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Junqing Liang,1,2 Baopeng Tang,1,2 Jun Shen,1,2 Manzeremu Rejiepu,1,2 Yankai Guo,1,2 Xiaoyan Wang,1,2 Shijie Shao,1,2 Fei Guo,3 Qin Wang,4 Ling Zhang1 1Xinjiang Key Laboratory of Cardiac Electrophysiology and Cardiac Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 2Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 3Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China; 4Department of Geriatrics and Cadre Ward, Second Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of ChinaCorrespondence: Qin Wang; Ling Zhang, Email w2036661q@126.com; ydzhangling@126.comBackground: The common occurrence of atrial fibrillation (AF) as a cardiac arrhythmia, along with its link to sleep deprivation (SD), is gaining more acknowledgment. Even with progress in comprehending the development of AF, the molecular connections between SD and AF are still not well-defined. The objective of this research was to pinpoint the shared molecular routes responsible for SD-induced AF and investigate possible treatment targets.Methods: Utilizing bioinformatics, we examined two transcriptome datasets from the Gene Expression Omnibus (GEO) database to pinpoint genes with differential expression (DEGs) common to SD and AF. Analyses focusing on functional enrichment, such as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), were conducted to pinpoint crucial biological mechanisms and pathways. Furthermore, we utilized immunofluorescence and Western blot techniques to evaluate YBX1 expression and its role in activating NLRP3 inflammasomes in a rat model induced by SD.Results: A total of 540 common DEGs were precisely identified between the AF and SD data collections. Studies emphasizing functional enrichment have highlighted the significance of inflammation pathways, particularly the NOD-like receptor signaling route. The application of machine learning uncovered four crucial genes—CDC5L, MAPK14, RAB5A, and YBX1—with YBX1 becoming the predominant gene in diagnostic processes. Investigating immune penetration revealed significant connections between YBX1 expression and specific immune cell types, notably CD8+ T cells and M1 macrophages. Live studies have demonstrated that SD amplifies the atrial electrical rearrangement, structural changes, the infiltration of inflammatory cells, and the heightened presence of YBX1 along with inflammasome elements.Conclusion: The research pinpoints YBX1 as a crucial gene in SD-related AF, possibly influencing its impact via the NOD-like receptor signaling route and the invasion of immune cells. The results offer crucial understanding of the molecular processes behind AF and propose YBX1 as a possible treatment focus to reduce the risk of AF caused by SD.Keywords: atrial fibrillation, sleep deprivation, bioinformatic analysis, inflammation, YBX1

Yanjun Liu,1 Zijuan Jian,1 Zhiqian Wang,1 Awen Yang,1 Peilin Liu,1 Bin Tang,1 Jiahui Wang,1,2 Qun Yan,1 Wenen Liu1,2 1Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Wenen Liu, Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, People’s Republic of China, Tel +86 13973128689, Email wenenliu@163.comPurpose: In clinical settings, CG23 Klebsiella pneumoniae (Kp) is the most virulent clonal group of Kp. Continuous fusions of hypervirulent (Hv) and highly resistant strains have been reported; however, few studies have analysed the molecular epidemiology and clinical characteristics of CG23 strains, especially MDR-sequence type ST23 strains. In this study, we investigated the molecular characteristics of ST23 Kp and analysed the clinical characteristics of ST23 Kp infections in a large teaching hospital of the third class in China.Methods: ST23 Kp isolates were screened using whole-genome sequencing data from a large single centre. We compared the clinical characteristics of ST23 strains isolated from community-acquired infections (CAI) and hospital acquired infection (HAI). In addition, the infection characteristics of MDR and poor-prognosis isolates were investigated. We analysed genetic characteristics of ST23 Kp and further investigated the evolutionary relationship based on single-nucleotide polymorphism phylogenetic trees.Results: We detected 184 ST23 strains between 2013 and July of 2018. There were no significant differences between the isolation rates of pulmonary, bloodstream, urinary tract, and cutaneous soft tissue infections in the community and hospitals, except for abscess infections. MDR strains primarily cause pulmonary infections and abscesses; infections with a poor prognosis are typically bloodstream and pulmonary infections. Fourteen MDR strains producing extended-spectrum or class C beta-lactamases, resulting in resistance to third-generation cephalosporins. In 3.8% of ST23 Kp strains, the clb locus was absent. The phylogenetic tree revealed that the isolates were primarily divided into three clades, and based on clinical data, it is inferred that three clonal transmission events have occurred, mainly in ICU causing lung infection.Conclusion: This study demonstrates that virulence and drug-resistance fusion events of ST23 strains occur gradually, and that the hypervirulent clones facilitate the widespread dissemination of CAI and HAI, particularly pulmonary. Monitoring genomics and developing antivirulence strategies are essential.Keywords: Klebsiella pneumoniae, ST23, multidrug-resistant, community-acquired infection, nosocomial infection, pneumonia

Yang Han,1 Bo Tang,2 Xian-Miao Li,3 Guo-Song-Rui Yang,4 Li Yang4 1Department of Finance and Accounting, School of Economics and Management, Anhui University of Science and Technology, Huainan, 232001, People’s Republic of China; 2Department of Management, Birmingham Business School, University of Birmingham, Birmingham, B15 2TT, UK; 3Department of Business and Administration, School of Economics and Management, Anhui University of Science and Technology, Huainan, 232001, People’s Republic of China; 4Department of Management Science and Engineering, School of Economics and Management, Anhui University of Science and Technology, Huainan, 232001, People’s Republic of ChinaCorrespondence: Yang Han, Department of Finance and Accounting, School of Economics and Management, Anhui University of Science and Technology, No. 168 of Taifeng Street, Shannan District, Huainan, 232001, People’s Republic of China, Tel +86 15375052657, Email yanghan3134hes@163.comBackground: This study aims to investigate how a team can be resilient in the face of crisis and adversity.Methods: This empirical study adopted a quantitative research method. The data were collected by questionnaire survey, and the stats analysis package in R language and AMOS 23 were used for empirical analysis of 98 teams. Based on complex adaptive system theory and conservation of resources theory, this study was constructed the theoretical framework of “environmental influence — team exchange — team resilience” with informational team faultline (ITF) as independent variable, team leader member exchange (TLMX) and team member exchange (TMX) as mediating and moderating variables, and team resilience as dependent variable in the context of Chinese culture.Results: We found that the ITF had a significant negative effect on the team resilience. TLMX and TMX played partial mediating role between ITF and team resilience. In addition, TLMX and TMX played moderating role between ITF and team resilience, that is, weakening the negative influence of ITF on team resilience.Conclusion: This study contributes to clarify the mechanism of the influence of ITF on team resilience, and provide reference for team leaders to improve team resilience in the face of adversity.Keywords: informational team faultline, team leader member exchange, team member exchange, team resilience, Chinese culture context

Jun Shen,1,2,* Junqing Liang,1,2,* Manzeremu Rejiepu,1,2,* Ping Yuan,3 Jie Xiang,1,2 Yankai Guo,1,2 Jiasuoer Xiaokereti,1,2 Ling Zhang,1,2 Baopeng Tang1,2 1Xinjiang Key Laboratory of Cardiac Electrophysiology and Cardiac Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 2Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 3Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling Zhang, Xinjiang Key Laboratory of Cardiac Electrophysiology and Cardiac Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China, Tel/Fax +86 18690280833, Email ydzhangling@126.com Baopeng Tang, Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, 137 Liyushan Road, Urumqi, Xinjiang, 830000, People’s Republic of China, Tel/Fax +86 13477301883, Email tangbaopeng1111@163.comObjective: This study aimed to identify a newly identified target involved in atrial fibrillation (AF) linked to chronic obstructive sleep apnea (COSA) through an integrative analysis of transcriptome and proteome.Methods: Fifteen beagle canines were randomly assigned to three groups: control (CON), obstructive sleep apnea (OSA), and OSA with superior left ganglionated plexi ablation (OSA+GP). A COSA model was established by intermittently obstructing the endotracheal cannula during exhalation for 12 weeks. Left parasternal thoracotomy through the fourth intercostal space allowed for superior left ganglionated plexi (SLGP) ablation. In vivo open-chest electrophysiological programmed stimulation was performed to assess AF inducibility. Histological, transcriptomic, and proteomic analyses were conducted on atrial samples.Results: After 12 weeks, the OSA group exhibited increased AF inducibility and longer AF durations compared to the CON group. Integrated transcriptomic and proteomic analyses identified 2422 differentially expressed genes (DEGs) and 1194 differentially expressed proteins (DEPs) between OSA and CON groups, as well as between OSA+GP and OSA groups (1850 DEGs and 1418 DEPs). The analysis revealed that differentially regulated DEGs were primarily enriched in mitochondrial biological processes in the CON-vs.-OSA and OSA-vs.-GP comparisons. Notably, the key regulatory molecule GSTZ1 was activated in OSA and inhibited by GP ablation.Conclusion: These findings suggest that GSTZ1 may play a pivotal role in mitochondrial damage, triggering AF substrate formation, and increasing susceptibility to AF in the context of COSA.Keywords: atrial fibrillation, obstructive sleep apnea, transcriptome, proteomic, ganglionated plexi ablation

