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Minmin Shen,1– 3,* Qiaojing Lin,1,2,* Xi Zou,1– 3 Yufan Wu,1,2 Zhihong Lin,1,2 Linglong Shao,1,2 JinSheng Hong,1– 3 Jinmei Chen1– 3 1Department of Radiotherapy, Cancer Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 2Department of Radiotherapy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, People’s Republic of China; 3Key Laboratory of Radiation Biology of Fujian Higher Education Institutions, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China*These authors contributed equally to this workCorrespondence: JinSheng Hong; Jinmei Chen, Department of Radiotherapy, Cancer Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China, Email hjs703@126.com; cjm1303@126.comPurpose: The aim of the present study was to assess the clinical outcomes and prognostic factors of lung adenocarcinoma patients with brain metastases (BMs) after intracranial local therapy.Patients and Methods: A total of 83 lung adenocarcinoma patients with BMs who underwent craniotomy combined with radiotherapy or intracranial radiotherapy alone were retrospectively analyzed. The intracranial tumor response was determined according to the Response Assessment in Neuro-Oncology of Brain Metastases (RANO-BM) criteria. The median overall survival (OS), intracranial progression-free survival (iPFS), and related prognostic factors were analyzed with the Kaplan‒Meier estimator method and Cox proportional hazards regression model.Results: Among 83 patients, 20 patients received craniotomy combined with radiotherapy, and 63 patients received intracranial radiotherapy alone. Following intracranial local therapy, 11 patients (13.3%) achieved complete response (CR); among them, 8 patients underwent neurosurgical resection. In addition, 32 patients (38.55%) achieved partial response (PR), 32 patients (38.55%) experienced stable disease (SD), and 8 (9.6%) experienced progressive disease (PD). The median follow-up period was 25.4 months (range 0.8– 49.6 months). The median follow-up time for the iPFS was 16.2 months (range 0.6– 41.2 months). The median OS, iPFS were 28.2 months and 24.7 months. Epidermal growth factor receptor (EGFR) / anaplastic lymphoma kinase (ALK) mutations (HR 3.216, 95% confidence interval (CI) 1.269– 8.150, p = 0.014) and iPFS (HR 0.881, 95% CI 0.836– 0.929, p < 0.001) were found to be beneficial factors for OS. An intracranial-tumor CR was associated with a longer iPFS (PR: HR 0.052, 95% CI 0.009– 0.297, p = 0.001; SD: HR 0.081, 95% CI 0.025– 0.259, p < 0.001; PD: HR 0.216, 95% CI 0.077– 0.606, p = 0.004).Conclusion: Prolonged iPFS was associated with better OS in lung adenocarcinoma patients with BMs following intracranial local therapy, and mutations of EGFR / ALK or an intracranial-tumor CR are independent prognostic factors for prolonged survival.Keywords: lung adenocarcinoma, brain metastases, intracranial local therapy, survival, prognostic factors

Lixia Li,1,&ast; Xiaohui Huang,1,&ast; Jingxian Liu,2,&ast; Chao Li,1 Zhiyan Lin,1 Rongrong Ren,3 Yan Zhang,3 Haoshu Ding,3 Jihui Chen,1 Yanfei Mao3 1Department of Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Clinical Laboratory, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Anesthesiology and SICU, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanfei Mao; Jihui Chen, Email maoyanfei@xinhuamed.com.cn; chenjihui@xinhuamed.com.cnBackground: Polymyxin B (PMB)-based combination therapies are used to treat severe carbapenem-resistant gram-negative bacterial (CR-GNB) infections. This observational study investigated the relationship between clinical factors, including PMB concentration, and clinical efficacy and safety.Patients and Methods: Polymyxin B regimens were optimized through therapeutic drug monitoring (TDM) and area under the concentration-time curve (AUC). In all, 382 samples were tested from 130 patients. Logistic regression was used to analyze the relationships between variables with clinical efficacy and 30-day mortality factors were analyzed by Cox regression. The sensitivity and specificity of Cmin and AUC for the occurrence of acute kidney injury (AKI) were determined by ROC curve analysis.Results: The clinical effectiveness of PMB was 65.4%. Multivariate logistic regression analysis revealed that lung infection, continuous renal replacement therapy, and C-reactive protein were independent factors significantly associated with efficacy. AKI occurred in 14.6% of the patients during treatment; age > 73 years (OR: 3.63; 95% CI: 1.035– 12.727; P = 0.044), Cmin greater than 2.3 μg/mL (OR: 7.37; 95% CI: 1.571– 34.580; P = 0.011), combined vancomycin (OR: 9.47; 95% CI: 1.732– 51.731; P = 0.009), and combined piperacillin-tazobactam (OR: 21.87; 95% CI: 3.139– 152.324; P = 0.002) were independent risk factors. The identified PMB cut-offs for predicting AKI were Cmin = 2.3 μg/mL and AUC = 82.0 mg h/L.Conclusion: Polymyxin B-based combination regimens are effective in treating CR-GNB infections, particularly bloodstream infections, but have shown unsatisfactory for lung infections. Cmin ≥ 2.3 μg /mL and AUC ≥ 82.0 mg h/L may increase PMB-associated AKI incidence. PMB dose should be adjusted based on TDM to ensure efficacy.Keywords: Polymyxin B, PMB therapeutic drug monitoring, TDM, carbapenem-resistant gram-negative bacteria, CR-GNB, clinical efficacy, acute kidney injury, AKI

Yitao Zheng,1,2,&ast; Yanjun Xiang,3,&ast; Hongqi Shi,2,&ast; Zhuoqun Lin,2 Shuqun Cheng,3 Jiuting Zhu1 1Department of Pancreatic and Gastrointestinal Surgery Division, Ningbo No.2 Hospital, Ningbo, People’s Republic of China; 2Department of Hepatological Surgery, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuqun Cheng, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200433, People’s Republic of China, Email chengshuqun@smmu.edu.cn Jiuting Zhu, Department of Pancreatic and Gastrointestinal Surgery Division, Ningbo No.2 Hospital, 41 Xibei Street, Ningbo, People’s Republic of China, Email zhujtingnbey@163.comPurpose: Combining transarterial chemoembolization (TACE) with systemic therapy has shown significant efficacy for intermediate-stage hepatocellular carcinoma (HCC) patients. This study aimed to validate the therapeutic efficacy of TACE combined with atezolizumab and bevacizumab (TACE + Atez/Bev) compared to TACE alone.Methods: A retrospective study was conducted across three centers in China, encompassing 155 patients at the intermediate-stage of HCC. Propensity Score Matching (PSM) was used to minimize selection bias, with a ratio of 1:1. Primary outcomes were TACE-specific Progression-Free Survival (PFS) and Overall Survival (OS). Objective Response Rate (ORR) and Disease Control Rate (DCR) were assessed based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Adverse events (AEs) related to treatment were analyzed to evaluate safety.Results: Before PSM, the TACE + Atez/Bev group demonstrated extended median OS (not reached vs 20.3 months, P = 0.004) and PFS (20.0 months vs 9.8 months, P = 0.029) compared to the TACE-alone group. The TACE + Atez/Bev group also had a higher ORR (60.9% vs 41.3%, P = 0.026) and DCR (89.1% vs 58.7%, P < 0.001) than the TACE-alone group. After applying the PSM, the study included 42 pairs of patients. Compared to the TACE-alone group, the combination therapy group also showed significantly longer median OS (not reached vs 21.4 months, P = 0.008) and PFS (21.7 vs 9.7 months, P = 0.009). The combination therapy group also had a higher ORR (66.7% vs 38.1%, P = 0.009) and DCR (92.9% vs 57.1%, P < 0.001). AEs in the combination therapy group were mostly manageable, with the most common being elevated liver transaminase.Conclusion: In treating intermediate-stage HCC, the survival benefit of combining TACE with atezolizumab and bevacizumab was significantly higher than TACE alone, and the treatment was well-tolerated.Keywords: atezolizumab, bevacizumab, hepatocellular carcinoma, prognosis, transarterial chemoembolization

Yufeng Yao,1,2 Zhenli Lin,3 Baikang Ye,1 Tingxi Long,1,4 Suting Li,1,4 Huixian Liang,1,4 Tianyi Luo,1,4 Xiaoyan Dou1 1Department of Ophthalmology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, People’s Republic of China; 2Shantou University Medical College, Shantou, Guangdong Province, People’s Republic of China; 3Department of Ophthalmology, Shenzhen University General Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 4Shenzhen University Medical College, Shenzhen University, Shenzhen, Guangdong Province, People’s Republic of ChinaCorrespondence: Xiaoyan Dou, Department of Ophthalmology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, No. 3002 Sungang West Road, Futian District, Shenzhen, Guangdong Province, 518035, People’s Republic of China, Tel/Fax +86 13600169183, Email douxy08@163.comPurpose: Previous studies simply linearized the relationship between low density lipoprotein (LDL) and diabetic macular edema’s (DME) probability, ignoring the possibility of a nonlinear relationship between them. We aimed to investigate the nonlinear relationship between LDL and DME probability in patients with type 2 diabetes mellitus (T2DM).Patients and methods: The study recruited 431 T2DM patients who attended Guangdong Provincial People’s Hospital from December 2017 to November 2018. A multivariate logistic regression model was conducted to evaluate the association between LDL and DME probability. The nonlinear relationship was identified by generalized additive model. Subgroup analyses were performed to assess the consistency of the association in different subgroups.Results: LDL was positively associated with DME probability (OR=1.60, 95% CI: 1.10~2.34, P=0.0145) after adjusting for covariates. A nonlinear relationship between LDL and DME probability was discovered, with an inflection point for LDL around 4.85 mmol/L (95% CI: 4.18~4.93, P=0.037). The effect sizes and the confidence intervals on the left and right sides of inflection point were 2.17 (1.31 to 3.58) and 0.26 (0.04 to 1.77), respectively. Subgroup analyses revealed other variables had no effect on the association between them.Conclusion: Our finding suggested LDL was positively correlated with DME probability in T2DM patients. And the relationship between LDL and DME probability was nonlinear. Our findings need to be confirmed by further causal researches.Keywords: low density lipoprotein, diabetic macular edema, nonlinearity, association

Peng Zhou,1,2,&ast; Ling Li,3,&ast; Zehua Lin,1,2,&ast; Xiaoping Ming,1,2 Yiwei Feng,1,2 Yifan Hu,1,2 Xiong Chen1,2 1Department of Otorhinolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Sleep Medicine Centre, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 3Department of Nuclear Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiong Chen, Department of Otorhinolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan, Hubei, 430071, People’s Republic of China, Email zn_chenxiong@whu.edu.cnPurpose: The reciprocal comorbidity of obstructive sleep apnea (OSA) and body mass index (BMI) has been observed, yet the shared genetic architecture between them remains unclear. This study aimed to explore the genetic overlaps between them.Methods: Summary statistics were acquired from the genome-wide association studies (GWASs) on OSA (Ncase = 41,704; Ncontrol = 335,573) and BMI (Noverall = 461,460). A comprehensive genome-wide cross-trait analysis was performed to quantify global and local genetic correlation, infer the bidirectional causal relationships, detect independent pleiotropic loci, and investigate potential comorbid genes.Results: A positive significant global genetic correlation between OSA and BMI was observed (rg = 0.52, P = 2.85e-122), which was supported by three local signal. The Mendelian randomization analysis confirmed bidirectional causal associations. In the meta-analysis of cross-traits GWAS, a total of 151 single-nucleotide polymorphisms were found to be pleiotropic between OSA and BMI. Additionally, we discovered that the genetic association between OSA and BMI is concentrated in 12 brain regions. Finally, a total 134 expression-tissue pairs were observed to have a significant impact on both OSA and BMI within the specified brain regions.Conclusion: Our comprehensive genome-wide cross-trait analysis indicates a shared genetic architecture between OSA and BMI, offering new perspectives on the possible mechanisms involved.Keywords: genome-wide cross-trait analysis, Mendelian randomization, genetic architecture

