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Jing He,1,&ast; Nan Lin,2,&ast; Ting Jin,2 Ming Lin,1 Zuowei Huang,1 Shuxian Li,1 Jinling Liu,1 Lin Su,1 Xian Ye,2 Lei Wu,1 Zhenghong Song,2 Hongzhen Xu,2 Zhimin Chen1 1Department of Pulmonology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China; 2Nursing Department, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhimin Chen, Department of Pulmonology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, People’s Republic of China, Email zmchen@zju.edu.cn Hongzhen Xu, Master of nursing, Nursing Department, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, People’s Republic of China, Email 6184020@zju.edu.cnBackground: Allergic conditions, identified as a significant global health challenge, are profoundly influenced by indoor allergens, especially house dust mites (HDM). Yet the relationship between mite sensitized components and respiratory allergies and asthma control remains poorly understood.Methods: A cohort of 96 children, either with allergic rhinitis (AR) or rhinitis with asthma syndrome (ARAS), was assessed. Protein microarray technology was deployed to quantify sIgE responses to the allergenic components of Der p and Der f.Results: The study cohort comprised 18 AR and 78 ARAS patients; with 43 mild and 53 moderate-to-severe AR; with 28 uncontrolled, 21 partially controlled, and 29 well-controlled asthma. Sensitization prevalence for HDM components was highest with Der p (97.9%), Der f 2 (97.9%), Der p 2 (94.8%), Der f 1(94.8%), Der p 1 (93.8%), Der p 23 (57.3%). Notably, sIgE concentrations for Der f and Der f 2 were significantly greater in the ARAS compared to AR (P < 0.05). While sIgE levels varied between mild and moderate-to-severe AR, the differences were not statistically significant (P > 0.05). However, Der p 23 sIgE levels demonstrated a significant fluctuation across the asthma control strata (P < 0.05), with the well-controlled group exhibiting the lowest readings.Conclusion: The sIgE levels to HDM allergens were higher in ARAS group compared to AR group, especially Der f and Der f 2, indicating an association between sIgE reactivity and the diagnosis of asthma. Reduced Der p 23 sIgE levels were indicative of enhanced asthma control.Keywords: house dust mite, allergic rhinitis, asthma, molecular sensitization, children

Keting Min,&ast; Yu Wang,&ast; Di Feng,&ast; Tian Jin, Wanli Zhu, Ruowang Duan, Xin Lv Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Lv; Ruowang Duan, Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 507 Zhengmin Road, Shanghai, 200032, People’s Republic of China, Tel +8613661869972 ; +8618019713255, Email xinlv@tongji.edu.cn; duanruowang@163.comBackground and Importance: Postoperative cough is a common complication of general anesthesia after bronchoscopy. The aim of the present study was to determine the safety profile and efficacy of piriform recess instillation with lidocaine in reducing the incidence of coughing.Objective: To what extent could piriform recess instillation with lidocaine decrease the incidence of cough at 10min after extubation?Outcome Measures and Analysis: Eighty-eight consecutive patients were equally randomized to a lidocaine group receiving piriform recess instillation with 2mL 2% lidocaine, and a normal saline group receiving piriform recess instillation with 2mL saline. The primary outcome was the incidence of cough after extubation, and the secondary outcomes were throat score at 10 min and 6 h after extubation assessed by the numerical rating scale, cough severity at 10 min and 6 h after extubation assessed by the Visual Analog Scale (VAS), 24 h 40-item Quality of Recovery Score (QoR-40), and subject-rated satisfaction score on a VAS.Main Results: Compared with saline group, the incidence of cough in lidocaine group was significantly lower (63.6% vs 86.4%, P=0.014). The sore throat score at 10 min after extubation was significantly lower (0[0,0] vs 1[0,2], P< 0.001). The subject-rated overall anesthesia satisfaction score was significantly higher (84.8[± 6.2] vs 76.6[± 8.6], P< 0.001). The severity of cough at 10 min after extubation was significantly lower (Mild: 36.4% vs 11.4%, P=0.006; Severe: 9.1% vs 43.2%, P< 0.001). There was no significant difference in the sore throat score at 6 h after extubation, severity of cough at 6 h after extubation, or QoR-40 at 24 h after extubation between the two groups.Conclusion: Piriform recess instillation with lidocaine before bronchoscopy is a simple and effective method for reducing early cough intensity and alleviating early sore throat. At 6 hours, there were no differences observed between the groups.Clinical Trial Registration: Chinese Clinical Trial Registry (identifier: ChiCTR2200067087).Keywords: piriform recess, lidocaine, general anesthesia, cough, bronchoscopy

Yingzi He,&ast; Jingjing Wang,&ast; Jianan Wang, Ruojun Qiu, Shuo Wang, Ting Jin, Hong Li, Fenping Zheng Department of Endocrinology, the Affiliated Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Zhejiang, 310016, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fenping Zheng, Department of Endocrinology, the Affiliated Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Zhejiang, 310016, People’s Republic of China, Email 3407004@zju.edu.cnObjective: This study assessed possible associations among physical activity (PA), sitting time (ST), metabolic syndrome (MetS), and the individual components thereof. We analyzed the entire study sample and subpopulations stratified by visceral fat area (VFA). We hypothesized that individuals with elevated VFA might respond differently to modifiers of metabolic health, including PA and ST.Methods: This cross-sectional study, conducted between March and May 2010, enrolled 957 adults with abdominal magnetic resonance imaging (MRI) aged 40– 65 years living in the urban communities in Hangzhou, China. PA and ST were recorded using the standard International Physical Activity Questionnaire (IPAQ) and categorized into three levels. The ethnicity-specific cutoff for central obesity was VFA ≥ 80 cm2 on MRI according to Chinese population-based research. Multiple logistic regression models were used to analyze the associations between PA, ST, MetS and its components.Results: In the total subject population, participants reporting high level of PA were at a lower risk of MetS (OR = 0.46, 95% CI: 0.25, 0.86) than those declaring low PA. In the subgroup population with VFA ≥ 80 cm2 (ie, with central obesity), moderate-to-high PA levels were associated with a lower risk of MetS (p for trend < 0.05) and a lower risk of decreased high-density lipoprotein cholesterol (HDL-C) concentrations (p for trend < 0.05). In addition, ST > 3 h/day was a risk factor for both MetS (p for trend < 0.05) and hypertriglyceridemia (p for trend < 0.05) in the total subject population. While in the central obesity subgroup, ST > 3 h/day was found a stronger risk factor.Conclusion: Our study suggests that moderate-to-high levels of PA may have a role in prevention of MetS, and ST > 3 h/day was associated with a higher risk of MetS, particularly in individuals with central obesity.Keywords: metabolic syndrome, physical activity, sitting time, central obesity, visceral fat area

