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Qin Xiao,1,* Jing Guo,1,* Yongzhou Lu,1 Jin Gao,1 Chuanlong Jia,1 Minghuan Huang,1 Weifang Chu,1 Wei Yao,1 Peng Ning,2 Qiannan Xu,1 Nan Xu1 1Department of Dermatology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Institute for Regenerative Medicine, Institute for Translational Nanomedicine, Shanghai East Hospital, Tongji University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiannan Xu; Nan Xu, Department of Dermatology, Shanghai East Hospital, School of Medicine, Tongji University, No. 150 Jimo Road, Shanghai, People’s Republic of China, Tel +86 38804518, Email greatfuturedoctor@hotmail.com; xnhrb1320@sohu.comPurpose: Atopic dermatitis (AD) is a chronic inflammatory skin condition that can affect individuals of all ages. Recent research has shown that oxidative stress plays a crucial role in the development of AD. Therefore, inhibiting oxidative stress may be an effective therapeutic approach for AD. Nano-molybdenum is a promising material for use as an antioxidant. We aimed to evaluate the therapeutic effects and preliminary mechanisms of molybdenum nanoparticles (Mo NPs) by using a murine model of chemically induced AD-like disease.Methods: HaCaT cells, a spontaneously immortalized human keratinocyte cell line, were stimulated by tumor necrosis factor-alpha /interferon-gamma after pre-treatment with Mo NPs. Reactive oxygen species levels, production of inflammatory factors, and activation of the nuclear factor kappa-B and the nuclear factor erythroid 2-related factor pathways were then evaluated. Mo NPs was topically applied to treat a murine model of AD-like disease induced by MC903, a vitamin D3 analog. Dermatitis scores, pruritus scores, transepidermal water loss and body weight were evaluated. AD-related inflammatory factors and chemokines were evaluated. Activation of the nuclear factor kappa-B and nuclear factor erythroid 2-related factor / heme oxygenase-1 pathways was assessed.Results: Our data showed that the topical application of Mo NPs dispersion could significantly alleviate AD skin lesions and itching and promote skin barrier repair. Further mechanistic experiments revealed that Mo NPs could inhibit the excessive activation of the nuclear factor kappa-B pathway, promote the expression of nuclear factor erythroid 2-related factor and heme oxygenase-1 proteins, and suppress oxidative stress reactions. Additionally, they inhibited the expression of thymic stromal lymphopoietin, inflammatory factors, and chemokines, thereby alleviating skin inflammation.Conclusion: Mo NPs present a promising alternative treatment option for patients with AD as they could address three pivotal mechanisms in the pathogenesis of AD concurrently.Keywords: oxidative stress, skin barrier function, chemokines, antioxidants, pro-inflammatory factors

Liqun Luo,1 Xiulin Wen,1 Jingrong Wang,2 Qian Xiao,3 Liuju Su,3 Min Zhou3 1Department of Nursing, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Department of Surgical, The Second Affiliated Hospital of the Air Force Military Medical University, Xi’an, People’s Republic of China; 3School of Public Health, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of ChinaCorrespondence: Xiulin Wen, Tel +86 13991893501, Email 332919997@qq.comBackground: Pressure injuries are present in all healthcare environments and not only pose a significant health risk to individuals but also impose a heavy economic burden on society and families. Nurses, as the primary caregivers responsible for the prevention and management of pressure injuries, have knowledge that directly determines the incidence of pressure injuries.Aim: To understand the current status of nurses’ knowledge of pressure injuries in Shaanxi Province and the factors influencing it.Design: A cross-sectional survey.Methods: In April - May 2022, 16,599 nurses from hospitals at all levels in Shaanxi Province were selected as survey subjects by convenience sampling method. They were surveyed using the general information questionnaire and the Pieper-Zulkowski pressure injury Knowledge Questionnaire through the Questionnaire Star platform.Results: 16,599 nurses had a pressure injury knowledge score of (44.32± 10.11). Wound description and pressure ulcer staging dimensions were less than 60% correct. Comparison of pressure injury knowledge scores of nursing staff with different genders, hospital levels, titles, education, whether they were specialized nurses in wound stoma when they last attended a lecture on pressure ulcers, when they last read literature or books on pressure ulcers, and whether they ever looked for information about pressure ulcers on the Internet showed that the differences were statistically significant (P < 0.05), which were the influencing factors of the knowledge scores of the nursing staff in Shaanxi Province.Conclusion: Clinical nurses’ awareness of stress-related injuries still needs to be improved, and nursing administrators can improve the quality of pressure-related injury care by increasing nursing staff’s awareness through continuing education, tiered training, and other measures.Keywords: pressure injury, knowledge, prevention, management, influencing factor

Yangyang Zhao,1,&ast; Qiuxiang Xiao,2,&ast; Tao Sun,1 Haiyun Yu,1 Muyun Luo3 1The First Clinical Medical College, Gannan Medical University, Ganzhou City, Jiangxi Province, People’s Republic of China; 2Department of Pathology, The First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, People’s Republic of China; 3Department of Neurosurgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Muyun Luo, Department of Neurosurgery, The First Affiliated Hospital of Gannan Medical University, No. 23, Qingnian Road, Zhanggong District, Ganzhou City, Jiangxi Province, 341000, People’s Republic of China, Tel +86- 13767715533, Email lmy771230@163.comObjective: The aims of this study are to screen novel differentially expressed genes (DEGs) for intracerebral hemorrhage (ICH) and reveal the role of Lipocalin-2 (LCN2) in ICH.Methods: We constructed the ICH model by injection of autologous whole blood into the right basal ganglia in rats. RNA-sequencing and bioinformatics analyses were performed to identify the DEGs between ICH and sham rats, and some important ones were confirmed using quantitative real-time PCR (qRT-PCR). LCN shRNA was used to knockdown of LCN2 in ICH rats. Pathological examination was carried out using 2,3,5-triphenyltetrazolium chloride (TTC) staining and Hematoxylin-eosin (HE) staining. Immunohistochemistry detected Caspase-3, and co-staining of Terminal dUTP nick end labeling (TUNEL) and NEUN staining were performed for neuron apoptosis assessment. Western blot analysis was performed to quantify pyroptosis-related proteins. Enzyme-linked immunosorbent assay (ELISA) was used to measure inflammatory cytokine levels.Results: ICH rats exhibited significant hematomas, higher brain water content, obvious interstitial edema, and inflammatory infiltration, as well as more apoptotic cells in brain tissues. RNA-seq analysis identified 103 upregulated and 81 downregulated DEGs. The expression of LCN2, HSPB1, CXCL10, and MEF2B were upregulated in ICH rats. ICH triggered the release of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-18, and promoted the expression of pyroptosis-related proteins Caspase-1, GSDMD, NLRP3, and ASC. LCN2 knockdown attenuated the pathological characteristics of ICH, and also reduced pyroptosis in brain tissues.Conclusion: Inhibition of LCN2 attenuates brain injury after ICH via suppressing pyroptosis, which provide guidance for ICH management.Keywords: intracerebral hemorrhage, pyroptosis, inflammation, lipocalin-2

Yongzheng Guo,1 Xiaofeng Li,2 Qianggu Xiao,3 Jie Yang,4 Ran Tao,1 Lijun Xu,1 Biao Zhu1 1The Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2The Department of Infectious Diseases, Huzhou Central Hospital, Huzhou, Zhejiang, People’s Republic of China; 3The Department of Infectious Diseases, Xiaoshan First People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China; 4The Department of Infectious Diseases, Lishui Municipal Central Hospital, Lishui, Zhejiang, People’s Republic of ChinaCorrespondence: Biao Zhu, Email zhubiao1207@zju.edu.cnBackground: Mycobacterium colombiense pneumonia in HIV-infected patients is relatively unusual but is associated with a high mortality rate, as well as high rates of misdiagnosis and delayed diagnosis. Clinical metagenome next-generation sequencing (mNGS) may have potential for its accurate and timely diagnosis.Case Presentation: We retrospectively reviewed the medical records of three HIV-infected patients who presented with M. colombiense pneumonia in Zhejiang Province between January 2019 and December 2020. No specific clinical presentations or radiological manifestations were found in any of the patients. The detection of M. colombiense is 28– 55 days earlier using mNGS on bronchoalveolar lavage fluid (BALF) compared to traditional culture methods. A combined treatment of rifabutin, clarithromycin, or azithromycin, and ethambutol did not provide timely relief of symptoms in these three patients. In the early stage of treatment, moxifloxacin and linezolid were used for several weeks. The average course of treatment for all three patients was close to 17 months.Conclusion: We recommend early BALF mNGS for fast and accurate diagnosis of M. colombiense pneumonia in HIV-infected patients with low CD4 counts and long duration of symptoms. Further, moxifloxacin and linezolid may be beneficial in the early stage of treatment.Keywords: metagenomic next-generation sequencing, nontuberculous mycobacteria, Mycobacterium colombiense, pneumonitis, HIV, AIDS

Yumi Wu,1 QiWei Xiao,1 ShouDong Wang,2 Huanfang Xu,1,3 YiGong Fang1,3 1Institute of Acupuncture and Moxibustion of China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2The Out-Patient Department of TCM of China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 3Acupuncture and Moxibustion Hospital of China Academy of Chinese Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: YiGong Fang; Huanfang Xu, Institute of Acupuncture and Moxibustion of China Academy of Chinese Medical Sciences, 16 Dongzhimennei South St, Dongcheng, Beijing, 100700, People’s Republic of China, Tel +86 13520175177, Fax +86 010-64089219, Email fangyigong@163.com; huanfang_xu@126.comBackground: To identify novel gene combinations and to develop an early diagnostic model for Polycystic Ovary Syndrome (PCOS) through the integration of artificial neural networks (ANN) and random forest (RF) methods.Methods: We retrieved and processed gene expression datasets for PCOS from the Gene Expression Omnibus (GEO) database. Differential expression analysis of genes (DEGs) within the training set was performed using the “limma” R package. Enrichment analyses on DEGs using gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), and immune cell infiltration. The identification of critical genes from DEGs was then performed using random forests, followed by the developing of new diagnostic models for PCOS using artificial neural networks.Results: We identified 130 up-regulated genes and 132 down-regulated genes in PCOS compared to normal samples. Gene Ontology analysis revealed significant enrichment in myofibrils and highlighted crucial biological functions related to myofilament sliding, myofibril, and actin-binding. Compared with normal tissues, the types of immune cells expressed in PCOS samples are different. A random forest algorithm identified 10 significant genes proposed as potential PCOS-specific biomarkers. Using these genes, an artificial neural network diagnostic model accurately distinguished PCOS from normal samples. The diagnostic model underwent validation using the independent validation set, and the resulting area under the receiver operating characteristic curve (AUC) values was consistent with the anticipated outcomes.Conclusion: Utilizing unique gene combinations, this research created a diagnostic model by merging random forest techniques with artificial neural networks. The AUC indicated a notably superior performance of the diagnostic model.Keywords: polycystic ovary syndrome, machine learning techniques, artificial neural network model, early diagnostic model, artificial neural networks, random forest

