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Hui Song,1,* Yang Luo,2,* Lingzhi Fang1 1The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, People’s Republic of China; 2Jiang You Third People Hospital, Mianyang, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui Song, Email 182321767@qq.comAbstract: Esketamine nasal spray has emerged as a promising rapid-relief therapy for treatment-resistant depression (TRD) and suicide prevention. This review examines the chemical structure and pharmacodynamics of esketamine, highlighting its primary action on NMDA receptors and additional effects on AMPA receptors, opioid receptors, monoaminergic receptors, and inflammatory pathways. Despite the synergistic mechanisms contributing to its clinical benefits not being fully understood, future studies are essential to refine our understanding and optimize clinical use. Clinical research indicates that esketamine effectively alleviates depressive symptoms and prevents suicidal behavior in TRD patients, demonstrating good safety and efficacy over extended periods. Specifically, multiple randomized controlled trials have shown that esketamine reduces depressive symptoms within hours and maintains these benefits over several weeks, with a favorable safety profile and minimal side effects observed in long-term use. The approval of esketamine for TRD has significant implications for healthcare practices and policies, offering a new therapeutic option that addresses the urgent needs of patients with severe depression.Keywords: esketamine, treatment-resistant depression, TRD, NMDA receptors, pharmacodynamics, clinical benefits, safety and efficacy

Ya-ru Liu,1,2,* Jie-Quan Wang,3– 5,* Ling Fang,1,2 Quan Xia1,2 1Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 2The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230022, People’s Republic of China; 3Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, 230000, People’s Republic of China; 4Department of Pharmacy, Hefei Fourth People’s Hospital, Hefei, 230000, People’s Republic of China; 5Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, 230000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling Fang; Quan Xia, Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China, Email fangling@ahmu.edu.cn; xiaquan2010@163.comAbstract: Rheumatoid arthritis (RA) is a systemic inflammatory disease whose precise pathogenesis remains mysterious. The involvement of epigenetic regulation in the pathogenesis of RA is one of the most anticipated findings, among which non-coding RNAs (ncRNAs) hold great application promise as diagnostic and therapeutic biomarkers for RA. Extracellular vesicles (EVs) are a heterogeneous group of nano-sized, membrane-enclosed vesicles that mediate intercellular communication and substance exchange, especially the transfer of ncRNAs from donor cells, thereby regulating the functional activities and biological processes of recipient cells. In light of the significant correlation between EVs, ncRNAs, and RA, we first documented expression levels of EVs and their-encapsulated ncRNAs in RA individuals, and methodically discussed their-implicated signaling pathways and phenotypic changes. The last but not least, we paied special attention to the therapeutic benefits of gene therapy reagents specifically imitating or silencing candidate ncRNAs with exosomes as carriers on RA animal models, and briefly highlighted their clinical application advantage and foreground. In conclusion, the present review may be conducive to a deeper comprehension of the diagnostic and therapeutic roles of EVs-enwrapped ncRNAs in RA, with special emphasis on exosomal ncRNAs, which may offer hints for the monitoring and treatment of RA. Keywords: rheumatoid arthritis, extracellular vesicles, non-coding RNAs, diagnostic and therapeutic role

Huiying Yan,1,* Wei Wang,2,* Tingting Cui,1 Yanxin Shao,3 Mingquan Li,1 Limei Fang,1 Lina Feng1 1Department of Neurology, The Third Affiliated Clinical Hospital of the Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 2Department of Intensive Care Unit, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 3Department of Neurology, The Second Affiliated Hospital of Shandong First Medical University, Taian, People’s Republic of China*These authors contributed equally to this workCorrespondence: Limei Fang; Lina Feng, Department of Neurology, The Third Affiliated Clinical Hospital of the Changchun University of Chinese Medicine, Changchun, People’s Republic of China, Email fanglm008@163.com; Fenglina0001@126.comAbstract: Alzheimer’s disease (AD) is a fatal neurodegenerative disease with a subtle and progressive onset and is the most common type of dementia. However, its etiology and pathogenesis have not yet been fully elucidated. The common pathological manifestations of AD include extraneuronal β-amyloid deposition (Aβ), intraneuronal tau protein phosphorylation leading to the formation of ‘neurofibrillary tangles’ (NFTs), neuroinflammation, progressive loss of brain neurons/synapses, and glucose metabolism disorders. Current treatment approaches for AD primarily focus on the ‘Aβ cascade hypothesis and abnormal aggregation of hyperphosphorylation of tau proteins’, but have shown limited efficacy. Therefore, there is an ongoing need to identify more effective treatment targets for AD. The central nervous system (CNS) inflammatory response plays a key role in the occurrence and development of AD. Neuroinflammation is an immune response activated by glial cells in the CNS that usually occurs in response to stimuli such as nerve injury, infection and toxins or in response to autoimmunity. Neuroinflammation ranks as the third most prominent pathological feature in AD, following Aβ and NFTs. In recent years, the focus on the role of neuroinflammation and microglia in AD has increased due to the advancements in genome-wide association studies (GWAS) and sequencing technology. Furthermore, research has validated the pivotal role of microglia-mediated neuroinflammation in the progression of AD. Therefore, this article reviews the latest research progress on the role of neuroinflammation triggered by microglia in AD in recent years, aiming to provide a new theoretical basis for further exploring the role of neuroinflammation in the process of AD occurrence and development.Keywords: neuroinflammation, microglia, Alzheimer’s disease, review, Trem2

Likui Fang, Fangming Zhong, Wenfeng Yu, Pengfei Zhu, Guocan Yu Department of Thoracic Surgery, Hangzhou Red Cross Hospital, Hangzhou, 310003, People’s Republic of ChinaCorrespondence: Likui Fang, Department of Thoracic Surgery, Hangzhou Red Cross Hospital, Hangzhou, 310003, People’s Republic of China, Email 21618100@zju.edu.cnBackground: The impact of coagulation indicators on postoperative outcomes of patients with constrictive pericarditis undergoing pericardiectomy has been poorly investigated. This study aimed to assess the prognostic role of preoperative coagulation indicators in these patients.Methods: We retrospectively included 158 patients with constrictive pericarditis undergoing pericardiectomy. The diagnostic values of coagulation indicators for postoperative complications were evaluated by ROC curves. Patients were divided into two groups according to the cutoff value calculated by ROC curve. Postoperative outcomes were compared between the two groups. Logistic regression analysis was performed to identify risk factors of postoperative complications.Results: ROC curve showed that among different coagulation indicators, preoperative D-dimer (DD) level could effectively identify patients with postoperative complications (AUC 0.771, 95% CI 0.696– 0.847, P < 0.001). Patients were divided into the low DD group and the high DD group. The comparison of postoperative outcomes suggested that high preoperative DD level was significantly associated with longer durations of vasoactive agents using (P = 0.018), intubation (P = 0.020), ICU stay (P = 0.008), chest drainage (P=0.004) and hospital stay (P = 0.002). Multivariable analysis showed that high preoperative DD level was the independent risk factor of postoperative complications (OR 6.892, 95% CI 2.604– 18.235, P < 0.001).Conclusion: High preoperative DD level was significantly linked to poor postoperative outcomes and could provide an effective prediction ability for postoperative complications in patients with constrictive pericarditis.Keywords: constrictive pericarditis, D-dimer, postoperative complications, outcomes

Likui Fang, Wenfeng Yu, Guocan Yu, Gang Chen, Bo Ye Department of Thoracic Surgery, Hangzhou Red Cross Hospital, Hangzhou, 310003, People’s Republic of ChinaCorrespondence: Likui Fang, Department of Thoracic Surgery, Hangzhou Red Cross Hospital, Hangzhou, 310003, People’s Republic of China, Email 21618100@zju.edu.cnBackground: Tuberculous constrictive pericarditis (TCP) is recommended to be treated with anti-tuberculosis (TB) therapy before pericardiectomy. Whether different preoperative anti-TB regimens may lead to different outcomes is unclear.Methods: We retrospectively collected patients diagnosed as TCP and received pericardiectomy from April 2016 to June 2023. The study patients were assigned into the active TCP (A-TCP) group and the inactive TCP (IA-TCP) group according to the results of Mycobacterium tuberculosis (MTB) culture and MTB RNA assay. Baseline characteristics including anti-TB regimens and surgical outcomes were compared between the two groups. Logistic regression analysis and subgroup analysis were conducted to identify the protective factors of A-TCP.Results: Of the 102 study patients, 24 was in the A-TCP group and 78 was in the IA-TCP group. The rate of preoperative anti-TB regimen containing pyrazinamide was 37.5% in the A-TCP group, as compared with 74.4% in the IA-TCP group (P = 0.001). Multivariate analysis showed that preoperative use of pyrazinamide was the protective factor of A-TCP (OR 0.194, 95% CI 0.053– 0.703, P = 0.013). Subgroup analysis based on age also showed consistent findings. In the analyses of surgical outcomes, A-TCP was the independent risk factor of postoperative cardiac complications (OR 4.231, 95% CI 1.317– 13.593, P = 0.015) and associated with longer hospital stay (P = 0.004) and higher hospitalization cost (P = 0.001).Conclusion: A strategy involving anti-TB regimen containing pyrazinamide before pericardiectomy was superior to that without pyrazinamide in the patients with TCP. The strategy was associated with lower risk of A-TCP and might lead to better postoperative recovery and cost-effectiveness.Keywords: tuberculous constrictive pericarditis, pericardiectomy, pyrazinamide, outcomes

Minglu Xu,1,2,&ast; Lingli Fang,1,2,&ast; Qin Xue,1,2 Xuyang Zhang,1,2 Yao He1,3 1Department of Orthodontics, Stomatological Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Oral Disease and Biomedical Sciences, Stomatological Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yao He, Department of Orthodontics, Stomatological Hospital of Chongqing Medical University, 426 North of Songshi Avenue, Chongqing, 401147, People’s Republic of China, Email yaohe@hospital.cqmu.edu.cnObjective: Oxidative stress is involved in the mechanisms associated with temporomandibular joint (TMJ) diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial oxidative stress marker, but the specific mechanisms of its regulation in the early stages of mandibular condylar cartilage (MCC) degeneration remain unclear. This study aimed to explore the regulatory role of Nrf2 and its related oxidative stress signaling pathway in the early stage of MCC degeneration.Materials and Methods: Overloading force-induced MCC degeneration was performed in wild-type and Nrf2 knockout mice, as well as in mice after treatment with the Nrf2 activator cardamonin. Changes in MCC degeneration and the expression of oxidative stress markers in the corresponding situations were observed.Results: Nrf2 and NADPH oxidase 2 (NOX2) expression were elevated during early MCC degeneration induced by an overloading force. MCC degeneration was aggravated when Nrf2 was knocked out, accompanied by increased NOX2 and superoxide dismutase 2 (SOD2) expression. The MCC degeneration process was alleviated after cardamonin treatment, with activation of the Nrf2 pathway and decreased NOX2 and SOD2 expression.Conclusion: Early MCC degeneration is accompanied by mild oxidative stress progression. Activated Nrf2 and related pathways could alleviate the degeneration of MCC.Keywords: NF-E2-related factor 2, oxidative stress, temporomandibular joint, cartilage, mechanical force