Mi-Mi Wan,1,&ast; Tuo Jin,2,&ast; Zhang-Yitian Fu,1 Si-Hua Lai,1 Wei-Ping Gao1 1Department of Ophthalmology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Department of Ophthalmology, Kunshan Hospital of Chinese Medicine, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei-Ping Gao, Department of Ophthalmology, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Qinhuai District, Nanjing, Jiangsu, People’s Republic of China, Tel +86 13057671767, Email 260790@njucm.edu.cnPurpose: This study aimed to examine electroacupuncture’s influence on ocular pain and its potential modulation of the TNF-ɑ mediated ERK1/2/P2X3R signaling pathway in dry eye-induced rat models.Methods: Male Sprague–Dawley rats with induced dry eye, achieved through extraorbital lacrimal gland removal, were treated with electroacupuncture. Comprehensive metrics such as the corneal mechanical perception threshold, palpebral fissure height, eyeblink frequency, eye wiping duration, behavioral changes in the open field test, and the forced swimming test were employed. Additionally, morphological changes in microglia and neurons were observed. Expression patterns of key markers, TNF-ɑ, TNFR1, p-ERK1/2, and P2X3R, in the trigeminal ganglion (TG) and spinal trigeminal nucleus caudalis (SpVc) regions, were studied with etanercept serving as a control to decipher the biochemistry of electroacupuncture’s therapeutic effects.Results: Electroacupuncture treatment demonstrated a notable decrease in the corneal mechanical perception threshold, improvement in palpebral fissure height, and significant reductions in both eyeblink frequency and eye wiping duration. Moreover, it exhibited a promising role in anxiety alleviation. Notably, the technique effectively diminished ocular pain by curbing microglial and neuronal activation in the TG and SpVc regions. Furthermore, it potently downregulated TNF-ɑ, TNFR1, p-ERK1/2, and P2X3R expression within these regions.Conclusion: Electroacupuncture attenuated damage to sensory nerve pathways, reduced pain, and eased anxiety in dry eye-afflicted rats. The findings suggest a crucial role of TNF-ɑ mediated ERK1/2/P2X3R signaling pathway inhibition by electroacupuncture in these benefits.Keywords: electroacupuncture, dry eye, ocular pain, TNF-ɑ, ERK1/2/P2X3R signaling pathway

Meirong Zhu,1,2 Tongyu Jin,1 Ding Wu,3 Shanchao Zhang,4,&ast; Aihua Wang1,4,&ast; 1Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, People’s Republic of China; 2Department of Critical Medicine, Jinan Central Hospital, Jinan, People’s Republic of China; 3Vascular Surgery, Jinan Central Hospital, Jinan, People’s Republic of China; 4Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong First Medical University, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Aihua Wang, Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, People’s Republic of China, Tel +8613791120819, Email wangah_0052@sina.com Shanchao Zhang, Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong First Medical University, Jinan, People’s Republic of China, Tel +8618678295562, Email zhangshanchao2012@163.comPurpose: Atherosclerosis (AS) is the most common cause of cardiovascular and cerebrovascular diseases. However, the mechanisms underlying atherosclerotic plaque progression remain unclear. This study aimed to investigate the genes associated with the development of atherosclerosis in the aorta of ApoE−/− male mice, which could serve as novel biomarkers and therapeutic targets in interventions to halt plaque progression.Methods: Eight-week-old ApoE−/− mice were fed a normal purified laboratory diet or a Western Diet (WD) for 6 or 22 weeks. High-throughput sequencing technology was used to analyze the transcriptomes of the aortas of four groups of mice that were exposed to different dietary conditions. We retrieved and downloaded the human Arteriosclerosis Disease Chip dataset GSE100927 from the Gene Expression Omnibus (GEO) database and selected 29 cases of carotid atherosclerotic lesions and 12 cases of normal carotid tissues as the experimental and control groups, respectively, to further verify our dataset. In addition, we used quantitative reverse transcription polymerase chain reaction (QT-PCR) to verify the expression levels of the core genes in an atherosclerosis mouse model.Results: There were 265 differentially expressed genes (DEGs) between the ApoE−/− Male mice AS22W group and Sham22W group. In addition to the well-known activation of inflammation and immune response, t the autophagy-lysosome system is also an important factor that affects the development of atherosclerosis. We identified five core genes (Atp6ap2, Atp6v0b, Atp6v0d2, Atp6v1a, and Atp6v1d) in the protein-protein interaction (PPI) network that were closely related to autophagosomes. Hub genes were highly expressed in the carotid atherosclerosis group in the GSE100927 dataset (P < 0.001). QT-PCR showed that the RNA level of Atp6v0d2 increased significantly during the development of atherosclerotic plaque in ApoE−/− male mice.Conclusion: Five core genes which affect the development of aortic atherosclerosis through the autophagy-lysosome system, especially Atp6v0d2, were screened and identified using bioinformatic techniques.Keywords: molecular mechanism, bioinformatics, core gene, lysosome, aortic plaque development

Fangzheng Cao,1,&ast; Yiqi Wang,2,&ast; Ruili Wei,3 Chunrong Li,2 Yifan Cheng,2 Yu Zhou,1 Tianyu Jin,1 Houwen Zhang,1 Luting Lin,4 Bin Xu5 1The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Neurology, Center for Rehabilitation Medicine, People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China; 3Department of Neurology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 5Department of Neurology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Xu, Department of Neurology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China, Email xubin2008.love@163.comPurpose: Neuromyelitis optica spectrum disorder (NMOSD) is a rare recurrent autoimmune disease of the central nervous system. However, to date, the peripheral blood profile of the T helper cell subsets in NMOSD remains controversial and poorly understood. This study aimed to compare the levels of helper T cell subsets in the peripheral blood from patients with NMOSD in different phases of the disease and studied their correlation with the clinical severity of the disease.Patients and methods: We used flow cytometry with cellular membrane surface staining to measure the levels of helper T cell subsets in 50 patients with NMOSD during the attack (n = 25) and remission (n = 25) phases and in 21 healthy controls.Results: Patients with NMOSD had higher levels of Th1 and Th17 cells in the attack phase compared to parallel populations in the remission phase and healthy controls. Th1/Th2 and Th17/Treg ratios were positively correlated with the severity of the disease in the attack phase of NMOSD. In contrast, Treg cell levels were negatively correlated with the severity of the disease in the attack phase in patients with NMOSD.Conclusion: The peripheral blood immune profile in NMOSD towards a Th1/Th17 cell-mediated pro-inflammatory immune response, which is associated with disease activity and severity of neuromyelitis optica spectrum disorder.Keywords: neuromyelitis optica spectrum disorder, helper T cell, flow cytometry, lymphocyte subsets

Weisheng Xu,1,2,&ast; Wangsheng Xue,1,&ast; Zeyu Zhou,3,&ast; Jiying Wang,1 Hui Qi,1 Shiyu Sun,1 Tong Jin,1 Ping Yao,1 Jian-Yuan Zhao,4 Fuqing Lin1 1Department of Pain Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China; 2School of Medicine, Tongji University, Shanghai, 200331, People’s Republic of China; 3School of Life Sciences, Fudan University, Shanghai, 200433, People’s Republic of China; 4Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200090, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fuqing Lin, Department of Pain Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China, Email fuqinglin@tongji.edu.cn Jian-Yuan Zhao, Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200090, People’s Republic of China, Email zhaojy@vip.163.comBackground: As one of the most frequent complications of type 2 diabetes mellitus (T2DM), diabetic peripheral neuropathy (DPN) shows a profound impact on 50% of patients with symptoms of neuropathic pain, numbness and other paresthesia. No valid serum biomarkers for the prediction of DPN have been identified in the clinic so far. This study is to investigate the potential serum biomarkers for DPN firstly based on 1H-Nuclear Magnetic Resonance (1H-NMR)-based metabolomics technique.Methods: Thirty-six patients enrolled in this study were divided into two groups: 18 T2DM patients without DPN (T2DM group) and 18 T2DM patients with DPN (DPN group). Serum metabolites were measured via 1H-NMR spectroscopy. Bioinformatic approaches including principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), independent sample t-test, Fisher’s test, Pearson and Spearman correlation analysis, Stepwise multiple linear regression analysis and receiver operating characteristic (ROC) curve analysis were used to identify the potential altered serum biomarkers.Results: A total of 20 metabolites were obtained and further analyzed. Formate was identified as the only potential biomarker that decreased in the DPN group with statistical significance after multiple comparisons (p< 0.05). Formate also displayed a negative relationship with some elevated clinical markers in DPN. ROC curve analysis showed a good discriminative ability for formate in DPN with an area under the curve (AUC) value of 0.981.Conclusion: Formate could be considered a potential serum metabolic biomarker for DPN. The reduced level of formate in DPN may be associated with mitochondrial dysfunction and gut microbiota alteration. Monitoring the level of serum formate would be an important strategy for the early diagnosis of DPN and a supplement of formate may be a promising treatment for DPN in the future.Keywords: diabetic peripheral neuropathy, type 2 diabetes mellitus, 1H-NMR, metabolomics, formate, uric acid

