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Huan Tang, Yizhuo Xie, Ming Zhu, Juan Jia, Rui Liu, Yujia Shen, Yucui Zheng, Xin Guo, Dongfanghui Miao, Jin Pei Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Jin Pei, Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, 1163 Xinmin Street, Changchun, 130021, People’s Republic of China, Tel +86 431 85619725, Email peijin@jlu.edu.cnPurpose: Ovarian cancer is the most lethal gynecologic malignancy. The combination of paclitaxel (PTX) and carboplatin (CBP) is the first-line remedy for clinical ovarian cancer. However, due to the limitations of adverse reaction and lacking of targeting ability, the chemotherapy of ovarian cancer is still poorly effective. Here, a novel estrone (ES)-conjugated PEGylated liposome co-loaded PTX and CBP (ES-PEG-Lip-PTX/CBP) was designed for overcoming the above disadvantages.Methods: ES-PEG-Lip-PTX/CBP was prepared by film hydration method and could recognize estrogen receptor (ER) over-expressing on the surface of SKOV-3 cells. The characterizations, stability and in vitro release of ES-PEG-Lip-PTX/CBP were studied. In vitro cellular uptake and its mechanism were observed by fluorescence microscope. In vivo targeting effect in tumor-bearing mice was determined. Pharmacokinetics and biodistribution were studied in ICR mice. In vitro cytotoxicity and in vivo anti-tumor efficacy were evaluated on SKOV-3 cells and tumor-bearing mice, respectively. Finally, the acute toxicity in ICR mice was explored for assessing the preliminary safety of ES-PEG-Lip-PTX/CBP.Results: Our results showed that ES-PEG-Lip-PTX/CBP was spherical shape without aggregation. ES-PEG-Lip-PTX/CBP exhibited the optimum targeting effect on uptake in vitro and in vivo. The pharmacokinetics demonstrated ES-PEG-Lip-PTX/CBP had improved the pharmacokinetic behavior. In vitro cytotoxicity showed that ES-PEG-Lip-PTX/CBP maximally inhibited SKOV-3 cell proliferation and its IC50 values was 1.6 times lower than that of non-ES conjugated liposomes at 72 h. The in vivo anti-tumor efficacy study demonstrated that ES-PEG-Lip-PTX/CBP could lead strong SKOV-3 tumor growth suppression with a tumor volume inhibitory rate of 81.8%. Meanwhile, acute toxicity studies confirmed that ES-PEG-Lip-PTX/CBP significantly reduced the toxicity of the chemo drugs.Conclusion: ES-PEG-Lip-PTX/CBP was successfully prepared with an optimal physicochemical and ER targeting property. The data of pharmacokinetics, anti-tumor efficacy and safety study indicated that ES-PEG-Lip-PTX/CBP could become a promising therapeutic formulation for human ovarian cancer in the future clinic.Graphical Abstract: Keywords: ovarian cancer, combination therapy, drug delivery system, liposome, estrogen receptor

Yu Pang,1 Rongmei Liu,2 Yanhua Song,2 Zizheng Lv,2 Mengqiu Gao,2 Lihui Nie,2 Qiping Ge,2 Xiaoguang Wu2 1Department of Science and Technology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China; 2Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of ChinaCorrespondence: Lihui Nie; Xiaoguang Wu, Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, People’s Republic of China, Tel +86-10-8950 9322 ; +86-10-8950 9122, Email nielihui666@sohu.com; yuewxg@hotmail.comObjective: Cycloserine (CS) is a group B anti-tuberculosis (TB) drug endorsed by the World Health Organization (WHO) for the treatment of drug-resistant (DR)-TB. Despite CS widespread acceptance and known efficacy, the high potential of drug-associated psychiatric disorders is a major concern to multidrug-resistant (MDR)-TB patients. In this study, we investigated CS-associated psychiatric disorders in a cohort of MDR-TB patients in Beijing, China. Our aim was to determine psychiatric disorder prevalence rates and associated risk factors in this population.Methods: This MDR-TB cohort study was conducted at Beijing Chest Hospital between February 2018 and February 2021. All patients received individualized treatment regimens that included CS at some point during the full treatment course. Patient psychological status was assessed using the Symptom Checklist (SCL-90) questionnaire during the post-treatment follow-up period.Results: Two hundred and thirty-seven MDR-TB patients were included in the final analysis. Overall, psychiatric disorders were recorded in 22 (9.28%) of the 237 patients in our cohort, with severity grades of 1 or 2 observed for the majority (8.44%) of psychiatric adverse events. As compared to results obtained for control group patients who were ≥ 40 years of age, patients who were < 40 years of age (77.3%, 17/22) were more likely to experience psychiatric disorders [adjusted odds ratio (aOR) = 3.060; 95% CI (1.060– 8.828)]. Additionally, patients with body mass index (BMI)s of < 18.5 kg/m2 [aOR = 3.824; 95% CI (1.502– 9.739)] had significantly higher odds of being afflicted with psychiatric disorders as compared with patients with BMIs that were ≥ 18.5 kg/m2.Conclusion: Our results demonstrated that approximately one-tenth of Chinese MDR-TB patients experienced psychiatric disorders during CS treatment, with the majority of adverse events of moderate severity. In addition, low BMI and age < 40 years were identified as independent risk factors for psychiatric disorders in MDR-TB patients receiving CS therapy.Keywords: cycloserine, multidrug-resistant tuberculosis, incidence, risk factor, psychiatric disorder

Yixin Sun,1,* Runzhu Liu,1,* Nanze Yu,1 Dingyue Zhang,2 Juan Chen,3 Jiuzuo Huang,1 Xiao Long1 1Division of Plastic Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Clinical Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Institute of Medical Information/Medical Library, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiuzuo Huang; Xiao Long, Division of Plastic Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, No. 1, Shuaifuyuan, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel/Fax +86-1069158730, Email hjz1983@126.com; pumclongxiao@126.comPurpose: Incisional double eyelid blepharoplasty is the most common cosmetic operation in East Asia. Although numerous articles on surgical techniques have been published, complications, such as fold loss, asymmetry, and visible scars, still exist. To create a stable and dynamic double-eyelid crease, the author has introduced a modified technique of double-eyelid blepharoplasty.Patients and Methods: The authors introduced a new surgical technique to reduce complications and create reliable and dynamic double eyelids. The orbicularis oculi muscle of the lower flap was anchored on the tarsus and sutured with the distal part of the septal flap. The skin incision was closed by skin–septal flap–skin suture. Postoperative evaluations were assessed at the twelfth postoperative month.Results: One hundred ninety-three patients underwent double eyelidplasty with the TOS fixation technique. The mean follow-up duration was 18.6 months (range, 12– 30 months). In the aesthetic outcome evaluation, 88 (45.6%) patients had very much improved results, 56 (29.0%) had much improved results, 29 (15.0%) had improved results, 8 (4.1%) had no change and 12 (6.2%) had worse results. Complications included crease asymmetry (n=7, 3.6%), partial fold loss (n=8, 4.1%) and complete fold loss (n =5, 2.6%).Conclusion: Tarsus-orbicularis-septum (TOS) fixation is a reliable and flexible surgical technique for creating stable and dynamic double-eyelid creases.Keywords: double eyelidplasty, primarily blepharoplasty, orbital septum, tarsus

Dan Mu,1,&ast; Xin Wang,1,&ast; Huiting Wang,1 Xuan Sun,2 Qing Dai,2 Pin Lv,1 Renyuan Liu,1 Yu Qi,2 Jun Xie,2 Biao Xu,2,3 Bing Zhang1,4 1Department of Radiology, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People’s Republic of China; 2Department of Cardiology, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People’s Republic of China; 3State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, 210023, People’s Republic of China; 4Institute of Brain Science, Nanjing University, Nanjing, Jiangsu, 210008, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Biao Xu; Bing Zhang, Email xubiao62@nju.edu.cn; zhangbing_nanjing@nju.edu.cnBackground: Photodynamic therapy (PDT) has achieved continued success in the treatment of tumors, but its progress in the treatment of atherosclerosis has been limited, mainly due to the low tissue-penetration ability of the excitation light for photosensitizers.Methods: In this study, we designed a chemiexcited system producing singlet oxygen in an attempt to apply PDT for the treatment of atherosclerosis without the irradiation of external light. The system designed was polymeric nanoparticles (NPs) equipped with chemical fuel and photosensitizers, cross-linked with an Fe3+–catechol complex for stabilization and magnetic resonance imaging (MRI).Results: The system (FeCNPs for short) accumulated effectively in plaques, providing persistent and enhanced T1-weighted contrast ability. FeCNPs also prevented progression of atherosclerosis via macrophage elimination, and obviously reduced plaque size and thickness revealed by T1-weighted MRI. Expression of CD68, MCP1, and TNFα was significantly reduced after treatment. However, low doses of FeCNPs exhibited better therapeutic efficacy than high doses. Furthermore, low-dose FeCNPs exhibited effective macrophage elimination in aortic arches and abdominal aortae, but inefficiency in the thoracic aorta, aortic hiatus, and aorta–iliac bifurcation.Conclusion: This study provides the first example of a combination of MRI and chemiexcited PDT for atherosclerosis, evidencing the effectiveness of PDT and providing significant pointers for developing nanotherapy on atherosclerosis.Keywords: photodynamic therapy, atherosclerosis, chemi-excited, macrophages, MRI

Junyi Jiang,1– 5,&ast; WeiJun Zhong,1– 4,&ast; WeiHua Huang,1– 4 Yongchao Gao,1– 4 Yijing He,1– 4 Xi Li,1– 4 Zhaoqian Liu,1– 4 Honghao Zhou,1– 4 Yacheng Fu,1,6 Rong Liu,1– 4 Wei Zhang1– 4 1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, People’s Republic of China; 3Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, People’s Republic of China; 4National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, People’s Republic of China; 5Aier Eye Institute, Changsha, Hunan, People’s Republic of China; 6Cofoe Medical Technology Co., Ltd, Changsha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Zhang; Rong Liu, Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China, Tel +86 731 84805380, Fax +86 731 82354476, Email csuzhangwei@csu.edu.cn; csuliurong@csu.edu.cnPurpose: To identify more objectively predictive factors of severe outcome among patients hospitalized for coronavirus disease 2019 (COVID-19).Patients and Methods: A retrospective cohort of 479 hospitalized patients diagnosed with COVID-19 in Hunan Province was selected. The prognostic effects of factors such as age and laboratory indicators were analyzed using the Kaplan–Meier method and Cox proportional hazards model. A prognostic nomogram model was established to predict the progression of patients with COVID-19.Results: A total of 524 patients in Hunan province with COVID-19 from December 2019 to October 2020 were retrospectively recruited. Among them, 479 eligible patients were randomly assigned into the training cohort (n = 383) and validation cohort (n = 96), at a ratio of 8:2. Sixty-eight (17.8%) and 15 (15.6%) patients developed severe COVID-19 after admission in the training cohort and validation cohort, respectively. The differences in baseline characteristics were not statistically significant between the two cohorts with regard to age, sex, and comorbidities (P > 0.05). Multivariable analyses included age, C-reactive protein, fibrinogen, lactic dehydrogenase, neutrophil-to-lymphocyte ratio, urea, albumin-to-globulin ratio, and eosinophil count as predictive factors for patients with progression to severe COVID-19. A nomogram was constructed with sufficient discriminatory power (C index = 0.81), and proper consistency between the prediction and observation, with an area under the ROC curve of 0.81 and 0.86 in the training and validation cohort, respectively.Conclusion: We proposed a simple nomogram for early detection of patients with non-severe COVID-19 but at high risk of progression to severe COVID-19, which could help optimize clinical care and personalized decision-making therapies.Keywords: nomogram, COVID-19, SARS-CoV-2, C-reactive protein, predictive model

