlas (TCGA) data from 31 types of solid tumors.Methods: The expression profiles of CDCA5 were investigated across pan-cancer samples from the TCGA. Cox regression and Kaplan–Meier analysis was performed to determine CDCA5’s prognostic value. CDCA5 expression was further validated by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) in lung adenocarcinoma (LUAD).Results: We found that CDCA5 was significantly overexpressed in 22 types of tumors. Up-regulated CDCA5 was significantly related to poor survival in 13 types of tumors. Furthermore, CDCA5 expression was significantly associated with immune cell infiltration. Tumor mutation burden (TMB), microsatellite instability (MSI), and immune checkpoint expression were significantly correlated with CDCA5 expression. Additional analysis of IMvigor 210 cohort validated that patients with high level of CDCA5 had superior response to anti-PD-L1 therapy.Conclusion: Our findings suggested that CDCA5 could provide prognostic information in most types of cancers and contributed to tumor immune microenvironment.Keywords: cell division cycle associated 5, pan-cancer, prognosis, immune infiltration, tumor mutation burden, microsatellite instability

Gangtie Liu,1,2 Guanglei Wang,2 Zhan Yang,2 Guangfu Liu,3 Haijun Ma,3 Yong Lv,2 Feiyan Ma,2 Weiwei Zhu1 1Department of Pediatrics, Jinan Central Hospital, Shandong University, Jinan, People’s Republic of China; 2Department of Pediatrics, Taian Maternity and Child Health Care Hospital, Taian, People’s Republic of China; 3Department of Radiology, Taian Maternity and Child Health Care Hospital, Taian, People’s Republic of ChinaCorrespondence: Weiwei Zhu, Department of Pediatrics, Jinan Central Hospital, Shandong University, No. 105 Jiefang Road, Jinan, 250013, People’s Republic of China, Tel +86-538-6620622, Email 198651020311@email.sdu.edu.cnPurpose: Early diagnosis of refractory Mycoplasma pneumoniae pneumonia (RMPP) is challenging because of the lack of practical diagnostic imaging tools. Lung ultrasound (LUS) is an emerging tool for diagnosing childhood pneumonia. Hence, we evaluated the role of a nomogram combining LUS findings, clinical features, and laboratory indices in the early prediction of RMPP in children.Patients and Methods: We retrospectively analyzed 225 children with Mycoplasma pneumoniae pneumonia (MPP) admitted to our hospital between Dec 2018 and Aug 2021. Logistic regression analysis incorporated LUS findings and clinical predictors into the nomogram. Ninety patients hospitalized from Sep 2021 to Dec 2021 were used for external validation of the prediction model. Receiver operating characteristics (ROC) and calibration curves were used to evaluate the performance of the nomogram in the early diagnosis of RMPP.Results: Ultimately, Consolidation size /BSA (odds ratio (OR) 1.015, 95% confidence interval (CI) 1.536– 2.446), Pleural Effusion (OR 3.551, 95% CI 1.921– 15.600), LDH (OR 1.044, 95% CI 1.006– 1. 021) and CRP (OR 3.293, 95% CI 1.019– 1.098) were independent risk factors for the development of RMPP. The prediction model was represented visually as a nomogram. The area under the ROC curve for the predictive nomogram was 0.955 (95% CI 0.919– 0.978) in the training cohort and 0.916 (95% CI 0.838– 0.964) in the validation cohort. The calibration curve is close to the diagonal.Conclusion: This is the first-time lung ultrasound was added to the predicted nomogram, which can more comprehensively assess the condition and more accurately predict the occurrence of RMPP early. Therefore, this nomogram can be widely used in the early diagnosis of RMPP, especially in primary care hospitals.Graphical Abstract: Keywords: predictive model, risk factors, diagnosis, Mycoplasma pneumoniae pneumonia

Fei Gao,&ast; Cheng Li,&ast; Jiahui Peng, Wei Lu, Wei Zhu, Jian Zhou, Jingyi Lu, Xiaojing Ma Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jingyi Lu; Xiaojing Ma, Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai, 200233, People’s Republic of China, Tel +86-21-64369181, Fax +86-21-64368031, Email lujingy1@126.com; maxiaojing@sjtu.edu.cnAim: Dickkopf-1 (DKK-1) is a major inhibitor of Wingless protein signaling pathway, which is involved in glucose metabolism and cardiovascular diseases. The aim of the study was to investigate the changes of serum DKK-1 levels after hypoglycemic treatments and the relationship between DKK-1 and clinical parameters.Materials and Methods: The study was a sub-study of a previously published clinical trial (the effect of Acarbose on glycemic variability in patients with type 2 diabetes mellitus using premixed insulin compared to metformin). All subjects underwent anthropometric and biochemical assessments at baseline and endpoint. Serum DKK-1 levels of 92 subjects were measured at baseline and after 12-week hypoglycemic treatment.Results: DKK-1 levels were significantly decreased after hypoglycemic treatment for 12 weeks (P < 0.001). ΔDKK-1 levels were not correlated with improvement of metabolic parameters (all P > 0.05) but were negatively correlated with baseline DKK-1 levels (r = − 0.263, P = 0.011). Spearman correlation showed that baseline DKK-1 levels were positively related to baseline total cholesterol (r = 0.226, P = 0.030) and low-density lipoprotein cholesterol (LDL-C) (r = 0.277, P = 0.007). Compared with the higher baseline DKK-1 group (≥ 3700 pg/mL), subjects in the lower baseline DKK-1 group (< 3700 pg/mL) had significantly lower baseline glycated hemoglobin A1c levels (P = 0.008) and LDL-C levels (P = 0.048). Systolic and diastolic pressure were decreased more significantly in the lower baseline DKK-1 group than that in the higher baseline DKK-1 group (both P < 0.05).Conclusion: Serum DKK-1 levels were decreased after hypoglycemic treatments. Patients with lower baseline DKK-1 levels were featured by more favorable cardiometabolic factors.Keywords: cardiovascular risk factor, dickkopf-1, hypoglycemic treatment, type 2 diabetes mellitus