Yehong Liu,1,&ast; Jie Liu,1,&ast; Longqun Liu,2,&ast; Shaoqing Cao,1,3 Tianhui Jin,1 Liang Chen,1,3 Gangyong Wu,1,3 Gangjun Zong1,3 1Department of Cardiology, The 904th Hospital of Joint Logistic Support Force of PLA, Wuxi, Jiangsu, People’s Republic of China; 2Department of Respirology, The 904th Hospital of Joint Logistic Support Force of PLA, Wuxi, Jiangsu, People’s Republic of China; 3Department of Cardiology, Wuxi Clinical College of Anhui Medical University, Wuxi, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gangyong Wu; Gangjun Zong, Email wuwangyi520@sina.com; zonggj@163.comAim: Reducing the high morbidity and mortality of ST-segment elevation myocardial infarction (STEMI) and improving patient prognosis remains a major global challenge. This study aimed to explore whether dynamic fluctuations in biomarkers are valuable predictors of prognosis in patients with STEMI.Methods: This study included 216 patients with STEMI. Blood routine tests were performed on admission, 12 h after percutaneous coronary intervention (PCI), and at discharge. Systemic immune-inflammation index (SII), systemic inflammatory response index (SIRI), and pan-immune-inflammation-value (PIV) serum immune-inflammatory markers were calculated. The Cox proportional hazard model was used to assess the factors independently associated with the prognosis of STEMI. The optimal cutoff values for the inflammatory markers were calculated.Results: Eighty-five (39.35%) of the 216 patients had major adverse cardiovascular events (MACEs) during the 1-year follow-up. Most were male (81.18%) with a median age of 64 years (interquartile, 55– 69.5). Killip class ≥ II on admission (hazard ratio [HR], 1.859; 95% CI, 1.169– 2.957; P = 0.009), total stent length (HR, 1.016; 95% CI, 1.003– 1.029; P = 0.019), values of SIRI at 12 h after PCI (HR, 1.079; 95% CI, 1.050– 1.108; P < 0.001), and the Gensini score (HR, 1.014; 95% CI, 1.007– 1.022; P < 0.001) were independently associated with an increased risk of MACEs. Compared with SII, SIRI and PIV calculated at various time points and dynamically fluctuating changes, SIRI (cutoff value, 4.15; 95% CI, 0.701– 0.819; P < 0.001) and PIV (cutoff value, 622.71; 95% CI, 0.674– 0.796; P < 0.001) at 12 h after PCI showed the best efficacy for the prognosis of STEMI.Conclusion: Our study provides relevant evidence to the notion that SIRI or PIV at 12 h after PCI may be more accurate and economical predictors of long-term adverse prognosis in patients with STEMI.Keywords: systemic inflammatory response index, pan-immune-inflammation-value, ST-segment elevation myocardial infarction, major adverse cardiovascular events, prognosis, percutaneous coronary intervention

Mingjun Hu,1– 4 Jie Wei,1– 3 Jie Hao,1– 3 Tianbo Jin,1– 3 Bin Li1– 3 1College of Life Sciences, Northwest University, Xi’an, Shaanxi Province, People’s Republic of China; 2Provincial Key Laboratory of Biotechnology of Shaanxi, Northwest University, Xi’an, Shaanxi Province, People’s Republic of China; 3Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, Shaanxi Province, People’s Republic of China; 4Department of Neurosurgery, Xi’an Chang’an District Hospital, Xi’an, Shaanxi Province, People’s Republic of ChinaCorrespondence: Mingjun Hu, College of Life Sciences, Northwest University, &num;229, Taibai North Road, Xi’an, Shaanxi Province, 710069, People’s Republic of China, Tel +86-15339228629, Email slhmj@tom.comBackground: Glioma is the main pathological subtype of brain tumors with high mortality.Objective: This study aimed to elucidate the correlation between TREM1 variants and glioma risk in the Chinese Han population.Methods: Genotyping of six variants of TREM1 was completed by Agena MassARRAY platform in 1061 subjects (503 controls and 558 glioma patients). The relationship between TREM1 polymorphisms and glioma risk was calculated using the logistic regression model, with odds ratio (OR) and 95% confidence intervals (CIs). A multifactor dimensionality reduction (MDR) method was performed to assess SNP–SNP interactions to predict glioma risk.Results: In this research, overall analysis illustrated an association between TREM1 rs9369269 and an increased risk of glioma. Rs9369269 was also related to the risk of glioma in patients aged ≤ 40 years and females. Subjects with rs9369269 AC genotype were likely to obtain glioma compared to people with CC genotype (patients with astroglioma vs healthy people). Compared to TT genotype carriers, carriers with AT genotype of rs1351835 were significantly associated with overall survival (OS).Conclusion: Taken together, the study identified the association between TREM1 variants and glioma risk and TREM1 variants were significantly associated with the prognosis of glioma. In the future, larger samples are needed to verify the results.Keywords: glioma, TREM1, single nucleotide polymorphisms, risk

Pingyi Wang,1– 3 Hongyan Lu,1– 3 Hao Rong,1– 3 Yuhe Wang,1– 4 Li Wang,1– 3 Xue He,1– 3 Dongya Yuan,1– 3 Yongjun He,1– 3 Tianbo Jin1– 3 1Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China; 2Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China; 3School of Basic Medical Sciences, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China; 4Department of Clinical Laboratory, the Affiliated Hospital of Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of ChinaCorrespondence: Tianbo Jin; Yongjun He, Tel +86-18681940990 ; +86-18691008772, Email jintb@xzmu.edu.cn; 545139647@qq.comBackground: High altitude pulmonary edema (HAPE) is still the most common fatal disease at high altitudes. DNA methylation proceeds with an important role in HAPE progression. This study was designed to investigate the association between CYP39A1 methylation and HAPE.Methods: Peripheral blood samples were enrolled from 106 participants (53 HAPE patients and 53 healthy subjects) to study the association of CYP39A1 methylation with HAPE. DNA methylation site in the promoter region of CYP39A1 was detected by Sequenom MassARRAY EpiTYPER platform.Results: Probability analysis showed that the methylation probabilities of CYP39A1_1_CpG_5 and CYP39A1_3_CpG_21 are significant differences between the cases and controls (p< 0.05). The methylation level analysis indicated that CYP39A1_1_CpG_2.3.4, CYP39A1_5_CpG_6.7, and CYP39A1_5_CpG_9.10 were higher methylation in HAPE compared to the controls (p< 0.05). CYP39A1_3_CpG_21 and CYP39A1_4_CpG_3 exhibited a lower methylation level in HAPE than that in the controls (p< 0.05). The association analysis given that CYP39A1_1_CpG_2.3.4 (OR 2.56, p= 0.035), CYP39A1_5_CpG_6.7 (OR 3.99, p= 0.003), CYP39A1_5_CpG_9.10 (OR 3.99, p= 0.003), CYP39A1_5_CpG_16.17.18 (OR 2.53, p= 0.033), and CYP39A1_5_CpG_20 (OR 3.05, p= 0.031) are associated with an increased risk of HAPE. Whereas CYP39A1_1_CpG_5 (OR 0.33, p= 0.016) and CYP39A1_3_CpG_21 (OR 0.18, p= 0.005) have a protective role in HAPE. Besides, age-stratification analysis showed that CYP39A1_1_CpG_5 (OR 0.16, p= 0.014) and CYP39A1_3_CpG_21 (OR 0.08, p= 0.023) had a protective impact on HAPE in people aged ≤ 32 years. CYP39A1_5_CpG_6.7 (OR 6.70, p= 0.008) and CYP39A1_5_CpG_9.10 (OR 6.70, p= 0.008) were related to an increased susceptibility to HAPE aged > 32 years. Moreover, the diagnostic value of CYP39A1_3_CpG_21 (AUC = 0.712, p< 0.001) was significantly better than other CpG sites.Conclusion: The methylation level of CYP39A1 was associated with a risk of HAPE in the Chinese population, which provided new perspective for preventing and diagnosing of HAPE.Keywords: HAPE, DNA methylation, CYP39A1, CpG, the Chinese population

