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Henan Li,* Didaer Talanaite,* Zitong Pan,* Zhiren Wang, Shuyi Wang, Hui Wang Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Henan Li; Hui Wang, Department of Clinical Laboratory, Peking University People’s Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People’s Republic of China, Email lihenan@pkuph.edu.cn; whuibj@163.comBackground: Patients with hematological malignancies are more susceptible to infections, leading to a poor prognosis. Acinetobacter colonization is a risk factor for secondary bacteremia.Methods: Antibiotic susceptibility phenotypes and genomic characteristics of 48 oral Acinetobacter spp. and one bloodstream Acinetobacter baumannii from patients with hematological malignancies were analyzed by antimicrobial susceptibility tests and whole-genome sequencing. We conducted comparative genomic analysis of oral and blood isolates from the same patient.Results: A. baumannii was the most common (72.92%, 35/48) Acinetobacter species in oral Acinetobacter spp. isolates. Seventeen different A. baumannii sequence types were identified using the Pasteur MLST scheme; however, the dominant global clones GC1 and GC2 were not present. Among the isolates, 46 (95.8%) were carbapenem-susceptible Acinetobacter spp. One patient treated with meropenem for 15 days developed A. baumannii bacteremia 46 days after the isolation of oral A. baumannii AOR07. Oral and bloodstream isolates from the same patient were closely related to only four non-synonymous mutations on the chromosome. The blaOXA-58 gene was transferred between plasmids through XerCD-mediated recombination, leading to an elevated copy number, causing carbapenem resistance in bloodstream isolates.Conclusion: Oral Acinetobacter spp. may cause secondary bacteremia. The amplification and transfer of blaOXA-58 in the plasmids explained the increased carbapenem resistance in the bloodstream isolate.Keywords: Acinetobacter, within-host evolution, oral colonization, bloodstream infection, hematological malignancies

Wendao Han, Nating Xiong, Renkai Zhong, Zhongyi Pan Department of Blood Transfusion, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of ChinaCorrespondence: Wendao Han, Department of Blood Transfusion, Meizhou People’s Hospital, Meizhou, People’s Republic of China, Email 443567914@qq.comObjective: Atherosclerosis (AS) is a sustained chronic vascular inflammatory response caused by lipid metabolism disorders and immune response disorders and is the main cause of premature (men ≤ 55 years old, women ≤ 65 years old) myocardial infarction (PMI). Cytochrome P450 2C19 (CYP2C19) (related to vascular function and lipid metabolism) and peripheral immune cell levels and plays an important role in the course of AS. The association CYP2C19 polymorphisms, comprehensive immunoinflammatory indices with PMI susceptibility is unclear.Methods: This study included 485 PMI patients, and 639 age-matched non-PMI individuals as controls, from January 2019 to March 2024. The relationship between CYP2C19 polymorphisms, peripheral immunoinflammatory indices (pan-immune inflammation value (PIV), systemic immune inflammation index (SII), and system inflammation response index (SIRI)) and PMI risk were analyzed.Results: The inflammatory indices levels in PMI patients were higher than those in controls (all p< 0.05). The frequencies of the CYP2C19 &ast;1/&ast;2 and &ast;2/&ast;2 genotypes were higher, while the frequency of the &ast;1/&ast;1 genotype was lower in the PMI patients than those in controls. The cut-off values of TC, TG, LDL-C, PIV, SII, and SIRI were 5.065, 1.305, 2.805, 410.485, 869.645, and 1.495 for distinguishing PMI, respectively. Logistic regression analysis showed that male (odds ratio (OR): 1.607, 95% confidence interval (CI): 1.134– 2.277, p=0.008), history of smoking (OR: 7.108, 95% CI: 4.351– 11.614, p< 0.001), diabetes mellitus (OR: 4.906, 95% CI: 3.333– 7.223, p< 0.001), CYP2C19 poor metabolizer (PM) (&ast;2/&ast;2, &ast;2/&ast;3, and &ast;3/&ast;3) (OR: 2.147, 95% CI: 1.279– 3.603, p=0.004), and high TG (≥ 1.305 vs < 1.305, OR: 2.598, 95% CI: 1.864– 3.623, p< 0.001) and SIRI level (≥ 1.495 vs < 1.495, OR: 2.495, 95% CI: 1.432– 4.349, p=0.001) were independent risk factors for PMI.Conclusion: CYP2C19 PM phenotype, high SIRI level (≥ 1.495) and TG level (≥ 1.305), male, history of smoking, and diabetes mellitus were independently associated with PMI susceptibility.Keywords: premature myocardial infarction, system inflammation response index, CYP2C19, polymorphism

Shuoshuo Li,1 Zhongtao Zhou,1 Ling Cheng,1 Weina Du,1 Zhengqun Pan,2 Jing Zhang3 1School of Nursing, Bengbu Medical University, Bengbu, People’s Republic of China; 2Forest Heights LTC, Kitchener, Ontario, Canada; 3School of Mental Health, Bengbu Medical University, Bengbu, People’s Republic of ChinaCorrespondence: Jing Zhang, School of Mental Health, Bengbu Medical University, Bengbu, 233030, People’s Republic of China, Email mini0217@126.comObjective: Fear of recurrence and reproductive concerns are great public health concerns among breast cancer patients in childbearing age. The purpose of this study was to explore whether psychological resilience and coping styles play mediating roles in fear of recurrence and reproductive concerns among Chinese breast cancer patients in childbearing age.Methods: A total of 1267 breast cancer patients of childbearing age completed the questionnaires, including a brief demographic questionnaire survey. The Chinese version of the Fear of Cancer Recurrence Scale and the Chinese version of the Reproductive Concerns Scale were used to assess the fear of recurrence and reproductive concerns, respectively. And the psychological resilience scale and the simple coping style questionnaire were used to evaluate breast cancer patients’ psychological resilience and coping style during childbearing age. Mediation analyses were conducted by using PROCESS macro in the SPSS software.Results: Fear of recurrence had both direct and indirect effects on Reproductive Concerns. psychological resilience and coping style were not only independent mediators in the relationship between fear of recurrence and Reproductive Concerns but also chain mediators.Conclusion: The results of the current study highlight the crucial role of early intervention for Reproductive Concerns with a focus on fear of recurrence of breast cancer patients of childbearing age, more especially, on those with poorer psychological resilience and coping style.Keywords: childbearing age, breast cancer, fear of recurrence, reproductive concerns, psychological resilience, coping style

Rui Shen,1,2,&ast; Kebin Cheng,3,&ast; Guanyi Li,1 Zhendong Pan,4 Xijier Qiaolongbatu,1 Yuting Wang,1 Cui Ma,1 Xucong Huang,1 Li Wang,1 Wenjing Li,1 Yuanyuan Wang,2 Lili Jing,1 Guorong Fan,2 Zhenghua Wu2 1School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, People’s Republic of China; 2Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People’s Republic of China; 4Department of Clinical Pharmacy, Eye and ENT Hospital, Fudan University, Shanghai, 200031, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhenghua Wu, Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 85 Wujin Road, Shanghai, 200080, People’s Republic of China, Tel +86-159-0161-7923, Email wuzhenghua@sjtu.edu.cnPurpose: Alisma orientale (AO, Alisma orientale (Sam). Juzep) has been widely employed for the treatment of macular edema (ME) in traditional Chinese medicine due to its renowned water-relief properties. Nonetheless, the comprehensive investigation of AO in alleviating ME remained unexplored. This study aims to identify the active components of AO that target the eye and investigate its pharmacological effects and mechanisms on ME.Methods: The study commenced with UPLC-Triple-TOF/MS analysis to identify the primary constituents of AO. Zebrafish eye tissues were then analyzed after a five-day administration of AO to detect absorbed components and metabolites. Subsequently, network pharmacology, molecular docking, and molecular dynamics simulations were employed to predict the mechanisms of ME treatment via biological target pathways. In vivo experiments were conducted to corroborate the pharmacological actions and mechanisms.Results: A total of 7 compounds, consisting of 2 prototype ingredients and 5 metabolites (including isomers), were found to traverse the blood-eye barrier and localized within eye tissues. Network pharmacology results showed that AO played a role in the treatment of ME mainly by regulating the pathway network of PI3K-AKT and MAPK with TNF-α centered. Computational analyses suggested that 11-dehydro-16-oxo-24-deoxy-alisol A, a metabolite of alisol A, mitigates edema through TNF-α inhibition. Furthermore, zebrafish fundus confocal experiments and HE staining of eyes confirmed the attenuating effects of alisol A on fundus angiogenesis and ocular edema, representing the first report of AO’s ME-inhibitory effects.Conclusion: In this study, computational analyses with experimental validation were used to understand the biological activity and mechanism of alisol A in the treatment of ME. The findings shed light on the bioactive constituents and pharmacological actions of AO, offering valuable insights and a theoretical foundation for its clinical application in managing ME. Keywords: Alisma orientale, macular edema, network pharmacology, zebrafish, TNF-&#x03B1

