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Chuang Cai,1,&ast; Wentan Zeng,2,&ast; Hongwei Wang,3 Shuqi Ren2 1Cancer Research Institute of Zhongshan City, Zhongshan City People’s Hospital, Zhongshan City, Guangdong Province, People’s Republic of China; 2Department of Laboratory Medicine, Tanzhou People’s Hospital of Zhongshan, Zhongshan City Hospital of Integration of TCM & Western Medicine, Zhongshan City, Guangdong Province, People’s Republic of China; 3Department of Pediatrics, Tanzhou People’s Hospital of Zhongshan, Zhongshan City hospital of integration of TCM & western medicine, Zhongshan City, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuqi Ren, Department of Laboratory Medicine, Tanzhou People’s Hospital of Zhongshan, Zhongshan City hospital of integration of TCM & western medicine, No. 10 Dexiu road, Zhongshan City, Guangdong Province, People’s Republic of China, Tel +8615521067602, Fax +860760-23639928, Email shuchijen@163.com Chuang Cai, Cancer Research Institute of Zhongshan City, Zhongshan City People’s Hospital, No. 2 Sunwen East Road, Zhongshan City, Guangdong Province, 528404, People’s Republic of China, Tel +86 18826431030, Fax +86 0760-88823566, Email caich6@foxmail.comPurpose: Hierarchical management is advocated in China to effectively manage chronic obstructive pulmonary disease (COPD) patients and reduce the incidence and mortality of acute exacerbation of COPD (AE-COPD). However, primary and community hospitals often have limited access to advanced equipment and technology. Complete blood count (CBC), which is commonly used in these hospitals, offers the advantages of being cost-effective and easily accessible. This study aims to evaluate the significance of routine blood indicators in aiding of diagnosing AE-COPD.Patients and Methods: In this research, we enrolled a total of 112 patients diagnosed with AE-COPD, 92 patients with stable COPD, and a control group comprising 60 healthy individuals. Clinical characteristics, CBC parameters, and serum CRP levels were collected within two hours. To assess the associations between NLR/PLR/MLR and CRP by Spearman correlation test. The diagnostic accuracy of NLR, PLR and MLR in AE-COPD was assessed using Receiver Operating Characteristic Curve (ROC) and the area under the curve (AUC). Binary Logistic Regression analysis was conducted for the indicators of NLR, PLR and MLR.Results: We found that patients with AE-COPD had significantly higher levels of NLR, PLR and MLR in contrast to patients with stable COPD. Additionally, the study revealed a noteworthy correlation between CRP and NLR (rs=0.5319, P< 0.001), PLR (rs=0.4424, P< 0.001), and MLR (rs=0.4628, P< 0.001). By utilizing specific cut-off values, the amalgamation of NLR, PLR and MLR augmented diagnostic sensitivity. Binary logistic regression analysis demonstrated that heightened NLR and MLR act as risk factors for the progression of AE-COPD.Conclusion: The increasing levels of NLR, PLR and MLR could function as biomarkers, akin to CRP, for diagnosis and assessment of acute exacerbations among COPD patients. Further research is required to validate this concept. Keywords: acute exacerbation of chronic obstructive pulmonary disease, AE-COPD, neutrophil-lymphocyte ratio, NLR, platelet-lymphocyte ratio, PLR, monocyte-lymphocyte ratio, MLR

Jingjing Li,1,&ast; Yabing Liu,1,&ast; Wenxuan Zeng,2 Yanrun Wu,3 Wei Ao,4 Xiwei Yuan,1 Chuanyi Zhou1 1Department of Oncology, Yueyang People’s Hospital, Yueyang City, Hunan Province, 414000, People’s Republic of China; 2Department of Cardiovascular, Yueyang Central Hospital, Yueyang City, Hunan Province, 414000, People’s Republic of China; 3Department of Ultrasonic, Yueyang Central Hospital, Yueyang City, Hunan Province, 414000, People’s Republic of China; 4Department of Cardiovascular, Yueyang People’s Hospital, Yueyang City, Hunan Province, 414000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiwei Yuan; Chuanyi Zhou, Department of Oncology, Yueyang People’s Hospital, No. 263, Baling East Road, Yueyanglou District, Yueyang City, Hunan Province, People’s Republic of China, Email csj13590308660@126.com; Zzbc138092@126.comObjective: To analyze the correlation between the expression of circFAT1 in serum and immune cells in patients with non-small cell lung cancer (NSCLC).Methods: A total of 96 patients with NSCLC admitted to our hospital from November 2019 to November 2022 were regarded as the study subjects. In the meantime, 96 volunteers who had physical examination in our hospital were regarded as the control group. The expression level of circFAT1 in serum was detected by real-time fluorescence quantitative PCR. NSCLC cancer tissue (NSCLC group) and paracancerous tissue (tissue ≥ 2cm away from the focus) (paracancerous group) were collected during the operation, the expression of CD4+, CD8+ and Foxp3+ in tissues was determined by immunohistochemistry; the expression level of circFAT1 mRNA in NSCLC tissue was analyzed using the Ualcan database. Spearman correlation was applied to analyze the correlation between the expression of circFAT1 and immune cells (CD4+, Foxp3+, CD8+).Results: The level of circFAT1 in NSCLC tissue was higher than that in normal tissue (P < 0.05). Compared with the control group, the expression level of circFAT1 in serum of NSCLC group was obviously higher (P < 0.05). The expression level of circFAT1 was related to lymph node metastasis, TNM stage and differentiation (P < 0.05). Compared with the paracancerous group, the positive expression rate of CD8+ in NSCLC group was obviously lower, and the positive expression rates of CD4+ and Foxp3+ were obviously higher (P < 0.05). The expression of CD4+, Foxp3+ and CD8+ in NSCLC patients’ cancer tissue was related to lymph node metastasis, TNM stage and differentiation degree (P < 0.05). Spearman correlation analysis showed that circFAT1 was positively correlated with the expression of CD4+ and Foxp3+ and negatively correlated with the expression of CD8+ (P < 0.05).Conclusion: CircFAT1 is highly expressed in the serum of NSCLC patients and is closely related to immune cells.Keywords: non-small cell lung cancer, circFAT1, immune microenvironment, correlation

Siyao Wu,1,&ast; Ting Guo,2,&ast; Hui Zhang,1 Zhiyi He,1 Jianquan Zhang,3 Wen Zeng1 1Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China; 2Department of Dermatology and Venereology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China; 3Department of Respiratory and Critical Medicine, the Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, 518000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen Zeng, Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China, Tel +86 18589883694, Email zengwen@stu.gxmu.edu.cnAbstract: Adult-onset acquired immunodeficiency caused by anti-IFN-γ autoantibodies is associated with severe opportunistic infection. Due to lack of specific symptoms and different manifestations, this form of infection can be easily misdiagnosed or overlooked. Herein, we present a case of Nocardia farcinica and Talaromyces marneffei co-infection in a patient with anti-IFN-γ autoantibodies (AIGAs). The patient, a 54-year-old man, presented with a 1-month history of fever, coughing and expectoration, dizziness, headache and gait imbalance. Laboratory workup revealed increased inflammatory markers, negative anti-HIV antibody and a high positive titer of AIGAs. Chest computed tomography (CT) showed multiple patches of high-density shadows in both lungs, and brain enhanced magnetic resonance imaging (MRI) showed an irregular lesion. The patient underwent a craniotomy for resection of the lesion. Pulmonary T. marneffei infection was diagnosed through sputum and bronchoalveolar lavage fluid culture, and brain nocardiosis was confirmed via purulent fluid culture of brain tissue. With regular antibiotic therapy, his symptoms improved and there was no recurrence during 18-month follow-up. This may be the first detailed case report detailing infection with these two distinct pathogens in disparate anatomical locations.Keywords: nocardia, Talaromyces marneffei, adult-onset acquired immunodeficiency, anti-IFN-γ autoantibodies, brain abscess

Jipeng Shi,1 Zhen-Qi Lu,1 Qing-Mei Lin,2 Wang Zeng,1 Ping-Jiao Gu,1 Qing Yu,3 Jing Long,1 Da-Gui Huang,1 Yi-Heng Dai1 1Department of Neonatal, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University (Foshan Maternity & Child Healthcare Hospital), Foshan, Guangdong, 528000, People’s Republic of China; 2Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University (Foshan Maternity & Child Healthcare Hospital), Foshan, Guangdong, 528000, People’s Republic of China; 3Department of Clinical Laboratory, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University (Foshan Maternity & Child Healthcare Hospital), Foshan, Guangdong, 528000, People’s Republic of ChinaCorrespondence: Yi-Heng Dai, Email daiyiheng@163.comBackground: There are many difficulties and uncertainties in the early diagnosis of neonatal sepsis. The aim of this study was to determine whether albumin (ALB) is useful for the early diagnosis of neonatal sepsis using ALB, C-reactive protein (CRP) and procalcitonin (PCT) together.Methods: ALB, CRP, PCT and white blood cell (WBC) data from 732 patients with neonatal sepsis and 1317 neonatal infection patients hospitalized in Foshan Maternal and Child Health Hospital from 2011 to 2022 were collected. Receiver operating characteristic (ROC) and logistic regression analyses were performed to assess the diagnostic value of ALB, CRP, PCT and the WBC count for neonatal sepsis. The roles of ALB, CRP, PCT and the WBC count in the diagnosis of neonatal sepsis were analysed by using subject working characteristics (ROC) and areas under the curve (AUCs), and the variables were combined to determine which combination had the best diagnostic efficacy.Results: In the sepsis group, the ALB, CRP, and PCT levels and the WBC count were significantly higher than those in the infection group (P< 0.001). In all infants, the sensitivities and specificities of ALB, CRP, PCT, and WBC count were 0.411, 0.596, 0.483 and 0.411, respectively, and 0.833, 0.846, 0.901 and 0.796, respectively. With a sensitivity of 0.646, a specificity of 0.929, and an AUC of 0.834, the best combination was that of ALB, CRP, and PCT, which was better than that of CRP + PCT, CRP + ALB and PCT + ALB.Conclusion: In neonatal sepsis, in the absence of blood culture results, the combination of ALB, CRP, and PCT is more reliable than CRP, PCT, or CRP+PCT alone. These results suggest that ALB is a useful inflammatory biomarker for the early diagnosis of neonatal sepsis, and can improve the diagnostic efficiency.Keywords: albumin, C-reactive protein, procalcitonin, diagnosis, neonatal sepsis

