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Wenyan Dong,1,* Mengshuang Xie,2,* Chunjie Ming,3 Haijun Li,2 Xia Xu,2 Liwei Cui,4 Wei Wang,5 Yi Li6 1Department of General Practice, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Geriatric Medicine, Laboratory of Gerontology and Anti-aging Research, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 3National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 5Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 6Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Wang; Yi Li, Email styw28@163.com; 202062009073@email.sdu.edu.cnPurpose: Airway disease is the main pathological basis of chronic obstructive pulmonary disease (COPD), but the underlying mechanisms are unknown. Bone morphogenetic protein-7 (BMP7) is a multi-functional growth factor that belongs to the transforming growth factor superfamily, which affects the regulation of proliferation, differentiation, and apoptosis. Previous research has shown that BMP7 is highly expressed in the airway epithelia of patients with COPD, but its role in airway disease has not been fully elucidated.Methods: A lung tissue cohort and a sputum cohort were included in the study. BMP7 expression in the airway epithelium and the BMP7 level in sputum supernatants were detected. Human primary bronchial epithelial cells (HPBECs) were isolated by bronchoscopy from healthy individuals. The functional consequences of adding recombinant human BMP7 or BMP7 overexpression to HPBECs were explored.Results: BMP7 expression in bronchial epithelial cells of patients with COPD was significantly higher than that in smoking and nonsmoking controls. The expression of BMP7 in the bronchial epithelia of patients with COPD was negatively correlated with the airway counts measured by quantitative computed tomography, positively correlated with airway wall thickness, and negatively correlated with FEV1. The BMP7 level in the induced sputum of patients with COPD was higher than that in controls, and was related to the levels of interleukin-6 (IL-6), IL-8, and IL-1β. The addition of rhBMP7 (100 ng/mL) inhibited the proliferation of HPBECs and promoted squamous metaplasia and inhibit ciliated cell differentiation in human bronchial epithelial cells. BMP7 overexpression promotes apoptosis in human bronchial epithelial cells, through regulating MKK7/JNK2 signaling pathway and activating the caspase-3 pathway.Conclusion: High expression of BMP7 in the bronchial epithelia may play a crucial role in airway disease of COPD through inhibiting proliferation and promoting abnormal differentiation and excessive apoptosis of human bronchial epithelial cells.Keywords: COPD, BMP7, airway disease, remodeling, apoptosis

Chang Jiang,1,2 Maichao Li,1,2 Ying Chen,3 Yuwei He,1,2 Xinde Li,1,2 Lingling Cui,1,2 Han Qi,1,2 Zan Cheng,1,2 Xiaoqing Zhang,3 Changgui Li,1– 3 Jie Lu1– 3 1Shandong Provincial Clinical Research Center for Immune Diseases and Gout, Qingdao, People’s Republic of China; 2Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 3Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of ChinaCorrespondence: Jie Lu, Shandong Provincial Clinical Research Center for Immune Diseases and Gout, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, People’s Republic of China, 266003, Email 13127006046@163.comPurpose: Previous studies have linked high-density lipoprotein cholesterol (HDL-C) to gout, but little is known about the dose-effect relationship between serum HDL-C levels and gout flares. This study aimed to quantify the association between the two during urate-lowering therapy initiation and develop a regression equation to predict gout flares.Patients and Methods: We conducted a prospective, observational, single-center cohort study of men with gout. Patients were identified and grouped according to the level of serum HDL-C (1.16 mmol/L) at baseline and followed-up every four weeks until 12 weeks.Results: A total of 394 participants completed the study (203 in the low HDL-C group; 191 in the high HDL-C group). The proportion of participants with gout flares in the low HDL-C group was significantly higher than in the high HDL-C group after 12 weeks follow-up (52.2% versus 35.6%, P=0.001). Patients with lower serum HDL-C level had higher risk of gout flares analyzed by restricted cubic spline and when serum HDL-C level = 1.15mmol/L, flareHR = 1. When combined with well-known risk factors, serum HDL-C predicted gout flares with an area under curve (AUC) of 0.75 (95% CI=0.70– 0.80). Based on the logistic regression coefficients, we derived the following regression equation: Logit (P)= − 2.282+0.05× [disease duration]+1.015× [recurrent flares in the last year]+0.698× [palpable tophus]+0.345× [serum urate]-1.349×[serum HDL-C].Conclusion: Patients with gout presented a negative linear relationship between serum HDL-C and gout flares. Together with common clinical indicators, the AUC for gout flare prediction increased to 0.75. For patients with gout, remaining serum HDL-C level above 1.15 mmol/L may reduce the risk of gout flares.Keywords: inflammation, prediction, AUC, life style intervention

Wanling Li,1,2,* Shufang Shi,2,* Yajie Shi,2 Xiaofang Feng,2 Yueqin Li,2 Yuli Guo,2 Jiajia Xu,2 Liping Cui,2 Mei Wang1 1Department of Comprehensive Medical, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2Department of Nursing, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mei Wang, Department of Comprehensive Medical, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, People’s Republic of China, Tel/Fax +86-0351-8379512, Email wm69520@126.com Liping Cui, Department of Nursing, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, 99 Longcheng Street, Taiyuan, Shanxi, 030032, People’s Republic of China, Tel/Fax +86-13934154909, Email sxtylsj-1@163.comBackground: Elderly patients, due to their complex medical conditions and extensive care needs, are at risk of experiencing low-quality or fragmented care during transitions between different healthcare settings. After transitioning from hospital to home, inadequate self-care abilities may result in further health deterioration and increased risks of adverse outcomes. Currently, China lacks effective transitional support services from hospital to home, hindering the smooth transition for elderly patients. Therefore, understanding the specific care needs of elderly patients during this period provides a scientific basis for establishing reasonable transitional support services.Objective: This study aims to explore the transitional care needs of elderly patients during the hospital-to-home transition, as perceived by key stakeholders—patients, caregivers, and nurses—using Shanxi Province as a case example.Methods: A descriptive phenomenological method was employed in this study. Purposeful sampling selected 10 elderly patients, 5 caregivers, and 5 nursing staff from a tertiary hospital in Shanxi Province, China, for semi-structured in-depth interviews. The Colaizzi’s analysis was used in data analysis.Results: The transitional care needs of elderly patients from hospital to home can be summarized into four themes: the need to enhance self-care abilities, the need for professional guidance, the need for social and psychological support, and the need for healthcare service resources.Conclusion: Elderly patients have diverse care needs during the hospital-to-home transition, which require urgent attention and support. To address these needs, healthcare professionals should conduct comprehensive assessments during the patients’ hospitalization, accurately identifying care issues and implementing team-based interventions. By fulfilling these needs, healthcare providers can ensure that elderly patients are well-prepared psychologically, possess sufficient knowledge and self-care skills, and have access to comprehensive support services from hospitals and communities as they transition from professional hospital care to home self-care.Keywords: elderly patients, transitional care, needs, stakeholders, qualitative study

Yan Wang,1– 4,* He Zhao,2– 4,* Kun Zhao,1– 4,* Huhuifen He,1– 4,* Xinyu Li,5 Jingjing Qiu,2– 4 Limei Cui,2– 4 Liang Chen,2– 4 Wenjing Shang,6,7 Yan Sun2– 4 1The Second Medical College, Binzhou Medical University, Yantai, Shandong, People’s Republic of China; 2Department of Otolaryngology and Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, Shandong, People’s Republic of China; 4Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, Shandong, People’s Republic of China; 5The First Medical College, Binzhou Medical University, Yantai, Shandong, People’s Republic of China; 6Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, Yantai, Shandong, 264003, People’s Republic of China; 7Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong, 264003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Sun; Wenjing Shang, Email entsunyan@126.com; wenjshang@bzmc.edu.cnIntroduction: Age-related hearing loss (ARHL) is a degenerative condition that involves both peripheral and central auditory system pathologies. There is a close relationship between chronic inflammation and ARHL, but there is currently a lack of in-depth exploration of this relationship, particularly regarding causality.Methods: Using age-appropriate mice for basic experiments to examine changes in central auditory nervous system inflammation, a cohort study was conducted to select relevant clinical data and observe inflammation changes in the elderly population with ARHL. Mendelian randomization was employed to investigate the causal relationship between chronic inflammation and ARHL.Results: Clinical results indicate that CRP levels in the ARHL group are significantly higher than those in the normal group. Chronic inflammation also occurs in the auditory centers. Mendelian randomization studies provide causal evidence that genetic chronic inflammation factors do not increase the risk of ARHL.Discussion: This article provides reliable causal evidence of the relationship between chronic inflammation and ARHL, confirming the accumulation of inflammatory factors in the auditory center, which provides a basis for the prevention and treatment of ARHL and has a good prevention prospect. However, due to the differences of research objects, this study has limitations and needs further research.Keywords: CRP, TNF-α, chronic inflammation, age-related hearing loss, Mendelian randomization

Yang Zheng,1,2,* Limei Cui,1,2,* Haoran Lu,1,2,* Zhen Liu,1,2 Zhaoxue Zhai,2,3 Huikang Wang,1,2 Liting Shao,1,2 Zhaoyang Lu,2,3 Xicheng Song,1,2,4 Yu Zhang1,2,4 1Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China; 2Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, People’s Republic of China; 3Second Clinical Medicine College, Binzhou Medical University, Yantai, People’s Republic of China; 4Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu Zhang, Department of Otolaryngology, Head and Neck Surgery. Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, People’s Republic of China, Tel +86535 6691999, Fax +86535 6240341, Email superzhang013@163.com Xicheng Song, Department of Otolaryngology, Head and Neck Surgery. Yantai Yuhuangding Hospital, Qingdao University, Yantai, 264000, People’s Republic of China, Tel +86535 6691999, Fax +86535 6240341, Email drxchsong@163.comAbstract: The intranasal (IN) route of drug delivery can effectively penetrate the blood-brain barrier and deliver drugs directly to the brain for the treatment of central nervous system (CNS) disorders via intra-neuronal or extra-neuronal pathways. This approach has several advantages, including avoidance of first-pass metabolism, high bioavailability, ease of administration, and improved patient compliance. In recent years, an increasing number of studies have been conducted using drugs encapsulated in solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), and delivering them to the brain via the IN pathway. SLNs are the first-generation solid lipid nanocarriers, known for their excellent biocompatibility, high drug-loading capacity, and remarkable stability. NLCs, regarded as the second-generation SLNs, not only retain the advantages of SLNs but also exhibit enhanced stability, effectively preventing drug leakage during storage. In this review, we examined in vivo studies conducted between 2019 and 2024 that used SLNs and NLCs to address CNS disorders via the IN route. By using statistical methods to evaluate pharmacokinetic parameters, we found that IN delivery of SLNs and NLCs markedly enhanced drug accumulation and targeting within the brain. Additionally, pharmacodynamic evaluations indicated that this delivery method substantially improved the therapeutic effectiveness of the drugs in alleviating symptoms in rat models of CNS diseases. In addition, methods for enhancing the efficacy of nose-to-brain delivery of SLNs and NLCs are discussed, as well as advances in clinical trials regarding SLNs and NLCs.Plain Language Summary: Traditional drug administration routes for the treatment of central nervous system diseases have many limitations due to the existence of the blood-brain barrier (BBB). The intranasal drug administration route crosses the BBB through intra-neuronal pathways as well as extra-neuronal pathways and delivers drugs directly to the brain. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are a type of nanoparticles whose surface is covered by amphoteric surfactants and whose interior is filled with a lipid core. They have the advantages of good biocompatibility, strong drug loading capacity, and strong stability, and can be obtained through a variety of reliable preparation methods. Encapsulating therapeutic drugs into SLNs and NLCs for intranasal delivery can significantly increase drug delivery efficiency and enhance efficacy. In addition, there are various ways to further enhance drug delivery of SLNs and NLCs, such as using gel systems such as chitosan to encapsulate the nanoparticles, piggybacking cell-penetrating peptides onto the surface of the nanoparticles, and modifying the nanoparticles, surface charge of particles, etc. Keywords: solid lipid nanoparticle, nanostructured lipid carrier, intranasal delivery, central nervous system diseases

Shen Liu, Bijia Song, Liang Zhang, Xiuliang Li, Lingli Cui Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of ChinaCorrespondence: Lingli Cui, Email clinly@126.comIntroduction: Liver transplantation is considered an effective treatment for end-stage liver disease. Laparoscopic donor hepatectomy (LDH) has become a new standard procedure. And it is important to minimize the pain of the donor. Good postoperative analgesia can reduce the occurrence of postoperative complications and promote the early recovery of the donor. Ultrasound-guided transversus abdominis plane (TAP) block can provide effective analgesia for liver donors and reduce postoperative opioid consumption. This study aims to use ultrasound-guided TAP block for LDH to improve postoperative analgesia for donors while reducing opioid consumption and improving patient rehabilitation quality.Methods/Analysis: This study is a prospective blinded, randomized, controlled clinical trial with a concealed allocation of patients (living liver donors) scheduled to receive laparoscopic partial hepatectomy 1:1 to receive local infiltration anesthesia or TAP block. This study will recruit a total of 80 patients. The primary outcome is the dosage of opioids within 24 hours after surgery.Ethics and Dissemination: This trial has been approved by the Institutional Review Board of Beijing Friendship Hospital of China Capital University. This trial study protocol was approved on 8 May 2023. The trial will start recruiting patients after being registered on the Chinese Clinical Trial Registry.Trial Registration Number: ChiCTR2300071694.Keywords: liver transplantation, liver donor, laparoscopic hepatectomy, TAP block, postoperative analgesia