Xiaohui Zhang,1– 3 Da Zhen,4 Xuemei Li,1,2,5 Faling Yi,1,2,5 Zhanhao Zhang,1,2,5 Wei Yang,1,2,6 Xuguang Li,1,2,5 Yemeng Sheng,1,2,5 Xiaoli Liu,1,2,5 Tianbo Jin,1,2,5 Yongjun He1,2,5 1Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, People’s Republic of China; 2Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, People’s Republic of China; 3Department of Ultrasound, the Affiliated Hospital of Xizang Minzu University, Xianyang, People’s Republic of China; 4Department of Medical, Tibet Autonomous Region Maternity and Children’s Hospital, Lhasa, People’s Republic of China; 5School of Medicine, Xizang Minzu University, Xianyang, People’s Republic of China; 6Department of Emergency, the Affiliated Hospital of Xizang Minzu University, Xianyang, People’s Republic of ChinaCorrespondence: Tianbo Jin; Yongjun He, Xizang Minzu University, &num;6 East Wenhui Road, Xianyang, Shaanxi, 712082, People’s Republic of China, Email tianbo__jin@163.com; 545139647@qq.comBackground: Ventricular septal defect (VSD) is the most common congenital cardiac abnormality in children and the second most common in adults. This study aimed to explore the potentially causative genes in VSD patients in the Chinese Tibetan population, and to provide a theoretical basis for the genetic mechanism of VSD.Methods: Peripheral venous blood was collected from 20 VSD subjects, and whole-genome DNA was extracted. High-throughput sequencing was performed on qualified DNA samples using whole-exome sequencing (WES) technology. After filtering, detecting, and annotating qualified data, single nucleotide variations (SNVs) and insertion-deletion (InDel) markers were analyzed, and data processing software such as GATK, SIFT, Polyphen, and MutationTaster were used for comparative evaluation and prediction of pathogenic deleterious variants associated with VSD.Results: A total of 4793 variant loci, including 4168 SNVs, 557 InDels and 68 unknown loci and 2566 variant genes were obtained from 20 VSD subjects through bioinformatics analysis. According to the screening of the prediction software and database, the occurrence of VSD was predicted to be associated with five inherited pathogenic gene mutations, all of which were missense mutations, including NOTCH2 (c.1396C >A:p.Gln466Lys), ATIC (c.235C >T:p.Arg79Cys), MRI1 (c.629G >A:p.Arg210Gln), SLC6A13 (c.1138G >A:p.Gly380Arg), ATP13A2 (c.1363C >T:p.Arg455Trp).Conclusion: This study demonstrated that NOTCH2, ATIC, MRI1, SLC6A13, ATP13A2 gene variants were potentially associated with VSD in Chinese Tibetan population.Keywords: ventricular septal defect, genes, genetic variation, whole-exome sequencing

Tianyu Jin,1,&ast; Danyu Chen,2,&ast; Zhicai Chen,3 Dujin Feng,4 Manqi Zheng,5 Peng Wang,6 Chao Xu6 1Department of Neurology, The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Neurology, Tongxiang First People’s Hospital, Tongxiang, People’s Republic of China; 3Department of Neurology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, People’s Republic of China; 4Department of Laboratory, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China; 5Department of Psychiatry, The Third Hospital of Quzhou, Quzhou, People’s Republic of China; 6Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chao Xu; Peng Wang, Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College. No.158 Shangtang Road, Hangzhou, People’s Republic of China, 310014, Email raymond1202@126.com; 1979wwww@163.comBackground: We aimed to investigate the association of post-thrombolytic D-dimer elevation with symptomatic intracranial hemorrhage (sICH) and functional outcome in AIS patients receiving intravenous thrombolysis.Methods: We retrospectively reviewed our database for patients with AIS who received intravenous thrombolysis between August 2018 and December 2021. ΔD-dimer was calculated as follow-up D-dimer minus baseline D-dimer. Poor functional outcome was defined as 3 months modified Rankin score (mRS) 3– 6. sICH was defined as cerebral hemorrhagic transformation in combination with clinical deterioration of National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 points at 24 hours. Binary logistic regression analysis was used to investigate the association of post-thrombolytic D-dimer parameters with sICH and poor functional outcome. The receiver operating characteristic (ROC) curve derived optimal cut-off of different D-dimer parameters was determined at the maximal Youden’s Index.Results: A total of 325 patients were finally included. After controlling for clinical variables, follow-up D-dimer level (OR 1.230; 95% CI 1.119 to 1.351; P < 0.001) and ΔD-dimer (OR 1.347; 95% CI 1.165 to 1.559; P < 0.001) were independently associated with poor functional outcome. Additionally, follow-up D-dimer level (OR 1.095; 95% CI 1.009 to 1.188; P = 0.030) was independently related to sICH. The optimal cut-off value of follow-up D-dimer level for predicting sICH was 4185 μg/L (area under the curve 0.760; sensitivity 76.0%; specificity 81.3%); and the optimal cut-off value of follow-up D-dimer level and ΔD-dimer as a predictor for poor functional outcome was projected to be 3838 μg/L and 2190 μg/L, which yielded a sensitivity and a specificity of 62.3%, 84.5% and 73.8%, 85.2%, respectively.Conclusion: Elevated follow-up D-dimer levels are associated with sICH and poor functional outcome in AIS patients following intravenous rt-PA. Moreover, post-thrombolytic D-dimer elevation, measured by ΔD-dimer, was a better predictive biomarker for long-term outcome at 3 months.Keywords: acute ischemic stroke, D-dimer, intravenous thrombolysis, hemorrhagic transformation, outcome

Hongliang Zhang,1 Jie Gao,1 Wenxiang Fang,1 Yujie Tang,1 Xuan Fang,1 Tengchuan Jin,2 Jinhui Tao1 1Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, People’s Republic of China; 2Laboratory of Structural Immunology, CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, People’s Republic of ChinaCorrespondence: Jinhui Tao; Tengchuan Jin, Email taojinhui@ustc.edu.cn; jint@ustc.edu.cnObjective: To determine the role of nerve injury-induced protein 1 (NINJ1) introduced plasma membrane rupture (PMR) and damage-associated molecular patterns (DAMPs) release in the pathogenesis and progression of gout and to explore the potential of NINJ1 as a therapeutic target in gout.Methods: Both peripheral blood mononuclear cells (PBMCs) and serum sample from gout patients (n = 58) and healthy controls (n = 16) were collected and processed to NINJ1 expression, lactate dehydrogenase (LDH) detection, NINJ1 inhibition, and NINJ1 expression experiments, respectively. NINJ1 knockdown was carried out by lentivirus in a monosodium urate (MSU) induced rat model, and NINJ1 neutralizing antibody was applied in a MSU induced mouse model.Results: Our results found that NINJ1 was upregulated during a gout flare, and the resulting induction of PMR correlated with gout progression. NINJ1 knockdown significantly reduced the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and joint swelling in the rat model, and NINJ1 neutralizing antibody also significantly reduced gout flare in the mouse model and PBMCs. Moreover, NINJ1 expression is under NLRP3 inflammasome produced interleukin (IL)-1β control.Conclusion: These results support the notion of a pathogenic role of NINJ1 introduced PMR in gout and provide a detailed mechanism for gout pathogenesis involving inflammatory cell death and DAMPs release introduced by IL-1β. In addition, targeting NINJ1 might be a potential therapeutic approach for gout.Keywords: gout arthritis, NINJ1, NLRP3 inflammasome, plasma membrane rupture, therapeutic target