Xu Zhang,1,&ast; Xue Zhou,2,&ast; Wenhao Zhai,1,&ast; Jing Cui,1 Ziyi Pan,1 Liuyi Du,1 Linlin Wen,1 Rongrong Ye,1 Boya Zhang,1 Lei Huang,1 Daowei Li,1 Chungang Wang,2 Hongchen Sun1 1Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China; 2Department of Chemistry, Northeast Normal University, Changchun, 130024, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Daowei Li; Lei Huang, Email jluldw@jlu.edu.cn; huanglei17@mails.jlu.edu.cnBackground: Vital pulp therapy (VPT) is considered a conservative treatment for preserving pulp viability in caries and trauma-induced pulpitis. However, Mineral trioxide aggregate (MTA) as the most frequently used repair material, exhibits limited efficacy under inflammatory conditions. This study introduces an innovative nanocomposite hydrogel, tailored to simultaneously target anti-inflammation and dentin mineralization, aiming to efficiently preserve vital pulp tissue.Methods: The L-(CaP-ZnP)/SA nanocomposite hydrogel was designed by combining L-Arginine modified calcium phosphate/zinc phosphate nanoparticles (L-(CaP-ZnP) NPs) with sodium alginate (SA), and was characterized with TEM, SEM, FTIR, EDX, ICP–AES, and Zeta potential. In vitro, we evaluated the cytotoxicity and anti-inflammatory properties. Human dental pulp stem cells (hDPSCs) were cultured with lipopolysaccharide (LPS) to induce an inflammatory response, and the cell odontogenic differentiation was measured and possible signaling pathways were explored by alkaline phosphatase (ALP)/alizarin red S (ARS) staining, qRT-PCR, immunofluorescence staining, and Western blotting, respectively. In vivo, a pulpitis model was utilized to explore the potential of the L-(CaP-ZnP)/SA nanocomposite hydrogel in controlling pulp inflammation and enhancing dentin mineralization by Hematoxylin and eosin (HE) staining and immunohistochemistry staining.Results: In vitro experiments revealed that the nanocomposite hydrogel was synthesized successfully and presented desirable biocompatibility. Under inflammatory conditions, compared to MTA, the L-(CaP-ZnP)/SA nanocomposite hydrogel demonstrated superior anti-inflammatory and pro-odontogenesis effects. Furthermore, the nanocomposite hydrogel significantly augmented p38 phosphorylation, implicating the involvement of the p38 signaling pathway in pulp repair. Significantly, in a rat pulpitis model, the L-(CaP-ZnP)/SA nanocomposite hydrogel downregulated inflammatory markers while upregulating mineralization-related markers, thereby stimulating the formation of robust reparative dentin.Conclusion: The L-(CaP-ZnP)/SA nanocomposite hydrogel with good biocompatibility efficiently promoted inflammation resolution and enhanced dentin mineralization by activating p38 signal pathway, as a pulp-capping material, offering a promising and advanced solution for treatment of pulpitis. Keywords: nanocomposite hydrogel, vital pulp therapy, pulpitis, p38 signaling pathway

Zhishuo Zhang,1,&ast; Lujia Tang,1,&ast; Yiran Guo,1 Xin Guo,2 Zhiying Pan,2 Xiaojing Ji,1,&ast; Chengjin Gao1,&ast; 1Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; 2School of Information Science and Technology, Sanda University, Shanghai, Pudong District, 201209, China&ast;These authors contributed equally to this workCorrespondence: Xiaojing Ji; Chengjin Gao, Email jixiaojing@xinhuamed.com.cn; gaochengjin@xinhuamed.com.cnBackground: As of 30 April 2023, the COVID-19 pandemic has resulted in over 6.9 million deaths worldwide. The virus continues to spread and mutate, leading to continuously evolving pathological and physiological processes. It is imperative to reevaluate predictive factors for identifying the risk of early disease progression.Methods: A retrospective study was conducted on a cohort of 1379 COVID-19 patients who were discharged from Xin Hua Hospital affiliated with Shanghai Jiao Tong University School of Medicine between 15 December 2022 and 15 February 2023. Patient symptoms, comorbidities, demographics, vital signs, and laboratory test results were systematically documented. The dataset was split into testing and training sets, and 15 different machine learning algorithms were employed to construct prediction models. These models were assessed for accuracy and area under the receiver operating characteristic curve (AUROC), and the best-performing model was selected for further analysis.Results: AUROC for models generated by 15 machine learning algorithms all exceeded 90%, and the accuracy of 10 of them also surpassed 90%. Light Gradient Boosting model emerged as the optimal choice, with accuracy of 0.928 ± 0.0006 and an AUROC of 0.976 ± 0.0028. Notably, the factors with the greatest impact on in-hospital mortality were growth stimulation expressed gene 2 (ST2,19.3%), interleukin-8 (IL-8,17.2%), interleukin-6 (IL-6,6.4%), age (6.1%), NT-proBNP (5.1%), interleukin-2 receptor (IL-2R, 5%), troponin I (TNI,4.6%), congestive heart failure (3.3%) in Light Gradient Boosting model.Conclusion: ST-2, IL-8, IL-6, NT-proBNP, IL-2R, TNI, age and congestive heart failure were significant predictors of in-hospital mortality among COVID-19 patients.Keywords: COVID-19, machine learning, prognosis model, ST2, IL-8, TNI, IL-6, IL-2R, congestive heart failure

Lu Li,1 Lin Li,1 Xianhui Cai,1 Zongfu Pan2 1Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Zongfu Pan, Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China, Email panzongfu@163.comAbstract: Coronavirus disease 2019 (COVID-19)-induced new-onset diabetes has raised widespread concerns. Increased glucose concentration and insulin resistance levels were observed in the COVID-19 patients. COVID-19 patients with newly diagnosed diabetes may have worse clinical outcomes and can have serious consequences. The types and exact mechanisms of COVID-19-caused diabetes are not well understood. Understanding the direct effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pancreatic beta cells and insulin target metabolism organs, such as the liver, muscle, and adipose tissues, will provide new ideas for preventing and treating the new-onset diabetes induced by COVID-19.Keywords: COVID-19, SARS-CoV-2, new-onset diabetes, hyperglycemia

Wendao Han,1,2 Nating Xiong,1,2 Renkai Zhong,1,2 Zhongyi Pan1,2 1Department of Blood Transfusion, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 2Center for Precision Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of ChinaCorrespondence: Wendao Han, Meizhou People’s Hospital, Meizhou, People’s Republic of China, Email 443567914@qq.comObjective: Apolipoprotein E (APOE) plays an important role in the lipid metabolism. APOE polymorphisms have been implicated in susceptibility to diabetes mellitus (DM). However, the association between APOE polymorphisms and the risk of DM among the hypertensive patients remains unclear. Our study aimed to evaluate this relationship to provide clues for further developing DM in hypertensive patients.Methods: The study included 808 hypertensive patients with DM and 1226 hypertensive patients without DM as controls. The APOE 388T>C (rs429358) and 526C>T (rs7412) polymorphisms were genotyped by polymerase chain reaction (PCR) - microarray. Differences in APOE genotypes between subjects and controls were compared. To analyze the relationship between APOE genotypes and DM risk, multiple logistic regression analysis was performed after adjusting for gender, age, smoking history, and drinking history.Results: The APOE E2/E4, E3/E3 genotype and &epsiv;2, &epsiv;3 allele frequency had significant difference between DM patients and controls (P< 0.05). The DM patients with ɛ4 allele had lower level in high-density lipoprotein cholesterol (HDL-C) and higher level in apolipoprotein B (ApoB) than those with ɛ2 allele. The results of logistic regression analysis indicated that the APOE genotype of E2/E3 with adjusted OR=1.350 (95% Cl=1.009– 1.806, P=0.043) and E3/E4 with adjusted OR=1.325 (95% Cl=1.034– 1699, P=0.026) may be independent risk factors for DM.Conclusion: APOE E2/E3 and E3/E4 genotypes may be risk factors for developing diabetes mellitus in hypertensive patients.Keywords: Apolipoprotein E, polymorphism, hypertension, diabetes mellitus

He Ma,1 Zhenxiang Pan,1 Bingjie Lai,2 Chunfang Zan,3,4 He Liu5 1Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Intensive Care Unit, The Second Hospital of Jilin University, Changchun, People’s Republic of China; 3Department of Nuclear Medicine, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 4Collaborative Innovation Center for Molecular Imaging of Precision Medicine, Shanxi Medical University, Taiyuan, People’s Republic of China; 5Department of Orthopedics, The Second Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence: He Liu, Department of Orthopedics, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China, Email heliu@jlu.edu.cnAbstract: From a clinical perspective, local anesthetics have rather widespread application in regional blockade for surgery, postoperative analgesia, acute/chronic pain control, and even cancer treatments. However, a number of disadvantages are associated with traditional local anesthetic agents as well as routine drug delivery administration ways, such as neurotoxicity, short half-time, and non-sustained release, thereby limiting their application in clinical practice. Successful characterization of drug delivery systems (DDSs) for individual local anesthetic agents can support to achieve more efficient drug release and prolonged duration of action with reduced systemic toxicity. Different types of DDSs involving various carriers have been examined, including micromaterials, nanomaterials, and cyclodextrin. Among them, nanotechnology-based delivery approaches have significantly developed in the last decade due to the low systemic toxicity and the greater efficacy of non-conventional local anesthetics. Multiple nanosized materials, including polymeric, lipid (solid lipid nanoparticles, nanostructured lipid carriers, and nanoemulsions), metallic, inorganic non-metallic, and hybrid nanoparticles, offer a safe, localized, and long-acting solution for pain management and tumor therapy. This review provides a brief synopsis of different nano-based DDSs for local anesthetics with variable sizes and structural morphology, such as nanocapsules and nanospheres. Recent original research utilizing nanotechnology-based delivery systems is particularly discussed, and the progress and strengths of these DDSs are highlighted. A specific focus of this review is the comparison of various nano-based DDSs for local anesthetics, which can offer additional indications for their further improvement. All in all, nano-based DDSs with unique advantages provide a novel direction for the development of safer and more effective local anesthetic formulations.Keywords: local anesthetics, pain, drug delivery system, nanotechnology, nanocarriers, nanoparticles

