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Changxia Liu,1,&ast; Li Chen,2,&ast; Dingming Sun,1 Yan Guo,1 Honghong Zhu,3 Lei Li,1 Shifu Sun,1 Guojun He,1 Yongqing Cheng1 1Department of Neurology, The Yancheng Clinical College of Xuzhou Medical University, The First People’s Hospital of Yancheng, Yancheng, Jiangsu Province, 224000, People’s Republic of China; 2Department of Ophtalmology, Funing People’s Hospital, Yancheng, Jiangsu Province, 224000, People’s Republic of China; 3Department of Rheumatology and Immunology, The Yancheng Clinical College of Xuzhou Medical University, The First People’s Hospital of Yancheng, the First People’s Hospital of Yancheng, Yancheng, Jiangsu Province, 224000, People’s Republic of China&ast;These authors contributed equally to this workCoresspondence: Guojun He; Yongqing ChengDepartment of Neurology, The Yancheng Clinical College of Xuzhou Medical University, The First People’s Hospital of Yancheng, Yancheng, Jiangsu Province, 224000, People’s Republic of China, Tel +86-15251131959, +86-13851190252, Email neuromed@163.com; 1146976426@qq.comPurpose: Inflammation plays a role in cerebral small vessel disease (CSVD) pathophysiology. This study aimed to explore the association of the fibrinogen-to-albumin ratio (FAR), a novel inflammatory marker, with CSVD burden in patients with transient ischemic attack (TIA).Patients and Methods: From October 1, 2022, to November 30, 2023, continuous patients with TIA were recruited in the study. The total CSVD burden score and modified total CSVD burden score were used to assess the severity of CSVD. Multivariable regression analysis was used to explore the correlation between the FAR and CSVD in TIA patients.Results: A total of 455 participants were recruited, of whom 225 (48.35%), according to the total CSVD burden score, and 181 (40.67%), according to the modified CSVD burden score were finally identified as moderate-severe CSVD. Spearman correlation analysis showed that levels of FAR correlated with the total CSVD (r=0.392, P< 0.001) and the modified total CSVD burden scores (r=0.379, P< 0.001). Multivariable logistic regression analysis showed that FAR was independently associated with moderate-severe CSVD, both as a continuous variable and as a tertile variable (P< 0.001).Conclusion: The level of FAR on admission was independently associated with the severity of CSVD in patients with TIA.Keywords: cerebral small vessel disease, fibrinogen-to-albumin ratio, transient ischemic attack, inflammatory marker

Jingyuan Zhang,1,2 Qiao Liao,1,2 Hengshu Chen,1,2 Fan Liu,1,2 Dongren Sun,1,2 Shihang Luo,1,2 Yeqing Xiao,3 Weiye Xu,4 Fafa Tian,1,2 Mingyu Song1,2 1Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410005, People’s Republic of China; 2National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410005, People’s Republic of China; 3Department of Neurology, Hengyang Central Hospital, Hengyang, Hunan, 421001, People’s Republic of China; 4Department of Human Anatomy and Neurobiology, School of Basic Medicine, Central South University, Changsha, Hunan, 410005, People’s Republic of ChinaCorrespondence: Mingyu Song, Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410005, People’s Republic of China, Tel +86 13548782904, Fax +86 73184327332, Email songmingyu1986@126.comBackground: Post-stroke depression (PSD) is a common neuropsychiatric complication after a stroke with complex mechanisms. However, few studies have identified the role of vitamin B12 and folate in the occurrence and pathophysiology of PSD. The aim of our study is to investigate the relationship among vitamin B12, folate, their transporter genes, and early-onset PSD.Method and Material: A total of 173 ischemic stroke patients were recruited in Xiangya Hospital of Central South University. We collected peripheral blood samples, clinical data, and demographics at admission. The 17-item Hamilton Depression Scale was used for screening for the existence of depression at 2 weeks after stroke onset. Serum vitamin B12 and folate level were measured based on double-antibody sandwich enzyme-linked immune-sorbent assay. Four single nucleotide polymorphisms (SNP) of transcobalamin 2 (TCN2) and solute carrier family 19 member 1 were genotyped using SNPscanTM multiplex SNP typing Kit.Results: Eighty-four patients were diagnosed with PSD at 2 weeks after stroke onset, and the incidence rate was 48.6%. Serum vitamin B12 level in PSD group was significantly lower than those in the non-PSD group (p=0.018). Binary logistic regression revealed that TCN2 rs1801198 GG genotype and G allele were associated with an increased risk of PSD after adjustment for confounding factors (for GG genotype, OR = 4.253, 95% CI = 1.711~10.572, p = 0.002; for G allele, OR = 2.134, 95% CI = 1.362~3.343, p = 0.001). Moreover, individuals with the rs1801198 G allele in the PSD group exhibited lower vitamin B12 level than those with the rs1801198 G allele in the non-PSD group (p= 0.045).Conclusion: TCN2 rs1801198 and vitamin B12 are associated with the risk of early-onset PSD, and they may be involved in the development of PSD. Our study presents a novel standpoint for the treatment of PSD and gains insights into the mechanistic underpinnings of PSD.Keywords: post-stroke depression, vitamin B12, folate, single nucleotide polymorphisms, TCN2, SLC19A1

Jiaxuan He,1,&ast; Peiye Xu,1,&ast; Rongbing Chen,2 Mengyan Chen,3 Beier Wang,4 Yilun Xie,4 Qinsi Yang,5 Da Sun,1 Mingxia Ji3 1Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, People’s Republic of China; 2Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, SAR 999077, People’s Republic of China; 3Department of Critical Care Medicine, Yiwu Central Hospital, the Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu, 322000, People’s Republic of China; 4Department of Hepatobiliary-Pancreatic Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 5Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingxia Ji; Da Sun, Email jmx529652@wmu.edu.cn; sunday@wzu.edu.cnAbstract: Sepsis, a severe condition instigated by infections, continues to be a primary global cause of death, typified by systemic inflammation and advancing immune dysfunction. Comprehending the complex pathological processes that underlie sepsis is integral to the creation of efficacious treatments. Despite the inability of animal models to entirely reproduce the clinical intricacies related to sepsis, they are invaluable instruments for the exploration and development of therapeutic approaches. Within this context, the zebrafish model is particularly noteworthy due to its genetic tractability, transparency, and appropriateness for high-throughput screening of genetic mutants and therapeutic compounds. This scholarly review emphasizes the crucial role that the zebrafish disease model plays in enhancing our comprehension of sepsis, by exploring its applications in deciphering immune and inflammatory responses, evaluating the consequences of genetic alterations, and examining novel therapeutic agents. The Insights derived from zebrafish research not only augment our understanding of the underlying mechanisms of sepsis, but also possess considerable potential for the transference of these discoveries into clinical therapies, thus potentially transforming the approach to sepsis management. The objective of this scholarly article is to underscore the importance of zebrafish in the realm of biomedical research pertaining to sepsis, and to delineate forthcoming opportunities for utilizing this model in clinical applications. Keywords: Sepsis, Zebrafish models, Inflammation, Immunology, Drug development

Xiaoying Cheng,1,2,&ast; Jianhua Wan,1,2,&ast; Denglong Sun,1,2 Yang Zhan,1,2 Jingting Yu,1,2 Yingmeng Li,1,2 Yanxia Xiong,1,2 Wenjun Liu1,2 1State Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Nanchang, 330096, People’s Republic of China; 2Research and Development Department, Jiangzhong Pharmaceutical Co., Ltd., Nanchang, 330103, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenjun Liu, Email crjzliuwenjun@163.comBackground: Jianweixiaoshi tablets (JWXS) is widely used in traditional Chinese medicine for treating functional dyspepsia with spleen deficiency (SD-FD) in China. However, the molecular mechanisms underlying the therapeutic effects of JWXS remain incompletely understood.Methods: Functional dyspepsia was induced in rats with spleen deficiency by iodoacetamide in combination with the modified multiple platform method. The SD-FD rats were administered JWXS at both low and high doses, as well as domperidone. We conducted a comprehensive evaluation of the treatment effects of JWXS, including body weight, gastrointestinal motility, immune organ index, biochemical analysis, gastrointestinal hormones, and hematological studies. Quantitative proteomic analysis based on data-independent acquisition (DIA) was used to determine the changes in protein profiles of gastric and duodenal tissues in SD-FD rats and JWXS intervention rats.Results: The results showed that JWXS effectively alleviated gastrointestinal motility disorders in SD-FD rats, as indicated by accelerated gastric emptying and intestinal propulsion, increased levels of gastrin, motilin, and ghrelin, and reduced levels of cholecystokinin-octapeptide, vasoactive intestinal peptide, and somatostatin. Additionally, JWXS increased the spleen and thymus index, increased %lymphocyte in blood, reduced white blood cell count and %neutrophil, and improved immune function. Through quantitative proteomic analysis of gastric tissues, we identified 333 differentially expressed proteins in the JWXS treatment group and the model group. Notably, the mechanism by which JWXS accelerated gastric emptying may be related to PLC-γ and SERCA2 in the calcium signaling pathway. Furthermore, JWXS treatment altered the expression of 732 proteins in rat duodenal samples. The differentially expressed proteins were enriched in immune-related functions and pathways, including antigen processing and presentation, as well as the intestinal immune network for IgA production.Conclusion: In conclusion, JWXS exhibits a multi-faceted impact on various pathways, demonstrating its efficacy in treating SD-FD. These findings provide a foundation for the clinical application of JWXS in managing SD-FD.Keywords: Jianweixiaoshi tablets, functional dyspepsia, spleen deficiency, traditional Chinese medicine, proteomic

Shenghao Zhang,1,&ast; Jiahui Ma,1,&ast; Yilei Ma,1,&ast; Jia Yi,1 Beier Wang,2 Hanbing Wang,3 Qinsi Yang,4 Kun Zhang,5 Xiaoqing Yan,6 Da Sun,1,7 Jinfeng You8 1Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, People’s Republic of China; 2Department of Hepatobiliary-Pancreatic Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 3Department of Biotechnology, The University of Hong Kong, Hong Kong SAR, 999077, People’s Republic of China; 4Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, People’s Republic of China; 5Chongqing Municipality Clinical Research Center for Endocrinology and Metabolic Diseases, Chongqing University Three Gorges Hospital, Chongqing, 404000, People’s Republic of China; 6The Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 7Department of Endocrinology, Yiwu Central Hospital, The Affiliated Yiwu hospital of Wenzhou Medical University, Yiwu, 322000, People’s Republic of China; 8Department of Obstetrics, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, 324000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinfeng You; Da Sun, Email Jincancanyjf@163.com; sunday@wzu.edu.cnBackground: Diabetes Mellitus (DM) is a substantial health concern worldwide, and its incidence is progressively escalating. Conventional pharmacological interventions frequently entail undesirable side effects, and while probiotics offer benefits, they are hindered by constraints such as diminished stability and effectiveness within the gastrointestinal milieu. Given these complications, the advent of bioengineered probiotics is a promising alternative for DM management.Aim of Review: The objective of this review is to provide an exhaustive synthesis of the most recent studies on the use of engineered probiotics in the management of DM. This study aimed to clarify the mechanisms through which these probiotics function, evaluate their clinical effectiveness, and enhance public awareness of their prospective advantages in the treatment of DM.Key Scientific Concepts of Review: Scholarly critiques have explored diverse methodologies of probiotic engineering, including physical alteration, bioenrichment, and genetic manipulation. These techniques augment the therapeutic potency of probiotics by ameliorating gut microbiota, fortifying the intestinal barrier, modulating metabolic pathways, and regulating immune responses. Such advancements have established engineered probiotics as a credible therapeutic strategy for DM, potentially providing enhanced results compared to conventional treatments. Keywords: engineered probiotics, diabetes mellitus, gut microbiota, genetic engineering, therapeutic efficacy