Yanan Yang,1,* Shuoye Yang,1,2,* Beibei Zhang,1 Jinpeng Wang,1 Di Meng,1 Lan Cui,1,2 Lu Zhang1,2 1School of Biological Engineering, Henan University of Technology, Zhengzhou, People’s Republic of China; 2Key Laboratory of Functional Molecules for Biomedical Research, Zhengzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuoye Yang, School of Biological Engineering, Henan University of Technology, Lianhua Street, Gaoxin District, Zhengzhou, 450001, People’s Republic of China, Tel/Fax: +86-371-67756513, Email yangshuoyehaut@163.comIntroduction: RNA interference (RNAi) stands as a widely employed gene interference technology, with small interfering RNA (siRNA) emerging as a promising tool for cancer treatment. However, the inherent limitations of siRNA, such as easy degradation and low bioavailability, hamper its efficacy in cancer therapy. To address these challenges, this study focused on the development of a nanocarrier system (HLM-N@DOX/R) capable of delivering both siRNA and doxorubicin for the treatment of breast cancer.Methods: The study involved a comprehensive investigation into various characteristics of the nanocarrier, including shape, diameter, Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), encapsulation efficiency, and drug loading. Subsequently, in vitro and in vivo studies were conducted on cytotoxicity, cellular uptake, cellular immunofluorescence, lysosome escape, and mouse tumor models to evaluate the efficacy of the nanocarrier in reversing tumor multidrug resistance and anti-tumor effects.Results: The results showed that HLM-N@DOX/R had a high encapsulation efficiency and drug loading capacity, and exhibited pH/redox dual responsive drug release characteristics. In vitro and in vivo studies showed that HLM-N@DOX/R inhibited the expression of P-gp by 80%, inhibited MDR tumor growth by 71% and eliminated P protein mediated multidrug resistance.Conclusion: In summary, HLM-N holds tremendous potential as an effective and targeted co-delivery system for DOX and P-gp siRNA, offering a promising strategy for overcoming MDR in breast cancer.Keywords: mesoporous silica nanoparticles, multidrug resistance, small interfering RNA, doxorubicin, hybrid nanoparticles

Dongdong Li,1 Lijun Bian,1 Lili Cui,2 Jingying Zhou,1 Gaotian Li,1 Xiaoyan Zhao,1 Liao Xing,1 Jiaxing Cui,1 Bo Sun,1 Chunlai Jiang,1,3,4 Wei Kong,1,3,4 Yong Zhang,1,3,4 Yan Chen1,3,4 1National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, People’s Republic of China; 2Beijing Institute of Drug Metabolism, Beijing, People’s Republic of China; 3Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun, People’s Republic of China; 4NMPA Key Laboratory of Humanized Animal Models for Evaluation of Vaccines and Cell Therapy Products, Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Yan Chen; Yong Zhang, National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130012, People’s Republic of China, Tel +86-431-85167751, Fax +86-431-85167674, Email chen_yan0417@126.com; zhypharm@jlu.edu.cnPurpose: Heterologous immunization using different vaccine platforms has been demonstrated as an efficient strategy to enhance antigen-specific immune responses. In this study, we performed a head-to-head comparison of both humoral and cellular immune response induced by different prime-boost immunization regimens of mRNA vaccine and adjuvanted protein subunit vaccine against varicella-zoster virus (VZV) in middle-aged mice, aiming to get a better understanding of the influence of vaccination schedule on immune response.Methods: VZV glycoprotein (gE) mRNA was synthesized and encapsulated into SM-102-based lipid nanoparticles (LNPs). VZV-primed middle-aged C57BL/6 mice were then subjected to homologous and heterologous prime-boost immunization strategies using VZV gE mRNA vaccine (RNA-gE) and protein subunit vaccine (PS-gE). The antigen-specific antibodies were evaluated using enzyme-linked immunosorbent assay (ELISA) analysis. Additionally, cell-mediated immunity (CMI) was detected using ELISPOT assay and flow cytometry. Besides, in vivo safety profiles were also evaluated and compared.Results: The mRNA-loaded lipid nanoparticles had a hydrodynamic diameter of approximately 130 nm and a polydispersity index of 0.156. Total IgG antibody levels exhibited no significant differences among different immunization strategies. However, mice received 2×RNA-gE or RNA-gE>PS-gE showed a lower IgG1/IgG2c ratio than those received 2×PS-gE and PS-gE> RNA-gE. The CMI response induced by 2×RNA-gE or RNA-gE>PS-gE was significantly stronger than that induced by 2×PS-gE and PS-gE> RNA-gE. The safety evaluation indicated that both mRNA vaccine and protein vaccine induced a transient body weight loss in mice. Furthermore, the protein vaccine produced a notable inflammatory response at the injection sites, while the mRNA vaccine showed no observable inflammation.Conclusion: The heterologous prime-boost strategy has demonstrated that an mRNA-primed immunization regimen can induce a better cell-mediated immune response than a protein subunit-primed regimen in middle-aged mice. These findings provide valuable insights into the design and optimization of VZV vaccines with the potentials to broaden varicella vaccination strategies in the future.Keywords: varicella-zoster Virus, mRNA vaccine, glycoprotein E, lipid nanoparticles, heterologous prime-boost, cell-mediated immunity

Na Li,1 Liufu Cui,1 Gary Tse,2,3 Panagiotis Korantzopoulos,4 Konstantinos P Letsas,5 George Bazoukis,6,7 Shuohua Chen,8 Nan Zhang,2 Xuemei Yang,9 Peipei Liu,10 Lili Wu,11 Gan-Xin Yan,12,13 Gregory Yoke Hong Lip,14,15 Shouling Wu,8 Tong Liu2 1Department of Rheumatology and Immunology, Kailuan General Hospital, Tangshan, Hebei Province, People’s Republic of China; 2Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 3School of Nursing and Health Studies, Hong Kong Metropolitan University, Hong Kong, People’s Republic of China; 4First Department of Cardiology, University of Ioannina Medical School, Ioannina, Greece; 5Arrhythmia Unit, Laboratory of Cardiac Pacing and Electrophysiology, Onassis Cardiac Surgery Center, Athens, Greece; 6Department of Cardiology, Larnaca General Hospital, Larnaca, Cyprus; 7European University Cyprus, Medical School, Nicosia, Cyprus; 8Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei Province, People’s Republic of China; 9School of Clinical Medicine, North China University of Science and Technology, Tangshan, Hebei Province, People’s Republic of China; 10School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, People’s Republic of China; 11Department of Cardiology, Shanghai Songjiang District Central Hospital, Shanghai, People’s Republic of China; 12Lankenau Medical Center and Lankenau Institute for Medical Research, Wynnewood, PA, USA; 13Department of Cardiology, Fuwai Huazhong Hospital, Zhengzhou, Henan Province, People’s Republic of China; 14Liverpool Centre for Cardiovascular Sciences, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK; 15Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, DenmarkCorrespondence: Tong Liu, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China, Email liutong@tmu.edu.cn; liutongdoc@126.com Shouling Wu, Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei Province, People’s Republic of China, Email drwusl@163.comObjective: This study aimed to explore the impact of a combination of hyperuricemia (HUA) and excessive high-sensitivity C-reactive protein (hs-CRP) levels on the likelihood of developing cardiac conduction block (CCB). Additionally, it sought to assess whether the influence of uric acid (UA) on CCB is mediated by hs-CRP.Methods: A prospective study was executed utilizing data from the Kailuan cohort, including 81,896 individuals initially free from CCB. The participants were categorized into four groups depending on the existence of HUA and low-grade inflammation (hs-CRP> 3 mg/L). Cox regression analysis was employed to ascertain hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of incident CCB. A mediation analysis was performed to determine if hs-CRP functioned as a mediator in the connection between UA levels and the incidence of CCB.Results: During a median observation period of 11.8 years, we identified 3160 cases of newly occurring CCB. Compared with the low UA/low CRP group, the combination of HUA and low-grade inflammation elevated the CCB risks (HR:1.56, 95% CI:1.22– 1.99), atrioventricular block (AVB) (HR:1.88, 95% CI:1.27– 2.77), and right bundle branch block (HR:1.47, 95% CI:1.02– 2.12), respectively. Mediation analysis revealed that in the HUA group, compared with the non-HUA group, the risk of CCB elevated by 14.0%, with 10.3% of the increase mediated through hs-CRP.Conclusion: HUA combined with elevated hs-CRP increased the risk of CCB, especially AVB. The connection between UA and the CCB risk was partly mediated by hs-CRP. Keywords: hyperuricemia, inflammation, cardiac conduction block, combined exposure, risk factors, mediation

Liuping Cui,1,2 Ran Liu,1 Fubo Zhou,1 Yumei Liu,1 Bing Tian,1 Ying Chen,2,* Yingqi Xing1,3,4,* 1Department of Vascular Ultrasound, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neurology, The First Hospital of Jilin University, Changchun, People’s Republic of China; 3Beijing Diagnostic Center of Vascular Ultrasound, Beijing, People’s Republic of China; 4Center of Vascular Ultrasound, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingqi Xing, Department of Vascular Ultrasonography, Xuanwu Hospital, Capital Medical University, 45 Changchun Road, Beijing, Xicheng District, 100053, People’s Republic of China, Tel +86-18610047846, Email xingyq2009@sina.comPurpose: Intraplaque neovascularization, assessed using contrast-enhanced ultrasound (CEUS), is associated with ischemic stroke. It remains unclear whether detection of intraplaque neovascularization combined with color Doppler ultrasound (CDUS) provides additional value compared with CDUS alone in assessing ischemic stroke risk. Therefore, we investigated the clinical value of combined CEUS, CDUS, and clinical features for ischemic stroke risk stratification.Patients and Methods: We recruited 360 patients with ≥ 50% carotid stenosis between January 2019 and September 2022. Patients were examined using CDUS and CEUS. Covariates associated with ischemic stroke were identified using multivariate logistic regression analysis. The discrimination and calibration were verified using the C-statistic and Hosmer–Lemeshow test. The incremental value of intraplaque neovascularization in the assessment of ischemic stroke was analyzed using the Delong test.Results: We analyzed the data of 162 symptomatic and 159 asymptomatic patients who satisfied the inclusion and exclusion criteria, respectively. Based on multivariate logistic regression analysis, we constructed a nomogram using intraplaque neovascularization, degree of carotid stenosis, plaque hypoechoicity, and smoking status, with a C-statistic of 0.719 (95% confidence interval [CI]: 0.666– 0.768) and a Hosmer–Lemeshow test p value of 0.261. The net reclassification index of the nomogram was 0.249 (95% CI: 0.138– 0.359), and the integrated discrimination improvement was 0.053 (95% CI: 0.029– 0.079). Adding intraplaque neovascularization to the combination of CDUS and clinical features (0.672; 95% CI: 0.617– 0.723) increased the C-statistics (p=0.028).Conclusion: Further assessment of intraplaque neovascularization after CDUS may help more accurately identify patients at risk of ischemic stroke. Combining multiparametric carotid ultrasound and clinical features may help improve the risk stratification of patients with ischemic stroke with ≥ 50% carotid stenosis.Plain Language Summary: We studied whether using contrast-enhanced ultrasound (CEUS) to detect intraplaque neovascularization could help better determine the risk of ischemic stroke. We compared the combined use of color Doppler ultrasound (CDUS) and CEUS with CDUS alone in patients with more than 50% carotid narrowing. Our findings showed that combining clinical details, CDUS, and CEUS was more effective (0.719 vs 0.672). This means that CEUS provides extra insight when gauging ischemic stroke risk compared with CDUS alone. This could help in accurately identifying patients at high risk of stroke. However, more extensive studies are needed to fully understand the role of these tests in the evaluation of stroke risk. Keywords: atherosclerosis, contrast-enhanced ultrasound, vulnerable plaque, carotid ultrasound

Wenyan Sun,1,&ast; Xuetong Zhao,2– 4,&ast; Nicola Dalbeth,5,&ast; Robert Terkeltaub,6 Lingling Cui,1 Zhen Liu,1 Lin Han,1 Can Wang,1 Hui Zhang,1,7 Yiming Bao,2– 4 Changgui Li,1,7 Jie Lu1,7 1Shandong Provincial Key Laboratory of Metabolic Diseases, Shandong Provincial Clinical Research Center for Immune Diseases, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, People’s Republic of China; 3CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Science and China National Center for Bioinformation, Beijing, People’s Republic of China; 4University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China; 5Department of Medicine, University of Auckland, Auckland, New Zealand; 6VA San Diego VA Healthcare Center, University of California San Diego, San Diego, CA, USA; 7Institute of Metabolic Diseases, Qingdao University, Qingdao, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Lu, Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, Shandong Provincial Clinical Research Center for Immune Diseases, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China, Email 13127006046@163.com Changgui Li, Shandong Provincial Key Laboratory of Metabolic Diseases, Shandong Provincial Clinical Research Center for Immune Diseases, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China, Email changguili@vip.163.comObjective: This study aimed to understand predictors of inadequate response (IR) to low-dose febuxostat treatment based on clinical variables.Methods: We pooled data from 340 patients of an observational cohort and two clinical trials who received febuxostat 20 mg/day for at least 3 months. IR was defined as failure to reach the target serum urate level (sUA< 6 mg/dL) at any time point during 3 months treatment. The potential predictors associated with short- or mid-term febuxostat IR after pooling the three cohorts were explored using mixed-effect logistic analysis. Machine learning models were performed to evaluate the predictors for IR using the pooled data as the discovery set and validated in an external test set.Results: Of the 340 patients, 68.9% and 51.8% were non-responders to low-dose febuxostat during short- and mid-term follow-up, respectively. Serum urate and triglyceride (TG) levels were significantly associated with febuxostat IR, but were also selected as significant features by LASSO analysis combined with age, BMI, and C-reactive protein (CRP). These five features in combination, using the best-performing stochastic gradient descent classifier, achieved an area under the receiver operating characteristic curve of 0.873 (95% CI [0.763, 0.942]) and 0.706 (95% CI [0.636, 0.727]) in the internal and external test sets, respectively, to predict febuxostat IR.Conclusion: Response to low-dose febuxostat is associated with early sUA improvement in individual patients, as well as patient age, BMI, and levels of TG and CRP.Keywords: gout, febuxostat, urate-lowering therapy, machine learning model