Wei Yang,1– 3 Xue He,1,2 Yuying Yao,2 Hongyan Lu,2 Yuliang Wang,2 Zhanhao Zhang,2 Yuhe Wang,1,2,4 Li Wang,1,2 Yongjun He,1,2 Dongya Yuan,1,2 Tianbo Jin1,2 1Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, 712082, People’s Republic of China; 2School of Basic Medical Sciences, Xizang Minzu University, Xianyang, Shaanxi, 712082, People’s Republic of China; 3Department of Emergency, The Affiliated Hospital of Xizang Minzu University, Xianyang, Shaanxi, 712082, People’s Republic of China; 4Department of Clinical Laboratory, The Affiliated Hospital of Xizang Minzu University, Xianyang, Shaanxi, 712082, People’s Republic of ChinaCorrespondence: Tianbo Jin, Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6 East Wenhui Road, Xianyang, Shaanxi, 712082, People’s Republic of China, Tel/Fax +86-29-88895902, Email tianbo__jin@163.comBackground: Hematological characteristics have positive reference value as clinical indicators in the evaluation of various diseases. The purpose of this study was to determine the gene loci associated with 20 hematological phenotypes in the Han population from northwest China.Methods: A genome-wide association study (GWAS) was conducted on hematological indicators of 1005 Han people from northwest China. Genotyping was performed with a GeneTitan multichannel instrument and Axiom Analysis Suite 6.0. Using the 1000 Genomes Project (phase 3) as a reference, haplotype imputation was performed with IMPUTE2. SNVs (single nucleotide variants) significantly associated with hematological phenotypes were identified. The top SNV (p < 5E-7) was then selected for replication detection.Results: Ninety genetic variations identified in the GWAS were significantly associated with hematological indicators. Among them, only rs35289401 (CCDC157) was significantly associated (genome-wide) with red blood cell distribution width (RDW) (p = 4.21E-08). The fourteen top SNVs were selected for replication verification and were significantly associated with hematological phenotypes. However, only HBS1 L-MYB rs1331309 was significantly associated with the mean hemoglobin content (p = 6.42E-07). We also found that the mean corpuscular hemoglobin (MCH) level in the rs1331309 GG/GT genotype was significantly higher than that in the TT genotype (p = 0.023).Conclusion: The GWAS identified a total of 90 genetic variants significantly associated with hematological phenotypic indicators. In particular, rs1331309 (HBS1 L-MYB) is expected to be a biomarker for monitoring the dynamics of MCH levels. This study provides a reference for related studies on the genetic structure of hematological characteristics. It provides a valuable reference for the clinical diagnosis or prediction of a variety of diseases.Keywords: hematological, GWAS, hematological phenotype, MCH, Han population from northwest China

Hylemariam Mihiretie Mengist,1 John Arnaud Kombe Kombe,2 Tengchuan Jin2,3 1Department of Obstetrics and Gynecology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China; 2Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China; 3CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Science, Shanghai, 200031, People’s Republic of ChinaCorrespondence: Tengchuan Jin, Email jint@ustc.edu.cnAbstract: The currently circulating SARS-CoV-2 Omicron variant posed a big challenge for the ongoing pandemic prevention and control activities. The critical concern is whether the current vaccines and therapeutics are capable of fully controlling this variant. Omicron has several mutations mainly concentrated in the receptor-binding domain (RBD) which is the main target for neutralizing antibodies and vaccine-elicited sera, and it is reportedly evading immunity. However, the degree to which the Omicron evades immunity and its impact on the prevention and control activities requires recent and continuous scrutiny. Despite several reports are available, updated and recent discussions are important to tackle the ongoing pandemic especially due to the emerging SARS-CoV-2 variants. Therefore, new insights on designing effective preventive and control measures is utmost important. This review discusses the extent of immune evasion by the Omicron variant and forwards important directions which could have valuable contributions to design alternative strategies in fighting against SARS-Co-2 variants.Keywords: SARSC-CoV-2, variant of concern, VOC, Omicron variant, immune evasion, receptor-binding domain, RBD

Jian Zhuo,1 Yingchun Wu,2 Wei Li,1 Zerong Li,1 Yipeng Ding,3 Tianbo Jin4,5 1Department of Emergency Service, People’s Hospital of Wanning, Wanning, Hainan, 571500, People’s Republic of China; 2Department of Intensive Care Unit, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan, People’s Republic of China; 3Department of General Practice, Hainan General Hospital, Hainan affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan, People’s Republic of China; 4Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi‘an, Shaanxi, 710069, People’s Republic of China; 5Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, People’s Republic of ChinaCorrespondence: Yipeng Ding, Department of General Practice, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, No. 19, Xinhua Road, Xiuying District, Haikou, 570311, Hainan, People’s Republic of China, Tel +86-18976335858, Email ypding@yeah.net Tianbo Jin, Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, #229 Taibai North Road, Xi’an, 710069, Shaanxi, People’s Republic of China, Tel/Fax +86-29-88895902, Email tianbo__jin@163.comBackground: The pathological basis of coronary heart disease (CHD) is atherosclerosis. BTNL2 can inhibit the activation of T cells. We aimed to explore the association between BTNL2 genetic variants and CHD risk in the southern Chinese Han population.Methods: We recruited 1419 participants to perform an association analysis between missense variants in BTNL2 and CHD risk through SNPStats online software. Genotyping of all candidate SNPs were completed by the Agena MassARRAY. In addition, we used false-positive report probability analysis to detect whether the positive findings were noteworthy observations. We also used Haploview 4.2 software and SNPStats online software to conduct the haplotype analysis and analysis of linkage disequilibrium (LD). Finally, the interaction of SNP-SNP in CHD risk was evaluated by multi-factor dimensionality reduction (MDR).Results: The results showed that BTNL2-rs35624343, -rs117896888, -rs41441651, -rs41417449, -rs28362680 and -rs2076523 were significantly associated with the CHD susceptibility. Especially for BTNL2-rs28362680, the allele A (OR = 0.68, p < 0.0001), genotype AA (OR = 0.40, p = 0.001) or GA (OR = 0.68, p < 0.0001) were associated with the reducing CHD risk. And -rs28362680 significantly reduced the CHD risk under all genetic models (dominant: OR = 0.64, p < 0.0001; recessive: OR = 0.47, p = 0.003; overdominant: OR = 0.73, p = 0.004; log-additive: OR = 0.66, p < 0.0001). And -rs28362680 was also closely associated with CHD risk reduction in all stratified analyses (age, gender, smoking, drinking, hypertension and diabetes). In addition, haplotype analysis showed that the “Crs117896888Crs41441651Trs41417449Ars28362680” (OR = 0.65, p < 0.0001) and “Grs117896888Trs41441651Crs41417449Ars28362680” (OR = 0.68, p = 0.013) may reduce CHD risk.Conclusion: Missense variants (rs35624343, rs117896888, rs41441651, rs41417449, rs28362680, rs2076523) may be protective factors for the CHD risk. In particular, there were sufficient evidences that BTNL2-rs28362680 can protective CHD risk.Keywords: coronary heart disease, BTNL2, missense variants, southern Chinese Han population