Qiulin Xiao,1,2 Bo Chen,1 Zhenya Zhu,1 Ting Yang,1 Enfu Tao,1 Chenmin Hu,1 Wei Zheng,3 Weihong Tang,2 Xiaoli Shu,1 Mizu Jiang1,3 1Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, Zhejiang, 310052, People’s Republic of China; 2Department of Gastroenterology, Hangzhou Children’s Hospital, Hangzhou, Zhejiang, 310014, People’s Republic of China; 3Department of Gastroenterology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, Zhejiang, 310052, People’s Republic of ChinaCorrespondence: Mizu Jiang, Department of Gastroenterology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, 3333 Bin Sheng Road, Hangzhou, Zhejiang, 310052, People’s Republic of China, Tel +86-571-87061007, Fax +86-571-86658672, Email mizu@zju.edu.cnObjective: To examine the association between the fecal microbiota of acute diarrhea in children and provide gut microbiota information related the acute diarrhea with rotavirus.Patients and Methods: Children with acute diarrhea aged 3– 60 months were selected for the study. Routine stool examination was performed, and stool samples were collected and stored at − 80 °C until further analysis. Fecal microbial DNA was extracted, and DNA concentration and quality were detected. PCR amplification and 16S rDNA high-throughput sequencing analysis using the Illumina MiSeq platform were performed, and intestinal flora was statistically analyzed.Results: Children with acute diarrhea exhibited gut microbial dysbiosis. Lower microbial diversity and richness were observed in the viral enteritis and bacterial enteritis groups than in the control group. Composition of the microbiota in acute diarrhea differed from that in the control group. The Bacteroidetes/Firmicutes dramatically decreased in the viral enteritis and bacterial enteritis groups. However, the relative abundance of Proteobacteria and Fusobacteria increased, especially in the bacterial enteritis group. In addition, the relative abundance of Actinobacteria had dramatically increased in the viral enteritis group. According to the Kyoto Encyclopedia of Genes and Genomes map analysis, the membrane transport dysfunction was caused by rotavirus infection, while the membrane transport dysfunction was more evident in bacterial infection.Conclusion: Acute diarrhea infections cause fecal microbiota dysbiosis in children. Changes in fecal microflora in children suggest that the regulation of intestinal flora in children with acute diarrhea should be strengthened.Keywords: acute diarrhea, microbiome, Fusobacteria, Firmicutes, Bacteroidetes, 16S rDNA sequencing, rotavirus

Xin Zhao,1,&ast; Pingyuan Ge,1,&ast; Shaohua Lei,1 Siqi Guo,1 Peng Zhou,1 Li Zhao,1 Yiyu Qi,1 Xiaotong Wei,2 Weizhen Wu,2 Ningjing Wang,2 Rui Guo,3 Nianyun Yang,1 Qingqing Xiao,1 Qichun Zhang,1,2 Huaxu Zhu1 1Department of Traditional Chinese Medicine Processing and Preparation, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 2Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 3School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qichun Zhang; Huaxu Zhu, Email zhangqichun@njucm.edu.cn; zhuhx@njucm.edu.cnIntroduction: Neuroinflammation is one of the major pathogeneses in Alzheimer’s disease (AD) and mainly involves abnormal inflammatory activation of microglia by multiple pathological stimuli. The treatment of AD remains a major challenge due to the multifactorial characterization of AD and the inefficient ability of therapeutic drugs to permeate through the blood‒brain barrier (BBB). Accordingly, drug combination treatment and drug carrier delivery have become important therapeutic tools for the treatment of multifactorial diseases, especially AD.Methods: Inflammatory cytokine levels in microglia, including NO, TNF-α, IL-1β, IL-4, and IL-10, were detected. The Morris water maze and object location task were used to investigate the learning and memory functions of APP/PS1 mice in different treatment groups. The number of neurons and plasticity of synapses were evaluated by immunofluorescence double labelling. Additionally, the ratio of β-amyloid plaques and the number of activated microglia were evaluated by immunofluorescence staining. The concentrations of β-amyloid plaques and inflammatory factors in the hippocampus were determined by ELISA. Microglia-derived exosomes (Exos) were extracted and purified by size exclusion chromatography. The distribution of exosomes and drugs was investigated in vitro and in vivo.Results: Compared to single drug interventions, the combination of Ber and Pal (Ber/Pal) modulated microglial inflammatory cytokine levels. Ber/Pal promoted the recovery of learning and memory impairment in APP/PS1 mice. Immunofluorescence staining indicated that Ber/Pal restored neurons, inhibited Aβ plaque formation and microglial activation, and regulated the secretion of inflammatory factors. Exos promoted the accumulation of drugs in cells and tissues and improved the targeting of drugs across the BBB.Conclusion: Ber/Pal could offer a synergistic and more comprehensive therapeutic effect in AD. Additionally, the microglia-derived Exos-Ber/Pal delivery system promoted the targeting and permeation of drugs into the brain, suggesting a creative strategy for targeting AD therapy by regulating neuroinflammation in microglial cells.Keywords: Alzheimer’s disease, neuroinflammation, phytoconstituents, drug combination, BBB permeability, exosomes

Yunxia Huang,1,&ast; Yi Guo,2,&ast; Qin Xiao,3,&ast; Shuyu Liang,2 Qiang Yu,4 Lang Qian,1 Jin Zhou,1 Jian Le,1 Yuchen Pei,5 Lei Wang,4 Cai Chang,1 Sheng Chen,4 Shichong Zhou1 1Department of Ultrasonography, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 2Department of Radiology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China; 3Department of Electronic Engineering, Fudan University and Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention of Shanghai, Shanghai, People’s Republic of China; 4Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China; 5Precision Cancer Medical Center Affiliated to Fudan University Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shichong Zhou, Department of Ultrasonography, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China, Tel +86 21-64175590, Email sczhou@hotmail.com Sheng Chen, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People’s Republic of China, Tel +86 21-64175590, Email 0456177@fudan.edu.cnPurpose: The emergence of genomic targeted therapy has improved the prospects of treatment for breast cancer (BC). However, genetic testing relies on invasive and sophisticated procedures.Patients and Methods: Here, we performed ultrasound (US) and target sequencing to unravel the possible association between US radiomics features and somatic mutations in TNBC (n=83) and non-TNBC (n=83) patients. Least absolute shrinkage and selection operator (Lasso) were utilized to perform radiomic feature selection. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was utilized to identify the signaling pathways associated with radiomic features.Results: Thirteen differently represented radiomic features were identified in TNBC and non-TNBC, including tumor shape, textual, and intensity features. The US radiomic–gene pairs were differently exhibited between TNBC and non-TNBC. Further investigation with KEGG verified radiomic–pathway (ie, JAK-STAT, MAPK, Ras, Wnt, microRNAs in cancer, PI3K-Akt) associations in TNBC and non-TNBC.Conclusion: The pivotal network provided the connections of US radiogenomic signature and target sequencing for non-invasive genetic assessment of precise BC treatment.Keywords: triple-negative breast cancer, radiomics, somatic mutation, signaling pathway

Siqin Chen,1,&ast; Minhong Su,2,&ast; Wei Lei,1,&ast; Zhida Wu,1 Shuhong Wu,1 Jing Liu,1 Xiaoyan Huang,1 Guiyang Chen,1 Qian Zhang,1 Hua Zhong,1 Fu Rong,1 Xi Li,1 Qiang Xiao1 1Pulmonary and Critical Care Medicine, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde Foshan), Foshan, Guangdong, People’s Republic of China; 2Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiang Xiao; Xi Li, Pulmonary and Critical Care Medicine, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde Foshan), No. 1, Jiazi Road, Lunjiao Street, Shunde District, Foshan, Guangdong, 528300, People’s Republic of China, Tel +86-757-22318689 ; +86-757-22318690, Email xiaoqiang@smu.edu.cn; kamaneal@163.comPurpose: There is a high disease burden associated with community-acquired pneumonia (CAP) around the world. A timely and correct diagnosis of CAP can facilitate early treatment and prevent illness progression. The present study aimed to find some novel biomarkers of CAP by metabolic analysis and construct a nomogram model for precise diagnosis and individualized treatment of CAP patients.Patients and Methods: 42 CAP patients and 20 controls were enrolled in this study. The metabolic profiles of bronchoalveolar lavage fluid (BALF) samples were identified by untargeted LC-MS/MS analysis. With a VIP score ≥ 1 in OPLS-DA analysis and P < 0.05, the significantly dysregulated metabolites were estimated as potential biomarkers of CAP, which were further included in the construction of the diagnostic prediction model along with laboratory inflammatory indexes via stepwise backward regression analysis. Discrimination, calibration, and clinical applicability of the nomogram were evaluated by the C-index, the calibration curve, and the decision curve analysis (DCA) estimated by bootstrap resampling.Results: The metabolic profiles differed obviously between CAP patients and healthy controls, as shown by PCA and OPLS-DA plots. Seven metabolites significantly dysregulated in CAP were established: dimethyl disulfide, oleic acid (d5), N-acetyl-a-neuraminic acid, pyrimidine, choline, LPC (12:0/0:0) and PA (20:4/2:0). Multivariate logistic regression revealed that the expression levels of PA (20:4/2:0), N-acetyl-a-neuraminic acid, and CRP were associated with CAP. After being validated by bootstrap resampling, this model showed satisfactory diagnostic performance.Conclusion: A novel nomogram prediction model containing metabolic potential biomarkers in BALF that was developed for the early diagnosis of CAP offers insights into the pathogenesis and host response in CAP.Keywords: community-acquired pneumonia, biomarker, precision medicine, metabolomics, prediction model, logistic regression

Qiang Xiao,1,&ast; Shukun Tan,1,2,&ast; Changzhi Liu,3,&ast; Bin Liu,1 Yingxiong Li,1 Yehui Guo,1 Peiyan Hu,1 Zhuoying Su,1 Siqin Chen,1 Wei Lei,1 Xi Li,1 Minhong Su,4 Fu Rong1 1Pulmonary and Critical Care Medicine, Shunde Hospital, Southern Medical University (the First People’s Hospital of Shunde Foshan), Foshan, 528300, People’s Republic of China; 2Respiratory Medicine of the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, 528222, People’s Republic of China; 3Critical Care Medicine, Shunde Hospital, Southern Medical University (the First People’s Hospital of Shunde Foshan), Foshan, 528300, People’s Republic of China; 4Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fu Rong, Pulmonary and Critical Care Medicine, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde Foshan), No. 1, Jiazi Road, Lunjiao Street, Shunde District, Foshan, 528300, People’s Republic of China, Tel +86-757-22318689, Email rongfu828@sina.com Minhong Su, Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, 253 Gongye Middle Avenue, Haizhu District, Guangzhou, 510280, People’s Republic of China, Tel +86-20-62782290, Email 878697159@qq.comPurpose: Community-acquired pneumonia (CAP) is one of the most frequently encountered infectious diseases worldwide. Few studies have explored the microbial composition of the lower respiratory tract (LRT) and host metabolites of CAP. We analyzed the microbial composition of the LRT and levels of host metabolites to explore new biomarkers for CAP.Patients and Methods: Bronchoalveolar lavage fluid (BALF) was collected from 28 CAP patients and 20 healthy individuals. Following centrifugation, BALF pellets were used for amplicon sequencing of a variable region of the bacterial 16S rDNA gene to characterize the microbial composition. Non-targeted metabolomics was used to detect host’s metabolites in the supernatant.Results: Compared with healthy individuals, the bacterial alpha diversity in the LRT of CAP patients was significantly lower in CAP patients (p< 0.05). On the bacterial genus level, over 20 genera were detected with lower relative abundance (p< 0.05), while the relative abundance of Ruminiclostridium-6 was significantly higher in CAP patients. The levels of the host metabolites dimethyldisulfide, choline, pyrimidine, oleic acid and N-acetyl-neuraminic acid were all increased in BALF of CAP patients (p< 0.05), while concentrations of lysophosphatidylcholines (LPC (12:0/0:0)) and phosphatidic acid (PA (20:4/2:0)) were decreased (p< 0.05). Furthermore, the relative abundance of Parvimonas, Treponema-2, Moraxella, Aggregatibacter, Filifactor, Fusobacterium, Lautropia and Neisseria negatively correlated with concentrations of oleic acid (p< 0.05). A negative correlation between the relative abundance of Treponema-2, Moraxella, Filifactor, Fusobacterium and dimethyldisulfide concentrations was also observed (p< 0.05). In contrast, the relative abundance of Treponema-2, Moraxella, Filifactor, and Fusobacterium was found to be positively associated with concentrations of LPC (12:0/0:0) and PA (20:4/2:0) (p< 0.05).Conclusion: The composition of the LRT microbiome differed between healthy individuals and CAP patients. We propose that some respiratory microbial components and host metabolites are potentially novel diagnostic markers of CAP.Keywords: community-acquired pneumonia, microbiome, metabolites, biomarker, diagnosis