Liqin Yuan, Lin Cui, Jie Wang, Li Gong Department of Gynecology, Rizhao People’s Hospital, Rizhao, Shandong Province, 276800, People’s Republic of ChinaCorrespondence: Li Gong, Rizhao People’s Hospital, Rizhao, Shandong Province, 276800, People’s Republic of China, Tel +86-18663351821, Email gongli0768@163.comPurpose: Meigs’ syndrome is a rare gynecological disease characterized by the triad of benign ovarian tumor, ascites, and pleural effusion. Ovarian malignancies should be highly suspected in a postmenopausal woman with a pelvic mass, ascites, hydrothorax, and an elevated carbohydrate antigen 125 (CA125) level. It can be challenging to make a preoperative diagnosis of Meigs’ syndrome. In this report, we present a case of Meigs’ syndrome caused by an ovarian fibrothecoma and review the relevant literature to raise awareness and avoid misdiagnosis.Case Presentation: An 82-year-old woman with a 2-week history of abdominal distension was admitted to the Department of Gynecology. Ultrasound and thoracoabdominal computed tomography scans showed a left-sided hypoechoic mass in the pelvic cavity with bilateral pleural effusion and massive ascites. The CA125 concentration was 1040 U/mL (normal, 0– 35 U/mL). With a working diagnosis of ovarian malignancy, the patient underwent ultrasound-guided fine-needle puncture of the pelvic mass and paracentesis to drain the ascites. The fine-needle puncture and paracentesis fluid analysis results revealed that the ascites did not contain any tumor cells, and the pelvic mass was identified as a spindle cell tumor. Immunohistochemistry confirmed that it was a sex-cord stromal tumor. Total abdominal hysterectomy and bilateral adnexectomy were performed under general anesthesia. The pathology results confirmed the mass to have been an ovarian fibrothecoma. At the 2-month postoperative follow-up, the ascites and hydrothorax had resolved and not recurred, and the CA125 level was normal.Conclusion: Despite the high suspicion of ovarian carcinoma in postmenopausal women presenting with pelvic mass, ascites, pleural effusion, and elevated CA125, Meigs’ syndrome should be considered.Keywords: Meigs’ syndrome, ascites, pleural effusion, CA125, ovarian fibrothecoma, ovarian cancer

Zhipeng Wang,1,&ast; You Yin,2,&ast; Yuhui Mu,1,3,&ast; Lili Cui,1 Xinhua Song,1 Jianhua Zhuang,2 Shouhong Gao,1 Xia Tao,1 Wansheng Chen1 1Department of Pharmacy, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, 200003, People’s Republic of China; 2Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, 200003, People’s Republic of China; 3College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianhua Zhuang, Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), No. 415, Fengyang Road, Shanghai, 200003, People’s Republic of China, Email jianhuazh11@126.com Xia Tao, Department of Pharmacy, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), No. 415, Fengyang Road, Shanghai, 200003, People’s Republic of China, Tel/Fax +86– 21– 81886191, Email taoxia@smmu.edu.cnObjective: This study aims to explore the mechanism underlying the induction of phlebitis by aescinate and create an early-warning model of phlebitis based on metabolomics.Methods: Patients with cerebral infarction enrolled had been treated with aescinate. Plasma samples were collected either before administration of aescinate, upon the occurrence of phlebitis, or at the end of treatment. Non-targeted metabolomics and targeted amino acid metabolomics were carried out to analyze metabolic profiles and quantify the metabolites.Results: Untargeted metabolomics revealed six differential metabolites in baseline samples versus post-treatment samples and four differential metabolites in baseline samples from patients with or without phlebitis. Pathways of these differential metabolites were mainly enriched in amino acid metabolism. Ten differential amino acids with a VIP value of > 1 were identified in the baseline samples, enabling us to distinguish between patients with or without phlebitis. A logistic regression model was constructed (AUC 0.825) for early warning of phlebitis of grade 2 or higher.Conclusion: The occurrence of aescinate-induced phlebitis, which can be predicted early during onset, may be associated with perturbations of the endogenous metabolic profile, especially the metabolism of amino acids. Keywords: aescinate, diagnostic model, mechanism, metabolomics, phlebitis

Kunjing Han,1,&ast; Yiping Chen,2,&ast; Min Li,2 Liping Cui1 1Department of Nursing, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People’s Republic of China; 2School of Nursing, Shanxi Medical University, Jinzhong, Shanxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liping Cui, Department of Nursing, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, No. 99, Longcheng Street, Taiyuan, 030032, People’s Republic of China, Tel +86 0351-8368114, Email cuiliiping@163.comBackground: Stroke is a critical public health issue in China that necessitates a closer examination of family resilience (defined here as the collective capacity of individuals, families and communities to effectively navigate challenges, recover from adverse events and foster positive adaptation). Amid rising stroke incidence, this study addresses the dearth of research on family resilience among stroke survivors in China, aiming to assess its level, identify influencing factors and establish coping strategies for family caregivers.Methods: This mixed-methods research employed a sequential explanatory design. Questionnaires were distributed to 258 stroke survivors and their family members at outpatient follow-up visits. In the first stage (ie the quantitative research stage), the research tools for data collection included a general demographic sociological data questionnaire, the Family Resilience Assessment Scale (FRAS), the Self-Efficacy for Managing Chronic Disease 6-Item Scale, the Caregiver Burden Scale, the Family Functioning Scale and the Social Support Rating Scale. Quantitative data were analysed using IBM SPSS 26.0 software, utilising descriptive statistics for summarising sociodemographic characteristics and conducting analyses, such as independent-sample t-tests, one-way analysis of variance and Spearman correlation analysis. The second stage (ie the qualitative research stage) involved complementing and validating the data, developing a quantitative–qualitative interview framework and selecting participants for interviews. Colaizzi’s seven-step analysis was applied to analyse interview data. In the third stage, the quantitative and qualitative research results were integrated, and a comprehensive analysis was performed to obtain an accurate conclusion.Results: A total of 242 families responded to the questionnaire (response rate: 93.8%). In total, the mean age of stroke survivors was 61.86 ± 8.76 years old, and 69.8% were male. The quantitative results showed that the FRAS mean score was (185.33 ± 24.78), which was above the medium level. The multiple linear regression analysis confirmed that family function was the strongest influencing factor on family resilience (β = 0.948, p

Yan Wang,1– 4,&ast; Limei Cui,2– 4,&ast; He Zhao,1– 4,&ast; Huhuifen He,1– 4 Liang Chen,2– 4 Xicheng Song,2– 4 Dawei Liu,2– 4 Jingjing Qiu,2– 4 Yan Sun2– 4 1The Second Medical College, Binzhou Medical University, Yantai, Shandong, People’s Republic of China; 2Department of Otolaryngology and Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, Shandong, People’s Republic of China; 4Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Sun, Department of Otorhinolaryngology & Head and Neck Surgery, Yuhuangding Hospital Affiliated to Qingdao University, No. 20 East, Yuhuangding Road, Yantai, Shandong, 264000, People’s Republic of China, Email entsunyan@126.comAbstract: Degenerative diseases affect people’s life and health and cause a severe social burden. Relevant mechanisms of microglia have been studied, aiming to control and reduce degenerative disease occurrence effectively. This review discussed the specific mechanisms underlying microglia in neurodegenerative diseases, age-related hearing loss, Alzheimer’s disease, Parkinson’s disease, and peripheral nervous system (PNS) degenerative diseases. It also reviewed the studies of microglia inhibitors (PLX3397/PLX5622) and activators (lipopolysaccharide), and suggested that reducing microglia can effectively curb the genesis and progression of degenerative diseases. Finally, microglial cells’ anti-inflammatory and pro-inflammatory dual role was considered the critical communication point in central and peripheral degenerative diseases. Although it is difficult to describe the complex morphological structure of microglia in a unified manner, this does not prevent them from being a target for future treatment of neurodegenerative diseases.Keywords: microglia, neurodegenerative diseases, neuroinflammation

Ping Lu,1 Lingyun Cui,1 Xinghu Zhang2 1Center for Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China; 2Department of Neuroinfection and Neuroimmunology, Center for Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of ChinaCorrespondence: Xinghu Zhang, Department of Neuroinfection and Neuroimmunology, Center for Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119, South Fourth Ring Road West, Beijing, 100070, People’s Republic of China, Tel + 86 10 5997 6585, Email xhzhtiantan@hotmail.comPurpose: Primary angiitis of the adult central nervous system (PACNS) is an increasingly recognized but limited disease. Using previous case reports, we sought to summarize the clinical symptoms, imaging manifestations, treatment, and prognosis of patients with biopsy-confirmed PACNS to guide clinical diagnosis and management.Methods: We searched the Web of Science database for studies published from January 2000 to April 2023, with the language set to English and the document type limited to [Article or Review or Letter or Editorial Material]. A systematic review of all case reports met the inclusion and exclusion criteria was performed. These patients’ clinical, pathological, and imaging characteristics were analyzed, and treatment and prognostic data were summarized.Results: We analyzed 69 articles, including 76 patients with biopsy-confirmed PACNS. And 57.9% of the patients were male, the median age at presentation was 47.0 years, and focal neurological deficits were the most common symptom in patients (78.9%), followed by headache (52.6%). The median duration of biopsy was 1.1 months, of which 49 (64.5%) patients were lymphocytic, 13 (17.1%) were granulomatous, 11 (14.5%) were amyloidotic, and 3 (3.9%) were necrotizing PACNS. Relapse events occurred in 41 (53.9%) patients, including 34 (44.2%) relapses and 8 (10.5%) deaths. Univariate logistic regression analysis revealed that symptomatic epilepsy, prolonged biopsy time window, and CD20 expression in pathological tissues might be independent risk factors for recurrent events in patients (HR=4.69, 95% CI: 1.51– 14.54, p=0.007; HR=1.11, 95% CI: 1.00– 1.22, p=0.043; HR=5.33, 95% CI: 1.07– 26.61, p=0.041).Conclusion: Adult PACNS is associated with frequent relapses and high mortality. Symptomatic epilepsy, prolonged biopsy time window, and CD20 expression in pathological tissue may be associated with recurrent events.Keywords: PACNS, biopsy, recurrence, CD20, comprehensive review

Weimin Wang,1,&ast; Shaohong Zhang,1,&ast; Lei Cui,2 Yu Chen,2 Xingxing Xu,2 Longchuan Wu2 1Department of Gerontology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, People’s Republic of China; 2Department of Respiratory Medicine, Huaian Hospital of Traditional Chinese Medicine, Affiliated to Nanjing University of Traditional Chinese Medicine, Huaian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Longchuan Wu; Xingxing Xu, Email wlc020711@163.com; blxxxbhl@163.comBackground: Bufei Yishen formula (BYF) is an effective prescription for the clinical treatment of chronic obstructive pulmonary disease (COPD). However, the molecular mechanism by which it exerts its pharmacological effects remains to be explored.Methods: The human bronchial cell line BEAS-2B was treated with cigarette smoke extract (CSE). Cellular senescence markers were detected by Western blot and ELISA. Potential transcription factor of klotho was predicted using JASPAR and USCS databases.Results: CSE induced cellular senescence with intracellular accumulation of cellular senescence biomarkers (p16, p21 and p27) and increased secretion of senescence-related secretory phenotypic (SASP) factors (IL-6, IL-8, and CCL3). In contrast, BYF treatment inhibited CSE-induced cellular senescence. CSE suppressed the transcription, expression and secretion of klotho, whereas BYF treatment rescued its transcription, expression and secretion. CSE downregulated the protein level of ZNF263, whereas BYF treatment rescued the expression of ZNF263. Furthermore, ZNF263-overexpressing BEAS-2B cells could inhibit CSE-induced cellular senescence and SASP factor secretion by upregulating the expression of klotho.Conclusion: This study revealed a novel pharmacological mechanism by which BYF alleviates clinical symptoms of COPD patients, and regulating ZNF263 and klotho expression may be beneficial to the treatment and prevention of COPD.Keywords: Bufei Yishen formula, cell senescence, ZNF263, klotho, senescence-related secretory phenotypic

Changhao Dong,1,2 Rui Xian,1,2 Guangxiang Wang,2,3 Lihong Cui1,2 1Department of Gastroenterology, School of Medicine, South China University of Technology, Guangzhou, People’s Republic of China; 2Department of Gastroenterology, The Sixth Medical Center of PLA General Hospital of Beijing, Beijing, People’s Republic of China; 3The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Lihong Cui, Department of Gastroenterology, the Sixth Medical Center of PLA General Hospital of Beijing, No. 6 Fucheng Road, Haidian Distract, Beijing, 100048, People’s Republic of China, Tel +86-10-66957541, Email cuilhkeyan@163.comPurpose: There is probably a high prevalence of small intestinal bacterial overgrowth (SIBO) in patients with gallbladder polyps (GBPs). To date, no study has evaluated the occurrence of SIBO in patients with GBPs. The aim of this study was to investigate the prevalence of SIBO in patients with GBPs and explore the possible association between these two conditions.Patients and Methods: The hydrogen-methane breath test was used to diagnose SIBO, and patients were divided into GBPs and control groups based on whether GBPs were found under ultrasound. Clinical and paraclinical factors were compared between the two groups.Results: A total of 297 subjects were included in this study. The prevalence of SIBO was significantly higher in the GBPs group than in the control group (50.0% vs.30.8%, p< 0.01). Multivariate logistic regression analysis showed that male (OR=2.26, 95% CI=1.12– 4.57, p=0.023), SIBO (OR=3.21, 95% CI=1.69– 6.11, p< 0.001), fatty liver (OR=2.91, 95% CI= 1.50– 5.64, p=0.002) and BMI (OR=1.13, 95% CI=1.01– 1.26, p=0.035) were independently associated with GBPs. And by subgroup analysis, we found that the association between SIBO and GBPs was stronger in females than in males (p for interaction< 0.001). In addition, SIBO (OR=5.11, 95% CI=1.42– 18.36, p=0.012) and fasting glucose (OR=3.04, 95% CI=1.27– 7.28, p=0.013) were found to be associated with solitary polyps.Conclusion: SIBO was highly prevalent in patients with GBPs, and this association seemed to be stronger among females.Keywords: gut microbiota, bacterial overgrowth, breath test, gallbladder polyps