Li Zhang,1 Xiaoling Liu,1 Min Huang,1 Rui Wang,1 Wenwei Zhu,1 Yu Li,2 Lin Shen,1 Chengxin Li1 1Department of Dermatology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 2Department of Dermatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100853, People’s Republic of ChinaCorrespondence: Chengxin Li, Department of Dermatology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China, Tel +86 15210866656, Email chengxinderm@163.comPurpose: Metformin (MET) has been proved to be effective for the treatment of psoriasis. The mechanisms of its action under the hyperlipidemia have yet to be fully elucidated. Here, we investigated the effect of metformin on the cell proliferation induced by hyperlipidemia and the underlying mechanism in immortalized human keratinocyte cell line (HaCat).Methods: Wild-type or FOXO3 knockdown HaCat cells were treated with free fatty acids (FFA) for 10 days and then co-treated with metformin for another 4 days. Triglyceride (TG) level, cell viability, proliferation, apoptosis, antioxidant enzymes, reactive oxygen species (ROS) levels, as well as the transcription activity of FOXO3 were analyzed.Results: Metformin decreased HaCaT cell proliferation and induced cell apoptosis after FFA treatment. Metformin was found to significantly increase the expressions and the activities of superoxide dismutase (SOD) as well as catalase (CAT), and reduced the reactive oxygen species (ROS) level. Metformin significantly promoted the autophagy and increase FOXO3 protein level in the nucleus under hyperlipidemia. However, all of the effects from metformin were partially blocked by FOXO3 knockdown.Conclusion: This study demonstrated that under the hyperlipidemia, metformin has significant antiproliferation and proapoptosis effects by reducing ROS level as well as increasing autophagy. All of these effects from metformin were through FOXO3-dependent pathway.Keywords: reactive oxygen species, ROS, apoptosis, autophagy, forkhead box O3, FOXO3

Liya Fu,1,2,&ast; Wanlong Zhu,1,2,&ast; Dongmei Tian,1,2 Yong Tang,2,3 Yun Ye,1 Qiming Wei,1 Chengbin Zhang,1 Wenqiao Qiu,2 Dalian Qin,2 Xuping Yang,1,2 Yilan Huang1,2 1Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2School of Pharmacy, Southwest Medical University, Luzhou, People’s Republic of China; 3State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, 999078, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuping Yang; Yilan Huang, Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China, Email yangxuping6552@163.com; lzyxyyxp123@163.comPurpose: Anoectochilus roxburghii (Wall.) Lindl. polysaccharides (ARPs) have been reported to exhibit multiple pharmacological activities including anti-inflammatory and anti-hyperglycemia. This study aims to investigate the effect of ARPs on cognitive dysfunction induced by high fat diet (HFD).Methods: Six-week-old male mice were treated with ARPs by dietary supplementation for 14 weeks. The effect of ARPs on cognitive function was determined by assessing the changes in spatial learning and memory ability, neurotrophic factors in hippocampus, inflammatory parameters, intestinal barrier integrity, and gut microbiota.Results: ARPs supplementation can effectively ameliorate cognitive dysfunction, decrease the phosphorylation levels of Tau protein in hippocampus. Meanwhile, the increased body weight, plasma glucose, total cholesterol, inflammatory factors induced by HFD were abolished by ARPs treatment. Furthermore, ARPs treatment restored the intestinal epithelial barrier as evidenced by upregulation of intestinal tight junction proteins. Additionally, ARPs supplementation significantly decreased the relative abundance of several bacteria genus such as Parabacteroides, which may play regulatory roles in cognitive function.Conclusion: These results suggest that ARPs might be a promising strategy for the treatment of cognitive dysfunction induced by HFD. Mechanistically, alleviation of cognitive dysfunction by ARPs might be associated with the “gut-brain” axis.Graphical Abstract: Keywords: Anoectochilus roxburghii (Wall.) Lindl. polysaccharides, diet-induced-obesity, cognitive dysfunction, gut microbiota, “gut-brain” axis

