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Meixin Yu,1,&ast; Ling Pei,1,&ast; Han Liu,1 Jiaxin Wang,1 Yun Wen,1 Xian Yang,1 Caixia Ma,1 Xiaofang Zhang,2,3 Liangyan Wu,1 Lihong Wang1,2 1Department of Endocrinology and Metabolism, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China; 2The Academician Cooperative Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, Guangdong, People’s Republic of China; 3The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lihong Wang, Department of Endocrinology and Metabolism, The First Affiliated Hospital of Jinan University, No. 613, Huang Pu Avenue West, Guangzhou, Guangdong, People’s Republic of China, Email nd6688@163.comPurpose: To explore the relationship between Red cell distribution width/albumin ratio (RAR) and vascular complications, including atherosclerosis of the lower limbs, diabetic nephropathy(DN), and diabetic retinopathy(DR), in patients with type 2 diabetes mellitus(T2DM).Patients and Methods: The study included 427 patients with type 2 diabetes mellitus who were hospitalized in the Department of Endocrinology of the First Affiliated Hospital of Jinan University (Guangzhou, China) between April 1, 2022 and May 31, 2023. Baseline characteristics were displayed according to the quartiles of the RAR. Logistic regression analysis and receiver operating characteristic curves (ROC) were used to analyze the data.Results: After adjusting for confounders, a higher RAR quartile(the fourth quartile) was associated with an increased risk of atherosclerosis of the lower limbs(OR: 2.973, 95% CI 1.281– 6.906, p = 0.011), and diabetic nephropathy(OR: 2.876, 95% CI 1.315– 6.287, p = 0.008) compared to the lowest RAR quartile. The patients were further divided into two groups according to urinary albumin to creatinine ratio (UACR≥ 30mg/g and UACR < 30mg/g) and Glomerular Filtration Rate (eGFR< 60 mL·min⁻¹ (1.73 m²) ⁻¹ and eGFR≥ 60 mL·min⁻¹ (1.73 m²) ⁻¹). Similar results were observed. However, We found that RAR quartile did not significantly increase the likelihood of developing diabetic retinopathy(OR: 1.183, 95% CI 0.633– 2.211, p = 0.598).Conclusion: The RAR ratio is associated with an increased risk of atherosclerosis of the lower limbs and diabetic nephropathy in patients with T2DM. The RAR ratio may be an important clinical marker of vascular complications in T2DM.Keywords: Type 2 diabetes mellitus, red blood cell distribution width, albumin, complications, inflammation

Zhigang Zuo,1– 3 Liu Pei,4 Tianzhi Liu,2 Xiujuan Liu,2 Yuhong Chen,1,3 Zhenjie Hu1,3 1Department of Critical Care Medicine, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China; 2Department of Critical Care Medicine, the First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, People’s Republic of China; 3Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, Hebei, 050011, People’s Republic of China; 4Department of Laboratory, the First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, People’s Republic of ChinaCorrespondence: Zhenjie Hu, Department of Critical Care Medicine, the Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Shijiazhuang, Hebei, 050011, People’s Republic of China, Email syicuhzj@163.comBackground: Sepsis is a life-threatening organ dysfunction caused by the host’s dysfunctional response to infection, which can cause acute gastrointestinal injury (AGI). The gut microbiota is dynamic and plays a role in the immune and metabolic. The aim of this study was to investigate the composition and function of gut microbiota in patients with sepsis, as well as the gut microbiome that may be involved in the occurrence of AGI.Methods: A total of 23 stool samples from healthy control individuals and 41 stool samples from sepsis patients were collected. Patients with sepsis were followed up for one week to observe whether AGI has occurred. Finally, 41 patients included 21 sepsis complicated with AGI (referred to as Com-AGI) and 20 sepsis without complicated with AGI (referred to as No-AGI). The gut microbiota was analyzed by 16S rRNA gene sequencing, followed by composition analysis, difference analysis, correlation analysis, functional prediction analysis.Results: The diversity and evenness of gut microbiota were decreased in patients with sepsis. Compared with No-AGI, the gut microbiota of Com-AGI has higher community diversity, richness, and phylogenetic diversity. Escherichia-Shigella, Blautia and Enterococcus may be important indicators of sepsis. The correlation analysis showed that aspartate aminotransferase (AST) and Barnesiella have the most significant positive correlation. Moreover, Clostridium_innocuum_group, Christensenellaceae_R-7_group and Eubacterium were all significantly correlated with LAC and DAO. Clostridium_innocuum_group, Barnesiella, Christensenellaceae_R-7_group and Eubacterium may play important roles in the occurrence of AGI in sepsis. PICRUSt analysis revealed multiple functional pathways involved in the relationship between gut microbiota and sepsis, including starch degradation V, glycogen degradation I (bacterial), Lipoic acid metabolism and Valine, leucine and isoleucine biosynthesis. BugBase analysis showed that the gut microbiota with Aerobic phenotype may play an important role in sepsis.Conclusion: Dysfunction of gut microbiota was associated with sepsis and AGI in patients with sepsis.Keywords: sepsis, acute gastrointestinal injury, gut microbiota, PICRUSt, classification model