Lijuan Xiong,1,&ast; Xu Long,1,&ast; Lijun Ni,2,&ast; Lili Wang,2 Yang Zhang,1 Lili Cui,1 Jian Guo,2 Chunying Yang1 1Department of Laboratory Medicine, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guizhou, People’s Republic of China; 2Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Guo, Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 1800 Yuntai Road, Pudong New Area, Shanghai, People’s Republic of China, Tel +86-17701810639, Email guojian1110@126.com Chunying Yang, Department of Laboratory Medicine, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 83 Feishan Street, Yunyan District, Guiyang City, Guizhou Province, People’s Republic of China, Tel +86-13658504875, Email 2590470591@qq.comPurpose: Matrix-assisted laser desorption-ionization-time of flight mass spectrometry (MALDI-TOF) has recently been widely used in clinical microbiology laboratories, with the advantages of being reliable, rapid, and cost-effective. Here, we reported the performance of two MALDI-TOF MS instruments, EXS3000 (Zybio, China) and Autof ms1000 (Autobio, China), which are commonly used in clinical microbiology field.Methods: A total of 209 common clinical common isolates, including 70 gram-negative bacteria strains, 58 gram-positive bacteria strains, 33 yeast strains, 15 anaerobic bacteria strains, and 33 mold strains, and 19 mycobacterial strains were tested. All strains were identified by EXS3000 (Zybio, China) and Autof ms1000 (Autobio, China). Sequence analysis of 16S rRNA or ITS regions was used to verify all strains.Results: Current study found that species-level discrimination was found to be 191 (91.39%) and 190 (90.91%) by EXS3000 and Autof ms1000, respectively. Genus-level discrimination was 205 (98.09%) by the EXS3000 and 205 (98.09%) by the Autof ms1000, respectively. The correct results at species level of the EXS3000 were 91.43% (64/70) for gram-negative bacteria, 93.1% (54/58) for gram-positive cocci, 93.94% (31/33) for yeast, 100% (15/15) for anaerobes and 81.82% (27/33) for filamentous fungi. The correct results at species level of the Autof ms1000 were 92.86% (65/70) for gram-negative bacteria, 91.38% (53/58) for gram-positive cocci, 93.94% (31/33) for yeast, 100% (15/15) for anaerobes and 78.79% (26/33) for filamentous fungi.Conclusion: Although the results show that the EXS3000 and Autof ms1000 systems are equally good choices in terms of analytical efficiency for routine procedures, the test result of EXS3000 is slightly better than Autof ms1000. It’s worth mentioning that the target plate of the EXS 3000 instrument is reusable, but the target plate of the Autof ms1000 is disposable, making the EXS3000 more effective in reducing costs.Keywords: evaluation, MALDI-TOF mass spectrometry, EXS3000, Autof ms1000, clinical isolates, identification, gram-negative bacteria, gram-positive bacteria, mycobacteria, yeast, anaerobic bacteria

Bai Yi Song1 &ast;, Chen Chen2 &ast;, Wen Hu Xu,1 Bai Lin Cong,3 Zheng Yi Guo,1 Zai Hao Zhao,4 Lan Cui,1 Yin Hua Zhang1,4,5 1Cardiovascular Medicine Department, Yanbian University Hospital, Yanji, 133000, People’s Republic of China; 2Department of Emergency Medicine, Yanbian University Hospital, Yanji, 133000, People’s Republic of China; 3Cardiovascular Medicine Department, Jilin City Central Hospital, Jilin, 132011, People’s Republic of China; 4Research Center, Yanbian University Hospital, Yanji, 133000, People’s Republic of China; 5Department of Physiology & Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University, College of Medicine, Seoul, 03080, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Yin Hua Zhang; Lan Cui, Yanbian University Hospital, Yanji, 133000, People’s Republic of China, Tel +86 433 2660129, Email yinzhang87@gmail.com; lancui@ybu.edu.cnBackground: There are clear gender differences in the pathological process and outcome in acute myocardial infarction (AMI) patients but inflammatory responses remain clarified. Here, we aimed to analyse the correlations between inflammatory cells and organ injury parameters in AMI patients and compared between male and female groups.Methods: A total of 603 AMI patients who underwent percutaneous coronary intervention (PCI) within 24 hours of the onset were analysed retrospectively. Basic information and hematological parameters detected 6 hours before the PCI were collected, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) were calculated. Renal, liver function indicators, and myocardial enzymes were measured. Left ventricular ejection fraction (EF) and fractional shortening (FS) on days 5– 7 after PCI were obtained. Western blot was performed to detect iNOS, eNOS and nNOS expression in H9C2 rat cardiomyocytes treated with IL-6 with and without estrogen and testosterone.Results: WBC, NEU, MON, MLR, CK, ALT and CREA of male patients were significantly higher than females, but FS was lower in females. NEU, MON and MLR were positively correlated with CK, CK-MB, AST, and ALT in males, whereas LYM were correlated with these parameters in female. NEU and NLR were inversely correlated with EF or FS only in female. Estrogen and testosterone reduced IL-6-induced iNOS protein expression in H9C2 cardiomyocytes, estrogen enhanced IL-6-induced nNOS protein expression.Conclusion: NEU, MON, MLR in male AMI patients, and LYM in female patients were associated with organ injury parameters. Estrogen regulation of nitric oxide pathway may mediate the protective effects in female.Keywords: acute myocardial infarction, gender differences, immune cells, renal function indicators, liver function indicators, nitric oxide synthases

Ping Yang,1,2 Chao Liu,3 Zhenchao Wu,2 Jiajia Zheng,4 Juan Yi,1 Nan Wu,2 Zhangli Wu,1,2 Ming Lu,2,3 Liyan Cui,4,&ast; Ning Shen1– 3,&ast; 1Institute of Medical Technology, Peking University Health Science Center, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 3Department of Infectious Diseases, Peking University Third Hospital, Beijing, People’s Republic of China; 4Department of Laboratory Medicine, Peking University Third Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liyan Cui; Ning Shen, Email cliyan@163.com; shenningputh@163.comPurpose: This study aimed to identify the clinical outcomes, microbiological features and risk factors for difficult-to-treat resistance (DTR) Klebsiella pneumoniae (Kp) infection.Materials and Methods: A retrospective study was conducted at Peking University Third Hospital from January 2020 to March 2021. DTR was defined as resistance to ≥ 1 carbapenem, ≥ 1 extended-spectrum cephalosporin, and ≥ 1 fluoroquinolone. Hypervirulent Kp (HvKp) was defined as peg-344-, iroB-, iucA-, rmpA-, or rmpA2-positive. Clinical data were collected. Antimicrobial susceptibility testing and string tests were performed to determine resistance and hypermucoviscosity phenotype. Whole genome sequencing was performed to analyze the sequence type (ST), capsular serotypes, resistance and virulence genes. Risk factors for 30-day mortality were analyzed.Results: Fifty DTR-Kp (50.0%) strains were identified among 100 patients. Compared to non-DTR-Kp group, a significant number of patients with DTR-Kp infection experienced ICU admission (44.0% versus 10.0%, P< 0.001) and mechanical ventilation after Kp detection (26.0% versus 10.0%, P=0.037). Notably, the percentage of hvKp among the DTR-Kp isolates increased consistently over the 15 months evaluated. Most DTR-Kp strains belonged to ST11 (82.0%), followed by ST15 (12.0%), ST86 (2.0%), ST996 (2.0%), and ST3157 (2.0%). DTR-Kp isolates possessed various resistance genes, such as blaKPC-2, blaTEM-1D and fosA3 (90.0%, 80.0% and 72.0%, respectively). Importantly, the yersiniabactin genes were significantly clustered in DTR group (48/50, 96.0%). The 30-day mortality was significantly higher in patients with DTR-Kp infection than non-DTR-Kp group (38.0% versus 8.2%, P=0.001). DTR-Kp infection (odds ratio [OR] = 4.196) was an independent risk factor for the 30-day mortality of Kp-infected patients. Additionally, cerebrovascular disease (OR = 2.780) and Charlson comorbidity index (OR= 1.584) were independent risk factors for DTR-Kp infections.Conclusion: DTR-hvKp is rapidly emerging. The DTR-Kp strains harbored various resistance genes and high rates of yersiniabactin siderophore genes. DTR-Kp infection was an independent risk factor for mortality, suggesting that enhanced awareness essential.Keywords: Klebsiella pneumoniae, difficult-to-treat resistance, mortality, risk factor

Yanqin Li,1,&ast; Xiaoqian Sun,1,&ast; Xiangning Liu,1,&ast; Junjun Li,2 Xuan Li,1 Gang Wang,1 Yizhou Liu,1 Xiangyu Lu,2 Lingwen Cui,2 Mingyan Shao,3 Yong Wang,1,3,4 Wei Wang,1,4,5 Chun Li2,4 1College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2Modern Research Center for Traditional Chinese Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 3School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 4Beijing Key Laboratory of TCM Syndrome and Formula, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 5Guangzhou University of Chinese Medicine, Guangdong, 510006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Wang, Guangzhou University of Chinese Medicine, Guangdong, 510006, People’s Republic of China, Tel +86 13910026960, Email wangwei26960@126.com Chun Li, Modern Research Center for Traditional Chinese Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China, Tel +86 15810068615, Email lichun19850204@163.comBackground: Acute myocardial ischemia (AMI) is a common heart disease with increasing morbidity and mortality year by year. Persistent and sterile inflammatory infiltration of myocardial tissue is an important factor triggering of acute myocardial ischemia secondary to acute myocardial infarction, and NLRP3 inflammasome activation is an important part of sterile inflammatory response after acute myocardial ischemia. Previous studies have shown that Qishen granule (QSG) can significantly inhibit the inflammatory injury of myocardial tissue caused by ischemia, but its effect and specific mechanism of inhibiting the activation of NLRP3 inflammasome have not been reported. This study was to investigate the specific mechanism of QSG inhibiting inflammation after AMI, and to validate the possible targets.Methods: The myocardial ischemia model in mice was established by ligation of the left anterior descending coronary artery. Echocardiography was used to evaluate the cardiac function of the mice. Plasma CK-MB and cTnl were detected by ELISA to evaluate the degree of myocardial injury. The extent of myocardial tissue inflammation in mice was assessed by HE staining and immunohistochemistry of IL-18, IL-1β. The expressions of NLRP3, ASC, Caspase-1, and CD86 were detected by immunofluorescence; detection of key pathway proteins P2X7R, NEK7, NLRP3, ASC, Caspase-1, and effector proteins IL-18, IL-1β by Western blot. In vitro experiments, ATP+LPS was used to construct a RAW264.7 macrophage NLRP3 inflammasome activation model. Immunofluorescence and Western blot analysis were performed to detect the expression of NLRP3 pathway activator and effector proteins. Plasmid-transfected P2X7R overexpression and immunoprecipitation assays were used to evaluate the QSG-regulated NLRP3 inflammasome activation pathway.Results: QSG rescued cardiac function and further reduced inflammatory effects in mice by inhibiting NLRP3 inflammasome activation. In vitro, QSG inhibited LPS combined with ATP-induced NLRP3 inflammasome activation in RAW264.7 macrophages by downregulating the expression of NLRP3 inflammasome key pathway proteins. In addition, inhibition or overexpression of P2X7R in RAW264.7 macrophages and immunoprecipitated protein interactions further confirmed that QSG reduces macrophages inflammasome activation via the P2X7R-NEK7-NLRP3 pathway.Conclusion: P2X7R-NEK7-NLRP3 inflammasome activation is a novel therapeutic mechanism of QSG in the treatment of acute myocardial ischemia.Keywords: acute myocardial ischemia, inflammation, macrophages, P2X7R-NEK7, NLRP3 inflammasome, Qishen granule

Qian Wang,1 Chen Yong,1 Min Wang,1 Lei Cui,1 Si-Ming Yuan1,2 1Department of Plastic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, People’s Republic of China; 2Department of Plastic Surgery, Jinling Hospital, Nanjing School of Clinical Medicine, Southern Medical University, Nanjing, 210002, People’s Republic of ChinaCorrespondence: Si-Ming Yuan, Department of Plastic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, People’s Republic of China, Email yuansm@163.comObjective: Refractory port-wine stain (PWS) usually contains hypertrophic, nodular lesions or severe scars due to improper treatment, making surgical treatment a necessity. This study aims to introduce our experiences in surgical management of refractory PWSs in the scalp and face.Methods: From January of 2013 to September of 2018, 25 patients with refractory PWSs in the scalp and face received surgeries in our department. Clinical manifestation of the disease, the surgical procedures and postoperative complications were reviewed. A Visual Analog Scale (VAS) was applied to evaluate the outcomes.Results: In this study, surgical procedures included serial resection (4 cases), complete resection followed by local flap transplantation (6 cases) or skin grafting (7 cases), and two-staged surgeries using expanded flaps (5 cases) or expanded prefabricated flap (3 cases). All the skin grafts and flaps survived well. Follow-up evaluation with VAS showed that most patients were satisfied with the surgery.Conclusion: The surgical procedures should depend on the site, area and type of the lesions and patients’ personal requirement. Individualized surgical treatment of refractory PWSs achieved satisfactory results in re-establishing symmetric facial contour and improving the overall appearance.Keywords: port-wine stain, surgery strategy, scalp and face