Yue Li,&ast; Dalei Zhou,&ast; Qing Liu, Weijie Zhu, Zulu Ye, Caiyun He Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Caiyun He; Zulu Ye, Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, No. 651, Dongfeng Road, Yuexiu District, Guangzhou, 510060, People’s Republic of China, Tel +86-18665593050 ; +86-15017590433, Fax +20-87340921, Email hecy@sysucc.org.cn; yezl@sysucc.org.cnPurpose: Fat mass and obesity-associated protein (FTO) and AlkB homolog 1 (ALKBH1) are m6A demethylases that have been demonstrated to be associated with the overall survival of patients with gastric cancer (GC). This study investigates the influence of genetic variants of FTO and ALKBH1 on susceptibility to GC.Patients and Methods: Potentially functional single nucleotide polymorphisms (SNPs) of FTO and ALKBH1 were genotyped in 419 patients with GC and 569 healthy controls by Kompetitive allele-specific PCR.Results: The AG and AG/AA variants of FTO rs2287142 were significantly associated with a decreased GC risk (for AG/AA vs GG: adjusted OR = 0.73, p = 0.020). The GA and GA/GG variants of ALKBH1 rs1076496 were closely correlated with an increased risk of GC in people aged ≥ 55 years (for GA/GG vs AA: adjusted OR = 1.51, p = 0.041) but showed a decreasing tendency of risk of GC in people aged < 55 years (adjusted OR = 0.85, p = 0.444). FTO rs2287142 and ALKBH1 rs1076496 conformed to the principle of a dominant model. FTO haplotype rs1421091-rs1421092-rs2287142-rs9939609 CTAT was closely associated with a lower risk of total GC (adjusted OR = 0.62, p = 0.023), while CTGA was linked with an increased risk of intestinal GC (adjusted OR = 2.51, p = 0.005). ALKBH1 rs1048147-rs1076496-rs11159286 CAC haplotype was significantly associated with a decreased risk of GC in people aged ≥ 55 years (adjusted OR = 0.41, p = 0.008). The FTO rs2287142-rs9939609 AG/AA-TT combination was associated with a decreased risk of GC only in the presence of rs1421091 TC/TT (adjusted OR = 0.70, p = 0.047), demonstrating that these FTO SNPs might have a cooperative effect on susceptibility to GC.Conclusion: FTO and ALKBH1 SNPs may have predictive value in evaluating susceptibility to GC with differing age or Lauren classification.Keywords: FTO, ALKBH1, gastric cancer, susceptibility, Lauren classification

Haoqiang Zhang,1– 3,&ast; Shufang Yang,2,4,&ast; Wenwen Zhu,1,2 Tong Niu,1,2 Zheng Wang,1,2 Ke An,1,2 Zuoling Xie,1,2 Pin Wang,2 Xi Huang,1,2 Chenchen Wang,1,2 Haiyan Shangguan,2 Yang Yuan,1 Shaohua Wang1 1Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, Nanjing, People’s Republic of China; 2School of Medicine, Southeast University, Nanjing, People’s Republic of China; 3Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, People’s Republic of China; 4Department of Endocrinology, Taizhou People’s Hospital, Taizhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaohua Wang; Yang Yuan, Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, People’s Republic of China, Tel +86-25-83262815 ; +86-13814003661, Fax +86-25-83285132, Email gyjwsh@126.com; yang_yuan000@sina.comPurpose: We aim to determine the role of free triiodothyronine (FT3), the main active ingredient of thyroid hormones (THs), in type 2 diabetes mellitus (T2DM) patients with mild cognitive impairment (MCI).Patients and Methods: A total of 255 T2DM patients without diagnosed thyroid diseases were recruited and divided into MCI group and healthy cognition group. Neuropsychological functions were observed by multidimensional cognitive function scales in including MoCA, Digit Span Test (DST), Verbal Fluency Test (VFT), Clock drawing test (CDT), Trail Making Test (TMT) A and B, Instantaneously Recalled Auditory Verbal Learning Test (AVLT-IR), Delayed Recalled Auditory Verbal Learning Test (AVLT-DR) and Logical Memory Test (LMT). Correlation and logistic regression analyses were performed to explore the association between FT3 and diabetic cognitive dysfunction.Results: Compared with 147 normal cognition patients, 108 MCI patients exhibited lower FT3 and higher HOMA-IR. FT3 level was not only positively correlated with MoCA scores, but DST, VFT and LMT, while negatively associated with TMTB. Furthermore, there is a negative association between FT3 and HOMA-IR. Logistic regression showed that decreased FT3 is a risk factor of MCI in T2DM patients. Although FT3 is not the risk factor of MCI after homeostasis model assessment of insulin resistance (HOMA-IR) was entered as an independent variable, lower FT3 is associated with VFT and LMT adjusted by age, education, BMI, DM duration, HBP duration, smoking, HbA1c and HOMA-IR.Conclusion: Lower FT3 levels may involve in MCI, especially for executive function and scene memory in T2DM patients without diagnosed thyroid diseases.Keywords: free triiodothyronine, mild cognitive impairment, insulin resistance, type 2 diabetes mellitus

Xiangji Wang,1 Qilong Cao,2 Shen Wu,3 Mohammad Reza Bahrani Fard,4 Ningli Wang,3 Jie Cao,1 Wei Zhu1,5 1School of Pharmacy, Qingdao University, Qingdao, People’s Republic of China; 2Qingdao Haier Biotech Co. Ltd, Qingdao, People’s Republic of China; 3Beijing Tongren Hospital Eye Center, Capital Medical University, Beijing, People’s Republic of China; 4George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; 5Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University & Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Wei Zhu; Jie Cao, Email wzhu@qdu.edu.cn; caojie0829@qdu.edu.cnPurpose: Transplantation of stem cells to remodel the trabecular meshwork (TM) has become a new option for restoring aqueous humor dynamics and intraocular pressure homeostasis in glaucoma. In this study, we aimed to design a nanoparticle to label induced pluripotent stem cell (iPSC)-derived TM and improve the delivery accuracy and in vivo tracking efficiency.Methods: PLGA-SPIO-Cypate (PSC) NPs were designed with polylactic acid-glycolic acid (PLGA) polymers as the backbone, superparamagnetic iron oxide (SPIO) nanoparticles, and near-infrared (NIR) dye cypate. In vitro assessment of cytotoxicity, iron content after NPs labeling, and the dual-model monitor was performed on mouse iPSC-derived TM (miPSC-TM) cells, as well as immortalized and primary human TM cells. Cell function after labeling, the delivery accuracy, in vivo tracking efficiency, and its effect on lowering IOP were evaluated following miPSC-TM transplantation in mice.Results: Initial in vitro experiments showed that a single-time nanoparticles incubation was sufficient to label iPSC-derived TM and was not related to any change in both cell viability and fate. Subsequent in vivo evaluation revealed that the use of this nanoparticle not only improves the delivery accuracy of the transplanted cells in live animals but also benefits the dual-model tracking in the long term. More importantly, the use of the magnet triggers a temporary enhancement in the effectiveness of cell-based therapy in alleviating the pathologies associated with glaucoma.Conclusion: This study provided a promising approach for enhancing both the delivery and in vivo tracking efficiency of the transplanted cells, which facilitates the clinical translation of stem cell-based therapy for glaucoma.Graphical Abstract: Keywords: magnetic fluorescent nanoparticle, induced pluripotent stem cell, trabecular meshwork, in vivo monitoring, specific targeting