Qing Xiao,1,2 Junyan Han,3– 6 Fengting Yu,1– 3 Liting Yan,1,2 Qun Li,1,2 Xiaojie Lao,1,2 Hongxin Zhao,1,2 Fujie Zhang1,2 1Department of Infectious Diseases, Capital Medical University Affiliated Beijing Ditan Hospital, Beijing, People’s Republic of China; 2Clinical Center for HIV/AIDS, Capital Medical University, Beijing, People’s Republic of China; 3Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Beijing, People’s Republic of China; 4National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 5Beijing Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 6Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Fujie Zhang, Beijing, Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China, Tel +86 10 84322581, Email treatment@chinaaids.cnObjective: Numerous studies have reported on the pathogenesis of poor immune reconstitution (PIR) after antiretroviral treatment in human immunodeficiency virus (HIV) patients. However, fewer studies focused on both immune-related genes (IRGs) and immune cells, and the correlation between IRGs and immune cells was evaluated via bioinformatics analyses.Methods: Gene expression profiling of GSE143742 from the Gene Expression Omnibus (GEO) database was analyzed to get differentially expressed immune-related genes (DEIRGs). The enrichment analysis and protein-protein interaction (PPI) networks of DEIRGs were established. The relative fractions of 22 immune cell types were detected using the “CIBERSORT”. The correlation analysis between DEIRGs and immune cells was constructed to discover the potential IRGs associated with immune cells. A logistic regression diagnostic model was built, and a receiver operating characteristic (ROC) curve was performed to evaluate the model’s diagnostic efficacy. The CMap database was used to find molecules with therapeutic potential. RT-qPCR was used to verify the expression of the hub DEIRGs.Results: We identified eight types of significantly changed immune cells and five hub IRGs in INRs. The DEIRGs were mainly enriched in lymphocyte activation, receptor-ligand activity, and T cell receptor signaling pathway. The correlation analysis showed that the expression of TNF, CXCR4 and TFRC correlate with CD8 cells, resting mast cells, activated NK cells, and naïve CD4 cells in INRs. Meanwhile, TFRC and IL7R relate to activated NK cells and resting memory CD4 cells respectively in IRs. A diagnostic model was constructed using multiple logistic regression and nine small molecules were identified as possible drugs.Conclusion: In this study, we suggested that the process of PIR might be related to TNF, CXCR4, TFRC, CD48, and IL7R. And these IRGs play roles in regulating immune-competent cells. And our constructed diagnostic model has excellent effectiveness. Moreover, some small-molecule drugs are screened to alleviate PIR.Keywords: HIV, immunological non-responders, immune-related genes, immune cells, bioinformatics

Poyu Chen1– 3&ast;, Chuangwei Zhang1– 3&ast;, Ping He,4 Shengyuan Pan,1– 3 Wenjie Zhong,1– 3 Yue Wang,1– 3 Qingyue Xiao,1– 3 Xinyan Wang,1– 3 Wenliang Yu,1– 3 Zhangmin He,1– 3 Xiang Gao,1– 3 Jinlin Song1– 3 1College of Stomatology, Chongqing Medical University, Chongqing, 401147, People’s Republic of China; 2Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, People’s Republic of China; 3Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, People’s Republic of China; 4Department of Stomatology, Dazhou Central Hospital, Dazhou, SiChuan, 635000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiang Gao; Jinlin Song, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, 401147, People’s Republic of China, Tel/Fax +86 23 88860105 ; Tel/Fax +86 23 88860026, Email xiangg@hospital.cqmu.edu.cn; songjinlin@hospital.cqmu.edu.cnIntroduction: The functional reconstruction of periodontal tissue defects remains a clinical challenge due to excessive and prolonged host response to various endogenous and exogenous pro-inflammatory stimuli. Thus, a biomimetic nanoplatform with the capability of modulating inflammatory response in a microenvironment-responsive manner is attractive for regenerative therapy of periodontal tissue.Methods: Herein, a facile and green design of engineered bone graft materials was developed by integrating a biomimetic apatite nanocomposite with a smart-release coating, which could realize inflammatory modulation by “on-demand” delivery of the anti-inflammatory agent through a pH-sensing mechanism.Results: In vitro and in vivo experiments demonstrated that this biocompatible nanoplatform could facilitate the clearance of reactive oxygen species in human periodontal ligament stem cells under inflammatory conditions via inhibiting the production of endogenous proinflammatory mediators, in turn contributing to the enhanced healing efficacy of periodontal tissue. Moreover, this system exhibited effective antimicrobial activity against common pathogenic bacteria in the oral cavity, which is beneficial for the elimination of exogenous pro-inflammatory factors from bacterial infection during healing of periodontal tissue.Conclusion: The proposed strategy provides a versatile apatite nanocomposite as a promising “inflammation scavenger” and propels the development of intelligent bone graft materials for periodontal and orthopedic applications.Graphical Abstract: Keywords: periodontal bone regeneration, pH-responsive, inflammatory modulation, antibacterial activity, biomimetic nanoplatform

Qun Li,1,2 Fengting Yu,1,2 Chuan Song,1– 3 Hongxin Zhao,1,2 Qing Xiao,1,2 Xiaojie Lao,1,2 Siyuan Yang,1,2 Yunxia Tang,1,2 Fujie Zhang1,2 1Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Clinical Center for HIV/AIDS, Capital Medical University, Beijing, People’s Republic of China; 3Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, People’s Republic of ChinaCorrespondence: Fujie Zhang, Clinical and Research Center of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China, Tel +86 10 84322581, Email treatment@chinaaids.cnObjective: In this study, we aimed to determine drug-resistance mutations (DRMs) in HIV-1 patients with low-level viremia (LLV) and explored the performance of next-generation sequencing (NGS) in detecting HIV DRMs by using LLV samples.Methods: Overall, 80 samples with LLV were amplified and sequenced using a commercial Sanger sequencing (SS) genotyping kit. Furthermore, 51 samples successfully sequenced using SS were simultaneously subjected to NGS. Genotyping success rates of various viremia categories by two sequencing methods were calculated. Stanford HIV-1 drug-resistance database (HIVdb version 8.9) was used to analyze the DRMs. In the NGS assay, a threshold of 5% was considered for reporting low-frequency variants, and the DRMs detected using SS and NGS were compared.Results: The overall success rate of PR/RT regions was 88.1% (67/80) using SS and 86.3% (44/51) using NGS. Furthermore, a significant linear trend was noted between viral load and the genotyping success rate. A total of 38.8% (26/67) participants harbored at least one mutation, as revealed through SS. Moreover, the prevalence of DRMs in persistent LLV was significantly higher than that in intermittent LLV (62.1% vs. 21.1%; P < 0.05). A total of 69 DRMs were detected using the two sequencing methods at the threshold of 5%. Moreover, 10 DRMs missed by SS were detected using NGS, whereas 8 DRMs missed by NGS were detected by SS.Conclusion: Our data suggested that the genotyping resistance testing is necessary to guide antiretroviral therapy optimization in LLV patients.Keywords: HIV-1, low-level viremia, drug-resistance mutation, next-generation sequencing

Siyu Gao1 &ast;, Lingfeng Li2 &ast;, Xiaolin Zhou,1 Xiangcheng Dai,1 Lu Lu,1 Yandong Chen,1 Jing Han,1 Xiaoli Huang,1 Qian Xiao,1 Huiqing He,3 Qiang Liu1 1Yichang Central People’s Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, People’s Republic of China; 2Department of Critical Care Medicine, Dongguan Institute of Respiratory and Critical Care Medicine, Dongguan People’s Hospital, Dongguan, Guangdong, People’s Republic of China; 3Centers for Disease Control and Prevention, Yichang, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiang Liu, Email stellarray@126.comBackground: Severe complications may cause a fatal or disabling outcome in patients with Rickettsia japonica infection but are poorly understood.Methods: We identified 11 patients with only Rickettsia japonica infection with metagenomics next generation sequencing (mNGS) during April to November 2021 at Yichang Central People’s Hospital, China. Clinical data were obtained through review of medical records.Results: Most patients realized that they had symptoms about one or two days after being bitten. Fever (91%), pulmonary effusion (91%), rash or erythema (100%), abnormal urine (100%), neutropenia (100%), lymphopenia (100%), and thrombocytopenia (100%) were the most common clinical signs. Six severely ill patients were admitted to the intensive care unit and five had mild symptoms. Systemic manifestations such as vomiting (83%), neurological manifestations (100%), and disseminated intravascular coagulation (100%) were more frequently observed in the severe cases, 33.3% of whom developed purpura fulminans requiring amputation or skin graft, and 16.6% died two days after admission. Some patients experienced sequelae.Conclusion: Our study found that patients with critical Rickettsia japonica infection complicating disseminated intravascular coagulation had high risk of poor outcome.Keywords: Rickettsia japonica, Japanese spotted fever, infection, tick, disseminated intravascular coagulation, purpura fulminans

Ruoyang Du,1 Qing Xiao,2 Jianfeng Huang,1 Wubing Feng,1 Xiangqi Zheng,1 Tong Yi1 1Department of Urology, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing, People’s Republic of China; 2Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Tong Yi, Chongqing Emergency Medical Center, Chongqing University Central Hospital, No. 1, Jiankang Road, Yuzhong District, Chongqing, 400014, People’s Republic of China, Email tongy09@sina.comIntroduction: Introduction. Renal cell carcinoma (RCC) is a common malignant tumor worldwide, and to explore, accurate prediction models are essential to the diagnosis and treatment.Methods: In the present study, the profile expression of RCC patients for long non-coding RNAs (lncRNAs) were obtained from the database of The Cancer Genome Atlas (TCGA). The Gene Set Enrichment Analysis (GSEA) showed that the gene sets related to autophagy are significantly differentially expressed among the paired normal tissues and RCC. Multivariate and univariate Cox analyses were used to construct the gene signature related to prognosis. Receiver Operating Characteristic (ROC) dependent on the time factor and the Kaplan-Meier curves are used for evaluating identified signatures. For gene signature combination, a nomogram with associated clinical constraints was designed.Results: Multivariate and Univariate Cox analyses presented seven autophagy-related lncRNAs were significantly correlated with Overall Survival (OS) for people with RCC. Risk scores of lncRNA prognostic signature, related to autophagy helped in distinguishing the patients accurately among the low-risk and high-risk RCC based on age, sex, grade of tumor, T, M, N, and AJCC stages. The RCC condition patients, as per their signature were put into the category of low and high-risk groups, having varying prognostic outcomes. Gene signature is an independent prognosticator for OS, accurately predicting 3– 5 year survival time for RCC patients from either of the two groups. GSEA revealed that high-risk scores of the prognostic seven-long non-coding signature correlate with immune-regulatory and cancer, signaling pathways, whereas a low-risk score correlates with metabolism. The quantitative reverse chain reaction of transcription-polymerase verified differential expression of seven lncRNAs autophagy-related samples.Conclusion: The results depict that seven autophagy-related lncRNA prognostic signature helps in predicting the prognosis accurately among people with RCC.Keywords: autophagy, lncRNA, renal cell carcinoma, prognosis, GSEA

Chunyu Zhang,1 Liping Liu,1 Qijie Xiao2 1School of Economics and Management, Guangxi Normal University, Guilin, 541004, People’s Republic of China; 2Suzhou Monash Research Institute of Science and Technology, Suzhou, 215300, People’s Republic of ChinaCorrespondence: Liping Liu, School of Economics and Management, Guangxi Normal University, 15 Yucai Road, Qixing District, Guilin, Guangxi, 541004, People’s Republic of China, Email 865248131@qq.comPurpose: We established a dual-pathway model in which Taoism at work can shape employee low-carbon behavior via two mediating mechanisms: perceived value as a psychological mediator and guanxi as a social mediator.Patients and Methods: Data were collected from 788 Chinese enterprises employees.Results: Our results confirm the direct positive effect of Taoism on employee low-carbon behavior and the partial mediating effects of perceived value and co-worker guanxi. However, supervisor-subordinate guanxi does not mediate the relationship between Taoism and employee low-carbon behavior.Conclusion: Despite the key role of employee low-carbon behavior, the individual-level antecedent to employees’ pro-environmental behavior remains underexplored. This study examines the influence of Taoism (an individual-level cultural value) on employee low-carbon behavior in the Chinese context. Theoretical and managerial implications were discussed.Keywords: Chinese traditional culture, social cognitive theory, employee sustainability, green