Luoyang Ma,1,2 Xiaoyan Zheng,1,3 Rui Lin,1 Antonia RuJia Sun,4 Jintong Song,1 Zhiqiang Ye,1 Dahong Liang,1 Min Zhang,1 Jia Tian,1 Xin Zhou,2 Liao Cui,1 Yuyu Liu,1 Yanzhi Liu1,3,5 1Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, School of Pharmacy, Guangdong Medical University, Zhanjiang City, Guangdong Province, 524023, People’s Republic of China; 2Marine Medical Research Institute of Zhanjiang, Zhanjiang City, Guangdong Province, 524023, People’s Republic of China; 3Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang city, Guangdong province, 524045, People’s Republic of China; 4Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen City, Guangdong Province, 518055, People’s Republic of China; 5Shenzhen Osteomore Biotechnology Co., Ltd., Shenzhen city, Guangdong Province, 518118, People’s Republic of ChinaCorrespondence: Yanzhi Liu; Yuyu Liu, Tel +86-759-2388405 ; +86-759-2388588, Email liuyanzhi02@163.com; liuyuyu77@163.comAbstract: Drug delivery for osteoarthritis (OA) treatment is a continuous challenge because of their poor bioavailability and rapid clearance in joints. Intra-articular (IA) drug delivery is a common strategy and its therapeutic effects depend mainly on the efficacy of the drug-delivery system used for OA therapy. Different types of IA drug-delivery systems, such as microspheres, nanoparticles, and hydrogels, have been rapidly developed over the past decade to improve their therapeutic effects. With the continuous advancement in OA mechanism research, new drugs targeting specific cell/signaling pathways in OA are rapidly evolving and effective drug delivery is critical for treating OA. In this review, recent advances in various IA drug-delivery systems for OA treatment, OA targeted strategies, and related signaling pathways in OA treatment are summarized and analyzed based on current publications.Keywords: osteoarthritis, knee, drug delivery, intra-articular

Dandan Zhao,1,2 Xiaoxiao Zhang,1,2 Yuhui Tang,1,2 Peilin Guo,1,2 Rong Ai,1,2 Mengmeng Hou,1,2 Yiqi Wang,1,2 Xiwei Yuan,1,2 Luyao Cui,1,2 Yuguo Zhang,1,2 Suxian Zhao,1,2 Wencong Li,1,2 Yang Wang,1,2 Xiaoye Sun,1,2 Lingdi Liu,1,2 Shiming Dong,1,2 Lu Li,1,2 Wen Zhao,1,2 Yuemin Nan1,2 1Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Yuemin Nan, Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, Hebei Province, 050051, People’s Republic of China, Tel +86 311-66781227, Fax +86 311-66781289, Email nanyuemin@163.comPurpose: The aim of this study was to identify and validate novel biomarkers for distinguishing among hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), liver fibrosis/liver cirrhosis (LF/LC) and chronic hepatitis B (CHB).Patients and Methods: Transcriptomic sequencing was conducted on the liver tissues of 5 patients with HCC, 5 patients with LF/LC, 5 patients with CHB, and 4 healthy controls. The expression levels of selected mRNAs and proteins were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical (IHC) staining, and were verified in validation set (n=200) and testing set (n=400) via enzyme-linked immunosorbent assay (ELISA).Results: A total of 9 hub mRNAs were identified by short time-series expression miner and weighted gene co-expression network analysis. Of note, the results of qRT-PCR and IHC staining demonstrated that SHC adaptor protein 1 (SHC1), SLAM family member 8 (SLAMF8), and interleukin-32 (IL-32) exhibited gradually increasing trends in the four groups. Subsequent ELISA tests on the validation cohort indicated that the plasma levels of SHC1, SLAMF8 and IL-32 also gradually increased. Furthermore, a diagnostic model APFSSI (age, PLT, ferritin, SHC1, SLAMF8 and IL-32) was established to distinguish among CHB, LF/LC and HCC. The performance of APFSSI model for discriminating CHB from healthy subjects (AUC=0.966) was much greater compared to SHC1 (AUC=0.900), SLAMF8 (AUC=0.744) and IL-32 (AUC=0.821). When distinguishing LF/LC from CHB, APFSSI was the most outstanding diagnostic parameter (AUC=0.924), which was superior to SHC1, SLAMF8 and IL-32 (AUC=0.812, 0.684 and 0.741, respectively). Likewise, APFSSI model with the greatest AUC value displayed an excellent performance for differentiating between HCC and LF/LC than other variables (SHC1, SLAMF8 and IL-32) via ROC analysis. Finally, the results in the test set were consistent with those in the validation set.Conclusion: SHC1, SLAMF8 and IL-32 can differentiate among patients with HCC, LF/LC, CHB and healthy controls. More importantly, the APFSSI model greatly improves the diagnostic accuracy of HBV-associated liver diseases.Keywords: HBV-associated liver diseases, transcriptome sequencing technology, SHC adaptor protein 1, SLAM family member 8, interleukin-32

Yu Zhang,1– 3,&ast; Li Cui,2,&ast; Yizeng Lu,4 Jixiang He,5 Hidayat Hussain,6 Lei Xie,4 Xuan Sun,2 Zhaoqing Meng,7 Guiyun Cao,7 Dawei Qin,1 Daijie Wang2,3 1School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, People’s Republic of China; 2School of Pharmaceutical Sciences and Key Laboratory for Applied Technology of Sophisticated Analytical Instruments of Shandong Province, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250014, People’s Republic of China; 3Biological Engineering Technology Innovation Center of Shandong Province, Heze Branch of Qilu University of Technology (Shandong Academy of Sciences), Heze, 274000, People’s Republic of China; 4Shandong Provincial Center of Forest and Grass Germplasm Resources, Jinan, 250102, People’s Republic of China; 5School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250353, People’s Republic of China; 6Department of Bioorganic Chemistry, Leibniz Institute of Plant BioChemistry, Halle, D-06120, Germany; 7Shandong Hongjitang Pharmaceutical Group Co., Ltd., Jinan, 250103, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dawei Qin, School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, People’s Republic of China, Tel/Fax +86 53189631208, Email qdw@qlu.edu.cn Daijie Wang, Biological Engineering Technology Innovation Center of Shandong Province, Heze Branch of Qilu University of Technology (Shandong Academy of Sciences), Heze, 274000, People’s Republic of China, Tel +86 53182605319, Fax +86 53182964889, Email wangdaijie@qlu.edu.cnBackground: The leaves of L. japonica (LLJ) are widely used as medicine in China. It is rich in caffeoylquinic acids, flavonoids and iridoid glycosides and has strong reducing capacities. Therefore, it can be used as a green material to synthesize silver nanoparticles.Methods: LLJ was used as a reducing agent to produce the LLJ-mediated silver nanoparticles (LLJ-AgNPs). The structure and physicochemical properties of LLJ-AgNPs were characterized by ultraviolet spectroscopy (UV-Vis), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and x-ray powder diffraction (XRD). Antioxidant activity of LLJ-AgNPs was determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging. Antibacterial activity was determined by 96 well plates (AGAR) gradient dilution, while the anticancer potential was determined by MTT assay.Results: The results showed LLJ-AgNPs had a spherical structure with the maximum UV-Vis absorption at 400 nm. In addition, LLJ-AgNPs exhibited excellent antioxidant properties, where the free radical scavenging rate of LLJ-AgNPs was increased from 39% to 92% at concentrations from 0.25 to 1.0 mg/mL. Moreover, LLJ-AgNPs displayed excellent antibacterial properties against E. coli and Salmonella at room temperature, with minimum inhibitory values of 10− 6 and 10− 5 g/L, respectively. In addition, the synthetic LLJ-AgNPs exhibited a better inhibition effect in the proliferation of cancer cells (HepG2, MDA-MB − 231, and Hela cells).Conclusion: The present study provides a green approach to synthesize LLJ-AgNPs. All those findings illustrated that the produced LLJ-AgNPs can be used as an economical and efficient functional material for further applications in food and pharmaceutical fields.Keywords: leaves of Lonicera japonica Thunb, LLJ-AgNO3-NPs, green approach, antioxidant, antibacterial, anticancer

Wanbing Feng,1– 6 Di Zhang,1– 6 Linlin Fu,1– 6 Jingmei Hu,1– 6 Shanshan Gao,1– 6 Xiaocui Song,1 Linlin Cui1– 6 1Center for Reproductive Medicine, Department of Reproductive Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 3Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, People’s Republic of China; 4Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China; 5Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, People’s Republic of China; 6National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Linlin Cui; Xiaocui Song, Center for Reproductive Medicine, Department of Reproductive Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 157, Jingliu Road, Shizhong District, Jinan, Shandong, People’s Republic of China, 250001, Tel +86 531 85651598, Fax +86 531 87068226, Email fdclear3@126.com; babyjuncong@163.comObjective: To investigate the effect of maternal estradiol (E2) elevation on long-term metabolic manifestations in the offspring.Study Design and Setting: This was a retrospective cohort study. Overall, 3690 children conceived by in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) between July 2014 and December 2017 were recruited and divided into four groups categorized by maternal E2 quartiles (Q1, < 2420; Q2, 2420– 3839; Q3, 3839– 5599; and Q4, ≥ 5599 pg/mL). The metabolic profiles were measured during childhood. Linear mixed models were used to evaluate the association between maternal E2 elevation and metabolic phenotypes of the offspring.Results: Lipoprotein cholesterol (LDL-C) was significantly higher in the highest quartile group than in the lowest quartile group during infancy (adjusted mean difference [95% confidence interval, CI]): 0.11 [0.02, 0.20], P = 0.005), but the difference disappeared in the later childhood phase. In children born after fresh embryo transfer, LDL-C showed an increasing trend with the increase in maternal E2 level (adjusted mean difference [95% CI]: Q2 vs Q1, − 0.01 [− 0.11, 0.08], Q3 vs Q1, 0.06 [− 0.04, 0.15], Q4 vs Q1, 0.10 [0, 0.20]). Other metabolic variables were comparable across increasing quartiles of maternal E2 levels.Conclusion: This study demonstrates a temporary increase in LDL-C levels in infants with higher levels of maternal preconception E2 levels. However, the long-term safety of hyperestrogens after ovarian stimulation in the next generation is favorable. The mechanism underlying the transiently increased metabolic dysfunction risk in infants conceived by IVF/ICSI requires investigation in future studies.Keywords: offspring, supraphysiologic estradiol, controlled ovarian hyperstimulation, assisted reproductive technology

Xi Zhang,1,&ast; Hongyan Wang,1,&ast; Chenzhen Du,1 Xiaoyun Fan,2 Long Cui,3 Heming Chen,4 Fang Deng,5 Qiang Tong,6 Min He,7 Mei Yang,8 Xingrong Tan,9 Lin Li,10 Zerong Liang,11 Yaqin Chen,12 Deqing Chen,13 David G Armstrong,14 Wuquan Deng1 1Department of Endocrinology, Chongqing University Central Hospital, Chongqing University, Chongqing, People’s Republic of China; 2Department of Endocrinology, Hospital for Occupational Diseases of Chongqing, Chongqing, People’s Republic of China; 3Department of Endocrinology, Armed Police Hospital of Chongqing, Chongqing, People’s Republic of China; 4Department of Endocrinology, Ankang Central Hospital, Ankang, Shaanxi, People’s Republic of China; 5Department of Endocrinology, Chongqing Southwest Hospital, Chongqing, People’s Republic of China; 6Department of Endocrinology, Chongqing Xinqiao Hospital, Chongqing, People’s Republic of China; 7Department of Endocrinology, The People’s Hospital of Shapingba District, Chongqing, People’s Republic of China; 8Department of Endocrinology, The First People’s Hospital of Chongqing Liangjiang New Area, Chongqing, People’s Republic of China; 9Department of Endocrinology, The 9th People’s Hospital of Chongqing, Chongqing, People’s Republic of China; 10Department of Endocrinology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, People’s Republic of China; 11Department of Endocrinology, Chongqing Red Cross Hospital, People’s Hospital of Jiangbei District, Chongqing, 400020, People’s Republic of China; 12Department of Endocrinology, The People’s Hospital of Shizhu, Chongqing, People’s Republic of China; 13Department of Endocrinology, The People’s Hospital of Rongchang, Chongqing, People’s Republic of China; 14Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA&ast;These authors contributed equally to this workCorrespondence: Wuquan Deng Email wuquandeng@cqu.edu.cnBackground: Recurrence of high-risk diabetic feet, after wound, healing is a common challenge among diabetic patients. Continuous use of an offloading device significantly prevents recurrence of high-risk diabetic feet, although patient adherence is imperative to ensuring this therapy’s clinical efficacy. In this study, we explored clinical outcomes of patients with a high-risk diabetic foot who had been prescribed with custom-molded offloading footwear under different adherence conditions.Methods: A total of 48 patients (17 females and 31 males) with high-risk diabetic feet, who had been with prescribed offloading footwear in 13 medical centers across 4 cities, were enrolled in the current study. The patients were assigned into either continuous offloading therapy (COT, n = 31) or interrupted offloading therapy (IOT, n = 17) groups, according to their adherence to the therapy. All patients were followed up monthly, and differences in recurrence, amputation, and deaths between the groups were analyzed at 4 months after therapy.Results: Forty-eight patients met our inclusion criteria and were therefore included in the final analysis. Among them, 31 were stratified into the COT group and adhered to offloading therapy throughout the study period, whereas 17 were grouped as IOT and exhibited interrupted adherence to offloading therapy. We found statistically significant differences in recurrence rates (0 vs 38.46%, p < 0.01), amputation (0 vs 11.76%, p < 0.01), and deaths (0% vs 5.88%, p < 0.01) between the groups during follow-up.Conclusion: Patients’ adherence is imperative to efficacy of custom-molded offloading footwear during treatment of high-risk diabetic foot. Further studies are needed to elucidate the role of improved design of the offloading device and the need for enhanced patient education for improved adherence.Keywords: custom-molded offloading footwear, high-risk diabetic foot, patient adherence

