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Xinfu Cao,1 Yi Sun,1 Yuqiao Chen,1 Chao Tang,2 Hongwen Yu,3 Xiaolong Li,1 Zhenhua Gu1 1Department of Cardiology, Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine, Changzhou, Jiangsu Province, People’s Republic of China; 2Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, People’s Republic of China; 3Department of Cardiology, Gaochun Branch of Nanjing Hospital of Traditional Chinese Medicine, Nanjing City, Jiangsu Province, People’s Republic of ChinaCorrespondence: Zhenhua Gu; Xiaolong Li, Department of Cardiology, Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine, Changzhou City, Jiangsu Province, People’s Republic of China, Email 18101490727@163.com; 15650796727@163.comObjective: To explore the risk factors of atrial fibrillation (AF) in patients with coronary heart disease (CHD), and to construct a risk prediction model.Methods: The participants in this case-control study were from the cardiovascular Department of Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine from June 2016 to June 2023, and they were divided into AF group and non-AF group according to whether AF occurred during hospitalization. The clinical data of the two groups were compared by retrospective analysis. Multivariate Logistic regression analysis was used to investigate the risk factors of AF occurrence in CHD patients. The nomogram model was constructed with R 4.2.6 language “rms” package, and the model’s differentiation, calibration and effectiveness were evaluated by drawing ROC curve, calibration curve and decision curve.Results: A total of 1258 patients with CHD were included, and they were divided into AF group (n=92) and non-AF group (n=1166) according to whether AF was complicated. Logistic regression analysis showed that age, coronary multiple branch lesion, history of heart failure, history of drinking, pulmonary hypertension, left atrial diameter, left ventricular end-diastolic diameter and diabetes mellitus were independent risk factors for the occurrence of AF in CHD patients (P < 0.05). The ROC curve showed that the AUC of this model was 0.956 (95% CI (0.916, 0.995)) and the consistency index was 0.966. The calibration curve of the model is close to the ideal curve. The analysis of decision curve shows that the prediction value of the model is better when the probability threshold of the model is 0.042~0.963.Conclusion: The nomogram model established in this study for predicting the risk of AF in patients with CHD has better predictive performance and has certain reference value for clinical identification of high-risk groups prone to AF in patients with CHD.keywords: coronary heart disease, atrial fibrillation, risk factors, logistic regression analysis, nomogram model

Jing Luo,1,2 Yi Luo,2 Maoru Zhao,3 Yulong Liu,2 Jiayin Liu,2 Zhulin Du,2 Hong Gong,2 Lian Wang,2 Jinghui Zhao,2 Xiaqing Wang,2 Zhanjun Gu,3 Wenhui Zhao,1 Tianyao Liu,2 Xiaotang Fan2 1School of Life Sciences, Chongqing University, Chongqing, 401331, People’s Republic of China; 2Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, 400038, People’s Republic of China; 3Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, Institute of High Energy Physics and National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing, 100049, People’s Republic of ChinaCorrespondence: Xiaotang Fan; Tianyao Liu, Email fanxiaotang2005@163.com; squall277@163.comBackground: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a type of carbon nanomaterial known for its neuroprotective properties, have not yet been studied for their potential in treating ASD. We aimed to investigate its role in improving autistic behaviors in BTBR T+Itpr3tf/J (BTBR) mice and its underlying mechanism, which could provide reliable clues for future ASD treatments.Methods: Our research involved treating C57BL/6J (C57) and BTBR mice with either 0.9% NaCl or fullerenols (10 mg/kg) daily for one week at seven weeks of age. We then conducted ASD-related behavioral tests in the eighth week and used RNA-seq to screen for vital pathways in the mouse hippocampus. Additionally, we used real-time quantitative PCR (RT-qPCR) to verify related pathway genes and evaluated the number of stem cells in the hippocampal dentate gyrus (DG) by Immunofluorescence staining.Results: Our findings revealed that fullerenols treatment significantly improved the related ASD-like behaviors of BTBR mice, manifested by enhanced social ability and improved cognitive deficits. Immunofluorescence results showed that fullerenols treatment increased the number of DCX+ and SOX2+/GFAP+ cells in the DG region of BTBR mice, indicating an expanded neural progenitor cell (NPC) pool of BTBR mice. RNA-seq analysis of the mouse hippocampus showed that VEGFA was involved in the rescued hippocampal neurogenesis by fullerenols treatment.Conclusion: In conclusion, our findings suggest that fullerenols treatment improves ASD-like behavior in BTBR mice by upregulating VEGFA, making nanoparticle- fullerenols a promising drug for ASD treatment. Keywords: fullerenols, BTBR, neurogenesis, autism spectrum disorder, hippocampus

Zhipeng Liu,1,&ast; Xinyu Yuan,2,&ast; Yan Huang,3 Zihan Gu,4 Lu Xue,5 Shanshan Xue,6 Jun Wang2 1Information Department, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu Province, 225300, People’s Republic of China; 2Emergency Department, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu Province, 225300, People’s Republic of China; 3Medical College, Yangzhou University, Yangzhou, 225009, People’s Republic of China; 4Nanjing University of Finance & Economics, Nanjing, 210023, People’s Republic of China; 5Department of Critical Care Medicine, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu Province, 225300, People’s Republic of China; 6Institute of Clinical Laboratory, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu Province, 225300, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Wang; Shanshan Xue, Email 15061008998@163.com; 245116999@qq.comBackground: Sepsis refers to a life-threatening organ dysfunction which can be resulted from the infection-induced dysregulated host response. A large number of inflammatory cytokines are released to act on the liver, making the liver one of the common target organs for the development of multiple organ dysfunction syndrome (MODS) in patients with sepsis. Sepsis-induced acute liver injury (SALI) can aggravate systemic disease. As a result, it is of great clinical significance to comprehend the molecular biological mechanism of SALI and to identify the markers for evaluating SALI. Interferon-induced proteins with tetratricopeptide repeats 1 and 2 (IFIT1, IFIT2) have been recognized as the anti-inflammatory factors that are widely expressed in various organs. The present study was aimed at clarifying the roles of IFIT1 and IFIT2 in the development of SALI.Methods: A two-sample Mendelian randomization (MR) analysis was employed. Summary statistics datas were obtained from GWAS for inflammatory factors [tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6)], IFIT2, and sepsis as well as liver injury. Independent SNPs were selected as instrumental variables (IVs). Inverse variance weighted (IVW) in the MR analysis was adopted as the primary method for estimating the causal associations of inflammatory factors and IFIT2 with two diseases, and the associations of inflammatory factors with IFIT2. Additionally, weighted median method, MR-Egger and sensitivity analyses were applied in assessing the robustness of the results and ensure the result reliability. Subsequently, 119 healthy volunteers, 116 patients with sepsis and 116 SALI patients were recruited. The ELISA method was employed to quantify the expression levels of TNF-α, IL-1β, and IL-6. Additionally, qRT-PCR was conducted to measure the expression of IFIT1 and IFIT2. Furthermore, the correlations of IFIT1 and IFIT2 with inflammatory factors, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were explored.Results: As shown by the MR analysis, the genetically predisposed sepsis was significantly associated with the risk of IL-1β, with an odds ratio (OR) of 1.069 (95% confidence interval (CI), 1.015– 1.127, p = 0.0119), and negatively associated with the risk of IL-6, with an OR of 0.880 (95% CI: 0.792– 0.979, p= 0.0184). Meanwhile, there were positive causal effects of IL-6 (OR = 1.269, 95% CI: 1.032– 1.561, p= 0.0238), IL-1β (OR = 1.106, 95% CI: 1.010– 1.211, p = 0.0299) and IFIT2 (OR = 1.191, 95% CI: 1.045– 1.359, p = 0.0090) on liver injury. Additionally, there was a positive causal effect of IFIT2 (OR = 1.164, 95% CI: 1.035– 1.309, p= 0.0110) on IL-1β. Upon sensitivity analyses, there was weak evidence of such effects, indicating that the findings of this study were robust and reliable. Our results revealed the elevated levels of TNF-α, IL-1β, and IL-6 in the blood samples of sepsis and SALI patients (p < 0.0001). Conversely, IFIT1 and IFIT2 demonstrated the significantly decreased levels in peripheral blood mononuclear cells (PBMCs) of SALI patients (p < 0.0001). Furthermore, the expression levels of IFIT1 and IFIT2 were both negatively correlated with ALT activity (r = − 0.3426, p = 0.0002; r = − 0.3069, p = 0.0008) and AST activity (r = − 0.2483, p = 0.0072; r = − 0.3261, p = 0.0004), respectively. Moreover, the expression of IFIT1 and IFIT2 was both negatively related to the levels of TNF-α (r = − 0.5027, p < 0.0001; r = − 0.4218, p < 0.0001), IL-1β (r = − 0.3349, p = 0.0002; r = − 0.4070, p < 0.0001) and IL-6 (r = − 0.2734, p = 0.0030; r = − 0.3536, p < 0.0001), respectively.Conclusion: IFIT1 and IFIT2 can serve as the diagnostic markers for sepsis-related liver injury, and IFIT1 and IFIT2 may participate in the pathological process of sepsis-related liver injury by regulating inflammation and liver function.Keywords: acute liver injury, sepsis, IFIT1, IFIT2, inflammation, Mendelian randomization