Weiya Zeng,1– 3 Yuan Fang,1– 3 Suifen Mo,1– 3 Caihong Shen,1– 3 Huiling Yang,1– 3 Guihua Luo,1– 3 Luhua Xiao,1– 3 Ruoting Zhan,1– 3 Ping Yan1– 3 1College of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Key Laboratory of Chinese Medicinal Resources from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou, People’s Republic of China; 3Joint Laboratory of Nation Engineering Research Center for the Pharmaceutics of Traditional Chinese Medicines, Guangzhou, People’s Republic of ChinaCorrespondence: Ruoting Zhan; Ping Yan, Guangzhou University of Chinese Medicine, No. 232, Outer Ring East Road, Guangzhou, Guangdong, People’s Republic of China, Tel/Fax +86 20-39358045, Email ruotingzhan@vip.163.com; yanping@gzucm.edu.cnPurpose: Rubia cordifolia L. (RC) is a classic herbal medicine for the treatment of rheumatoid arthritis (RA) and has been used since ancient times. The ethanol extract of Rubia cordifolia L. (RCE) showed obvious anti-RA effects in our previous study. However, further potential mechanisms require more exploration. We aimed to investigate the mechanism of RCE for the treatment of RA by integrating metabolomics and network pharmacology in this study.Methods: An adjuvant-induced arthritis (AIA) rat model was established, and we evaluated the therapeutic effects of RCE. Metabolomics of serum and urine was used to identify the differential metabolites. Network pharmacology was applied to determine the key metabolites and potential targets. Finally, the potential targets and compounds of RCE were verified by molecular docking.Results: The results indicated that RCE suppressed foot swelling and alleviated joint damage and also had anti-inflammatory properties by inhibiting the expressions of tumor necrosis factor (TNF)-α, Interleukin (IL)-1β, prostaglandin E2 (PGE2), and P65. Ten and seven differential metabolites were found in the serum and urine, respectively, of rats. Six key targets, ie, phospholipase A2 group IIA (PLA2G2A), phospholipase A2 group X (PLA2G10), cytidine deaminase (CDA), uridine-cytidine kinase 2 (UCK2), charcot-leyden crystal galectin (CLC), and 5′,3′-nucleotidase, mitochondrial (NT5M), were discovered by network pharmacology and metabolite analysis and were found to be related to glycerophospholipid metabolism and pyrimidine metabolism. Molecular docking confirmed that the favorable compounds showed affinities with the key targets, including alizarin, 6-hydroxyrubiadin, ruberythric acid, and munjistin.Conclusion: This study revealed the underlying mechanisms of RCE and provided evidence that will allow researchers to further investigate the functions and components of RCE against RA.Keywords: inflammtion, AIA rats, molecular docking, chronic disease

Yang Yang1,2 &ast;, Yujing Lin1,2 &ast;, Ruogu Xu,1,2 Zhengchuan Zhang,1,2 Wenyi Zeng,1,2 Qiong Xu,1,2 Feilong Deng1,2 1Department of Oral Implantology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiong Xu; Feilong Deng, Department of Oral Implantology, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, No. 56, Ling Yuan Xi Road, Guangzhou, 510055, People’s Republic of China, Tel +86 20 83862537, Fax +86 20 83822807, Email xqiong@mail.sysu.edu.cn; dengfl@mail.sysu.edu.cnBackground and Purpose: In clinical application of dental implants, the functional state of dendritic cells (DCs) has been suggested to have a close relationship with the implant survival rate or speed of osseointegration. Although microscale surfaces have a stable osteogenesis property, they also incline to trigger unfavorable DCs activation and threaten the osseointegration process. Nanoscale structures have an advantage in regulating cell immune response through orchestrating cell adhesion, indicating the potential of hierarchical micro/nanostructured surface in regulation of DCs’ activation without sacrificing the advantage of microscale topography.Materials and Methods: Two micro/nanostructures were fabricated based on microscale rough surfaces through anodization or alkali treatment, the sand-blasted and acid-etched (SA) surface served as control. The surface characteristics, in vitro and in vivo DC immune reactions and β 2 integrin-FAK signal expression were systematically investigated. The DC responses to different surface topographies after FAK inhibition were also tested.Results: Both micro/nano-modified surfaces exhibited unique composite structures, with higher hydrophilicity and lower roughness compared to the SA surface. The DCs showed relatively immature functional states with round morphologies and significantly downregulated β 2 integrin-FAK levels on micro/nanostructures. Implant surfaces with micro/nano-topographies also triggered lower levels of DC inflammatory responses than SA surfaces in vivo. The inhibited FAK activation effectively reduced the differences in topography-caused DC activation and narrowed the differences in DC activation among the three groups.Conclusion: Compared to the SA surface with solely micro-scale topography, titanium surfaces with hybrid micro/nano-topographies reduced DC inflammatory response by influencing their adhesion states. This regulatory effect was accompanied by the modulation of β 2 integrin-FAK signal expression. The β 2 integrin-FAK-mediated adhesion plays a critical role in topography-induced DC activation, which represents a potential target for material–cell interaction regulation.Graphical Abstract: Keywords: micro/nanostructure, dendritic cell, osteoimmunology, β 2 integrin-FAK signal, surface modification

Suke Xing,1,2 Hui Zhang,2 Ye Qiu,3 Mianluan Pan,1 Wen Zeng,2 Jianquan Zhang1 1Department of Respiratory and Critical Medicine, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518000, People’s Republic of China; 2Department of Respiratory Medicine, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 3Department of Comprehensive Internal Medicine, the Affiliated Tumour Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of ChinaCorrespondence: Jianquan Zhang, Department of Respiratory and Critical Medicine, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518000, Guangdong, People’s Republic of China, Tel +8613978123845, Fax +86755-23482484, Email jqzhang2002@126.comPurpose: To summarize the clinical characteristics, treatment and outcomes of transplant recipients infected with Talaromyces marneffei (TM).Materials and Methods: A retrospective analysis was performed on 2 patients with Talaromycosis marneffei (TSM) and transplants at the First Affiliated Hospital of Guangxi Medical University, and a systematic literature review was conducted simultaneously.Results: This article reported two patients after kidney transplantation who developed fever, cough within 3– 4 months. Their haemoglobin was decreased. Their chest computed tomography (CT) showed nodules. TM was detected in their blood or bronchoalveolar lavage fluid samples by next-generation sequencing (NGS). After antifungal treatment with voriconazole (VOR), one patient worsened, the other patient died. A total of 21 patients with TSM after transplants were reported in the literature review. Fourteen underwent kidney transplantation, 4 underwent liver transplantation, 2 underwent lung transplantation, and 1 underwent bone marrow transplantation. The median time from initiating the postoperative immunosuppressive therapy to the onset of symptoms or disease changes was 18 (0.5– 140) months. Among them, 9 patients developed fever, 7 patients developed cough or expectoration and 4 patients developed dyspnoea. Haemoglobin was decreased in 10 patients. Pulmonary nodules were found in 7 patients. Among the 21 patients, 7 were diagnosed by positive culture, 6 by biopsy, 5 by culture and biopsy. Of the 21 patients, 13 patients improved by antifungal therapy, 8 patients worsened or died. Seven patients who received amphotericin B followed by itraconazole (ITR) therapy all improved. Regarding the use of immunosuppressants in 12 patients, 9 patients had to discontinue or reduce their medications (6 patients improved, 3 patients worsened or died).Conclusion: Patients with TSM after transplant often have disseminated infections, involving the respiratory, hematopoietic and so on. Fever, cough, decreased haemoglobin and pulmonary nodules often occur approximately 18 months after surgery. The combined applications of culture, biopsy, NGS are helpful for an early diagnosis. Antifungal therapy with amphotericin B followed by itraconazole is recommended, and the dosage of the immunosuppressant should be adjusted timely.Keywords: Talaromyces marneffei, Talaromycosis marneffei, transplant recipients, immunosuppressants, antifungal drug

Mengxin Tang,1,2,&ast; Mianluan Pan,1,&ast; Ye Qiu,1 Jie Huang,3 Wen Zeng,2 Jianquan Zhang1 1Department of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, 518000, People’s Republic of China; 2Department of Respiratory and Critical Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 3Department of Tuberculosis Ward, Nanning Fourth People’s Hospital, Nanning, Guangxi, 530021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen Zeng, Department of Respiratory and Critical Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China, Tel +8618589883694, Fax +86771-5350031, Email guigao0302@163.com Jianquan Zhang, Department of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, 518000, People’s Republic of China, Tel +8613978123845, Fax +86755-23482484, Email jqzhang2002@126.comBackground: Anti-IFN-γ autoantibodies (AIGAs) are closely related to the disseminated infection of multiple pathogens. Mycobacterium phlei (M. phlei) is a nonpathogenic nontuberculous mycobacteria (NTM), and M. phlei infection of the bone is extremely rare. We report a rare case of high-titer AIGAs presenting with Sweet’s syndrome (SS) accompanied by opportunistic coinfection with multiple pathogens during 12 years of follow-up. The patient in this case also developed disseminated M. phlei infection with osteolytic destruction after treatment for SS.Case Presentation: A 68-year-old Chinese woman was admitted to our hospital in August 2009 due to fever and cough with expectoration for 3 months. The patient was successively infected with Klebsiella pneumoniae, herpes zoster virus and Candida. Chest computed tomography (CT) showed recurrent consolidations in different lung fields. After 15 months of antimicrobial treatment, the patient experienced partial recovery. In September 2010, the patient was pathologically diagnosed with SS due to the presence of multiple rashes. After prednisone and thalidomide treatment, the rashes subsided, and the pulmonary lesions had completely absorbed. In May 2011, the patient was diagnosed with disseminated tuberculosis and was administered anti-tuberculosis therapy for 3 months without improvement. NTM was subsequently cultured from her sputum and chest wall pus, and she improved after 20 months of anti-NTM therapy. In March 2016, the patient developed osteolytic destruction of the C7-T2 vertebral bodies with a back abscess. NTM was eventually cultured from the dorsal abscess pus and further identified as M. phlei. High-titer AIGAs were detected in the patient’s serum. After another round of aggressive anti-NTM therapy, the patient was finally cured.Conclusion: Patients with AIGA-associated anti-cytokine autoantibody disease can present with multiple opportunistic infections and SS involving the lung. AIGA-associated immunodeficiency leads to infection with nonpathogenic M. phlei, which is refractory, can cause relapse, and even leads to osteolytic destruction.Keywords: Mycobacterium phlei, sweet’s syndrome, osteolytic destruction, anti-IFN-γ autoantibodies

