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Chunjiao Lu,* Xuewei Wu,* Xin Meng,* Yi Liu, Ting Yang, Yan Zeng, Yang Chen, Yishan Huang, Zhou Fang, Xiaojun Yang, Juanjuan Luo Engineering Research Center of Key Technique for Biotherapy of Guangdong Province, Shantou University Medical College, Shantou, 515041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaojun Yang; Juanjuan Luo, Shantou University Medical College, 22 Xinling Road, Shantou, 515041, People’s Republic of China, Email yangx@stu.edu.cn; 15jjluo1@stu.edu.cnIntroduction: The potential toxic effects of wastewater discharges containing silver nanoparticles (AgNPs) and their release into aquatic ecosystems on aquatic organisms are becoming a major concern for environmental and human health. However, the potential risks of AgNPs to aquatic organisms, especially for cardiac development by Focal adhesion pathway, are still poorly understood.Methods: The cardiac development of various concentrations of AgNPs in zebrafish were examined using stereoscopic microscope. The expression levels of cardiac development-related genes were analyzed by qRT-PCR and Whole-mount in situ hybridization (WISH). In addition, Illumina high-throughput global transcriptome analysis was performed to explore the potential signaling pathway involved in the treatment of zebrafish embryos by AgNPs after 72 h.Results: We systematically investigated the cardiac developing toxicity of AgNPs on the embryos of zebrafish. The results demonstrated that 2 or 4 mg/L AgNPs exposure induces cardiac developmental malformations, such as the appearance of pericardial edema phenotype. In addition, after 72 h of exposure, the mRNA levels of cardiac development-related genes, such as myh7, myh6, tpm1, nppa, tbx5, tbx20, myl7 and cmlc1, were significantly lower in AgNPs-treated zebrafish embryos than in control zebrafish embryos. Moreover, RNA sequencing, KEGG (Kyoto Encyclopedia of Genes) and Genomes and GSEA (gene set enrichment analysis) of the DEGs (differentially expressed genes) between the AgNPs-exposed and control groups indicated that the downregulated DEGs were mainly enriched in focal adhesion pathways. Further investigations demonstrated that the mRNA levels of focal adhesion pathway-related genes, such as igf1ra, shc3, grb2b, ptk2aa, akt1, itga4, parvaa, akt3b and vcla, were significantly decreased after AgNPs treatment in zebrafish.Conclusion: Thus, our findings illustrated that AgNPs could impair cardiac development by regulating the focal adhesion pathway in zebrafish.Keywords: AgNPs, focal adhesion, cardiac development, zebrafish

Fangyuan Kuang,1,2 Yang Gao,3 Qingyun Zhou,4 Chenying Lu,3 Qiaomei Lin,4 Abdullah Al Mamun,5 Junle Pan,6 Shuibo Shi,7 Chaoyong Tu,4,* Chuxiao Shao2,* 1School of Medicine, Shaoxing University, Shaoxing, Zhejiang, 312000, People’s Republic of China; 2Department of Hepatopancreatobiliary Surgery, People Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui, Zhejiang, 323000, People’s Republic of China; 3Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, People’s Republic of China; 4Department of Hepatopancreatobiliary Surgery, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, People’s Republic of China; 5Key Laboratory of Joint Diagnosis and Treatment of Chronic Liver Disease and Liver Cancer of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, 323000, People’s Republic of China; 6First Academy of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 7The First Clinical Medical College of Nanchang University, Nanchang City, Jiangxi, 330000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chaoyong Tu, Department of Hepatopancreatobiliary Surgery, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, People’s Republic of China, Email tcy7409@163.comBackground: A limited number of studies have examined the use of radiomics to predict 3-year overall survival (OS) after hepatectomy in patients with hepatocellular carcinoma (HCC). This study develops 3-year OS prediction models for HCC patients after liver resection using MRI radiomics and clinicopathological factors.Materials and Methods: A retrospective analysis of 141 patients who underwent surgical resection of HCC was performed. Patients were randomized into two set: the training set (n=98) and the validation set (n=43) including the survival groups (n=111) and non-survival groups (n=30) based on 3-year survival after hepatectomy. Furthermore, x2 or Fisher’s exact test, univariate and multivariate logistic regression analyses were conducted to determine independent clinicopathological risk factors associated with 3-year OS. 1688 quantitative imaging features were extracted from preoperative T2-weighted imaging (T2WI) and contrast-enhanced magnetic resonance imaging (CE-MRI) of arterial phase (AP), portal venous phases (PVP)and delay period (DP). The features were selected using the variance threshold method, the select K best method and the least absolute shrinkage and selection operator (LASSO) algorithm. By using Bernoulli Naive Bayes (BernoulliNB) and Multinomial Naive Bayes (MultinomialNB) classifiers, we constructed models based on the independent clinicopathological factors and Rad-scores. To determine the best model, receiver operating characteristics (ROC) and Delong’s test were used. Moreover, calibration curves were used to determine the calibration ability of the model, while decision curve analysis (DCA) was implemented to evaluate its clinical benefit.Results: The fusion model showed excellent prediction precision with AUC of 0.910 and 0.846 in training and validation set and revealed significant diagnostic accuracy and value in the calibration curve and DCA analysis.Conclusion: Nomograms based on MRI radiomics and clinicopathological factors have significant predictive value for 3-year OS after hepatectomy and can be used for risk classification.Keywords: hepatocellular carcinoma, hepatectomy, MRI radiomics

Cuiting Wang,1,2 Tian An,1,2 Cong Lu,1,2 Tiantian Liu,1,2 Xiaomeng Shan,1,2 Zhiyao Zhu,1,2 Yanbin Gao1,2 1School of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Key Laboratory of TCM Collateral Disease Theory Research, Beijing, People’s Republic of ChinaCorrespondence: Yanbin Gao; Zhiyao Zhu, School of Traditional Chinese Medicine, Capital Medical University, No. 10 You An Men Wai, Xi Tou Tiao, Feng Tai District, Beijing, 100069, People’s Republic of China, Tel +86 10 8391 1640 ; +86 10 8391 1626, Email gyb@ccmu.edu.cn; 20120103@ccmu.edu.cnBackground: Prediabetes, characterized by a series of metabolic abnormalities, increases the risk of diabetes and cardiovascular diseases. Tangzhiping (TZP), a clinically validated traditional Chinese medicine formula, is used to treat impaired glucose tolerance. However, the underlying mechanism of TZP in intervening prediabetes is not fully elucidated.Purpose: The current study aimed to evaluate the protective effect of TZP against prediabetes mice and explore its potential mechanism.Methods: After establishing a prediabetic animal model through 12 weeks of high-fat diet (HFD) feeding, mice were subjected to TZP for 8 weeks. Various parameters related to body weight, glucose and lipid metabolism, and insulin sensitivity were measured. Histopathological examinations observed adipose cell size and liver lipid deposition. The Sable Promethion system assessed energy metabolism activity. Transcriptomic analysis of Epididymal white adipose tissue (EWAT) identified enriched pathways and genes. The key genes in the enriched pathways were identified through RT-PCR.Results: Our data revealed that the administration of TZP reduced body weight and fat mass in a prediabetes mouse model. TZP normalized the glucose and insulin levels, improved insulin resistance, and decreased plasma TC and FFA. The alleviation of adipose tissue hypertrophy and lipid deposition by TZP was demonstrated through pathological examination. Indirect calorimetry measurements indicated a potential increase in VO2 and EE levels with TZP. The results of EWAT transcription showed that TZP reversed pathways and genes related to inflammation and catabolic metabolism. RT-PCR demonstrated that the mRNA expression of inflammation and lipolysis, including Tlr2, Ccr5, Ccl9, Itgb2, Lipe, Pnpla2, Cdo1, Ces1d, Echs1, and Acad11, were changed by TZP treatment.Conclusion: TZP effectively alleviates obesity, impaired glucose and lipid metabolism, and insulin resistance. The effect of TZP might be associated with the regulation of gene expression in dysfunctional adipose tissue. Keywords: traditional Chinese medicine, Tangzhiping, prediabetes, adipose tissue, inflammation, lipolysis

Yue Lu,1– 3,* Simin Pan,4,* Wenzhen Li,5 Yao Qi,6,7 Li Li,1– 3 Yu-Hong Yan,1– 3 Jianan Wei,1– 3 Dan-Ni Yao,1– 3 Jingjing Wu,1– 3 Hao Deng,1– 3 Shuyan Ye,1– 3 Haiming Chen,1– 3 Qubo Chen,1– 3 Hengjun Gao,6,7 Ling Han,1– 3 Chuanjian Lu1– 3 1State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, People’s Republic of China; 3Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 5The Clinical College of Acupuncture Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 6Shanghai Molecular Medicine Engineering Technology Research Center, Shanghai, People’s Republic of China; 7Shanghai National Engineering Research Center of Biochip, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling Han; Chuanjian Lu, Email linghan99@gzucm.edu.cn; lcj@gzucm.edu.cnBackground: Psoriasis is a widespread chronic, immune-mediated skin disease with frequent recurrences, and is extremely harmful to the physical and mental health of patients, causing enormous suffering and exerting considerable economic burdens on the health care system as a whole. In more than a decade of clinical use, the optimized formula of Yinxieling (PSORI-CM01) has consistently demonstrated its effectiveness for treating psoriasis. However, its underlying mechanism remains largely unexplored.Methods: The network pharmacology analysis was conducted to predict the mechanism and protective effect of PSORI-CM01 in treating psoriasis. Subsequently, we collected blood samples from 21 patients with psoriasis as part of a randomized, double-blind, and double-dummy clinical trial for microRNA expression profiling. Finally, it was experimentally confirmed that PSORI-CM01 improved psoriasis by regulating miR-20a-3p and miR-3184-3p expression.Results: As a result of the network pharmacology analysis, PSORI-CM01 improved psoriasis through the regulation of autophagy, cellular apoptosis, cellular proliferation, and anti-inflammatory processes. In the target-miRNA regulatory network, these key targets were mainly associated with the regulation of hsa-miR-20a-3p, hsa-miR-155-5p, has-miR-3184-3p, hsa-miR-328-3p and hsa-miR-124-3p. Based on the microRNA expression profiling results, the PSORI-CM01 treatment group exhibited five up-regulated genes and 16 down-regulated genes compared with the healthy control group. In particular, miR-20a-3p and miR-3184-3p were the primary differentially expressed microRNAs, and they were significantly enriched in the signaling pathways involving autophagy, apoptosis, proliferation, and anti-inflammation. Further experiments confirmed that PSORI-CM01 effectively regulates miR-20a-3p and miR-3184-3p, resulting in increased autophagy.Conclusion: We demonstrated by combining network pharmacology and clinical studies of miRNA expression profiles in PBMCs that PSORI-CM01 effectively modulated miR-20a-3p and miR-3184-3p, leading to an increase in autophagy and a decrease in keratinocyte proliferation.Keywords: PSORI-CM01, Psoriasis vulgaris, MicroRNA expression profile, network pharmacology, autophagy

Minli Hu,1,* Hao Fang,2,* Yibing Hu,1 Chong Lu,1 Yuan Chen,1 Zhifeng Zhong,3 Hongqi Shi,4 Qunying Wang1 1Department of Gastroenterology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China; 2Department of Traumatology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China; 3Department of Anus & Intestine Surgery, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China; 4Department of Pathology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qunying Wang, Department of Gastroenterology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China, Email wqy616717@126.comBackground: Allied disorders of Hirschsprung’s disease (ADHD) exhibit symptoms akin to those of Hirschsprung’s disease, primarily characterized by intestinal obstruction, bowel dilatation, and chronic constipation. The occurrence of amyloid complications in patients with ADHD is infrequent. In this report, we present a case of ADHD with intestinal ulcers as the initial gastrointestinal manifestation, and subsequent pathological examination revealed the presence of amyloid deposits in the colonic mucosa.Case Report: A male patient, aged 20, exhibited recurring abdominal distension and intestinal obstruction for a duration of three years. Multiple colonoscopies revealed the presence of recurrent colonic ulcers, with pathological examination indicating the existence of amyloid deposits within the mucosal layer of the colon. Abdominal CT scans suggested colonic dilatation. Following a multidisciplinary consultation, a subtotal resection of the colon was performed, and subsequent postoperative pathology confirmed a decrease and absence of myenteric plexus ganglion cells. Considering the patient’s symptoms and the findings from the postoperative pathology, a diagnosis of ADHD was made. The patient’s symptoms resolved postoperatively and he was discharged from the hospital and followed up for 1 year in stable condition.Conclusion: Our study highlights the potential association between ADHD and the initial presentation of recurrent colonic ulcers, accompanied by amyloid deposition in the intestinal mucosa. This finding suggests a possible pathogenic mechanism for ADHD and offers a novel perspective on its diagnosis.Keywords: allied disorders of Hirschsprung’s disease, colonic ulcer, amyloid, intestinal obstruction, colonoscopy biopsy colonic