Xiaoyue Feng,&ast; Jianli Shang,&ast; Zhengping Gu, Xingyi Luo, Yong Chen, Youting Liu Product Research & Development Center, Beijing Underproved Medical Technology Co., LTD, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Youting Liu, Product Research & Development Center, Beijing Underproved Medical Technology Co., LTD, Beijing, 102699, People’s Republic of China, Tel +86 1 851 025 6963, Email YtLiu.adpt@outlook.comAbstract: Lactic acid is the most widely occurring natural organic acid in nature. It not only exhibits mild and safe properties but also possesses multiple physiological activities, such as antibacterial effects, immune regulation, and promotion of wound healing, making it one of the most popular chemical peeling agents. Chemical peels are commonly used in the field of aesthetic dermatology as a non-invasive therapeutic approach. This research aims to provide valuable references for clinical dermatologists by summarizing the characteristics of lactic acid, elucidating its mechanism of action in peeling, and investigating the clinical applications of this compound. Furthermore, it anticipates the potential for lactic acid to be the most suitable chemical peeling agent for Chinese skin.Keywords: lactic acid, physiological activities, clinical applications, Chinese skin

Zhihui Liu,1,&ast; Zhuo Li,2,&ast; Lingling Wang,3 Zhenpeng Gu,4 Lixin Ma5 1Department of Obstetrics and Gynecology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2School of Medicine, Nankai University, Tianjin, People’s Republic of China; 3Department of General Practice, Binzhou People’s Hospital, Binzhou, People’s Republic of China; 4Department of Obstetrics and Gynecology, Binzhou Medical University Hospital, Binzhou, People’s Republic of China; 5Department of Neurosurgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lixin Ma, Department of Neurosurgery, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongti South Road, Chaoyang District, Beijing, People’s Republic of China, Email mlx_182019@163.comBackground: Pregnant women are highly susceptible to periodontal disease due to changes in hormonal and immune levels, which places a huge burden on the healthcare system and requires multidisciplinary interventions. This study aimed to assess the scientific profile and research trends related to periodontal disease in pregnancy through a bibliometric approach.Methods: Publications about periodontal disease in pregnancy from 2000 to 2022 were extracted from Science Citation Index Expanded. The knowledge networks of countries, institutions, authors, journals, references, and keywords in this field were constructed using the Citespace, VOSviewer, Bibliometrix, and BIBLIOMETRIC.COM platforms. Furthermore, correlations between the characteristics of countries and the number or impact of publications were analyzed.Results: 1162 original studies and reviews were included. There was a trend toward increased publications and citations in this field. The United States had the highest academic productivity and impact by a significant margin, while correlation analyses indicated that economic power may correlate with national scientific activity. The University of North Carolina and Offenbacher S were the most influential institution and author, respectively, taking center stage in the collaborative networks. However, only several loose connections between countries or institutions were identified in the global collaborative network analysis. Six of the top ten most productive journals were in Q1 in the Journal Citation Report, and there was intensive interaction between different research subfields, such as immunology, molecular biology, and microbiology. Frontier topics were primarily clustered in two areas: (1) oral microbiology, such as microbiome, oral bacteria, and Fusobacterium nucleatum; and (2) public health, such as quality of life, pregnancy outcomes, oral health, obesity, and classification.Conclusion: Since 2000, periodontal disease in pregnancy is receiving increasingly widespread attention and is rapidly evolving at a multidisciplinary level. Oral microbiological pathogenesis and public health impact-related research deserve more exploration and may be the future direction of research. Enhanced Collaboration and interdisciplinary communication may further facilitate progress in this discipline.Keywords: bibliometric analysis, periodontal disease, pregnancy, multidisciplinary issue, oral microbiology, public health

Shi Chen,1,&ast; Jiaqi Qiang,1,2,&ast; Bin Zhao,3 Ran Tian,4 Tao Yuan,1 Ming Li,1 Mei Li,1 Zhaoqi Gu,5 Liping Yang,6 Huijuan Zhu,1 Hui Pan,1,7 Yan Tang,3 Yuxiu Li1 1Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 2Eight-Year Program of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 3Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 4Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 5Department of Radiotherapy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 6Department of Pharmacy, Handan First Hospital, Handan, Hebei Province, People’s Republic of China; 7State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuxiu Li, Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, People’s Republic of China, Email liyuxiu@medmail.com.cn Yan Tang, Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, People’s Republic of China, Email tangyan@pumch.cnAbstract: The sulfhydryl group of clopidogrel metabolite could induce insulin autoimmune syndrome (IAS) with hypoglycemia as the major symptom. For patients with cardiovascular disease taking clopidogrel for vascular protection, this adverse event hypoglycemia increases the risk of cardiovascular events. However, discontinuing clopidogrel leaves patients without appropriate antiplatelet therapy. Treating IAS with glucocorticoids is also risky for these patients’ primary cardiovascular diseases. Early recognition and appropriate treatment of clopidogrel-induced IAS (CIAS) would be beneficial for patients. This research aimed to discover the clinical features and investigate optimal therapeutic management of CIAS. We systematically searched for cases of CIAS in PubMed and Embase and performed data mining in Food and Drug Administration Adverse Event Reporting System (FAERS). In the CIAS series, clinical features were summarized and compared to 287 IAS cases, including demographic information, HLA alleles, onset, and symptoms. The therapeutic effect of glucocorticoids was compared between the receiving group and the not-receiving group. The possibilities of common antiplatelet drugs to induce hypoglycemia/IAS were investigated with chemical structure and FAERS reports. A CIAS series of 51 patients was established. CIAS had an onset age of 74.8± 8.6 years old, 92.2% male, and a balanced proportion of East Asians and non-East Asians. Confusion occurred more frequently in CIAS than in IAS from various causes, while the other symptoms and hypoglycemia types were similar. The recovery time was approximately the same whether using glucocorticoids/immunotherapy in CIAS or not. Among common antiplatelet drugs, ticagrelor and rivaroxaban were unlikely to induce hypoglycemia/IAS. Clopidogrel is a distinctive cause of IAS featuring an elderly male presenting confusion as the symptom of hypoglycemia. Glucocorticoids/immunotherapy might not be necessary for the long-term recovery of CIAS. To balance the risks of hypoglycemia and cardiovascular events, substituting clopidogrel with ticagrelor and rivaroxaban might be considered.Keywords: autoimmune hypoglycemia, antiplatelet therapy, glucocorticoids, cardiovascular diseases, ticagrelor