Hao Liu,1 Ruirui Zhang,1 Dan Zhang,1 Chun Zhang,1 Zhuo Zhang,1 Xiujuan Fu,1 Yu Luo,1 Siwei Chen,1 Ailing Wu,2 Weiling Zeng,3 Kunyan Qu,1 Hao Zhang,1 Sijiao Wang,1 Houyin Shi4 1School of Pharmacy, Southwest Medical University, Luzhou City, Sichuan, People’s Republic of China; 2Department of Anesthesiology, The First People’s Hospital of Neijiang, Neijiang, Sichuan, People’s Republic of China; 3Department of Scientific Research, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou City, Sichuan, People’s Republic of China; 4Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou City, Sichuan, People’s Republic of ChinaCorrespondence: Hao LiuSchool of Pharmacy, Southwest Medical University, No. 1 Section 1, Xiang Lin Road, Longmatan District, Luzhou City, Sichuan Province, 646000, People’s Republic of ChinaTel +86 830 3162291Email h_lewis@126.comHouyin ShiDepartment of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, No. 182 Chunhui Road, Longmatan District, Luzhou City, Sichuan Province, 646000, People’s Republic of ChinaTel +86 830 3162209Email 623340767@qq.comIntroduction: (-)-Gossypol (AT-101), the (-)-enantiomer of the natural compound gossypol, has shown significant inhibitory effects on various types of cancers such as osteosarcoma, myeloma, glioma, lung cancer, and prostate cancer. However, the clinical application of (-)-gossypol was often hindered by its evident side effects and the low bioavailability via oral administration, which necessitated the development of suitable (-)-gossypol preparations to settle the problems. In this study, injectable cyclic RGD (cRGD)-decorated liposome (cRGD-LP) was prepared for tumor-targeted delivery of (-)-gossypol.Methods: The cRGD-LP was prepared based on cRGD-modified lipids. For comparison, a non-cRGD-containing liposome (LP) with a similar chemical composition to cRGD-LP was specially designed. The physicochemical properties of (-)-gossypol-loaded cRGD-LP (Gos/cRGD-LP) were investigated in terms of the drug loading efficiency, particle size, morphology, drug release, and so on. The inhibitory effect of Gos/cRGD-LP on the proliferation of tumor cells in vitro was evaluated using different cell lines. The biodistribution of cRGD-LP in vivo was investigated via the near-infrared (NIR) fluorescence imaging technique. The antitumor effect of Gos/cRGD-LP in vivo was evaluated in PC-3 tumor-bearing nude mice.Results: Gos/cRGD-LP had an average particle size of about 62 nm with a narrow size distribution, drug loading efficiency of over 90%, and sustained drug release for over 96 h. The results of NIR fluorescence imaging demonstrated the enhanced tumor targeting of cRGD-LP in vivo. Moreover, Gos/cRGD-LP showed a significantly enhanced inhibitory effect on PC-3 tumors in mice, with a tumor inhibition rate of over 74% and good biocompatibility.Conclusion: The incorporation of cRGD could significantly enhance the tumor-targeting effect of the liposomes and improve the antitumor effect of the liposomal (-)-gossypol in vivo, which indicated the potential of Gos/cRGD-LP that warrants further investigation for clinical applications of this single-isomer drug.Keywords: RGD peptide, αvβ3 integrin, targeted therapy, AT-101, liposome, fluorescence imaging

Sheng Hu, Wenxiong Zhang, Qiang Guo, Jiayue Ye, Deyuan Zhang, Yang Zhang, Weibiao Zeng, Dongliang Yu, Jinhua Peng, Yiping Wei, Jianjun Xu Department of Thoracic Surgery, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, People’s Republic of ChinaCorrespondence: Yiping Wei; Jianjun XuThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of ChinaTel +86 13687919322; +86 13907913526Email weiyip2000@hotmail.com; xujianjun3526@163.comBackground: On April 15, 2021, the Surveillance, Epidemiology, and End Results (SEER) database released the latest lung cancer follow-up data. We selected 922,317 lung cancer patients diagnosed from 2000 to 2017 for survival analysis to provide updated data for lung cancer researchers.Research Question: This study explored the latest trends of survival time in terms of gender, race, nationality, age, income, address, histological type and primary site.Study Design and Methods: The SEER database covers 27.8% of the US population. We used life table, Kaplan–Meier, log-rank, Breslow and Tarone-Ware tests to calculate survival rate, time, and curve and to compare differences in survival distribution. We performed univariate and multivariate Cox proportional hazards analyses.Results: The median survival time of all lung cancer patients diagnosed in 2017 increased by 41.72% compared to 2000. Median survival time of female patients diagnosed in 2017 increased by 70.94% compared to 2000. Median survival time of those diagnosed in 2017 for different primary sites was as follows: right middle lobe was the longest, then left lower lobe, right upper lobe, right lower lobe, and left upper lobe. Lung cancer patients older than 75 years had a significantly shorter median survival time. Patients living in metropolitan areas of 250,000 to 1 million had a longer median survival time. Median survival time in the adenocarcinoma group was significantly greater than other patients. Median survival of Asian and other races diagnosed in 2017 was 97.87% higher than those diagnosed in 2000. Survival rate of lung cancer increased gradually with the year of diagnosis.Interpretation: The rapid improvement of the prognosis of female and young lung cancer patients contributes to the improvement of the overall prognosis. Primary lung cancer in the right middle lobe has the best prognosis.Keywords: Cox regression analysis, Kaplan Meier survival analysis, lung cancer, prognosis, SEER

Zhenming Yang,1,2 Wen Zeng,2 Ye Qiu,3 Guangnan Liu,4 Jianquan Zhang1 1Department of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518000, People’s Republic of China; 2Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 3Department of Comprehensive Internal Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 4Department of Respiratory Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530005, People’s Republic of ChinaCorrespondence: Jianquan ZhangDepartment of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025, Shennan Middle Road, Shenzhen, 518000, Guangdong, People’s Republic of ChinaTel +8613978123845Fax +86755-23482484Email jqzhang2002@126.comBackground: Talaromyces marneffei (TM) is the only temperature-biphasic pathogen among Penicillium spp. that causes talaromycosis marneffei (TSM). Clinical manifestations include fever, cough, expectoration, superficial and deep lymph node enlargement, hepatosplenomegaly, subcutaneous nodules, and bone and joint infections. Cases of TSM in Hodgkin lymphoma (HL) patients are uncommon. The clinical manifestations and imaging findings are similar in TSM and HL, which make it difficult for clinicians to distinguish between TSM and HL. Both diseases can present with symptoms, can involve the blood or the respiratory system and can include other symptoms. We report a rare case of HIV-negative nodular sclerosing Hodgkin lymphoma (NSHL) combined with T. marneffei infection to improve clinical knowledge.Case Presentation: The patient was a 51-year-old man who presented with a 1-month history of cough, expectoration, intermittent fever in the afternoon and night, cervical lymph node enlargement, diabetes and previous lung surgery. He had markedly elevated serum inflammatory markers and moderate diffuse lung dysfunction. Chest computed tomography (CT) showed diffuse nodular lesions in both lungs with mediastinal lymph node enlargement. The patient did not respond to antibacterial and diagnostic antituberculosis therapy. After lymph node biopsy and lung culture, we obtained a definite diagnosis of NSLH with T. marneffei infection and administered antifungal therapy. His symptoms improved, and he was discharged for further treatment. Unfortunately, he died of Salmonella sepsis 7 months later.Conclusion: It is rare for NSLH patients to be infected with T. marneffei. Both diseases can present with fever, lymphadenopathy, and hepatosplenomegaly and involve the blood and respiratory system or can cause other symptoms. Clinically, a misdiagnosis or missed diagnosis may occur. A multisite biopsy or culture should be performed to make a definitive diagnosis. Early antifungal therapy combined with standard chemotherapy can achieve satisfactory clinical efficacy.Keywords: Talaromyces marneffei, nodular sclerosing Hodgkin lymphoma, identification, treatment

Lingbo Wang,1,&ast; Ying Zhang,2,&ast; Shixing Liu,1 Na Huang,1 Weiliang Zeng,1 Wenya Xu,1 Tieli Zhou,1 Mo Shen1 1Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China; 2School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mo Shen; Tieli ZhouDepartment of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaTel +86-577-8668-9885Email shenmo601@163.com; wyztli@163.comBackground: The emergence and spread of linezolid-resistant Enterococcus faecalis (E. faecalis) have emerged as a serious threat to human health globally. Therefore, this study aims to compare the anti-microbic as well as the anti-biofilm activity of linezolid, tedizolid, and radezolid against linezolid-resistant E. faecalis.Methods: A total of 2128 E. faecalis isolates were assessed from the First Affiliated Hospital of Wenzhou Medical University from 2011 to 2019. Antibiotic sensitivity was evaluated using the micro broth dilution method. Oxazolidinone-resistant chromosomal and plasmid-borne genes such as cfr, cfr(A), cfr(B), cfr(C), cfr(D), optrA, and poxtA were detected by PCR and then sequenced to detect the presence of mutations in the domain V of the 23S rRNA and the ribosomal proteins L3, L4, and L22. Conjugation experiments were conducted using the broth method. The inhibition and eradication of biofilm were evaluated through crystal violet staining, whereas the efflux pump activities were detected by agar dilution.Results: Out of 2128 isolated E. faecalis, 71 (3.34%) were linezolid-resistant isolates in which the MICs of tedizolid and radezolid ranged from 1 to 4 μg/mL and 0.5– 1 μg/mL, respectively. The MIC50/MIC90 of tedizolid and radezolid were 4 and 8-fold lower than the linezolid, respectively. Out of 71 resistant isolates, 57 (80.28%) carried optrA, 1 (1.41%) carried cfr, 4 (5.63%) carried optrA and cfr, and 6 (8.45%) carried optrA and cfr(D), with no mutations of 23S rRNA gene and ribosomal proteins L3, L4, and L22. Besides, the transfer rate of the optrA, cfr, and cfr(D) was 17.91%, 0% and 0%, respectively. Radezolid showed more effectiveness in eradicating biofilm (8 × MIC). However, tedizolid was more effective than radezolid and linezolid in inhibiting the biofilm formation (1/4 MIC, 1/8MIC, and 1/16MIC). Additionally, in combination with CCCP, the MICs of radezolid in all linezolid-resistant isolates decreased ≥ 4-fold.Conclusion: Radezolid showed greater antimicrobial activity than tedizolid and linezolid against linezolid-resistant E. faecalis. However, both tedizolid and radezolid showed differential activity on biofilm inhibition, eradication, and efflux pump compared to linezolid. Thus, our study might bring important clinical value in the application of these drugs for resistant pathogenic strains.Keywords: Enterococcus faecalis, linezolid, tedizolid, radezolid, in vitro activity, anti-biofilm activity

