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Zhuhong Lai, Tingqiao Ye, Mingjun Zhang, Ying Mu Department of Cardiology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People’s Republic of ChinaCorrespondence: Ying Mu, Department of Cardiology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People’s Republic of China, Email muyingdr123@yeah.netAbstract: Exosomes have grown as promising carriers for noncoding RNAs (ncRNAs) in the treatment of inflammation, particularly in conditions like ischemic stroke and myocardial infarction. These ncRNAs, which include microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), play a crucial role in regulating inflammatory pathways, presenting new therapeutic opportunities. In both ischemic stroke and myocardial infarction, inflammation significantly influences disease progression and severity. Exosomes can deliver ncRNAs directly to specific cells and tissues, providing a targeted approach to modulate gene expression and reduce inflammation. Their biocompatibility and low risk of inducing immune responses make exosomes ideal therapeutic vehicles. Ongoing research is focused on optimizing the loading of ncRNAs into exosomes, ensuring efficient delivery, and understanding the mechanisms by which these ncRNAs mitigate inflammation. In ischemic stroke, exosome-derived ncRNAs originate from various cell types, including neurons, M2 microglia, patient serum, genetically engineered HEK293T cells, and mesenchymal stromal cells. In the case of myocardial infarction, these ncRNAs are sourced from mesenchymal stem cells, endothelial cells, and patient plasma. These exosome-loaded ncRNAs play a significant role in modulating inflammation in both ischemic stroke and myocardial infarction. As this research advances, therapies based on exosomes may completely change how diseases linked to inflammation are treated, offering new avenues for patient care and recovery. This review explores the latest advancements in understanding how exosomes impact specific inflammatory components, with a particular emphasis on the role of ncRNAs contained in exosomes. The review concludes by highlighting the clinical potential of exosome-derived ncRNAs as innovative therapeutic and diagnostic tools.Keywords: exosomes, noncoding RNA, inflammation, ischemic stroke, myocardial infarction

Xuebing Zhang,1 Lianjie Wang,1 Ge Wang,1 Jiayue Li,1 Yiming Mu,2 Shidong Wang,1 Xiaoran Li1 1Department of Endocrinology, Dongzhimen Hospital Beijing University of Chinese Medicine, Beijing 100700, People’s Republic of China; 2Department of Endocrinology, First Medical Centre of Chinese PLA General Hospital, Beijing 100853, People’s Republic of ChinaCorrespondence: Shidong Wang; Xiaoran Li, Email A2082@bucm.edu.cn; 466187309@qq.comBackground: Nonalcoholic fatty liver disease (NAFLD) has become a major global health burden, which increases the risk of extra-hepatic complications such as type 2 diabetes mellitus (T2DM), dyslipidemia, metabolic syndrome (MetS), and cardiovascular disease (CVD). However, NAFLD remains underappreciated and underdiagnosed. Our study aimed to explore the prevalence of NAFLD and the association between NAFLD and CVD events among adults aged 40 and older in Northern China.Methods: This study was conducted in the Shijingshan district of Beijing, China from November 2011 to August 2012. A total of 18891 subjects were recruited in the study. The information including demographical information, lifestyle, previous history of diabetes, hypertension, dyslipidemia, CVD, and liver disease were gathered. Data on physical examination, blood lipid profile, fasting blood glucose, and 2-hour blood glucose were recorded. Determination of MetS was according to T2DM guideline of Chinese Diabetes Society (2020 edition). The association between CVD and NAFLD was evaluated by multivariate logistic regression.Results: The prevalence of NAFLD was 15.2%. After adjustment for age, smoking status, alcohol intake, WC, hypertension, dyslipidemia and hyperglycemia, the odds ratios (ORs) of CVD in men were 1.622 (95%CI: 1.345– 1.957) and 1.990 (95%CI: 1.709– 2.316) in women with NAFLD, compared with the subjects without NAFLD.Conclusions: NAFLD is independently associated with increased risk of CVD development.Keywords: nonalcoholic fatty liver disease, metabolic syndrome, cardiovascular disease, middle-aged and elderly, Chinese

Yuzhu Mu, Ting Pan, Lingling Chen Department of Dermatology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, 215000, People’s Republic of ChinaCorrespondence: Lingling Chen, Email chenlingling031@126.comAbstract: Vitiligo and alopecia areata are both autoimmune skin diseases, and the chances of co-occurrence are very low. Conventional treatments often include glucocorticoids, which have many adverse reactions with long-term use and are difficult to achieve satisfactory results. Upadacitinib has been found to be effective in both vitiligo and alopecia areata due to partial overlap in pathogenic pathways. We report the successful treatment of vitiligo combined with alopecia areata in a nine-year-old child with upadacitinib in combination with UVB. The area of vitiligo and alopecia areata decreased significantly, and satisfactory results were obtained. It provides a new idea for the treatment of vitiligo complicated with alopecia areata in children.Keywords: vitiligo, alopecia areata, JAK inhibitor, children

Yiting Hua,1,2,* Yutong Zhou,1,2,* Ziyue Qin,1,2 Yuan Mu,1,2 Ting Wang,1,2 Haoyu Ruan1,2 1Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haoyu Ruan; Ting Wang, Department of Laboratory Medicine, the First Affiliated Hospital, Nanjing Medical University, 300 Guang Zhou Road, Nanjing, Jiangsu Province, 210029, People’s Republic of China, Email rhy1170871576@163.com; wangting0622@njmu.edu.cnBackground: The surge in the number of patients diagnosed with COVID-19 since China’s open-door policy has placed a huge burden on the public healthcare system, especially the intensive care system. This study’s objective was to discover possible clinical outcome predictors in COVID-19 patients treated in intensive care units (ICUs) and to provide useful information for future preventative efforts and therapies.Methods: This retrospective study included 173 COVID-19 critically ill patients and reviewed the 28-day survival outcome in the First Affiliated Hospital of Nanjing Medical University. Competing risk analysis was performed to predict the cumulative incidence function (CIF) of mortality in hospital. The independent prognostic factors were identified by applying the Fine–Gray proportional subdistribution hazard model. Receiver operating characteristic (ROC) curves were used to evaluate model efficacy, and calibration curves were used to validate the model. Finally, we compared the competing risk model with the traditional proportional hazards model (Cox regression model) using CIF.Results: Of these 173 patients, 66 (38.2%) survived, 55 (31.8%) died, and 52 (30.0%) discharged. In univariate analysis, 12 variables were significantly correlated with mortality. In multivariate analysis, Age, Neutrophil ratio, Direct Bilirubin (DBIL) and Renal disease were independent predictors of 28-day outcome. The ROC curve of the multivariate prediction model showed an AUC (area under the curve) of 0.790. The results of the calibration curve and the concordance index (C-index) show that the model has good discriminatory power. The competing risk model we applied was more accurate than the Cox model.Conclusion: We presented a more accurate multivariate prediction model for 28-day in-hospital mortality for ICU COVID-19 patients using a competing risk model.Keywords: COVID-19, 28-day mortality, competing-risk analysis, ICU

Yonglin Mu, Dawei He Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Dawei He, Department of Urology, Children’s Hospital of Chongqing Medical University, No. 136, Zhongshan 2nd Road, Yuzhong District, Chongqing, 400014, People’s Republic of China, Tel +86 18680856616, Email hedawei@hospital.cqmu.edu.cnAbstract: ChatGPT, an AI-driven conversational large language model (LLM), has garnered significant scholarly attention since its inception, owing to its manifold applications in the realm of medical science. This study primarily examines the merits, limitations, anticipated developments, and practical applications of ChatGPT in clinical practice, healthcare, medical education, and medical research. It underscores the necessity for further research and development to enhance its performance and deployment. Moreover, future research avenues encompass ongoing enhancements and standardization of ChatGPT, mitigating its limitations, and exploring its integration and applicability in translational and personalized medicine. Reflecting the narrative nature of this review, a focused literature search was performed to identify relevant publications on ChatGPT’s use in medicine. This process was aimed at gathering a broad spectrum of insights to provide a comprehensive overview of the current state and future prospects of ChatGPT in the medical domain. The objective is to aid healthcare professionals in understanding the groundbreaking advancements associated with the latest artificial intelligence tools, while also acknowledging the opportunities and challenges presented by ChatGPT.Keywords: ChatGPT, clinical practice, healthcare, medical education, medical research, challenges