Kaixin Xiong,1,* Peng Yang,2,* Yujia Cui,1 Jia Li,1 Yan Li,1 Boyu Tang1,3 1State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China; 2Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Center for Oral Diseases & Department of Conservation Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Li, State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China, Email feifeiliyan@163.com Boyu Tang, Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Center for Oral Diseases & Department of Conservation Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China, Email boyutang@126.comAbstract: Periodontitis is a common chronic bacteria-initiated inflammatory disease that is closely associated with various systemic diseases, including chronic obstructive pulmonary disease (COPD). Periodontitis and COPD share similar risk factors, pathology and microorganisms. Epidemiological and clinical research have shown positive correlation between the two diseases. Individuals with severe periodontitis had a higher risk of developing COPD. Moreover, the relative risk of COPD in severe periodontitis was much higher compared to people without periodontal disease and patients with mild to moderate periodontitis. COPD patients with periodontitis had a higher frequency of COPD exacerbation and periodontal treatment demonstrated some control of COPD. However, the nature of periodontitis affecting COPD still needs further exploration. Periodontitis caused microbial and immune imbalances of the lung through several aspects: (I) under periodontitis status, periodontal pathogens directly caused the lung inflammatory reaction after inhalation and colonization on the lung, (II) periodontitis status promoted the oral colonization of pneumonia-associated pathogens, (III) periodontitis status affected the respiratory epithelium structure and (IV) periodontitis status caused imbalances in neutrophils, macrophages and inflammatory cytokines. In this review, we conclude the association between periodontitis and COPD through several aspects and further discuss the potential mechanism by which periodontitis affects COPD.Plain Language Summary: Epidemiological and clinical research have shown positive correlation between periodontitis and COPD. Individuals with severe periodontitis had a higher risk of developing COPD. COPD patients with periodontitis had a higher frequency of COPD exacerbation. Meanwhile, periodontal treatment demonstrated some control of COPD. In this review, we concluded the association between periodontitis and further summarized that periodontitis caused microbial and immune imbalances of the lung through several aspects: (I) under periodontitis status, periodontal pathogens directly caused the lung inflammatory reaction after inhalation and colonization on the lung, (II) periodontitis status promoted the oral colonization of pneumonia-associated pathogens, (III) periodontitis status affected the respiratory epithelium structure and (IV) periodontitis status caused imbalances in neutrophils, macrophages and inflammatory cytokines.Keywords: COPD, microorganism, immune, inflammation

Wanyue Sang,1,2,* Lu Wang,1,2,* Xiaoji Yan,3,* Huaxin Sun,1,2 Yafan Han,1,2 Feifei Wang,1,2 Baopeng Tang,1,2 Yaodong Li1,2 1Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 2Xinjiang Key Laboratory of Cardiac Electrophysiology and Cardiac Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 3Department of Emergency, Sir Run Run Shaw Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yaodong Li; Baopeng Tang, Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, 137 Liyushan Road, Urumqi, Xinjiang, 830000, People’s Republic of China, Tel/Fax +86 15099538881 ; +86 9914362614, Email lyd123@xjmu.edu.cn; tangbaopeng1111@163.comObjective: Atrial fibrillation (AF) is a common tachyarrhythmia whose pathogenesis remains elusive. In the present study, we aimed to investigate the pathological mechanism of mitophagy and immunoinfiltration in AF.Methods: First, we identified differentially expressed mitophagy-related genes (DEMRGs) based on the GSE79768 and GSE115574 datasets, subjecting them to functional enrichment analysis. STRING, TRRUST, miRNet, miRwalk, and Cytoscape were used to explore the potential regulatory roles of downstream signaling pathways. Subsequently, the random forest method was used to construct the AF risk model, and the DEMRGs most correlated with AF risk were determined by combining the Gini index. ssGSEA algorithm, NMF algorithm, and unsupervised clustering were used to subdivide AF molecular types. We then studied the characteristics of mitophagy- and immune infiltration-related genes in AF. Ultimately, we detected the expression of key genes in canine atrial tissues and HL-1 cells by immunofluorescence and Western blot.Results: Mitophagy and immune infiltration were significantly enriched and activated in AF samples. Thirty-seven DEMRGs were screened, of which MAPK1, VDAC1, MAPK14, and MTERF3 were most associated with AF risk. The risk model based on these could identify patients at a high risk of AF. The infiltration of immunocells such as mast cells and neutrophils was significantly different among AF types. Finally, expression verification indicated that the expression trend of four key genes in canine atrial muscle tissue and HL-1 cells was consistent.Conclusion: We found that mitophagy may participate in AF progression through immune activation. In addition, the AF risk prediction model composed of VDAC1, MAPK1, MAPK14, and MTERF3 has a good AF prediction performance, which provides new ideas for the study of AF pathogenesis and potential therapeutic targets.Keywords: atrial fibrillation, mitophagy, molecular subtypes, immune infiltration, random forest

Bei Tang, Ze Zhong, Jinping Wu, Jianping Ma, Li Li, Xuzheng Zhong, Dongmei Lin, Jiayuan Hu, Pingan Yu Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of ChinaCorrespondence: Ze Zhong, Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of China, Tel/Fax +86 571 64096607, Email jdsytbzz@126.comObjective: Involvement of NLR CARD domain containing 4 (NLRC4) in neuroinflammation has been demonstrated. The aim of this study was to ascertain the prognostic role of serum NLRC4 in severe traumatic brain injury (sTBI).Methods: In this prospective cohort study including 140 sTBI patients and 140 controls, serum NLRC4 levels were quantified. Follow-up time was 180 days after trauma and poor prognosis was designated as extended Glasgow outcome scale (GOSE) scores of 1– 4. Severity correlations and prognosis associations were determined under multivariate models.Results: Enhanced serum NLRC4 levels after sTBI, in comparison to controls (median, 0.8 ng/mL versus 0.1 ng/mL; P < 0.001), were independently correlated with Glasgow coma scale (GCS) scores (β, − 0.091; 95% confidence interval (CI), − 0.161— 0.021; P = 0.011), Rotterdam computed tomography (CT) scores (β, 0.136; 95% CI, 0.024– 0.248; P = 0.018), serum C-reactive protein levels (β, 0.016; 95% CI, 0.002– 0.030; P = 0.025) and 180-day GOSE scores (β, − 0.906; 95% CI, − 1.632— 0.180; P = 0.015); and were independently predictive of 180-day death (odds ratio, 4.307; 95% CI, 1.706– 10.879; P = 0.014)), overall survival (hazard ratio, 2.360; 95% CI, 1.118– 4.981; P = 0.040) and poor prognosis (odds ratio, 6.705; 95% CI, 2.889– 15.561; P = 0.016). Under receiver operating characteristic curve, combination of serum NLRC4 levels, GCS scores and Rotterdam CT scores had significantly higher death predictive ability than Rotterdam CT scores (P = 0.040), but not than GCS scores (P = 0.070); and exhibited substantially higher predictive capability for poor prognosis than Rotterdam CT scores (P < 0.001) and GCS scores alone (P = 0.023).Conclusion: There is a dramatical elevation of serum NLRC4 levels after sTBI, which has strong correlation with severity and inflammation, and is significantly associated with long-term death and poor outcome, substantializing serum NLRC4 as an inflammatory, prognostic biomarker in sTBI.Keywords: traumatic brain injury, nucleotide-binding domain leucine-rich repeat-containing protein family caspase activation and recruitment domain-containing protein 4, severity, prognosis, biomarkers, inflammation

Qian Cao,1,&ast; Yu Shen,1,2,&ast; Zhuo Hou,1 Defu Li,3 Boji Tang,1 Lijun Xu,1 Yanping Li4 1Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 3Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University School of Public Health, Nanchang, Jiangxi, People’s Republic of China; 4Department of Neuroelectrophysiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lijun Xu, Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China, Email xulijun20050901@sina.com Yanping Li, Department of Neuroelectrophysiology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, Jiangxi, People’s Republic of China, Email 359173628@qq.comIntroduction: Patent foramen ovale (PFO) is potentially associated with abnormal embolisms, and it results in mixing of arteriovenous blood when its right-to-left shunt (RLS) emerges. Present studies have found that PFO is a risk factor that can lead to many diseases. However, few studies have examined the relationship between PFO and dizziness.Methods: This study was a large single-center, prospective, controlled study. From March 2019 to March 2021, we recruited patients with dizziness were divided into two groups: “explained” and “unexplained”. All patients were submitted to contrast-enhanced transcranial Doppler ultrasound and screened for PFO. Transesophageal heart ultrasound or right heart catheterization was used to confirm PFO. Additionally, multiple factors were collected and statistical analysis was performed between the two groups.Results: Among the 244 patients included, 123 were in the “explained” group and 121 were in the “unexplained” group. The prevalence of PFO in the “explained” group was 34 (27.4%) compared to 79 (64.7%) in the “unexplained” group. In the “explained” group, 7 were RLS level IV, 6 were level III, 7 were level II, and 14 were level I. For the “unexplained” group, the numbers of patients with levels IV, III, II and I were 27, 26, 12 and 14, respectively. Univariate analysis revealed that PFO (χ2= 34.77, P < 0.001) and age (t = − 3.49, P < 0.001) seemed to be potential risk factor candidates for “unexplained” dizziness. In multiple regression analysis, age (OR = 0.97; 95% CI 0.95– 0.99) and the prevalence of PFO (OR = 4.37; 95% CI 2.50– 7.63) were statistically significant. Massively shunted PFO showed more pronounced risk factors (OR = 8.76; 95% CI 4.04– 19.03).Conclusion: There was a high prevalence of PFO and a greater RLS level in unexplained dizziness. PFO and age were independent risk factors for unexplained dizziness. When treating with unexplained dizziness, especially among young people, we must pay attention to the presence of PFO.Keywords: patent foramen ovale, PFO, right to left shunt, RLS, unexplained dizziness, contrast-enhanced transcranial Doppler ultrasound, cTCD