Shuxiu Xiao,1,&ast; Lili Lu,1,&ast; Zhiyuan Lin,2,&ast; Xinming Ye,3 Sheng Su,3 Chenlu Zhang,4 Yang You,4 Wei Li,4 Xiaowu Huang,3 Weizhong Wu,5 Yuhong Zhou1,4 1Clinical Center for Biotherapy, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 3Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 4Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 5Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuhong Zhou; Weizhong Wu, Email zhou.yuhong@zs-hospital.sh.cn; wu.weizhong@zs-hospital.sh.cnBackground: Layilin (LAYN) represents a valuable prognostic biomarker across various tumor types, while also serving as an innovative indicator of dysfunctional or exhausted CD8+ T cells and exhibiting correlation with immune context. However, the immune function and prognostic significance of LAYN in hepatocellular carcinoma (HCC) remain unexplored. Therefore, our objective is to investigate the role of LAYN in CD8+ T cell exhaustion, clinical prognosis, and the tumor microenvironment within HCC.Methods: TIMER or GEPIA databases were used to analyze LAYN expression level and its correlation with immune infiltration in HCC. Bioinformatics analysis was conducted on TCGA and scRNA-seq cohorts. The evaluation of LAYN expression level in fresh specimens was performed through IF, IHC, and ELISA assays. Flow cytometry and mRNA-seq were employed to investigate co-expressed genes of LAYN, the LAYN+CD8+ T cell exhaustion signature and immune function. Cell proliferation ability and killing activity were assessed using CCK8 and CFSE/PI.Results: The expression level of LAYN in HCC tumors was significantly higher compared to peri-tumors. Patients with high levels of LAYN exhibited poorer OS. GO or KEGG analysis confirmed that LAYN was involved in immune response and was positively associated with CD8+ T cell immune infiltration levels. Furthermore, LAYN negatively regulated the immune function of CD8+ T cells, leading to dysfunctional phenotypes characterized by elevated levels of CD39, TIM3 and reduced levels of perforin, TNF-α, Ki-67. CFSE/PI assays demonstrated that LAYN+CD8+ T cells displayed decreased cytotoxic activity. Additionally, there was a positive correlation between LAYN and CD146 levels, which are involved in adhesion and localization processes of CD8+ T cells. Interestingly, blocking LAYN partially restored the exhaustion properties of CD8+ T cells.Conclusion: LAYN exhibits a strong correlation with immune infiltration in the TME and represents a novel biomarker for predicting clinical prognosis in HCC. Moreover, targeting LAYN may hold promise as an effective strategy for HCC immunotherapy. Keywords: hepatocellular carcinoma, layilin, CD8+ T cell exhaustion, prognosis

Lichen Tang,1 Zheng Lin1,2 1School of Nursing, Nanjing Medical University, Nanjing, 211166, People’s Republic of China; 2Nursing Department, the First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of ChinaCorrespondence: Zheng Lin, School of Nursing, Nanjing Medical University, Tianyuan East Road No.818, Jiangning District, Nanjing, Jiangsu, Email linzheng100@163.comBackground: Stigma is assumed to lead to negative illness identity in one who got chronic illness, and there is a lack of understanding regarding the underly mechanisms. However, no research has examined the extent to which stigma was associated with illness identity in people with IBD. Therefore, we investigated the relationship between stigma and illness identity, specifically to examine whether resilience mediated or moderated the relationship.Methods: A cross-sectional study was performed among patients diagnosed with inflammatory bowel disease from three tertiary hospitals in Jiangsu Province, China. Measurement instruments included the Stigma Scale for Chronic Illness (SSCI), the Resilience Scale for Patients with Inflammatory Bowel Disease (RS-IBD), and the Illness Identity questionnaire (IIQ). Mediation and moderated mediation analyses were conducted.Results: A total of 322 patients with IBD were involved in the current study. We observed that there was a strong connection between stigma and rejection and engulfment. Moreover, resilience played a partial or complete mediating role in stigma and engulfment, acceptance and enrichment, and resilience moderates the relationship between stigma and rejection.Conclusion: The current study examined whether resilience mediated or moderated the relationship between stigma and illness identity. These finding add to the theoretical basis of how stigma influences illness identity and help guide the resilience into engulfment reduction programs for IBD.Keywords: inflammatory bowel disease, stigma, illness identity, resilience

Ruiwei Guo,1,2 Jin Wu,1,2 Yanmin Zheng,1,2 Xiaona Lin,1,2 Zelin Zhuang,1,2 Jingjing Yin,1,2 Zhirong Lin,1 Lei Xie,1,2 Shuhua Ma1,2 1Department of Radiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of China; 2Laboratory of Medical Molecular Imaging, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of ChinaCorrespondence: Shuhua Ma; Lei Xie, Email shuhua6633@163.com; 13lxie1@stu.edu.cnBackground: Inflammatory Bowel Disease (IBD) patients may experience cognitive impairments in Visuospatial Working Memory (VSWM), significantly impacting their quality of life. However, the mechanisms underlying these impairments remain poorly understood.Methods: We studied functional MRI and graph theory analysis to investigate changes in functional connectivity networks during the Mental Rotation Task (MRT) in IBD patients. Twenty IBD patients (13 males, 7 females; mean age = 34.95 ± 13.80 years; mean disease duration = 2.43 ± 2.37 years) participated in the study. Exclusion criteria encompassed recent use of analgesics, 5-Aminosalicylate, corticosteroids, or immunosuppressants within the past three months. Additionally, we recruited 20 age-, gender-, and education-matched healthy controls for comparison.Results: Compared to a control group, IBD patients exhibited significantly longer reaction times and reduced accuracy during the MRT. Our analysis revealed abnormalities in multiple nodal attributes within the functional connectivity network, particularly in regions such as the bilateral orbitofrontal cortex, right supplementary motor area, bilateral parahippocampal gyrus, and bilateral anterior temporal lobe. We observed that the nodal efficiency in the left temporal pole is negatively correlated with Red Blood Cell Distribution Width (RDW) and positively correlated with response time of MRT.Conclusion: Our findings revealed notable abnormalities in multiple node attributes among IBD patients during MRT, providing evidence of cognitive impairments in VSWM in IBD patients. This study found RDW maybe can serve as a clinical indicator for predicting early VSWM impairment in patients with IBD.Keywords: inflammatory bowel disease, graph theory, visuospatial working memory, cognitive impairment, mental rotation task

Quan Hu,1,&ast; Yingxiao Li,2,&ast; Zhaochen Lin,3 Hao Zhang,4 Haoyue Chen,4 Cui Chao,3 Chuanliang Zhao5 1Department of Neurosurgery, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China; 2Department of Gynecology, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China; 3Hydrogen Medical Research Center, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China; 4Department of Rehabilitation Medical Center, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China; 5Department of Orthopedics, the Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chuanliang Zhao, Department of Orthopedics, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China, Tel +8615621539631, Email zhaochuanliang2003@163.comAbstract: Hydrogen, which is a novel biomedical molecule, is currently the subject of extensive research involving animal experiments and in vitro cell experiments, and it is gradually being applied in clinical settings. Hydrogen has been proven to possess anti-inflammatory, selective antioxidant, and antiapoptotic effects, thus exhibiting considerable protective effects in various diseases. In recent years, several studies have provided preliminary evidence for the protective effects of hydrogen on spinal cord injury (SCI). This paper provides a comprehensive review of the potential molecular biology mechanisms of hydrogen therapy and its application in treating SCI, with an aim to better explore the medical value of hydrogen and provide new avenues for the adjuvant treatment of SCI.Keywords: hydrogen, spinal cord injury, selective antioxidant, anti-inflammatory

Chen Lin,1 Jing Wang,2 Kexin Cai,2 Yuqing Luo,2 Wensi Wu,1 Siming Lin,2 Zhihong Lin,2 Shaodan Feng2 1Department of Emergency, The Third Affiliated People’s Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, People’s Republic of China; 2Department of Emergency, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of ChinaCorrespondence: Zhihong Lin; Shaodan Feng, Department of Emergency, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China, Tel +86 59187981975, Email fzlinzh@163.com; sdfeng@fjmu.edu.cnPurpose: To address the critical mortality rates among sepsis-associated acute kidney injury (SA-AKI) patients, early prognosis is vital. This study investigates the relationship between coagulation indices and the 28-day mortality rate in patients with SA-AKI.Patients and Methods: This study was a retrospective cohort analysis including patients with SA-AKI admitted to the First Hospital of Fujian Medical University as a training cohort (n = 119) and patients admitted to the Third People’s Hospital of Fujian University of Traditional Chinese Medicine as a validation cohort (n = 51). We examined the relationship between coagulation indices and 28-day mortality in SA-AKI, the cumulative mortality at different activated partial thromboplastin time (APTT) levels, and the nonlinear relationship between APTT and 28-day mortality. Receiver operating characteristic curves were plotted, and the area under the curve was calculated to assess the predictive power of APTT. Finally, subgroup analyses were performed to assess the robustness of the association.Results: Overall, 119 participants with a mean±standard deviation age of 70.47± 15.20 years were included in the training cohort: 54 died, 65 survived. According to univariate and multivariate COX regression analyses, APACHE II score, CRP level, Lac level, and APTT level were independent risk factors for 28-day adverse prognosis. After controlling for some variables, an elevated baseline APTT (≥ 37.7 s) was associated with an elevated risk of 28-day mortality (HR, 1.017; 95% CI, 1.001– 1.032), and Kaplan–Meier analyses further confirmed the increased mortality in the group with a higher APTT. The same results were shown when the validation cohort was analyzed (HR, 1.024; 95% CI, 0.958– 1.096). Subgroup analyses showed the stability of the association between APTT and poor prognosis in SA-AKI.Conclusion: In essence, APTT elevation is synonymous with increased 28-day mortality rates, indicating a poor prognosis in SA-AKI scenarios.Keywords: APTT, prognosis, retrospective studies, critical illness

Abstract Maintaining sufficient cerebral oxygen metabolism is crucial for human survival, especially in challenging conditions such as high-altitudes. Human cognitive neural activity is sensitive to fluctuations in oxygen levels. However, there is a lack of publicly available datasets on human behavioural responses and cerebral dynamics assessments during the execution of conflicting tasks in natural hypoxic environments. We recruited 80 healthy new immigrant volunteers (males, aged 20 ± 2 years) and employed the Stroop cognitive conflict paradigm. After a two-week exposure to both high and low-altitudes, the behavioural performance, prefrontal oxygen levels, and electroencephalography (EEG) signals were recorded. Comparative analyses were conducted on the behavioural reaction times and accuracy during Stroop tasks, and statistical analyses of participants’ prefrontal oxygen levels and EEG signals were performed. We anticipate that our open-access dataset will contribute to the development of monitoring devices and algorithms, designed specifically for measuring cerebral oxygen and EEG dynamics in populations exposed to extreme environments, particularly among individuals suffering from oxygen deficiency.

Baojun Guo,1,2 Hui Gan,1 Mingshan Xue,1,3 Zhifeng Huang,1 Zhiwei Lin,1 Shiyun Li,1 Peiyan Zheng,1 Baoqing Sun1 1Department of Clinical Laboratory of the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, 510120, People’s Republic of China; 2School of Medicine, Henan University, Kaifeng, 475004, People’s Republic of China; 3Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, 510060, People’s Republic of ChinaCorrespondence: Baoqing Sun; Peiyan Zheng, Email sunbaoqing@vip.163.com; gdmcslxx@126.comBackground: This study analyzed the burden of chronic obstructive pulmonary disease (COPD) in China, the United States, and India from 1990 to 2019 and projected the trends for the next decade.Methods: This study utilized the GBD 2019 to compare the age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), age-standardized disability-adjusted life years (DALYs) rate, and the proportion attributed to different risk factors in China, the United States, and India. Joinpoint models and autoregressive integrated moving average (ARIMA) models were employed to capture the changing trends in disease burden and forecast outcomes.Results: From 1990 to 2019, China’s age-standardized COPD incidence and mortality rates decreased by 29% and 70%, respectively. In the same period, India’s rates decreased by 8% and 33%, while the United States saw an increase of 9% in COPD incidence and a 22% rise in mortality rates. Smoking and ambient particulate matter pollution are the two most significant risk factors for COPD, while household air pollution from solid fuels and low temperatures are the least impactful factors in the United States and India, respectively. The proportion of risk from household air pollution from solid fuels is higher in India than in China and the United States. Predictions for 2030 suggest that the age-standardized DALY rates, ASIR, and ASMR in the United States and India are expected to remain stable or decrease, while China’s age-standardized incidence rate is projected to rise.Conclusion: Over the past three decades, the incidence of COPD has been decreasing in China and India, while showing a slight increase in the United States. Smoking and ambient particulate matter pollution are the primary risk factors for men and women, respectively. The risk of household air pollution from solid fuels in India needs attention.Keywords: COPD, global burden of disease, risk factors, DALYs

Ke Ma,1,&ast; Zhixiang Cheng,2,&ast; Hao Jiang,3,&ast; Zhangya Lin,4,&ast; Chuansheng Liu,5,&ast; Xianguo Liu,6,&ast; Lijuan Lu,7,&ast; Yan Lu,8,&ast; Wei Tao,9,&ast; Suoliang Wang,10,&ast; Xiaoqiu Yang,11,&ast; Qishan Yi,12,&ast; Xiaomei Zhang,13,&ast; Ying Zhang,14,&ast; Yanqing Liu15,&ast; 1Department of Algology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Algology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Algology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 4Department of Neurosurgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 5Department of Algology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 6Pain Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 7Department of Pain Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 8Department of Algology, Xijing Hospital, The Fourth Military Medical University, Xian, People’s Republic of China; 9Department of Neurosurgery, Shenzhen University General Hospital, Shenzhen, People’s Republic of China; 10Department of Algology, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 11Department of Algology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 12Department of Algology, The Yibin First People’s Hospital Affiliated Chongqing Medical University, Yibin, People’s Republic of China; 13Department of Algology, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 14Department of Algology. Hospital (T.C.M) Affiliated to Southwest Medical University, Luzhou, People’s Republic of China; 15Department of Algology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ke Ma, Department of Algology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University school of medicine, Shanghai, 200092, People’s Republic of China, Tel +86133618792160, Email marke72@163.com Yanqing Liu, Department of Algology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China, Tel +8618601203409, Email lyqttyy@126.comAbstract: Ion channel drugs have been increasing used for chronic pain management with progress in the development of selective calcium channel modulators. Although ion channel drugs have been proven safe and effective in clinical practice, uncertainty remains regarding its use to treat chronic pain. To standardize the clinical practice of ion channel drug for the treatment of chronic pain, the National Health Commission Capacity Building and Continuing Education Center for Pain Diagnosis and Treatment Special Ability Training Project established an expert group to form an expert consensus on the use of ion channel drugs for the treatment of chronic pain after repeated discussions on existing medical evidence combined with the well clinical experience of experts. The consensus provided information on the mechanism of action of ion channel drugs and their recommendations, caution use, contraindications, and precautions for their use in special populations to support doctors in their clinical decision-making.Keywords: chronic pain, ion channel drugs, voltage-gated calcium channels, voltage-gated sodium channel

