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Fengyi Yang,1,2,* Qiaoyan Dong,3,* Zhuo Chen,1,2,* Benjian Gao,1,2,* Dongning Zheng,1,2 Rui Wang,1,2 Shu Qin,1,2 Fangyi Peng,1,2 Ming Luo,1,2 Jin Yang,1,2 Mengmei Nie,4 Bo Li,1,2 Xiaoli Yang1,2 1Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Academician (Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3Luzhou Senior High School, Luzhou, 646000, People’s Republic of China; 4Department of Urological Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo Li; Xiaoli Yang, Email liboer2002@126.com; 344920646@qq.comPurpose: The efficacy of systemic therapy for hepatocellular carcinoma (HCC) is limited mainly by the complex tumor defense mechanism and the severe toxic side-effects of drugs. The efficacy of apatinib (Apa), a key liver cancer treatment, is unsatisfactory due to inadequate targeting and is accompanied by notable side-effects. Leveraging nanomaterials to enhance its targeting represents a crucial strategy for improving the effectiveness of liver cancer therapy.Patients and Methods: A metal polyphenol network-coated apatinib-loaded metal-organic framework-based multifunctional drug-delivery system (MIL-100@Apa@MPN) was prepared by using metal-organic frameworks (MOFs) as carriers. The nanoparticles (NPs) were subsequently characterized using techniques such as X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential measurements, and particle size analysis. In vitro experiments were conducted to observe the drug release kinetics and cytotoxic effects of MIL-100@Apa@MPN on HepG2 cells. The in vivo anti-tumor efficacy of MIL-100@Apa@MPN was evaluated using the H22 tumor-bearing mouse model.Results: The formulated MIL-100@Apa@MPN demonstrates remarkable thermal stability and possesses a uniform structure, with measured drug-loading (DL) and encapsulation efficiency (EE) rates of 28.33% and 85.01%, respectively. In vitro studies demonstrated that HepG2 cells efficiently uptake coumarin-6-loaded NPs, and a significant increase in cumulative drug release was observed under lower pH conditions (pH 5.0), leading to the release of approximately 73.72% of Apa. In HepG2 cells, MIL-100@Apa@MPN exhibited more significant antiproliferative activity compared to free Apa. In vivo, MIL-100@Apa@MPN significantly inhibited tumor growth, attenuated side-effects, and enhanced therapeutic effects in H22 tumor-bearing mice compared to other groups.Conclusion: We have successfully constructed a MOF delivery system with excellent safety, sustained-release capability, pH-targeting, and improved anti-tumor efficacy, highlighting its potential as a therapeutic approach for the treatment of HCC.Keywords: metal-organic frameworks nanoparticles, apatinib, drug-targeting delivery, ferroptosis therapy, hepatocellular carcinoma

Weiyu Cai,1– 3,&ast; Le Chen,1– 3,&ast; Yanyuan Dai,1– 3 Baixin Chen,1– 3 Dandan Zheng,1– 3 Yun Li1– 3 1Department of Sleep Medicine, Shantou University Mental Health Center, Shantou University Medical College, Shantou, Guangdong, People’s Republic of China; 2Sleep Medicine Center, Shantou University Medical College, Shantou, Guangdong, People’s Republic of China; 3Joint Laboratory of Biological Psychiatry Shantou University-University of Manitoba, Shantou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yun Li, Department of Sleep Medicine, Shantou University Mental Health Center, North Taishan Road, Wanji District, Shantou, Guangdong Province, 515041, People’s Republic of China, Email s_liyun@stu.edu.cnPurpose: Major depressive disorder (MDD) is associated with cognitive impairment through unclear mechanisms. We examined the relationship between sleep electroencephalogram (EEG) power and attention level in MDD.Patients and Methods: Forty-seven untreated patients with MDD and forty-seven age- and sex-matched controls were included. We examined relative EEG power during non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep by fast Fourier transform. The Attention Network Test (ANT) was performed to evaluate attention levels.Results: Compared to controls, patients with MDD had lower theta power during NREM (P = 0.018) and REM (P = 0.002) sleep, while higher beta power (P = 0.050) during NREM sleep and delta power (P = 0.018) during REM sleep. Regarding attention level, patients with MDD had lower levels of accuracy (P = 0.021), longer mean reaction time (P < 0.001), poorer manifestations of the alerting effect (P = 0.038) and worse executive control (P = 0.048). Moreover, decreased theta power during NREM sleep was correlated with worsened accuracy (β = 0.329, P = 0.040), decreased theta power during REM sleep was correlated with worsened alerting effect (β = 0.355, P = 0.020), and increased delta power during REM sleep was correlated with longer mean reaction time (β = 0.325, P = 0.022) in patients with MDD. No association between ANT performance and other frequency bands was observed in patients with MDD.Conclusion: Our findings suggest that patients with MDD manifest impaired selective attention function that is associated with decreased theta power during NREM/REM sleep and increased delta power during REM sleep.Keywords: major depressive disorder, sleep, EEG power, attention

Wu Lin,1,&ast; Yuxiang Yan,2,&ast; Qingling Huang,1 Dali Zheng2 1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, People’s Republic of China; 2Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dali Zheng, Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, 88 Jiao Tong Road, Fuzhou, 350004, People’s Republic of China, Email dalizheng@fjmu.edu.cnAbstract: The p53 tumor suppressor protein plays an important role in physiological and pathological processes. MDM2 and its homolog MDMX are the most important negative regulators of p53. Many studies have shown that MDMX promotes the growth of cancer cells by influencing the regulation of the downstream target gene of tumor suppressor p53. Studies have found that inhibiting the MDMX-p53 interaction can effectively restore the tumor suppressor activity of p53. MDMX has growth-promoting activities without p53 or in the presence of mutant p53. Therefore, it is extremely important to study the function of MDMX in tumorigenesis, progression and prognosis. This article mainly reviews the current research progress and mechanism on MDMX function, summarizes known MDMX inhibitors and provides new ideas for the development of more specific and effective MDMX inhibitors for cancer treatment.Keywords: MDMX, P53, cancer, inhibitors

Yichen Peng,1,2,&ast; Xia Wu,1,2,&ast; Yurong Zhang,1 Yue Yin,1 Xianglin Chen,2 Ding Zheng,1 Jing Wang1 1The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Hepatobiliary Department, Luzhou, People’s Republic of China; 2Department of Integrated Traditional Chinese & Western Medicine, The Southwest Medical University, Luzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ding Zheng; Jing Wang, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Hepatobiliary Department, No. 182, Chunhui Road, Luzhou, 646000, People’s Republic of China, Tel +86 19937071324, Email 793436166@qq.com; lywj68@126.comAbstract: According to the Barcelona Clinic Liver Cancer (BCLC) system, radical resection of early stage primary hepatocellular carcinoma (HCC) mainly includes liver transplantation, surgical resection, and radiofrequency ablation (RFA), which yield 5-year survival rates of about 70– 79%, 41.3– 69.5%, and 40– 70%, respectively. The tumor-free 5-year rate for HCC patients undergoing radical resection only reach up to 13.7 months, so the prevention of recurrence after radical resection of HCC is very important for the prognosis of patients. The traditional Chinese medicine (TCM) takes the approach of multitarget and overall-regulation to treat tumors, it can also independently present the “component-target-pathway” related to a particular disease, and its systematic and holistic characteristics can provide a personalized therapy based on symptoms of the patient by treating the patient as a whole. TCM as postoperative adjuvant therapy after radical resection of HCC in Barcelona Clinic liver cancer A or B stages, and the numerous clinical trials confirmed that the efficacy of TCM in the field of HCC has a significant effect, not only improving the prognosis and quality of life but also enhancing patient survival rate. However, with the characteristics of multi-target, multi-component, and multi-pathway, the specific mechanism of Chinese medicine in the treatment of diseases is still unclear. Because of the positive pharmacological activities of TCM in combating anti-tumors, the mechanism studies of TCM have demonstrated beneficial effects on the regulation of immune function, chronic inflammation, the proliferation and metastasis of liver cancer cells, autophagy, and cell signaling pathways related to liver cancer. Therefore, this article reviews the mechanism of traditional Chinese medicine in reducing the recurrence rate of HCC after radical resection.Keywords: traditional Chinese medicine, radical resection, hepatocellular carcinoma, recurrence

Benjian Gao,1,2,&ast; Fengyi Yang,1,2,&ast; Dongning Zheng,1,2 Shuai Hu,1,2 Jie Liu,1,2 Hong Liu,1,2 Yongfa Liu,1,2 LinXin Liu,1,2 Rui Wang,1,2 Yi Zhao,1,2 Cheng Cui,1,2 Cheng Fang,1,2 Jin Yang,1,2 Song Su,1,2 Yunwei Han,3 Xiaoli Yang,1,2 Bo Li1,2 1Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2Academician (Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 3Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoli Yang; Bo Li, Email 344920646@qq.com; liboer2002@126.comPurpose: This study aimed to explore the clinical efficacy of transarterial chemoembolization (TACE) in combination with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) (triple therapy) compared to TACE alone (monotherapy) for advanced hepatocellular carcinoma (HCC).Material and Methods: Data of consecutive advanced HCC patients receiving triple therapy or monotherapy at our center between January 2019 and December 2022 were collected and retrospectively analyzed. Propensity score matching (PSM) and subgroup analyses were performed to reduce the bias between the two groups. The primary outcomes of the study were the overall survival (OS) and progression-free survival (PFS). The secondary outcomes were the objective response rate (ORR) and disease control rate (DCR).Results: A total of 104 patients were enrolled in this study: 41 in the triple therapy group and 63 in the monotherapy group. After PSM analysis, each group included 37 patients. The median OS and PFS were significantly longer in the triple therapy group than in the monotherapy group in the whole cohort (median OS, 18.8 vs 11.7 months, P = 0.022; median PFS, 10.5 vs 6.4 months, P = 0.012) and after PSM (median OS, 19.6 vs 12.5 months, P = 0.030; median PFS, 10.5 vs 6.7 months, P = 0.008). Furthermore, the treatment modality was an independent prognostic factor for OS (hazard ratio [HR]: 0.449, 95% confidence interval [CI]: 0.240– 0.840, P = 0.012) and PFS (HR: 0.406, 95% CI: 0.231– 0.713, P = 0.002) according to the multivariate cox regression analysis. A greater ORR was also observed in the triple therapy group (ORR: 56.7% vs 32.4%, P = 0.035). No significant difference was observed in DCR between the two groups (83.7% vs 72.9%, P = 0.259).Conclusion: The triple therapy was superior to the monotherapy regarding OS, PFS, and ORR of advanced HCC patients.Keywords: hepatocellular carcinoma, transarterial chemoembolization, tyrosine kinase inhibitors, immune checkpoint inhibitors, efficacy

Qingsong Liu,1,2,&ast; Lunyu Li,2,&ast; Dan Zheng,1 Songlin Jin,2 Xiaotian Guan,2 Zeting Fu,2 Zhigang Xiong,1 Haili Ding3 1Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2School of Sports Medicine and Health, Chengdu Sport University, Chengdu, People’s Republic of China; 3Insititute of Sports Medicine and Health, Chengdu Sport University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haili Ding, No. 2, Gymnasium Road, Chengdu, Sichuan, People’s Republic of China, Tel +86 13688467479, Email dingdingtang111@163.comPurpose: This study examined the underlying mechanisms of SJD’s anti-inflammatory and analgesic effects on acute GA flares.Methods: This study used pharmacology network and molecular docking methods. The active ingredients of ShuiJingDan (SJD) were obtained from the Traditional Chinese Medicine Systems Pharmacology Analysis Platform (TCMSP), and the relevant targets of GA were obtained from the Online Mendelian Inheritance in Man (OMIM) database and Therapeutic Target Database (TTD). The core drug group–target–disease Venn diagram was formed by crossing the active ingredients of SJD and the relevant targets. Gene Ontology (GO) analysis was conducted for functional annotation, DAVID was used for Kyoto Encyclopedia of Genes, and Genomes pathway enrichment analysis, and R was used to find the core targets. The accuracy of SJD network pharmacology analysis in GA treatment was verified by molecular docking simulations. Finally, a rat GA model was used to further verify the anti-inflammatory mechanism of SJD in the treatment of GA.Results: SJD mainly acted on target genes including IL1B, PTGS2, CXCL8, EGF, and JUN, as well as signal pathways including NF-κB, Toll-like receptor (TLR), IL-17, and MAPK. The rat experiments showed that SJD could significantly relieve ankle swelling, reduce the local skin temperature, and increased the paw withdrawal threshold. SJD could also reduce synovial inflammation, reduced the concentrations of interleukin-1β (IL-1β), IL-8, and COX-2 in the synovial fluid, and suppressed the expression of IL1B, CXCL8, and PTGS2 mRNA in the synovial tissue.Conclusion: SJD has a good anti-inflammatory effect to treat GA attacks, by acting on target genes such as IL-1β, PTGS2, and CXCL8.Keywords: ShuiJingDan, gouty arthritis, network pharmacology, molecular docking, IL-1β, COX-2