Ruhan Liu,1,2,&ast; Chenyang Li,1,&ast; Huajun Xu,1 Kejia Wu,1 Xinyi Li,1 Yupu Liu,1 Jie Yuan,1 Lili Meng,1 Jianyin Zou,1 Weijun Huang,1 Hongliang Yi,1 Bin Sheng,2 Jian Guan,1 Shankai Yin1 1Department of Otolaryngology Head and Neck Surgery and Shanghai Key Laboratory of Sleep Disordered Breathing & Otolaryngological Institute of Shanghai Jiao Tong University, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China; 2Department of Computer Science and Engineering, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Sheng; Jian Guan, Tel +86 13124853285, Email shengbin@sjtu.edu.cn; guanjian0606@sina.comPurpose: Misdiagnosis and missed diagnosis of sleep-disordered breathing (SDB) is common because polysomnography (PSG) is time-consuming, expensive, and uncomfortable. The use of recording methods based on the oxygen saturation (SpO2) signals detected by wearable devices is impractical and inaccurate for extracting signal features and detecting apnoeic events. We propose a method to automatically detect the apnoea-based SpO2 signal segments and compute the apnoea–hypopnea index (AHI) for SDB screening and grading.Patients and Methods: First, apnoea-related desaturation segments in raw SpO2 signals were detected; global features were extracted from whole night signals. Then, the SpO2 signal segments and global features were fed into a bi-directional long short-term memory convolutional neural network model to identify apnoea-related and non-apnoea-related events. The apnoea-related segments were used to assess the AHI.Results: The model was trained on 500 individuals and tested on 8131 individuals from two public hospitals and one private centre. In the testing data, the classification accuracy for apnoea-related segments was 84.3%. Individuals with SDB (AHI 15) were identified with a mean accuracy of 88.95%.Conclusion: Using automatic SDB detection based on SpO2 signals can accurately screen for SDB.Keywords: sleep apnea hypopnea syndrome, AHI, SDB severity classification, Bi-LSTM-CNN, desaturation events

Yu Qin,1,2,&ast; Rui Liu,1,2,&ast; Yongxiang Wang,1– 3 Jiyou Tang,4 Lin Cong,1– 3 Juan Ren,1,2 Shi Tang,1– 3 Yifeng Du1– 3 1Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Neurological Diseases, Jinan, Shandong, People’s Republic of China; 4Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yifeng Du; Shi Tang, Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, No. 324 Jingwuweiqi Road, Jinan, Shandong, 250021, People’s Republic of China, Tel +86 531 68776354 ; +86-18678780912, Fax +86 531 68776354, Email duyifeng2013@163.com; tangshi@sdfmu.edu.cnPurpose: To investigate the cross-sectional associations of self-reported sleep characteristics with cardiovascular diseases (CVDs) and cardiovascular multimorbidity in older adults living in rural Eastern China.Patients and Methods: This population-based study included 4618 participants (age ≥ 65 years; 56.5% women) living in rural Eastern China. In March–September 2018, data were collected through interviews, clinical examinations, neuropsychological testing, and laboratory tests. Sleep parameters were assessed using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Score, and Berlin questionnaire. Coronary heart disease (CHD), heart failure (HF), and stroke were defined according to in-person interviews, clinical and neurological examinations, and electrocardiogram examination. Data were analyzed using logistic regression and restricted cubic spline regression.Results: CHD was diagnosed in 991 participants, HF in 135 participants, and stroke in 696 participants. The multivariable-adjusted odds ratio (OR) of CHD was 1.27 (95% CI, 1.09– 1.49) for sleep duration ≤ 6 hours/night (vs > 6– 8 hours/night), 1.40 (1.20– 1.62) for poor sleep quality, and 1.22 (1.04– 1.43) for high risk for obstructive sleep apnea (OSA). The OR of HF was 2.16 (1.38– 3.39) for sleep duration > 8 hours/night, and 1.76 (1.22– 2.54) for high risk for OSA. In addition, the OR of stroke was 1.23 (1.04– 1.46) for poor sleep quality, 1.32 (1.01– 1.72) for excessive daytime sleepiness, and 1.42 (1.19– 1.70) for high risk for OSA. The associations of poor sleep with cardiovascular multimorbidity (≥ 2 CVDs) were stronger than that of sleep problems with a single CVD.Conclusion: Extreme sleep duration, high risk for OSA, and other sleep problems were associated with CVDs, especially cardiovascular multimorbidity.Keywords: sleep, coronary heart disease, heart failure, stroke, cardiovascular multimorbidity

Xiaolong Ma,1,&ast; Xiaodong Lv,1,&ast; Sihan Feng,1 Ruishan Liu,2,3 Hao Fu,2 Feng Gao,1 Hao Xu2 1Department of Respiratory Medicine, the First Hospital of Jiaxing (Affiliated Hospital of Jiaxing University), Jiaxing, People’s Republic of China; 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3Department of Laboratory Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China&ast;These authors have contributed equally to this workCorrespondence: Feng Gao, Department of Respiratory Medicine, the First Hospital of Jiaxing (Affiliated Hospital of Jiaxing University), No. 1882 South Zhonghuan Road, Jiaxing, 314000, People’s Republic of China, Tel +86 573 825 198 70, Fax +86 573 820 830 06, Email guti-gf@163.com Hao Xu, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qing chun Road, Hangzhou, 310003, People’s Republic of China, Tel +86 571 872 364 23, Fax +86 571 872 364 21, Email xuhao0523@zju.edu.cnPurpose: To investigate the phenotypic and genomic characteristics of the multi-drug resistant and hypervirulent Klebsiella pneumoniae strain recovered from bacteremia.Methods: Antimicrobial susceptibility testing (AST) was performed by the microdilution method. Antimicrobial resistance genes, virulence-associated genes, multilocus sequence typing (MLST), and plasmid replicon were characterized by next-generation sequencing (NGS) and nanopore sequencing. S1 nuclease-pulsed field gel electrophoresis (S1-PFGE) and Southern blotting were performed to characterize the plasmid profile.Results: The hypervirulent colistin- and carbapenem-resistant K. pneumoniae strain DY2009 was identified as ST5571, co-carrying mcr-1, blaNDM-1, and blaOXA-10. In silico analysis found that it was K2 serotype. AST results revealed that DY2009 was resistant to carbapenems, cephalosporins, ciprofloxacin, chloramphenicol, and colistin but remained susceptible to aztreonam, gentamicin, amikacin, and tigecycline. Through the whole-genome analysis, a variety of virulence determinants were identified, including rmpA. Plasmid analysis confirmed that the mcr-1 and blaNDM-1 gene harbored a ∼ 33 kb IncX4 plasmid and a ∼ 44 kb IncX3 plasmid. In contrast, blaOXA-10 was encoded by chromosome.Conclusion: To the best of our knowledge, we first report the clinical hypervirulent K. pneumoniae isolate co-producing MCR-1, NDM-1, and OXA-10 causing bacteremia. We found that mcr-1 and blaNDM-1 genes were located on two self-conjugative epidemic plasmids, contributing to the widespread MCR-1 and NDM-1 in China. The results of this work improve our understanding of the genetic background of colistin- and carbapenem-resistant K. pneumoniae isolate from bacteremia and the resistance mechanisms. Our findings highlight the urgent need for infection control of such strain to prevent it from becoming an extensive-drug resistant clone.Keywords: Klebsiella pneumoniae, NDM-1, MCR-1, OXA-10, rmpA, bacteremia

Jingxue Zhang,1,2,&ast; Xuejing Yan,1,&ast; Rui Liu,3 Shen Wu,1,2 Qian Liu,1,2 Jing Li,3 Jianmin Ma3 1Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, 100730, People’s Republic of China; 2Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, People’s Republic of China; 3Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, 100730, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianmin Ma, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, No. 1 Dongjiaominxiang Street, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +8610-5826-9968, Fax +8610-5826-9930, Email jmma@sina.comPurpose: Adenoid cystic carcinoma (ACC) of the lacrimal gland (LGACC) is an aggressive malignant lacrimal gland tumor with a generally poor prognosis. Survival rates for LGACC are 56% at 5 years and 49% at 10 years. Recent studies have indicated that anti-vascular endothelial growth factor (VEGF) therapy can inhibit angiogenesis in ACC cells. This study was designed to explore the efficacy of the antiangiogenic drug bevacizumab in a LGACC patient-derived xenograft (PDX) animal model.Methods: The histological structure of PDX was determined by hematoxylin-eosin staining to confirm successful xenografting. Immunohistochemistry (IHC) was used to detect the expression of neovascularization-related genes in LGACC patients and in the PDX model, including VEGF, VEGFR1, and FGFR. In order to compare the efficacy of antiangiogenic drug and traditional chemotherapy drug, PDX models were treated with bevacizumab and cisplatin respectively, and body weight was evaluated. Subsequently, the neovascularization-related proteins VEGF, VEGFR2, and CD34, tumor suppressor P53 and proliferation-related protein Ki67 were analyzed by IHC. Quantitative real-time PCR was employed to examine the mRNA expression of apoptosis-related genes BAD and Caspase 9, and of HIF1α.Results: VEGF, VEGFR1, and FGFR were highly expressed in patients with LGACC and PDX models. Both bevacizumab and cisplatin treatment inhibited PDX tumor growth. The body weight of PDX models treated with cisplatin significantly decreased from day 15, while those treated with bevacizumab did not markedly change. Bevacizumab reduced the expression of VEGF, CD34, and Ki67 in PDX tumors; whereas, bevacizumab upregulated P53 and downregulated HIF1α levels.Conclusion: The present study indicates that antiangiogenic drugs may be a promising treatment strategy for LGACC.Keywords: LGACC, VEGF, PDX, bevacizumab, cisplatin

Hui-Ping Duan,1 Rong Liu2 1Department of Ophthalmology, Shanxi Province Fenyang Hospital, Fenyang, 032200, Shanxi Province, People’s Republic of China; 2Department of Ophthalmology, Shanxi Datong University, Datong, 037000, Shanxi Province, People’s Republic of ChinaCorrespondence: Hui-Ping Duan, Department of Ophthalmology, Shanxi Province Fenyang Hospital, Fenyang, 032200, Shanxi Province, People’s Republic of China, Tel +86-13037099450, Email duanhuiping2002@163.comBackground: Open-angle glaucoma is a common ophthalmic disease, which has a great impact on the vision of middle-aged and elderly people. Medication plays an important role in the treatment of glaucoma, so finding effective drug treatment is of great significance to improve the quality of life of glaucoma patients.Objective: To explore the curative effect of nimodipine combined with latanoprost in the treatment of open-angle glaucoma and its effect on ocular hemodynamics and visual field defects.Methods: This study retrospectively analyzed the clinical data of 87 patients with open-angle glaucoma who came to the Shanxi Province Fenyang Hospital and The First Affiliated Hospital of Shanxi Datong University for treatment from January 2019 to January 2021. According to different treatment plans, the patients were divided into two groups: an observation group (n = 46) treated with nimodipine combined with latanoprost, and a control group (n = 41) treated by latanoprost monotherapy. Treatment efficacy, hemodynamics, visual field defects, 24-hour peak intraocular pressure, binocular optic disc parameters, adverse reactions and quality of life were recorded and compared between two groups of patients.Results: The overall therapeutic effect of the observation group was significantly better than that in the control group. After treatment, ocular hemodynamics, visual field defects, 24-hour peak intraocular pressure, binocular optic disc parameters and life quality of both groups were obviously improved compared to those before treatment, with more significant improvements in the observation group. In addition, there was no significant difference in the incidence of adverse reactions between the two groups.Conclusion: Nimodipine combined with latanoprost eye drops is effective in the treatment of primary open-angle glaucoma, which could effectively improve the ocular hemodynamics and visual field defects of patients with fewer adverse reactions and higher safety. Therefore, it can be further promoted and used in clinical practice.Keywords: nimodipine, latanoprost, open-angle glaucoma, ocular hemodynamics, degree of visual field defects

Guiqiang Miao,&ast; Zhaohui Li,&ast; Linjian Chen, Wenyong Li, Guobo Lan, Qiyuan Chen, Zhen Luo, Ruijia Liu, Xiaodong Zhao Department of Orthopedics, Foshan Fosun Chancheng Hospital, Foshan, 528010, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaodong Zhao, Department of Orthopedics, Foshan Fosun Chancheng Hospital, Foshan, 528010, People’s Republic of China, Email CY1002358969@163.comObjective: Bone and bone marrow are the third most frequent sites of metastases from many cancers and are associated with low survival and high morbidity rates. Currently, there are no effective bedside tools to predict the morbidity risk of these patients in general intensive care units (ICUs). The main objective of this study was to establish and validate a nomogram to predict the morbidity risk of patients with bone and bone marrow metastases.Methods: Data on patients with bone and bone marrow metastases were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The patients were divided into training and validation cohorts. The data were analyzed using univariate and multivariate Cox regression methods. Factors significantly and independently prognostic of survival were used to construct a nomogram predicting 30-day morbidity. The nomogram was validated by various methods, including Harrell’s concordance index (C-index), area under the receiver operating characteristic curve (AUC), calibration curve, integrated discrimination improvement (IDI), net reclassification index (NRI), and decision curve analysis (DCA).Results: The study included 610 patients in the training cohort and 262 in the validation cohort. Multivariate Cox regression analysis showed that temperature, SpO2, Sequential Organ Failure Assessment (SOFA) score, Oxford Acute Severity of Illness Score (OASIS), comorbidities with coagulopathy, white blood cell count, heart rate, and respiratory rate were independent predictors of patient survival. The resulting nomogram had good discriminative ability, as shown by high AUCs, and was well calibrated, as demonstrated by calibration curves. Improvements in NRI and IDI values suggested that the nomogram was superior to the SOFA scoring system. DCA curves revealed that the nomogram showed good value in clinical applications.Conclusion: This prognostic nomogram, based on demographic and laboratory parameters, was predictive of the 30-day morbidity rate in patients with secondary malignant neoplasms of the bone and bone marrow, suggesting its applicability in clinical practice.Keywords: secondary malignant neoplasm of bone and bone barrow, MIMIC-III database, prognosis, nomogram