Shaoguang Li,1 Zhan Lin,1 Haobo Chen,1 Qiu Luo,1 Shengnan Han,1 Kunlong Huang,1 Ruichan Chen,1 Yuying Zhan,1 Bing Chen,2 Hong Yao1– 3 1Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, FuJian, People’s Republic of China; 2Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 3Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, Fujian Medical University, Fuzhou, Fujian, People’s Republic of ChinaCorrespondence: Shaoguang Li; Hong Yao, Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, Fujian, 350122, People’s Republic of China, Email lsg941@126.com; yauhung@126.comBackground: The preclinical diagnosis of tumors is of great significance to cancer treatment. Near-infrared fluorescence imaging technology is promising for the in-situ detection of tumors with high sensitivity.Methods: Here, a fluorescent probe was synthesized on the basis of Au nanoclusters with near-infrared light emission and applied to fluorescent cancer cell labeling. Near-infrared methionine-N-Hydroxy succinimide Au nanoclusters (Met-NHs-AuNCs) were prepared successfully by one-pot synthesis using Au nanoclusters, methionine, and N-Hydroxy succinimide as frameworks, reductants, and stabilizers, respectively. The specific fluorescence imaging of tumor cells or tissues by fluorescent probe was studied on the basis of SYBYL Surflex-DOCK simulation model of LAT1 active site of overexpressed receptor on cancer cell surface. The results showed that Met-NHs-AuNCs interacted with the surface of LAT1, and C_Score scored the conformation of the probe and LAT1 as five.Results: Characterization and in vitro experiments were conducted to explore the Met-NHs-AuNCs targeted uptake of cancer cells. The prepared near-infrared fluorescent probe (Met-NHs-AuNCs) can specifically recognize the overexpression of L-type amino acid transporter 1 (LAT1) in cancer cells so that it can show red fluorescence in cancer cells. Meanwhile, normal cells (H9c2) have no fluorescence.Conclusion: The fluorescent probe demonstrates the power of targeting and imaging cancer cells.Keywords: Au nanoclusters, fluorescence imaging, cancer cell imaging, molecular docking

Liao X, Shen M, Li T, et al. Int J Nanomedicine. 2023;18:5925–5942. The authors wish to advise, following publication of the article they identified errors were made during the collection and organization of data for Figures 3 and 4 on pages 5934 and 5935, respectively. The correct Figures 3 and 4 are as follows. Figure 3 Antioxidant properties of POM or hydrogel. (A) DCFH-DA assay showing intracellular ROS of MC3T3-E1 after incubation with POM in the presence of H2O2 (100 μM). (B) Quantification analysis of DCFH-DA staining (*And #Indicate p < 0.05 in comparison with the H2O2 group and GelMA group, respectively.) (C) Cell capacity of migration (scratch test). (D) Quantitative analysis of percent migration in scratch assay. (*And #Indicate p < 0.05 in comparison with the H2O2 group and GelMA group, respectively.) (E) Live/dead staining showing MC3T3-E1 cell viability after culturing on hydrogel in the presence of H2O2. (F) Quantification analysis of live cells. (*And #Indicate p < 0.05 in comparison with the H2O2 group and GelMA group, respectively.) (G) LSCM images showing MC3T3-E1 cultured on different hydrogels following H2O2 treatment. (n = 3, each group). (H2O2, cells cultured on the tissue culture plate with H2O2). Scale bar: 200 μm (A), 200 μm (C), 100 μm (E) and 100 μm (G). Figure 4 The osteogenesis properties of GelMA/POM hydrogel in vitro. In vitro assay of effects of hydrogel on ALP activity and extracellular calcium nodule production during osteogenesis differentiation of MC3T3-E1. (A) Alizarin red S staining. (B) Quantitative analysis of mineralized nodules. (C) Alkaline phosphatase activity. (D) Alkaline phosphatase staining. (*, # And a indicate p < 0.05 in comparison with the Control group, H2O2 group and GelMA group, respectively). (Control, cells cultured without H2O2). (n = 3, each group). Scale bar: 200 μm (A) and 200 μm (D). The authors advise these corrections do not significantly impact the overall findings and conclusions of the article or alter the interpretations or validity of the research. The authors apologize for any confusion these errors may have caused and appreciate the opportunity to rectify them.

Linfei Su,1,2 Zehui Lin,1 Youyuan Li,1 Xiaoyan Wang,3 Zengping Lin,3 Lanjuan Dong,3 Ling Wei1 1Department of Psychology, School of Health, Fujian Medical University, Fuzhou, People’s Republic of China; 2Institute of Psychology, School of Education Science, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Fuzhou Xingyu School, Fuzhou, People’s Republic of ChinaCorrespondence: Ling Wei, Tel +86-15960096260, Email ysyang-78@163.comBackground: The own-age effect is the phenomenon in which individuals perceive and recognize faces of their own age better than others in terms of cognitive processing. Previous eye movement studies on children with autism spectrum disorders (ASD) have reported that children with ASD have an attentional bias toward own-age faces and own-age scenes.Methods: The present study used own-age faces as the intervention material and examined the application of the own-age effect in the emotional recognition of faces in ASD. The length of the intervention was 12 weeks, and 2 sessions were conducted each week.Results: The results revealed that the own-age face intervention group gazed at children’s faces significantly more often than before the intervention, gazed at children’s angry faces significantly longer than before the intervention, and gazed at adults’ happy faces significantly longer and more often than before the intervention; the other-age faces intervention group did not differ significantly from the preintervention in gazing at children’s and adults’ faces after the intervention.Conclusion: The results suggest that own-age faces as teaching materials can better promote the emotion recognition ability of children with ASD than other-age faces.Plain language summary: ASD have difficulties with facial emotion recognition and previous study found that children with ASD correctly identified emotions in own-age faces more often than in other-age faces. Therefore, using pictures of children’s faces to intervene in children with ASD is beneficial to improve their facial emotion recognition ability. Previous studies have mostly used questionnaires to assess the effects of peer-matched interventions, and few have used an eye-movement technique that can effectively monitor changes in eye gaze patterns across different emotions.We found that the own-age face intervention group gazed at children’s faces significantly more often than before the intervention, gazed at children’s angry faces significantly longer than before the intervention, and gazed at adults’ happy faces significantly longer and more often than before the intervention. It indicates that own-age faces as teaching materials can better promote the emotion recognition ability of children with ASD than other-age faces.The own-age effect can be applied to experimental materials, the attribute settings of intervention materials, and the selection of accompanying objects to further expand the own-age effect in the educational intervention and training of social and cognitive abilities in ASD. It is expected to help autism improve its social skills and better integrate into the society.Keywords: children with autism spectrum disorders, own-age faces, intervention, eye tracking

Lina Yu,1,&ast; Guanxiong Zhu,1,&ast; Zeyu Zhang,1,&ast; Zidan Xu,1 Weijie Peng,1,2 Liting Zeng,1 Yang Yu,3 Siran Wang,1 Zhongxiao Lin,1,2,4 Xin Zhang,4 Na Zhou,4 Lingmin Zhang,1,2 Lu Liang1,2 1Department of Preventive Dentistry, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182, People’s Republic of China; 2Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, People’s Republic of China; 3Department of Sports and Health, Guangzhou Sport University, Guangzhou, People’s Republic of China; 4State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wailong, Taipa, Macau, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lingmin Zhang; Lu Liang, Email zhanglm@gzhmu.edu.cn; lliangaa@gzhmu.edu.cnBackground: Photodynamic therapy (PDT) has emerged as a promising strategy for oral cancer treatment. Verteporfin is a powerful photosensitizer and widely used in the treatment of macular degeneration. However, rare work has reported its potential in the treatment of oral cancer.Methods: In this study, we introduce an innovative approach of nano-photosensitizer based on Verteporfin, which was prepared by utilizing macrophage membrane to coat Verteporfin-loaded zeolitic imidazolate framework 8 (ZIF-8) for effective photodynamic therapy against oral cancer. Nanoparticle characteristics were assessed including size, zeta potential, and PDI. Cellular uptake studies were conducted using CAL-27 cells. Furthermore, inhibitory effects in both in vitro and in vivo settings were observed, ensuring biosafety. Assessment of anticancer efficacy involved tumor volume measurement, histological analyses, and immunohistochemical staining.Results: In vitro experiments indicated that the nano-photosensitizer showed efficient cellular uptake in the oral cancer cells. Upon the laser irradiation, the nano-photosensitizer induced the generation of reactive oxygen species (ROS), leading to cancer cell apoptosis. The in vivo experiments indicated that the coating with cell membranes enhanced the circulation time of nano-photosensitizer. Moreover, the specificity of the nano-photosensitizer to the cancer cells was also improved by the cell membrane-camouflaged structure in the tumor-bearing mouse model, which inhibited the tumor growth significantly by the photodynamic effect in the presence of laser irradiation.Conclusion: Overall, our findings demonstrate the potential of macrophage membrane-coated ZIF-8-based nanoparticles loaded with Verteporfin for effective photodynamic therapy in oral cancer treatment. This nano-system holds promise for synergistic cancer therapy by combining the cytotoxic effects of PDT with the activation of the immune system, providing a novel therapeutic strategy for combating cancer.Keywords: photodynamic therapy, verteporfin, oral cancer, macrophages, zeolitic imidazolate framework 8

Adenine nucleotide translocator (ANT) is a mitochondrial protein involved in the exchange of ADP and ATP across the mitochondrial inner membrane. It plays a crucial role in cellular energy metabolism by facilitating the transport of ATP synthesized within the mitochondria to the cytoplasm. The isoform ANT1 predominately expresses in cardiac and skeletal muscles. Mutations or dysregulation in ANT1 have been implicated in various mitochondrial disorders and neuromuscular diseases. We aimed to examine whether ANT1 deletion may affect mitochondrial redox state in our established ANT1-deficient mice. Hearts and quadriceps resected from age-matched wild type (WT) and ANT1-deficient mice were snap-frozen in liquid nitrogen. The Chance redox scanner was utilized to perform 3D optical redox imaging. Each sample underwent scanning across 3–5 sections. Global averaging analysis showed no significant differences in the redox indices (NADH, flavin adenine dinucleotide containing-flavoproteins Fp, and the redox ratio Fp/(NADH+Fp) between WT and ANT1-deficient groups. However, quadriceps had higher Fp than hearts in both groups ([Formula: see text] and 0.01, respectively). Furthermore, the quadriceps were also more oxidized (a higher redox ratio) than hearts in WT group ([Formula: see text]). NADH levels were similar in all cases. Our data suggest that under non-stressful physical condition, the ANT1-deficient muscle cells were in the same mitochondrial state as WT ones and that the significant difference in the mitochondrial redox state between quadriceps and hearts found in WT might be diminished in ANT1-deficient ones. Redox imaging of muscles under physical stress can be conducted in future.