It has been suggested that aberrant excitation/inhibition (E/I) balance and dysfunctional structure and function of relevant brain networks may underlie the symptoms of autism spectrum disorder (ASD). However, the nomological network linking these constructs to quantifiable measures and mechanistically relating these constructs to behavioral symptoms of ASD is lacking. Herein we describe a within-subject, controlled, proof-of-mechanism study investigating the pathophysiology of auditory/language processing in adolescents with ASD. We utilize neurophysiological and neuroimaging techniques including magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG) metrics of language network structure and function. Additionally, we apply a single, individually targeted session of continuous theta burst stimulation (cTBS) as an experimental probe of the impact of perturbation of the system on these neurophysiological and neuroimaging outcomes. MRS, fMRI, and MEG measures are evaluated at baseline and immediately prior to and following cTBS over the posterior superior temporal cortex (pSTC), a region involved in auditory and language processing deficits in ASD. Also, behavioral measures of ASD and language processing and DWI measures of auditory/language network structures are obtained at baseline to characterize the relationship between the neuroimaging and neurophysiological measures and baseline symptom presentation. We hypothesize that local gamma-aminobutyric acid (GABA) and glutamate concentrations (measured with MRS), and structural and functional activity and network connectivity (measured with DWI and fMRI), will significantly predict MEG indices of auditory/language processing and behavioral deficits in ASD. Furthermore, a single session of cTBS over left pSTC is hypothesized to lead to significant, acute changes in local glutamate and GABA concentration, functional activity and network connectivity, and MEG indices of auditory/language processing. We have completed the pilot phase of the study (n=20 Healthy Volunteer adults) and have begun enrollment for the main phase with adolescents with ASD (n=86; age 14-17). If successful, this study will establish a nomological network linking local E/I balance measures to functional and structural connectivity within relevant brain networks, ultimately connecting them to ASD symptoms. Furthermore, this study will inform future therapeutic trials using cTBS to treat the symptoms of ASD.

The equine hoof wall has a complex, hierarchical structure that can inspire designs of impact-resistant materials. In this study, we utilized micro-computed tomography (μ-CT) and serial block-face scanning electron microscopy (SBF-SEM) to image the microstructure and nanostructure of the hoof wall. We quantified the morphology of tubular medullary cavities by measuring equivalent diameter, surface area, volume, and sphericity. High-resolution μ-CT revealed that tubules are partially or fully filled with tissue near the exterior surface and become progressively empty towards the inner part of the hoof wall. Thin bridges were detected within the medullary cavity, starting in the middle section of the hoof wall and increasing in density and thickness towards the inner part. Porosity was measured using three-dimensional (3D) μ-CT, two-dimensional (2D) μ-CT, and a helium pycnometer. The highest porosity was obtained using the helium pycnometer (8.07%), followed by 3D (3.47%) and 2D (2.98%) μ-CT. SBF-SEM captured the 3D structure of the hoof wall at the nanoscale, showing that the tubule wall is not solid, but has nano-sized pores, which explains the higher porosity obtained using the helium pycnometer. The results of this investigation provide morphological information on the hoof wall for the future development of hoof-inspired materials and offer a novel perspective on how various measurement methods can influence the quantification of porosity.

Jie Pan,1 Qiuyan Li,1 Yan Sun,1 Yingying Gu,1 Yijie Ding,1 Nengzhi Pang,1 Yujia Zhou,1 Lei Pei,1 Mengqi Gao,1 Sixi Ma,1 Ying Xiao,1 Feilong Wu,1 De Hu,1 Yu-Ming Chen,2 Lili Yang1 1Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of ChinaCorrespondence: Lili Yang, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74, Zhongshan Road 2, Yuexiu District, Guangzhou, Guangdong, 510080, People’s Republic of China, Tel +86-20-87330625, Email yangll7@mail.sysu.edu.cnPurpose: A panel of international experts proposed a new definition of fatty liver in 2020, namely metabolic dysfunction-associated fatty liver disease (MAFLD). As an adipokine, adipsin is closely related to metabolic-related diseases. In this study, we aimed to evaluate the relationship among MAFLD, serum adipsin, and metabolic risk abnormalities.Methods: Our study was a cross-sectional study based on the first follow-up of the Guangzhou Nutrition and Health Study (GNHS). A total of 908 patients with hepatic steatosis were involved in our study. Detailed data of patients were collected based upon questionnaire information, physical examination, and blood biochemical test.Results: Among the 908 patients, 789 patients were diagnosed with MAFLD. The levels of serum adipsin in the MAFLD group and non-MAFLD group were (3543.00 (3187.94– 3972.50) ng/mL) and (3095.33 (2778.71– 3354.77) ng/mL) (P < 0.001), respectively. After adjusting for potential confounders, adipsin levels were found to be associated with MAFLD. The OR was 3.46 (95% CI: 1.57– 7.64) for adipsin when comparing subjects in the highest tertile with those in the lowest tertile. With the increase in the number of metabolic risk abnormalities, both the levels of serum adipsin and the proportion of moderate to severe fatty liver increased (all p-trend < 0.001).Conclusion: Increased serum adipsin correlates with MAFLD. Both adipsin levels as well as fatty liver severity increase with higher numbers of metabolic risk abnormalities.Keywords: metabolic dysfunction-associated fatty liver disease, adipsin, metabolic risk abnormalities, hepatic steatosis