Fengjin Shao,1– 3 Rui Liu,1 Xun Tan,1– 4 Qiaoyan Zhang,1– 3 Lujie Ye,1– 3 Bingxuan Yan,1– 3 Ying Zhuang,1,2,4 Jiaxue Xu1,2,4 1Department of Veterinary Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 2Veterinary Medical Center, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 3Institute of Preventive Veterinary Sciences, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 4Hainan Institute of Zhejiang University, Sanya, Hainan Province, People’s Republic of ChinaCorrespondence: Xun Tan, Department of Veterinary Medicine, Zhejiang University, Yuhangtang Road 866, Hangzhou, 310058, People’s Republic of China, Tel +86 571 8898 2393, Fax +86 571 8898 2310, Email tanxun@zju.edu.cnPurpose: Pulmonary arterial hypertension (PAH) is a progressive and fatal pulmonary vascular disease initiated by endothelial dysfunction. Mesenchymal stromal cells (MSCs) have been shown to ameliorate PAH in various rodent models; however, these models do not recapitulate all the histopathological alterations observed in human PAH. Broiler chickens (Gallus gallus) can develop PAH spontaneously with neointimal and plexogenic arteriopathy strikingly similar to that in human patients. Herein, we examined the protective effects of MSC transplantation on the development of PAH in this avian model.Methods: Mixed-sex broilers at 15 d of age were received 2× 106 MSCs or PBS intravenously. One day later, birds were exposed to cool temperature with excessive salt in their drinking water to induce PAH. Cumulative morbidity from PAH and right-to-left ventricle ratio were recorded. Lung histologic features were evaluated for the presence of endothelial damage, endothelial proliferation and plexiform lesions. Expression of proinflammatory mediators and angiogenic factors in the lung was detected. Matrigel tube formation assay was performed to determine the angiogenic potential of endogenous MSCs.Results: MSC administration reduced cumulative PAH morbidity and attenuated endothelial damage, plexiform lesions and production of inflammatory mediators in the lungs. No significant difference in the expression of paracrine angiogenic factors including VEGF-A and TGF-β was determined between groups, suggesting that they are not essential for the beneficial effect of MSC transplantation. Interestingly, the endogenous MSCs from birds receiving MSC transplantation demonstrated endothelial differentiatial capacity in vitro whereas those from the mock birds did not.Conclusion: Our results support the therapeutic use of MSC transplantation for PAH treatment and suggest that exogenous MSCs produce beneficial effects through modulating inflammation and endogenous MSC-mediated vascular repair.Graphical Abstract: Keywords: plexiform lesion, right ventricular hypertrophy, VEGF-A, TGF-β, angiogenesis, bone marrow

JunJie Yu1 &ast;, WeiPu Mao1 &ast;, Si Sun,1 Qiang Hu,1 Can Wang,1 ZhiPeng Xu,1 RuiJi Liu,1 SaiSai Chen,1 Bin Xu,2,3 Ming Chen2,4 1Medical College, Southeast University, Nanjing, 210009, People’s Republic of China; 2Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, People’s Republic of China; 3Institute of Urology, Southeastern University, Nanjing, People’s Republic of China; 4Department of Urology, Affiliated Lishui People’s Hospital of Southeast University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Xu; Ming ChenDepartment of Urology, Affiliated Zhongda Hospital of Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, 210009, Jiangsu, People’s Republic of ChinaTel/Fax +86 13913009977Email mingchenseu@126.com; 547594963@qq.comPurpose: The study aimed to identify an autophagy-related molecular subtype and characterize a novel defined autophagy-immune related genes score (AI-score) signature and prognosis model in bladder cancer (BLCA) patients using public databases.Methods: The transcriptome cohorts downloaded from TCGA and GEO database were carried out with genomic analysis and unsupervised methods to obtain autophagy-related molecular subtypes. The single-sample gene-set enrichment analysis (ssGSEA) was utilized to perform immune subtype clustering. We defined a novel autophagy subtype and evaluated the role in TME cell infiltration. Then, the principal-component analysis (PCA) was applied to construct an AI-score signature. Subsequently, two immunotherapeutic cohorts were used to evaluate the predictive value in immunotherapeutic benefits and immune response. Finally, univariate, Lasso and multivariate Cox regression algorithm were used to construct and evaluate an autophagy-immune-related genes prognosis model. Also, qRT-PCR and IHC was applied to validate the expression of the 6 genes in the model.Results: Three distinct autophagy clusters and immune-related clusters were identified, and a novel autophagy-related molecular subtypes were defined. Furthermore, the roles in TME cell infiltration and clinical traits for the autophagy subtypes were characterized. Meanwhile, we constructed an AI-score signature and demonstrated it could predict genetic mutation, clinicopathological traits, prognosis, and TME stromal activity. We found that it could accurately predict the clinicopathological characteristics and immune response of individual BLCA patients and provide guidance for selecting immunotherapy. Ultimately, we constructed and verified an autophagy-immune-related prognostic model of BLCA patients and established a prognostic nomogram with a good prediction accuracy.Conclusion: We constructed AI-score signatures and prognosis risk model to characterize their role in clinical features and TME immune cell infiltration. It revealed that the AI-score signature and prognosis model could be a valid predictive tool, which could accurately predict the prognosis of BLCA patients and contribute to choosing effective personalized immunotherapy strategies.Keywords: bladder cancer, The Cancer Genome Atlas, Gene Expression Omnibus, tumor microenvironment, immunotherapy, mutation burden

Bing Xu, Mengmeng Yan, Fei Zhou, Desheng Cai, Wenbo Guo, Xiaohui Jia, Runping Liu, Tao Ma, Tong Li, Feng Gao, Penglong Wang, Haimin Lei School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of ChinaCorrespondence: Penglong Wang; Haimin Lei Email wpl581@126.com; hm_lei@126.comBackground: The clinical utility of camptothecin (CPT) is restricted by poor aqueous solubility, high lipophilicity, active lactone ring instability, and off-targeted toxicities. We report here a prostate-specific membrane antigen (PSMA) and esterase dual responsive self-assembled nanoparticles (CPT-WT-H NPs) for highly efficient CPT delivery and effective cancer therapy.Methods and Results: In this study, smart self-assembled nanoparticles CPT-WT-H NPs were elaborately designed and synthesized by combing hydrophobic CPT with hydrophilic PSMA-responsive penta-peptide via a cleavable ester bond. This dual responsive nanoparticle with negatively charged surface first respond to the extracellular PSMA and then to the intracellular esterase, achieving a programmable release of CPT at the tumor site and producing the byproducts of biocompatible glutamic acid and aspartic acid. Our data demonstrated that CPT-WT-H NPs exhibited greatly improved water solubility and stability. Results from MTT and flow cytometry showed CPT-WT-H NPs exhibited significantly higher cytotoxicity as well as apoptosis-inducing activity against PSMA-expressing LNCaP-FGC cells than the non-PSMA-expressing cancer cells, showing excellent cytotoxic selectivity. Moreover, the unique nanostructure provided the efficient transportation of CPT to tumor site, which resulted in the effective inhibition of tumor growth and low systemic toxicity in vivo.Conclusion: CPT-WT-H NPs exhibited excellent in vitro PSMA-response ability and in vivo antitumor activity and safety, holding the promise to become a new and potent anticancer drug. The current research presents a promising strategy for efficient drug delivery.Keywords: CPT prodrug, dual responsive, sequential drug release, prostate-specific membrane antigen, self-assembly

Yuxin Sun,&ast; Yizhuo Xie,&ast; Huan Tang, Zhihui Ren, Xue Luan, Yan Zhang, Ming Zhu, Zhe Lv, Han Bao, Yan Li, Rui Liu, Yujia Shen, Yucui Zheng, Jin Pei Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, ChangChun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jin PeiSchool of Pharmaceutical Sciences, Jilin University, 1163 Xinmin Street, ChangChun, 130021, Jilin Province, People’s Republic of ChinaTel +86 431 85619725Email peijin@jlu.edu.cnBackground: Chemotherapy is still the main first-line treatment for advanced metastatic gastric cancer, but it has the limitations of serious side effects and drug resistance. Conventional liposome has been substantially used as drug carriers, but they lack targeting character with lower drug bioavailability in tumor tissues. Based on the above problems, a novel estrogen-targeted PEGylated liposome loaded with oxaliplatin (ES-SSL-OXA) was prepared to further improve the metabolic behavior, the safety profile, and the anti-tumor efficacy of oxaliplatin.Methods: Four kinds of oxaliplatin (OXA) liposomes were prepared by film hydration method. The obtained formulations were characterized in terms of entrapment efficiency (EE), particle size, and so on by HPLC and DLS (dynamic light scanning). The morphology of ES-SSL-OXA was detected by transmission electron microscope (TEM). The in vitro and in vivo targeting effect of ES-SSL-OXA was verified by fluorescence microscopy and in vivo imaging system in gastric cancer cells (SGC-7901) and tumor-bearing athymic mice. The in vitro and in vivo antitumor efficacies of ES-SSL-OXA were investigated on SGC-7901 cells and athymic tumor-bearing mice. Pharmacokinetic, biodistribution, and acute toxicity tests of ES-SSL-OXA were performed on ICR mice.Results: The ES-SSL-OXA exhibited an average particle size of about 153.37 nm with an encapsulation efficiency of 46.20% and low leakage rates at 4°C and 25°C. In vivo and in vitro targeting study confirmed that ES-SSL-OXA could effectively target the tumor site. The antitumor activity demonstrated the strongest inhibition in tumor growth of ES-SSL-OXA. Pharmacokinetics and acute toxicity study showed that ES-SSL-OXA could significantly improve the metabolic behavior and toxicity profile of oxaliplatin.Conclusion: In this study, a novel estrogen-targeted long-acting liposomal formulation of OXA was successfully prepared. ES fragment effectively targeted the delivery system to tumor tissues which highly express estrogen receptor, providing a promising therapeutic method for gastric cancer in clinic.Keywords: estrogen receptors, chemotherapy, long-acting liposomes, targeted drug delivery, pharmacokinetics, antitumor activity

Jingying Wang, Yinghao Pan, Guangmin Wei, Hanxiao Mao, Rulan Liu, Xia Xiong, Jixiang Xu, Yuanmin He Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of ChinaCorrespondence: Yuanmin He, Department of Dermatology, The Affiliated Hospital of Southwest Medical University, No. 25 of Taiping Road, Luzhou, Sichuan, 646000, People’s Republic of China, Email heym88@163.comAbstract: Most patients are anxious about the skin lesions on the penis. This study reports a case of lichen nitidus on the penis and reviews related literature. A 40-year-old male has presented with small papules with skin color on the penis for one year. The patient was diagnosed with lichen nitidus, and tacrolimus cream and humectant were topically administered after diagnosis. The symptoms were alleviated after treatment. We first report a series of the cases with lichen nitidus on the penis, knowing the clinical and pathological manifestations of this disease can reduce misdiagnosis and unnecessary treatment.Keywords: Lichen nitidus, penis, pathological feature, treatment, prognosis