Sunghwan Ji,1 Ji Yeon Baek,2 Taeyang Jin,1 Eunju Lee,2 Il-Young Jang,2 Hee-Won Jung2 1Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2Division of Geriatrics, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaCorrespondence: Ji Yeon Baek, Division of Geriatrics, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea, Tel +82-2-3010-0020, Email complete_flow@naver.comPurpose: Although the association between a single assessment of frailty index (FI) and clinical outcomes has been revealed in prior studies, there is a lack of knowledge about the prognostic value of FI at different time points and the changes in repeated measurements of FI. Hence, we sought to determine the clinically meaningful changes in FI and reveal the association with the changes and a composite outcome of mortality and institutionalization.Participants and Methods: This study was based on a longitudinal study of the Pyeongchang Rural Area cohort that included people aged 65 years or older, ambulatory and living at home. Individuals were divided into the worsened group (changes in FI ≥ 0.03 during 2 years) and the stable group (changes in FI < 0.03 during 2 years). The incidence of a composite outcome was compared between the two groups and the relationship was adjusted for age, sex, baseline FI, and follow-up FI.Results: Of the 953 participants, 403 (42.3%) and 550 (57.7%) were included in the worsened group and the stable group, respectively. The worsened group had a significantly higher risk of the composite outcome than the stable group (HR, 2.37 [95% CI, 1.54– 3.67]; p < 0.001). Although the higher risk remained significant after adjusting for age, sex, and baseline FI, the statistical significance disappeared after adjusting for follow-up FI (p = 0.614). The aggravation of FI in the worsened group was predominantly due to aggravation of FI domains, such as activities in daily living, cognitive function and mood, and mobility rather than comorbidity burden.Conclusion: Aggravation of FI was associated with a composite outcome regardless of baseline FI, and the association was significantly reflected in the follow-up measurement of FI. The worsening FI was mainly attributable to functional geriatric domains.Keywords: frailty index, changes in frailty index, mortality, geriatric domains

Han Cen,1– 3 Qin-Wen Wen,4 Han-Qing Zhang,4 Hang Yu,4 Zhen Zeng,2 Ting Jin,2 Ting-Hui Wang,4 Wen Qin,4 Hua Huang,4 Xiu-Di Wu4 1Institute of Geriatrics, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang, People’s Republic of China; 2Department of Preventive Medicine, Medical School of Ningbo University, Ningbo, Zhejiang, People’s Republic of China; 3Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, People’s Republic of China; 4Department of Rheumatology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, Ningbo, Zhejiang, People’s Republic of ChinaCorrespondence: Xiu-Di Wu, Department of Rheumatology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, 59 Liuting Road, Ningbo, Zhejiang, 315010, People’s Republic of China, Tel +86 574 87085588, Fax +86 574 87291583, Email awu1100@aliyun.comPurpose: To investigate the associations between genetic polymorphisms within transporter genes and clinical response to methotrexate (MTX) in Chinese rheumatoid arthritis (RA) patients.Patients and Methods: A total of 100 RA patients receiving MTX were prospectively followed up for approximately 3 months to determine the clinical response based on several criteria, including European League Against Rheumatism (EULAR) good and moderate response, disease activity score in 28 joint counts – erythrocyte sedimentation rate (DAS28-ESR) low disease activity (LDA), change in DAS28-ESR (ΔDAS28-ESR) and ΔDAS28-ESR > 0.6. Fifty-four single nucleotide polymorphisms (SNPs) within seven transporter genes, including SLC19A1, ABCB1, ABCC1∼ 4 and ABCG2, were genotyped.Results: Multivariable analysis revealed that SLC19A1 rs12659 and rs3788200, ABCC2 rs3740066, rs4148396 and rs717620 were significantly associated with EULAR good and moderate response, and ABCC2 rs3740066 and rs717620 were significantly associated with DAS28-ESR LDA, and ABCB1 rs1128503, rs4148737 and ABCC3 rs2277624, rs4148416 were significantly associated with ΔDAS28-ESR. Moreover, 12 genetic polymorphisms were found to be significantly associated with ΔDAS28-ESR > 0.6. With adjustment for corresponding confounders, SLC19A1 TGAA haplotype consisting of rs1051266, rs1131596, rs12659 and rs3788200 was significantly associated with EULAR good and moderate response and ΔDAS28-ESR > 0.6 compared with the most common haplotype CAGG. The ABCC2 haplotype TTT composed of rs717620, rs4148396 and rs3740066 was significantly associated with EULAR good and moderate response and ΔDAS28-ESR > 0.6 compared with the most common haplotype CCC.Conclusion: Our results highlight the potential of genetic polymorphisms within transporter genes, particularly SLC19A1 and ABCC2, as predictors of clinical response to MTX in Chinese RA patients.Keywords: rheumatoid arthritis, methotrexate, transporter, single-nucleotide polymorphism, clinical response

Can Hao &ast;, Bingjie Ma &ast;, Nan Gao, Tian Jin, Xiaoming Liu Pain Management Center, Shanghai Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 210092, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoming Liu, Pain Management Center, Shanghai Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665# Kongjiang Road, Shanghai, 210092, People’s Republic of China, Tel +86-17721213706, Fax +86-21-25078707, Email brightlxm@gmail.comPurpose: Recent studies showed promotion of astrocyte autophagy in the spinal cord would provide analgesic effects. Silent information regulator T1 (SIRT1) and α subunit of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1α) are two master regulators of endogenous antioxidant defense and mitochondrial biogenesis. They play vital roles in both autophagy and neuropathic pain (NP). Our previous study showed that TSPO agonist Ro5-4864 elicited potent analgesic effects against NP, but the mechanisms remain unclear. This study aims to investigate the effects of TSPO agonist Ro5-4864 on autophagy and nuclear SIRT1/PGC-1α signaling in spinal dorsal horn.Methods: A rat model of L5 spinal nerve ligation (SNL) was adopted. Rats were randomly assigned to the Sham group, the SNL group, the Ro (TSPO agonist Ro5-4864) group and the Ro+3-MA group. The behavior assessments were conducted at baseline, on Day 1, 3, 7 and 14 after SNL. The autophagy-related proteins (ATG7, Beclin1, LC3, and P62) in spinal dorsal horn were assayed and the nuclear SIRT1/PGC-1α and downstream factors were analyzed.Results: Ro5-4864 alleviated the mechanical allodynia induced by SNL (P < 0.01 vs the SNL group), which could be totally abrogated by autophagy inhibitor 3-MA (P < 0.01 vs the Ro group). SNL induced elevated ATG7 (P < 0.01), Beclin1 (P < 0.01) and LC3-II/LC3-I (P < 0.01) contents and P62 accumulation (P < 0.01) on Day 7 and Day 14, which suggested an autophagy flux impairment. Ro5-4864 augmented ATG7 (P < 0.01), Beclin1 (P < 0.01) and LC3-II/LC3-I (P < 0.05) with decreased P62 (P < 0.01), which indicated a more fluent autophagic process. These effects were also totally abrogated by 3-MA (P < 0.01). Furthermore, Ro5-4864 activated the spinal nuclear SIRT1/PGC-1α signaling pathway.Conclusion: TSPO improved both autophagy impairment and mitochondrial biogenesis, which may provide a new strategy for the treatment of NP.Keywords: translocator protein, TSPO, neuropathic pain, autophagy, silent information regulator T1, SIRT1, α subunit of peroxisome proliferator-activated receptor-γ coactivator-1, PGC-1&#x03B1