Hui Xiao,&ast; Ni Guo,&ast; Junyi Li, Ling Jin, Yuan Liu, Shufen Lin, Lei Fang, Xing Liu, Chengguo Zuo State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xing Liu; Chengguo Zuo, Zhongshan Ophthalmic Center, Sun Yat-sen University, 7 Jinsui Road, Guangzhou, 510000, People’s Republic of China, Email liuxing@mail.sysu.edu.cn; zuochengguo@mail.sysu.edu.cnPurpose: To report the prevalence, clinical characteristics and risk factors for paracentral acute middle maculopathy (PAMM) following acute primary angle closure (APAC) and acute primary angle closure glaucoma (APACG).Methods: This retrospective study consecutively recruited patients diagnosed with APAC or APACG. Based on the spectral domain optical coherence tomography characteristics, PAMM eyes were divided into three stages. Characteristics of different stages such as the time from symptoms to treatment (TST), retinal thickness and BCVA improvement were analyzed. The risk factors of PAMM were evaluated by binary logistic regression models.Results: A total of 781 eyes of 781 APAC or APACG patients were included, and PAMM was found in 22 (2.9%) of them. Stage III eyes had a significantly longer TST than stage I eyes (P = 0.008) while exhibiting significantly thinner retinal thicknesses (P < 0.0001). The BCVA improvement was significantly worse in the eyes treated in stage III than in those treated in stage I (P = 0.008). Older age, longer axial length and without type 2 diabetes were associated with a lower risk of incident PAMM (OR = 0.95, P = 0.028; OR = 0.52, P = 0.019; OR = 3.92, P = 0.022).Conclusion: PAMM can be secondary to APAC or APACG at a rate of 2.9%. Different visual outcomes were observed in patients who received the intervention at different stages of PAMM. Younger patients with a shorter axial length and type 2 diabetes were found to be more susceptible to PAMM.Keywords: paracentral acute middle maculopathy, acute primary angle closure, acute primary angle closure glaucoma, risk factors, spectral domain optical coherence tomography

Zishuai Li,1– 3,&ast; Zihan Zhang,4,&ast; Letian Fang,1– 3,&ast; Jiayi Zhao,1– 3,&ast; Zheyun Niu,4 Hongsen Chen,1– 3 Guangwen Cao1– 3 1Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai, 200433, People’s Republic of China; 2Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai, 200433, People’s Republic of China; 3Department of Epidemiology, Second Military Medical University, Shanghai, 200433, People’s Republic of China; 4Department of Epidemiology, Tongji University School of Medicine Tongji University, Shanghai, 200120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangwen Cao, Department of Epidemiology, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433, People’s Republic of China, Tel/Fax +86 21-8187-1060, Email gcao@smmu.edu.cnAbstract: Globally, primary liver cancer is the third leading cause of cancer death, and hepatocellular carcinoma (HCC) accounts for 75%– 95%. The tumor microenvironment (TME), composed of the extracellular matrix, helper cells, immune cells, cytokines, chemokines, and growth factors, promotes the immune escape, invasion, and metastasis of HCC. Tumor metastasis and postoperative recurrence are the main threats to the long-term prognosis of HCC. TME-related therapies are increasingly recognized as effective treatments. Molecular-targeted therapy, immunotherapy, and their combined therapy are the main approaches. Immunotherapy, represented by immune checkpoint inhibitors (ICIs), and targeted therapy, highlighted by tyrosine kinase inhibitors (TKIs), have greatly improved the prognosis of HCC. This review focuses on the TME compositions and emerging therapeutic approaches to TME in HCC. Keywords: hepatocellular carcinoma, tumor microenvironment, immunotherapy, targeted therapy

Hantong Hu,1,2,&ast; Xiaoqi Lin,3,&ast; Lianqiang Fang,1 Yang Li,1 Hong Gao1 1Department of Acupuncture and Moxibustion, the Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China; 2Department of Neurobiology and Acupuncture Research, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou City, People’s Republic of China; 3The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Gao, Department of Acupuncture and Moxibustion, the Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 219 Moganshan Road, Hangzhou City, People’s Republic of China, Email qtgh@vip.qq.comObjective: This study aims to evaluate the efficacy and safety of acupuncture for chronic subjective tinnitus and explore the central mechanism underlying acupuncture for chronic subjective tinnitus using functional near-infrared spectroscopy (fNIRS).Methods: We will randomly assign 60 tinnitus patients to either an acupuncture group or a waiting-list control group. The acupuncture group will undergo 12 treatment sessions over 4 weeks, whereas the waiting-list control group will receive no intervention concurrently. Clinical outcome measures include the Tinnitus Handicap Inventory (THI) score, tinnitus loudness assessed by 11-point NRS, average pure-tone threshold, and Hamilton Anxiety Scale (HAM-A) score. Neuroimaging outcomes assessed by fNIRS included blood oxygen concentration and resting-state functional connectivity (RSFC). All outcome measurements will be assessed at the baseline, after 4-week treatment, and at 3-month follow-ups.Results: Our investigation will determine if significant differences exist between the two groups regarding THI, NRS, average pure-tone threshold, and HAM-A scores. Moreover, the analysis will reveal whether the acupuncture group demonstrates significant change in blood oxygen concentration and RSFC between specific brain regions compared to the waiting-list control group.Conclusion: With the novel technique of fNIRS, in addition to efficacy evaluation of acupuncture, this study’s findings are anticipated to partly elucidate the neural mechanisms underlying acupuncture treatment for subjective tinnitus and offer an objective assessment method for its therapeutic impact, thereby contributing to filling the research gap.Trial Registration: Clinicaltrials registry (identification code NCT05829278).Keywords: acupuncture, functional near-infrared spectroscopy, randomized controlled trial, subjective tinnitus, neural mechanisms

Ling Yang,1,2 Maolin Cao,3 Jing Tian,1 Peijin Cui,1 Ling Ai,3 Xue Li,4 Hua Li,5 Menghan Gao,1 Liang Fang,1,2,6 Libo Zhao,1,2 Fang Gong,2,6 Chanjuan Zhou1,3,4,6 1Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Cerebrovascular Disease Research, Chongqing, People’s Republic of China; 3Department of General Practice, Yongchuan Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Central Laboratory, Yongchuan Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 5Department of Ophthalmology, Yongchuan Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 6Chongqing Clinical Research Center for Geriatric Disease, Chongqing, People’s Republic of ChinaCorrespondence: Fang Gong; Chanjuan Zhou, Yongchuan Hospital of Chongqing Medical University, No. 439 Xuanhua Road, Yongchuan, Chongqing, 402160, People’s Republic of China, Email 1512367841@qq.com; chanjuanzhou@hospital.cqmu.edu.cnPurpose: The quality of life of worldwide adolescents has been seriously affected by depression. Notably, the inflammatory response is closely associated with the pathophysiology of depression. The present study applied a novel targeted proteomics technology, Olink proximity extension assay (PEA), to profile circulating immune-related proteins in adolescents with depression.Methods: In the present study, the expression levels of 92 inflammation-related proteins were compared between adolescents with depression (ADs) (n=15) and healthy controls (HCs) (n=15), using the OLINK PEA inflammation panel. We further validated 5 top proteins that were identified through KEGG and GO analyses between 40 HCs and 50 ADs, including CCL4, CXCL5, CXCL6, CXCL11, and IL-18 using enzyme linked immunosorbent assay (ELISA).Results: We identified 13 differentially expressed proteins between the two cohorts, including 5 up-regulated and 8 down-regulated proteins. Among them, the TRAIL protein levels were significantly negatively correlated with the HAMA-14 score (r=− 0.538, p= 0.038), and the levels of transforming growth factor α (TGF-α) were significantly associated with a change in appetite (r = -0.658, p = 0.008). After validation by ELISA, CCL4, CXCL5, CXCL11, and IL-18 showed significant changes between ADs and HCs (p < 0.05), while CXCL6 showed an up-regulated tendency in ADs (p=0.0673). The pooled diagnostic efficacy (area under the curve [AUC]) of these five inflammation markers in clinical diagnosis for adolescent depression was 0.819 (95% CI: 0.735– 0.904).Conclusion: We report a number of inflammation-related plasma biomarkers, which uncover a potential involvement of chemokines, cytokines, and cytokine receptors in adolescent depression. Their roles in the pathophysiology of depression need to be further elucidated.Keywords: olink proximity extension assay, biomarkers, adolescent depression, inflammation

Li Fang,1,2 Chun-Hao Li,1,3 Qian Zhang,1,3 Tian-Jiao Jiang,1,3 Yuan Liu,1,2 Feng-Po Shi,1,3 Peng Yu,1,3 Liang Yu,1,3 Ai-Ping Chen,1,3 Tao Li,1,3 Yu-Zhu Wan,1,3 Li Shi1,3 1Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Otolaryngology Head & Neck Surgery, The Second People’s Hospital of Shenzhen, Shenzhen, Guangdong, People’s Republic of China; 3Department of Allergy, Shandong Second Provincial General Hospital, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Tao Li; Yu-Zhu Wan, Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Duanxing West Road, Jinan, Shandong, 250033, People’s Republic of China, Tel +86 531 83086279 ; +86 531 83086280, Fax +86 531 87980304, Email ltwfmc@163.com; wanyuzhu001@126.comBackground: Mounting research indicates that brain-derived neurotrophic factor (BDNF), has great potential to increase neuro-hyperresponsiveness and airway resistance in airway allergic disease. The expression level of BDNF has been found to be notably elevated in lung/nasal lavage (NAL) fluid. However, the expression and position of BDNF in ciliated cells with allergic rhinitis remains unclear.Methods: Nasal mucosal cells were collected from patients with allergic rhinitis (AR) and mice which were performed under different allergen challenge time, then observed the expression and position of BDNF located in ciliated cells through the immunofluorescence staining. Nasal mucosa, serum and NAL fluid were collected also. The expression level of BDNF and IL-4/5/13 were detected by RT-PCR. The expressions of BDNF (in serum and NAL fluid), and total-IgE, ovalbumin sIgE (in serum) were detected by ELISA.Results: We found that MFI of BDNF in AR group’s ciliated cells was obviously lower than that in the control group, and a negative correlation was discovered between MFI and VAS score. It can be roughly divided into 5 patterns according to its location in the cytoplasm of ciliated cells. In the mouse model, the expressions of BDNF in serum and NAL fluid increased temporarily after allergen stimulation. The MFI of BDNF in ciliated cells displayed an initial increase followed by a subsequent decrease.Conclusion: Our study shows for the first time that, the expression and localization of BNDF were observed in the human nasal ciliated epithelial cells of allergic rhinitis, and the expression of level was less than the control group under the persistent state of allergy. BDNF expression in ciliated cells was transient increased after allergen stimulation and decreased to normal level after 24h in mouse model of allergic rhinitis. This might be the possible source of the transient increase of BNDF in serum and NAL fluid.Keywords: allergic rhinitis, BDNF, ciliated cell, NAL fluid