Neurostimulation devices that use rotating permanent magnets are being explored for their potential therapeutic benefits in patients with psychiatric and neurological disorders. This study aims to characterize the electric field (E-field) for ten configurations of rotating magnets using finite element analysis and phantom measurements. Various configurations were modeled, including single or multiple magnets, and bipolar or multipolar magnets, rotated at 10, 13.3, and 350 revolutions per second (rps). E-field strengths were also measured using a hollow sphere (r=9.2 cm) filled with a 0.9% sodium chloride solution and with a dipole probe. The E-field spatial distribution is determined by the magnets’ dimensions, number of poles, direction of the magnetization, and axis of rotation, while the E-field strength is determined by the magnets’ rotational frequency and magnetic field strength. The induced E-field strength on the surface of the head ranged between 0.0092 and 0.52 V/m. In the range of rotational frequencies applied, the induced E-field strengths were approximately an order or two of magnitude lower than those delivered by conventional transcranial magnetic stimulation. The impact of rotational frequency on E-field strength represents a confound in clinical trials that seek to tailor rotational frequency to individual neural oscillations. This factor could explain some of the variability observed in clinical trial outcomes.

High-frequency repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (L-DLPFC) shows promise as a treatment for treatment-resistant depression in adolescents. Conventional rTMS coil placement strategies include the 5 cm, the Beam F3, and the magnetic resonance imaging (MRI) neuronavigation methods. The purpose of this study was to use electric field (E-field) models to compare the three targeting approaches to a computational E-field optimization coil placement method in depressed adolescents. Ten depressed adolescents (4 females, age: 15.9±1.1) participated in an open-label rTMS treatment study and were offered MRI-guided rTMS five times per week over 6–8 weeks. Head models were generated based on individual MRI images, and E-fields were simulated for the four targeting approaches. Results showed a significant difference in the induced E-fields at the L-DLPFC between the four targeting methods (χ2=24.7, p<0.001). Post hoc pairwise comparisons showed that there was a significant difference between any two of the targeting methods (Holm adjusted p<0.05), with the 5 cm rule producing the weakest E-field (46.0±17.4V/m), followed by the F3 method (87.4±35.4V/m), followed by MRI-guided (112.1±14.6V/m), and followed by the computational approach (130.1±18.1V/m). Variance analysis showed that there was a significant difference in sample variance between the groups (K2=8.0, p<0.05), with F3 having the largest variance. Participants who completed the full course of treatment had median E-fields correlated with depression symptom improvement (r=−0.77, p<0.05). E-field models revealed limitations of scalp-based methods compared to MRI guidance, suggesting computational optimization could enhance dose delivery to the target.

Wenxian Sun,1 Luyang Zhang,1 Weishi Liu,1 Mengke Tian,1 Xin Wang,1 Jing Liang,1 Yuying Wang,1 Lan Ding,1 Lulu Pei,1 Jie Lu,2 Yuming Xu,1 Bo Song1 1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Department of Epidemiology and Health Statistics College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of ChinaCorrespondence: Bo SongDepartment of Neurology, The First Affiliated Hospital of Zhengzhou University, 1st Jianshe Eastern Road, Zhengzhou, 450052, Henan Province, People’s Republic of ChinaTel +86-13603983297Fax +86-371-66975140Email fccsongb@zzu.edu.cnBackground: Stroke and myocardial infarction (MI) are associated with each other, as demonstrated in observational studies. However, it is unclear whether this relationship is causal, and the purpose of this study was to explore the bidirectional causality between stroke and MI.Methods: Causality between stroke and MI was assessed using two-sample Mendelian randomization (MR). All genetic instruments related to stroke (40,585 cases; 406,111 controls) and MI (43,676 cases; 128,199 controls) were derived from large published genome-wide association study. The MR analysis was calculated with inverse-variance weighting, MR-Egger, weighted mode, weighted median, and simple mode methods, and sensitivity analyses are used to detect the heterogeneity or pleiotropy.Results: Genetically predicted large-artery stroke (LAS) was causally related to higher odds of MI (odds ratio [OR] = 1.13, 95% confidence interval [CI]: 1.06– 1.20, p = 1.0× 10− 4), and the causal effect of LAS on MI was significantly weakened (OR = 1.09, 95% CI: 1.02– 1.17, p = 0.017) after excluding the multipotent single-nucleotide polymorphisms (SNPs). MI phenotypes were genetically correlated with all ischemic strokes (OR = 1.15, 95% CI: 1.03– 1.28, p = 0.013) and LAS (OR = 1.39, 95% CI: 1.14– 1.71, p = 0.001); but a causal effect of MI on all ischemic strokes (OR = 1.00, 95% CI: 0.95– 1.28, p = 0.219) and LAS (OR = 1.26, 95% CI: 0.93– 1.69, p = 0.130) was not observed after excluding the multipotent SNPs.Conclusion: This MR analysis provides evidence to support the causal effect of LAS subtype on MI, and some factors act as confiding factors whereas others may act as mediators.Keywords: causal inference, single-nucleotide polymorphism, genome-wide association study, epidemiologic methods, large-artery stroke

