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Haoyang Xin,1,&ast; Man Wang,2,&ast; Shuo Wang,3 Haiyan Han,3 Nan Jiang1 1Department of Nephrology and Rheumatology, Second Affiliated Hospital of Tianjin University of TCM, Tianjin, People’s Republic of China; 2Department of Pharmacy, Tianjin Forth Central Hospital, Tianjin, People’s Republic of China; 3Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nan Jiang, Department of Nephrology and Rheumatology, Second Affiliated Hospital of Tianjin University of TCM, No. 69, Zengchan Street, Hebei District, Tianjin, 300250, People’s Republic of China, Tel +86 18622997255, Email jingnan_jn@126.comObjective: This study aimed to explore the potential active components and therapeutic targets of Shentong Zhuyu Decoction (SZD) in the treatment of ankylosing spondylitis (AS) through network pharmacology and animal experiments.Methods: Targets for AS and related pathways were obtained by network pharmacology, and the pathways with the best binding affinity in molecular docking were verified by animal experiments.Results: The network pharmacology analysis found 248 chemical components, 1068 drug targets and 803 AS-related targets in SZD. After intersection targets analysis, 116 common drug–disease targets were obtained, and matrix metalloproteinase-9, nucleotide-binding oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) and cytochrome P450 2D6 were identified as the key targets of SZD for the treatment of AS. A total of 2152 biological processes, 38 cellular component expressions and 150 molecular function terms were obtained in gene ontology enrichment analysis, and 153 Kyoto Encyclopedia of Genes and Genomes (KEGG) signalling pathways were obtained in KEGG enrichment analysis. Molecular docking analysis showed that the absolute binding energies of glypallichalcone and NLRP3, quercetin and NLRP3 and kaempferol and NLRP3 were > 7. Animal experiments showed that the expressions of NLRP3, Caspase-1, interleukin (IL)-1β and IL-18 were significantly increased in the model group and the treatment group compared with those in the blank group, and the expression levels in the treatment group were significantly decreased compared with those in the model group (p < 0.05).Conclusion: The active components in SZD, such as baicalin, quercetin, kaempferol and glypallichalcone, may reduce the expression of IL-1β and IL-18 via the NLRP3/Caspase-1 signalling pathway to inhibit the development and progression of inflammation and play a role in the treatment of AS.Keywords: Shentong Zhuyu Decoction, ankylosing spondylitis, network pharmacology, mechanism of action

Caigui Yu,1– 3,&ast; Lu Zhong,1– 3,&ast; Yanxiang Zhou,1– 3,&ast; Nan Jiang,1– 3 Jinling Chen,1– 3 Sheng Cao1– 3 1Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 2Hubei Key Laboratory of Cardiology, Wuhan, 430060, People’s Republic of China; 3Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinling Chen; Sheng Cao, Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, 238&num; Jiefang Road, Wuhan, 430060, People’s Republic of China, Email jenny2774@163.com; caosheng209@126.comObjective: To explore the feasibility of using cRGD-GNR-PFP-NPs to assess plaque vulnerability in an atherosclerotic plaque mouse model by dual-modal photoacoustic/ultrasonic imaging.Methods: A nanomolecular probe containing gold nanorods (GNRs) and perfluoropentane (PFP) coated with the cyclic Arg-Gly-Asp (cRGD) peptide were prepared by double emulsion solvent evaporation and carbodiimide methods. The morphology, particle size, potential, cRGD conjugation and absorption features of the nanomolecular probe were characterized, along with its in vitro phase transformation and photoacoustic/ultrasonic dual-modal imaging properties. In vivo fluorescence imaging was used to determine the distribution of cRGD-GNR-PFP-NPs in vivo in apolipoprotein E-deficient (ApoE−/−) atherosclerotic plaque model mice, the optimal imaging time was determined, and photoacoustic/ultrasonic dual-modal molecular imaging of integrin αvβ 3 expressed in atherosclerotic plaques was performed. Pathological assessments verified the imaging results in terms of integrin αvβ 3 expression and plaque vulnerability.Results: cRGD-GNR-PFP-NPs were spherical with an appropriate particle size (average of approximately 258.03± 6.75 nm), a uniform dispersion, and a potential of approximately − 9.36± 0.53 mV. The probe had a characteristic absorption peak at 780~790 nm, and the surface conjugation of the cRGD peptide reached 92.79%. cRGD-GNR-PFP-NPs were very stable in the non-excited state but very easily underwent phase transformation under low-intensity focused ultrasound (LIFU) and had excellent photoacoustic/ultrasonic dual-modal imaging capability. Mice fed a high-fat diet for 20 weeks had obvious hyperlipidemia with larger, more vulnerable plaques. These plaques could be specifically targeted by cRGD-GNR-PFP-NPs as determined by in vivo fluorescence imaging, and the enrichment of nanomolecular probe increased with the increasing of plaque vulnerability; the photoacoustic/ultrasound signals of the plaques in the high-fat group were stronger. The pathological assessments were in good agreement with the cRGD-GNR-PFP-NPs plaque accumulation, integrin αvβ 3 expression and plaque vulnerability results.Conclusion: A phase variant photoacoustic/ultrasonic dual-modal cRGD nanomolecular probe was successfully prepared and can be used to identify plaque vulnerability safely and effectively.Keywords: atherosclerosis, vulnerability, photoacoustic, ultrasound, low-intensity focused ultrasound

Xin Qiu,1,2,&ast; Shuang Shen,1,&ast; Donghong Lu,2 Nizhen Jiang,3 Yifei Feng,3 Jindu Li,1 Chenglei Yang,1 Bangde Xiang1,4,5 1Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 2Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 3Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 4Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, People’s Republic of China; 5Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bangde Xiang; Chenglei Yang, Email xiangbangde@gxmu.edu.cn; chenglei2017yang@163.comBackground: Hepatocellular carcinoma (HCC) presents a significant global health challenge due to its poor prognosis and high recurrence rates post-surgery. This study examines the predictive efficacy of the Advanced Lung Cancer Inflammation Index (ALI) in assessing the post-hepatectomy prognosis of patients with HCC.Methods: A cohort comprising 1654 HCC patients who underwent hepatectomy at Guangxi Medical University Cancer Hospital from 2013 to 2019 was enrolled. Patients were stratified into two groups according to the median ALI level, and then subjected to propensity score matching (PSM) in a 1:1 ratio. Kaplan-Meier survival curves, the traditional Cox proportional hazards (CPH) model, and machine learning (ML) models were employed to analyze and evaluate ALI’s prognostic significance. Furthermore, ALI’s prognostic value in digestive system tumors was validated via analysis of the National Health and Nutrition Examination Survey (NHANES) database.Results: After applying PSM, a final cohort of 1284 patients, categorized into high and low ALI groups, revealed a significantly reduced survival time in the low ALI cohort. Univariate and multivariate Cox analyses identified ALI, BCLC stage, CK19, Hepatitis B virus (HBV) DNA, lymph node metastasis, and microvascular invasion (MVI) as independent predictors of prognosis. Both traditional CPH and ML models incorporating ALI demonstrated excellent predictive accuracy, validated through calibration curves, time-dependent ROC curves, and decision curve analysis. Furthermore, the prognostic value of ALI in digestive tumors was confirmed in the NHANES database.Conclusion: The ALI exhibits potential as a prognostic predictor in patients with HCC following hepatectomy, providing valuable insights into postoperative survival.Keywords: advanced lung cancer inflammatory index, ALI, hepatocellular carcinoma, HCC, prognosis, Cox regression, machine learning, ML

Zhaohua Xiao,1,&ast; Jiangfeng Zhao,1,&ast; Guanhong Ji,1 Xiangqing Song,1 Xia Xue,2 Wenhao Zhang,1 Guomeng Sha,1 Yongjia Zhou,1 Jie Zhou,1 Zhongxian Tian,1,3 Xiaogang Zhao,1,3 Ning Jiang1 1Department of Thoracic Surgery, the Second Hospital of Shandong University, Jinan, 250033, People’s Republic of China; 2Department of Pharmacy, the Second Hospital of Shandong University, Jinan, People’s Republic of China; 3Key Laboratory of Chest Cancer, Shandong University, the Second Hospital of Shandong University, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning Jiang, Department of Thoracic Surgery, the Second Hospital of Shandong University, Jinan, 250033, People’s Republic of China, Tel +86-17660081908, Email sdujiangning@163.comBackground: Exosomal microRNAs (miRNAs) in the tumor microenvironment play crucial roles in tumorigenesis and tumor progression by participating in intercellular cross-talk. However, the functions of exosomal miRNAs and the mechanisms by which they regulate esophageal squamous cell carcinoma (ESCC) progression are unclear.Methods: RNA sequencing and GEO analysis were conducted to identify candidate exosomal miRNAs involved in ESCC development. Receiver operating characteristic curve analysis was performed to assess the diagnostic value of plasma exosomal miR-493-5p. EdU, tube formation and Transwell assays were used to investigate the effects of exosomal miR-493-5p on human umbilical vein endothelial cells (HUVECs). A subcutaneous xenograft model was used to evaluate the antitumor effects of miR-493-5p and decitabine (a DNA methyltransferase inhibitor). The relationship between miR-493-5p and SP1/SP3 was revealed via a dual-luciferase reporter assay. A series of rescue assays were subsequently performed to investigate whether SP1/SP3 participate in exosomal miR-493-5p-mediated ESCC angiogenesis.Results: We found that miR-493-5p expression was notably reduced in the plasma exosomes of ESCC patients, which showed the high potential value in early ESCC diagnosis. Additionally, miR-493-5p, as a candidate tumor suppressor, inhibited the proliferation, migration and tube formation of HUVECs by suppressing the expression of VEGFA and exerted its angiostatic effect via exosomes. Moreover, we found that SP1/SP3 are direct targets of miR-493-5p and that re-expression of SP1/SP3 could reverse the inhibitory effects of miR-493-5p. Further investigation revealed that miR-493-5p expression could be regulated by DNA methyltransferase 3A (DNMT3A) and DNMT3B, and either miR-493-5p overexpression or restoration of miR-493-5p expression with decitabine increased the antitumor effects of bevacizumab.Conclusion: Exosomal miR-493-5p is a highly valuable ESCC diagnosis marker and inhibits ESCC-associated angiogenesis. miR-493-5p can be silenced via DNA methylation, and restoration of miR-493-5p expression with decitabine increases the antitumor effects of bevacizumab, suggesting its potential as a therapeutic target for ESCC treatment.Keywords: esophageal squamous cell carcinoma, exosomes, miR-493-5p, VEGFA, angiogenesis

Nan Jiang,1,2 Chun Mei Yang,1,2 Jia Le Wang,1,2 Xiao Fei Ye,1 Bin Yang1,2 1Children’s Medical Centre of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2The Fifth Clinical College Affiliated to Anhui Medical University, Hefei, Anhui, People’s Republic of ChinaCorrespondence: Bin Yang, Children’s Medical Centre of Anhui Medical University, The Fifth Clinical College Affiliated to Anhui Medical University, Hefei, People’s Republic of China, Tel +86-13866127496, Email yangbin691202@163.comPurpose: To investigate sleep problems in children with self-limited epilepsy with central temporal spiking (SeLECTS) and to assess the relationship between sleep problems and attention network dysfunction.Patients and methods: 107 children 6– 14 years of age with SeLECTS and 90 age- and sex-matched healthy controls were recruited for this study. The sleep status of these participants was evaluated using the Children’s Sleep Habits Questionnaire (CSHQ), while attentional network function was assessed with the attention network function test (ANT).Results: Together, these analyses revealed that children with SeLECTS exhibited higher total CSHQ scores and sleep disorder incidence relative to healthy controls (P< 0.001). Children with SeLECTS had higher scores in delayed sleep onset, sleep duration, night awakenings, parasomnias, daytime sleepiness and sleep anxiety (P< 0.01). Total CSHQ scores were negatively correlated with average ANT correct rates (ρ= − 0.253, P< 0.01), while they were positively correlated with total reaction time (ρ=0.367, P< 0.01) and negatively correlated with the efficiency of the alerting and executive control networks (ρ=− 0.344 P< 0.01; ρ=− 0.418 P< 0.01).Conclusion: Children with SeLECTS face a higher risk of experiencing sleep disorders relative to age-matched healthy children, while also demonstrating that the magnitude of the impairment of attentional network function in these children is positively correlated with sleep disorder severity. Thus, the prognosis and quality of life of children with SeLECTS can be improved by interventions addressing sleep disorders.Keywords: SeLECTS, attention network function, sleep disorders, CSHQ