Liping Yang,1,&ast; Xingling Li,1,&ast; Lianqiang Fang,1 Lei Wu,1,2 Hantong Hu,1,2 YingYing Cheng1 1Department of Acupuncture and Moxibustion, the Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China; 2Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: YingYing Cheng; Hantong Hu, Department of Acupuncture and Moxibustion, the Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 219 Moganshan Road, Hangzhou City, People’s Republic of China, Email cyysince@163.com; 413351308@qq.comBackground: Acupuncture is considered as a potential treatment option for primary tinnitus, as there is a lack of conventional therapies with well-established efficacy. However, there are limited studies that compare the effectiveness of different acupuncture therapies. Thus, this systematic review and network meta-analysis protocol aims to compare the efficacy of various acupuncture-related therapies for primary tinnitus, and determine the optimal treatment.Methods: A comprehensive search of 10 representative databases will be conducted to identify eligible randomized controlled trials (RCTs) regarding multiple acupuncture-related therapies for primary tinnitus. Two independent researchers will extract data individually, and the methodological quality of each RCT will be assessed using Cochrane’s risk of bias 2.0 tool. Standard pairwise meta-analysis and Bayesian network meta-analysis will be conducted, and WinBUGS V.1.4.3 and R 3.6.2 software will be adopted to synthesize network data and generate relevant graphs. Subgroup analyses, sensitivity analyses, and assessment of publication bias will be conducted as appropriate.Discussion: This study’s results are anticipated to identify the optimal acupuncture technique for treating primary tinnitus, thereby providing evidence-based clinical decisions for patients and clinicians to select the most effective acupuncture treatment.Prospero Registration Number: CRD42023399621.Keywords: acupuncture, moxibustion, tinnitus, meta-analysis, protocol

Yang Yang,1,2 Jie Zhang,3 Liqun Fang,2 Xue Jia,1,2 Wensheng Zhang1,2 1Laboratory of Anaesthesia & Critical Care Medicine, Translational Neuroscience Center, The Research Units of West China (2018RU012), Chinese Academy of Medical Sciences, West China Hospital of Sichuan University, Chengdu, People’s Republic of China; 2Department of Anaesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Anaesthesiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Wensheng Zhang, Laboratory of Anaesthesia & Critical Care Medicine, Translational Neuroscience Center, The Research Units of West China (2018RU012), Chinese Academy of Medical Sciences, West China Hospital of Sichuan University, Chengdu, People’s Republic of China, Tel/Fax +81-28-85164144, Email zhang_ws@scu.edu.cnPurpose: Alpha-adrenergic blockers are used in the preoperative preparation of patients with pheochromocytomas and paragangliomas (PPGLs) despite the controversial on perioperative hemodynamics. We aimed to determine whether selective or non-selective α-adrenergic blockers can provide better efficacy on patients’ intraoperative hemodynamics.Patients and Methods: This single-center retrospective study was conducted in 2507 adult patients undergoing PPGL resections, patients received alpha-adrenergic receptor blockers as a binary variable (selective or non-selective). Propensity score matching was performed and 201 patients were matched successfully.Results: A total of 201 patients with PPGL were included in this study. The HI score scores were higher in the selective group than in the non-selective group (60.5 [44.5– 84.0] vs 49.0 [37.0– 67.25], P=0.027), as well as in the hemodynamic variables section [14.0 [8.0– 20.0] vs 10 [6.0– 16.0], P=0.009). In terms of specific indicators for each component, the lowest MAP in the selective group (55± 10 mmHg vs 59± 8 mmHg, P=0.038), the time to MAP below 60 mmHg (0.011% vs 0.022%, P=0.033) and the use of other vasoconstrictors (56.5% vs 35.5%, P=0.019) were significantly lower than in the non-selective group. Among the secondary outcome indicators, the incidence of intraoperative maximum SBP was significantly higher in the selective group than in the non-selective group (32.3% vs 11.3%, P=0.005). There were no significant differences in postoperative outcome indicators between the two groups.Conclusion: In patients with PPGL, patients prepared preoperatively with non-selective alpha-blockers presented more stable hemodynamics intraoperatively compared to selective alpha1-blockers.Keywords: α-adrenergic blockers, PPGLs, hemodynamic instability, perioperative management

Lili Fang,1– 3,&ast; Minxue Liu,4,&ast; Chunlan Huang,5,&ast; Xiaobo Ma,1– 3 Yanqing Zheng,1– 3 Wenjuan Wu,6 Jian Guo,6,&ast; Jiangshan Huang,1– 3 Heping Xu1– 3 1Department of Laboratory Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, People’s Republic of China; 2Xiamen Key Laboratory of Genetic Testing, Xiamen, Fujian, People’s Republic of China; 3School of Public Health, Xiamen University, Xiamen, Fujian, People’s Republic of China; 4The Maternal & Child Health Hospital, The Children’s Hospital, The Obstetrics & Gynecology Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, People’s Republic of China; 5Department of Clinical Laboratory, Liuzhou People’s Hospital, Liuzhou, Guangxi, People’s Republic of China; 6Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Heping Xu; Jiangshan, Hung Department of Laboratory Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, People’s Republic of China, Email xmsunxhp@163.com; 13600918159@163.comIntroduction: Talaromyces marneffei is a life-threatening pathogen that causes systemic talaromycosis in immunocompromised and acquired immunodeficiency syndrome (AIDS) patients. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) as a tool to cluster T. marneffei isolates is rarely reported and the data on antifungal susceptibility of T. marneffei isolated in the southern region of China, especially in Fujian, is hardly found.Methods: MALDI-TOF MS was used to cluster 135 T. marneffei isolates, and the minimum inhibitory concentration (MIC) values of amphotericin B, itraconazole, posaconazole, voriconazole, fluconazole, anidulafungin, micafungin, caspofungin and 5-fluorocytosine with Sensititre YeastOne™ YO10 assay were measured during January 2017 to October 2020 in Fujian and Guangxi.Results: MALDI-TOF MS correctly identified 100% of the T. marneffei isolates. Hierarchical clustering of MALDI-TOF peak profiles identified four different clusters. MICs for itraconazole, posaconazole, voriconazole and amphotericin B were as follows: ≤ 0.015– 0.03 μg/mL, ≤ 0.008– 0.03 μg/mL, ≤ 0.008– 0.06 μg/mL, ≤ 0.12– 1 μg/mL, respectively. MICs for echinocandins and fluconazole were comparatively high.Conclusion: Since only simple sample preparation is required and since results are available in a short period of time, MALDI-TOF MS can be considered as a method for identification and clustering of T. marneffei. Itraconazole, posaconazole, voriconazole and amphotericin B can be used to treat T. marneffei infected patients due to the low MICs.Keywords: Talaromyces marneffei, MALDI-TOF, antifungal susceptibility, HIV-infected, non-HIV-infected

Guocan Yu,1,&ast; Linhua Wang,2 Yanqin Shen,1 Likui Fang,1 Jun Yang,1 Bo Ye,1 Kan Xu,1 Fangming Zhong1,&ast; 1Zhejiang Tuberculosis Diagnosis and Treatment Center, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Hospital Infection, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guocan Yu; Fangming Zhong, Zhejiang Tuberculosis Diagnosis and Treatment Center, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China, Email dabaitwo@163.com; zhongfangm@126.comPurpose: We evaluated CapitalBio Mycobacterium RT-PCR assay diagnosing tuberculous pericarditis (TBP), performed a head-to-head comparison with Xpert MTB/RIF, and assessed the impact of a parallel test (positive result for either of these two tests).Methods: We reviewed suspected TBP patients with Xpert MTB/RIF, CapitalBio Mycobacterium RT-PCR assay, and Mycobacterium tuberculosis (MTB) culture. We analyzed sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC).Results: Seventy-four patients were included. Overall sensitivity, specificity, PPV, NPV, and AUC of CapitalBio Mycobacterium RT-PCR assay compared with culture were 50%, 91.1%, 64.3%, 85%, and 0.71, respectively. Overall sensitivity, specificity, PPV, NPV, and AUC of Xpert MTB/RIF for TBP were 61.1%, 91.1%, 68.8%, 87.9%, and 0.76. Parallel test values were 72.2%, 91.1%, 72.2%, 91.1%, and 0.82. The diagnostic accuracy of Xpert MTB/RIF was higher than CapitalBio Mycobacterium RT-PCR assay but was not significant (P > 0.05). The parallel test could improve diagnostic accuracy, but it was not significant compared to single tests (P > 0.05).Conclusion: CapitalBio Mycobacterium RT-PCR assay had a moderate diagnostic accuracy, similar to Xpert MTB/RIF. The parallel test maximized diagnostic efficacy, but differences were not significant. CapitalBio Mycobacterium RT-PCR assay and Xpert MTB/RIF for TBP could be an initial option for early diagnosis.Keywords: tuberculosis pericarditis, polymerase chain reaction, Xpert MTB/RIF, CapitalBio, accuracy