Jiali Yang,1,&ast; Zhixia Jia,1,&ast; Zhigang Xiao,1 Jing Zhao,2 Ye Lu,2 Li Chu,3 Hui Shao,1,2 Lin Pei,1,2 Shaodan Zhang,4 Yuan Chen4 1School of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, People’s Republic of China; 2Hebei Key Laboratory of Turbidity, Hebei Academy of Chinese Medicine Sciences, Shijiazhuang, Hebei, 050011, People’s Republic of China; 3School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, People’s Republic of China; 4Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaodan Zhang; Lin PeiPaediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of ChinaTel/Fax +86 13653115066; +86 13831190309Email 13653115066@163.com; peilin13831190309@126.comPurpose: This study aims to evaluate the beneficial effects of anti-epileptic mechanisms of baicalin (BA) on cognitive dysfunction and neurodegeneration in pentylenetetrazol (PTZ)-induced epileptic rats.Methods: First, PTZ-induced epileptic rats were administered intraperitoneally a sub-convulsive dose of PTZ (40 mg/kg) daily, and the seizure susceptibility (the degree of seizures and latency) was evaluated using Racine’s criterion. Then, classical behavioral experiments were performed to test whether BA ameliorated cognitive dysfunction. Neurodegeneration was assessed using Fluoro Jade-B (FJB), and NeuN staining was used to determine whether BA offered a neuroprotective role. After BA had been proven to possess anti-epileptic effects, its possible mechanisms were analyzed through network pharmacology. Finally, the key targets for predictive mechanisms were experimentally verified.Results: The epileptic model was successfully established, and BA had anti-epileptic effects. Epileptic rats displayed significant cognitive dysfunction, and BA markedly ameliorated cognitive dysfunction. Further, we also discovered that BA treatment mitigated neurodegeneration of the hippocampus CA3 regions, thereby ameliorated cognitive dysfunction of epileptic rats. Subsequent network pharmacology analysis was implemented to reveal a possible mechanism of BA in the anti-epileptic process and the TLR4/MYD88/Caspase-3 pathway was predicted. Finally, experimental studies showed that BA exerted an anti-epileptic effect by activating the TLR4/MYD88/Caspase-3 pathway in PTZ-induced epileptic rats.Conclusion: In conclusion, BA had a protective effect against PTZ-induced seizures. BA improved cognitive dysfunction and exerted a neuroprotective action. The anti-epileptic effects of BA may be potentially through activation of the TLR4/MYD88/Caspase-3 pathway.Keywords: baicalin, pentylenetetrazol, epilepsy, cognitive dysfunction, network pharmacology, TLR4/MYD88/Caspase-3

Lixia Yang, Liangyan Pei, Jilong Yi Department of Neurology, The First People’s Hospital of Jingmen Affiliated to Hubei Minzu University, Jingmen, 434000, People’s Republic of ChinaCorrespondence: Jilong YiDepartment of Neurology, The First People’s Hospital of Jingmen Affiliated to Hubei Minzu University, No.168 Xiangshan Avenue, Jingmen, 434000, People’s Republic of ChinaEmail gxhkah@163.comBackground: Long noncoding RNAs (lncRNAs) are related to the development and treatment of neuroblastoma. The lncRNA LINC00839 is dysregulated in neuroblastoma, while its function and mechanism in neuroblastoma development remain largely unclear.Methods: The tumor and adjacent noncancerous tissues were collected from 48 neuroblastoma patients. LINC00839, glucose transporter 1 (GLUT1) and microRNA-338-3p (miR-338-3p) abundances were examined via quantitative reverse transcription polymerase chain reaction or Western blot. Cell proliferation, apoptosis, migration, invasion and glycolysis were assessed via Cell Counting Kit-8, colony formation, flow cytometry, wound healing, transwell, glucose uptake and lactate production. The target relationship of miR-338-3p and LINC00839 or GLUT1 was tested via dual-luciferase reporter analysis and RNA immunoprecipitation. The function of LINC00839 on neuroblastoma cell growth in vivo was tested via a xenograft model.Results: LINC00839 and GLUT1 abundances were increased in neuroblastoma tissues and cell lines. The high expression of LINC00839 and GLUT1 indicated the lower overall survival. LINC00839 interference constrained neuroblastoma cell proliferation, migration, invasion and glycolysis, and facilitated apoptosis. GLUT1 overexpression or miR-338-3p knockdown could mitigate the influence of LINC00839 silence on neuroblastoma cell processes. LINC00839 could regulate GLUT1 expression via miR-338-3p. LINC00839 knockdown reduced neuroblastoma cell growth in xenograft model.Conclusion: LINC00839 silence repressed neuroblastoma cell proliferation, migration, invasion and glycolysis and promoted apoptosis via regulating miR-338-3p/GLUT1 axis.Keywords: neuroblastoma, LINC00839, GLUT1, miR-338-3p