Zhaobing Pan,1– 3,&ast; Qiaoshan Yang,1– 3,&ast; Xiaojing Zhang,1– 3 Xiaoqing Xu,1– 3 Yao Sun,1– 3 Fusheng Zhou,1– 4 Leilei Wen1– 3 1Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Institute of Dermatology, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, People’s Republic of China; 4Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fusheng Zhou; Leilei Wen, Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, No. 218, Jixi Road, Shushan District, Hefei, 230000, Anhui, People’s Republic of China, Tel +86-138-5698-5934 ; +86-183-5609-9275, Fax +86-0551-63633742, Email biozhoufs@163.com; wenleilei_2012@163.comPurpose: Systemic lupus erythematosus (SLE) is a typical autoimmune disease characterized by the involvement of multiple organs and the production of antinuclear antibodies. This study aimed to investigate the molecular mechanism of SLE.Patients and Methods: We retrieved genome-wide gene expression levels from five public datasets with relatively large sample sizes from the Gene Expression Omnibus (GEO), and we compared the expression profiles of peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy controls (HCs). The expression of seven target genes in PBMCs from 25 cases and 3 HCs was further validated by reverse-transcription quantitative PCR (RT‒qPCR). Flow cytometry was used for verifying the proportion of naive CD4(+) T cells and M2 macrophages in PBMCs from 5 cases and 4 HCs.Results: We found 14 genes (TRIM5, FAM8A1, SHFL, LHFPL2, PARP14, IFIT5, PARP12, DDX60, IRF7, IF144, OAS1, OAS3, RHBDF2, and RSAD2) that were differentially expressed among all five datasets. The heterogeneity test under the fixed effect model showed no obvious heterogeneity of TRIM5, FAM8A1, and SHFL across different populations. TRIM5 was positively correlated with the remaining 13 genes. By separating patient samples into TRIM5-high and TRIM5-low groups, we found that up-regulated genes in the TRIM5-high group were mainly enriched in virus-related pathways. Immune cell proportion analysis and flow cytometry revealed that naive CD4(+) T cells were significantly decreased while M2 macrophages were increased in the SLE group. TRIM5 expression levels were negatively correlated with naive CD4(+) T cells but positively correlated with M2 macrophages.Conclusion: Our data indicated that TRIM5 might be a key factor that modulates SLE etiology, possibly through naive CD4(+) T cells and M2 macrophages.Keywords: differential gene expression analysis, gene, virus, autoimmune disease

Xiaochong Li,1,&ast; Bowen Hu,1,&ast; Jiachen Zheng,2,3 Zhiyong Pan,1 Yuxiang Cai,4 Mingjuan Zhao,1 Xiaoqing Jin,2 Zhi-Qiang Li1 1Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China; 2Emergency Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China; 3The Second Clinical School, Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China; 4Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoqing Jin; Zhi-Qiang Li, Email redjin@whu.edu.cn; lizhiqiang@whu.edu.cnIntroduction: Temozolomide (TMZ) induces intestinal mucosa injury that cannot be fully counteracted by supportive treatment. Probiotics regulate gut microbial composition and the host immune system and may alleviate this side effect. We aimed to investigate the potential and mechanism of Lactobacillus rhamnosus GG (LGG) in relieving intestinal mucosal injury induced by TMZ.Methods: Glioblastoma mice were divided into four groups: CON (control), LGG (109 CFU/mL, treated for 7 days), TMZ (50 mg/kg·d, treated for 5 days), LGG+TMZ (LGG for 7 days and TMZ subsequently for 5 days). Body weight, food intake, and fecal pH were recorded. Intestinal tissue samples were collected 1 day after the end of TMZ treatment. Degree of damage to intestine, expression of IL1β, IL6, TNFα, and IL10 in jejunum were determined. Levels of tight-junction proteins (ZO1, occludin), TLR4, IKKβ, IκBα, and P65 with their phosphorylation in jejunum were measured.Results: Decreases in body weight, food intake, spleen index in the TMZ group were mitigated in the LGG+TMZ group, and the degree of intestinal shortening and damage to jejunum villus were also alleviated. The expression of tight-junction proteins in the LGG+TMZ group was significantly greater than that in the TMZ group. IκBα in intestinal tissue significantly decreased in the TMZ group, phos–IKKβ and phos-P65 increased compared to the CON group, and LGG reversed such changes in IκBα and phos-P65 in the LGG+TMZ group. Intestinal inflammatory cytokines were significantly increased in the TMZ group, but lower in the LGG+TMZ group. Moreover, expression of TLR4 in LGG group was significantly lower than that in the CON group. LGG inhibited the rise of TLR4 after TMZ in the LGG+TMZ group compared to the TMZ group.Conclusion: LGG inhibits the activation of the TLR4–NFκB pathway and alleviates intestinal mucosal inflammation induced by TMZ, thereby protect the jejunum villi and mucosal physical barrier.Keywords: Lactobacillus rhamnosus GG, temozolomide, intestinal mucosal injury, TLR4, NFκB

Juan Guo,1,&ast; Zhiyu Pan,1,&ast; Lvyuan Fan,1 Yilin Zhong,1 Rui Pang,2 Yubin Su1 1Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yubin Su, Email suyb7@jnu.edu.cnBackground: The issue of methicillin-resistant Staphylococcus aureus (MRSA) resistant to many antibiotics and causing serious infectious diseases is a growing healthcare concern.Purpose: In recent years, exogenous administration of metabolites in combination with antibiotics can re-sensitize resistant bacteria to antibiotics; however, their effects vary, and their underlying mechanism of action remains elusive.Methods: We assessed the bactericidal effects of the three amino acids in combination with gentamicin in vitro and in vivo. Subsequently, we explored the role of these amino acids on the metabolomics of MRSA using Liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, we performed the downstream analyses using MetaboAnalyst and Interactive Pathways Explorer.Results: Exogenous threonine showed the best bactericidal efficacy with gentamicin, followed by glycine, wherein serine had no effect. Amino acid treatments mainly up-regulated the metabolites, increased the amino acid abundance, and significantly activated metabolisms; these effects were consistent with the bactericidal efficacy of the three amino acids. Most amino acids participated in the tricarboxylic acid cycle, and threonine supplementation increased the activities of citrate synthase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase, whereas glycine increased activities of citrate synthase and α-ketoglutarate dehydrogenase, and serine did not affect the activities of any of the three key enzymes. We identified 24 biomarkers in the three groups, among which glutamic acid and cysteine showed a gradient decrease and increase, respectively. Subsequent analyses revealed that glutamic acid but not cysteine promoted the bactericidal effect of gentamicin synergistically.Conclusion: Threonine has the best synergistic effect in reversing bacterial resistance compared to glycine and serine. We show that different amino acids combined with an antibiotic mainly affect amino acid metabolism and act via different metabolic regulatory mechanisms, which could help develop effective strategies for tackling MRSA infections.Keywords: methicillin-resistant Staphylococcus aureus, metabolomics, gentamicin, amino acid, metabolic regulation

Yanyan Ma,1,&ast; Ying Cao,2,&ast; Hong Gao,3 Rui Tong,1 Jing Yi,3 Zhongwei Zhang,1 Rui Chen,1 Zhijun Pan1 1School of Anesthesia, Guizhou Medical University, Guiyang, People’s Republic of China; 2Department of Anesthesiology, The Second People’s Hospital of Guiyang, Guiyang, People’s Republic of China; 3Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Gao, Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, No. 9 Beijing Road, Guiyang, People’s Republic of China, Email 2169617@qq.com; anesth@qq.comPurpose: This study investigated the effect of exosomes derived from sevoflurane-treated cardiac fibroblasts (Sev-CFs-Exo) on reperfusion arrhythmias (RA), ventricular conduction, and myocardial ischemia-reperfusion injury (MIRI).Methods: Primary cardiac fibroblasts (CFs) were isolated from the hearts of neonatal rats and identified by morphology and immunofluorescence. Exosomes were isolated from CFs at passages 2– 3 after they had been treated with 2.5% sevoflurane for an hour and cultivated for 24– 48 hours. The control group was CFs that did not receive any treatment. The hypothermic global ischemia-reperfusion injury model was established using the Langendorff perfusion technique following injection with exosomes through the caudal vein. Multi-electrode array (MEA) mapping was used to investigate the changes in RA and ventricular conduction in isolated hearts. Western blots and immunofluorescence were used to examine the relative expression and location of connexin 43 (Cx43). In addition, the MIRI was evaluated with triphenyl tetrazolium chloride and Hematoxylin-Eosin staining.Results: The primary CFs had a variety of morphologies, no spontaneous pulsation, and were vimentin-positive, which confirmed their successful isolation. Sev-CFs-Exo increased the heart rate (HR) at reperfusion for 15 minutes (T2) and 30 minutes (T3) and lowered the score and duration of RA and the time for restoration of heartbeat in reperfusion. Meanwhile, Sev-CFs-Exo increased conduction velocity (CV), decreased absolute inhomogeneity (P5-95) and inhomogeneity index (P5-95/P50) at T2 and T3, as well as promoted the recovery of HR, CV, P5-95 and P5-95/P50 after hypothermic global ischemia-reperfusion injury. Furthermore, Sev-CFs-Exo raised expression and reduced lateralization of Cx43, and improved myocardial infarct sizes and cellular necrosis. However, while cardiac fibroblast-derived exosomes (CFs-Exo) showed similar cardioprotective effects, the outcomes were not as significant.Conclusion: Sevoflurane reduces the risk of RA and improves ventricular conduction and MIRI by CFs-Exo, and this may be driven by the expression and location of Cx43.Keywords: anesthetic, extracellular vesicles, arrhythmia, electrophysiology, electrical mapping, connexin 43, Cx43