Yanqin Shen, Likui Fang, Bo Ye, Xudong Xu, Guocan Yu,&ast; Lihong Zhou&ast; Zhejiang Tuberculosis Diagnosis and Treatment Center, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Zhejiang Chinese Medicine and Western Medicine Integrated Hospital, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guocan Yu; Lihong Zhou, Email dabaitwo@163.com; zhoulh198508@163.comBackground: Early lymph node tuberculosis (LNTB) diagnosis is still difficult. The majority of LN specimens require the undertaking of invasive and unpleasant procedures.Purpose: To evaluate the diagnostic efficacy of pathology when combined with molecular tests for the diagnosis of LNTB in core needle biopsy (CNB) specimens and to compare that diagnostic efficacy with that deriving from tissue specimens’ examination alone.Methods: We retrospectively analyzed the medical records of LNTB patients who met the inclusion criteria. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of pathology, molecular tests, and parallel test (positive result for either of these two assays) were calculated to evaluate their diagnostic efficacy compared with a composite reference standard.Results: A total of 289 patients were included in the study. The overall sensitivity, specificity, PPV, NPV, and AUC of pathology, molecular tests, and parallel test were 94.5%, 97.2%, 99.6%, 71.4%, 0.96; 73.1%, 100.0%, 100.0%, 34.6%, 0.87; and 98.4%, 97.2%, 99.6%, 89.7%, 0.98, respectively. For CNB specimens, these values for pathology, molecular tests, and parallel test were 93.3%, 96.2%, 99.4%, 69.4%, 0.95; 76.4%, 100.0%, 100.0%, 40.0%, 0.88; and 99.4%, 96.2%, 99.4%,96.2%,0.98, while those same values for the tissue were 96.6%, 100.0%, 100.0%, 76.9%, 0.98; 67.1%, 100.0%, 100.0%, 25.6%, 0.84; and 96.6%, 100.0%, 100.0%, 76.9%,0.98, respectively.Conclusion: The validity of pathology and molecular testing when using CNB specimens was similar to that of tissue specimens for relevant assessment approaches. For the LNTB diagnosis, CNB specimens were preferred for the simultaneous undertaking of pathological examination and molecular testing.Keywords: pathology, molecular tests, CapitalBio assay, Xpert, lymph node tuberculosis, CNB, tissue, accuracy

Yue Ding,1,&ast; Lei Fang,2,&ast; Xiao-Ping Yang,3 Qi Zou1 1Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, People’s Republic of China; 2Department of Radiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, People’s Republic of China; 3Department of Hepatobiliary Pancreatic Surgery, First Hospital of Ningbo City, Ningbo, 315010, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qi ZouDepartment of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, People’s Republic of ChinaTel +86 18918355163Fax +86 021-68035001Email zouqi_abc@163.comXiao-Ping YangDepartment of Hepatobiliary Pancreatic Surgery, First Hospital of Ningbo City, No. 59 of Liuting Street, Haishu District, Ningbo, 315010, People’s Republic of ChinaTel +86 18757177966Fax +86 0574-87085588Email yangxp_dr@163.comBackground: RNA binding proteins (RBPs) are now under discussion as novel promising bio-markers for patients with colon cancer. The purpose of our study is to identify several RBPs related to the progression and prognosis of colon cancer and to further investigate the mechanism of their influence on tumor progression.Methods: The transcriptome data of colon cancer and clinical characteristics were downloaded from The Cancer Genome Atlas (TCGA) database. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Set Enrichment Analysis (GSEA) were performed to elucidate the gene functions and relative pathways. Cox and Lasso regression analyses were used to analyze the effect of immune genes on the prognosis of colon cancer. An immune risk scoring model was constructed based on the statistical correlation between hub immune genes and survival. Meanwhile, multivariate Cox regression analysis was utilized to investigate whether the immune gene risk score model was an independent factor for predicting the prognosis of colon cancer. A nomogram was constructed to comprehensively predict the survival rate of colon cancer. P < 0.05 was considered statistically significant.Results: The results showed that 473 RBPs exhibited differential expression between normal and colon cancer tissues (P < 0.05). Univariate Cox regression analysis revealed 25 RBPs statistically correlated with colon cancer-related survival risk (P < 0.05). In addition, a 10-RBPs based risk scoring model was constructed through multivariate Cox regression analysis. A K–M curve indicated that high-risk patients were associated with poor outcomes (P < 0.001). A ROC curve indicated that the immune risk score model was reliable in predicting survival risk (5-year overall survival (OS), area under curve (AUC) = 0.782). Our model showed satisfying AUC and survival correlation in the validation dataset (5-year OS, AUC = 0.744). Furthermore, multivariate Cox regression analysis confirmed that the immune risk score model was an independent factor for predicting the prognosis of colon cancer. Finally, we found that 10-RBPs and risk scores were significantly associated with clinical factors and prognosis and were involved in multiple oncogenic pathways.Conclusion: Collectively, RBPs play an essential role in the progression and prognosis of colon cancer by regulating multiple biological pathways. Furthermore, the RBP risk score was an independent predictive factor of colon cancer, indicating poor survival.Keywords: RNA binding proteins, RBPs, colon cancer, prognosis, risk model

Li Hu, Lei Fang, Zhiping Zhang, Zhilong Yan Department of Gastroenterology, Ningbo No.1 Hospital, Ningbo, People’s Republic of ChinaCorrespondence: Zhilong YanDepartment of Gastroenterology, Ningbo No.1 Hospital, 59 Liuting Street, Haishu District, Ningbo, 315000, Zhejiang Province, People’s Republic of ChinaEmail yanzhilong@nbu.edu.cnBackground: Colorectal cancer (CRC) is one of the leading causes of cancer-related death around the world, becoming a severe public health problem. Mounting evidence has proven that circRNAs act as pivotal modulators in the initiation and development of CRC. Although the function of circTADA2A has been explored in osteosarcoma and breast cancer, the specific role of circTADA2A in CRC remains unknown.Methods: Bioinformatics analysis based on GEO datasets was used to evaluate the dysregulated circRNAs in CRC. CCK-8 and transwell assays were used to detect the functions of CRC cells. qRT-PCR and Western blot were performed to evaluate the expression of RNAs and proteins. Luciferase assay and RNA pull down experiment were carried out to verify the interaction between miR and its targets.Results: CircTADA2A was downregulated in CRC tissues compared with normal samples. CircTADA2A exhibited greater stability than its linear form when exposed to RNase R and actinomycin D treatment. qRT-PCR analysis validated the lower expression level of circTADA2A in CRC. The loss-of-function and gain-of-function assays indicated that circTADA2A exerted the inhibitory role in CRC cell proliferation and migration. Mechanistically, circTADA2A functioned as a sponge of miR-1229. Further experiments manifested that circTADA2A regulated BCL2L10 expression via competitively binding to miR-1229. More importantly, the tumor suppressor role of circTADA2A in the malignant behaviors of CRC cells was mediated by BCL2L10.Conclusion: circTADA2A suppressed cell proliferation and migration in CRC through regulation of miR-1229/BCL2L10 axis, which suggested that circTADA2A might represent a novel potential target for the treatment of CRC.Keywords: colorectal cancer, circTADA2A, miR-1229, BCL2L10

Dong Guo,1 Liang Fang,2 Xuelai Yu,3 Congyang Wang,4 Yan Wang,4 Wenwen Guo4 1Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China; 2Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China; 3Department of Neurology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, People’s Republic of China; 4Department of Pathology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, People’s Republic of ChinaCorrespondence: Wenwen Guo; Yan WangDepartment of Pathology, The Second Affiliated Hospital of Nanjing Medical University, No. 121 Jiangjiayuan Road, Nanjing, 210011, Jiangsu, People’s Republic of ChinaTel +86-25-58509910; +86-25-58509909Email hguowen@163.com; wangyan_9999@sina.comObjective: The purpose of this study was to investigate the relationships between TP53 Pro72Arg (rs1042522) polymorphism and susceptibility to type 2 diabetes (T2DM) and its related complications.Methods: The TP53 Pro72Arg polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 206 T2DM patients and 446 healthy controls. Mitochondrial DNA (mtDNA) content, mtDNA transcriptional level and large-scale mtDNA deletion were evaluated in leukocytes of T2DM patients using fluorescence-based quantitative PCR (FQ-PCR), reverse transcriptase-quantitative PCR (RT-qPCR) and long-range PCR approaches, respectively. The data of our study were processed by GraphPad Prism software (version 7.00).Results: The distribution of TP53 Pro72Arg differed in T2DM patients from the controls, with a moderately increased proportion of TP53 Arg72 variant carriers (Pro/Arg and Arg/Arg genotypes) (88.3% vs 81.2%, p=0.022; OR=1.089, 95% CI=1.018– 1.164). T2DM patients with Arg/Arg genotype had significantly decreased prevalences of diabetic neuropathy and retinopathy compared to those without (6.5% vs 19.4%, p=0.018 and 14.8% vs 30.7%, p=0.018, respectively). T2DM patients with Arg/Arg genotype had higher mtDNA content and mtRNA expression level than those who were not Arg/Arg genotype (p< 0.05 for all), and we did not observe mtDNA 4977-base pair (bp) deletion mutations in the leukocytes of T2DM patients.Conclusion: There was a significant association of the TP53 Pro72Arg polymorphism with susceptibility to T2DM, and the homozygous Arg/Arg genotype of this gene locus might be a protective factor for diabetic complications. Those results suggested that the TP53 Arg72 variant had a different association with type 2 diabetes and its complications, and it might be related to mtDNA maintenance of the TP53 Arg72 variant under hyperglycemia-induced stress.Keywords: TP53, type 2 diabetes mellitus, complication, mtDNA content, mtRNA, mtDNA maintenance

Yang Liu, Lijun Fang,* Weixian Liu* Department of Oral Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weixian Liu; Lijun Fang Email liuweixiansj@163.com; fanglj@sj-hospital.orgObjective: Squalene epoxidase (SQLE) is considered a metabolic oncogene, but its biological function and prognostic value in head and neck squamous cell carcinoma (HNSCC) remain unclear. We aimed to evaluate the role of SQLE in the occurrence and development of HNSCC through bioinformatics analysis, and validation experiments.Methods: Transcriptomic, genomic, and clinical data from The Cancer Genome Atlas were used for pan-cancer analysis. SQLE expression in HNSCC was evaluated using Gene Expression Omnibus datasets and immunohistochemistry. The biological significance of SQLE in the tumor microenvironment (TME) of HNSCC was determined using TISCH, HuRI, LinkedOmics, and TIMER 2.0. The prognostic value of SQLE in HNSCC was analyzed using univariate Cox regression and Kaplan–Meier survival curves. Effect of SQLE on the Cal27 HNSCC cell line was evaluated using cell counting kit 8, wound healing, and EdU assays.Results: SQLE was overexpressed and amplified in various cancers, including HNSCC. High SQLE expression promoted cell proliferation, associated with T stage in HNSCC patients. Copy number amplification and DNA demethylation contributed to high SQLE expression in HNSCC, which was associated with poor prognosis. SQLE was related to HNSCC TME, and its mRNA expression/copy number alterations were negatively correlated with the infiltration of CD8+ T cells, follicular helper T cells, and regulatory T cell infiltration and mast cell activation and positively correlated with the infiltration of M0 macrophages and resting mast cells in HNSCC.Conclusion: SQLE was identified as a prognostic biomarker and a potential pharmaceutical target for HNSCC.Keywords: copy number amplification, DNA methylation, head and neck squamous cell carcinoma, immune cell infiltration, multi-omics analysis, squalene epoxidase