Linlan Yang,1,&ast; Kaijiong Zhang,2,&ast; Dongming Zheng,1 Yuxin Bai,1 Daifan Yue,1 Lichun Wu,2 Han Ling,2 Sujiao Ni,2 Haimin Zou,2 Bo Ye,2 Chang Liu,2 Yao Deng,2 Qiancheng Liu,3 Yan Li,1 Dongsheng Wang1,2 1College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2Department of Clinical Laboratory, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Department of Clinical Laboratory of Mianyang People’s Hospital, Mianyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongsheng Wang, Department of Clinical Laboratory, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, People’s Republic of China, Email wangdongshengnc@163.com Yan Li, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China, Email Liliana@cdutcm.edu.cnAbstract: In addition to hemostasis and coagulation, years of studies have proved that platelets are involved in the whole process of tumor progression, including tumor invasion, intravasation, extravasation, and so on. It means that this property of platelets can be used in anti-tumor therapy. However, traditional platelet-based antitumor drugs often cause autologous platelet damage due to lack of targeting, resulting in serious side effects. Therefore, the researchers designed a variety of anti-tumor drug delivery systems based on platelets by targeting platelets or platelet membrane coating. The drug delivery systems have special response modes, which is crucial in the design of nanoparticles. These modes enhance the targeting and improve the anti-tumor effect. Here, we present a review of recent discoveries in the field of the crosstalk between platelets and tumors and the progress of platelet-based anti-tumor nanoparticles.Keywords: platelet, tumor, targeted platelet, platelet membranes, stimuli-responsive drug delivery system, nanoparticle

Doudou Zheng,&ast; Liqin Yang,&ast; Meijuan Li, Yuying Qiu, Ying Gao, Jie Li Tianjin Mental Health Institute, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Li, Tianjin Mental Health Centre, Tianjin Anding Hospital, 13 Liulin Road, Hexi District, Tianjin, 300222, People’s Republic of China, Tel/Fax +86-22-88188006, Email jieli@tjmhc.comPurpose: Sex differences in depression have been well recognized. However, sex differences in depression among Omicron-infected individuals have received little systematic study. This study compared sex differences in depression in infected individuals during the 2022 Omicron pandemic in China.Patients and Methods: 506 individuals infected with Omicron (males/females = 268/238) were recruited from Tianjin and Shanghai in China. Self-developed Scale of Demographics were used to collect demographic and clinical data, Zung Self-Rating Depression Scale (SDS), Zung Self-Rating Anxiety Scale (SAS), the Connor-Davidson Resilience Scale (CD-RISC), De Jong Gierveld Scale (DJGLS), and the Penn State Worry Questionnaire (PSWQ) were used to measure respondents’ depression, anxiety, resilience, loneliness and worry, respectively.Results: The prevalence rate of depression in male patients was significantly higher than in female patients (42.2% versus 31.9%; χ2 = 5.64, p = 0.018). Regression analysis showed that in female patients, depression was associated with anxiety [OR = 1.26, 95% CI (1.16– 1.36), p < 0.001], and resilience [OR = 0.98, 95% CI (0.96– 1.00), p < 0.05], while in male patients, depression was associated with anxiety [OR = 1.24, 95% CI (1.15– 1.33), p < 0.001].Conclusion: This on-site study demonstrates that depression is more frequent in male than female Omicron-infected patients and suggests that sex differences should be considered in prevention and treatment strategies for depression during the Omicron pandemic.Keywords: depression, sex difference, Omicron-infected, China

Xiaohang Chen,1,2 Shuaiqi Ji,1,2 Yuxiang Yan,1 Shuoqi Lin,1,2 Lianghang He,1,2 Xiaoyu Huang,2 Lin Chang,2 Dali Zheng,1 Youguang Lu1,2 1Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, People’s Republic of China; 2Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, People’s Republic of ChinaCorrespondence: Youguang Lu; Dali Zheng, Email fjlyg63@fjmu.edu.cn; dalizheng@fjmu.edu.cnAbstract: Tumors are the second-most common disease in the world, killing people at an alarming rate. As issues with drug resistance, lack of targeting, and severe side effects are revealed, there is a growing demand for precision-targeted drug delivery systems. Plant-derived nanovesicles (PDNVs), which arecomposed of proteins, lipids, RNA, and metabolites, are widely distributed and readily accessible. The potential for anti-proliferative, pro-apoptotic, and drug-resistant-reversing effects on tumor cells, as well as the ability to alter the tumor microenvironment (TME) by modulating tumor-specific immune cells, make PDNVs promising anti-tumor therapeutics. With a lipid bilayer structure that allows drug loading and a transmembrane capacity readily endocytosed by cells, PDNVs are also expected to become a new drug delivery platform. Exogenous modifications of PDNVs enhance their circulating stability, tumor targeting ability, high cell endocytosis rate, and controlled-release capacity. In this review, we summarize PDNVs’ natural antitumor activity, as well as engineered PDNVs as efficient precision-targeted drug delivery tools that enhance therapeutic effects. Additionally, we discuss critical considerations related to the issues raised in this area, which will encourage researchers to improve PDNVs as better anti-tumor therapeutics for clinic applications.Graphical Abstract: Keywords: plant-derived nanovesicles, cancer therapy, natural bioactivity, drug delivery platform, engineered EVs, targeted precision therapy

Rifeng Chen, Xiuying Li, Dongyan Zheng, Cunwei Cao, Jiaguang Su Department of Dermatology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of ChinaCorrespondence: Jiaguang Su, Department of Dermatology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Qingxiu District, Nanning, Guangxi Province, 530021, People’s Republic of China, Tel +86 13878106965, Email 503389699@qq.comAbstract: Talaromyces marneffei (TM) and Pneumocystis jirovecii (PJ) infection are opportunistic infections that typically affect individuals with compromised immune systems, such as those with HIV or immunodeficiency. However, these infections are rarely seen in patients with systemic lupus erythematosus (SLE). We present a case study of a 52-year-old woman diagnosed with SLE who developed a co-infection of TM and PJ after receiving glucocorticoids, mycophenolate mofetil (MMF), and belimumab therapy. The patient’s pneumonia improved following treatment with voriconazole, clarithromycin, and compound sulfamethoxazole. This case highlights the potential risk of serious opportunistic infections in SLE patients receiving a combination of glucocorticoids, MMF, and belimumab. Close monitoring of lymphocyte count, immunoglobulin levels, and chest computed tomography scans can aid in the early detection of infections. To the best of our knowledge, this is the first reported case of TM and PJ co-infection in an SLE patient.Keywords: Talaromyces marneffei, Pneumocystis jirovecii, systemic lupus erythematosus, co-infection, belimumab

Wenqian Chen,1 Dali Zheng,2 Changyi Yang1 1Department of Neonatology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 2Key Laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, People’s Republic of ChinaCorrespondence: Changyi Yang, Department of Neonatology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, 350001, People’s Republic of China, Tel +86 15959000599, Fax +86 87279676, Email yangchangyi@fjmu.edu.cnAbstract: Ferroptosis is a novel type of programmed cell death involved in many diseases’ pathological processes. Ferroptosis is characterized by lipid peroxidation, reactive oxygen species accumulation, and iron metabolism disorder. Newborns are susceptible to ferroptosis due to their special physiological state, which is prone to abnormal iron metabolism and the accumulation of reactive oxygen species. Recent studies have linked ferroptosis to a variety of diseases in the neonatal period (including hypoxic-ischemic encephalopathy, bronchopulmonary dysplasia, and necrotizing enterocolitis). Ferroptosis may become an effective target for the treatment of neonatal-related diseases. In this review, the ferroptosis molecular mechanism, metabolism characteristics of iron and reactive oxygen species in infants, the relationship between ferroptosis and common infant disorders, and the treatment of infant diseases targeted for ferroptosis are systematically summarized.Keywords: ferroptosis, neonatal disease, reactive oxygen species, iron metabolism, lipid peroxidation

Xiaoyu Huang,1,2 Ming Zhang,1,3 Lin Chang,1,2 Dali Zheng,2 Wei Lin,4 Yan Feng,1,2 Youguang Lu1,2 1Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 2Fujian Key Laboratory of Oral Diseases, School of Stomatology, Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 3Department of Conservative and Endodontic Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 4College of Chemistry, Fuzhou University, Fuzhou, Fujian Province, People’s Republic of ChinaCorrespondence: Youguang Lu, Tel +86-591-83736429, Fax +86-591-83720599, Email fjlyg63@fjmu.edu.cn; Yan Feng, Tel/Fax +86-591-22862632, Email fengyan@fjmu.edu.cnObjective: The study aims to enhance the anti-caries performance of pit and fissure sealants through the synthesis of novel silver nanocomposites, and to evaluate their mechanical properties and biological safety in vitro and in vivo.Methods: The antibacterial properties of synthetic eggshell/Ag were detected by bacterial inhibition zone, minimum bacteriostatic concentration, fluorescence staining and scanning electron microscopy. The synthetic products were then combined with pit and fissure sealants to prepare specimens, and their effects on mechanical properties, antibacterial properties and cytotoxicity were evaluated. Furthermore, an oral mucosal contact model of golden hamsters was established according to the ISO10933 standard to evaluate local stimulation and systemic effects.Results: The novel nanocomposite eggshell/Ag was confirmed to exhibit strong broad-spectrum antibacterial activity, and that the eggshell/Ag-modified pit and fissure sealant had strong antibacterial properties against common dental caries bacterial biofilms, without any significant change in mechanical properties. The gradient dilution extract showed acceptable cytotoxicity, and in the golden hamster oral contact model, there were no visible abnormalities in local mucosal tissues, blood indices, or liver and kidney histopathology.Conclusions: These findings suggest that eggshell/Ag combined with pit and fissure sealants has strong antibacterial activity and excellent biosafety in vitro and in vivo, making it a promising candidate for clinical applications.Keywords: silver nanocomposites, antibacterial, pit and fissure sealants, biosafety

Zhishu Li,1 Jiayue Chen,1 Jia Zeng,2 Ping Shi,2 Xiaomin Xiong,2 Meng Wang,1 Dong Zheng,1 Rui Zhao,1 Lixia Dong1 1Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, People’s Republic of ChinaCorrespondence: Lixia Dong, Email luckydonglixia@163.comBackground: In patients with tuberculous pleural effusion (TPE) of various ages, the diagnostic accuracy of pleural biomarkers varies, and there are insufficient studies specifically in different age groups. Therefore, we investigated the adenosine deaminase cut-off value and its combination with the gamma interferon release assay for the diagnosis of TPE among patients aged ≥ 40 years.Methods: A retrospective analysis of 198 patients who underwent medical thoracoscopy and were admitted to the hospital between 2015 and 2020 with exudative pleural effusion and either fever, night sweats, fatigue, cough, or other clinical manifestations was performed. The medical thoracoscopy, ADA, and T-SPOT results were analysed in the pleural fluid. The patients were divided into groups based on age: 18– 39, 40– 59, and 60– 87.Results: The best cut-off values of ADA were 29.5, 31.5 and 19.5 U/L, respectively, for the aged 18– 39, aged 40– 87 and aged 60– 87 groups. The accuracy of 31.5 U/L was higher than 40 U/L for aged ≥ 40 years (86 vs 83%). The ADA diagnostic accuracy was higher than that of people under 40 years (83 vs 77%) when cut-off value of ADA was 40 U/L, but the IGRA accuracy was lower than that of people under 40 (87 vs 91%). The sensitivity of ADA or IGRA detection in patients over 40 years was 99%, and the specificity was 78%. The ADA specificity combined with IGRA for TPE was the highest (100%) in the ≥ 40 age group, and the sensitivity was 69%.Conclusion: Our study revealed the best cut-off values of ADA for TBE in different age groups. Combining ADA and IGRA in pleural fluid improves the detection rate of TPE in patients over 40 years of age with exudative pleural effusion. ADA combined with IGRA increases specificity, and ADA or IGRA increases sensitivity substantially.Keywords: adenosine deaminase, interferon gamma releasing assays, aged, diagnosis, pleural effusion, tuberculosis