Cong Chen,1,&ast; Jian Liu,2,&ast; Zhuxin Gu,1 Yanjun Sun,1 Wenwu Lu,3 Xiaokan Liu,4 Kang Chen,1 Tianzhi Ma,5 Suming Zhao,1 Hui Zhao1 1Department of Interventional & Vascular Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, People’s Republic of China; 2Dalian Medical University and Affiliated Hospital of Nantong University, Nantong, 226001, People’s Republic of China; 3Department of Medical Ultrasound, Affiliated Hospital of Nantong University, Nantong, 226001, People’s Republic of China; 4Department of Interventional Radiology, Affiliated Hospital 2 of Nantong University, Nantong, 226001, People’s Republic of China; 5Nanjing University of Aeronautics and Astronautics, Nanjing, 210000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Suming Zhao; Hui Zhao, The Affiliated Hospital of Nantong University, No. 20, Xisi Road, Chongchuan District, Nantong City, Jiangsu Province, People’s Republic of China, Tel +86-513-85052071, Email 5201120@ntu.edu.cn; zhaohui8868@sina.comBackground: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Patients with HCC choose postoperative adjuvant transarterial chemoembolization (PA-TACE) after surgical resection to reduce the risk of recurrence. However, many of them have recurrence within a short period.Methods: In this retrospective analysis, a total of 173 patients who underwent PA-TACE between September 2016 and March 2020 were recruited. Radiomic features were derived from the arterial and venous phases of each patient. Early recurrence (ER)-related radiomics features of HCC and the spleen were selected to build two rad-scores using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Logistic regression was applied to establish the Radiation (Rad)_score by combining the two regions. We constructed a nomogram containing clinical information and dual-region rad-scores, which was evaluated in terms of discrimination, calibration, and clinical usefulness.Results: All three radiological scores showed good performance for ER prediction. The combined Rad_score performed the best, with an area under the curve (AUC) of 0.853 (95% confidence interval [CI], 0.783– 0.908) in the training set and 0.929 (95% CI, 0.789– 0.988) in the validation set. Multivariate analysis identified total bilirubin (TBIL) and the combined Rad_score as independent prognostic factors for ER. The nomogram was found to be clinically valuable, as determined by the decision curves (DCA) and clinical impact curves (CIC).Conclusion: A multimodal dual-region radiomics model combining HCC and the spleen is an independent prognostic tool for ER. The combination of dual-region radiomics features and clinicopathological factors has a good clinical application value.Keywords: hepatocellular carcinoma, radiomics, nomogram, transcatheter arterial chemoembolization, computed tomography

Qian Ma,1,&ast; Lei Chang,2,&ast; Wenwen Wang,2,&ast; Lingyi Che,1 Xiaoqin Song,3 Gailing Li,2 Ying Zhang,2 Yibing Chen,1 Zhuoyu Gu,4 Xin Ge5 1Genetics and Prenatal Diagnosis Center, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 2Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 3Physical Examination Center, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 4Department of Thoracic Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 5Department of Breast Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Ge, Department of Breast Surgery, First Affiliated Hospital, Zhengzhou University, 1 Jianshe Road East, Zhengzhou, Henan, 450052, People’s Republic of China, Email Gexin1981@126.com Zhuoyu Gu, Department of Thoracic Surgery, First Affiliated Hospital, Zhengzhou University, 1 Jianshe Road East, Zhengzhou, Henan, 450052, People’s Republic of China, Email guzhuoyu@hotmail.comBackground: It was indicated that tumor intrinsic heterogeneity and the tumor microenvironment (TME) of ovarian cancer (OV) influence immunotherapy efficacy and patient outcomes. Leucyl and cystinyl aminopeptidase (LNPEP) encodes a zinc-dependent aminopeptidase, which has been proved to participant in the vesicle-mediated transport and class I MHC mediated antigen processing and presentation. However, the function of LNPEP in TME of OV and its potential molecular mechanisms have not been determined. Therefore, we aimed to investigate a prognostic biomarker which may be helpful in identifying TME heterogeneity of ovarian cancer.Methods: In this study, bioinformatics databases were used to explore the expression profile and immune infiltration of LNPEP. Bioinformatics analyses of survival data and interactors of LNPEP were conducted to predict the prognostic value of LNPEP in OV. The protein levels of LNPEP were validated by Western blot and immunohistochemistry.Results: Based on the TCGA data, our data displayed that the mRNA expression of LNPEP was markedly down-regulated in ovarian cancer than that in para-cancer tissues, contrary to the protein level. Importantly, high LNPEP expression was associated with poor prognosis in patients with OV. Furthermore, Cox regression analysis showed that LNPEP was an independent prognostic factor in OV. GO and KEGG pathway analyses indicated the co-expressed genes of LNPEP were mainly related to a variety of immune-related pathways, including Th1 and Th2 cell differentiation, Th17 cell differentiation, and immunoregulatory interaction. Our data also demonstrated that the expression of LNPEP was strongly correlated with immune infiltration levels, immunomodulators, chemokines and chemokine receptors.Conclusion: In our study, we identified and established a prognostic signature of immune-related LNPEP in OV, which will be of great value in predicting the prognosis of clinical trials and may become a new therapeutic target for immunological research and potential prognostic biomarker in OV.Keywords: LNPEP, ovarian cancer, prognosis, immune infiltration, tumor microenvironment

Changqiang Chen,1,&ast; Pu Li,1,&ast; Jiuming Chen,1,&ast; Chunxiao Liu,2 Xiaodan Wang,3 Jialin Cai,4 Enfei Xiang,4 Zhidong Gu,1,5 Peizhan Chen4 1Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 5Department of Laboratory Medicine, Ruijin-Hainan Hospital, Shanghai Jiao Tong University School of Medicine (Hainan Boao Research Hospital), Hainan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Peizhan Chen, Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China, Tel +86 13918550745, Email pzchen@me.com Zhidong Gu, Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China, Tel +86 13801653534, Email guzhidongruijin@163.comPurpose: Vitamin D, an essential nutrient and a pleiotropic steroid hormone, has been reported to be associated with the risk and severity in patients infected with Coronavirus Disease-2019 (COVID-19). The role of vitamin D in predicting clinical outcome for COVID-19 patients is unknown. Here, we aimed to determine the prognostic value of plasma 25(OH)D level in COVID-19 patients.Patients and Methods: A total of 158 patients infected with novel COVID-19 Omicron variants in Shanghai were recruited in this study and were categorized into three groups by the tertile levels of plasma 25(OH)D. Plasma 25(OH)D level was determined along with routine blood tests related to liver and renal functions in newly diagnosed COVID-19 patients at admission. The nucleic acid negative conversion time of throat swab samples was evaluated as the primary clinical outcome. The prognostic value of clinical characteristics and plasma 25(OH)D level was assessed using the Kaplan–Meier plot and Cox proportional hazards regression tests.Results: Higher level of plasma 25(OH)D level in COVID-19 patients was independently associated with shorter nucleic acid negative conversion time from COVID-19 infection (multivariate adjusted HR: 0.54, 95%CI: 0.35– 0.82, P=0.004, tertile 2 vs 1; multivariate adjusted HR: 0.60, 95%CI: 0.39– 0.90, P=0.014, tertile 3 vs 1).Conclusion: Plasma 25(OH)D level may serve as an independent prognostic factor in COVID-19 patient. Our findings indicate the protective roles of vitamin D supplementation in the regiment of patients with COVID-19.Keywords: SARS-CoV-2, COVID-19, plasma 25(OH)D level, nucleic acid negative conversion time