Sheng Liu,1,&ast; Guanyun Shi,1 Zhengbo Pan,1 Weisong Cheng,1 Linfei Xu,1 Xingzhang Lin,1 Yongfeng Lin,1 Liming Zhang,1 Guanghua Ji,1 Xin Lv,1 Dongguo Wang2,&ast; 1Department of Urinary Surgery, Taizhou Municipal Hospital Affiliated with Taizhou University, Taizhou, Zhejiang Province, People’s Republic of China; 2Department of Central Laboratory, Taizhou Municipal Hospital Affiliated with Taizhou University, Taizhou, Zhejiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongguo Wang, Department of Central Laboratory, Taizhou Municipal Hospital Affiliated with Taizhou University, 381-1 Eastern Road of Zhongshan, Taizhou, Zhejiang Province, 318000, People’s Republic of China, Tel +86-13566871738, Email wdgtzs@163.comPurpose: The overall survival of clear cell renal cell carcinoma (ccRCC) is poor. Markers for early detection and progression could improve disease outcomes. This study aims to reveal the potential pathogenesis of ccRCC by integrative bioinformatics analysis and to further develop new therapeutic strategies.Patients and Methods: RNA-seq data of 530 ccRCC cases in TCGA were downloaded, and a comprehensive analysis was carried out using bioinformatics tools. Another 14 tissue samples were included to verify the expression of selected lncRNAs by qRT-PCR. DGIdb database was used to screen out potential drugs, and molecular docking was used to explore the interaction and mechanism between candidate drugs and targets.Results: A total of 58 differentially expressed lncRNAs (DElncRNAs) and 660 differentially expressed mRNAs (DEmRNAs) were identified in ccRCC. LINC02038, FAM242C, LINC01762, and PVT1 were identified as the optimal diagnostic lncRNAs, of which PVT1 was significantly correlated with the survival rate of ccRCC. GO analysis of cell components showed that DEmRNAs co-expressed with 4 DElncRNAs were mainly distributed in the extracellular area and the plasma membrane, involved in the transport of metal ions, the transport of proteins across membranes, and the binding of immunoglobulins. Immune infiltration analysis showed that MDSC was the most correlated immune cells with PVT1 and key mRNA SIGLEC8. Validation analysis showed that GABRD, SIGLEC8 and CDKN2A were significantly overexpressed, while ESRRB, ELF5 and UMOD were significantly down-regulated, which was consistent with the expression in our analysis. Furthermore, 84 potential drugs were screened by 6 key mRNAs, of which ABEMACICLIB and RIBOCICLIB were selected for molecular docking with CDKN2A, with stable binding affinity.Conclusion: In summary, 4 key lncRNAs and key mRNAs of ccRCC were identified by integrative bioinformatics analysis. Potential drugs were screened for the treatment of ccRCC, providing a new perspective for disease diagnosis and treatment.Keywords: clear cell renal cell carcinoma, bioinformatics analysis, lncRNA, mRNA, drugs prediction, molecular docking

Shenglan Ma,1– 3,&ast; Peijun Ju,4,&ast; Qingrong Xia,1– 3 Zhongde Pan,5 Jianliang Gao,1– 3 Loufeng Zhang,1– 3 Hua Gao,1– 3 Junwei Yan,1– 3 Jie Zhang,1– 3 Keming Wang,1– 3 Chao Li,1– 3 Wen Xie,1– 3,&ast; Cuizhen Zhu1– 3,&ast; 1Affiliated Psychological Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 2Clinical Center for Psychiatry and Mental Health, Hefei Fourth People’s Hospital, Hefei, 230022, People’s Republic of China; 3Anhui Mental Health Center, Hefei, People’s Republic of China; 4Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Traditional Chinese Medicine for Mental Health, Shanghai, People’s Republic of China; 5Shanghai Key Laboratory of Forensic Medicine, Academy of Forensic Science, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen Xie; Cuizhen Zhu, Affiliated Psychological Hospital of Anhui Medical University, No. 316 Huangshan Road, Shushan District, Hefei, Anhui, People’s Republic of China, Tel +86 13339102285 ; +86 13705535258, Fax +86 055163616000, Email xiewen0808@sina.com; zhucuizhen88@126.comPurpose: The study aims to clarify the negative psychological state and resilience impairments of schizophrenia (SCZ) with metabolic syndrome (MetS) while evaluating their potential as risk factors.Patients and Methods: We recruited 143 individuals and divided them into three groups. Participants were evaluated using the Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale (HAMD)-24, Hamilton Anxiety Rating Scale (HAMA)-14, Automatic Thoughts Questionnaire (ATQ), Stigma of Mental Illness scale and Connor–Davidson Resilience Scale (CD-RISC). Serum biochemical parameters were measured by automatic biochemistry analyzer.Results: The score of ATQ was highest in the MetS group (F = 14.5, p < 0.001), and the total score of CD-RISC, subscale tenacity score and subscale strength score of CD-RISC were lowest in the MetS group (F = 8.54, p < 0.001; F = 5.79, p = 0.004; F = 10.9, p < 0.001). A stepwise regression analysis demonstrated that a negative correlation was observed among the ATQ with employment status, high-density lipoprotein (HDL-C), and CD-RISC (β=− 0.190, t=− 2.297, p = 0.023; β=− 0.278, t=− 3.437, p = 0.001; β=− 0.238, t=− 2.904, p = 0.004). A positive correlation was observed among the ATQ with waist, TG, WBC, and stigma (β=0.271, t = 3.340, p = 0.001; β=0.283, t = 3.509, p = 0.001; β=0.231, t = 2.815, p = 0.006; β=0.251, t=− 2.504, p = 0.014). The area under the receiver-operating characteristic curve analysis showed that among all independent predictors of ATQ, the TG, waist, HDL-C, CD-RISC, and stigma presented excellent specificity at 0.918, 0.852, 0.759, 0.633, and 0.605, respectively.Conclusion: Results suggested that the non-MetS and MetS groups had grievous sense of stigma, particularly, high degree of ATQ and resilience impairment was shown by the MetS group. The TG, waist, HDL-C of metabolic parameters, CD-RISC, and stigma presented excellent specificity to predict ATQ, and the waist showed excellent specificity to predict low resilience level.Keywords: years of education, negative symptoms, waist circumstance

Zhengshuo Jin,1,2,&ast; Zhouxian Pan,2,&ast; Ziran Wang,3,&ast; Lingjun Kong,3 Min Zhong,3 Yongshi Yang,2 Yaling Dou,3 Jin-Lyu Sun2 1Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China; 2Allergy Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yaling Dou; Jin-Lyu Sun, Email douyl@pumch.cn; sunjinlv@pumch.cnBackground and Objective: Asthma and allergic rhinitis have been reported to be strongly associated with genetic factors. The aim of this study was to evaluate the accuracy of the TaqMan-MGB (minor groove binder) qPCR method for detecting CYSLTR1 rs320995 (T927C) and GSDMB rs7216389 (G1199A) gene polymorphisms as well as to explore the association of CYSLTR1 rs320995 and GSDMB rs7216389 polymorphisms with genetic susceptibility of Chinese patients with asthma and allergic rhinitis.Methods: In this study, 310 asthmatic patients and 60 healthy individuals were recruited in Peking Union Medical College Hospital. The CYSLTR1 rs320995 (T927C) and GSDMB rs7216389 (G1199A) gene polymorphisms in each group were analyzed by TaqMan-MGB qPCR and DNA sequencing which was regarded as the gold standard. After the validation of this method, additional 71 patients with allergic rhinitis and 72 patients with asthma combined with allergic rhinitis were selected and tested by using TaqMan-MGB qPCR.Results: The TaqMan-MGB qPCR results were fully consistent with DNA sequencing results (Kappa = 1, P< 0.001). In addition, the results of the TaqMan-MGB qPCR assay were not affected by bilirubin and lipids. We found differential distribution of CYSLTR1 rs320995 genotypes in female patients with asthma combined with allergic rhinitis (χ2=6.172, P=0.046, statistical power = 0.591). Specifically, the TT genotype is more frequent in women suffering from asthma with allergic rhinitis, whereas the TC genotype is more prevalent in healthy women. However, no such associations were observed in the GSDMB rs7216389 polymorphism.Conclusion: We have established a reliable TaqMan-MGB qPCR method for the detection of CYSLTR1 rs320995 and GSDMB rs7216389 polymorphisms. Moreover, the CYSLTR1 rs320995 polymorphism may be associated with genetic susceptibility of Chinese female patients with asthma and allergic rhinitis. Multicenter studies with larger sample sizes are required in the future.Keywords: asthma, allergy treatment, gene polymorphism, CYSLTR1, GSDMB

Yiting Zhang,1 Jing Zhang,2 Zhaoyu Pan,1 Xingxiang He1 1Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 2Foshan Hospital Affiliated to Sun Yat-sen University, FoShan, People’s Republic of ChinaCorrespondence: Xingxiang He, Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, No. 19, Nonglinxia Road, Guangzhou, 510062, People’s Republic of China, Email hexingxiang@gdpu.edu.cnPurpose: Autism spectrum disorder is a highly complex neurological and psychosocial disorder characterized by social dysfunction, severe reduction in speech, and a single stereotyped behavior. The treatment methods are currently limited, and children with autism generally suffer from constipation and sleep disorders. It is urgent to find an alternative psychotropic drug, given the drug dependence and adverse reactions that may occur with long-term medication.Patients and Methods: This retrospective study included 49 children with autism at the first affiliated Hospital of Guangdong Pharmaceutical University, who received washed fecal microbiota transplantation (WMT) treatment between June 2019 and July 2021 and compared the sleep disorder scores between the constipation group, control group and blank group.Results: Second WMT could significantly improve the sleep disorder scores in the constipation group (p=0.026) and the decrease in sleep disturbance scale for children (SDSC) score was synchronized with the increase in Bristol stool form scale (BSFS) score. However, there was no significant difference between patients without constipation (p=0.54), and the behavior of autism improved in both groups.Conclusion: WMT could relieve constipation and improve sleep disorders in children with autism, with no deterioration in stool morphology and sleep disorders in other children. Moreover, there were no obvious serious adverse clinical events after WMT.Keywords: SDSC, ABC, CARS, BSFS, microbiota-gut-brain axis