Ru Liu,1,2 Yinjiang Tang,2 Ting Fu,2 Jianli Zhou,2 Lijiao Ma,2 Jinqing Yuan,1 Ou Xu2 1Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Pulmonary Vascular and General Medicine, Fuwai Yunnan Cardiovascular Hospital, Yunnan Provincial Cardiovascular Disease Clinical Medical Center, Kunming, Yunnan Province, People’s Republic of ChinaCorrespondence: Ou XuFuwai Yunnan Cardiovascular Hospital, Yunnan Provincial Cardiovascular Disease Clinical Medical Center, No. 528 North Shahe Road, Wuhua District, Kunming, 650102, People’s Republic of ChinaTel +86-10-15901098523Email fwxuou@163.comJinqing YuanFuwai Hospital, Chinese Academy of Medical Sciences, No. 167 North Lishi Road, Xicheng District, Beijing, 100037, People’s Republic of ChinaTel +86-10-88322457Email dr_jinqingyuan@sina.comAbstract: Dasatinib was identified to be associated with pulmonary arterial hypertension, also called dasatinib-induced pulmonary arterial hypertension. There was still little data on clinical characteristics of this rare but severe complication during hematological therapy in China. A 40-year-old female with worsening dyspnoea was diagnosed with severe pulmonary arterial hypertension and progressive right heart failure, and stabilized by standardized comprehensive management, including replacement of other tyrosine kinase inhibitor, administration of pulmonary vasodilators according to the right-heart catheterization-based risk stratification and traditional anti-heart failure drug therapy. Our case suggests that dasatinib-induced pulmonary arterial hypertension may be partially reversible, with a relatively good prognosis under formal target therapy of pulmonary arterial hypertension, providing new insight into its treatment algorithm.Keywords: dasatinib-induced pulmonary arterial hypertension, right heart failure, pulmonary vasodilator, tyrosine kinase inhibitor

Jidong Guo,1,2,&ast; Qiang Li,1,&ast; Xuxia Zhang,2 Cong Yao,2 Rongmei Liu,1 Yu Pang,2 Mengqiu Gao1 1Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China; 2Department of Bacteriology and Immunology, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: : Yu PangDepartment of Bacteriology and Immunology, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, People’s Republic of ChinaTel/Fax +86-10-8950 9162Email pangyupound@163.comMengqiu GaoDepartment of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, People’s Republic of ChinaTel/Fax +86-10-8950 9322Email gaomqwdm@aliyun.comIntroduction: Interferon-γ release assays (IGRAs) can have high false-negative rates for active tuberculosis (TB) cases. Here we investigated factors, including potential anti-inflammatory mechanisms, that contributed to false-negative IGRA results.Methods: We established two cohorts. In the first cohort, we reviewed IGRA results for confirmed TB cases diagnosed in our hospital in 2018. Cases with false-negative IGRA results were analysed to identify factors contributing to false-negative results. In the second cohort, we prospectively studied IL-10 expression levels in peripheral blood mononuclear cells (PBMCs) of IGRAs-positive and IGRAs-negative TB cases after antigenic stimulation to correlate IL-10 expression with IGRAs results.Results: Of 1232 culture-confirmed TB cases, 1124 produced true-positive IGRA results and 108 had false-negative IGRA results. Multivariate logistic regression analysis identified glucocorticoid use and extrapulmonary TB as independent risk factors for false-negative IGRA results. Notably, IL-10 expression of the IGRA-negative group was significantly up-regulated as compared to that of the IGRA-positive group. The average cell supernatant IL-10 concentration of the IGRA-negative group was 4.77 pg/mL, a value that was statistically greater than the IGRA-positive group concentration (1.47 pg/mL, P = 0.007). After PBMCs pretreatment with BRD6989 (to enhance IL-10 secretion), average IFN-γ concentrations in cell supernatants from the IGRA-positive group significantly decreased from 59.73 pg/mL to 33.79 pg/mL (P = 0.011). By contrast, addition of AS101 (to inhibit IL-10 secretion) to false-negative group PBMCs led to an increase of average IFN-γ concentration in cell supernatants from 19.01 pg/mL to 45.10 pg/mL (P = 0.030), a result that was inversely correlated with IL-10 concentration.Conclusion: Our data demonstrate that increased IL-10 secretion by PBMCs is inversely correlated with IGRA assay results in culture-confirmed TB patients. Glucocorticoids use and extrapulmonary TB are significantly associated with false-negative IGRA results. Combination testing to measure IL-10 secretion and IFN-γ release is recommended to improve IGRAs specificity.Keywords: tuberculosis, interferon-γ release assay, interleukin 10

Shuxiu Liu,1,2 Hao Xu,2 Xiaobing Guo,1 Shuang Li,3 Qian Wang,1,2 Yuan Li,4 Ruishan Liu,1,2 Jianjun Gou1 1Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 2State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, People’s Republic of China; 3Department of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 4Department of Nuclear Medicine, The First Affiliated Hospital of ZhengZhou University, Zhengzhou, 450052, People’s Republic of ChinaCorrespondence: Jianjun Gou Tel +86 371 6627 8237Fax +86 371 6691 3569Email jianjung@zzu.edu.cnPurpose: To investigate the genomic and plasmid characteristics of a newly discovered Pseudomonas stutzeri strain with a blaVIM-2-carrying plasmid and novel integron In 1998 isolated from a cerebrospinal fluid specimen in a teaching hospital.Methods: Species identification was performed by MALDI-TOF MS, and blaVIM-2 was identified by PCR and Sanger sequencing. Whole-genome sequencing analysis was conducted using the Illumina NovaSeq 6000 and Oxford Nanopore platforms. Integron detection was performed using INTEGRALL. The phylogenetic tree was constructed by using kSNP3.0. Plasmid characteristics were assessed by S1-pulsed-field gel electrophoresis (S1-PFGE), Southern blotting, conjugation experiments, and whole-genome sequencing analysis. Comparative genomics analysis of the plasmid and genetic context of blaVIM-2 were conducted by using BLAST Ring Image Generator (BRIG) and Easyfig 2.3, respectively.Results: ZDHY95, an MDR strain of P. stutzeri harboring blaVIM-2, was identified. It was sensitive only to amikacin and was resistant to carbapenems, β-lactams, aztreonam, fluoroquinolones, and aminoglycosides. Joint S1-PFGE, Southern blot, conjugation assay, and whole-genome sequencing experiments confirmed that the blaVIM-2 gene was located within class I integron In 1722 of the plasmid and that the surrounding genetic environment was 5ʹCS-aacA4ʹ-30-blaVIM-2-aacA4ʹ-3ʹCS. The novel class I integron In 1998 was detected on the chromosome of P. stutzeri ZDHY95, and the gene cassette array was 5ʹCS-aacA3-aadA13-cmlA8-blaOXA-246-arr3-dfrA27-3ʹCS. Phylogenetic analysis showed that antimicrobial resistance gene-carrying P. stutzeri isolates were divided into two clusters, mainly containing isolates from the USA and Pakistan.Conclusion: A novel blaVIM-2-carrying conjugative plasmid, pZDHY95-VIM-2, was reported for the first time in P. stutzeri, elucidating the genetic environment and transfer mechanism. The gene structure of the novel class I integron In 1998 was also clarified. We explored the phylogenetic relationship of P. stutzeri with drug resistance genes and suggested that Pseudomonas with metallo-β-lactamases (MBLs) in the hospital environment may cause infection in patients with long-term intubation or after interventional surgery.Keywords: Pseudomonas stutzeri, blaVIM-2, In 1998, In 1722, Tn 5563, whole-genome sequencing, bacterial genomics, antibiotic resistance

Tianxing Dai,1,2 Linsen Ye,1,2 Haoyuan Yu,1,2 Kun Li,1,2 Jing Li,3 Rongqiang Liu,4 Xu Lu,1,2 Mingbin Deng,1,2 Rong Li,1,2 Wei Liu,2 Yang Yang,1 Guoying Wang4 1Department of Hepatic Surgery and Liver Transplant Program, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People’s Republic of China; 2Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People’s Republic of China; 3Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 4Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, People’s Republic of ChinaCorrespondence: Yang YangDepartment of Hepatic Surgery and Liver Transplant Program, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People’s Republic of ChinaTel +86-020-85252177Fax +86-020-85252276Email yysysu@163.comGuoying WangDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, People’s Republic of ChinaTel +86-020-83062703Fax +86-020-83395651Email wanggy3@126.comPurpose: The aldo-keto reductase (AKR) superfamily members have been proposed with multiple roles in various tumors. Here, a comprehensive analysis on the integral role of AKR genes was conducted to evaluate the expression profile, regulation network, and prognostic significance in hepatocellular carcinoma (HCC).Materials and Methods: Transcriptome datasets of HCC were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus. Univariate and multivariate Cox regression analyses were used to build a novel risk score model, and then were further used to identify independent prognostic factors for overall survival (OS) of HCC. A prognostic nomogram was developed and validated. The expression of these critical AKR members was also evaluated by quantitative real-time polymerase chain reaction and immunohistochemistry in HCC specimens.Results: Eight differentially expressed AKR genes were identified in HCC. The dysregulation of most AKR genes was negatively correlated with DNA methylation, and a regulation network with transcription factors (TFs) was also established. Then, three critical AKR genes (AKR1B10, AKR1D1, and AKR7A3) were screened out to build a novel risk score model. Worse OS was observed in high-risk patients. Besides, a prognostic nomogram based on the model was further established and validated in both the TCGA and GSE14520 cohorts, which showed superior performance in predicting the OS of HCC patients. Notably, close correlations were identified between the risk score and tumor immune microenvironment, somatic mutation profiles, and drug susceptibilities of HCC. Finally, the upregulated AKR1B10 and downregulated AKR1D1 and AKR7A3 were further verified in HCC tumor and adjacent tissues from our institution.Conclusion: The dysregulated AKR genes could be mediated by DNA methylation and TFs in HCC. The risk model established with superior prognostic performance further suggested the significant role of AKR genes involved in the progression of HCC.Keywords: hepatocellular carcinoma, aldo-keto reductase, AKR, risk score model, nomogram, prognosis

Yanhong Jia,1– 3,&ast; Rui Liu,1,&ast; Shi Tang,1,2,4 Dongming Zhang,5 Yongxiang Wang,1,2,4 Lin Cong,1,2,4 Tingting Hou,1,2,4 Juan Ren,1 Yifeng Du1,2,4 1Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 3Department of Neurology, Baotou Central Hospital, Baotou, Inner Mongolia, People’s Republic of China; 4Shandong Provincial Clinical Research Center for Neurological Diseases, Jinan, Shandong, People’s Republic of China; 5Department of General Surgery, Baotou Central Hospital, Baotou, Inner Mongolia, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yifeng DuDepartment of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, No. 324 Jingwuweiqi Road, Jinan, Shandong, 250021, People’s Republic of ChinaTel/ Fax +86 531 68776354Email duyifeng@email.sdu.edu.cnPurpose: To examine the associations of impaired fasting glucose (IFG) and glycaemic control of diabetes with dementia, global cognitive function and physical function among rural-dwelling Chinese older adults.Patients and Methods: This population-based cross-sectional study included 4583 participants (age ≥ 65 years, 57.3% women) living in Yanlou Town, Yanggu County, western Shandong Province, China. In 2018, data were collected through interviews, clinical examinations, neuropsychological tests, and laboratory tests. Diabetes status was defined by self-reported physician-diagnosed diabetes, current use of antidiabetic agents, and fasting blood glucose tests. Global cognitive function was assessed using the Mini-Mental State Examination. Dementia was diagnosed following DSM-IV criteria, and Alzheimer’s disease (AD) was diagnosed following the National Institute on Aging-Alzheimer’s Association criteria. Physical function was assessed by the Short Physical Performance Battery. Data were analysed using multiple logistic and general linear regression models.Results: IFG was found in 267 participants, and diabetes was diagnosed in 658 participants (257 with well-controlled diabetes, 401 with poorly controlled diabetes). Dementia was diagnosed in 166 participants (116 with AD), and physical functional impairment was found in 1973 participants. The multi-adjusted odds ratio (OR) of dementia associated with poorly controlled diabetes (vs without IFG or diabetes) was 2.41 (95% CI 1.52– 3.84), and the OR of AD associated with poorly controlled diabetes was 2.32 (1.34– 4.04). In addition, the adjusted OR of physical functional impairment was 1.40 (1.06– 1.85) for well-controlled diabetes and 1.69 (1.35– 2.12) for poorly controlled diabetes. However, IFG was not associated with cognitive or physical function.Conclusion: The glycaemic control status of diabetes patients was associated with cognitive impairment and physical functional impairment.Keywords: impaired fasting glucose, Alzheimer’s disease, cognitive function, physical functional impairment