Qing Xiao,1 Runke Zhou,1 Yu Li,1 Lingyun Zhao,1 Lidan Xiong,2,3 Jie Tang,2,3 Li Li1– 3 1Department of Dermatology, West China Hospital of Sichuan University, Chengdu, People’s Republic of China; 2Cosmetics Safety and Efficacy Evaluation Center, West China Hospital of Sichuan University, Chengdu, People’s Republic of China; 3Sichuan Engineering Technology Research Center of Cosmetic, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Li Li, Tel +86 13882285741, Fax +86 28-85422300, Email lily_hxyy@163.comAbstract: The current study explores a case of symmetrical acrokeratoderma, and related literature is reviewed. A 27-year-old male presented with brownish-black plaques distributed symmetrically on the dorsum of the hands and feet for 3 years, and white maceration of the lesions was observed after immersion in water. The patient was diagnosed with symmetrical acrokeratoderma, and Hirudoid ointment was topically administered twice a day for a month. The symptoms were partially alleviated, and the patient is currently under follow-up observation.Keywords: symmetrical acrokeratoderma, differential diagnosis, keratotic, treatment

Yuehui Jia,1,&ast; Shuli Ma,1,&ast; Lianjie Bai,2 Qiong Xiao,3 Yu Wu,3 Ying Gao,4 Yunfeng Han,1 Zhiping Xie,1 Xiaowei Tang,5 Jie Ge1 1School of Public Health, Qiqihar Medical University, Qiqihar, Heilongjiang, People’s Republic of China; 2The Second Affiliated Hospital, Qiqihar Medical University, Qiqihar, Heilongjiang, People’s Republic of China; 3School of Nursing, Qiqihar Medical University, Qiqihar, Heilongjiang, People’s Republic of China; 4School of Mental Health, Qiqihar Medical University, Qiqihar, Heilongjiang, People’s Republic of China; 5Sanitary Analysis Center, Scientific Research Office, Qiqihar Medical University, Qiqihar, Heilongjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie GeSchool of Public Health, Qiqihar Medical University, 333 Bukui Street, Jianhua District, Qiqihar, 161000, People’s Republic of ChinaTel +86452-2663409Fax +86452-2663755Email gejieqiao@126.comPurpose: This study aimed to assess the knowledge, attitude and practice (KAP) towards COVID-19 of Chinese college students during the COVID-19 outbreak and identify the determinants considerably associated with KAP.Methods: An online cross-sectional questionnaire survey was conducted in February 2020 in China to recruit participants on the Wen-Juan-Xing online platform. A self-made questionnaire was used to assess the KAP towards COVID-19.Results: The average scores of COVID-19-related KAP among college students were 32.16 ± 4.09, 16.84 ± 3.18 and 15.36 ± 1.83, respectively. The average correct response rate of COVID-19-related knowledge was 84.62%. 94.59% of the respondents believed China could control and conquer the pandemic; 98.92% of the respondents wore a mask when they went out. The multiple linear regression showed that the female students had higher scores of COVID-19-related knowledge than male students (β = 0.79, P = 0.01), and the students from 985 or 211 universities (β = − 2.22, P < 0.01) were significantly associated with higher knowledge scores. Furthermore, a significantly positive correlation was found between the scores of COVID-19-related KAP among students.Conclusion: The college students had a good KAP towards the COVID-19 pandemic. The present study was able to access the COVID-19-related KAP among college students during the pandemic and identify their weaknesses in pandemic prevention. Consequently, the results of this study provide theoretical basis for implementing precision health education among college students and reference for campuses to conduct scientific prevention and control during a pandemic. Results also provide beneficial experience to curb similar major public health emergencies in the future.Keywords: COVID-19, knowledge, attitude, practice, college students

Jingsheng Wang, Qiang Xiao, Yuanmin Li Department of Cardiology, the Second Affiliated Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, People’s Republic of ChinaCorrespondence: Yuanmin LiDepartment of Cardiology, the Second Affiliated Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, No. 366 Taishan Street, Taian, 271000, People’s Republic of ChinaTel +86-13583843518Fax +86-538-6222036Email Liym575@126.comAbstract: Elevated red blood cell distribution width (RDW) is a powerful predictor of poor prognosis in a variety of diseases, but a single measurement of RDW cannot reflect the dynamic change of diseases. ΔRDW, as a risk stratification tool, can be used to record changes in RDW before and after treatment; also, it allows investigators to name the unit change of RDW in the studied population. So far, there have been few relevant studies on the predictive value of ΔRDW for different diseases; this article aims to review the studies and summaries of the current understandings on the correlation between ΔRDW and disease outcomes.Keywords: red cell distribution width, increment, diagnosis, prognosis

Yu Li,1– 3 Qing Xiao,1– 3 Jie Tang,2– 4 Lidan Xiong,2– 4 Li Li1– 4 1Department of Dermatology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Cosmetics Safety and Efficacy Evaluation Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 3NMPA Key Laboratory for Human Evaluation and Big Data of Cosmetics, Chengdu, 610041, People’s Republic of China; 4Sichuan Engineering Technology Research Center of Cosmetic, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Li LiDepartment of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of ChinaEmail lilihx_scu@scu.edu.cnLidan XiongCosmetics Safety and Efficacy Evaluation Center, West China Hospital, Sichuan University, No. 5, Gong Xing Road, Chengdu, Sichuan, 610041, People’s Republic of ChinaEmail beardan0505@163.comAbstract: Extracellular vesicles (EVs), as nanoscale membranous vesicles containing DNAs, RNAs, lipids and proteins, have emerged as promising diagnostic and therapeutic agents for skin diseases. Here, we summarize the basic physiology of the skin and the biological characteristic of EVs. Further, we describe the applications of EVs in the treatment of dermatological conditions such as skin infection, inflammatory skin diseases, skin repair and rejuvenation and skin cancer. In particular, plant-derived EVs and clinical trials are discussed. In addition, challenges and perspectives related to the preclinical and clinical applications of EVs are highlighted.Keywords: extracellular vesicles, skin diseases, plant, clinical trials

Jia Xu, Yinu Zhao, Hongjing Sun, Qing Xiao, Panpan Ye Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, People’s Republic of ChinaCorrespondence: Panpan YeEye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, People’s Republic of ChinaTel +86 13806506267Email yepanpan@zju.edu.cnObjective: To assess the role of versican (VCAN) in uveal melanoma (UVM) from its expression, prognostic value and biological function.Methods: The general profile of VCAN mRNA and protein expression levels were obtained using bioinformatic approaches. Then, UALCAN database was adopted to examine the association of VCAN mRNA expression and clinical factors in UVM. The prognostic value of VCAN was assessed by UALCAN, GEPIA and TISIDB databases. Besides, Cox regression analysis was performed to predict the independent prognostic factors for UVM. Further, functional enrichment analysis was conducted to reveal the biological functions of VCAN involved in UVM through DAVID, Cytoscape and GSEA analyses.Results: VCAN showed a relative low expression level in normal eye but was highly expressed in UVM cell lines. Tumor histology and stage in UVM were significantly related to VCAN mRNA expression (all P < 0.05). Besides, high VCAN mRNA expression led to unfavorable prognosis of UVM patients, especially in female patients and those aged < 60 years (all P < 0.05). Cox regression analysis indicated that VCAN mRNA expression was an independent prognostic factor for overall survival in UVM. Enrichment analysis suggested that VCAN was mainly involved in cytokine–cytokine receptor interaction, chemokine signaling pathway and T cell receptor signaling pathway (all P < 0.05). Meanwhile, hyaluronic acid was revealed to be a potential drug for the UVM treatment.Conclusion: VCAN served as an independent prognostic factor for UVM. Further analysis found that VCAN was positively correlated with metastasis-related pathway, which might imply the metastasis risk of UVM. Our study initially revealed the vital role of VCAN in the process of UVM and provided a therapeutic target for UVM treatment.Keywords: bioinformatic approach, versican, uveal melanoma, prognosis, pathway

Haoming Mai,1,&ast; Jiaxuan Chen,1,&ast; Haitao Chen,1,2,&ast; Zhiwei Liu,3,&ast; Guanlin Huang,1 Jialin Wang,1 Qianyi Xiao,4 Weihua Ren,5 Bin Zhou,1 Jinlin Hou,1 Deke Jiang1 1State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 2School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, People’s Republic of China; 3Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; 4School of Public Health, Fudan University, Shanghai, 200032, People’s Republic of China; 5Central Laboratory, First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan Province, 471009, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Deke Jiang; Jinlin HouState Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of ChinaTel +86-20-62786533; +86-20-61641941Email dekejiang17@smu.edu.cn; jlhousmu@163.comIntroduction: Genome-wide association studies identified susceptibility loci in the major histocompatibility complex region for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the causal variants underlying HBV-related HCC pathogenesis remain elusive.Methods: With a total of 1,161 HBV-related HCC cases and 1,353 chronic HBV carriers without HCC, we imputed human leukocyte antigen (HLA) variants based on a Chinese HLA reference panel and evaluated the associations of these variants with the risk of HBV-related HCC. Conditional analyses were used to identify independent signals associated with the risk of HBV-related HCC (P false-discovery rate (FDR) < 0.20). A total of 14,930 variants within the MHC region were genotyped or imputed.Results: We identified two variants, rs114401688 (P = 1.05 × 10− 6, PFDR = 2.43 × 10− 3) and rs115126566 (P = 9.04 × 10− 5, PFDR = 1.77 × 10− 1), that are independently associated with the risk of HBV-related HCC. Single nucleotide polymorphism (SNP) rs114401688 is in linkage disequilibrium with a previously reported SNP rs9275319. In the current study, we found that its association with HCC could be explained by HLA-DQB1&ast;04 and HLA-DRB1&ast;04. SNP rs115126566 is a novel risk variant and may function by regulating transcriptions of HLA-DPA1/DPB1 through enhancer-mediated mechanisms. HLA zygosity analysis showed that homozygosity at HLA-DQB1 gene is suggestively associated with a higher risk of HCC (P = 0.10) and the risk was more pronounced in the older age group (age ≥ 50, P = 0.03).Discussion: Our findings further the understanding of the genetic basis for HBV-related HCC predisposition in chronic HBV carriers.Keywords: fine mapping, susceptibility, MHC, hepatocellular carcinoma, HBV

Lu Tang,1,2,&ast; Yijun Mei,1,2,&ast; Yan Shen,1,2,&ast; Shun He,1,2 Qiaqia Xiao,1,2 Yue Yin,1,2 Yonggang Xu,3 Jie Shao,3 Wei Wang,1,2 Zihao Cai3 1State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 2NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 3Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei WangState Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of ChinaTel +86-25-83271102Email wangcpu209@cpu.edu.cnZihao CaiDepartment of General Surgery, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, 200040, People’s Republic of ChinaTel +86-21-66895079Email davidcai1@163.comAbstract: Advanced research has revealed the crucial role of tumor microenvironment (TME) in tumorigenesis. TME consists of a complicated network with a variety of cell types including endothelial cells, pericytes, immune cells, cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs) as well as the extracellular matrix (ECM). The TME-constituting cells interact with the cancerous cells through plenty of signaling mechanisms and pathways in a dynamical way, participating in tumor initiation, progression, metastasis, and response to therapies. Hence, TME is becoming an attractive therapeutic target in cancer treatment, exhibiting potential research interest and clinical benefits. Presently, the novel nanotechnology applied in TME regulation has made huge progress. The nanoparticles (NPs) can be designed as demand to precisely target TME components and to inhibit tumor progression through TME modulation. Moreover, nanotechnology-mediated drug delivery possesses many advantages including prolonged circulation time, enhanced bioavailability and decreased toxicity over traditional therapeutic modality. In this review, update information on TME remodeling through NPs-based targeted drug delivery strategies for anticancer therapy is summarized.Keywords: tumor microenvironment, nanotherapeutics, cancer treatment, targeted delivery, regulation strategy

Load forecasting for industrial customers is essential for reliable operation decisions in the electric power industry. However, most of the load forecasting literature has been focused on deterministic load forecasting (DLF) without considering information on the uncertainty of industrial load. This article proposes a probabilistic density load forecasting model comprising convolutional long short-term memory (ConvLSTM) and a mixture density network (MDN). First, a sliding window strategy is adopted to convert one-dimensional (1D) data into two-dimensional (2D) matrices to reconstruct input features. Then the ConvLSTM is utilized to capture the deep information of the input features. At last, the mixture density network capable of directly predicting probability density functions of loads is adopted. Experimental results on the load datasets of three different industries show the accuracy and reliability of the proposed method.