Zhuhua Jin,1,2 Lei Zhu,3 Shuping Zhou,2,4 Chao Lu2,4 1Department of Information Management, First Affiliated Hospital of Anhui University of Science and Technology, First People’s Hospital of Huainan, Huainan, Anhui Province, People’s Republic of China; 2School of Economics and Management, Anhui University of Science and Technology, Huainan, 232001, People’s Republic of China; 3Department of Neurology, First Affiliated Hospital of Anhui University of Science and Technology, First People’s Hospital of Huainan, Huainan, Anhui Province, People’s Republic of China; 4First Affiliated Hospital of Anhui University of Science and Technology, First People’s Hospital of Huainan, Huainan, Anhui Province, People’s Republic of ChinaCorrespondence: Lei Zhu, Department of Neurology, Department of Neurology, First Affiliated Hospital of Anhui University of Science and Technology, First People’s Hospital of Huainan, Huainan, Anhui Province, People’s Republic of China, Email salimai@126.com Chao Lu, First Affiliated Hospital of Anhui University of Science and Technology, First People’s Hospital of Huainan, Huainan, Anhui Province, People’s Republic of China, Email 765385306@qq.comBackground: Post-stroke Fatigue (PSF) after Intracerebral Hemorrhage (ICH) is a long-term symptom in stroke survivors. However, the pathogenesis of PSF remains inadequately understood and sufficient evidence-based treatments are lacking. Mobile health (mHealth) technology offers a promising approach to expanding access to high-quality and culturally tailored evidence-based mental care.Aim: This study examined the role of mHealth called iHealth in the management of PSF after ICH.Methods: A total of 225 patients diagnosed with intracerebral hemorrhage (ICH) were included in the study and randomly assigned to either the Mobile Health Intervention Group (mHI Group) or the non-Mobile Health Intervention Group (non-mHI). The management involved the utilization of a digital healthcare application named iHealth, which incorporated digital questionnaires, fatigue scale tests, and online videos for the purpose of administering the Patient Fatigue Reporting Measurement Information System (PFRMIS) short form as part of the initial patient assessment following ICH. The study was conducted remotely via video conferencing over a 12-week period in mHI Group, with fatigue assessments being conducted 3 months post-ICH onset in two groups.Results: Following the administration of PSF by iHealth, Univariate Logistic analyses indicated a significant association between fatigue and the type of activity, with patients who were sedentary or did nothing experiencing higher levels of fatigue (β=2.332, p< 0.001; β=2.517, p< 0.001). Multivariate Logistic analyses demonstrated a positive association between the intensity of physical activity and decreased emotional well-being and family support, as well as increased fatigue. (p=0.001, p=0.002, p=0.001). The FSS results demonstrated a significantly reduced incidence of PSF in the MHI group in comparison to non-mHI group following the conclusion of the programme. (13.1% vs 40%, p< 0.001).Conclusion: This study explored the effectiveness of the iHealth app for PSF following ICH, indicating that iHealth is a clinically valuable tool that warrants further dissemination.Keywords: post-stroke fatigue, mobile health intervention, fatigue severity scale, intracerebral hemorrhage, iHealth

Ruipeng Wu,1– 3,&ast; Qiong Niu,1,2,&ast; Yingting Wang,1,2 Yundan Dawa,4 Zixuan Guang,1,2 Dongji Song,1 Bei Xue,1 Ciyong Lu,5 Shaokang Wang1,3 1Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, 712082, People’s Republic of China; 2Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, 712082, People’s Republic of China; 3Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, 210009, People’s Republic of China; 4Department of Tibetan Medicine, University of Tibetan Medicine(UTC), Lhasa, 850000, People’s Republic of China; 5Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-Sen University 510080, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this work Correspondence : Ciyong Lu; Shaokang Wang, Email luciyong@mail.sysu.edu.cn; shaokangwang@seu.edu.cnBackground: Sleep disorders are a significant health issue that urgently needs to be addressed among undergraduate students, and one of the potential underlying problems could be problematic smartphone use (PSU). This study aimed to clarify the relationship between PSU and poor sleep quality by investigating the independent and serial mediating roles of anxiety and depressive symptoms in a population of university students in Tibet, China.Methods: A total of 2993 Tibetan college students completed three waves of data surveys, with all participants completing questionnaires on PSU, anxiety, depressive symptoms, and sleep quality (Time 1 (T1) -Time 3 (T3)). Bootstrapped mediation analysis was used to explore the mediating role of anxiety and depressive symptoms in the longitudinal relationship between PSU and sleep quality.Results: Both direct and indirect effects of PSU on poor sleep quality were found. PSU (T1) can had not only a direct negative influence on poor sleep quality (T3) among young adults (direct effect = 0.021, 95% CI = 0.010– 0.033) but also an indirect negative impact via three pathways: the independent mediating effect of anxiety symptoms (T2) (indirect effect 1 = 0.003, 95% CI = 0.001– 0.006), the independent mediating effect of depressive symptoms (T2) (indirect effect 2 = 0.004, 95% CI = 0.002– 0.006), and the serial mediating effects of anxiety (T2) and depressive symptoms (T2) (indirect effect 3 = 0.008, 95% CI=0.005– 0.011).Conclusion: These findings highlight the role of anxiety and depression symptoms as joint mediating factors in the relationship between PSU and sleep disturbances. Interventions focused on improving sleep that incorporate behavioural measures could benefit from treatment approaches targeting mental disorders.Keywords: sleep quality, problematic smartphone use, anxiety, depressive symptoms, longitudinal study

Jiayan Li,1,&ast; Jie Ding,1,&ast; Haoyang Wu,1 Chenyan Lu,1 Jian Wu,2 Qianqian Luo1 1Department of Hypoxic Biomedicine, Institute of Special Environmental Medicine and Coinnovation Center of Neuroregeneration, Nantong University, Nantong, 226019, People’s Republic of China; 2Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Wu, Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai, 200040, People’s Republic of China, Tel +86-21-54601295, Email jianwu12@fudan.edu.cn Qianqian Luo, Department of Hypoxic Biomedicine, Institute of Special Environmental Medicine and Coinnovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, Jiangsu, 226019, People’s Republic of China, Tel +86-513-85503378, Email qianqianluo@ntu.edu.cnBackground: Frostbite is a chemia resulting from cold-induced skin damage. The process of frostbite is often accompanied by inflammation, and the therapeutic strategies focusing on anti-inflammation are the main direction to data. Tat-CIRP is a 15 amino acid peptide containing HIV protein and cold-inducible RNA-binding protein (CIRP), which is believed to compete with endogenous CIRP for myeloid differentiation 2 (MD2) binding. This study aims to investigate the efficacy of Tat-CIRP in the treatment of frostbite.Methods: A mouse model of frostbite was established, and on the first day after frostbite occurrence, Tat-CIRP peptide was administered intravenously via the tail with a dosage interval of one day for a total of three doses. Frozen mouse skin sections were subjected to histological analysis, including hematoxylin–eosin (HE) staining, Masson staining, and immunohistochemical examination. Western blotting was performed to detect the expression level of Ki-67 in mouse skin tissue.Results: One day after frostbite, mice exhibited skin swelling and a solid appearance. From day 1 to 5 after frostbite, MD2 expression was significantly upregulated, while CIRP expression was downregulated. Compared to the frostbite group, mice treated with Tat-CIRP showed accelerated frostbite recovery, reduced levels of inflammatory factors and MD2. Furthermore, the expression of cell proliferation-associated protein Ki-67 and angiogenesis-related protein CD31 was upregulated.Conclusion: Tat-CIRP promotes frozen wound healing via inhibiting inflammation and promoting angiogenesis in frostbitten mice.Keywords: frostbite, Tat-CIRP, inflammation, angiogenesis

Tao Jiang,1,2 Weijian Chen,3 Chao Lu,1,2 Jiyong Yang,3 Ziquan Zeng,1,2 Wenqiang Li,4 Hongsheng Liu,5 Nana Huang,5 Yuhui Chen,6 Wengang Liu1,2 1Department of Orthopedics, Guangdong Provincial Second Hospital of Traditional Chinese Medicine, Guangzhou, 510095, People’s Republic of China; 2Department of Orthopedics, Guangdong Provincial Engineering Technology Research Institute of Traditional Chinese Medicine, Guangzhou, 510095, People’s Republic of China; 3The Fifth Clinical School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510095, People’s Republic of China; 4Engineering Technology Research Center for Sports Assistive Devices of Guangdong, School of Sport and Health, Guangzhou Sport University, Guangzhou, 510500, People’s Republic of China; 5Guangdong Huayan Biomedical Science and Technology Center, Guangzhou, 511441, People’s Republic of China; 6Department of Traumatic Surgery, Center for Orthopaedic Surgery, Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, People’s Republic of ChinaCorrespondence: Wengang Liu, Department of Orthopedics, Guangdong Provincial Second Hospital of Traditional Chinese Medicine, Hengfu Road 60, Yuexiu District, Guangzhou, Guangdong, People’s Republic of China, Email liuwengang74@163.com Yuhui Chen, Department of Traumatic Surgery, Center for Orthopaedic Surgery, Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, People’s Republic of China, Email ah1990726@163.comBackground: Skin wounds are a prevalent issue that can have severe health consequences if not treated correctly. Nanozymes offer a promising therapeutic approach for the treatment of skin wounds, owing to their advantages in regulating redox homeostasis to reduce oxidative damage and kill bacteria. These properties make them an effective treatment option for skin wounds. However, most of current nanozymes lack the capability to simultaneously address inflammation, oxidative stress, and bacterial infection during the wound healing process. There is still great potential for nanozymes to increase their therapeutic functional diversity and efficacy.Methods: Herein, copper-doped hollow mesopores cerium oxide (Cu-HMCe) nanozymes with multifunctional of antioxidant, antimicrobial and pro-vascularity is successfully prepared. Cu-HMCe can be efficiently prepared through a simple and rapid solution method and displays sound physiological stability. The biocompatibility, pro-angiogenic, antimicrobial, and antioxidant properties of Cu-HMCe were assessed. Moreover, a full-thickness skin defect infection model was utilized to investigate the wound healing capacity, as well as anti-inflammatory and pro-angiogenic properties of nanozymes in vivo.Results: Both in vitro and in vivo experiments have substantiated Cu-HMCe’s remarkable biocompatibility. Moreover, Cu-HMCe possesses potent antioxidant enzyme-like catalytic activity, effectively clearing DPPH radicals (with a scavenging rate of 80%), hydroxyl radicals, and reactive oxygen species. Additionally, Cu-HMCe exhibits excellent antimicrobial and pro-angiogenic properties, with over 70% inhibition of both E. coli and S. aureus. These properties collectively promote wound healing, and the wound treated with Cu-HMCe achieved a closure rate of over 90% on the 14th day.Conclusion: The results indicate that multifunctional Cu-HMCe with antioxidant, antimicrobial, and pro-angiogenic properties was successfully prepared and exhibited remarkable efficacy in promoting wound healing. This nanozymes providing a promising strategy for skin repair.Keywords: Cu-HMCe nanozyme, antioxidation, antibacterial, vascularization, wound healing

Zhengyi Lyu,1,&ast; Qiongying Shen,1,&ast; Shuxin Tian,1,&ast; Liyan Gong,2 Haizhou Lou,3 Guanai Bao,2 Zhuoxuan Wu,3 Chao Lu,2 Weiping Zhang,4 Rui Huang,5 Conghua Ji,6 Siyi Zheng,1 Wei Pan,1 Yinyin Ying,4 Jianwei Jin,4 Yi Liang4 1The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Medical Oncology, Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, People’s Republic of China; 4Department of Acupuncture, the Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 5Department of Acupuncture and Tuina, Wenzhou Central Hospital, Wenzhou, Zhejiang, People’s Republic of China; 6Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Liang, Department of Acupuncture, the Third Affiliated Hospital of Zhejiang Chinese Medical University, 219 Moganshan Road, Hangzhou City, Zhejiang Province, 310053, People’s Republic of China, Email liangyiwww@126.comBackground: Transcutaneous Electrical Acupoint Stimulation (TEAS) therapy opens up the possibility for individuals with Cancer-induced bone pain (CIBP) to receive a home-based, patient-controlled approach to pain management. The aim of this study is designed to evaluate the efficacy of patient-controlled TEAS (PC-TEAS) for relieving CIBP in patients with non-small cell lung cancer (NSCLC).Methods/Design: This is a study protocol for a prospective, triple-blind, randomized controlled trial. We anticipate enrolling 188 participants with NSCLC bone metastases who are also using potent opioid analgesics from 4 Chinese medical centers. These participants will be randomly assigned in a 1:1 ratio to either the true PC-TEAS or the sham PC-TEAS group. All participants will receive standard adjuvant oncology therapy. The true group will undergo patient-controlled TEAS intervention as needed, while the sham group will follow the same treatment schedule but with non-conductive gel patches. Each treatment course will span 7 days, with a total of 4 courses administered. There will be 4 assessment time points: baseline, the conclusion of weeks 4, 8, and 12. The primary outcome of this investigation is the response rate of the average pain on the Brief Pain Inventory (BPI) scale at week 4 after treatment. Secondary outcomes include pain related indicators, quality of life scale, mood scales, and routine blood counts on the assessment days. Any adverse events will be promptly addressed and reported if they occur. We will manage trial data using the EDC platform, with a data monitoring committee providing regular quality oversight.Discussion: PC-TEAS interventions offer an attempt to achieve home-based acupuncture treatment and the feasibility of achieving triple blinding in acupuncture research. This study is designed to provide more rigorous trial evidence for the adjuvant treatment of cancer-related pain by acupuncture and to explore a safe and effective integrative medicine scheme for CIBP.Trial Registration: ClinicalTrials.gov NCT05730972, registered February 16, 2023.Keywords: bone cancer pain, TEAS, transcutaneous electrical nerve stimulation, patient-controlled analgesia, integrative medicine, home-based treatment

Ci Lu,1,&ast; Panpan Lv,2,&ast; Xiaoying Zhu,1 Yongmei Han1 1Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Ultrasound, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoying Zhu; Yongmei Han, Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3&num; Qingchun East Road, Hangzhou, 310016, People’s Republic of China, Email 3202091@zju.edu.cn; 3408235@zju.edu.cnAbstract: Cogan’s syndrome (CS) is a rare chronic inflammatory disease, characterized by interstitial keratitis and vestibular auditory dysfunction. Hypertrophic pachymeningitis (HP) is a rare chronic aseptic inflammatory disease of the central nervous system. This article reports a patient with CS coexisting with HP. The patient was a 66-year-old male with fever, headache, red eyes, hearing loss, and significantly elevated inflammatory markers. Cerebrospinal fluid examination, blood culture, and tests for autoantibodies such as antinuclear antibodies were negative. Pure tone audiology (PTA) indicated bilateral sensorineural deafness. Both Positron emission tomography–computed tomography (PET/CT) and vascular color Doppler ultrasound suggest the presence of vasculitis. Considering Cogan’s syndrome, the patient received 40 mg of methylprednisolone intravenously once daily. The brain’s magnetic resonance imaging (MRI) revealed slightly thickened and enhanced dura mater, suggesting HP. The dose of methylprednisolone was increased to 40 mg intravenously every 8 hours, leading to the patient’s improved symptoms and decreased inflammatory markers. Both CS and HP are rare chronic inflammatory diseases, and their coexistence is even rarer, with only two reported cases in literature up to date. The coexistence of CS and HP should be considered when the CS patients with headaches do not respond well to treatment.Keywords: Cogan’s syndrome, hypertrophic pachymeningitis, vasculitis