Liuli Xu,* Yujuan Wang,* Yunzhu Mu, Qing Huang, Wenlong Shuai, Hao Yang Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hao Yang, Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan South Road, Shunqing District, Nanchong, Sichuan Province, 63700, People’s Republic of China, Tel +8615882626833, Email cbyxyyh423@163.comAbstract: We described a 58-year-old female diagnosed with zosteriform cutaneous metastases from breast carcinoma. She was initially diagnosed with herpes zoster. Correct diagnosis was obtained after pathological biopsy. Various forms of cutaneous metastases have various forms, which require careful discrimination by dermatologists to reduce the rate of misdiagnosis.Keywords: breast carcinoma, zosteriform, cutaneous metastasis

Zhipeng Wang,1,* You Yin,2,* Yuhui Mu,1,3,* Lili Cui,1 Xinhua Song,1 Jianhua Zhuang,2 Shouhong Gao,1 Xia Tao,1 Wansheng Chen1 1Department of Pharmacy, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, 200003, People’s Republic of China; 2Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, 200003, People’s Republic of China; 3College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianhua Zhuang, Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), No. 415, Fengyang Road, Shanghai, 200003, People’s Republic of China, Email jianhuazh11@126.com Xia Tao, Department of Pharmacy, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), No. 415, Fengyang Road, Shanghai, 200003, People’s Republic of China, Tel/Fax +86– 21– 81886191, Email taoxia@smmu.edu.cnObjective: This study aims to explore the mechanism underlying the induction of phlebitis by aescinate and create an early-warning model of phlebitis based on metabolomics.Methods: Patients with cerebral infarction enrolled had been treated with aescinate. Plasma samples were collected either before administration of aescinate, upon the occurrence of phlebitis, or at the end of treatment. Non-targeted metabolomics and targeted amino acid metabolomics were carried out to analyze metabolic profiles and quantify the metabolites.Results: Untargeted metabolomics revealed six differential metabolites in baseline samples versus post-treatment samples and four differential metabolites in baseline samples from patients with or without phlebitis. Pathways of these differential metabolites were mainly enriched in amino acid metabolism. Ten differential amino acids with a VIP value of > 1 were identified in the baseline samples, enabling us to distinguish between patients with or without phlebitis. A logistic regression model was constructed (AUC 0.825) for early warning of phlebitis of grade 2 or higher.Conclusion: The occurrence of aescinate-induced phlebitis, which can be predicted early during onset, may be associated with perturbations of the endogenous metabolic profile, especially the metabolism of amino acids. Keywords: aescinate, diagnostic model, mechanism, metabolomics, phlebitis

Yanfei Lu,1,2,* Wenying Xia,1,2,* Shuxian Miao,1,2 Min Wang,1,2 Lei Wu,1,2 Ting Xu,1,2 Fang Wang,1,2 Jian Xu,1,2 Yuan Mu,1,2 Bingfeng Zhang,1,2 Shiyang Pan1,2 1Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, People’s Republic of China; 2National Key Clinical Department of Laboratory Medicine, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shiyang Pan, Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Guangzhou Street No. 300, Nanjing, 210029, People’s Republic of China, Tel +8625-6830-6287, Fax +8625-8372-4440, Email sypan@njmu.edu.cnObjective: This study aimed to investigate the clinical characteristics and risk factors of death in severe coronavirus disease 2019 (COVID-19) during the epidemic of Omicron variants, assess the clinical value of plasma cell-free DNA (cfDNA), and construct a prediction nomogram for patient mortality.Methods: The study included 282 patients with severe COVID-19 from December 2022 to January 2023. Patients were divided into survival and death groups based on 60-day prognosis. We compared the clinical characteristics, traditional laboratory indicators, and cfDNA concentrations at admission of the two groups. Univariate and multivariate logistic analyses were performed to identify independent risk factors for death in patients with severe COVID-19. A prediction nomogram for patient mortality was constructed using R software, and an internal validation was performed.Results: The median age of the patients included was 80.0 (71.0, 86.0) years, and 67.7% (191/282) were male. The mortality rate was 55.7% (157/282). Age, tracheal intubation, shock, cfDNA, and urea nitrogen (BUN) were the independent risk factors for death in patients with severe COVID-19, and the area under the curve (AUC) for cfDNA in predicting patient mortality was 0.805 (95% confidence interval [CI]: 0.713– 0.898, sensitivity 81.4%, specificity 75.6%, and cut-off value 97.67 ng/mL). These factors were used to construct a prediction nomogram for patient mortality (AUC = 0.856, 95% CI: 0.814– 0.899, sensitivity 78.3%, and specificity 78.4%), C-index was 0.856 (95% CI: 0.832– 0.918), mean absolute error of the calibration curve was 0.007 between actual and predicted probabilities, and Hosmer-Lemeshow test showed no statistical difference (χ 2=6.085, P=0.638).Conclusion: There was a high mortality rate among patients with severe COVID-19. cfDNA levels ≥ 97.67 ng/mg can significantly increase mortality. When predicting mortality in patients with severe COVID-19, a nomogram based on age, tracheal intubation, shock, cfDNA, and BUN showed high accuracy and consistency.Keywords: severe COVID-19, Omicron, clinical characteristics, mortality, CfDNA, predicting nomogram

Xinrui Liu,1 Yuan Mu2 1Zhengzhou Key Laboratory of Children’s Infection and Immunity, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, People’s Republic of China; 2Institute of Thermology, Henan Institute of Metrology and Testing Sciences, Zhengzhou, People’s Republic of ChinaCorrespondence: Xinrui Liu, Email 13526523661@163.comBackground: Neonatal sepsis is an acute and severe disease that seriously threatens the life and health of newborns. Neonates with pneumonia may also have unrecognized neonatal sepsis. Early diagnosis of neonatal sepsis is beneficial for early treatment. This study aimed to evaluate the clinical significance of the lymphocyte-to-C-reactive protein ratio (LCR) as an early biomarker to distinguish sepsis from pneumonia.Methods: This retrospective study enrolled 1635 neonates with pneumonia from February 2016 to March 2022. Among them, 182 cases were diagnosed with sepsis based on the positive blood culture results. Clinical and laboratory data were extracted from the electronic medical records. LCR was calculated as the ratio of the total lymphocyte count (× 109 cells/L) to the C-reactive protein level (mg/L). Binary logistic regression analysis was conducted to evaluate the clinical significance of LCR as an early biomarker in distinguishing sepsis from pneumonia. Receiver operating characteristic (ROC) analysis was performed to assess the diagnostic value of LPCR in sepsis cases. All statistical analyses were conducted using Statistical Product and Service Solutions, version 24.0.Results: The neonates with pneumonia combined with sepsis had a lower LCR than that of the neonates with pneumonia. Further analysis showed that the prevalence of neonatal pneumonia combined with sepsis was significantly higher in the low-LCR group than in the high-LCR group (20.7% vs 5.5%, P < 001). Binary logistic regression revealed that LCR was an independent risk factor for identifying pneumonia combined with sepsis. The ROC curve analysis revealed that LCR had better power than the lymphocyte count and CRP level individually in diagnosing neonatal pneumonia combined with sepsis (0.72 vs 0.65 vs 0.66, P < 0.001), with 62% sensitivity and 72% specificity.Conclusion: LCR can be a potential early biomarker in distinguishing neonates with sepsis from those with pneumonia.Keywords: lymphocyte to C-reactive protein ratio, neonates, pneumonia, sepsis