Jun Wu,1 Xuefeng Leng,1 Zhengbo Pan,2 Linfei Xu,2 Haitao Zhang2 1Department of Urology, Naval 971 Hospital of Chinese People’s Liberation Army, Qingdao City, Shandong Province, People’s Republic of China; 2Department of Urology, Municipal Hospital Affiliated to Taizhou University, Taizhou City, Zhejiang Province, People’s Republic of ChinaCorrespondence: Haitao ZhangDepartment of Urology, Municipal Hospital Affiliated to Taizhou University, Taizhou City, Zhejiang Province, People’s Republic of ChinaEmail zhanghaitao_123@yeah.netBackground: Growing findings have demonstrated that interferon regulatory transcription factor (IRF) family members are linked to the progression of various cancers. However, the roles of IRFs in clear cell renal cell carcinoma (ccRCC) remain undefined. Herein, we conducted a comprehensive analysis using the bioinformatics method to evaluate the expression patterns, clinical significance, and regulation of IRFs-related mechanisms in patients with ccRCC.Methods: Data from the Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGA), and Gene Expression Omnibus (GEO) databases were used for investigation comprehensively. Specifically, we carried out a series of analyses to identify the candidate IRF and to explore its potential action mechanisms using the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. What is more, we emphatically investigate the association of candidate IRF with tumor immunity in ccRCC through the CIBERSORT algorithm, TIMER and GEPIA databases.Results: Herein, IRF3 was identified as candidate IRF, which was highly expressed in ccRCC, and its overexpression was significantly associated with worse clinical outcomes and adverse overall survival. Uni- and multi-variate Cox regression analysis demonstrated that IRF3 overexpression was an independent predictor of worse prognosis. Functional enrichment analysis showed that IRF3 might participate in several cancer-related biological processes and signaling pathways, thereby promoting the progression of ccRCC. Additionally, we found that IRF3 was remarkably associated with tumor-infiltrating immune cells (TIICs) and various immune-related genes.Conclusion: Herein, we identified IRF3 from the IRF gene family members, which could serve as promising prognostic marker and therapeutic target in ccRCC.Keywords: kidney renal clear cell carcinoma, bioinformatics, interferon regulatory transcription factor, prognosis

Sijia Ma,1 Mingming Zhao,1 Jiao Fan,1 Meiying Chang,1 Zhiyu Pan,1 Ziyan Zhang,1 Shunxuan Xue,1 Qi Li,2 Yu Zhang1 1Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Department of Clinical Laboratory, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Yu Zhang Email zhangyu8225@126.comIntroduction: Renal clear cell carcinoma (ccRCC) is a common tumor of the urinary system, most of which are primary malignant tumors with high metastatic rate and remaining incurable. Ferroptosis is a newly discovered form of iron-dependent programmed cell necrosis in recent years, which is inextricably linked to the occurrence and development of tumors progression. Due to the complexity of the interaction between genes in ccRCC, the research on the pathogenesis of ccRCC is still not remarkably accurate. Therefore, whether ferroptosis-related genes (FRGs) can play a role in predicting prognosis in ccRCC needs to be discussed.Methods: We entered the Cancer Genome Mapping Project (TCGA) database and downloaded the relevant genes and clinical research data of ccRCC patients. Lasso Cox regression was used to construct a multi-gene prognostic model in the TCGA cohort. R language software was used for drawing pictures related to our study.Results: Most of the genes involved in ferroptosis (86.2%) existing differences between the tumor and normal tissues in the TCGA public gene database. In terms of univariate Cox regression analysis, 20 differentially expressed genes (DEGs) were associated with prognosis and survival (P< 0.05). A prognostic model of 12 FRGs was constructed, and patients were segmented into two different groups depending on how risky they are. Considering overall survival, the high-risk group is dramatically lower than the low-risk group (P< 0.001). In multivariate Cox regression analysis, risk scores and stage turned out be an independent prognostic factor (P< 0.001). GO and KEGG analysis and ssGSEA analysis of DEGs revealed that these genes were related to immune-related pathways (P< 0.05).Conclusion: This study established and identified the changes in FRGs expression and prognostic factors of ccRCC, which can be helpful for prognosis evaluation and clinical treatment of this disease.Keywords: renal clear cell carcinoma, ferroptosis, TCGA database, the prognosis

Zhonglin Wang,1 Jian Yu,2 Shangrui Rao,2 Zhe Lin,2 Zhongliang Pan,2 Xian Shen1 1Department of General Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China; 2Department of General Surgery, Wenzhou Central Hospital, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaCorrespondence: Xian ShenDepartment of General Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaTel/Fax +86-577-88002609Email 13968888872@163.comBackground: Increased surgical technology has led broad acceptance endoscopic thyroidectomy and its application in the treatment of thyroid diseases, including thyroid carcinoma. Although the incidence of complications and mortality of thyroid surgery has been significantly reduced, serious complications still occur from time to time. The purpose of this retrospective study is to identify the factors that influence the complications of endoscopic thyroidectomy.Methods: This study was carried out between January 2012 and December 2019, where a total of 630 patients undergoing endoscopic thyroidectomy via the total areola approach were retrospectively evaluated to identify the key influencing factors of complications.Results: The study established that the common complications included recurrent laryngeal nerve injury (3.33%), superior laryngeal nerve injury (2.54%), hypocalcemia (8.57%), and the incidence of complications was acceptable. Both univariate and multivariate analysis showed that thyroid carcinoma (P = 0.041), operation time lasting more than 150 minutes (P = 0.034) and operation before 2017 (P = 0.001) were risk factors of recurrent laryngeal nerve injury. We established that operation after 2017 (P < 0.005) was the only protective factor of superior laryngeal nerve injury. Thyroid carcinoma (P=0.04), operation mode (P=0.001), and surgery before 2017 (P< 0.001) are risk factors for parathyroid injury. Among the clinical groups, operation before 2017 was an independent risk factor for all complications.Conclusion: For thyroid specialists, after the early learning curve, with the continuous improvement of endoscopic operation technology, high-definition equipment and more sophisticated operation equipment can be used in clinical practice, which can prevent and reduce the occurrence of complications.Keywords: thyroidectomy, endoscopy, surgical complications, influencing factors

Hua Yang,1,* Jian Gao,2,* Shuyu Li,1 Huiling Xia,1 Zhangyan Chen,1 Shanzhu Zhu,1 Zhigang Pan1 1Department of General Practice, Zhongshan Hospital of Fudan University, Shanghai, 200030, People’s Republic of China; 2Department of Nutrition, Zhongshan Hospital of Fudan University, Center of Clinical Epidemiology and Evidence-Based Medicine, Fudan University, Shanghai, 200030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shanzhu Zhu; Zhigang PanDepartment of General Practice, Zhongshan Hospital of Fudan University, No. 180, Road Fenglin, Shanghai, 200030, People’s Republic of ChinaTel +86 13501770447; +86 13681971967Email shanzhu_zhu@163.com; zhigang_pan@163.comBackground and Objectives: Serum uric acid (sUA) level has been reported to be associated with arteriosclerotic cardiovascular risk, yet remains poorly defined in Chinese type 2 diabetes patients. The purpose of the current study was to evaluate gender differences in the association between sUA level and arteriosclerotic cardiovascular risk in Chinese type 2 diabetes patients.Methods: The cross-sectional study was conducted in six community health service centers in Shanghai, China from December 2014 to December 2016. A stratified random sampling method was used to recruit participants. From a total of 3977 type 2 diabetic patients, 2537 were included for the analysis of the association between sUA level and arteriosclerotic cardiovascular risk. Clinical and biochemical data were obtained from participants. Arteriosclerotic cardiovascular risk was evaluated by the ten-year risk profile for arteriosclerotic cardiovascular disease. The associations between sUA level and arteriosclerotic cardiovascular risk were assessed via multiple logistic regression.Results: Of the 2537 participants, the average sUA level was 317± 77umol/L in men and 294± 73 umol/L in women, and 54.8% (1391/2537) of participants had high ten-year risk of arteriosclerotic cardiovascular disease (ASCVD), which was ≥ 20%. High ten-year risk of ASCVD odds ratio was increased by 1.596 (95% CI, 1.113– 2.289, p for trend 0.004) comparing fourth to first quartiles of sUA in women. However, no significant association was found between sUA and high ten-year risk of ASCVD in men.Conclusion: This community-based study indicated that sUA levels were independently associated with high ten-year risk of ASCVD in women with type 2 diabetes mellitus, but not in men.Keywords: serum uric acid, ten-year risk, arteriosclerotic cardiovascular disease, type 2 diabetes mellitus

Zhiying Pang,1,* Zhangyi Pan,1,* Min Ma,1 Zhiyan Xu,2 Shiqi Mei,2 Zengxin Jiang,3 Feng Yin1 1Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, People’s Republic of China; 2Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, People’s Republic of China; 3Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zengxin Jiang Tel +86 21-64041990Email Dr_Jiangzx@163.comFeng Yin Tel +86 21-64041990Email 001yinfeng@sina.comPurpose: As a dental material, polyetheretherketone (PEEK) is bioinert that does not induce cellular response and bone/gingival tissues regeneration. This study was to develop bioactive coating on PEEK and investigate the effects of coating on cellular response.Materials and Methods: Tantalum pentoxide (TP) coating was fabricated on PEEK surface by vacuum evaporation and responses of rat bone marrow mesenchymal stem (RBMS) cells/human gingival epithelial (HGE) were studied.Results: A dense coating (around 400 nm in thickness) of TP was closely combined with PEEK (PKTP). Moreover, the coating was non-crystalline TP, which contained many small humps (around 10 nm in size), exhibiting a nanostructured surface. In addition, the roughness, hydrophilicity, surface energy, and protein adsorption of PKTP were remarkably higher than that of PEEK. Furthermore, the responses (adhesion, proliferation, and osteogenic gene expression) of RBMS cells, and responses (adhesion and proliferation) of HGE cells to PKTP were remarkably improved in comparison with PEEK. It could be suggested that the nanostructured coating of TP on PEEK played crucial roles in inducing the responses of RBMS/HGE cells.Conclusion: PKTP with elevated surface performances and outstanding cytocompatibility might have enormous potential for dental implant application.Keywords: polyetheretherketone, tantalum pentoxide, nanostructured coating, cytocompatibility, dental implant applications