Danni Zheng,1 Jiawen Yang,2 Jiali Qian,2 Lingli Jin,1 Guanli Huang3,4 1Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Breast and Thyroid Surgery Department, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, Zhejiang, People’s Republic of China; 4Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Lingli Jin, Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Shangcai Village, Nanbaixiang Street, Ouhai District, Wenzhou, Zhejiang, People’s Republic of China, Tel +86 577 5557 8527, Email jll0992021@163.com Guanli Huang, Department of Breast and Thyroid Surgery Department, The Quzhou Affiliated Hospital of Wenzhou Medical University Quzhou People’s Hospital, Kecheng District, Minjiang Avenue No. 100, Quzhou, Zhejiang, People’s Republic of China, Tel +86 570 8895 120, Email huangguanli66@163.comBackground: Many patients have a higher risk of thyroid cancer if they have both papillary thyroid carcinoma (PTC) and Type 2 diabetes mellitus (T2DM). Meanwhile, the primary reason for local PTC recurrence is cervical lymph node metastasis. Therefore, the prognosis of patients affects how cervical lymph nodes are managed during surgery. Due to surgical complications such as laryngeal nerve palsy and hypocalcemia, it is still debatable whether to prevent central lymph node dissection (CLND). Predicting central lymph node metastasis (CLNM) is crucial to direct CLND. It is unclear how important the fibrinogen-to-neutrophil ratio (FNR) is in thyroid cancer, so we looked into how it might help patients with PTC and T2DM predict CLNM.Patients and methods: Wenzhou Medical University’s First Affiliated Hospital provided us with 413 patients with PTC and T2DM, randomly divided into a training set (N = 292) and a validation set (N = 121). Univariate and multivariate logistic regression analyses were used to identify independent risk factors. After constructing a nomogram, the validity of the model was evaluated.Results: The maximum tumor diameter, high-density lipoprotein, thyroxine, triglyceride, lymphocyte, and FNR were all identified as independent risk factors by multivariate logistic regression analysis. The C index of the training set was 0.775, and the validation set was 0.654.Conclusion: In patients with PTC and T2DM, preoperative FNR was an independent risk factor for CLNM.Keywords: FNR, PTC, nomogram, CLNM, predictor

Yi Sun,1,&ast; Aiming Chen,2,&ast; Minjie Zou,3,&ast; Zhenzhen Liu,3 Charlotte Aimee Young,4 Danying Zheng,3 Guangming Jin3 1Department of Ophthalmology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People’s Republic of China; 2The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 3State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, People’s Republic of China; 4Department of Ophthalmology, Third Affiliated Hospital, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangming Jin; Danying Zheng, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, #54 Xianlie South Road, Yuexiu District, Guangzhou, 510060, People’s Republic of China, Email jingm@mail2.sysu.edu.cn; zhengdyy@163.comPurpose: To provide evidence for future strategies in preventing glaucomatous blindness by investigating the disease burden in terms of age, year, and gender from 1990 to 2019 in China.Methods: The prevalence and disability-adjusted life years (DALYs) of blindness and vision loss due to glaucoma in China were extracted from the Global Burden of Disease (GBD) 2019 study. Age-standardized data is presented in comparison to China’s neighboring countries.Results: From 1990 to 2019, the prevalent cases and DALYs number with glaucomatous blindness and vision loss increased by 129.53% and 67.29%, respectively. Overall, higher age-standardized prevalence and DALYs rate were detected in males than in females between 1990 and 2019, and people aged 60 to 89 years suffered from a higher DALY number than other age groups in 2019. Among the neighboring countries, China ranked from fourth in 1990 (88.52, 95% uncertainty interval [UI]: 74.62 to 103.24, per 100,000 population) to third in 2019 (71.14, 95% UI: 59.34 to 84.42, per 100,000 population) in age-standardized prevalence while from fourth in 1990 (10.13, 95% UI: 6.68 to 14.46, per 100,000 population) to sixth in 2019 (5.98, 95% UI: 4.14 to 8.42, per 100,000 population) in age-standardized DALYs. Compared with other GBD regions, the largest decrease in age-standardized DALY rate due to glaucoma was found in China (− 40.87%, 95% UI: − 43.97% to − 37.82%). A higher percentage decrease in age-standardized prevalence was also found in China (− 19.66%, 95% UI: − 22.44% to − 17.09%).Conclusion: Substantial increases in the prevalence of visual impairment and DALYs number of glaucoma were observed from 1990 to 2019. Efforts targeting glaucoma prevention and treatment in China are urgently required, especially for the elderly population and men.Keywords: glaucoma, epidemiology, disability-adjusted life years, health burden

Yifan Song,1,&ast; Liping Wang,2,&ast; Danni Zheng,3,4 Lin Zeng,5 Yan Wang3,4 1Department of General Practice, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 2Department of Neurology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 3Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 4National Clinical Research Center for Obstetrics and Gynecology, Beijing, 100191, People’s Republic of China; 5Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Wang, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100026, People’s Republic of China, Tel +13311165106, Email wjgqhn@263.net Lin Zeng, Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China, +86 13811401686, Email zlwhy@163.comPurpose: To investigate the relationship between sleep disturbances before pregnancy and the subsequent risk for gestational diabetes mellitus (GDM).Patients and Methods: Pregnant women who attended antenatal clinic before the 12th gestational week between September 2019 and June 2020 were enrolled. The sleep status at the month before the last menstrual period was collected by filling the Pittsburgh Sleep Quality Index (PSQI) and Berlin Questionnaire (BQ) to evaluate the sleep duration, quality and the risk of obstructive sleep apnea (OSA). With monthly antenatal care, the oral glucose tolerance test (OGTT) was performed during 24– 28 gestational weeks. According to the results, GDM and non-GDM group were classified. The sleep status and baseline characters were compared between the two groups.Results: A total of 355 pregnant women were enrolled in this study, and 63 of them (17.7%) were diagnosed with GDM. Univariate analysis showed that maternal age, body mass index (BMI), family history of diabetes, PSQI score and positive BQ were associated with GDM (p < 0.05). Maternal age (aOR 1.10, 95% CI, 1.01– 1.17), BMI before pregnancy (aOR 1.12, 95% CI, 1.02– 1.23), family history of diabetes (aOR 2.35, 95% CI, 1.33– 4.17), positive BQ (aOR 4.03, 95% CI, 1.04– 15.63) were independent risk factors for GDM in multivariate analysis. The decision tree indicated that among the pregnant women with BMI > 20.6 kg/m2 and age > 28.5, the risk for GDM with positive BQ increased from 27.5% to 66.7%.Conclusion: The high risk of OSA before pregnancy may increase the risk for GDM during pregnancy.Graphical Abstract: Keywords: sleep, gestational diabetes mellitus, obstructive sleep apnea, women

Jun Hou,1,&ast; Dezhi Zheng,2,&ast; Xudong Wen,3,&ast; Wenjing Xiao,4 Fei Han,5 Hongmei Lang,6 Shiqiang Xiong,1 Wei Jiang,5 Yonghe Hu,4 Mengshan He,7 Pan Long4,5 1Department of Cardiology, Chengdu Third People’s Hospital/Affiliated Hospital of Southwest Jiaotong University, Chengdu, People’s Republic of China; 2Department of Cardiovascular Surgery, the 960th Hospital of the PLA Joint Logistic Support Force, Jinan, People’s Republic of China; 3Department of Gastroenterology and Hepatology, Chengdu First People’s Hospital, Chengdu, People’s Republic of China; 4School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, People’s Republic of China; 5Department of Ophthalmology, the General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 6The Center of Obesity and Metabolic Diseases, Department of General Surgery, Chengdu Third People’s Hospital & the Affiliated Hospital of Southwest Jiaotong University, Chengdu, People’s Republic of China; 7Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pan Long, Department of Ophthalmology, the General Hospital of Western Theater Command, Rongdu Avenue #270, Chengdu, People’s Republic of China, Tel +86-181-9125-6132, Email longpan1005@qq.com Yonghe Hu, School of Materials Science and Engineering, Southwest Jiaotong University, No. 111, North First Section of the Second Ring Road, Chengdu, People’s Republic of China, Tel +86-138-8059-6789, Email huyonghe789@sina.comPurpose: High-altitude environment mainly with hypobaric hypoxia could induce pathological alterations in ocular tissue. Previous studies have mostly focused on sporadic case reports and simulated high-altitude hypoxia experiments. This aim of this study was to explore the proteomic and morphological changes of ocular tissue in mice at real altitude environment.Methods: In this study, mice were flown from Chengdu (elevation: 500 m) to Lhasa (elevation: 3600 m). After exposure for 1day, 3, 6, 10, 20, 30, and 40days, the mice were euthanatized to obtain blood and ocular tissue. Serological tests, ocular pathological examinations, integral ocular proteomics analysis, and Western blot were conducted.Results: We focused on acute phase (1– 3 days) and chronic phase (> 30 days) during high-altitude acclimatization. Serum interleukin-1 was increased at 3 days, while superoxide dismutase, interleukin-6, and tumor necrosis factor-α showed no statistical changes. H&E staining demonstrated that the cornea was edematous at 3 days and exhibited slower proliferation at 30 days. The choroid showed a consistently significant thickening, while there existed no noticeable changes in retinal thickness. Overall, 4073 proteins were identified, among which 71 and 119 proteins were detected to have significant difference at 3 days and 40 days when compared with the control group. Functional enrichment analysis found the differentiated proteins at 3 days exposure functionally related with response to radiation, dephosphorylation, negative regulation of cell adhesion, and erythrocyte homeostasis. Moreover, the differential profiles of the proteins at 40 days exposure exhibited changes of regulation of complement activation, regulation of protein activation cascade, regulation of humoral immune response, second-messenger-mediated signaling, regulation of leukocyte activation, and cellular iron homeostasis. Interestingly, we found the ocular proteins with lactylation modification were increased along high-altitude adaptation.Conclusion: This is the first work reporting the ocular proteomic and morphological changes at real high-altitude environment. We expect it would deep the understanding of ocular response during altitude acclimatization.Keywords: altitude response, ocular proteomics analysis, cornea edema, choroid thickening, post-translational modification

Danni Zheng,1,&ast; Weida Fu,1,&ast; Lingli Jin,1,&ast; Xiaofang Jiang,2 Wenjie Jiang,1 Yaoyao Guan,3 Rutian Hao1 1Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Plastic Surgery, Sir Run-Run Hospital Affiliated to Zhejiang University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yaoyao Guan, 3 Qingchun East Road, Jianggan District, Hangzhou, Zhejiang, People’s Republic of China, Tel +86 571-86006618, Fax +86 571-86044817, Email gyykq748@163.com Rutian Hao, South White Elephant Warm hospital first New Area, Ouhai District, Wenzhou, Zhejiang, People’s Republic of China, Tel +86 577 5557, Fax +86 577-55578033, Email hrtwenzhou@163.comPurpose: To explore the mechanism of AP1S1 in breast cancer.Methods and Results: In different datasets, we found that AP1S1 is more highly expressed in breast tumors, which was furthermore verified in our local cohort.Immune infiltration analysis showed that AP1S1 was related to a variety of immune cells. The higher AP1S1 expression was negatively correlated with a variety of immune infiltrating cells, suggesting that AP1S1 may affect cellular immunity.Clinical analysis showed that patients with higher AP1S1 expression had higher estrogen receptor gene expression and were more prone to distant metastasis and lymph node metastasis.The overall survival rate, disease-specific survival rate, and progression-free interval time were worse in the group with higher AP1S1 expression. AP1S1 may be a potential oncogene of breast cancer, and overexpression is related to the poor prognosis of breast cancer.Therefore, a nomogram was constructed, along with correlated gene analysis and functional analysis to further explore the carcinogenic mechanism, practical clinical issues, and value of AP1S1.Conclusion: AP1S1 is a potential oncogene of breast cancer.Keywords: breast cancer, AP1S1, immune infiltration, prognosis, oncogene