Jin Sun,1– 3 Yingnan Li,1– 3 Mengjiao Shi,1,2 Hongwei Tian,1– 3 Jun Li,1– 3 Kai Zhu,1– 3 Ying Guo,1– 3 Yanhua Mu,1– 3 Jing Geng,1– 3 Zongfang Li1– 4 1National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Center for Tumor and Immunology, the Precision Medical Institute, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 4Department of Geriatric General Surgery, the Second Affiliated Hospital of Xi’ an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Jing Geng; Zongfang Li, National & Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, the second affiliated hospital, Xi’an Jiaotong University, No. 157 West 5th Road, Xi’an, 710004, People’s Republic of China, Tel +86-29-87679700 ; Tel/Fax +86-29-87679508, Email jgeng18@xjtu.edu.cn; lzf2568@xjtu.edu.cnPurpose: HOX cluster-embedded long noncoding RNAs (HOX-lncRNAs) have been shown to be tightly related to hepatocellular carcinoma (HCC). However, the potential biological roles and underlying molecular mechanism of HOX-lncRNAs in HCC largely remains to be elucidated.Methods: The expression signature of eighteen HOX-lncRNAs in HCC cell lines were measured by qRT-PCR. HOXD-AS2 expression and its clinical significance in HCC was investigated by bioinformatics analysis utilizing the TCGA data. Subcellular localization of HOXD‐AS2 in HCC cells was observed by RNA-FISH. Loss‑of‑function experiments in vitro and in vivo were conducted to probe the roles of HOXD-AS2 in HCC. Potential HOXD-AS2-controlled genes and signaling pathways were revealed by RNA-seq. Rescue experiments were performed to validate that SMYD3 mediates HOXD-AS2 promoting HCC progression. The positive feedback loop of HOXD-AS2 and SMYD3 was identified by luciferase reporter assay and ChIP-qPCR.Results: HOXD-AS2 was dramatically elevated in HCC, and its up-regulation exhibited a positive association with aggressive clinical features (T stage, pathologic stage, histologic grade, AFP level, and vascular invasion) and unfavorable prognosis of HCC patients. HOXD-AS2 was distributed both in the nucleus and the cytoplasm of HCC cells. Knockdown of HOXD-AS2 restrained the proliferation, migration, invasion of HCC cells in vitro, as well as tumor growth in subcutaneous mouse model. Transcriptome analysis demonstrated that SMYD3 expression and activity of MEK/ERK pathway were impaired by silencing HOXD-AS2 in HCC cells. Rescue experiments revealed that SMYD3 as downstream target mediated oncogenic functions of HOXD-AS2 in HCC cells through altering the expression of cyclin B1, cyclin E1, MMP2 as well as the activity of MEK/ERK pathway. Additionally, HOXD-AS2 was uncovered to be positively regulated at transcriptional level by its downstream gene of SMYD3.Conclusion: HOXD-AS2, a novel oncogenic HOX-lncRNA, facilitates HCC progression by forming a positive feedback loop with SMYD3 and activating the MEK/ERK pathway.Keywords: hepatocellular carcinoma, HOXD-AS2, SMYD3, MEK/ERK signaling

Liuli Xu, Qing Huang, Ting Wu, Yunzhu Mu Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of ChinaCorrespondence: Yunzhu Mu, Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of China, Email hymyz@126.comAbstract: Riehl’s melanosis (RM) is a contact photodermatitis, with fast progressive gray-brown skin pigmentation as the main manifestation, which can seriously affect the psychology and physiology of patients. Currently, although the etiological factors of Riehl’s melanosis is still be unknown, the existing literature proves clearly the cause of it is related to the contacting with suspected allergens. For decades, there has been no standard method for the treatment of RM, but with both conventional drug therapy and laser therapy having been attempted. Topical application of bleaching agents is mainly used as an auxiliary treatment modality. The laser treatment modality remains a hot spot, among which Q-switched Nd:YAG laser is well received for RM. Positive outcomes have been achieved by the combined treatment modalities attempted in recent years also achieve positive outcomes. The purpose of this paper is to review and summarize recent advances in the treatment of the disease.Keywords: Riehl’s melanosis, pigmented contact dermatitis, therapy

Yang Mei,1,2 Yang Mu,3 Win Wang,2 Bo-Tao Tan,1 Yao-Hua Chen,4 Yu-Ping Li,4 Dan Zhu,4 Wei Li,2 Jian Cui,4 Le-Hua Yu1 1Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Pain Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, People’s Republic of China; 3Department of Rehabilitation Medicine, Chongqing University Fuling Hospital, Chongqing, People’s Republic of China; 4Department of Pain Medicine, Southwest Hospital, Army Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Jian Cui; Le-Hua Yu, Email cqjian211@163.com; 300895@cqmu.edu.cnIntroduction: Adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) can influence energy metabolism. Energy metabolism imbalance is closely associated with the occurrence of neuropathic pain (NeP). Rs10789038 and rs2796498 are genetic polymorphisms of PRKAA2, the gene encoding AMPK, which is closely related to energy metabolism imbalance. This study aimed to explore the relationship between PRKAA2 and postherpetic neuralgia (PHN) in the southwestern Chinese Han population.Methods: This study enrolled 132 PHN patients and 118 healthy subjects. The rs10789038 and rs2796498 PRKAA2 genotypes were identified in all participants. The association between these single nucleotide polymorphisms and PHN susceptibility was evaluated in the dominant and recessive models. Haplotype analysis of patients with PHN and healthy controls was performed.Results: The PHN patients were older than the healthy subjects (P < 0.05); however, the other clinical characteristics between two groups were not significantly different (all P > 0.05). Genotypes and allele frequencies differed significantly between PHN patients and healthy subjects in the rs10789038 polymorphism (P < 0.05), but not in rs2796498 (P > 0.05). In addition, the GG haplotype of rs10789038-rs2796498 correlated negatively with PHN occurrence in haplotype analysis (P < 0.05).Conclusion: PHN occurrence may be related to the PRKAA2 rs10789038 A>G genetic polymorphism in the southwestern Chinese Han population.Keywords: AMPK, PRKAA2, polymorphism, postherpetic neuralgia

Lei Zhang,1 Yixiong Li,2 Hao Yang,1 Yunzhu Mu,1 Jingjing Jiang,1 Xi Duan1 1Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, People’s Republic of China; 2Department of Anorectal, The First Affiliated Hospital of Chengdu Medical College, Chengdu, People’s Republic of ChinaCorrespondence: Xi Duan, Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, 1 Maoyuan South Road, Shunqing District, Nanchong City, Sichuan Province, 637000, People’s Republic of China, Tel +8618783983097, Email dancing@126.comAbstract: We describe a 62-year-old woman with a 1-month-old unhealed cat bite wound caused by Mycobacterium chelonae presenting with persistent infection despite treatment with cefazolin and amoxicillin. This is the first reported case of M. chelonae infection caused by a cat bite. Cat bites are affected by the cat’s food microbiome, so clinicians should consider the cat’s diet if wounds are not responding as expected to first-line therapy.Keywords: cat bite, Mycobacterium chelonae, wound infection

Jia He, Xi Duan, Ting Liu, Hao Yang, Jingjing Jiang, Yunzhu Mu Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of ChinaCorrespondence: Yunzhu Mu, Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan South Road, Shunqing District, Nanchong City, Sichuan Province, 637000, People’s Republic of China, Tel +8615983785601, Email hymyz@126.comAbstract: Immune-related adverse events have been reported in relation to programmed cell death protein-1 (PD-1). However, there are few reports on PD-1 inhibitor-induced bullous pemphigoid. We report the case of a patient who developed bullous pemphigoid following long-term administration of sintilimab for renal cell carcinoma. He developed scattered erythema, blisters, and generalized pruritus for 1 week before admission. Histopathology showed subepidermal blisters and direct immunofluorescence showed linear deposition of immunoglobulin G and complement 3 on the basement membrane; the level of BP180 was 146.93U/mL. A regimen containing methylprednisolone, minocycline, and niacinamide was administered and the patient was discharged following resolution of symptoms.Keywords: bullous pemphigoid, PD-1, PD-L1, sintilimab