Xuejiao Liao,1,&ast; Yuan Guan,1,2,&ast; Zixun Lin,1 Qingrong Tang,3 Zhenghua Ma,1 Shuting Wu,1 Xiaobin Wang,1 Jingke Dong,1 Liping Zhang,1 Jiayu Deng,1 Zhonghui Liao,1,4 Sumei Yang,1,4 Cheng Wang,1,4 Shuo Song,1 Hongyang Yi,1 Song Wu,5 Tetsuya Asakawa,6 Hongzhou Lu1 1Institute for Hepatology, National Clinical Research Center for Infectious Disease, The Third People’s Hospital of Shenzhen, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, People’s Republic of China; 2Department of Epidemiology, School of Public Health Fudan University, Shanghai, People’s Republic of China; 3The First Hospital of Changsha, Infectious Diseases Department, Changsha, People’s Republic of China; 4School of Public Health, Bengbu Medical College, Bengbu, People’s Republic of China; 5Department of Central Laboratory, South China Hospital, Medical School, Shenzhen University, Shenzhen, People’s Republic of China; 6Institute of Neurology, National Clinical Research Center for Infectious Diseases, the Third People’s Hospital of Shenzhen, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongzhou Lu, Institute for Hepatology, National Clinical Research Center for Infectious Disease, The Third People’s Hospital of Shenzhen, The Second Hospital Affiliated with the School of Medicine, Southern University of Science and Technology, No. 29 Bulan Road, Long Gang District, Shenzhen, Guangdong, 518112, People’s Republic of China, Email luhongzhou@fudan.edu.cn Tetsuya Asakawa, Institute of Neurology, National Clinical Research Center for Infectious Diseases, the Third People’s Hospital of Shenzhen, No. 29 Buji Bulan Road, Shenzhen, Guangdong, 518112, People’s Republic of China, Email asakawat1971@gmail.comPurpose: The purpose was to review relevant clinical data and formulate recommendations supporting the use of saline as a simple rinse for an early reassuring intervention to reduce the occurrence of re-positive COVID-19 patients.Methods: We conducted a single-centre retrospective cohort study, which enrolled patients with confirmed re-testing positive COVID-19 during 7– 60 days after discharge from Third People’s Hospital of Shenzhen. By one-to-two propensity score matching for age and sex, the control group of those not re-testing positive during the same period served as matched control.Results: A total of 223 patients were included in our study, 94 in re-positive group and 129 in non-re-positive group. The result shows that the rates of nasal douche treatment in the non-re-positive group were considerably higher than that of the re-positive group. And the Ct value of nasal douche group increased faster than that of non-nasal douche group after the Ct value reaching ≥ 35. Further analysis revealed that the higher the Ct value at the time of readmission, the shorter the time of average Ct values to reach ≥ 35.Conclusion: These findings suggest that nasal douche is beneficial to shorten the time of virus nucleic acid turning negative, thereby reducing the incidence of re-positive. The prevention and control of epidemics focuses on re-positive patients with Ct values < 35.Keywords: COVID-19, nasal douche, re-positive, RT-PCR

Emerging data indicate that lung macrophages (LM) may provide a novel biomarker to classify disease endotypes in bronchopulmonary dysplasia (BPD), a form of infant chronic lung disease, and that augmentation of the LM phenotype may be a potential therapeutic target. To contribute to this area of research, we first used Optical Redox Imaging (ORI) to characterize the responses to H2O2-induced oxidative stress and caffeine treatment in an in vitro model of mouse alveolar macrophages (AM). H2O2 caused a dose-dependent decrease in NADH and an increase in FAD-containing flavoproteins (Fp) and the redox ratio Fp/(NADH + Fp). Caffeine treatment did not affect Fp but significantly decreased NADH with doses of ≥50 µM, and 1000 µM caffeine treatment significantly increased the redox ratio and decreased the baseline level of mitochondrial ROS (reactive oxygen species). However, regardless of whether AM were pretreated with caffeine or not, the mitochondrial ROS levels increased to similar levels after H2O2 challenge. We then investigated the feasibility of utilizing ORI to examine macrophage redox status in tracheal aspirate (TA) samples obtained from premature infants receiving invasive ventilation. We observed significant heterogeneity in NADH, Fp, Fp/(NADH + Fp), and mitochondrial ROS of the TA macrophages. We found a possible positive correlation between gestational age and NADH and a negative correlation between mean airway pressure and NADH that provides hypotheses for future testing. Our study demonstrates that ORI is a feasible technique to characterize macrophage redox state in infant TA samples and supports further use of this method to investigate lung macrophage-mediated disease endotypes in BPD.

To develop imaging biomarkers for tumors aggressiveness, our previous optical redox imaging (ORI) studies of the reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp, containing flavin adenine dinucleotide, i.e., FAD) in tumor xenografts of human melanoma associated the high optical redox ratio (ORR = Fp/(Fp + NADH)) and its heterogeneity to the high invasive/metastatic potential, without having reported quantitative results for NADH and Fp. Here, we implemented a calibration procedure to facilitate imaging the nominal concentrations of tissue NADH and Fp in the mouse xenografts of two human melanoma lines, an indolent less metastatic A375P and a more metastatic C8161. Images of the redox indices (NADH, Fp, ORR) revealed the existence of more oxidized areas (OAs) and more reduced areas (RAs) within individual tumors. ORR was found to be higher and NADH lower in C8161 compared to that of A375P xenografts, both globally for the whole tumors and locally in OAs. The ORR in the OA can differentiate xenografts with a higher statistical significance than the global averaged ORR. H&E staining of the tumors indicated that the redox differences we identified were more likely due to intrinsically different cell metabolism, rather than variations in cell density.

Zhongyuan Lin,&ast; Changliang Luo,&ast; Yulin Yuan Department of Clinical Laboratory, The People’s Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yulin Yuan, Department of Clinical Laboratory, The People’s Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, (No. 6 Tao Yuan Road), Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China, Email yiran2020221007@126.comObjective: To explore the predictive value of the ratio of monocyte to apolipoprotein A1 (MAR) (a new index related to inflammation and lipid in breast cancer (BC)) and its relationship with clinicopathological staging.Methods: The hematological test results of 394 patients with breast diseases, including 276 cases of BC, 118 cases of benign breast disease (BBD), and 219 healthy volunteers (HV), were retrospectively collected. The clinical value of MAR was analyzed with binary logistic regression.Results: Using statistical software analysis, the results showed that MAR level (P< 0.001) was the largest in the BC group, followed by BBD, and the lowest in the HV group, and it was found to be an indicator to distinguish BC from BBD, also an independent risk factor for BC. The increase in MAR level showed that the risk of BC was 3.733 times higher than that of HV (P< 0.001). In addition, there was a notable difference in MAR between early, middle and late stages of BC patients (P=0.047), with the highest MAR level in late stage (0.510± 0.078) and the lowest MAR level in early stage (0.392± 0.011); the MAR level of those with tumor invasion depth of Phase 4 was the highest (0.484± 0.072), and that of Phase 1/2 was the lowest (0.379± 0.010), with a statistically significant difference (P< 0.001). MAR was positively correlated with tumor invasion depth (P< 0.001, r=0.210), that’s, the size of MAR increased when there was more deeper tumor invasion.Conclusion: MAR is a new indicator for the auxiliary differential diagnosis of benign and malignant breast diseases, and is also an independent risk factor for BC. High-level MAR is closely related to late staging and tumor invasion depth of BC. It can be seen that MAR is a potentially valuable predictor of BC, and this is the first study to explore the clinical value of MAR in BC.Keywords: breast cancer, breast benign disease, the ratio of monocyte to apolipoprotein A1, Monocyte, Apolipoprotein A1

Minli Zhu,1 Leying Wang,1 Zhangming Zhuge,1 Wei Li,1,2 Yihui Zheng,1 Jingyun Mai,1 Zhenlang Lin,1 Jing Lin1,3 1Key Laboratory of Perinatal Medicine of Wenzhou, Department of Neonatology, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, People’s Republic of China; 2Zhijin People’s Hospital of Guizhou Province, Guizhou, 552100, People’s Republic of China; 3Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USACorrespondence: Jing Lin, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA, Tel +1-212-241-6186, Fax +1-212534-5207, Email jing.lin@mssm.edu Zhenlang Lin, Department of Neonatology, the Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, 325027, People’s Republic of China, Tel +86 13806689800, Email linzhenlang@hotmail.comBackground and Objective: An increasing number of cases of neonatal sepsis due to extended-spectrum beta-lactamase (ESBL)-producing multi-drug resistant (MDR) Escherichia coli (E. coli) have been reported worldwide. The aim of this study was to explore the risk factors associated with ESBL-producing MDR E. coli among neonates with culture-confirmed E. coli sepsis and thereby to help selection of appropriate empirical antibiotics.Patients and Methods: All newborn infants with a confirmed pathogen isolated from blood or cerebrospinal fluid (CSF) from 2016 to 2021 were identified and those with E. coli infection were included in this analysis. We compared a group of neonatal patients with ESBL-producing MDR E. coli sepsis (n=69) to a group with ESBL-negative E. coli (n=70) based on antimicrobial susceptibility reports. We used multivariable regression analysis to determine the risk factors associated with ESBL-producing MDR E. coli strains among the neonates with culture-confirmed E. coli sepsis.Results: ESBL-producing MDR E. coli sepsis was more common in premature infants and newborns with hospital-acquired late-onset sepsis (HALOS). The mortality rate of neonatal sepsis caused by ESBL-producing E. coli was about twice as that of sepsis caused by ESBL-negative E. coli. Antepartum exposure to cephalosporins (OR=25.191, 95% CI: 3.184– 199.326, P< 0.01) and parenteral nutrition for more than 1 week (OR=4.495, 95% CI: 2.009– 10.055, P< 0.01) were independent risk factors for neonatal infection with ESBL-producing stains among infants with E. coli sepsis.Conclusion: E. coli remains the most common Gram-negative bacterial pathogen causing neonatal sepsis. A higher proportion of ESBL-producing MDR E. coli is seen in premature infants and those newborns with HALOS and is associated with higher mortality. Antepartum use of cephalosporins and prolonged use of parenteral nutrition may be important factors to consider in the selection of empirical antibiotics for use in neonatal sepsis caused by gram-negative rods prior to the availability of the results of antimicrobial susceptibility.Keywords: infant, newborn, neonatal sepsis, Escherichia coli, drug resistance, extended-spectrum beta-lactamase

Mingxun Wang,1,&ast; Xinfei Yao,2,&ast; Zhiyuan Bo,3,4,&ast; Jiuyi Zheng,3 Haitao Yu,3 Xiaozai Xie,3 Zixia Lin,3 Yi Wang,5 Gang Chen,3,4 Lijun Wu3 1Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2The First Clinical College, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 5Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lijun Wu; Gang Chen, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Fuxue Road, Wenzhou, Zhejiang, 325035, People’s Republic of China, Tel +86 577 55579-453, Fax +86 577 55579-555, Email wumolijun@163.com; chen.gang@wmu.edu.cnPurpose: The current study aimed to evaluate the synergistic efficacy of lenvatinib and FOLFOX (infusional fluorouracil (FU), folinic acid, and oxaliplatin) in hepatocellular carcinoma (HCC) using patient-derived xenograft (PDX) and PDX-derived organotypic spheroid (XDOTS) models in vivo and in vitro.Methods: PDX and matched XDOTS models originating from three patients with HCC were established. All models were divided into four groups and treated with drugs alone or in combination. Tumor growth in the PDX models was measured and recorded, and angiogenesis and phosphorylation of the vascular endothelial growth factor receptor (VEGFR2), rearranged during transfection (RET), and extracellular signal-regulated kinase (ERK) were detected using immunohistochemistry and Western blot assays. The proliferative ability of XDOTS was evaluated through active staining and immunofluorescence staining, and the effect of the combined medication was evaluated using the Celltiter-Glo luminescent cell viability assay.Results: Three PDX models with genetic characteristics similar to those of the original tumors were successfully established. Combining lenvatinib with FOLFOX led to a higher tumor growth inhibition rate than individual therapies (P < 0.01). Immunohistochemical analysis demonstrated that the combined treatment significantly inhibited the proliferation and angiogenesis of PDX tissues (P < 0.05), and Western blot analysis showed that the combined treatment significantly inhibited the phosphorylation of VEGFR2, RET, and ERK compared with single-agent treatment. Additionally, all three matched XDOTS models were successfully cultured with satisfactory activity and proliferation, and the combined therapies led to better suppression of XDOTS growth compared with individual therapy (P < 0.05).Conclusion: Lenvatinib combined with FOLFOX had a synergistic antitumor effect in HCC PDX and XDOTS models by inhibiting the phosphorylation of VEGFR, RET, and ERK.Keywords: hepatocellular carcinoma, lenvatinib, chemotherapy, patient-derived xenografts, angiogenesis

Jing Huang, Zhijian Lin, Yu Wang, Xueli Ding, Bing Zhang School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of ChinaCorrespondence: Bing Zhang, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, Email zhangb@bucm.edu.cnBackground: Hyperuricemia (HUA) is a major public health issue with a high prevalence worldwide. Wuling San (WLS) is an effective treatment for HUA. However, the active compounds and the related mechanism are unclear. In this study, we aimed to explore the active compounds and the underlying pharmacological mechanisms of WLS against HUA.Methods: First, a network pharmacology approach was used to detect active compounds of WLS, and potential targets and signaling pathways involved in the treatment of HUA were predicted. Then, a molecular docking strategy was used to predict the affinity between active compounds and key targets. Finally, to verify the prediction, the HUA rat model was established.Results: 49 active compounds with 108 common targets were obtained. Besides, cerevisterol, luteolin, ergosterol peroxide, beta-sitosterol, and sitosterol were identified as key active compounds. In PPI analysis, TNF, IL6, CASP3, PPARG, STAT3, and other 12 core targets were obtained. GO enrichment analysis indicated that WLS was likely to interfere with oxidative stress in the treatment of HUA, and KEGG enrichment analysis indicated multiple inflammation-related signaling pathways possibly involved in the treatment of HUA by WLS, including TNF, and NOD-like receptor, HIF-1, PI3K-Akt, and IL-17 signaling pathways. The results of molecular docking indicated that the active compounds had good binding properties to their key targets. In the validation experiments, WLS significantly reduced the levels of serum uric acid (SUA) and serum malondialdehyde (MDA). Moreover, WLS not only significantly increased the levels of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD), but also inhibited the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).Conclusion: In the present study, we demonstrate that WLS has multicomponent, multitarget, and multi-pathway properties in the treatment of HUA. Its potential capability to reduce SUA could be ascribed to oxidative stress improvement and inflammation inhibition.Keywords: hyperuricemia, Wuling San, oxidative stress, inflammation