Jingsun Wei,1,2,* Yucheng Qian,1,2,* Yang Tang,1,2 Xiaoxu Ge,1,2 Kai Jiang,1,2 Yimin Fang,1,2 Dongliang Fu,1,2 Xiangxing Kong,1 Qian Xiao,1 Kefeng Ding1,2 1Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kefeng DingDepartment of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, People’s Republic of ChinaTel/Fax +86-571-87784820Email dingkefeng@zju.edu.cnPurpose: N6-methyladenosine (m6A) modifications represent one of the most common methylation modifications, and they are mediated by m6A RNA methylation regulators. However, their functions in renal cell carcinoma (RCC) are not completely understood. The aim of this study was to investigate the effects of the regulators in RCC.Materials and Methods: The expression levels of the 13 main m6A RNA methylation regulators in RCC were detected and consensus clustering was performed to explore their relationships with RCC. Thereafter, a risk signature based on the regulators was established. This risk model was fully verified by conducting prognostic analyses using two datasets (The Cancer Genome Atlas [TCGA] and Gene Expression Omnibus [GEO] datasets) and a ROC curve analysis.Results: Of the 13 main m6A regulators, six were significantly upregulated and four were significantly downregulated in 893 RCC cases compared to 128 normal controls in the TCGA database. Consensus clustering based on the regulators identified two clusters of RCC cases, which were significantly associated with a pathological characteristic (T status). Thus, these results indicated that m6A RNA methylation regulators were associated with RCC. Thereafter, a risk model involving two of the regulators (METTL14 and WTAP) was established. The alterations in the mRNA and protein expression levels of these two regulators were further confirmed based on Human Protein Atlas data and real-time PCR in RCC and normal cell lines. The results indicated that the risk model may serve as an independent prognostic marker of overall survival, and it was also associated with clinicopathological characteristics (T status, M status, pathological stage, and gender) in RCC.Conclusion: Collectively, the results of this study indicated that the risk model (based on two m6A RNA methylation regulators) may serve as an independent prognostic indicator of RCC, which may aid further investigation into m6A RNA modification in RCC.Keywords: renal cell carcinoma, m6A methylation, TCGA, prognostic signature

Abstract Background The currently available treatments for colorectal cancer (CRC) are often associated with serious side-effects. Therefore, the development of a novel nutraceutical agent may provide an alternative complementary therapy for CRC. Overexpression of the epidermal growth factor receptor (EGFR) associates with a range of cancers while downregulation of EGFR signalling can inhibit cancer growth. Our previous studies have shown that the free fatty acid extract (FFAE) of krill oil exhibits anti-proliferative and pro-apoptotic properties. This study determines the effects of krill oil extract on the migration of human CRC cells, and its potential role in modulating EGFR signalling pathway and the expression of programmed death ligand 1 (PD-L1). Methods Human CRC cells, DLD-1 and HT-29 were treated with FFAE of KO at 0.03 and 0.12 μL/100 μL for 8 or 24 h. Cell migration was determined by Boyden chamber migration assay. The expression of EGFR, phosphorylated EGFR (pEGFR), protein kinase B (AKT), phosphorylated AKT (pAKT), extracellular signal regulated kinase (ERK1/2), phosphorylated ERK1/2 (pERK1/2) as well as PD-L1 were assessed by western blotting and immunohistochemistry. Results The FFAE of krill oil significantly inhibited cell migration compared to ethanol-treated (vehicle control) cells (P

Qiuke Xiao,* Jinwei Ran,* Weizhong Lu, Ruijie Wan, Lujue Dong, Zhenyu Dai Department of Orthopedics, Chongqing Traditional Chinese Medicine Hospital, No.4 Clinical Medicine School of Chengdu University of Traditional Chinese Medicine, Chongqing 400021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenyu DaiDepartment of Orthopedics, Chongqing Traditional Chinese Medicine Hospital, No.4 Clinical Medicine School of Chengdu University of Traditional Chinese Medicine, Jiangbei District, Chongqing 400021, People’s Republic of ChinaTel/Fax +86 23 6798 3672Email zhenyudai@cdutcm.edu.cnBackground: Increasing attention has been paid to posttraumatic affective disorders. However, orthopedic surgeons dealing with trauma often ignore the harm of such diseases.Objective: To investigate the point prevalence and influencing factors of acute stress disorder (ASD) in elderly patients with osteoporotic fractures (EPOFs) from the perspective of orthopedic surgeons.Patients and Methods: A total of 595 cases of EPOFs were treated at our hospital from January 1, 2018, to June 30, 2019. The patients meeting our inclusion criteria were assessed using a structured interview based on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria to verify the presence of ASD. After diagnosis, the participants were divided into two groups (those with and without ASD). The sociodemographic characteristics, disease characteristics, and Social Support Rating Scale (SSRS) scores were assessed. The chi-square test was used for univariate analysis, and multivariate analysis was performed using binary logistic regression.Results: Of the 524 participants, 32 (6.1%) met the criteria for the diagnosis of ASD. The results of the univariate analysis showed that gender, personality, living alone, monthly family income, initial fear, poor prognosis expectation, anxiety/depression, pain, and social support were associated with ASD in EPOFs (P< 0.05). The multivariate regression analysis showed that isolation, low monthly family income, introversion, poor prognosis expectation, previous traumatic history, and intense pain were the main influencing factors and risk factors (OR> 1) for ASD in EPOFs.Conclusion: Being female, living alone, introversion, poor family income, intense initial fear, poor prognosis expectation, anxiety/depression, intense pain perception and low social support were significantly related to the occurrence of ASD in EPOFs. To achieve optimal recovery in EPOFs, orthopedic surgeons should meet both the physiological and psychological needs of the patients.Keywords: acute stress disorder, gender, trauma, fracture, elderly

Qin Li,1,2,* Qin Xiao,2,3,* Jianwei Li,3,4 Shaofeng Duan,5 He Wang,6 Yajia Gu2,3 1Shanghai Institute of Medical Imaging, Shanghai, China; 2Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China; 3Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; 4Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; 5PDx, GE Healthcare, Shanghai, China; 6Shanghai Center for Mathematical Sciences, Fudan University, Shanghai, China*These authors contributed equally to this workCorrespondence: Yajia GuDepartment of Radiology, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, Shanghai 200032, China, Tel +8618017312040Fax +862164174774Email guyajia@126.comPurpose: To identify MRI-based radiomics signature (Rad-score) as a biomarker of risk stratification for disease-free survival (DFS) in patients with HER2-positive invasive breast cancer treated with trastuzumab-based neoadjuvant chemotherapy (NAC) and establish a radiomics-clinicoradiologic-based nomogram that combines Rad-score, MRI findings, and clinicopathological variables for DFS estimation.Patients and Methods: A total of 127 patients were divided into a training set and testing set according to the ratio of 7:3. Radiomic features were extracted from multiphase CE-MRI (CEm). Rad-score was calculated using the LASSO (least absolute shrinkage and selection operator) regression analysis. The cutoff point of Rad-score to divide the patients into high- and low-risk groups was determined by receiver operating characteristic curve analysis. A Kaplan–Meier survival curves and the Log rank test were used to investigate the association of the Rad-score with DFS. Univariate and multivariate Cox proportional hazards model were used to determine the association of Rad-score, MRI features, and clinicopathological variables with DFS. A radiomics-clinicoradiologic-based nomogram combining the Rad-score, MRI features, and clinicopathological findings was plotted to validate the radiomic signatures for DFS estimation.Results: The Rad-score stratified patients into high- and low-risk groups for DFS in the training set (P< 0.0001) and was validated in the testing set (P=0.002). The radiomics-clinicoradiologic-based nomogram estimated DFS (training set: C-index=0.974, 95% confidence interval (CI)= 0.954– 0.994; testing set: C-index=0.917, 95% CI= 0.842– 0.991) better than the clinicoradiologic-based nomogram (training set: C-index=0.855, 95% CI= 0.739– 0.971; testing set: C-index=0.831, 95% CI=0.643– 0.999).Conclusion: The Rad-score is an independent biomarker for the estimation of DFS in invasive HER2-positive breast cancer with NAC and the radiomics-clinicoradiologic-based nomogram improved individualized DFS estimation.Keywords: radiomics, breast cancer, prognosis, magnetic resonance imaging

Obesity is a leading global health problem contributing to various chronic diseases, including type II diabetes mellitus (T2DM). The aim of this study was to investigate whether blueberries, yoghurt, and their respective bioactive components, Cyanidin-3-O-β-glucoside (C3G) and peptides alone or in combinations, alter the expression of genes related to glucose metabolism in skeletal muscles from diet-induced obese mice. In extensor digitorum longus (EDL), yoghurt up-regulated the expression of activation of 5'adenosine monophosphate-activated protein kinase (AMPK), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-3 kinase (PI3K) and glucose transporter 4 (GLUT4), and down-regulated the expression of angiotensin II receptor type 1 (AGTR-1). The combination of blueberries and yoghurt down-regulated the mRNA expression of AGTR-1 and Forkhead box protein O1 (FoxO1) in the EDL. Whereas the combination of C3G and peptides down-regulated AGTR-1 and up-regulated GLUT4 mRNA expression in the EDL. In the soleus, blueberries and yoghurt alone, and their combination down-regulated AGTR-1 and up-regulated GLUT4 mRNA expression. In summary blueberries and yoghurt, regulated multiple genes associated with glucose metabolism in skeletal muscles, and therefore may play a role in the management and prevention of T2DM.