Mengxin Tang,1,2,&ast; Jie Huang,3,&ast; Wen Zeng,1,2 Yanmei Huang,4 Yaoqiang Lei,5 Ye Qiu,6 Jianquan Zhang1,2,4 1Department of Respiratory and Critical Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 2Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 3Department of Tuberculosis Ward, Nanning Fourth People’s Hospital, Nanning, Guangxi, 530021, People’s Republic of China; 4Department of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518000, People’s Republic of China; 5Department of Infectious Diseases, Yongning District People’s Hospital, Nanning, Guangxi, 530021, People’s Republic of China; 6Department of Comprehensive Internal Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ye QiuDepartment of Comprehensive Internal Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of ChinaTel +8615676192180Fax +86771– 5719573Email yeqiu2013graduated@163.comJianquan ZhangDepartment of Respiratory and Critical Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of ChinaTel +8613978123845Fax +86755-23482484Email jqzhang2002@126.comPurpose: Disseminated nontuberculous mycobacterial (DNTM) infection can involve multiple organs, including the lungs, skin and soft tissues and lymph nodes. However, NTM infection leading to osteolysis has been rarely reported. Here, we analyzed the clinical features, osteolytic mechanisms, treatment and prognosis of patients with DNTM disease with osteolytic lesions.Patients and Methods: This retrospective study was conducted between January 1, 2011, and December 31, 2020, at the First Affiliated Hospital of Guangxi Medical University and the Fourth People’s Hospital of Nanning City. Patients who had culture and/or histopathological proof of DNTM disease with osteolytic lesions were included.Results: Ten HIV-negative patients with DNTM disease with osteolytic lesions were enrolled. Five of these patients had underlying diseases. Seven and three of the patients were positive and negative for anti-interferon-γ autoantibodies (AIGAs), respectively. The AIGA positivity rate was 70% (7/10). Ostealgia and anemia were the most common symptoms, followed by fever, emaciation, cough, expectoration, anorexia, subcutaneous abscesses and lymphadenopathy. Leukocyte and neutrophil counts were increased. The most common sites were the vertebrae, sternum, clavicle and ribs, although the femur, ilium, humerus, and scapula were also involved. Radiography and computed tomography (CT) showed moth-eaten or irregular destruction of bone, bone defects, pathological fracture, periosteal proliferation and surrounding abscesses. Emission CT (ECT) bone scans showed significantly increased uptake in many skeletal regions. Positron emission tomography(PET)/CT showed metabolic activity in multiple bones. All patients received anti-nontuberculous therapy, and five underwent surgery. Two died during treatment.Conclusion: DNTM infection of bone and leading to osteolysis usually occurs in patients with AIGA-positive antibodies. DNTM disease with osteolysis is characterized by increased leukocytes and neutrophil counts, focal suppurative granulomas, and multiple areas with moth-eaten or irregular destruction of bone with increased radioactive concentrations. Early diagnosis and timely, effective combination anti-NTM therapy can improve the prognosis.Keywords: HIV-negative, nontuberculous mycobacteria, osteolytic lesion, anti-IFN-γ autoantibodies

Fanhai Lin,1,2,&ast; Zhenming Yang,1,3,&ast; Ye Qiu,4 Wen Zeng,3 Guangnan Liu,5 Jianquan Zhang1 1Department of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, Guangdong, 518000, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530016,People’s Republic of China; 3Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 4Department of Comprehensive Internal Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 5Department of Respiratory Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530005,People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianquan ZhangDepartment of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, No. 3025, Shennan Middle Road, Shenzhen, 518000, Guangdong, People’s Republic of ChinaTel +8613978123845Fax +86755-23482484Email jqzhang2002@126.comBackground: Talaromyces marneffei is considered to commonly cause infection in individuals with human immunodeficiency virus (HIV) infection. However, the epidemiology of T. marneffei has changed, and an increasing number of HIV-negative but immunodeficient patients are infected with T. marneffei. The mechanisms of T. marneffei infection of HIV-negative hosts are complex and diverse. We report 2 cases of HIV-negative lung cancer with T. marneffei infection and positive anti-interferon-gamma autoantibodies (AIGAs) to provide clinical experience.Case Presentation: We report lung adenocarcinoma combined with T. marneffei infection in HIV-negative patients, and their AIGAs were measured. Both patients were male with a family history of cancer and presented with recurrent fever and cough. The patients were negative for HIV antibodies but positive for AIGAs. Chest computed tomography (CT) showed pulmonary nodules, exudative lesions and solid changes. The patients were diagnosed with lung adenocarcinoma and Talaromycosis marneffei (TSM) by pathological examination and tissue culture. Patient 1 received only antifungal treatment, refused antitumor treatment and died in February 2019, and Patient 2 unfortunately died in April 2019 after antifungal and antitumor treatments.Conclusion: An increasing number of HIV-negative but immunodeficient patients are infected with T. marneffei. The 2 patients in this report had lung cancer and positive AIGAs, causing immunodeficiencies, but the mechanism of T. marneffei infection in such patients is complex. Clinically, we should consider a comprehensive immunological examination to avoid the omission of other immunodeficiencies. We recommend routine testing for AIGA levels in HIV-negative marneffei patients. It is difficult to distinguish between lung cancer and disseminated TSM due to similar clinical characteristics and imaging, and multiple biopsies and cultures of diseased tissue are necessary. Early antifungal treatment and standard antitumor treatment can achieve satisfactory curative effects when a patient has both diseases.Keywords: Talaromyces marneffei, lung adenocarcinoma, adult immunodeficiency, anti-interferon-γ antibodies

Dongzhu Lu,&ast; Lichang Chen,&ast; Chaofan Fan, Wenyi Zeng, Huizhen Fan, Xiping Wu, Huapeng Yu Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huapeng YuDepartment of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510220, People’s Republic of ChinaTel +86 20 61643175Fax +86 20 84306143Email huapengyu@aliyun.comPurpose: To evaluate the value of impulse oscillometry (IOS) and quantitative HRCT parameters for differentiating asthma–COPD overlap (ACO) in COPD patients.Patients and Methods: We enrolled 44 controls and 66 COPD patients, divided into the pure COPD group (n=40) and the ACO group (n=26). Spearman correlation analysis was utilized to assess the relationship between the quantitative HRCT and IOS parameters. A binary logistic regression analysis was performed to analyze the associations between the different variables and the risk of ACO. Receiver operating characteristic (ROC) curves were employed to identify the optimal cutoff and assess the diagnostic value of relative volume change − 856 HU to − 950 HU (RVC− 856 to − 950), decrease in the resistance from 5 Hz to 20 Hz (R5-R20) and their combination in predicting ACO. Bootstrapping validation was used to evaluate the internal validation. The concordance index (C-index) and calibration plot were calculated to assess the discrimination and calibration of the prediction model.Results: Binary logistic regression analysis indicated that RVC− 856 to − 950 and the IOS parameters (R5-R20, R5, X5) were independently correlated with a higher risk of developing ACO after adjusting for age, sex, body mass index (BMI), history of smoking, exacerbation and atopy or allergic rhinitis. A correlation analysis showed a good correlation between the pulmonary function parameters and RVC− 856 to − 950, with a weaker correlation with the % area of low attenuation (LAA%) in ACO patients. Combining RVC− 856 to − 950 and R5-R20 to predict ACO, the AUC was 0.909, and the optimal cutoff value was >-0.62 for RVC− 856 to − 950 and > 0.09 for R5-R20. Good calibration and favorable discrimination were displayed with a higher C-index.Conclusion: More serious small airway impairment exists in ACO patients. The combination of RVC− 856 to − 950 and R5-R20 could be applied to differentiate ACO from COPD patients.Keywords: relative volume change − 856 HU to − 950 HU, decrease in resistance from 5 Hz to 20 Hz, quantitative HRCT, ROC curve, diagnosis

Huaiyu Jia,1 Ying Zhang,2 Jianzhong Ye,1 Wenya Xu,1 Ye Xu,1 Weiliang Zeng,2 Wenli Liao,1 Tao Chen,1 Jianming Cao,2 Qing Wu,1 Tieli Zhou1 1Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China; 2Department of Medical Laboratory Science, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Tieli Zhou; Qing WuDepartment of Clinical Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaTel/Fax +86-0577-8668-9885Email wyztli@163.com; wuqing830@163.comBackground: OXA-232-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) has the potential to become the “third epidemic” of carbapenem-resistant Klebsiella strain after KPC-2 and NDM in China. We investigated the first outbreak of CRKP in the First Affiliated Hospital of Wenzhou Medical University.Methods: We collected 610 clinical isolates of CRKP from the First Affiliated Hospital of Wenzhou Medical University between January 2019 and September 2020 and screened them by Polymerase Chain Reaction (PCR). The multilocus sequence typing and pulsed-field gel electrophoresis were used to determine the genetic relatedness of the strains. The antimicrobial susceptibility test was performed to determine the drug resistance of the clinical isolates. The molecular mechanism underlying carbapenem resistance was elucidated by performing PCR and conjugation experiments. The virulence potential of the strains was determined by the string test, detection of virulence-associated genes and capsular serotypes, and Galleria mellonella larval infection model.Results: Between September 2019 and May 2020, 26 OXA-232-producing CRKP were obtained from 12 patients in our hospital. Ten patients were hospitalized in the intensive care units (ICU) and the overall mortality of the inpatients involved in the outbreak was 50% (6/12). Epidemiological investigations reported that all the OXA-232-producing CRKP strains belonged to the sequence type ST15 and can be clonally transmitted among the inpatients in the ICU. All the strains had low virulence and were resistant to commonly used clinical antibiotics except for ceftazidime/avibactam, colistin, and tigecycline. The OXA-232-producing CRKP was sensitive to triclosan and chlorhexidine, and its eradication from our hospital can be achieved by the use of disinfectants in the ICU.Conclusion: In our study, OXA-232-producing CRKP isolates appeared to be clonally transmitted and the sequence type ST15 was responsible for the outbreak. Therefore, effective measurements for the infection control of CRKP are urgently needed to prevent its epidemic in the nearby region in the future.Keywords: Klebsiella pneumoniae, carbapenem-resistance, virulence, OXA-232, outbreak