Tingting Zhao,1,* Jing Guo,1,* Yafang Song,2 Hao Chen,2 Mengzhu Sun,1 Lu Chen,3 Hao Geng,3 Lixia Pei,3 Jianhua Sun3 1Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China; 2Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China; 3Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianhua Sun; Lixia PeiDepartment of Acupuncture Rehabilitation, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, People’s Republic of ChinaEmail 377201634@qq.com; 11801758@qq.comBackground: Migraine is the second-leading cause of disability worldwide. It is often characterized by attacks of severe, mostly unilateral, pulsating headache associated with symptoms such as photophobia, phonophobia, nausea, vomiting, and cutaneous allodynia. Acupuncture therapy has been used worldwide for the treatment of migraine. However, no visual bibliometric analysis has been conducted on the effects of acupuncture on migraine over the past 20 years. Therefore, this study aimed to explore the current status and trends on the use of acupuncture in the treatment of migraine from 2000 to 2020.Purpose: The objective of this study is to identify the current status and emerging trends of the global use of acupuncture on migraine from 2000 to 2020 using CiteSpace and VOSviewer.Methods: Web of Science databases were searched for publications related to acupuncture therapy for treating migraine between 2000 and 2020. CiteSpace and VOSviewer were used to analyze the number of publications per year, countries, institutions, authors, journals, references, and keywords.Results: A total of 572 publications were included in the final analysis. The total number of publications has continued to increase with some fluctuations over the past 20 years. The most productive country and institution in this field were the USA, and Chengdu University of Traditional Chinese Medicine, respectively. The most active and cited authors were Liang FR and Linde K, respectively. Cephalalgia was the most productive, cited, and co-cited journal. The Linde K (2005) had the highest co-citation, citation number and centrality. The keywords “migraine” ranked first in frequency. The common type of migraine (tension-type headache), research method (randomized controlled trial, multicenter, double-blind), acupuncture’s role (prophylactic, quality of life, pain), and evaluation (meta-analysis, systematic review) were the hotspots and frontier trends of acupuncture therapy on migraine between 2000 and 2020.Conclusion: The present study examined the research-related trend in acupuncture therapy on migraine using bibliometric methods and identified the statement and research frontiers over the past two decades. This may help researchers to identify potential hotspots and new directions for future research in this field.Keywords: acupuncture, migraine, bibliometric analysis, CiteSpace, VOSviewer, network

Shan Lin,1,2,* Wenji Xiong,3,* Huibo Liu,4 Liping Pei,5 Huanfa Yi,1 Yinghui Guan2 1Central Laboratory, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 3Department of Radiology, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 4Department of Dermatology and Venerology, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 5Department of Echocardiography, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huanfa YiCentral Laboratory, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin 130021, People’s Republic of ChinaEmail yihuanfa@sina.comYinghui GuanDepartment of Respiratory Medicine, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin 130021, People’s Republic of ChinaEmail yinghuig2016vip@163.comPurpose: Exosomes contain abundant circRNAs and are determined to be involved in the pathogenesis of lung adenocarcinoma (LUAD). Thus, our study aimed to explore new circRNAs in plasma exosomes that could be involved in such pathogenesis.Patients and Methods: High-throughput sequencing was used in identifying the alterations in exosomal circRNA expression. Gene ontology functional analysis (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to determine the significant functions and pathways associated with differentially expressed circRNAs. TargetScan and miRanda were used to predict circRNA-targeted microRNAs and mRNAs. CircRNA expression profiles were then validated by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Wound healing and Transwell assays were performed to determine the roles of has_circ_0102537 in LUAD progression.Results: We identified six significantly upregulated and 214 significantly downregulated circRNAs. GO and KEGG pathway analysis suggested that the differentially expressed circRNAs are involved in the occurrence and development of LUAD. A circRNA–miRNA–mRNA meshwork was established to predict the potential interactions among these RNAs. The circRNA expression profile was then subjected to qRT-PCR for validation. We identified hsa_circ_0102537 to be downregulated in both LUAD plasma exosomes and tissues. GO, KEGG pathway analysis, circRNA–miRNA–mRNA meshwork, and further experiments suggest that hsa_circ_0102537 could be involved in LUAD progression.Conclusion: Our study explored a large number of circRNAs that may be involved in the LUAD pathogenesis, thereby supporting the need for further research on both diagnosis biomarkers and the potential intervention therapeutic targets.Keywords: advanced-stage lung adenocarcinoma, plasma, exosomes, circular RNA, microRNA

Yanwei Sun,1 Lina Pei,2 Ningning Luo,3 Dongsheng Chen,3 Lingxin Meng1 1Department of Oncology, People’s Hospital of Rizhao, Rizhao, People’s Republic of China; 2Department of Pharmacy, People’s Hospital of Rizhao, Rizhao, People’s Republic of China; 3The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, People’s Republic of ChinaCorrespondence: Lingxin MengDepartment of Oncology, People’s Hospital of Rizhao, Rizhao, People’s Republic of ChinaEmail menglingxinrz@126.comBackground: Osimertinib is a novel and irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) targeting EGFR sensitive mutations and EGFR exon20 p.T790M mutation, which demonstrated superior progression-free survival (PFS) and overall survival (OS).Case Presentation: We report a patient with lung adenocarcinoma harboring EGFR exon 19 deletion mutant treatment with icotinib. After 6 months, she developed EGFR exon20 p.T790M and then the patient received osimertinib treatment. A novel MYH9 (exon41)-RET (exon12) fusion and EGFR exon20 p.T790M loss were identified using plasma circulation tumor DNA (ctDNA) after osimertinib treatment, which led to rapid progression after osimertinib five months and suggested a potential resistance mechanism.Conclusion: Our findings expanded the spectrum of RET arrangement types and provided the basis for this hypothesis: acquired RET rearrangement and EGFR exon20 p.T790M loss potentially serve an additional resistance mechanism to osimertinib in EGFR-mutated non-small-cell lung cancer (NSCLC).Keywords: MYH9-RET fusion, EGFR exon20 p.T790M loss, lung adenocarcinoma, acquired resistance, osimertinib