Nan Jiang,1,&ast; Wei Jin,2,&ast; Zhenghui Fu,3,&ast; He Cao,1 Hong Zheng,3 Quqing Wang,1 Qiongting Zhang,3 Kang Ju,3 Jiwei Wang1 1Key Laboratory of Health Technology Assessment of Ministry of Health, School of Public Health, Fudan University, Shanghai, People’s Republic of China; 2Department of Patriotic Public Health and Health Promotion instruction, Shanghai Municipal Center for Health Promotion, Shanghai, People’s Republic of China; 3Shanghai Changning Mental Health Center (Affiliated to East China Normal University), Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiwei Wang, Key Laboratory of Health Technology Assessment of Ministry of Health, School of Public Health, Fudan University, Shanghai, People’s Republic of China, Email jiweiwang@fudan.edu.cn Kang Ju, Shanghai Changning Mental Health Center (Affiliated to East China Normal University), Shanghai, People’s Republic of China, Email jukang2009@163.comPurpose: This study aims to explore the serial mediating effect of stigma and depression on the association between social support and medication adherence.Patients and Methods: A cross-sectional survey was undertaken in the Changning District of Shanghai using a five-part questionnaire from August to December 2023. A convenient sampling method was employed, and 35 patients with schizophrenia were invited from each of the 9 streets in Changning District to participate in the survey, resulting in a total of 305 valid questionnaires collected. The questionnaire measured social support, stigma, depression, medication adherence, and demographic characteristics. Data analysis involved descriptive statistics, independent samples t-tests, ANOVA, Pearson correlation analysis, and the bootstrap method.Results: There was a direct and significantly positive association between social support and medication adherence (β = 0.69, p < 0.001). Moreover, increased levels of stigma (β = - 0.45, p = 0.013) and depression (β = - 0.09, p = 0.017) were both associated with a decline in medication adherence. Bootstrapping analysis revealed that the association between social support and medication adherence operated indirectly through stigma (β = 0.11, 95% CI: 0.03, 0.18). Additionally, social support was indirectly associated with medication adherence through depression (β = 0.15, 95% CI: 0.04, 0.30). Further analysis indicated that social support had an indirect association with medication adherence through both stigma and depression (β = 0.04, 95% CI: 0.01, 0.07).Conclusion: Stigma and depression serially mediate the association between social support and medication adherence among patients with schizophrenia. This serial multiple mediation model underscores the importance of integrating social support interventions with psychological interventions aimed at reducing stigma and depression, thereby effectively enhancing medication adherence in patients with schizophrenia.Keywords: social support, stigma, depression, medication adherence, schizophrenia

Qian Yang,1 Lingfeng Liu,1 Jing Wang,2 Ying Zhang,2 Nan Jiang,3 Meiyun Zhang2 1Tianjin Union Medical Center, Tianjin Medical University, Tianjin, 300070, People’s Republic of China; 2Department of Neurology, Tianjin Union Medical Center, Tianjin, 300121, People’s Republic of China; 3School of Mechanical Engineering, Tianjin University, Tianjin, 300354, People’s Republic of ChinaCorrespondence: Meiyun Zhang, Email zmy22202@aliyun.comObjective: To investigate the changes in the wavelet entropy during wake and different sleep stages in patients with insomnia disorder.Methods: Sixteen patients with insomnia disorder and sixteen normal controls were enrolled. They underwent scale assessment and two consecutive nights of polysomnography (PSG). Wavelet entropy analysis of electroencephalogram (EEG) signals recorded from all participants in the two groups was performed. The changes in the integral wavelet entropy (En) and individual-scale wavelet entropy (En(a)) during wake and different sleep stages in the two groups were observed, and the differences between the two groups were compared.Results: The insomnia disorder group exhibited lower En during the wake stage, and higher En during the N3 stage compared with the normal control group (all P < 0.001). In terms of En(a), patients with insomnia disorder exhibited lower En(a) in the β and α frequency bands during the wake stage compared with normal controls (β band, P < 0.01; α band, P < 0.001), whereas they showed higher En(a) in the β and α frequency bands during the N3 stage than normal controls (β band, P < 0.001; α band, P < 0.001).Conclusion: Wavelet entropy can reflect the changes in the complexity of EEG signals during wake and different sleep stages in patients with insomnia disorder, which provides a new method and insights about understanding of pathophysiological mechanisms of insomnia disorder. Wavelet entropy provides an objective indicator for assessing sleep quality.Keywords: insomnia disorder, sleep stages, wavelet entropy, polysomnography

Shu-Tong Huang,1,2,&ast; Jin-Chong Luo,1,3,&ast; Guo-Hui Zhong,1,2 Li-Ping Teng,4 Cai-Yan Yang,4 Chun-Li Tang,1 Lin Jing,1 Zhong-Bo Zhou,4 Jing Liu,1,3 Neng Jiang1,2 1Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People’s Republic of China; 2Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 3School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China; 4School of Pharmacy, Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Liu, School of Pharmacy, Jiangxi University of Chinese Medicine, No. 56, Yangming Road, Donghu District, Nanchang, Jiangxi, 330006, People’s Republic of China, Email liujing860828@163.com Neng Jiang, Department of Pharmacy, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Qingxiu District, Nanning, Guangxi, 530021, People’s Republic of China, Tel/Fax +86-17307711726, Email cpujnh@163.comPurpose: Alzheimer’s disease (AD) is the most common neurodegenerative disease, and its multifactorial nature increases the difficulty of medical research. To explore an effective treatment for AD, a series of novel tacrine-selegiline hybrids with ChEs and MAOs inhibitory activities were designed and synthesized as multifunctional drugs.Methods: All designed compounds were evaluated in vitro for their inhibition of cholinesterases (AChE/BuChE) and monoamine oxidases (MAO-A/B) along with their blood-brain barrier permeability. Then, further biological activities of the optimizing compound 7d were determined, including molecular model analysis, in vitro cytotoxicity, acute toxicity studies in vivo, and pharmacokinetic and pharmacodynamic property studies in vivo.Results: Most synthesized compounds demonstrated potent inhibitory activity against ChEs/MAOs. Particularly, compound 7d exhibited good and well-balanced activity against ChEs (hAChE: IC50 = 1.57 μM, hBuChE: IC50 = 0.43 μM) and MAOs (hMAO-A: IC50 = 2.30 μM, hMAO-B: IC50 = 4.75 μM). Molecular modeling analysis demonstrated that 7d could interact simultaneously with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE in a mixed-type manner and also exhibits binding affinity towards BuChE and MAO-B. Additionally, 7d displayed excellent permeability of the blood-brain barrier, and under the experimental conditions, it elicited low or no toxicity toward PC12 and BV-2 cells. Furthermore, 7d was not acutely toxic in mice at doses up to 2500 mg/kg and could improve the cognitive function of mice with scopolamine-induced memory impairment. Lastly, 7d possessed well pharmacokinetic characteristics.Conclusion: In light of these results, it is clear that 7d could potentially serve as a promising multi-functional drug for the treatment of AD. Keywords: Alzheimer’s disease, cholinesterase, monoamine oxidase, multi-target, designed

Guan-Qiao Liu,1,2,&ast; Peng Chen,1,3,&ast; Mou-Zhang Huang,1,4 Ming-Rui Song,2 Chen-Sheng Song,1 Run-Jiu Zhu,1 Jun Xiong,3 Nan Jiang,1,2 Bin Yu1,2 1Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Orthopaedics, Hainan General Hospital, Hainan Hospital affiliated to Hainan Medical University, Haikou, People’s Republic of China; 4Department of Orthopaedics and Traumatology, Ganzhou Hospital Affiliated to Nanfang Hospital, Southern Medical University, Ganzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nan Jiang; Bin Yu, Division of Orthopaedics & Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515, People’s Republic of China, Email hnxyjn@smu.edu.cn; yubin@smu.edu.cnBackground: Current information were still limited regarding clinical characteristics, diagnosis, and treatment efficacy of calcaneal osteomyelitis (CO). The present study summarized similarities and differences between diabetes-related CO (DRCO) and trauma-related CO (TRCO) based on synthesis analysis of literature-reported cases.Methods: We searched the PubMed, Embase, and Cochrane Library databases to find English studies reporting DRCO and TRCO published between January 2000 and December 2021. Effective data were extracted and synthesized for comparisons.Results: Altogether 108 studies with 278 DRCO and 403 TRCO patients were analyzed. The ratio of females among the DRCO patients was significantly higher than that of the TRCO patients (37.4% vs 24.3%, P < 0.001). The median age at diagnosis of the DRCO patients was statistically older than the TRCO patients (56 vs 44 years, P < 0.001). The median symptom duration of the DRCO patients was longer than the TRCO patients (4 vs 2 months, P = 0.136), with ulcer and sinus as the top symptoms for the DRCO and TRCO patients, respectively. The positive rate of pathogen culture for the DRCO patients was significantly higher than that for the TRCO patients (94.8% vs 69.5%, P < 0.001). The DRCO patients had higher risks of infection relapse (32.3% vs 16.3%, P < 0.001) and amputation (24.8% vs 1.4%, P < 0.001), and a higher all-cause mortality (4.9% vs 1.3%, P = 0.03) than the TRCO patients.Conclusion: DRCO and TRCO shared similar and different clinical features and diagnostic issues. However, compared with TRCO, the clinical efficacy and prognosis of DRCO were worse.Keywords: calcaneal osteomyelitis, diabetic foot, post-traumatic osteomyelitis, fracture-related infection, synthesis analysis

Hui Gao,1,&ast; Nan Jiang,2,&ast; Qiannan Niu,3 Shenglin Mei,4,5 Håvard Jostein Haugen,6 Qianli Ma6,7 1Department of Stomatology, the Eighth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Department of Community Dentistry, Institute of Clinical Dentistry, University of Oslo, Oslo, Norway; 3State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China; 4Xingrui Dental Clinic, Xi’an, Shaanxi Province, People’s Republic of China; 5Department of Physics & Materials Science, City University of Hong Kong, Hong Kong, People’s Republic of China; 6Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Oslo, Norway; 7Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Håvard Jostein Haugen; Qianli Ma, Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Oslo, 0317, Norway, Email h.j.haugen@odont.uio.no; qianlima@odont.uio.noIntroduction: Titanium (Ti) and its alloys are widely utilized in endosseous implants. However, their clinical efficacy is marred by complications arising from bacterial infections owing to their inadequate antibacterial properties. Consequently, enhancing the antibacterial attributes of implant surfaces stands as a pivotal objective in the realm of implantable materials research.Methods: In this study, we employed sequential anodization and plasma immersion ion implantation (PIII) technology to fabricate a silver-embedded sparsely titania nanotube array (SNT) on the near-β titanium alloy Ti-5Zr-3Sn-5Mo-15Nb (TLM) implants. The surface characteristics, antimicrobial properties, biocompatibility, and osteogenic activity of the silver-nanomodified SNT implant (SNT Ag) surface, alongside peri-implant inflammatory responses, were meticulously assessed through a combination of in vitro and in vivo analyses.Results: Compared with polished TLM and SNT, the silver-embedded SNT (SNT Ag) surface retained the basic shape of nanotubes and stably released Ag+ at the ppm level for a long time, which demonstrated an effective inhibition and bactericidal activity against Staphylococcus aureus (SA) while maintaining ideal cytocompatibility. Additionally, the subtle modifications in nanotubular topography induced by silver implantation endowed SNT Ag with enhanced osteogenic activity and mitigated inflammatory capsulation in soft tissue peri-implants in a rat model.Conclusion: Incorporating a silver-embedded SNT array onto the implant surface demonstrated robust antibacterial properties, impeccable cytocompatibility, exceptional osteogenic activity, and the potential to prevent inflammatory encapsulation around the implant site. The Silver-PIII modification strategy emerges as a highly promising approach for surface applications in endosseous implants and trans-gingival implant abutments.Keywords: implant surface modification, silver PIII, anti-bacterial activity, cytocompatibility, osteogenic differentiation, host inflammatory response

Nannan Jiang,1– 3 Li Xiang,1– 3 Hui Guan,1– 3 Xudong Zhang1– 3 1Department of Allergy, Beijing Children′s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 2Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, People’s Republic of China; 3China National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of ChinaCorrespondence: Li Xiang, Department of Allergy, Beijing Children′s Hospital, Capital Medical University, National Center for Children′s Health, No. 56 Nanlishi Road, Xicheng District, Beijing, 100045, People’s Republic of China, Tel/Fax +861059616934, Email dr_xiangli2022@126.comPurpose: Fruits have been identified as the primary triggers of anaphylaxis in older children in the Chinese population, especially among individuals with pollen sensitization. To date, no allergies have been reported after blueberry ingestion in the Chinese population.Case Report: A 12-year-old girl experienced one episode of anaphylaxis within 30 minutes of having breakfast (including milk, egg, wheat bread, and blueberry) while walking to school. She menstruated during this episode. Prompt treatment with epinephrine and fluid therapy led to full recovery within 24 h. Specific IgE was conducted using ImmunoCAP, and the patient exhibited sensitization to several pollens, mainly Japanese hop (74.3 kUa/L) and mugwort (26.5 kUa/L). Regarding specific IgE to allergen components, the patient showed sensitization primarily to lipid transfer protein (LTP) components from mugwort Art v 3 (79.7 kUa/L), wheat Tri a 14 (12.4 kUa/L) and peach Pru p 3 (2.15 kUa/L), but tested negative for omega-5 gliadin. The prick test results were positive for blueberries (wheal size 9.5 mm), cherries (wheal size 6.5 mm), kiwifruits (wheal size 6 mm), and pears (wheal size 4.5 mm). Our patient was provided with an epi-pen and was advised to avoid consuming relevant fruits. After four months of follow-up, the patient had not experienced any episodes of anaphylaxis since these recommendations were implemented.Conclusion: We report for the first time a Chinese child with severe IgE-mediated immediate-type anaphylactic reaction to blueberries, in whom we identified LTP as the suspected allergen component.Keywords: anaphylaxis, lipid transfer protein, food allergy