Li Zhang,1,&ast; Jing Xu,1,&ast; Xiaoling Qi,1 Zheying Tao,1 Zhitao Yang,2 Wei Chen,3 Xiaoli Wang,1 Tingting Pan,1 Yunqi Dai,1 Rui Tian,1 Yang Chen,1 Bin Tang,1 Zhaojun Liu,1 Ruoming Tan,1 Hongping Qu,1 Yue Yu,1 Jialin Liu1 1Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Emergency Department, Ruijin Hospital affiliate to Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, Ruijin Hospital Affiliate to Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jialin Liu; Yue Yu, Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People’s Republic of China, Email ljl11243@rjh.com.cn; yy12356@rjh.com.cnBackground: Since the outbreak of coronavirus disease (COVID-19) in December 2019 in Wuhan, it has spread rapidly worldwide. We aimed to establish and validate a nomogram that predicts the probability of coronavirus-associated acute respiratory distress syndrome (CARDS).Methods: In this single-centre, retrospective study, 261 patients with COVID-19 were recruited using positive reverse transcription–polymerase chain reaction tests for severe acute respiratory syndrome coronavirus 2 in Tongji Hospital at Huazhong University of Science and Technology (Wuhan, China). These patients were randomly distributed into the training cohort (75%) and the validation cohort (25%). The factors included in the nomogram were determined using univariate and multivariate logistic regression analyses based on the training cohort. The area under the receiver operating characteristic curve (AUC), consistency index (C-index), calibration curve, and decision curve analysis (DCA) were used to evaluate the efficiency of the nomogram in the training and validation cohorts.Results: Independent predictive factors, including fasting plasma glucose, platelet, D-dimer, and cTnI, were determined using the nomogram. In the training cohort, the AUC and concordance index were 0.93. Similarly, in the validation cohort, the nomogram still showed great distinction (AUC: 0.92) and better calibration. The calibration plot also showed a high degree of agreement between the predicted and actual probabilities of CARDS. In addition, the DCA proved that the nomogram was clinically beneficial.Conclusion: Based on the results of laboratory tests, we established a predictive model for acute respiratory distress syndrome in patients with COVID-19. This model shows good performance and can be used clinically to identify CARDS early.Trial Registration: Ethics committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (No.:(2020) Linlun-34th).Keywords: COVID-19, CARDS, nomogram, risk factor, prediction

Xuan Liu,1,&ast; Xin Li,1,&ast; A-wen Yang,1 Bin Tang,1 Zi-juan Jian,1 Yi-ming Zhong,1 Hong-ling Li,1 Yan-ming Li,1 Qun Yan,1 Xiang-hui Liang,1,2 Wen-en Liu1,2 1Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China; 2National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen-en Liu; Xiang-hui Liang, Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, People’s Republic of China, Tel +86-731-84327437, Fax +86-731-84327332, Email wenenliu@163.com; 1677344146@qq.comBackground: Fecal carriage of extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) and carbapenemase-producing E. coli (CP-EC) is well reported among hospitalized adults and children. However, there are few studies on the carriage prevalence and ESBL-EC and CP-EC genotypes among healthy children in China.Patients and Methods: Stool samples were collected from 330 students in 2021 from three randomly selected primary schools in Changsha, China. ESBL-EC and CP-EC were screened using CHROMagarTM chromogenic plates. ESBL and carbapenemase production was confirmed using the double-disc synergy test and a modified carbapenem inactivation method, respectively. Antimicrobial susceptibility was tested using the broth microdilution method. Resistance determinants, virulence factors, and phylogenetic groups were determined by PCR and sequencing. Multi-locus sequence typing (MLST) was performed (seven housekeeping genes were amplified and sequenced) on the phylogenic group B2 E. coli to detect high-risk clonal strains such as ST131 E. coli. Then, ST131 E. coli were characterized based on ST131 clades, O-type, and fimH alleles.Results: In total, 118 (35.8%) ESBL-EC and 3 (0.9%) CP-EC were isolated. blaCTX-M was the most common genotype (27.1%), identified in all ESBL-EC, except one, which carried blaSHV-12. One isolate with mcr-1 was found amongst ESBL-EC, whereas all three CP-EC carried blaNDM-1. The predominant sequence type (ST) clones in group B2 were ST131 and ST1193. The prevalence of ST131 E. coli was 9.9%, displaying serotypes O16 and O25b, fimH alleles 30, 41, and 89, and ST131 clades A and C1-M27.Conclusion: In this study, high carriage rate of ESBL-EC was found among healthy children, and the dominant ESBL was CTX-M-14. In addition, high-risk clones (ST131 and ST1193) were also detected. This emphasizes the importance of monitoring ESBL-EC in community settings.Keywords: community children, ESBL, CPE, ST131, mcr-1

Keli Wen, Hu Du, Binfei Tang, Bin Xiong, An Zhang,&ast; Pengfei Wang&ast; Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: An Zhang; Pengfei Wang, Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, People’s Republic of China, Tel +86 23-63693452, Email zhangan@Hospital.cqmu.edu.cn; 13436027816@163.comPurpose: The purpose of our study was to explore the prognostic value of complete blood count and myocardial markers combination with Sequential Organ Failure Assessment (SOFA) score in predicting the 28-day mortality among sepsis patients.Patients and methods: A retrospective observational cohort study was performed. Three hundred and nineteen sepsis patients who were hospitalized at the Second Affiliated Hospital of Chongqing Medical University, China, from January 2019 to September 2021 were included. The clinical and laboratory data, the Acute Physiological and Chronic Health Evaluation II (APACHE II) score and SOFA score at the time of the initial sepsis diagnosis were collected, and the predictive values of the single and combination variables for 28-day mortality were compared.Results: The derivation cohort consisted of 221 patients and included 59 (26.7%) died. The area under the curve (AUC) [95% confidence interval (CI)] of RDW and cTnT were 0.735 (0.663– 0.807) and 0.753 (0.678– 0.827) for mortality, and the cut-off value were 14.05% and 0.039 ng/mL, respectively. The combination of RDW, cTnT and the SOFA score showed a better performance for the prediction of mortality, and the AUC was significantly higher than that of the SOFA score (0.791 vs 0.726, DeLong test: P=0.032). Multivariate Cox analysis identified that the combination of RDW, cTnT and the SOFA score (HR=6.133, P=0.004) and APACHE II score (HR=1.093, P< 0.001) were independent detrimental factors for 28-day mortality. The validation cohort consisted of 98 patients and included 23 (23.5%) died. Similarly, the AUC of the RDW, cTnT and the SOFA score combination is significantly higher than that of the SOFA score (0.821 vs 0.739, DeLong test: P=0.035).Conclusion: RDW and cTnT showed good performance in predicting 28-day mortality rates among patients with sepsis. Combined RDW and cTnT with the SOFA score can significantly improve the predictive value of SOFA score for the prognosis of sepsis.Keywords: sepsis, septic shock, Sequential Organ Failure Assessment score, red blood cell distribution width, cardiac troponin T, marker

Tao He,1,&ast; Gang Li,2,&ast; Shoujia Xu,1 Leyun Guo,1 Bing Tang1 1Department of Orthopedics, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, 442008, People’s Republic of China; 2Department of Sports Medicine, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, 442008, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Leyun Guo; Bing TangDepartment of Orthopedics, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Daling Road 16#, Shiyan, Hubei, 442008, People’s Republic of China, Tel +86 0719-8210666, Email guoleyun@sohu.com; tangbingsy@163.comBackground: We hypothesized that the blood urea nitrogen (BUN) to serum albumin ratio (BAR) could serve as an independent predictor for incident acute kidney injury (AKI) in intensive care unit (ICU) patients with rib fracture.Methods: Rib fracture patients in ICU were extracted from Medical Information Mart for Intensive Care IV (MIMIC-IV v1.0) database. The primary outcome in this study was the incidence of AKI. Univariate and multivariate logistic regression analyses were used to determine the relationship between BAR and AKI and propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were also applied to assure the robustness of our results.Results: The optimal cut-off value for BAR was 5.26 based on receiver operator characteristic curve. Among the 953 patients who diagnosed with rib fracture, 197 high-BAR group (≥ 5.26) patients and 197 low-BAR group (< 5.26) patients who had similar propensity scores were finally included in the matched cohort. High-BAR group patients had a significantly higher incidence of AKI (odds ratio, OR, 3.85, 95% confidence index, 95% CI, 2.58– 5.79, P< 0.001) in the original cohort, in the matched cohort (OR, 4.47, 95% CI 2.71– 7.53, P< 0.001), and in the weighted cohort (OR, 4.28, 95% CI 2.80– 6.53, P< 0.001). Furthermore, BAR was superior to that of acute physiology score III for predicting AKI and could add more net benefit for incident AKI in critical care patients with rib fracture.Conclusion: As an easily access and cost-effective parameter, BAR could serve as a good diagnostic predictor for AKI in ICU patients with rib fracture.Keywords: blood urea nitrogen to serum albumin ratio, rib fracture, intensive care unit, acute kidney injury, medical information mart for intensive care