Xuebing Zhang,1,&ast; Wenhua Yan,2,&ast; Bing Wang,3 Lianjie Wang,1 Yiming Mu,2 Shidong Wang1 1Department of Endocrinology, Dongzhimen Hospital Beijing University of Chinese Medicine, Beijing, 100700, People’s Republic of China; 2Department of Endocrinology, First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 3Department of Endocrinology, Emergency General Hospital, Beijing, 100028, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shidong Wang, Tel +86 13910965659, Email A2082@bucm.edu.cnBackground: Obesity can lead to the development of type 2 diabetes mellitus (T2DM). However, the predictive power of different obesity anthropometric indices (ObAIs) for T2DM varies with race and geographical area. Therefore, the study aimed to investigate the association between different ObAIs and T2DM and determine the best index for screening T2DM in middle-aged and elderly men and women in Beijing, China.Methods: A cross-sectional study was conducted in Shijingshan district (Beijing, China) from November 2011 to August 2012, involving a total of 14,558 subjects aged ≥ 40 years. Data on demographic information, lifestyle, history of T2DM, hypertension and dyslipidemia were collected. Body height, body weight, waist circumference (WC), hip circumference, and blood pressure were recorded. The oral glucose tolerance test or a standard meal test and blood lipid test were performed. The relationship between different ObAIs and T2DM was analyzed using multiple logistic regression.Results: After adjustment for age, smoking status, alcohol intake, occupation and education degree, diabetes family history, hypertension and dyslipidemia, body mass index (BMI), WC, waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were positively associated with T2DM in both men and women. Compared with the lowest BMI, WC, WHR, and WHtR quartiles, ORs of the highest quartiles were 2.131 (95% CI: 1.465– 3.099), 1.752 (95% CI: 1.270– 2.417), 1.342 (95% CI: 1.072– 1.678), 2.739 (95% CI: 2.293– 3.271) in men and 1.837 (95% CI: 1.584– 2.130), 3.122 (95% CI: 1.980– 4.924), 3.781 (95% CI: 2.855– 5.007), 2.379 (85% CI: 2.040– 2.775), respectively, in women. The areas under ROC curve of BMI, WC, WHR, and WHtR for men were 0.584 (95% CI: 0.568– 0.600), 0.509 (95% CI: 0.492– 0.525), 0.501 (95% CI: 0.485– 0.518), and 0.642 (95% CI: 0.627– 0.658) and 0.619 (95% CI: 0.607– 0.632), 0.709 (95% CI: 0.697– 0.720), 0.741 (95% CI: 0.730– 0.752), and 0.654 (95% CI: 0.642– 0.666), respectively, for women.Conclusion: WHtR and WHR have been found to perform better as predictors of T2DM in middle-aged and elderly Chinese men and women, respectively.Keywords: obesity, anthropometric indices, type 2 diabetes mellitus, middle-aged and elderly, Chinese

Juan Xu,1,2,&ast; Ziwei Sun,1,2,&ast; Huanyu Ju,1,2 Erfu Xie,1,2 Yuan Mu,1,2 Jian Xu,1,2 Shiyang Pan1,2 1Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shiyang Pan, Tel +86 139 5181 4639, Email sypan@njmu.edu.cnPurpose: Mucinous adenocarcinoma (MA) and signet ring cell carcinoma (SRCC) are aggressive colorectal cancer histological subtypes with dismal prognosis. This study investigated prognostic factors and constructed novel nomograms for MA and SRCC patients who survived for over 5 years to optimize the follow-up regime, especially for early-onset patients.Patients and Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database registered between 2004 and 2018 were extracted. MA and SRCC patients were divided into two groups with survival time of 5 years as a cut-off point. Prognostic factors for overall survival (OS) and cancer-specific survival (CSS) were determined by Cox regression models, and survival curves were plotted by the Kaplan–Meier method.Results: We identified 8286 MA patients (45.73%) and 551 SRCC patients (20.32%) who survived for over 5 years. Multivariable Cox analyses identified age, tumor location, N stage, metastasis, CEA level, surgery, and lymph nodes dissection as independent risk factors for MACSS. SRCC was more aggressive and only N2 stage (P = 0.011) and metastasis (P = 0.043) were inversely associated with SRCCSS. Furthermore, we observed that small tumor size, well differentiation, and chemotherapy no longer provided survival benefit to ≥ 5-year survivors. Therefore, we constructed novel nomograms appropriate for MA patients who survived for over 5 years. The consistency indexes for predicting 10-year OS and CSS were respectively 0.717, 0.712 in the training cohort and 0.727, 0.735 in the validation cohort.Conclusion: Our well-calibrated nomograms represent the first clinical prognostic models developed especially for MA patients with a survival longer than 5 years. For both MA and SRCC patients, TNM stage was a stable prognostic factor, while the prognostic values of tumor size, differentiation grade, and chemotherapy changed over time. We are hopeful that our prognostic models will help define personalized follow-up managements to further prolong patient survival.Keywords: mucinous and signet ring cell colorectal cancer, survival over 5 years, changes in prognostic factors, nomogram, chemotherapy, SEER

Fanping Wang,1,2 Yonghui Yang,1,3 Zhixin Li,1,2 Yan Wang,1,4 Zhenchao Zhang,2,5 Wei Zhang,2,5 Yonghui Mu,2,5 Jingwen Yang,1,2 Lili Yu,2,5 Mingyong Wang1,2 1Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China; 2Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China; 3Henan Center for Disease Control and Prevention, Zhengzhou, Henan, 450000, People’s Republic of China; 4Department of Laboratory Medicine, Luoyang Oriental Hospital, Luoyang, Henan, 471000, People’s Republic of China; 5School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of ChinaCorrespondence: Mingyong Wang; Lili Yu, Email wmy118@126.com; merrys222@126.comBackground: Mannan-binding lectin (MBL) is a key molecule in innate immunity and activates the lectin complement pathway, which plays an important role in resisting Candida albicans (C. albicans) infection. However, the underlying mechanism of this resistance to infection remains unclear.Methods: In this study, we investigated how MBL regulates the differentiation of CD4+ T cells into T helper type 17 (Th17) and T regulatory (Treg) cells against C. albicans in mice, as well as the underlying mechanisms. We generated MBL double-knockout (KO) mice and infected them with C. albicans by intraperitoneal injection.Results: Compared with that in wild-type (WT) mice, the percentage of Th17 cells increased in MBL-null mice, whereas Treg cells decreased, indicating that MBL might regulate the Th17/Treg balance. In addition, in MBL-null mice, the expression levels of interleukin (IL)-17A, IL-21, and the master transcription factor of Th17 cells, RORγt, significantly increased. Conversely, IL-10, IL-2, and the Treg-specific transcription factor, Foxp3, decreased. Moreover, we found that the levels of TGF-β and IL-6 upregulated in MBL-null mice. Mechanistically, we found that MBL regulated the TGF-β/SMAD pathway through the inhibition of p-SMAD2 and promotion of p-SMAD3, and mediated the JAK/STAT pathway through the inhibition of p-JAK2 and p-STAT3 and promotion of p-JAK3 and p-STAT5. MBL double-KO mice showed a more severe inflammatory response and significantly lower survival rates with C. albicans infection.Conclusion: These results suggest that MBL regulates the Th17/Treg cell balance to inhibit inflammatory responses, possibly via IL-6- and TGF-β-mediated JAK/STAT and TGF-β/SMAD signaling, and play an important role in anti-C. albicans infection.Keywords: mannan-binding lectin, Th17/Treg axis, JAK/STAT, TGF-β/SMAD, Candida albicans

Yinyu Mu,1 Fuyi Xie,1 Dongdong Yang,1 Guodong Xu2 1Department of Clinical Laboratory, Ningbo Medical Centre, Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, 315040, People’s Republic of China; 2Department of Cardiothoracic Surgery, Ningbo Medical Centre, Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, 315040, People’s Republic of ChinaCorrespondence: Yinyu Mu; Fuyi Xie, Department of Clinical Laboratory, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 57 Xingning Road, Ningbo, Zhejiang, 315040, People’s Republic of China, Email muyu606@sina.com; 528715297@qq.comPurpose: Circular RNA (circRNA) serves an important role in tumour genesis and development. But, little is known about its role in lung adenocarcinoma (LA). This study aimed to investigate circRNA6783 expression in peripheral whole blood (PWB) of LA and controls and explore its effect on proliferation and apoptosis in human lung adenocarcinoma cells (LAC).Patients and Methods: The levels of circRNA6783 in LA cell lines and peripheral whole blood (PWB) of 40 patients and 30 controls were detected by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). In order to explore the effect of circRNA6783 on LA behavior, we overexpressed circRNA6783 in NCI-H1975 cells. The impact on the proliferation of tumor cells was then examined by Cell Counting Kit 8 (CCK8) assay, and the effects on apoptosis in the cell line were detected using flow cytometry.Results: The expression levels of circRNA6783 were significantly higher in LA cell lines and PWB (P < 0.05). The diagnostic value of the area under the receiver operating characteristic curve (AUC) was 0.830, with a sensitivity of 60% and specificity of 96.7%. In addition, functional experiments showed that overexpression of circRNA6783 restrained cell proliferation, significantly increased spontaneous apoptosis.Conclusion: CircRNA6783 was upregulated in LA PWB. In vitro assessment demonstrated that circRNA6783 could act as a potential biomarker for LA diagnosis.Graphical Abstract: Keywords: lung adenocarcinoma, circular RNA6783, proliferation, apoptosis