Yuxuan Xu,&ast; Zhihui Lin,&ast; Chenxi Zhu,&ast; Dongyan Song, Bosen Wu, Kangting Ji, Jin Li Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kangting Ji; Jin Li, Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Xueyuanxi Road, No. 109, Wenzhou, 325027, People’s Republic of China, Tel/Fax +86-577-85676627, Email jikt@wmu.edu.cn; lijin1982@wzhealth.comObjective: The present study aimed to evaluate the relationship between all-cause mortality and the neutrophil percentage-to-albumin ratio (NPAR) in patients with atrial fibrillation (AF).Methods: We obtained clinical information from patients with AF from the Medical Information Mart for Intensive Care-IV version 2.0 (MIMIC-IV) database and the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (WMU). The clinical endpoints were all-cause death measured at 30-day, 90-day, and one-year intervals. For endpoints associated with the NPAR, logistic regression models were used to calculate odds ratios (OR) with 95% confidence intervals (CI). Receiver operating characteristic (ROC) curves and area under the curve (AUC) were developed to compare the ability of different inflammatory biomarkers to predict 90-day mortality in patients with AF.Results: Higher NPAR was associated with a higher risk of 30-day (OR 2.08, 95% CI 1.58– 2.75), 90-day (OR 2.07, 95% CI 1.61– 2.67), and one-year mortality (OR 1.60, 95% CI 1.26– 2.04) in patients with AF in 2813 patients from MIMIC-IV. The predictive performance of NPAR (AUC = 0.609) for 90-day mortality was better than that of neutrophil-to-lymphocyte ratio (NLR) (AUC = 0.565, P < 0.001), and platelet-to-lymphocyte ratio (PLR) (AUC = 0.528, P < 0.001). When NPAR and sequential organ failure assessment (SOFA) were combined, the AUC increased from 0.609 to 0.674 (P < 0.001). Higher NPAR was associated with a higher risk of 30-day mortality (OR 2.54, 95% CI 1.02– 6.30) and 90-day mortality (OR 2.76, 95% CI 1.09– 7.01) in 283 patients from WMU.Conclusion: An increased 30-day, 90-day, and one-year mortality risk among patients with AF were linked to a higher NPAR in MIMIC-IV. NPAR was thought to be a good predictor of 90-day all-cause mortality. Higher NPAR was associated with a higher risk of 30-day and 90-day mortality in WMU.Keywords: atrial fibrillation, neutrophil percentage-to-albumin ratio, mortality, inflammatory biomarker

Meilian Xie,1,2 Aiping Wang,1 Zhaoxia Lin3 1Department of Public Service, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of China; 2Department of Nursing, Beijing Ditan Hospital Capital Medical University, Beijing, People’s Republic of China; 3Infection Center, Beijing Ditan Hospital Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Aiping Wang, Department of Public Service, the First affiliated Hospital of China Medical University, Shenyang, People’s Republic of China, Email jianghaoran88@hotmail.comObjective: Our study aims to completely understand the experience of gynecological related symptoms (GRS) and the association between GRS and quality of life (QOL) among HIV-infected women in China.Design: A cross-sectional, multicenter survey.Setting: The HIV/AIDS designated medical institutions of seven regions in China.Participants: One hundred and fifty-three women with HIV infection.Primary and Secondary Outcome Measures: Primary outcome measures included the score of GRS and QOL from analysis sample.Results: Among 153 participants, 60.13% were asymptomatic, and 39.87% were symptomatic according to their self-report data. In the symptomatic group, 47.54% reported only one symptom, 18.03% reported 2 symptoms, others reported more than 3 symptoms. The most common symptoms were vaginal discharge (25.49%), followed by irregular period (18.95%), bad cramps (13.07%), vaginal odor (11.11%), and vaginal itching (10.46%). The mean score of QOL was 86.82 ± 15.53. The symptomatic group had higher score than the asymptomatic group on each domain of QOL. GRS were negatively correlated with QOL after adjustment for confounding factors. Correlation matrix of GRS and six domains of QOL demonstrated significant negative correlation with each domain of QOL, especially the most strongly negative correlation with physical function of participants. But the association between GRS and environmental domain was weaker.Conclusion: These findings present the multidimensionality of common gynecologic related symptoms and highlight the clinically meaningful associations between GRS and quality of life among women with HIV infection in China. There is an urgent need to take measures to increase vaginal care and education in advance, delivered by trusted health professionals.Keywords: women living with HIV/AIDS, symptoms, gynecologic related symptoms, quality of life

Ya-Fei Ye,1,2 Mei-Xian Zhang,3 Zhi Lin,4 Leiwen Tang5 1Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of China; 2Health Management Centre, Taizhou Hospital, Zhejiang University, Linhai, 317000, People’s Republic of China; 3Evidence-Based Medicine Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, People’s Republic of China; 4Operating Rooms, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, People’s Republic of China; 5Nursing Department, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of ChinaCorrespondence: Leiwen Tang, Nursing Department, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 East Qingchun Road, Hangzhou, 310016, People’s Republic of China, Tel/Fax +86-571-86006438, Email tanglw@zju.edu.cnAbstract: As a popular weight management intervention, intermittent fasting (IF) has been widely applied to the treatment of overweight and obesity in adults. This review describes the different forms and implementation protocols of IF and their effects on body weight, body composition, cardiometabolic risk factors and other diseases. The existing evidence suggests that IF is as effective as continuous energy restriction and may be a feasible and effective approach to weight loss.Keywords: overweight, obesity, intermittent fasting, continuous energy restriction, weight management

Yeshen Zhang,1,2,&ast; Zhengrong Xu,3,&ast; Wenfei He,4,&ast; Zehuo Lin,1,2 Yaoxin Liu,1,2 Yining Dai,1,2 Wei Chen,5 Weikun Chen,1,2 Wenlong He,1,2 Chongyang Duan,6 Pengcheng He,1,2 Yuanhui Liu,1,2 Ning Tan1,2 1Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 3Department of Cardiology, People’s Hospital of Baoan Shenzhen, Guangzhou, People’s Republic of China; 4Department of Cardiology, Guangdong Provincial People’s Hospital’s Nanhai Hospital, the Second People’s Hospital of Nanhai District Foshan City, Foshan, People’s Republic of China; 5Department of Cardiology, Fujian Provincial Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fujian Institute of Cardiovascular Disease, Fuzhou, People’s Republic of China; 6Department of Biostatistics, School of Public Health, Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning Tan; Yuanhui Liu, Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China, Tel +86-20-83819161, Fax +86-20-83824369, Email gdtanning@126.com; liuyuanhui@gdph.org.cnBackground: The serum uric acid/albumin ratio (sUAR), a novel inflammatory marker, effectively predicts acute kidney injury (AKI) and cardiovascular outcomes. However, whether the sUAR predicts post-contrast acute kidney injury (PC-AKI) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) remains uncertain. In this study, we evaluated the association between the sUAR and PC-AKI in patients with STEMI undergoing PCI.Methods: We consecutively recruited patients with STEMI who underwent PCI and stratified them into three groups according to the terciles of the sUAR. The primary outcome was the incidence of PC-AKI. The association between the sUAR and PC-AKI was assessed by multivariate logistic regression analysis.Results: A total of 2861 patients with STEMI were included in this study. The incidence of PC-AKI increased stepwise with increasing sUAR tercile (2.6% vs 4.0% vs 11.6%, p < 0.001), and the incidence of in-hospital major adverse clinical events (MACEs) was highest among patients in the Q3 group. Multivariate logistic regression analysis revealed that the sUAR was also an independent predictor of PC-AKI (continuous sUAR, per 1-unit increase, odds ratio [OR] [95% confidence interval (CI)]: 1.06 [1.02– 1.10], p = 0.005; tercile of sUAR, OR [95% CI] for Q2 and Q3: 1.18 [0.69– 2.01] and 1.85 [1.12– 3.06], respectively, with Q1 as a reference) but not in-hospital MACEs. In the receiver operating characteristic (ROC) analysis, the area under the curve (AUC) of the sUAR for predicting PC-AKI was 0.708 (95% CI: 0.666– 0.751), and ROC analysis also showed that the sUAR was superior to uric acid and albumin alone in predicting PC-AKI.Conclusion: Increasing sUAR was significantly associated with a higher risk of PC-AKI but not in-hospital MACEs in patients with STEMI who underwent PCI, suggesting that sUAR had a predictive value for PC-AKI after PCI in patients with STEMI. Further studies are required to confirm this finding.Keywords: serum uric acid/albumin ratio, post-contrast acute kidney injury, ST-segment elevation myocardial infarction

Hanshu Liu,1,&ast; Jingwen Li,1,&ast; Xinyi Wang,1 Jinsha Huang,1 Tao Wang,1 Zhicheng Lin,2 Nian Xiong1 1Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Laboratory of Psychiatric Neurogenomics, McLean Hospital; Harvard Medical School, Belmont, MA, 02478, USA&ast;These authors contributed equally to this workCorrespondence: Nian Xiong, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China, Tel +86 13995516750, Email nianxiong@hust.edu.cnAbstract: Excessive daytime sleepiness (EDS) is one of the most common sleep disorders in Parkinson’s disease (PD). It has attracted much attention due to high morbidity, poor quality of life, increased risk for accidents, obscure mechanisms, comorbidity with PD and limited therapeutic approaches. In this review, we summarize the current literature on epidemiology of EDS in PD to address the discrepancy between subjective and objective measures and clarify the reason for the inconsistent prevalence in previous studies. Besides, we focus on the effects of commonly used antiparkinsonian drugs on EDS and related pharmacological mechanisms to provide evidence for rational clinical medication in sleepy PD patients. More importantly, degeneration of wake-promoting nuclei owing to primary neurodegenerative process of PD is the underlying pathogenesis of EDS. Accordingly, altered wake-promoting nerve nuclei and neurotransmitter systems in PD patients are highlighted to providing clues for identifying EDS-causing targets in the sleep and wake cycles. Future mechanistic studies toward this direction will hopefully advance the development of novel and specific interventions for EDS in PD patients.Keywords: excessive daytime sleepiness, Parkinson’s disease, epidemiology, wakefulness, dopaminergic neurons, dopaminergic agents

Xingxing Chen,&ast; Xue Xia,&ast; Tiancheng Dong, Zhiwei Lin, Leilei Du, Hao Zhou Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao Zhou, Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, NanBai Xiang Avenue, Ouhai District, Wenzhou, 325000, People’s Republic of China, Tel +86 1 396 880 1939, Fax +86 577 555 79796, Email wyzh66@126.comPurpose: Endothelial-to-mesenchymal transition (EndMT) is an important mechanism underlying cardiac fibrosis. The anti-ischemic drug trimetazidine (TMZ) is reportedly useful in ventricular remodeling and associated with NADPH oxidase (NOX) 2. This study aimed to investigate the possible effect of TMZ on cardiac fibrosis exerted via the inhibition of NOX2-mediated EndMT.Methods: A cardiac fibrosis model was established in Sprague-Dawley rats through a subcutaneous injection of isoproterenol (ISO, 5 mg/kg/d). Echocardiographic parameters, myocardial fibrosis, NOX2 expression and EndMT were assessed. An in vitro model of EndMT was developed using human umbilical vein endothelial cells (HUVECs) via treatment with transforming growth factor-β (TGF-β) at 10 ng/mL for 24 h. HUVECs were administrated with TMZ or TMZ and lentivirus, the expression of EndMT and related proteins was observed by wound healing assay, immunoblotting, and immunofluorescence.Results: Rats injected with ISO exhibited severe interstitial cardiac fibrosis and perivascular fibrosis, decreased left ventricular ejection fraction, and increased NOX activity. TMZ treatment mitigated cardiac fibrosis, ameliorated left ventricular dysfunction, and reduced NOX activity. In addition, TMZ effectively inhibited EndMT in ISO-treated rat hearts and TGF-β-treated HUVECs, as manifested by increased CD31 expression, decreased α-SMA expression, and suppressed cell migration. Compared with the control group, the expression of NOX2, nuclear factor-κB (NF-κB), and Snail was increased in vivo and in vitro but decreased with TMZ treatment. Furthermore, the overexpression of NOX2 by lentivirus abolished the protective effects of TMZ on TGF-β-induced EndMT.Conclusion: TMZ may ameliorate EndMT and ISO-induced cardiac fibrosis through the NOX2/NF-κB/Snail pathway. The findings of the study may provide new insights into the potential role of TMZ in the pathophysiology of cardiac fibrosis.Keywords: trimetazidine, endothelial-to-mesenchymal transition, cardiac fibrosis, NADPH oxidase 2