Li Wang, Na Zhao, Li Zhou, Juan Tong, Lei Xue, Lei Zhang, Yongsheng Han, Xingbing Wang, Liangquan Geng, Baolin Tang, Huilan Liu, Weibo Zhu, Xiaoyan Cai, Xin Liu, Xiaoyu Zhu, Zimin Sun, Changcheng Zheng Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of ChinaCorrespondence: Changcheng ZhengDepartment of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Lujiang Road No. 17, Hefei, 230001, People’s Republic of ChinaTel/Fax +86-551-62284476Email zhengchch1123@ustc.edu.cnBackground: There is great uncertainty in the treatment of elderly patients with acute myeloid leukemia (AML), which leads to great challenges in treatment decision. The aim of this study is to find more suitable induction therapy and consolidation therapy for elderly AML patients.Methods: A total of 149 consecutive newly diagnosed elderly AML patients (aged ≥ 60 years) who received induction chemotherapy in our medical center from January 2015 to December 2019 were retrospectively analyzed.Results: After the first induction treatment, the complete remission/or complete remission with incomplete hematologic recovery (CR/CRi) rates in the standard-intensity chemotherapy group was significantly higher than that in the low-intensity chemotherapy group (58.2% vs 32.9%, p = 0.003). Compared with the low-intensity chemotherapy, the incidence of severe infection in the standard-intensity chemotherapy was significantly increased (p < 0.001), but the early mortality was comparable. One hundred and seven patients received minimal residual disease (MRD) examination after the first induction treatment; and MRD was negative accounting for 51.9% in the standard-intensity chemotherapy group, while only 32.7% in the low-intensity group (p = 0.05). The 2-year-overall survival (OS) of patients in standard-intensity induction chemotherapy group (37.2%) was slightly higher than that in low-intensity induction chemotherapy group (23.4%) (p = 0.075). Eighty-one CR/CRi patients received intermediate or high dose cytarabine (n = 35) or sequential chemotherapy regimens (n = 46) as consolidation treatment. The 2-year OS and event-free survival (EFS) of patients in the intermediate or high-dose cytarabine group were significantly higher than those in the sequential chemotherapy regimens group (73.0% vs 38.5%, p = 0.002; 54.8% vs 35.0%, p = 0.035).Conclusion: Our results showed that standard-intensity induction chemotherapy can significantly improve the CR rate for elderly AML patients, and does not increase the early mortality; consolidation therapy with intermediate or high-dose cytarabine can significantly improve EFS and OS for elderly AML patients achieved CR.Keywords: acute myeloid leukemia, elderly patients, minimal residual disease, standard-intensity chemotherapy, intermediate or high dose cytarabine

Qingmei Xu,1 Xin Tan,1 Wei Xian,1 Jiayi Geng,2 Haoyu Li,3 Bi Tang,1,4 Heng Zhang,1 Hongju Wang,1,4 Qin Gao,5 Pinfang Kang1,4 1Department of Cardiology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233004, People’s Republic of China; 2Department of Preventive Medicine, Bengbu Medical College, Bengbu, Anhui, 233000, People’s Republic of China; 3Clinic Medical College of AnHui Medical University, Hefei, Anhui, 230000, People’s Republic of China; 4Cardiovascular Disease Research Center of Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 5Department of Physiology, Bengbu Medical College, Bengbu, Anhui, 233000, People’s Republic of ChinaCorrespondence: Pinfang KangDepartment of Cardiology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233004, People’s Republic of ChinaTel +86 552-3086107Email kangpinfang.1016@163.comBackground: Diabetic cardiomyopathy (DCM) is strongly linked to microvascular disease, renin-angiotensin system (RAS) activation, cardiac inflammation and cell apoptosis. Irbesartan is an angiotensin II (Ang II) receptor antagonist in RAS system, which inhibited the conversion of Ang I into Ang II, while the specific mechanism is still obscure.Objective: This study aims to investigate the expressions necroptosis RIP1-RIP3-MLKL pathway in myocardium of diabetic rats, and the protective action of irbesartan on myocardial damage.Materials and Methods: In our study, 30 Sprague–Dawley rats were divided into 5 groups: CON4W, high glucose and high caloric (HC4W), diabetes mellitus 4 weeks (DM4W group), diabetes mellitus 8 weeks (DM8W group), and irbesartan diabetes 8 weeks (Ir DM8W group).Results: We discovered that as diabetes progresses, the rats gradually lost weight, the HW/BW ratio were increased gradually, and the cardiac function became worse accompanied with the aggravation of inflammatory injury. Meanwhile, the myocardial fibers and cells were disordered, and the expression of positive substances, RIP1 and RIP3 increased significantly. The mRNA and protein levels of myocardial RIP1, RIP3 and MLKL were all increased with the progression of DM. After the intervention of irbesartan in diabetic rats, the cardiac function was improved, whereas inflammatory injury and HW/BW ratio were decreased. Also, the myocardial fibrosis injury was attenuated, and the PAS positive substances, RIP1 and RIP3 were significantly decreased. The curative effect of irbesartan was related to decreased myocardial RIP1, RIP3 and MLKL mRNA and protein levels.Conclusion: In conclusion, irbesartan has a cardioprotective effect on the diabetic rats, and its mechanism may be connected with inhibition of RIP1-RIP3-MLKL pathway.Keywords: cardiomyocyte, high glucose, irbesartan, inflammatory, necroptosis

Jinyu Zhu,1,2,&ast; Bufu Tang,1,3,&ast; Yang Gao,1,4 Suqin Xu,5 Jianfei Tu,1,4 Yajie Wang,4 Weibin Yang,1,4 Shiji Fang,4 Qiaoyou Weng,4 Zhongwei Zhao,1,4 Min Xu,1,4 Yang Yang,1,4 Minjiang Chen,1,4 Chenying Lu,1,4 Jiansong Ji1,4 1Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People’s Republic of China; 2Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China; 3Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of China; 4Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People’s Republic of China; 5Clinical Laboratory, Fuyuan Hospital of Yiwu, Jinhua, 321000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiansong Ji; Chenying Lu Email jijiansong@zju.edu.cn; luchenying@zju.edu.cnIntroduction: Hepatocellular carcinoma (HCC) is a heterogeneous molecular disease with complex molecular pathogenesis that influences the efficacy of therapies. Exosomes play a crucial role in tumorigenesis and poor disease outcomes in HCC.Objective: The aim of this study was to identify the optimal gene set derived from exosomes in HCC with substantial predictive value to construct models for determining prognosis, recurrence risk and diagnosis and to identify candidates suitable for immunotherapy and chemotherapy, thereby providing new ideas for the individualized treatment of patients and for improving prognosis.Methods: Weighted correlation network analysis (WGCNA) and univariate and multivariate Cox PH regression analyses were applied to identify exosome-related signatures in the TCGA and exoRbase databases associated with clinical relevance, immunogenic features and tumor progression in HCC. Cell experiments were performed to further confirm the oncogenic effect of MYL6B and THOC2.Results: The models for prognosis and recurrence risk prediction were built based on two exosomal genes (MYL6B and THOC2) and were confirmed to be independent predictive factors with superior predictive performance. Patients with high prognostic risk had poorer prognosis than patients with low prognostic risk in all HCC datasets, namely, the TCGA cohort (HR=2.5, P< 0.001), the ICGC cohort (HR=3.15, P< 0.001) and the GSE14520 cohort (HR=1.85, P=0.004). A higher recurrence probability was found in HCC patients with high recurrence risk than in HCC patients with low recurrence risk in the TCGA cohort (HR=2.44, P< 0.001) and the GSE14520 cohort (HR=1.54, P=0.025). High prognostic risk patients had higher expression of immune checkpoint genes, such as PD1, B7H3, B7H5, CTLA4 and TIM3 (P< 0.05). Diagnostic models based on the same two genes were able to accurately distinguish HCC patients from normal individuals and HCC from dysplastic nodules.Conclusion: Our findings lay the foundation for identifying molecular markers to increase the early detection rate of HCC, improve disease outcomes, and determine more effective individualized treatment options for patients.Keywords: exosome, hepatocellular carcinoma, HCC, immune checkpoint, prognosis

Luxiang Shang,1 Rui Li,2 Yang Zhao,3 Huaxin Sun,3 Baopeng Tang,3 Yinglong Hou1 1Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Cardiac Electrophysiology and Arrhythmia, Jinan, Shandong, People’s Republic of China; 2Shandong Provincial Center for Disease Control and Prevention, Jinan, Shandong, People’s Republic of China; 3Department of Pacing and Electrophysiology, Xinjiang Key Laboratory of Cardiac Electrophysiology and Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of ChinaCorrespondence: Yinglong HouDepartment of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan, Shandong, 250014, People’s Republic of ChinaTel +86 531-89269317Email yinglonghou@hotmail.comBackground: Obesity is a well-known risk factor for type 2 diabetes mellitus (T2DM). Studies have shown that the Chinese visceral adiposity index (CVAI), a novel visceral adiposity indicator, is positive associated with the risk of T2DM in the Chinese population. This study aimed to investigate the correlation between CVAI and incident T2DM in a Japanese population.Methods: We performed a secondary analysis of open-access data from a retrospective cohort study. This study included 15,464 participants who received regular medical examinations at Murakami Memorial Hospital. All participants underwent a questionnaire survey, physical examination, and blood biochemical testing at baseline. The main outcome was new-onset T2DM during follow-up. Cox regression analysis and Kaplan–Meier analysis were used to analyze the risk of CVAI on T2DM, and we conducted smooth curve fitting. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value of CVAI, body mass index (BMI), and waist circumference (WC) for incident T2DM.Results: During a median follow-up time of 5.39 years, 373 new-onset T2DM events were observed. Kaplan–Meier curves showed that the incidence of T2DM increased as the CVAI increased (log-rank χ2 = 187.1076 and 129.6067 in males and females, respectively, both P < 0.001). After adjustment for covariates, per 1 increase of CVAI was associated with a 1.0133-fold and 1.0246-fold higher risk of incident T2DM in males and females, respectively (both P < 0.001). Those individuals in the top CVAI quartile group had the highest risk of new-onset T2DM (HR = 3.1568 and 5.8415 in males and females, respectively, both P < 0.05). A nonlinear relationship was identified by the smooth fitting curve between CVAI and T2DM events in both genders. ROC analysis indicated that CVAI had better predictive power than BMI and WC in both genders.Conclusion: Our results demonstrate that CVAI was significantly associated with an increased risk of new-onset T2DM in Japanese adults.Keywords: diabetes mellitus, type 2 diabetes mellitus, Chinese visceral adiposity index, obesity, cohort study, Japanese adults