Xinting Wang,1,&ast; Jiahui Yang,1,&ast; Cheng Lu,2 Yinqin Hu,1 Zhaohui Xu,1 Qiqi Wan,1 Meng Zhang,1 Tianyun Shi,1 Zhirui Liu,1 Yongming Liu1 1Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, People’s Republic of China; 2Department of Cardiology, Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongming Liu, Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No. 185, Pu’an Road, Huangpu District, Shanghai, 200021, People’s Republic of China, Email liuyongming@foxmail.comPurpose: This study aimed to elucidate the protective mechanism of Traditional Chinese Medicine (TCM) Qifu Yixin formula (QFYXF) to improve heart failure (HF) by promoting β-arrestin2 (β-arr2)-mediated SERCA2a SUMOylation.Materials and Methods: The transverse aortic constriction (TAC)-induced HF mice were treated with QFYXF or carvedilol for 8 weeks. β-arr2-KO mice and their littermate wild-type (WT) mice were used as controls. Neonatal rat cardiomyocytes (NRCMs) were used in vitro. Cardiac function was evaluated by echocardiography and serum NT-proBNP. Myocardial hypertrophy and myocardial fibrosis were assessed by histological staining. β-arr2, SERCA2a, SUMO1, PLB and p-PLB expressions were detected by Western blotting, immunofluorescence and immunohistochemistry. SERCA2a SUMOylation was detected by Co-IP. The molecular docking method was used to predict the binding ability of the main active components of QFYXF to β-arr2, SERCA2a, and SUMO1, and the binding degree of SERCA2a to SUMO1 protein.Results: The HF model was constructed 8 weeks after TAC. QFYXF ameliorated cardiac function, inhibiting myocardial hypertrophy and fibrosis. QFYXF promoted SERCA2a expression and SERCA2a SUMOylation. Further investigation showed that QFYXF promoted β-arr2 expression, whereas Barbadin (β-arr2 inhibitor) or β-arr2-KO reduced SERCA2a SUMOylation and attenuated the protective effect of QFYXF improved HF. Molecular docking showed that the main active components of QFYXF had good binding activities with β-arr2, SERCA2a, and SUMO1, and SERCA2a had a high binding degree with SUMO1 protein.Conclusion: QFYXF improves HF by promoting β-arr2 mediated SERCA2a SUMOylation and increasing SERCA2a expression.Keywords: heart failure, Qifu Yixin Formula, β-arrestin2, SERCA2a, SUMOylation

Yuanyuan Zhao,1 Yang Liu,1 Cheng Lu,1 Daokuan Sun,2 Shiqi Kang,1 Xin Wang,2,&ast; Laijin Lu1,&ast; 1Department of Hand and Podiatric Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2School of Materials Science and Engineering, Jilin University, Changchun, Jilin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Laijin Lu, Department of Hand and Podiatric Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China, Tel +86-13756661203, Fax +86 431 84808391, Email ljlu@jlu.edu.cn Xin Wang, School of Materials Science and Engineering, Jilin University, Changchun, Jilin, People’s Republic of China, Tel +86-18 626 655 395, Fax +86 431 84 808 391, Email wang_xin@jlu.edu.cnBackground: The treatment of long-gap peripheral nerve injury (PNI) is still a substantial clinical problem. Graphene-based scaffolds possess extracellular matrix (ECM) characteristic and can conduct electrical signals, therefore have been investigated for repairing PNI. Combined with electrical stimulation (ES), a well performance should be expected. We aimed to determine the effects of reduced graphene oxide fibers (rGOFs) combined with ES on PNI repair in vivo.Methods: rGOFs were prepared by one-step dimensionally confined hydrothermal strategy (DCH). Surface characteristics, chemical compositions, electrical and mechanical properties of the samples were characterized. The biocompatibility of the rGOFs were systematically explored both in vitro and in vivo. Total of 54 Sprague-Dawley (SD) rats were randomized into 6 experimental groups: a silicone conduit (S), S+ES, S+rGOFs-filled conduit (SGC), SGC+ES, nerve autograft, and sham groups for a 10-mm sciatic defect. Functional and histological recovery of the regenerated sciatic nerve at 12 weeks after surgery in each group of SD rats were evaluated.Results: rGOFs exhibited aligned micro- and nano-channels with excellent mechanical and electrical properties. They are biocompatible in vitro and in vivo. All 6 groups exhibited PNI repair outcomes in view of neurological and morphological recovery. The SGC+ES group achieved similar therapeutic effects as nerve autograft group (P > 0.05), significantly outperformed other treatment groups. Immunohistochemical analysis showed that the expression of proteins related to axonal regeneration and angiogenesis were relatively higher in the SGC+ES.Conclusion: The rGOFs had good biocompatibility combined with excellent electrical and mechanical properties. Combined with ES, the rGOFs provided superior motor nerve recovery for a 10-mm nerve gap in a murine acute transection injury model, indicating its excellent repairing ability. That the similar therapeutic effects as autologous nerve transplantation make us believe this method is a promising way to treat peripheral nerve defects, which is expected to guide clinical practice in the future.Keywords: peripheral nerve defects, sciatic nerve injury, functional recovery, tissue engineering, conductive materials

Lingbo Bi,&ast; Chaofan Wang,&ast; Yimei Du,&ast; Changpei Lu, Min Zhao, Yunbu Ding, Weiling Sun, Weixin Fan Department of Dermatology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weixin Fan; Weiling Sun, Department of Dermatology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, 210029, People’s Republic of China, Tel +86-13327805737 ; +86-13813955963, Email swl0560@sina.com; hairmanfwx@163.comPurpose: To investigate whether increased levels of lipids-related metabolites (LRMs) result in androgenic alopecia (AGA).Patients and Methods: A two-sample Mendelian randomization (MR) study was designed, and single nucleotide polymorphisms (SNPs) respectively related to nine LRMs were selected from the genome-wide association study (GWAS) dataset. An MR analysis was performed to assess the causal association between LRMs and AGA.Results: Through the fixed-effect inverse variance weighting (IVW) method, MR analysis indicated that Apolipoprotein B (ApoB), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) had a causal relationship with AGA. No obvious heterogeneity or pleiotropy was observed.Conclusion: The risk of AGA increases significantly when the serum levels of ApoB, LDL, and VLDL increase. This causal relationship is solid and free of interference from confounding factors.Keywords: androgenic alopecia, apolipoprotein B, VLDL, LDL

Chenqi Chang,1 Heng Liu,2 Xiaotong Li,2 Dandan Song,1 Yue Liu,1 Chang Lu,1 Yu Zhen,1 Ying Chen,1 Jinguo Xu,1 Weidong Li,1 Xiaobin Jia,3 Zhipeng Chen,1 Rui Chen1 1School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China; 2Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, 671003, People’s Republic of China; 3School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, People’s Republic of ChinaCorrespondence: Rui Chen; Zhipeng Chen, Email chenrui@njucm.edu.cn; czpcpu2000@hotmail.comIntroduction: Enhancing the efficacy of berberine (BBR) in the treatment of ulcerative colitis (UC) through the development of dopamine-coated berberine nanoparticles (PDA@BBR NPs) with ROS-responsive and adhesive properties.Methods: Berberine nanoparticles (BBR NPs) were synthesized using the nonsolvent precipitation method, and their surfaces were coated with polydopamine (PDA) through oxidative polymerization. The PDA@BBR NPs were characterized by transmission electron microscopy (TEM), size analysis, and zeta potential analysis. Drug loading and encapsulation efficiency were analyzed using fluorescence spectroscopy. The responsiveness of these nanoparticles to reactive oxygen species (ROS) was assessed in vitro, while their adhesive properties and therapeutic efficacy on UC were evaluated in vivo.Results: Physicochemical property studies showed that PDA coated BBR NPs nanoparticles have good dispersion and stability. In vitro results showed that PDA@BBR NPs could prolong the retention time of the drug at the colonic site and could realize the gradual drug release under ROS environment. In addition, animal studies showed that PDA@BBR NPs exhibited significant anti-inflammatory effects on DSS-induced colitis and effectively reduced intestinal mucosal damage.Conclusion: PDA@BBR NPs are ROS-responsive nanoparticles that adhere well and have a high drug loading capacity. They have shown therapeutic effects in mice with UC, indicating that this formulation may be a promising treatment option. Keywords: berberine, polydopamine, ROS-responsive, adhesion retention, ulcerative colitis

Yin Li,1,&ast; Manling Jiang,2,3,&ast; Yongqi Wei,1,&ast; Xiang He,2 Guoping Li,2,&ast; Chunlai Lu,1 Di Ge1 1Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, Sichuan, People’s Republic of China; 3State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science & Technology, Taipa, Macao Special Administrative Region of China&ast;These authors contributed equally to this workCorrespondence: Chunlai Lu; Di Ge, Email lu.chunlai@zs-hospital.sh.cn; ge.di@zs-hospital.sh.cnBackground: The pyrimidine salvage pathway plays a critical role in tumor progression and patient outcomes. The roles of pyrimidine salvage pathway-related genes (PSPGs) in cancer, however, are not fully understood. This study aims to depict the characteristics of PSPGs across various cancers.Methods: An integrative pan-cancer analysis of six PSPGs (CDA, UCK1, UCK2, UCKL1, UPP1, and UPP2) was conducted using TCGA data, single-cell RNA sequencing datasets, and patient samples. Single-cell transcriptome analysis and RT-qPCR were used to validate the relation between UPP1 and cytokines. Flow cytometry was performed to validate the role of UPP1 in immune checkpoint regulation. The correlation between UPP1 and tumor associated neutrophils (TAN) were investigated and validated by single-cell transcriptome analysis and tissue microarrays (TMAs).Results: PSPGs showed low mutation rates but significant copy number variations, particularly amplifications in UCKL1, UPP1, and UCK2 across various cancers. DNA methylation patterns varied, with notable negative correlations between methylation and gene expression in UPP1. PSPGs were broadly up-regulated in multiple cancers, with correlations to clinical staging and prognosis. Proteomic data further confirmed these findings. Functional analysis revealed PSPGs’ associations with tumor proliferation, metastasis, and various signaling pathways. UPP1 showed strong correlations with the tumor microenvironment (TME), particularly with cytokines, immune checkpoints, and various immune cells. Single-cell transcriptome analysis confirmed these associations, highlighting UPP1’s influence on cytokine expression and immune checkpoint regulation. In esophageal squamous cell carcinoma (ESCC), UPP1-high tumor cells were significantly associated with immunosuppressive cells in the TME. Spatial analysis using TMAs revealed that UPP1+ tumor cells were predominantly located at the invasive margin and closely associated with neutrophils, correlating with poorer patient prognosis.Conclusion: Our study depicted the multi-dimensional view of PSPGs in cancer, with a particular focus on UPP1’s role in the TME. Targeting UPP1 holds promise as a potential strategy for cancer therapy.Keywords: pyrimidine salvage pathways, UPP1, microenvironment

Zhengjia Zhang,1,&ast; Xinyi Luo,1,&ast; Xiaoxia Xue,1 Mingshi Pang,1 Xiangpeng Wang,1 Liuchunyang Yu,1 Jinxiu Qian,1 Xiaoyu Li,1 Meng Tian,1 Aiping Lu,2 Cheng Lu,3 Yuanyan Liu1 1School of Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hongkong, People’s Republic of China; 3Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuanyan Liu; Cheng Lu, Email yyliu_1980@163.com; lv_cheng0816@163.comBackground: The morbidity and mortality of triple-negative breast cancer (TNBC) are still high, causing a heavy medical burden. CCL5, as a chemokine, can be involved in altering the composition of the tumor microenvironment (TME) as well as the immunosuppressive degree, and has become a very promising target for the treatment of TNBC. Dysregulation of microRNAs (miRNAs) in tumor tissues is closely related to tumor progression, and its utilization can be used to achieve therapeutic purposes. Engineered exosomes can avoid the shortcomings of miRNAs and also enhance their targeting and anti-tumor effects through engineering. Therefore, we aimed to create a cRGD-modified exosome for targeted delivery of miR-588 and to investigate its effect in remodeling immunosuppressive TME by anchoring CCL5 in TNBC.Methods: In this study, we loaded miR-588 into exosomes using electroporation and modified it with cRGD using post insertion to obtain cRGD-Exos/miR-588. Transmission electron microscopy (TEM), nanoparticle tracking assay technique (NTA), Western Blots, qPCR, and flow cytometry were applied for its characterization. CCK-8, qPCR and enzyme-linked immunosorbent assay (ELISA), in vivo fluorescence imaging system, immunohistochemistry and H&E staining were used to explore the efficacy as well as the mechanism at the cellular level as well as in subcutaneous graft-tumor nude mouse model.Results: The cRGD-Exos/miR-588 was successfully constructed and had strong TNBC tumor targeting in vitro and in vivo. Meanwhile, it has significant efficacy on TME components affected by CCL5 and the degree of immunosuppression, which can effectively control TNBC with good safety.Conclusion: In this experiment, cRGD-Exos/miR-588 was prepared to remodel immunosuppressive TME by anchoring CCL5, which is affected by the vicious cycle of immune escape. Overall, cRGD-Exos/miR-588 explored the feasibility of targeting TME for the TNBC treatment, and provided a competitive delivery system for the engineered exosomes to deliver miRNAs for antitumor therapy drug.Keywords: engineered exosome, triple negative breast cancer, miR-588, CCL5, tumor environment