Cheng Wang,1 Hong Wang,2 Luming Dai,1 Jianqing Zhang,1 Lizhou Fang,1 Ling Liu,1 Weiping Fu,1 Dang Tang3 1Second Department of Respiratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of China; 2Department of Burns Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, People’s Republic of China; 3First Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of ChinaCorrespondence: Dang Tang Email tangdangdemao@126.comBackground: Chronic obstructive pulmonary disease (COPD) is often combined with type 2 diabetes mellitus (T2DM) in clinical, and with poor prognosis. In recent years, research shows that inflammation is a common characteristic of COPD and T2DM. T-helper 17 cell (Th17)/regulatory T-cell (Treg) balance controls inflammation and may be important in the pathogenesis of COPD combined with T2DM patients. This study investigated the characteristics of Th17, Treg and related inflammatory factors in COPD combined with T2DM patients and the potential mechanism.Methods: Application of flow cytometry technology, real-time fluorescent quantitative PCR and ELISA to detect the changes in peripheral blood of Th17 and Treg number and the expression of key transcription factors and related cytokines in COPD combined T2DM patients were performed.Results: Patients with COPD combined with T2DM revealed significant increase in peripheral Th17, Th17 related cytokines (IL-17A, IL-17F, IL-21, IL-23, IL-6) and transcription factor (RORγt) levels and significant decrease in Treg, Treg-related cytokines (IL-10, TGFβ 1) and transcription factor (Foxp3) as compared with patients with COPD, T2DM and healthy controls.Conclusion: Th17/Treg functional imbalance exists in patients with COPD combined with T2DM, indicating a potential role of Th17/Treg imbalance in the formation and progression of COPD combined with T2DM.Keywords: COPD combined with T2DM, Th17/Treg, cytokine, transcription factor

Yijie Liu,1,2,* Chaoyang Guo,1,* Shuting Liu,1 Shuai Zhang,3 Yun Mao,4 Lei Fang1 1School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2Institute of Rehabilitation Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 3Department of Orthopaedics, Shanghai Pudong New District Hospital of Traditional Chinese Medicine, Shanghai, 201200, People’s Republic of China; 4Department of Rehabilitation Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 201803, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei Fang Email fanglei586@126.comBackground: Sarcopenia is a syndrome characterized by the loss of skeletal muscle mass and strength. Most studies have focused on dynamic resistance exercises for preventing muscular decline and maintaining the muscle strength of older individuals. However, this training mode is impractical for older people with osteoarthritis and a limited range of motion. The static strength training mode is more suitable for older people. Therefore, a determination of the effect and mechanism of static strength training on sarcopenia is critical.Methods: In this study, we developed a training device designed to collect training data and evaluate the effects of static training on the upper limbs of rats. The expression of PGC-1α was locally blocked by injecting a siRNA at the midpoint of the biceps to determine whether PGC-1α signal transduction participates in the effects of high-intensity interval static training on muscle strength. Then, the rat’s motor capacity was measured after static strength training. Immunohistochemistry and Western blotting were applied to determine PGC-1α/FNDC5/UCP1 expression levels in the muscle and adipose tissue. The serum irisin level was also detected using an enzyme-linked immunosorbent assay (ELISA).Results: Increased levels of serum irisin and local expression of FNDC5, PGC-1α, and UCP1 were observed in the biceps brachii and surrounding fatty tissue after static strength training. Static strength training showed an advantage in reducing body weight and white fat accumulation while increasing the muscle fiber volume, which resulted in a longer training time and shorter rest time.Conclusion: Overall, these results indicated that high-intensity interval static training prevents skeletal muscle atrophy and improves the motor function of aged rats through the PGC-1α/FNDC5/UCP1 signaling pathway.Keywords: sarcopenia, static strength training, muscle function, PGC-1α, FNDC5

Shunjie Bai,1 Liang Fang,2,3 Jing Xie,4 Huili Bai,1 Wei Wang,5 Jian-jun Chen6 1Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Chongqing Key Laboratory of Cerebral Vascular Disease Research, Yongchuan Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Endocrinology and Nephrology, The Fourth People’s Hospital of Chongqing, Chongqing, People’s Republic of China; 5Department of Neurology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 6Institute of Life Sciences, Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Jian-jun Chen, Email chenjianjun@cqmu.edu.cnBackground: Major depressive disorder (MDD) and suicide are two major health problems, but there are still no objective methods to diagnose MDD or suicidal ideation (SI). This study was conducted to identify potential biomarkers for diagnosing MDD patients with SI.Methods: First-episode drug-naïve MDD patients with SI and demographics-matched healthy controls (HCs) were recruited. First-episode drug-naïve MDD patients without SI were also included. The serum lipids, C-reactive protein (CRP), transferring (TRSF), homocysteine (HCY) and alpha 1-antitrypsin (AAT) in serum were detected. The univariate and multivariate statistical analyses were used to identify and validate the potential biomarkers.Results: The 86 HCs, 53 MDD patients with SI and 20 MDD patients without SI were included in this study. Four potential biomarkers were identified: AAT, TRSF, high-density lipoprotein cholesterol (HDLC), and apolipoprotein A1 (APOA1). After one month treatment, the levels of AAT and APOA1 were significantly improved. The panel consisting of these potential biomarkers had an excellent diagnostic performance, yielding an area under the ROC curve (AUC) of 0.994 and 0.990 in the training and testing set, respectively. Moreover, this panel could effectively distinguish MDD patients with SI from MDD patients without SI (AUC=0.928).Conclusion: These results showed that these potential biomarkers could facilitate the development of an objective method for diagnosing MDD patients with SI, and the decreased AAT levels in MDD patients might lead to the appearance of SI by resulting in the elevated inflammation.Keywords: major depressive disorder, suicidal ideation, biomarkers

Chenmeiyi Wang,1,2,* Yiting Wang,1,2,* Xiulin Chang,1,2 Xiaoyun Ba,1,2 Na Hu,1,2 Qing Liu,1,2 Liaoqiong Fang,1,2 Zhibiao Wang1,2 1State Key Laboratory of Ultrasound Engineering in Medicine, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, People’s Republic of China; 2National Engineering Research Center of Ultrasound Medicine, Chongqing 401121, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhibiao Wang; Liaoqiong Fang Tel/Fax +0086-023-68485021Email wangzb@cqmu.edu.cn; lqfang06@163.comBackground: Tumor-derived exosomes are messengers that participate in tumor progression. Fibroblasts are associated with the metastasis of cancer depending on their cellular plasticity. We hypothesize that tumor-derived exosomes endow the fibroblasts in tumor microenvironment with invasive phenotype to the benefit of tumor metastasis.Materials and Methods: Exosomes derived from B16-F10 cells were identified by nanoparticle tracking analyzer (NTA), dynamic light scattering (DLS), Western blot (WB), and transmission electron microscopy (TEM). Cell invasion and migration assays were performed using the xCELLigence real-time cell analyzer (RTCA). Role of tumor-derived exosomal miR-21 in cell invasion was determined by qPCR.Results: The invasion analysis showed that exosome-treated fibroblast cells had greater invasive capability as compared to untreated fibroblast cells, with the higher expressions of MMP2 and MMP9. miR-21 is at least partially responsible for this effect. After ingestion of melanoma-derived exosomes during incubation, mouse embryonic fibroblasts cells emerged cellular invasiveness with the presentation of a marked increase in miR-21 expression. MiR-21 promoted invasion of fibroblasts by down-regulation of tissue inhibitor of metalloproteinase 3 (TIMP3) expression and increasing of matrix metalloprotein (MMP) expression in fibroblast cells via melanoma-derived exosomes in a time-dependent manner.Conclusion: Our results suggest that tumor-derived exosomes may facilitate stromal fibroblasts an aggressive phenotype to equip the tumor progression.Keywords: melanoma, exosomes, miR-21

Huan Cai,1,* Jialin Liang,2,* Zhonghua Liu,1 Liang Fang,1 Jinghong Zheng,3 Jiahe Xu,3 Liyi Chen,1 Wen Sun,4 Hao Zhang5 1Department of Rehabilitation, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong, People’s Republic of China; 2Department of Endocrinology and Metabolism, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong, People’s Republic of China; 3Department of Neurology, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong, People’s Republic of China; 4Division of Life Sciences and Medicine, Stroke Center and Department of Neurology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230026, Anhui, People’s Republic of China; 5Department of Neurology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hao ZhangDepartment of Neurology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, People’s Republic of ChinaTel +86-13450989238Fax +86 760-87727692Email zh_hao_neurol@163.comZhonghua LiuDepartment of Rehabilitation, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong, People’s Republic of ChinaTel 86-13923308898Email zhonghua_reha@163.comBackground: Unfavorable sleep habits have been linked with ischemic stroke in observational studies, but the causality remains unclear. The aim of this study is to investigate the potential causal role of three sleep traits, including sleep duration, insomnia, and chronotype, in ischemic stroke and its subtypes.Methods: We conducted two-sample Mendelian randomization (MR) analysis using single nucleotide polymorphisms associated with sleep duration, insomnia, and chronotype as instruments to estimate causal associations with ischemic stroke and its subtypes, among 34,217 ischemic stroke cases and 406,111 controls from the MEGASTROKE consortium. Inverse-variance weighted method was used as the main analyses. Alternative MR methods and sensitivity analyses were further performed.Results: We found suggestive evidence that per doubling of genetic liability for short sleep duration (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.01– 1.58) and frequent insomnia symptoms (OR, 1.19; 95% CI, 1.00– 1.41) were associated with a modest increase in risk of large artery stroke (LAS) but not with small vessel stroke, cardioembolic stroke, or any ischemic stroke. The association of frequent insomnia symptoms with LAS was stronger after the exclusion of the outlier (OR, 1.25; 95% CI, 1.04– 1.50). No significant association was observed for chronotype with any ischemic stroke subtype. Results were overall robust to sensitivity analyses, and there was little evidence of horizontal pleiotropy.Conclusion: We provided suggestive evidence for a potential causal role of short sleep duration and insomnia symptoms in LAS. Future researches are required to investigate whether improved sleep habits could help to mitigate LAS risk.Keywords: sleep, large artery stroke, ischemic stroke, Mendelian randomization