Qian Li, Leipeng Ren, Weitong Wu, Dangze Sun, Lin Wei, Chao Ding, Peijia Luo Department of Thoracic Surgery, Xi’an Chest Hospital, Xi’an, Shaanxi, 710100, People’s Republic of ChinaCorrespondence: Peijia Luo, Department of Thoracic Surgery, Xi’an Chest Hospital, Xi’an, Shaanxi, 710100, People’s Republic of China, Email 1171185306@qq.comBackground: To establish and validate a nomogram for predicting the culture results of Mycobacterium tuberculosis in superficial lymph nodes.Methods: The clinical data of patients with superficial lymph node tuberculosis admitted to Xi’an City Chest Hospital from November 23, 2018, to May 30, 2024, were selected and divided into a training set and a validation set according to a ratio of 7:3. Influencing factors were identified through multivariate logistic regression analyses. Using R version 4.3.2, we developed a predictive model and generated a nomogram based on this model. The performance of the nomogram was evaluated using receiver operating characteristic (ROC) curves, calibration curve analysis (CCA), and decision curve analysis (DCA).Results: The positive rate of superficial lymph node tuberculosis culture was 23.0% (103/446). Multivariate Logistic regression analysis showed that anti-tuberculosis treatment duration (OR=0.98, 95% CI: 0.97 ~ 0.99), initial treatment or retreatment (OR=0.12, 95% CI: 0.05 ~ 0.28), and adenosine deaminase (OR=1.12, 95% CI: 1.03 ~ 1.22) were independent factors affecting the culture results of Mycobacterium tuberculosis in superficial lymph nodes. The areas under the ROC curves were 0.86 (95% CI: 0.82– 0.91) for the training set and 0.89 (95% CI: 0.84– 0.95) for the validation set. The P values of calibration curves were 1.000 and 0.961, respectively, and the predicted values were in good agreement with the actual values. The threshold probabilities of clinical decision curves were 3%~64% and 1%~68%, respectively.Conclusion: The positive rate of Mycobacterium tuberculosis culture in superficial lymph nodes is low. The increase in retreatment patients and anti-tuberculosis treatment time are obstacle factors for Mycobacterium tuberculosis culture positivity, while an increase in adenosine deaminase is a promoting factor for Mycobacterium tuberculosis culture positivity. The nomogram model established based on these factors can be used to predict the results of Mycobacterium tuberculosis culture in superficial lymph nodes.Keywords: superficial lymph node tuberculosis, mycobacterium culture, predictive model, nomogram

Tianqing Cao,1,&ast; Fei Liu,2,&ast; Yan Yao,2 Danghong Sun,2 Rong Wang,3 Junxia Cao,3 Jie Meng,2 Ling Zhang,4 Weiming Li1 1Shanghai Tenth People’s Hospital, Clinical Medical College of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Cardiology, Northern Jiangsu People’s Hospital, Yangzhou, Jiangsu, People’s Republic of China; 3Department of Pulmonology, Northern Jiangsu People’s Hospital, Yangzhou, Jiangsu, People’s Republic of China; 4Department of Nursing, Changshu No.2 People’s Hospital/Affiliated Changshu Hospital of Nantong University, Changshu, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weiming Li; Ling Zhang, Email 18917683469@189.cn; nancy120312@163.comObjective: Current scoring systems for short-term prognosis in patients with acute myocardial infarction (AMI) lack coverage of risk factors and have limitations in risk stratification. The aim of this study was to develop a novel assessment system based on laboratory indicators and frailty quantification to better infer short-term prognosis and risk indication in patients with AMI.Methods: A total of 365 patients with MI from January 2022 to June 2023 in Northern Jiangsu Province Hospital were included. The primary endpoint was all-cause mortality and major adverse cardiac events (MACE) during follow-up. A novel scoring model ranging from 0 to 12 was constructed, and the predictive ability of this scoring system was evaluated using the area under the receiver operating characteristic curve (AUC).Results: During follow-up, 68 patients experienced MACE. Five scoring indicators were selected through multivariate logistic regression analysis, resulting in a composite score with an AUC of 0.925, demonstrating good prognostic accuracy.Conclusion: The novel prognostic assessment system, which integrates age, Stress Hyperglycemia Ratio (SHR), Neutrophil to Lymphocyte Ratio (NLR), lactate, and frailty score, exhibits good predictive value for short-term MACE in patients with acute myocardial infarction and may enable more accurate risk classification for future use in MI patient risk management.Keywords: myocardial infarction, frailty index, major adverse cardiac events, prognosis, cohort study

Yuanyuan Zhao,1 Yang Liu,1 Cheng Lu,1 Daokuan Sun,2 Shiqi Kang,1 Xin Wang,2,&ast; Laijin Lu1,&ast; 1Department of Hand and Podiatric Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2School of Materials Science and Engineering, Jilin University, Changchun, Jilin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Laijin Lu, Department of Hand and Podiatric Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China, Tel +86-13756661203, Fax +86 431 84808391, Email ljlu@jlu.edu.cn Xin Wang, School of Materials Science and Engineering, Jilin University, Changchun, Jilin, People’s Republic of China, Tel +86-18 626 655 395, Fax +86 431 84 808 391, Email wang_xin@jlu.edu.cnBackground: The treatment of long-gap peripheral nerve injury (PNI) is still a substantial clinical problem. Graphene-based scaffolds possess extracellular matrix (ECM) characteristic and can conduct electrical signals, therefore have been investigated for repairing PNI. Combined with electrical stimulation (ES), a well performance should be expected. We aimed to determine the effects of reduced graphene oxide fibers (rGOFs) combined with ES on PNI repair in vivo.Methods: rGOFs were prepared by one-step dimensionally confined hydrothermal strategy (DCH). Surface characteristics, chemical compositions, electrical and mechanical properties of the samples were characterized. The biocompatibility of the rGOFs were systematically explored both in vitro and in vivo. Total of 54 Sprague-Dawley (SD) rats were randomized into 6 experimental groups: a silicone conduit (S), S+ES, S+rGOFs-filled conduit (SGC), SGC+ES, nerve autograft, and sham groups for a 10-mm sciatic defect. Functional and histological recovery of the regenerated sciatic nerve at 12 weeks after surgery in each group of SD rats were evaluated.Results: rGOFs exhibited aligned micro- and nano-channels with excellent mechanical and electrical properties. They are biocompatible in vitro and in vivo. All 6 groups exhibited PNI repair outcomes in view of neurological and morphological recovery. The SGC+ES group achieved similar therapeutic effects as nerve autograft group (P > 0.05), significantly outperformed other treatment groups. Immunohistochemical analysis showed that the expression of proteins related to axonal regeneration and angiogenesis were relatively higher in the SGC+ES.Conclusion: The rGOFs had good biocompatibility combined with excellent electrical and mechanical properties. Combined with ES, the rGOFs provided superior motor nerve recovery for a 10-mm nerve gap in a murine acute transection injury model, indicating its excellent repairing ability. That the similar therapeutic effects as autologous nerve transplantation make us believe this method is a promising way to treat peripheral nerve defects, which is expected to guide clinical practice in the future.Keywords: peripheral nerve defects, sciatic nerve injury, functional recovery, tissue engineering, conductive materials

Xiaojing Chen,1– 3,&ast; Qilin Yang,4,&ast; Li Gao,1– 3 Weinan Chen,1 Xiaoyu Gao,1– 3 Yameng Li,1– 3 Liying Ao,5 Dejun Sun1– 3 1Department of Respiratory and Critical Care Medicine, Inner Mongolia People’s Hospital, Hohhot, 010017, People’s Republic of China; 2NHC Key Laboratory of Diagnosis & Treatment of COPD, Inner Mongolia People’s Hospital, Hohhot, 010017, People’s Republic of China; 3Inner Mongolia Key Laboratory of Respiratory Diseases, Inner Mongolia People’s Hospital, Hohhot, 010017, People’s Republic of China; 4Department of Critical Care, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 5Department of Otolaryngology, Inner Mongolia People’s Hospital, Hohhot, 010017, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dejun Sun, Department of Respiratory and Critical Care Medicine, Inner Mongolia People’s Hospital, No. 26 Zhaowuda Road, Saihan District, Hohhot, 010017, People’s Republic of China, Email nmg_sdj@163.comBackground: Serum anion gap (AG) has been proven to be associated with prognosis in critically ill patients. However, few studies have investigated the association between AG and all-cause mortality in critically ill patients with chronic obstructive pulmonary disease (COPD).Objective: We hypothesized that the initial AG level would predict the mortality risk in critically ill patients with COPD.Methods: This retrospective cohort study was based on the Medical Information Mart for Intensive Care (MIMIC) IV database. We extracted demographics, vital signs, laboratory tests, comorbidity, and scoring systems from the first 24 hours after patient ICU admission. Multivariable logistic regression analysis models were used to explore the association between serum AG levels and mortality. Interaction and stratified analyses were conducted including age, gender and comorbidity.Results: A total of 5531 critically ill patients with COPD were enrolled, composed of 53.6% male and 46.4% female with a median age of 73 years. The all-cause mortality of these patients during ICU hospitalization was 13.7%. The risk of all-cause mortality increased as the AG level increased in the univariate logistic regression analysis (OR=1.13, 95% CI: 1.11– 1.15, p< 0.01). After adjusting for all the covariates in multivariate logistic regression analysis, the odds ratio was 1.06 (95% CI: 1.04– 1.09, p< 0.01). Compared with the lowest AG group Q1 (≤ 11mmol/L), the adjusted OR value for AG and mortality in Q2 (12– 13mmol/L) was 0.89 (95% CI: 0.63– 1.25, p=0.502), Q3 (14– 15mmol/L) was 0.95 (95% CI: 0.68– 1.34, p=0.788), and Q4 (≥ 16mmol/L) was 1.49 (95% CI: 1.10– 2.02, p=0.009) respectively. In addition, the results of the subgroup and stratified analyses were robust.Conclusion: AG is positively related to all-cause mortality in critically ill patients with COPD.Keywords: AG, COPD, mortality, MIMIC IV

Yongjun Huang,1,&ast; Yong Chen,2,&ast; Guoyun Cheng,1,&ast; Wenqiang Li,3 Hongan Zhang,1,4 Chaoqun Yu,1 Jia Fang,1 Jieyi Zuo,1 Ying Li,1 Lei Xu,1 Dawei Sun1 1Department of Orthopedics, Guangdong Second Provincial General Hospital, Guangzhou, 510317, People’s Republic of China; 2Department of Orthopedics, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, People’s Hospital, Qingyuan, 511518, People’s Republic of China; 3Engineering Technology Research Center for Sports Assistive Devices of Guangdong, Guangzhou Sport University, Guangzhou, 510500, People’s Republic of China; 4The Second Clinical School of Medicine, Southern Medical University, Guangzhou, 510260, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lei Xu; Dawei Sun, Department of Orthopedics, Guangdong Second Provincial General Hospital, 11th Floor, Building 3, No. 466, Xingang Middle Road, Guangzhou, Guangdong Province, 510317, People’s Republic of China, Email orthoxl@163.com; sundw@gd2h.org.cnBackground: As the first line of immune defense and the largest organ of body, skin is vulnerable to damage caused by surgery, burns, collisions and other factors. Wound healing in the skin is a long and complex physiological process that is influenced by a number of different factors. Proper wound care can greatly improve the speed of wound healing and reduce the generation of scars. However, traditional wound dressings (bandages, gauze, etc.) often used in clinical practice have a single function, lack of active ingredients and are limited in use. Hydrogels with three-dimensional network structure are a potential biomedical material because of their physical and chemical environment similar to extracellular matrix. In particular, hydrogel dressings with low price, good biocompatibility, degradability, antibacterial and angiogenic activity are favored by the public.Methods: Here, a carboxymethyl chitosan-based hydrogel dressing (CMCS-TA/Cu2+) reinforced by copper ion crosslinked tannic acid (TA/Cu2+) nanoparticles was developed. This study investigated the physical and chemical characteristics, cytotoxicity, and angiogenesis of TA/Cu2+ nanoparticles and CMCS-TA/Cu2+ hydrogels. Furthermore, a full-thickness skin defect wound model was employed to assess the in vivo wound healing capacity of hydrogel dressings.Results: The introduction of TA/Cu2+ nanoparticles not only could increase the mechanical properties of the hydrogel but also continuously releases copper ions to promote cell migration (the cell migration could reach 92% at 48 h) and tubule formation, remove free radicals and promote wound healing (repair rate could reach 90% at 9 days).Conclusion: Experiments have proved that CMCS-TA/Cu2+ hydrogel has good cytocompatibility, antioxidant and wound healing ability, providing an advantageous solution for skin repair. Keywords: TA/Cu2+ nanoparticles, carboxymethyl chitosan, wound dressing, antioxidant activity