The present paper investigated the thermodynamics and kinetics of carbothermal reduction of fayalite by non-isothermal method combining with thermogravimetric analyzer and applying the Flynn-Wall-Ozawa (FWO) and Málek models. According to the thermodynamic analysis, the starting temperature of direct reduction reaction of fayalite was 806.79℃ in the standard state. The indirect reduction reaction could not take place in the standard state. While the volume percentage of CO was higher than 86 vol.% in nonstandard state, the indirect reduction could take place in the range of experimental temperature. Meanwhile, Boudouard reaction could promote the indirect reduction process. The kinetic analysis results showed that at the temperature below 1100℃, the main reduction reaction was the direct reduction between fayalite and graphite. With the temperature increasing, the fayalite reacted with CO generated from the gasification of graphite. When the reduction rate increased from 0% to 50%, the activation energy of the reaction increased to 524.41 kJ/mol. Then, the activation energy decreased with the increase of reduction rate. The carbothermal reduction of fayalite was a multistep reaction. The controlling step in the initial stage was the gasification of graphite. As the reaction proceeded, the generated CO provided a good kinetics condition for the carbothermal reduction of fayalite, and the controlling step of the reaction was the nucleation and growth of the metallic iron.

Kai Ma,* Jing Li,* Guoqi Shen, Di Zheng, Yongli Xuan, Yuan Lu, Wenhua Li Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenhua Li, Tel +86 18052268293, Email xzwenhua0202@163.comObjective: To establish a nomogram model to predict the risk of contrast-induced acute kidney injury (CI-AKI) by analyzing the risk factors of CI-AKI and to evaluate its effectiveness.Methods: Retrospectively analyze the clinical data of non-ST-elevation acute coronary syndrome (NSTE-ACS) patients who underwent percutaneous coronary intervention (PCI) in our cardiology department from September 2018 to June 2021. Of these, patients who underwent PCI in an earlier period formed the training cohort (70%; n = 809) for nomogram development, and those who underwent PCI thereafter formed the validation cohort (30%; n = 347) to confirm the model’s performance. The independent risk factors of CI-AKI were determined by LASSO regression and multivariable logistic regression analysis. By using R software from which nomogram models were subsequently generated. The nomogram was developed and evaluated based on discrimination, calibration, and clinical efficacy using the concordance statistic (C-statistic), calibration plot, and decision curve analysis (DCA), respectively.Results: The nomogram consisted of six variables: age > 75, left ventricular ejection fraction, diabetes mellitus, fibrinogen-to-albumin ratio, high-sensitive C-reactive protein, and lymphocyte count. The C-index of the nomogram is 0.835 (95% CI: 0.800– 0.871) in the training cohort and 0.767 (95% CI: 0.711– 0.824) in the validation cohort, respectively. The calibration plots exhibited that the nomogram was in good agreement between prediction and observation in the training and validation cohorts. Decision curve analysis and clinical impact curve suggested that the predictive nomogram had clinical utility.Conclusion: The nomogram model established has a good degree of differentiation and accuracy, which is intuitively and individually to screen high-risk groups and has a certain predictive value for the occurrence of CI-AKI in NSTE-ACS patients after PCI.Keywords: nomogram, risk forecasting model, non-ST-elevation acute coronary syndrome, percutaneous coronary intervention, contrast-induced acute kidney injury

Tingting Yin,1,&ast; Yuhui Zhao,1,&ast; Ying Yang,1 Huaxiu Xu,1 Dongxiang Zheng,2 Jun Lyu,3 Guanglei Fu4 1School of Nursing, Jinan University, Guangzhou, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 3Clinical Research Department, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 4Infectious Disease Department, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun LyuClinical Research Department, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of ChinaTel +86 13922274169Email lyujun2020@jnu.edu.cnGuanglei FuInfectious Disease Department, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of ChinaTel +86 18922217029Email 1623805741@qq.comBackground: The objective of this study was to establish a nomogram for predicting the overall survival (OS) of patients with acral lentiginous melanoma (ALM).Materials and Methods: The study sample was selected from 1785 patients diagnosed with ALM from 2004 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database, and R software was used to divide patients into the training cohort and validation cohort at a ratio of 7: 3. Stepwise selection method in the Cox regression model was used in the training cohort to select predictive variables to construct the nomogram, and model validation parameters were used in the validation cohort to evaluate the performance of the nomogram.Results: The nomogram showed that age at diagnosis had the greatest impact on OS in patients with ALM, followed by AJCC stage, surgical treatment, SEER stage, sex, race, and marital status. The index of concordance, area under the receiver operating characteristic curve, calibration plots, net reclassification improvement, integrated discrimination improvement, and decision curve analysis demonstrate the good performance of this nomogram.Conclusion: The prognostic value of the nomogram is superior to that of the AJCC staging system alone, and it helps clinicians to better predict 3-, 5-, and 8-year OS in patients with ALM.Keywords: acral lentiginous melanoma, nomogram, overall survival, SEER

Xuan Chen,1,&ast; Mingrui Duan,1,2,&ast; Rui Hou,1,2,&ast; Manqi Zheng,1,2 Haibin Li,3 Manjot Singh,4,5 Changwei Li,6 Kuo Liu,1,2 Feng Zhang,1,2 Xinghua Yang,1,2 Yanxia Luo,1,2 Yan He,1,2 Lijuan Wu,1,2 Deqiang Zheng1,2,7 1Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, People’s Republic of China; 3Heart Center & Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, University of Western Australia, Crawley, WA, Australia; 5School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia; 6Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA; 7Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden&ast;These authors contributed equally to this workCorrespondence: Deqiang ZhengDepartment of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, People’s Republic of ChinaTel/Fax +86 10 8391 1497Email dqzheng@ccmu.edu.cnLijuan WuDepartment of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, People’s Republic of ChinaTel +86 10 8391 1497Email xiaowu@ccmu.edu.cnBackground: Few studies have focused on the prevalence of abdominal obesity in Chinese middle-aged and older adults with a normal body mass index (BMI). Furthermore, it is still unclear whether abdominal obesity is an independent risk factor for type 2 diabetes mellitus (T2DM). Participants with a normal BMI are usually neglected during assessments of abdominal obesity-associated T2DM risk since the current recommendations for medical interventions are mainly focused on overall body mass index rather than fat deposition patterns.Methods: In this study, 7942 normal-BMI participants aged over 45 years from the China Health and Retirement Longitudinal Study were included to assess the prevalence of abdominal obesity defined by waist circumference (WC) or waist-to-height ratio (WHtR). In addition, 4348 normal-BMI individuals with no diabetes at baseline were included to evaluate the association between abdominal obesity and the risk of T2DM with the Cox proportional hazards model.Results: The prevalence (95% confidence interval, CI) of increased WC and substantially increased WC among adults with a normal BMI was 22.0% (21.1%-22.9%) and 18.1% (17.3%-19.0%), respectively. The adjusted hazard ratios and 95% CIs for T2DM incidence were 1.39 (1.05– 1.85) and 1.89 (1.42– 2.53) for those with increased WC and substantially increased WC, respectively, compared to the individuals with a normal WC. Similar HRs were obtained for the association between WHtR and the risk of T2DM. In prediabetic patients, the HRs (95% CIs) for new-onset T2DM for those with increased WC and substantially increased WC were 1.85 (1.27– 2.69) and 2.46 (1.67– 3.61), respectively, when compared with individuals with normal WC. This positive association was observed in women but not in men or adults with normal glucose tolerance (NGT).Conclusion: Abdominal obesity is highly prevalent among middle-aged and older Chinese adults with a normal BMI, and maintaining a normal waist circumference may be beneficial in the prevention of T2DM.Keywords: abdominal obesity, normal body mass index, prevalence, type 2 diabetes mellitus, hazard ratio

Xiaoying Chen,1,&ast; Dezhi Zheng,2,&ast; He Ma,3 Wen Luo2 1The 2nd Ward of Knee Trauma Department, Tianjin Hospital, Tianjin, People’s Republic of China; 2The 2nd Ward of Joint Surgery Department, Tianjin Hospital, Tianjin, People’s Republic of China; 3The Emergency Treatment Department, Tianjin Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen LuoThe 2nd Ward of Joint Surgery Department, Tianjin Hospital, No. 406 Jiefangnan Road, Tianjin, 300211, People’s Republic of ChinaTel +86 22-131 1619 0054Email wl1984@yahoo.comAim: To explore the association between the exercise anticipation, function and self-efficacy in patients after knee surgeries over six months and to identify the predictors for rehabilitation.Methods: This observational study used the cross-sectional survey method and was divided into two stages: (1) designing the experimental video materials and answer cards about exercise anticipation, and (2) analyzing the correlation of the level of exercise anticipation, knee function, modified gait efficacy scale (mGES), self-efficacy for rehabilitation outcome scale (SER), self-efficacy for exercise scale (SEE), time up and go task (TUG) and knee joint angle in walking. We used IBM SPSS modeler 18.0 software for establishing the Bayesian network data mining model, which can identify strong positive and negative associations.Results: A total of 110 patients were included in this study. Our research confirmed that the exercise anticipation score exhibited the significant correlation with SER (r=0.552, P< 0.01), SEE (r=0.457, P< 0.01), TUG (r=− 0.419, P< 0.01) and knee joint angle in walking (r=− 0.342, P< 0.01). There is only one parent node of exercise expectation, that is, rehabilitation self-efficacy, which shows that the rehabilitation self-efficacy of patients after knee surgery is directly related to their ability to judge exercise expectation. Meanwhile this study verified the model results, and the area under the ROC curve (AUC) is 0.572 (755/1320), indicating that the prediction performance is acceptable.Conclusion: This preliminary study confirmed that improving the exercise anticipation and rehabilitation self-efficacy is an important method of enhancing the knee function in patients after knee surgeries over six months. In the future, the long-term effect of the exercise anticipation and self-efficacy should be researched.Keywords: exercise anticipation, function, self-efficacy, knee surgeries

Hui Zhang1 &ast;, Dandan Chen2 &ast;, Nianqi Cui,3 Ping Zou,4 Jing Shao,2 Xiyi Wang,5 Yichi Zhang,6 Jiao Du,6 Chunxue Du,6 Guanglan Zhou,6 Deyi Zheng6 1Department of Cardiology, Guizhou Provincial People’s Hospital, Guiyang, People’s Republic of China; 2Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou, People’s Republic of China; 3The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4School of Nursing, Nipissing University, Toronto, Ontario, Canada; 5Shanghai JiaoTong University, School of Nursing, Shanghai, People’s Republic of China; 6Department of Burn and Plastic Surgery, Guizhou Provincial People’s Hospital, Guiyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Deyi ZhengDepartment of Burn and Plastic Surgery, Guizhou Provincial People’s Hospital, Guiyang, People’s Republic of ChinaTel +86 13984826262Email deyizheng@126.comBackground: Despite a flood of research on job satisfaction, few studies have examined how and why social support influences job satisfaction. This study aimed to explore how social support has an indirect effect on job satisfaction by examining its impact on emotional exhaustion and anxiety symptoms among residents of the physicians standardized residency training program in China.Methods: This cross-sectional study adopted questionnaires to collect data from residents in the standardized residency training program in China. The PROCESS macro for SPSS based on ordinary least-squares regression and the bootstrap method was used. The indirect effect of social support was examined using bootstrapping procedures. A serial multiple mediation model was examined in which social support was associated with job satisfaction via emotional exhaustion and anxiety symptoms.Results: There were 269 residents who provided usable data for the analysis. The mean age of residents was 25.98 years old. Close to half (52%) of the participants were female. The total indirect effect of social support on job satisfaction was significant (ab=0.21, SE=0.05, CI=0.12 to 0.32). The specific indirect effect 1 (social support→emotional exhaustion→job satisfaction) was significant (a1b1=0.12, SE=0.04, CI=0.05 to 0.19). The specific indirect effect 2 (social support→anxiety symptoms→job satisfaction) was significant (a2b2=0.07, SE=0.03, CI=0.02 to 0.13).The specific indirect effect 3 (social support→emotional exhaustion→anxiety symptoms→job satisfaction) was also found to be significant through both optimism and work engagement (a1a3b2=0.03, SE=0.01, CI=0.01 to 0.05).Conclusion: It seems critical for hospital management to develop a supportive work environment to improve the effects of emotional exhaustion and anxiety symptoms and to provide sufficient support to improve job satisfaction among residents in standardized residency training programs.Keywords: residents, social support, emotional exhaustion, job satisfaction, anxiety symptoms, standardized residency training programs