Guangshao Cao,&ast; Yuyan Liu,&ast; Lupeng Li, Xiaoyang Zhao, Ruiqing Liu, Jian Liu, Jianwen Liu, Huicun Cao Department of Intervention, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huicun Cao; Jianwen LiuDepartment of Intervention, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, 7 Weiwu Road, Jinshui District, Zhengzhou, 450003, People’s Republic of ChinaTel +86-371-87160215Email caodao022315@163.com; jian061409322@163.comBackground: There has been very limited investigation regarding the comparison of adverse events (AEs) among radiofrequency ablation (RFA), conventional transarterial chemoembolization (cTACE), and drug-eluting bead TACE (DEB-TACE) in treating HCC patients; therefore, the present study aimed to resolve this issue.Methods: Two-hundred and forty-six HCC patients (with a total of 267 procedures [treatment times]) treated with RFA (73 patients with 79 procedures), cTACE (86 patients with 94 procedures), or DEB-TACE (87 patients with 94 procedures) were included. Demographic and clinical data were collected. The information on AEs was also retrieved and analyzed.Results: Total AEs incidence was notably different among the RFA group, cTACE group, and DEB-TACE group and was the highest in cTACE group (86.2%), then in DEB-TACE group (76.6%), and the lowest in RFA group (63.3%). Regarding specific AEs incidence, the incidences of fever, fatigue, and nausea were distinctive among the three groups, while no distinctiveness was found in incidence of other AEs. Furthermore, multivariate logistic regression revealed that cTACE (versus RFA) was independently correlated with increased risk of total AEs, fatigue, and nausea/vomiting; however, the interventional therapies were not independently correlated with the risk of pain, fever or constipation. Other independent predictive factors for total AEs risk were male gender, bronchial asthma, and disease duration.Conclusion: cTACE resulted in the highest AEs incidence compared with RFA and DEB-TACE in treating HCC patients.Keywords: hepatocellular carcinoma, conventional transarterial chemoembolization, drug-eluting bead transarterial chemoembolization, radiofrequency ablation, adverse events

Jidong Guo,1,&ast; Rongmei Liu,1,&ast; Jin Shi,1,&ast; Fengmin Huo,2 Yuanyuan Shang,3 Fen Wang,2 Mengqiu Gao,1 Shanshan Li3 1Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China; 2National Clinical Laboratory on Tuberculosis, Beijing Key laboratory on Drug-resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China; 3Department of Bacteriology and Immunology, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shanshan LiDepartment of Bacteriology and Immunology, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, People’s Republic of ChinaTel +86-10-8950 9368Fax +86-10-8950 9366Email Lss9011@126.comMengqiu GaoDepartment of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, People’s Republic of ChinaTel +86-10-8950 9322Fax +86-10-8950 9322Email gaomqwdm@aliyun.comBackground: Early and accurate diagnosis of rifampicin (RIF)-resistant Mycobacterium tuberculosis (MTB) is essential for controlling community spread of drug-resistant tuberculosis (TB). In order to discover mutations residing outside the rifampicin resistance-determining region (RRDR) of the MTB rpoB gene, we conducted this retrospective study.Methods: We retrospectively screened patient records to obtain Xpert MTB/RIF assay results for patients who received care at the Beijing Chest Hospital from 2016 to 2019 in order to identify subjects who met study selection criteria. Stored frozen patient isolates were cultured, harvested, and then subjected to drug susceptibility testing. Concurrently, entire rpoB gene DNA of each isolate was amplified and then sequenced to reveal rpoB mutations.Results: Overall, 104 RIF-susceptible tuberculosis patients who were tested using the Xpert MTB/RIF assay also had poor first-line regimen treatment responses. Isolates obtained from these cases included 101 MTB isolates that possessed wild-type rpoB allelic profiles, as demonstrated using Sanger sequencing. However, sequences from the other three isolates confirmed that rpoB of one isolate harbored a mutation encoding the amino acid substitution Ile491Phe and that rpoB genes of two isolates contained a mutation encoding the amino acid substitution Ser450Leu.Conclusion: Our data demonstrated that mutations found outside the RRDR of MTB rpoB are rare in Beijing, China, indicating that World Health Organization-approved molecular diagnostics are generally suitable for diagnosing RIF resistance.Keywords: tuberculosis, rifampicin-resistance, rpoB, diagnosis

Di Zhang,1 Jinghong Yang,2 Chuang Liu,1 Sheng Ye,1 Qianbing Zhang,2 Ruiyuan Liu1 1Guangdong Provincial Key Laboratory of Medical Image Processing, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 2Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of ChinaCorrespondence: Ruiyuan LiuGuangdong Provincial Key Laboratory of Medical Image Processing, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of ChinaTel/Fax +86-20-61647496Email ruiyliu@smu.edu.cnQianbing ZhangCancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of ChinaTel/Fax +86-20-61648378Email carl@smu.edu.cnIntroduction: It will be challenging to develop high-performance organic chromophores for light-triggered thermal ablation of the tumor. Besides, the mechanisms of organic chromophores for tumor therapy remain unclear. Herein, an acceptor-π-donor (A-π-D) structured organic chromophore based on 2-dicyanomethylenethiazole named PTM was developed for photothermal therapy (PTT) of tumors.Methods and Results: Biocompatible PTM nanoparticles (PTM NPs) were fabricated by enclosing PTM with Pluronic F-127. The results of optical and photothermal properties of PTM NPs showed robust near-infrared (NIR) absorption, excellent photostability and high photothermal conversion efficiency (56.9%). The results of flow cytometry, fluorescence microscopy, apoptosis, CCK-8 assays and animal experiments showed that PTM NPs had a good killing effect on tumors under NIR laser irradiation. Furthermore, mechanistic studies, RNA-seq and biological analysis revealed that PTM NPs can cause tumor cell death via DNA damage-mediated apoptosis.Conclusion: Light-induced thermal ablation effects of PTM NPs in vitro and vivo were surveyed. Collectively, our studies provided a new approach to developing a safe and effective photothermal agent for cancer treatment.Keywords: NIR absorbing chromophore, 2-dicyanomethylenethiazole, photothermal therapy, DNA damage induced apoptosis, RNA-seq, biological analysis

Honglei Zhao,1 Hongyan Wu,2 Meitao Duan,2 Ruixuan Liu,2 Quanhong Zhu,1 Kai Zhang,2 Lili Wang1 1Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, People’s Republic of China; 2Research Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences, Shenzhen, People’s Republic of ChinaCorrespondence: Kai ZhangResearch Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences, Shenzhen, People’s Republic of ChinaTel +86-13076878540Email kai.zhang@siat.ac.cnLili WangFuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, People’s Republic of ChinaEmail 1248532808@qq.comPurpose: The aim of the present study was to examine the protective effects of cinnamaldehyde (CA) on type 1 diabetes mellitus (T1DM) and explore the underlying molecular mechanisms by using multiple omics technology.Methods: T1DM was induced by streptozotocin in the mice. Immunostaining was performed to evaluate glycogen synthesis in the liver and morphological changes in the heart. Gut microbiota was analyzed using 16S rRNA gene amplification sequencing. The serum metabolomics were determined by liquid chromatography–mass spectrometry. The relevant gene expression levels were determined by quantitative real-time PCR.Results: CA treatment significantly improved the glucose metabolism and insulin sensitivity in T1DM mice. CA increased glycogen synthesis in the liver and protected myocardial injury in T1DM mice. CA affected the gut microbiota particularly by increasing the relative abundance of Lactobacillus johnsonii and decreasing the relative abundance of Lactobacillus murinus in T1DM mice. The glucose level was positively correlated with 88 functional pathways of gut microbiota and negatively correlated with 2 functional pathways of gut microbiota. Insulin resistance was positively correlated with 11 functional pathways. The analysis of serum metabolomics showed that CA treatment significantly increased the levels of taurochenodeoxycholic acid, tauroursodeoxycholic acid, tauro-α-muricholic acid and tauro-β-muricholic acid, taurodeoxycholic acid, taurocholic acid and taurohyodeoxycholic acid in T1DM mice. Taurohyodeoxycholic acid level was highly correlated with the blood glucose levels. Furthermore, the abundance of Faecalibacterium prausnitzii was positively correlated with AKT2, insulin like growth factor 1 receptor, E2F1 and insulin receptor substrate 1 mRNA expression levels, while taurohyodeoxycholic acid level was negatively correlated with IRS1 mRNA expression level.Conclusion: Our results indicated that CA may interfere with gut microbiota to affect host metabolomics, especially the bile acids, so as to directly or indirectly modulate the expression levels of glucose metabolism-related genes, thus subsequently reducing the blood glucose level in the T1DM mice.Keywords: cinnamaldehyde, type 1 diabetes, glucose, insulin, gut microbiota, serum metabolomics

Nan Guo,1 Peng Qu,2 Hao Li,2 Liuli Liu,2 Hao Jin,3 Renqi Liu,3 Zhen Zhang,3 Xuan Zhang,2 Yingchun Li,4 Xiaobo Lu,2 Yuejiao Zhao1 1Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People’s Republic of China; 2Department of Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China; 3Jin Zhou Center for Disease Control and Prevention, Jinzhou, People’s Republic of China; 4Department of Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People’s Republic of ChinaCorrespondence: Yuejiao ZhaoDepartment of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning Province, People’s Republic of ChinaTel +86 24 31916833Email yuejiaozhao@126.comXiaobo LuDepartment of Toxicology, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, People’s Republic of ChinaTel +86 24 31939077Email xblu@cmu.edu.cnObjective: To investigate the associations of polymorphisms in the following DNA double-strand break repair (DSBR) genes with papillary thyroid carcinoma (PTC) risk (including RAD51 rs11852786, RAD51B rs963917, BRCA1 rs12516 and rs8176318, BRCA2 rs15869, XRCC4 rs2035990 and XRCC5 rs2440).Materials and Methods: A matched case–control study was implemented to examine associations between PTC risk and the above polymorphisms. Subsequently, we evaluated the effects of the potential PTC susceptibility-related variant rs15869 on BRCA2 mRNA secondary structure and BRCA2 expression through bioinformatics analysis and experiment validation. Additionally, luciferase assay was used to identify whether rs15869 polymorphism can substantially affect the binding of hsa-miR-1178-3p to BRCA2 mRNA. Finally, Pearson correlation analysis was performed to determine the correlation between the expression of hsa-miR-1178-3p and BRCA2 mRNA and protein in thyroid tissues harboring rs15869 different genotypes.Results: BRCA2 rs15869 CC genotype was associated with a higher risk of PTC than its AA genotype. Subsequently, stratified analyses came to the same conclusion in the female or age< 50 population. Furthermore, we confirmed that the A-to-C substitution of rs15869 changed BRCA2 mRNA secondary structure and contributed to a decreased BRCA2 expression. Mechanistically, a significantly decreased luciferase activity verified a greater binding between hsa-miR-1178-3p and rs15869 C allele, but not the A allele, which was evidenced by the significant negative correlation between hsa-miR-1178-3p with BRCA2 mRNA and protein levels in thyroid tissues with AC and CC genotype but not AA genotype at rs15869.Conclusion: BRCA2 rs15869 is characterized as a potential biomarker associated with PTC risk, highlighting the contribution of the hsa-miR-1178-3p via functional exploration.Keywords: papillary thyroid carcinoma, DNA double-strand break repair, BRCA2, rs15869 polymorphism, hsa-miR-1178-3p

Yueting Han,1,* Haiyang Zhang,1,* Zhengyang Zhou,1,* Rui Liu,1 Dongying Liu,1 Ming Bai,1 Qian Fan,1 Jialu Li,2 Kegan Zhu,1 Hongli Li,1 Tao Ning,1 Guoguang Ying,1 Yi Ba1 1Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China; 2Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Jiao-Tong University School of Medicine Renji Hospital, Shanghai, 200001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Ba; Guoguang Ying Email bayi@jtmuch.com; yingguoguang163@163.comBackground: Biliary tract cancers (BTCs) are aggressive malignancies with difficult early diagnosis and poor prognosis. Studies have shown that microRNAs (miRNAs) are expected to be biomarkers of the disease, which indicates that we can diagnose cancers according to the miRNAs that have significant changes. The aim of this study was to explore miRNA biomarkers of BTCs.Methods: A total of 163 samples were collected and divided into the control group, the benign group and the malignant group. High-throughput low-density chips were used to screen miRNAs with significant changes. Then, the preliminary screening test and the verification test were performed by quantitative real time PCR (qRT-PCR). Finally, the level of miRNAs in serum exosomes was measured.Results: MiR-10a, miR-21, miR-135b, miR-221, and miR-214 were upregulated in the BTCs group compared to the control group. The change in the miR-221 level was statistically significant when the malignant group was compared with the benign group (P< 0.01). Meanwhile, miR-135b and miR-214 were enriched in serum exosomes.Conclusion: Five miRNAs in the serum were found to be significantly upregulated in patients with BTCs. Among them, miR-221 can serve as an early diagnostic marker for BTCs patients. MiR-10a, miR-21, miR-135b and miR-214 can be used as biomarkers for the diagnosis of biliary diseases.Keywords: biliary tract cancers, microRNAs, biomarker, noninvasive diagnosis