Chun Gao,1 Long Fang,1 Hui Zhang,2 Wei-Shuo Zhang,1 Xiao-Ou Li,1 Shi-Yu Du1 1Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, People’s Republic of China; 2Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, People’s Republic of ChinaCorrespondence: Shi-Yu DuDepartment of Gastroenterology, China-Japan Friendship Hospital, Ministry of Health, No. 2 Yinghua East Road, Beijing 100029, People’s Republic of ChinaTel/ Fax +86-10-84205503Email dushiyu@zryhyy.com.cnBackground: Metformin may exert the anticancer effect on multiple types of cancers and some potential mechanisms have been suggested. Our study was designed to determine the effect of metformin on the cell autophagy and autophagic flux via the AMPK-mTOR signaling pathway in human hepatocellular carcinoma (HCC) cells.Methods: MHCC97H and HepG2 cell lines were cultured and treated without and with metformin at various concentrations (2, 5, 10 and 20 mM) for 48 h. Then, 10 mM was determined as the optimal concentration and the HCC cells were treated with metformin for 12, 24, 48, and 72 h. MTT assay was used to assess the cell viability and Western blotting was used to determine the expression of proteins (LC3-II, p62, phospho-AMPKα, phospho-mTOR, mTOR, phospho-p70 S6 Kinase, p70 S6 Kinase, PARP1, Caspase-9 and Caspase-3). Autophagy inhibitor 3-methyladenine, EGFP-LC3 and mCherry-GFP-LC3B plasmid transfection were used for further study.Results: Metformin inhibited significantly the viability of MHCC97H and HepG2 cells in a dose- and time-dependent manner. For the apoptotic properties, activation of Caspase-9 and Caspase-3 and PARP cleavage were not observed after treatment with metformin. MHCC97H cells were transfected with a EGFP-LC3 plasmid and treatment with metformin could lead to the increased level of LC3-II and decreased level of p62. In metformin-induced autophagy, AMPK expression was activated, and the phosphorylation levels of mTOR and p70 S6 Kinase were inhibited. Metformin treatment and mCherry-GFP-LC3B plasmid transfection showed that metformin could induce the autophagic flux. 3-Methyladenine (3-MA) partly abolished this effect.Conclusion: Metformin could induce the autophagy, autophagic flux, and activate the AMPK-mTOR signaling pathway in human HCC cells.Keywords: metformin, hepatocellular carcinoma, autophagy, autophagic flux, AMPK-mTOR signaling pathway

Wei-Shuo Zhang,1 Xiao-Ou Li,1 Hui Zhang,2 Chun Gao,1 Long Fang,1 Hua-Yuan Yang1 1Department of Gastroenterology, China-Japan Friendship Hospital, Ministry of Health, Beijing 100029, People’s Republic of China; 2Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, People’s Republic of ChinaCorrespondence: Chun GaoDepartment of Gastroenterology, China-Japan Friendship Hospital, Ministry of Health, Beijing 100029, People’s Republic of ChinaTel/Fax +86-10-84205503Email gaochun@bjmu.edu.cnBackground: More than 50% of patients with type 2 diabetes mellitus (DM) also have hypertension. Moreover, hypertension has been regarded as one paraneoplastic phenomenon of hepatocellular carcinoma (HCC). Our study was designed to determine the relationship between blood pressure and DM in HCC patients.Patients and Methods: A total of 879 HCC patients were included and 151 (17.2%) were diagnosed with DM. Multivariable logistic regression analysis was used to determine the relationship and the results were expressed as adjusted odds ratios (AORs) and their 95% confidence intervals (CIs). Considering the effect of potential confounders, sub-group analysis was performed. We would further study the association of systolic blood pressure (SBP) with fasting glucose, and the association between DM duration/treatment and SBP level.Results: Compared with non-diabetic patients, the diabetic patients had increased levels of SBP (133.7± 18.5 mmHg vs 128.3± 15.2 mmHg, P=0.001) and fasting blood glucose (9.13± 3.04 mmol/L vs 5.18± 1.08 mmol/L, P< 0.001), an elder age (58.5± 10.2 years vs 55.3± 11.2 years, P=0.001), a higher percentage of cirrhosis diagnosis (60.9% vs 48.2%, P=0.004), lower percentages of drinking (18.5% vs 30.8%, P=0.002) and smoking (30.5% vs 43.7%, P=0.003), and decreased levels of GGT (median/interquartile-range 88/53-177 U/L vs 117/58-248 U/L, P=0.037), platelet count (121.4± 76.6 × 109/L vs 151.2± 82.8 × 109/L, P< 0.001) and hemoglobin (124.3± 25.5 g/L vs 133.6± 24.2 g/L, P< 0.001). Multivariable analysis showed that, statistically significant differences were found for SBP ≥ 140 mmHg (AOR=2.101; 95% CI, 1.424– 3.100; P< 0.001), smoking (AOR=0.637; 95% CI, 0.415– 0.979; P=0.040), hemoglobin (AOR=0.990; 95% CI, 0.983– 0.998; P=0.010) and platelet count (AOR=0.996; 95% CI, 0.994– 0.999; P=0.009). For the relationship between SBP and DM, the positive result was supported by most (10/14) of the subgroup analyses.Conclusion: SBP level was increased in HCC patients with diabetes mellitus.Keywords: hepatocellular carcinoma, diabetes mellitus, systolic blood pressure

Jing Xie,1,* Chang Chen,2,* Li-juan Hou,3 Chan-juan Zhou,4 Liang Fang,5,6 Jian-jun Chen2 1Chongqing Emergency Medical Center, Department of Endocrinology and Nephrology, The Fourth People’s Hospital of Chongqing, Central Hospital of Chongqing University , Chongqing, 400014, People’s Republic of China; 2Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, People’s Republic of China; 3Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihu 453100, Henan, People’s Republic of China; 4NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, Chongqing Medical University, Chongqing 400016, People’s Republic of China; 5Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, People’s Republic of China; 6Chongqing Key Laboratory of Cerebral Vascular Disease Research, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian-jun ChenInstitute of Life Sciences, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People’s Republic of ChinaEmail chenjianjun@cqmu.edu.cnLiang FangDepartment of Neurology, Yongchuan Hospital of Chongqing Medical University, 439 Xuanhua Road, Yongchuan District, Chongqing 402160, People’s Republic of ChinaTel/Fax +86-23-63664754Email fangliang@hospital.cqmu.edu.cnObjective: Depression could make the treatment outcome worse. However, up to now, no objective methods were developed to diagnose depression in hepatitis B virus (HBV)-infected patients. Therefore, the dual metabolomic platforms were used here to identify potential biomarkers for diagnosing HBV-infected patients with depression (dHB).Methods: Both gas chromatography-mass spectrometry-based and nuclear magnetic resonance-based metabolomic platforms were used to conduct urine metabolic profiling of dHB subjects and HBV-infected patients without depression (HB). Orthogonal partial least-squares discriminant analysis was used to identify the differential metabolites between dHB subjects and HB subjects, and the step-wise logistic regression analysis was used to identify potential biomarkers.Results: In total, 21 important metabolites responsible for distinguishing dHB subjects from HB subjects were identified. Meanwhile, seven potential biomarkers (α-ydroxyisobutyric acid, hippuric acid, azelaic acid, isobutyric acid, malonic acid, levulinic acid, and phenylacetylglycine) were viewed as potential biomarkers. The simplified biomarker panel consisting of these seven metabolites had an excellent diagnostic performance in discriminating dHB subjects from HB subjects. Moreover, this panel could yield a higher accuracy in separating dHB subjects from HB subjects than our previous panels (identified by single metabolomic platform) did.Conclusion: These results suggested that the dual metabolomic platforms could yield a better urinary biomarker panel for dHB subjects than any single metabolomic platform did, and our results could be helpful for developing an objective method in future to diagnose depression in HBV-infected patients.Keywords: hepatitis B virus, depression, metabolomics, biomarker

Ning Wang,1,2 Shu Cong,1 Jing Fan,1 Heling Bao,1 Baohua Wang,1 Ting Yang,3 Yajing Feng,1 Yang Liu,4 Linhong Wang,1 Chen Wang,3,5 Wenbiao Hu,2 Liwen Fang1 1National Center for Chronic Non-Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 100050, People’s Republic of China; 2School of Public Health and Social Work, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia; 3Center of Respiratory Medicine, China–Japan Friendship Hospital, Beijing, People’s Republic of China; 4Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA; 5Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Liwen FangNational Center for Chronic Non-Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 27 Nanwei Road, Xicheng District, Beijing 100050, People’s Republic of ChinaTel +86 135 5239 3376Fax +86 010 6304 2350Email fangliwen@ncncd.chinacdc.cnWenbiao HuSchool of Public Health and Social Work, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4059, AustraliaTel/Fax +61 7 3138 5724Email w2.hu@qut.edu.auPurpose: COPD prevalence has rapidly increased in China, but the geographical disparities in COPD prevalence remain largely unknown. This study aimed to assess city-level disparities in COPD prevalence and identify the relative importance of COPD related risk factors in mainland China.Patients and Methods: A nationwide cross-sectional study of COPD recruited 66,752 adults across the mainland China between 2014 and 2015. Patients with COPD were ascertained by a post-bronchodilator pulmonary function test. We estimated the city-specific prevalence of COPD by spatial kriging interpolation method. We detected spatial clusters with a significantly higher prevalence of COPD by spatial scan statistics. We determined the relative importance of COPD associated risk factors by a nonparametric and nonlinear classification and regression tree (CART) model.Results: The three spatial clusters with the highest prevalence of COPD were located in parts of Sichuan, Gansu, and Shaanxi, etc. (relative risks (RRs)) ranging from 1.55 (95% CI 1.55– 1.56) to 1.33 (95% CI 1.33– 1.33)). CART showed that advanced age (≥ 60 years) was the most important factor associated with COPD in the overall population, followed by smoking. We estimated that there were about 28.5 million potentially avoidable cases of COPD among people aged 40 or older if they never smoked. PM2.5 was an important associated risk factor for COPD in the north, northeast, and southwest of China. After adjusting for age and smoking, the spatial cluster with the highest prevalence shifted to most of Sichuan, Gansu, Qinghai, and Ningxia, etc. (RR 1.65 (95% CI 1.63– 1.67)).Conclusion: The spatial clusters of COPD at the city level and regionally varied important risk factors for COPD would help develop tailored interventions for COPD in China. After adjusting for the main risk factors, the spatial clusters of COPD shifted, indicating that there would be other potential risk factors for the remaining clusters which call for further studies.Keywords: COPD, spatial clusters, kriging, classification and regression tree