Jiaying Tan,1,* Wenjin Yu,2,* Gang Wu,1 Jun Shen,1 Yong Fang,1 Hechen Zhu,1 Qianyi Xiao,3 Weixia Peng,3 Yukun Lan,3 Ye Gong1 1Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, People’s Republic of China; 2Department of Pharmacy , Huashan Hospital, Fudan University, Shanghai 200040, People’s Republic of China; 3Department of Preventive Medicine and Health Education, School of Public Health, Fudan University, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ye Gong Email gong_ye@fudan.edu.cnBackground: We conducted a real-world analysis of the effectiveness of different antibiotic regimens for bloodstream infections (BSIs) caused by carbapenem-resistant gram-negative bacilli (CR-GNB) in a Chinese population.Methods: A retrospective observational study was conducted between January 2010 and December 2017. Patients with BSIs caused by CR-GNB confirmed by in vitro susceptibility tests were enrolled, and patient medical record data on antimicrobial agents and microbiological and clinical outcomes were extracted.Results: A total of 175 individuals were included; 127 individuals (72.6%) received combination therapy (two or more antibiotics), while 48 individuals (27.4%) received monotherapy (single antibiotic). The all-cause 28-day mortality was 20.0%. Treatment success or presumed success rates were very similar between the monotherapy and combination therapy groups (58.3% versus 59.1%; P = 0.931). Combination therapy had a higher success rate trend than monotherapy in septic shock patients (40.7% versus 18.2%; P = 0.268). Improved therapeutic effects were observed in the active agent-containing group, although the differences were not significant.Conclusion: Combination therapy likely has better therapeutic effects on critical BSIs caused by CR-GNB than monotherapy. Choosing a proper active agent in an antimicrobial regime is relatively crucial to the ultimate treatment outcome.Keywords: bloodstream infection, carbapenem-resistant gram-negative bacilli, antimicrobial regimen, treatment success rate, real-world, Chinese population

Kai Huang,1 Yehua Wang,1 Xiao Gu,1 Qin Xiao,2 Xiangan Tu3 1Department of Urology, College of Clinical Medicine, Yangzhou University, Northern Jiangsu People’s Hospital, Yangzhou, Jiangsu Province, People’s Republic of China; 2Department of Pathology, College of Clinical Medicine, Yangzhou University, Northern Jiangsu People’s Hospital, Yangzhou, Jiangsu Province, People’s Republic of China; 3Department of Urology and Andrology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of ChinaCorrespondence: Kai HuangDepartment of Urology, College of Clinical Medicine, Yangzhou University, Northern Jiangsu People’s Hospital, No. 98 West Nantong Road, Yangzhou, Jiangsu Province 225001, People’s Republic of ChinaEmail huangkai_2015@163.comXiangan TuDepartment of Urology and Andrology, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou, Guangdong Province 510080, People’s Republic of ChinaEmail txabs9988@163.comPurpose: To explore the laparoscopic technique with the retroperitoneal approach for complex adrenal tumors.Patients and Methods: The clinical data of 11 patients with complex adrenal tumors from July 2017 to July 2018 were analyzed retrospectively. Among them, there were 4 males and 7 females, 4 with adrenal myelolipomas, 3 with adrenal pheochromocytomas, 2 with adrenal cysts, 1 with adrenocortical adenoma and 1 with adrenal ganglioneuroma. The average tumor diameter was 6.5 ± 1.2 cm, and the average age of the patients was 48 ± 13 years.Results: All the operations were successfully completed. The average operation time was 95 ± 15 min, the average amount of blood loss was 50 ± 15 mL, and the average postoperative hospital stay was 2.6 ± 1.3 days. No tumor recurrence was found after 1 year of follow-up.Conclusion: Retroperitoneal laparoscopic surgery is effective for the treatment of complex adrenal tumors, but it requires good surgical skills. Surgeons skilled in laparoscopic technology can safely carry out retroperitoneal laparoscopic surgery for complex adrenal tumors.Keywords: laparoscopy, retroperitoneal approach, complex adrenal tumor, surgery

Kun Wu,1 Zhu Yu,1 Zhenyong Tang,1 Weiyuan Wei,1 Dongyi Xie,1 Yubo Xie,2 Qiang Xiao1 1Department of Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of ChinaCorrespondence: Yubo Xie; Qiang XiaoDepartment of Anesthesiology, Department of Surgery, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaTel/Fax +86 771 535 8325Email 1157817791@qq.com; xiaoqiang@gxmu.edu.cnPurpose: miR-877-5p has been reported as a tumor suppressor in multiple cancers. Its role in gastric cancer, however, remains unclear. Hence, the purpose of this study was to elucidate the function, and underlying molecular mechanism, of miR-877-5p in the development of gastric cancer.Materials and Methods: We first analyzed miR-877-5p expression using the Gene Expression Omnibus (GEO) database and detected its expression in gastric cancer and gastric epithelial cells via real-time quantitative PCR (qRT-PCR). We then assessed the role of miR-877-5p in gastric cancer proliferation, apoptosis, and cell cycling. The gene targeted by miR-877-5p was predicted by bioinformatic analysis and confirmed by dual luciferase assay. Subsequently, rescue assays were carried out to validate whether the miR-877-5p effects on gastric cancer growth are dependent on the proposed target gene.Results: miR-877-5p levels were lower in gastric cancer than in controls, based on the GEO and qRT-PCR analyses. Overexpression of miR-877-5p significantly inhibited cell growth and cell cycle progression, whereas it promoted apoptosis. Furthermore, forkhead box M1 (FOXM1) was predicted as a target of miR-877-5p, the overexpression of which diminished the suppressive effect that upregulation of miR-877-5p had on gastric cancer cells.Conclusion: Our study results indicate that the miR-877-5p/FOXM1 axis plays an important role in gastric cancer progression, while suggesting miR-877-5p as a novel potential therapeutic target for gastric cancer.Keywords: gastric carcinoma, microRNA-877-5p, forkhead box M1, tumor growth, cell cycle arrest, tumor suppressor function

Ziyu Li, 1,* Qiyan Xiao, 1,* Yinkui Wang, 1,* Wei Wang, 2,* Shuangxi Li, 1 Fei Shan, 1 Zhiwei Zhou, 2 Jiafu Ji 1 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiafu JiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Beijing 100142, People’s Republic of ChinaTel +86-10-88196598Fax +86-10-8819-6698Email jijiafu@hsc.pku.edu.cnZhiwei ZhouState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of ChinaTel +86-20-87343123Fax +86-20-87343910Email zhouzhw@sysucc.org.cnPurpose: Neoadjuvant chemotherapy is now widely used in gastric cancer patients. However, the current 8th ypTNM staging system is developed based on patients with less extensive lymph node dissection and the predictive value is relatively limited. In this study, we aim to develop and validate a nomogram that predicts overall survival in gastric cancer patients received neoadjuvant chemotherapy.Patients and Methods: From January, 2007 to December, 2014, 471 patients receiving neoadjuvant chemotherapy at our center were enrolled in the study. Based on the Cox proportional hazard model, a nomogram was developed from them and then an external validation was conducted on a cohort of 239 patients from another cancer center.Results: The overall survival (OS) rates of 1 year and 3 years were 90.0% and 64.1%, respectively. Body mass index category, tumor location, T stage and N stage were independent prognostic factors for the survival outcome. The C-index of the model was 0.74 in the development cohort and 0.69 in the validation cohort. Our nomogram also showed good calibration in both cohorts.Conclusion: We developed and validated a nomogram to predict the 1- and 3-year OS of patients who received neoadjuvant chemotherapy and radical gastrectomy with D2 lymph node dissection. This nomogram predicts survival more accurately than the AJCC TNM staging system, which is the current golden standard.Keywords: stomach neoplasms, perioperative chemotherapy, survival, nomograms

Yunfei Liu, 1 Li Xia, 2 Luo Dong, 1 Jiale Wang, 1 Qiangsheng Xiao, 1 Xiao Yu, 1 Hongwei Zhu 3 1Department of Hepatobiliary and Pancreatic Surgery‖, Third Xiangya Hospital, Central South University, Changsha 410006, People’s Republic of China; 2Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha, 410006, People’s Republic of China; 3Department of Gastroenterology and Hepatology, Third Xiangya Hospital, Central South University, Changsha, 410006, People’s Republic of ChinaCorrespondence: Xiao YuDepartment of Hepatobiliary and Pancreatic Surgery‖, Third Xiangya Hospital, Central South University, Changsha 410006, People’s Republic of ChinaTel/Fax +86 731-88618831Email lyfxys@sina.com Hongwei ZhuDepartment of Gastroenterology and Hepatology, Third Xiangya Hospital, Central South University, Changsha, 410006, Republic of ChinaTel/Fax +86 731-88618831Email wsqjms123456@163.comBackground: Pancreatic cancer is one of the most common malignant diseases in the world. Gemcitabine chemotherapy remains the most important clinical treatment. However, research found that pancreatic cancer cells have chemoresistance to gemcitabine and the effect is not satisfactory. Therefore, it is urgent to find an effective early diagnosis and treatment strategy. Circular RNA is one of the most popular prognostic biomarkers in GEM-resistant PC.Materials and Methods: The present study was designed to evaluate the role of circHIPK3 in PC. The expression of circHIPK3 in PC tissues and cells and its effect on proliferation, migration, invasion, EMT, and apoptosis were investigated in vitro; its effect on tumor xenografts was assessed in vivo. Used bioinformation analysis to predict which miRNAs could potentially interact with circHIPK3, mRNA, and miR-330-5p.Results: RT-PCR showed that the level of circHIPK3 was increased in PC tumor tissues; moreover, circHIPK3 was also increased in GEM-resistant PC tumors tissues and GEM-resistant PC cells. Sh-circHIPK3 could knockdown circHIPK3 in PANC-1-GEM and SW-1990-GEM and could significantly inhibit cell proliferation, invasion, migration, EMT and enhance cell apoptosis, compare with control group, the tumor xenografts of circHIPK3 knockdown group were significantly smaller. CircHIPK3 served as a sponge for miR-330-5p, and miR-330-5p directly bound to the 3′ UTR of RASSF1 were revealed by dual luciferase assay and RIP in PC cells. CircHIPK3 knockdown of RASSF1 expression could neutralize the cytological function of PC cells by miR-330-5p inhibitor mediated GEM-resistance.Conclusion: CircHIPK3 promote gemcitabine (GEM) resistance in pancreatic cancer cells by targeting RASSF1 via miR-330-5p and regulates proliferation, invasive, migration, EMT, and apoptosis. Our research revealed that circHIPK3 may be a novel biomarker in GEM-resistant PC and could be used as a prognostic target.Keywords: pancreatic cancer, circular RNA, gemcitabine resistance, biomarker

Yanyi Zhang, Yi Wen, Qiulin Xiao, Wei Zheng, Gao Long, Bo Chen, Xiaoli Shu, Mizu Jiang Department of Gastroenterology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Mizu JiangDepartment of Gastroenterology, Children’s Hospital, Zhejiang University School of Medicine,National Clinical Research Center for Child Health, Hangzhou 310003, Zhejiang, People’s Republic of ChinaTel +86-571-86670046Fax +86-571-86658653Email mizu@zju.edu.cnPurpose: This study aimed to characterize common mutations of antibiotic-resistant gene of clarithromycin, metronidazole and levofloxacin in Helicobacter pylori (H. pylori) and determine their association with antibiotic resistance of H. pylori for providing a strategy for eradication therapy of H. pylori infection in children.Patients and Methods: The antibiotic resistance to clarithromycin, metronidazole and levofloxacin for H. pylori strains isolated from children was determined by E-test. The mutation of domain V of 23S rRNA, rdxA and frxA genes, gyrA and gyrB genes was performed by PCR-based sequencing of DNA fragments.Results: Out of the 79 H. pylori strains examined, 66 (83.5%) were resistant to at least one of the tested antibiotics and 13 (16.5%) were fully sensitive. A total of 29 (36.7%) strains were resistant to clarithromycin. Analysis of the 23S rRNA gene showed that most mutations occurred at the A2143G and T2182C sites, showing a frequency of 82.8% (24/29) and 89.7% (26/29) respectively. In the 11 sensitive strains to clarithromycin, the frequency of A2143G mutation was only 45.5%, which was significantly lower than that in resistant strains (P< 0.05). There were 54 strains (68.4%) resistant to metronidazole, with most mutations occurring at G47A and T184G in the rdxA gene. T184G mutation was recognized in metronidazole-sensitive strains, but no G47A mutation was identified. Twelve strains (15.2%) were resistant to levofloxacin. Position 91 mutation of the gyrA gene occurred only in resistant strains, whereas position 87 mutations were detected in both sensitive and resistant strains to levofloxacin.Conclusion: In H. pylori resistant strains isolated from children in China, most mutations occurred at A2143G of the 23S rRNA gene for clarithromycin; G47A mutation of rdxA gene for metronidazole; and at 91 mutation of gyrA gene for levofloxacin. It is suggested that susceptibility testing together with screening the mutation of antimicrobial-resistant gene prior to treatment is important for the eradication of H. pylori in children.Keywords: Helicobacter pylori, Metronidazole, Clarithromycin, Levofloxacin, antibiotic resistant, gene

It is widely acknowledged that type 2 diabetes mellitus (T2DM) is associated with obesity, insulin resistance and hypertension. Cyanidin-3-O-β-glucoside (C3G), an anthocyanin in blueberry, and peptides with angiotensin converting enzyme (ACE) inhibitory activity derived from yoghurt are potentially beneficial for numerous health conditions including improving insulin resistance and glucose intolerance. In this study, the synergistic/additive effects of combined supplementations with blueberry and yoghurt, and C3G and peptides were determined. Blueberry and yoghurt alone, and the combination of C3G and peptides significantly reduced both systolic and diastolic blood pressure in diet-induced obese mice. Yoghurt supplementation significantly reduced body weight, percentage body fat and improved intraperitoneal glucose tolerance. Furthermore, peptides and the combination of peptides and C3G resulted in a significant reduction of percentage body fat and improved intraperitoneal glucose tolerance. As widely available, safe and nutritious foods, blueberry and yoghurt showed therapeutic potential in the treatment of obesity, diabetes and hypertension.