Xinyuan Yu, Yanping Feng, Renzhong Liu, Qianxue Chen Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of ChinaCorrespondence: Qianxue ChenDepartment of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of ChinaTel +86 13607141618Email chen_qx2006@163.comBackground: Therapeutic hypothermia (TH) has been proven to be protective in ischemic stroke (IS) due to its anti-inflammatory capacity. Recently, the interferon regulatory factor 4 (IRF4) has been characterized as a central regulator of neuroinflammation in IS. Here we aim to determine whether IFR4 contributes to the neuroprotective effects of TH in IS.Methods: In the present study, IRF4 knockout (IRF4−/-) and wild-type (IRF4+/+) mice were treated with or without TH after IS. Cerebral IRF4 expression, the production of pro-inflammatory and anti-inflammatory cytokines and macrophage polarization were determined at 8 hours after reperfusion. In addition, cerebral infarct volume and neurological function were evaluated at 7 days after IS.Results: TH attenuates IS together with enhanced IRF4 expression as well as reduced production of pro-inflammatory cytokines. In addition, TH increased M2 macrophage polarization while inhibited M1 macrophage polarization. However, IRF4 knockout worsens neurological outcomes of stoke mice. The expression of pro-inflammatory cytokines were markedly increased in IRF4−/- mice as compared with IRF4+/+ mice at 8 h after stroke. Moreover, IRF4 knockout driven the macrophage polarization toward M1phenotype at 8 h after stroke. Most importantly, IRF4 knockout abolished the neuroprotective and anti-inflammatory effects of TH in IS.Conclusion: Together, we report for the first time that TH attenuates neuroinflammation following IS by modulating M1/M2 macrophage polarization through the upregulation of IRF4 expression.Keywords: therapeutic hypothermia, interferon regulatory factor 4, ischemic stroke, inflammation, macrophage polarization

Jie Jiang,1 Bin Liu,2 Ruilin Liu,3 Wenzhuo Yang1 1Department of Gastroenterology and Hepatology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 2Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Pulmonary, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Ruilin LiuDepartment of Pulmonary, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, People’s Republic of ChinaEmail 18721881628@163.comWenzhuo YangDepartment of Gastroenterology and Hepatology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, People’s Republic of ChinaEmail yangwenzhuo2002@163.comBackground: Taspase 1 (TASP1) is a highly conserved protease involved in site-specific proteolysis. Existing researches have revealed a link between TASP1 expression and carcinogenesis. However, limited data are available regarding the prognosis and functions of TASP1 in hepatocellular carcinoma (HCC).Methods: Western Blotting and qRT-PCR were employed to evaluate the level of TASP1 in HCC cell lines and clinical specimens. TASP1 expression was further calculated in clinical specimens by immunohistochemistry and the mRNA level of TASP1 in HCC was analyzed using Oncomine and UALCAN databases. The TASP1 promoter methylation modification was shown via MEXPRESS and UALCAN. The association between TASP1 expression and postoperative prognosis was evaluated using Kaplan–Meier and Cox regression analysis in clinical patients. The effect of TASP1 on HCC prognosis was analyzed via Kaplan-Meier plotter, GEPIA and UALCAN. Additionally, the regulators, kinases, miRNA and transcription factor targets of TASP1 were identified using LinkedOmics. Moreover, cBioPortal was used to detect the genetic alteration of TASP1. Finally, TIMER was utilized to assess the relation between TASP1 and the immune cell infiltration, whereas the correlation of TASP1 with three immune factors was detected through TISIDB.Results: TASP1 expression was increased in HCC cell lines and HCC tissues. CNV and DNA methylation of TASP1 were changed. Survival analysis revealed that high TASP1 expression was correlated with overall survival (OS). Functional network analysis about TASP1 in HCC showed that the double-strand break repair, peptidyl-threonine modification, spindle organization, peptidyl-lysine modification and microtubule-based movement were modulated. Furthermore, TASP1 expression revealed puissant relation to the infiltration of immune cells and three immune factors in HCC.Conclusion: These data indicate that TASP1 may act as a potential prognostic marker in HCC and regulate HCC via multiple mechanisms.Keywords: hepatocellular carcinoma, TASP1, prognosis, biological functional networks

Xu Chen,1,2,* Qingxue Zhou,3,* Shilei Dong,4 Shuoshi Wang,2 Rui Liu,2 Xueli Wu,2 Shijun Li5 1The Second Clinical College, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, 550003, People’s Republic of China; 2Central Laboratory of the Second Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, 550003, People’s Republic of China; 3Clinical Laboratory, Hangzhou Women’s Hospital, Hangzhou, Zhejiang, 310008, People’s Republic of China; 4Department of Clinical Laboratory, Zhejiang Hospital, Hangzhou, Zhejiang, 310013, People’s Republic of China; 5Laboratory of Bacterial Infectious Disease of Experimental Centre, Guizhou Provincial Centre for Disease Control and Prevention, Guiyang, Guizhou, 550004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shijun LiGuizhou Provincial Centre for Disease Control and Prevention, 115 Bageyan Road, Guiyang, Guizhou, 550004, People’s Republic of ChinaTel/Fax +86 851 86824290Email zjumedjun@163.comXu ChenThe Second Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, 83 Feishan Road, Guiyang, Guizhou, 550003, People’s Republic of ChinaTel/Fax +86 851 85514432Email xuchen1220@126.comBackground: Hepatitis B virus (HBV) is a common pathogen that predominantly causes severe liver disease, and remains one of a huge challenge worldwide, especially in many resource-constrained areas. Developing a low-cost, sensitive, specific, and rapid approach for screening HBV is critical for its treatment and prevention. In the current study, a novel molecular detection approach, multiple cross displacement amplification (MCDA) coupled with polymer nanoparticle-based lateral flow biosensor (MCDA-LFB), was applied for detection of HBV in blood samples.Methods: HBV standard substance and clinical donor serum samples were collected and used for the establishment and confirmation of the HBV-MCDA-LFB assay. A set of 10 MCDA primers was designed according to HBV-specific gene S. The HBV-MCDA-LFB assay conditions, including genomic template concentration, MCDA reaction temperature and time were optimized. The sensitivity and specificity of the HBV-MCDA -LFB assay were evaluated in this report. The HBV-MCDA-LFB assay was applied to detect the HBV agent from clinical samples.Results: The HBV-MCDA primers based on the S gene were valid for establishment of MCDA assay. The HBV-MCDA reaction with optimized conditions could be carried out at a constant temperature 64°C for 35 min. The whole process, including sample preparation (5 min), genomic template extraction (∼ 30 min), MCDA amplification (35 min), and LFB reading (∼ 2 min), could be completed within 80 min. The sensitivity of this assay was 5 IU per reaction. The specificity was 100% for HBV-MCDA-LFB assay.Conclusion: These results confirmed that the HBV-MCDA-LFB is a low-cost, sensitive, specific, simple, and rapid method for detecting HBV agents. This technique has great potential to develop a point-of-care testing (POCT) method in clinical practice, especially in endemic and resource-constrained regions.Keywords: hepatitis B virus, HBV, multiple cross displacement amplification, MCDA, lateral flow biosensor, LFB, rapid detection, molecular detection

Roushan Liu,1,* Jian Zhang,2,* Xiaoli Du,3 Yingying Lv,1 Xiangyu Gao,1 Yanyan Wang,1 Junrui Wang1 1Department of Laboratory Medicine, Affiliated Hospital of Inner Mongolian Medical University, Hohhot, 010050, People’s Republic of China; 2Department of Laboratory Medicine, Bayannur People’s Hospital, Bayannur City, 015000, People’s Republic of China; 3National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junrui WangDepartment of Laboratory Medicine, Affiliated Hospital of Inner Mongolian Medical University, Hohhot, 010050, People’s Republic of ChinaTel +86 13347104892Email wangjunrui123@yeah.netPurpose: This study investigates the phenotypic and genotypic resistance features of OS-MRSA clinical isolates and their distinctive sensitivities to oxacillin.Methods: 1200 clinical isolates of Staphylococcus aureus were enrolled in this study. Automated antibiotics susceptibility tests on VITEK-2 and BD Phoenix-100TM, cefoxitin disc diffusion method, oxacillin broth microdilution method, mecA, and mecC gene detection were performed to identify OS-MRSA. MLST, PFGE, SCCmec, and spa typing methods were employed to determine genotypes of OS-MRSA isolates. Heterogeneous resistance of OS-MRSA isolates was detected using the population analysis profiling method, and PBP2a latex agglutination assay was used to detect the expression of PBP2a protein for 14 OS-MRSA isolates and their highly resistant subpopulations.Results: A total of 14 OS-MRSA isolates (1.17%, 14/1200) were identified, and all of the isolates were confirmed to be positive with the mecA gene and negative with the mecC gene. All of the 14 OS-MRSA isolates were identified as MSSA by VITEK-2, BD Phonenix-100, and oxacillin broth microdilution methods, while 21.43% (3/14) isolates were determined to be MRSA by the cefoxitin disk diffusion method. Genotypes of the 14 OS-MRSA isolates were diverse, and no dominant clones were identified. The prevalence of pvl gene among 14 OS-MRSA isolates was high up to 64.29% (9/14). All of the isolates showed heterogeneous resistance to oxacillin, while frequencies of the oxacillin-resistant subpopulations ranged from 10− 9 to 10− 5 and differed significantly among different isolates.Conclusion: The overall prevalence of OS-MRSA was relatively lower, but lower oxacillin MICs, low testing sensitivity of routine antibiotics susceptibility testing methods and weak PBP2a protein expression were observed in this study. 14 OS-MRSA showed diverse genotypes and universal heterogeneous resistance, and inaccurate laboratory identification and improper antimicrobial usage may promote the induction of highly resistant subpopulations and lead to treatment failure.Keywords: oxacillin sensitive MRSA, molecular typing, heterogeneous resistance

Yan Yao,1 Tingting Zhang,2 Lingyu Qi,2 Ruijuan Liu,3 Gongxi Liu,3 Jie Li,2 Changgang Sun3,4 1Clinical Medical Colleges, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China; 2College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China; 3Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong Province, People’s Republic of China; 4Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Changgang SunInnovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of ChinaTel +86 13583690699Email zhongliuyike@163.comBackground: Tumor microenvironment (TME) cells constitute a vital element of tumor tissues. Increasing evidence has shown that immune response in the microenvironment plays an active role in tumor invasion, metastasis, and recurrence, and is an important factor affecting tumor prognosis. Our study aimed to identify the gene signatures in lung adenocarcinoma (LUAD) microenvironment for prognosis and immunotherapy.Methods: In this study, we evaluated, for the first time, the stromal and immune scores of 594 patients from The Cancer Genome Atlas (TCGA) database with LUAD using the ESTIMATE algorithm. Three hundred and sixty-seven dysregulated immune-related genes were identified. Then, we performed functional enrichment analysis of these genes, and found the best gene model and construct the signature through univariate, Lasso and multivariate COX regression analysis. To assess the independently prognostic ability of the signature, the Kaplan–Meier survival analysis and Cox’s proportional hazards model were performed.Results: Functional enrichment analysis and protein–protein interaction networks showed that the immune-related genes mainly played a role in immune response, activation/proliferation of immune-related cells, and chemokine activity. A prognostic model involving 6 genes was constructed and the signature was identified as an independent prognostic factor and significantly associated with the overall survival (OS) of LUAD. The area under curve (AUC) of the receiver operating characteristic curve (ROC curve) for the 6 genes signature in predicting the 3-year survival rate was 0.708. Finally, four genes (FOXN4, KLHL4, FAM83F and CCR2) can be used as candidate prognostic biomarkers for LUAD.Conclusion: Our findings will help evaluate the prognosis of LUAD and provide new ideas for exploring the potential relationship between TME and LUAD treatment and prognosis.Keywords: lung adenocarcinoma, tumor microenvironment, ESTIMATE algorithm, immune-related gene, prognosis signatures