Chun Gao, 1 Shi-Yu Du, 1 Long Fang, 1 Yan-Hua Fan, 1 Ai-Ping Song, 2 Huang Chen 2 1Department of Gastroenterology, China-Japan Friendship Hospital, Ministry of Health, Beijing 100029, People’s Republic of China; 2Department of Pathology, China-Japan Friendship Hospital, Ministry of Health, Beijing 100029, People’s Republic of ChinaCorrespondence: Yan-Hua FanDepartment of Gastroenterology, China-Japan Friendship Hospital, Ministry of Health, No. 2 Yinghua East Road, Beijing 100029, People’s Republic of ChinaTel/Fax +86-10-84205503Email fanyanhua@zryhyy.com.cnBackground: Unfortunately, the eradication rate of Helicobacter pylori (H. pylori) treatment is markedly decreasing in recent years and the major reason is antibiotic resistance. Our study was designed to determine the effect and safety of H. pylori eradication treatment based on the molecular pathologic antibiotic resistance.Methods: 261 patients were analyzed retrospectively, including 111 patients who were treated for the first time (one group as First-treated) and 150 patients who failed at least once in bismuth quadruple therapy (another group as Re-treatment). Antibiotic resistance was examined by Real-time PCR detection and conventional PCR and sequencing method. The eradication rate (ER) was compared per intention to treat (ITT) and per protocol (PP) between the two groups.Results: The resistance rates to amoxicillin, clarithromycin, fluoroquinolone and tetracycline were 5.5%, 42.1%, 41.7% and 12.9% in the 111 first-treated patients, and 11.7%, 79.7%, 70.7% and 30.0% in the 150 re-treatment patients. The ERs in the ITT and PP analyses were 92.79% (95% CI, 87.98– 97.60%, n=111) and 98.10% (95% CI, 95.48– 100%, n=105), respectively, in the first-treated patients and 90.67% (95% CI, 86.01– 95.32%, n=150) and 95.10% (95% CI, 91.57– 98.64%, n=143), respectively, in the re-treatment patients. No significant differences were shown in the ERs between two group patients, and no serious adverse events were found.Conclusion: H. pylori eradication treatment based on molecular pathologic antibiotic resistance showed good effect and safety in both first and re-treated patients.Keywords: Helicobacter pylori, antibiotic resistance, eradication, first treatment, re-treatment, molecular pathology

Qian Wang,1–4 Dongmei Zheng,1–3 Jia Liu,1–3 Li Fang,1–3 Qiu Li1–31Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China; 2Shandong Clinical Medical Center of Endocrinology and Metabolism, Jinan, Shandong, People’s Republic of China; 3Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, People’s Republic of China; 4Department of Ultrasound, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of ChinaBackground: Skeletal muscle mass to visceral fat area ratio (SVR) were shown to be related to some chronic diseases, such as non-alcoholic fatty liver diseases. The aim of this study is to determine whether the SVR is associated with metabolic syndrome (MS) and type 2 diabetes (T2DM).Methods: A total of 798 subjects were included in this cross-sectional study. Lipid profiles, plasma glucose, blood pressure, waist circumference (WC) and body mass index (BMI) were grouped by the SVR. The associations between the SVR and T2DM and MS were examined using logistic regression to determine whether the SVR was associated with T2DM and MS.Results: Lipid profiles, glucose levels, blood pressure, WC and BMI showed significant differences when stratified based on the extent of SVR. The SVR levels were also significantly higher in subjects without MS or T2DM than in those with MS or T2DM. The SVR was inversely correlated with lipid profiles and WC and was especially correlated with BMI, with an r>0.5. The SVR was identified as a risk factor for T2DM and MS after adjusting age and sex. SVR can predict T2DM [area under the curve =0.726, 95% CI (0.669–0.782), p

Zicheng Hu,1–3 Songhua Fan,1–3 Meiling Liu,1–3 Jiaju Zhong,1–3 Du Cao,1–3 Peng Zheng,1–3 Ying Wang,1–3 Youdong Wei,1–3 Liang Fang,1–3 Peng Xie1–31Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, People’s Republic of China; 3Chongqing Key Laboratory of Neurobiology, Chongqing, People’s Republic of ChinaBackground: Post-stroke depression (PSD) is a frequent and serious complication of stroke. However, the underlying molecular basis of PSD remains largely unknown, and no empirical laboratory tests were available to diagnose this disorder.Materials and methods: A proton nuclear magnetic resonance (1H NMR)-based metabonomic approach was employed to profile plasma samples from 32 PSD, 35 stroke patients and 35 healthy comparison subjects (the training set) in order to identify metabolite biomarkers for PSD. Then, 10 PSD, 11 stroke patients and 11 healthy comparison subjects (test set) were used to validate the diagnostic performance of these biomarkers.Results: The multivariate statistical analysis demonstrated that PSD group was significantly distinguishable from non-PSD groups (non-depression stroke patients and healthy comparison group). Five plasma metabolites (phenylalanine, tyrosine, 1-methylhistidine, 3-methylhistidine and LDL CH3-(CH2)n-) were identified responsible for distinguishing PSD from non-PSD subjects. These metabolites were mainly involved in neurotransmitter metabolism and oxidative stress. The biomarker panel composing of these metabolites was capable of distinguishing test samples with a sensitivity of 100.0% and a specificity of 95.5%.Conclusion: Our findings suggest that plasma disturbances of neurotransmitter levels and oxidative stress were implicated in the onset of PSD; these disturbed metabolites biomarkers facilitate to the development of diagnostic tool for PSD.Keywords: post-stroke depression, stroke, metabonomics, diagnosis, NMR

Qiang Zhou, Yi-chuan Shao, Zheng-qi Gan, Li-shu Fang Department of Endocrinology, First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang Province, China Background: Depression is commonly observed among patients with gout. Low levels of vitamin D have been associated with depression in non-gout subjects. We examined the association of vitamin D levels with depression in patients with gout. Methods: We conducted a cross-sectional study of 186 gout patients at the Endocrinology Department of First Affiliated Hospital of Jiaxing University. Levels of serum 25-hydroxyvitamin D (25(OH)D) were determined using a competitive protein-binding assay. The 17-item Hamilton Depression Scale was used for screening for depressive symptoms. Diagnosis of depression in gout patients was made in accordance with Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria for depression. Multivariate analysis was performed using logistic regression models. Results: Thirty-two gout patients (17.2%) were diagnosed as having depression. Patients with depression showed significantly lower 25(OH)D levels as compared to patients without depression (46.4±19.0 vs 57.0±17.3 nmol/L, P

Meng Lan, Jia Zipu, Shen Ying, Ren Hao, Luo Fang Department of Anesthesiology and Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China Background: There is a lack of prospective studies for the long-term results of percutaneous pulsed radiofrequency (PRF) of the Gasserian ganglion in the treatment of patients with medically refractory trigeminal neuralgia (TN).Methods and results: We prospectively observed the outcomes of 28 idiopathic TN patients (between July 2013 and July 2016) who received CT-guided percutaneous PRF treatment of the Gasserian ganglion. All of the patients had stopped responding to drug therapy before PRF treatment. The effective treatment standard was a reduction in the pain numeric rating scale (NRS) by ≥50% after the procedure. The postoperative NRS score decreased gradually from preoperative 7.6±0.8 months to 1.5±2.4, 0.2±0.4, 0.2±0.4, 0.1±0.4, and 0.1±0.4 at 1, 3, and 6 months and 1 and 2 years after the PRF treatment. The response rates at 1, 3, and 6 months were 85.7%, and the rates at 12 months and 2 years were maintained at 78.6%. No serious side effects were observed.Conclusion: CT-guided PRF invention is an effective and safe technique for medically intractable idiopathic TN patients. This minimally invasive alternative treatment has the potential as a first-line therapy for TN. Keywords: trigeminal neuralgia, pulsed radiofrequency, efficacy, safety

Jinjin Wang,1,2,* Fanhui Meng,3,* Wen Song,3,* Jingyi Jin,2 Qianli Ma,2 Dongdong Fei,1 Liang Fang,2 Lihua Chen,2 Qintao Wang,1 Yumei Zhang3 1State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shannxi Province, China; 2Department of Immunology, School of Basic Medicine, The Fourth Military Medical University, Xi’an, Shannxi Province, China; 3State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shannxi Province, China *These authors contributed equally to this work Introduction: Fabricating nanostructured surface topography represents the mainstream approach to induce osteogenesis for the next-generation bone implant. In the past, the bone implant was designed to minimize host repulsive reactions in order to acquire biocompatibility. However, increasing reports indicate that the absence of an appropriate immune response cannot acquire adequate osseointegration after implantation in vivo. Materials and methods: We prepared different topographies on the surface of titanium (Ti) specimens by grinding, etching and anodizing, and they were marked as polished specimen (P), specimen with nanotubes (NTs) in small diameters (NT-30) and specimen with NTs in large diameters (NT-100). We evaluated the ability of different topographies of the specimen to induce osteogenic differentiation of mice bone marrow mesenchymal stem cells (BMSCs) in vitro and to induce osseointegration in vivo. Furthermore, we investigated the effect of different topographies on the polarization and secretion of macrophages, and the effect of macrophage polarization on topography-induced osteogenic differentiation of mice BMSCs. Finally, we verified the effect of macrophage polarization on topography-induced osseointegration in vivo by using Cre*RBP-Jfl/fl mice in which classically activated macrophage was restrained. Results: The osteogenic differentiation of mice BMSCs induced by specimen with different topographies was NT-100>NT-30>P, while the osseointegration induced by specimen with different topographies in vivo was NT-30>NT-100>P. In addition, specimen of NT-30 could induce more macrophages to M2 polarization, while specimen of P and NT-100 could induce more macrophages to M1 polarization. When co-culture mice BMSCs and macrophages on specimen with different topographies , the osteogenic differentiation of mice BMSCs was NT-30>NT-100≥P. The osseointegration induced by NT-100 in Cre*RBP-Jfl/fl mice was much better than that of wild type mice. Conclusion: It is suggested that the intrinsic immunomodulatory effects of nanomaterials are not only crucial to evaluate the in vivo biocompatibility but also required to determine the final osseointegration. To clarify the immune response and osseointegration may be beneficial for the designation and optimization of the bone implant. Keywords: nanomaterials, topography, immunomodulatory effects, macrophage polarization, osseointegration