Zhichao Lin,&ast; Wenhai Huang,&ast; Zehua Xie,&ast; Yongsheng Yi, Zumei Li Department of Thoracic Surgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhichao Lin, Department of Thoracic Surgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, No. 23 Haibang Street, Beijie, Jiangmen, 529030, People’s Republic of China, Tel +86 750-3989432, Email 230160549@qq.comBackground: Based on bioinformatics analysis and experimental validation, we investigated the expression, clinical significance, immune infiltration, and potential signaling pathways of miR-3940-5p in lung adenocarcinoma (LUAD).Methods: 521 LUAD tissue samples and 46 normal lung tissue samples from The Cancer Genome Atlas (TCGA) database. We evaluated the relationship between clinical features and miR-3940-5p expression using Kruskal–Wallis, Wilcoxon sign-rank, and logistic regression, explored the relationship between miR-3940-5p expression and the prognosis of LUAD patients using Kaplan–Meier survival curve analysis. Several databases were used to identify miRNA targets. MiR-3940-5p target genes were analyzed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The significant role of miR-3940-5p in function was evaluated using immune infiltration analysis. LUAD cell lines were tested for miR-3940-5p expression using QRT-PCR.Results: There was a significant association between high miR-3940-5p expression in LUAD and T stage (P=0.005), pathologic stage (P=0.047), race (White vs Asian & Black or African American) (P=0.041), residual tumor (P=0.043), and anatomic neoplasm subdivision2 (P=0.030). MiR-3940-5p expression predicted poor overall survival (HR: 1.35; 95% CI: 1.01– 1.81; P=0.045), disease-specific survival (HR: 1.53; 95% CI: 1.05– 2.23; P=0.026), and progression-free survival (HR: 1.35; 95% CI: 1.03– 1.77; P=0.032). BAP1, BBS1, CCR2, KCNE3, PEBP1, and RABL2A were all associated with poor OS in LUAD patients with low miR-3940-5p expression levels. According to GO and KEGG analyses, miR-3940-5p may play a role in LUAD development by regulating pathways such as measles, PI3K-Akt signaling pathway, and p53 signaling pathway. There was a correlation between the expression level of miR-3940-5p and immune infiltration. LUAD cell lines showed significantly higher levels of miR-3940-5p than Beas-2B cells.Conclusion: A high expression of miR-3940-5p is significantly associated with a poor prognosis in patients with LUAD, suggesting that it could be used as a prognostic biomarker.Keywords: microRNA-3940-5p, lung adenocarcinoma, clinical significance, immune infiltration, regulation network

Yiyang Zhou,1,&ast; Wei Lin,1,&ast; Tian Rao,1 Jinyu Zheng,2 Tianlei Zhang,1 Min Zhang,1 Zhenlang Lin1 1Department of Pediatrics, The Second School of Medicine, Taizhou Women and Children’s Hospital of Wenzhou Medical University, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China; 2Department of Clinical Medicine, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhenlang Lin, Email lzlprof2020@163.comAbstract: Ferroptosis is a novel regulated cell death characterized by metabolic disorders and iron-dependent oxidative destruction of the lipid bilayer. It is primarily caused by the imbalance of oxidation and anti-oxidation in the body and is precisely regulated by numerous factors and pathways inside and outside the cell. Recent studies have indicated that ferroptosis plays a vital role in the pathophysiological process of multiple systems of the body including the nervous system. Ferroptosis may be closely linked to the occurrence and development of neurodegenerative diseases, strokes, and brain tumors. It may also be involved in the development, maturation, and aging of the nervous system. Therefore, this study aims to investigate ferroptosis’s occurrence and regulatory mechanism and summarize its research progress in the pathogenesis and treatment of neurological diseases. This would allow for novel ideas for basic and clinical research of neurological diseases.Keywords: ferroptosis, iron, lipid peroxidation, molecular mechanism, neurodevelopment, neurological diseases

Guilan Cheng,1,&ast; Dingxi Wang,1,&ast; Ping Zhu,2 Ziqi Lin,2 Shichao Zhu,3 Juan Li,1 Linqian Li,1 Yipeng Zhang,4 Guixiang Li1 1Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, People’s Republic of China; 2Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Department of Infection Control, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Department of Information Centre, West China Hospital, Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guixiang Li, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, No. 37 Wainan Guoxue Alley, Chengdu, 610041, People’s Republic of China, Tel +86 18980601726, Email liguixiang@wchscu.cnBackground: There are few published reports describing the clinical characteristics of acute pancreatitis (AP) patients with multidrug-resistant organism (MDRO) infection.Methods: This was a retrospective analysis of AP patients with MDRO infection in West China Hospital between July 2015 and June 2020. Basic clinical data, disease progression states, and prognoses of the MDRO and non-MDRO infection groups were compared and analyzed. Logistic regression analysis was performed to explore the related risk factors for MDRO infection. The prognoses of different MDRO infection types were compared.Results: In total, 9812 AP patients were included, 2436 (24.83%) of whom had healthcare-associated infections (641 [26.31%] MDRO infections and 1795 [73.69%] non-MDRO infections). The main MDRO strain was carbapenem-resistant Acinetobacter baumannii (CRAB) (400/62.40%). The rate of discharge against doctor’s advice, mortality, hospitalization expenses, and hospitalization days was higher in the MDRO infection group than in the noninfection group. By logistic regression analysis, the independent risk factors associated with MDRO infection included male sex (OR 1.36, 95% CI 1.09∼ 1.70), severity (OR 1.40, 95% CI 1.10∼ 1.78), ICU referral (OR 2.48, 95% CI 1.79∼ 3.44), abdominal puncture (OR 2.78, 95% CI 1.93∼ 4.02), fiberoptic bronchoscopy (OR 1.95, CI 1.35∼ 2.81), and PICC/CVC placement (OR 1.48, CI 1.06∼ 2.06). Compared with biliary and hypertriglyceridemia (HTG) (OR 0.94, 95% CI 0.73∼ 1.23), alcohol (OR 0.30, 95% CI 0.19∼ 0.47) and other etiologies (OR 0.58, 95% CI 0.41∼ 0.81) conferred a lower risk of MDRO infection. The carbapenem-resistant Klebsiella pneumoniae (CRKP) infection rate was highest in the patients who died.Conclusion: The CRAB proportion was highest in AP patients with MDRO infection. MDRO infection is related to many factors, has a poor prognosis, and increases the patient burden. CRKP infection is directly related to poor prognosis.Keywords: acute pancreatitis, multidrug-resistant organisms, infection

Zhoumeng Lin,1– 4,&ast; Wei-Chun Chou,1– 4,&ast; Yi-Hsien Cheng,3,4 Chunla He,5 Nancy A Monteiro-Riviere,6,7 Jim E Riviere7,8 1Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida, Gainesville, FL, USA; 2Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, USA; 3Institute of Computational Comparative Medicine, Kansas State University, Manhattan, KS, USA; 4Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA; 5Department of Biostatistics, College of Public Health and Health Professions, University of Florida, Gainesville, FL, USA; 6Nanotechnology Innovation Center of Kansas State, Kansas State University, Manhattan, KS, USA; 7Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, Raleigh, NC, USA; 8 1Data Consortium, Kansas State University, Olathe, KS, USA&ast;These authors contributed equally to this workCorrespondence: Zhoumeng Lin, Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida, 1225 Center Dr., Gainesville, FL, 32610, USA, Tel +1 352-273-6160, Email linzhoumeng@ufl.eduBackground: Low delivery efficiency of nanoparticles (NPs) to the tumor is a critical barrier in the field of cancer nanomedicine. Strategies on how to improve NP tumor delivery efficiency remain to be determined.Methods: This study analyzed the roles of NP physicochemical properties, tumor models, and cancer types in NP tumor delivery efficiency using multiple machine learning and artificial intelligence methods, using data from a recently published Nano-Tumor Database that contains 376 datasets generated from a physiologically based pharmacokinetic (PBPK) model.Results: The deep neural network model adequately predicted the delivery efficiency of different NPs to different tumors and it outperformed all other machine learning methods; including random forest, support vector machine, linear regression, and bagged model methods. The adjusted determination coefficients (R2) in the full training dataset were 0.92, 0.77, 0.77 and 0.76 for the maximum delivery efficiency (DEmax), delivery efficiency at 24 h (DE24), at 168 h (DE168), and at the last sampling time (DETlast). The corresponding R2 values in the test dataset were 0.70, 0.46, 0.33 and 0.63, respectively. Also, this study showed that cancer type was an important determinant for the deep neural network model in predicting the tumor delivery efficiency across all endpoints (19– 29%). Among all physicochemical properties, the Zeta potential and core material played a greater role than other properties, such as the type, shape, and targeting strategy.Conclusion: This study provides a quantitative model to improve the design of cancer nanomedicine with greater tumor delivery efficiency. These results help to improve our understanding of the causes of low NP tumor delivery efficiency. This study demonstrates the feasibility of integrating artificial intelligence with PBPK modeling approaches to study cancer nanomedicine.Graphical Abstract: Keywords: artificial intelligence, machine learning, physiologically based pharmacokinetic modeling, nanomedicine, drug delivery, nanotechnology

Qing Wang,1,&ast; Song Zhang,2,&ast; Qiaodong Xu,1 Jiahong Liang,1 Peidong Zhang,1 Wenlong Huang,1 Zhihuan Lin,1 Shaodong Zheng,1 Songgang Gu,1 Jiang Yan1 1Department of Biliary-Pancreatic Minimally Invasive Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, People’s Republic of China; 2Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiang Yan; Songgang Gu, Email jyan@stu.edu.cn; gusonggang@163.comPurpose: Polymerase δ (POLD) proteins is a pivotal B-family DNA polymerase in the process of genome replication and repair and are comprised of POLD1-4. The predictive value of POLDs in hepatocellular carcinoma (HCC) has not been evaluated until now.Patients and Methods: A total of 369 hepatocellular carcinoma samples and 50 adjacent normal samples were enrolled from the TCGA-LIHC database, and the GSE10186 database was also used. Transcription, methylation and genetic alteration status of HCC patients were evaluated by GEPIA, Kaplan–Meier plotter, cBioPortal, MethHC, MethSurv. SurvExpress was employed to generate the overall prognosis prediction signature of POLDs. POLDs coexpressed genes were explored and enriched in potential pathways. K-M curves were generated to compare the different survival results in different groups, while ROC curves were used to validate the efficiency of the POLD signature.Results: All four POLD subunits were highly expressed in HCC tumor tissues. POLD1-3 and increased mRNA levels were also positively associated with advanced tumor stage and OS prognosis. Methylation in the promoter of POLDs affects mRNA expression and OS, especially for some specific CpG sites. Meanwhile, POLDs could preferably predict the prognosis for patients who suffered from a high gene mutation burden. We evaluated the combined prognostic predictive value of four POLD subunits in both the TCGA-LIHC and GSE10186 databases and recognized the statistically significant HR of the high-risk group, along with the reliable predictive value. The coexpressed gene sets and annotation results showed that the POLD coexpressed genes were mostly associated with DNA repair and cell cycle regulation pathways.Conclusion: POLD is an essential predictive factor for the prognosis of HCC. The united signature could precisely identify unfavorable clinical outcome of HCC.Keywords: DNA polymerase δ subunits, hepatocellular carcinoma, DNA repair, prognosis

Zicong Lin,1,&ast; Zhiqin Deng,1,&ast; Jianquan Liu,1,&ast; Zhongshi Lin,2 Siyu Chen,3 Zhenhan Deng,3 Wencui Li1 1Hand and Foot Surgery Department, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, 518035, People’s Republic of China; 2Shenzhen Institute for Drug Control (Shenzhen Testing Center of Medical Devices), Shenzhen, Guangdong, 518057, People’s Republic of China; 3Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, 518035, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhenhan Deng, Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, 3002 Sungang West Road, Shenzhen City, 518025, People’s Republic of China, Tel +86 13928440786, Fax +86 755-83366388, Email dengzhenhan@email.szu.edu.cn Wencui Li, Department of Hand and Foot Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, 3002 Sungang West Road, Shenzhen City, 518025, People’s Republic of China, Tel +86 13923750767, Email liwencui@email.szu.edu.cnAbstract: Articular cartilage allows the human body to buffer and absorb stress during normal exercise. It is mainly composed of cartilage cells and the extracellular matrix and is surrounded by the extracellular microenvironment formed by synovial fluid and various factors in it. Studies have shown that chondrocytes are the metabolic center of articular cartilage. Under physiological conditions, the extracellular matrix is in a dynamic balance of anabolism and catabolism, and various factors and physical and chemical conditions in the extracellular microenvironment are also in a steady state. This homeostasis depends on the normal function of proteins represented by various ion channels on chondrocytes. In mammalian chondrocyte species, ion channels are mainly divided into two categories: cation channels and anion channels. Anion channels such as chloride channels have become hot research topics in recent years. These channels play an extremely important role in various physiological processes. Recently, a growing body of evidence has shown that many pathological processes, abnormal concentration of mechanical stress and chloride channel dysfunction in articular cartilage lead to microenvironment disorders, matrix and bone metabolism imbalances, which cause partial aseptic inflammation. These pathological processes initiate extracellular matrix degradation, abnormal chondrocyte death, hyperplasia of inflammatory synovium and bony. Osteoarthritis (OA) is a common clinical disease in orthopedics. Its typical manifestations are joint inflammation and pain caused by articular cartilage degeneration, but its pathogenesis has not been fully elucidated. Focusing on the physiological functions and pathological changes of chloride channels and pathophysiology of aseptic inflammation furthers the understanding of OA pathogenesis and provides possible targets for subsequent medication development.Keywords: osteoarthritis, chondrocyte, ion channel, inflammatory factors