Shilei Bai,1,&ast; Xiaojing Shen,2,&ast; Jianwei Liu,1,&ast; Caixia Lu,1 Jie Wang,1 Liu Liu,1 Chunyan Wang,1 Huifeng Wang,3 Kai Liu,4 Yanfu Sun,1 Feng Xue1 1Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, People’s Republic of China; 2Department of Pathology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 3Department of Hepatic Surgery, the Fifth Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 4Department of Biliary Tract Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng Xue; Yanfu Sun, Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), 225 Changhai Road, Shanghai, 200433, People’s Republic of China, Tel +86-21-81875513, Fax +86-21-65562400, Email xuefeng@smmu.edu.cn; sunyanfu@hotmail.comPurpose: When hepatocellular carcinoma (HCC) is closely associated with the left branch of the portal vein, there is still controversy regarding the surgical approach.Methods: This study enrolled 330 HCC patients with tumors adjacent to the left branch of the portal vein. Among them, 85 patients underwent left hemihepatectomy (LH), while the remaining 235 underwent liver lobectomy (LL), which included left medial segmentectomy or left lateral sectionectomy. Perioperative complications, time to recurrence and overall survival (OS) were compared using propensity score matching.Results: LH resulted in a lower 5-year recurrence rate and higher 5-year OS rate than LL (56.5% vs 74.0%, p=0.002; 67.4% vs 53.5%, p=0.029). The LL group showed a higher tendency for early recurrence (ER) and intrahepatic recurrence (IR). The cumulative IR rates at 1- 3-, and 5-years for the LH group and the LL group were 17.0%, 36.7%, 45.1% and 33.8%, 57.1%, 63.7%, respectively, with a p-value of 0.007. There was no statistically significant difference in the cumulative ER rates between the two groups at 1-, 3-, and 5- years. Furthermore, the LH group and the LL group had similar perioperative complications, and no cases of liver failure occurred.Conclusion: LH, compared to LL, reduced the IR rate and ER rate in HCC patients with tumor adjacent to the left branch of the portal vein. It improved the OS outcome of the patients, and there was no significant difference in perioperative complications between the two groups.Keywords: hepatocellular carcinoma, left hemihepatectomy, liver lobectomy, propensity score matching, recurrence, overall survival

Kedan Cen, Caide Lu Department of Hepatopancreatobiliary Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, People’s Republic of ChinaCorrespondence: Caide Lu, Department of Hepatopancreatobiliary Surgery, The Affiliated Lihuili Hospital, Ningbo University, 1111 Jiangnan Road, Ningbo, 315040, Zhejiang, People’s Republic of China, Email lucaide@nbu.edu.cnBackground: Transaldolase 1 (TALDO1) deficiency was associated with hepatocellular carcinoma (HCC), but the association between TALDO1 and prognosis in HCC remains unclear.Material and Methods: RNA-seq and clinical data of HCC from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were analyzed. CCK8 and EdU assays were utilized to examine the effect of TALDO1 on HCC proliferation. Transwell assay was used to explore the effect of TALDO1 on HCC migration. Western Blot was applied to detected the expression levels of pathway-related proteins.Results: TALDO1 mRNA level was higher in HCC tissues than in control normal tissues in TCGA and GEO databases (P< 0.001, P< 0.001). Expression of TALDO1 mRNA was associated with histologic grade (P=0.021). Multivariate regression analysis revealed that high TALDO1 mRNA expression was an independent risk factor for prognosis (P< 0.001). High expression of TALDO1 had poor overall survival (OS) (P=0.046). Additionally, Nomogram prognostic model of TALDO1 and clinicopathological parameters could predict the prognostic OS of HCC patients. Functional enrichment and immune infiltration analysis revealed that TALDO1 negatively regulates immune response. Furthermore, knockdown TALDO1 expression suppressed the proliferation and migration ability of HCC cells. Mechanistically, TALDO1 leaded to activation of the mitogen-activated protein kinase (MAPK) pathway and enhancement of epithelial-mesenchymal transition (EMT).Conclusion: Our findings demonstrated that TALDO1 could serve as a promising novel biomarker for HCC patients, which might modulate the immune microenvironment resulting in a poor prognosis.Keywords: transaldolase 1, prognosis, immune infiltration, proliferation, migration

Qiaona Jiang,1,&ast; Xiaofei Zhang,1,&ast; Xiaohui Lu,2 Yanzhe Li,3 Chenghao Lu,1 Jinghui Chi,1 Yanyan Ma,1 Xiaomei Shi,1 Lili Wang,1 Shen Li3 1Department of Psychiatry, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, People’s Republic of China; 2Department of Psychiatry, Qingdao Mental Health Center, Qingdao, People’s Republic of China; 3Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lili Wang, Department of Psychiatry, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, No. 13, Liulin Road, Hexi District, Tianjin, 300222, People’s Republic of China, Tel +00-86-022-88188796, Email tjadyywll@163.com Shen Li, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, No. 13, Liulin Road, Hexi District, Tianjin, 300222, People’s Republic of China, Tel +00-86-022-88188875, Email lishen@tmu.edu.cnObjective: Tardive dyskinesia (TD) is a severe rhythmic movement disorder caused by long-term antipsychotic medication in chronic patients with schizophrenia (SCZ). We aimed to investigate the association between polymorphisms in oxidative stress-related genes (GSTM1, SOD2, NOS1, and NOS3) and adenosine receptor gene (ADORA2A), as well as their interactions, with the occurrence and severity of TD, and cognitive impairments in a Chinese Han population of SCZ patients.Methods: Two hundred and sixteen SCZ patients were recruited and divided into TD group (n=157) and non-TD group (n=59). DNA extraction was performed by a high-salt method, followed by SNP genotyping using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The severity of TD, psychopathology and cognitive functioning were assessed using the Abnormal Involuntary Movement Scale (AIMS), the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively.Results: The combination of GSTM1-rs738491, NOS1-rs738409 and ADORA2A-rs229883 was identified as the best three-point model to predict TD occurrence (p=0.01). Additionally, GSTM-rs738491 CC or NOS3-rs1800779 AG genotypes may be protective factors for psychiatric symptoms in TD patients. TD patients carrying the NOS1-rs738409 AG or ADORA2A-rs229883 TT genotypes exhibited poorer cognitive performance.Conclusion: Our findings suggest that the interaction of oxidative stress-related genes and adenosine receptor gene may play a role in the susceptibility and severity of TD in Chinese Han SCZ patient. Furthermore, these genes may also affect the psychiatric symptoms and cognitive function of TD patients.Keywords: tardive dyskinesia, schizophrenia, oxidative stress, adenosine receptor, polymorphisms, cognitive impairments

Meiju Zhou,1 Ci Lu,2 Fang Yuan1 1Department of Rheumatology and Immunology, Zhejiang Hospital, Hangzhou, Zhejiang Province, People’s Republic of China; 2Department of Rheumatology and Immunology, Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Fang Yuan, Department of Rheumatology and Immunology, Zhejiang Hospital, No. 1299 Gudun Road, Hangzhou, Zhejiang Province, 310012, People’s Republic of China, Tel +86-18072963566, Email yuanfany@126.comObjective: To assess physicians’ knowledge and awareness of chronic pain associated with rheumatoid arthritis (RA) in Rheumatology departments throughout Zhejiang province to improve chronic pain relief in RA patients.Methods: A cross-sectional questionnaire survey was conducted onsite and online among rheumatologists in tertiary and secondary hospitals across Zhejiang province, China. The questionnaire inquired about rheumatoid arthritis-related pain cognition, pain assessment, pain management protocols, and medication choice.Results: Among the 150 questionnaires included, 98 were from tertiary hospitals, and 52 were from secondary hospitals. There was no difference in rheumatologists’ perceptions of chronic pain in RA patients between tertiary and secondary hospitals. About 55.1% of rheumatologists from tertiary hospitals and 44.2% of rheumatologists from secondary hospitals utilized unstandardized pain assessment scales. About 46.9% of rheumatologists in tertiary hospitals and 36.5% of rheumatologists in secondary hospitals favored the numerical rating scale (NRS). About 87.8% of rheumatologists in tertiary hospitals and 71.7% of rheumatologists in secondary hospitals conducted pain assessment within 4 hours of admission. About 66.3% of rheumatologists working in tertiary hospitals and 32.7% of rheumatologists practicing in secondary hospitals believed their hospitals had pain departments. For RA patients who complained of pain for the first time, secondarily, or repeatedly, 48%, 26%, and 36.7% of rheumatologists preferred nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and opioid analgesics, respectively. For RA patients with mild, moderate, or severe pain, 74%, 6%, and 16% of rheumatologists preferred NSAIDs, glucocorticoids, and opioid analgesics, respectively.Conclusion: The assessment and treatment of chronic pain associated with RA are not standardized. For management, more rheumatologists preferred NSAIDs and glucocorticoids.Keywords: rheumatoid arthritis, chronic pain, survey and questionnaire

Lu C, Chen X, Wang Q, Xu X, Xu B. Onco Targets Ther. 2018;11:7213–7227. We, the Editors and Publisher of OncoTargets and Therapy, have retracted the following article. Following publication of the article, concerns were raised about the duplication of images from Figures 1, 2, 3, 4, 5, and 6 with images from other unrelated articles. Specifically, Images for Figure 1E have been duplicated with images for Figure 2a from Li X, Wu M, An D, et al. Suppression of Tafazzin promotes thyroid cancer apoptosis via activating the JNK signaling pathway and enhancing INF2-mediated mitochondrial fission. J Cell Physiol. 2019;234:16238–16251. https://doi.org/10.1002/jcp.28287 and 5I from Jieensinue S, Zhu H, Li G, et al. Tanshinone IIA reduces SW837 colorectal cancer cell viability via the promotion of mitochondrial fission by activating JNK-Mff signaling pathways. BMC Cell Biol. 2018;19:21. https://doi.org/10.1186/s12860-018-0174-z. Images for Figure 2A have been duplicated with images for Figure 5H from Li R, Xin T, Li D, et al. Therapeutic effect of Sirtuin 3 on ameliorating nonalcoholic fatty liver disease: The role of the ERK-CREB pathway and Bnip3-mediated mitophagy. Redox Biology. 2018;18:229–243. https://doi.org/10.1016/j.redox.2018.07.011. Images for Figure 3G have been duplicated with images for Figures 4A and 5C from Yu W, Xu M, Zhang T, et al. Mst1 promotes cardiac ischemia–reperfusion injury by inhibiting the ERK-CREB pathway and repressing FUNDC1-mediated mitophagy. J Physiol Sci. 2019;69:113–127. https://doi.org/10.1007/s12576-018-0627-3. Images for Figure 4A have been duplicated with images for Figure 2C from Zheng Z, Xiang S, Wang Y, et al. NR4A1 promotes TNF‑α‑induced chondrocyte death and migration injury via activating the AMPK/Drp1/mitochondrial fission pathway. International Journal of Molecular Medicine. 2020;45:151–161. https://doi.org/10.3892/ijmm.2019.4398. Images for Figure 4D have been duplicated with images for Figure 4K from Qin R, Zhang L, Lin D, Xiao F, Guo L. Sirt1 inhibits HG-induced endothelial injury: Role of Mff-based mitochondrial fission and F‑actin homeostasis-mediated cellular migration. International Journal of Molecular Medicine. 2019;44:89–102. https://doi.org/10.3892/ijmm.2019.4185. Images for Figure 5D have been duplicated with images for Figure 7d from Wang Q, Xu J, Li X, et al. Sirt3 modulate renal ischemia-reperfusion injury through enhancing mitochondrial fusion and activating the ERK-OPA1 signaling pathway. J Cell Physiol. 2019;234:23495–23506. https://doi.org/10.1002/jcp.28918. Images for Figure 5H have been duplicated with images for Figure 2A from Xie Y, Lv Y, Zhang Y, et al. LATS2 promotes apoptosis in non-small cell lung cancer A549 cells via triggering Mff-dependent mitochondrial fission and activating the JNK signaling pathway. Biomedicine & Pharmacotherapy. 2019;109:679–689. https://doi.org/10.1016/j.biopha.2018.10.097; Figure 3A from Ouyang H, Zhou E, Wang H. RETRACTED ARTICLE: Mst1-Hippo pathway triggers breast cancer apoptosis via inducing mitochondrial fragmentation in a manner dependent on JNK–Drp1 axis. Onco Targets Ther. 2019;12:1147–1159. https://doi.org/10.2147/OTT.S193787 and Figure 5H from Li R, Xin T, Li D, et al (2018). Images for Figure 6A have been duplicated with images for Figure 2A from Li J, Li N, Yan S, et al. Liraglutide protects renal mesangial cells against hyperglycemia‑mediated mitochondrial apoptosis by activating the ERK‑Yap signaling pathway and upregulating Sirt3 expression. Molecular Medicine Reports. 2019;19:2849–2860. https://doi.org/10.3892/mmr.2019.9946. Images for Figure 6C have been duplicated with images for Figure 3I from Zhang W, Liu K, Pei Y, Ma J, Tan J, Zhao J. Mst1 regulates non-small cell lung cancer A549 cell apoptosis by inducing mitochondrial damage via ROCK1/F‑actin pathways. International Journal of Oncology. 2018;53:2409–2422. https://doi.org/10.3892/ijo.2018.4586; Figure 3g from Qin R, Lin D, Zhang L, Xiao F, Guo L. Mst1 deletion reduces hyperglycemia-mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway. J Cell Physiol. 2019;235:294–303. https://doi.org/10.1002/jcp.28969; Figure 5D from Xu P, Zhang G, Sha L, Hou S. RETRACTED: DUSP1 alleviates cerebral ischaemia reperfusion injury via inactivating JNKMff pathways and repressing mitochondrial fission. Life Sciences. 2018;210:251–262. https://doi.org/10.1016/j.lfs.2018.08.049 and Figure 5g from Li X, et al (2019). Images for Figure 6F have been duplicated with images for Figure 1d from Zhang Y, Wang M, Xu X, Liu Y, Xiao C. Matrine promotes apoptosis in SW480 colorectal cancer cells via elevating MIEF1-related mitochondrial division in a manner dependent on LATS2-Hippo pathway. J Cell Physiol. 2019;234:22731–22741. https://doi.org/10.1002/jcp.28838 and Figure 1I from Zhang L, Li S, Wang R, et al. Anti-tumor effect of LATS2 on liver cancer death: Role of DRP1-mediated mitochondrial division and the Wnt/β-catenin pathway. Biomedicine & Pharmacotherapy. 2019;114:108825. https://doi.org/10.1016/j.biopha.2019.108825. The authors did not respond to our queries and were unable to provide an explanation for the duplicated images or provide data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors were notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Fei Zhang,1 Yicen Ding,1 Bohan Zhang,1 Mengju He,1 Zhijiang Wang,2 Chunbo Lu,3 Yani Kang1 1School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Pharmaceutical Engineering, Zhejiang Pharmaceutical University, Ningbo, People’s Republic of China; 3Department of Obstetrics and Gynecology, Qiuai Central Health Center, Ningbo, People’s Republic of ChinaCorrespondence: Chunbo Lu, Department of Obstetrics and Gynecology, Qiuai Central Health Center, Ningbo, 315100, People’s Republic of China, Tel +86-13567881644, Email lucbnb@126.com Yani Kang, School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, 200240, People’s Republic of China, Tel +86-13661848623, Email kangyani@sjtu.eduPurpose: This study aimed to identify differentially methylated genes (DMGs) and differentially expressed genes (DEGs) to investigate new biomarkers for the diagnosis and treatment of polycystic ovary syndrome (PCOS).Methods: To explore the potential biomarkers of PCOS diagnosis and treatment, we performed methyl-binding domain sequencing (MBD-seq) and RNA sequencing (RNA-seq) on ovarian granulosa cells (GCs) from PCOS patients and healthy controls. MBD-seq was also performed on the ovarian tissue of constructed prenatally androgenized (PNA) mice. Differential methylation and expression analysis were implemented to identify DMGs and DEGs, respectively. The identified gene was further verified by real-time quantitative PCR (RT-qPCR) and methylation-specific PCR (MSP) in clinical samples. Furthermore, ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) was carried out on PCOS patients and healthy controls to identify differential lipid metabolites.Results: Compared to the control group, 13,526 DMGs related to the promoter region and 2429 DEGs were found. The function analysis of DMGs and DEGs showed that they were mainly enriched in glycerophospholipid, ovarian steroidogenesis, and other lipid metabolic pathways. Moreover, 5753 genes in DMGs related to the promoter region were screened in the constructed PNA mice. Integrating the DMGs data from PCOS patients and PNA mice, we identified the following 8 genes: CDC42EP4, ERMN, EZR, PIK3R1, ARHGEF18, NECTIN2, TSC2, and TACSTD2. RT-qPCR and MSP verification results showed that the methylation and expression of TACSTD2 were consistent with sequencing data. Additionally, 15 differential lipid metabolites were shown in the serum of PCOS patients. The differential lipids were involved in glycerophospholipid and glycerolipid metabolism.Conclusion: Using integration of methylome and lipid metabolites profiling we identified 8 potential epigenetic markers and 15 potential lipid metabolite markers for PCOS. Our results suggest that aberrant DNA methylation and lipid metabolite disorders may provide novel insights into the diagnosis and etiology of PCOS.Keywords: polycystic ovary syndrome, DNA methylation, transcriptome, lipid metabolites, granulosa cell