Yu Wang, Jianmei Zhao, Lu Jiang, Yunzhu Mu Department of Dermatology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, People’s Republic of ChinaCorrespondence: Yunzhu Mu Email hymyz@126.comAbstract: Melasma is an acquired and chronic hyperpigmentation disorder which is recognized as one of the most psychologically distressing and difficult to cure forms of skin hyperpigmentation. It is associated with substantial quality of life impairments. Treatments of melasma include local application, oral medication, physical laser therapy and program combination therapy. However, routine treatment usually leads to the damage of skin barrier function, resulting in adverse reactions such as erythema, pruritus, post-inflammatory pigmentation and even scar. Skin care products contain a variety of active ingredients, which are widely concerned by cosmetic dermatologists because of high safety, good tolerance and the effect of improving the damaged skin barrier. Using skin care products alone or in combination with routine treatment not only can improve the curative effect for melasma, reduce side effects and recurrence rate, but also improve patient satisfaction. This article mainly describes the application of skin care products in the treatment of melasma.Keywords: skin care product, melasma, treatment

Chen Yuan,1,&ast; Yanhong Li,1,&ast; Liyun Liu,1 Baihetiya Tayier,1 Lingjie Yang,1 Lina Guan,1– 3 Yuming Mu1– 3 1Department of Echocardiography, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People’s Republic of China; 2State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 3Xinjiang Key Laboratory of Medical Animal Model Research, Clinical Medical Research Institute of First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuming Mu; Lina GuanDepartment of Echocardiography, The First Affiliated Hospital of Xinjiang Medical University, 137 Liyushan Road, Ürümqi, Xinjiang Uyghur, Autonomous Region, 830054, People’s Republic of ChinaEmail mym1234@126.com; sanjin_lsx@163.comObjective: To prepare a new type of dual-target microbubble loaded with anti-miR-33 (ANM33).Methods: Carrier core nanobubbles (NBs) were prepared by thin film hydration, and microbubbles loaded with PM1 (PCNBs) were prepared by grafting DSPE-PEG2000-maleimide-PM1 onto the NB surface. ANM33 was connected via electrostatic adsorption and covalent bonding, and hyaluronic acid (HA) was covalently connected. PM1 and HA were the targets, and ANM33 was the intervention drug. To evaluate the general physical and chemical properties of the prepared dual-target microbubbles loaded with ANM33 (HA-PANBs), we observed their morphology, particle size and surface potential while monitoring their stability and in vitro imaging ability, evaluated their toxic effect on cells and verified their ability to target cells.Results: HA-PANBs had a regular morphology and good stability. The average particle size measured by a Malvern potentiometer was 1421.75± 163.23 nm, and the average surface potential was − 5.51± 1.87 mV. PM1 and ANM33 were effectively connected to the NBs. The PM1, ANM33, and HA binding reached 89.0± 1.1%, 65.02± 5.0%, and 61.4± 3.5%, respectively, and the maximum binding reached 2 μg, 5 μg, and 7 μg/108 microbubbles, respectively. HA-PANBs had no obvious toxic effects on cells, and their ability to continuously enhance imaging in vitro persisted for more than 15 minutes, obviously targeting foam cells in the early stage of AS.Conclusion: HA-PANBs are ideal ultrasound contrast agents. The successful, firm connection of PM1 and HA to the NBs significantly increased the amount of carried ANM33. When microbubbles prepared with 2:4:7 PM1:ANM33:HA were used as a contrast agent, they had a high ANM33 carrying capacity, stable physical properties, and significantly enhanced imaging and targeting of foam cells in the early stage of AS.Keywords: ultrasound microbubbles, molecular targeting, dual targeting, atherosclerosis

Yang Liu,1,2,* Yun Wang,1,2,* Jie Wang,2 Kang Chen,2 Lingzi Jin,3 Weiqing Wang,4 Zhengnan Gao,5 Xulei Tang,6 Li Yan,7 Qin Wan,8 Zuojie Luo,9 Guijun Qin,10 Lulu Chen,11 Yiming Mu2 1Graduate School, Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Department of International Medical Services, Peking Union Medical College Hospital (Xidan Campus), Beijing, People’s Republic of China; 4Shanghai National Research Centre for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 5Department of Endocrinology, Dalian Central Hospital, Dalian, Liaoning, People’s Republic of China; 6Department of Endocrinology, First Hospital of Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 7Department of Endocrinology, Zhongshan University Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, People’s Republic of China; 8Department of Endocrinology, Southwest Medical University Affiliated Hospital, Luzhou, Sichuan, People’s Republic of China; 9Department of Endocrinology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 10Department of Endocrinology, First Affiliated Hospital of Zhengzhou University, Zhenzhou, Henan, People’s Republic of China; 11Department of Endocrinology, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yiming MuDepartment of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, People’s Republic of ChinaTel +86-10-5549 9001Email muyiming@301hospital.com.cnBackground: Lipid accumulation product (LAP) as a powerful marker of visceral obesity is an independent risk factor of chronic kidney disease. The present study attempted to explore the association between LAP and albuminuria in prediabetic individuals.Methods: We conducted a cross-sectional study and enrolled 26,529 participants with prediabetes over 40 years old with prediabetes from seven provinces in China. LAP was calculated from waist circumference and fasting triglycerides. Elevated albuminuria was defined by urinary albumin-creatinine ratio (uACR) ≥ 30 mg/g. Propensity score matching was applied to reduce bias, comparison between LAP and other traditional visceral obesity indices was performed and multiple logistic regression models were conducted to assess the association between LAP and albuminuria in the prediabetic population.Results: Individuals with uACR ≥ 30 mg/g were older and had higher BP, BMI, WC, TG, fasting insulin, glycohemoglobin and LAP, as well as lower eGFR and HDL level. Multiple logistic regression analysis showed elevated LAP was associated with increased odds of albuminuria (OR [95%CI]Q2 vs Q1 1.09 [0.94, 1.27], OR [95%CI]Q3 vs Q1 1.13 [0.97, 1.31], OR [95%CI]Q4 vs Q1 1.42 [1.21, 1.67], P for trend=0.018), and superior over waist-to-hip ratio or waist-to-height ratio. Stratification indicated that the prediabetic population with higher LAP level and characterized by female gender, middle age, being overweight, and rise in blood pressure were more likely to have increased uACR.Conclusion: Elevated level of LAP was associated with increased albuminuria in the prediabetic population in China.Keywords: albuminuria, lipid accumulation product, prediabetes, visceral obesity

Mingyan Yao,1,2,* Hongzhou Liu,1,* Bing Li,1 Yang Liu,1 Yiming Mu1 1Department of Endocrinology, Chinese People’s Liberation Army General Hospital, Beijing, 100853, People’s Republic of China; 2Department of Endocrinology, Baoding NO.1 Central Hospital, Baoding, 071000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yiming MuDepartment of Endocrinology, Chinese People’s Liberation Army General Hospital, No. 28 Fuxing Road, Beijing, 100853, People’s Republic of ChinaEmail muyiming@301hospital.com.cnPurpose: There is a close correlation between menopausal age and cardiovascular disease (CVD) risk. Some research suggests that this risk is attributable to an elevated urinary albumin-creatinine ratio (UACR), but further work is needed to explore the link between UACR and age at time of menopause.Patients and Methods: Data analyzed in the present study were derived from seven regional centers participating in the REACTION study. A total of 21,672 postmenopausal women met with our study inclusion and exclusion criteria, and were split into three groups based upon their age at onset of natural menopause. A UACR ≥ 30 mg/g was the primary outcome measure for this study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with a logistic regression approach.Results: Relative to women who were 46– 50 years old at time of natural menopause, those with an earlier onset of menopause (≤ 45 years) exhibited an increased risk of UACR elevation following adjustment for confounding variables (OR: 1.18, 95% CI: 1.04– 1.33), whereas the opposite was true for women with a later age of menopause onset (> 50 years) (OR: 0.86, 95% CI: 0.78– 0.94). For every 1-year delay in the onset of menopause, UACR risk fell by 3% (OR: 0.97, 95% CI: 0.96– 0.98).Conclusion: In summary, early menopause (≤ 45 years old) was linked to a higher risk of UACR elevation in postmenopausal women. However, further work will be needed to understand the mechanistic basis for these findings.Keywords: age, urinary albumin-creatinine ratio, menopause