Pan He,1 Bingtong Tang,1 Yusheng Li,1 Yu Zhang,2 Xinming Liu,2 Xin Guo,1 Dong Wang,3 Peng She,3,4 Chunsheng Xiao2 1School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun, 130022, People’s Republic of China; 2Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, People’s Republic of China; 3Department of Orthopaedics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, People’s Republic of China; 4Joint Surgery Department, The First Hospital, Jilin University, Changchun, 130021, People’s Republic of ChinaCorrespondence: Pan He; Peng SheSchool of Materials Science and Engineering, Changchun University of Science and Technology, Changchun, 130022, People’s Republic of ChinaTel +86-431-85583188Fax +86-431-85583188Email hepan@cust.edu.cn; shep@mail.sysu.edu.cnBackground: High levels of oxidants, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), are typical characteristics of an inflammatory microenvironment and are closely associated with a various inflammatory pathologies, eg, cancer, diabetes, atherosclerosis, and neurodegenerative diseases. Therefore, the delivery of anti-inflammatory drugs by oxidation-responsive smart systems would be an efficient anti-inflammatory strategy that benefits from the selective drug release in an inflammatory site, a lower treatment dose, and minimizes side effects.Purpose: In this study, we present the feasibility of an oxidation-sensitive PEGylated alternating polyester, methoxyl poly(ethylene glycol)-block-poly(phthalic anhydride-alter-glycidyl propargyl ether) (mPEG-b-P(PA-alt-GPBAe)), as novel nanocarrier for curcumin (CUR), and explore the application in anti-inflammatory therapy.Methods: The copolymers used were obtained by combining a click reaction and a ring-opening-polymerization method. CUR was loaded by self-assembly. The in vitro drug release, cytotoxicity toward RAW 264.7 cells and cellular uptake were investigated. Furthermore, the anti-inflammatory effects of CUR-loaded polymeric nanoparticles (NPs-CUR) were investigated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and tested in a murine model of ankle inflammation.Results: Fast drug release from NPs-CUR was observed in trigger of 1 mM H2O2 in PBS. Compared with NPs and free drugs, the significant anti-inflammatory potential of NPs-CUR was proven in activated RAW 264.7 cells by inhibiting the production of TNF-α, IL-1β, and IL-6 and increasing the level of an anti-inflammatory cytokine IL-10. Finally, a local injection of NPs-CUR at a dose of 0.25 mg/kg suppressed the acute ankle inflammatory response in mice by histological observation and further reduced the expression of pro-inflammatory cytokines in the affected ankle joints compared to that of free CUR.Conclusion: Both the significant in vitro and in vivo anti-inflammatory results indicated that our oxidation responsive polymeric nanoparticles are promising drug delivery systems for anti-inflammatory therapy.Keywords: oxidation responsiveness, PEGylated polyesters, nanosized micelles, anti-inflammatory therapy, curcumin delivery

Fengshou Chen, Jie Han, Bing Tang Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of ChinaCorrespondence: Bing Tang No. 155 Nangjing North Street, Shenyang, Liaoning Province, People’s Republic of ChinaTel +86 24 83283100Email tangbing527@126.comBackground: Immune-inflammatory mechanisms contribute greatly to the complex process leading to type A aortic dissection (TAAD). This study aims to explore immune infiltration and key immune-related genes in acute TAAD.Methods: ImmuCellAI algorithm was applied to analyze patterns of immune infiltration in TAAD samples and normal aortic vessel samples in the GSE153434 dataset. Differentially expressed genes (DEGs) were screened. Immune-related genes were obtained from overlapping DEGs of GSE153434 and immune genes of the ImmPort database. The hub genes were obtained based on the protein–protein interaction (PPI) network. The hub genes in TAAD were validated in the GSE52093 dataset. The correlation between the key immune-related genes and infiltrating immune cells was further analyzed.Results: In the study, the abundance of macrophages, neutrophils, natural killer T cells (NKT cells), natural regulatory T cells (nTreg), T-helper 17 cells (Th17 cells) and monocytes was increased in TAAD samples, whereas that of dendritic cells (DCs), CD4 T cells, central memory T cells (Tcm), mucosa associated invariant T cells (MAIT cells) and B cells was decreased. Interleukin 6 (IL-6), C-C motif chemokine ligand 2 (CCL2) and hepatocyte growth factor (HGF) were identified and validated in the GSE52093 dataset as the key immune-related genes. Furthermore, IL-6, CCL2 and HGF were correlated with different types of immune cells.Conclusion: In conclusion, several immune cells such as macrophages, neutrophils, NKT cells, and nTreg may be involved in the development of TAAD. IL-6, CCL2 and HGF were identified and validated as the key immune-related genes of TAAD via bioinformatics analyses. The key immune cells and immune-related genes have the potential to be developed as targets of prevention and immunotherapy for patients with TAAD.Keywords: acute type A aortic dissection, immune infiltration, ImmuCellAI, bioinformatics

Ning Xu,1 Yan Liu,1 Yansong Li,1 Bin Tang,1 Xiongyan Liang,2 Yuying Yang,2 Mingyuan Liu,1 Xiaolei Liu,1 Yu Zhou1,2 1Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, People’s Republic of China; 2College of Animal Sciences, Yangtze University, Jingzhou, People’s Republic of ChinaCorrespondence: Yu ZhouCollege of Animal Science, Yangtze University, Jingzhou, People’s Republic of ChinaEmail zhouyurunye@sina.comXiaolei LiuKey Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, People’s Republic of ChinaEmail liuxlei@163.comPurpose: Sensitive and selective point-of-care biosensor is an urgent pursuit of serological antibody detection to control parasite pathogen. For specific, quantitative and on-site screening of Trichinella spiralis infection in livestock, a quantum dot nanobead-monoclonal antibody (QB-mAb) probe-based immunochromatographic assay (ICA) was developed by introducing a competitive sandwich strategy (QB-CICA).Methods: In the QB-CICA, QB-mAb probes competed with serum antibody for a particular epitope, followed by immunocomplexes binding to capture antibody on the test line. With the accumulation of target antibody, captured probes served as signal elements for fluorescent readout in a “turn off” mode, along with the fluorescence gradually weakened. The sensitivity and standard calibration curve of the QB-CICA were quantified using swine sera as negative control (n = 200) and artificial infected swine sera (n = 80) compared with a commercial ELISA kit. Besides, Trichinella spiralis-antibody targeting test ability of the QB-CICA, instead of other parasites or viruses antibodies (n = 10), was evaluated.Results: The QB-CICA exhibited a good linear range, a low detection limit of 189.92 ng mL− 1 and 100% selectivity that was higher than commercial ELISA kit (90%), as well as the same serological positive rate (100%) with commercial ELISA kit in different infection dose models.Conclusion: Taking advantage of its simplicity, short response time (25 min), sensitivity and specificity, the proposed QB-CICA has potential applications for parasite-related antibody monitoring in food safety and clinical diagnosis fields.Keywords: rapid serological antibody test, competitive sandwich immunochromatographic assay, quantum dot nanobead, Trichinella spiralis

Ao Zhou,1 Hongjing Liu,2 Bin Tang1,3 1Basic Medical College, Southwest Medical University, Luzhou 646100, People’s Republic of China; 2The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou 646100, People’s Republic of China; 3Key Laboratory of Process Analysis and Control of Sichuan Universities, Yibin University, Yibin 644000, People’s Republic of ChinaCorrespondence: Bin TangBasic Medical College, Southwest Medical University, Luzhou 646100, People’s Republic of ChinaEmail tangbin8888@163.comBackground: Secretory carrier membrane proteins 3 (SCAMP3) is an endocytosis-associated protein involved in regulating endosomal pathways and the trafficking of vital signaling receptors. This study aimed to comprehensively assess the role of SCAMP3 in hepatocellular carcinoma (HCC) by integrated bioinformatics analysis.Methods: In this study, bioinformatics databases were used to explore the differential expression status and prognostic value of SCAMP3 gene in HCC, and bioinformatics analyses of survival data and interactors of SCAMP3 were conducted to predict the prognostic value of SCAMP3 in HCC.Results: Using the TCGA data, our data shows that SCAMP3 mRNA expression is most significantly different between liver and hepatocellular carcinoma tissues and higher expression of SCAMP3 has unfavorable prognostic significance in HCC. Tumor grade, stage, and gender also showed a significant relevance with SCAMP3 expression. High SCAMP3 expression of males revealed significantly poorer survival and progression compared with low SCAMP3 expression of males. BioGRID statistics explores 79 unique interactions with SCAMP3 and multiple post translational modifications. Further analysis finds that SOCS2 may negatively correlate with SCAMP3, while GBA, MX1, and DDOST positively correlate with SCAMP3. Moreover, ncRNA analysis shows that SCAMP3 gene expression is positively associated with lncRNA SBF2-AS1 and negatively related with Has-miR-145. The expressions of SBF2-AS1 and Has-miR-145 are also significantly related with survival in HCC.Discussion: SCAMP3 expression can be affected by multiple genes or ncRNAs expression that are associated with survival, thus suggesting that SCAMP3 can be used as a clinical diagnosis and prognostic biomarker in HCC.Keywords: SCAMP3, hepatocellular carcinoma, prognosis, interaction, ncRNA, Kaplan–Meier plotter