Juan Jin,* Fengmei Qian,* Danna Zheng, Wenfang He, Jianguang Gong, Qiang He Department of Nephrology, Zhejiang Provincial People’s Hospital and Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianguang Gong; Qiang HeDepartment of Nephrology, Zhejiang Provincial People’s Hospital and Affiliated People’s Hospital, Hangzhou Medical College, 158 Shangtang Road, Xiacheng District, Hangzhou, Zhejiang, 310014, People’s Republic of ChinaEmail gojigu311@163.com; qianghe1973@126.comBackground: Renal fibrosis is a chronic and progressive process affecting kidneys in chronic kidney disease (CKD). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been shown to alleviate renal fibrosis and injury, but the mechanism of MSCs-Exo-induced renal protection remains unknown.Methods: In this study, MSCs were transfected with let-7i-5p antagomir (anti-let-7i-5p), and then exosomes were isolated from the transfected MSCs to deliver anti-let-7i-5p oligonucleotides to inhibit the level of let-7i-5p in kidney tubular epithelial cells (NRK-52E).Results: In both NRK-52E cells stimulated by TGF-β 1 and the mouse kidneys after unilateral ureteral obstruction (UUO), we demonstrated increased level of let-7i-5p. In addition, MSCs-Exo can deliver anti-let-7i-5p to reduce the level of let-7i-5p in NRK-52E cells and increase the expression of its target gene TSC1. Moreover, exosomal anti-let-7i-5p reduced extracellular matrix (ECM) deposition and attenuated epithelial–mesenchymal transition (EMT) process in transforming growth factor beta 1 (TGF-β 1)-stimulated NRK-52E cells and in the kidneys of UUO-treated mice. Meanwhile, mice received exosomal anti-let-7i-5p displayed reduced renal fibrosis and improved kidney function when challenged with UUO. Furthermore, exosomal anti-let-7i-5p promoted the activation the tuberous sclerosis complex subunit 1/mammalian target of rapamycin (TSC1/mTOR) signaling pathway in vivo and in vitro.Conclusion: In conclusion, exosomal anti-let-7i-5p from MSCs exerts anti-fibrotic effects in TGF-β 1-induced fibrogenic responses in NRK52E cells in vitro as well as in UUO-induced renal fibrosis model in vivo. These results provided a novel perspective on improving renal fibrosis by MSCs-Exo.Keywords: chronic kidney disease, renal fibrosis, mesenchymal stem cells, exosomes and microRNAs

Li Li,1,* Xuemei Zhong,1,* Aifang Zheng,1 Chen JianKun,2,3 Ayiguzali A Budukadeer,1 Paierda Aini,1 Maimaitiaili Tuerxun,1 Mukeremu Yasen,1 Tao Ma,1 Jie Ren,1 Rukeyamu Semaiti,1 Chengxin Xie,1 Feifei Li,1 Mireban Rexiati,1 Lifeng Tang,1 Gulanbaier Abudurexiti,1 Dayong Zheng,1 Ji-Qiang Li1– 3 1Department of Respiratory and Critical Care Medicine, The First People’s Hospital of Kashi Prefecture, Kashi, Xinjiang, People’s Republic of China; 2The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3The Third Comprehensive Department, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dayong ZhengDepartment of Respiratory and Critical Care Medicine, The First People’s Hospital of Kashi Prefecture, 120 Yingbin Road, Kashi City, Xinjiang, 844000, People’s Republic of ChinaTel +13570029702Email zdy525679@163.comJi-Qiang LiThe Second Clinical College, Guangzhou University of Chinese Medicine, 232 Waihuan East Road, Guangzhou University City, Panyu District of Guangzhou, Guangzhou, 510120, People’s Republic of ChinaTel +13527675982Email Ljq525679@126.comObjective: To investigate the prevalence and the risk factors of COPD in the Uyghur population in the Kashi region.Methods: From August 2018 to March 2019, we recruited participants of Uyghur ethnicity and aged ≥ 40 years old from the Kashi region using a combined cluster sampling and random sampling method. We collected potential risk factors using questionnaire, and conduced lung function using a portable pulmonary function instrument.Results: A total of 2963 participants were included in this analysis, of whom 1268 were males and 1695 were females. There were 504 participants with COPD, generating a prevalence of 17.01%. With the increase of age, the prevalence of COPD in different genders increased significantly. The results of different regions were χ2= 627.89, p < 0.01, indicating significant differences in the prevalence in different regions. Among them, based on the existing survey data, it is speculated that Shache county has the highest crude prevalence, but the sample size needs to be further expanded. The participants with high age, smoking, lower BMI, high waist circumference, systolic blood pressure, fried cooking and barbecue share more COPD than those who partake of fruits and vegetables in this study.Conclusion: The prevalence of COPD among the Uyghur population in the Kashi region is higher than the national rural average. Among them, high age, smoking, low BMI, high waist circumference, high systolic blood pressure, cooking methods that may be stir-fried and deep-fried barbecue are risk factors for COPD, and vegetable and fruit intake may be a protective factor for COPD.Keywords: Uyghur population, chronic obstructive pulmonary disease, prevalence, risk factors, epidemiology study

Jun Dou,1,* Luoyang Li,1,* Mei Guo,1,* Feng Mei,1 Danfeng Zheng,1 Hui Xu,1 Rui Xue,1 Xueyang Bao,1 Fengshu Zhao,1 Yu Zhang2 1Department of Pathogenic Biology and Immunology, Medical College, Southeast University, Nanjing, 210009, People’s Republic of China; 2State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210009, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun DouDepartment of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, 210009, People’s Republic of ChinaEmail njdoujun@seu.edu.cnYu ZhangSchool of Biological Science and Medical Engineering, Southeast University, Nanjing, 210009, People’s Republic of ChinaEmail zhangyu@seu.edu.cnBackground and Aim: Acute myeloid leukemia (AML), initiated and maintained by leukemia stem cells (LSCs), is often relapsed or refractory to therapy. The present study aimed at assessing the effects of nanozyme-like Fe3O4 nanoparticles (IONPs) combined with cytosine arabinoside (Ara-C) on LSCs in vitro and in vivo.Methods: The CD34+CD38–LSCs, isolated from human AML cell line KG1a by a magnetic activated cell sorting method, were treated with Ara-C, IONPs, and Ara-C+ IONPs respectively in vitro. The cellular proliferation, apoptosis, reactive oxygen species (ROS), and the related molecular expression levels in LSCs were analyzed using flow cytometry, RT-qPCR, and Western blot. The nonobese diabetic/severe combined immune deficiency mice were transplanted with LSCs or non-LSCs via tail vein, and then the mice were treated with Ara-C, IONPs and IONPs plus Ara-C, respectively. The therapeutic effects on the AML bearing mice were further evaluated.Results: LSCs indicated stronger cellular proliferation, more clone formation, and more robust resistance to Ara-C than non-LSCs. Compared with LSCs treated with Ara-C alone, LSCs treated with IONPs plus Ara-C showed a significant increase in apoptosis and ROS levels that might be regulated by nanozyme-like IONPs via improving the expression of pro-oxidation molecule gp91-phox but decreasing the expression of antioxidation molecule superoxide dismutase 1. The in vivo results suggested that, compared with the AML bearing mice treated with Ara-C alone, the mice treated with IONPs plus Ara-C markedly reduced the abnormal leukocyte numbers in peripheral blood and bone marrow and significantly extended the survival of AML bearing mice.Conclusion: IONPs combined with Ara-C showed the effectiveness on reducing AML burden in the mice engrafted with LSCs and extending mouse survival by increasing LSC’s ROS level to induce LSC apoptosis. Our findings suggest that targeting LSCs could control the AML relapse by using IONPs plus Ara-C.Keywords: acute myeloid leukemia, leukemia stem cells, Fe3O4 nanoparticles, cytosine arabinoside, reactive oxygen species

Zheng D, Bi X, Zhang T, et al. Psychol Res Behav Manag. 2020;13:997–1008. The authors have advised that there are several errors in the published paper which were introduced by the Editorial staff during the publication process. Pages 1001-1003, Figure 1 parts N, R, X, Y, Z, CC and DD are incorrect. The correct figure is shown below. Page 1006, Table 2, part F, the formatting of the table is incorrect. The correct formatting is shown below. Read the original article

Lingdun Zhuge,1,2,* Binhao Huang,1,2,* Juntao Xie,1,2 Zhendong Gao,1,2 Difan Zheng,1,2 Shanbo Zheng,1,2 Jiaqing Xiang,1,2 Jie Zhang3 1Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie ZhangDepartment of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaTel +86 189 30598097Email zhangjie2289@hotmail.comObjective: The aim of this study was to construct the immunoscore (IS) to facilitate the prediction of postoperative survival and benefit from adjuvant chemotherapy (ACT) in esophageal squamous cell carcinoma (ESCC).Methods: A total of 249 patients who received radical esophagectomy at Fudan University Shanghai Cancer Center were divided into training set and testing set. Eighty-nine patients with ESCC from TCGA database were enrolled into the validation set. Myeloid cells in tumor microenvironment were evaluated by immunohistochemistry or CIBERSORT, and then were included into a LASSO Cox regression model to construct the immunoscore. The predictive value of the immunoscore for prognosis after surgery or ACT was analyzed.Results: The immunoscore was constructed by four types of myeloid cells including macrophages, neutrophils, mast cells, and dendritic cells and was demonstrated as IS=2^(0.527719*M&phis; − 0.2604269*MC-0.4812935*DC-0.4519706*Neu). The overall survival was significantly different between two immunotypes, which were divided according to the immunoscore, in all sets (P< 0.001, P=0.005, and P=0.002, respectively). Immunotype A was identified as an independent predictor for survival benefit in all three sets (HR=2.068, P=0.005; HR=2.028, P=0.007; HR=6.474, P=0.007; respectively). In patients who received ACT, immunotype A was significantly related to longer overall survival both in the training set (P< 0.001) and in the testing set (P=0.011). The nomogram based on immunotype and other clinicopathological factors showed good efficiency of predicting response to ACT. Finally, several important cytokines and pathways were highly enriched in immunoscore A subgroup.Conclusion: The immunoscore was an effective prognostic predictor in ESCC for patients undergoing surgical resection and receiving ACT.Keywords: adjuvant chemotherapy, prognosis, immunoscore, esophageal squamous cell carcinoma