Xiaojiao Zheng,1,2 Xiuyi Lv,1 Linyan Zhu,1 Kejun Xu,1 Cong Shi,1 Lining Cui,1 Huiqing Ding1 1Department of Obstetrics and Gynecology, Ningbo First Hospital, Ningbo, Zhejiang, 315035, People’s Republic of China; 2Department of Biochemistry & Genetics, The National Education Base for Basic Medical Sciences, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang Province, People’s Republic of ChinaCorrespondence: Lining Cui; Huiqing Ding Email 1935148739@qq.com; 1209256240@qq.comBackground: Mounting evidence indicates altered circadian rhythm represents a critical factor affecting carcinogenesis and tumor progression. The circadian gene neuronal PAS domain protein 2 (NPAS2) constitutes a newly discovered prognostic biomarker. NPAS2 dysregulation is found in multiple malignancies, although its functions in uterine corpus endometrial carcinoma (UCEC) remain largely unknown.Objective: To evaluate NPAS2’s roles in UCEC and to explore the underlying mechanisms.Methods: NPAS2 transcription levels, patient prognosis, different clinical stages and target microRNAs in UCEC cases were comparatively assessed based on public databases, including UALCAN, GEPIA, TIMER, Kaplan–Meier plotter, starBase database, LinkedOmics and String. Then, qRT-PCR and immunohistochemical analysis were applied to analyze the expression of NPAS2 in UCEC tissue samples. CCK-8, clonogenic assay and flow cytometry were carried out for detecting cell viability, colony formation ability and cell apoptosis, respectively.Results: NPAS2 was upregulated in tissue samples from UCEC cases compared with the corresponding control specimens. NPAS2 overexpression was associated with decreased overall (OS), disease free (DFS) and relapse free (RFS) survival in UCEC. In addition, NPAS2 overexpression was associated with clinical stage, tumor grade, estrogen receptor status, myometrial invasion in UCEC. Furthermore, NPAS2 knockdown or overexpression altered cell proliferation and apoptosis in UCEC. Moreover, NPAS2 showed significant negative correlations with miR-17-5p and miR-93-5p, and positive correlations with miR-106a-5p and miR-381-3p in UCEC.Conclusion: NPAS2 overexpression is associated with poor prognosis and clinicopathological characteristics in UCEC and promotes proliferation and colony formation while inhibiting apoptosis. Finally, NPAS2 is associated with several miRNAs in UCEC.Keywords: NPAS2, circadian rhythm, cell cycle, apoptosis, uterine corpus endometrial carcinoma

Lingyun Cui,1 Ping Lu,1 Shiyu Li,1 YueSong Pan,2 Mengxing Wang,2 Zixiao Li,1,2 Xiaoling Liao,1,2 Yongjun Wang1,2 1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of ChinaCorrespondence: Yongjun WangDepartment of Neurology, Beijing Tiantan Hospital, Capital Medical University, 119#Nan Si Huan Xi Lu, Beijing, 100070, People’s Republic of ChinaTel +86 10-59978351Email yongjunwang@ncrcnd.org.cnPurpose: To investigate the associations among homocysteine (Hcy), inflammation and cognitive impairment in patients with acute ischemic stroke (AIS) and transient ischemic attack (TIA).Patients and Methods: Patients included were enrolled from a subgroup of China National Stroke Registry-III (CNSR-III). We used a Chinese version of Montreal Cognitive Assessment (MoCA) to screen for cognitive impairment. We used high-sensitivity C-reactive protein (hsCRP) level to reflect the inflammatory status, which was assessed at baseline together with Hcy concentration. The primary outcome was the incidence of post-stroke cognitive impairment (PSCI) at 3 months after AIS and TIA. Multivariable logistic regression analysis was used to evaluate the correlation between Hcy and hsCRP, and their effects on cognition.Results: We enrolled 1466 patients with a median age of 62 (54– 70) years old, including 895 (61.05%) patients with elevated Hcy levels, 466 (31.79%) with increased hsCRP concentrations, and 755 (51.50%) with PSCI. In the group of patients with hyperhomocysteinemia (HHcy), higher hsCRP levels were related to cognitive impairment, whether or not adjusted for multiple potential confounders (crude OR: 1.71,95% CI: 1.29– 2.27, p < 0.01; adjusted OR: 1.42, 95% CI: 1.04– 1.93, p = 0.03). No significant interactions for the impact on PSCI were observed in subgroups stratified by age, sex or Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification (P interaction > 0.05 for all).Conclusion: High inflammatory levels increase the risk of cognitive impairment in HHcy patients after AIS and TIA.Keywords: stroke, transient ischemic attack, inflammation, homocysteine, cognitive function

Luyao Zhang,&ast; Shujuan Dong,&ast; Wenbo Zhao, Jingchao Li, Luqian Cui, Yongmei Han, Yingjie Chu Department of Cardiology, Henan Provincial People’s Hospital, Zhengzhou, Henan Province, 450003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingjie Chu Email Chuyingjie59@163.comBackground: This study determined the ischaemic J wave pattern associated with ventricular fibrillation (VF).Methods: A total of 262 patients diagnosed with ST-elevation myocardial infarction (STEMI) were recruited from October 2017 to September 2020. All data were collected and analysed, including baseline characteristics, electrocardiogram (ECG), coronary angiography (CAG), and examination outcomes.Results: There were 193 STEMI patients with J wave elevation but without an ischaemic J wave (NJ group) and 69 patients with an ischaemic J wave; the latter were then subgrouped into early repolarization pattern (ERP; n=62) and Brugada pattern groups (BrP [anteroseptal ERP]; n=7). Univariate and multivariate logistic regression analyses were used to clarify high-risk factors and characteristics of ischaemic J waves. Multivariate logistic regression analysis revealed that an ischaemic J wave (odds ratio [OR], 9.708; 95% CI, 2.570– 36.664; P=0.01) independently predicted VF. In the subgroup analysis, BrP (OR, 31.214; 95% CI, 3.949– 246.742; P=0.001), slur morphology of the ERP (OR, 8.15; 95% CI, 1.563– 42.558; P< 0.05), and the number of leads with an ischaemic J wave > 3 (OR, 16.174; 95% CI, 3.064– 85.375; P=0.001) were significantly associated with VF occurrence after adjusting for multiple variables.Conclusion: An ischaemic J wave is an independent risk factor for VF in STEMI patients. BrP, slur morphology, and > 3 leads with an ischaemic J wave could increase the incidence of VF.Keywords: STEMI, ischaemic J wave, classification, predictor, ventricular fibrillation

Yajun Zhang,1,* Biao Meng,2,3,* Xiao Wei,2,* Yan Li,2 Xiaohui Wang,1 Yan Zheng,1 Changjun Wang,2,3 Lihong Cui,1 Xiangna Zhao2,3 1Department of Gastroenterology, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China; 2Centre for Disease Control and Prevention of China PLA, Beijing, People’s Republic of China; 3Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lihong Cui; Xiangna Zhao Tel +86-10-66948393Fax +86-10-66948304Email luckycui861@sina.com; xnazhao@163.comBackground: Pseudomonas aeruginosa is an important nosocomial infectious bacterium, more and more multidrug resistant P. aeruginosa have been isolated and posed severe challenges to clinical antibiotic treatment, bringing additional morbidity, mortality, and economic burden. Bacteriophages can lyse bacteria specificity and are feasible alternatives to antibiotics.Methods: A Pseudomonas aeruginosa-infecting phage vB_PaeP_PA01EW was isolated. Phage plaque assays, transmission electron microscopy, host-range determination, infection assay analyses, whole-genome sequencing and annotation were performed for the phage. Mice pneumonia model using liquid aerosol-exposure Pseudomonas aeruginosa was established, and phage therapy was evaluated.Results: vB_PaeP_PA01EW belongs to the family Podoviridae according to transmission electron microscopy and was identified as a Luz24likevirus according to the genome analysis. For the phage therapy, compared with the bacteria-infected group, the phage-rescue group has some characteristics. First, adventitial edema and diffuse infiltration of inflammatory cells in tissues were alleviated, Second, bronchial epithelial cell proliferation was reduced. Third, the bacterial burden was significantly decreased.Conclusion: This study provided data support and theoretical basis for the clinical application of bacteriophages. It has important guiding significance and reference value for the application of bacteriophage therapy of other pathogenic bacteria.Keywords: P. aeruginosa, bacteriophage, vB_PaeP_PA01EW, aerosol-exposure

Ping Lu,1 Lingyun Cui,1 Xingquan Zhao1– 3 1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2China National Clinical Research Center for Neurological Diseases, Capital Medical University, Beijing, People’s Republic of China; 3Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Xingquan ZhaoDepartment of Neurology, Beijing Tiantan Hospital, Capital Medical University, Chinese Academy of Medical Sciences, 119#Nan Si Huan Xi Lu, Beijing, 100070, People’s Republic of ChinaTel +86 180-1021-2600Email zxq@vip.163.comPurpose: We aimed to determine the prognostic impact of prominent veins (PVS) after an acute ischemic stroke identified on susceptibility-weighted imaging (PVS-SWI).Methods: We searched for studies published in PubMed, Embase, Cochrane Library and Chinese Biomedical Literature Database. Poor functional prognosis, early neurological deterioration, and hemorrhagic transformation were evaluated. Risk ratios (RR) were pooled implementing a random effect model. We performed a subgroup analysis by treatment, location (cortical/medullary) and a sensitivity analysis by follow-up time.Results: Sixteen studies were included (a total of 1605 patients) in the quantitative meta-analysis. PVS-SWI were related with a poor functional outcome (RR 1.62, 95% CI 1.25 to 2.10), especially in the patients receiving thrombolysis (RR 2.19, 95% CI 1.53 to 3.15) and an augmented risk of early neurological damage (RR 2.85, 95% CI 2.31 to 3.51). Both cortical and medullary prominent veins were accompanied by a poor functional outcome (RR 1.82, 95% CI 1.30 to 2.56/RR 2.59, 95% CI 1.98 to 3.38). PVS-SWI were not associated with poor functional outcomes when patients were treated conservatively (RR 1.35, 95% CI 0.82 to 2.22), or with an increased risk of hemorrhagic transformation (RR 0.97, 95% CI 0.64 to 1.47).Conclusion: PVS-SWI were related to a poor functional prognosis and an increased risk of early neurological damage. In patients treated conservatively, PVS-SWI were not accompanied by a poor prognosis. PVS-SWI were not associated with an augmented risk of hemorrhagic transformation.Keywords: SWI, prominent veins, stroke, ischemic stroke, meta-analysis

Li Cui,1 Zirong Zhu,2 Yiguo Feng,3 Yanfei Zhang3 1Department of Dermatology, Shaanxi Provincial People’s Hospital, Xian, People’s Republic of China; 2Department of Dermatology, Xi’an People’s Hospital, Xian, People’s Republic of China; 3Department of Dermatology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xian, People’s Republic of ChinaCorrespondence: Yanfei ZhangDepartment of Dermatology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xian, People’s Republic of ChinaEmail zhangyanfei723@163.comPurpose: Keratin 17 (K17) is an embryonic keratin and overexpression is seen in psoriasis, which is a hyperproliferation skin disease. Nonetheless, whether it is also highly expressed in other proliferative skin diseases remains unclear. The aim of this study is to explore the expression of K17 in cutaneous lichen planus (CLP), lichen simplex chronicus (LSC), and prurigo nodularis (PN).Methods: A total of 20 skin samples from CLP lesions, 20 from LSC lesions, 20 from PN lesions, and 10 healthy adult skin tissues were obtained. Then, the expression of K17 was analyzed using immunohistochemistry on paraffin-embedded tissue sections. Furthermore, quantitative and semi-quantitative immunohistochemical scores of K17 were independently evaluated under a microscope by 2 dermatologists.Results: Immunohistochemical analysis revealed that in normal skin, K17 was minimally expressed. Nevertheless, it was highly expressed in all epidermal layers in CLP lesions (P-value < 0.01), and negatively expressed in LSC and PN lesions (all P-value > 0.05). The average gray value of K17 in CLP was 151.153± 13.985 (P-value < 0.001), while the average values of K17 in LSC and PN were 178.720± 12.001 and 181.316± 8.920, respectively (all P-value > 0.05).Conclusion: K17 is potentially expressed in certain inflammatory skin diseases, including psoriasis and lichen planus. Besides, it is not always a marker of hyperproliferation of keratinocytes in skin diseases.Keywords: keratin 17, proliferation of keratinocytes, inflammatory skin diseases

Qingqing Sun, Pingping Shen, Jiayi Tang, Hongmei Meng, Jiachun Feng, Zan Wang, Li Cui Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Zan Wang; Li Cui Email wangzan@jlu.edu.cn; wangzanprof@163.com; lcui@jlu.edu.cnAbstract: Creutzfeldt–Jakob disease (CJD) subtypes are difficult to identify due to the heterogeneity of the clinical phenotype, and early accurate identification of sporadic CJD (sCJD) subtypes aids prognosis prediction. Currently, the diagnosis of sCJD subtypes is mainly based on brain tissue biopsy or autopsy. In this report, we present a case of confirmed sCJD initially presenting as insomnia. We described detailed information including clinical, electroencephalographic, polysomnographic, positron emission tomography-computed tomographic and other neuroimaging findings, cerebrospinal fluid biomarkers, skin tissue biopsy and whole blood PRNP gene sequencing in this patient. An extensive literature search was performed in order to better understand the diagnosis of various sCJD subtypes, particularly the thalamic form, sCJDMM2 (also known as sporadic fatal insomnia). Our study highlights sporadic fatal insomnia as a differential diagnosis of sCJD.Keywords: sporadic Creutzfeldt–Jakob disease, sporadic fatal insomnia, sCJDMM, polysomnography, PET