Mei-ling Wu, Yi-ping Lin, Yan-li Wei, Hong-jian Du, Xiao-qian Ying, Wen-zhuang Tan, Bi-e Tang Faculty of Medicine, Jinhua Polytechnic, Zhejiang, People’s Republic of ChinaCorrespondence: Bi-e TangFaculty of Medicine, Jinhua Polytechnic, No. 1188 Wuzhou Street, Jinhua City, Zhejiang Provinc, People’s Republic of ChinaEmail tangbiejh@163.comBackground: Calycosin (CAL), a type of O-methylated isoflavone extracted from the herb Astralagusmembranaceus (AM), is a bioactive chemical with antioxidative, antiphlogistic and antineoplastic activities commonly used in traditional alternative Chinese medicine. AM has been shown to confer health benefits as an adjuvant in the treatment of a variety of diseases.Aim: The main objective of this study was to determine whether CAL influences the cytochrome P450 (CYP450) system involved in drug metabolism.Methods: Midazolam, tolbutamide, omeprazole, metoprolol and phenacetin were selected as probe drugs. Rats were randomly divided into three groups, specifically, 5% Carboxymethyl cellulose (CMC) for 8 days (Control), 5% CMC for 7 days + CAL for 1 day (single CAL) and CAL for 8 days (conc CAL), and metabolism of the five probe drugs evaluated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).Results: No significant differences were observed for omeprazole and midazolam, compared to the control group. Tmax and t1/2 values of only one probe drug, phenacetin, in the conc CAL group were significantly different from those of the control group (Tmax h: 0.50± 0.00 vs 0.23± 0.15; control vs conc CAL). Cmax of tolbutamide was decreased about two-fold in the conc CAL treatment group (conc vs control: 219.48 vs 429.56, P< 0.001).Conclusion: Calycosin inhibits the catalytic activities of CYP1A2, CYP2D6 and CYP2C9. Accordingly, we recommend caution, particularly when combining CAL as a modality therapy with drugs metabolized by CYP1A2, CYP2D6 and CYP2C9, to reduce the potential risks of drug accumulation or ineffective treatment.Keywords: calycosin, herb-drug interactions, UPLC-MS/MS, cocktail, CYP450

Shanglong Feng,1,* Li Zhou,2,* Xinhui Zhang,1,* Baolin Tang,2 Xiaoyu Zhu,2 Huilan Liu,2 Zimin Sun,2 Changcheng Zheng1,2 1Department of Hematology, Anhui Provincial Hospital, Anhui Medical University, Hefei, People’s Republic of China; 2Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changcheng ZhengDepartment of Hematology, Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, People’s Republic of ChinaTel/fax +86-551-62284476Email zhengchch1123@ustc.edu.cnBackground: Hyperleukocytic acute myeloid leukemia (AML) (initial white blood cell count≥100 × 109/L) is a clinical emergency often accompanied by leukostasis syndrome, tumor lysis syndrome (TLS), and disseminated intravascular coagulation (DIC), with a poor clinical prognosis. The aim of this study retrospectively analyzed the clinical features of hyperleukocytic AML, focusing on high-risk factors affecting prognosis, the selection of initial induction therapy, and the impact of hematopoietic stem cell transplantation (HSCT) on prognosis.Patients and methods: A total of 558 AML patients at our center from January 2013 to December 2017 were diagnosed, and 52 (9.32%) patients presented with hyperleukocytosis were retrospectively reviewed.Results: The 3-year overall survival (OS) rate in the 15–39 years old and 40–60 years old group was 58.8% and 25.4%, respectively; the longest survival time in patients aged >60 years was only 8 months, and the 8-month OS rate was 8.3% (p=0.002). The 3-year OS rate of the patients in the favorable risk group, intermediate risk group and high risk group, according to the 2017 ELN risk stratification, was 50%, 28.0%, and 29.5%, respectively (p=0.374). The 3-year OS rate of patients carrying CEBPA or NPM1 mutation and those with FLT3-ITD or MLL mutation was 37.5% and 30.0%, respectively (p=0.63). The 3-year OS rate of patients employing an induction regimen of a standard IA regimen was 58.4%, and of those employing a non-standard IA regimen was 22.2% (p=0.065). The 3-year OS rate of the transplantation patients reached 73.8%, while the 9-month OS rate of patients without transplantation was 11.4% (p

Yu Wang,1 Emmanuel Enoch Dzakah,2,3 Ye Kang,1 Yanxue Cai,4 Peidian Wu,5 Bo Tang,5 Run Li,5 Xiaowei He11College of Food Science and Engineering, South China University of Technology, Guangzhou 510641, People’s Republic of China; 2Dermatology Hospital, Southern Medical University, Guangzhou 510091, People’s Republic of China; 3Department of Molecular Biology and Biotechnology, School of Biological Sciences, College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast, Ghana; 4School of Chemical Engineering and Energy Technology, Dongguan University of Technology, Dongguan 523808, People’s Republic of China; 5National & Local United Engineering Lab of Rapid Diagnostic Test, Guangzhou Wondfo Biotech Co., Ltd, Guangzhou 5l0663, People’s Republic of ChinaPurpose: Antibodies are key reagents in the development of immunoassay. We attempted to develop high-performance CPP immunoassays using high-affinity monoclonal antibodies prepared via cytokine-assisted immunization.Methods: We used fetal liver tyrosine kinase 3 ligand (Flt3L), CC subtype chemokine ligand 20 (CCL20), and granulocyte-macrophage colony-stimulating factor (GM-CSF) to assist traditional subcutaneous immunization of preparing high-affinity monoclonal antibodies, and further to develop high-performance immunoassay methods for CPP.Results: This novel immune strategy significantly enhanced immune response against CPP. Six anti-CPP monoclonal antibodies (mAbs) with high affinity were successfully screened and selected for application in a fully automated magnetic chemiluminescence immunoassay (CLIA). This robust and rapid assay can efficiently detect CPP in the range of 1.2–1250 pmol L–1, with a detection limit of 6.25 pmol L–1,. Significantly, the whole incubation process can be completed in 30 min as compared to about 4.5 hr for the control ELISA kit. Furthermore, this assay exhibited high sensitivity and specificity, low intra-assay and inter-assay coefficients of variation (CVs < 15%). The developed assay was applied in the detection of CPP in 115 random serum samples and results showed a high correlation with data obtained using a commercially available ELISA kit (correlation coefficient, 0.9737).Conclusion: Our assay could be applied in the point-of-care testing of CPP in the serum samples, and also the method developed in this study could be adopted to explore the detection and diagnosis of other biomarkers for various diseases.Keywords: copeptin, cytokine-assisted immunization, high-affinity antibodies, chemiluminescence immunoassay, point-of-care tests, clinical application

The ethnic Bugis migration to Kupang besides being a source of income, also as a means or means that determine access to resources power in city Kupang. Various dynamics encourage a number of people to migrate permanently to the city of Kupang. This study aims to identify the motives for migration and social change in the people of Kupang. This study was conducted at Kota Kupang East Nusa Tenggara by using a qualitative approach. Her results showed that the migration of ethnic motif Bugis because of the driving factors originating from the area of origin and the pull factors that are in the city of Kupang. The driving factor consists of low income as a result of lack of employment opportunities in the area of origin. Factors above are where broader employment opportunities, and high income and wages. Ethnic Bugis the profession trader has spawned a new social class in the structure of society. The social class of the merchant consists of the upper class (Large merchant group), middle class (medium merchant group), lower class (retailer group).

Bin Tang,1 Jun Wang,1 Lin-lin Luo,1 Qiu-gen Li,1,* Dan Huang2,* 1Department of Respiratory Medicine, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, No. 92 Aiguo Road, Nanchang, 330006, Jiangxi, China; 2Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, 330006, Jiangxi, China *These authors contributed equally to this work Purpose: The aim of this study was to investigate the comparative risks of budesonide/formoterol, versus placebo or monotherapies, for the treatment of patients with stable COPD.Materials and methods: We undertook a systematic search of the literature in PubMed, Embase, and the Cochrane Central Register of Controlled Trials, for randomized controlled trials (RCTs) comparing budesonide/formoterol with control regimens for the treatment of patients with stable COPD and at least 12 weeks of follow-up, meeting the inclusion criteria. Studies were reviewed, and OR with corresponding 95% CI was used to pool the results.Results: A total of eight studies involving 9,254 patients met the inclusion criteria of this meta-analysis. Compared with placebo, combination therapy with budesonide/formoterol was associated with a significantly higher risk of adverse effects including oral candidiasis (OR: 3.09, 95% CI: 1.95–4.91) and dysphonia (OR: 2.76, 95% CI: 1.40–5.44), but not pneumonia (OR: 0.94, 95% CI: 0.64–1.37) or bronchitis (OR: 1.36, 95% CI: 0.95–1.95). A similar pattern was also evident for the comparison of formoterol with budesonide/formoterol, with increased occurrence of oral candidiasis (OR: 2.72, 95% CI: 1.33–5.58) and dysphonia (OR: 4.13, 95% CI: 1.95–8.76); however, there were no significant differences in pneumonia (OR: 1.31, 95% CI: 0.98–1.74) or bronchitis (OR: 1.05, 95% CI: 0.83–1.31). In contrast, compared with budesonide, combined budesonide/formoterol was associated with similar risks of adverse effects, including pneumonia (OR: 1.20, 95% CI: 0.60–2.39), bronchitis (OR: 0.95, 95% CI: 0.41–2.20), oral candidiasis (OR: 0.79, 95% CI: 0.41–1.53), and dysphonia (OR: 1.00, 95% CI: 0.40–2.47).Conclusion: Combination therapy does not cause more adverse events, including pneumonia and bronchitis, than control (placebo, formoterol, or budesonide) treatment in patients with stable COPD, while there were higher risks of oral candidiasis and dysphonia compared with the non-inhaled corticosteroid group (placebo, formoterol). Keywords: budesonide/formoterol, risk, COPD, meta-analysis, randomized controlled trial