Yuliang Wang,1– 3 Linna Peng,1– 3 Hongyan Lu,1– 3 Zhanhao Zhang,1– 3 Shishi Xing,1– 3 Dandan Li,1– 3 Chunjuan He,1– 3 Tianbo Jin,1– 3 Li Wang1– 3 1Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, 712082, Shaanxi, People’s Republic of China; 2Engineering Research Center of Tibetan Medicine Detection Technology, Ministry of Education, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, 712082, People’s Republic of China; 3Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, 712082, People’s Republic of ChinaCorrespondence: Li Wang Tel +86-15706028826Email wangli_xzmd@163.comBackground: We aimed to enrich the pharmacogenomic information of a Blang population (BP) from Yunnan Province in China.Methods: We genotyped 55 very important pharmacogene (VIP) variants from the PharmGKB database and compared their genotype distribution (GD) in a BP with that of 26 populations by the χ2 test. The minor allele frequency (MAF) distribution of seven significantly different single-nucleotide polymorphisms (SNPs) was conducted to compare the difference between the BP and 26 other populations.Results: Compared with the GD of 55 loci in the BP, among 26 studied populations, GWD, YRI, GIH, ESN, MSL, TSI, PJL, ACB, FIN and IBS were the top-10 populations, which showed a significantly different GD > 35 loci. CHB, JPT, CDX, CHS, and KHV populations had a significantly different GD < 20 loci. A GD difference of 27– 34 loci was found between the BP and 11 populations (LWK, CEU, ITU, STU, PUR, CLM, GBR, ASW, BEB, MXL and PEL). The GD of five loci (rs750155 (SULT1A1), rs4291 (ACE), rs1051298 (SLC19A1), rs1131596 (SLC19A1) and rs1051296 (SLC19A1)) were the most significantly different in the BP as compared with that of the other 26 populations. The genotype frequency of rs1800764 (ACE) and rs1065852 (CYP2D6) was different in all populations except for PEL and LWK, respectively. MAFs of rs1065852 (CYP2D6) and rs750155 (SULT1A1) showed the largest fluctuation between the BP and SAS, EUR, AFR and AMR populations.Conclusion: Our data can provide theoretical guidance for safe and efficacious personalized drug use in the Blang population.Keywords: Blang population, single-nucleotide polymorphism, SNP, very important pharmacogene, genotype distribution, pharmacogenomics, personalized drug use

Yinfeng Liu,1,2 Jun Hao,3 Guanli Yuan,4 Mengyu Wei,1 Yuhui Bu,1 Tingting Jin,3 Li Ma1 1Department of Breast Disease Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 2Department of Breast Surgery, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, People’s Republic of China; 3Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, People’s Republic of ChinaCorrespondence: Li MaDepartment of Breast Disease Center, The Fourth Hospital of Hebei Medical University, No. 169, Tianshan Street, Shijiazhuang, Hebei, 050000, People’s Republic of ChinaTel +86 -0311-66696348Email mali1021@126.comBackground: Circadian clock genes play a crucial role in physiological and pathological processes, and their aberrant expressions were involved in various human cancers. The objective of this study was to investigate the expression level of Period circadian regulator 1 (PER1), an important circadian clock gene, and its biological roles in the development and progression of breast cancer.Methods: The expression level of PER1 in breast cancer samples was analyzed using the Oncomine database, and the correlation between PER1 expression and clinicopathologic parameters was assessed by bc-GenExMiner v4.5. In addition, Kaplan–Meier plotter database was used to determine the prognostic significance of PER1 expression for breast cancer patients. The expressions of PER1 in breast cancer tissues and cells were validated by Western blot. The loss-or-gain assay of PER1 was conducted to investigate the effects of its expression on cell proliferation, migration and invasion of breast cancer. The relationship between PER1 expression and epigenetic modifications was further explored by Western blot.Results: The results of the bioinformatics analysis revealed that the expression level of PER1 was markedly reduced in breast cancer tissues (P< 0.001), and patients with high expression of PER1 had a better overall survival (HR:0.78, 95% CI:0.63– 0.97, P=0.026) and recurrence-free survival (HR:0.83, 95% CI:0.75– 0.93, P=0.001) than those with low expression. The assay of gene loss-or-gain indicated that downregulation of PER1 expression markedly promoted cell proliferation, migration and invasion (P< 0.05), whereas these malignant phenotypes of breast cancer cells were inhibited by PER1 overexpression (P< 0.05). Further studies showed that trichostatin A (TSA), a histone deacetylase inhibitor, induced the expression of PER1 protein in breast cancer cells (P< 0.05).Conclusion: PER1 functions as a tumor suppressor in the development and progression of breast cancer, and its expression silencing might be regulated by epigenetic modifications.Keywords: breast cancer, circadian clock gene, Period circadian regulator 1, PER1, tumor suppressor

Cuixiao Shi,1 Dongmei Lv,1 Kai Zhou,1 Tengchuan Jin,2 Gang Wang,3 Bo Wang,1 Yajuan Li,1 Yuanhong Xu1 1Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 2Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, People’s Republic of China; 3The Second Hospital of Anhui Medical University, Hefei, 230601, People’s Republic of ChinaCorrespondence: Yuanhong Xu; Yajuan LiDepartment of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, People’s Republic of ChinaEmail xyhong1964@163.com; liyajuan@ahmu.edu.cnBackground: Human listeriosis is a severe foodborne infection caused by Listeria monocytogenes and the data of patients with this infection are largely limited for the Hefei population.Purpose: This is a retrospective study that evaluated the clinical and laboratory data of patients with listeriosis at a tertiary hospital in Hefei City.Patients and Methods: A total of 24 listeriosis patients were admitted to the First Affiliated Hospital of Anhui Medical University from January 2003 to July 2021. Data from all patients were collected from the hospital’s electronic medical records.Results: The most common symptom of all patients was fever (91.7%), followed by altered consciousness (50.0%), rashes (45.8%), respiratory distress symptoms (37.5%), nuchal rigidity (29.2%), and headaches (20.8%). Laboratory results also indicated elevated C-reactive protein (CRP) (79.1%), hypoproteinemia (75.0%), anemia (62.5%), leukocytosis (45.8%), and neutrophilia (45.8%). The mean value of 5.1 μg/mL (SD, 3.8) for D‐dimer (D‐D) was significantly higher than the normal value ((0.00– 0.50) μg/mL), while both altered consciousness (6 vs 4, P = 0.034) and headaches (4 vs 1, P = 0.036) occurred more frequently in the neurolisteriosis group compared with the bacteremia one. Additionally, the mean maximal body temperature (°C) (40.5 ± 0.7) as well as white blood cell (WBC) (15.3 vs 7.5 × 109/L, P = 0.014) and neutrophil (NEUT#) (13.2 vs 6.1 × 109/L, P = 0.026) counts of neurolisteriosis patients were higher than those of bacteremia (39.4 ± 0.4) (P = 0.001). Of all patients, four (50%) from the maternal-neonatal group remained uncured.Conclusion: Listeriosis is a rare disease with extremely variable clinical characteristics in Hefei City. Our data indicated that unexplained fever, altered consciousness, hypoproteinemia, anemia, elevated CRP and DD should be considered to assist diagnosis of listeriosis for early treatment interventions.Keywords: Listeria monocytogenes, listeriosis, clinical and laboratory characteristics