Yijin Yu,1 Lingyan Cui,1 Lu Qian,1 Min Lei,1 Qi Bao,1 Qingxin Zeng,2 Zhao Chen,2 Shaohua Xu,2 Junran Xie1 1Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Junran XieDepartment of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun Road East, Jianggan District, Hangzhou, Zhejiang, People’s Republic of ChinaTel +86 13858126216Email xiejunran@zju.edu.cnBackground: Chronic post-thoracotomy pain is still an obstacle for lung-cancer patients even after less invasive surgical procedures. It is unclear whether intercostal analgesia is as useful in the prevention of postoperative chronic pain as it is for acute pain for video-assisted thoracoscopic surgery (VATS). The purpose of this study was to evaluate the efficacy of perioperative intercostal analgesia for chronic pain via a multimodal analgesic regimen for VATS during 6 months of postoperative follow-up.Methods: We identified 837 cases of VATS from August 2016 to August 2018. Patients were treated by perioperative intercostal analgesia with 0.75% ropivacaine 50 mg through the intercostal catheter every 8 hours until chest tube extubation (INA group) or conventional analgesia with preoperative 0.75% ropivacaine 50 mg at incision once (CON group). Numerical rating scale (NRS) and neuropathic pain were evaluated in 6 months of post-surgery follow-up. Postoperative adverse effects were recorded.Results: In total, there were 419 patients in INA group and 418 patients in CON group. Scores of NRS with motion was lower in INA group at 3 postoperative days (P = 0.032). Occurrence of chronic pain was 28.4% in INA group and 32.8% in CON group at 6 postoperative months, 10.6% of patients experienced increasing pain from 3 to 6 months. Occurrence of considerable neuropathic pain (ID pain score ≥ 2) was 2.1% in INA group and 3.1% in CON group at 6 postoperative months. No differences were found between the two groups. Occurrence of numbness was lower in INA group (6.7% vs 10.5%, P = 0.031), and other pain symptoms did not differ between the groups. The incidence of dizziness, nausea, vomiting and atelectasis was not different between the two groups.Conclusion: In a multimodal analgesic regimen of VATS, perioperative intercostal analgesia with 0.75% ropivacaine infusion 50 mg three times in a day does not have an obvious effect on chronic post-thoracotomy pain.Keywords: chronic pain, neuropathic pain, intercostal analgesia, video-assisted thoracoscopic surgery

Jun-Da Li,1– 3 Le Cui,1– 3 Ying-Yang Xu,1– 3 Kai Guan1– 3 1Department of Allergy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2Beijing Key Laboratory of Precision Medicine for Diagnosis and Treatment on Allergic Diseases, Beijing, People’s Republic of China; 3National Clinical Research Center for Dermatologic and Immunologic Disease, Beijing, People’s Republic of ChinaCorrespondence: Kai GuanDepartment of Allergy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan, Wangfujing, Beijing, 100730, People’s Republic of ChinaTel/Fax +86 10-69156346Email dr_guankai@126.comPurpose: Royal jelly and honeycomb are commonly consumed in China, and anaphylaxis caused by ingestion of royal jelly is rare. To date, there is no report of anaphylaxis after ingestion of royal jelly in China. Its cross-reactivity with honeycomb is still unclear.Case Report: A 56-year-old Chinese female experienced two episodes of anaphylaxis within 1 hour after ingestion of royal jelly within one month. After avoiding royal jelly and other bee products, no anaphylactic reaction occurred again. The skin prick test and basophil activation test showed positive reactivity to royal jelly and honeycomb. In immunoblotting and immunoblotting inhibition tests, a 60 kDa protein was recognized in royal jelly and cross-reactivity with honeycomb. The mass spectrometry data revealed that the 62kDa protein belongs to major royal jelly protein 3.Conclusion: Our data suggest that major royal jelly protein 3 of royal jelly is a main allergen that induces anaphylaxis and cross-reactivity with honeycomb. Therefore, the patient was allergic to royal jelly to avoid other bee products.Keywords: royal jelly, honeycomb, major royal jelly protein 3, anaphylaxis

Hai Luo,1,* Lingzhi Cui,2,* Kexin Shen,1 Ruiqi Li,1 Zeming Wang,1 Zhongshi Xie1 1Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2General Surgery, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhongshi XieChina-Japan Union Hospital of Jilin University, 126 Xian Tai Street, Changchun, Jilin Province, 130033, People’s Republic of ChinaTel +86 13944108332Email surgeonxzs@163.comPurpose: This study was designed to investigate the correlation between the expression of human epidermal growth factor receptor 2 (HER2), mismatch repair (MMR), and clinicopathological parameters and serum tumor markers in a total of 522 resection samples materials from colorectal cancer (CRC) patients. These data were also used to determine the links between HER2 and MMR expression and prognosis.Methods: We conducted a retrospective analysis of the clinical data from 522 CRC patients. Immunohistochemistry (IHC) was used to detect HER2 overexpression and MMR deficiency (dMMR) in tumor specimens which were then correlated with various clinicopathological parameters. Prognostic value for HER2 and MMR expression was then evaluated using the data from 105 CRC patients.Results: HER2 overexpression was identified in 35.63% of the samples evaluated in this study, while the total dMMR rate was 12.64%. Expression of HER2 and several, MMR proteins (MLH1, MSH-2, MSH-6, and PMS-2) were then correlated with tumor location. HER2 overexpression is significantly associated with increased depth of tumor invasion, lymph node metastasis, distant metastases, pTNM staging, vascular invasion, nerve infiltration, and serum carcinoembryonic antigen (CEA) levels. HER2 overexpression and dMMR increased with advancing clinical stage. In addition, deficiencies in MLH1 and PMS2 correlated with HER2 overexpression. Finally, the prognostic evaluations revealed that HER2 overexpression was closely associated with poorer clinical outcomes.Conclusion: HER2 overexpression is significantly correlated with multiple clinicopathological parameters resulting in a poorer prognosis. Moreover, the prognosis of patients with HER2 overexpression was worse, confirming its significance during disease assessment. In clinical practice, clinicians should pay close attention to the HER2 profile of patients as they may require more extensive clinical intervention. In addition, deficiencies in MLH1, MSH-2, MSH-6, or PMS-2 correlate with tumor location, and MLH1 and PMS2 expression is associated with lymph node metastasis and pTNM stage, suggesting that these may be additional markers in CRC risk assessments.Keywords: human epidermal growth factor receptor 2, mismatch repair deficiency, colorectal cancers, prognosis

Tong Yu,1,2,* Jinglue Song,1,2,* Hui Zhou,1,2 Tingyu Wu,1,2 Zhonglin Liang,1,2 Peng Du,1,2 Chen-Ying Liu,1,2 Guanghui Wang,3 Long Cui,1,2 Yun Liu1,2 1Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Shanghai Colorectal Cancer Research Center, Shanghai, People’s Republic of China; 3Guizhou Provincial People’s Hospital, Guizhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun Liu Tel + 86-021-25078825Email liuyun@xinhuamed.com.cnGuanghui Wang Email wangguanghui0625@163.comIntroduction: Stage I–III colorectal cancer patients are under risk of tumor recurrence and metachronous metastasis after radical surgery. An increased expression of transcription factor TEAD4 is associated with epithelial-mesenchymal transition, metastasis and poor prognosis in colorectal cancer. However, the mechanistic role of TEAD4 in driving colon cancer progression and its prognostic value in early stage of CRC remains unclear.Methods: In this study, the regulation, function and prognostic significance of TEAD4 and its new direct target gene SIX1 in CRC progression were evaluated using human tissues, molecular and cell biology.Results: We show that TEAD4 directly upregulates the expression of SIX1 at transcriptional level in CRC cells, establishing that SIX1 is a new direct target gene of TEAD4. TEAD4 promotes EMT and cell migration of CRC cells, while SIX1 knockdown attenuates this effect and SIX1 overexpression enhances this effect, indicating that SIX1 mediates the function of TEAD4 in promoting cell migration in CRC cells. Clinically, nuclear TEAD4, overexpression of SIX1 and nuclear TEAD4 with SIX1 overexpression predict poor prognosis in CRC patients.Discussion: Our study identifies TEAD4-SIX1-CDH1 form a novel signaling axis, which contributes to CRC progression, and its aberrant expression and activation predicts poor prognostic for CRC patients in stage I–III.Keywords: colorectal cancer, TEAD4, SIX1, hippo pathway

Liwei Cui,1 Haijun Li,2 Mengshuang Xie,1 Xia Xu,2 Yingmei Zhang,3 Wei Wang,1 Shuang Dou,1 Wei Xiao1 1Department of Pulmonary Medicine, Qilu Hospital, Shandong University, Jinan, People’s Republic of China; 2Department of Cadre Health Care, Qilu Hospital, Shandong University, Jinan, People’s Republic of China; 3Department of Pulmonary Medicine, Linyi People’s Hospital, Linyi, People’s Republic of ChinaCorrespondence: Wei XiaoDepartment of Pulmonary Medicine, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan 250012, People’s Republic of ChinaEmail xiaowei4226@163.comBackground and Objective: The link between ADAM9 and airway remodeling and emphysema severity in COPD patients has not been elucidated. Here, we investigated the relationship between ADAM9 levels in sputum and airway epithelium and the clinical characteristics of COPD patients.Methods: A sputum cohort and a lung tissue cohort were included in the study. Pulmonary function and computed tomography data were analyzed in COPD patients, non-COPD smokers, and non-smokers. Soluble ADAM9 and interleukin 8 (IL-8) levels in sputum supernatants as well as surface ADAM9 expression in airway epithelium were detected. Emphysema scores were calculated by the percentage of low attenuation area (%LAA-950), and airway remodeling was measured via airway thickening and loss of airway counts.Results: Both soluble ADAM9 levels in sputum and relative surface ADAM9 expression in airway epithelium were increased in COPD patients. Sputum ADAM9 levels were negatively correlated with forced expiratory volume in 1 s of predicted (FEV1% of predicted) and positively correlated with sputum IL-8 levels, but not with CT measured emphysema nor airway remodeling. The ADAM9 expression in airway epithelia was positively correlated with %LAA-950 and airway wall thickening parameters (wall area percentage, WA%; the square root of the wall area in a standard airway with a 10 mm internal perimeter, Pi-10), while negatively correlated with airway counts derived from the 4th to 9th bronchial generations.Conclusion: Airway ADAM9 levels in sputum and airway epithelium were both elevated in COPD patients compared to non-COPD controls. Sputum ADAM9 seemed to be associated with inflammatory responses in COPD, while epithelial ADAM9 was more correlated with emphysema and airway remodeling.Keywords: chronic obstructive pulmonary disease, proteinase with a disintegrin and a metalloproteinase domain-9, computed tomography, emphysema, airway remodeling

Lan Cui,1,* Wentao Liu,1,* Hao Liu,1 Qian Qin,1,2 Shuangxia Wu,1 Suqin He,1,3 Zhenya Zhang,4 Xinchang Pang,1 Chengshen Zhu1 1School of Materials Science and Engineering, Zhengzhou University, Zhengzhou 450001, People’s Republic of China; 2Bio & Soft Matter, Institute of Condensed Matter and Nanosciences, Universite Catholique de Louvain, Louvain-la-Neuve B-1348, Belgium; 3Henan Key Laboratory of Advanced Nylon Materials and Application, Zhengzhou University, Zhengzhou 450001, People’s Republic of China; 4Department of Chemistry, Changwon National University of Korea, Changwon-city, Gyeongnam-do 51140, Republic of Korea*These authors contributed equally to this workCorrespondence: Wentao Liu; Hao LiuSchool of Materials Science and Engineering, Zhengzhou University, Zhengzhou 450001, Henan Province, People’s Republic of ChinaEmail wtliu@zzu.edu.cn; hliu@zzu.edu.cnBackground: Although pH and redox sensitiveness have been extensively investigated to improve therapeutic efficiency, the effect of disulfide bonds location and pH-triggered charge-reversal on cascade-targeting still need to be further evaluated in cancer treatment with multi-responsive nanoparticles.Purpose: The aim of this study was to design multi-responsive DOX@MSNs-COS-NN-CMC, DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS and systematically investigate the effects of disulfide bonds location and charge-reversal on the cancer cell specificity, endocytosis mechanisms and antitumor efficiency.Results: In vitro drug release rate of DOX@MSNs-COS-SS-CMC in tumor environments was 7-fold higher than that under normal physiological conditions after 200 h. Furthermore, the fluorescence intensity of DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS was 1.9-fold and 1.3-fold higher than free DOX at pH 6.5 and 10 mM GSH. In addition, vesicular transport might be a factor that affects the uptake efficiency of DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS. The clathrin-mediated endocytosis and endosomal escape of DOX@MSNs-COS-SS-CMC enhanced cellular internalization and preserved highly controllable drug release into the perinuclear of HeLa cells. DOX@MSNs-COS-SS-CMC exhibited a synergistic chemotherapy in preeminent tumor inhibition and less side effects of cardiotoxicity.Conclusion: The cascade-targeting of charge-reversal and disulfide bonds shielding would be a highly personalized strategy for cervical cancer treatment.Keywords: disulfide bonds, pH-triggered charge-reversal, redox sensitive, chitosan oligosaccharide, human cervical carcinoma therapy

Xu Zhou,1 Jun Chen,2 Hua Tao,1,2 Yujie Cai,1 Lidan Huang,1 Haihong Zhou,2 Yanyan Chen,1 Lili Cui,1 Wangtao Zhong,2 Keshen Li3 1Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People’s Republic of China; 2Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People’s Republic of China; 3Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524001 China; Stroke Center, Neurology & Neurosurgery Division, Clinical Medicine Research Institute & The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510630, People’s Republic of ChinaCorrespondence: Hua Tao; Keshen LiAffiliated Hospital of Guangdong Medical University No. 57, Renmindadaonan Road, Xiashan District, Zhanjiang, Guangdong 524001, People’s Republic of ChinaTel/ Fax +86 759 2387 427; +86 759 2386 772 Email taohua1943@126.com; likeshen1971@126.comIntroduction: To confront the resistance to existing antiepileptic drugs, studies have gradually begun to investigate alternative pathologies distinct from the traditional treatments that overwhelmingly target ion channels. Microglia activation is the first inflammatory response in the brain, in which miR-155-5p plays a key proinflammatory role and thus represents a promising target for inflammatory modulation in epilepsy pathologies.Methods: In this study, a pentetrazol-induced acute seizure model was established, and the seizure degree was evaluated within 60 min after pentetrazol administration. Animals were then sacrificed for hippocampal tissue collection for biological experiments.Results: Intranasal delivery of miR-155-5p antagomir (30 min before pentetrazol administration) increased the percentage of animals with no induced seizures by 20%, extended the latency to generalized convulsions, and decreased seizure severity. In addition, miR-155-5p antagomir treatment alleviated hippocampal damage and decreased the expression of typical inflammatory modulators (TNF-α, IL-1β and IL-6). Further research revealed that intranasal delivery of miR-155-5p antagomir significantly decreased the relative level of miR-155-5p and increased the expression of its targets LXRα and SOCS1 in IBA1-labeled microglial cells in the hippocampus.Conclusion: These findings demonstrate that intranasal delivery of miR-155-5p antagomir alleviated acute seizures, likely by blocking hippocampal inflammation. However, other potential mechanisms of the effects of miR-155-5p antagomir and its long-term safety for epilepsy treatment remain to be investigated.Keywords: intranasal delivery, epilepsy, pentetrazol, inflammatory response, miR-155-5p