Yan Lan,1,2,&ast; Yu-Kun Zheng,3,&ast; Liu-Yi Wu,3 Zi-Jun Zhou,3 Ruo-Xin Guan,3 Heng Xu,3 Ji-Yuan Tu,3 Xin Gu,3 Rui Wang,3 Nan Jiang,3 Yuan Wu,4 Cheng-Ren Shu,1,2 Zhong-Shi Zhou3 1Department of Pharmacy, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, Hubei, People’s Republic of China; 2Hubei Key Laboratory of Kidney Disease Pathogenesis and Intervention, Hubei, People’s Republic of China; 3College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, People’s Republic of China; 4Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cheng-Ren Shu, Department of Pharmacy, Huangshi Central Hospital, NO. 141, Tianjin Road, Huangshi, Hubei, People’s Republic of China, Tel +86-27-13986590438, Email 397112615@qq.com Zhong-Shi Zhou, College of Pharmacy, Hubei University of Chinese Medicine, No. 1, Huangjiahu West Road, Hongshan District, Wuhan City, Hubei Province, People’s Republic of China, Tel +86-27-15871745189, Email monkeyzzs@126.comObjective: Traditional Chinese medicine Polygonum cuspidatum (PC) has significant effects on reducing pain. In this study, we investigated the analgesic effects of the alcohol extract of PC on three types of inflammatory pain and explored its mechanism.Methods: Potential targets for the analgesic effects of the main active components of PC alcohol extract were screened by network pharmacology and molecular docking. Three different inflammatory pain mouse models (acetic acid twisting, formalin foot swelling, and xylene ear swelling) were used to study the analgesic effects of PC. The expression of latent signaling pathways in L4-6 spinal cord tissues in formalin foot swelling mice was evaluated using real-time qPCR (RT-qPCR), Western blot (WB), and immunohistochemistry (IHC) analyses.Results: Network pharmacology analysis shows that PC analgesic mechanism is related to the MAPK/ERK signaling pathway. The five main active components of PC have good docking ability with JNK and p38. PC alcohol extract significantly reduced the pain behavior and alleviated inflammatory reactions in three mouse models, inhibited the mRNA and protein phosphorylation levels of JNK, ERK, p38, and CREB in spinal cord tissues.Conclusion: PC alcohol extract can inhibit inflammation and alleviate pain, which is related to its inhibition of the MAPK/ERK signaling pathway in spinal cord. Thus, PC alcohol extract is a promising candidate for pain treatment.Keywords: Polygonum cuspidatum, network pharmacology, MAPK/ERK, analgesic

Lu Liu,1,&ast; Xiaojiu Zhang,1,2,&ast; Nan Jiang,3,&ast; Yufeng Liu,1 Qing Wang,1 Guanghui Jiang,1 Xuejing Li,4 Liandong Zhao,1 Qijin Zhai1 1Department of Neurology, Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China; 2Department of Neurology, Hongze People’s Hospital, Huai’an, Jiangsu, People’s Republic of China; 3Department of Neurology, Lianshui PEople’s Hospital Affiliated to Kangda College of Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China; 4Rehabilitation Centre, Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liandong Zhao; Qijin Zhai, Email zld18796201519@163.com; qjzhai1983@163.comPurpose: The plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker of cerebral microbleeds (CMBs) and may be related to the occurrence, development, and prognosis of cognitive impairment. The present study aimed to investigate the impact of plasma Lp-PLA2 level on the cognitive impairment in patients with CMBs.Methods: In this study, 213 patients with CMBs confirmed by 3.0 T brain magnetic resonance imaging (MRI) were analyzed. Lp-PLA2 levels were determined by magnetic particle chemiluminescence immunoassay technology, and cognitive function was assessed using the Montreal Cognitive Assessment Scale (MoCA). The cognitive functions of patients with CMBs were divided into three groups according to the MoCA scale, including normal cognition (NC), mild cognitive impairment (MCI), and moderate-severe cognitive impairment (MSCI). Clinical, laboratory and radiological data of the three groups were analysed. The relationship between plasma Lp-PLA2 and MoCA score in patients with CMBs was investigated through rank correlation analysis and multivariate regression analysis, and receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of Lp-PLA2.Results: CMBs were detected in 213 (30.2%) of 705 patients who underwent 3.0 T MRI. Multiple comparisons showed that plasma Lp-PLA2 in patients with CMBs with normal cognitive scores was significantly lower than that in the other two groups with cognitive impairment (p < 0.05). In the single factor correlation analysis, high level of plasma Lp-PLA2 was negatively correlated with the decrease of MoCA score in patients with CMBs (r =− 0.389, p < 0.01). Multivariate regression analysis showed that high plasma Lp-PLA2 was an independent risk factor for a low MoCA score in patients with CMBs (odds ratio [OR]=1.014; 95% confidence interval [CI], 1.002– 1.026; p=0.025).Conclusion: A high level of plasma Lp-PLA2 is positively correlated with the generation of cognitive impairment in patients with CMBs and negatively correlated with the degree of impairment. Plasma Lp-PLA2 is an important indicator of cognitive impairment in patients with CMBs and may provide a therapeutic target for preventing CMB-induced cognitive impairment.Keywords: cerebral microbleeds, lipoprotein-associated phospholipase A2, cognitive impairment, risk factors, cerebral small vessel disease

Zhan Su,&ast; Jie Zhang,&ast; Peijie Tan, Songsong Zhu,&ast; Nan Jiang&ast; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral & Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Songsong Zhu; Nan Jiang, Email zss_1977@163.com; dent_jn@163.comIntroduction: Polyetheretherketone (PEEK) has good biosafety and chemical stability for bone repair. However, PEEK is biologically inert and cannot promote bone apposition. This study investigated whether graphene-modified PEEK (G-PEEK) could improve cell adhesion and osteogenic differentiation.Methods: G-PEEK was prepared by melted blending and was characterized. In vitro, the biocompatibility of G-PPEK and the ability to promote cell adhesion and osteogenic differentiation in rabbit bone marrow mesenchymal stem cells (rBMSCs) were examined using live and dead cell double staining, the cell counting kit-8 (CCK-8) assay, immunofluorescence and quantitative real-time PCR (qRT‒PCR). An in vivo rabbit extra-articular graft-to-bone healing model was established. At 4 and 12 weeks after surgery, CT analysis and histological evaluation were performed.Results: In vitro, G-PEEK significantly improved the adhesion and proliferation of rBMSCs, with good biocompatibility. In vivo, G-PEEK promoted new bone formation at the site of the bone defect.Conclusion: G-PEEK showed excellent osteogenesis performance, which promises new applications in implant materials.Keywords: polyetheretherketone, graphene, nanocomposites, cell adhesion, osteogenic differentiation

Jin-Tao Huang,&ast; Bin-Yan Zhong,&ast; Nan Jiang,&ast; Wan-Ci Li, Shuai Zhang, Yu Yin, Jun Yang, Jian Shen, Wan-Sheng Wang, Xiao-Li Zhu Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiao-Li Zhu, Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Suzhou, 215006, People’s Republic of China, Tel/Fax +86 512 67780375, Email zhuxiaoli90@163.comObjective: This study aimed to evaluate the effectiveness and safety of transarterial chemoembolization (TACE) in combination with immune checkpoint inhibitors (ICIs) plus tyrosine kinase inhibitors (TKIs) (TACE+IT) versus ICIs plus TKIs (IT) for advanced hepatocellular carcinoma (HCC).Materials and Methods: Data of consecutive advanced HCC patients receiving TACE+IT or IT between January 2019 and December 2021 were included and were retrospectively analyzed. Propensity score matching (PSM) was performed to reduce bias due to confounding variables. The primary outcome of the study was overall survival (OS). The secondary outcomes were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs), respectively.Results: Sixty-four patients were enrolled in the study, among which 24 and 40 received TACE+IT and IT, respectively. The PSM cohort included 24 patients receiving TACE+IT (TACE+IT group) and 24 patients receiving IT (IT group) alone. During a median follow-up of 23 months, patients in TACE+IT group had significantly longer OS (median, 17.3 vs 11.8 months, P = 0.023), better ORR (41.7% vs 12.5%, P = 0.023) and DCR (79.2% vs 50.0%, P = 0.035) than those in the IT group, whereas a non-significant trend in PFS (median, 7.4 vs 6.7 months, P = 0.23) was observed. According to multivariable cox regression analysis, it was found that treatment modality was the only independent risk factor for OS (HR = 0.404, 95% CI = 0.179– 0.911, P < 0.05). There were no remarkable differences in AEs associated with ICIs and TKIs between the two groups, with the exception of gastrointestinal reaction.Conclusion: TACE combined with ICIs plus TKIs significantly improved OS, ORR, and DCR and showed a relatively longer PFS trend over ICIs combined with TKIs for advanced HCC.Keywords: hepatocellular carcinoma, transarterial chemoembolization, immune checkpoint inhibitors, tyrosine kinase inhibitors

Yi Li, Hui Dong, Yudi Dong, Qiaoyuan Wu, Ni Jiang, Qing Luo, Fang Chen Department of Cancer Research Laboratory, Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of ChinaCorrespondence: Qing Luo; Fang Chen, Department of Cancer Research Laboratory, Department of Pathology, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi, Guizhou, 563003, People’s Republic of China, Tel +85128608074, Email zlsysluoqing@163.com; 819448232@qq.comObjective: The purpose of this study was to explore the expression and distribution of tumor-infiltrating immune cells (TIICs) and their relationship with recurrence and metastasis of nasopharyngeal carcinoma (NPC).Methods: The gene expression profiles of NPC were downloaded from GEO database (GSE53819 and GSE64634). The abundance of TIICs in NPC samples was calculated by the CIBERSORT algorithm, and TIICs with higher expression were screened in NPC. Then, we performed immunohistochemistry experiments to evaluate the expression of selected TIICs in 94 NPC samples from the Affiliated Hospital of Zunyi Medical University. We further explored the relationship between TIICs and recurrence and metastasis of NPC.Results: The results based on the GEO database showed that the expression of CD8 T cells, NK cells, macrophages and plasma cells was higher than that in normal tissues. Immunohistochemistry results showed that CD8 T cells, NK cells, macrophages and plasma cells were mainly expressed in the stroma, and the expression of CD8 T cells and NK cells in the stroma of patients without recurrence or metastasis was significantly higher than that in patients with recurrence or metastasis of NPC. Kaplan–Meier analysis showed that patients with high CD8 T cells and high NK cells expression in the stroma had favorable recurrence or metastasis-free survival and overall survival (P< 0.05). Univariate and multivariate Cox analyses indicated that CD8 T cells and NK cells in the stroma were independent factors for the recurrence or metastasis of NPC.Conclusion: The expression of CD8 T cells, NK cells, macrophages and plasma cells is significantly higher than that in normal tissues. Among them, the expression of CD8 T cells and NK cells is closely related to the recurrence and metastasis of NPC. They are independent factors affecting the recurrence and metastasis of NPC.Keywords: TIICs, nasopharyngeal carcinoma, recurrence and metastasis, CD8 T cells, NK cells