Tingting Xu,1,2,* Xiaoyue Xu,1,* Yan Gu,1 Lei Fang,3 Feng Cao1 1School of Pharmacy, China Pharmaceutical University, 2Nanjing Chia Tai Tian Qing Pharmaceutical Co., Ltd, 3Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing, China *These authors contributed equally to this work Background: To enhance ocular bioavailability, the traditional strategies have focused on prolonging precorneal retention and improving corneal permeability by nano-carriers with positive charge, thiolated polymer, absorption enhancer and so on. Glycylsarcosine (GS) as an active target ligand of the peptide tranpsporter-1 (PepT-1), could specific interact with the PepT-1 on the cornea and guide the nanoparticles to the treating site.Purpose: The objective of the study was to explore the active targeting intercalated nanocomposites based on chitosan-glutathione-glycylsarcosine (CG-GS) and layered double hydroxides (LDH) as novel carriers for the treatment of mid-posterior diseases.Materials and methods: CG-GS-LDH intercalated nanocomposites were prepared by the coprecipitation hydrothermal method. In vivo precorneal retention study, ex vivo fluorescence images, in vivo experiment for distribution and irritation were studied in rabbits. The cytotoxicity and cellular uptake were studied in human corneal epithelial primary cells (HCEpiC).Results: CG-GS-LDH nanocomposites were prepared successfully and characterized by FTIR and XRD. Experiments with rabbits showed longer precorneal retention and higher distribution of fluorescence probe/model drug. In vitro cytological study, CG-GS-LDH nanocomposites exhibited enhanced cellular uptake compared to pure drug solution. Furthermore, the investigation of cellular uptake mechanisms demonstrated that both the active transport by PepT-1 and clathrin-mediated endocytosis were involved in the internalization of CG-GS-LDH intercalated nanocomposites. An ocular irritation study and a cytotoxicity test indicated that these nanocomposites produced no significant irritant effects.Conclusions: The active targeting intercalated nanocomposites could have great potential for topical ocular drug delivery due to the capacity for prolonging the retention on the ocular surface, enhancing the drug permeability through the cornea, and efficiently delivering the drug to the targeted site. Keywords: active targeting, intercalated nanocomposites, peptide transporter-1, layered double hydroxides, glycylsarcosine

Haishen Kong,1,2 Lingmei Fang,3 Rujin Jiang,4 Jixiang Tong2 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; 2Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; 3Clinical Laboratory, Chunan First People’s Hospital, Zhejiang Province People’s Hospital Chunan Branch, Hangzhou, China; 4Clinical Laboratory, Yuhang Hospital of Traditional Chinese Medicine, Hangzhou, China Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen. Various virulence and antiseptic-resistant factors increase the pathogenicity of MRSA strains and allow for increased infection rates.Purpose: The purpose of this study was to investigate the prevalence and distribution of virulence-associated and antiseptic-resistant genes from epidemic MRSA strains isolated from East China.Methods: A newly designed multiplex PCR assay was used to assess whether the virulence-associated genes sasX and pvl and the chlorhexidine tolerance gene qacA/B were present in 189 clinical isolates of MRSA. Multilocus sequence typing (MLST) and Staphylococcal protein A (spa) typing of these isolates were also performed. The frequency of these genes in isolates with epidemic sequence types (STs) was investigated. Results: Twenty STs and 36 spa types with five epidemic clones (ST5-t311, ST59-t437, ST5-t002, ST239-t030, and ST239-t037) were identified. The prevalence of sasX, pvl, and qacA/B in all isolates was 5.8%, 10.1%, and 20.1%, respectively. The prevalences of these genes in isolates with ST5, ST59, ST239, and other ST genetic backgrounds were all significantly different (P

Abstract Introduction Type 2 diabetes (T2D) is characterized by worsening pancreatic β‐cell function often requiring treatment escalation with oral antidiabetic drugs (OADs), glucagon‐like peptide‐1 and eventually insulin. Although there is much evidence available on the initiation of basal insulins, fewer studies have investigated the effects of switching from one basal insulin to another. This study aims to evaluate treatment persistence and hypoglycaemia in adult patients with T2D on prior basal insulin who were switched to insulin glargine 300 units/mL (Gla‐300) or other basal insulins in a real‐world setting. Materials and methods This study is a retrospective cohort analysis of patient‐level data extracted from the Optum® Clinformatics™ database between 1 October 2014 and 30 June 2016. Adult patients (≥18 years) with T2D who were being treated with basal insulin during the 6‐month baseline period, who switched to either Gla‐300 or other basal insulins, were followed up for ≥3 months after switching. Outcomes included treatment persistence, and incidence and number of hypoglycaemic events. Results Of the included patients, 1204 switched to Gla‐300 and 616 switched to other basal insulins. Adjusting for baseline confounders, patients who switched to Gla‐300 were 34% less likely to discontinue their basal insulin than patients who switched to other basal insulins (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.54‐0.81; P

Lianghua Fang,1,3 Baoan Chen,2 Shenlin Liu,3 Ruiping Wang,3 Shouyou Hu,3 Guohua Xia,2 Yongli Tian,3 Xiaohui Cai21No 1 Clinical Medical College of Nanjing University of Chinese Medicine, 2Department of Hematology, Zhongda Hospital, Medical School, Southeast University, 3Department of Oncology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, People's Republic of ChinaBackground: The present study evaluated whether magnetic nanoparticles containing Fe3O4 could enhance the activity of gambogic acid in human colon cancer cells, and explored the potential mechanisms involved.Methods: Cytotoxicity was evaluated by MTT assay. The percentage of cells undergoing apoptosis was analyzed by flow cytometry, and cell morphology was observed under both an optical microscope and a fluorescence microscope. Reverse transcriptase polymerase chain reaction and Western blot assay were performed to determine the transcription of genes and expression of proteins, respectively.Results: Gambogic acid could inhibit proliferation of LOVO cells in a dose-dependent and time-dependent manner and induce apoptosis, which was dramatically enhanced by magnetic nanoparticles containing Fe3O4. The typical morphological features of apoptosis in LOVO cells were observed after treatment comprising gambogic acid with and without magnetic nanoparticles containing Fe3O4. Transcription of cytochrome c, caspase 9, and caspase 3 genes was higher in the group treated with magnetic nanoparticles containing Fe3O4 and gambogic acid than in the groups that received gambogic acid or magnetic nanoparticles containing Fe3O4, but transcription of phosphatidylinositol 3-kinase, Akt, and Bad genes decreased. Notably, expression of cytochrome c, caspase 9, and caspase 3 proteins in the group treated with gambogic acid and magnetic nanoparticles containing Fe3O4 was higher than in the groups receiving magnetic nanoparticles containing Fe3O4 or gambogic acid, while expression of p-PI3K, p-Akt, p-Bad, pro-caspase 9, and pro-caspase 3 degraded.Conclusion: Magnetic nanoparticles containing Fe3O4 can enhance apoptosis induced by gambogic acid which may be closely related to regulation of the PI3K/Akt/Bad pathway in the treatment of human colon cancer.Keywords: Fe3O4, magnetic nanoparticles, gambogic acid, LOVO cells, apoptosis, PI3K, Akt, Bad, pathway

Ni Zeng,1,3,* Xiaoling Gao,2,* Quanyin Hu,1 Qingxiang Song,2 Huimin Xia,1 Zhongyang Liu,1 Guangzhi Gu,1 Mengyin Jiang,1,4 Zhiqing Pang,1 Hongzhuan Chen,2 Jun Chen,1 Liang Fang3 1Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai, 2Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, 3Department of Pharmaceutical Science, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 4School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong People's Republic of China, *These authors contributed equally to this workBackground: Lipid-based liquid crystalline nanoparticles (LCNPs) have attracted growing interest as novel drug-delivery systems for improving the bioavailability of both hydrophilic and hydrophobic drugs. However, their cellular interaction and in vivo behavior have not been fully developed and characterized.Methods: In this study, self-assembled LCNPs prepared from soy phosphatidylcholine and glycerol dioleate were developed as a platform for oral delivery of paclitaxel. The particle size of empty LCNPs and paclitaxel-loaded LCNPs was around 80 nm. The phase behavior of the liquid crystalline matrix was characterized using crossed polarized light microscopy and small-angle X-ray scattering, and showed both reversed cubic and hexagonal phase in the liquid crystalline matrix. Transmission electron microscopy and cryofield emission scanning electron microscopy analysis revealed an inner winding water channel in LCNPs and a "ball-like"/"hexagonal" morphology.Results: Cellular uptake of LCNPs in Caco-2 cells was found to be concentration-dependent and time-dependent, with involvement of both clathrin and caveolae/lipid raft-mediated endocytosis. Under confocal laser scanning microscopy, soy phosphatidylcholine was observed to segregate from the internalized LCNPs and to fuse with the cell membrane. An in vivo pharmacokinetic study showed that the oral bioavailability of paclitaxel-loaded LCNPs (13.16%) was 2.1 times that of Taxol® (the commercial formulation of paclitaxel, 6.39%).Conclusion: The findings of this study suggest that this LCNP delivery system may be a promising candidate for improving the oral bioavailability of poorly water-soluble agents.Keywords: soy phosphatidylcholine, glycerol dioleate, liquid crystalline nanoparticles, paclitaxel, cellular interaction

The exchange coupling between a hard magnetic layer MnBi and a soft magnetic layer Co-Fe has been found to significantly improve the maximum energy product. In this work, the spin structure of exchange-coupled MnBi:Co-Fe bilayers is experimentally investigated by X-ray magnetic circular dichroism (XMCD) and polarized neutron reflectometry (PNR). We find that the out-of-plane magnetization reversal process of the MnBi:Co-Fe bilayer structure involves formation of a curling-type twisting of the magnetization in the film plane at low or intermediate reversal fields. Micromagnetic simulations are further performed to provide a detailed view of the spins at the curling center. Reminiscent of chiral spin structures known as spin bobbers, this curling in the exchange-coupled hard-soft magnetic bilayers is a new type of skyrmionic spin structure and worth further investigation.