Weiyuan Wei,1,* Wenlong Cao,1,* Zexu Zhan,1 Linhai Yan,2 Yubo Xie,3 Qiang Xiao11Department of Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 2Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 3Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China *These authors contributed equally to this workBackground: MicroRNAs (miRNAs) play a key role in the development of gastric cancer (GC). MiRNA arrays showed that lymph node metastasis in GC is correlated with the expression of miR-1284. Although its function and mechanisms in GC have not been fully described, the regulation of EIF4A1 by miR-1284 and its role in drug-resistant GC has been reported in our previous studies.Methods: qRT-PCR was used to study the level of miR-1284 expression in GC cell lines and tissues. Subsequently, the CCK-8 assay was used to detect cell proliferation, while transwell assay was used to detect invasion and migration of the GC cells. Flow cytometry was used to detect the effect of miR-1284 on GC cells in vivo by building subcutaneous GC nude mice transplantation tumor model. In addition, the influence of miR-1284 gene expression profile in SGC-7901 cells was detected by total gene expression chip, and the target gene of miR-1284 was detected by luciferase reporter assay, qRT-PCR, and western blotting.Results: The miR-1284 level was down-regulated in GC tssues and cell lines. MiR-1284 was significantly associated with tumor size, degree of differentiation and patients’ distant metastasis. MiR-1284 inhibited invasion, migration, and proliferation of GC cells. During the G1/S phase, miR-1284 arrested the cycle of GC cells in vitro. MiR-1284 also suppressed tumor from growing and metastasizing in xenograft models as well as influenced the gene expression profile in SGC-7901 cells. Also, EIF4A1 was the direct target gene for miR-1284. Further, an inverse correlation between the miR-1284 expression and EIF4A1 was found in GC tissues. Over-expressed miR-1284 decreased c-Myc, MMP12, JUN expression, while increased CDH1 expression.Conclusion: These data suggested that miR-1284 acts as a tumor suppressor, and directly blocked EIF4A1 in GC.Keywords: MiR-1284, gastric cancer, EIF4A1, metastasis, proliferation

Changwu Wu,1 Jun Su,1 Xiangyu Wang,1 Junquan Wang,1 Kai Xiao,1 Yang Li,1 Qun Xiao,1 Min Ling,1 Yao Xiao,1 Chaoying Qin,1 Wenyong Long,1,2 Fengqi Zhang,1 Yimin Pan,1 Feng Xiang,1 Qing Liu1,21Department of Neurosurgery, Xiangya Hospital, Central-South University, Changsha, Hunan, People’s Republic of China; 2Institute of Skull Base Surgery and Neuro-Oncology at Hunan Neurosurgery Institute of Central South University, Changsha, Hunan, People’s Republic of ChinaPurpose: Gliomas are the most common primary malignant neoplasms of the central nervous system. Secreted phospholipases A2 (sPLA2s) are known to play an important role in various physiological processes, including bioactive lipid production, defense mechanisms, and cell signaling. However, their roles and clinical importance in gliomas remain unclear.Patients and methods: In this study, we analyzed the association between the expression of various sPLA2-encoding genes and the clinicopathology of gliomas, using the data of 1047 patients obtained from a public database. Immunohistochemical analysis of 82 glioma tissues was also carried out to assess the relationship between phospholipase A2 group V (PLA2G5) protein expression and the World Health Organization (WHO) glioma grades.Results: We found that high PLA2G5 gene expression was associated with unfavorable prognosis in both low-grade and high-grade gliomas. The immunohistochemistry of the 82 glioma tissues further confirmed that PLA2G5 protein expression was dependent on the WHO glioma grade. In addition, we found a correlation between PLA2G5 gene expression and both epithelial–mesenchymal transition and the isocitrate dehydrogenase 1 mutation status in these tumors.Conclusion: Our results indicate that PLA2G5 could be a potential biomarker for predicting poor prognosis in patients with gliomas.Keywords: secretory phospholipases A2, glioma, PLA2G5, biomarker

Abstract Growing evidence suggests that ethanolamine plasmalogens (PlsEtns), a subtype of phospholipids, have a close association with Alzheimer’s disease (AD). Decreased levels of PlsEtns have been commonly found in AD patients, and were correlated with cognition deficit and severity of disease. Limited studies showed positive therapeutic outcomes with plasmalogens interventions in AD subjects and in rodents. The potential mechanisms underlying the beneficial effects of PlsEtns on AD may be related to the reduction of γ–secretase activity, an enzyme that catalyzes the synthesis of β-amyloid (Aβ), a hallmark of AD. Emerging in vitro evidence also showed that PlsEtns prevented neuronal cell death by enhancing phosphorylation of AKT and ERK signaling through the activation of orphan G-protein coupled receptor (GPCR) proteins. In addition, PlsEtns have been found to suppress the death of primary mouse hippocampal neuronal cells through the inhibition of caspase-9 and caspase-3 cleavages. Further in-depth investigations are required to determine the signature molecular species of PlsEtns associated with AD, hence their potential role as biomarkers. Clinical intervention with plasmalogens is still in its infancy but may have the potential to be explored for a novel therapeutic approach to correct AD pathology and neural function.

Youbing Tu,1 Yubing Liang,2 Yong Xiao,1 Jing Lv,1 Ruicong Guan,1 Fei Xiao,1 Yubo Xie,1,* Qiang Xiao3,* 1Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China; 2Department of Anesthesiology, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, China; 3Department of Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China *These authors contributed equally to this work Background: Propofol is a commonly used general anesthetic for the induction and maintenance of anesthesia and critical care sedation in children, which may add risk to poor neurodevelopmental outcome. We aimed to evaluate the effect of propofol toward primary hippocampal neurons in vitro and the possibly neuroprotective effect of dexmedetomidine pretreatment, as well as the underlying mechanism.Materials and procedures: Primary hippocampal neurons were cultured for 8 days in vitro and pretreated with or without dexmedetomidine or phosphorylation inhibitors prior to propofol exposure. Cell viability was measured using cell counting kit-8 assays. Cell apoptosis was evaluated using a transmission electron microscope and flow cytometry analyses. Levels of mRNAs encoding signaling pathway intermediates were assessed using qRT-PCR. The expression of signaling pathway intermediates and apoptosis-related proteins was determined by Western blotting.Results: Propofol significantly reduced cell viability, induced neuronal apoptosis, and downregulated the expression of the BDNF mRNA and the levels of the phospho-Erk1/2 (p-Erk1/2), phospho-CREB (p-CREB), and BDNF proteins. The dexmedetomidine pretreatment increased neuronal viability and alleviated propofol-induced neuronal apoptosis and rescued the propofol-induced downregulation of both the BDNF mRNA and the levels of the p-Erk1/2, p-CREB, and BDNF proteins. However, this neuroprotective effect was abolished by PD98059, H89, and KG501, further preventing the dexmedetomidine pretreatment from rescuing the propofol-induced downregulation of the BDNF mRNA and p-Erk1/2, p-CREB, and BDNF proteins.Conclusion: Dexmedetomidine alleviates propofol-induced cytotoxicity toward primary hippocampal neurons in vitro, which correlated with the activation of Erk1/2/CREB/BDNF signaling pathways. Keywords: hippocampus, propofol, dexmedetomidine, extracellular signal-regulated MAP kinases, cyclic AMP response element-binding protein, brain-derived neurotrophic factor

Xiaohui Ren,1,2 Le Zhang,3 Qiuxia Xiao,2 Daxue Huang,1 Qing Liu,2 Ying Zhang2 1Department of Anesthesiology, Neijiang City Central Maternal and Child Health Care Hospital, Neijiang 641000, Sichuan, China; 2Department of Anesthesiology and Pain Management, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China; 3Department of Anesthesiology, Sichuan Provincial Armed Police Corps Hospital, Leshan 614000, Sichuan, China Background: COMT gene polymorphism is associated with mental disorders and sensitivity to pain. In this study, we investigated the association between the COMT gene polymorphism and labor anxiety and analgesia in pregnant women.Subjects and methods: A total of 425 pregnant women undergoing labor analgesia were selected from May 2016 to February 2018. The COMT gene polymorphism was detected through the PCR with restriction fragment length polymorphism technique before childbirth. According to a COMT genotype, the enrolled pregnant women were subdivided into the Val/Val (allele GG) group, the Met/Met (allele AA) group, and the Val/Met (allele GA) group. Then, the intervertebral space of all pregnant women was injected with 3 mL of 2% lidocaine +6 mL of 0.08% ropivacaine and 6 µg of fentanyl. Labor analgesia was administered as follows: 80 mg of 0.08% ropivacaine +100 µg of fentanyl + normal saline to 100 mL. The general characteristics of the women were examined and recorded. In addition, the State Anxiety Inventory (SAI), VAS, Ramsay sedation score, and epinephrine and norepinephrine levels were compared and analyzed.Results: A total of 391 pregnant women were enrolled in this study; among these pregnant women, there were 180 pregnant women in the GG group, 132 in the GA group, and 99 in the AA group. The minor allele frequency of COMT polymorphism among these pregnant women was 32.8%. Compared with the GG group, the SAI and VAS scores were higher, the Ramsay sedation score was lower, and the epinephrine and norepinephrine levels were higher in AA and GA groups (P0.05).Conclusion: The COMT gene polymorphism was associated with labor anxiety and analgesia among pregnant women, and the Val158Met mutation in the COMT gene could lead to worse labor anxiety and less-effective labor analgesia in pregnant women. Keywords: COMT, polymorphism, labor anxiety, labor analgesia

Incidence of type II diabetes mellitus (T2DM) is rapidly increasing worldwide. This study aimed to investigate whether cyanidin-3-O-β-glucoside (C3G), or peptides with angiotensin converting enzyme (ACE) inhibitory activity, alone or in combination, alter glucose regulation in human primary myotubes derived from obese and obese T2DM participants. In the obese group, both low and high concentration of peptides and the combination of these peptides with high C3G concentration significantly enhanced glucose uptake in the presence or absence of insulin, and high concentration of peptide alone and its combination with low C3G down-regulated the mRNA expression of angiotensin II receptor, type 1 (AGTR-1), and up-regulated the mRNA expression of insulin receptor substrate 1 (IRS-1), and glucose transporter 4 (GLUT4). However, only high peptide concentration increased glucose uptake in the absence of insulin in the obese T2DM group, and the expression of AGTR-1 was decreased with high peptide and its combinations of C3G.