Shuo Zhang,1,2 Wen-chong Sun,2 Zuo-di Liang,2 Xiu-ru Yin,2 Zhen-rong Ji,2 Xiao-huan Chen,2 Min-jie Wei,1 Ling Pei2 1Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People’s Republic of ChinaCorrespondence: Min-jie Wei; Ling Pei Email koxu078nzod@163.com; lingpei49@sina.comBackground: Inflammatory response mediated by microglia plays a key role in cerebral ischemia-reperfusion injury. This study intends to probe the role of lncRNA SNHG4 in regulating the inflammatory response of the microglia during cerebral ischemia reperfusion.Materials and Methods: Blood samples and cerebrospinal fluid samples were collected from acute cerebral infarction (ACI) patients and healthy controls. The middle cerebral artery occlusion (MCAO) models were constructed with rats. LPS induction and oxygen-glucose deprivation methods were respectively applied to simulate the activation of microglia in vitro. qRT-PCR was employed to determine the expressions of SNHG4, miR-449c-5p and related inflammatory factors in vivo and in vitro. The inflammatory responses of the microglia subject to the varied expressions of SNHG4 and miR-449c-5p were detected. Luciferase assays were conducted to verify the crosstalk involving SNHG4, miR-449c-5p and STAT6.Results: Compared with the control group, the expression of SNHG4 derived from the samples of ACI patients and the microglia of MCAO group were remarkably down-regulated, but the expression of miR-449c-5p was dramatically up-regulated. Overexpression of SNHG4 and knock-down of miR-449c-5p could inhibit the expression of pro-inflammatory cytokine in the microglia and promote the expression of anti-inflammatory factors. Meanwhile, the phospho-STAT6 was up-regulated, whereas the knock-down of SNHG4 and over-expression of miR-449c-5p in microglia had the opposite effects. Luciferase assay confirmed that SNHG4 could target miR-449c-5p, while miR-449c-5p could target STAT6.Conclusion: SNHG4 can regulate STAT6 and repress inflammation by adsorbing miR-449c-5p in microglia during cerebral ischemia-reperfusion injury.Keywords: SNHG4, STAT6, miR-449c-5p, ischemia-reperfusion injury

Hao Chen,1 Lingyu Pei,2 Peng Xie,1 Guancheng Guo1 1Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Department of Digestive System, Yongcheng People’s Hospital, Shangqiu, Henan, People’s Republic of ChinaCorrespondence: Guancheng GuoDepartment of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou 450052, Henan, People’s Republic of ChinaTel +86 371 66271227Email engyichangehimp@163.comPurpose: Diverse circular RNAs (circRNAs) participate in the regulation of drug resistance in human cancers. However, the role of circRNAs in drug resistance in colorectal cancer (CRC) is dismal. In this study, we aimed to explore the effect of circ-PRKDC on 5-fluorouracil (5-FU) resistance in CRC.Materials and Methods: The levels of circ-PRKDC, microRNA-375 (miR-375) and forkhead box protein M1 (FOXM1) mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR). IC50 of 5-FU, cell colony formation ability and invasion were assessed by Cell Counting Kit-8 (CCK-8) assay, colony formation assay and transwell assay, respectively. The protein levels of P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), FOXM1, β-catenin and c-Myc were measured via Western blot assay. The targeting relationship between miR-375 and circ-PRKDC or FOXM1 was investigated by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The effect of circ-PRKDC in vivo was explored by murine xenograft model assay.Results: Circ-PRKDC was upregulated in 5-FU-resistant CRC tissues and cells. Circ-PRKDC silencing repressed 5-FU resistance, cell colony formation and invasion in 5-FU-resistant CRC cells in vitro and inhibited 5-FU resistance in vivo. MiR-375 was a target of circ-PRKDC and miR-375 inhibition reversed the effects of circ-PRKDC silencing on 5-FU resistance, cell colony formation and invasion. FOXM1 was a direct target gene of miR-375. MiR-375 suppressed 5-FU resistance by targeting FOXM1. Moreover, circ-PRKDC knockdown decreased FOXM1 expression by targeting miR-375. Additionally, circ-PRKDC knockdown impeded wnt/β-catenin pathway by regulating miR-375 and FOXM1.Conclusion: Circ-PRKDC enhanced 5-FU resistance in CRC by regulating FOXM1/miR-375 axis and wnt/β-catenin pathway.Keywords: CRC, 5-FU, circ-PRKDC, miR-375, FOXM1, wnt/β-catenin