Dongdong Zheng,1,* Caifeng Wan,1,* Hong Yang,2 Li Xu,1 Qi Dong,1 Chengrun Du,3 Jing Du,1 Fenghua Li1 1Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2College of Chemistry and Materials Science, Shanghai Normal University, Shanghai, People’s Republic of China; 3Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jing Du; Fenghua Li Email beautydujing@163.com; fenghua-li@163.comPurpose: The treatment of breast cancer is often ineffective due to the protection of the tumor microenvironment and the low immunogenicity of tumor cells, leading to a poor therapeutic effect. In this study, we designed a nano-theranostic platform for these obstacles: a photothermal effect mediated by a gold shell could remodel the tumor microenvironment by decreasing cancer-associated fibroblasts (CAFs) and promote the release of doxorubicin (DOX) from nanoparticles. In addition, it could realize photoacoustic (PA)/MRI dual-model imaging for diagnose breast cancer and targeted identification of Her2-positive breast cancer.Methods: Her2-DOX-superparamagnetic iron oxide nanoparticles (SPIOs)@Poly (D, L-lactide-co-glycolide) acid (PLGA)@Au nanoparticles (Her2-DSG NPs) were prepared based on a single emulsion oil-in-water (O/W) solvent evaporation method, gold seed growing method, and carbon diimide method. The size distribution, morphology, PA/MRI imaging, drug loading capacity, and drug release were investigated. Cytotoxicity, antitumor effect, cellular uptake, immunogenic cell death (ICD) effect, and targeted performance on human Her2-positive BT474 cell line were investigated in vitro. BT474/Adr cells were constructed and the antitumor effect of NPs on it was evaluated in vitro. Moreover, chemical-photothermal therapy effect, PA/MRI dual-model imaging, ICD effect induced by NPs, and tumor microenvironment remodeling in human BT474 breast cancer nude mice model were also investigated.Results: Nanoparticles were spherical, uniform in size and covered with a gold shell. NPs had a photothermal effect, and can realize photothermal-controlled drug release in vitro. Chemical-photothermal therapy had a good antitumor effect on BT474/Adr cells and on BT474 cells in vitro. The targeting evaluation in vitro showed that Her2-DSG NPs could actively target and identify Her2-positive tumor cells. The PA/MRI imaging was successfully validated in vitro/vivo. Similarly, NPs could enhance the ICD effect in vitro/vivo, which could activate an immune response. Immunofluorescence results also proved that photothermal effect could decrease CAFs to remodel the tumor microenvironment and enhance the accessibility of NPs to tumor cells. According to the toxicity results, targeted drug delivery combined with photothermal-responsive drug release proved that NPs had good biosafety in vivo. Chemical-photothermal therapy of Her2-targeted NPs has a good antitumor effect in the BT474 nude mice model.Conclusion: Our study showed that chemical-photothermal therapy combined with tumor microenvironment remodeling and immune activation based on the Her2-DSG NPs we developed are very promising for Her2-positive breast cancer.Keywords: tumor microenvironment remodeling, chemoimmunotherapy, photothermal effect, targeted nano-theranostic platform, dual-modal imaging

Abstract HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA (lncRNA) that plays a pivotal role in regulating myeloid cell development via targeting HOXA1 gene expression. We and others have previously shown that myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells, expand during chronic viral (HCV, HIV) infections. However, the role of HOTAIRM1 in the development and suppression of MDSCs during viral infection remains unknown. In this study, we demonstrate that the expressions of HOTAIRM1 and its target HOXA1 are substantially upregulated to promote the expressions of immunosuppressive molecules, including arginase 1, inducible nitric oxide synthase, signal transducer and activator of transcription 3, and reactive oxygen species, in CD33+ myeloid cells derived from hepatitis C virus (HCV)-infected patients. We show that HCV-associated exosomes (HCV-Exo) can modulate HOTAIRM1, HOXA1, and miR124 expressions to regulate MDSC development. Importantly, overexpression of HOTAIRM1 or HOXA1 in healthy CD33+ myeloid cells promoted the MDSC differentiation and suppressive functions; conversely, silencing of HOTAIRM1 or HOXA1 expression in MDSCs from HCV patients significantly reduced the MDSC frequency and their suppressive functions. In essence, these results indicate that the HOTAIRM1-HOXA1-miR124 axis enhances the differentiation and suppressive functions of MDSCs and may be a potential target for immunomodulation in conjunction with antiviral therapy during chronic viral infection.

Guangxu Liu,1,2 Jingtao Dou,3,4 Deqiang Zheng,1,2 Jie Zhang,1,2 Meiping Wang,1,2 Wei Li,1,2 Jing Wen,1,2 Juming Lu,3 Linong Ji,5 Yan He1,2 1Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, People’s Republic of China; 3Department of Endocrinology, Chinese PLA General Hospital, Beijing, People’s Republic of China; 4Department of Endocrinology, Hainan Branch of Chinese PLA General Hospital, Sanya, People’s Republic of China; 5Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, People’s Republic of ChinaCorrespondence: Yan He; Jingtao Dou Email yanhe1220@126.com; jingtaodou@163.comPurpose: The objective of this study was to investigate the association of abnormal glycemic phenotypes with microvascular complications in type 2 diabetes patients.Participants and Methods: A total of 24,266 participants who were from the multicenter cross-sectional survey of China National HbA1c Surveillance System across China were included in the present study. Diabetes patients with abnormal glucose were divided into three groups according to phenotype: isolated fasting hyperglycemia (IFH), isolated postprandial hyperglycemia (IPH), or combined hyperglycemia (CH). The main outcomes were isolated diabetic retinopathy, isolated diabetic nephropathy, and combined diabetic retinopathy with nephropathy. Multivariate logistic regression was used to assess the association of abnormal glycemic phenotypes with microvascular complications.Results: The CH phenotype had the highest prevalence of isolated diabetic retinopathy, isolated diabetic nephropathy and combined diabetic retinopathy with nephropathy, followed by IPH. Multivariate analysis showed that the CH phenotype was associated with the highest risk of isolated diabetic retinopathy (OR: 1.20, 95% CI: 1.02– 1.41), isolated diabetic nephropathy (OR: 1.59, 95% CI: 1.27– 2.01) and combined diabetic retinopathy with nephropathy (OR: 1.93, 95% CI: 1.44– 2.59). More importantly, participants with IPH phenotype also showed significantly higher risks of isolated diabetic retinopathy (OR: 1.16, 95% CI: 1.05– 1.28), isolated diabetic nephropathy (OR: 1.37, 95% CI: 1.09– 1.37) and combined diabetic retinopathy with nephropathy (OR:1.64, 95% CI: 1.21– 2.21) compared to the IFH phenotype. After stratifying by age, sex, diabetes duration and BMI, the higher risks of isolated diabetic retinopathy, isolated diabetic nephropathy and combined diabetic retinopathy with nephropathy were confirmed in IPH phenotype group, compared to the IFH phenotype group.Conclusion: Diabetic patients with IPH phenotype had higher risks of isolated diabetic retinopathy, isolated diabetic nephropathy and combined diabetic retinopathy with nephropathy compared with the participants phenotype of IFH, but lower than the phenotype of CH.Keywords: abnormal glycemic phenotype, diabetic nephropathy, diabetic retinopathy, type 2 diabetes mellitus

Doudou Zheng,1,* Xiaojiao Bi,2,* Tianliang Zhang,3 Chao Han,3 Tantan Ma,3 Lina Wang,2 Mengmeng Sun,3 Kaiyan Cui,3 Limin Yang,3 Lanfen Liu3 1Department of Psychiatry, School of Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Psychology, Shandong Mental Health Center Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China; 3Department of Psychiatry, Shandong Mental Health Center Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lanfen LiuShandong Mental Health Center Affiliated to Shandong University, 49# Wenhua Eastern Road, Jinan, Shandong 250014, People’s Republic of ChinaTel +86 18705317358Email liulf521@163.comPurpose: The incidence of nonsuicidal self-injury (NSSI) behavior among adolescents increases year by year. Patients with a history of both depression and NSSI behaviors tend to have greater risk of suicide. At present, the mechanism of adolescent depressive disorder patients with NSSI behaviors is not clear, epigenetic mechanism may be involved. Proopiomelanocortin (POMC) gene may be associated with depressive disorder. The purpose of this study was to investigate DNA methylation of POMC gene promoter region of adolescent depressive disorder patients with NSSI behaviors.Methods: Bisulfite Sequencing PCR (BSP) was used to test the methylation level of POMC promoter of 15 adolescent depressive disorder patients with NSSI behaviors and 15 healthy controls (HC). Self-made questionnaires were used to collect clinical data of the case group and control group. Hamilton depression scale-24 (HAMD-24), Hamilton anxiety scale (HAMA), Symptom Checklist-90 (SCL-90) were used to evaluate the characteristics and severity of depressive, anxiety and psychotic symptoms. Adolescent self-injury questionnaire was used to assess NSSI behaviors and its severity.Results: BSP analysis found that the POMC methylation level of cytosine-guanine dinucleotide 1 (CpG1) site was higher in the case group than that of HC (P< 0.05). The significance in POMC methylation at CpG1 between case group and HC was gender-independent, and CpG1 methylation level was higher in both male (P< 0.05) and female (P< 0.05) patients than that in HC. The CpG1 methylation level had a little correlation trends with family history of psychosis (P=0.05). We also found that POMC methylation level at CpG17 in female patients was significantly higher than that of the female HC (P< 0.05).Conclusion: There was abnormal methylation in the POMC promoter region of adolescent depressive disorder patients with NSSI behaviors, the methylation of CpG1 may act as epigenetic markers for those adolescents.Keywords: adolescent, depressive disorder, POMC, methylation, nonsuicidal self-injury behavior

Lin Chen,1,* Xiujuan Zhang,2,* Li Zhang,3 Dongmei Zheng2 1Department of Breast and Thyroid Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 3Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongmei ZhengDepartment of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province 250021, People’s Republic of ChinaTel + 86 531 68776375Email zhengdongmei1971@163.comBackground and Aim: Non-alcoholic fatty liver disease (NAFLD) represents a broad spectrum of chronic liver disease characterized by aberrant accumulation of triglycerides (TG) in hepatocytes without excessive alcohol consumption. Hepatic lipotoxicity derived from overaccumulation of free fatty acids is considered as one of the typical hallmarks of NAFLD. Insulin resistance (IR) and chronic inflammation are widely recognized as the key etiological factors associated with NAFLD. Dipeptidyl peptidase 4 inhibitor (DPP4i) is a novel pharmacological agent extensively applied in the treatment of Type 2 Diabetes Mellitus (T2DM) for decades which also have a liver protective effect.Methods: In order to invest the therapeutic efficiency and underlying mechanism of DPP4i saxagliptin, we used high-fat diet (HFD) and streptozotocin-induced NAFLD treated with saxagliptin. Biochemical, histomorphological, genetic and protein expression of related pathways were investigated.Results: Fasting blood glucose (FBG), TG, total cholesterol (TC), and low-density lipoprotein cholesterin significantly increased in NAFLD group, which also exhibited severe steatosis. Other remarkable findings were hyperinsulinemia, increased DPP4, PTP-1B and TNF-α level and decreased GLP-1, ACOX-1, CPT-1A expression, concomitant with liver DPP4 expression enhancement and serum DPP4 elevation. These undesirable consequences were alleviated by saxagliptin to a certain degree.Conclusion: DPP4i saxagliptin improves NAFLD by ameliorating IR, inflammation, downregulation of hepatic DPP4 and sDPP4, as well as subsequent steatosis. The elevation of hepatic DPP4 and sDPP4 and succedent post-treatment decrease suggested that DPP4 may involve in the development of NAFLD. The anti-lipotoxic effect of DPP4i may involve the activation of CPT1A and ACOX1 related β-oxidation signaling pathway suppression of TNF-α mediated inflammatory and PTP-1B. The results covered in this article showed that saxagliptin affects many aspects of the pathological characteristics of NAFLD, suggesting that DPP4i saxagliptin may offer a novel therapeutic option for NAFLD.Keywords: dipeptidyl peptidase 4 inhibitor DPP4i, non-alcoholic fatty liver disease NAFLD, inflammation, insulin resistance IR