Nina Jiang,1,&ast; Ye Hu,1,&ast; Meiling Wang,2,&ast; Zuowei Zhao,2 Man Li1 1Department of Oncology, the Second Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 2Department of Breast Surgery, the Second Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zuowei Zhao, Department of Breast Surgery, the Second Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China, Tel +86-0411-84671291, Fax +86-0411-84671230, Email dmuzhaozuowei@163.com Man Li, Department of Oncology, the Second Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China, Tel +86-0411-84671291, Fax +86-0411-84671230, Email man_li@dmu.edu.cnAbstract: Breast cancer in women is the first leading tumor in terms of incidence worldwide. Some subtypes of BC lack distinct molecular targets and exhibit therapeutic resistance; these patients have a poor prognosis. Thus, the search for new molecular targets is an ongoing challenge for BC therapy. The Notch signaling pathway is found in both vertebrates and invertebrates, and it is a highly conserved in the evolution of the species, controlling cellular fates such as death, proliferation, and differentiation. Numerous studies have shown that improper activation of Notch signaling may lead to excessive cell proliferation and cancer, with tumor-promoting and tumor-suppressive effects in various carcinomas. Thus, inhibitors of Notch signaling are actively being investigated for the treatment of various tumors. The role of Notch signaling in BC has been widely studied in recent years. There is a growing body of evidence suggesting that Notch signaling has a pro-oncogenic role in BC, and the tumor-promoting effect is largely a result of the diverse nature of tumor immunity. Immunological abnormality is also a factor involved in the pathogenesis of BC, suggesting that Notch signaling could be a target for BC immunotherapies. Furthermore, angiogenesis is essential for BC growth and metastasis, and the Notch signaling pathway has been implicated in angiogenesis, so studying the role of Notch signaling in BC angiogenesis will provide new prospects for the treatment of BC. We summarize the potential roles of the current Notch signaling pathway and its inhibitors in BC angiogenesis and the immune response in this review and describe the pharmacological targets of Notch signaling in BC, which may serve as a theoretical foundation for future research into exploring this pathway for novel BC therapies.Keywords: Notch signaling pathway, angiogenesis, tumor immunity, breast cancer, PD-1/PD-L1

Nannan Jiang,1– 3 Wei Xu,1– 3 Huijie Huang,1– 3 Xiaoling Hou,1– 3 Li Xiang1– 3 1Department of Allergy, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 2Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, People’s Republic of China; 3China National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of ChinaCorrespondence: Li Xiang, Department of Allergy, Beijing Children′s Hospital, Capital Medical University, National Center for Children′s Health, Beijing, People’s Republic of China, Tel/Fax +861059616934, Email dr_xiangli2022@126.comPurpose: Asthma and recurrent wheezing (RW) have been identified as risk factors for anaphylaxis; however, little is known about the characteristics of anaphylaxis in children with a history of asthma or RW in Chinese children.Patients and Methods: This was a retrospective, observational chart review of children who were diagnosed with anaphylaxis in a tertiary children’s hospital between 2014 and 2021. Patients’ demographics, symptoms, triggers and presence of physician-diagnosed asthma/RW history were collected from medical charts.Results: A total of 399 anaphylactic reactions in 264 patients were analyzed; 119 patients (45.1%) had a history of asthma/RW. Food was the most common cause (85.5%, 341/399). Compared with patients without a history of asthma/RW, buckwheat-induced anaphylaxis was significantly more common in the asthma/RW group (9.4% vs 0.5%, p < 0.001), patients with a history of asthma/RW had higher rates of oropharyngeal symptoms (17.3% vs 8.6%, p = 0.011) and wheezing (34.5% vs 15.9%, p < 0.001). Ninety-one reactions (22.8%, 91/399) presented as severe anaphylaxis, but no difference existed between asthma/RW and non-asthma/RW groups. Children with a history of asthma/RW were more likely to receive inhaled β agonists than children without a history of asthma/RW (11.8% vs 2.5%, p = 0.003). A larger proportion of children without asthma/RW history were treated with epinephrine (11.7%) than children with asthma/RW history (6.9%).Conclusion: Our finding revealed that different clinical profiles of anaphylaxis in children with and without a history of asthma/RW. Our study did not find that children with a history of asthma/RW have more severe anaphylactic reactions compared with children without asthma/RW. Buckwheat-induced anaphylaxis was more common in the asthma/RW group, wheezing and oropharyngeal symptoms affected a higher proportion of the asthma/RW group.Keywords: anaphylaxis, asthma, epinephrine, wheezing, children

Yi Zhang,1,&ast; Shenglei Yu,1,&ast; Chen Chen,1,&ast; Feng Sun,1,&ast; Lei Zhou,1 Haijun Yao,2 Jin Hu,2 Shirong Li,3 Jingwen Ai,1 Ning Jiang,1 Jing Wang,1 Qihui Liu,1 Jialin Jin,1 Wenhong Zhang1,4,5 1Department of Infectious Diseases, National Medical Center for Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; 2Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, China; 3Department of Clinical Laboratory, Huashan Hospital, Fudan University, Shanghai, China; 4National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; 5Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, China&ast;These authors contributed equally to this workCorrespondence: Wenhong Zhang; Jialin Jin, Email wenhongzhang_hs@126.com; jinjialin@fudan.edu.cnPurpose: Carbapenem-resistant organisms (CROs) have posed a great threat to antibiotic use and induce multi-drug resistance. Contamination of the hospital environment and infection of healthcare workers (HCWs) are reported as sources of nosocomial infections. Here, we performed a comprehensive environment sampling and timely epidemiological investigation during outbreaks to investigate the role of the environment and HCWs in CRO transmission.Patients and Methods: We enrolled carbapenem-resistant organism outbreaks in ICU-1 of Huashan Hospital from January 2019 to March 2019, and ICU-2 located at west branch of Huashan Hospital from October 2019 to November 2019. Carbapenem-resistant Klebsiella pneumoniae (CRKP) and carbapenem-resistant Acinetobacter baumannii (CRAB) isolates were collected from the patients. We performed a real-time comprehensive environmental and HCW sampling in the two ICUs. Isolated strains from patients and the positive colonies from the screening were sent for whole-genome sequencing. Finally, phylogenetic trees were constructed.Results: CRAB and CRKP outbreaks simultaneously occurred in ICU-1; the outbreak involved 13 patients. Meanwhile, the CRKP outbreak in ICU-2 included 11 patients. Twelve out of 146 environment and HCWs samples in ICU-1 were carbapenem-resistant bacteria, including six CRKP and six CRAB strains. For ICU-2, hospital surfaces and HCWs were negative for CRKP. Phylogenetic analyses showed that CRKP strains in ICU-1 were classified into two clades: Clade 1 and Clade 2, sharing a high similarity of isolates from the environment and HCWs. The same phenomenon was observed in CRAB.Conclusion: A timely comprehensive sampling combined with genome-based investigation may aid in tracking the transmission route of and controlling the infections. The environment and HCWs could be contaminated during CRO transmission, which calls for strengthened prevention and control measures.Keywords: carbapenem-resistant, environment, whole-genome sequencing, prevention, control

Jianying Song,1,2,&ast; Lixin Hu,1,2,&ast; Bo Liu,2 Nan Jiang,3 Houqiang Huang,4 JieSi Luo,3 Long Wang,3 Jing Zeng,3 Feihong Huang,3 Min Huang,5 Luyao Cai,2 Lingyu Tang,2 Shunli Chen,2 Yinyi Chen,2 Anguo Wu,3 Silin Zheng,4 Qi Chen1,2,6,7 1Department of Endocrinology and Metabolism, the Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2School of Nursing, Southwest Medical University, Luzhou, People’s Republic of China; 3Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, People’s Republic of China; 4Department of Nursing, the Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 5Department of Respiratory and Critical Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 6Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, People’s Republic of China; 7Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qi Chen, Department of Endocrinology and Metabolism, the Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China, Tel +0086-18383008873, Email qichen@swmu.edu.cn Silin Zheng, Department of Nursing, the Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China, Tel +86-13002866667, Email 1400223549@qq.comAbstract: Poor wound healing in individuals with diabetes has long plagued clinicians, and immune cells play key roles in the inflammation, proliferation and remodeling that occur in wound healing. When skin integrity is damaged, immune cells migrate to the wound bed through the actions of chemokines and jointly restore tissue homeostasis and barrier function by exerting their respective biological functions. An imbalance of immune cells often leads to ineffective and disordered inflammatory responses. Due to the maladjusted microenvironment, the wound is unable to smoothly transition to the proliferation and remodeling stage, causing it to develop into a chronic refractory wound. However, chronic refractory wounds consistently lead to negative outcomes, such as long treatment cycles, high hospitalization rates, high medical costs, high disability rates, high mortality rates, and many adverse consequences. Therefore, strategies that promote the rational distribution and coordinated development of immune cells during wound healing are very important for the treatment of diabetic wounds (DW). Here, we explored the following aspects by performing a literature review: 1) the current situation of DW and an introduction to the biological functions of immune cells; 2) the role of immune cells in DW; and 3) existing (or undeveloped) therapies targeting immune cells to promote wound healing to provide new ideas for basic research, clinical treatment and nursing of DW.Keywords: diabetic wounds, wound healing, immune cells, inflammation, targeted therapy

Nannan Jiang, Wei Xu, Huijie Huang, Xiaoling Hou, Li Xiang Department of Allergy, Beijing Children′s Hospital, Capital Medical University, National Center for Children′s Health; Key Laboratory of Major Diseases in Children, Ministry of Education; National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of ChinaCorrespondence: Li Xiang, Department of Allergy, Beijing Children’s Hospital, Capital Medical University, National Center for Children′s Health, No. 56 Nanlishi Road, Xicheng District, Beijing, 100045, People’s Republic of China, Tel +861059616934, Fax +861059616934, Email drxiangli@163.comPurpose: Pollen sensitization is increasing in children. However, there is little evidence regarding the characteristics of anaphylaxis in individuals with pollen sensitization.Patients and Methods: We conducted a retrospective study of patients with anaphylaxis combined with pollen sensitization who attended an allergy department in a tertiary children’s hospital from 2014 to 2021.Results: A total of 157 anaphylaxis events in 108 patients were analyzed; the mean age at the reaction was 5.8 ± 4.17 years. A total of 99.1% (107/108) of the patients came from northern China. The most common sensitizing pollen was mugwort (93.5%,101/108), followed by ragweed (68.5%, 74/108) and birch (40.7%, 44/108). A total of 76.9% (83/108) of the patients showed polysensitization to pollen. Allergic rhinitis/conjunctivitis was the most common comorbidity (87.0%, 94/108). Children with severe anaphylaxis were more likely to have a history of recurrent urticaria (16.1% vs 3.9%, p = 0.028). The most frequently implicated foods were fruits/vegetables (22.3%, 35/157), followed by wheat (8.9%, 14/157) and milk (8.3%, 13/157), and the most common fruit allergen was peach (n = 7). Of 14% (22/157) exercise-induced reactions, 63.6% (14/22) occurred in pollen season. Skin symptoms were the most frequent (86.0%, 135/157) symptoms, followed by respiratory (73.9%, 116/157) and gastrointestinal (21%, 33/157) symptoms. Regarding acute management, only 7.4% of the patients were treated with epinephrine.Conclusion: Our findings revealed the characteristics of anaphylaxis in children with pollen sensitization. Fruits/vegetables accounted for a substantial percentage of anaphylaxis triggers. The suboptimal use of epinephrine highlights the need for educational programs promoting the use of epinephrine.Keywords: anaphylaxis, pollen, exercise, epinephrine

Jianwu Li,1,2,&ast; Na Jiang,1,2,&ast; Qing-Lei Zeng,3,&ast; Yue Zhang,4 Xinyuan He,4 Yao Chu,1,2 Wenni Jin,1,2 Yi Liu,4 Wan Shi,1,2 Miao Yang,1,2 Weihan He,1,2 Qing Han,5 Le Ma,4 You Xu,1,2 Yaling Guo,1,2 Lei Zhang,6– 9 Fanpu Ji2,4,10,11 1Isolation Ward for Covid-19, the Eighth Hospital of Xi’an City, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Shaanxi Provincial Clinical Medical Research Center of Infectious Diseases, Xi’an, Shaanxi, People’s Republic of China; 3Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 4Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 5Department of Integrated Traditional Chinese and Western Medicine, the Eighth Hospital of Xi’an City, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 6China-Australia Joint Research Centre for Infectious Diseases, School of Public Health, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, People’s Republic of China; 7Artificial Intelligence and Modelling in Epidemiology Program, Melbourne Sexual Health Centre, Alfred Health, Melbourne, Australia; 8Central Clinical School, Faculty of Medicine, Monash University, Melbourne, Australia; 9Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 10National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 11Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education of China, Xi’an, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fanpu Ji, Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China, Tel/Fax +862987678223, Email jifanpu1979@163.com Yaling Guo, Isolation ward for COVID-19, the Eighth Hospital of Xi’an City, Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, People’s Republic of China, Tel/Fax +8629 85230200, Email 15102915638@126.comBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination had been demonstrated as an effective way to reduce the risk of coronavirus disease 2019 (COVID-19), and only a few vaccines suffered from SARS-CoV-2 infection. However, limited data concerning the clinical features of these vaccines infected with SARS-CoV-2 can be identified.Methods: We retrospectively collected and analyzed epidemiological and clinical characteristics data of the imported COVID-19 cases who received Chinese inactivated vaccines abroad. Data were extracted from electronic medical records from a designated hospital in the Shaanxi Province of China between March 22 and May 17, 2021.Results: Totally, 46 confirmed SARS-CoV-2 infection patients were enrolled. The mean age was 40.5 years (range 20– 61), 41 (89.1%) are male. Eighteen (39.1%) patients were from Pakistan. Fourteen (30.4%) patients had at least one comorbidity. Forty (87.0%) and 6 cases were fully vaccinated and partly vaccinated. The time interval between vaccination and infection was 88 days (IQR, 33– 123), 31 (67.4%) and 15 (32.6%) were asymptomatic and symptomatic cases, respectively. Fever (3/46, 6.5%) was the most common symptom; however, none had a body temperature higher than 38.0°C, and no severe case was observed. Notably, the rate of SARS-CoV-2 shedding discontinuation at 7 days after hospitalization in asymptomatic cases was higher than symptomatic one (93.5% vs 40%, P < 0.0001).Conclusion: Individuals who received Chinese inactivated vaccines abroad remain to have the probability of being infected with SARS-CoV-2, but all the vaccines infected with SARS-CoV-2 were asymptomatic or had mild symptoms with favorable clinical outcomes.Keywords: SARS-CoV-2, COVID-19, vaccination, reinfection, asymptomatic infection