Wenmin Zeng,1 Guojing Liu,1 Qingxian Luan,1 Chunyu Yang,1 Shiyi Li,1 Xiaoqian Yu,1 Li Su2 1Department of Periodontology, Peking University School and Hospital of Stomatology, Beijing, People’s Republic of China; 2Center of Medical and Health Analysis, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Xiaoqian YuDepartment of Periodontology, Peking University School and Hospital of Stomatology, Beijing, 100081, People’s Republic of ChinaEmail Y_PK@163.comLi SuCenter of Medical and Health Analysis, Peking University, Beijing, 100191, People’s Republic of ChinaEmail lisu76@bjmu.edu.cnObjective: Periodontitis, one of the most prevalent chronic oral infectious diseases in humans, is induced by the breakdown in the balance between the biofilm and host immune system. Previous studies have shown the presence of large numbers of B cells in periodontitis lesions, implicating that B lymphocytes play a predominant role during the pathogenesis of periodontitis. This study aimed to investigate the role of all B cells in the initiation of periodontitis.Methods: Experimental periodontitis was induced in B cell-deficient (CD19Cre) mice and wild-type (WT) control mice by 5-0 silk ligation around the maxillary second molar. Four weeks after ligation, alveolar bone loss was determined by micro-computed tomography. The levels of inflammatory cytokines and receptor activator of NF-κB ligand (RANKL)/osteoprotegerin in periodontal lesions were analyzed using real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry. Lymphocyte populations in the cervical lymph nodes and spleen and among the peripheral blood mononuclear cells were detected by flow cytometry.Results: B-cell deficiency resulted in increased severity of alveolar bone loss in mouse experimental periodontitis, which was associated with increased osteoclast activity and upregulated RANKL expression in the periodontal lesions. In addition, gingiva cytokine expression profiles were shifted to T helper type 1 (Th1) and Th17 in the CD19Cre mice with ligature-induced periodontitis compared with WT mice. In addition, a reduced CD4+/CD8+ T cell ratio was observed in the CD19Cre mice.Conclusion: B-cell deficiency exacerbates the inflammation and alveolar bone loss in ligature-induced experimental periodontitis in mice, implicating that B cells may overall play a protective role in the initiation of periodontitis.Keywords: periodontitis, experimental periodontitis, alveolar bone loss, B lymphocytes

Jiang Yang,* Bingshu Li,* Jin Liu, Wanlin Zeng, Li Hong Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li HongDepartment of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei, 430060, People’s Republic of ChinaEmail drhongli77@gmail.comObjective: To introduce a modified hysteroscopic-laparoscopic operation for cesarean scar pregnancy (CSP) of stable type III.Patients and Methods: We retrospectively studied the case notes of 31 patients with stable type III cesarean scar pregnancy who underwent hysteroscopic-laparoscopic surgery in our hospital. Thirteen patients received the modified hysteroscopic-laparoscopic surgery (modified surgery group), and eighteen patients received traditional hysteroscopic-laparoscopic surgery (traditional surgery group).Results: There was no significant difference in patients’ age, gestational age, number of previous cesarean sections, the serum human chorionic gonadotropin (hCG) level before surgery, gestational sac diameter, myometrium thickness between the two groups. In the modified hysteroscopic-laparoscopic surgery, the mean surgical time was 50.45± 24.45 mins, the mean length of stay in hospital was 4.50± 0.50 days, which was significantly shorter than the traditional surgery group (84.75± 33.28 mins and 5.50± 0.75 days, respectively). And the intraoperative hemorrhage in the modified group was also less than that in the traditional group (40.50± 12.25 mL vs 75.33± 25.45mL). Whereas the time for hCG normalization, postoperative vaginal bleeding and menstrual recovery had no significant difference between the modified surgery group and the traditional surgery group. There was no recurrence of CSP in both groups.Conclusion: The modified hysteroscopic-laparoscopic surgery had shorter operation time, less blood loss, and sooner recovery time after surgery compared to traditional hysteroscopic-laparoscopic surgery, which could be more beneficial to our patients and should be applied in clinics generally.Keywords: cesarean scar pregnancy, hysteroscopic-laparoscopic surgery, modified surgery, traditional surgery

Wen Zeng,1,2 Ye Qiu,1,2 Mengxin Tang,1,2 Hui Zhang,2 Mianluan Pan,1 Shudan Tang,2 Jianquan Zhang1 1Department of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, 518000, People’s Republic of China; 2Department of Respiratory and Critical Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of ChinaCorrespondence: Jianquan ZhangDepartment of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, 518000, People’s Republic of ChinaTel +8613978123845Fax +86755-23482484Email jqzhang2002@126.comAbstract: A high titer of neutralizing anti-interferon-γ autoantibodies can cause immunodeficiency associated with severe or disseminated infections caused by Talaromyces marneffei in human immunodeficiency virus-negative patients. Herein, we reported a rare case of disseminated Talaromyces marneffei and Burkholderia cepacia infection. The patient’s lungs, lymph nodes, and bronchi were involved, and he had neck abscesses and osteomyelitis. We measured the neutralizing anti-interferon-γ autoantibodies in the peripheral blood and found that the patient had a persistently high positive titer. Despite aggressive treatment, the patient developed disseminated intravascular coagulation and died. Thus, high-titer nAIGAs may be associated with multiple opportunistic, persistent and disseminated infections.Keywords: Burkholderia cepacia, Talaromyces marneffei, adult immunodeficiency, neutralizing anti-interferon-γ autoantibodies

Ying Zhang,1 Lingbo Wang,2 Cui Zhou,2 Yishuai Lin,1 Shixing Liu,2 Weiliang Zeng,1 Kaihang Yu,1 Tieli Zhou,2 Jianming Cao1 1Department of Medical Lab Science, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, People’s Republic of China; 2Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, People’s Republic of ChinaCorrespondence: Jianming CaoDepartment of Medical Lab Science, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of ChinaTel +86-0577-88069595Email wzcjming@163.comTieli ZhouDepartment of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of ChinaTel +86-0577-86689885Email wyztli@163.comPurpose: Multidrug-resistant (MDR) Enterococcus faecium is an important nosocomial pathogen causing urinary tract infection, and the reapplication of nitrofurantoin (NIT) in the clinic has attracted great attention. This study aims to explore the NIT resistance mechanisms and epidemiological characteristics of E. faecium clinical isolates.Patients and Methods: A total of 633 E. faecium clinical isolates was obtained from urine samples in a clinical teaching hospital during 2017– 2018. Among them, 40 NIT-resistant strains, and a similar number of -intermediate and -susceptible strains were isolated. The minimum inhibitory concentrations (MICs) of NIT were detected by agar dilution method. The prevalence and mutations of nitroreductase-encoding genes ef0404 and ef0648 were explored by polymerase chain reaction (PCR), followed by efflux pump inhibition test and quantitative real-time PCR (qRT-PCR) to investigate the resistance mechanisms of NIT. Furthermore, the epidemiological characteristics were detected by multilocus sequence typing (MLST).Results: The carrying rates of nitroreductase in NIT-susceptible, -intermediate, and -resistant isolates were 100%, 50%, and 20%, respectively. After exposure to the efflux pump inhibitor, the MIC of 12 E. faecium decreased by ≥ 4-fold. However, the efflux pump genes efrAB, emeA, and oqxAB were not overexpressed in NIT-resistant E. faecium isolates. Moreover, MLST analysis revealed that all the NIT-resistant isolates belonged to CC17, of which 30 (75%) were associated with ST78.Conclusion: This study has established for the first time that the absence of EF0404 and EF0648 is the main mechanism of NIT resistance in E. faecium. Our findings are likely to fill the knowledge gap pertaining to the NIT resistance mechanism in E. faecium and provide important insights for molecular epidemiological characteristics analysis.Keywords: Enterococcus faecium, nitrofurantoin, nitroreductase, resistance mechanism, epidemiology

Xiangkuo Zheng,1,* Renchi Fang,2,* Chong Wang,3 Xuebin Tian,4 Jie Lin,1 Weiliang Zeng,4 Tieli Zhou,1 Chunquan Xu1 1Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 2Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, People’s Republic of China; 3Department of Laboratory Medicine, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China; 4School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunquan Xu; Tieli ZhouDepartment of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of ChinaTel +86-577-5557-9725; +86-577-8668-9885Email 417242374@qq.com; wyztli@163.comBackground: Staphylococcus aureus (S. aureus) is a major contributor to nosocomial and community-acquired infections. S. aureus small colony variants (SCVs) which changed in relevant phenotype have made more limited and difficult for therapeutic options against S. aureus infections increasingly. Rifampicin is considered as the “last-resort” antibiotic against S. aureus. Our study investigated resistance profiles and biological characteristics of rifampicin-resistant S. aureus SCVs.Methods: We collected S. aureus SCVs that were selected from 41 rifampicin-resistant clinical isolates. Then, biological characteristics, resistance spectrum, and rifampicin resistance mechanisms of tested S. aureus SCVs and corresponding parental strains were investigated by classic microbiological methods, agar dilution method, polymerase chain reaction (PCR). Moreover, the fitness cost of S. aureus SCVs, including growth, biofilm formation ability, and virulence profile, was also determined by bacterial growth curve assay, biofilm formation assay, and Galleria mellonella infection model.Results: There were three S. aureus SCVs (JP310 SCVs, JP1450 SCVs, JP1486 SCVs) that were selected from 41 rifampicin-resistant S. aureus. S. aureus SCVs colonies were tiny, with decreased pigmentation, and the hemolysis circle was not obvious compared with corresponding parental strains. And SCVs could not be restored to normal-colony phenotype after hemin, menaquinone, or thymidine supplementation. Different rpoB mutations occurred in JP1486 SCVs. Antimicrobial susceptibility testing revealed MICs of SCVs were higher than corresponding parental strains. Besides, the growth ability and virulence of SCVs were lower, and biofilm formation ability of which increased compared with parental strains.Conclusion: S. aureus SCVs share the rifampicin resistance mechanisms with parental strains, although there were some differences in the position of rpoB mutations. Moreover, we found that the biological characteristics of SCVs were significantly different from corresponding parental strains. In contrast, decreased susceptibility to other antibiotics of SCVs was observed during phenotype switch. Furthermore, SCVs incur the fitness cost.Keywords: Staphylococcus aureus, small-colony variant, rifampicin resistance, resistance profile, biological characteristic