Yanfeng Bao,1,2,&ast; Chen Dong,2,&ast; Qian Liang,2 Xiaoming Zhang,3 Zhifeng Gu,2 Chun Cheng1 1School of Medicine & Holistic Integrative Medicine, Nanjing University of Traditional Chinese Medicine, Jiangsu, People’s Republic of China; 2Department of Rheumatology, Affiliated Hospital of Nantong University, Jiangsu, People’s Republic of China; 3Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhifeng Gu; Chun Cheng, Tel +86-13706291941 ; +86-13962952110, Email guzf@ntu.edu.cn; ccheng@ntu.edu.cnPurpose: The outbreak of coronavirus disease has become an evolving global health crisis with wide-ranging implications. Clinical researches from several countries have reported greater morbidity and mortality from COVID-19 patients with diabetes. SARS-CoV-2/COVID-19 vaccines are currently the relatively effective means of prevention. The research was aimed to explore the attitudes of diabetic patients towards COVID-19 vaccine and the knowledge of COVID-19 related epidemiology and epidemic prevention.Methods: This case–control study was carried out in China via online and offline surveys. Knowledge questionnaire of COVID-19 and drivers of COVID-19 Vaccination Acceptance Scale (DrVac-COVID19S) were used to compare the difference of COVID-19 vaccination attitude, preventive measures, and knowledge of SARS-COV-2 between diabetic patients and healthy citizens.Results: The diabetic patients showed lower vaccination willingness and insufficient knowledge of the transmission route and common symptoms of COVID-19. Only 60.99% diabetic patients were willing to be vaccinated. Less than half of diabetics knew the COVID-19 spread by surface touch (34.04%) or aerosol (20.57%). The common symptoms like shortness of breath/ anorexia/ fatigue/ nausea/vomiting/diarrhea (34.04%) and panic and chest tightness (19.15%) were not well comprehend too. Diabetes patients shown lower report intentions when they contact a person infected with the virus (81.56%) or have any of the disease symptoms (74.47%). Values, knowledge, and autonomy assessed by the DrVac-COVID19S scale also showed negative attitude of vaccination in patients with diabetes. Also, patient with diabetes pay less attention to national (56.03%) and international (51.77%) COVID-19 updates. The willingness to attend COVID-19 lectures (27.66%) or read information leaflets (70.92%) was low.Conclusion: Vaccination is the effective available method for preventing the virus. Social and medical workers can increase the vaccination of diabetic patients through knowledge’s popularization and patient’s education based on the above differences.Keywords: COVID-19, diabetic patients, COVID-19 vaccination, SARS-COV-2, knowledge-attitude-behavior

Pu Li,1,&ast; Xiaoqiong Wu,1,&ast; Peizhan Chen,2 Zhidong Gu1,3 1Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China; 3Department of Laboratory Medicine, Ruijin-Hainan Hospital, Shanghai Jiao Tong University School of Medicine (Hainan Boao Research Hospital), Hainan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhidong Gu, Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China, Tel +86 13801653534, Email guzhidongruijin@163.com Peizhan Chen, Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China, Tel +86 13918550745, Email pzchen@me.comBackground: Iron metabolism related genes participate in cell proliferation, cell growth, and redox cycling in multiple cancers. Limited studies have revealed the roles and clinical significance of iron metabolism in the pathogenesis and prognosis of lung cancer.Methods: A total of 119 iron metabolism related genes were extracted from MSigDB database and their prognostic values were determined in The Cancer Genome Atlas lung adenocarcinoma (TCGA-LUAD) dataset and the Gene Expression Profiling Interactive Analysis 2 (GEPIA 2) database. Immunohistochemistry technique and correlations with immune cell infiltration, gene mutation and drug resistance were used to identify the potential and underlying mechanisms of STEAP1 and STEAP2 as prognostic biomarkers of LUAD.Results: The expression of STEAP1 and STEAP2 are negatively associated with the prognosis of LUAD patients both at the mRNA and protein level. The expression of STEAP1 and STEAP2 was not only negatively correlated with the trafficking degree of CD4+ T immune cells and positively related to most immune cells’ trafficking degree, but also significantly associated with gene mutation status, particularly with mutations on TP53 and STK11. Four types of drug resistance showed significant correlation with the expression level of STEAP1 while 13 types of drug resistance were associated with the expression level of STEAP2.Conclusion: Multiple iron metabolism related genes including STEAP1 and STEAP2 are significantly associated with the prognosis of LUAD patients. STEAP1 and STEAP2 might affect the prognosis of LUAD patients partially through immune cell infiltration, gene mutation and drug resistance, which indicated they were independent prognostic factors for LUAD patients.Keywords: iron metabolism related genes, lung adenocarcinoma, prognosis, STEAP1, STEAP2

Zhihui Liu,1,&ast; Zhuo Li,2,&ast; Qian Meng,3 Zhenpeng Gu,4 Jinxiu Cui4 1Department of Obstetrics and Gynecology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2School of Medicine, Nankai University, Tianjin, People’s Republic of China; 3Department of Obstetrics and Gynecology, Zibo Maternal and Child Health Hospital, Zibo, People’s Republic of China; 4Department of Obstetrics and Gynecology, Binzhou Medical University Hospital, Binzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinxiu Cui, Department of Obstetrics and Gynecology, Binzhou Medical University Hospital, No. 661 Huanghe 2nd Road, Binzhou, Shandong Province, 256603, People’s Republic of China, Email doctorcuijx@126.comPurpose: Dysmenorrhea is the most common gynecological condition among women of childbearing age and remains a challenging public health issue. This study aimed to visualize profiles and hotspots in dysmenorrhea research through a bibliometric analysis to deepen the understanding of knowledge in this field.Methods: Articles and reviews on dysmenorrhea published from 2000 to 2021 were collected. We summarized standard bibliometric indicators. Publications were systematically assessed in terms of country, institution, author, journal, reference, and keywords using Citespace, VOSviewer, Bibliometric, and an online platform. Besides, correlation analyses of country-specific characteristics and bibliometric indicators were performed.Results: 3407 publications were included. Dysmenorrhea-related publications have been increasing steadily annually. China and the United States were the most productive and academically influential countries, respectively. Correlation analysis revealed that economic power is an essential factor influencing scientific activity. However, collaboration in dysmenorrhea research remained weak. Natl Yang Ming Univ and Vercellini P were the most productive institution and influential author, respectively. A significant proportion of dysmenorrhea research was published in high-impact journals and it was explored at a multidisciplinary level. Current research topics focus on two primary areas: (1) pathophysiology, such as pathogenesis, oxidative stress, and functional connectivity, and (2) public health impacts, such as quality of life, burden, depression, and exercise.Conclusion: Dysmenorrhea research has received extensive attention from scholars and is rapidly evolving. Improved collaboration and interdisciplinary exploration may advance this field. Public health research and pathophysiological exploration of dysmenorrhea are current research hotspots and may also be a focus of research in the coming years.Keywords: bibliometric analysis, dysmenorrhea, women, pain, research hotspots

Mohan Wang,1,2 Zheyuan Gu,2 Beibei Li,2 Jingyi Zhang,2 Lu Yang,2 Xianyu Zheng,2 Faming Pan,1 Jiacai He1,2 1Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, 230032, People’s Republic of China; 2Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, 230032, People’s Republic of ChinaCorrespondence: Jiacai He; Faming Pan, Email hejiacai@ahmu.edu.cn; famingpan@ahmu.edu.cnIntroduction: Micro-sized sponge particulates have attracted extensive attention because of their potential to overcome the intrinsic limitations of conventional monolithic scaffolds in tissue engineering. Bioactive nanocomposite microsponges are regarded as potential bone substitute materials for bone regeneration.Methods: Based on a combination of microfluidic emulsion with further freezing and in situ thawing, chitosan (CS)-hydroxyapatite (HAP) microsponges were prepared and characterized in terms of their morphology and elemental distribution using a scanning electron microscope equipped with an X-ray detector. The swelling ratio, porosity, degradability, antibacterial activity, and bioactivity were detected and analyzed. The biological functions of the CS-HAP microsponges were examined to assess the adhesion, proliferation, and differentiation of in vitro co-cultured rat bone marrow mesenchymal stem cells (rBMSCs). Furthermore, the CS-HAP microsponges were used as cell-free scaffolds and implanted into calvarial defects in a rat model to evaluate the in vivo osteogenesis.Results: The CS-HAP microsponges have a porous structure with high porosity (~76%), good swelling capacity (~1900%), and shape-memory properties. The results of in vitro experiments show that the CS-HAP microsponges achieve good bioactivity and promote osteogenic differentiation of rBMSCs. Furthermore, the CS-HAP microsponges significantly promote bone regeneration in rat calvarial defects.Conclusion: The bioactive CS-HAP microsponges have the potential to be used as bone substitute materials for bone tissue engineering.Keywords: bioactive, hydroxyapatite, chitosan, nanocomposite microsponges, bone tissue engineering