Qianqian Liang,1– 3 Difang Sun,1– 3 Shuyue Xue,1– 3 Xinying Li,1– 3 Xin Liu,1– 3 Qing Du,1– 3 Zhichun Zhang,1– 3 Xiubin Ma,1– 3 Jun Li1– 3 1Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, Shandong, People’s Republic of China; 2State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao, Shandong, People’s Republic of China; 3School of Ophthalmology, Shandong First Medical University, Qingdao, Shandong, People’s Republic of ChinaCorrespondence: Jun Li; Xiubin Ma, Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, 266071, People’s Republic of China, Tel +86-532-85876380, Email doctor_li@126.com; maxiubin2005@126.comPurpose: To compare the effectiveness and safety of adjustable and free postoperative positioning after pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD).Design: Prospective, randomized controlled study.Methods: A total of 94 eyes with RRD were enrolled from April 2020 to April 2023 and monitored postoperatively for at least 3 months. All patients underwent PPV combined with silicone oil injection or gas tamponade and were randomly divided postoperatively into two groups: an adjustable positioning group and a free positioning group. The success of the outcome was based on the retinal reattachment rate, best corrected visual acuity (BCVA), postoperative complications, and ocular biometric parameters such as anterior chamber depth (ACD) and lens thickness (LT).Results: The initial retinal reattachment rate was 97.9% in the adjustable positioning group and 95.7% in the free positioning group, manifesting no statistical difference between the two groups. Similarly, no statistical difference was observed between the two groups in the final BCVA, which was significantly improved compared to the preoperative BCVA. The comparison of the 1-month postoperative ACD and LT with the preoperative values showed no statistically significant differences in the two groups. The rates of complications were not statistically different in the two groups.Conclusion: After treating RRD using PPV, neither the adjustable nor the free postoperative positioning affected the retinal reattachment rate or the incidence of complications. Therefore, our study showed that it is safe and effective to adopt free positioning postoperatively, which may provide more options for patients with RRD undergoing PPV.Keywords: rhegmatogenous retinal detachment, pars plana vitrectomy, adjustable positioning, free positioning

Yan Teng,1 Yibin Fan,1 Danying Shang,1 Xiaohua Tao,1,&ast; Dongsheng Sun2,&ast; 1Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China; 2Geriatric Medicine Center, Department of Geriatric Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongsheng Sun, Geriatric Medicine Center, Department of Geriatric Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China, Email sunds@163.com Xiaohua Tao, Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China, Email taoxiaohua@hmc.edu.cnAbstract: Drug-induced alopecia areata is a rare adverse event wherein medications such as antimicrobials, anticonvulsants, and biologics, trigger the premature transition of actively growing hairs into the telogen phase. Herein, a unique case of alopecia universalis observed during a clinical trial involving sacubitril/alisartan, a novel angiotensin receptor-neprilysin inhibitor (ARNI) has been reported. This case contributes to the range of cutaneous reactions that might be observed in association with ARNI therapy.Keywords: alopecia universalis, sacubitril/alisartan, angiotensin receptor-neprilysin inhibitor

Xiaonan Liang,1,&ast; Chenyang Li,1,&ast; Jia Song,1 Airu Liu,1 Chen Wang,1 Wenxin Wang,1 Yaxing Kang,1,2 Donglei Sun,1 Jiaming Qian,1,3 Xiaolan Zhang1 1Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 3Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaolan Zhang, Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, Hebei, 050000, People’s Republic of China, Tel +86 0311-66007370, Email xiaolanzh@hebmu.edu.cn Jiaming Qian, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China, Tel +86 010-69158100, Email qianjiaming1957@126.comBackground: Mucosal healing has emerged as a crucial therapeutic goal for inflammatory bowel diseases (IBD). Exosomes (Exo) as a potential acellular candidate for stem cell therapy might be competent to promote mucosal healing, while its mechanism remains unexplored.Methods: Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) were subjected to experimental colitis mice intraperitoneally to estimate the role in mucosal healing and the regeneration of intestinal stem cells (ISCs) and epithelium. The intestinal organoid model of IBD was constructed utilizing tumor necrosis factor (TNF)-α for subsequent function analysis in vitro. Transcriptome sequencing was performed to decipher the underlying mechanism and Wnt-C59, an oral Wnt inhibitor, was used to confirm that further. Finally, the potential specific components of hucMSC‑exo were investigated based on several existing miRNA expression datasets.Results: HucMSC-exo showed striking potential for mucosal healing in colitis mice, characterized by decreased histopathological injuries and neutrophil infiltration as well as improved epithelial integrity. HucMSC-exo up-regulated the expression of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), a specific marker for ISCs and accelerated the proliferation of intestinal epithelium. HucMSC-exo endowed intestinal organoids with more excellent capacity to grow and bud under TNF-α stimulation. More than that, the fact that hucMSC-exo activated the canonical Wnt signaling pathway to promote mucosal healing was uncovered by not only RNA-sequencing but also relevant experimental data. Finally, bioinformatics analysis of the existing miRNA expression datasets indicated that several miRNAs abundant in hucMSC-exo involved widely in regeneration or repair related biological processes and Wnt signaling pathway might be one of the most important signal transduction pathways.Conclusion: Our results suggested that hucMSC-exo could facilitate mucosal healing in experimental colitis by accelerating ISCs and intestinal epithelium regeneration via transferring key miRNAs, which was dependent on the activation of Wnt/β-catenin signaling pathway.Keywords: inflammatory bowel disease, mesenchymal stem cells, exosome, mucosal healing, Wnt/β-catenin signaling pathway

Huijun Wang,1,2 Wen Xu,1,2 Anqi Zhao,1,2 Dance Sun,1,2 Yanru Li,1,2 Demin Han1,2 1Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Key Laboratory of Otolaryngology-Head and Neck Surgery, Ministry of Education, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Demin Han; Yanru Li, Beijing Tongren Hospital, Capital Medical University, 1 Dongjiaominxiang, Dongcheng District, Beijing, People’s Republic of China, Email deminhan_ent@hotmail.com; liyanruru@aliyun.comPurpose: Distinguishing obstructive sleep apnea (OSA) in a high-risk population remains challenging. This study aimed to investigate clinical features to identify children with OSA combined with craniofacial photographic analysis.Methods: One hundred and forty-five children (30 controls, 62 with primary snoring, and 53 with OSA) were included. Differences in general demographic characteristics and surface facial morphology among the groups were compared. Risk factors and prediction models for determining the presence of OSA (obstructive sleep apnea-hypopnea index> 1) were developed using logistic regression analysis.Results: The BMI (z-score), tonsil hypertrophy, and lower face width (adjusted age, gender, and BMI z-score) were showed significantly different in children with OSA compared with primary snoring and controls (adjusted p< 0.05). The screening model based on clinical features and photography measurements correctly classified 79.3% of the children with 64.2% sensitivity and 89.1% specificity. The area under the curve of the model was 81.0 (95% CI, 73.5– 98.4%).Conclusion: A screening model based on clinical features and photography measurements would be helpful in clinical decision-making for children with highly suspected OSA if polysomnography remains inaccessible in resource-stretched healthcare systems.Keywords: obstructive sleep apnea, clinical features, photographic measurements, children

Zhiwei Zhang,1,&ast; Jiawei Zhuang,2,&ast; Daohan Sun,3,&ast; Qingwei Ding,1 Hui Zheng,1 Haixiang Li,1 Xiaoyu Zhang,1 Yaming Du,3 Teng Ma,1 Qingyou Meng1 1Department of Vascular Surgery, General Surgery Clinical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Cardiovascular Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 3Department of Vascular Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingyou Meng; Teng Ma, Email mengqy@163.com; m_aeolus@163.comBackground: Abdominal aortic aneurysms (AAAs) are a global health and economic burden. Therapeutic strategies to inhibit the progression of AAAs are currently lacking. Recently, the therapeutic effect of metformin on aneurysms has attracted considerable interest. However, the unfavorable pharmacokinetic properties of metformin limit its feasibility for AAA treatment.Methods and Results: We constructed a metformin-loaded netrin-1-responsive AAA-targeted nanoparticle (Tgt-NP-Met) for AAA management. Evaluation of the therapeutic effect of Tgt-NP-Met was performed by in vitro and in vivo experiments. Our results showed that the binding of netrin-1 monoclonal antibodies enhanced the AAA-targeting capability of nanoparticles (NPs). Moreover, Tgt-NP-Met administration prevented AAA development and reduced the aneurysm diameter in apolipoprotein E (ApoE)-deficient (ApoE−/−) mice that received continuous infusion of angiotensin II. Furthermore, metformin prevented AAA progression by inhibiting the transformation of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a synthetic phenotype, which is mediated by macrophage infiltration and activation.Conclusion: Our findings identify metformin as a functional suppressor for macrophage-mediated phenotypic transformation of VSMCs and Tgt-NP-Met as an efficient therapeutic strategy for AAA management.Graphical Abstract: Keywords: abdominal aortic aneurysm, nanoparticle, metformin, macrophage

Fayin Mo,1,2 Minjun Zhang,1 Xuewei Duan,1 Chuyan Lin,1 Duanping Sun,2,3 Tianhui You1 1School of Nursing, Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 2Center for Drug Research and Development, Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 3Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, People’s Republic of ChinaCorrespondence: Duanping Sun; Tianhui You, Email sundp@gdpu.edu.cn; youth888cn@aliyun.comAbstract: Bacterial-infected wounds are a serious threat to public health. Bacterial invasion can easily delay the wound healing process and even cause more serious damage. Therefore, effective new methods or drugs are needed to treat wounds. Nanozyme is an artificial enzyme that mimics the activity of a natural enzyme, and a substitute for natural enzymes by mimicking the coordination environment of the catalytic site. Due to the numerous excellent properties of nanozymes, the generation of drug-resistant bacteria can be avoided while treating bacterial infection wounds by catalyzing the sterilization mechanism of generating reactive oxygen species (ROS). Notably, there are still some defects in the nanozyme antibacterial agents, and the design direction is to realize the multifunctionalization and intelligence of a single system. In this review, we first discuss the pathophysiology of bacteria infected wound healing, the formation of bacterial infection wounds, and the strategies for treating bacterially infected wounds. In addition, the antibacterial advantages and mechanism of nanozymes for bacteria-infected wounds are also described. Importantly, a series of nanomaterials based on nanozyme synthesis for the treatment of infected wounds are emphasized. Finally, the challenges and prospects of nanozymes for treating bacterial infection wounds are proposed for future research in this field.Graphical Abstract: Keywords: nanozyme, wound healing, bacterial infections, antibacterial, antibiofilms

Dayan Yang,&ast; Qiqing Chen,&ast; Min Zhang, Guiying Feng, Dandan Sun, Ling Lin, Xiangxiang Jing Department of Ultrasonography, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Hainan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling Lin, Tel +86-8-9868642515, Email 13876673666@163.com Xiangxiang Jing, Email ljjxx2000@126.comBackground: Chemotherapy is an important approach to treating nasopharyngeal carcinoma (NPC). Unfortunately, the lack of selectivity, insufficient tumor accumulation, uneven tumor distribution and severe systemic toxicity lead to the unsatisfactory performance of these drugs. While a more precise drug delivery, on-demand drug release, and deep diffusion of drugs (homogeneous distribution of drugs in the tumor) could improve the application, they remain challenging. Chemotherapeutic drug-loaded acoustic nanodroplet with dual-imaging capacity is expected to solve these problems.Methods: Folate (Fa)-modified and doxorubicin (Dox)-loaded acoustic poly (lactic‐co‐glycolic acid) (PLGA), low intensity focused ultrasound (LIFU)-responsive perfluoropentane (PFP) and Fe3O4 nanoparticles (designated as Fa-Fe@P-PFP-Dox) were integrated by a double-emulsion method. After the synthesis, the LIFU-triggered acoustic droplet vaporization (ADV) effect, LIFU-triggered drug release, cell targeting capability, in vitro cell-killing effects, biodistribution, PA/MR dual imaging (PA: photoacoustic; MR: magnetic resonance), LIFU-augmented Dox distribution in tumors and chemotherapeutic efficacy of Fa-Fe@P-PFP-Dox were investigated.Results: The distribution of these drug-loaded nanodroplets was clearly monitored via PA/MR dual imaging. Upon LIFU irradiation, PFP within the Fa-Fe@P-PFP-Dox nanodroplets underwent ADV, which led to the release of Dox and promoted the deep penetration of Dox in tumor tissue, eventually achieving highly efficient chemotherapy against NPC. As a result, LIFU-triggered chemotherapy exerted a highly efficient therapeutic effect with a tumor inhibition rate of 74.24 ± 7.95%.Conclusion: Fa-modified and drug-loaded acoustic nanodroplets have been successfully constructed for dual-imaging guided highly efficient chemotherapy against NPC. This novel tumor drug delivery method is expected to provide an efficient, visualized, and precise personalized treatment method for NPC patients with minimal side effects.Keywords: nasopharyngeal carcinoma, drug delivery, low intensity focused ultrasound, chemotherapy, deep penetration