Lin-lin Pei,1,* Wen-zhu Yang,1,* Jing-yuan Fu,1,* Meng-xi Liu,1 Ting-ting Zhang,1 Dong-bo Li,1 Ruo-yue Huang,1 Li Zhang,1 Guang-neng Peng,1 Gang Shu,1 Zhi-xiang Yuan,2 Ju-chun Lin,1 Wei Zhang,1 Zhi-jun Zhong,1 Ling Zhao,1 Hua-lin Fu1 1Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, People’s Republic of China; 2College of Pharmacy, Southwest Minzu University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hua-lin FuDepartment of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, People’s Republic of ChinaTel +86 028-86291162Email fuhl2005@sohu.comIntroduction: Enrofloxacin is used in the treatment of a wide variety of bacterial infections in mammals. However, its poor solubility limits the clinical use.Methods: In order to improve the solubility of enrofloxacin, the enrofloxacin mesylate (EM) were obtained by a chemical synthesis method. The characterization of EM was carried out using ultraviolet scan (UV), synchronous thermal analysis (SDT), fourier transform infrared spectrometer (FTIR) and mass spectrometry (MS), nuclear magnetic resonance (NMR) and X-ray powder diffraction analysis (XRPD). Acute toxicity of EM in Kunming mice was studied. Besides, pharmacokinetic studies were performed in New Zealand rabbits at a single oral dose of 10 mg/kg, and the antibacterial activity of EM was also evaluated.Results: EM was successfully synthesized and purified. The stoichiometric ratio of mesylate to enrofloxacin was 1:1 and the aqueous solubility of EM was 483.01± 4.06 mg/mL, the solubility of EM was about 2000 times higher than enrofloxacin. The oral lethal dose (LD50) of EM was 1168.364 mg/kg, and the pharmacokinetics indicated that the oral relative bioavailability of EM was about 1.79 times and 1.48 times higher than that of enrofloxacin and enrofloxacin hydrochloride, respectively. In addition, the in vitro antibacterial activity of EM was not significantly changed compared with enrofloxacin and enrofloxacin hydrochloride.Conclusion: EM has higher solubility, low toxicity for oral use, and increases the oral bioavailability in rabbit. This study may be of benefit for the development of new enrofloxacin drugs.Keywords: enrofloxacin mesylate, characterization, antibacterial effect, acute toxicity, pharmacokinetics

Ru-rong Tang,1 Yan Wang,2 Chao-nan Liang,3 Wei Li,3 Ling Pei,1 Jian Kang,3 Gang Hou3 1Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China; 2Department of Otolaryngology, The First Hospital of China Medical University, Shenyang, China; 3Department of Respiratory and Critical Care Medicine, Institute of Respiratory Disease, The First Hospital of China Medical University, Shenyang, China Abstract: Extramedullary plasmacytoma (EMP) is an infrequent form of plasma cell dyscrasia that presents as a mass of monoclonal plasma cells located in extramedullary soft tissues with no skeletal component. EMP constitutes ~4% of all plasma cell neoplasms and occurs mostly in the upper respiratory tract. Here, we report a rare case of multiple EMPs involving the trachea, laryngopharynx, and oropharynx, which caused symptoms of airway obstruction as the only clinical manifestation. The patient was diagnosed by histopathology of the tissue from bronchoscopic resection and successfully managed with bronchoscopic intervention to treat lesions in the trachea and radiotherapy combined with surgical resection to treat lesions in the pharynx. There was no recurrence after 14 months of follow-up. Endoscopic intervention plays a key role in the rapid diagnosis and treatment of EMP involving the central airways. Keywords: tracheal tumors, bronchoscopy, interventional pulmonology, cryotherapy, plasmacytoma

Jie Jin,1,2 Rumiko Okamoto,3 Sung-Soo Yoon,4 Lee-Yung Shih,5 Jun Zhu,6 Ting Liu,7 Xiaonan Hong,8 Lixia Pei,9 Brendan Rooney,10 Helgi van de Velde,11 Huiqiang Huang12 1Department of Hematology, The First Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang, China; 2Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China; 3Department of Chemotherapy, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan; 4Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; 5Division of Hematology–Oncology, Chang Gung Memorial Hospital-Linkou, Chang Gung University, Taoyuan, Taiwan; 6Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China; 7Division of Hematology, Department of Internal Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China; 8Lymphoma and GI Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; 9Janssen Research & Development, LLC, Raritan, NJ, USA; 10Janssen Research & Development, High Wycombe, Buckinghamshire, UK; 11Oncology Clinical Research, Millennium Pharmaceuticals, Inc., Boston, MA, USA; 12Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China Introduction: This subgroup analysis of the LYM-3002 Phase III study (NCT00722137) investigated whether substituting bortezomib for vincristine in frontline R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy could improve outcomes in East Asian patients with newly diagnosed mantle-cell lymphoma (MCL). Materials and methods: A total of 121 East Asian patients from China, Taiwan, Japan, and the Republic of Korea with stage II–IV MCL who were ineligible or not considered for stem-cell transplantation were enrolled to six to eight 21-day cycles of R-CHOP or VR-CAP (R-CHOP with bortezomib replacing vincristine). Results: The primary end point was progression-free survival. After a median follow-up of 42.4 months, median progression-free survival in East Asian patients was 13.9 (R-CHOP) versus 28.6 (VR-CAP) months (HR 0.7, P=0.157; 43% improvement with VR-CAP). Secondary end points (R-CHOP vs VR-CAP), including complete response rate (47% vs 63%), duration of complete response (median 16.6 vs 46.7 months), and treatment-free interval (median 21 vs 46.5 months), were improved with VR-CAP. VR-CAP was associated with increased but manageable toxicity. The most frequent adverse events were hematologic toxicities. Conclusion: VR-CAP was effective in East Asian patients with newly diagnosed MCL, and could be considered for patients in whom stem-cell transplantation is not an option. Keywords: mantle-cell lymphoma, bortezomib, VR-CAP, R-CHOP