Xing Liu,1 Jianxin Sui,2 Cui Li,1 Xudong Peng,1 Qian Wang,1 Nan Jiang,1 Qiang Xu,1 Luokai Wang,2 Jing Lin,1 Guiqiu Zhao1 1Department of Ophthalmology, Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2College of Food Science and Engineering, Ocean University of China, Qingdao, People’s Republic of ChinaCorrespondence: Jing Lin; Guiqiu ZhaoDepartment of Ophthalmology, Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, Shandong, People’s Republic of China, Email linjing_yk@126.com; zhaoguiqiu_good@126.comObjective: To prepare a nanobody specific to dectin 1 and verify its specificity and anti-inflammatory effects on Aspergillus fumigatus keratitis.Methods: The nanobody was selected from a high-quality shark-antibody library constructed with phage-display technology. The nanobody was developed in the expression systems of Escherichia coli. Indirect ELISA was used to determine the specificity of the nanobody to recombinant dectin 1 protein. The potential of the nanobody to be recognized and expressed on the surfaces of cells and corneas was detected by immunofluorescence, and its anti-inflammatory effect on A. fumigatus keratitis was further verified. After infection with A. fumigatus, eyes of C57B L/6 mice were treated with nanobodies. Human corneal epithelial cells (HCECs) were pretreated with nanobodies and then incubated with A. fumigatus. Clinical scores and slit-lamp photography were used to assess disease response in mouse corneas. RT-PCR and ELISA were used to evaluate mRNA and protein expression of IL1β and IL6 in both mouse corneas and HCECs.Results: The nanobody was successfully expressed through microbial system and showed specific high-affinity binding to recombinant dectin 1. Furthermore, it exhibited specific binding to dectin 1 expressed on the surfaces of cells and recognized dectin 1 in mouse corneas. Importantly, it reduced clinical scores of A. fumigatus keratitis in mice compared with a PBS-treatment group. In addition, it decreased mRNA and protein expression of IL1β and IL6 in infected corneas and HCECs stimulated with A. fumigatus.Conclusion: These results suggest that this nanobody can bring about anti-inflammatory effects. This highlights the potential of these nanobodies as innovative therapeutic agents in A. fumigatus.Keywords: nanobody, Aspergillus fumigatus, dectin 1, inflammation, cornea

Nan Jiang, Shuaiwei Zhao, Shilei Wang, Zhong Lu Key Laboratory for Green Chemical Process of Ministry of Education, School of Environmental Ecology and Biological Engineering, Wuhan Institute of Technology, Wuhan, 430205, People’s Republic of ChinaCorrespondence: Zhong LuWuhan Institute of Technology, Wuhan, 430205, People’s Republic of ChinaTel +86-18062036269Fax +86-27-67905262Email zhonglu@wit.edu.cnIntroduction: As a biofilm-associated disease, dental caries benefits from nanoparticle (NP)-based therapies. Streptococcus mutans (S. mutans) is a primary aetiologic agent for dental caries development. We successfully applied a synergistic therapy of Ag/ZnO nanocomposites combined with light-emitting diode (LED) radiation to inhibit S. mutans biofilms. However, the antibiofilm mechanism has not been fully elucidated, and little is known about the biofilm formation ability of bacteria that survive NP-based therapies.Methods: This study explored the antibiofilm formation mechanism of this synergistic therapy by an integrated approach based upon proteomics.Results: Synergistic therapy killed 99.8% of bacteria, while the biofilm formation ability of 0.2% surviving bacteria was inhibited. The proteomic responses of S. mutans to synergistic therapy were comprehensively characterized to unveil the mechanism of bacterial death and biofilm formation inhibition of the surviving bacteria. In total, 55 differentially expressed proteins (12 upregulated and 43 downregulated) were recorded. The bioinformatic analysis demonstrated that cellular integrity damage and regulated expression of structure-associated proteins were the main reasons for bacterial death. In addition, the proteomic study indicated the potential inhibition of metabolism in surviving bacteria and provided a biofilm-related network consisting of 17 differentially expressed proteins, explaining the multiantibiofilm formation actions. Finally, we reported and verified the inhibitory effects of synergistic therapy on sucrose metabolism and D-alanine metabolism, which disturbed the biofilm formation of surviving bacteria.Conclusion: Our findings demonstrated that synergistic therapy killed most bacteria and inhibited the surviving bacteria from forming biofilms. Furthermore, the antibiofilm formation mechanism was revealed by proteomics analysis of S. mutans after synergistic therapy and subsequent metabolic studies. Our success may provide a showcase to explore the antibiofilm formation mechanism of NP-based therapies using proteomic studies.Keywords: antibiofilm, protein profiling, nanoparticles, S. mutans, biofilm-associated diseases

Mi Zhang,1 Wei Zhao,2 Shanshan Liu,1 Haichuan Liu,1 Liang Liu,2 Qiling Peng,2 Chengyou Du,1 Ning Jiang3 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2School of Basic Medical Science, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Department of Pathology, Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Chengyou Du; Ning Jiang Email duchengyou@126.com; jiangning@cqmu.edu.cnBackground: The H/ACA small nucleolar ribonucleoprotein (snoRNP) gene family, including GAR1 ribonucleoprotein (GAR1), NHP2 ribonucleoprotein (NHP2), NOP10 ribonucleoprotein (NOP10), and dyskerin pseudouridine synthase 1 (DKC1), play important roles in ribosome biogenesis. However, the potential clinical value of the H/ACA snoRNP gene family in hepatocellular carcinoma (HCC) has not yet been reported.Methods: Bioinformation databases were used to analyze the expression and roles of the H/ACA snoRNP gene family in HCC. Survival analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment pathway (KEGG) analyses were performed using R software. Tumor Immune Estimation Resource (TIMER) was used to analyze the correlation between the expression of the H/ACA snoRNP gene family and immune infiltration in HCC. Finally, immunohistochemistry and Western blotting were performed to verify the protein expression of the H/ACA snoRNP gene family in HCC tissues and adjacent tissues.Results: The expression of the H/ACA snoRNP gene family was significantly increased in HCC samples compared to normal tissues, and the area under the curve (AUC) of GAR1, NHP2, NOP10, and DKC1 was 0.898, 0.962, 0.884, and 0.911, respectively. Increased expression of the H/ACA snoRNP gene family was associated with poor prognosis in HCC patients (Hazard Ratio, HR = 1.44 [1.02– 2.04], 1.70 [1.20– 2.40], 1.53 [1.09– 2.17], and 1.43 [1.02– 2.03], respectively; log-rank P = 0.036, 0.003, 0.014, 0.039, respectively). GO and KEGG analyses showed that co-expressed genes were primarily enriched in ribosome biogenesis. In addition, upregulated expression of H/ACA snoRNP gene family was related to the infiltration of various immune cells and multiple T cell exhaustion markers in HCC patients. Immunohistochemical analysis and Western blotting showed that the protein expression of H/ACA snoRNP gene family was higher in HCC tissues than in adjacent tissues of clinical samples.Conclusion: H/ACA snoRNP gene family expression was higher in HCC tissues than in normal or adjacent tissues and was highly associated with poor prognosis of HCC patients and, therefore, has the potential to serve as diagnostic and prognostic biomarkers for HCC.Keywords: hepatocellular carcinoma, H/ACA snoRNP gene family, diagnosis, prognosis, biomarker

Liping Xu,&ast; Xinyu Tang,&ast; Nan Jiang,&ast; Sheng Zhang, Yuandong Cao, Xinchen Sun Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinchen Sun; Yuandong CaoDepartment of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, Jiangsu Province, 210029, People’s Republic of ChinaEmail sunxinchen2012@163.com; yuandongcao@163.comPurpose: Lymphomas of the orbit and ocular adnexa are histologically heterogeneous and their incidence rate has been increasing lately. However, because of their rarity and diversity, few cases have been analyzed. This study evaluated patients with orbital and ocular adnexal mucosa-associated lymphoid tissue (OAMALT), who received radiotherapy, and categorized their clinical characteristics, treatment outcomes, and complications.Patients and Methods: We collected data on clinical presentation, age, sex, imaging, tumor location, treatment methods, pathological diagnosis, cataract incidence, cataract incidence periods, overall survival (OS), and disease-free survival (DFS) from 32 patients with orbital involvement and pathologically confirmed marginal zone B-cell lymphoma of MALT who were treated between 2009 and 2018. Twenty-two patients received 20 Gy/10 Fr using intensity-modulated radiation therapy (IMRT) plus 14 Gy/7 Fr using a 6– 14-MeV electron beam therapy using a lens-sparing approach. Ten patients received 32 Gy/16 Fr or 34 Gy/17 Fr using IMRT without the lens shield technique. Kaplan–Meier analysis was used to estimate DFS and OS.Results: The median follow-up time was 83.4 ± 24.5 months. No patient had local recurrence, although three patients developed distant metastases. The 5-year and 10-year OS rates were both 100%. The 5-year and 10-year DFS rates were 96.7% and 74.2%, respectively. Overall, 11 (32.4%) of the 34 lenses developed cataracts. The estimated 5-year, 7-year, and 10-year cumulative cataract rates were 6.9%, 30.9%, and 60.8%, respectively. The median cumulative cataract incidence period was 107.0 months. Age was the only significant parameter associated with cataract formation.Conclusion: A radiation dose of 32– 34 Gy yields excellent local control, DFS, and OS for OAMALT. Some patients may have systemic relapse, and better identification of these patients is necessary. Reducing the prescription radiation dose or using better radiation techniques to spare the ipsilateral lens could reduce cataract formation.Keywords: orbital lymphoma, adnexal lymphoma, mucosa-associated lymphoid tissue, radiotherapy

Nan Jiang,1,2,* Xiao-Lin Ge,2,* Zhao-Yue Zhang,2 Jia Liu,2 Pei-Pei Wang,2 Xin-Chen Sun,1,2 Min Yang1 1The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, 210000, People’s Republic of China; 2Department of Radiotherapy, Jiangsu Province Hospital, Nanjing, Jiangsu, 210000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Min YangThe First School of Clinical Medicine, Nanjing Medical University, No. 818 of Tianyuan Road, Jiangning District, Nanjing, Jiangsu, 210000, People’s Republic of ChinaTel +86 13701516659Email yangmin@jsinm.orgXin-Chen SunDepartment of Radiotherapy, Jiangsu Province Hospital, No. 300 of Guangzhou Road, Gulou District, Nanjing, Jiangsu, 210000, People’s Republic of ChinaTel +86 13770662828Email sunxinchen2012@163.comPurpose: Intensity-modulated radiotherapy (IMRT) can improve the prognosis of patients with esophageal cancer. This study aimed to evaluate clinical factors relevant to the prognosis of patients with esophageal cancer who received intensity-modulated radiotherapy (IMRT) alone.Patient and Methods: Data of 103 patients with pathologically confirmed esophageal cancer who were admitted to our hospital between October 2011 and November 2017 were retrospectively reviewed. All patients had squamous cell carcinoma. All patients received IMRT. Patients with stage I–IVA tumors were included to represent the real-world clinical practice. We performed univariate and multivariate analyses to identify prognostic factors for overall survival (OS) and progression-free survival (PFS). In univariate analyses, the Kaplan–Meier method was used to estimate OS and PFS for various subgroups. In multivariate analyses, hazard ratios were calculated.Results: Single-factor analysis revealed that T stage (P=0.019), N stage (P =0.047), and lesion length (P =0.000) were associated with the prognosis of esophageal cancer patients who received IMRT. Cox regression analysis revealed that T stage (odds ratio [OR] = 4.68; P < 0.05), N stage (OR = 0.28; P < 0.05), and lesion length (OR = 0.09; P < 0.05) were independent factors relevant to prognosis.Conclusion: T stage, N stage, and lesion length influenced the long-term curative effects of IMRT for esophageal cancer and were prognostic factors for patients with esophageal cancer receiving definitive radiotherapy alone. The higher the stage and the longer the tumor, the lower the survival rate.Keywords: esophageal neoplasms, prognosis, intensity-modulated radiotherapy, retrospective studies