Rui Wang,1– 4 Wei Zhang,1– 3 Yuanyuan Li,1– 3 Yuting Jiang,1– 3 Hongqi Feng,1– 3 Yang Du,1– 3 Zhe Jiao,1– 3 Li Lan,4 Xiaona Liu,1– 3 Bingyun Li,1– 3 Chang Liu,1– 3 Xingbo Gu,5 Fang Chu,1– 3 Yuncheng Shen,1– 3 Chenpeng Zhu,1– 3 Xinhua Shao,1– 3 Simeng Tong,1– 3 Dianjun Sun1– 3 1Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, People’s Republic of China; 2National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, 150081, People’s Republic of China; 3Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, 150081, People’s Republic of China; 4Harbin Center for Disease Control and Prevention, Harbin, 150056, People’s Republic of China; 5Department of Biostatistics, School of Public Health, Hainan Medical University, Haikou, 571199, People’s Republic of ChinaCorrespondence: Dianjun Sun, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Baojian Road 157, Harbin, Heilongjiang Province, 150081, People’s Republic of China, Tel +86-13313685318, Fax +86 45186612695, Email hrbmusdj@163.comPurpose: To investigate the environmental, immune, and inflammatory factors associated with chronic obstructive pulmonary disease (COPD) in middle-aged and older Chinese individuals.Patients and Methods: A community-based case–control study was conducted among 471 patients with COPD and 485 controls. The information on COPD of the participants was collected through face-to-face interviews, and serum samples were measured at the laboratory. The main risk factors for COPD were analyzed using principal component analysis (PCA) and logistic regression.Results: Nine hundred and fifty-six respondents were included in the analysis. The results of the PCA-logistic regression analysis showed significant differences in the environmental factors, medical history, and serum C-reactive protein (CRP) levels between patients and controls. COPD was markedly more usual in those with smoking index > 200 (OR, 1.42; 95% CI, 1.28– 1.57); exposure to outdoor straw burning (OR, 1.64; 95% CI, 1.47– 1.83); use of coal, wood, and straw indoors (OR, 2.31; 95% CI, 1.92– 2.78); history of respiratory disease and coronary heart disease (OR, 3.58; 95% CI, 3.12– 4.10), congestive heart failure (OR, 1.23; 95% CI, 1.09– 1.38), and cerebrovascular disease (OR, 1.15; 95% CI,1.02– 1.31); and higher serum level of CRP (OR, 1.20; 95% CI, 1.11– 1.30). Compared to the logistic regression analysis, PCA logistic regression analysis identified more important risk factors for COPD.Conclusion: PCA-logistic regression analysis was first utilized to explore the influencing factors among rural residents in Northeast China Environmental aged 40 years and above, it was found that environmental factors, medical history, and serum CRP levels mainly affected the prevalence of COPD.Keywords: chronic obstructive pulmonary disease, collinearity, principal component, logistic regression

Xu Wang,&ast; Yi-Nan Liu,&ast; Di Sun, Si Chen, Bao-Lei Huang, Jian-Dong Tai Department of Colorectal Surgery, The First Hospital of Jilin University, Changchun, 130000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian-Dong Tai, Department of Colorectal Surgery, the First Hospital of Jilin University, No. 1 of Xinmin Street, Chaoyang District, Changchun, 130000, People’s Republic of China, Tel +86 431-88782291, Fax +86 431-85612352, Email taijdmed@163.comObjective: The aim of this study was to investigate the clinical effectiveness of modified perineal reconstruction combined with anal sphincter repair in the treatment of obstetric anal sphincter injuries (OASIS).Methods: Twenty consecutive patients with an OASI who underwent modified perineal reconstruction combined with anal sphincter repair in the Department of Colorectal and Anal Surgery of the First Hospital of Jilin University from October 2015 to September 2017 were retrospectively enrolled in this study. Anal function was evaluated using the Williams grade, the Wexner score, anorectal manometry, and transrectal ultrasound.Results: Differences in both the Williams grade and the Wexner score prior to operation and following surgery indicated that anal function had improved, and these differences were statistically significant (P < 0.05). These indices also showed further improvement six months after surgery as compared with values at one month, and again, these differences were statistically significant (P < 0.05). In addition, anorectal manometry at six months following surgery showed statistically significant differences in the maximum anal resting pressure, maximum anal systolic pressure, and anal defecation pressure as compared with values prior to operation (P < 0.05). Postoperative endorectal ultrasound revealed that the anal sphincter presented with close imbricated overlapping.Conclusion: Modified perineal reconstruction combined with anal sphincter repair in the treatment of female perineal defect is associated with a good clinical outcome, strengthening anal function, and reconstructing the perineum, and is a possible method for clinical treatment.Keywords: modified perineal reconstruction, bilateral V-Y island flap, perineal laceration, fecal incontinence, anal function

Ziyuan Zhang,1,2 Yaling Hu,1,2 Wenyuan Liu,2 Xiaodong Zhang,2 Ruihua Wang,2 Hui Li,2 Dalin Sun,1,2 Jingai Fang2 1Shanxi Medical University, Taiyuan, People’s Republic of China; 2Department of Nephrology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Jingai Fang, Department of Nephrology, First Hospital of Shanxi Medical University, 85 Jiefangnan Road, Taiyuan, 030001, People’s Republic of China, Email jingaifang2017003@126.comPurpose: To explore the mechanism of Yishen capsule against diabetic nephropathy (DN) based on the analysis of transcriptomics.Material and Methods: SD rats (Male, SPF grade) were randomly divided into four groups, the normal group, the DN group, the Yishen capsule group and the resveratrol group. Urine and renal tissue samples were collected after feeding with physiological saline and above drugs for 8 weeks. 24-hour urine microalbumin protein was detected by ELISA. HE staining and PAS staining were performed on renal tissues. Differential gene expression in renal tissues was analyzed by transcriptome sequencing. The differentially expressed genes were analyzed by GO enrichment and KEGG enrichment, and verified by RT-PCR and immunohistochemistry staining.Results: The level of 24-hour urinary microalbumin in DN group was increased, while Yishen capsule treatment reversed the increasement of urinary microalbumin. Mesangial cell proliferation, matrix accumulation, edema and vacuolar degeneration of renal tubular epithelial cells and glycogen accumulation were observed in DN group. However, pathological phenotypes mentioned above were alleviated after Yisen capsule administration. This result indicates that Yishen capsule reversed pathological phenotypes of DN in rats. The expression of 261 genes were changed in Yishen capsule group compared with DN group. GO enrichment analysis and KEGG pathway analysis showed that these genes were implicated in pathways, including mineral absorption, adipocytokine signaling pathway, fatty acid biosynthesis, thyroid hormone synthesis, renin–angiotensin system, and NOD-like receptor signaling pathway. Based on previous reported study, the expression of key factors in NOD-like receptor signaling pathway was verified. RT-PCR and immunohistochemistry staining showed that the expression of NLRP3, Caspase-1 and IL-1β in renal tissues of DN group were increased (P < 0.05), which were decreased in Yishen capsule group (P < 0.05).Conclusion: Yishen capsule reduced microalbuminuria and alleviated pathological changes in DN rats, which may be achieved by regulating NOD-like receptor signaling pathway.Keywords: Yishen capsule, diabetic nephropathy, transcriptome sequencing, NOD-like receptor signaling pathway

Liming Fan,1,&ast; Deyang Sun,1,&ast; Jia Yang,1 Xiawei Shi,1 Fenglin Shen,1 Ke Chen,1 Junchao Yang1,2 1The First Clinical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Junchao Yang, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, Shangcheng District, Hangzhou City, Zhejiang Province, People’s Republic of China, Tel +86-13858036093, Email yangjunchaozj@zcmu.edu.cnPurpose: The purpose of our study was to investigate the relationship between serum sodium levels and 1-year and 3-year mortality in critically ill patients with comorbid chronic obstructive pulmonary disease using real-world data.Methods: The data of this study were collected from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. First of all, we used the Kaplan–Meier curves and multivariable Cox regression analyses to measure the relationship between serum sodium levels and 1-year and 3-year mortality for critically ill patients with comorbid COPD. Next, a restricted cubic spline was used to analyze non-parametrically the relationship between mortality and serum sodium as a continuous variable. In addition, we also analyzed the mortality of different subgroups.Results: A total of 5540 eligible subjects were extracted. Compared to normal serum sodium levels, adjusted multivariable Cox regression analysis confirmed that hyponatremia and hypernatremia were still significantly associated with 1-year mortality (HR = 1.551, 95% CI = 1.333∼ 1.805, P< 0.001; HR = 1.683, 95% CI = 1.317∼ 2.151, P< 0.001, respectively) and 3-year mortality (HR = 1.507, 95% CI = 1.302∼ 1.744, P< 0.001; HR = 1.612, 95% CI = 1.269∼ 2.048, P< 0.001, respectively). In patients with or without adjustment variables, there was an obvious U-shaped non-linear relationship between serum sodium levels and 1-year and 3-year mortality with a reference level of 139 mmol/L, which indicated that patients in both hyponatremia and hypernatremia had higher mortality than normal serum sodium levels.Conclusion: This study showed that both hyponatremia and hypernatremia were related to increased 1-year and 3-year mortality in critically ill patients with comorbid COPD, which provides a new reference for the control strategy of correcting serum sodium levels.Keywords: serum sodium, chronic obstructive pulmonary disease, intensive care unit, MIMIC-IV

Zhenxing Feng,1 Yan Yin,2 Bin Liu,2 Lei Wang,2 Miaomiao Chen,2 Yue Zhu,2 Hong Zhang,1 Daqiang Sun,3 Jianwen Qin2 1Department of Radiology, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China; 2Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China; 3Department of Thoracic Surgery, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of ChinaCorrespondence: Jianwen Qin, Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China, Email qinjianwen2005@aliyun.com Daqiang Sun, Department of Thoracic Surgery, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China, Email sdqmd@163.comBackground: Chronic obstructive pulmonary disease (COPD) is an inflammatory-related disease highly associated with increased lung cancer risk. Studies have explored the tumor promoting roles for zinc finger protein 143 (ZNF143). However, the role of ZNF143 in COPD and tumor microenvironment of non-small cell lung cancer (NSCLC) has not been fully elucidated.Methods: COPD-related key genes were identified by differential gene expression evaluation, WGCNA and SVM-RFE analysis using mRNA expression data retrieved from public databases. ROC analysis was conducted to evaluate the diagnostic value of ZNF143. Correlation between ZNF143 and clinic-pathological features, associations with tumor-infiltrating immune cells (TICs) and the relationship with predictors of immunotherapy efficacy were explored. ZNF143 gene expression was validated by qRT-PCR using an independent cohort.Results: Bioinformatic and machine learning analysis showed that ZNF143 was a COPD-related gene. ZNF143 expression was significantly upregulated in COPD and is a potential diagnostic biomarker in COPD with AUC > 0.85. ZNF143 expression was significantly upregulated in lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). ZNF143 expression levels were significantly higher in LUAD patients with COPD relative to the levels in patients only with LUAD. Upregulation of ZNF143 in patients with comorbidity of NSCLC and COPD was further confirmed by qRT-PCR analysis. High expression of ZNF143 was significantly correlated with advanced TNM stage in LUSC. High ZNF143 expression was associated with activated TICs in both LUAD and LUSC samples. Moreover, ZNF143 expression was significantly correlated with the levels of several known predictors of immunotherapy efficacy, including PD-L1, PD-L2, TMB and TIDE in NSCLC.Conclusion: ZNF143 is a novel COPD biomarker. High expression level of ZNF143 is associated with immune microenvironment and high risk of progression of COPD to NSCLC.Keywords: COPD, NSCLC, ZNF143, bioinformatic, tumor microenvironment, PD-L1