Lu Chen,1 Shan-Yong Zhou,2 Wei Zhu,3 Sheng-Ping Liu,4 Jing-Xi Zhang,5 He Zhuang,5 Jing-Ling Zhang,5 Yong-Sheng Li,6 Fei Gao4 1Department of paediatrics, Fujian Maternity and Child Health Hospital, Fuzhou, 350000, People’s Republic of China; 2Fujian Key Laboratory of Nanomaterials, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350002, People’s Republic of China; 3Department of Urology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, People’s Republic of China; 4Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China; 5Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China; 6Department of Urology, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of ChinaCorrespondence: Fei Gao; Yongsheng Li, Tel/Fax +86 591-83357896-8242, Email xuzhougaofei@126.com; Lysdr163@163.comIntroduction: Cardiac troponin I (cTnI) has been regarded as a gold standard for early diagnosis and prognosis monitoring of acute myocardial infarction (AMI) in clinical practice. Owing to its low concentration in blood, accurate determination of cTnI often requires high sensitivity. However, current established point-of-care (POC) assays are insufficient to meet clinically analytical requirements due to their low sensitivity.Methods: To this end, we established a highly sensitive and reliable POC lateral flow strip based on lanthanide-doped nanoparticles (NPs) for cTnI determination in human blood samples. The capture of cTnI on the lateral flow strip was performed in a sandwich assay, where Eu3+-doped vanadate nanoparticles (GdVO4:30% Eu NPs) were used as luminescent probes to allow quantification.Results: Our platform realized the analytical sensitivity enhancement with limit-of-detection (LOD) as low as 17 pg mL− 1 for cTnI detection, which was lower than the commercial counterpart; meanwhile, it displayed high specificity, excellent reproducibility and outstanding accuracy for analyzing clinical serum samples.Conclusion: Overall, this strategy provided an ultrasensitive, cost-effective and user-friendly platform for on-site cTnI detection, demonstrating the prospect of lanthanide-doped NPs-based POC diagnosis of disease-related biomarkers.Keywords: cardiac troponin I, GdVO4:30% Eu NPs, lateral flow test strip, point-of-care test

Zhibo Chen,1 Dewei Xie,1 Yun Li,1 Zebin Dai,2 Saina Xiang,2 Zhiyuan Chen,2 Weiqian Zhu1 1Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China; 2College of the First Clinical Medical Sciences of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Weiqian ZhuDepartment of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, People’s Republic of ChinaTel +86 577 55579372Fax +86 577 55579318Email zhuwqfyxy@aliyun.comObjective: The novel biomarker, neutrophil percentage-to-albumin ratio (NPAR), as a prognostic tool for inflammation in relation to all-cause mortality for patients afflicted by strokes has yet to be explored.Methods: Data sets associated with patient files stored within the MIMIC-III V1.4 database were obtained. Data files from 940-patients were obtained for this retrospective analysis. Clinical endpoints were determined to represent a month (30-), three months (90-) and year (365-) all-cause mortality in stroke patients were determined. In order to determine NPAR and clinical endpoint relationships, Cox proportional hazards models were utilized.Results: For all-cause mortality within a 30-day period, in an unadjusted model, the HR (95% CIs) in group B (NPAR 20.5– 25.0) and C (NPAR > 25.0) was 1.17 (0.85, 1.63) and 1.55 (1.13, 2.11) compared with group A (NPAR < 20.5). Proceeding adjustment for more confounding factors, higher NPAR still obtained significant predictive power for 30-day all-cause mortality (HR= 1.45, 95% CI: 1.05, 2.00). Statistical significance (P = 0.0196) was also observed for the other time-based subgroupings for all-cause mortality.Conclusion: A strong correlation was present between increased levels of the novel biomarker NPAR and increased risk of mortality in stroke patients.Keywords: neutrophil-albumin ratio, mortality, stroke, biomarker