Yang Dong,* Dongfei Wang,* Jialan Lv, Zhicheng Pan, Rui Xu, Jie Ding, Xiao Cui, Xudong Xie, Xiaogang Guo Department of Cardiology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaogang GuoDepartment of Cardiology, The First Affiliated Hospital of Zhejiang University School of Medicine, No. 79 Qing Chun Road, Hangzhou 310006, People’s Republic of ChinaTel + 86-13867441856Email gxg22222@zju.edu.cnPurpose: We aimed to study the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) risk model’s prognostic value and relationship with left ventricular remodeling in dilated cardiomyopathy.Patients and Methods: Dilated cardiomyopathy patients were prospectively recruited and underwent clinical assessments. MAGGIC risk score was calculated. Patients were followed up for adverse events and echocardiography. Primary endpoints were all-cause mortality and first rehospitalization due to heart failure. Secondary endpoint was left ventricular remodeling defined as a decline in left ventricular ejection fraction > 10% or an increase in left ventricular end-diastolic diameter > 10%. Survival status was examined using Cox regression analysis. The model’s ability to discriminate adverse events and left ventricular remodeling was calculated using a receiver operating characteristics curve.Results: In total, 114 patients were included (median follow-up time = 31 months). The risk score was independently related to adverse events (2-year all-cause mortality: hazard ratio [HR] = 1.122; 95% confidence interval [CI], 1.043– 1.208; 1-year first rehospitalization due to heart failure: HR = 1.094; 95% CI, 1.032– 1.158; 2-year first rehospitalization due to heart failure: HR = 1.088; 95% CI, 1.033– 1.147, all P < 0.05). One-year change in left ventricular end-diastolic diameter was correlated with the risk score (r = 0.305, P = 0.002). The model demonstrated modest ability in discriminating adverse events and left ventricular remodeling (all areas under the curve were 0.6– 0.7).Conclusion: The MAGGIC risk score was related to adverse events and left ventricular remodeling in dilated cardiomyopathy.Keywords: dilated cardiomyopathy, left ventricular remodeling, prognosis, risk model

Piyun Sun, Yuchen Feng, Hui Guo, Rong Li, Peng Yu, Xingguang Zhou, Zhige Pan, Yanyan Liang, Bihan Yu, Yanyi Zheng, Yu Shi, Lingbo Wen, Minmei Wei, Yanhua Chen Department of Oncology, Liuzhou Hospital of Traditional Chinese Medicine, Liuzhou City, Guangxi Province 545001, People’s Republic of ChinaCorrespondence: Yanhua Chen Tel +86 772-3357233Email rp0571@163.comIntroduction: MCM3AP-AS1 has been characterized as an oncogenic lncRNA in several types of cancer, while its role in nasopharyngeal carcinoma (NPC) is unknown. This study aimed to investigate the role of MCM3AP-AS1 in NPC.Patients and Methods: Paired NPC tissues and non-tumor tissues were collected from 55 NPC patients. Expression of MCM3AP-AS1 and miR-34a in paired tissues was analyzed by RT-qPCR. Interactions between MCM3AP-AS1 and miR-34a were analyzed by overexpression experiments. The roles of MCM3AP-AS1 and miR-34a in regulating NPC cell proliferation and apoptosis were explored by cell proliferation assay and cell apoptosis assay, respectively.Results: Our bioinformatics analysis showed that MCM3AP-AS1 may be targeted by miR-34a, which is a well-studied tumor suppressor miRNA. In this study, we showed that miR-34a was downregulated and MCM3AP-AS1 was upregulated in NPC. An inverse correlation between the expression of MCM3AP-AS1 and miR-34a was found across NPC tissue samples. High expression level of MCM3AP-AS1 and low levels of miR-34a in NPC tissues predicted the poor survival. In NPC cells, overexpression of MCM3AP-AS1 did not affect the expression of miR34a, while overexpression of miR-34a led to downregulated MCM3AP-AS1. Cell proliferation and apoptosis assay showed that overexpression of miR-34a reduced the enhancing effects of overexpressing MCM3AP-AS1 on cell proliferation and the inhibitory effects on cell apoptosis.Conclusion: MiR-34a inhibits cell proliferation and induces apoptosis in human NPC by targeting MCM3AP-AS1.Keywords: MCM3AP-AS1, miR-34a, nasopharyngeal carcinoma, proliferation, apoptosis

Zhenyu Pan,1– 3 Jun Zhang,1,2,4 Qingting Bu,5 Hairong He,1 Ling Bai,1 Jin Yang,1,2 Qingqing Liu,1,2 Jun Lyu1,2,6 1Clinical Research Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, People’s Republic of China; 3Department of Pharmacy, Xi’an Children’s Hospital, Xi’an, Shaanxi, People’s Republic of China; 4Department of Orthopaedics, Baoji Municipal Central Hospital, Baoji, Shaanxi, People’s Republic of China; 5Department of Genetics, Northwest Women’s and Children’s Hospital, Xi’an, Shaanxi, People’s Republic of China; 6Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Jun LyuClinical Research Center, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an, Shaanxi 710061, People’s Republic of ChinaTel +86 29 8532 3614Fax +86 29 8532 3473Email lujun2006@xjtu.edu.cnObjective: The first milestone (in 2020) of the End Tuberculosis (TB) Strategy of the World Health Organization was a 20% reduction in TB incidence rate compared with the 2015 baseline. This study aimed to determine the incidence rate of TB and how it has changed since 2015 at the global, regional, and country levels.Methods: This study used the most recent data from the Global Burden of Disease study in 2017 to extract TB incidence rates at the global, regional, and country levels. The annual percentage change in the incidence rate (APCIR) of TB based on 2015 was calculated to evaluate the trend in the changes at various levels, including globally and at the regional and country levels. An APCIR of – 4% from 2015 to 2020 is considered acceptable.Results: The global APCIR was only – 1.1% from 2015 to 2017. Only 2 of the 21 analyzed regions had APCIRs lower than – 4%: Southern Sub-Saharan Africa and Eastern Europe. Worse still, six regions exhibited increasing TB incidence rates. At the country level, although 143 of 195 countries and territories showed reductions in TB incidence rates, the APCIR was lower than – 4% in only 11 of them.Conclusion: This study suggests that it will be difficult to achieve the 2020 incidence rate milestone of the End Tuberculosis Strategy. This indicates the need to design and implement suitable strategies to address the current situation in order to achieve the next milestone and targets of the End Tuberculosis Strategy.Keywords: GBD, tuberculosis, incidence, End Tuberculosis Strategy

Kun Li,1,* Yanli Gao,1,* Zhenyu Pan,1 Xiuqin Jia,1 Yuchang Yan,1 Xiaohong Min,1 Kewu Huang,2 Tao Jiang1 1Department of Radiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, Republic of China; 2Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tao JiangDepartment of Radiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of ChinaTel +86 13718875778Fax +86 1065935237Email jiangt8166@hotmail.comPurpose: To explore the influence of emphysema and air trapping heterogeneity on pulmonary function changes in patients with stable chronic obstructive pulmonary disease (COPD).Patients and methods: One hundred and seventy-nine patients with stable COPD were enrolled in this prospective study. All patients underwent low-dose inspiratory and expiratory CT scanning and pulmonary-function tests. CT quantitative data for the emphysema index (EI) on full-inspiration and air trapping (AT) on full-expiration were measured for the whole lung, the right and left lungs, and the cranial-caudal lung zones. The heterogeneity index (HI) values for emphysema and air trapping were determined as the ratio of the difference to the sum of the respective indexes. The cranial-caudal HI and left–right lung HI were compared between mild-to-moderate (GOLD stage I and II) and severe (GOLD stage III and IV) disease groups. The associations between HI and pulmonary-function measurements adjusted for age, sex, height, smoking history, EI and AT of the total lung were assessed using multiple linear regression analysis.Results: The absolute values for cranial-caudal HI (AT_CC_HI) and left–right lung HI (AT_LR_HI) on full-expiration were significantly larger in the mild-to-moderate group, while no significant intergroup differences were observed on full-inspiration. COPD patients with lower-zone and/or left-lung predominance showed significantly lower pulmonary function than those with upper-zone and/or right-lung predominance on full-expiration, whereas no significant differences were observed on full-inspiration. The absolute values of AT_CC_HI and AT_LR_HI significantly correlated with pulmonary-function measurements. Higher AT_CC_HI and lower AT_LR_HI absolute values indicated better pulmonary function, after adjusting for age, sex, height, smoking history, EI and AT of the total lung.Conclusion: Subjects with more heterogeneous distribution and/or upper-zone predominant and/or right-lung predominant patterns on full-expiration tend to have better pulmonary function. Thus, in comparison with emphysema heterogeneity, AT heterogeneity better reflects the pulmonary function changes in COPD patients.Keywords: pulmonary disease, chronic obstructive, small airway disease, heterogeneous distribution, tomography, X-Ray computed