Chuan Lu,1,&ast; Yan Chen,1,&ast; Yue Zhang,2 Xin Zhao1 1Department of Cardiology, The Second Hospital of Dalian Medical University, Dalian, 116023, People’s Republic of China; 2Department of Gastroenterology, The Second Hospital of Dalian Medical University, Dalian, 116023, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Zhao; Yue Zhang, Tel +86-17709870535 ; +86-17709870662, Email zx81830@163.com; 278536582@qq.comBackground: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a recently proposed term as a more appropriate definition for nonalcoholic fatty liver disease (NAFLD). Previous studies have shown an association between liver fibrosis scores and cardiovascular disease (CVD) in patients with NAFLD. In this study, we aimed to investigate the relationship between liver fibrosis scores and coronary artery disease (CAD) severity in patients with MAFLD.Methods: This study was conducted on 1346 patients with MAFLD at the Second Hospital of Dalian Medical University between January 2018 and December 2021. We calculated the liver fibrosis scores, including the fibrosis 4 (FIB-4) score, nonalcoholic fatty liver disease fibrosis score (NFS), and aspartate aminotransferase-to-platelet ratio index (APRI). We divided the participants into three groups based on the degree of coronary artery stenosis assessed using coronary computed tomography angiography (CCTA): CAD (≥ 50%), non-obstructive (1– 49%), and normal (no stenosis).Results: An increased FIB-4 score and NFS were significantly associated with CAD severity in patients with MAFLD. The percentage of patients with a high FIB-4 score was higher in the CAD group than in the other two groups (5.80%, 4.31%, and 2.24%, respectively; p< 0.001), as was the percentage of patients with NFS (11.12%, 5.19%, and 0.93%, respectively; p< 0.001). Carotid atherosclerosis, creatinine levels, and CAC scores were significant predictors of CAD. The FIB-4 score and NFS were independently associated with CAD even after adjusting for sex and well-known cardiovascular risk factors. The APRI was not a significant factor for CAD in any model. In the bivariate correlation analysis, the FIB-4 score and NFS were directly correlated with CAC scores.Conclusion: Non-invasive liver fibrosis scores (FIB-4 and NFS) were significantly associated with the CAD severity and CAC scores in patients with MAFLD. Screening for CAD may be beneficial for subjects with high liver fibrosis risk MAFLD.Keywords: metabolic dysfunction-associated fatty liver disease, coronary artery disease, liver fibrosis scores, coronary artery calcium scores, nonalcoholic fatty liver disease

Wei Zhang,1,2,&ast; Qing Wang,3,&ast; Liru Zhang,4,&ast; Jiangxiong Wu,5 Jinlu Liu,2 Cheng Lu,2 Xinsheng Wang,1 Zhihua Zhang6 1Central Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, People’s Republic of China; 2Microbiology Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, People’s Republic of China; 3Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, People’s Republic of China; 4Clinical Laboratory, Zhangjiakou Wanquan District Hospital, Zhangjiakou, Hebei, People’s Republic of China; 5Inspection Center, Qujing No.1 People’s Hospital, Affiliated Qujing Hospital of Kunming Medical University, Qujing, Yunnan, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhihua Zhang, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 36 Changqing Road, Qiaoxi District, Zhangjiakou City, Hebei Province, People’s Republic of China, Tel +86-03138043503, Fax +86-1088326317, Email zzh19641229@163.com Xinsheng Wang, Central Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 36 Changqing Road, Qiaoxi District, Zhangjiakou City, Hebei Province, People’s Republic of China, Email Wxinsheng1968@sina.comPurpose: This single-center study aims to investigate the epidemiological characteristics of clinically isolated Escherichia coli from 2014 to 2022.Methods: In vitro drug sensitivity of E. coli to 20 antibiotics was examined using the microbroth dilution method. A total of 7580 clinical E. coli strains were isolated from 2014 to 2022, among which 56.9% were identified as extended spectrum beta-lactamase-producing strains. The data were analyzed using the software WHONET5.6 and the R language platform.Results: Over the study period, carbapenem resistance rates increased by more than 50% (2022 [1.34%] vs 2014 [0.8%]) and the annual number of isolates showed an upward trend (1264 in 2022 vs 501 in 2014). Drug resistance rates were the highest for penicillin (75– 85%) and lowest for imipenem (1%). The resistance rate of strains isolated from male patients and sputum was found to be higher than that of female patients and urine, except for quinolones (p < 0.05). The drug resistance rates from high to low were penicillins (75– 85%), tetracycline (64%), quinolones (64– 67%), sulfamethoxazole (59.3%), cephalosporins (22– 72%), aztreonam (34%), chloramphenicol (21%), amikacin (2.8%), colistin (1.4%), meropenem (1.1%), and imipenem (1%). Urine, sputum, and blood accounted for 51%, 16.6%, and 10.6% of the samples, respectively. A greater number of female patients were included more than male patients (4798[63.3%] vs 2782[26.7%]). Patients aged 50– 80 accounted for 64.2% of those surveyed.Conclusion: Carbapenems remain the optimal choice for treating extended spectrum beta-lactamase-producing E. coli infections (sensitivity rate: 98%). Colistin (87.7%) and amikacin (87%) exhibited good antibacterial activities against carbapenem-resistant E. coli. Long-term and continuous epidemiological surveillance of E. coli can facilitate the development of preventive strategies and control policies.Keywords: antibiotic resistance, bacteria, ESBL, carbapenems, cephalosporin, quinolones

Min Yin,1,&ast; Chunli Lu,2,&ast; Huimei Zhou,1 Qian Liu,1 Jiaxin Yang1 1National Clinical Research Center for Obstetric and Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Neurospine Center, China International Neuroscience Institute (CHINA-INI), Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huimei Zhou; Jiaxin Yang, Email zhmpumch@126.com; yjxpumch@163.comBackground: A poor prognosis is often associated with ovarian clear cell carcinoma (OCCC) due to its relative resistance to platinum-based chemotherapy. Although several studies have been launched to explore the pathogenesis of OCCC, the mechanism of chemoresistance has yet to be uncovered.Methods: Nanostring nCounter PanCancer Pathways Panel was performed to explore the expression profiles of OCCC tissues from patients showing different platinum sensitivity. Bioinformatic analysis was performed to select genes associated with chemoresistance and cell function assays, including colony formation, wound healing, transwell and flow cytometric analysis, were used to explore the role of the target gene in the progression of OCCC and resistance to cisplatin (DDP).Results: Gene expression profiles and bioinformatic analysis verified that the expression of fibroblast growth factor 11 (FGF11) was significantly increased in platinum-resistant OCCC tissues and increased FGF11 expression was related to poorer survival. Downregulation of FGF11 inhibited the proliferation, migration, and invasion, reversing the DDP resistance of OCCC cells. Mechanically, FGF11 was regulated by hypoxia-inducible factor-1α (HIF-1α) to modulate the DDP sensitivity.Conclusion: FGF11 was highly expressed in platinum-resistant OCCC tissues, promoting progression and resistance to DDP through the HIF-1α/FGF11 signaling axis.Keywords: ovarian clear cell carcinoma, cisplatin chemoresistance, FGF11, HIF-1&#x03B1

Chengbo Lu,1,&ast; Fanghui Zhou,2,&ast; Huimin Xian,3,&ast; Siyuan Sun,4 Jingkun Yue,4 Ying Zhang,5 Qi Zhao,6 Xing Luo,3 Yang Li7 1Department of Cardiology, 1st Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China; 2Department of Hematology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; 3Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; 4Department of Cardiology, People’s Hospital of Taihe County, Taihe, Anhui, People’s Republic of China; 5Department of Gynaecology and Obstetrics, 1st Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China; 6Department of Cardiology, 1st Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; 7Department of Cardiology, 4th Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xing Luo; Yang Li, Email luoxing321@163.com; jacksonbiotechlab@gmail.comBackground: The relationship between serum IL-38 and major adverse cardiovascular events (MACE) in patients with ST elevation myocardial infarction (STEMI) remains unclear.Methods: In the present study, 589 STEMI patients were included, the serum level of IL-38 was measured. The median follow-up time was 720 days, the STEMI patients were divided into high IL-38 (IL-38> 6.49ng/mL) and low IL-38 groups (IL-38≤ 6.49ng/mL) to compare the probability of MACE.Results: Plasma IL-38 levels were significantly lower in STEMI patients than in SAP patients (4.0± 2.2 vs 6.9± 3.2 ng/mL, P < 0.001). Ninety-three STEMI patients met the defined MACE study endpoint. The incidence of MACE was significantly lower in patients with high IL-38 group than in patients with low IL-38 group (7.8% vs 23.7%, P < 0.001). Low plasma IL-38 levels were independently associated with the occurrence of MACE (OR = 0.90, P < 0.001).Conclusion: We get a conclusion that low plasma levels of IL-38 are independently associated with the occurrence of MACE.Graphical Abstract: Keywords: inflammatory response, SAP, IL-38, STEMI, MACE

Chunjiao Lu,&ast; Yi Liu,&ast; Yao Liu, Guanhua Kou, Yang Chen, Xuewei Wu, Yuhang Lv, Jiahao Cai, Renyuan Chen, Juanjuan Luo, Xiaojun Yang Guangdong Provincial Key Laboratory of Infectious Disease and Molecular Immunopathology, Shantou University Medical College, Shantou, 515041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Juanjuan Luo; Xiaojun Yang, Guangdong Provincial Key Laboratory of Infectious Disease and Molecular Immunopathology, Shantou University Medical College, Shantou, 515041, People’s Republic of China, Tel +86-754-88900236, Fax +86-754-88900276, Email lujj770@163.com; yangx@stu.edu.cnIntroduction: Silver nanoparticles (AgNP) are widely used as coating materials. However, the potential risks of AgNP to human health, especially for neural and vascular systems, are still poorly understood.Methods: The vascular and neurotoxicity of various concentrations of AgNP in zebrafish were examined using fluorescence microscopy. In addition, Illumina high-throughput global transcriptome analysis was performed to explore the transcriptome profiles of zebrafish embryos after exposure to AgNP. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to elucidate the top 3000 differentially expressed genes (DEGs) between AgNP-exposed and control groups.Results: We systematically investigated the neural and vascular developmental toxicities of AgNP exposure in zebrafish. The results demonstrated that AgNP exposure could cause neurodevelopmental anomalies, including a small-eye phenotype, neuronal morphology defects, and inhibition of athletic abilities. In addition, we found that AgNP exposure induces angiogenesis malformation in zebrafish embryos. Further RNA-seq revealed that DEGs were mainly enriched in the neuroactive ligand-receptor interaction and vascular endothelial growth factor (Vegf) signaling pathways in AgNP-treated zebrafish embryos. Specifically, the mRNA levels of the neuroactive ligand-receptor interaction pathway and Vegf signaling pathway-related genes, including si:ch73-55i23.1, nfatc2a, prkcg, si:ch211-132p1.2, lepa, mchr1b, pla2g4aa, rac1b, p2ry6, adrb2, chrnb1, and chrm1b, were significantly regulated in AgNP-treated zebrafish embryos.Conclusion: Our findings indicate that AgNP exposure transcriptionally induces developmental toxicity in neural and vascular development by disturbing neuroactive ligand-receptor interactions and the Vegf signaling pathway in zebrafish embryos.Keywords: silver nanoparticles, neurological development, vascular development, developmental toxicity, zebrafish