Haihong Zhang,1 Fang Wu,1 Hongli Yi,2 Dongjuan Xu,3 Nana Jiang,4 Yonghong Li,5 Ming Li,1 Kefang Wang1 1School of Nursing and Rehabilitation, Shandong University, Jinan City, Shandong Province, People’s Republic of China; 2Department of Respiratory Medicine, Shandong Provincial Hospital, Jinan City, Shandong Province, People’s Republic of China; 3School of Nursing, Purdue University, West Lafayette, IN, USA; 4Department of Respiratory Medicine, Dongfang Hospital Affiliated to Tongji University, Shanghai City, People’s Republic of China; 5Department of Respiratory Medicine, Jinan Central Hospital, Jinan City, Shandong Province, People’s Republic of ChinaCorrespondence: Ming LiSchool of Nursing and Rehabilitation, Shandong University, No.44 Wenhua Xi Road, Lixia District, Jinan City, Shandong Province, 250012, People’s Republic of ChinaTel +86-531-88382000Email liming74@sdu.edu.cnPurpose: Previous research has indicated that female and male patients may experience different levels of symptoms. However, no studies of chronic obstructive pulmonary disease (COPD) patients have compared the number and types of symptom clusters identified in male and female patients. Therefore, the purpose of this study was to investigate gender differences in symptom clusters among COPD patients.Patients and Methods: A total of 371 eligible patients were enrolled in the study. We assessed nine COPD symptoms, namely, dyspnea, cough, sputum, chest tightness, sleep quality, fatigue, frailty, anxiety, and depression. Exploratory factor analyses were used to explore the underlying clusters of the COPD symptoms.Results: Underlying the nine symptoms, female patients had 2 clusters, and male patients had 3 clusters. Specifically, the three general symptoms poor sleep, fatigue, and frailty loaded on the same symptom cluster with anxiety and depression in female patients, while the same 3 general symptoms loaded on the same symptom cluster with chest tightness and dyspnea in male patients. Moreover, cough and sputum not only were more common in male patients but also loaded together on a separate symptom cluster.Conclusion: Our findings suggest that in order to improve fatigue, frailty, and poor sleep quality, symptom management strategies should more closely address anxiety and depression in female patients as well as chest tightness and dyspnea in male patients. Smoking cessation is particularly important in male COPD patients because they account for a much higher proportion of smokers and are more likely to have cough and sputum. These findings signify the importance of identifying and implementing gender-tailored symptom management strategies to relieve symptom burden in COPD patients to enhance their quality of life.Keywords: quality of life, symptom burden, symptom management, factor analysis

Xiao-Mei Li,1,2,* Mao-Ting Li,2,3,* Ni Jiang,1 Ya-Chen Si,3 Meng-Mei Zhu,2 Qiao-Yuan Wu,1 Dong-Chen Shi,4 Hui Shi,4 Qing Luo,1 Bing Yu2 1Cancer Research Laboratory, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, 563003, People’s Republic of China; 2Department of Cell Biology, Center for Stem Cell and Medicine, Navy Medical University (Second Military Medical University), Shanghai, 200433, People’s Republic of China; 3Student Brigade, Second Military Medical University, Shanghai, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Shanghai Changhai Hospital, Shanghai, 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bing Yu; Qing Luo Email smmucellyu@163.com; zlsysluoqing@163.comPurpose: Sinomenine has been known to inhibit the proliferation of breast cancer cells. However, its targets have not been found yet. This study aimed to search for molecular targets of sinomenine for treating breast cancer via network pharmacology.Methods: Potential targets of sinomenine or breast cancer were separately screened from indicated databases. The common targets of both sinomenine and breast cancer were considered as the targets of sinomenine for treating breast cancer. A sinomenine-target-pathway network was constructed based on the obtained results from Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The putative targets of sinomenine were further determined by using protein–protein interaction (PPI) analysis and molecular docking. Finally, the putative targets were verified in vitro and in vivo.Results: Twenty predicted targets were identified through network pharmacological analysis. Gene Ontology (GO) and KEGG pathway enrichment indicated that these predicted targets enriched in the process of MAP kinase activity, VEGF signaling pathway, Relaxin signaling pathway, Growth hormone synthesis, secretion and action. MAPK1, NOS3, NR3C1, NOS1 and NOS2 were further identified as the putative targets by using PPI and molecular docking analysis. Expression of MAPK1, NR3C1, NOS1, NOS2 and NOS3 genes were significantly regulated by sinomenine in both MCF-7 cells and MDA-MB-231 cells. Furthermore, the expression of NR3C1 in human breast cancer specimens was lower than that in para-tumor normal tissues. Meanwhile, the expression of NR3C1 in xenograft tumors was up-regulated after sinomenine treatment.Conclusion: MAPK1, NR3C1, NOS1, NOS2 and NOS3 were identified as the putative targets of sinomenine for treating breast cancer. NR3C1 was preliminarily confirmed as a target of sinomenine in two breast cancer cell lines, xenograft tumor models and human breast cancer specimens. These data indicated that the network pharmacology-based prediction of sinomenine targets for treating breast cancer could be reliable.Keywords: sinomenine, breast cancer, network pharmacology, targets screen, NR3C1

Nan Jiang,1,* Pingting Yang,2,* Shengyun Liu,3,* Hongbin Li,4 Lijun Wu,5 Xiaofei Shi,6 Yongfei Fang,7 Yi Zhao,8 Jian Xu,9 Zhenyu Jiang,10 Zhenbiao Wu,11 Xinwang Duan,12 Qian Wang,1 Xinping Tian,1 Mengtao Li,1 Xiaofeng Zeng1 1Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, People’s Republic of China; 2Department of Rheumatology and Immunology, First Affiliated Hospital, China Medical University, Shenyang, People’s Republic of China; 3Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 4Department of Rheumatology, Affiliated Hospital of Inner Mongolia Medical College, Hohhot, Inner Mongolia, People’s Republic of China; 5Department of Rheumatology and Immunology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region, People’s Republic of China; 6Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, People’s Republic of China; 7Department of Rheumatology, Southwest Hospital, Third Military Medical University, Chongqing, People’s Republic of China; 8Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 9Department of Rheumatology and Immunology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 10Department of Rheumatology, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 11Department of Clinical Immunology and Rheumatology, Xijing Hospital Affiliated to the Fourth Military Medical University, Shanxi, People’s Republic of China; 12Department of Rheumatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaofeng Zeng; Mengtao LiDepartment of Rheumatology, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing Ave, Beijing 100730, People’s Republic of ChinaTel/ Fax + 86-10-69158793Email zengxfpumc@163.com; mengtao.li@cstar.org.cnPurpose: Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by chronic destructive synovitis and possible multisystem involvement. This study aimed to survey the treatment satisfaction of physicians and patients with RA, and to explore the potential factors.Patients and Methods: This cross-sectional study was conducted in 12 centers across China between March 2018 and April 2018. The Treatment Satisfaction Questionnaire for Medication version II was used to assess the treatment satisfaction of patients and physicians. Multivariable regression analysis was used to determine the factors independently associated with treatment satisfaction of patients.Results: The patients’ satisfaction (n=335) with biological disease-modifying antirheumatic drugs (bDMARDs) was higher than physicians’ satisfaction (n=146) regarding the side effects (95.0± 14.3 vs 84.6± 15.7, P< 0.001) and convenience (74.6± 21.2 vs 69.1± 16.5, P=0.002). Among physicians, global satisfaction with bDMARDs was higher than that with conventional synthetic DMARDs (csDMARDs). The multivariable regression analysis showed that age was positively associated with satisfaction of patients, while college or above education and self-assessment of disease severity were inversely associated with satisfaction. Treatment satisfaction was associated positively with the quality of communication with the physician and inversely with treatment costs.Conclusion: For bDMARDs, the treatment satisfaction of patients with RA is generally higher than that of physicians’. Physicians’ satisfaction with bDMARDs is higher than with csDMARDs. Age, education, disease severity, communication with the physician, and treatment costs are independently associated with the treatment satisfaction among patients. Physician–patient communication should be improved in clinical practice. Treatment costs should be taken into account when physicians make decisions.Keywords: patient, physician, rheumatoid arthritis, treatment satisfaction, TSQM-II

Lan Li,1 Hui Dai,2 Jun Ke,2 Cen Shi,2 Nan Jiang,2 Chun-Mei Yang3 1Department of Endocrinology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 215006, People’s Republic of China; 2Department of Radiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People’s Republic of China; 3Department of Endocrinology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People’s Republic of ChinaCorrespondence: Hui DaiDepartment of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People’s Republic of ChinaTel/Fax +86512-67780633Email huizi198208@126.comChun-Mei YangDepartment of Endocrinology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People’s Republic of ChinaTel/Fax +86512-67780633Email muyi1979yang@163.comPurpose: To explore the functional connection strength (FCS) changes of brain networks in diabetic retinopathy (DR) patients and uncover the underlying mechanism.Methods and Materials: Twenty-one patients with DR and 21 age- and sex-matched healthy controls were enrolled from August 2012 to September 2014. Subjects were scanned using 3T MR with blood-oxygen-level dependent (BOLD) and 3-dimension fast spoiled gradient echo (3D-FSPGR) sequences. MR data was analyzed via preprocessing and functional network construction. After a group comparison, components of brain networks with significant group differences were extracted and the FCS of the brain network was evaluated. The brain areas were compared between patients and controls. P-values less than 0.05 were considered statistically significant. Connection strength was evaluated with alphasim, P

Yong-Liang Yuan,1,* Neng Jiang,2,* Ze-Yun Li,1 Zhi-Zhen Song,1 Zhi-Heng Yang,1 Wen-Hua Xue,1 Xiao-Jian Zhang,1 Yue Du11Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Department of Pharmacy, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of ChinaCorrespondence: Yong-Liang Yuan; Yue DuDepartment of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Jianshe East Road 1, Zhengzhou, Henan 450052, People’s Republic of ChinaTel/fax +86 03 716 629 5651Email yylcpu@126.com; fccduy@zzu.edu.cn*These authors contributed equally to this workPurpose: Polyphyllin VI, a main active saponin isolated from traditional medicinal plant Paris polyphylla, has exhibited antitumor activities in several cancer cell lines. In the present study, we investigated the antitumor effect of Polyphyllin VI against human osteosarcoma cells (U2OS) and the underlying molecular mechanisms.Methods: The U2OS cell lines were used to determine the antiproliferative effect of Polyphyllin VI by CCK8 assay. Cell cycle was analyzed by flow cytometry. The Polyphyllin VI-induced apoptosis was determined by Annexin V-APC/7-AAD apoptosis detection kit and JC-1 staining. Meanwhile, the autophagy was determined by acridine orange staining. The apoptosis and autophagy-related proteins were monitored by Western blot assay. Subsequently, intracellular hydrogen peroxide (H2O2) and the activation of ROS/JNK pathway were detected.Results: Polyphyllin VI could potently inhibit cell proliferation by causing G2/M phase arrest. Polyphyllin VI induced mitochondria-mediated apoptosis with the upregulation of proapoptotic proteins Bax and poly ADP-ribose polymerase, and downregulation of antiapoptotic protein Bcl-2 in U2OS cells. Concomitantly, Polyphyllin VI provoked autophagy with the upregulation of critical Atg proteins and accumulation of LC3B-II. Intracellular H2O2 production was triggered upon exposure to Polyphyllin VI, which could be blocked by ROS scavenger. Polyphyllin VI dramatically promoted JNK phosphorylation, whereas it decreased the levels of phospho-p38 and ERK.Conclusion: Our results reveal that Polyphyllin VI may effectively induce apoptosis and autophagy to suppress cell growth via ROS/JNK activation in U2OS cells, suggesting that Polyphyllin VI is a potential drug candidate for the treatment of osteosarcomas.Keywords: Polyphyllin VI, osteosarcoma, apoptosis, autophagy, JNK activation

Dan Zong, Ning Jiang, Jian-Hua Xu, De-Jun Wang, Huan-Feng Zhu, Li-Rong Wu, Cheng Chen, Li Yin, Xia HeJiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210009, People’s Republic of ChinaBackground: ZNF488 acts as an oncogene which promotes cell invasion and endows tumor cells stem cell capacity in nasopharyngeal carcinoma (NPC), but its correlation with clinicopathologic characteristics and patients’ survival in NPC remain undefined.Methods: In this study, 158 cases of confirmed NPC were subjected to immunohistochemistry staining for evaluating endogenous expression. Kaplan–Meier method and log-rank test were used to estimate the survival rates. The relationship between ZNF488 and clinicopathological characteristics was statistically calculated by chi-squared test, univariate and multivariate analysis. In addition, adhesion assay, MTT and colony formation assays were performed for measuring adhesion and proliferation capacity. Cell cycle analysis via flow cytometry was conducted to explore cell cycle distribution. Western blot was used to detect pathway protein levels, and the pFAK (Y397) kit was used for focal adhesion kinase (FAK) activation.Results: We demonstrated that high expression of ZNF488 was significantly correlated with locoregional failure (P=0.018) and distant metastasis (P=0.001). Patients with high ZNF488 expression had poorer overall survival (P