Peijing Li,1,2,&ast; Qun Zhang,3,&ast; Donghua Luo,4– 6 Feng Jiang,1,2 Qifeng Jin,1,2 Yonghong Hua,1,2 Ting Jin,1,2 Xiaozhong Chen1,2 1Department of Radiation Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310000, People’s Republic of China; 2Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, 310000, People’s Republic of China; 3Department of Radiation Oncology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China; 4Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 5State Key Laboratory of Oncology in South China, Guangzhou, 510060, People’s Republic of China; 6Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaozhong Chen; Ting JinDepartment of Radiation Oncology, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, 310022 Email chenxiaozhong2016@163.com; jinting22222@163.comPurpose: Patients with T3-4N0M0 nasopharyngeal carcinoma (NPC) are a unique subgroup of locoregional advanced NPC, which generally have a better prognosis than others and are often excluded in most randomized controlled clinical trials focusing on locoregional advanced NPC. The management of this population is still controversial. This study aims to evaluate the outcomes of T3-4N0M0 NPC patients treated with sequential induction chemotherapy and concurrent chemoradiotherapy (IC+CCRT) or chemoradiotherapy (CCRT) alone.Patients and Methods: We included 362 patients diagnosed with T3-4N0M0 NPC from two hospitals between December 2005 and December 2014. All patients were received IC + CCRT (n=146) or CCRT (n=216). Locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were retrospectively estimated.Results: The median follow-up was 95 (range: 11– 168) months. Univariable analyses have shown that 5-year LRFFS, DFS and OS in the IC+CCRT group and the CCRT group were 87.4% vs 93.4% (P = 0.035), 80.4% vs 87.0% (P = 0.047) and 86.3% vs 93.0% (P = 0.040). Multivariate analyses demonstrated that only the T stage was the independent prognostic factor for LRFFS, DFS, and OS in the entire group analysis. Subgroup analysis revealed that patients with T3 tumors who received IC+CCRT had significantly lower LRFFS, DFS, and OS than those treated with CCRT. For T4 patients, the outcomes had no significant difference between the two groups.Conclusion: This retrospective study showed that T3N0M0 patients who received CCRT had better prognosis than those treated with IC+CCRT. In terms of T4N0M0 disease, treatment outcomes are similar in both treatment groups. However, these results require further confirmation of large sample size, prospectively, randomized controlled trials.Keywords: nasopharyngeal carcinoma, chemotherapy, intensity-modulated radiation therapy

Chunjuan He,1 Linna Peng,1 Shishi Xing,1 Dandan Li,1 Li Wang,1 Tianbo Jin1,2 1Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, 712082, People’s Republic of China; 2Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, Xizang Minzu University, Xianyang, Shaanxi, 712082, People’s Republic of ChinaCorrespondence: Tianbo JinKey Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6, Wenhui East Road, Xianyang, 712082, Shaanxi, People’s Republic of ChinaTel/Fax +86-29-88895902Email jintianbo@gmail.comBackground: Genetic variation influences drug reaction or adverse prognosis. The purpose of this research was to genotype very important pharmacogenetic (VIP) variants in the Tibetan population.Methods and Materials: Blood samples from 200 Tibetans were randomly collected and 59 VIP variants were genotyped, and then compared our data to 26 other populations in the 1000 project to further analyze and identify significant difference.Results: The results showed that on comparing with most of the 26 populations from the 1000 project, rs4291 (ACE), rs1051296 (SLC19A1) and rs1065852 (CYP2D6) significantly differed in the Tibetan population. Furthermore, three significant loci were related to drug response. In addition, the allele frequency of Tibetans least differed from that of East Asian populations, and most differed from that of Americans.Conclusion: Three significant loci of variation ACE rs4291, SLC19A1 rs1051296 and CYP2D6 rs1065852 were associated with drug response. This result will contribute to improving the information of the Tibetan in the pharmacogenomics database, and providing a theoretical basis for clinical individualised drug use in Tibetans.Keywords: the Tibetan population, pharmacogenomics, VIP variants

Da Wang,1,&ast; Chao Chen,1,&ast; Xiaoxu Ge,1,2 Qi Yang,2 Yuhuai Huang,1 Tianyi Ling,1 Tian Jin,1 Shaojun Yu,1 Jian Wang,1 Lifeng Sun1 1Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China; 2Department of Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Da Wang; Lifeng SunDepartment of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of ChinaTel +86-571-87784720; +86-571-87783586Email wangda0618@zju.edu.cn; sunlifeng@zju.edu.cnPurpose: This study aimed to analyze clinicopathological, survival, prognostic factors, as well as the timing of brain metastases (BM) in colorectal cancer (CRC) using data from a Chinese center.Patients and Methods: Data of 65 consecutive CRC patients with BM were collected from a single institution in China. The time from primary tumor surgery to the occurrence of BM was calculated. Kaplan-Meier analysis was used to evaluate cumulative survival of patients. Factors associated with prognosis of overall survival (OS) were explored using Cox’s proportional hazard regression models.Results: The median time interval from CRC surgery to the diagnosis of BM was 24 months. After diagnosis of BM, median OS values for patients were 11 months. Extracranial metastases occurred in 45 cases (69.2%) when BM was diagnosed, and 58.5% of these patients with lung metastases Time of BMs (P=0.018), presence of extracranial metastases (P=0.033), treatment (P=0.003), CA199 (P=0.034), CA125 (P< 0.001), CA242 (P=0.018), and CA211 (P=0.012) were associated with OS of patients through univariate analysis. Multivariate analysis using a Cox regression model showed that only treatment was an independent predictor for OS (conservative treatment; HR=1.861, 95% CI=1.077– 3.441; P=0.048).Conclusion: Surgical treatment of metastatic lesions may be an alternative choice for CRC patients with BM. Identifying the timing of brain metastases can help to detect this disease early, leading to a better survival outcome.Keywords: colorectal cancer, brain metastases, prognosis factors, surgery

Cuixiao Shi,1 Lianzi Wang,1 Dongmei Lv,1 Gang Wang,1 Hylemariam Mihiretie Mengist,2 Tengchuan Jin,2 Bo Wang,1 Ying Huang,1 Yajuan Li,1 Yuanhong Xu1 1Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 2Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, People’s Republic of ChinaCorrespondence: Yuanhong Xu; Yajuan Li Email xyhong1964@163.com; liyajuan@ahmu.edu.cnBackground: Brucellosis is currently one of the most widespread zoonotic diseases caused by Brucella genus, and the Brucella melitensis is the major pathogen. The number of people infected with Brucella has gradually increased in Anhui Province.Purpose: To retrospectively evaluate the epidemiological, clinical, and laboratory data of brucellosis patients in Anhui Province.Patients and Methods: A total of 109 brucellosis patients were admitted to the First Affiliated Hospital of Anhui Medical University from January 2012 to March 2021. Data from all patients were retrieved from the hospital’s electronic medical system. The final results were grouped and compared according to the presence or absence of bacteremic brucellosis and three phases of brucellosis.Results: The most common symptoms among all 109 brucellosis patients were fever (89.0%), followed by chills (52.3%), arthralgia (48.6%), and weight loss (30.3%), and laboratory results presented with anemia (65.1%), elevate of C-reactive protein (CRP) (91.7%), erythrocyte sedimentation rate (ESR) (86.2%), aspartate aminotransferase (AST) (40.4%), and lactate dehydrogenase (LDH) (43.1%). The percentage of fever (96.1%), arthralgia (58.8%), anorexia (35.3%), leukopenia (31.4%), and the AST (51.0%) were higher in bacteremic than nonbacteremic group. Additionally, the median level of LDH (332.0 mg/L, IQR, 209.0– 553.0) was higher in bacteremic than nonbacteremic group. Nevertheless, the albumin (36.0 mg/L, IQR, 33.9– 38.2) was lower in the bacteremic group. The percentage of fever (94.9%) and the median LDH level (316.0 U/L (IQR,218.0– 517.5)) in the acute phase of brucellosis were higher than the percentage of fever (72.0%) and the median LDH level (209.0 U/L (IQR,162.0– 276.0)) in the subacute phase of brucellosis.Conclusion: Brucellosis has become an important public health issue in Anhui Province. Brucellosis is a disease with diverse clinical manifestations. Our data showed that unexplained fever, arthralgia, and elevated AST and LDH should be considered as a diagnosis of bacteremia brucellosis for early treatment intervention.Keywords: Brucella melitensis, brucellosis, bacteremia, epidemiological, clinical and laboratory features