Jie Shi, Ruyue Su, Danwei Zheng, Yankun Zhu, Xiaoguang Ma, Shaohua Wang, Hui Li, Dingyong Sun Henan Province Center for Disease Control and Prevention, Zhengzhou, Henan Province, People’s Republic of ChinaCorrespondence: Jie Shi; Dingyong Sun Tel +86-15803829002; +86-13703865596Email shijie2280@126.com; sundy2222@126.comPurpose: This study was designed to identify the phenotypic and genotypic characteristics of pyrazinamide (PZA) resistance among multidrug-resistant Mycobacterium tuberculosis (MDR-TB) from Henan and to evaluate the efficacy of pncA, rpsA, and panD mutations in predicting PZA resistance.Materials and Methods: A total of 152 MDR strains were included in this study. The Bactec MGIT system was used to determine PZA susceptibility for all strains. The pncA, rpsA, and panD genes were sequenced to identify any mutations, and the sequences were then aligned with the sequence of standard strain H37Rv. Moreover, the correlations between PZA-resistant phenotypes and treatment outcomes were analysed.Results: Of the152 strains, 105 had a PZA-resistant phenotype, and 102 harboured the pncA mutation. The PZA resistance rate was higher in the strains with resistance to all four first-line drugs and those that were pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR). A total of 100 different pncA mutation patterns were identified, including 80 point mutations and 20 insertions/deletions, and 32 new pncA mutation patterns were detected. In this study, 13 strains had multiple mutations. Of the11 PZA-resistant strains without pncA mutations, two harboured the rpsA mutation, and one harboured the panD mutation. With PZA susceptibility results as the reference, single-gene pncA sequencing had sensitivity of 89.52% and specificity of 89.36%. With the combination of rpsA and panD, the sensitivity increased to 92.38%, and the specificity remained the same. No significant differences were observed in the sputum smear/culture conversion rate between PZA-resistant patients and PZA-sensitive patients. However, PZA resistance was related to the time to sputum smear/culture conversion (P = 0.018).Conclusion: The combination of pncA, rpsA, and panD was beneficial for the timely diagnosis of PZA resistance and could provide a laboratory basis for customizing treatment regimens for MDR-TB patients.Keywords: Mycobacterium tuberculosis, multidrug-resistant, pyrazinamide, pncA, rpsA, panD

Meng Pang,1 Chunyuan Li,1 Dong Zheng,1 Ying Wang,2 Jing Wang,1 Weilong Zhang,1 Fang Li,1 Hongmei Jing1 1Department of Hematology, Third Hospital of Peking University, Beijing, People’s Republic of China; 2Department of Immunology, Key Laboratory of Medical Immunology of Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of ChinaCorrespondence: Fang Li; Hongmei Jing Email lifang19611962@163.com; hongmeijing@bjmu.edu.cnBackground: The presence of circulating plasma cells (cPCs) was associated with a worse prognosis in multiple myeloma patients. However, the underlying mechanisms involved in the migration and invasion of bone marrow myeloma cells (BMMCs) to cPCs remains unclear. Here, we investigate the possible factors related to hematogenous myeloma cell dissemination and potential regulatory mechanisms.Methods: BMMCs and cPCs of five extramedullary plasmacytoma (EMP) patients were selected for single cell RNA sequencing, We found that the expression level of sphingosine-1-phosphate receptor 2 (S1RP2) was lower in cPCs compared with that in BMMCs. Then, we investigated the effect of S1PR2 in cell migration and invasion through pharmacologic inhibition with a S1PR2-selective antagonist JTE-013 or knockdown of S1PR2 expression in MM cell line U266.Results: The results showed that S1PR2 inhibition with JTE-013 or S1PR2-shRNA significantly promoted cell migration and invasion in U266 cells. We measured the expression of invasion-related proteins by Western blot and found that knockdown of S1PR2 could reduce MMP-9 expression in U266 cells. Furthermore, we found NF-κB pathway may mediate the inhibition effects of S1PR2 on cell migration and invasion in MM cells.Conclusion: Our findings demonstrated that S1PR2 downregulation may contribute to the initial extramedullary translocation by promoting cell migration and invasion through NF-κB pathway activation.Keywords: multiple myeloma, extramedullary plasmacytoma, circulating plasma cells, NF-κB, S1PR2

Yanping Liu,1,* Jing Liu,2,* Yinjie Gao,3 Dan Zheng,2 Wei Pan,2 Min Nie,3 Liangkun Ma4 1Department of Clinical Nutrition, Peking Union Medical College Hospital, CAMS and PUMC, Beijing 100730, People’s Republic of China; 2Guiyang Maternal and Child Health Care Hospital, Guiyang Children’s Hospital, Beijing 100730, People’s Republic of China; 3NHC Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China; 4Department of Obstetrics & Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China*These authors contributed equally to this work.Correspondence: Min Nie; Liangkun Ma Email nm_pumch@aliyun.com; MaLiangKun@pumch.cnObjective: Gestational diabetes mellitus (GDM) causes both short- and long-term harm to mothers and fetuses. It is important to predict the occurrence of GDM as early as possible and take adequate measures to prevent it. The purpose of this study was to investigate the association between body composition of pregnant women in early pregnancy and the risk of GDM.Subjects and Methods: A total of 1318 pregnant women in the early stage of pregnancy were recruited from the Guiyang Maternal and Child Health Care Hospital. Detailed clinical data were recorded. Body composition was determined using the bioimpedance method at 13 weeks of gestation. The association between BMI before pregnancy (pre-BMI), fat mass percentage (FMP) and skeletal muscle mass percentage (SMMP) and the results of glucose tolerance screening in the second trimester of pregnancy were analyzed. Fat mass index (FMI) was calculated using fat mass in kilograms as measured using BIA at 13 weeks of pregnancy divided by the square of the woman’s height in meters (kg/m2) and was analyzed to determine the predictive effect of body fat on GDM.Results: Of the 1318 participants, 249 were diagnosed with GDM and 1069 with normal blood glucose. The FMI and FMP in GDM were higher than in NGT (P< 0.001), while the SMMP in GDM was lower than in NGT (P< 0.001). Overweight women (pre-BMI≥ 24kg/m2) had a higher risk of developing GDM than women with normal pre-BMI (adjusted OR 2.604, 95% CI 1.846– 3.673). Women with FMP greater than 28% had a higher risk of developing to GDM than women with normal-range FMP (adjusted OR 1.572, 95% CI 1.104– 2.240). When FMI is used to predict the incidence of GDM, the area under the curve (AUC) is 65.8%, which is comparable to BMI (AUC=67.2%).Conclusion: Body composition early during gestation is associated with the risk of GDM. The fat mass index in early pregnancy is a predictor of GDM, and it could be an indicator of the efficacy of any intervention to reduce the risk of GDM.Keywords: gestational diabetes mellitus, body composition, fat mass percentage, fat mass index, skeletal muscle mass percentage

Lingyu Zhang,1,* Wenshu Chen,2,* Guihui Tu,1 Xingyong Chen,2 Youguang Lu,3 Lixian Wu,1 Dali Zheng3 1School of Pharmacy, Fujian Medical University, University Town, Fuzhou 350122, People’s Republic of China; 2Shengli Clinical College, Fujian Medical University, Fuzhou 350001, People’s Republic of China; 3Key Laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dali ZhengKey Laboratory of Stomatology of Fujian Province, Hospital of Stomatology, Fujian Medical University, 88 Jiaotong Road, Fuzhou 350004, People’s Republic of ChinaEmail dalizheng@fjmu.edu.cnLixian WuSchool of Pharmacy, Fujian Medical University, 1 Xueyuan Road, University Town, Fuzhou 350122, People’s Republic of ChinaEmail 18259000966@126.comPurpose: Currently, the clinical benefits of tea polyphenols have contributed to the development of efficient systemic delivery systems with adequate bioavailability and stability. In this study, we aimed to establish a nanoparticle model to overcome the shortcomings of epigallocatechin gallate (EGCG) in the treatment of lung cancer.Materials and Methods: Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with EGCG were prepared by the oil-in-water emulsion solvent evaporation technique. The characteristics of NPs, entrapment efficiency, and in vitro release were systematically evaluated. The cellular uptake, cytotoxic activity, and the effect of the formulation on cellular apoptosis of free-from EGCG and the NPs were compared. The interaction between protein-NF-κB and EGCG was detected by bio-layer interferometry (BLI). NF-κB signaling was evaluated by Western blotting and q-RT-PCR. The efficacy of the optimized nanoformulation was evaluated using a patient-derived tumor xenograft (PDX) model.Results: EGCG-loaded NPs (175.8± 3.8 nm in size) demonstrated its optimal efficacy, with approximately 86.0% of encapsulation efficiency and 14.2% of loading efficiency. Additionally, EGCG-encapsulated PLGA-NPs offered a 3-4-fold dose advantage compared to free EGCG in terms of exerting antiproliferative effects and inducing apoptosis at lower doses (12.5, 25 μM). Molecular interaction assays demonstrated that EGCG binds to NF-κB with high affnity (KD=4.8× 10− 5 M). EGCG-NPs were more effective at inhibiting NF-κB activation and suppressing the expression of NF-κB-regulated genes than free EGCG. Furthermore, EGCG-NPs showed superior anticancer activity in the PDX model than free EGCG.Conclusion: These findings indicated that the prepared EGCG-NPs were more effective than free EGCG in inhibiting lung cancer tumors in the PDX model.Keywords: anticancer, tea polyphenol, nanoparticles, NF-κB

Xiujuan Zhang,1 Dandan Liu,2 Yong He,3 Kai Lou,4 Dongmei Zheng,1 Wenxia Han1 1Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People’s Republic of China; 2Department of Respiratory and Intensive Care Unit, Shandong Provincial Chest Hospital, Jinan, People’s Republic of China; 3School of Management, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 4Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Dongmei Zheng; Wenxia HanDepartment of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jing 5 Road, Jinan, Shandong Province 250021, People’s Republic of ChinaTel +86 531 6877 6375Email zhengdongmei1971@163.com; hanwx97@163.comAim: Branched-chain amino acids (BCAAs) have been reported owning curative effects in early diabetic nephropathy. However, the mechanisms of its action have not been elucidated. The aim of this study is to investigate the effect of possible mechanism(s) of BCAAs on cultured rat mesangial cells (RMCs).Methods: RMCs were treated with high glucose (30 mmol/L) and BCAAs (10 mmol/L) respectively. Cell proliferation was detected using an MTT assay. Expression of transforming growth factor (TGF)-β1 and gremlin mRNA was detected by semiquantitative reverse-transcription (RT) PCR. TGF-β1 and fibronectin (FN) protein levels were measured using enzyme-linked immunosorbent assays (ELISAs). Gremlin, bone morphogenic protein (BMP)-7, and Smad2/3 proteins were detected by immunofluorescence. Smad1/5/8 and phosphorylated (p)-Smad1/5/8 were detected by Western blotting.Results: The proliferation rate of the RMCs in the high glucose group alone was 1.45-times of cells in the CON group, and it was reduced by 32% upon co-treatment with BCAAs. The expression of TGF-β1, gremlin, p-Smd2/3 and FN mRNA or protein in the HG group was higher than that in the CON group. In the BCAAs group, the corresponding levels were lower than that in HG group. The expression of BMP-7 and p-Smad1/5/8 were significantly lower in the HG group than in the CON group. Moreover, the expression of BMP-7 and p-Smad1/5/8 were higher in the BCAAs group than in the HG group.Conclusion: BCAAs showed an antidiabetic effect via reducing TGF-β1-Smad2/3 pathway and Gremlin expression and upregulating BMP-7-Smad1/5/8 pathway in rat mesangial cells, consequently lessening ECM deposition in renal tissue.Keywords: diabetic nephropathy, branched chain amino acids, TGF-β1, BMP-7, Smad