Xiaoqiong Wu,1,&ast; Pu Li,1,&ast; Maimaitiaili Yimiti,1 Zhiqiu Ye,2 Xuqian Fang,2 Peizhan Chen,3 Zhidong Gu1,4 1Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Laboratory Medicine, Ruijin-Hainan Hospital, Shanghai Jiao Tong University School of Medicine (Hainan Boao Research Hospital), Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhidong Gu, Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China, Tel +86 13801653534, Email guzhidongruijin@163.com Peizhan Chen, Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China, Tel +86 13918550745, Email pzchen@me.comBackground: Chromosome is the basic framework for eukaryotic cells to store genetic information, but certain genes exist in circulation, such as extrachromosomal circular DNA (eccDNA). The unique genetic characteristics and structure of eccDNA provide a new vision on the early diagnosis of cancer; however, whether eccDNA contributes to the early diagnosis and progression of lung cancer remains unclear.Methods: We performed next-generation sequencing (NGS) analysis of eccDNA from the plasma of 6 lung adenocarcinoma (LUAD) patients. The data of plasma eccDNA of healthy people were obtained from public available database. We compared size distribution, chromosome origin, formation and expression patterns of eccDNA between LUAD patients and those of 6 healthy people and 4 healthy gravidas.Results: A total number of 716,059 eccDNA ranging from 22 bp to 3,297,519 bp were detected with an average size less than 800bp and distinctive bimodality in size around 191 bp and 320 bp. After comparison of eccDNA abundance in each sequencing sample, nine eccDNA were ranked on top with higher frequency in lung adenocarcinoma patients than healthy people. Among them, four eccDNA (DOCK1, PPIC, TBC1D16, and RP11-370A5.1) were uniquely expressed in lung adenocarcinoma patients, which may serve as potential biomarkers for early diagnosis LUAD.Conclusion: Cancer-specific eccDNA was presented in LUAD compared to normal people, which might serve as a promising biomarker in LUAD.Keywords: eccDNA, lung adenocarcinoma, plasma, early diagnosis

Boyue Han,1,2,&ast; Zhangyuan Gu,3,&ast; Zhebin Liu,1,2 Hong Ling1,2 1Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China; 3Department of Breast Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhebin Liu; Hong Ling, Email zhebinliu@shca.org.cn; linghong98@aliyun.comPurpose: The objective of this study was to compare the demographic characteristics, clinicopathological factors and survival outcomes between infiltrating lobular carcinoma (ILC) and infiltrating ductal carcinoma (IDC) using our single-center database.Methods: Seventeen thousand two hundred and three breast cancer patients were treated at Fudan University Shanghai Cancer Center (FUSCC) from January 2000 to December 2017. We identified 365 cases with ILC and 16,838 cases with IDC. The Pearson chi-square test was used to compare tumor characteristics, and the Kaplan–Meier methods were used to perform the survival analysis.Results: ILC had some distinctive characteristics from IDC such as older age (ranged from 61 to 80: ILC 26.8% vs IDC 19.9%, P < 0.001; over 80: ILC 1.6% vs IDC 0.8%, P < 0.001), larger tumor size (ranged from 2 to 5: ILC 45.2% vs IDC 37.1%, P = 0.011), much more hormone receptor expression (ILC 92.9% vs IDC 73.0%, P < 0.001), extremely less HER-2 expression (ILC 7.1% vs IDC 25.9%, P < 0.001). The overall survival and disease-free survival of ILC were worse than IDC (5-year OS, ILC 93.6% vs IDC 94.5%, P < 0.001; 5-year DFS, ILC 88.5% vs IDC 91.6%, P = 0.008). It was worth noting that the ILC patients had a worse overall survival than IDC patients after our propensity score matching study (P = 0.037). The univariate analysis concluded that positive HR (hormone receptor), high expression of Ki-67 and higher pathologic tumor stage were poor prognostic markers of ILC. Multivariate analysis demonstrated that tumor stage was a poor prognostic marker after adjustment for the effects of the above three factors. The most common primary site of metastasis was bone, but the proportion in the ILC group was much higher than that in the IDC group (56.25% vs 36.40%, P = 0.003).Conclusion: Compared with IDC, ILC survived worse and was more prone to bone metastasis. Therefore, a comprehensive understanding of ILC and specific treatments are needed for further research.Keywords: infiltrating lobular carcinoma, infiltrating ductal carcinoma, survival, prognosis

Tianyong Han,1,&ast; Tao Cheng,1,&ast; Ye Liao,2 Shiyuan Tang,1 Bofu Liu,1 Yarong He,1 Zhihan Gu,1 Chenxi Lei,1 Yuling Cao,3 Yu Cao1 1Emergency Department, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Medical Intensive Care Unit, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Operations Management Department, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Cao, Emergency Department, West China Hospital of Sichuan University, 37 Guoxue Lane, Wuhou District, Chengdu, 610041, Sichuan, People’s Republic of China, Tel +028-85422288, Email caoyu@wchscu.cnPurpose: At present, simple, accurate, and efficient prognostic tools for the evaluation of cases with early-stage sepsis in the emergency department (ED) are lacking. An increased blood urea nitrogen to albumin ratio (BAR) has previously been shown to be a valuable biomarker with predictive utility in several diseases. The relationship between BAR and sepsis patient outcomes, however, is not well-understood. This exploration was thus developed for the exploration of the link between BAR values and the short-term prognosis of cases with sepsis.Methods: This was a retrospective cohort research of sepsis cases admitted to the West China Hospital of Sichuan University ED from July 2015 to June 2016. Laboratory data were collected upon ED admission, and 7-day all-cause mortality was the primary study endpoint. Relationships between BAR values and APACE II and SOFA scores were generated assessed with correlation coefficient heatmaps. Independent risk factors were identified through multivariate analyses, with the curves of receiver operating characteristic (ROC) being employed to gauge the value of BAR as a predictor of the risk of mortality in sepsis cases.Results: In sum, 801 patients participated in the present investigation. BAR values were strongly correlated with APACHE II and SOFA scores. In a multivariate logistic regression assessment, BAR was identified as an independent predictor of mortality among patients with sepsis (HR=1.032, 95% CI: 1.010– 1.055, P=0.004). BAR exhibited an AUC of 0.741 (95% CI: 0.688– 0.793, P< 0.001) when used to predict patient mortality risk, with 5.27 being the optimal BAR cut-off.Conclusion: We found that BAR can be used as a reliable biomarker to predict mortality in patients with sepsis.Keywords: sepsis, blood urea nitrogen-to-albumin ratio, risk factors, prognosis