Yanhua Song,1,* Yifeng Ma,2,* Rongmei Liu,1,* Yuanyuan Shang,3,* Liping Ma,1 Fengmin Huo,3 Yunxu Li,3 Wei Shu,4 Yufeng Wang,5 Mengqiu Gao,1 Yu Pang3 1Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, People’s Republic of China; 2Clinical Laboratory, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People’s Republic of China; 3Department of Bacteriology and Immunology, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, People’s Republic of China; 4Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, People’s Republic of China; 5Department of Laboratory Quality Control, Innovation Alliance on Tuberculosis Diagnosis and Treatment (Beijing), Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mengqiu GaoDepartment of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing 101149, People’s Republic of ChinaTel/Fax +86-10-8950 9322Email gaomqwdm@aliyun.comYu PangDepartment of Bacteriology and Immunology, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing 101149, People’s Republic of ChinaTel/Fax +86-10-8950 9359Email pangyupound@163.comObjective: A prospective study was conducted to ascertain the accuracy of oral swab specimens collected in the early morning, spot and at night for detecting pulmonary tuberculosis (TB).Methods: We prospectively enrolled patients with symptoms suggestive of pulmonary TB in Beijing Chest Hospital. An early morning sputum specimen was collected from each patient for GeneXpert MTB/RIF (Xpert) and mycobacterial culture. In addition, three oral swabs were collected for TB-LAMP testing.Results: With the combined results of three oral swab specimens, the proportion of Mycobacterium tuberculosis (MTB)-positive cases achieved 40.6%, which was comparable to results for Xpert and MGIT (P=0.603). Using Xpert plus MGIT as reference, the sensitivity of OS-LAMP on a single specimen ranged from 32.6% on the night oral swab to 50.0% on the morning swab. The combination of three oral swab specimens correctly identified 38 MTB-positive cases, indicating an overall sensitivity of 82.6%, which was significantly higher than that of a single oral swab specimen (P< 0.001, P=0.001).Conclusion: Oral swab can be used as an alternative specimen for diagnosis of pulmonary TB using TB-LAMP. Morning oral swab exhibits the highest sensitivity, and the inclusion of more specimens at different time points provides compensation in diagnostic sensitivity with single oral swab.Keywords: diagnosis, oral swab, TB-LAMP, pulmonary tuberculosis, China

Yanhua Song,1 Guirong Wang,2 Qiang Li,1 Rongmei Liu,1 Liping Ma,1 Qi Li,3 Mengqiu Gao1 1Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing 101149, People’s Republic of China; 2National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing 101149, People’s Republic of China; 3Clinical Center on Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing 101149, People’s Republic of ChinaCorrespondence: Qi LiClinical Center on Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing 101149, People’s Republic of ChinaTel +86 10 89509322Fax +86 1069546790Email liqi88_dr@163.comMengqiu GaoDepartment of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing 101149, People’s Republic of ChinaTel +86 10 89509322Fax +86 1069546790Email gaomengqi55_dr@163.comObjective: This study aims to analyze the correlation between gene inhA mutations by melting curve technology and phenotypic drug susceptibility (DST) results of ethionamide (ETH), and evaluate whether gene inhA mutations detection can serve as a molecular marker in predicting ETH resistance.Methods: A retrospective analysis was conducted on 382 strains of Mycobacterium tuberculosis (MTB) with the anti-tuberculosis drugs isoniazid (INH), rifampicin (RIF), ETH, and others. Phenotypic drug susceptibility and the results of inhA and katG genotypes (mutation and no mutation) were obtained using the melting curve technology MeltPro TB assay.Results: Of the 382 clinical strains of MTB tested, 118 (30.9%) were resistant to INH, and 28 (7.3%) were resistant to ETH. Among the 28 phenotypically ETH-resistant strains, inhA mutations accounted for 42.9% (12/28). These ETH-resistant strains comprise 35.3% (12/34) of the 34 inhA mutant strains. Of 8 single inhA mutation strains (without katG or rpoB mutation), 4(50%) were resistant to INH; however, all of these 8 strains were sensitive to ETH.Conclusion: The inhA mutation test may not be a reliable predictor of ETH resistance. Mutant inhA strains are not necessarily resistant to ETH. The strains with single inhA mutation (without katG or rpoB mutation) may be effective for ETH treatment. The use of ETH in clinical medicine should be guided by gene (other than inhA alone) detection and phenotypic drug susceptibility testing.Keywords: melting curve technique, Mycobacterium tuberculosis, drug resistance, inhA, gene mutation, prothionamide, ethionamide

Yin Liu,1,2 Yanbing Yu,2 Zheng Wang,1,2 Zhu Deng,2,3 Ruiquan Liu,2,3 Na Luo,1,2 Li Zhang2 1Graduate School of Peking University Health Science Center, Beijing, People’s Republic of China; 2Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 3Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Li ZhangDepartment of Neurosurgery, China-Japan Friendship Hospital, No. 2 Yinghua Dongjie, Hepingli, Chaoyang District, Beijing, People’s Republic of ChinaTel +86 18910586699Fax +86-10-64217749Email allan18910586699@163.comPurpose: Microvascular decompression (MVD) is the most effective surgical procedure for the treatment of refractory primary trigeminal neuralgia (TN), but due to the presence of non-neurovascular compression (NVC), the application of MVD is limited. In some cases, partial sensory rhizotomy (PSR) is required. The purpose of this study was to compare the outcome of MVD and MVD+PSR in the treatment of primary TN and to evaluate the application value of PSR in the treatment of TN.Patients and Methods: We retrospectively analyzed the postoperative outcomes of patients who received MVD or MVD+PSR for the first time from the same surgeon in the neurosurgery department of China-Japan Friendship Hospital from March 2009 to December 2017. A total of 105 patients were included in the data analysis, including 40 in the MVD group and 65 in the MVD+PSR group.Results: The MVD group had an effectiveness rate of 60% and a recurrence rate of 31.4% after an average follow-up of 49.4 months. The MVD+PSR group had an average effectiveness rate of 69.2% and a recurrence rate of 28.6% after an average follow-up of 71.4 months. There was no statistically significant intergroup difference in long-term effectiveness (p=0.333) or recurrence rates (p=0.819). The incidence of facial numbness was significantly higher in the MVD+PSR group than in the MVD group (83.1% vs 7.5%; p< 0.001). However, facial numbness had no significant effect on the patients’ daily life.Conclusion: MVD+PSR and MVD have the same effectiveness in the treatment of primary TN. MVD+PSR is associated with a higher incidence of facial numbness than MVD, but the difference does not affect the patients’ daily life. PSR should have a place in the treatment of TN by posterior fossa microsurgery.Keywords: trigeminal neuralgia, microvascular decompression, partial sensory rhizotomy, posterior fossa microsurgery

We present the model we developed to reconstruct the CUORE radioactive background based on the analysis of an experimental exposure of 1038.4 kg yr. The data reconstruction relies on a simultaneous Bayesian fit applied to energy spectra over a broad energy range. The high granularity of the CUORE detector, together with the large exposure and extended stable operations, allow for an in-depth exploration of both spatial and time dependence of backgrounds. We achieve high sensitivity to both bulk and surface activities of the materials of the setup, detecting levels as low as 10 nBq kg-1 and 0.1 nBq cm-2, respectively. We compare the contamination levels we extract from the background model with prior radio-assay data, which informs future background risk mitigation strategies. The results of this background model play a crucial role in constructing the background budget for the CUPID experiment as it will exploit the same CUORE infrastructure.

Junjun Sun,1 Yanyan Luo,1 Hongjuan Chang,1 Ruiqin Zhang,1 Rui Liu,1 Yuanyuan Jiang,1 Huifang Xi2 1School of Nursing, Xinxiang Medical University, Xinxiang, People’s Republic of China; 2The First Affiliated Hospital of Xinxiang Medical University, Weihui, People’s Republic of ChinaCorrespondence: Yanyan LuoSchool of Nursing, Xinxiang Medical University, 601 Jinsui Avenue, Hongqi District, Xinxiang 453000, People’s Republic of ChinaTel +86-13937315599Email 13937315599@163.comBackground: The behavioral inhibition system (BIS) and behavioral activation system (BAS), which primarily underlie emotions and behaviors, are associated with depression and anxiety. However, the reasons behind these associations require further exploration.Objective: This study aims to examine the mediating effects of cognitive emotion regulation between BIS/BAS and depression/anxiety among community-dwelling elderly Chinese.Methods: A cross-sectional survey was conducted with a sample of 836 elderly individuals. Structural equation modeling was used to determine relationships among BIS/BAS, cognitive emotion regulation, and depression/anxiety.Results: Participants reporting higher BIS sensitivity were more likely to use maladaptive cognitive emotion regulation strategies, which were in turn associated with higher rates of depression and anxiety. BAS sensitivity was more likely to lead to adaptive cognitive emotion regulation strategies, which resulted in lower levels of depression and anxiety.Conclusion: Our findings suggest that incorporating emotional regulation in interventions targeting BIS/BAS sensitivities may enhance the accuracy and efficiency of these treatments for depression and anxiety.Keywords: behavioral inhibition system, behavioral activation system, cognitive emotion regulation, depression, anxiety

Hong-xue Meng,1,2,* Xin-xin Yang,1,* Rui-qi Liu,3,* Jun-jie Bao,4 Yun-jing Hou,1 Ji Sun,5 Su-sheng Miao,5 Guo-fan Qu4 1Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 2Department of Pathology, Harbin Medical University, Harbin, People’s Republic of China; 3Department of Radiation Oncology, Sun Yat-Sen University Cancer Hospital, Guangzhou, People’s Republic of China; 4Department of Orthopedics, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 5Department of Otolaryngology, Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong-xue MengDepartment of Pathology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, People’s Republic of ChinaTel +86-451-85718261Email menghongxue15@163.comGuo-fan QuDepartment of Orthopedics, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, People’s Republic of ChinaTel +86-451-85718262Email 18846719333@163.comPurpose: Infection with human papillomavirus (HPV) has been indicated to be a important risk factor for oropharyngeal squamous cell carcinoma (OPSCC). Primary ciliogenesis defects contribute to tumorigenesis, and OFD1 at centriolar satellites is a crucial suppressor of primary ciliogenesis. To identify novel markers associated with HPV-induced carcinogenesis, the interactions between HPV infection and primary ciliogenesis in the tumorigenesis and progression of OPSCC were investigated in this study.Patients and Methods: The 1530 OPSCC patients recruited in this research were treated from 2000 to 2017. Immunohistochemistry and RT-PCR were performed on tissue samples to compare the expression of p16, TSLP, TGFβ 1, IFNγ, OFD1, and their relationship with clinical characteristics of patients.Results: We speculate that the positive expression of p16 is related to early primary OPSCC, and the survival rate of p16 positive patients after radiotherapy and surgery is higher. Expression of TSLP on dendritic cells in HPV-positive OPSCC correlated with the expression of OFD1. HPV-positive OPSCC showed increased expression of OFD1 combined with reduced ciliogenesis. Hence, TSLP induced by HPV infection may reduce the invasive potential of OPSCC cells by promoting OFD1 expression, thereby inhibiting primary ciliogenesis.Conclusion: Our study demonstrated that HPV may be related to the progression of OPSCC by regulating OFD1 expression and primary ciliogenesis, making this protein a potential therapeutic target.Keywords: HPV, p16, oropharyngeal cancer, pathogenesis, prognosis