Cheng-Tao Yu,1,&ast; Tongqing Chen,1,&ast; Sicheng Lu,1,&ast; Wenlong Hu,1 Qinchang Zhang,1 Jiani Tan,1 Dongdong Sun,1 Liu Li,1 Xin Sun,1 Changliang Xu,1 Yueyang Lai,1 Minmin Fan,1 Zhengjie Shen,2 Weixing Shen,1 Haibo Cheng1 1The First Clinical Medical College, Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Medical Oncology Department, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weixing Shen; Haibo Cheng, The First Clinical Medical College, Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China, Tel +86 13815857118, Fax +86 2585811006, Email haibocheng@njucm.edu.cn; weixingshen@njucm.edu.cnPurpose: Colorectal cancer (CRC) remains the third most common tumor worldwide. Ulcerative colitis (UC) could cause chronic inflammation and ulcers in the colon and rectum. UC is a risk factor for a high incidence of CRC, and the incidence of UC-associated CRC (UC-CRC) is still increasing. Chinese medicine prescription, Xian-Lian-Jie-Du decoction (XLJDD), has been proven its efficacy in some UC-CRC patients. However, the mechanism of XLJDD in treating UC-CRC remains unknown. This study aimed to investigate the mechanism of XLJDD in treating UC-CRC.Methods: We constructed an AOM/DSS mouse model that could simulate the various stages of UC-CRC in humans. XLJDD and its 5 main components are used to treat the AOM/DSS model, respectively. With the power of high-throughput sequencing technology, we described the mechanism of XLJDD from transcriptomics, proteomics, and single-cell transcriptomics.Results: Our results showed that XLJDD could effectively suppress the occurrence and development of colorectal tumors. Using the weighted correlation network analysis (WGCNA), several mRNA and protein modules that respond to XLJDD have been identified. Moreover, two essential genes, Mfsd2a and Ccdc85c, were caught our attention. They were prognostic markers in CRC patients, and their expression could be significantly modulated by XLJDD, showing their potential as effective targets of XLJDD. In addition, we also discovered that XLJDD could affect the cell composition of the colorectal tumor environment, especially in the infiltration of B cells.Conclusion: We demonstrated that XLJDD could prevent the initiation and development of colorectal tumors by modulating the expression of Mfsd2a and Ccdc85c and reducing the infiltration of B cells in the tumor microenvironment of colorectal tumor.Keywords: colorectal tumor, Mfsd2a, Ccdc85c, inflammation pathway, B cell infiltration

Lin Wang,1 Qingqing Liu,2 Dongsheng Sun,1 Jianhong Xie,1 Dibo Lao,1 Li Zhang1 1Heart Center, Department of Geriatrics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Shulan (Hangzhou) Hospital, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Li Zhang, Heart Center, Department of Geriatrics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), No. 158 Shangtang Road, Hangzhou, 310014, Zhejiang, People’s Republic of China, Tel/Fax +86 571-85893957, Email blueapplezl@163.comBackground: Hypertension commonly co-exists with depression and is associated with adverse health outcomes. This meta-analysis aimed to examine whether combination treatment can improve the outcomes of patients with comorbid hypertension and depression.Methods: We searched for relevant randomized controlled trials (RCTs) published through July 2021 using PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang Data. RCTs on patients with an antihypertensive outcome and data on mean blood pressure differences were extracted for both intervention and control groups. Continuous and dichotomous measures of outcomes were pooled using weighted mean differences (WMD) and risk ratios (RR) with 95% confidence intervals (CI) by random or fixed effects. Subgroup and meta-regression analyses were performed to identify any existing heterogeneous sources.Results: A total of 27 RCTs with 2606 participants were included. Combination treatment significantly improved systolic blood pressure (SBP) by 11.27 mmHg (WMD = − 11.27, 95% CI: − 14.12 to − 8.43), I2 = 95.4%), diastolic blood pressure (DBP) by 8.21 mmHg (WMD = − 8.21, 95% CI: − 10.73 to − 5.69), I2 = 96.9%), and antihypertensive efficiency by 42% (RR = 1.42, 95% CI: 1.32 to 1.52, I2 = 0.0%) compared with in the control group. Combination treatment improved SBP and DBP levels in patients aged < 65 years compared with those in patients aged ≥ 65 years (p = 0.020 and 0.007, respectively).Conclusion: Pooled evidence suggests that combination treatment significantly improves both blood pressure levels and antihypertensive efficiency in hypertensive patients with depression. Elderly patients with comorbid hypertension and depression may require a more collaborative approach to improve their outcome.Registration: PROSPERO registration number CRD42020213430. Registered on November 08, 2020.Keywords: hypertension, depression, combination treatment, meta-analysis, RCTs

Yaling Hu,1,2 Shuang Liu,3 Wenyuan Liu,2 Ziyuan Zhang,2 Yuxiang Liu,1 Sufen Li,2 Dalin Sun,2 Guang Zhang,2 Jingai Fang2 1Shanxi Medical University, Taiyuan, Shanxi, 030001, People’s Republic of China; 2Department of Nephrology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, People’s Republic of China; 3Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, People’s Republic of ChinaCorrespondence: Jingai Fang, Department of Nephrology, First Hospital of Shanxi Medical University, 85 Jiefangnan Road, Taiyuan, Shanxi, 030001, People’s Republic of China, Email jingaifang2017003@126.comPurpose: Using network pharmacology and molecular docking to explore the mechanism of Yishen Capsule in the treatment of diabetic nephropathy.Materials and Methods: Active components of Yishen Capsule were obtained using database such as TCMSP and TCMID. UniProt protein database was used to screen and standardize the human-derived targets of the active chemical components. Diabetic nephropathy (DN) targets were obtained from databases such as GeneCards, OMIM, TTD, DisGeNET and DrugBank. A network of “Yishen Capsule Components-diabetic nephropathy Targets-Pathways” was constructed by analyzing data above to screening out core targets for molecular docking verification. DN is induced by streptozocin in rats after left nephrectomy. Renal tubular epithelial cells (RTECs) was isolated and cultured under high glucose conditions. Based on these experimental models, key pathway target genes screened by network pharmacology were verified both in vitro and in vivo.Results: The main active components of Yishen Capsule in the treatment of DN include quercetin, kaempferol, gallic acid, astragaloside IV, etc. Some key targets (such as AR, AKT1, TP53, ESR1, JUN) and important signal pathways (such as AGE-RAGE, HIF-1 and JAK-STAT signal pathway) were included in the treatment of DN with Yishen Capsule. Molecular docking assay showed that most of the targets have good binding activity with the components of Yishen Capsule. Based on the results of network pharmacology, key target proteins in HIF-1α and JAK2/STAT3 signaling pathways were selected for experimental verification. Results presented that HIF-1α, JAK2, STAT3, TGF-β and MCP-1 were increased under high glucose environment. With the treatment of Yishen Capsule, the expression of HIF-1α further increased, while the expression of JAK2, STAT3, MCP-1 and TGF-β was decreased.Conclusion: This study revealed the mechanism of Yishen Capsule in the treatment of DN, which possesses the characteristics of multi-component, multi-target, and multi-pathway. Further experiments confirmed that Yishen Capsule interfered with HIF-1α and JAK/STAT signaling pathways to reduce inflammation and fibrosis damage in the kidney tissue of rats with diabetic nephropathy.Keywords: diabetic nephropathy, network pharmacology, molecular docking, HIF-1α, JAK/STAT

Dongdong Yuan,1 Xiangfen Shi,2 Liping Gao,1 Gaobiao Wan,1 Hanjuan Zhang,1 Yuling Yang,1 Yujie Zhao,1 Didi Sun1 1Department of Medicine, The 7th People’s Hospital of Zhengzhou, Zhengzhou, 450000, Henan, People’s Republic of China; 2The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, People’s Republic of ChinaCorrespondence: Didi Sun, Email y19847816@163.comBackground: Generally, many individual factors can affect the clinical application of drugs, of which genetic factors contribute more than 20%. Ticagrelor is a new class of receptor inhibitors receptor antagonist of P2Y12 and is used as an antiplatelet agents. But it is not affected by the influence of CYP2C19 polymorphism. With lack of predicted biomarkers, especially the research data of Chinese, it has the important significance in studying individual differences of ticagrelor in the antiplatelet efficacy and safety, through pharmacogenomics research.Methods: Whole-exome sequencing (WES) was performed in 100 patients after PCI with ticagrelor treatment. Clinical characteristics and WES of patients were used to performed genome-wide association analysis (GWAS), region-based tests of rare DNA variant to find the influencing factors of antiplatelet effect to ticagrelor and bleeding events. Co-expression, protein–protein interaction (PPI) network and pathway enrichment analysis were then used to find possible genetic mechanisms. Atlas of GWAS (https://atlas.ctglab.nl/) were used for external data validation.Results: DNAH17, PGS1 and ABCA1 as the potential variant genes are associated with the expected antiplatelet effect to ticagrelor. The affected pathways may include the synthesis and metabolism of lipoprotein cholesterol and the catabolic process of pyrimidine-containing compound (GO:0072529). Age, sex and PLT were found may be potential factors for ticagrelor bleeding events.Conclusion: We systematically identified new genetic variants and some risk factors for reduced efficacy of ticagrelor and highlighted related genes that may be involved in antiplatelet effects and bleeding event of ticagrelor. Our results enhance the understanding of the absorption and metabolic mechanisms that influence antiplatelet response to ticagrelor treatment.Trial Registration: ClinicalTrials.gov Identifier: NCT03161002. First Posted: May 19, 2017. https://clinicaltrials.gov/ct2/show/study/NCT03161002.Keywords: ticagrelor, percutaneous coronary intervention, bleeding, inhibition of platelet aggregation, pharmacogenetic, whole-exome sequencing

Yuhao Zhang,1,2 Dawei Sun3 1Department of Otolaryngology Head and Neck Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People’s Republic of China; 2Department of Otolaryngology Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 3Department of Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of ChinaCorrespondence: Dawei SunDepartment of Thyroid Surgery, The Affiliated Hospital of Qingdao University, #16 Jiangsu Road, Qingdao, Shandong, 266000, People’s Republic of ChinaEmail sundawei18669@sina.comPurpose: This study aimed to evaluate the associations between immune-related gene (FCRL3, NLRP3 and IL2) polymorphisms and the risk of head and neck cancer (HNC).Methods: Six polymorphisms of FCRL3, NLRP3 and IL2 were genotyped in 400 HNC cases and 400 controls using a MassARRAY platform.Results: rs11264799-T was a protective variant against HNC risk, while rs7528684-G, rs35829419-A and rs6822844-T were all risk alleles for HNC (p < 0.05). rs11264799-TT was correlated with reduced HNC risk, while rs7528684-GG and rs6822844-TG were associated with an elevated risk of disease (p < 0.05). Moreover, rs11264799 was correlated with a declining risk of HNC in three genetic models (p < 0.05). In contrast, rs7528684 exhibited an elevated risk of HNC in recessive and additive models; rs35829419 and rs6822844 were associated with an increased risk of disease in dominant and additive models (p < 0.05). Finally, an interaction was observed between the above SNPs and drinking (p < 0.05).Conclusion: The results expand our knowledge on immune-related gene polymorphisms in HNC and provide clues for further functional study on the pathogenesis of HNC.Keywords: head and neck cancer, HNC, Fc receptor-like 3, FCRL3, NLR family pyrin domain containing 3, NLRP3, interleukin 2, IL2, genetic polymorphisms