Tingting Wei,&ast; Xiaocen Wang,&ast; Ke Lang,&ast; Cuicui Chen, Yansha Song, Jinlong Luo, Zhaolin Gu, Xianglin Hu, Dong Yang Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dong Yang; Xianglin Hu, Email yang.dong@zs-hospital.sh.cn; xianglinhero@163.comRationale: Eosinophilic inflammation is related to the progression and outcomes of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Till now, few studies have focused on low EOS in AECOPD.Objective: To reveal the clinical characteristics, therapeutic responses and prognosis of patients hospitalized of AECOPD with low EOS.Methods: The electronic database of Zhongshan Hospital, Fudan University was used. Cohort 1 included 608 patients with hospitalized AECOPD. Study population 2 consisted of 166 patients with AECOPD admission at least twice. Impact of low EOS on NIMV treatment, length of hospital stays and 12-month AECOPD-related readmission were analyzed with multivariable logistic regression model. Thirty-five hospitalized AECOPD patients were prospectively recruited as cohort 3 to explore the association between EOS and other immune cells using Spearman correlation coefficient for ranked data.Results: EOS level was suppressed on admission in AECOPD patients, and significantly improved after hospitalized treatment (P < 0.05). For inflammatory markers, leucocytes, neutrophils and lactate dehydrogenase levels were higher, while lymphocytes, monocytes and interleukin-6 levels were lower in the low-EOS group than those in the non-low EOS group (P < 0.05). Low EOS (EOS < 50 cells/μL) was an independent risk factor of NIMV use (OR = 1.86, 95% CI = 1.26 ∼ 2.73). The EOS percentage was positively correlated with the T cell percentage (r = 0.46, P < 0.05) and negatively correlated with the natural killer cell percentage (r = − 0.39, P < 0.05). The patients with low EOS had lower level of CD4+ T cell (P < 0.05) than that of patients with non-low EOS.Conclusion: Low EOS might be a stable phenotype in patients with hospitalized AECOPD and could be used to inform NIMV management, hyperinflammatory state and impaired immunity situation.Keywords: chronic obstructive pulmonary disease, acute exacerbation, eosinophilic inflammation, prognostic phenotype, noninvasive mechanical ventilation

Creating oxide interfaces with precise chemical specificity at the atomic layer level is desired for the engineering of quantum phases and electronic applications, but highly challenging, owing partially to the lack of in situ tools to monitor the chemical composition and completeness of the surface layer during growth. Here we report the in situ observation of atomic layer-by-layer inner potential variations by analysing the Kikuchi lines during epitaxial growth of strontium titanate, providing a powerful real-time technique to monitor and control the chemical composition during growth. A model combining the effects of mean inner potential and step edge density (roughness) reveals the underlying mechanism of the complex and previously not well-understood reflection high-energy electron diffraction oscillations observed in the shuttered growth of oxide films. General rules are proposed to guide the synthesis of atomically and chemically sharp oxide interfaces, opening up vast opportunities for the exploration of intriguing quantum phenomena at oxide interfaces.

Lin Zhai, Yiran Hu, Xiang Li, Xuan Zhang, Zhe Gu, Zhenyan Zhao, Xu Yang Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Xu YangDepartment of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaTel +86 10-88322133Email yangxuyx1981@sina.comBackground: Implantable cardioverter–defibrillator (ICD) is the most effective strategy for prevention of ventricular tachyarrhythmia in patients with arrhythmogenic cardiomyopathy (ACM). However, some patients receive ventricular electrical storm (VES), characterized by multiple episodes of sustained ventricular tachyarrhythmia. The purpose of this study was to determine the incidence, predictors and prognostic implications of VES in ACM patients with an ICD.Methods: A total of 88 patients with definite ACM who received an ICD and followed up continuously were included in this study. VES was defined as the occurrence of ≥ 3 separate episodes of sustained ventricular arrhythmias within a 24-hour period.Results: During a median follow-up time of 4.0 years (range 1.6– 6.9), VES occurred in 19/88 patients (21.6%). The interval between the ICD implantation and the first VES ranged from 1 month to 128 months. The median number of ventricular tachyarrhythmia events per VES was 7.5 (range 3– 32). Multivariate analysis showed that VES was associated with a high body mass index (BMI) [adjusted hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.00– 1.45, P=0.048)] and extensive T-wave inversion (TWI) (HR 23.39, 95% CI 1.74– 314.58, P=0.017). Kaplan–Meier method showed that patients with VES did not have a worse cardiac mortality compared to those without such an event.Conclusion: There is a relatively high incidence of VES in ACM patients. The presence of high BMI and extensive TWI were strong predictors of VES occurrence in ACM patients with ICD. VES does not independently confer increased cardiac mortality.Keywords: ventricular electrical storm, arrhythmogenic cardiomyopathy, implantable cardioverter–defibrillator, predictors, mortality

Lin Wei,1 Yugang Liu,1 Huijun Zhang,1 Yuefeng Ma,2 Zenghui Lu,1 Zhenning Gu,1 Chao Ding1 1Department of Thoracic Surgery, Xi’an Chest Hospital, Xi’an 710100, People’s Republic of China; 2Department of Thoracic Surgery, The Second Affiliated Hospital of Xi’an Jiao Tong University, Xi’an 710004, People’s Republic of ChinaCorrespondence: Chao DingDepartment of Thoracic Surgery, Xi’an Chest Hospital, Xi’an, Shaanxi Province 710100, People’s Republic of ChinaTel/Fax +86-29-62500053Email abroad2014@sohu.comBackground: TMPO-AS1, an antisense lncRNA located at human chromosome 12p23.1, has been identified as an oncogene involved in cell proliferation in various cancers, including LUAD. In this study, we aimed to explore the novel molecular mechanism of TMPO-AS1 underlying LUAD growth.Materials and Methods: The transcription levels of TMPO-AS1, miR-326, and SOX12 in LUAD tissues and cell lines were detected by quantitative real-time PCR (qRT-PCR). The cell proliferation ability was evaluatect 3d by cell counting kit-8 (CCK-8) assay. Cell cycle and apoptosis analysis was assessed by flow cytometry. The target relationship among TMPO-AS1, miR-326, and SOX12 and promoter activity of TMPO-AS1 was measured using dual-luciferase reporter assay. The protein levels of SOX12 in LUAD cells were determined by Western blot. ChIP-qPCR assay was performed to validate the direct binding between E2F1 and TMPO-AS1 promoter.Results: TMPO-AS1 was up-regulated in LUAD tissues as well as cell lines. Boosted TMPO-AS1 expression was positively correlated with poor prognosis and pathological stage in LUAD. Down-regulation of TMPO-AS1 could restrain the proliferation of LUAD cells through arresting the cell cycle at G0/G1 phase and inducing apoptosis in vitro. Mechanically, we demonstrated that TMPO-AS1 could modulate the proliferation of LUAD cells through increasing SOX12 expression level via sponging miR-326 in accordance with bioinformatics analysis and experimental validation. Furthermore, we identified that TMPO-AS1 could be activated by E2F transcription factor 1 (E2F1) as a novel target gene.Conclusion: TMPO-AS1 can modulate LUAD cell proliferation through E2F1/miR-326/SOX12 pathway.Keywords: lung adenocarcinoma, TMPO-AS1, cell proliferation, miR-326, SOX12, E2F1

Zhengzhong Gu,1 Xiaohan Cui,2 Pengda Sun,1 Xudong Wang1 1Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 2Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of ChinaCorrespondence: Xudong WangDepartment of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun 130041 Jilin Province, People’s Republic of ChinaTel +86 13514406378Email wangxudong1971@126.comAbstract: Tumor necrosis factor-alpha (TNF-α)-induced protein 8 (TNFAIP8/TIPE) family, including TNFAIP8 (TIPE), TNFAIP8 like-protein 1 (TNFAIP8L1/TIPE1), TNFAIP8 like-protein 2 (TNFAIP8L2/TIPE2), and TNFAIP8 like-protein 3 (TNFAIP8L3/TIPE3), plays a vital role in regulating inflammatory responses, immune homeostasis, and cancer development. Over the last decade, studies have shown that TIPE2 protein is differentially expressed in diverse cells and tissues. The dysregulation of TIPE2 protein can lead to dysregulation of inflammatory responses and immune homeostasis, and change the basic characteristics of cancers. In consideration of the immeasurable values of TIPE2 in diagnosis, treatment, and prognosis of various human diseases, this review will focus on the expression pattern, structure, and regulatory roles of TIPE2 in inflammation, immunity, and cancers.Keywords: TIPE2, inflammation, immune homeostasis, tumor, tumorigenesis, metastasis