Yu-rong Mu1,2 ,* Meng-yuan Zhou1,2 ,* Li Cai,3 Ming-ming Liu,1,2 Rong Li1,2 1School of Pharmacy, Anhui Medical University, Hefei, Anhui Province, People’s Republic of China; 2Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, People’s Republic of China; 3Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei, Anhui Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rong LiSchool of Pharmacy, Anhui Medical University, Hefei, Anhui Province, People’s Republic of ChinaEmail aydlirong@163.comIntroduction: Previous studies have confirmed that aquaporin 1 (AQP1) is up-regulated in synovium of rheumatoid arthritis (RA), but its exact pathogenic mechanisms in RA are unclear. This study revealed the pathogenic role of AQP1 in rat collagen-induced arthritis (CIA) and the underlying mechanisms related to β-catenin signaling.Materials and Methods: Secondary paw swelling and pathological changes of ankle joints were used to evaluate the severity of rat CIA. Synovial AQP1 and β-catenin expression were measured by immunohistochemistry (IHC) and Western blot assay. AQP1 siRNA was applied to knockdown AQP1 in cultured CIA fibroblast-like synoviocyte (FLS). Assays of MTT, PCNA immunofluorescence and transwell were performed to detect cell proliferation, migration and invasion. The protein levels of β-catenin pathway members and ratio of TOP/FOP luciferase activity were also measured.Results: In vivo, we revealed that synovial AQP1 and β-catenin expressions in CIA rats were higher than normal rats, and synovial AQP1 expression of CIA rats increased in parallel with secondary paw swelling and total pathological score on joint damage. Correlation analysis of IHC results indicated that synovial AQP1 expression positively correlated with β-catenin expression in CIA rat. In vitro, AQP1 siRNA apparently reduced the proliferation, migration and invasion of CIA FLS by inhibiting β-catenin signaling pathway. As an activator of β-catenin signaling, lithium chloride (an inhibitor of GSK-3β) reversed the inhibitory effects of AQP1 siRNA on the cultured CIA FLS.Conclusion: We concluded that the overexpression of synovial AQP1 aggravated rat CIA by promoting the activation of FLS through β-catenin signaling pathway.Keywords: aquaporin 1, collagen-induced arthritis, fibroblast-like synoviocyte, rheumatoid arthritis, β-catenin signaling

Yongle Qiu,1 Jieming Sun,2 Junping Qiu,2 Guoling Chen,2 Xiao Wang,2 Yaxu Mu,2 Kunshan Li,1 Wenjing Wang1 1Department of Stomatology, Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, Hebei 050017, People’s Republic of China; 2Department of Stomatology, Xianghe County People ‘S Hospital, Langfang, Hebei 065400, People’s Republic of ChinaCorrespondence: Kunshan Li Email likunshan5566@163.comIntroduction: TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) can induce apoptosis in a variety of cancer cells. However, drug resistance of tumor and short half-life seriously affects its clinical targeted therapy. Cabazitaxel (CTX) is a taxane drug, which can induce apoptosis or autophagy by inhibiting the phosphorylation of PI3K/Akt/mTOR and sensitive to some drug-resistant tumors. Therefore, we explored the possibility of developing a mesenchymal stem cell-derived exosomes (MSC-EXO) vector for oral squamous cell carcinoma (OSCC) to deliver CTX/TRAIL combinations.Methods: After ultracentrifugation and dialysis, CTX/TRAIL loaded exosomes transfected MSC (MSCT)-derived exosome (EXO) (MSCT-EXO/CTX) were isolated and purified. The expression of CD63, CD9 and TRAIL was detected by BCA to confirm the origin of EXO. High-performance liquid chromatography (HPLC) was used to determine the drug loading of VPF and draw the in vitro release profile. MTT assay, flow cytometry and Western blot were used to detect the antitumor effect of MSCT-EXO/CTX in vitro. Subsequently, the antitumor effect of MSCT-EXO/CTX in vivo was verified by mouse model.Results: The diameter of the membrane particles was about 60– 150 nm. We have proved that the incorporation and release of CTX in MSCT-EXO can inhibit the activation of PI3K, Akt and mTOR, which is a possible synergistic mechanism of CTX. MSCT-EXO and CTX can induce the apoptosis of SCC25 tumor cells in a dose-dependent manner and exert a good synergistic effect in the proportion range of 10:1– 5:1. The inherent activity of MSCT-EXO and the direct effect of MSCT-EXO/CTX on OSCC confirm that MSCT-EXO/CTX makes MSCT-EXO and CTX have an efficient synergistic effect and a highly effective pharmacological inhibition on cancer cells, as verified by the subsequent mouse model. MSCT-EXO/CTX showed the lowest relative tumor volume and the highest tumor inhibition rate (P< 0.05) in vivo.Conclusion: An MSCT-EXO-based CTX delivery system might be an effective anticancer method.Keywords: cabazitaxel, extracellular vesicles, mesenchymal stromal cells, oral squamous cell carcinoma

Wanlu Su,1,2,* Jie Wang,1,2,* Yiming Mu1,2 1Medicine School of Nankai University, No. 94 Weijin Road, Tianjin 300071, People’s Republic of China; 2Department of Endocrinology, Chinese People’s Liberation Army General Hospital, Beijing 100853, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yiming MuDepartment of Endocrinology, Chinese People’s Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, People’s Republic of ChinaEmail muyiming@301hospital.com.cnPurpose: The hypertriglyceridemic waist (HTGW) phenotype can predict cardiovascular disease (CVD) risk. Additionally, strong evidence indicates that elevated urinary albumin–creatinine ratio (UACR) is associated with increased prevalence of CVD. However, few studies have explored the association between the HTGW phenotype and UACR.Patients and Methods: In this cross-sectional descriptive study, a total of 40,674 subjects (28,562 women and 12,112 men older than 40 years) were recruited from seven different geographic regional centres. The HTGW phenotype was defined as increased triglyceride levels (triglyceride ≥ 1.5 mmol/L for female and ≥ 2.0 mmol/L for male) and waist circumference (WC; WC ≥ 85 for female and WC ≥ 90 cm for male). Logistic regression analyses were performed to assess the relationship between UACR and the HTGW phenotype.Results: Subjects with the HTGW phenotype showed a more significant trend towards increased excretion of UACR [among all subjects, odds ratio (OR) = 1.303, 95% CI: 1.132– 1.499, P < 0.001; among men, OR = 1.406, 95% CI: 1.057– 1.870, P = 0.019; among women, OR = 1.268, 95% CI: 1.074– 1.496, P = 0.005]. Furthermore, the stratified analysis showed that the OR for high-risk significantly increased in individuals in the HTGW group aged below 65 years, with 5.6 ≤ fasting blood glucose < 7.0 or 7.8 ≤ post-load blood glucose < 11.1 mmol/L, 120 ≤ systolic blood pressure < 140 or 80 ≤ diastolic blood pressure < 90, 24 ≤ body mass index < 28 kg/m2, and estimated globular filtration rate > 90 mL/min per 1.73 m2.Conclusion: This study has advanced the understanding of visceral obesity and our results supported the fact that the HTGW phenotype is associated with elevated UACR excretion among general Chinese adults.Keywords: waist circumference, hypertriglyceridemia, chronic kidney disease, urinary albumin-creatinine ratio