Wenfang Zhu,1,&ast; Yao Ma,2,&ast; Wen Guo,1 Jing Lu,1 Xiaona Li,1 Juan Wu,1 Pei Qin,1 Chen Zhu,1 Qun Zhang1 1Department of Health Management Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China; 2Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qun Zhang Tel +86 25 68303925Fax +86 25 68303925Email lucyqzhang@126.comIntroduction: Lactate dehydrogenase (LDH) is an important oxidoreductase in the anaerobic metabolic pathway. The role of LDH in arterial stiffness (AS) and 10-year cardiovascular disease (CVD10) risk has not been established.Methods: This retrospective, cross-sectional, and observational study evaluated the relationships between the LDH level and AS and CVD10 risk in 12,597 health-examined people (6988 men and 5609 women; mean age, 49.49 years) in China. Brachial–ankle pulse wave velocity (baPWV) was used to estimate AS. The Framingham CVD 10-year risk prediction model was used to calculate the CVD10 risk score.Results: In both sexes, an increased LDH level was associated with increased AS and CVD10 (men: β = 0.032, P < 0.001; women: β = 0.025, P < 0.001). Half of the population with a high LDH level (≥ 172 U/L) showed significantly increased AS and CVD10 risk score. Men and women with baPWV ≥ 1400 cm/s had a higher LDH level, and the latter was significantly different from that of the group with baPWV < 1400 cm/s (men: 176.93± 30.99 vs 173.00± 33.36, P < 0.001; women: 189.10± 34.20 vs 171.39± 31.08, P < 0.001). In both sexes, a higher level of LDH was noted in groups with higher CVD10 risk score (men: 176.65± 32.51 vs 172.94± 32.46, P < 0.001; women: 202.51± 44.05 vs 175.73± 32.39, P < 0.001).Discussion: An increased LDH level may be associated with AS and CVD10 risk. The LDH level could be a new predictor of AS and CVD10 risk in health-examined populations.Keywords: lactate dehydrogenase, arterial stiffness, 10-year cardiovascular disease risk, brachial–ankle pulse wave velocity, Framingham CVD 10-year risk prediction model

Li Wang, Na Zhao, Li Zhou, Juan Tong, Lei Xue, Lei Zhang, Yongsheng Han, Xingbing Wang, Liangquan Geng, Baolin Tang, Huilan Liu, Weibo Zhu, Xiaoyan Cai, Xin Liu, Xiaoyu Zhu, Zimin Sun, Changcheng Zheng Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of ChinaCorrespondence: Changcheng ZhengDepartment of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Lujiang Road No. 17, Hefei, 230001, People’s Republic of ChinaTel/Fax +86-551-62284476Email zhengchch1123@ustc.edu.cnBackground: There is great uncertainty in the treatment of elderly patients with acute myeloid leukemia (AML), which leads to great challenges in treatment decision. The aim of this study is to find more suitable induction therapy and consolidation therapy for elderly AML patients.Methods: A total of 149 consecutive newly diagnosed elderly AML patients (aged ≥ 60 years) who received induction chemotherapy in our medical center from January 2015 to December 2019 were retrospectively analyzed.Results: After the first induction treatment, the complete remission/or complete remission with incomplete hematologic recovery (CR/CRi) rates in the standard-intensity chemotherapy group was significantly higher than that in the low-intensity chemotherapy group (58.2% vs 32.9%, p = 0.003). Compared with the low-intensity chemotherapy, the incidence of severe infection in the standard-intensity chemotherapy was significantly increased (p < 0.001), but the early mortality was comparable. One hundred and seven patients received minimal residual disease (MRD) examination after the first induction treatment; and MRD was negative accounting for 51.9% in the standard-intensity chemotherapy group, while only 32.7% in the low-intensity group (p = 0.05). The 2-year-overall survival (OS) of patients in standard-intensity induction chemotherapy group (37.2%) was slightly higher than that in low-intensity induction chemotherapy group (23.4%) (p = 0.075). Eighty-one CR/CRi patients received intermediate or high dose cytarabine (n = 35) or sequential chemotherapy regimens (n = 46) as consolidation treatment. The 2-year OS and event-free survival (EFS) of patients in the intermediate or high-dose cytarabine group were significantly higher than those in the sequential chemotherapy regimens group (73.0% vs 38.5%, p = 0.002; 54.8% vs 35.0%, p = 0.035).Conclusion: Our results showed that standard-intensity induction chemotherapy can significantly improve the CR rate for elderly AML patients, and does not increase the early mortality; consolidation therapy with intermediate or high-dose cytarabine can significantly improve EFS and OS for elderly AML patients achieved CR.Keywords: acute myeloid leukemia, elderly patients, minimal residual disease, standard-intensity chemotherapy, intermediate or high dose cytarabine