Jingyu Xu,1,* Zhenbiao Guan,2,* Xiaowei Wang,1,* Dazhi Sun,1 Yongjin Li,1 Bei Pei,1 Ye Lu,1 Liangxi Yuan,3 Xuan Zhang1 1Department of Traditional Chinese Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, People’s Republic of China; 2Department of Respiration, Changhai Hospital, Naval Medical University, Shanghai 200433, People’s Republic of China; 3Department of Vascular Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liangxi YuanDepartment of Vascular Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, People’s Republic of ChinaEmail yuanlx116@163.comXuan ZhangDepartment of Traditional Chinese Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, People’s Republic of ChinaEmail zhangx@smmu.edu.cnBackground and Objective: Neurotoxicity is a common side effect of oxaliplatin; the effect of current drugs such as methylcobalamin and gabapentine is not obvious. Astragaloside IV (AS-IV) is an important active ingredient of Astragali Radix, which can protect the nervous system and inhibit tumor growth to a certain extent. However, whether AS-IV can reduce oxaliplatin neurotoxicity and its molecular mechanism remain unclear.Methods: The network pharmacology method was used to determine the collective targets of AS-IV and oxaliplatin neurotoxicity. The model of neurotoxicity was established by intraperitoneal injection of oxaliplatin in rats. Bodyweight, mechanical withdrawal threshold (MWT), cold allodynia, and nerve conduction velocity (NCV) were examined, pathological changes were observed by hematoxylin-eosin staining, number of Nissl bodies were assessed by Nissl staining, the key collective targets were measured by spectrophotometry and immunohistochemistry.Results: Through network pharmacological analysis, 25 collective targets of AS-IV and oxaliplatin neurotoxicity were identified, mainly related to inflammation and oxidative stress. AS-IV could increase body weight, elevate MWT, and reduce cold allodynia of model rats, it also raised NCV. Neuropathology was improved and the number of Nissl bodies was increased by AS-IV administration. It reduced TNF-α, IL-6, and IL-1β in the spinal cord of model rats to inhibit inflammation; it also decreased MDA, raised SOD, CAT, and GSH-Px in the spinal cord of model rats to block oxidative stress.Conclusion: AS-IV improves oxaliplatin neurotoxicity by regulating neuroinflammation and oxidative stress; the results can provide a new perspective for the potential treatment strategy of oxaliplatin neurotoxicity.Keywords: network pharmacology, astragaloside IV, oxaliplatin neurotoxicity, neuroinflammation, oxidative stress

Xiumei Hu,1,* Changmeng Wu,1,* Bo Situ,1,* Peifu Tian,2,* Taixue An,1 Qiang Li,1 Weilun Pan,1 Ruyi Zhang,1 Biao Yang,3 Dehua Sun,1 Yuhai Hu,2 Qian Wang,1,3 Lei Zheng1 1Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of China; 2Department of Medicine Laboratory, Hankou Hospital of Wuhan, Wuhan 430010, People’s Republic of China; 3Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei Zheng; Qian Wang Email nfyyzhenglei@smu.edu.cn; wangqian@smu.edu.cnObjective: The coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is now rapidly spreading globally. Serological tests are an important method to assist in the diagnosis of COVID-19, used for epidemiological investigations. In this study, we aimed to investigate the impact of different types of vacuum collection tubes on the detection of SARS-CoV-2 IgM and IgG antibodies, using the colloidal gold immunochromatographic assay (GICA).Patients and Methods: A total of 112 patients with COVID-19 and 200 healthy control subjects with no infection were enrolled in this study. Their serum and plasma were collected into four different types of vacuum blood collection tubes. SARS-CoV-2 IgM and IgG specific antibodies in the plasma and serum were then detected by GICA and chemiluminescence assay (CA), respectively. In addition, the particle sizes of different colloidal gold solutions in the presence of different anticoagulants and coagulants were evaluated by both laser diffraction (Malvern) and confocal laser microscope, respectively.Results: Our results revealed that anticoagulated plasma with EDTA-K2 improved the positive detection rate of SARS-CoV-2 IgM antibodies. Furthermore, our results shown that the detection results by GICA and CA were highly consistent, especially, the results of EDTA-K2 anticoagulated plasma detected by GICA was more consistent with CA results. We confirmed that EDTA-K2 could improve the detection sensitivity of SARS-CoV-2 IgG antibodies by chelating excessive colloidal gold compared with sodium citrate or lithium heparin, these methodologies did not appear to cause false positives. Colloidal gold particles could be chelated and aggregated by EDTA-K2, but not by sodium citrate, lithium heparin and coagulants.Conclusion: GICA is widely used to detect antibodies for the advantages of convenient, fast, low cost, suitable for screening large sample and require minimal equipment. In this study, we found that EDTA-K2 amplified the positive antibody signal by chelating colloidal gold and improved the detection sensitivity of SARS-CoV-2 IgM and IgG antibodies when using the GICA. Therefore, we suggested that EDTA-K2 anticoagulated plasma was more suitable for the detection of SARS-CoV-2 antibodies.Keywords: EDTA-K2, SARS-CoV-2, antibodies, gold immunochromatographic assay; GICA

Yan Zhang,1,* Yuan Dong,1,* Zhenyu Xiong,1,* Zhengru Zhu,2 Fanya Gao,3 Tingting Wang,1 Wanrong Man,1 Dong Sun,1 Jie Lin,1 Tongbin Li,1 Congye Li,1 Zhijing Zhao,1 Min Shen,1 Dongdong Sun,1 Yanhong Fan1 1Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China; 2Department of Otolaryngology Head and Neck Surgery, First Hospital of Lanzhou University, Lanzhou, People’s Republic of China; 3Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an Medical University, Xi’an, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongdong Sun; Yanhong FanDepartment of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi’an, Shaanxi 710032, People’s Republic of ChinaTel +86 18691569930; +86 18829395402Email wintersun3@gmail.com; 18829395402@189.cnBackground: Endothelial-to-mesenchymal transition (EndMT) is an important source of myofibroblasts that directly affects cardiac function in diabetic cardiomyopathy (DCM) via an unknown underlying mechanism. Sirt6 is a member of the Sirtuin family of NAD(+)-dependent enzymes that plays an important role in glucose and fatty acid metabolism. In this study, we investigated whether Sirt6 participates in EndMT during the development of T2DM and the possible underlying regulatory mechanisms.Methods: Endothelium-specific Sirt6 knockout (Sirt6-KOEC) mice (C57BL/6 genetic background) were generated using the classic Cre/loxp gene recombination system. T2DM was induced in eight-week-old male mice by feeding with a high-fat diet for three weeks followed by i.p. injection with 30 mg/kg of streptozotocin. The weight, lipids profiles, insulin, food intake and water intake of experimental animals were measured on a weekly basis. Cardiac microvascular endothelial cells (CMECs) were obtained from adult male mice; the isolated cells were cultured with high glucose (HG; 33 mmol/L) and palmitic acid (PA; 500 μmol/L) in DMEM for 24 h, or with normal glucose (NG; 5 mmol/L) as the control.Results: Sirt6 expression is significantly downregulated in CMECs treated with HG+PA. Additionally, Sirt6-KOEC was found to worsen DCM, as indicated by aggravated perivascular fibrosis, cardiomyocyte hypertrophy, and decreased cardiac function. In vitro, Sirt6 knockdown exacerbated the proliferation, and migration of CMECs exposed to HG+PA. Mechanistically, Sirt6 knockdown significantly enhanced Notch1 activation in CMECs treated with HG+PA, whereas Notch1 adenoviral interference significantly blunted the effects of Sirt6 knockdown on CMECs.Conclusion: This study is the first to demonstrate that Sirt6 participates in EndMT via the Notch1 signaling pathway in CMECs stimulated with HG+PA. Therefore, the findings of this study suggest that Sirt6 could provide a potential treatment strategy for DCM.Keywords: diabetic cardiomyopathy, endothelial-to-mesenchymal transition, cardiac function, fibrosis, Sirt6

Dan Sun,1,* Tao Zhang,1,* Jie Mi,2 Yuzhu Dong,3 Yang Liu,1 Ying Zhang,1 Di Zhang,1 Taotao Wang,1 Hua Cheng,2 Yalin Dong1 1Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, People’s Republic of China; 2Department of Pharmacy, Xi’an Children’s Hospital, Xi’an, Shaanxi 710003, People’s Republic of China; 3Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yalin DongDepartment of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, People’s Republic of ChinaTel/ Fax +86-29-85323241Email dongyalin@mail.xjtu.edu.cnHua ChengDepartment of Pharmacy, Xi’an Children’s Hospital, Xi’an, Shaanxi 710003, People’s Republic of ChinaTel/ Fax +86-29-87692090Email chhyjk@163.comPurpose: This study aims to 1) describe the distribution characteristics of teicoplanin trough concentration (Cmin) and explore the related influencing factors and 2) evaluate the nephrotoxicity of teicoplanin in children.Patients and Methods: A cohort of children who were treated with teicoplanin intravenously were included in this retrospective study. Regression analysis was performed to explore the factors associated with the fluctuations of teicoplanin Cmin and the development of nephrotoxicity. Classification and regression tree analysis was used to identify the population at high risk for teicoplanin nephrotoxicity.Results: A total of 269 plasma samples from 186 children were collected. Underexposure (Cmin < 10 mg/L) was documented in 52.7% of cases. The Cmin/dose after administering the loading dose was strongly associated with age (P = 0.008), weight (P = 0.039), and serum creatinine (P = 0.022). The Cmin/dose after administering the maintenance dose was strongly associated with gender (P = 0.014) and serum creatinine (P = 0.006). Cmin (P = 0.012) and the concomitant treatment with amphotericin B (P = 0.001) were the independent risk factors for teicoplanin-related nephrotoxicity. Children who were concomitantly treated by amphotericin B with teicoplanin Cmin > 9.81 mg/L or patients with teicoplanin Cmin > 21.94 mg/L were at high risk for nephrotoxicity.Conclusion: The fluctuations of teicoplanin Cmin could be affected by age, weight, gender, and serum creatinine. Cmin and concomitant treatment with amphotericin B were the independent risk factors for nephrotoxicity. We suggested that the therapeutic drug monitoring of teicoplanin should be performed in children.Keywords: teicoplanin, trough concentration, children, nephrotoxicity, factor

Xiaojun Shao1 *,* Ci Yan1 *,* Dongxue Sun,1 Chunfeng Fu,1 Chunsheng Tian,1 Li Duan,1 Gang Zhu1,2 1Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Central Laboratory, The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gang ZhuDepartment of Psychiatry, Tthe First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of ChinaTel/ Fax +86-24-83282184Email gzhu@cmu.edu.cnObjective: The dopamine and oxidative stress hypotheses are leading theories of the pathoetiology of schizophrenia (SCZ). Glutathione Peroxidase 1 (GPx-1), a major antioxidant enzyme, and the most abundantly expressed member of the GPx family, plays an important role in metabolic dopamine changes, which are closely related to neurological and psychiatric disorders. The impact of GPx-1 polymorphisms has rarely been explored in the field of SCZ. Here, we explored the possible relationship between GPx-1 gene polymorphisms and SCZ in Chinese Han subjects by using the polymerase chain reaction-restriction fragment length polymorphism method.Methods: DNA from 786 patients (360 patients with schizophrenia and 426 healthy controls) was genotyped for the single-nucleotide polymorphisms rs1800668 C/T and rs1050450 C/T in GPx-1 using polymerase chain reaction-restriction fragment length polymorphism analysis. Analysis of the association between GPx-1 and SCZ was performed using SPSS 22.0, while Haploview 4.2 software and SHEsis software were used to perform linkage disequilibrium analysis and haplotype analysis.Results: The results indicated that the GPx-1 polymorphisms rs1050450 and rs1800668 were associated with SCZ. We found that the C-allele of rs1800668 C/T may be a protection factor against SCZ in general, but in particular, for males. Furthermore, the CT and TC (GPx-1 rs1800668 C/T and rs1050450 C/T) haplotypes may be susceptible to SCZ in the population. Finally, no significant differences in allelic or genotypic frequencies of rs1050450 were detected between cases and controls from whole or stratification analyses by gender.Conclusion: GPx-1 polymorphisms are related to SCZ in Chinese Han subjects. Our results suggested that GPx-1 may be a potential gene that influences SCZ.Keywords: case-control study, Chinese Han population, GPx1, polymorphism, schizophrenia