Li Zhou,1,* Shanglong Feng,1,2,* Guangyu Sun,1 Baolin Tang,1 Xiaoyu Zhu,1 Kaidi Song,1 Xuhan Zhang,1 Huaiwei Lu,3 Huilan Liu,1 Zimin Sun,1 Changcheng Zheng1,2 1Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; 2Department of Hematology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China; 3Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China *These authors contributed equally to this work Background: Extensively drug-resistant Gram-negative bacterial (XDR-GNB) bloodstream infection (BSI) is difficult to treat and is associated with a high mortality rate in patients with hematological diseases. The aim of this study is to investigate the predisposing risk factors and the efficacy of the antibiotic treatment in these patients, including exploration of efficacy and adverse effects of high-dose tigecycline. Methods: Between January 2013 and December 2017, 27 XDR-GNB BSI patients with hematological diseases were diagnosed and retrospectively reviewed in the current study. Results: Clinical response in patients with severe complications (such as severe neutropenia >10 days, grade III–IV acute graft-versus-host disease (aGVHD), and concurrent pneumonia) was significantly lower than in patients without or with only mild complications (P=0.033). The efficacy rate was 62.5% (10/16) in patients with tigecycline-based combination therapy regimen, 77.8% (7/9) with a high-dose tigecycline regimen, and 42.9% (3/7) with a standard-dose tigecycline regimen (P=0.36). The 30-day survival rates of patients undergoing high-dose or standard-dose tigecycline treatment were 66.7% (95% CI: 28.2–87.8) and 57.1% (95% CI: 17.2–83.7), respectively, (P=0.603). Patients with mild complications were associated with superior 30-day survival rates than patients with severe complications (93.8% vs 36.4%, P=0.001), >10 days of neutropenia (90.9% vs 33.3%, P=0.012), severe aGVHD (100% vs 40%, P=0.049), and concurrent pneumonia (84.6% vs 57.1%, P=0.048). Conclusion: Our study indicated that XDR-GNB BSI in patients of hematological diseases with severe complications, such as long duration of neutropenia (>10 days) and severe aGVHD were associated with poor clinical response and short survival. We first indicated that these patients undergoing high-dose tigecycline treatment had an improved clinical response and an increased 30-day survival rate compared with the standard-dose group, although the differences were not statistically significant. This might be due to more severe complicated patients enrolled in high-dose group and the limited number size in our study. Keywords: carbapenem resistant bacterial infection, bloodstream infection, high-dose tigecycline, hematological malignancies

Pierre Zitoun,1 Jaya Parikh,2 Martine Nijs,3 Wenjie Zhang,4 Rachel Levy-Toledano,5 Boxiong Tang6 1American Hospital of Paris, Neuilly-sur-Seine, France; 2Lister Fertility Clinic, London, UK; 3Nij Geertgen, Elsendorp, the Netherlands; 4WG Group, New York, NY, USA; 5Theramex HQ UK Limited, London, UK; 6Teva Pharmaceuticals, Frazer, PA, USA Purpose: The purpose of this study was to assess product-specific features for a variety of self-administered injection devices and identify key factors that patients and nurses in select European markets find most important when selecting injection devices for self-administration of recombinant human follicle-stimulating hormone and urinary human follicle-stimulating hormone for fertility/reproductive therapy.Patients and methods: Patients (N=402) in France, Italy, Spain, Germany, the UK, the Netherlands, and Belgium, as well as reproductive/fertility nurses (N=40) in Germany, Italy, France, Spain, and the Czech Republic were surveyed. All patients were previously prescribed a follicle-stimulating hormone (FSH) treatment for either in vitro fertilization or ovulation induction. Patient and nurse preferences for attributes across all injection devices in the market were obtained via an online questionnaire and evaluated using the maximum differential scaling (MaxDiff) and conjoint analyses, which captured the relative importance of the selected FSH injection device attributes to determine specific qualities in overall product preference.Results: Both the MaxDiff and conjoint analyses indicated that, for patients and nurses, the ideal FSH injection device would be a highly accurate, multi-use reusable pen injector with a dial-back function that would be easy for both use and education/instruction. Patients and nurses each selected attributes pertinent to their own experiences with the FSH injection device. Categorically, patients valued factors that resulted in minimal impact on daily life, including reduced injection volume to minimize injection-site pain, as well as a reusable device that would be easy to use; nurses placed greater value on a device that would be easy to teach in order to instruct the greatest number of patients while minimizing risk.Conclusion: Patient and nurse preferences were aligned on certain selected attributes of the FSH products. Although this study was an unbranded examination of attributes across all injection devices currently in the market, results demonstrated that the preferred product attributes were all characteristics of the Ovaleap® Pen. Keywords: infertility, prefilled pen device, recombinant human follicle-stimulating hormone, urinary follicle-stimulating hormone, preference

Bo Tang,1,2,* Fang Tang,1,2,* Zhenran Wang,1,2,* Guangying Qi,3 Xingsi Liang,1,2 Bo Li,1,2 Shengguang Yuan,1,2 Jie Liu,1,2 Shuiping Yu,1,2 Songqing He1,2 1Department of Hepatobiliary Surgery, Guilin Medical University Affiliated Hospital, 2Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, 3Department of Pathology and Physiopathology, Guilin Medical University, Guilin, Guangxi, People’s Republic of China *These authors contributed equally to this work Abstract: Primary liver cancer is globally the sixth most frequent cancer, and the second leading cause of cancer death and its incidence is increasing in many countries, becoming a serious threat to human health. Many researches focused on the treatment and prevention of liver cancer. However, due to the underlying molecular mechanism of liver cancer still not fully understood, the studies and development of treatments were forced to be delayed. Akt has been suggested to play an essential role in the progression of inflammation response and apoptosis. Hence, in this study, Akt-knockout mice and cells of liver cancer were used as a model to investigate the molecular mechanism of Akt-associated inflammatory and apoptotic signaling pathway linked with NF-κB and Bcl-2-associated death promoter (Bad) for the progression of liver cancer. Carnosic acid (CA), as a phenolic diterpene with anticancer, antibacterial, antidiabetic, as well as neuroprotective properties, is produced by many species from Lamiaceae family. Administration of CA nanoparticles was sufficient to lead to considerable inhibition of liver cancer progression. The results indicated that, compared to the normal liver cells, the expression of Akt was significantly higher in liver cancer cell lines. Also, we found that Akt-knockout cancer cell lines modulated inflammation response and apoptosis via inhibiting NF-κB activation and inducing apoptotic reaction. Our results indicated that the downstream signals, including cytokines regulated by NF-κB and caspase-3-activated apoptosis affected by Bad, were re-modulated for knockout of Akt. And CA nanoparticles, acting as Akt-knockout, could inhibit inflammation and accelerate apoptosis in liver cancer by altering NF-κB activation and activating caspase-3 through Bad pathway. These findings demonstrated that the nanoparticulate drug CA performed its effective role owing to its ability to reduce inflammatory action and enhance apoptosis for the overexpression of NF-κB and Bad via Akt signaling pathway, playing a direct role in liver cancer progression. Thus, nanoparticle CA might be an important and potential choice for the clinical treatment in the future. Keywords: liver cancer, Akt-knockout, carnosic acid nanoparticle, inflammation, apoptosis

Yu-Feng Xiao,1 Jian-Mei Li,2 Su-Min Wang,1 Xin Yong,1 Bo Tang,1 Meng-Meng Jie,1 Hui Dong,1 Xiao-Chao Yang,2 Shi-Ming Yang1 1Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, People’s Republic of China; 2School of Biomedical Engineering, Third Military Medical University, Chongqing, People’s Republic of China Abstract: Gastric cancer is one of the leading causes of tumor-related deaths in the world. Current treatment options do not satisfy doctors and patients, and new therapies are therefore needed. Cerium oxide nanoparticles (CNPs) have been studied as a potential therapeutic approach for treating many diseases. However, their effects on human gastric cancer are currently unknown. Therefore, in this study, we aimed to characterize the effects of CNPs on human gastric cancer cell lines (MKN28 and BGC823). Gastric cancer cells were cocultured with different concentrations of CNPs, and proliferation and migration were measured both in vitro and in vivo. We found that CNPs inhibited the migration of gastric cancer cells when applied at different concentrations, but only a relatively high concentration (10 µg/mL) of CNPs suppressed proliferation. Furthermore, we found that CNPs increased the expression of DHX15 and its downstream signaling pathways. We therefore provide evidence showing that CNPs may be a promising approach to suppress malignant activity of gastric cancer by increasing the expression of DHX15. Keywords: cerium oxide nanoparticles, gastric cancer, DHX15, p38