Lingwen Ying,1,&ast; Yong Zhang,2,&ast; Jun Yin,1,&ast; Yufei Wang,1 Wei Lu,1 Wei Zhu,1 Yuqian Bao,1 Jian Zhou1 1Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Clinical Center for Diabetes; Shanghai Diabetes Institute; Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, 200233, People’s Republic of China; 2Department of Immunology and Microbiology, Shanghai Jiao Tong University, School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian ZhouDepartment of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai, 200233, People’s Republic of ChinaTel +86-21-64369181Fax +86-21-64368031Email zhoujian@sjtu.edu.cnPurpose: We aimed to explore the immunological characteristics and cytokine profile of the initial stage of type 1 diabetes.Patients and Methods: In total, 123 age- and sex-matched subjects with newly diagnosed classic type 1 diabetes mellitus (T1ADM), fulminant type 1 diabetes mellitus (FT1DM), and normal glucose tolerance (NGT) were enrolled. Serum cytokine levels were measured using Milliplex MAP multifactor detection.Results: There was a significant increase in the levels of transforming growth factor β (TGFβ 1) and TGFβ 2 and decrease in programmed death-1 (PD-1), PD ligand 1 (PD-L1), pro-inflammatory cytokines, and anti-inflammatory cytokines in type 1 diabetes patients compared with the NGT subjects (all P < 0.05). There was no significant difference in C-reactive protein (CRP) and blood routine indicators between the two groups. Type 1 diabetes was further divided into T1ADM and FT1DM subgroups. FT1DM patients had much higher CRP levels than T1ADM patients (4.90 [0.95– 26.05] mg/L vs 0.39 [0.20– 0.74] mg/L, P < 0.01). Blood routine results showed that the number of leukocytes was significantly increased in FT1DM compared with that in T1ADM (9.2 [5.1– 18.8] × 109 cells/L vs 5.4 [4.5– 6.7] × 109 cells/L, P < 0.01). In FT1DM patients, neutrophil% was increased, and lymphocyte% was declined significantly, compared with that in T1ADM patients (neutrophil%: 80.2 [59.2– 85.2]% vs 59.5 [54.8– 64.0]%; lymphocyte%: 18.3 [10.1– 32.3]% vs 32.6 [26.8– 35.9]%; both P < 0.01). However, there was no difference between FT1DM and T1ADM in cytokine profile except for the decrease in CTLA-4 in T1ADM (P < 0.05).Conclusion: Compared with T1ADM, CRP and leukocytes’ levels were increased significantly in FT1DM, with an increase in neutrophil% and decline in lymphocyte%, suggesting that FT1DM may have more abrupt onset and occur as a more serious subtype of type 1 diabetes mellitus.Keywords: cytokine profile, fulminant type 1 diabetes mellitus, immune response, multifactor detection, type 1 diabetes mellitus

Wenjun Peng,1,&ast; Yuanyuan Wu,1,&ast; Ge Zhang,1,&ast; Wensi Zhu,1,&ast; Meijia Chang,1 Ainiwaer Rouzi,1 Weipeng Jiang,1 Lin Tong,1 Qin Wang,1 Jie Liu,1 Yuanlin Song,1– 4 Huayin Li,1 Ka Li,5 Jian Zhou1– 4 1Department of Pulmonary and Critical Care Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, 200540, People’s Republic of China; 3Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai, 200032, People’s Republic of China; 4Shanghai Engineering Research Center of Internet of Things for Respiratory Medicine, Shanghai, 200032, People’s Republic of China; 5Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian ZhouDepartment of Pulmonary and Critical Care Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of ChinaEmail zhou.jian@fudan.edu.cnKa LiInstitute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of ChinaEmail li.ka@zs-hospital.sh.cnBackground: Chronic obstructive pulmonary disease (COPD) is a major health problem associated with high mortality worldwide. Cigarette smoke (CS) exposure is the main cause of COPD. Glioma pathogenesis-related protein 1 (GLIPR1) plays a key role in cell growth, proliferation, and invasion; however, the role of GLIPR1 in COPD remains unclear.Methods: To clarify the involvement of GLIPR1 in COPD pathogenesis, Glipr1 knockout (Glipr1-/-) mice were generated. Wild-type (WT) and Glipr1-/- mice were challenged with CS for 3 months. To illustrate how GLIPR1 regulates CS-induced airway damage, knockdown experiments targeting GLIPR1 and PLAU, as well as overexpression experiments of PLAU, were performed with human bronchial epithelial cells.Results: Compared with WT mice, Glipr1-/- mice showed exacerbated CS-induced airway damage including lung inflammation, airway wall thickening, and alveolar destruction. After CS exposure, total proteins, total white cells, neutrophils, lymphocytes, IL-6, and matrix metalloproteinase-9 increased significantly in lung of Glipr1-/- mice than those in lung of WT mice. Furthermore, in vivo and in vitro experiments demonstrated that silencing of GLIPR1 inactivated PLAU/EGFR signaling and promoted caspase-1-dependent pyroptosis (a mode of inflammatory cell death) induced by CS and CS extract exposure, respectively. In vitro experiments further revealed the interaction between GLIPR1 and PLAU, and silencing of PLAU blocked EGFR signaling and promoted pyroptosis, while overexpression of PLAU activated EGFR signaling and reversed pyroptosis.Conclusion: To conclude, GLIPR1 played a pivotal role in COPD pathogenesis and protected against CS-induced inflammatory response and airway damage, including cell pyroptosis, through the PLAU/EGFR signaling. Thus, GLIPR1 may play a potential role in COPD treatment.Keywords: chronic obstructive pulmonary disease, cigarette smoke, GLIPR1, PLAU, pyroptosis