Guoming Zeng,1,2,* Libo Jin,3,4,* Qinsi Ying,5 Haojie Chen,3 Murinda Charmaine Thembinkosi,3 Chunguang Yang,6 Jinlong Zhao,6 Hao Ji,3 Sue Lin,3 Renyi Peng,3 Maolan Zhang,1,3 Da Sun3 1Chongqing University of Science and Technology, Chongqing 401331, People’s Republic of China; 2China Metallurgical Construction Engineering Group Co., Ltd., Chongqing 400044, People’s Republic of China; 3Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang 325035, People’s Republic of China; 4Biomedical Collaborative Innovation Center of Zhejiang Province & Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, Wenzhou, Zhejiang 325035, People’s Republic of China; 5Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325035, People’s Republic of China; 6Institute of Metal Research, Chinese Academy of Sciences, Shenyang, Liaoning 110016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Da SunInstitute of Life Sciences, Wenzhou University, Higher Educational Park, Wenzhou City 325035, Zhejiang Province, People’s Republic of ChinaEmail sunday@wzu.edu.cnMaolan ZhangChongqing University of Science and Technology, No. 19, Xijiao Branch Road, Jiulongpo District, Chongqing 400050, People’s Republic of ChinaEmail zml@cqu.edu.cnAbstract: Cancer immunotherapy is a promising approach that has recently gained its importance in treating cancer. Despite various approaches of immunotherapies being used to target cancer cells, they are either not effective against all types of cancer or for all patients. Although efforts are being made to improve the cancer immunotherapy in all possible ways, one important hindrance that lowers the immune response to kill cancer cells is the infiltration of Regulatory T (Treg) cells into the tumor cells, favoring tumor progression, on one hand, and inhibiting the activation of T cells to respond to cancer cells, on the other hand. Therefore, new anti-cancer drugs and vaccines fail to show promising results against cancer. This is due to the infiltration of Treg cells into the tumor region and suppression of anti-cancer activity. Thus, regardless of various types of immunotherapies being practiced, understanding the mechanisms of how Treg cells favor tumor progression and inhibition of anti-cancer activity is worthwhile. Therefore, the review highlights the importance of Tregs cells and how depletion of Treg cells can pave the way to an effective immunotherapy by activating the immune responses against cancer.Keywords: cancer immunotherapy, Treg cells, FoxP3, targeting Treg cells, anti-cancer

Xudong Ma,1 Jing Luo,1 Yi Zhang,2 Dali Sun,1 Yueying Lin1 1Gastrointestinal Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming City, Yunnan Province 650031, People’s Republic of China; 2The General Surgery Department, The Teng-Chong People’s Hospital, Tengchong City, Yunan Province, 679100, People’s Republic of ChinaCorrespondence: Yueying Lin Email us5010@163.comIntroduction: This study aimed to investigate the role of lncRNA MCM3AP-AS1 in colorectal cancer (CRC).Methods: Paired tumor and non-tumor tissues were collected from 60 CRC patients. Expression of MCM3AP-AS1 was determined by RT-qPCR. Overexpression of MCM3AP-AS1, miR-545, and CDK4 in CRC cells was achieved to explore the interactions between them. Cell cycle assay was performed to analyze the roles of MCM3AP-AS1, miR-545, and CDK4 in regulating the cell cycle progression of CRC cells.Results: We found that MCM3AP-AS1 was upregulated in CRC and its high expression levels predicted poor survival of CRC patients. MCM3AP-AS1 is predicted to interact with miR-545. In CRC cells, overexpression of MCM3AP-AS1 and miR-545 was achieved, while their overexpression did not affect the expression of each other. Instead, overexpression of MCM3AP-AS1 led to the increased expression levels of CDK4, which is a downstream target of miR-545. Cell cycle analysis showed that overexpression of MCM3AP-AS1 and CDK4 suppressed G1 arrest induced by miR-545. In addition, overexpression of MCM3AP-AS1 reduced the enhancing effects of overexpressing miR-545 on cell cycle progression.Conclusion: MCM3AP-AS1 may upregulate CDK4 by sponging miR-545 to induce G1 arrest in CRC cells.Keywords: MCM3AP-AS1, colorectal cancer, miR-545, CDK4, G1 arrest

Juan Li,1 Lei Zheng,2 Rongmei Wang,1 Deqing Sun,1 Shuang Liang,3 Jing Wu,1 Yongqing Liu,1 Xiaona Tian,1 Tingting Li,4 Yang Yang,5 Leiqiang Han1 1Department of Clinical Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, People’s Republic of China; 2Department of Pharmacy, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250031, People’s Republic of China; 3School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People’s Republic of China; 4Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA; 5China National Center for Biotechnology Development, Beijing 100039, People’s Republic of ChinaCorrespondence: Leiqiang HanDepartment of Clinical Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Road, Jinan, Shandong 250033, People’s Republic of ChinaTel +86-531-85875083Fax +86-531-88962544Email hanlq007@sina.cnBackground: The development of paclitaxel (PTX) resistance seriously restricts its clinical efficacy. An attractive option for combating resistance is inhibiting the expression of P-glycoprotein (P-gp) in tumor cells. We have reported that flavokawain A (FKA) inhibited P-gp protein expression in PTX-resistant A549 (A549/T) cells, indicating that FKA combined with PTX may reverse PTX resistance. However, due to the variable pharmacokinetics of FKA and PTX, the conventional cocktail combination in clinics may cause uncertainty of treatment efficacy in vivo.Materials and Methods: To synergistically elevate the anti-cancer activity of PTX and FKA in vivo, the national medical products administration (NMPA) approved sodium aescinate (Aes) was utilized to stabilize hydrophobic PTX and FKA to form polymer-free twin like PTX-A nanoparticles (NPs) and FKA-A NPs.Results: The resulting nanoparticles prepared simply by nanoprecipitation possessed similar particle size, good stability and ultrahigh drug loadings of up to 50%. With the aid of Aes, these two drugs accumulated in tumor tissue by passive targeting and were efficiently taken up by A549/T cells; this resulted in significant suppression of tumor growth in A549/T homograft mice at a low PTX dose (2.5 mg·kg− 1). Synergistic effects and reversed PTX resistance were achieved by the combination of PTX-A NPs and FKA-A NPs by inhibiting P-gp expression in tumor cells.Conclusion: Using NMPA-approved Aes to prepare twin-like nanoparticles without introducing any new materials provides an efficient platform for combination chemotherapy and clinical translation.Keywords: paclitaxel resistance, flavokawain A, sodium aescinate, polymer-free nanoparticles, combination therapy

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

Yan Li,1 Maria Palmisano,1 Duxin Sun,2 Simon Zhou1 1Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ 07920, USA; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USACorrespondence: Simon ZhouTranslational Development and Clinical Pharmacology, Celgene Corporation, 556 Morris Avenue, Summit, NJ 07920, USATel +1 908-673-9284Fax +1 908-673-2842Email szhou@celgene.comBackground: Voclosporin, a more potent derivative of cyclosporine, has been studied extensively in patients with immunologic disorders such as psoriasis, organ transplantation, uvetitis and lupus nephritis. Although better tolerated and safer than cyclosporine, voclosporin is inferior to cyclosporine in treating psoriasis, non-inferior to tacrolimus in organ transplantation and efficacious in treating lupus nephritis.Methods: The pharmacokinetic dispositions of voclosporin and cyclosporine in central and peripheral compartments were analyzed and correlated with their distinct clinical efficacy and safety profiles.Results: Both drugs demonstrated non-linear pharmacokinetics with increasing doses, more prominently at lower doses of voclosporin than at 10-fold higher doses of cyclosporine. Repeated lower dosing of voclosporin produced preferential calcineurin inhibition in and near blood circulation, leading to relatively lower cardiovascular and renal adverse effects but inferior efficacy for psoriasis compared to cyclosporine. With 10-fold higher plasma levels and deeper tissue penetration, cyclosporine has more prevalent renal and cardiac toxicities but superior efficacy to treat psoriasis.Conclusion: Although the two drugs are similar in structure and mechanism of action, the high potency and low dose compounded by the non-linear disposition of voclosporin resulted in more systemic versus local calcineurin inhibition than with cyclosporine. The dispositional difference between voclosporin and cyclosporine accounted for the puzzling efficacy and safety observations in different patients and was the basis for their optimal and differential use in treating diverse immunologic disorders.Keywords: pharmacokinetic, disposition, cyclosporine and voclosporin

Jian Long,1,2 Yao Ouyang,1 Haizhen Duan,3 Zhongyong Xiang,2 Hongchang Ma,2 Mingliang Ju,4 Desheng Sun1 1Department of Respiratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi City, Guizhou, People’s Republic of China; 2Zunyi Fifth People’s Hospital (Zunyi Mental Health Center), Zunyi City, Guizhou, People’s Republic of China; 3Department of Emergency Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi City, Guizhou, People’s Republic of China; 4Shanghai Mental Health Center Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai City, People’s Republic of ChinaCorrespondence: Yao OuyangDepartment of Respiratory Medicine, Affiliated Hospital of Zunyi Medical University, 149 Daliang Road, Zunyi City, Guizhou 563003, People’s Republic of ChinaTel +8613885216891Email ouyangyao116@sohu.comObjective: To reveal the risk factors, the symptom distribution characteristics, the clinical values of white blood cell counts (WBC counts), red blood cell distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR) in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) combined with depression and/or anxiety.Methods: The study included prospective cross-sectional and case–control studies, and was executed in the Affiliated Hospital of Zunyi Medical University, Guizhou, China. Previously diagnosed chronic obstructive pulmonary disease (COPD) patients who admitted to the hospital with AECOPD, patients with depression and/or anxiety, and healthy people were enrolled in the study. The Hamilton Rating Scales were used to assess all subjects, and the complete blood counts (CBC) were collected. Baseline data and clinical measurement data [spirometry, arterial blood gas analysis, and COPD evaluation test (the CAT scale)] from patients with AECOPD were collected.Results: Of the 307 patients with AECOPD included, 63.5% (N=195) had depressive and/or anxiety symptoms, and 36.5% (N=112) had no symptoms. Sex, respiratory failure, number of comorbidities, number of acute exacerbations in the previous year and the CAT score were closely related to AECOPD combined with depression and/or anxiety (p< 0.05). The CAT scale score were the independent risk factor (OR=6.576, 95% CI 3.812– 11.342) and significant predictor of AECOPD with depression and/or anxiety (AUC=0.790,95% CI 0.740– 0.834); the patients with depression and/or anxiety were more severe and characteristic than the patients with AECOPD combined with depression and/or anxiety; RDW was associated with AECOPD with depression and/or anxiety (p=0.020, OR1.212,95% CI1.03– 1.426), and had certain clinical diagnostic value (AUC=0.570,95% CI 0.531– 0.626).Conclusion: Depression and anxiety should not be ignored in patients with AECOPD. The severity and quality of life of COPD were closely related to the occurrence of depression and/or anxiety symptoms. In most cases, perhaps depression and anxiety in AECOPD are only symptoms and not to the extents of the diseases. RDW had clinical diagnostic value in AECOPD combined with depression and/or anxiety. NLR, PLR, MLR, and RDW may become the novel indicators for evaluating the degree of inflammation of AECOPD and deserve further research.Keywords: AECOPD, anxiety, depression, comorbidities, Hamilton Rating Scale, inflammatory markers, symptomatology