Yuou Zhang,1 Xuan Liu,1 Linghe Yang,1 Guifang Zhang,2 Zhaoru Gu,3 Zhongdan Chen,4 Jing Sun1 1School of Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Institute of Geriatrics, Beijing Hospital, Beijing, People’s Republic of China; 3Institute of Cancer, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 4Hepatitis/TB/HIV/STI, World Health Organization, Office of the WHO Representative in China, Beijing, People’s Republic of ChinaCorrespondence: Jing Sun Email sunjing@sph.pumc.edu.cnAbstract: This study analyzed the barriers of patient access to affordable MDR-TB medication in China and the reasons behind, and proposed strategies towards removing the barriers based on literature review and key informant interviews. Reasons behind the high financial burden of MDR-TB patients in China are the lack of a coordinated and multi-sourced financing model to secure patients’ access to the expensive novel medicines, and the absence of the safety-net for the patients with low ability to pay the costs. Appropriate health insurance benefit packages and provider payment mechanisms, supportive legal framework, coordinated policies as well as incentives for off-label use of evidence-based repurposed medicines are missing. The observations identified key intervention areas including continued efforts to make the novel effective medicines affordable and to strengthen the legislative protection for off-label use of evidence-based medicines; increase incentives for pharmaceutical companies to expand indications of established medicines based on the evidence; implement public initiatives to support the use of repurposed medicines for diseases with major public health significance, and scale up good practices from local pilots to create a coordinated multi-sourced financing model. A comprehensive approach to address the barriers in the full treatment course of MDR-TB and a safety-net for low-ability-to-pay patients are also critical to secure universal access to affordable MDR-TB medication.Keywords: MDR-TB, medication, affordable, financing, safety-net, off-label use, repurposed medicines

Zhan Gu,1,* Yan Bi,2,* Fan Yuan,2,* Ruirui Wang,1 Dong Li,3 Jianying Wang,1 Xiaojuan Hu,1 Guang He,2 Lei Zhang,1 Bao-cheng Liu1 1Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China; 2Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, People’s Republic of China; 3Zhangjiang Community Health Service Center of Pudong New District, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bao-cheng Liu Email baochliu@shutcm.edu.cnBackground: As fat and obesity play a vital role in the pathophysiology of metabolic dysfunction-associated fatty liver disease (MAFLD), this study aims to investigate the association between the fat mass and obesity-associated gene (FTO) and MAFLD.Methods: Six SNPs (rs6499640, rs1421085, rs8050136, rs3751812, rs9939609 and rs9930506) within FTO were genotyped for 741 MAFLD patients (median age, 69.98; interquartile range, 66.55– 75.93) and 825 healthy people (median age, 69.94; interquartile range, 66.39– 75.64). Allele and genotype frequencies, pairwise linkage disequilibrium (LD) and haplotype analysis were calculated.Results: BMI, waist circumference, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, triglyceride, alanine transaminase, glutamyl transpeptidase and the prevalence of diabetes were found to be higher in the MAFLD individuals comparing to the control ones (P < 0.05). For rs1421085, the C allele frequency was remarkably higher in MAFLD after Bonferroni correction (OR [95% CI] =1.353 [1.095– 1.671]; Pcorr =0.030), and a significantly different genotype result was observed in log-additive model (OR [95% CI] =1.369 [1.108– 1.691]; Pcorr =0.024). For rs8050136, significantly increased A allele frequency was observed in MAFLD (OR [95% CI] =1.371 [1.109– 1.695]; Pcorr =0.024), and A-allele carriers showed increased MAFLD risk (OR [95% CI] =1.393 [1.103– 1.759]; Pcorr =0.030). For rs3751812, the T allele frequency was remarkably higher in MAFLD (OR [95% CI] =1.369 [1.108– 1.691]; Pcorr =0.024), and T-allele carriers demonstrated high MAFLD risk (OR [95% CI] =1.392 [1.103– 1.756]; Pcorr =0.030). For rs9939609, A allele frequency was also remarkably high in MAFLD (OR [95% CI] =1.369 [1.108– 1.691]; Pcorr =0.024), and A-allele carriers were more susceptible to MAFLD (OR [95% CI] =[1.103– 1.756]; Pcorr =0.030). A strong LD was found among rs1421085, rs8050136, rs3751812 and rs9939609 (r2 > 0.8), and individuals with C-A-T-A haplotype had an elevated MAFLD risk (P =0.005).Conclusion: The case-control study indicated that C variant of rs1421085, A variant of rs8050136, T variant of rs3751812 and A variant of rs9939609 are associated with elevated MAFLD risk in the older Chinese Han population.Keywords: MAFLD, FTO, polymorphism, genetic association, susceptibility

Xiaoke Yao,1,* Lingna Wu,2,* Zuchao Gu,1 Jianhua Li1 1Department of Orthopedics, Chengdu First People’s Hospital, Chengdu 610041, Sichuan, People’s Republic of China; 2Intensive Care Unit, Chengdu First People’s Hospital, Chengdu, Sichuan, 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianhua LiDepartment of Orthopedics, Chengdu First People’s Hospital, Chengdu 610041, Sichuan, People’s Republic of ChinaEmail jianzh14881@163.comBackground: Osteosarcoma (OS) is the most common primary bone tumor in group of children and adolescents. Increasing studies showed that long non-coding RNAs (lncRNAs) exerted important functions in the development of tumors, including OS. LINC01535 is an lncRNA which has been studied in cervical cancer but not in OS.Aim of the Study: This study was aimed to explore the biological function and mechanism of LINC01535 in OS.Methods: LINC01535 expression was detected by qRT-PCR. Colony formation assay, EdU assay and CCK-8 assay were applied to check cell proliferation ability in OS. Flow cytometry analysis was conducted to measure cell apoptosis capacity. Wound healing assay and transwell assay were performed to assess cell migration and invasion. Luciferase reporter assay and RNA pull-down assay were carried out to verify the molecular mechanism.Results: The high expression of LINC01535 was presented in OS tissues and cell lines compared with adjacent normal tissues and human osteoblasts. Moreover, OS patients with high LINC01535 expression exhibited poor prognosis. Loss-of-function assay revealed that silenced LINC01535 significantly attenuated cell proliferation, migration and invasion, and enhanced cell apoptosis in OS. Through mechanistic exploration, we found that LINC01535 interacted with miR-214-3p, and KCNC4 was validated to be a target gene of miR-214-3p. The levels of KCNC4 mRNA and protein were positively modulated by LINC01535 and reversely mediated by miR-214-3p. Based on rescue experiments, KCNC4 overexpression reserved the suppressive function of silenced LINC01535 on OS cell growth, migration and invasion.Conclusion: LINC01535, miR-214-3p and KCNC4 constituted an effective axis that exerted a pregnant regulation in OS development, which is a quite meaningful discovery for exploring potential therapeutic methods for OS patients.Keywords: LINC01535, miR-214-3p, KCNC4, osteosarcoma