Yuxin Mu, Puyuan Xing, Xuezhi Hao, Yan Wang, Junling Li National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Junling LiNational Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Number 17 Panjiayuan Nan Li, Chao Yang District, Beijing 100021, People’s Republic of ChinaTel +86 13801178891Email lijunling@cicams.ac.cnPurpose: Osimertinib is an oral, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeted for both EGFR sensitizing mutations and T790M resistance mutation in patients with non-small-cell lung cancer (NSCLC). We assessed efficacy and safety of osimertinib in patients with pretreated NSCLC in a real-world setting.Patients and methods: Ninety-four patients with advanced NSCLC who received osimertinib after progression of prior EGFR-TKIs or chemotherapy treatments were retrospectively collected.Results: In patients evaluable for response analysis (n = 91), overall objective response rate (ORR) was 47.3%, and disease control rate (DCR) was 90.1%. Median duration of response (DoR) in responding patients was 12.5 months (95% confidence interval [CI], 10.7 to 14.3). Median progression-free survival (PFS) was 8.5 months (95% CI, 7.4 to 9.6) in 2nd line group, 9.1 months (95% CI, 6.6 to 11.6) in ≥3rd line group, and 8.6 months (95% CI, 7.2 to 10.0) in overall population. For subgroup analysis, DCR and median PFS were 91.9% and 8.6 months (95% CI, 7.2 to 10.0) in patients with detectable T790M mutation, respectively, while 80.0% and 3.2 months (95% CI, 0.5 to 5.9) for those without. Median PFS was significantly longer for T790M-positive patients co-occurring with exon19del than with L858R (17.9 months vs 7.3 months; P

Wei Xu,1,2 Honglan Wang,3 Lihui Dong,3 Pan Zhang,3 Yan Mu,2 Xueyan Cui,2 Jianping Zhou,3 Meirong Huo,3 Tingjie Yin31Department of Pharmacy, Shandong Provincial Qian Foshan Hospital, Shandong University, Jinan 250014, People’s Republic of China; 2Qianfoshan Hospital, The First Hospital Affiliation with Shandong First Medical University, Jinan 250012, People’s Republic of China; 3State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People’s Republic of ChinaIntroduction: Herein, a hyaluronic acid (HA)-coated redox-sensitive chitosan-based nanoparticle, HA(HECS-ss-OA)/GA, was successfully developed for tumor-specific intracellular rapid delivery of gambogic acid (GA).Materials and methods: The redox-sensitive polymer, HECS-ss-OA, was prepared through a well-controlled synthesis procedure with a satisfactory reproducibility and stable resulted surface properties of the assembled cationic micelles. GA was solubilized into the inner core of HECS-ss-OA micelles, while HA was employed to coat outside HECS-ss-OA/GA for CD44-mediated active targeting along with protection from cation-associated in vivo defects. The desirable redox-sensitivity of HA(HECS-ss-OA)/GA was demonstrated by morphology and particle size changes alongside in vitro drug release of nanoparticles in different simulated reducing environments.Results: The results of flow cytometry and confocal microscopy confirmed the HA-receptor mediated cellular uptake and burst drug release in highly reducing cytosol of HA(HECS-ss-OA)/GA. Consequently, HA(HECS-ss-OA)/GA showed the highest apoptosis induction and cytotoxicity over the non-sensitive (HA(HECS-cc-OA)/GA) and HA un-coated (HECS-ss-OA/GA) controls against A549 NSCLC model both in vitro and in vivo. Furthermore, a diminished systemic cytotoxicity was observed in HA(HECS-ss-OA)/GA treated mice compared with those treated by HA un-coated cationic ones and GA solution.Keywords: gambogic acid, nanoparticles, redox-sensitive, intracellular drug delivery, tumor

Jinjing Wang,1,2,* Kang Chen,1,* Xinye Jin,1 Xueqiong Li,3 Ping An,1 Nan Yang,4 Yaolong Chen,4 Yi Fang,2 Yiming Mu11Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, People’s Republic of China; 2Department of Endocrinology, Fifth Medical Center of PLA General Hospital, Beijing 100071, People’s Republic of China; 3Department of Gerontology, First Affiliated Hospital of Kunming Medical University, Kunming 650031, People’s Republic of China; 4Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, People’s Republic of China*These authors contributed equally to this work Objective: To evaluate the prognostic factors for cesarean section outcome of pregnant women with diabetes mellitus.Methods: MEDLINE, EMBASE, Cochrane Library, CBM, CNKI and Wanfang database were searched. Two researchers independently screened the literature, extracted data, and evaluated the risk of bias of included studies. For pooled data with factors of perioperative outcome, the RevMan software was used for data translation and meta-analysis. The result is shown intuitively with the bubble diagram of evidence mapping by Excel 2016.Results: We included 12 randomized controlled trials (RCTs) in the meta-analysis. Twelve RCTs with 1,390 patients were included in the systematic review. The results show that the perioperative blood glucose management regimens, preoperative fasting and water deprivation, anesthesia regimens, postoperative fluid regimens, postoperative analgesia regimens, postoperative wound care regimens, psychological interventions, different dosing regimens for antibiotics, and obesity may affect the cesarean section outcome of diabetic mothers and newborns. The evidence for all the outcomes was low quality.Conclusion: Many prognostic factors have shown significant association with postoperative outcomes of cesarean section. More clinical research evidence with high-quality is needed.Keywords: gestational diabetes mellitus, caesarean section, prognostic factors, systematic review, meta-analysis, evidence mapping

Tingting Che,1 Xiaochun Teng,1 Qun Huang,1 Yanfei Mu,2 Xianjun Tang,2 Xiaosong Mu,2 Youneng Wei1 1Department of Endocrinology, Chongqing Public Health Medical Center, Chongqing, China; 2Chongqing Cancer Institute, Hospital and Cancer Center, Chongqing, China Background: Depressive and anxiety symptoms could seriously affect the quality of life of type 2 diabetes mellitus (T2DM) subjects. Currently, little is known about the efficacy and acceptability of agomelatine versus fluoxetine in treating these symptoms in T2DM subjects. Therefore, this study was performed to find out which one was better in treating these symptoms in T2DM subjects.Materials and methods: T2DM subjects with depressive and anxiety symptoms were randomly assigned to receive either fluoxetine (30–40 mg/day) or agomelatine (25–50 mg/day). The treatment was continued for 12 weeks. The data of the Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) were collected (at baseline and also at weeks 4, 8 and 12) to assess the depressive and anxiety symptoms, respectively. The metabolic parameters, including body mass index (BMI), fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c), were assessed at baseline and after 12 weeks of treatment. The treatment-related adverse events during the scheduled treatment period were recorded to compare the acceptability of these two drugs.Results: After 12 weeks of treatment, the average HDRS and HARS scores were significantly decreased in both groups. The average HDRS scores were not significantly different between the two groups, although the agomelatine group had a lower average HDRS score. The response and remission rates were similar between the two groups, and these two drugs had no significant effects on BMI and FPG. However, compared with the fluoxetine group, the agomelatine group had the significantly lower average HARS score (p=0.0017) and lower average HbA1c level (p

Michael S Taitel, Ying Mu, Angshuman Gooptu, Youbei Lou Health Analytics, Research & Reporting, Walgreen Co., Deerfield, IL, USA Objectives: This study evaluates a nationwide pharmacy chain’s late-to-refill (LTR) reminder program that entails local pharmacists placing reminder calls to Medicare Part D patients. Methods: We conducted a randomized controlled study among 735,218 patients who exhibited nonadherent behavior by not refilling a maintenance medication 3 days from an expected refill date. Patients were randomly assigned to an intervention group who received LTR reminder calls or to a control group. We used Walgreens pharmaceutical claims data from 2015 to estimate the impact of LTR calls on short-term and annual adherence. Results: The initial refill rate within the first 14 days of the expected refill date significantly increased in the intervention group by 22.8% (6.09 percentage points) compared to the control group (P

Yalong Dang,1 Yalin Mu,2 Kun Wang,3 Ke Xu,2 Jing Yang,1 Yu Zhu,1 Bin Luo2,3 1Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Ophthalmology, Yellow-River Hospital, Sanmenxia City, People’s Republic of China; 3Clinical Laboratory, Yellow-River Hospital, Sanmenxia City, People’s Republic of China Objective: To investigate the effects of papaverine (PAP) on lipopolysaccharide (LPS)-induced microglial activation and its possible mechanisms. Materials and methods: BV2 microglial cells were first pretreated with PAP (0, 0.4, 2, 10, and 50 µg/mL) and then received LPS stimulation. Transcription and production of proinflammatory factors (IL1β, TNFα, iNOS, and COX-2) were used to evaluate microglial activation. The transcriptional changes undergone by M1/M2a/M2b markers were used to evaluate phenotype transformation of BV2 cells. Immunofluorescent staining and Western blot were used to detect the location and expression of P65 and p-IKK in the presence or absence of PAP pretreatment. Results: Pretreatment with PAP significantly inhibited the expression of IL1β and TNFα, and suppressed the transcription of M1/M2b markers Il1rn, Socs3, Nos2 and Ptgs2, but upregulated the transcription of M2a markers (Arg1 and Mrc1) in a dose-dependent manner. In addition, PAP pretreatment significantly decreased the expression of p-IKK and inhibited the nuclear translocation of P65 after LPS stimulation. Conclusion: PAP not only suppressed the LPS-induced microglial activity by inhibiting transcription/production of proinflammatory factors, but also promoted the transformation of activated BV2 cells from cytotoxic phenotypes (M1/M2b) to a neuroprotective phenotype (M2a). These effects were probably mediated by NF-κB signaling pathway. Thus, it would be a promising candidate for the treatment of neurodegenerative diseases. Keywords: papaverine, microglia, neuroprotection, neuroinflammation