Ding-Yun Feng,1,* Yu-Qi Zhou,1,* Yan-Fang Xing,2,* Chuang-Feng Li,3 Qing Lv,4 Jie Dong,5 Jie Qin,3 Yue-Fei Guo,3 Nan Jiang,6 Chencui Huang,7 Hai-Tao Hu,8 Xing-Hua Guo,9 Jie Chen,10 Liang-Hong Yin,11 Tian-Tuo Zhang,1 Xing Li12 1Department of Respiration, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People’s Republic of China; 2Department of Nephrology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, People’s Republic of China; 3Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People’s Republic of China; 4Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People’s Republic of China; 5Department of Radiotherapy, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People’s Republic of China; 6Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People’s Republic of China; 7The Associated Laboratory for AI, Cross-strait TsingHua Research Institute and Huiying Medical Technology, Dongsheng Science and Technology Park, HaiDian District, Beijing 100192, People’s Republic of China; 8Department of Surgery, ChanCheng District Center Hospital, Foshan 528000, People’s Republic of China; 9Department of Rheumatology, The LingNan Hospital of Sun Yat-sen University, Guangzhou 510000, People’s Republic of China; 10Department of Oncology, HengYang City Center Hospital, Hengyang 421001, People’s Republic of China; 11Department of Nephrology, The First Affiliated Hospital of JINAN University, Guangzhou 510630, People’s Republic of China; 12Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People’s Republic of China *These authors contributed equally to this work Purpose: The effect of glucocorticoid(s) on connective tissue disease (CTD)-related interstitial lung disease (ILD) is controversial. This multicenter study aimed to identify glucocorticoid-sensitive patients using a radiomics approach. Methods: A total of 416 CTD-ILD patients who began glucocorticoid treatment at the discretion of the attending physician, with or without cyclophosphamide, were included in this study. High doses were defined as pulsed intravenous methylprednisolone, an initial dose of 1 mg/kg/day of prednisolone or 0.8 mg/kg/day of methylprednisolone. Low doses were defined as those less than high doses. Radiomics features were manually extracted from primary lung lesions delineated on computed tomography images, and selected by variance, univariate feature selection, and least absolute shrinkage and selection operator regression model. The prediction models were developed using data from 309 patients from two centers and externally validated in 107 patients from four other hospitals. Results: Treatment response in the training and validation groups was 38.5% and 36.4%, respectively. Eleven radiomics features were selected from 1,029 features with predictive value. Random forest models built for radiomics features to predict treatment response yielded a sensitivity of 0.897. The calibration curve of a nomogram demonstrated good agreement between prediction and observation. Decision curve analysis indicated that glucocorticoid was beneficial if the predicted response rate was 50%–60% for an individual. High doses of glucocorticoids and cyclophosphamide yielded superior efficacy. Conclusion: Radiomics-based predictive models reliably identified glucocorticoid-sensitive CTD-ILD patients. Short-term, high-dose glucocorticoid with cyclophosphamide yielded promising results as a potential therapy. Keywords: radiomics, connective tissue diseases, interstitial lung diseases, glucocorticoid

You-Lan Min,1,* Ting Su,2,* Yong-Qiang Shu,3 Wen-Feng Liu,1 Ling-Long Chen,3 Wen-Qing Shi,1 Nan Jiang,2 Pei-Wen Zhu,1 Qing Yuan,1 Xiao-Wei Xu,1 Lei Ye,1 Yi Shao1 1Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province Clinical Ophthalmology Institute, Nanchang 330006 Jiangxi, China; 2Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen 361102, Fujian, China; 3Department of Radiology, The First Affiliated Hospital of Nanchang University, Nanchang 330006 Jiangxi, China *These authors contributed equally to this work Objective: Previous studies have demonstrated that strabismus or amblyopia can result in markedly brain function and anatomical alterations. However, the differences in spontaneous brain activities of strabismus with amblyopia (SA) patients still remain unclear. This current study intended to use the amplitude of low-frequency fluctuation (ALFF) technique to investigate the intrinsic brain activity changes in SA subjects. Patients and methods: A total of 16 patients with SA (6 males and 10 females) and 16 healthy controls (HCs; 6 males and 10 females) similarly matched in age, gender, and education status were recruited and examined with the resting-state functional MRI. The spontaneous brain activity changes were investigated using the ALFF technique. The receiver operating characteristic curve was performed to classify the mean ALFF signal values of the SA patients from HCs. The correlations between the ALFF values of distinct brain regions and the clinical manifestations in SA patients were evaluated in terms of the Pearson’s correlation analysis. Results: Compared with HCs, SA patients had significantly decreased ALFF in the left cerebellum posterior lobe, left middle frontal gyrus, and bilateral thalamus. In contrast, SA patients showed increased ALFF values in the right superior frontal gyrus, right precuneus, left cuneus, and bilateral precentral gyrus. Nonetheless, there was no linear correlation between the mean ALFF values in brain regions and clinical features. Conclusion: Diverse brain regions including vision-related and motion-related areas exhibited aberrant intrinsic brain activity patterns, which imply the neuropathologic mechanisms of oculomotor disorder and vision deficit in the SA patients. Keywords: strabismus, amblyopia, functional MRI, ALFF, spontaneous brain activity

Zhun Wang,* Shuanghe Peng,* Hui Xie, Linpei Guo, Ning Jiang, Zhiqun Shang, Yuanjie Niu Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China *These authors contributed equally to this work Background: The prognostic value of neutrophil–lymphocyte ratio (NLR) in patients with castration-resistant prostate cancer (CRPC) had been investigated in previous studies; however, the results remain inconsistent. This study was aimed to investigate the prognostic value of NLR in CRPC patients.Materials and methods: Literature was identified from PubMed, Embase, Web of Science, and Cochrane, which investigated the relationship between pretreatment NLR and prognosis in CRPC patients. HRs for overall survival (OS) and progression-free survival (PFS) were extracted from eligible studies. Heterogeneity was assessed using the I2 value. The fixed-effects model was used if there was no evidence of heterogeneity; otherwise, the random-effects model was used. Publication bias was evaluated using Begg’s funnel plot test.Results: A total of 5,705 patients from 16 studies were included in this analysis. The pooled results showed that an elevated NLR predict poor OS (pooled HR = 1.52, 95% CI: 1.41–1.63, P

Nan Jiang,1–3 Lu Chen,1–3 Qianli Ma,4,5 Jianping Ruan1–3 1Department of Preventive Dentistry, College of Stomatology, Xi’an JiaoTong University, Xi’an, People’s Republic of China; 2Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an JiaoTong University, Xi’an, People’s Republic of China; 3Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi’an JiaoTong University, Xi’an, People’s Republic of China; 4Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi’an, People’s Republic of China; 5Department of Prosthodontics, College of Stomatology, Xi’an JiaoTong University, Xi’an, People’s Republic of China Purpose: To investigate the amelogenesis-inductive effects of surface structures at the nanoscale. For this purpose, variable nanostructured titanium dioxide (TiO2) surfaces were used as a framework to regulate the amelogenic behaviors of ameloblasts with the administration of retinoic acid (RA)/dexamethasone (DEX). Materials and methods: TiO2 nanotubular (NT) surfaces were fabricated via anodization. Mouse ameloblast-like LS-8 cells were seeded and cultured on NT surfaces in the presence or absence of RA/DEX for 48 h. The amelogenic behaviors and extracellular matrix (ECM) mineralization of LS-8 cells on nanostructured Ti surfaces were characterized using field emission scanning electron microscope, laser scanning confocal microscope, quantitative polymerase chain reaction, MTT assay, and flow cytometry. Results: TiO2 NT surfaces (tube size ~30 and ~80 nm) were constructed via anodization at 5 or 20 V and denoted as NT5 and NT20, respectively. LS-8 cells exhibited significantly increased spread and proliferation, and lower rates of apoptosis and necrosis on NT surfaces. The amelogenic gene expression and ECM mineralization differed significantly on the NT20 and the NT5 and polished Ti sample surfaces in standard medium. The amelogenic behaviors of LS-8 cells were further changed by RA/DEX pretreatment, which directly drove maturation of LS-8 cells. Conclusion: Controlling the amelogenic behaviors of ameloblast-like LS-8 cells by manipulating the nanostructure of biomaterials surfaces represents an effective tool for the establishment of a systemic framework for supporting enamel regeneration. The administration of RA/DEX is an effective approach for driving the amelogenesis and maturation of ameloblasts. Keywords: TiO2 nanotube, LS-8, surface nanostructure, amelogenesis, retinoic acid

Li-Yuan Tang,1,* Hai-Jun Li,2,* Xin Huang,1 Jing Bao,1 Zubin Sethi,3 Lei Ye,1 Qing Yuan,1 Pei-Wen Zhu,1 Nan Jiang,1 Gui-Ping Gao,1 Yi Shao1 1Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; 2Department of Radiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; 3The Department of Medicine, University of Miami, Coral Gables, FL, USA *These authors contributed equally to this work Objective: Previous neuroimaging studies have demonstrated that pain-related diseases are associated with brain function and anatomical abnormalities, whereas altered synchronous neural activity in acute eye pain (EP) patients has not been investigated. The purpose of this study was to explore whether or not synchronous neural activity changes were measured with the regional homogeneity (ReHo) method in acute EP patients.Methods: A total of 20 patients (15 males and 5 females) with EP and 20 healthy controls (HCs) consisting of 15 and 5 age-, sex-, and education-matched males and females, respectively, underwent resting-state functional magnetic resonance imaging. The ReHo method was applied to assess synchronous neural activity changes.Results: Compared with HCs, acute EP patients had significantly lower ReHo values in the left precentral/postcentral gyrus (Brodmann area [BA]3/4), right precentral/postcentral gyrus (BA3/4), and left middle frontal gyrus (BA6). In contrast, higher ReHo values in acute EP patients were observed in the left superior frontal gyrus (BA11), right inferior parietal lobule (BA39/40), and left precuneus (BA7). However, no relationship was found between the mean ReHo signal values of the different areas and clinical manifestations, which included both the duration and degree of pain in EP patients.Conclusion: Our study highlighted that acute EP patients showed altered synchronous neural activities in many brain regions, including somatosensory regions. These findings might provide useful information for exploration of the neural mechanisms underlying acute EP. Keywords: acute eye pain, corneal pain, regional homogeneity, resting state, functional magnetic resonance imaging

Wenting Jiang,1,* Han Wang,1,* Yongmei Cui,1,* Yiyan Lei,2 Yuefeng Wang,1 Di Xu,3 Neng Jiang,1 Yangshan Chen,1 Yu Sun,1 Yang Zhang,4 Jessica Cao,5 Zunfu Ke1 1Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; 2Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; 3Department of Thoracic Surgery, The Central Hospital of Wuhan, Jiang’an District, Wuhan, Hubei, China; 4Biomedical Engineering, The University of Texas at El Paso, El Paso, TX, USA; 5Cumming School of Medicine, University of Calgary, Calgary, AB, Canada *These authors contributed equally to this work Background: Circulating tumor cells (CTCs) detection, an approach considered to be “liquid biopsy”, is a potential alternative method in clinical use for early diagnosis of solid tumor progression.Methods: In this study, we developed a poly (lactic-co-glycolic acid) (PLGA) – nanofiber (PN)-NanoVelcro chip as an efficient device for simple and rapid capture of CTCs from peripheral blood. We evaluated the device performance by assessing the capture efficiency and purity. Single CTC was isolated via laser microdissection system for subsequent genetic analysis, with an aim to find the concordance of epidermal growth factor receptor (EGFR) mutations between tumor tissue and CTCs. Results: PN-NanoVelcro chip exhibits great performance in capture efficiency and high purity. The genetic analysis results showed that most EGFR mutation in tumor tissue could also be detected in CTCs.Conclusion: Compared to computed tomography image results, CTC detection can be implemented throughout the course of diseases and provides an accurate and earlier diagnosis of tumor progression, which make it possible for patients to acquire suitable and timely treatment. Keywords: PN-NanoVelcro chip, CTCs, EGFR mutation, prognosis, lung adenocarcinoma