Zhen Chen1 &ast;, Liming Zeng2 &ast;, Genglong Liu,3,4 Yangpeng Ou,5 Chuangang Lu,6 Ben Yang,7 Liuer Zuo1 &#x002A1Department of Intensive Care Unit, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, Guangdong Province, 528308, People’s Republic of China; 2Medical Research Center, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, Guangdong Province, 528308, People’s Republic of China; 3Department of Pathology, Guangzhou Medical University, Guangzhou, Guangdong Province, 511495, People’s Republic of China; 4Baishideng Publishing Group Inc, Pleasanton, CA, 94566, USA; 5Department of Oncology, Huizhou Third People’s Hospital, Guangzhou Medical University, Huizhou, Guangdong Province, 516000, People’s Republic of China; 6Department of Thoracic Surgery, Sanya Central Hospital, Sanya, Hainan Province, 572000, People’s Republic of China; 7Department of Burn Surgery, Huizhou Municipal Central Hospital, Huizhou, Guangdong Province, 516000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhen Chen; Liuer Zuo, Department of Intensive care Unit, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, Guangdong Province, 528308, People’s Republic of China, Email jeanyz@foxmail.com; 13500276597@163.comBackground: The immune system plays a fundamental role in the pathophysiology of sepsis, and autophagy and autophagy-related molecules are crucial in innate and adaptive immune responses; however, the potential roles of autophagy-related genes (ARGs) in sepsis are not comprehensively understood.Methods: A systematic search was conducted in ArrayExpress and Gene Expression Omnibus (GEO) cohorts from July 2005 to May 2022. Machine learning approaches, including modified Lasso penalized regression, support vector machine, and artificial neural network, were applied to identify hub ARGs, thereby developing a prediction model termed ARG classifier. Diagnostic and prognostic performance of the model was comprehensively analyzed using multi-transcriptome data. Subsequently, we systematically correlated the ARG classifier/hub ARGs with immunological characteristics of multiple aspects, including immune cell infiltration, immune and molecular pathways, cytokine levels, and immune-related genes. Further, we collected clinical specimens to preliminarily investigate ARG expression levels and to assess the diagnostic performance of ARG classifier.Results: A total of ten GEO and three ArrayExpress datasets were included in this study. Based on machine learning algorithms, eight key ARGs (ATG4C, BAX, BIRC5, ERBB2, FKBP1B, HIF1A, NCKAP1, and NFKB1) were integrated to establish ARG classifier. The model exhibited excellent diagnostic values (AUC > 0.85) in multiple datasets and multiple points in time and superiorly distinguished sepsis from other critical illnesses. ARG classifier showed significant correlations with clinical characteristics or endotypes and performed better in predicting mortality (AUC = 0.70) than other clinical characteristics. Additionally, the identified hub ARGs were significantly associated with immune cell infiltration (B, T, NK, dendritic, T regulatory, and myeloid-derived suppressor cells), immune and molecular pathways (inflammation-promoting pathways, HLA, cytolytic activity, apoptosis, type-II IFN response, complement and coagulation cascades), levels of several cytokines (PDGFRB, IL-10, IFNG, and TNF), which indicated that ARG classifier/hub ARGs adequately reflected the immune microenvironment during sepsis. Finally, using clinical specimens, the expression levels of key ARGs in patients with sepsis were found to differ significantly from those of control patients, and ARG classifier exhibited superior diagnostic performance, compared to procalcitonin and C-reactive protein.Conclusion: Collectively, a diagnostic and prognostic model (ARG classifier) based on eight ARGs was developed which may assist clinicians in diagnosis of sepsis and recognizing patient at high risk to guide personalized treatment. Additionally, the ARG classifier effectively reflected the immune microenvironment diversity of sepsis and may facilitate personalized counseling for specific therapy.Keywords: sepsis, autophagy-related genes, machine learning, model, multi-transcriptome, immune microenvironment

Yuying Shan, Xi Yu, Yong Yang, Jiannan Sun, Shengdong Wu, Shuqi Mao, Caide Lu Department of Hepatopancreatobiliary Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, 315041, People’s Republic of ChinaCorrespondence: Caide Lu; Shuqi Mao, Department of Hepatopancreatobiliary Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, 315041, People’s Republic of China, Email lucaide@nbu.edu.cn; mmmaoshuqi@163.comBackground: The macrotrabecular-massive subtype of hepatocellular carcinoma (MTM-HCC) is an aggressive histological type and results in poor prognosis. We developed a nomogram model based on laboratory results to predict the presence of MTM-HCC.Methods: A total of 357 HCC patients who underwent radical surgery between January 2015 and December 2020 at Ningbo Medical Center Lihuili Hospital were grouped according to histological type. After propensity score matching (PSM), 267 patients were divided into MTM-HCC (n = 76) and non-MTM-HCC (n = 191) groups. A LASSO regression analysis model was used to select predictive factors. Finally, a nomogram for predicting the presence of MTM-HCC was established. Decision curve analysis (DCA) was conducted to determine the clinical usefulness of the nomogram model by quantifying the net benefits along with the increase in threshold probabilities.Results: The 1-, 3-, and 5-year disease-free survival (DFS) and overall survival (OS) rates for MTM-HCC were 60.0%, 36.0%, 32.4% and 92.1%, 68.7%, 52.2%, respectively. Survival analysis indicated that the probabilities of achieving DFS and OS were significantly worse in the MTM-HCC group than in the non-MTM-HCC group (P < 0.05). The nomogram model that included AST levels, PT and AFP levels achieved a better C-index of 0.723 (95% CI: 0.659– 0.787). DCA revealed that the nomogram model could lead to net benefits and exhibited a wider range of threshold probabilities in the prediction of MTM-HCC.Conclusion: The nomogram model included AST, PT and AFP could achieve an optimal performance in the preoperative prediction of MTM-HCC.Keywords: hepatocellular carcinoma, macrotrabecular-massive subtype, prognosis, nomogram, aggressiveness

Mingyu Gu,1,2,&ast; Yi Lin,2,&ast; Xianying Gai,3,&ast; Xiaohui Wei,2 Chunhua Lu,4 Yufan Wang,2 Xiaoying Ding,2,&ast; Yongde Peng,1,2 Yuhang Ma2 1Department of Endocrinology and Metabolism, Shanghai General Hospital of Nanjing Medical University, Shanghai, 200080, People’s Republic of China; 2Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, People’s Republic of China; 3Department of Endocrinology, Shanghai Sijing Hospital, Shanghai, 201601, People’s Republic of China; 4Community Health Service Center of Sijing, Shanghai, 201601, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongde Peng, Department of Endocrinology and Metabolism, Shanghai General Hospital of Nanjing Medical University, 100 Haining Road, Shanghai, 200080, People’s Republic of China, Email pengyongde0908@126.com Yuhang Ma, Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, People’s Republic of China, Email mayuhang5992@163.comObjective: To explore the relationship between the level of fatty acid-binding protein 4 (FABP4) and reversion from prediabetes to normal glucose tolerance (NGT).Methods: A two-year retrospective cohort study was conducted on 398 participants with complete information. These 398 participants were divided into an NGT group and an abnormal glucose metabolism (AGM) group after 2 years of follow-up. The baseline level of FABP4 was determined, and the role of FABP4 in predicting reversion from prediabetes to NGT was investigated using an unconditional logistic regression model.Results: Over the two-year follow-up period, 37.4% (149/398) of the participants reverted from prediabetes to NGT. The participants with AGM had a higher baseline level of FABP4 than those with NGT. The baseline level of FABP4 was significantly negatively correlated with reversion from prediabetes to NGT. After adjusting for age, sex, body mass index and waist-to-hip ratio, the level of fasting blood glucose (FBG) [odds ratio (OR) 0.336, 95% confidence interval (CI) (0.196– 0.576)], 2-h post-challenge blood glucose (2hBG) [OR 0.697, 95% CI (0.581– 0.837)], and FABP4 [OR 0.960, 95% CI (0.928– 0.993)] at baseline were significant independent predictors of reversion from prediabetes to NGT. The area under the curve (AUC) value of the receiver operating characteristic curve for FABP4 was 0.605 (95% CI: 0.546– 0.665), and the AUC for FABP4 combined with FBG and 2hBG was 0.716 (95% CI: 0.663– 0.769).Conclusion: A higher baseline level of FABP4 was positively correlated with an adverse profile of diabetes risk factors and negatively correlated with reversion from prediabetes to NGT. FABP4, FBG and 2hBG were predictors of reversion from prediabetes to NGT.Keywords: fatty acid-binding protein 4, FABP4, prediabetes, normal glucose tolerance, abnormal glucose metabolism

Binyi Yang,1– 3,* Cheng Lei,1– 3,* Danhui Yang,1– 3 Chenyang Lu,1– 3 Yingjie Xu,1– 3 Lin Wang,1– 3 Ting Guo,1– 3 Rongchun Wang,1– 3 Hong Luo1– 3 1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Research Unit of Respiratory Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Hunan Diagnosis and Treatment Center of Respiratory Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rongchun Wang; Hong Luo, Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China, Email 198202060@csu.edu.cn; luohonghuxi@csu.edu.cnBackground: OFD1 encodes a protein with 1012 amino acids, which is a component of basal bodies and centrioles, essential for cilia biogenesis. OFD1 was reported to be associated with X-chromosome linked dysmorphology syndrome in early studies and recent studies reported a few cases with primary ciliary dyskinesia (PCD) caused by OFD1 deficiency.Case Presentation: We report a 31-year-old man who suffered from recurrent respiratory infections with typical manifestations of primary ciliary dyskinesia. In addition to respiratory manifestations, the patient also had situs inversus, obesity, gastroesophageal reflux, and hearing impairment. Clubbing fingers and mild streblomicrodactyly were also observed.Examination Result: We performed whole-exome sequencing to identify a novel variant c.2795delA:p.(Lys932Argfs*3) in OFD1. The hemizygous variant was predicted to be likely pathogenic by bioinformatic analysis software and ACMG guideline. High-speed video microscopy (HSVM), transmission electron microscopy (TEM), and immunofluorescence were performed to analyze the respiratory cilia. A high beating frequency and a stiff beating pattern were observed under HSVM, while there were no significant abnormalities in TEM and immunofluorescence. The sperm flagella examinations were also generally normal.Conclusion: Our study identified a novel frameshift variant in OFD1 causing PCD, enriched the genetic spectrum of OFD1 variants, and verified that OFD1 mutation can lead to only a PCD characteristic phenotype, while other OFD1-associated syndromic symptoms such as dysmorphic features and renal symptoms were not present.Keywords: OFD1, primary ciliary dyskinesia, cilia, situs inversus

Jiaxin Chen,1,2 Johannah L Shergis,3 Xinfeng Guo,1,2 Anthony Lin Zhang,3 Hanlin Wang,1,2 Chuanjian Lu,1,2 Charlie C Xue,3 Changcai Xie1,2 1Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, and The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine, and Immune Disease Research Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, 510120, People’s Republic of China; 3The China-Australia International Research Centre for Chinese Medicine, School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, AustraliaCorrespondence: Changcai Xie, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, and The Second Clinical College, Guangzhou University of Chinese Medicine, 111 Dade Road, Yuexiu District, Guangzhou, 510120, People’s Republic of China, Tel +86 13650997551, Email hxie114@163.comPurpose: An increasing number of people are affected by overweight or obesity, and the personal and social health burden is growing rapidly. Acupuncture is gaining popularity as an alternative treatment to manage weight. This research aims to update and synthesize the evidence of acupuncture therapies from systematic reviews for treating overweight and obesity.Methods: Nine databases were searched from their inception to March 2022. Overweight or obesity was classified using standard diagnostic criteria. Published systematic reviews that included randomized controlled trials and quasi-randomized studies were eligible. Quality was assessed via the AMSTAR-2 scale and risk of bias using the ROBIS tool.Results: Thirty-eight systematic reviews were identified. Acupuncture therapies and auricular acupoint stimulation showed benefits in terms of reducing body weight and body mass index. Catgut embedding therapy and abdominal acupuncture are currently not in widespread use with insufficient evidence. Acupuncture therapies appear to be safe. Most of the reviews were assessed as having high risk of bias and low confidence in the findings.Conclusion: There is a need for larger and more methodologically sound randomized controlled trials to evaluate the effectiveness of acupuncture therapies for individuals who are affected by overweight or obesity.Keywords: acupuncture, overweight, obesity, systematic review

Yingjie Xu,1– 3,* Binyi Yang,1– 3,* Cheng Lei,1– 3 Danhui Yang,1– 3 Shuizi Ding,1– 3 Chenyang Lu,1– 3 Lin Wang,1– 3 Ting Guo,1– 3 Rongchun Wang,1– 3 Hong Luo1– 3 1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Research Unit of Respiratory Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Hunan Diagnosis and Treatment Center of Respiratory Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rongchun Wang; Hong Luo, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Furong District, Changsha, Hunan, 410011, People’s Republic of China, Email 198202060@csu.edu.cn; luohonghuxi@csu.edu.cnAbstract: Primary ciliary dyskinesia (PCD) is a rare genetic disease caused by mutations of genes coding motile-cilia-related proteins. CCDC40 variants can cause PCD via disrupting the assembling of inner dynein and dynein regulating complex in cilia and flagella, but none has been reported associated with multiple morphological abnormalities of the sperm flagella (MMAF). We identified and validated the disease-causing variants in our patient via whole-exome and Sanger sequencing. We used high-speed video microscopy analysis (HSVA) and immunofluorescence to analyze the functional and structural deficiency of respiratory cilia. Papanicolaou staining and scanning electron microscope was applied to analyze the morphological sperm defects resulted from the PCD associated variants. We identified novel compound variants (c.901C>T, p.(Arg301*); c.2065_2068dup, p.(Ala690Glyfs*67)) in CCDC40 in a male patient with male infertility. HSVA revealed the rigid and stiff ciliary beating pattern. Immunofluorescence indicated loss of inner dynein arm protein DNAH2 both in cilia and the sperms of the patient. Diagnosis of MMAF was confirmed through sperm Papanicolaou staining and scanning electron microscope. We first describe a patient with a combination of PCD and MMAF associated with novel compound heterozygous variants in CCDC40. Our results present initial evidence that CCDC40 associated with MMAF, which expands the genetic spectrum of PCD and MMAF and provides precise clinical genetic counseling to this family.Keywords: PCD, MMAF, CCDC40, male infertility