Wei Zeng,1,2 Chunyuan Zhang,2 Qingshan Long,3 Yalan Li1 1Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, Guangdong, People’s Republic of China; 2Department of Anesthesiology, Affiliated Boai Hospital of Zhongshan, Southern Medical University, Zhongshan, 528400, Guangdong, People’s Republic of China; 3Department of Neurosurgery, Huizhou Third People’s Hospital, Guangzhou Medical University, Huizhou, 516002, Guangdong, People’s Republic of ChinaCorrespondence: Yalan LiDepartment of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, Guangdong, People’s Republic of ChinaEmail tyalan@jnu.edu.cnObjective: Dexmedetomidine, an α 2-adrenergic receptor agonist, mitigates cognitive dysfunction in elderly patients after surgery with general anesthesia. However, the underlying mechanism by which dexmedetomidine reduces cognitive dysfunction remains to be fully elucidated. The aim of this study was to investigate the effects of dexmedetomidine on lipopolysaccharide (LPS)-induced neuronal dysfunction in cultured hippocampal neurons.Methods: LPS, in the presence and absence of dexmedetomidine, was applied to cultured hippocampal neurons to mimic post-surgical inflammation. Neuronal morphology, including neurite outgrowth and synaptic transmission, was observed, and miniature excitatory postsynaptic currents were recorded by electrophysiological patch-clamp.Results: LPS significantly impaired neurite outgrowth in hippocampal neurons in a concentration- and time-dependent manner, which was reversed by dexmedetomidine treatment. Electrophysiological patch-clamp results showed that LPS induced synaptic transmission dysfunction, which was restored after dexmedetomidine addition. Furthermore, Western blotting assays showed that LPS suppressed the AKT/GSK-3β/CRMP-2 signaling pathway and dexmedetomidine countered the inhibitory effect of LPS by re-activating this pathway.Conclusion: In general, dexmedetomidine protected against the effects of LPS-induced hippocampal neuron damage, including neurite outgrowth and synaptic transmission. Overall, dexmedetomidine modulated the AKT/GSK-3β/CRMP-2 signaling pathway to alleviate LPS-induced neurological dysfunction.Keywords: dexmedetomidine, postoperative cognitive dysfunction, neurological impairment, AKT, GSK-3β, CRMP-2

Jingshan Wei,1 Ye Qiu,1 Wen Zeng,1 Mianluan Pan,1 Jianquan Zhang1,2 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, Pepole’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong 518033, Pepole’s Republic of ChinaCorrespondence: Jianquan ZhangDepartment of Respiratory and Critical Care Medicine, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong 518033, Pepole’s Republic of ChinaTel +86 139 7812 3845Fax +86 0771 535 0031Email jqzhang2002@126.comPurpose: Talaromyces marneffei is a highly invasive fungus, causing fatal mycosis in patients with or without HIV in Southeast and Eastern Asia. However, its presence in patients with systemic lupus erythematosus is rarely reported.Methods: We reported two SLE patients infected by T. marneffei and reviewed other patients reported in the English literature. All cases were pooled for analysis.Results: Eleven patients with SLE infected with T. marneffei infection were identified, including the two presented here. Three were male and eight were female; all were HIV negative. All the patients, except two where data were missing, had received immunosuppressants before T. marneffei infection. The main clinical features included fever, cough, lymph node enlargement, gastrointestinal symptoms, and rash. Five patients were misdiagnosed as having SLE exacerbation. T. marneffei was detected via culture or histopathologic analysis, with the fungus most commonly found in the blood. Seven of the 11 patients were successfully treated by timely antifungal therapy with concomitant SLE control, while four patients who did not receive antifungal therapy died.Conclusion: T. marneffei infection should be excluded when SLE patients, especially if on long-term immunosuppressants, present with fever, cough, lymph node enlargement, gastrointestinal symptoms, and rash. Controlling the lupus and timely antifungal treatment can improve the outcomes of SLE patients with T. marneffei infection.Keywords: Talaromyces marneffei, systemic lupus erythematosus, immunosuppressant

Fan Yang,1 Pengzhen Lei,2 Weihui Zeng,3 Jianwu Gao,1 Na Wu1 1Department of Dermatology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, People’s Republic of China; 2Department of Orthopedics, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, People’s Republic of China; 3Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi 710048, People’s Republic of ChinaCorrespondence: Fan YangDepartment of Dermatology, Shaanxi Provincial People’s Hospital, No. 256 Youyi West Road, Xi’an, Shaanxi 710068, People’s Republic of ChinaEmail fanfanniu1985@126.comPurpose: Long intergenic non-protein-coding RNA 173 (LINC00173) plays crucial roles in lung cancer. However, the expression and biological functions of LINC00173 in melanoma have not yet been investigated. In this study, we aimed to characterize the involvement of LINC00173 in melanoma and elucidate its mechanisms of action.Materials and Methods: Reverse-transcription quantitative PCR was performed to measure LINC00173 expression in melanoma. A CCK-8 assay, flow cytometry, and migration and invasion assays were applied to examine melanoma cell proliferation, apoptosis, migration, and invasion, respectively. A xenograft tumor experiment was performed to determine the tumorous growth of melanoma cells in vivo.Results: We found that LINC00173 was upregulated in melanoma tissues and cell lines. High LINC00173 expression was closely associated with TNM stage, lymph node metastasis, and shorter overall survival of patients with melanoma. Functional assays revealed that LINC00173 downregulation inhibited melanoma cell proliferation, migration, and invasion and induced apoptosis, suggesting that LINC00173 acts as an oncogenic RNA. LINC00173 knockdown retarded the tumorous growth of melanoma cells in vivo. Mechanistically, LINC00173 increased insulin receptor substrate 4 (IRS4) expression by sponging microRNA-493 (miR-493), thereby acting as a competing endogenous RNA. The effects of LINC00173 knockdown on the malignant phenotype of melanoma cells were reversed by overexpression of IRS4 or knockdown of miR-493.Conclusion: The LINC00173–miR-493–IRS4 pathway regulates melanoma characteristics by increasing the expression of IRS4 via competitive binding of LINC00173 to miR-493, suggesting that this pathway is a potential target for the diagnosis, prognosis, and/or treatment of melanoma.Keywords: LINC00173, miR-493, melanoma, therapeutic target

Ye Xu,1 Xiangkuo Zheng,2 Weiliang Zeng,2 Tao Chen,1 Wenli Liao,1 Jiao Qian,1 Jie Lin,1 Cui Zhou,1 Xuebin Tian,2 Jianming Cao,2 Tieli Zhou1 1Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China; 2Department of Medical Laboratory Science, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Jianming Cao; Tieli Zhou Tel +86-577-88069595; +86-577-86689885Email wzcjming@163.com; wyztli@163.comBackground: Heteroresistance is a phenomenon that occurs in all bacteria and can cause treatment failure. Yet, the exact mechanisms responsible for heteroresistance still remain unknown. The following study investigated the mechanisms of imipenem-heteroresistance and -resistance in Pseudomonas aeruginosa clinical isolates from Wenzhou, China.Methods: Imipenem resistance was detected by the agar dilution method; heteroresistance was determined by population analysis profiles. Biofilm formation assay and modified carbapenem inactivation methods were also performed. Polymerase chain reaction (PCR) was conducted to detect oprD, and quantitative real-time PCR was used to determine expression levels of oprD, ampC and four efflux pump coding genes (mexB, mexD, mexE and mexY).Results: Six imipenem-heteroresistant and -resistant P. aeruginosa isolates were selected respectively. Deficient oprD was detected in all resistant isolates and two heteroresistant isolates. No strains produced carbapenemases. Expression levels of oprD were down-regulated in heteroresistant isolates. Transcription levels of the mexE and mexY were significantly increased in all heterogeneous subpopulations compared with their respective native ones. Compared with the susceptible group, increased mean relative expression levels of mexE and mexY or the decreased mean relative expression levels of oprD were observed in the resistant group (P < 0.05), whereas transcription levels of the mexB and mexD remained unchanged.Conclusion: Down-regulation of oprD contributed to the resistance and heteroresistance of imipenem in our P. aeruginosa clinical isolates. In addition, the marginal up-regulation of efflux systems may indirectly affect imipenem resistance. Contrarily, defective oprD was less common in our experimental heteroresistant strains than resistant strains.Keywords: Pseudomonas aeruginosa, imipenem, resistance, heteroresistance, molecular mechanism, oprD

Bingqing Lu,1 Wenqi Zeng,2 Zhuyue Li,3 Jin Wen2 1Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2Institute of Hospital Management, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 3West China Hospital/West China School of Nursing, Sichuan University, Chengdu 610041, People’s Republic of ChinaCorrespondence: Jin Wen Tel/Fax +86-28-85424666Email huaxiwenjin@163.comBackground: Post-traumatic stress disorder (PTSD) is common psychological distress after natural disasters, which is persistent. Chronic PTSD leads to a heavy disease burden. The purpose of this study is to explore the prevalence and influencing factors of chronic PTSD among survivors in the hard-hit areas ten years after the Wenchuan earthquake.Materials and Methods: A cross-sectional survey was conducted on residents aged 16 or above in hard-hit areas through a multi-stage sampling approach ten years after the Wenchuan earthquake. The items of the questionnaire included demographic characteristics and earthquake exposure factors, and the PTSD Checklist-Civilian Version (PCL-C) was used to evaluate the PTSD of the respondents.Results: A total of 1039 complete questionnaires were obtained. The median age of 1039 respondents was 60 years, 63.2% of whom were female, 70.2% were illiterate or had received primary education, and 58% had an annual household income of less than 20,000 yuan (US$ 2871.3). The rate of PTSD was 9.1% (95/1039). After controlling for confounding factors, it was found that higher income level and education level, and moving to concentrated rural settlement (CRS) after the earthquake might be protective factors for the long-term mental health of survivors in the hard-hit areas, and the loss of immediate families in the earthquake was an important risk factor.Conclusion: Even though ten years have passed since the Wenchuan earthquake, the survivors in the hard-hit areas still have a serious mental disorder. The local government and health-care institutions should take appropriate measures to improve the mental health of residents.Keywords: Wenchuan earthquake, natural disaster, mental health, post-traumatic stress disorder, PTSD