Liubo Chen,1,2,* Kai Jiang,1,2,* Haiyan Chen,1,3,* Yang Tang,1,2 Xinyi Zhou,1,2 Yinuo Tan,1,4 Ying Yuan,1,4 Qian Xiao,1,2 Kefeng Ding1,2 1Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; 2Department of Surgical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; 3Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; 4Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China *These authors contributed equally to this work Objectives: Deguelin, a rotenoid extracted from Mundulea sericea (Leguminosae), exhibits antitumor effects on several types of human cancers. Due to the limited studies of deguelin on colorectal cancer (CRC), the present study was designed to investigate the antitumor effect of deguelin and to explore the underlying mechanism in CRC. Materials and methods: Cell viability was assessed by the cell counting kit-8 (CCK-8) assay, and cell apoptosis was determined by the annexin v-propidium iodide staining using flow cytometry and Western blot in CRC cell lines after incubation with deguelin. The antitumor effect of deguelin was further evaluated in tumor xenograft models. Moreover, SB203580, a specific inhibitor of p38 MAPK, was used to confirm the involvement of p38 MAPK pathway in deguelin-induced apoptosis. Results: Deguelin significantly inhibited cell proliferation and induced apoptosis in CRC cell lines (SW620 and RKO) in a time-dependent and dose-dependent manner. Western blot analysis also showed that the expression of proapoptotic proteins (cleaved caspase 3 and cleaved PARP) was upregulated, while that of antiapoptotic proteins (Bcl-2 and survivin) was downregulated after deguelin treatment in CRC cell lines. Moreover, oral administration of deguelin significantly suppressed tumor growth and induced apoptosis in subcutaneous xenograft mouse models without obvious toxicity. Additionally, Western blot revealed that deguelin-induced apoptosis might be regulated by the p38 MAPK pathway and inhibition of p38 MAPK could attenuate deguelin-induced proliferative inhibition and apoptosis in CRC cells. Conclusion: Collectively, these results demonstrated that deguelin inhibited CRC cell growth by inducing apoptosis via activation of p38 MAPK pathway. Keywords: deguelin, colorectal cancer, apoptosis, p38 MAPK pathway

Han Yu,1,* Weiyuan Wei,1,2,* Wenlong Cao,1 Zexu Zhan,1 Linhai Yan,2 Kun Wu,1 Dongyi Xie,1 Bin Cai,1 Yubo Xie,3 Qiang Xiao1 1Department of Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China; 2Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China; 3Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China *These authors contributed equally to this work Background: MicroRNA (miRNA) array analysis has reported that the expression of miR-593-5p is associated with lymph node metastasis in gastric cancer (GC); however, the function and mechanism of miR-593-5p in GC have not been described yet. miR-593-5p has also not been elucidated widely in other cancers. Methods: miR-593-5p expression was detected by quantitative RT-PCR (qRT-PCR) in human GC tissues and cell lines. Cell proliferation was investigated using CCK-8 assays, cell cycle was detected by flow cytometric method, and cell migration and invasion abilities were evaluated by wound-healing and transwell assays. miR-593-5p-influenced gene expression profiles were detected by total gene expression chip method in MGC-803 cells, and miR-593-5p candidate target genes were predicted using bioinformatics methods. The candidate target gene and downstream of miR-593-5p were determined by qRT-PCR, Western blot, and dual-luciferase reporter assays. The effects of miR-593-5p on the growth and metastasis of GC were evaluated by tumor xenograft experiment in vivo. Results: miR-593-5p was frequently downregulated in GC patients and GC cell lines. miR-593-5p was significantly correlated with tumor size and distant metastasis in GC patients. miR-593-5p inhibited cell proliferation, migration, and invasion and also arrested cell cycle at the G0/G1 phase in SGC-7901 and MGC-803 cells in vitro. miR-593-5p also suppressed tumor growth and metastasis in vivo. miR-593-5p influenced gene expression profile in MGC-803 cells. MST4 was indirectly targeted by miR-593-5p. miR-593-5p also downregulated FAK, MMP12, and JUN protein expression. Conclusion: Our study suggests that miR-593-5p may function as a tumor suppressor in GC through a mechanism that regulates JUN pathway via indirectly targeting the MST4 gene. Keywords: miR-593-5p, gastric cancer, MST4, JUN pathway

ABSTRACT The microbiome in fermentation has direct impacts on the quality of fermented foods and is of great scientific and commercial interest. Despite considerable effort to explain the microbial metabolism associated with food fermentation, the role of the microbiome in pu-erh tea fermentation remains unknown. Here, we applied integrated meta-omics approaches to characterize the microbiome in two repeated fermentations of pu-erh tea. Metabarcoding analysis of bacterial 16S rRNA genes showed a decrease in the proportion of Proteobacteria and an increase in the abundance of Firmicutes during fermentation. Metabarcoding analysis of fungal internal transcribed spacer (ITS) sequence demonstrated that Rasamsonia, Thermomyces, and Aspergillus were dominant at the intermediate stage, whereas Aspergillus was dominant at other stages in fermentation. Metaproteomics analysis assigned primary microbial metabolic activity to metabolism and identified microbial carbohydrate-active enzymes involved in the degradation of polysaccharides including cellulose, xylan, xyloglucan, pectin, starch, lignin, galactomannan, and chitin. Metabolomics and high-performance liquid chromatography analysis revealed that levels of phenolic compounds, including gallates, decreased whereas contents of gallic acid and ellagic acid significantly increased after fermentation (P

Haoyu Ren,1 Yifan Shen,2 Daixing Hu,1 Wei He,1 Jing Zhou,1 Yijia Cao,1 Yu Mao,1 Yi Dou,1 Wei Xiong,1 Qi Xiao,1 Yuhong Zhang,2 Xinliang Su1 1Department of Endocrine and Breast Surgery, 2The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China Background: Mutations of BRAFV600E and TERT promoters are associated with thyroid cancer development. This study further investigated association of these mutations with clinicopathological characteristics from patients with papillary thyroid carcinoma (PTC). Methods: Tumor tissues from 342 PTC patients were obtained for DNA extraction and polymerase chain reaction amplification to detect the BRAFV600E mutation using amplification-refractory mutation system-polymerase chain reaction. TERT promoter mutations were assessed using Sanger DNA sequencing. The association of these gene mutations with clinicopathological characteristics was then statistically analyzed. Results: Two hundred and seventy of 342 (78.9%) PTC patients harbored the BRAFV600E mutation, which was associated with older age male patients. Moreover, TERT promoter mutations occurred in 12 of 342 (3.5 %) PTC patients, all of whom also had the BRAF mutation. One hundred thirty-three patients with papillary thyroid microcarcinoma (PTMC) had no TERT mutations. Statistically, the coexistence of BRAF and TERT promoter mutations were significantly associated with older age, larger tumor size, extrathyroidal extension, and advanced tumor stage, but not with central lymph node metastasis, lateral lymph node metastasis, numbers of lymph node metastasis >5, and numbers of involved/harvested lymph nodes (No. of LNs involved or harvested). The multivariate analyses showed older age (odds ratio [OR], 2.194; 95% CI: 1.117–4.311; p=0.023), larger tumor size (OR, 4.100; 95% CI: 2.257–7.450; p

Zhifeng Zhong,1 Jing Han,1 Jizhou Zhang,1 Qing Xiao,1 Juan Hu,1,2 Lidian Chen1,2 1Institute of Materia Medica, Fujian Academy of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China; 2School of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China Abstract: The primary objective of this review article was to summarize comprehensive information related to the neuropharmacological activity, mechanisms of action, toxicity, and safety of salidroside in medicine. A number of studies have revealed that salidroside exhibits neuroprotective activities, including anti-Alzheimer’s disease, anti-Parkinson’s disease, anti-Huntington’s disease, anti-stroke, anti-depressive effects, and anti-traumatic brain injury; it is also useful for improving cognitive function, treating addiction, and preventing epilepsy. The mechanisms underlying the potential protective effects of salidroside involvement are the regulation of oxidative stress response, inflammation, apoptosis, hypothalamus-pituitary-adrenal axis, neurotransmission, neural regeneration, and the cholinergic system. Being free of side effects makes salidroside potentially attractive as a candidate drug for the treatment of neurological disorders. It is evident from the available published literature that salidroside has potential use as a beneficial therapeutic medicine with high efficacy and low toxicity to the central nervous system. However, the definite target protein molecules remain unclear, and clinical trials regarding this are currently insufficient; thus, guidance for further research on the molecular mechanisms and clinical applications of salidroside is urgent. Keywords: salidroside, Alzheimer’s disease, Parkinson’s disease, stroke, cognitive impairment, clinical trials

Yue Jing,1,2,* Gang Wang,1,* Qi Xiao,1 Yachun Zhou,1 Yingjie Wei,3 Zhunan Gong1 1Center for New Drug Research and Development, College of Life Science, Nanjing Normal University, Nanjing, China; 2Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China; 3Key Laboratory of Oral Drug Delivery System of Chinese Materia Medica of State Administration of Traditional Chinese Medicine, Jiangsu Branch of China Academy of Chinese Medical Science, Nanjing, China *These authors contributed equally to this work Abstract: Angiogenesis plays a vital role in many physiological and pathological processes and several diseases are connected with its dysregulation. Asiatic acid (AA) has demonstrated anticancer properties and we suspect this might be attributable to an effect on angiogenesis. A modified derivative of AA, N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-L-proline methyl ester (AA-PMe), has improved efficacy over its parent compound, but its effect on blood vessel development remains unclear. Methods: In this study, we investigated the antiangiogenic activity of AA and AA-PMe in zebrafish embryos and human umbilical vein endothelial cells (HUVECs). First of all, we treated HUVECs with increasing concentrations of AA-PMe or AA, with or without vascular endothelial growth factor (VEGF) present, and assessed cell viability, tube formation, and cell migration and invasion. Quantitative real-time polymerase chain reaction and Western blot analysis were later used to determine the role of vascular endothelial growth factor receptor 2 (VEGFR2)-mediated signaling in AA-PMe inhibition of angiogenesis. We extended these studies to follow angiogenesis using Tg(fli:EGFP) transgenic zebrafish embryos. For these experiments, embryos were treated with varying concentrations of AA-PMe or AA from 24 to 72 hours postfertilization prior to morphological observation, angiogenesis assessment, and endogenous alkaline phosphatase assay. VEGFR2 expression in whole embryos following AA-PMe treatment was also determined. Results: We found AA-PMe decreased cell viability and inhibited migration and tube formation in a dose-dependent manner in HUVECs. Similarly, AA-PMe disrupted the formation of intersegmental vessels, the dorsal aorta, and the posterior cardinal vein in zebrafish embryos. Both in vitro and in vivo AA-PMe surpassed AA in its ability to block angiogenesis by suppressing VEGF-induced phosphorylation of VEGFR2 and disrupting downstream extracellular regulated protein kinase and AKT signaling. Conclusion: For the first time, this study reveals that AA-PMe acts as a potent VEGFR2 kinase inhibitor and exerts powerful antiangiogenic activity, suggesting it to be a promising therapeutic candidate for further research. Keywords: AA-PMe, angiogenesis inhibitor, zebrafish, HUVEC

Recent experimental and clinical studies suggest that consumption of blueberry products has potential health benefits in ameliorating the development of obesity and its related comorbidities, including type 2 diabetes (T2D) and chronic inflammation. Blueberry fruits are enriched with numerous bioactive components such as vitamins, phenolic acid and anthocyanins which could contribute to these protective effects. Possible mechanisms by which blueberries exert their beneficial properties include counteracting oxidative stress, regulating glucose metabolism, improving lipid profile, and lowering inflammatory cytokine levels in animal models and preliminary human trials. This review focuses on the potential role of blueberries as a functional food in the prevention and treatment of obesity and its comorbidities. Although the current evidence is promising, further randomized controlled studies in the longer term are needed to evaluate the role of blueberries and blueberry extracts to support human health.

Limited studies have shown that Coleus forskohlii extract may aid in weight management. This randomized, double blind placebo-controlled clinical study assessed the effects of supplementation with C. forskohlii extract on key markers of obesity and metabolic parameters in overweight and obese individuals. Thirty participants completed the trial and they were randomly assigned to receive either 250 mg of C. forskohlii extract (n = 15) or a placebo twice daily for 12 weeks. All participants were advised to follow a hypocaloric diet throughout the study. Body weight, body mass index (BMI), waist and hip circumference, and waist to hip ratio, were monitored fortnightly. Dietary intake was assessed at the baseline and weeks 4, 8 and 12. Appetite was assessed using visual analogue scales and blood samples were analyzed for plasma lipids, ghrelin, leptin, glucose and insulin at the baseline and end of the intervention. Significant reductions to waist and hip circumference (p = 0.02; p = 0.01, respectively) were recorded in both experimental and placebo groups after the 12 week intervention. Furthermore, high density lipoprotein-cholesterol (HDL-C) was significantly increased (p = 0.01) in both groups. The experimental group showed a favorable improvement in insulin concentration and insulin resistance (p = 0.001; 0.01 respectively) compared to the placebo group. These findings suggest that C. forskohlii extract in conjunction with a hypocaloric diet may be useful in the management of metabolic risk factors.