In this contribution, we achieve the primary goal of the active galactic nucleus (AGN) STORM campaign by recovering velocity-delay maps for the prominent broad emission lines (Lyα, C iv, He ii, and Hβ) in the spectrum of NGC 5548. These are the most detailed velocity-delay maps ever obtained for an AGN, providing unprecedented information on the geometry, ionization structure, and kinematics of the broad-line region. Virial envelopes enclosing the emission-line responses show that the reverberating gas is bound to the black hole. A stratified ionization structure is evident. The He ii response inside 5-10 lt-day has a broad single-peaked velocity profile. The Lyα, C iv, and Hβ responses extend from inside 2 to outside 20 lt-day, with double peaks at ±2500 km s-1 in the 10-20 lt-day delay range. An incomplete ellipse in the velocity-delay plane is evident in Hβ. We interpret the maps in terms of a Keplerian disk with a well-defined outer rim at R = 20 lt-day. The far-side response is weaker than that from the near side. The line-center delay days gives the inclination i ≈ 45°. The inferred black hole mass is M BH ≈ 7 × 107 M o˙. In addition to reverberations, the fit residuals confirm that emission-line fluxes are depressed during the "BLR Holiday"identified in previous work. Moreover, a helical "Barber-Pole"pattern, with stripes moving from red to blue across the C iv and Lyα line profiles, suggests azimuthal structure rotating with a 2 yr period that may represent precession or orbital motion of inner-disk structures casting shadows on the emission-line region farther out.

We model the ultraviolet spectra of the Seyfert 1 galaxy NGC 5548 obtained with the Hubble Space Telescope during the 6 month reverberation mapping campaign in 2014. Our model of the emission from NGC 5548 corrects for overlying absorption and deblends the individual emission lines. Using the modeled spectra, we measure the response to continuum variations for the deblended and absorption-corrected individual broad emission lines, the velocity-dependent profiles of Ly and C iv, and the narrow and broad intrinsic absorption features. We find that the time lags for the corrected emission lines are comparable to those for the original data. The velocity-binned lag profiles of Ly and C iv have a double-peaked structure indicative of a truncated Keplerian disk. The narrow absorption lines show a delayed response to continuum variations corresponding to recombination in gas with a density of ∼105 cm-3. The high-ionization narrow absorption lines decorrelate from continuum variations during the same period as the broad emission lines. Analyzing the response of these absorption lines during this period shows that the ionizing flux is diminished in strength relative to the far-ultraviolet continuum. The broad absorption lines associated with the X-ray obscurer decrease in strength during this same time interval. The appearance of X-ray obscuration in ∼2012 corresponds with an increase in the luminosity of NGC 5548 following an extended low state. We suggest that the obscurer is a disk wind triggered by the brightening of NGC 5548 following the decrease in size of the broad-line region during the preceding low-luminosity state.

Rocks are heterogeneous multiscale porous media: two rock samples with identical bulk properties can vary widely in microstructure. The advent of digital rock technology and modern 3-D printing provides new opportunities to replicate rocks. However, the inherent trade-off between imaging resolution and sample size limits the scales over which microstructure and macrostructure can be identified and related to each other. Here, we develop a multiscale digital rock construction strategy by combining X-ray computed microtomography and focused-ion beam (FIB)-scanning electron microscope (SEM) images, and we apply the technique to a tight sandstone. The computed tomography (CT) scanning images characterize macroscale pore structures, while the FIB-SEM images capture microscale pore textures. The FIB-SEM images are then coupled to CT images via a template-matching algorithm and superposition. Bulk properties, including porosity and pore and throat size distribution, can be recovered with this approach. Permeability prediction with a pore network model for the largest connected pore network are 3 orders and 1 order of magnitude greater than the bulk rock measured value using the CT-only and the SEM-CT coupled images, respectively.

We present the first results from a reverberation-mapping campaign undertaken during the first half of 2012, with additional data on one active galactic nucleus (AGN) (NGC 3227) from a 2014 campaign. Our main goals are (1) to determine the black hole masses from continuum-Hβ reverberation signatures, and (2) to look for velocity-dependent time delays that might be indicators of the gross kinematics of the broad-line region. We successfully measure Hβ time delays and black hole masses for five AGNs, four of which have previous reverberation mass measurements. The values measured here are in agreement with earlier estimates, though there is some intrinsic scatter beyond the formal measurement errors. We observe velocity-dependent Hβ lags in each case, and find that the patterns have changed in the intervening five years for three AGNs that were also observed in 2007.

We present optical continuum lags for two Seyfert 1 galaxies, MCG+08-11-011 and NGC 2617, using monitoring data from a reverberation mapping campaign carried out in 2014. Our light curves span the ugriz filters over four months, with median cadences of 1.0 and 0.6 days for MCG+08-11-011 and NGC 2617, respectively, combined with roughly daily X-ray and near-UV data from Swift for NGC 2617. We find lags consistent with geometrically thin accretion-disk models that predict a lag-wavelength relation of τ ∝ λ 4/3. However, the observed lags are larger than predictions based on standard thin-disk theory by factors of 3.3 for MCG+08-11-011 and 2.3 for NGC 2617. These differences can be explained if the mass accretion rates are larger than inferred from the optical luminosity by a factor of 4.3 in MCG+08-11-011 and a factor of 1.3 in NGC 2617, although uncertainty in the SMBH masses determines the significance of this result. While the X-ray variability in NGC 2617 precedes the UV/optical variability, the long (2.6 day) lag is problematic for coronal reprocessing models.