Wen-Yu Liu,1,&ast; Yu-Ting Zhu,2,&ast; Xian-Ming Xu,1 Jia-Rong Zhang,3 Xu-Pei Gan,1 De-Cui Cheng,1 Feng Lu,4 Cong Lu1 1Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, People’s Republic of China; 2Department of Gynecology Maternal and Child Health Hospital of Jiading District, Shanghai, 201800, People’s Republic of China; 3Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, 200030, People’s Republic of China; 4Department of Obstetrics and Gynecology, Songjiang Maternal and Child Health-Care Hospital, Shanghai, 201600, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cong Lu, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 of Xinsongjiang Road, Songjiang District, Shanghai, 201600, People’s Republic of China, Tel +86-021-37798537, Email lucongtr5@163.com Feng Lu, Department of Obstetrics and Gynecology, Songjiang Maternal and Child Health-Care Hospital, No. 1010 of Xilin North Road, Songjiang District, Shanghai, 201600, People’s Republic of China, Tel +86-18918282005, Email rlufengni@163.comObjective: The present study aims to evaluate the relationship of thyroid function during the first trimester of pregnancy with lipid levels and pregnancy outcomes.Methods: Women who delivered babies at the Shanghai General Hospital between March 2019 and December 2019 with a known pregnancy outcome and complete data were included in the present study (n = 1779). A retrospective cohort study of all subjects with available first-trimester thyroid function testing and lipid levels data was conducted, and the relationship of thyroid function with lipid levels and pregnancy outcomes was evaluated. The data were analyzed using the SPSS software for statistical correlation.Results: The proportion of caesarean sections was higher in women with hypothyroxinemia (HIA) and hypothyroidism than in women with euthyroidism. Hypothyroidism was shown to be related with polyhydramnios, preterm labor and hypertriglyceridemia. HIA was correlated with increased rates of gestational diabetes mellitus (GDM), preeclampsia, gestational hypertension and hypertriglyceridemia. Compared with the euthyroidism group, the hypothyroidism group had a higher apolipoprotein A1 (Apo A1) level and apolipoprotein B level; the subclinical hypothyroidism group had a higher total cholesterol (TC) level and low-density lipoprotein cholesterol level; the HIA group had higher triglyceride, high-density lipoprotein cholesterol levels and lower TC, Apo A1 levels. TC levels were positively correlated with the thyroid-stimulating hormone level and negatively correlated with free thyroxine (FT4) level, and free triiodothyronine and FT4 levels were positively correlated with GDM occurrence.Conclusion: Thyroid function in early pregnancy is associated with dyslipidemia and pregnancy outcomes; conventional screening of thyroid diseases in early pregnancy may help improve lipid levels and decrease adverse pregnancy outcomes.Keywords: first trimester, thyroid function tests, adverse pregnancy outcome, dyslipidemia

Yuxia Wang,1,2 Chaoyin Lu,2,3 Mauro Augusto Monteiro Cardoso Lopes,2 Lingqiao Chen,1,2 Yan Luo,1,2 Wenjun Wu,1,2 Xuemei Gu1,2 1Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2The First Clinical School of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Endocrinology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, People’s Republic of ChinaCorrespondence: Xuemei Gu, Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Road, Wenzhou, 325006, People’s Republic of China, Tel +86-577-55579385, Fax +86-577-88069555, Email guxm@wmu.edu.cnPurpose: To investigate the prevalence, clinical and metabolic characteristics of atherosclerosis (AS) in newly diagnosed patients with ketosis-prone type 2 diabetes (KPT2D) or non-ketotic type 2 diabetes (NKPT2D).Patients and Methods: About 1072 subjects with non-autoimmune new-onset diabetes were included in the cross-sectional study. Patients were classified as non-ketotic type 2 diabetes (NKPT2D, n = 662) or ketosis-prone type 2 diabetes (KPT2D, n = 410). Blood samples were collected to determine the levels of glucose, HbA1c, insulin and C-peptide. Routine liver and kidney function tests were also performed. AS was determined by vascular ultrasonography.Results: The levels of fasting blood glucose and HbA1c were significant higher in the KPT2D group when compared to the NKPT2D group (P< 0.001). The levels of fasting C-peptide, 2 h C-peptide and HOMA-β were lower in the KPT2D group than those in NKPT2D group (P< 0.001). However, no significant difference was observed for HOMA-IR between the two groups. The onset age of the patients with KPT2D was significantly lower compared to NKPT2D patients (38± 13 vs 49± 14, P< 0.001). After adjusting age of the two groups, the KPT2D patients had a higher prevalence of AS compared to the NKPT2D patients (31.4% vs 21.1%, P=0.005). In both groups, age and gender were independent risk factors for AS, whereas estimated glomerular filtration rate (eGFR) was an independent risk factor in the NKPT2D patients and 2-h postprandial plasma glucose (2h-PPG) was an independent risk factor in the KPT2D patients.Conclusion: AS was more prevalent in KPT2D patients compared to the NKPT2D cohort, which was independent of age and gender. These data suggest that KPT2D patients may have a higher risk of macrovascular complications compared to NKPT2D of the same age.Keywords: ketosis, diabetes, atherosclerosis

Sijia Ge,1,* Hua Huang,2,* Wei Huang,1 Ran Ji,1 Jing Chen,1 Shuzhen Wu,1 Liyang Wang,1 Tianxin Huang,1 Yu Sheng,1 Haiou Yan,1 Cuihua Lu,1 Lin Ma3 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu, People’s Republic of China; 2Department of Pathology, Affiliated Hospital of Nantong University, Jiangsu, People’s Republic of China; 3Department of Gastroenterology, Affiliated Haian Hospital of Nantong University, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lin MaDepartment of Gastroenterology, Affiliated Haian Hospital of Nantong University, Nantong, 226600, Jiangsu, People’s Republic of China, Email 1908397778@qq.comCuihua LuDepartment of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People’s Republic of China, Email lch670608@sina.comBackground: As hepatocellular carcinoma (HCC) having the second-highest mortality rate globally, the early diagnosis and prognosis of HCC have always been the focus of various studies. Although PSME4 has been reported to be closely related to several malignancies, its role in HCC remains unclear.Materials and Methods: The TCGA-LIHC database and HCC tissues were used to explore the expression of PSME4 in HCC. Gene set enrichment analysis (GSEA) was used to forecast the biological behavior of HCC cells that PSME4 might be involved in regulation. In addition, CCK-8, colony formation and flow cytometry assays were used to explore the effect of PSME4 on HCC cells. Furthermore, the underlying PSME4-related signaling pathways in HCC were further confirmed using GSEA.Results: We found that the expression of PSME4 in HCC tissues was significantly higher than that in adjacent normal tissues, and patients with high PSME4 expression have a poor prognosis. CCK-8, colony formation and flow cytometry assays shown that knockdown of PSME4 inhibits HCC cell proliferation of HCC cells, promotes cell apoptosis and moves the cell cycle away from the S phase. Mechanistically, PSME4 may promote the development of HCC through mTOR signaling pathway.Conclusion: The high expression of PSME4 in HCC promotes the proliferation of HCC cells via the mTOR signalling pathway. Therefore, PSME4 is an emerging tumour marker for the early diagnosis and prognosis of HCC.Keywords: hepatocellular carcinoma, mTOR signaling, liver cancer prognosis, PSME4

Chenyang Lu,1– 3,* Danhui Yang,1– 3,* Cheng Lei,1– 3 Rongchun Wang,1– 3 Ting Guo,1– 3 Hong Luo1– 3 1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Research Unit of Respiratory Disease, Central South University, Changsha, People’s Republic of China; 3Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong Luo; Ting GuoDepartment of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Furong District, Changsha, Hunan, 410011, People’s Republic of ChinaEmail luohonghuxi@csu.edu.cn; guotingxy@csu.edu.cnBackground: Dynein axonemal assembly factor 2 (DNAAF2) is involved in the early preassembly of dynein in the cytoplasm, which is essential for motile cilia function. Primary ciliary dyskinesia (PCD) associated with DNAAF2 variants has rarely been reported in females with infertility. Moreover, there is no report linking DNAAF2 to scoliosis in human.Materials and Methods: We recruited patients from two consanguineous families with a clinical diagnosis of PCD and collected their clinical history, laboratory tests, and radiographic data. Sequencing and bioinformatics analysis were then performed. Immunofluorescence and high-speed microscope analysis were used to support the pathogenicity of the variant.Results: Proband 1, a 26-year-old female from family I, exhibited scoliosis, bronchiectasis, sinusitis, situs inversus, and infertility. We found a novel homozygous missense variant in DNAAF2, c.491T>C, p.(Leu164Pro) in this patient. Subsequent immunofluorescence indicated the absence of outer dynein arm and inner dynein arm of cilia, and high-speed microscopy analysis showed that the most of the cilia are static, which support the pathogenicity of this variant. Proband 2, a 53-year-old female, presented with bronchiectasis, sinusitis, and infertility. In this patient, a new homozygous frameshift variant DNAAF2, c.822del, p.(Ala275Profs*10) was identified. The disease-causing variants mentioned above are not included in the current authorized genetic databases.Conclusion: Our findings expand the spectrum of DNAAF2 variants and link DNAAF2 to female infertility and likely scoliosis in patients with PCD.Keywords: primary ciliary dyskinesia, scoliosis, DNAAF2, bronchiectasis, situs inversus, female infertility

Shuqi Mao,1 Xi Yu,1 Yuying Shan,1 Rui Fan,2 Shengdong Wu,1 Caide Lu1 1Department of Hepatopancreatobiliary Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, 315040, People’s Republic of China; 2Medical Quality Management Office, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, 315040, People’s Republic of ChinaCorrespondence: Caide Lu; Shengdong WuDepartment of Hepatopancreatobiliary Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, 315040, People’s Republic of ChinaTel +86 13957800900; +86 13567886669Email lucaide@nbu.edu.cn; 13567886669@139.comPurpose: In this study, we aimed to develop a novel liver function and inflammatory markers-based nomogram to predict recurrence-free survival (RFS) for AFP-negative (< 20 ng/mL) HCC patients after curative resection.Patients and Methods: A total of 166 pathologically confirmed AFP-negative HCC patients were included at the Ningbo Medical Center Lihuili Hospital. A LASSO regression analysis was used for data dimensionality reduction and element selection. Univariate and multivariate Cox regression analyses were performed to identify the independent risk factors relevant to RFS. Finally, clinical nomogram prediction model for RFS of HCC was established. Nomogram performance was assessed via internal validation and calibration curve statistics. Receiver operating characteristic (ROC) and decision curve analysis (DCA) curve were used to validate the performance and clinical utility of the nomogram.Results: Multivariate Cox regression analysis indicated that ALBI grade (hazard ratio, [HR] = 2.624, 95% confidence interval [CI]: 1.391– 4.949, P = 0.003), INR (HR = 2.605, 95% CI: 1.061– 6.396, P = 0.037), MLR (HR = 1.769, 95% CI: 1.073– 2.915, P = 0.025) and MVI (HR = 4.726, 95% CI: 2.365– 9.444, P < 0.001) were independent prognostic factors of RFS. Nomogram with independent factors was established and achieved a better concordance index of 0.753 (95% CI: 0.672– 0.834) for predicting RFS. The ROC found that the area under curve (AUC) was consistent with the C-index and the sensitivity was 85.4%. The risk score calculated by nomogram could divide AFP-negative HCC patients into high-, moderate- and low-risk groups (P < 0.05). DCA analysis revealed that the nomogram could augment net benefits and exhibited a wider range of threshold probabilities by the risk stratification than the AJCC T and BCLC stage in the prediction of AFP-negative HCC recurrence.Conclusion: The ALBI grade- and MLR-based nomogram prognostic model for RFS showed high predictive accuracy in AFP-negative HCC patients after surgical resection.Keywords: HCC, MLR, ALBI grade, AFP-negative, recurrence-free survival, nomogram

Jinyu Zhu,1,2,&ast; Bufu Tang,1,3,&ast; Yang Gao,1,4 Suqin Xu,5 Jianfei Tu,1,4 Yajie Wang,4 Weibin Yang,1,4 Shiji Fang,4 Qiaoyou Weng,4 Zhongwei Zhao,1,4 Min Xu,1,4 Yang Yang,1,4 Minjiang Chen,1,4 Chenying Lu,1,4 Jiansong Ji1,4 1Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People’s Republic of China; 2Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China; 3Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of China; 4Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People’s Republic of China; 5Clinical Laboratory, Fuyuan Hospital of Yiwu, Jinhua, 321000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiansong Ji; Chenying Lu Email jijiansong@zju.edu.cn; luchenying@zju.edu.cnIntroduction: Hepatocellular carcinoma (HCC) is a heterogeneous molecular disease with complex molecular pathogenesis that influences the efficacy of therapies. Exosomes play a crucial role in tumorigenesis and poor disease outcomes in HCC.Objective: The aim of this study was to identify the optimal gene set derived from exosomes in HCC with substantial predictive value to construct models for determining prognosis, recurrence risk and diagnosis and to identify candidates suitable for immunotherapy and chemotherapy, thereby providing new ideas for the individualized treatment of patients and for improving prognosis.Methods: Weighted correlation network analysis (WGCNA) and univariate and multivariate Cox PH regression analyses were applied to identify exosome-related signatures in the TCGA and exoRbase databases associated with clinical relevance, immunogenic features and tumor progression in HCC. Cell experiments were performed to further confirm the oncogenic effect of MYL6B and THOC2.Results: The models for prognosis and recurrence risk prediction were built based on two exosomal genes (MYL6B and THOC2) and were confirmed to be independent predictive factors with superior predictive performance. Patients with high prognostic risk had poorer prognosis than patients with low prognostic risk in all HCC datasets, namely, the TCGA cohort (HR=2.5, P< 0.001), the ICGC cohort (HR=3.15, P< 0.001) and the GSE14520 cohort (HR=1.85, P=0.004). A higher recurrence probability was found in HCC patients with high recurrence risk than in HCC patients with low recurrence risk in the TCGA cohort (HR=2.44, P< 0.001) and the GSE14520 cohort (HR=1.54, P=0.025). High prognostic risk patients had higher expression of immune checkpoint genes, such as PD1, B7H3, B7H5, CTLA4 and TIM3 (P< 0.05). Diagnostic models based on the same two genes were able to accurately distinguish HCC patients from normal individuals and HCC from dysplastic nodules.Conclusion: Our findings lay the foundation for identifying molecular markers to increase the early detection rate of HCC, improve disease outcomes, and determine more effective individualized treatment options for patients.Keywords: exosome, hepatocellular carcinoma, HCC, immune checkpoint, prognosis