Yanping Tang,* Hui Zhang,* Haiguang Xu, Wen Zeng, Ye Qiu, Caimei Tan, Shudan Tang, Jianquan Zhang Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianquan ZhangDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of ChinaTel/ Fax +86 7715350031Email jqzhang2002@126.comBackground: Dendritic cells (DCs) with both proinflammatory and tolerogenic properties have been implicated in modulation of CD4+ T cell responses in many fungal diseases. However, the role of DC in the context of Talaromyces marneffei (T. marneffei) infection has not been determined. In this study, we aimed to study the effect of the yeast form of T. marneffei yeasts on DCs, as well as the role of DCs in modulating T helper 17 (Th17) and regulatory T (Treg) cell responses to the pathogen.Methods: Mouse bone marrow-derived DCs were stimulated with T. marneffei yeasts for 24 h. Frequencies of CD80 and CD86 expression on DCs and the levels of IL-6, IL-10 and TGF-β in the culture supernatant of yeast-stimulated DCs were detected by flow cytometry and ELISA, respectively. In co-culture experiments, CD4+ T lymphocytes of mice were isolated from the spleen using magnetic beads and co-cultured with T. marneffei yeasts, with or without DCs for 24 h. The proportions of Th17 and Treg cells in co-culture were detected by flow cytometry. The mRNA levels of RORγt and Foxp3 were detected by RT-PCR. Levels of IL-10 and TGF-β in the co-culture supernatant were detected by ELISA.Results: The expressions of CD80 and CD86 on DCs were increased, as well as IL-6, IL-10 and TGF-β levels in the culture supernatant of T. marneffei-stimulated DCs were higher than those in DCs cultured without T. marneffei. In co-culture experiments, in the presence of DCs, T. marneffei promoted Treg expansion and Foxp3 up-regulation but limited Th17 and downregulated RORγt. Levels of IL-10 and TGF-β were higher in the co-culture containing DCs than without DCs.Conclusion: Our findings demonstrated that the interaction between DCs and T. marneffei could promote Treg expansion but not Th17 generation. These findings provide a mechanism by which DCs may promote immune tolerance in T. marneffei infection.Keywords: dendritic cells, Talaromyces marneffei, Th17 cells, Treg cells

Mianluan Pan, Ye Qiu, Wen Zeng, Shudan Tang, Xin Feng, Jingmin Deng, Xuan Wei, Zhiyi He, Jianquan Zhang Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of ChinaCorrespondence: Jianquan ZhangDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of ChinaTel +86 139 7812 3845Fax +86 0771 535 0031Email jqzhang2002@126.comPurpose: Talaromyces marneffei (T.M) is an intracellular opportunistic fungus that causes invasive mycosis in patients with or without human immunodeficiency virus (HIV) infection. Hemophagocytic lymphohistiocytosis (HLH) caused by T.M infection is extremely rare. Here, we analyzed the clinical features, immune mechanisms, treatment, and prognosis related to this comorbidity.Patients and Methods: This retrospective study was conducted between August 2012 and February 2019 at multiple research centers. Patients who presented with culture and/or histopathological proof of talaromycosis-associated HLH were included.Results: HIV-negative patients (n = 126) were enrolled. Of nine patients with T.M infection combined with secondary HLH, six were preschool children (five boys and one girl), and three were adults (two men and one woman). Seven of these nine had underlying diseases or recurrent infections. The most common symptoms were fever, anemia, hypoproteinemia, cough, weight loss, oral thrush, lymphadenopathy, hepatomegaly, splenomegaly, digestive symptoms, joint pain, and dyspnea. All patients showed reduced hemoglobin concentrations and platelet numbers. Liver dysfunction, hyperferritinemia, elevated lactate dehydrogenase, and low natural killer cell numbers were observed. Eight of nine patients received antifungal therapy, one patient did not receive therapy, and two of nine patients received anti-HLH therapy. Four died during treatment.Conclusion: T.M fungemia associated with HLH was related to high mortality. Once diagnosed, timely and effective antifungal treatments and supportive care are essential.Keywords: Talaromyces marneffei, hemophagocytic lymphohistiocytosis, human immunodeficiency virus, prognosis

Oscar Olvera-Montaño,1 Leopoldo Baiza-Duran,1 Juan D Quintana-Hau,2 Mayra G Quiñonez-Alvarado,2 Wen Zeng,3 Li Gong,3 Patricia Muñoz-Villegas1 1Clinical Research Department, Laboratorios Sophia, SA De CV, Zapopan, Jalisco, Mexico; 2Research and Development Department (CIS), Zapopan, Jalisco, Mexico; 3Sichuan Primed Shines Bio-Tech Co, Ltd, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Patricia Muñoz-VillegasLaboratorios Sophia, SA de CV, Paseo del Norte 5255, Guadalajara Technology Park, Zapopan 45010, Jalisco, MexicoTel +52 3301 4200, Ext: 1018Fax +52 3301 4200Email patricia.munoz@sophia.com.mxPurpose: To evaluate the efficacy of a therapy on improving characteristics of laser-induced choroidal neovascularization (CNV) via single intravitreal injection of a humanized anti-human VEGF monoclonal antibody (PRO-169) versus bevacizumab in a rhesus monkey model.Methods: To induce experimental CNV, small high-energy laser spots were used to treat several areas, around the macula in the retinas of monkeys at Day −21. Eighteen rhesus monkeys were used for CNV induction. The efficacy endpoints were fluorescein leakage by FFA and retinal thickness by OCT. FFA examinations were performed 19 days after induction. Appropriate animals were enrolled for treatment and randomly divided into 3 groups: bevacizumab (n=5, 7 eyes), PRO-169 (n=5, 7 eyes), and vehicle controls (n=4, 7 eyes).Results: In 25 of 36 (69.4%) eyes, CNV lesions were identified. The average percent change of retinal thickness in the eyes of bevacizumab group was −159.3±62.2% and −154.0±45.1% (p

Shudan Tang,* Tingting Ma,* Hui Zhang,* Jianquan Zhang, Xiaoning Zhong, Caimei Tan, Ye Qiu, Wen Zeng, Xin Feng Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianquan ZhangDepartment of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Qingxiu, Nanning, Guangxi 530021, People’s Republic of ChinaTel/Fax +86 771 535 1176Email jqzhang2002@126.comPurpose: Elastin peptides (EP) can induce lung inflammation and emphysema. Erythromycin has been shown to decrease acute exacerbation frequency and delay lung function decline in chronic obstructive pulmonary disease patients and ameliorate emphysema in murine models; however, the mechanism remains unclear. We aimed to observe the preventive and immunomodulatory effects of erythromycin in a mouse model of EP-induced emphysema.Methods: In the in vivo study, Balb/c mice were treated with EP intranasally on day 0, and then administered erythromycin (100 mg/kg) or vehicle orally on day 1, which was continued every other day. Mice exposed to cigarette smoke were used as an emphysema positive control. The severity of emphysema and inflammation in the lungs of EP-exposed mice with or without erythromycin treatment were observed on day 40 after EP administration. In the in vitro study, naïve CD4+T cells were isolated from healthy mice spleens and stimulated by EP with or without erythromycin incubation. Flow cytometry was used to measure the proportions of Th1, Th17, and Treg cells. ELISA was used to detect cytokine levels of IFN-γ, IL-17, IL-6, and TGF-β. Transcript levels of Ifnγ, IL17a, and Foxp3 were evaluated by qRT-PCR.Results: After exposure to EP, Th1 and Th17 cell percentages and the levels of inflammatory cytokines increased in vivo and in vitro, while Treg cells decreased in vivo. Erythromycin reduced IFN-γ, IL-17, IL-6 inflammatory cytokines, MLI, and the inflammation score in the lungs of EP-exposed mice. In vitro, erythromycin also limited Th17 and Th1 cell differentiation and downregulated transcript levels of Ifnγ and IL17a in the EP-stimulated CD4+T cells.Conclusion: The Th1 and Th17 cell responses were increased in EP-induced emphysema. Prophylactic use of erythromycin effectively ameliorated emphysema and modulated CD4+T cells responses in EP-induced lung inflammation in mice.Keywords: Th1, Th17, Treg cells, inflammation, lungs

Yang F, Lei P, Zeng W, Gao J, Wu N. Cancer Manag Res. 2020;12:3131–3144. The Editor and Publisher of Cancer Management and Research wish to retract the published article. Concerns were raised over the tumor xenograft data presented in the article. The authors responded to our initial queries but were unable to provide satisfactory original data for their study. Given concerns relating to the validity of the study’s findings the Editor advised for the article to be retracted. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Jing Jiang,1 Yimeng Xia,2 Yi Liang,1 Meiling Yang,1 Wen Zeng,1 Xiaocong Zeng3 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China; 2Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People’s Republic of China; 3Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China Purpose: miR-190a-5p expression alters dynamically in response to hypoxia. However, the role of miR-190a-5p expression in hypoxia-induced pulmonary hypertension (PH) remains unclear. We sought to correlate the miR-190a-5p expression levels with the severity, diagnosis, and prognosis of PH in relation to chronic obstructive pulmonary disease (COPD-PH). Additionally, we evaluated the effect of miR-190a-5p through in vitro experiments on human pulmonary endothelial cells (HPECs) that were exposed to hypoxia and in vivo experiments using an animal model of hypoxia-induced PH.Methods: Circulating miR-190a-5p levels were measured from 73 patients with PH and 32 healthy controls through quantitative real-time PCR. The levels of miR-190a-5p and the expression of Krüppel-like factor 15 (KLF15) were analyzed in HPECs that were exposed to hypoxia, and the effects of antagomir-190a-5p in mice with chronic hypoxia-induced PH were tested. Target gene analysis was performed by Western blot and luciferase assay.Results: The miR-190a-5p level was significantly higher in patients with COPD-PH than in the healthy controls. Higher miR-190a-5p levels were associated with a greater severity of COPD-PH. In vitro experiments on HPECs showed that exposure to hypoxia increased the miR-190a-5p levels significantly. KLF15 was validated as a target of miR-190a-5p. Transfection with miR-190a-5p mimicked inhibition of KLF15 expression in HPECs. In the mouse model of PH, antagomir-190a-5p reduced right ventricular systolic pressure and enhanced the KLF15 expression levels in lung tissue.Conclusion: miR-190a-5p regulates hypoxia-induced PH by targeting KLF15. The circulating levels of miR-190a-5p correlate with the severity of COPD-PH, thereby confirming the diagnostic and prognostic value of this parameter in COPD-PH. Keywords: hypoxia, pulmonary hypertension, COPD, miR-190a-5p, KLF15