ZhaoHui Xu,1,2 Hui Qu,1,2 YanYing Ren,1 ZeZhong Gong,1,2 Hyok Ju Ri,1– 3 Fan Zhang,1 XiaoLiang Chen,1 WanJi Zhu,1 Shuai Shao,1 Xin Chen1 1Department of Hernia and Colorectal Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, People’s Republic of China; 2Dalian Medical University, Dalian, People’s Republic of China; 3Department of Colorectal Surgery, The Hospital of Pyongyang Medical College, Pyongyang, 999093, People’s Republic of KoreaCorrespondence: Xin Chen Tel +86 17709872266Email chenxincjz@gmail.comBackground: The coronavirus disease 2019 (COVID-19) pandemic is ravaging the world. To date, there are no standard therapies available to cure the disease. Consequently, research on COVID-19 vaccines is booming. This report aimed to assess the research trends of the global COVID-19 vaccines.Methods: The relevant publications on the COVID-19 vaccines were searched in the Web of Science Core Collection Database (WOSCC) database from December 2019 to 11 August 2021. The VOSviewer1.6.16 was used to assess the co-authorship, co-occurrence, citation of countries, institutions, authors, journals, and hotspot keywords. The HistCiteTM (http://www.histcite.com/) software was used to calculate the total local citation score (TLCS) and total global citation score (TGCS) of each variable and generate the citation historiography graph of COVID-19 vaccine development using the citation time series analysis method.Results: A total of 5070 studies authored by 21,151 researchers and published by 1364 different journals were eventually included in this study. The bulk of the retrieved studies were original articles (n = 2401, 47.36%). Among these studies, 1204 (23.75%) were published in 2020. A total of 3863 (76.19%) were published in 2021 and 4295 (84.71%) were open access. The highest number of studies was conducted in the USA, followed by England, China, and Germany. The main partners of the USA were China, England, and Canada. The University of Maryland (TLCS: 1618, TGCS: 2991) and Prof. Ugur Sahin from the University Medical Center of the Johannes Gutenberg University (TLCS: 1397, TGCS: 2407) were the most cited institution and author, respectively. The vaccines featured the highest number of papers, with 294 publications (TLCS: 0, TGCS: 1226). The most cited journal was the New England Journal of Medicine (TLCS: 3310, TGCS: 5914), with an impact factor (IF) of 91.245. The related topics included the following six aspects: attitudes towards vaccination, immunoinformatics analysis, clinical research, effectiveness and side effects, and the public management of vaccines. The timing diagram revealed that the research hotspots focused on the side effects of vaccines and public attitude towards vaccination.Conclusion: This novel comprehensive bibliometric analysis can help researchers and non-researchers to rapidly identify the potential partners, landmark studies, and research topics within their domains of interest. Through this study, we hope to provide more data to combat the COVID-19 pandemic.Keywords: bibliometric analysis, COVID-19, vaccines

Zhenhui Zhou,1,&ast; Meng Mao,2,&ast; Xuechun Cai,1 Wei Zhu,1 Jie Sun3 1Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Anesthesiology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 3Department of Anesthesiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie SunDepartment of Anesthesiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, People’s Republic of ChinaTel +8615895971012Email dgsunjie@hotmail.comWei ZhuDepartment of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210009, People’s Republic of ChinaTel +8618905182820Email zhuweijsph@163.comPurpose: The mechanisms of remifentanil-induced postoperative hyperalgesia (RIPH) remain unclear. Store-operated calcium channels (SOCCs) are mainly comprised of stromal interaction molecules 1 (STIM1) and pore-forming subunits (Orai1). They were found to take a pivotal part in Ca2+-dependent procedures and involved in the development of central sensitization and pain. Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα), regulated by Ca2+/calmodulin complex, has been shown to have a crucial role in RIPH. This study aims to determine whether SOCCs contribute to RIPH via activating CaMKIIα.Materials and Methods: Intra-operative infusion of remifentanil (1.0 μg kg− 1 min− 1, 60 min) was used to establish a RIPH rat model. The SOCCs blocker (YM-58483) was applied intrathecally to confirm the results. Animal behavioral tests including paw withdrawal thermal latency (PWTL) and paw withdrawal mechanical threshold (PWMT) were performed at − 24, 2, 6, 24, 48 h after incision and remifentanil treatments. The protein expression of STIM1, Orai1, CaMKIIα, and p-CaMKIIα was assayed with Western blot, and the number of STIM1 and Orai1 positive cells was shown by immunofluorescence.Results: Remifentanil administration significantly induced postoperative mechanical and thermal hyperalgesia, as well as increased STIM1 and Orai1 protein expression in the spinal dorsal horn. Furthermore, the intrathecal administration of YM-58483 effectively alleviated remifentanil-induced postoperative mechanical and thermal hyperalgesia according to the behavioral tests. In addition, YM-58483 suppressed the phosphorylation of CaMKIIα but had no effect on the expression of STIM1 and Orai1.Conclusion: Our study demonstrated that SOCCs are involved in RIPH. The over-expressed STIM1 and Orai1 in the spinal cord contribute to RIPH via mediating the phosphorylation of CaMKIIα. Blockade of SOCCs may provide an effective therapeutic approach for RIPH.Keywords: remifentanil, hyperalgesia, SOCCs, CaMKII&#x03B1