Yun Fu, Xiaoyin Sun, Zhangyuan Gu, Zhigang Zhuang Department of Breast Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Zhigang ZhuangShanghai First Maternity and Infant Hospital, No. 2699, West Gaoke Road, Shanghai 201204, People’s Republic of ChinaTel +86 21 20261056Fax +86 21 20261477Email zhuang_zg@163.comBackground: Triple-negative breast cancer has become an intricate part and hotspot in the clinical and experimental research. Connexins, serving as functional proteins in gap junctions, play an important role in tumorigenesis, cell proliferation and metastasis.Methods: We constructed and employed the Connexin 43 (Cx43) overexpression lentiviral vectors and Cx43 siRNA in paclitaxel-treated MDA-MB-231 cells. We performed the experiments of clonal formation and flow cytometry to gauge the effect of paclitaxel on cellular behaviors and immunofluorescence and subsequent quantitative RT-PCR and Western blot to examine the expression of genes and corresponding proteins. Experiments of scrape loading/dye transfer were utilized to explore the gap junctions. The targets of Cx43 were identified via the experiments of co-immunoprecipitation (Co-IP), GST pull-down assays and proximal ligation assay (PLA).Results: The results showed that Cx43 hindered cell proliferation and promoted apoptosis in the paclitaxel-treated MDA-MB-231 cells. Overexpressed Cx43 suppressed the expression of resistance genes such as BRCP, Txr-1, α-tubulin and β-tubulin and promoted the expression of apoptosis gene as TSP-1 and Bcl-2. Cx43 was also positively related to ITGα 9 and negatively related to ITGαV and ITGα 11. The gap junctions altered magnificently under different expressions of Cx43, which indicated that Cx43 could promote the number of intercellular gap junctions. The immunofluorescent experiment revealed that both of Cx43 and β-tubulin were mainly localized in the cytoplasm. The assays of Co-IP and GST pull-down demonstrated that there existed a direct interaction between Cx43 and β-tubulin. Furthermore, the result of PLA also showed that Cx43 interacts with β-tubulin in MDA-MB-231 cells.Conclusion: Overexpression of Cx43 could modulate the cellular resistance to paclitaxel via targeting β-tubulin in triple-negative breast cancer.Keywords: Cx43, β-tubulin, paclitaxel, chemoresistance, gap junctions

Cuixia Li,1 Feng Wang,2 Pei Miao,1 Libo Yan,1 Silin Liu,1 Xian Wang,1 Zuolin Jin,1 Zexu Gu1 1State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, the Fourth Military Medical University, Xian 710032, People’s Republic of China; 2Department of Stomatology, 546 Hospital of PLA, Malan City, Xinjiang Province 841200, People’s Republic of ChinaCorrespondence: Zuolin Jin; Zexu GuState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xian 710032, People’s Republic of ChinaEmail ghh6801764@126.com; men6533naijia163@126.comBackground: Major depressive disorder (MDD) is a serious and common mood disorder with unknown etiology. Emerging evidence has demonstrated the critical roles of SIRT1 and microRNAs (miRNAs) in the progression of MDD. However, the underlying molecular mechanisms remain to be fully understood.Methods: In the present study, the expression level of miR-138 and SIRT1 were analyzed by RT-PCR or Western blotting in a chronic unpredictable mild stress (CUMS) model. The depressive-like behaviors were analyzed by forced swimming test (FST) and sucrose preference test (SPT) in mice injected with miR-138 and SIRT1 overexpression lentivirus. The luciferase reporter assay was used to assess the direct regulation of miR-138 on SIRT1 expression.Results: The upregulation of miR-138 was found in the hippocampus of the CUMS mice and correlated with decreased SIRT1 expression. C57BL/6J mice treated with SIRT1- and miR-138-expressing (miR-138) lentivirus showed increased depressive-like behaviors. In contrast, SIRT1 or si-miR-138 lentivirus treated C57BL/6J mice showed decreased depressive-like behaviors. Moreover, the Sirt1/PGC-1α/FNDC5/BDNF pathway was downregulated following miR-138 overexpression and increased upon miR-138 knockdown in hippocampus in CUMS mice and cultured primary neuronal cells. Mechanistically, luciferase reporter assay demonstrated that SIRT1 gene was a downstream transcriptional target of miR-138.Conclusion: Our data demonstrated the regulation role of miR-138 on SIRT1 gene expression, miR-138 increased depressive-like behaviors by regulating SIRT1 expression in hippocampus.Keywords: depression, microRNA, miR-138, SIRT1, chronic unpredictable mild stress, CUMS

Changjie Lin,* Jing Xia,* Zhiwei Gu, Yunpeng Meng, Dekang Gao, Shaohua Wei Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaohua WeiDepartment of General Surgery, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, Jiangsu 215000, People’s Republic of ChinaEmail shaohuawei215@126.comBackground: Pancreatic cancer (PC) is a highly lethal malignancy worldwide. Our previous study indicated that overexpression of USP34 could promote tumor growth in PC cells. Therefore, this study aimed to further investigate the role of USP34 during the tumorigenesis of PC.Methods: The level of USP34 in PANC-1 and MiaPaCa-2 cells transfected with USP34-shRNAs was detected by RT-qPCR. Moreover, transwell migration and Annexin V/PI analysis were conducted to detect cell migration and apoptosis, respectively.Results: In this study, downregulation of USP34 markedly inhibited proliferation and migration, and induced apoptosis in PANC-1 cells. Moreover, silencing of USP34 obviously downregulated the levels of PRR11 and p-p38 in PANC-1 cells. An in vivo study in nude mice bearing PANC-1 cell xenografts confirmed these results.Conclusion: Downregulation of USP34 could inhibit proliferation and migration in PANC-1 cells via inhibiting PRR11, and inactivating p38 MAPK signaling. Therefore, USP34 might be a potential therapeutic target for the treatment of PC.Keywords: pancreatic cancer, ubiquitin-specific protease USP34, proline-rich 11, apoptosis

Zhihong Chai,1,* Yufei Yang,2,3,* ZhongYi Gu,4,* Xianli Cai,1 Wenwei Ye,1 Lin Kong,1 Xiaoxiao Qiu,1 Lingxiao Ying,1 Ziliang Wang,2,3 Linyou Wang1 1Department of Gynecology and Department of Radiology, Taizhou Municipal Hospital Affiliated to Taizhou University School of Medicine, Taizhou 318000, People’s Republic of China; 2Department of Obstetrics and Gynecology, Xihua Hospital Affiliated to Shanghai Jiaotong University School Medicine, Shanghai 200092, People’s Republic of China; 3Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 4Department of Nephrology, Children’s Hospital of Fudan University, Shanghai 201102, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziliang WangDepartment of Obstetrics and Gynecology, Xihua Hospital Affiliated to Shanghai Jiaotong University School Medicine, 1665 Kongjiang Road, Shanghai 200092, People’s Republic of ChinaEmail huf_zlwang@126.comLinyou WangDepartment of Radiology, Taizhou Municipal Hospital, 381 East Zhongshan Road, Taizhou 318000, People’s Republic of ChinaEmail wanglinyou2007@163.comPurpose: Capsid protein L2 is the minor capsid protein of human papillomavirus 16 (HPV16). Although L2-based vaccines were developed, the therapeutic effect of recombinant viral capsid protein L2 (rVL2) was still to be illustrated.Methods: We used glucose uptake and lactate production assay to verify the inhibitory effect of rVL2 on the glucose metabolism in cervical cancer cells. Secondly, we performed gene-chip assay, RT-PCR, and Western blot to determine the role of ITGB7/C/EBPβ signaling pathway in rVL2-mediated glucose metabolism in vitro. Finally, we used an animal model to verify the function of rVL2 in cervical cancer.Results: We found that rVL2 reduced glucose uptake and lactate production levels in cervical cancer cells, which caused the inhibition of cell proliferation. rVL2 decreased the expression levels of key metabolic enzymes, including GLUT1, LDHA, and ALDOA, to affect cell metabolism in cervical cancer cells by inhibiting ITGB7/C/EBPβ signaling pathway in vitro and in vivo.Conclusion: These results demonstrated the vital role of rVL2 in the glycolysis-induced cell growth and proliferation via suppressing ITGB7/C/EBPβ signaling axis.Keywords: recombinant viral capsid protein L2, rVL2, C/EBPβ, glucose metabolism, cervical cancer