Wenfeng Li,&ast; Yuanshen Mao,&ast; Yufei Gu, Chao Lu, Xin Gu, Bao Hua, Weixin Pan, Qinghong Xi, Bin Xu Department of Urology, The Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Xu; Qinghong XiDepartment of Urology, The Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaTel +862156691101Email kuangfeng0612@126.com; 13611829161@163.comBackground: Effective pain management is limited for patients during prostate biopsy (PBx). Touch support, such as hand holding, has stress-buffering benefits and effective analgesic effects. We conducted a prospective, single-center randomized clinical trial to assess whether hand holding can reduce patient anxiety, pain, and dissatisfaction during PBx.Methods: Between April 2020 and October 2020, 120 male patients were randomized into three groups: a hand holding with relatives (HR) group, a hand holding with strangers (HS) group and a control group. A visual analog scale (VAS) was used for self-assessments of pain and satisfaction. Anxiety levels were quantified according to the State-Trait Anxiety Inventory (STAI). Hemodynamic changes were also measured.Results: The degree of pain and anxiety in the hand-holding groups was significantly better than that in the control group (P< 0.001), and the patients were more willing to undergo repeat PBx (P=0.017). The anxiety levels in the HR group were significantly lower than those in the HS group (P=0.019). During PBx, the changes in systolic blood pressure and heart rate in the hand-holding groups were more stable than those in the control group (P< 0.01), and the fluctuations in heart rate in the HR group were smaller than those in the HS group (P< 0.01).Conclusion: Hand holding, especially with relatives, can promote incremental reductions in anxiety, pain and dissatisfaction in patients during PBx. Hence, we recommend hand holding with relatives as an effective adjunct during PBx.Keywords: anxiety, transrectal prostate biopsy, hand holding, pain, satisfaction

Shidong Tan,1 Guangyao Zang,1 Ying Wang,1 Zhen Sun,1 Yalan Li,1 Cheng Lu,2 Zhongqun Wang1 1Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China; 2General Office, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of ChinaCorrespondence: Cheng LuGeneral Office, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, 212001, People’s Republic of China, +86 511 88986902Email jdfylz@sina.comZhongqun WangDepartment of Cardiology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, 212001, People’s Republic of ChinaTel +86 511 85030586Email wangtsmc@126.comAbstract: Angiogenesis, as a process occurring under the regulation of a variety of factors, is one of the important ways of vascular development. It coexists in a variety of pathological and physiological processes. Now a large number of studies have proved that tumor growth, metastasis, and various vascular complications of diabetes are closely related to angiogenesis, and an increasing number of studies have shown that there are many common factors between the two. But angiogenesis is the opposite of the two: it is enhanced in tumors and suppressed in diabetes. Therefore, this review discusses the causes of the phenomenon from the expression of various factors affecting angiogenesis in these two diseases and their effects on angiogenesis in the relevant microenvironment, as well as the application status of these factors or cells as therapeutic targets in the treatment of these two diseases.Keywords: diabetes mellitus, tumor, angiogenesis, differences, tumor microenvironment, hypoxia

Yueyue Liu, Qian Zhang, Chao Lu, Wei Hu Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, People’s Republic of ChinaCorrespondence: Chao Lu; Wei HuDepartment of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, People’s Republic of ChinaTel/Fax + 86-551 63806057Email 765385306@qq.com; huwei@ahmu.edu.cnPurpose: Pyrotinib, an irreversible human epidermal growth factor receptor 2 (HER2), is a epidermal growth factor receptor double-target tyrosine kinase inhibitor used for treating HER2-positive breast cancer. This study aimed to evaluate the impact of the strong CYP3A4 inhibitor itraconazole on the safety and pharmacokinetics of pyrotinib in Chinese healthy adults.Patients and Methods: This was an open-label, randomized, self-control study. Eighteen healthy adults were included in this trial. They received a single 80 mg dose of pyrotinib orally on days 1 and 9, and a 200 mg once-daily dose of itraconazole on days 6 through 22. Blood samples were obtained, and the drug concentration was detected using liquid chromatography/tandem mass spectrometry.Results: Compared with pyrotinib alone, the exposure to pyrotinib co-administered with itraconazole substantially increased, and the Cmax and AUC0-t increased by 2.78- and 10.8-fold, respectively. No serious adverse events were reported in this trial, and no participant dropped out of the trial because of adverse events.Conclusion: The exposure to pyrotinib was substantially affected by the action of itraconazole. The concomitant use of pyrotinib with itraconazole might require dose modification of pyrotinib. All treatments were well tolerated in healthy participants.Clinical Trial Registry: http://www.chinadrugtrials.org.cn/clinicaltrials.prosearch.dhtml, CTR20191866.Keywords: drug–drug interaction, itraconazole, pharmacokinetics, pyrotinib, safety

Chong Lu,1,* Yikui Zhao,2,* Yan Cao,3,* Li Liu,1 Shanshan Wu,1 Dongbin Li,1 Shuang Liu,1 Shuyuan Xiao,1 Yafen Wei,1 Xinyu Li3 1Department of Neurology, Heilongjiang Provincial Hospital, Harbin, People’s Republic of China; 2HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, People’s Republic of China; 3Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinyu Li; Yafen Wei Tel +86-13796658016; Tel +86-13796658016Email 13796658016@163.com; weiyafen2008@sina.comAim: High glucose (HG)-induced activation of mTOR promotes tau phosphorylation and leads to diabetes-associated dementia. This study aimed to explore the role of metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) in HG-induced neuronal cell injury.Methods: Hippocampus cells were isolated from C57BL/6J mice. After 6 days of culture, the cells were incubated with 5.5 mM glucose in normal medium or 75 mM glucose for 4 days. Cells were transfected with miR-144 mimic, miR-144 inhibitor, siRNA for MALAT1 or corresponding controls. Gene expression was detected by PCR and Western blot analysis.Results: HG increased the levels of MALAT1 and p-tau in hippocampal cells. Knockdown of MALAT1 partially reversed the effects of HG on mTOR activity and p-tau protein levels. MALAT1 functioned as competing endogenous RNA (ceRNA) for miR-144, and pre-treatment with MALAT1 siRNA decreased mTOR activity and p-tau protein level in HG-treated hippocampal cells, which was significantly attenuated by miR-144 mimics. Moreover, miR-144 negatively regulated the expression of mTOR and knockdown of MALAT1 suppressed mTOR, while overexpression of mTOR abrogated protective effects of MALAT1 knockdown in HG-treated hippocampal cells.Conclusion: MALAT1 knockdown prevented HG-induced mTOR activation and inhibited tau phosphorylation. MALAT1 may be a therapy target for diabetes associated dementia.Keywords: diabetes mellitus, tau, MALAT1, mTOR, miR-144

Chun Zeng,1,2 Jing Wang,3 Mingwei Li,4 Huina Wang,4 Feng Lou,4 Shanbo Cao,4 Changyu Lu3 1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China; 3Department of Neurosurgery, Peking University International Hospital, Beijing, People’s Republic of China; 4Acornmed Biotechnology Co., Ltd, Beijing, People’s Republic of ChinaCorrespondence: Changyu LuDepartment of Neurosurgery, Peking University International Hospital, Beijing, People’s Republic of ChinaTel +8669006144Email luchangyu2020@163.comShanbo CaoAcornmed Biotechnology Co., Ltd, Floor 18, Block 5, Yard 18, Kechuang 13 Road, Beijing, 100176, People’s Republic of ChinaTel +8653606156Email shanbocao@acornmed.comBackground: Tremendous efforts have been made to explore biomarkers for classifying and grading glioma. However, the majority of the current understanding is based on public databases that might not accurately reflect the Asian population. Here, we investigated the genetic landscape of Chinese glioma patients using a validated multigene next-generation sequencing (NGS) panel to provide a strong rationale for the future classification and prognosis of glioma in this population.Methods: We analyzed 83 samples, consisting of 71 initial treatments and 12 recurrent surgical tumors, from 81 Chinese patients with gliomas by performing multigene NGS with an Acornmed panel targeting 808 cancer-related hotspot genes, including genes related to glioma (hotspots, selected exons or complete coding sequences) and full-length SNPs located on chromosomes 1 and 19.Results: A total of 76 (91.57%) glioma samples had at least one somatic mutation. The most commonly mutated genes were TP53, TERT, IDH1, PTEN, ATRX, and EGFR. Approximately one-third of cases exhibited more than one copy number variation. Of note, this study identified the amplification of genes, such as EGFR and PDGFRA, which were significantly associated with glioblastoma but had not been previously used for clinical classification (P< 0.05). Significant differences in genomic profiles between different pathological subtypes and WHO grade were observed. Compared to the MSKCC database primarily comprised of Caucasians, H3F3A mutations and MET amplifications exhibited higher mutation rates, whereas TERT mutations and EGFR and CDKN2A/B copy number variations presented a lower mutation rate in Chinese patients with glioma (P< 0.05).Conclusion: Our multigene NGS in the simultaneous evaluation of multiple relevant markers revealed several novel genetic alterations in Chinese patients with glioma. NGS-based molecular analysis is a reliable and effective method for diagnosing brain tumors, assisting clinicians in evaluating additional potential therapeutic options, such as targeted therapy, for glioma patients in different racial/ethnic groups.Keywords: glioma, molecular pathology, molecular biomarker, copy number variations, multigene NGS panel

Yubo Wang,1,* Rui Han,1,* Qiushi Wang,2 Jie Zheng,1 Caiyu Lin,1 Conghua Lu,1 Li Li,1 Hengyi Chen,1 Rongbing Jin,3 Yong He1 1Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China; 2Department of Pathology, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China; 3Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yong HeDepartment of Respiratory Medicine, Daping Hospital, Army Medical University, 10# Changjiangzhilu Daping, Yuzhong District, Chongqing, 400042, People’s Republic of ChinaTel +86-2368757791Fax +86-2368700970Email heyong@tmmu.edu.cnRongbing JinDepartment of Nuclear Medicine, Daping Hospital, Army Medical University, 10# Changjiangzhilu Daping, Yuzhong District, Chongqing, 400042, People’s Republic of ChinaTel +86-2368757641Email jinrb99@126.comPurpose: To investigate the potential of maximum standardized uptake value (SUVmax) in predicting epidermal growth factor receptor (EGFR) mutation status in non-small cell lung cancer (NSCLC) patients.Methods: Clinical data of 311 NSCLC patients who had undergone both EGFR mutation test and 18F-FDG PET/CT scans between January 2013 and December 2017 at our hospital were retrospectively analyzed. Patients were sub-grouped by their origin of SUVmax. Univariate and multivariate analyses were performed to investigate the association between clinical factors and EGFR mutations. Receiver operating characteristic curve (ROC) analysis was performed to confirm the predictive value of clinical factors. In vitro experiments were performed to confirm the correlation between EGFR mutations and glycolysis.Results: EGFR-mutant patients had higher SUVmax than the wild-type patients in both primary tumors and metastases. In the multivariate analysis, SUVmax, gender and histopathologic type were determined as independent predictors of EGFR mutation status for patients whose SUVmax were obtained from the primary tumors; while for patients whose SUVmax were obtained from the metastases, SUVmax, smoking status and histopathologic type were regarded as independent predictors. ROC analysis showed that SUVmax of the primary tumors (cut off > 10.92), not of the metastases, has better predictive value than other clinical factors in predicting EGFR mutation status. The predict performance was improved after combined SUVmax with other independent predictors. In addition, our in vitro experiments demonstrated that lung cancer cells with EGFR mutations have higher aerobic glycolysis level than wild-type cells.Conclusion: SUVmax of the primary tumors has the potential to serve as a biomarker to predict EGFR mutation status in NSCLC patients.Keywords: non-small cell lung cancer, epidermal growth factor receptor, SUVmax, receiver operating characteristic curve

Chao Lu, Wei Yang, Jianliang Zhou, Zulei Zhang, Yi Gong, Fajia Hu, Wenpeng Yu, Xiao Dong Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, People’s Republic of ChinaCorrespondence: Xiao Dong Email dongxiao145@163.comObjective: Pre-B cell colony enhancing factor (PBEF) is an important proinflammatory cytokine involved in acute lung injury. However, whether PBEF participates in lung injury caused by cardiopulmonary bypass (CPB) is still unknown. This study aimed to investigate the effects of silencing PBEF on lung injury and the sodium and water transport system in rats receiving CPB.Methods: Morphological changes in lung tissues were evaluated using hematoxylin and eosin (H&E) staining. PBEF was detected using immunohistochemistry. The sodium and water transport system-related proteins and cellular signaling pathways were detected by Western blotting.Results: Rats receiving CPB (model group) had more severe alveolar wall damage and higher expression of PBEF in free form than the control rats. Western blotting showed that the expression of PBEF, surfactant protein D (SP), aquaporin (AQP) 1, AQP5, and epithelial sodium channel (ENaC) was significantly higher in the lung tissue of CPB rats than control rats. By contrast, adenovirus-encoding sh-PBEF significantly reduced the expression of PBEF, SP, AQP1, AQP5, and ENaC in the lung tissues of rats treated with CPB. The phosphorylation levels of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), protein kinase B (AKT), and p38 mitogen-activated protein kinase (MAPK) were significantly increased in the lung tissue of rats that received CPB, and were downregulated by adenovirus-encoding sh-PBEF.Conclusion: Adenovirus-encoding sh-PBEF could reduce lung injury and repair the sodium–water transport system in rats receiving CPB, likely through reducing MAPK, ERK1/2, and Akt signaling pathways.Keywords: pre-B cell colony enhancing factor, epithelial sodium channel, aquaporin, cardiopulmonary bypass