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

Zhun Wang, Hui Xie, Linpei Guo, Qiliang Cai, Zhiqun Shang, Ning Jiang, Yuanjie Niu Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China Background: Previous studies have investigated the prognostic significance of Ki-67/MIB-1 expression in renal cell carcinoma (RCC), however, the reports are controversial and inconsistent. This study aimed to investigate Ki-67/MIB-1 expression in RCC and its correlation with prognosis and clinicopathological features.Methods: We searched relevant studies that reported associations between Ki-67/MIB-1 expression and prognosis in RCC from PubMed, Embase, Web of Science, and Cochrane Library studies published until April 14, 2017. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted from eligible studies. Fixed and random effects models were used to calculate pooled HRs and 95% CIs according to heterogeneity.Results: A total of 4579 participants from 23 eligible studies were included in this analysis. The results showed that Ki-67/MIB-1 expression was associated with poor overall survival (HR=2.06, 95% CI: 1.64–2.57) and cancer specific survival (HR=2.01, 95% CI: 1.66–2.44). In addition, Ki-67/MIB-1 expression was also correlated with TNM stage (III/IV vs I/II: OR=1.92, 95% CI: 1.61–2.28), pathological T stage (pT3/pT4 vs pT1/pT2: OR=1.56, 95% CI: 1.21–2.02), distant metastasis (M1 vs M0: OR=1.81, 95% CI: 1.34–2.43), and Fuhrman grade (III/IV vs I/II: OR=1.94, 95% CI: 1.21–3.10).Conclusion: Our study demonstrates that the presence of high Ki-67/MIB-1 expression and advanced clinicopathological features were correlated with poor prognosis in RCC patients. Keywords: Ki-67/MIB-1, renal cell carcinoma, prognosis, meta-analysis

Yu Sun,1,* Yangshan Chen,1,* Shuhua Li,1,* Yiyan Lei,2 Di Xu,3 Neng Jiang,1 Yang Zhang,4 Jessica Cao,5 Zunfu Ke1,* 1Department of Pathology, 2Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Thoracic Surgery, The Central Hospital of Wuhan, Wuhan, Hubei, People’s Republic of China; 4Biomedical Engineering, The University of Texas at El Paso, El Paso, TX, USA; 5Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada *These authors contributed equally to this work Abstract: Lung adenocarcinoma (LADC) is among the most malignant cancers that frequently develops micrometastases even in early stages of the disease. Circulating tumor cell (CTC) number, matrix metalloproteinase (MMP) 7, and MMP9 show great prospects as predictive biomarkers in many tumors. However, the interactions between these biomarkers and the molecular basis of their roles in the metastasis and prognosis of LADC remain unclear. The present study revealed that an elevated CTC count and overexpression of MMP7 and MMP9 correlate with metastasis and clinical progression in LADC patients (n=143). Furthermore, MMP7 and MMP9 upregulation facilitates LADC cell migration in vitro and enhances serum CTC levels in a xenograft mouse model. More importantly, receiver operating characteristic (ROC) curves and Kaplan–Meier analysis confirmed more accurate prediction of metastasis and overall survival (OS) with a combination panel of CTC, MMP7, and MMP9. Taken together, our data show, for the first time, the involvement of MMP7 and MMP9 in the release of CTCs into the peripheral blood, and our data reveal that CTC count and expression of MMP7 and MMP9 can be used together as an effective clinical prediction panel for LADC metastasis and prognosis. Keywords: lung adenocarcinoma, circulating tumor cell, MMP7/MMP9, metastasis, prognosis

Qing Li,1,2,* Xin Huang,2,3,* Lei Ye,2 Rong Wei,2 Ying Zhang,2 Yu-Lin Zhong,2,4 Nan Jiang,2 Yi Shao2 1Department of Pharmacy, The Jiangxi Provincial People’s Hospital, Nanchang, Jiangxi, People’s Republic of China; 2Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province Clinical Ophthalmology Institute and Oculopathy Research Centre, Nanchang, Jiangxi, People’s Republic of China; 3Department of Ophthalmology, The First People’s Hospital of Jiujiang City, Jiujiang, Jiangxi, People’s Republic of China; 4Department of Ophthalmology, The Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, People’s Republic of China *These authors contributed equally to this work Objective: Previous reports have demonstrated significant brain activity changes in bilateral blindness, whereas brain activity changes in late monocular blindness (MB) at rest are not well studied. Our study aimed to investigate spontaneous brain activity in patients with late middle-aged MB using the amplitude of low-frequency fluctuation (ALFF) method and their relationship with clinical features. Methods: A total of 32 patients with MB (25 males and 7 females) and 32 healthy control (HC) subjects (25 males and 7 females), similar in age, sex, and education, were recruited for the study. All subjects were performed with resting-state functional magnetic resonance imaging scanning. The ALFF method was applied to evaluate spontaneous brain activity. The relationships between the ALFF signal values in different brain regions and clinical features in MB patients were investigated using correlation analysis. Results: Compared with HCs, the MB patients had marked lower ALFF values in the left cerebellum anterior lobe, right parahippocampal gyrus, right cuneus, left precentral gyrus, and left paracentral lobule, but higher ALFF values in the right middle frontal gyrus, left middle frontal gyrus, and left supramarginal gyrus. However, there was no linear correlation between the mean ALFF signal values in brain regions and clinical manifestations in MB patients. Conclusion: There were abnormal spontaneous activities in many brain regions including vision and vision-related regions, which might indicate the neuropathologic mechanisms of vision loss in the MB patients. Meanwhile, these brain activity changes might be used as a useful clinical indicator for MB. Keywords: ALFF, monocular blindness, resting state, spontaneous activity

Nan Jiang,1,2 Pinggong Du,2 Weidong Qu,2 Lin Li,2 Zhonghao Liu,2 Songsong Zhu1 1State Key Laboratory of Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 2Yantai City Stomatological Hospital, Yantai, People’s Republic of China Abstract: For several decades, titanium and its alloys have been commonly utilized for endosseous implantable materials, because of their good mechanical properties, chemical resistance, and biocompatibility. But associated low bone mass, wear and loss characteristics, and high coefficients of friction have limited their long-term stable performance, especially in certain abnormal bone-metabolism conditions, such as postmenopausal osteoporosis. In this study, we investigated the effects of platelet-rich plasma (PRP) treatment and TiO2 nanoporous modification on the stability of titanium implants in osteoporotic bone. After surface morphology, topographical structure, and chemical changes of implant surface had been detected by scanning electron microscopy (SEM), atomic force microscopy, contact-angle measurement, and X-ray diffraction, we firstly assessed in vivo the effect of PRP treatment on osseointegration of TiO2-modified implants in ovariectomized rats by microcomputed tomography examinations, histology, biomechanical testing, and SEM observation. Meanwhile, the potential molecular mechanism involved in peri-implant osseous enhancement was also determined by quantitative real-time polymerase chain reaction. The results showed that this TiO2-modified surface was able to lead to improve bone implant contact, while PRP treatment was able to increase the implant surrounding bone mass. The synergistic effect of both was able to enhance the terminal force of implants drastically in biomechanical testing. Compared with surface modification, PRP treatment promoted earlier osteogenesis with increased expression of the RUNX2 and COL1 genes and suppressed osteoclastogenesis with increased expression of OPG and decreased levels of RANKL. These promising results show that PRP treatment combined with a TiO2-nanomodified surface can improve titanium-implant biomechanical stability in ovariectomized rats, suggesting a beneficial effect to support the success of implants in osteoporotic bone. Keywords: TiO2 nanotubes, PRP, titanium implants, ovariectomized rats

Nan Jiang,1,* Rongtong Sun,2,* Qing Sun3 1Shandong University School of Medicine, Jinan, Shandong Province, People’s Republic of China; 2Weihai Municipal Hospital, Weihai, Shandong Province, People’s Republic of China; 3Department of Pathology, QianFoShan Hospital Affiliated to Shandong University, Jinan, Shandong Province, People’s Republic of China *These authors contributed equally to this work Abstract: Previous reports indicate that over 13 different tumors, including hepatocellular carcinoma (HCC), are related to obesity. Obesity-associated inflammatory, metabolic, and endocrine mediators, as well as the functioning of the gut microbiota, are suspected to contribute to tumorigenesis. In obese people, proinflammatory cytokines/chemokines including tumor necrosis factor-alpha, interleukin (IL)-1 and IL-6, insulin and insulin-like growth factors, adipokines, plasminogen activator inhibitor-1, adiponectin, and leptin are found to play crucial roles in the initiation and development of cancer. The cytokines induced by leptin in adipose tissue or tumor cells have been intensely studied. Leptin-induced signaling pathways are critical for biological functions such as adiposity, energy balance, endocrine function, immune reaction, and angiogenesis as well as oncogenesis. Leptin is an activator of cell proliferation and anti-apoptosis in several cell types, and an inducer of cancer stem cells; its critical roles in tumorigenesis are based on its oncogenic, mitogenic, proinflammatory, and pro-angiogenic actions. This review provides an update of the pathological effects of leptin signaling with special emphasis on potential molecular mechanisms and therapeutic targeting, which could potentially be used in future clinical settings. In addition, leptin-induced angiogenic ability and molecular mechanisms in HCC are discussed. The stringent binding affinity of leptin and its receptor Ob-R, as well as the highly upregulated expression of both leptin and Ob-R in cancer cells compared to normal cells, makes leptin an ideal drug target for the prevention and treatment of HCC, especially in obese patients. Keywords: hepatocellular carcinoma, leptin, leptin antagonist, leptin signaling, tumor angiogenesis, drug target

Tanja Schaffran,1 Nan Jiang,1 Markus Bergmann,2,3 Ekkehard Küstermann,4 Regine Süss,5 Rolf Schubert,5 Franz M Wagner,6 Doaa Awad,7 Detlef Gabel1,2,8 1Department of Chemistry, University of Bremen, 2Institute of Neuropathology, Klinikum Bremen-Mitte; 3Cooperative Center Medicine, University of Bremen, 4“In-vivo-MR” AG, FB2, University of Bremen, Bremen, 5Pharmaceutical Technology, University of Freiburg, Freiburg im Breisgau, 6Forschungsneutronenquelle Heinz Maier-Leibnitz (FRM II), Technische Unversitaet Muenchen, Garching, Germany; 7Department of Biochemistry, Alexandria University, Alexandria, Egypt; 8School of Engineering and Science, Jacobs University Bremen, Bremen, Germany Abstract: The potential of boron-containing lipids with three different structures, which were intended for use in boron neutron capture therapy, was investigated. All three types of boron lipids contained the anionic dodecaborate cluster as the headgroup. Their effects on two different tumor models in mice following intravenous injection were tested; for this, liposomes with boron lipid, distearoyl phosphatidylcholine, and cholesterol as helper lipids, and containing a polyethylene glycol lipid for steric protection, were administered intravenously into tumor-bearing mice (C3H mice for SCCVII squamous cell carcinoma and BALB/c mice for CT26/WT colon carcinoma). With the exception of one lipid (B-THF-14), the lipids were well tolerated, and no other animal was lost due to systemic toxicity. The lipid which led to death was not found to be much more toxic in cell culture than the other boron lipids. All of the lipids that were well tolerated showed hemorrhage in both tumor models within a few hours after administration. The hemorrhage could be seen by in vivo magnetic resonance and histology, and was found to occur within a few hours. The degree of hemorrhage depended on the amount of boron administered and on the tumor model. The observed unwanted effect of the lipids precludes their use in boron neutron capture therapy. Keywords: liposomes, histology, magnetic resonance imaging, pharmacodynamics

Qiaocheng Chang1,*, Xiaodong Sun2,*, Jian Wang2,*, Jigang Yin1, Junpeng Song1, Shuai Peng1, Huijun Lu1, Hongning Zhou2, Ning Jiang1, Qijun Chen1,31Key Laboratory of Zoonosis, Jilin University, Changchun; 2Institute for Parasitic Disease Control of Yunnan Province, Puer City, Yunnan; 3Institute of Pathogen Biology, Chinese Academy of Medical Sciences, Beijing, China *These authors contributed equally to this workBackground: Long-tailed and pig-tailed macaque monkeys are natural hosts of Plasmodium knowlesi, which has been identified as a fifth malaria parasite infecting humans. In this study, we investigated possible infection by this Plasmodium parasite in macaque monkeys using a combination of polymerase chain reaction amplification and sequencing.Methods: Forty-five blood samples were obtained in 2010 from macaques in northern Myanmar near Yunnan Province of China and investigated for possible infection with Plasmodium species using a nested polymerase chain reaction method for amplification of 18S SSU rRNA genes.Results: Positive amplification was obtained from one monkey, and both sequence and phylogenetic analysis indicated that the parasite was of the Hepatocystis species lineage.Conclusion: The results suggest that a combination of polymerase chain reaction amplification and sequence identification would be necessary for detection of Plasmodium knowlesi infection in both humans and its natural hosts.Keywords: Plasmodium knowlesi, monkey, parasite, malaria