Xingsi Liang,1,2,* Bin Zhang,3,* Quan Chen,4,* Jing Zhang,1,5 Biao Lei,1,5 Bo Li,5 Yangchao Wei,1,5 Run Zhai,1,5 Zhiqing Liang,2 Songqing He,1,5 Bo Tang1,5 1Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, 2Department of Infectious Diseases, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, 3Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 4Department of Anesthesiology, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, 5Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People’s Republic of China *These authors contributed equally to this work Abstract: Characterized by its acute onset, critical condition, poor prognosis, and high mortality rate, severe acute pancreatitis (SAP) can cause multiple organ failure at its early stage, particularly acute lung injury (ALI). The pathogenesis of ALI is diffuse alveolar damage, including an increase in pulmonary microvascular permeability, a decrease in compliance, and invasion of many inflammatory cells. Corticosteroids are the main treatment method for ALI; however, the associated high toxicity and side effects induce pain in patients. Recent studies show that the effective components in many traditional Chinese medicines can effectively inhibit inflammation with few side effects, which can decrease the complications caused by steroid consumption. Based on these observations, the main objective of the current study is to investigate the effect of alpinetin, which is a flavonoid extracted from Alpinia katsumadai Hayata, on treating lung injury induced by SAP and to explore the mechanism underlying the alpinetin-mediated decrease in the extent of ALI. In this study, we have shown through in vitro experiments that a therapeutic dose of alpinetin can promote human pulmonary microvascular endothelial cell proliferation. We have also shown via in vitro and in vivo experiments that alpinetin upregulates aquaporin-1 and, thereby, inhibits tumor necrosis factor-α expression as well as reduces the degree of lung injury. Overall, our study shows that alpinetin alleviates SAP-induced ALI. The likely molecular mechanism includes upregulated aquaporin expression, which inhibits tumor necrosis factor-α and, thus, alleviates SAP-induced ALI. Keywords: alpinetin, aquaporin-1, severe acute pancreatitis, acute lung injury, HPMVEC, tumor necrosis factor-α

Yi Liu,1 Hongyu Piao,1 Ying Gao,1 Caihong Xu,2 Ye Tian,1 Lihong Wang,1 Jinwen Liu,1 Bo Tang,1 Meijuan Zou,1 Gang Cheng1 1Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People’s Republic of China; 2Department of Food Science, Shenyang Normal University, Shenyang, Liaoning Province, People’s Republic of China Abstract: 7-Ethyl-10-hydroxycamptothecin (SN38), an active metabolite of irinotecan (CPT-11), is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C10-OH)SN38 and chitosan-(C20-OH)SN38) to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C10-OH)SN38 (CS-(10s)SN38) and chitosan-(C20-OH)SN38 (CS-(20s)SN38) were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC)0–24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P

Hongwu Sun,1,* Kaiyun Liu,1,* Wei Liu,1 Wenxiu Wang,2 Chunliang Guo,1 Bin Tang,1 Jiang Gu,1 Jinyong Zhang,1 Haibo Li,1 Xuhu Mao,1 Quanming Zou,1 Hao Zeng11National Engineering Research Center for Immunological Products, Third Military Medical University, Chongqing, China; 2Key Lab of Preventive Veterinary Science and Animal Biological Technology, Shandong Binzhou Animal Science and Veterinary Medicine Institute, Binzhou, China *These authors contributed equally to this work.Background: The stability of protein drugs remains one of the key hurdles to their success in the market. The aim of the present study was to design a novel nanoemulsion drug-delivery system (NEDDS) that would encapsulate a standard-model protein drug – bovine serum albumin (BSA) – to improve drug stability.Methods: The BSA NEDDS was prepared using a phase-inversion method and pseudoternary phase diagrams. The following characteristics were studied: morphology, size, zeta potential, drug loading, and encapsulation efficiency. We also investigated the stability of the BSA NEDDS, bioactivity of BSA encapsulated within the NEDDS, the integrity of the primary, secondary, and tertiary structures, and specificity.Results: The BSA NEDDS consisted of Cremophor EL-35, propylene glycol, isopropyl myristate, and normal saline. The average particle diameter of the BSA NEDDS was about 21.8 nm, and the system showed a high encapsulation efficiency (>90%) and an adequate drug-loading capacity (45 mg/mL). The thermodynamic stability of the system was investigated at different temperatures and pH levels and in room-temperature conditions for 180 days. BSA NEDDS showed good structural integrity and specificity for the primary, secondary, and tertiary structures, and good bioactivity of the loaded BSA.Conclusions: BSA NEDDS showed the properties of a good nanoemulsion-delivery system. NEDDS can greatly enhance the stability of the protein drug BSA while maintaining high levels of drug bioactivity, good specificity, and integrity of the primary, secondary, and tertiary protein structures. These findings indicate that the nanoemulsion is a potential formulation for oral administration of protein drugs.Keywords: nanoemulsion, drug-delivery system, protein drug, oral administration, stability

Tuck-yun Cheang1,*, Bing Tang1,*, An-wu Xu2, Guang-qi Chang1, Zuo-jun Hu1, Wei-ling He1, Zhou-hao Xing2, Jian-bo Xu1, Mian Wang1, Shen-ming Wang11Department of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; 2Division of Nanomaterials and Chemistry, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China *Both authors contributed equally to this workAbstract: Nanoparticles have an enormous potential for development in biomedical applications, such as gene or drug delivery. We developed and characterized aminopropyltriethoxysilane-functionalized silicon dioxide nanoparticles (APTES-SiNPs) for gene therapy. Lipofectamine® 2000, a commonly used agent, served as a contrast. We showed that APTES-SiNPs had a gene transfection efficiency almost equal to that of Lipofectamine 2000, but with lower cytotoxicity. Thus, these novel APTES-SiNPs can achieve highly efficient transfection of plasmid DNA, and to some extent reduce cytotoxicity, which might overcome the critical drawbacks in vivo of conventional carriers, such as viral vectors, organic polymers, and liposomes, and seem to be a promising nonviral gene therapy vector.Keywords: aminopropyltriethoxysilane, silicon dioxide nanoparticles, Lipofectamine® 2000, gene therapy vector, nanomedicine

R Karim, R Ghabrial, TF Lynch, B TangSchool of Public Health, Faculty of Medicine, University of Sydney, Sydney, AustraliaPurpose: To compare success rates of external dacryocystorhinostomy (DCR) and endoscopic endonasal DCR for acquired nasolacrimal duct obstruction (NLDO).Design: Historical cohort study.Participants: 100 patients who underwent external DCR and 105 patients who underwent endoscopic endonasal DCR.Methods: A retrospective review of medical records of patients with acquired NLDO who underwent DCR from 2004–2010 was performed. Data regarding the lacrimal drainage system, eye examination, surgical outcomes, patient symptom control, and postoperative care were analyzed.Main outcome measures: Surgical success was defined by patient's resolution of symptoms with patency on irrigation. Surgical failure was defined as no symptomatic reduction in epiphora and/or an inability to irrigate the lacrimal system postoperatively.Results: A total of 205 patients underwent surgeries for acquired NLDO. The average age was 69 years, and 62.4% of subjects were female. Pooled results showed that both surgical approaches had similar success rates (endoscopic endonasal DCR 82.4% versus external DCR 81.6%; P = 0.895). Complication rates were low in both types of surgery. This included three patients with postoperative hemorrhage (two who had endonasal DCR surgery and one having external DCR surgery). This resolved with conservative treatment. Postoperative problems with lacrimal patency (including canalicular obstruction) occurred to 6.8% of endoscopic patients and 9% of those with the external DCR surgery. Of the 14 patients who had their silicone tubes fall out before the 2-month assessment, 10 were classified as failures (71%), in contrast to only a failure rate of 13.9% of those whose tubes were present for the recommended time. This difference was statistically significant (P < 0.01).Conclusion: The success rate of DCR for acquired NLDO in our group of patients was high overall with a low complication rate between the two types of surgery. There was no statistically significant difference between endoscopic and external DCR. Endoscopic surgery may have a benefit of preserving the lacrimal pump system and leaving no surgical scar. Patient preference and availability of each service should direct management. Hence endoscopic endonasal DCR surgery should be considered for primary treatment of nasolacrimal duct obstruction.Keywords: lacrimal sac, postoperative, irrigation, epiphora

BackgroundDepression is a debilitating and difficult-to-treat condition in people with HIV (PWH) despite viral suppression on antiretroviral therapy (ART). Depression is associated with activation of the PKR-like ER kinase (PERK) pathway, which regulates protein synthesis in response to metabolic stress. We evaluated common PERK haplotypes that influence PERK expression in relation to depressed mood in PWH.MethodsPWH from 6 research centers were enrolled in the study. Genotyping was conducted using targeted sequencing with TaqMan. The major PERK haplotypes A, B, and D were identified. Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II). Covariates including genetically-defined ancestry, demographics, HIV disease/treatment parameters and antidepressant treatments were assessed. Data were analyzed using multivariable regression models.ResultsA total of 287 PWH with a mean (SD) age of 57.1±7.8 years were enrolled. Although the largest ethnic group was non-Hispanic white (n=129, 45.3%), African-American (n=124, 43.5%) and Hispanic (n=30, 10.5%) made up over half the sample. 20.3% were female and 96.5% were virally suppressed. Mean BDI-II was 9.6±9.5, and 28.9% scored above the cutoff for mild depression (BDI-II>13). PERK haplotype frequencies were AA57.8%, AB25.8%, AD 10.1%, and BB4.88%. PERK haplotypes were differentially represented according to genetic ancestry (p=6.84e-6). BDI-II scores were significantly higher in participants with the AB haplotype (F=4.45, p=0.0007).This finding was robust to consideration of potential confounds.ConclusionPERK haplotypes were associated with depressed mood in PWH.Consequently, pharmacological targeting of PERK-related pathways might amelioratedepression in PWH.