Libo Wang,1 Gan Li,1 Chang Yuan,1 Yuele Yang,1 Gongxia Ling,1 Jinyu Zheng,1 Yiyang Zhou,1 Tianlei Zhang,1 Wei Lin,2 Zhenlang Lin2 1Department of Clinical Medicine, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China; 2Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaCorrespondence: Wei Lin; Zhenlang Lin Email linwei1110@163.com; lzlprof2020@163.comAbstract: Coronavirus disease 2019 (COVID-19) has been circulating in many countries around the world, characterized by long incubation period, strong infectivity, strong variability, high population susceptibility and diversified transmission methods. Its causative agent is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compared with adult patients, the clinical manifestations of COVID-19 in children are often dominated by mild or asymptomatic infections, but children are also important virus carriers and play an important role in the transmission of the virus. In addition, some children will show excessive inflammatory response and experience serious complications such as multisystem inflammatory syndrome in children (MIS-C). At present, the research on COVID-19 in children is still imperfect. This article will review epidemiological characteristics, the mechanism of action, variant characteristics, clinical manifestations, auxiliary examinations and treatment of children with COVID-19, in order to provide help for the diagnosis, treatment and research of children with COVID-19.Keywords: children, COVID-19, mutation, clinical manifestations, treatment

Zhengjun Lin,1,2 Yiting Xu,2 Xianghong Zhang,1 Jia Wan,1 Tao Zheng,1 Hongxuan Chen,1 Shijie Chen,3 Tang Liu1 1Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People’s Republic of China; 2Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People’s Republic of China; 3Department of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, People’s Republic of ChinaCorrespondence: Shijie ChenDepartment of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, 410006, Hunan, People’s Republic of ChinaTel +86-73185292111Email shijiechencsu@163.comTang LiuDepartment of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People’s Republic of ChinaTel +86-73185292111Email liutang1204@csu.edu.cnBackground: Pyroptosis is critically associated with cancer initiation and progression, which can be modulated by diverse long noncoding RNAs (lncRNAs). However, the roles of pyroptosis-related lncRNAs in soft tissue sarcomas (STS) are still largely unknown.Methods: Our study included a total of 259 STS patients extracted from The Cancer Genome Atlas Sarcoma (TCGA-SARC) dataset. Gene expression data fragments per kilobase of transcript per million mapped reads (FPKM) values were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) for the investigation of the expression pattern of pyroptosis-related lncRNAs. Unsupervised clustering based on pyroptosis-related lncRNAs was performed, and the associations of pyroptosis-related lncRNAs with clinical outcomes and immune microenvironment were investigated. Two risk signatures for overall survival (OS) and disease-free survival (DFS) were constructed and validated in independent cohorts.Results: A total of 166 pyroptosis-related lncRNAs were identified in STS. Patients were clustered into two subgroups by unsupervised clustering, and cluster 2 had better prognoses, higher immune scores, higher abundance of immune cells, and higher expression of some immune checkpoints. OS- and DFS-risk signatures based on 10 and 13 pyroptosis-related lncRNAs, respectively, with favorable discrimination were constructed and validated. High-risk patients had favorable prognoses, and receiver operating characteristic (ROC) curves showed that both risk signatures could function as excellent predictors for prognoses of STS patients. Besides, the OS-risk signature could also excellently predict the immune landscape of STS.Conclusion: In conclusion, our study revealed the clinical significance and critical roles of pyroptosis-related lncRNAs in STS, and constructed novel risk signatures based on pyroptosis-related lncRNAs that could effectively predict clinical outcomes and immune microenvironment in STS.Keywords: pyroptosis, immune microenvironment, prognostic signature, soft tissue sarcomas

Zhichao Lin,1,&ast; Wenhai Huang,1,&ast; Yongsheng Yi,1,&ast; Dongbing Li,2,&ast; Zehua Xie,1 Zumei Li,1 Min Ye1 1Department of Thoracic Surgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, Guangdong, People’s Republic of China; 2MyGene Diagnostics Co., Ltd., Guangzhou, 510000, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhichao Lin; Min YeDepartment of Thoracic Surgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, No. 23 Haibang Street, Beijie, Jiangmen, 529030, Guangdong, People’s Republic of ChinaTel +86-750-3989432Email 230160549@qq.com; Yeminzhangcuiyuan@126.comBackground: The role of long noncoding RNA (LncRNA) ADAMTS9 antisense RNA 2 (ADAMTS9-AS2) is unclear in lung adenocarcinoma (LUAD). The aim of this study was to explore the relationship between ADAMTS9-AS2 and LUAD, based on The Cancer Genome Atlas (TCGA) database and bioinformatics analysis.Methods: Various statistical methods, Kaplan–Meier method, Cox regression analysis, GSEA, and immune infiltration analysis were used to evaluate the relationship between clinical features and ADAMTS9-AS2 expression, prognostic factors, and the significant involvement of ADAMTS9-AS2 in function.Results: In LUAD patients, low expression of ADAMTS9-AS2 was associated with N stage (P=0.011), gender (P=0.002), number of packs smoked (P=0.024) and smoker (P< 0.001). Low ADAMTS9-AS2 expression predicted a poorer overall survival (OS) (HR: 0.68; 95% CI: 0.51– 0.91; P=0.01). And ADAMTS9-AS2 expression (HR: 0.626; 95% CI: 0.397– 0.986; P=0.043) was independently correlated with OS in LUAD patients. Unwinding of DNA, extrinsic pathway, polo-like kinase-mediated events, cori cycle, MCM pathway, proteasome pathway, lagging strand synthesis and PCNA-dependent long patch base excision repair were differentially enriched in ADAMTS9-AS2 high expression phenotype. ADAMTS9-AS2 expression was correlated with certain immune infiltrating cells.Conclusion: In LUAD patients, ADAMTS9-AS2 expression was significantly associated with poor survival and immune infiltration. ADAMTS9-AS2 may be a promising biomarker of prognosis and response to immunotherapy for LUAD.Keywords: lung adenocarcinoma, ADAMTS9-AS2 antisense RNA 2, prognosis, immune infiltration, biomarker

Yanqi Qi,&ast; Jiawen Xu,&ast; Zhe Lin,&ast; Yijing Tao, Fenglei Zheng, Yujia Wang, Yameng Sun, Songling Fu, Wei Wang, Chunhong Xie, Yiying Zhang, Fangqi Gong Department of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fangqi GongDepartment of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People’s Republic of ChinaTel/Fax +86-571-88873008Email gongfangqi@zju.edu.cnIntroduction: Kawasaki disease (KD) is an acute febrile systemic vasculitis, but the etiology remains unknown. We studied serum levels of CD147, DcR3, and IL33 in different stages of KD to explore the value of CD147, DcR3, and IL33 in the pathophysiology of KD.Methods: We measured serum levels of CD147, DcR3, and IL33 by enzyme-linked immunosorbent assay (ELISA) at different stages with 71 KD patients and 66 healthy control children. We apply for network tools GeneMANIA and Cytoscape APP to analyze the functions of these pro-inflammatory factors at the gene and protein level.Results: Serum levels of CD147, DcR3, and IL33 were significantly increased in KD patients before IVIG treatment. Serum levels of CD147, DcR3, and IL33 gradually decreased over time after the treatment of IVIG. Eight cases were IVIG non-responders, while nine KD patients got CALs, but they did not overlap. And there were no statistical differences between group IVIG responders and IVIG non-responders or between groups without CALs and with CALs. We explored the functions of CD147, DcR3, and IL33 from GeneMANIA and Cytoscape APP and found these third pro-inflammatory factors were coexpressed, physical interactions, genetic interactions with other KD-related factors.Conclusion: CD147, DcR3, and IL33 are involved in the pathophysiology of KD, which provides novel evidence for diagnosing and treating KD with their inhibitors.Keywords: Kawasaki disease, coronary artery lesions, CD147, DcR3, IL33, PI3K/AKT pathway

Tong Lin,1 E Zhang,1 Zhimei Lin,1 Lisheng Peng2 1The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China; 2Department of Science and Education, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, People’s Republic of ChinaCorrespondence: Lisheng PengDepartment of Science and Education, Shenzhen Traditional Chinese Medicine Hospital, No. 1 Fuhua Road, Futian District, Shenzhen, Guangdong Province, People’s Republic of ChinaEmail pls0556@gzucm.edu.cnBackground: The prognosis of patients with advanced hepatocellular carcinoma (HCC) remains poor. Lipid remodeling modulators are considered promising therapeutic targets of cancers, owing to their functions of facilitating cancer cells’ adaption to the limited environment. Lysophosphatidylcholine acyltransferases (LPCATs) are enzymes regulating bio-membrane remodeling, whose roles in HCC have not been fully illuminated.Methods: Multiple bioinformatic tools were applied to comprehensively evaluate the expression, genetic alterations, clinical relevance, prognostic values, DNA methylation, biological functions, and correlations with immune infiltration of LPCATs in HCC.Results: We found LPCAT1 was significantly overexpressed and the most frequently altered in HCC. The high-expression of LPCAT1/4 indicated clinicopathological advancements and poor prognoses of HCC patients. Even though the global DNA methylation of LPCATs in HCC showed no significant difference with that in normal liver, the hypermethylation of numerous CpG sites of them implied worse survivals of HCC patients. Thirty LPCATs’ interactive genes were identified, which were generally membrane components and partook in phospholipid metabolism pathways. Finally, we found the expression of LPCATs was extensively positively correlated with the infiltration of various stimulatory and suppressive tumor-infiltrating immune cells (TIICs) in the tumor microenvironment.Conclusion: This study addressed LPCAT1/4 were potential prognostic and immunotherapeutic biomarkers of HCC targeting bio-membrane lipid remodeling.Keywords: hepatocellular carcinoma, LPCATs, bioinformatics, biomarker, immune infiltration

Zhi Dong,1,&ast; Yingyu Lin,1,&ast; Fangzeng Lin,2,&ast; Xuyi Luo,3 Zhi Lin,1 Yinhong Zhang,1 Lujie Li,1 Zi-Ping Li,1 Shi-Ting Feng,1 Huasong Cai,1 Zhenpeng Peng1 1Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People’s Republic of China; 2Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People’s Republic of China; 3Department of Emergency, Guangzhou First People’s Hospital, Guangzhou, Guangdong, 510180, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huasong Cai; Zhenpeng PengDepartment of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58th, The Second Zhongshan Road, Guangzhou, Guangdong, People’s Republic of ChinaTel +86 20-87755766, extension 8471Fax +86 20-87615805Email caihuas@mail.sysu.edu.cn; pengzhp@mail.sysu.edu.cnPurpose: The treatment response to initial conventional transarterial chemoembolization (cTACE) is essential for the prognosis of patients with hepatocellular carcinoma (HCC). This study explored and verified the feasibility of machine-learning models based on clinical data and contrast-enhanced computed tomography (CT) image findings to predict early responses of HCC patients after initial cTACE treatment.Patients and Methods: Overall, 110 consecutive unresectable HCC patients who were treated with cTACE for the first time were retrospectively enrolled. Clinical data and imaging features based on contrast-enhanced CT were collected for the selection of characteristics. Treatment responses were evaluated based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) by postoperative CT examination within 2 months after the procedure. Python (version 3.70) was used to develop machine learning models. Least absolute shrinkage and selection operator (LASSO) algorithm was applied to select features with the impact on predicting treatment response after the first TACE procedure. Six machine learning algorithms were used to build predictive models, including XGBoost, decision tree, support vector machine, random forest, k-nearest neighbor, and fully convolutional networks, and their performances were compared using receiver operator characteristic (ROC) curves to determine the best performing model.Results: Following TACE, 31 patients (28.2%) were described as responsive to TACE, while 72 patients (71.8%) were nonresponsive to TACE. Portal vein tumor thrombosis type, albumin level, and distribution of tumors within the liver were selected for predictive model building. Among the models, the RF model showed the best performance, with area under the curve (AUC), accuracy, sensitivity, and specificity of 0.802, 0.784, 0.904, and 0.480, respectively.Conclusion: Machine learning models can provide an accurate prediction of the early response of initial TACE treatment for HCC, which can help in individualizing clinical decision-making and modification of further treatment strategies for patients with unresectable HCC.Keywords: hepatocellular carcinoma, transarterial chemoembolization, machine learning, prediction model, treatment response