Chenchen Wang,1,2 Demei Ye,1 Zuoling Xie,1,2 Xi Huang,1 Zheng Wang,2 Haiyan Shangguan,2,3 Wenwen Zhu,2 Shaohua Wang1 1Department of Endocrinology, The Affiliated ZhongDa Hospital of Southeast University, Nanjing, 210009, People’s Republic of China; 2School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China; 3Nanjing Central Hospital, Nanjing, 210008, People’s Republic of ChinaCorrespondence: Shaohua WangDepartment of Endocrinology, The Affiliated ZhongDa Hospital of Southeast University, Nanjing, 210009, People’s Republic of ChinaTel +86 25 83262810Fax +86 25 83285132Email gyjwsh@126.comPurpose: In addition to hyperglycemia and hyperlipidemia, obesity and hypertension are important cardiovascular risk factors for coronary heart disease (CHD) in patients with type 2 diabetes mellitus (T2DM). This study aims to explore the interaction of these risk factors.Patients and Methods: Data of hospitalized patients with T2DM from 2013 to 2018 were collected. A multivariate logistic regression model was established. Patients with normal weight and blood pressure were recruited as controls. The interaction on the risk of CHD was evaluated by relative excess risk due to interaction (RERI).Results: Among the 30,693 patients with T2DM, 7202 (23.5%) had CHD. In the low weight group, the prevalence of CHD in patients with hypertension was nearly four times higher than that in patients without hypertension (42.7% vs 11.3%, P < 0.01). The OR value of hypertension alone on CHD increased from 1.29 (95% CI 1.06– 1.56) in the body mass index (BMI) 30.0– 34.9 kg/m2 group to 1.35 (95% CI 1.11– 1.62) in the BMI ≤ 18.5 kg/m2 group. Additive interaction was observed between hypertension and BMI in CHD risk, especially in the low weight group (RERI:2.2, 95% CI 0.9– 3.5). BMI and CHD risk showed a smile curve relationship. The attributive proportion in the low weight group was higher than that in the severe obesity group, that is, 0.52 (95% CI 0.35– 0.69) vs 0.18 (95% CI − 0.59 to 0.95).Conclusion: Maintaining normal weight and avoiding low weight are particularly important for patients with co-occurring diabetes and hypertension to prevent the risk of CHD.Keywords: type 2 diabetes, cardiovascular, hypertension, body mass index, interaction

Hua Jiang,1,2 Lili Li,3 Jing Liu,1 Bin Xu,1 Shuqiu Chen,1 Weidong Zhu,1 Ming Chen1 1Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, People’s Republic of China; 2Department of Medical College, Southeast University, Nanjing, 210009, People’s Republic of China; 3Department of Periodontology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210009, People’s Republic of ChinaCorrespondence: Ming Chen; Shuqiu ChenDepartment of Urology, Affiliated Zhongda Hospital of Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, 210009, People’s Republic of ChinaTel/Fax +86-13913009977; Tel/Fax +86-15951815171Email mingchenseu@126.com; chenshuqiuseu@163.comBackground: Triglyceride–glucose (TyG) index has been considered as the reliable marker of insulin resistance (IR), which is one risk factor of kidney stone. This study aimed to evaluate the TyG index in the occurrence of kidney stones among the United States (US) population.Methods: Participants who received assessment were retrieved from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2018. The logistic regression analysis was conducted to assess the relationship between the TyG index and kidney stones occurrence. A 1:1 matched-pair analysis was established to optimize the bias in kidney stones by propensity score matching (PSM). The dose–response curve was performed to verify the association between the TyG index and risk of kidney stones.Results: Of the 14,158 eligible enrolled participants, 1346 (9.5%) self-reported a history of kidney stones. All participants were divided into two groups (high TyG index group and low TyG index group) based on the median TyG index. The dose–response curve exhibited a positive non-linear correlation between the TyG index and kidney stones risk. High TyG index was related to increased kidney stones occurrence in participants, with adjusted odds ratios (AOR) of 1.14 (95% confidence intervals (CI): 1.01– 1.30, P = 0.038) compared with the low TyG index subgroup before PSM. After PSM, the risk of kidney stones was 19% higher in the high TyG group compared with the low TyG group (AOR = 1.19, 95% CI: 1.02– 1.38, P = 0.026), and the dose–response curve still showed a positive association between TyG index and kidney stone risk.Conclusion: The TyG index was independently associated with kidney stones and would be a novel biomarker in predicting occurrence for clinical decision.Keywords: kidney stone, triglyceride–glucose index, insulin resistance, cross-sectional, National Health and Nutrition Examination Survey

Yalin Cheng, Ke Chai, Wanrong Zhu, Yuhao Wan, Yaodan Liang, Minghui Du, Yingying Li, Ning Sun, Jiefu Yang, Hua Wang Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Hua WangDepartment of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaTel/Fax +86-10-85133852Email wanghua2764@bjhmoh.cnPurpose: Elderly heart failure (HF) patients have different clinical characteristics and poorer prognosis compared with younger patients. Prognostic risk scores for HF have not been validated well in elderly patients. We aimed to validate the Seattle Heart Failure Model (SHFM) and the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score in an elderly Chinese HF cohort.Patients and Methods: This retrospective study enrolled 675 elderly HF patients (age≥ 70 years) discharged from our hospital between 2012 and 2017. The performance of the two risk scores was evaluated in terms of discrimination, using receiver-operating characteristic analysis, and calibration using a calibration plot and Hosmer–Lemeshow (H-L) test. Absolute risk reclassification was used to compare the two scores.Results: During the mean follow-up time of 32.6 months, 193 patients (28.6%) died, and 1-year mortality was 10.5%. The predicted median 1-year mortality was 8% for the SHFM and 18% for the MAGGIC score. A Kaplan–Meier survival curve demonstrated that event rates of all-cause mortality significantly increased with increasing SHFM and MAGGIC scores. The discriminatory capacity of the SHFM was greater than that of the MAGGIC score (c-statistics were 0.72 and 0.67, respectively; P = 0.05). The calibration plot for the SHFM was better than that for MAGGIC score for 1-year mortality (SHFM: H-L χ2 =8.2, P = 0.41; MAGGIC: H-L χ2 =18.8, P =0.02). Compared with the MAGGIC score, the net reclassification index (NRI) of the SHFM was 2.96% (Z=5.88, P< 0.0001).Conclusion: The SHFM performs better than MAGGIC score, having good discrimination, calibration and risk classification for the prediction of 1-year mortality in elderly Chinese HF patients.Keywords: heart failure, risk score, prognosis, elderly patient