Ting Cheng,1,2,* Yong Li,1,2,* Shuai Pang,1,2 HuanYing Wan,1,2 GuoChao Shi,2,3 QiJian Cheng,1,2 QingYun Li,2,3 ZiLai Pan,4 ShaoGuang Huang2,31Department of Respiratory Medicine, Ruijin Hospital North, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Institute of Respiratory Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Respiratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Radiology, Ruijin Hospital North, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workBackgroud and objectives: Although lung attenuation distribution and lung volume on computed tomography (CT) have been widely used in evaluating COPD and interstitial lung disease, there are only a few studies regarding the normal range of these indices, especially in Chinese subjects. We aimed to describe the normal range of lung attenuation distribution and lung volume based on CT.Methods: Subjects with normal lung function and basically normal chest CT findings (derivation group) at Ruijin Hospital, Shanghai (from January 2010 to June 2014) were included according to inclusion and exclusion criteria. The range of the percentage of lung volume occupied by low attenuation areas (LAA%), percentile of the histogram of attenuation values (Perc n), and total lung volume were analyzed. Relationships of these measures with demographic variables were evaluated. Participants who underwent chest CT examination for disease screening and had basically normal CT findings served as an external validation group.Results: The number of subjects in the derivation group and external validation groups were 564 and 1,787, respectively. Mean total lung volumes were 4,468±1,271 mL and 4,668±1,192 mL, and median LAA%(-950 HU) was 0.19 (0.03–0.43) and 0.17 (0.01–0.41), in the derivation and external validation groups, respectively. Reference equations for lung volume and attenuation distribution (LAA% using -1,000–210 HU, Perc 1 to Perc 98) were generated: Lung volume (mL) = -1.015 *10^4+605.3*Sex (1= male, 0= female)+92.61*Height (cm) –12.99*Weight (kg) ±1766; LAA% (-950 HU)=[0.2027+0.05926*Sex (1= male, 0= female) –4.111*10^-3*Weight (kg) +4.924*10^-3*Height (cm) +8.504*10^-4*Age]^7.341–0.05; Upper limit of normal range: [0.2027+0.05926*Sex-4.111*10^-3*Weight+4.924*10^-3*Height+8.504*10^-4*Age+0.1993]^7.341–0.05.Conclusion: This large population-based retrospective study demonstrated the normal range of LAA%, Perc n, and total lung volume measured on CT scans among subjects with normal lung function and CT findings. Reference equations are provided.Keywords: lung attenuation, emphysema, lung volumes, quantitative computed tomography, reference equations, normal range, densitometry

Lu Li,1,* Zongfu Pan,2,* Xi Yang11Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this work Background: Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by the immune destruction of islet β cells. Gene expression in peripheral blood mononuclear cells (PBMCs) could offer new disease and treatment markers in T1DM. The objective of this study was to explore the coexpression and dynamic molecular networks in PBMCs of T1DM patients.Methods: Dataset GSE9006 contains PBMC samples of healthy volunteers, newly diagnosed T1DM patients, T1DM patients after insulin treatment, and newly diagnosed type 2 diabetes mellitus (T2DM) patients. Weighted correlation network analysis (WGCNA) was used to generate coexpression networks in T1DM and T2DM. Functional pathways in highly correlated modules of T1DM were enriched by gene set enrichment analysis (GSEA). We next filtered the differentially expressed genes (DEGs) and revealed their dynamic expression profiles in T1DM with or without insulin treatment. Furthermore, dynamic clusters and dynamic protein–protein interaction networks were identified. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was developed in dynamic clusters.Results: WGCNA disclosed 12 distinct gene modules, and distinguished between correlated networks in T1DM and T2DM. Two modules were closely associated with T1DM. GSEA showed that the immune response and response to cytokines were enriched in the T1DM highly correlated module. Next, we screened 44 DEGs in newly diagnosed T1DM compared with healthy donors, and 71 DEGs in 1-month and 97 DEGs in 4-month insulin treatment groups compared with newly diagnosed T1DM. Dynamic expression profiles of DEGs indicated the potential targets for T1DM treatment. Moreover, four molecular dynamic clusters were analyzed in newly diagnosed and insulin-treated T1DM. Functional annotation showed that these clusters were mainly enriched in the IL-17 signaling pathway, nuclear factor-ϰB signaling pathway, and tumor necrosis factor signaling pathway.Conclusion: The results indicate potential drug targets or clinical efficacy markers, as well as demonstrating the underlying molecular mechanisms of T1DM treatment.Keywords: type 1 diabetes mellitus, dynamic molecular networks, coexpression networks, peripheral blood mononuclear cells

Hengbiao Sun,1,* Gang Xiao,1,* Jing Zhang,1 Zuhan Pan,1 Youming Chen,1 Fu Xiong,21Department of Clinical Laboratory, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, People’s Republic of China; 2Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People’s Republic of China*These authors contributed equally to this work Objective: The aim of this study was to develop a multiplex PCR system for the rapid and simultaneous detection of blaoxa-23, Ade-B, int-1, and ISCR-1 genes in multidrug-resistant Acinetobacter baumannii (MDRAB) using high resolution melting (HRM) assay.Methods: Four pairs of primers were designed, and PCR amplification products were sequenced and compared with NCBI GeneBank sequences to ensure primer specificity. Multiplex PCR was performed using a dedicated HRM reagent, and melting curves and temperatures were able to distinguish the four genes. This method was subsequently used to detect these genes in 79 MDRAB isolates from the Third Affiliated Hospital of Southern Medical University in southern China.Results: Using the HRM assay, 73 out of 79 isolates were found to carry both blaoxa-23 and Ade-B, one isolate carried int-1, two isolates carried both int-1 and ISCR-1, and three isolates carried Ade-B, int-1, and ISCR-1. No isolates carried all four genes. Conclusion: Compared with traditional resistance gene detection methods–PCR and agarose gel electrophoresis-based resistance gene detection methods–the multiplex PCR and HRM assay method was simple, rapid, highly efficient, and cost-effective. Our results showed that blaoxa-23 and Ade-B were the main resistance genotypes in MDRAB.Keywords: blaoxa-23, Ade-B, int-1, ISCR-1, multiplex PCR, high resolution melting

Zhenyu Pan,1–3,* Qingting Bu,4,* Haisheng You,5 Jin Yang,1,2 Qingqing Liu,1,2 Jun Lyu1,2 1Clinical Research Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, People’s Republic of China; 3Department of Pharmacy, The Affiliated Children Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 4Department of Genetics, Northwest Women’s and Children’s Hospital, Xi’an, Shaanxi, People’s Republic of China; 5Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China *These authors contributed equally to this work Objective: Previous studies showed that the lymph node density (LND) was a predictor of survival in Wilms’ tumor (WT). However, the optimal LND cutoff point is controversial due to methodological shortcomings of previous studies, and no studies have shown the effect of LND on survival in children with WT. The purpose of this study was to remedy this situation.Methods: We identified 376 children with WT. LND cutoff point was determined using the median value, the X-tile program, the survival-tree algorithm, and the time-dependent ROC curve analysis. Survival functions were estimated by the Kaplan–Meier method. We used Cox regression analysis to determine the impact of LND on survival. Smooth curve fitting between relative mortality risk and LND was performed.Results: The LND cutoff point was 0.44, 0.65, 0.65, and 0.64 according to the median value, the X-tile program, the survival-tree algorithm, and the time-dependent ROC curve analysis, respectively. The 5-, 10-, and 20-year overall survival rates were 86.9%, 86.9%, and 84.7%, respectively, in the

Shi-yin Xiao,1 Ji Zhang,2,* Zheng-quan Zhu,3,* You-ping Li,4,* Wei-ying Zhong,5 Jian-bin Chen,6 Zhen-yu Pan,7 Hai-chen Xia3 1Department of Neurosurgery, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China; 2Department of Neurosurgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; 3Department of Neurosurgery, Tumor Hospital Affiliated of Xinjiang Medical University, Xinshi District, Urumqi, Xinjiang 830011, China; 4Department of Neurosurgery, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330046, China; 5Department of Neurosurgery, Qilu Hospital, Shandong University, Jinan 250012, China; 6Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; 7Department of Radiation-Oncology, First Hospital of Jilin University, Changchun 130021, China *These authors contributed equally to this work Objective: Surgical resection serves an important role in the multidisciplinary treatment of cerebral metastases (CMs). Conventional white-light, microsurgical, and circumferential stripping of CMs is standard neurosurgical procedure, but is associated with a high recurrence rate. Based on this outcome, there is an urgent need for a new surgical strategy, such as fluorescence-guided resection, for CMs, in order to achieve total removal. Methods: A retrospective study was carried out in 38 patients clinically and pathologically diagnosed with breast cancer brain metastasis at three medical centers from May 2012 to June 2016. The study comprised group 1 (fluorescein-guided surgery) and group 2 (standard microsurgery). In group 1, 5 mg/kg of fluorescein sodium was injected intravenously after an allergy test and before general anesthesia for 17 patients. A yellow 560 filter was employed for microsurgical tumor resection. Group 2 consisted of 21 patients for whom fluorescein was not administered. Results: Surgical outcomes were assessed concerning the extent of resection and Karnofsky performance status. Gross total resection was achieved in these patients, with high fluorescence markedly enhancing tumor visibility. The extent of resection had a powerful influence on performance status. Overall survival after CM was 24.1 months in patients given fluorescein and was 22.8 months in the nonfluorescein group. Conclusion: Fluorescein-guided surgery is a simple, safe, and practical method to resect breast cancer brain metastasis, and leads to a higher proportion of resection compared to common microsurgery. This offers a tremendous advantage when navigating a tiny tumor, and improves the quality of life of patients with CM. Keywords: fluorescein sodium, breast cancer brain metastasis, fluorescence-guided surgery, extent of resection, KPS

Lu Li,1,* Zongfu Pan,2,* Si Yang,1 Wenya Shan,1 Yanyan Yang1 1Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China *These authors contributed equally to this work Purpose: The number of people with type 2 diabetes (T2D) is growing rapidly worldwide. Islet β-cell dysfunction and failure are the main causes of T2D pathological processes. The aim of this study was to elucidate the underlying pathways and coexpression networks in T2D islets. Materials and methods: We analyzed the differentially expressed genes (DEGs) in the data set GSE41762, which contained 57 nondiabetic and 20 diabetic samples, and developed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Protein–protein interaction (PPI) network, the modules from the PPI network, and the gene annotation enrichment of modules were analyzed as well. Moreover, a weighted correlation network analysis (WGCNA) was applied to screen critical gene modules and coexpression networks and explore the biological significance. Results: We filtered 957 DEGs in T2D islets. Then GO and KEGG analyses identified that key pathways like inflammatory response, type B pancreatic cell differentiation, and calcium ion-dependent exocytosis were involved in human T2D. Three significant modules were filtered from the PPI network. Ribosome biogenesis, extrinsic apoptotic signaling pathway, and membrane depolarization during action potential were associated with the modules, respectively. Furthermore, coexpression network analysis by WGCNA identified 13 distinct gene modules of T2D islets and revealed four modules, which were strongly correlated with T2D and T2D biomarker hemoglobin A1c (HbA1c). Functional annotation showed that these modules mainly enriched KEGG pathways such as NF-kappa B signaling pathway, tumor necrosis factor signaling pathway, cyclic adenosine monophosphate signaling pathway, and peroxisome proliferators-activated receptor signaling pathway. Conclusion: The results provide potential gene pathways and underlying molecular mechanisms for the prevention, diagnosis, and treatment of T2D. Keywords: type 2 diabetes, islet β cell, bioinformatics analysis, differentially expressed genes, WGCNA