Zhongyang Liu,1,* Shu Zhu,1,* Liang Liu,2,* Jun Ge,3,4,* Liangliang Huang,1 Zhen Sun,1 Wen Zeng,5 Jinghui Huang,1 Zhuojing Luo1 1Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 2Department of Orthopedics, No 161 Hospital of PLA, Wuhan, Hubei, 3Department of Orthopedics, No 323 Hospital of PLA, Xi’an, Shaanxi, 4Department of Anatomy, Fourth Military Medical University, Xi’an, Shaanxi, 5Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China *These authors contributed equally to this work Abstract: Peripheral nerve repair is still challenging for surgeons. Autologous nerve transplantation is the acknowledged therapy; however, its application is limited by the scarcity of available donor nerves, donor area morbidity, and neuroma formation. Biomaterials for engineering artificial nerves, particularly materials combined with supportive cells, display remarkable promising prospects. Schwann cells (SCs) are the absorbing seeding cells in peripheral nerve engineering repair; however, the attenuated biologic activity restricts their application. In this study, a magnetic nanocomposite scaffold fabricated from magnetic nanoparticles and a biodegradable chitosan–glycerophosphate polymer was made. Its structure was evaluated and characterized. The combined effects of magnetic scaffold (MG) with an applied magnetic field (MF) on the viability of SCs and peripheral nerve injury repair were investigated. The magnetic nanocomposite scaffold showed tunable magnetization and degradation rate. The MGs synergized with the applied MF to enhance the viability of SCs after transplantation. Furthermore, nerve regeneration and functional recovery were promoted by the synergism of SCs-loaded MGs and MF. Based on the current findings, the combined application of MGs and SCs with applied MF is a promising therapy for the engineering of peripheral nerve regeneration. Keywords: peripheral nerve repair, magnetic nanoparticle, nanocomposite, magnetic field, Schwann cell, functional recovery

Ronglin Wang,1,* Yuqian Li,1,* Gang Zhu,1,* Bo Tian,1 Wen Zeng,1 Yang Yang,2 Zhihong Li1 1Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 2Department of Neurosurgery, The 451th hospital of PLA, Xi’an, Shaanxi, People’s Republic of China *These authors contributed equally to this work Background: Previous studies have demonstrated that long noncoding RNA cancer susceptibility candidate 2 (lncRNA CASC2) is frequently downregulated in several types of tumors and functions as a tumor-suppressive factor. However, the clinical significance and function of CASC2 in human glioma remain largely unknown. The purpose of this study was to identify the clinical values of CASC2, as well as investigate the potential molecular mechanisms in glioma. Methods: This retrospective study first analyzed the expression levels of CASC2 using quantitative real-time polymerase chain reaction. Then, CASC2 expression levels were associated with various clinicopathologic characteristics and the survival rate of patients with glioma. Finally, the function and underlying molecular mechanisms of CASC2 in human glioma were investigated in U251 cell line. Results: By quantitative real-time polymerase chain reaction analysis, our data showed that CASC2 expression was significantly downregulated in glioma tissues and cell lines (U87 and U251) compared to adjacent normal brain tissues or normal human astrocytes. Moreover, its expression negatively correlated with tumor grade in glioma patients. Furthermore, Kaplan–Meier curves with log-rank analysis revealed a close correlation between downregulated CASC2 and shorter survival time in glioma patients. In addition, Cox regression analysis indicated that CASC2 could be considered as an independent risk factor for poor prognosis. Finally, in vitro experiment demonstrated that CASC2 overexpression remarkably suppressed glioma cell proliferation, migration, and invasion through suppressing Wnt/β-catenin signaling pathway. Conclusion: This study suggested that CASC2 may potentially serve as a valuable diagnostic and prognostic biomarker and a therapeutic target for glioma patients. Keywords: glioma, lncRNA, CASC2, biomarker, Wnt/β-catenin

Yan Zhao,1,* Yue Zhang,2,* Gaofeng Qin,1 Jinjun Cheng,1 Wenhao Zeng,2 Shuchen Liu,1 Hui Kong,1 Xueqian Wang,1 Qingguo Wang,1 Huihua Qu3 1School of Basic Medical Sciences, 2School of Chinese Materia Medica, 3Center of Scientific Experiment, Beijing University of Chinese Medicine, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: The unique features of quantum dots (QDs) make them desirable fluorescent tags for cell and developmental biology applications that require long-term, multitarget, and highly sensitive imaging. In this work, we imaged fluorescent cadmium telluride/zinc sulfide (CdTe/ZnS) QDs in organs, tissues, and cells, and analyzed the mechanism of their lymphatic uptake and cellular distribution. We observed that the fluorescent CdTe/ZnS QDs were internalized by lymph nodes in four cell lines from different tissue sources. We obtained the fluorescence intensity–QD concentrations curve by quantitative analysis. Our results demonstrate that cells containing QDs can complete mitosis normally and that distribution of QDs was uniform across cell types and involved the vesicular transport system, including the endoplasmic reticulum. This capacity for CdTe/ZnS QD targeting provides insights into the applicability and limitations of fluorescent QDs for imaging biological specimens. Keywords: quantum dots, lymph nodes, fluorescence imaging, biodistribution

Zhen-hua Zhou,1 Jing Peng,1 Zhao-you Meng,1 Lin Chen,1 Jia-Lu Huang,1 He-qing Huang,1 Li Li,2 Wen Zeng,2 Yong Wei,2 Chu-Hong Zhu,2 Kang-Ning Chen1 1Department of Neurology, Cerebrovascular Disease Research Institute, Southwest Hospital, 2Department of Anatomy, Key Laboratory for Biomechanics of Chongqing, Third Military Medical University, Chongqing, People’s Republic of China Background: Carotid artery stenosis is a major risk factor for ischemic stroke. Although carotid angioplasty and stenting using an embolic protection device has been introduced as a less invasive carotid revascularization approach, in-stent restenosis limits its long-term efficacy and safety. The objective of this study was to test the anti-restenosis effects of local stent-mediated delivery of the A20 gene in a porcine carotid artery model.Materials and methods: The pCDNA3.1EHA20 was firmly attached onto stents that had been collagen coated and treated with N-succinimidyl-3-(2-pyridyldithiol)propionate solution and anti-DNA immunoglobulin fixation. Anti-restenosis effects of modified vs control (the bare-metal stent and pCDNA3.1 void vector) stents were assessed by Western blot and scanning electron microscopy, as well as by morphological and inflammatory reaction analyses.Results: Stent-delivered A20 gene was locally expressed in porcine carotids in association with significantly greater extent of re-endothelialization at day 14 and of neointimal hyperplasia inhibition at 3 months than stenting without A20 gene expression.Conclusion: The A20-gene-eluting stent inhibits neointimal hyperplasia while promoting re-endothelialization and therefore constitutes a novel potential alternative to prevent restenosis while minimizing complications. Keywords: restenosis, A20, gene therapy, stent, endothelialization

Yushu Chen,1 Li Gong,2 Ning Gao,3 Jichun Liao,1 Jiayu Sun,1 Yuqing Wang,1 Lei Wang,1 Pengjin Zhu,1 Qing Fan,1 Yongqiang Andrew Wang,4 Wen Zeng,2 Hui Mao,3 Lily Yang,5 Fabao Gao11Molecular Imaging Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, 2Sichuan Primed Bio-Tech Group Co, Ltd, Chengdu, People’s Republic of China; 3Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, 4Ocean NanoTech, LLC, San Diego, CA, 5Department of Surgery, Emory University School of Medicine, Atlanta, GA, USAPurpose: To translate a recombinant peptide containing the amino-terminal fragment (ATF) of urokinase plasminogen activator receptor-targeted magnetic iron oxide (IO) nanoparticles (uPAR-targeted human ATF-IONPs) into clinical applications, we conducted a pilot study to evaluate the toxicity and pharmacokinetics of this nanoparticle in normal rhesus monkeys.Methods: We assessed the changes in the following: magnetic resonance imaging (MRI) signals from pretreatment stage to 14 days posttreatment, serum iron concentrations from 5 minutes posttreatment to 12 weeks posttreatment, routine blood examination and serum chemistry analysis results from pretreatment stage to 12 weeks after administration, and results of staining of the liver with Perls’ Prussian Blue and hematoxylin–eosin at 24 hours and 3 months posttreatment in two rhesus monkeys following an intravenous administration of the targeted nanoparticles either with a polyethylene glycol (ATF-PEG-IONP) or without a PEG (ATF-IONP) coating.Results: The levels of alkaline phosphatase, alanine transaminase, and direct bilirubin in the two monkeys increased immediately after the administration of the IONPs but returned to normal within 20 days and stayed within the normal reference range 3 months after the injection. The creatinine levels of the two monkeys stayed within the normal range during the study. In addition, red blood cells, white blood cells, hemoglobin level, and platelets remained normal during the 3 months of the study.Conclusion: All of the results suggest that a transient injury in terms of normal organ functions, but no microscopic necrotic lesions, was observed at a systemic delivery dose of 5 mg/kg of iron equivalent concentration in the acute phase, and that no chronic toxicity was found 3 months after the injection. Therefore, we conclude that uPAR-targeted IONPs have the potential to be used as receptor-targeted MRI contrasts as well as theranostic agents for the detection and treatment of human cancers in future studies. Keywords: uPAR-IONP, nonhuman primates, transient harm, self-healing

Wei Zeng,1,2,* Jinfeng Zhu,3,* Li Shan,2 Zhigang Han,2 Patiguli Aerxiding,2 Amina Quhai,2 Fanye Zeng,4 Ziwei Wang,5 Huiwu Li6 1College of Public Health, Xinjiang Medical University, Xinjiang, People’s Republic of China; 2First Department of Lung Cancer Chemotherapy, The Affiliated Cancer Hospital of Xinjiang Medical University, Xinjiang, People’s Republic of China; 3Department of Gastrointestinal Surgery, The Affiliated Cancer Hospital of Xinjiang Medical University, Xinjiang, People’s Republic of China; 4Department of Oncology, Traditional Chinese Medical Hospital Affiliated to Xinjiang Medical University, Xinjiang, People’s Republic of China; 5Department of Gastrointestinal Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 6School of Basic Medicine, Xinjiang Medical University, Xinjiang, People’s Republic of China *These authors contributed equally to this work Background: CDH1 is a protein encoded by the CDH1 gene in humans. Loss of CDH1 function contributes to cancer progression by increasing proliferation, invasion, and/or metastasis. However, the association and clinicopathological significance between CDH1 hypermethylation and gastric cancer (GC) remains unclear. In this study, we systematically reviewed the studies of CDH1 hypermethylation and GC, and evaluated the association between CDH1 hypermethylation and GC using meta-analysis methods.Methods: A comprehensive search of the PubMed and Embase databases was performed for publications up to July 2014. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analyses of pooled data were performed. Odds ratios (ORs) were calculated and summarized.Results: A final analysis of 1,079 GC patients from 14 eligible studies was performed. CDH1 hypermethylation level in the cancer group was significantly higher compared to the normal gastric mucosa (OR =8.55, 95% confidence interval [CI]: 2.39–33.51, Z=5.47, P

C22H34CdN4O6, monoclinic, P121/n1 (no. 14), a = 9.236(4) Å, b = 21.102(9) Å, c = 12.987(6) Å, β = 97.638(6)°, V = 2508.7 Å3, Z = 4, Rgt(F) = 0.039, wRref(F2) = 0.117, T = 298 K.