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

Chunni Fan,1 Ning Liu,1 Dan Zheng,1 Jianshi Du,2 Keren Wang11Department of Breast Surgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, People’s Republic of China; 2Department of Vascular Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, People’s Republic of ChinaPurpose: Breast cancer (BC) is a common malignancy in women, but the survival rate for BC is not very encouraging. Especially for triple-negative breast cancer (TNBC), a kind of breast cancer that does not have any of the receptors that are commonly found in BC. We investigated the impact of microRNA-206 (miR-206) on transmembrane 4 L6 family member 1 (TM4SF1) in TNBC for therapeutic purpose.Patients and methods: Twenty BC tissues from diagnosed BC patients were analyzed via real-time PCR and Western blotting for expression of TM4SF1 and miR-206. The expression of TM4SF1 was studied in relationship with miR-206 in MDA-MB-231 cells. The biological impact of TM4SF1 and miR-206 on MDA-MB-231 cells and BALB/c nude mice model was studied using proliferation, transwell migration, and invasion assays both in vitro and in vivo.Results: The expression of TM4SF1 in BC tissues was significantly higher than that in adjacent normal breast tissues. In contrast, miR-206 showed a decreased expression level in BC tissues, especially for subtype basal like. Overexpression of miR-206 in MDA-MB-231 cells by transfecting miR-206 resulted in downregulation of TM4SF1. In contrast, knockdown miR-206 expression reversed miR-206-mediated phenotype in MDA-MB-231 cells. Expression level of TM4SF1 in MDA-MB-231 cells was associated with cell migration and invasion capabilities in vitro. Breast tumor burden was correlated with the expression level of TM4SF1 in vivo.Conclusion: Taken together, our results showed the involvement of TM4SF1 in TNBC migration and invasion. miR-206 negatively regulated gene expression of TM4SF1. These findings indicate that miR-206 could be used as a potential therapeutic agent for TNBC.Keywords: miR-206, TM4SF1, TNBC, migration, invasion

Abstract Background T cells play a key role in controlling viral infections; however, the underlying mechanisms regulating their functions during human viral infections remain incompletely understood. Here, we used CD4 T cells derived from individuals with chronic viral infections or healthy T cells treated with camptothecin (CPT) - a topoisomerase I (Top 1) inhibitor - as a model to investigate the role of DNA topology in reprogramming telomeric DNA damage responses (DDR) and remodeling T cell functions. Results We demonstrated that Top 1 protein expression and enzyme activity were significantly inhibited, while the Top 1 cleavage complex (TOP1cc) was trapped in genomic DNA, in T cells derived from individuals with chronic viral (HCV, HBV, or HIV) infections. Top 1 inhibition by CPT treatment of healthy CD4 T cells caused topological DNA damage, telomere attrition, and T cell apoptosis or dysfunction via inducing Top1cc accumulation, PARP1 cleavage, and failure in DNA repair, thus recapitulating T cell dysregulation in the setting of chronic viral infections. Moreover, T cells from virally infected subjects with inhibited Top 1 activity were more vulnerable to CPT-induced topological DNA damage and cell apoptosis, indicating an important role for Top 1 in securing DNA integrity and cell survival. Conclusion These findings provide novel insights into the molecular mechanisms for immunomodulation by chronic viral infections via disrupting DNA topology to induce telomeric DNA damage, T cell senescence, apoptosis and dysfunction. As such, restoring the impaired DNA topologic machinery may offer a new strategy for maintaining T cell function against human viral diseases.

Cong Geng,1,2,* Yapeng Lin,3,* Qin Tang,3 Yifang Tang,3 Xiaoqing Wang,3 Jun-shan Zhou,1 Jie Yang,3 Danni Zheng,4,5 Ying-dong Zhang1 For the Nanjing First Hospital Stroke Registry Investigators 1Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China; 2Department of Emergency, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China; 3Department of Neurology, The First Affiliated Hospital of Chengdu Medical College, Xindu, Chengdu 610500, China; 4Centre for Big Data Research in Health, Faculty of Medicine, University of New South Wales, Sydney 2033, NSW, Australia; 5The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney 2033, NSW, Australia *These authors contributed equally to this work Background: Data concerning sex differences in clinical characteristics and outcomes of young ischemic stroke (IS) patients in Eastern China are scarce. Understanding sex differences in clinical characteristics and long-term outcomes of young IS patients might provide valuable evidence for designing preventative measures and therapeutic interventions. Methods: The study included 228 acute IS patients aged up to 50 years recruited in the prospective Nanjing First Hospital Stroke Registry over a 5-year period. Univariable and multivariable logistic regression analyses were performed to determine whether there were sex differences in clinical characteristics and outcomes of young IS patients. Results: Admission systolic blood pressure (130.12±24.3 vs 137.96±24.3 mmHg, P=0.005) of women was significantly lower than that of men. Logistic regression showed that young women had poorer outcomes defined as having modified Rankin Scale score of 3–6 at 12 months after the adjustment for history of prior stroke, NIHSS score, and complication of pneumonia (adjusted OR: 3.45; 95% CI: 1.43–8.32). Conclusion: Our study indicates that there may be significant differences in clinical characteristics between young women and men with acute IS in East China. Young women were more likely to be dead or dependent at 12 months after stroke onset. More attention should be paid to young women’s IS prevention and management in East China. Keywords: sex differences, young ischemic stroke, clinical characteristics, outcomes

The hallmark of HIV/AIDS is a gradual depletion of CD4 T cells. Despite effective control by antiretroviral therapy (ART), a significant subgroup of people living with HIV (PLHIV) fails to achieve complete immune reconstitution, deemed as immune non-responders (INRs). The mechanisms underlying incomplete CD4 T cell recovery in PLHIV remain unclear. In this study, CD4 T cells from PLHIV were phenotyped and functionally characterized, focusing on their mitochondrial functions. The results show that while total CD4 T cells are diminished, cycling cells are expanded in PLHIV, especially in INRs. HIV-INR CD4 T cells are more activated, displaying exhausted and senescent phenotypes with compromised mitochondrial functions. Transcriptional profiling and flow cytometry analysis showed remarkable repression of mitochondrial transcription factor A (mtTFA) in CD4 T cells from PLHIV, leading to abnormal mitochondrial and T cell homeostasis. These results demonstrate a sequential cellular paradigm of T cell over-activation, proliferation, exhaustion, senescence, apoptosis, and depletion, which correlates with compromised mitochondrial functions. Therefore, reconstituting the mtTFA pathway may provide an adjunctive immunological approach to revitalizing CD4 T cells in ART-treated PLHIV, especially in INRs.

T cells are critical for the control of viral infections and T cell responses are regulated by a dynamic network of non-coding RNAs, including microRNAs (miR) and long non-coding RNAs (lncRNA). Here we show that an activation-induced decline of lncRNA growth arrest-specific transcript 5 (GAS5) activates DNA damage response (DDR), and regulates cellular functions and apoptosis in CD4 T cells derived from people living with HIV (PLHIV) via upregulation of miR-21. Notably, GAS5-miR21-mediated DDR and T cell dysfunction are observed in PLHIV on antiretroviral therapy (ART), who often exhibit immune activation due to low-grade inflammation despite robust virologic control. We found that GAS5 negatively regulates miR-21 expression, which in turn controls critical signaling pathways involved in DNA damage and cellular response. The sustained stimulation of T cells decreased GAS5, increased miR-21 and, as a result, caused dysfunction and apoptosis in CD4 T cells. Importantly, this inflammation-driven T cell over-activation and aberrant apoptosis in ART-controlled PLHIV and healthy subjects (HS) could be reversed by antagonizing the GAS5-miR-21 axis. Also, mutation of the miR-21 binding site on exon 4 of GAS5 gene to generate a GAS5 mutant abolished its ability to regulate miR-21 expression as well as T cell activation and apoptosis markers compared to the wild-type GAS5 transcript. Our data suggest that GAS5 regulates TCR-mediated activation and apoptosis in CD4 T cells during HIV infection through miR-21-mediated signaling. However, GAS5 effects on T cell exhaustion during HIV infection may be mediated by a mechanism beyond the GAS5-miR-21-mediated signaling. These results indicate that targeting the GAS5-miR-21 axis may improve activity and longevity of CD4 T cells in ART-treated PLHIV. This approach may also be useful for targeting other infectious or inflammatory diseases associated with T cell over-activation, exhaustion, and premature immune aging.

CD4 T cell death or survival following initial HIV infection is crucial for the development of viral reservoirs and latent infection, making its evaluation critical in devising strategies for HIV cure. Here we infected primary CD4 T cells with a wild-type HIV-1 and investigated the death and survival mechanisms in productively infected and bystander cells during early HIV infection. We found that HIV-infected cells exhibited increased programmed cell death, such as apoptosis, pyroptosis, and ferroptosis, than uninfected cells. However, productively infected (p24+) cells and bystander (p24-) cells displayed different patterns of cell death due to differential expression of pro-/anti-apoptotic proteins and signaling molecules. Cell death was triggered by an aberrant DNA damage response (DDR), as evidenced by increases in γH2AX levels, which inversely correlated with telomere length and telomerase levels during HIV infection. Mechanistically, HIV-infected cells exhibited a gradual shortening of telomeres following infection. Notably, p24+ cells had longer telomeres compared to p24- cells, and telomere length positively correlated with the telomerase, pAKT, and pATM expressions in HIV-infected CD4 T cells. Importantly, blockade of viral entry attenuated the HIV-induced inhibition of telomerase, pAKT, and pATM as well as the associated telomere erosion and cell death. Moreover, ATM inhibition promoted survival of HIV-infected CD4 T cells, especially p24+ cells, and rescued telomerase and AKT activities by inhibiting cell activation, HIV infection, and DDR. These results indicate that productively infected and bystander CD4 T cells employ different mechanisms for their survival and death, suggesting a possible pro-survival, pro-reservoir mechanism during early HIV infection.

Zhang X, Liu D, He Y, Lou K, Zheng D, Han W. Diabetes Metab Syndr Obes. 2019;12:2433– 2440. The authors of this paper have advised of an error with affiliation 1.Read the original paper here

HIV infection leads to a phenomenon of inflammaging, in which chronic inflammation induces an immune aged phenotype, even in individuals on combined antiretroviral therapy (cART) with undetectable viremia. In this study, we investigated T cell homeostasis and telomeric DNA damage and repair machineries in cART-controlled HIV patients at risk for inflammaging. We found a significant depletion of CD4 T cells, which was inversely correlated with the cell apoptosis in virus-suppressed HIV subjects compared to age-matched healthy subjects (HS). In addition, HIV CD4 T cells were prone to DNA damage that extended to chromosome ends—telomeres, leading to accelerated telomere erosion—a hallmark of cell senescence. Mechanistically, the DNA double-strand break (DSB) sensors MRE11, RAD50, and NBS1 (MRN complex) remained intact, but both expression and activity of the DNA damage checkpoint kinase ataxia-telangiectasia mutated (ATM) and its downstream checkpoint kinase 2 (CHK2) were significantly suppressed in HIV CD4 T cells. Consistently, ATM/CHK2 activation, DNA repair, and cellular functions were also impaired in healthy CD4 T cells following ATM knockdown or exposure to the ATM inhibitor KU60019 in vitro, recapitulating the biological effects observed in HIV-derived CD4 T cells in vivo. Importantly, ectopic expression of ATM was essential and sufficient to reduce the DNA damage, apoptosis, and cellular dysfunction in HIV-derived CD4 T cells. These results demonstrate that failure of DSB repair due to ATM deficiency leads to increased DNA damage and renders CD4 T cells prone to senescence and apoptotic death, contributing to CD4 T cell depletion or dysfunction in cART-controlled, latent HIV infection.

T cells in chronic viral infections are featured by premature aging with accelerated telomere erosion, but the mechanisms underlying telomere attrition remain unclear. Here, we employed human CD4 T cells treated with KML001 (a telomere-targeting drug) as a model to investigate the role of telomere integrity in remodeling T cell senescence. We demonstrated that KML001 could inhibit cell proliferation, cytokine production, and promote apoptosis via disrupting telomere integrity and DNA repair machineries. Specifically, KML001-treated T cells increased dysfunctional telomere-induced foci (TIF), DNA damage marker γH2AX, and topoisomerase cleavage complex (TOPcc) accumulation, leading to telomere attrition. Mechanistically, KML001 compromised telomere integrity by inhibiting telomeric repeat binding factor 2 (TRF2), telomerase, topoisomerase I and II alpha (Top1/2a), and ataxia telangiectasia mutated (ATM) kinase activities. Importantly, these KML001-induced telomeric DNA damage and T cell senescent phenotype and machineries recapitulated our findings in patients with clinical HCV or HIV infection in that their T cells were also senescent with short telomeres and thus more vulnerable to KML001-induced apoptosis. These results shed new insights on the T cell aging network that is critical and essential in protecting chromosomal telomeres from unwanted DNA damage and securing T cell survival during cell crisis upon genomic insult.