Deting Xue,1,* Erman Chen,1,* Huiming Zhong,2,* Wei Zhang,1 Shengdong Wang,1 Muhammad Umar Joomun,1 Tianyi Yao,3 Yanbin Tan,1 ShiSheng Lin,3 Qiang Zheng,1 Zhijun Pan1 1Department of Orthopaedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, People’s Republic of China; 2Department of Emergency, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, People’s Republic of China; 3Department of Information Science and Electronic Engineering and State Key Laboratory of Modern Optical Instrumentation, Zhejiang University, Hangzhou 310027, People’s Republic of China *These authors contributed equally to this work Background: The osteo-immunomodulatory properties of biomaterials play an important role in the outcomes of bone regeneration. Graphene oxide (GO) has been widely applied in many research fields due to its unique properties. However, the immunomodulatory properties of GO as a biomaterial for bone tissue engineering are still unclear. Materials and methods: In this study, we evaluated the Inflammatory response of RAW264.7 cells influenced by GO. Then the osteogenic differentiation of BMSCs, and angiogenic differentiation of human umbilical vein endothelial cells (HUVECs) by stimulation with GO/RAW 264.7-conditioned culture medium were accessed. We also further investi­gated the possible mechanisms underlying the osteo- and angio-immunomodulatory effects of GO. Results: Our results showed that GO stimulates the secretion of oncostatin M, tumor necrosis factor alpha and other factors through the nuclear factor-κB pathway. GO/RAW264.7-conditioned medium promoted the osteogenic differentiation of BMSCs, stimulated upregulation of the HUVECs of vascular-related receptors, and promoted their tube formation in vitro. Conclusion: In conclusion, our research shows that GO, as a biomaterial, can induce the formation of a beneficial osteo-immunomodulatory environment and is a promising biomaterial for bone tissue engineering. Keywords: graphene oxide, osteo-immunomodulatory, bone marrow mesenchymal stem cells, osteogenesis, angiogenesis, RAW264.7 cells, HUVECs

Jianhong Peng,1,* Cong Li,1,* Fulong Wang,1 Huizhong Zhang,2 Weiwei Xiao,3 Hui Li,4 Zhenhai Lu,1 Zhizhong Pan,1 Xiaojun Wu,1 Rongxin Zhang1 1Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China; 2Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China; 3Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China; 4Department of Gynecological Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510060, People’s Republic of China *These authors contributed equally to this work Background: Growing evidence has suggested that right-sided colon cancer (RCC) and left-sided colon cancer (LCC) should be considered as different tumor entities. However, stage III colon cancer is currently treated as the same entity with uniform therapy. This study was aimed at investigating the prognostic influence of tumor location in patients with stage III colon cancer receiving adjuvant chemotherapy after curative resection.Patients and methods: We retrospectively analyzed 274 eligible patients with stage III colon cancer undergoing curative tumor resection followed by adjuvant chemotherapy with oxaliplatin and capecitabine between December 2007 and December 2013. Disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan–Meier and log-rank tests, and prognostic factors were identified by Cox regression methods.Results: Patients with RCC exhibited lower hemoglobin levels (23.6% vs. 9.8%; P = 0.002), larger tumor size (60.6% vs. 40.9%; P = 0.001), and a higher proportion of 12 or more resected lymph nodes (86.4% vs. 64.6%; P < 0.001) than patients with LCC. Grade 1 neurotoxicity was more common in patients with RCC than in those with LCC (53.6% vs. 40.9%; P = 0.037). RCC was significantly associated with a shorter 3-year OS than LCC, whereas a difference was noted only for stage IIIC and not stage IIIA or stage IIIB colon cancer. Multivariate analyses revealed that RCC was independently associated with a worse 3-year OS (hazard ratio: 2.213; 95% CI: 1.063–4.606; P = 0.002). In addition, an increase in 3-year OS and DFS after 6–8 cycles of adjuvant chemotherapy was only observed in patients with RCC and not in those with LCC.Conclusion: This study indicated that RCC has a worse prognostic outcome for stage III colon cancer, and a full course of adjuvant chemotherapy should be suggested for patients with RCC. Keywords: left-sided colon cancer, right-sided colon cancer, stage III, adjuvant chemotherapy, outcome, colon cancer, location, resection, prognosis

Haisheng You,1,* Jin Yang,2,3,* Qingqing Liu,2,3 Lina Tang,1 Qingting Bu,4 Zhenyu Pan,5 Jun Lyu2,3 1Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Clinical Research Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, People’s Republic of China; 4Department of Genetics, Northwest Women’s and Children’s Hospital, Xi’an, Shaanxi, People’s Republic of China; 5Department of Pharmacy, The Affiliated Children Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China *These authors contributed equally to this work Objective: The objective of this study was to determine the impact of the lymph node density (LND) on overall survival of patients with Wilms’ tumor (WT) using the Surveillance, Epidemiology, and End Results (SEER) database.Methods: Data from the SEER database were extracted from patients with WT in whom the LND could be obtained. Patients were divided into a low LND group and high LND group. Survival curves based on the LND stratification were plotted using the Kaplan–Meier method and compared with the log-rank test. The impact of prognostic factors on overall survival was analyzed using Cox regression models.Results: A total of 1,924 patients were identified from the database. Overall survival for the low LND group at 5, 10, and 20 years was significantly better than the high LND group (5-year survival: 94.1% vs 81.4%; 10-year survival: 92.6% vs 80.8%; 20-year survival: 90.6% vs 79.1%; P

Zhi-Ming Pan,1 Hai-Jun Li,1 Jing Bao,1 Nan Jiang,1 Qing Yuan,1 Shelby Freeberg,2 Pei-Wen Zhu,1 Lei Ye,1 Ming-Yang Ma,1 Xin Huang,1 Yi Shao1 1Department of Ophthalmology and Radiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Ophthalmology, University of Florida, Gainesville, FL, USA Objective: Many previous studies have reported that pain symptoms can lead to significant brain function and anatomical changes, whereas the intrinsic brain activity changes in acute eye pain (EP) patients remain unknown. Using the amplitude of low-frequency fluctuation (ALFF) method, this study aimed to evaluate the spontaneous brain activity alterations and their relationships with clinical features in acute EP patients.Participants and methods: A total of 20 patients with EP (15 males and 5 females) and 20 healthy controls (HCs; 15 males and 5 females) closely matched in age, sex, and education underwent resting-state functional magnetic resonance imaging scans. The ALFF method was applied to assess spontaneous brain activity changes. The ALFF values of the EP patients were distinguished from those of the HCs using a receiver operating characteristic curve. Pearson’s correlation analysis was used to investigate the relationships between the mean ALFF signal values from many brain regions and the clinical features in EP patients.Results: Compared with the HCs, acute EP patients had significantly lower ALFF in the left and right precentral/postcentral gyrus and left precuneus. In contrast, acute EP patients showed higher ALFF values in the right and left parahippocampal gyri and left caudate. However, no relationship was observed between the mean ALFF signal values from the different areas and clinical manifestations in the acute EP patients.Conclusion: We demonstrated that acute EP patients showed abnormal intrinsic brain activities in the precentral/postcentral gyrus and limbic system, which might provide useful information for explaining neural mechanisms in EP patients. Keywords: eye pain, ALFF, blood oxygenation level dependent, resting state, functional magnetic resonance imaging

Yu-Jie Zhao,1 Wei-Peng Sun,2 Jian-Hong Peng,1 Yu-Xiang Deng,1 Yu-Jing Fang,1 Jun Huang,2 Hui-Zhong Zhang,3 De-Sen Wan,1 Jun-Zhong Lin,1,* Zhi-Zhong Pan,1,* 1Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 2Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 3Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China *These authors contributed equally to this work Objective: Increased expression of programmed death-ligand 1 (PD-L1) on tumor cells can be found in various malignancies; however, very limited information is known about its role in anal squamous cell carcinoma (ASCC). This study explored PD-L1 expression in ASCC patients and its association with patients’ clinicopathological features, CD8+ T cell infiltration, and prognosis.Methods: Formalin-fixed paraffin-embedded tumor samples from 26 patients with ASCC were retrieved. The levels of PD-L1 expression on the membrane of both tumor cells and tumor-infiltrating mononuclear cells (TIMCs) were evaluated by immunohistochemistry. CD8+ T cell densities, both within tumors and at the tumor–stromal interface, were also analyzed. Baseline clinicopathological characteristics, human papilloma virus (HPV) status, and outcome data correlated with PD-L1-positive staining.Results: PD-L1 expression on tumor cells and TIMCs was observed in 46% and 50% of patients, respectively. Nineteen patients (73%) were HPV positive, with 7 showing PD-L1-positive staining on tumor cells and 9 showing PD-L1-positive staining on TIMCs. Increasing CD8+ density within tumors, but not immune stroma, was significantly associated with decreased PD-L1 expression by both tumor cells and TIMCs (P=0.0043 and P=0.0007). Patients with negative PD-L1 expression had significantly better progression-free survival (P=0.038 and P=0.0443) and a non-statistically significant trend toward longer overall survival (P=0.0882 and P=0.1222) compared with patients with positive PD-L1 expression.Conclusion: PD-L1 is widely expressed on the membrane of tumor cells and TIMCs in ASCCs. Its negative impact on prognosis may be due to the diminished CD8+ T cell infiltration within tumors. Keywords: CD8, PD-L1, HPV, tumor infiltrating mononuclear cells