Yalong Dang,1,* Yalin Mu,2,* Lin Li,3,* Yahui Mu,2 Shujing Liu,2 Chun Zhang,4 Yu Zhu,1 Yimin Xu4 1Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 2Department of Ophthalmology, Yellow River Hospital, Henan University of Science and Technology, Sanmenxia, Henan Province, 3Department of Ophthalmology, the First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan Province, 4Department of Ophthalmology, Peking University Third Hospital, Haidian District, Beijing, People's Republic of China *These authors contributed equally to this work. Background and objective: Our objective was to investigate the efficacy and safety of dexamethasone (DEX) implant for the treatment of pseudophakic cystoid macular edema (PCME) in diabetic patients. Study design: This was a prospective, non-randomized, interventional case series of 43 participants. Eighteen patients were enrolled in the DEX implant group and 25 were enrolled in an intravitreal triamcinolone acetonide (IVTA) group. Main outcome measures: The primary efficacy measurement was the percentage of patients who gained improvements of more than ten letters in best corrected visual acuity (BCVA) during 6 months of follow-up. Other efficacy measurements included change in BCVA, change in central macular thickness (CMT), and number of retreatments. The primary safety evaluation was the percentage of patients with intraocular hypertension and variation in intraocular pressure (IOP) during 6 months of follow-up. Other adverse events, such as conjunctival hemorrhage, eye pain, secondary infection, endophthalmitis, noninfectious inflammation, retinal detachment, and implant migration, were also recorded during follow-up. Results: At month 1, we observed that the percentage of patients gaining improvement of more than ten letters was similar in both groups (P=0.625). As patients in the IVTA group were retreated several times, this effect persisted throughout the study (P=0.941 at month 2, P=0.553 at month 3, P=0.856 at month 6). Variations in CMT were noticed at week 1 and reached their maximum at month 1. No significant difference was found between the two groups (P=0.831 at week 1, P=0.783 at month 1). At month 1, the variation in IOP reached its maximum in the DEX implant group and then decreased slightly. However, in the IVTA group, it increased continuously throughout the study. Conjunctival hemorrhage and eye pain were found in both groups, but both were rated as mild in severity, and no significant difference was found (P=0.184, P=0.766, respectively). Conclusion: Both IVTA and DEX implants could effectively restore visual function and recover morphological change in diabetic patients with PCME for at least 6 months, but repeated intravitreal injection was required in the IVTA group. DEX implant is well tolerated. We suggest that intravitreal injection of DEX implant is a promising new therapeutic option for diabetic patients with PCME. Keywords: dexamethasone implant, intravitreal triamcinolone acetonide, pseudophakic cystoid macular edema, diabetic retinopathy, corticosteroid, inflammation

Yalong Dang,1–3,# Xinfeng Sun,2,# Yongsheng Xu,3,# Yalin Mu,2 Manli Zhao,2 Jing Zhao,2 Yu Zhu,1 Chun Zhang31Department of Ophthalmology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 2Department of Ophthalmology, Yellow River Hospital, Henan University of Science and Technology, Sanmenxia, Henan Province, 3Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, People's Republic of China #These authors contributed equally to this work Background: The purpose of this study was to evaluate changes in subfoveal choroidal thickness after photodynamic therapy in patients with acute idiopathic central serous chorioretinopathy (ICSCR). Methods: This was a retrospective observational study conducted in 63 participants. The primary outcome measure was subfoveal choroidal thickness at baseline and 3 days, one week, 4 weeks, and 12 weeks after photodynamic therapy. The secondary outcome measure was indocyanine green angiography at baseline and 4 weeks and 12 weeks after photodynamic therapy. Results: Four weeks after photodynamic therapy, 20 (64.51%) symptomatic eyes showed hypofluorescence corresponding to the area of photodynamic therapy irradiation at the posterior pole. The mean subfoveal choroidal thickness increased significantly from 422±132 µm at baseline to 478±163 µm at day 3 after treatment (P=0.022) and then decreased to 362±113 µm at week 4 (P

Yalong Dang,1,2,* Yalin Mu,2,* Manli Zhao,2 Lin Li,3 Yaning Guo,4 Yu Zhu1,2 1Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China; 2Department of Ophthalmology and Visual Science, Yellow River Hospital of Henan University of Science and Technology, Sanmenxia City, Henan, People's Republic of China; 3Department of Ophthalmology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang City, Henan, People's Republic of China; 4Gu-Cheng Eye Hospital, Xi'an City, Shanxi, People's Republic of China *These authors contributed equally to this work Purpose: To evaluate the effect of Helicobacter pylori (H. pylori) eradication on the remission of acute idiopathic central serous chorioretinopathy (ICSCR). Study design: A prospective, randomized, placebo-controlled study of 53 participants. Main outcome measure: Twenty-seven acute ICSCR patients tested positive for H. pylori were given an eradication H. pylori therapy, and another 26 patients with the same diagnosis received matching placebo medication. All participants were tested for the following items: (1) disappearance rate of subretinal fluid (SRF); (2) best-corrected visual acuity (BCVA); and (3) central retinal sensitivity at baseline, 2 weeks, 4 weeks, 8 weeks, and 12 weeks after treatment. The difference between the two groups was analyzed by PASW statistics version 18.0. Results: At each follow-up, the disappearance rate of SRF in the active treatment group seemed slightly better than in the control group, but no statistically significant differences were observed (P > 0.05 at each follow-up). The BCVA between the two groups also did not demonstrate statistically significant differences (P > 0.05 at each follow-up). Unlike the BCVA and the disappearance rate of SRF, we compared the change in central retinal sensitivity at 12 weeks after treatment; a statistical difference was observed (P = 0.042). Conclusion: Our findings suggested that H. pylori eradication does not improve BCVA and the disappearance rate of SRF, but it could improve the central retinal sensitivity in acute ICSCR patients. We recommend that chronic ICSCR patients and more sensitive methods for H. pylori diagnosis should be involved in evaluating the effect of H. pylori eradication. Keywords: Helicobacter pylori, acute idiopathic central serous chorioretinopathy, best-corrected visual acuity, subretinal fluid, central retinal sensitivity

Epithelial ovarian cancer (EOC) has poor prognosis and rapid recurrence because of widespread dissemination of peritoneal metastases at diagnosis. Multiple pathways contribute to the aggressiveness of ovarian cancer, including hypoxic signaling mechanisms. In this study, we have determined that the hypoxia-inducible histone demethylase KDM4B is expressed in ∼60% of EOC tumors assayed, including primary and matched metastatic tumors. Expression of KDM4B in tumors is positively correlated with expression of the tumor hypoxia marker CA-IX, and is robustly induced in EOC cell lines exposed to hypoxia. KDM4B regulates expression of metastatic genes and pathways, and loss of KDM4B increases H3K9 trimethylation at the promoters of target genes like LOXL2, LCN2 and PDGFB. Suppressing KDM4B inhibits ovarian cancer cell invasion, migration and spheroid formation in vitro. KDM4B also regulates seeding and growth of peritoneal tumors in vivo, where its expression corresponds to hypoxic regions. This is the first demonstration that a Jumonji-domain histone demethylase regulates cellular processes required for peritoneal dissemination of cancer cells, one of the predominant factors affecting prognosis of EOC. The pathways regulated by KDM4B may present novel opportunities to develop combinatorial therapies to improve existing therapies for EOC patients.