Tong Lin,1 Yingzhao Zhang,1 Zhimei Lin,1 Lisheng Peng2 1The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China; 2Department of Science and Education, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, People’s Republic of ChinaCorrespondence: Lisheng PengDepartment of Science and Education, Shenzhen Traditional Chinese Medicine Hospital, No. 1 Fuhua Road, Futian District, Shenzhen, Guangdong Province, People’s Republic of ChinaEmail pls0556@gzucm.edu.cnBackground: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is still poor, effective therapeutic targets are needed. ZW10 interacting kinetochore protein (Zwint) is an essential component of the mitotic spindle checkpoint and is upregulated in cancers. Disappointing, the role of ZWINT in HCC has not been fully illuminated.Methods: Multiple tools, including TIMER2.0, Oncomine, GEPIA2, UALCAN, LinkedOmics, Kaplan–Meier Plotter, cBioPortal, and MethSurv, etc. were applied to comprehensively analyze the expression, genetic alternations, clinicopathological relevance, prognostic value, and DNA methylation of ZWINT, along with its correlations with immune infiltration in HCC. Besides, gene set enrichment analysis (GSEA) and protein–protein interaction (PPI) analysis were performed for the correlated genes of ZWINT, closely interconnected clusters and hub proteins in the PPI network were discovered to learn the underlying biological mechanisms.Results: We found ZWINT was significantly upregulated in diverse cancers including HCC, compared with the corresponding normal controls. ZWINT upregulation was significantly associated with unfavorable clinicopathological features and survivals of HCC patients. Genetic alternations of ZWINT frequently occurred, which were linked to worse outcomes of HCC patients. The results of GSEA displayed ZWINT and its correlated genes might be components of condensed chromosomes and spindles, which participated in biological processes and signaling pathways involving DNA replication, cytokinesis, and cell cycle checkpoint, etc. Three highly interconnected clusters and 10 hub proteins were identified from the PPI network constructed with the correlated genes of ZWINT. Moreover, ZWINT expression was found positively correlated with infiltration levels of various immune cells, especially myeloid-derived suppressor cells.Conclusion: This study demonstrated ZWINT might be a promising unfavorable prognostic biomarker and a therapeutic target of HCC, which could regulate HCC progression through cell division and immunosuppression.Keywords: hepatocellular carcinoma, ZWINT, prognosis, immune infiltration, kinetochore

Qing Li,1,2,&ast; Jingjing Ma,1,2,&ast; Yan Ma,1,2 Zhiguang Lin,1,2 Hui Kang,1,2 Bobin Chen1,2 1Department of Hematology, Huashan Hospital North, Fudan University, Shanghai, 201907, People’s Republic of China; 2Department of Hematology, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bobin ChenDepartment of Hematology, 108 Luxiang Road, Baoshan District, Shanghai, People’s Republic of ChinaTel +86 21-52889999Email bbchen@fudan.edu.cnPurpose: High‐dose methotrexate (HD‐MTX)-based chemotherapy regimen is the first-line treatment of primary central nervous system lymphoma (PCNSL). At present, doses of MTX in the range of 3.5– 8 g/m2 are frequently used. However, the optimal dose of methotrexate for PCNSL remains controversial. The purpose of this real-world study was to compare the efficacy and toxicity of HD-MTX in patients with untreated PCNSL.Methods: Immunocompetent adults with newly diagnosed PCNSL between January 2015 and December 2018 were investigated and followed up to June 2019. All patients’ initial treatments were based on HD‐MTX chemotherapy regimens.Results: A total of 73 patients were reviewed. For patients who received HD-MTX at 8 g/m2 vs.3.5 g/m2, the complete response (CR) rates were 68.29% vs 43.75% (p = 0.03), and the median PFS times were 17.7 months vs 9.05 months (HR=0.455, 95% CI 0.239– 0.865, p=0.016). There was no significant difference in OS between the two groups. Serious adverse effects were uncommon and clinically manageable.Conclusion: There is a correlation of treatment response and clinical outcomes between the dosage of MTX in initial induction therapy in newly diagnosed PCNSL. MTX dose of 8 g/m2 provided a higher CR rate and PFS benefits with acceptable adverse effects.Keywords: primary central nervous system lymphoma, high-dose methotrexate, chemotherapy, prognosis

Jiang Zhu,1,&ast; Xia Zhang,2,&ast; Hong Xie,1 Yuye Wang,1 Xiaoxiao Zhang,1 Zhaoheng Lin3 1Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, 215008, Jiangsu, People’s Republic of China; 2Department of Anesthesiology, Wuzhong People’s Hospital, Suzhou, Jiangsu, 215128, People’s Republic of China; 3Intensive Care Unit, People’s Hospital of Xishuangbanna Dai Nationality Autonomous Prefecture, Jinghong City, 666100, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhaoheng LinIntensive Care Unit, People’s Hospital of Xishuangbanna Dai Nationality Autonomous Prefecture, Galan South Road, Jinghong City, 666100, Yunnan, People’s Republic of ChinaTel +86691-2123836Fax +8615198406999Email linzh_med@163.comIntroduction: Doxorubicin (Dox) is an effective anticancer agent; however, its cardiotoxicity remains a challenge. Dysfunction of intracellular calcium ion (Ca2+) is implicated in the process of Dox-induced cardiomyocyte apoptosis. Although store-operated Ca2+ entry (SOCE) is suggested to be responsible for Ca2+ entry in cardiomyocytes, the direct role of store-operated Ca2+ channels in Dox-related cardiomyocyte apoptosis is unknown.Materials and Methods: Cardiomyocyte Stim1-specific knockout or overexpression mice were treated with Dox. Cardiomyocytes were pretreated with Stim1 adenovirus or siRNA followed by Dox incubation in vitro. Cardiac function and underlying mechanisms echocardiography were assessed via immunofluorescence, flow cytometry, real-time PCR, Western blotting and immunoprecipitation.Results: We observed the inhibition of Stim1 expression, association of Stim1 to Orai1 or Trpc1, and SOCE in Dox-treated mouse myocardium and cardiomyocytes. Orai1 and Trpc1 expression remained unchanged. Cardiomyocyte-specific deficiency of Stim1 exacerbated Dox-induced cardiac dysfunction and myocardial apoptosis. However, specific overexpression of Stim1 in the myocardium was associated with amelioration of cardiac dysfunction and myocardial apoptosis. In vitro, STIM1 knockdown potentiated Dox-induced AC16 human cardiomyocyte apoptosis. This apoptosis was attenuated by STIM1 upregulation. Moreover, STIM1 downregulation enhanced Dox-induced endoplasmic reticulum (ER) stress in cardiomyocytes. In contrast, STIM1 overexpression inhibited the activation of the above molecular markers of ER stress. Immunoprecipitation assay showed that STIM1 interacted with GRP78 in cardiomyocytes. This interaction was attenuated in response to Dox treatment.Conclusion: Our data demonstrate that cardiomyocyte STIM1 binding to GRP78 ameliorates Dox cardiotoxicity by inhibiting pro-apoptotic ER stress.Keywords: doxorubicin, cardiotoxicity, cardiomyocyte apoptosis, STIM1, endoplasmic reticulum stress

Xinyang Fu,1,&ast; Zhiqiang Lin,1,&ast; Sumei Chen,2 Limian Hong,1 Xueping Yu,2 Shuifa Wu1 1Department of Pharmacy, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, People’s Republic of China; 2Department of Infectious Disease, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuifa WuDepartment of Pharmacy, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 250 East Street, Licheng District, Quanzhou, Fujian, 362000, People’s Republic of ChinaEmail shfw0116@126.comXueping YuDepartment of Infectious Disease, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 250 East Street, Licheng District, Quanzhou, Fujian, 362000, People’s Republic of ChinaEmail xpyu15@fudan.edu.cnAbstract: The pharmacokinetic/pharmacodynamic (PK/PD) parameter for evaluating the efficacy of vancomycin is now recommended to target an AUC/MIC (area under the curve, AUC; minimum inhibitory concentration, MIC) ratio of 400 to 600, and trough concentration should not be used as a substitute. We report a case of intracranial infection caused by methicillin-resistant Staphylococcus epidermidis (MRSE), which was sensitive to vancomycin (MIC=2μg/mL) and linezolid (MIC=4μg/mL). The trough concentration of vancomycin in serum was 18.3 μg/mL, and the vancomycin concentration in CSF was 5.0 μg/mL, all within normal range. However, the AUC/MIC ratio was calculated to be 125 mg·h·L− 1, unable to reach target AUC/MIC. Vancomycin was replaced with linezolid after 36 days of treatment due to poor outcome, and the patient was eventually cured. Further, 23 cases of intracranial methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant coagulase-negative Staphylococcus (MRCoNS) infections were reported, of which 1 case with MRSA had a vancomycin MIC of 1 μg/mL, while the remaining 22 cases had vancomycin MICs > 1 μg/mL. The linezolid-containing regimen was used after drug susceptibility results or if the initial treatment failed, leading to recovery in 19 patients, microbial clearance in 3 patients, and treatment failure in 1 case. In conclusion, vancomycin dosing should be based on AUC-guided dosing and monitoring. When the vancomycin MIC of MRSA/MRCoNS is > 1 μg/mL, the target AUC/MIC may not be achieved. In such cases, linezolid can effectively be considered as a good alternative to vancomycin.Keywords: AUC/MIC, trough concentration, intracranial infection, vancomycin, linezolid

Xiaonan Zhang,1,&ast; Huimin Fang,1,&ast; Zhigang Zeng,1 Kaijun Zhang,1 Zhanyi Lin,1,2 Gang Deng,1 Weiping Deng,1 Lichang Guan,1 Xuebiao Wei,1 Xinyi Li,2 Lei Jiang,1– 3 Lishu Xu1– 3 1Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 2School of Medicine, South China University of Technology, Guangzhou, 510641, People’s Republic of China; 3The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lei Jiang; Lishu Xu Tel +86-20-83827812; +86-20-13660032429Email jianglei@smu.edu.cn; xulishu70@163.comPurpose: Gastric cancer is a common tumor type associated with nutritional and immune status. The aim of the current study was to investigate the prognostic value of a preoperative prognostic nutritional index (PNI), composed of nutritional factors and immune factors in elderly patients undergoing gastric cancer surgery.Patients and Methods: A total of 454 patients undergoing gastric cancer surgery were divided into two groups based on preoperative PNI scores: ≤ 45.1 (n = 307) and > 45.1 (n = 147). Survival analysis was performed using the Kaplan–Meier method and Log rank tests. Univariate and multivariate analyses were conducted to identify independent prognostic factors using a Cox proportional hazards model.Results: According to the X-tile program, the optimal cutoff value for predicting overall survival (OS) with the PNI was 45.1. The receiver operating characteristic analysis revealed that PNI exhibited 70.6% sensitivity and 56.5% speci&filig;city for predicting death during long-term follow-up. The cumulative incidence of postoperative 4-year mortality indicated that the risk of death increased significantly for PNI ≤ 45.1. In multivariate analysis, preoperative PNI was a significant independent predictor of mortality. In the age-stratified subgroup analysis, preoperative PNI was more sensitive for the old elderly subgroup than for the young elderly subgroup.Conclusion: Preoperative PNI is a sensitive and specific prognostic predictor among elderly patients undergoing gastric cancer surgery.Keywords: elderly patients, gastric cancer, prognostic nutritional index, radical gastrectomy

Yuying Chen,1,&ast; Jia Chen,2,&ast; Yu Zhang,3,&ast; Zhi Lin,1 Meng Wang,1 Lifei Huang,2 Mengqi Huang,1 Mimi Tang,1 Xiaoqi Zhou,1 Zhenpeng Peng,1 Bingsheng Huang,2 Shi-Ting Feng1 1Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 2Medical AI Lab, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong, People’s Republic of China; 3Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bingsheng HuangMedical AI Lab, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong, People’s Republic of ChinaTel +86 755-86172208Fax +86 755-86171820Email huangb@szu.edu.cnShi-Ting FengDepartment of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of ChinaTel +86 20-87755766 Ext 8471Fax +86 20-87615805Email fengsht@mail.sysu.edu.cnPurpose: Cytokeratin 19 (CK19) expression is a proven independent prognostic predictor of hepatocellular carcinoma (HCC). This study aimed to develop and validate the performance of a deep learning radiomics (DLR) model for CK19 identification in HCC based on preoperative gadoxetic acid-enhanced magnetic resonance imaging (MRI).Patients and Methods: A total of 141 surgically confirmed HCCs with preoperative gadoxetic acid-enhanced MRI from two institutions were included. Prediction models were established based on hepatobiliary phase (HBP) images using a training set (n=102) and validated using time-independent (n=19) and external (n=20) test sets. A receiver operating characteristic curve was used to evaluate the performance for CK19 prediction. Recurrence-free survival (RFS) was also analyzed by incorporating the CK19 expression and other factors.Results: For predicting CK19 expression, the area under the curve (AUC) of the DLR model was 0.820 (95% confidence interval [CI]: 0.732– 0.907, P< 0.001) with sensitivity, specificity, accuracy of 0.800, 0.766, and 0.775, respectively, and reached 0.781 in the external test set. Combined with alpha fetoprotein, the AUC increased to 0.833 (95% CI: 0.753– 0.912, P

Wei Lin,1 Tianlei Zhang,1 Yiyang Zhou,2 Jinyu Zheng,2 Zhenlang Lin1 1Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China; 2Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaCorrespondence: Zhenlang LinDepartment of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaEmail lzlprof2020@163.comAbstract: Fibroblast growth factor 21 (FGF21) regulates many crucial biological processes in human and mammals, particularly metabolic modulation and protective effect after injury. Therefore, determining complex regulatory mechanisms and elucidating the signaling pathway may greatly promote the prevention, diagnosis, and treatment of related injury and metabolic diseases. This review focused on the metabolic modulation and protective effect of FGF21 and summarized the molecular mechanisms and clinical research developments.Keywords: fibroblast growth factor 21, molecular mechanisms, metabolic modulation, protective effect, clinical application