Lei Gao,1,2 Andrew SP Lim,3 Patricia M Wong,4 Arlen Gaba,2 Longchang Cui,2 Lei Yu,5 Aron S Buchman,5 David A Bennett,5 Kun Hu,2,6 Peng Li2,6 1Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; 2Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA 02115, USA; 3Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, USA; 4Department of Psychology, University of Pittsburgh, Pittsburgh, PA 15260, USA; 5Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA; 6Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USACorrespondence: Lei GaoDepartment of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USATel +1 617 888-2941Fax +1 617 732-7337Email lgao@mgh.harvard.eduPeng LiDivision of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA 02115, USATel +1 617 278-0061Fax +1 617 732-7337Email pli9@bwh.harvard.eduStudy Objectives: Heart failure has previously been linked to sleep disorders that are often associated with frequent disturbances to human rest/activity patterns. We tested whether fragmentation of sustained rest/activity patterns derived from actigraphic recordings at baseline predicts incident heart failure in community-based elderly individuals.Methods: We studied 1099 community-based elderly adults participating in the Rush Memory and Aging Project who had baseline motor activity monitoring up to 11 days and were followed annually for up to 14 years. Fragmentation was assessed using previously validated indexes, derived from the probability of transitions once sustained rest or activity has been established. Heart failure was recorded via a clinical interview during the annual follow-up. Cox proportional hazards models were constructed to examine the relationship between rest fragmentation index and incident heart failure. Covariates grouped in terms of demographics, lifestyle factors and co-morbidities and cardiovascular risk factors/diseases were included.Results: Increased rest fragmentation (but not activity fragmentation) was associated with higher risk for incident heart failure. Specifically, a subject with a rest fragmentation at the 90th percentile showed a 57% increased risk of developing incident heart failure compared to a subject at the 10th percentile in this cohort. This effect was equivalent to that of being over a decade older. These observations were consistent after adjusting for all covariates.Conclusion: Increased rest fragmentation, a potential surrogate for sleep fragmentation, is independently associated with a higher risk of developing heart failure in community-based elderly adults during up to 14 years of follow-up. Further work is required to examine the specific contributions from daytime napping versus nighttime sleep periods in the elderly, as well as the underlying autonomic and cardio-dynamic pathways that may explain the effects on heart function.Keywords: sleep fragmentation, heart failure, mobile health, unobtrusive monitoring

Mengshuang Xie, Liwei Cui, Jinhuan Liu, Wei Wang, Jun Li, Wei Xiao Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Wei XiaoDepartment of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, People’s Republic of ChinaTel/ Fax +86 53182166294Email xiaowei4226@163.comBackground and Objective: The reference equations and diagnostic criteria play a critical role in the interpretation of pulmonary function tests (PFTs). The aim was to investigate the impacts of different reference equations and diagnostic criteria on the frequency of airway obstruction in adult people of a large teaching hospital of North China.Methods: The spirometry data of all adult people who underwent PFTs in Qilu hospital from April 2012 to November 2015 were collected. Two spirometry reference equations, namely, Zhongshan-2011 and Global Lung Function Initiative 2012 (GLI-2012) were compared. The frequency of airway obstruction using different spirometry prediction equations and diagnostic criteria including forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 92% of predicted value and FEV1/FVC

Mária Budai-Szűcs, 1 Attila Léber, 1 Lu Cui, 2, 3 Muriel Józó, 2, 3 Péter Vályi, 4 Katalin Burián, 5 Balázs Kirschweng, 2, 3 Erzsébet Csányi, 1 Béla Pukánszky 2, 3 1Institute of Pharmaceutical Technology and Regulatory Affairs, Faculty of Pharmacy, University of Szeged, Szeged, Hungary; 2Laboratory of Plastics and Rubber Technology, Department of Physical Chemistry and Materials Science, Budapest University of Technology and Economics, Budapest H-1521, Hungary; 3Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest H-1519, Hungary; 4Department of Periodontology, Faculty of Dentistry, University of Szeged, Szeged, Hungary; 5Institute of Clinical Microbiology, Faculty of Medicine, University of Szeged, Szeged, HungaryCorrespondence: Mária Budai-SzűcsInstitute of Pharmaceutical Technology and Regulatory Affairs, Faculty of Pharmacy, University of Szeged, Eötvös utca 6, Szeged 6720, HungaryTel +36 62 545-573Fax +36 62 545-571Email maria.szucs@pharm.u-szeged.huPurpose: Electrospun PLA fiber devices were investigated in the form of fiber mats and disks. Metronidazole was used as an active agent; its concentration was 12.2 and 25.7 wt% in the devices.Methods: The structure was studied by X-ray diffraction and scanning electron microscopy, drug release by dissolution measurements, while the antimicrobial efficiency was tested on five bacterial strains.Results: The XRD study showed that the polymer was partially crystalline in both devices, but a part of metronidazole precipitated and was in the form of crystals among and within the fibers. Liquid penetration and dissolution were different in the two devices, they were faster in disks and slower in fiber mats, due to the morphology of the device and the action of capillary forces. Disks released the drug much faster than fiber mats. Although the release study indicated fast drug dissolution, the concentration achieved a plateau value in 24 hrs for the disks; the inhibition effect lasted much longer, 13 days for bacteria sensitive to metronidazole. The longer inhibition period could be explained by the slower diffusion of metronidazole located inside the fibers of the device.Conclusion: The results suggest that the devices may be effective in the treatment of periodontitis.Keywords: drug release devices, fiber mats, disks, morphology, dissolution, capillary forces, diffusion, antimicrobial, inhibition

Wan-mei Song,1,2,* Yang Shao,1,* Jin-yue Liu,3 Ning-ning Tao,4 Yao Liu,1 Qian-yun Zhang,1,2 Ting-ting Xu,1 Shi-jin Li,1,2 Chun-Bao Yu,5 Lei Gao,6 Liang-liang Cui,7,8 Yi-fan Li,1 Huai-chen Li1,91Department of Respiratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, People’s Republic of China; 2Department of Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, People’s Republic of China; 3Department of Clinical Medicine, School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan 250200, Shandong, People’s Republic of China; 4Department of Clinical Medicine, Medical College, Graduate School of Peking Union Medical College, Beijing 100005, People’s Republic of China; 5Department of Respiratory Medicine, Shandong Provincial Chest Hospital, Jinan 250013, Shandong, People’s Republic of China; 6National Health Commssion Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, and Center for Tuberculosis Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People’s Republic of China; 7Department of Environmental Health, Jinan Municipal Center for Disease Control and Prevention, Jinan 250021, Shandong, People’s Republic of China; 8Department of Biostatistics, School of Public Health, Shandong University, Jinan 250012, Shandong, People’s Republic of China; 9Department of Chinese Medicine Integrated with Western Medicine, College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong, People’s Republic of China*These authors contributed equally to this workBackground: Given the high burden of tuberculosis (TB) and diabetes mellitus (DM) in China and the worse outcome of TB-DM cases (refers to TB patients with diabetes), and drug-resistant tuberculosis cases (DR-TB), it is of great significance to explore the association between diabetes and primary DR-TB for TB elimination target in China. We assessed the clinical characteristics, drug-resistance profile, and increased risk of resistance among TB-DM patients across China from 2004 to 2017.Method: 7223 cases with drug-susceptibility data were collected from Shandong, China. Categorical baseline characteristics of new TB cases were compared by DM status using Fisher’s exact or Pearson Chi-square test. Univariable analysis and multivariable logistic models were used to estimate the association between diabetes and different drug-resistance profiles and the risk factors of primary drug resistance among TB-DM cases.Result: Of 7223 newly diagnosed TB patients, 426 (5.90%) were TB-DM cases. TB-DM csaes were more likely to be older，accompanied by higher body mass index (BMI) and hypertension than TB-no DM cases (refers to TB patients without diabetes). The rates of DR-TB (21.83% vs 16.96%), polydrug resistant TB (PDR-TB, 6.10% vs 3.80%), isoniazid (INH)+streptomycin (SM)-resistant TB (4.93% vs 3.13%), and SM-resistant TB (16.20% vs 11.7%) among TB-DM group were higher than TB-no DM group, P

Yun Shan Chen,*,1 Fen Liu,*,1 Yi Hong Luo,1 Yue Fan,1 Fang Gui Xu,1 Pin Li,1 Bei Zhou,1 Xiu Yu Pan,1 Chi Chiu Wang,2–4 Long Cui1,41Department of Obstetrics and Gynaecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, People’s Republic of China; 2Reproduction and Development Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong; 3School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong; 4Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong*These authors contributed equally to this workBackground: The role of endothelin receptor type B (EDNRB) isoform 3 involved in Temozolomide (TMZ)-induced melanoma cell death has not yet been elucidated.Methods: The subcellular localization of EDNRB isoform 3 was determined by confocal and immunoblotting assays. Silencing EDNRB isoform 3 was performed by CRISPR/Cas9. Apoptosis was assessed by annexin V/propium iodide staining and caspases 3/7/9 activity. Mitochondrial membrane potential, reactive oxygen species and mitochondrial Ca2+ were measured by flow cytometry. Apoptosis protein array was applied.Results: Confocal and immunoblot analyses indicate mitochondrial localization of EDNRB isoform 3 and the first N-terminal (1–22) amino acids are sufficient for its mitochondrial targeting. EDNRB isoform 3 depleted A375 cells significantly confers chemoresistance with mitochondrial depolarization, reduced reactive oxygen species, enhanced mitochondrial Ca2+ uptake and decreased caspase 9 activation. Additionally, apoptosis array shows that lack of EDNRB isoform 3 has relatively lower expression of phosphorylation of p53 at S392 and a slightly higher expression of Paraoxonase 2.Conclusion: Our findings raise the possibility of targeting EDNRB isoform 3 as a new therapeutic strategy in combination with TMZ for melanoma treatment.Keywords: melanoma, Temozolomide, mitochondrial targeting sequence, apoptosis, reactive oxygen species

Hui Xie,1 Shengtao Tian,1 Li Cui,2 Jieyu Yan,2 Yanhua Bai,2 Xiaohui Li,2 Maoqiang Wang,2 Fangfang Zhang,3 Feng Duan21Department of Interventional Therapy, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, People’s Republic of China; 2Department of Interventional Radiology, The First Medical Center of PLA General Hospital, Beijing, 100853, People’s Republic of China; 3Department of Outpatient, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, People’s Republic of ChinaBackground: Transcatheter arterial chemoembolization (TACE) is one of the local therapies most commonly used to treat intermediate-stage or advanced-stage hepatocellular carcinoma (HCC). However, the clinical benefits of PA-TACE (postoperative adjuvant TACE) for improving prognosis (progress-free survival [PFS] or overall survival [OS]) of low-risk HCC patients with R0-stage HCC after hepatectomy were not very clear.Methods: From January 2005 to December 2012, 180 patients who underwent hepatectomy for HCC treatment were enrolled in this study, and the follow-up of these patients was ended in December 2017. Among these patients, 102 patients were performed PA-TACE 1 month later after R0 hepatectomy and 78 patients without adjuvant TACE after R0 hepatectomy. Survival analysis was calculated using the Kaplan–Meier statistical method. Differences between survival curves of different groups were tested using the univariate log-rank test. Multivariate Cox model was used to search for independent prognostic factors for progression or death and to acquire the adjusted HR.Results: PA-TACE significantly improved the survival of HCC patients received surgical resection. The PFS (progress-free survival) of PA-TACE group (median PFS 52.0 months; 95% CI: 14.0–90.0) was significantly longer than the control group (median PFS 11.1 months; 95% CI: [7.9–14.3]; log-rank P

Seong Jin Wang,1–3 Xue Wei Liu,1 Xiaojuan Shen,1,2 Xiu Guo Hua,1,2 Li Cui1,2 1Department of Animal Science, Shanghai Key Laboratory of Veterinary Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; 2Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China; 3Animal and Plant Quarantine Agency, Gimcheon 39660, Republic of Korea Background: Human infections with a novel avian influenza A virus (H7N9) were reported in Shanghai municipality, China, at the beginning of 2013. High-pathogenic avian influenza (HPAI) H7N9 virus emerged in late February 2017 along with existing low-pathogenic avian influenza (LPAI) H7N9 virus, and this has the potential to develop into a pandemic that could be harmful to humans. Methods: To elucidate the epidemiological characteristics of H7N9-infected cases from 2013 to 2017 in Shanghai, data on the 59 laboratory-confirmed human cases and 26 bird and environmental contamination cases were collected from the WHO website and Food and Agriculture Organization Emergency Prevention System for Animal Health (FAO EMPRES-AH). Full-length sequences of H7N9 viruses that emerged in Shanghai were collected from the Global Initiative on Sharing Avian Influenza Data to analyze the evolutionary and genetic features. Results: We found that genetically different strains emerged in every epidemic in Shanghai, and most of the circulating H7N9 strains had affinity to human-type receptors, with the characteristics of high-virulence and low-pathogenic influenza viruses. Furthermore, our findings suggest that the Shanghai chicken strains are closely related to the HPAI H7N9 virus A/Guangdong/17SF003/2016, indicating that this viral strain is of avian origin and generated from the LPAI H7N9 viruses in Shanghai. The gradual decrease in H7N9 human infection in Shanghai was probably due to the control measures taken by the Shanghai government and the enhanced public awareness leading to a reduced risk of H7N9 virus infection. However, LPAI H7N9 viruses from poultry and environmental samples were continually detected in Shanghai across the epidemics, increasing the risk of new emerging H7N9 outbreaks. Conclusion: It is important to consistently obtain sufficient surveillance data and implement prevention measures against H7N9 viruses in Shanghai municipality. Keywords: epidemiology, H7N9 virus, phylogenetic tree, molecular evolutionary study