Kun Zhang,1,2 Ran Liu,1,2 Yuan Gao,2 Wen Ma,2 Weidong Shen1,2 1Department of Acupuncture, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Institute of Acupuncture and Anesthesia, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Weidong Shen; Wen MaDepartment of Acupuncture, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No. 528, Zhang Heng Road, Pu Dong New District, Shanghai 201203, People’s Republic of ChinaTel +86 21 2025 6337; +86 21 2025 6336Fax +86 212 025 6699; +86 21 2025 6336Email shenweidong1018@163.com; 13524650702@126.comBackground: Neuroinflammation is an important pathological mechanism of depression that leads to an increase in indoleamine-2,3-dioxygenase (IDO) activity and NMDAR activation. This study aimed to observe the effects of electroacupuncture on depression-like behaviour in lipopolysaccharide (LPS)-treated rats and the underlying mechanism.Methods: Wistar rats were intraperitoneally administered LPS (0.5 mg/kg) for 7 consecutive days to establish a depression model. Electroacupuncture treatment was administered 1 hour after daily LPS injection. The open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were used to evaluate the depressive-like behaviours. IL-1β, IL-6, and TNF-α levels were determined by enzyme-linked immunosorbent assay (ELISA); Trp, 5-hydroxytryptamine (5-HT), kynurenine (Kyn) and quinolinic acid (Quin) were detected by ultra-high-performance liquid chromatography-tandem mass spectrometry; and N-methyl-D-aspartate receptor (NMDAR) protein and mRNA were assessed by Western blot and real-time qPCR.Results: The results showed that electroacupuncture treatment successfully corrected LPS-induced depressive-like behaviour, reduced the inflammatory factor (IL-1β, IL-6 and TNF-α) levels in the blood and hippocampus, prevented IDO over-activation and recovered NR2B expression after challenge by LPS.Conclusion: Electroacupuncture treatment provided protection against LPS-induced depressive-like behaviour, and the associated mechanisms may be related to inhibiting the inflammatory response, regulating the IDO-mediated tryptophan-degrading pathway, and inhibiting NR2B activation.Keywords: depression, electroacupuncture, LPS, IDO

Zhiwen Cao,1 Wen Li,1 Rui Liu,1 Chenxi Li,1 Yurong Song,1 Guangzhi Liu,1 Youwen Chen,1 Cheng Lu,2 Aiping Lu,3 Yuanyan Liu1 1School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, People’s Republic of China; 2Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, People’s Republic of China; 3School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hongkong, People’s Republic of ChinaCorrespondence: Yuanyan Liu; Aiping Lu Tel +86 10 84738658Email yyliu_1980@163.com; lap64067611@126.comIntroduction: Auraptene (AUR), a natural bioactive prenyloxy coumarin, is a highly pleiotropic molecule that can bind to the MT1 receptor and can effectively reduce the proliferation and migration of breast cancer cells. Cisplatin (CDDP), as the first synthetic platinum-based anticancer drug, is widely used in the clinic due to its definite mechanism and therapeutic effect on diverse tumors. However, both of AUR and CDDP exhibit some disadvantages when used alone, including poor solubility, low bioavailability, lack of selectivity and systemic toxicity when they are used singly.Methods: Therefore, the biodegradable materials hyaluronic acid (HA) and β-cyclodextrin derivative (mono-(6-amino-mono-6-deoxy)-β-CD, CD) were employed as carriers to load AUR and CDDP to form nanogel (CDDPHA-CD@AUR) capable of dual-targeted delivery and synergistic therapy for breast cancer and cell imaging.Results: With the help of the CDDP-crosslinked CD-loaded structure, the newly synthesized nanogel exhibited excellent physiological stability and fluorescence effects. The release of AUR and CDDP was affected by the pH value, which was beneficial to the selective release in the tumor microenvironment. Cell experiments in vitro demonstrated that the nanogel could be selectively internalized by MCF-7 cells and exhibited low cytotoxicity to HK-2 cells. Antitumor experiments in vivo showed that the nanogel have better antitumor effects and lower systemic toxicity.Conclusion: Based on these, the nanogel loaded with AUR and CDDP have the potential for targeted delivery against breast cancer.Keywords: auraptene, cisplatin, cell imaging, tumor targeting, pH-responsive

Jun Wang,1,* Weijie Zhao,2,* Rongmei Liu,1,* Fengmin Huo,3 Lingling Dong,3 Yi Xue,3 Yufeng Wang,4 Zhongtan Xue,4 Liping Ma,1 Yu Pang3 1Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing 101149, People’s Republic of China; 2Clinical Trial Agency Office, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing 101149, People’s Republic of China; 3National Clinical Laboratory on Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing 101149, People’s Republic of China; 4Department of Laboratory Quality Control, Innovation Alliance on Tuberculosis Diagnosis and Treatment (Beijing), Beijing 101149, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu PangNational Clinical Laboratory on Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing 101149, People’s Republic of ChinaTel/Fax +86-10-8950 9359Email pangyupound@163.comLiping MaDepartment of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing 101149, People’s Republic of ChinaTel/Fax +86-10-8950 9322Email malipinghm@hotmail.comObjective: We conducted a retrospective study to evaluate the performance of MeltPro assay for detecting ethambutol (EMB) susceptibility of Mycobacterium tuberculosis (MTB) isolates in sputum specimens in Beijing, China.Methods: Smear-positive TB patients undergoing MeltPro assay in the Beijing Chest Hospital between January 2019 and December 2019 were included. Phenotypic drug susceptibility testing (DST) was used as the reference standard to calculate the diagnostic accuracy of MeltPro assay for EMB resistance. Sanger sequencing of embB gene was conducted to resolve the discrepancies between MeltPro assay and phenotypic DST.Results: A total of 222 smear-positive patients were included in our analysis. The overall agreement rate between the two assays was 91.4%, with a kappa value of 0.78. Among 59 EMB-resistant TB cases diagnosed by DST, 49 were identified by MeltPro assay, demonstrating a sensitivity of 83.1%. In addition, 154 out of 163 EMB-susceptible patients diagnosed by DST were correctly detected with MeltPro assay, yielding a specificity of 93.9%. The probe frequency associated with the observed EMB-resistance was as follows: A (45/58), B (7/58), and D (6/58), and no EMB-resistance was associated with probe C. The presence of amino acid substitution was observed among all 9 cases with potentially “false-negative” results, including 7 with Met306Ile, 1 with Met306Val, 1 with Gly406Asp, respectively.Conclusion: MeltPro assay is a promising diagnostic tool for the detection of EMB resistance in China. The specific amino acid substitution in embB gene is the major reason for discrepancies between MeltPro assay and phenotypic DST.Keywords: tuberculosis, ethambutol, molecular diagnostic, embB, China

Xiaoyi Ning,1,* Yun Kuang,1,* Shuwei Zhao,2 Wenjing Hou,2 Guoping Yang,1,3,4 Xuerui Zhu,5 Ruiling Liu,6 Jie Huang1 1Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Center of Clinical Medical Trial, Medical University General Hospital, Tianjin, People’s Republic of China; 3Research Center for Drug Clinical Evaluation of Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 5Department of clinical research and development, Zhejiang Wolwo Biopharmaceuticals, Deqing, Zhejiang, People’s Republic of China; 6Department of Allergy, Medical University General Hospital, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ruiling LiuDepartment of Allergy, Medical University General Hospital, Tianjin 300052, People’s Republic of ChinaTel/Fax +8618622930966Email lrly05@163.comJie HuangCenter for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, 138 TongZiPo Road, Changsha, Hunan 410013, People’s Republic of ChinaTel/Fax +8615116469024Email cellahuang1988@163.comBackground: Eight extracts from common native allergens, Artemisia annua pollen, Platanus pollen, Humulus pollen, Betula platyphylla pollen, Ambrosia artemisiifolia pollen, Blattella germanica, cat dander and dog dander were developed for skin prick test (SPT). Since standardization and composition alone cannot guarantee that the allergen extracts are within the concentration range that give the best chance of a true diagnosis, it is necessary to explore the optimal diagnostic concentration (ODC) of allergens in SPT.Objective: To identify the optimal diagnostic concentration of eight allergen extracts in SPT and assess the safety of simultaneous administration.Patients and Methods: Patients with a history of allergic disease were enrolled in this two-part open-label, parallel study. In Study 1, 92 patients were enrolled into eight groups according to their disease-causing allergens and were given three increasing concentrations of the corresponding allergen. In Study 2, 20 patients were divided into two concentration groups and were given all of the eight allergens. Safety and sensitivity were evaluated to determine the optimal diagnostic concentration.Results: In Study 1, the sensitivity of seven allergen extracts was > 80% at middle and high concentrations, except for Ambrosia artemisiifolia pollen. The optimal diagnostic concentration (in DU/mL) for eight allergens was 33,333, 12,000, 8667, 50,000, 40,000, 3333, 7000, and 5000. In Study 2, the prevalence of adverse events in the two groups was 70% and 80%, respectively. A total of 10 wheals of 8 patients did not subside < 24 h after SPTs.Conclusion: The eight allergens showed high sensitivity and safety at a certain concentration, which was defined as optimal diagnostic concentration. The results support further clinical research of investigated allergens and our study offers a scheme to determine the ODC of allergens in SPT.Keywords: skin prick test, allergen, optimal diagnostic concentration

Qiong Huang,1– 3,* Rong Liu,1– 3,* Jing Liu,1– 3 Qi Huang,1– 3 Shao Liu,1– 3 Yueping Jiang1– 3 1Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China; 2Institute of Hospital Pharmacy, Central South University, Changsha 410008, People’s Republic of China; 3Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shao Liu; Yueping JiangDepartment of Pharmacy, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 4100080, People’s Republic of ChinaEmail liushao999@csu.edu.cn; jiangyueping@126.comBackground and Purpose: Insulin resistance (IR) is one of the factors that results in metabolic syndrome, type 2 diabetes mellitus and different aspects of cardiovascular diseases. Moringa oleifera seeds (MOS), traditionally used as an antidiabetic food and traditional medicine in tropical Asia and Africa, have exhibited potential effects in improving IR. To systematically explore the pharmacological mechanism of the anti-IR effects of MOS, we adopted a network pharmacology approach at the molecular level.Methods: By incorporating compound screening and target prediction, a feasible compound-target-pathway network pharmacology model was established to systematically predict the potential active components and mechanisms of the anti-IR effects of MOS. Biological methods were then used to verify the results of the network pharmacology analysis.Results: Our comprehensive systematic approach successfully identified 32 bioactive compounds in MOS and 44 potential targets of these compounds related to IR, as well as 37 potential pathways related to IR. Moreover, the network pharmacology analysis revealed that glycosidic isothiocyanates and glycosidic benzylamines were the major active components that improved IR by acting on key targets, such as SRC, PTPN1, and CASP3, which were involved in inflammatory responses and insulin-related pathways. Further biological research demonstrated that the anti-IR effects of MOS were mediated by increasing glucose uptake and modulating the expression of SRC and PTPN1.Conclusion: Our study successfully predicts the active ingredients and potential targets of MOS for improving IR and helps to illustrate mechanism of action at a systemic level. This study not only provides new insights into the chemical basis and pharmacology of MOS but also demonstrates a feasible method for discovering potential drugs from traditional medicines.Keywords: network pharmacology, Moringa oleifera seeds, IR, active components, action mechanism

Yun-jing Hou,1 Xin-xin Yang,1 Rui-qi Liu,2 Di Zhao,1 Chen-xu Guo,1 An-chao Zhu,1 Mei-na Wen,1 Zhao Liu,3 Guo-fan Qu,4 Hong-xue Meng1 1Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 2Department of Radiation Oncology, Sun Yat-Sen University Cancer Hospital, Guangzhou, People’s Republic of China; 3Department of Ultrasound, Harbin Medical University, Harbin, People’s Republic of China; 4Department of Orthopedics, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Hong-xue Meng Department of PathologyHarbin Medical University Cancer Hospital, 150 Haping Road, Harbin, People’s Republic of ChinaTel +86-451-85718261Email menghongxue15@163.comAbstract: The ultimate goal of phototherapy based on nanoparticles, such as photothermal therapy (PTT) which generates heat and photodynamic therapy (PDT) which not only generates reactive oxygen species (ROS) but also induces a variety of anti-tumor immunity, is to kill tumors. In addition, due to strong efficacy in clinical treatment with minimal invasion and negligible side effects, it has received extensive attention and research in recent years. In this paper, the generations of nanomaterials in PTT and PDT are described separately. In clinical application, according to the different combination pathway of nanoparticles, it can be used to treat different diseases such as tumors, melanoma, rheumatoid and so on. In this paper, the mechanism of pathological treatment is described in detail in terms of inducing apoptosis of cancer cells by ROS produced by PDT, immunogenic cell death to provoke the maturation of dendritic cells, which in turn activate production of CD4+ T cells, CD8+T cells and memory T cells, as well as inhibiting heat shock protein (HSPs), STAT3 signal pathway and so on.Keywords: pathological mechanism, nanoparticles, photothermal therapy, PTT, photodynamic therapy, PDT