Zhenming Gao,1,* Jidong Sui,1,* Rong Fan,2 Weikun Qu,1 Xuepeng Dong,1 Deguang Sun1 1Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, People’s Republic of China; 2Department of International Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenming Gao; Rong FanDepartment of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Dalian Medical University Department of International Medicine, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, Liaoning 116027, People’s Republic of ChinaEmail gaozhenmingdl@163.com; fanrongdl@126.comAim: Lung injury is a common complication of acute pancreatitis (AP), which leads to the development of acute respiratory distress syndrome and causes high mortality. In the present study, we investigated the therapeutic effect of emodin on AP-induced lung injury and explored the molecular mechanisms involved.Materials and Methods: Thirty male Sprague-Dawley rats were randomly divided into AP (n=24) and normal (n=6) groups. Rats in the AP group received a retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct and then randomly assigned to untreated, emodin, combined emodin and ML385, and dexamethasone (DEX) groups. Pancreatic and pulmonary injury was assessed using H&E staining. In in vitro study, rat alveolar epithelial cell line L2 cells were exposed to lipopolysaccharide and treated with emodin. Nrf2 siRNA pool was applied for the knockdown of Nrf2. The contents of the pro-inflammatory cytokines in the bronchoalveolar lavage fluid and lung were determined using enzyme-linked immunosorbent assay. The expressions of related mRNAs and proteins in the lung or L2 cells were detected using real-time polymerase chain reaction, Western blot, immunohistochemistry and immunofluorescence.Key Findings: Emodin administration alleviated pancreatic and pulmonary injury of rats with AP. Emodin administration suppressed the production of proinflammatory cytokines, downregulated NLRP3, ASC and caspase-1 expressions and inhibited NF-κB nuclear accumulation in the lung. In addition, Emodin increased Nrf2 nuclear translocation and upregulated HO-1 expression. Moreover, the anti-inflammatory effect of emodin was blocked by Nrf2 inhibitor ML385.Conclusion: Emodin effectively protects rats against AP-associated lung injury by inhibiting NLRP3 inflammasome activation via Nrf2/HO-1 signaling.Keywords: emodin, acute pancreatitis, lung injury, Nrf2, NLRP3 inflammasome

Yuzhu Dong,1,* Ying Li,2,* Ying Zhang,1 Dan Sun,1 Qian Du,1 Tao Zhang,1 Mengmeng Teng,1 Ruiying Han,1 Yan Wang,3 Li Zhu,4 Jin’e Lei,5 Yalin Dong,1 Taotao Wang1 1Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, People’s Republic of China; 2Department of Pharmacy, Xi’an NO.3 Hospital, Xi’an 710082, People’s Republic of China; 3Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, People’s Republic of China; 4Department of Infections, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, People’s Republic of China; 5Department of Laboratory, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yalin DongDepartment of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, People’s Republic of ChinaTel/Fax +86-29-85323240Email dongyalin@mail.xjtu.edu.cnTaotao WangDepartment of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, People’s Republic of ChinaTel/Fax +86-29-85323243Email wangtaotao1989@mail.xjtu.edu.cnBackground: Gram-negative bacteria bloodstream infection (GNB-BSI) results in considerable mortality and hospitality costs in cirrhotic patients. β-lactam/β-lactamase inhibitor combinations (BLBLIs) and carbapenems (CARs) are widely recommended for treating GNB-BSI in cirrhotic patients, while the efficacy and cost-effectiveness of two strategies have never been evaluated. Therefore, we conducted a retrospective cohort study to evaluate the efficacy and the cost-effectiveness of BLBLIs and CARs.Patients and Methods: Cirrhotic patients with GNB-BSI treated by BLBLIs or CARs were included. A propensity score-matching analysis was performed to compare the efficacy between BLBLIs and CARs. A decision tree was used to estimate the clinical outcomes and direct costs of treating BSI using two strategies from the patients’ perspective.Results: No statistically significant difference was found between the BLBLIs (n = 41) group and the CARs (n = 43) group regarding the time to defervescence (2.4 ± 0.2 vs 2.5 ± 0.3, P = 0.94). Thirty-seven patients from each group were matched in propensity-score-matched cohort, and there was no significant difference between two groups in terms of the time to defervescence (2.4 ± 0.3 vs 2.4 ± 0.3, P = 0.75) and success rate (86.5% vs 78.4%; OR = 0.57; P = 0.36). Based on the drug and hospital costs in China, cefoperazone/sulbactam was cost-effective in the present analysis under the willingness-to-pay threshold (¥ 64,644).Conclusion: The efficacy of BLBLIs is similar to CARs. Cefoperazone/sulbactam could be a cost-effective therapy in cirrhotic patients with GNB-BSI. Carbapenems-sparing regimens should be encouraged in regions with a low prevalence of MDR bacteria.Keywords: liver cirrhosis, gram-negative bacteria, bloodstream infection, efficacy, cost-effectiveness

Dongjun Sun,1 Hengming Liu,2 Tiantian Wang3 1Department of General Surgery, Chiping District People’s Hospital, Liaocheng, Shandong, People’s Republic of China; 2Department of Anesthesiology, Chiping District People’s Hospital, Liaocheng, Shandong, People’s Republic of China; 3Department of Thyroid and Breast Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Tiantian WangDepartment of Thyroid and Breast Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of ChinaEmail wangtiantianpaper@163.comBackground: RP11-334E6.12 is a dysregulated long noncoding RNA (lncRNA) that has never been studied in breast cancer. The biological function and potential mechanism of RNA RP11-334E6.12 in tumorigenesis are still unknown.Methods: We scanned the Cancer Genome Atlas (TCGA) database and identified RP11-334E6.12 as one of the most dysregulated lncRNAs. The level of RP11-334E6.12 was assessed in breast cancer (BC) tissue samples and BC cell lines. The survival and RP11-334E6.12 expression of patients were analysed. The biological influence of RP11-334E6.12 on BC cell lines was studied using proliferation, Transwell migration, and invasion assays.Results: RP11-334E6.12 was upregulated in both the TCGA database and our own database. Moreover, survival analyses indicated that RP11-334E6.12 was related to poor overall survival. Moreover, RP11-334E6.12 promoted the proliferation, migration and invasion of BC cells. RP11-334E6.12 promotes the epithelial mesenchymal transition of BC by activating the STAT3 pathway.Conclusion: Taken together, our results demonstrate that RP11-334E6.12 is associated with the progression of breast cancer. Our findings indicate that long noncoding RNA RP11-334E6.12 promotes the proliferation, migration and invasion of breast cancer cells by activating the STAT3 pathway.Keywords: breast cancer, RP11-334E6.12, survival, proliferation, migration, invasion

Helei Hou,* Dantong Sun,* Kewei Liu, Man Jiang, Dong Liu, Jingjuan Zhu, Na Zhou, Jing Cong, Xiaochun ZhangDepartment of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, People’s Republic of China*These authors contributed equally to this workBackground: A total of 2%–7% of non-small cell lung cancer (NSCLC) patients have anaplastic lymphoma kinase (ALK) mutations. At present, three or more generations of ALK inhibitors have been used for ALK-positive NSCLC treatment, including crizotinib, alectinib, ceritinib, and brigatinib. Although most adverse events (AEs) of ALK inhibitors are grades 1 to 2 and generally can be well tolerated, serious adverse events (SAEs) of ALK inhibitors lack data analysis, and the lung toxicity of ALK inhibitors needs attention. Thus, we performed this meta-analysis to evaluate the safety of ALK inhibitors, especially in terms of drug-related SAEs.Methods: A total of 19 studies from 4 databases (PubMed, Science Direct, ClinicalTrials.gov and Cochrane Library) were included in this meta-analysis. All statistical analyses in this meta-analysis were performed with the STATA 14.0 software. We analyzed the incidences of total AEs, total SAEs and SAEs for different ALK inhibitors.Results: AEs of the ALK inhibitors occurred in almost all participants, and SAEs occurred in more than 20% of the participants. For ceritinib and brigatinib, SAEs occurred in more than 40% of the participants. Alectinib is most likely the safest of the two generations of ALK inhibitors. Generally, the ALK inhibitors showed significant lung toxicity.Conclusion: In conclusion, attention should be focused on ALK inhibitor-related SAEs, especially lung toxicity. According to this meta-analysis, alxectinib seems to be the safest ALK inhibitor. Physicians should focus on the related SAEs when prescribing ALK inhibitors.Keywords: ALK inhibitors, safety, serious adverse events, lung toxicity

Guangchen Zu,1,* Baoyang Luo,2,* Yong Yang,1 Yuwei Tan,1 Tianyu Tang,1 Yue Zhang,1 Xuemin Chen,1 Donglin Sun1 1Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People’s Republic of China; 2Department of Hepatobiliary Surgery, Taizhou People’s Hospital, Taizhou 225300, People’s Republic of China *These authors contributed equally to this work Background: Expression of C-C chemokine receptor type 7 (CCR7) is associated with the prognosis of several cancers. The aim of this study was to conduct the meta-analysis to determine the prognostic value of CCR7 expression in solid tumors. Materials and methods: We searched for relevant literature in the PubMed, Embase, and Cochrane Library databases (last updated on January 15, 2018). The associations of CCR7 expression with overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), progress-free survival (PFS), and disease-specific survival (DSS) were estimated. Results: In total, 30 qualified studies including 3,413 patients were enrolled. The results revealed that higher expression of CCR7 predicted poorer OS (pooled HR =1.79; 95% CI =1.49–2.16; P

Qiang Cai,1 Qiao Guo,1 Fan Zhang,2 Daofa Sun,2 Wenfei Zhang,1 Baowei Ji,1 Zhibiao Chen,1 Shanping Mao3 1Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province 430060, China; 2Department of Neurosurgery, Xiantao First People’s Hospital, Xiantao, Hubei Province 433000, China; 3Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province 430060, China Objective: To evaluate the effectiveness and safety of neuroendoscopic surgery for chronic or subacute subdural hematoma. Patients and methods: Between September 2016 and September 2018, neuroendoscopic surgery was performed on 25 patients with chronic and subacute subdural hematoma. Hematoma evacuation was performed with a 0°, 4 mm diameter rigid neuroendoscope via a transcranial neuroendoscopic approach. Results: All patients successfully underwent neuroendoscopic surgery, and no surgical complications or rebleeding was observed. Postoperative computed tomography scans showed that the hematoma was successfully evacuated. All patients had recovered well at discharge, the observed 30-day mortality rate was 0%, and no patients suffered recurrence for 2–26 months after surgery. Conclusion: Neuroendoscopic surgery was a safe and effective approach for the treatment of chronic and subacute subdural hematoma. This approach has the advantages of decent visualization and minimal invasiveness and could reduce recurrence and the mortality rate. Keywords: subacute subdural hematoma, chronic subdural hematoma, transcranial neuroendoscopic approach

Dongying Sun,* Wei Lei,* Xiaodong Hou, Hui Li, Wenlu Ni Department of Medical Imaging, Henan University First Affiliated Hospital, Kaifeng, Henan, China *These authors contributed equally to this work Background: PUF60 is a splicing variant of far upstream element binding protein 1-interacting repressor, which is abnormally expressed in a variety of tumors and is closely involved in their progression. However, whether PUF60 participates in the occurrence and development of breast cancer remains unknown. Therefore, the objective of the current study is to explore the effects and mechanism of PUF60 in the progression of breast cancer. Methods: PUF60 expression patterns in breast cancer tissues and cells were determined by RT-PCR and Western blotting. The relationship between PUF60 expression and patients’ clinical features and outcome was evaluated to assess the potential of PUF60 as a marker for progression and prognosis prediction. CCK-8, flow cytometry, transwell and in vivo tumor formation assays were used to detect cell proliferation, apoptosis, migration, invasion and tumorigenesis. The effects of PUF60 on the activation of PTEN/PI3K/AKT were also evaluated by Western blotting and immunofluorescence assays. Results: The expression of PUF60 was elevated in breast cancer tissue samples and cell lines, and its high expression was closely associated with the high incidence of lymph node metastasis and advanced TNM stage. Besides, upregulation of PUF60 with lentivirus infection significantly increased the growth, migration, and invasion and repressed the apoptosis of breast cancer HCC1937 and MDA-MB-231 cells, while silencing of PUF60 with shRNA showed the opposite results. Moreover, PUF60 upregulation promoted the expression of p-AKT, PI3K, and mTOR, while decreased PTEN expression through inhibiting its stability and enhancing its ubiquitination. Furthermore, upregulation of PUF60 promoted the tumorigenesis in vivo, whereas this effect was impaired when PTEN expression was upregulated in MDA-MB-231 and HCC1937 cells. Conclusion: This study demonstrates that PUF60 is highly expressed in breast cancer; upregulation of PUF60 accelerates the progression of breast cancer through PTEN inhibition. Keywords: PUF60, PTEN, PI3K/AKT, breast cancer, proliferation, tumorigenesis