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Caige Li,1,2 Yu Xue,1 Yiwei Liu,1 Kangning Zheng,1 Yuting Gao,1,3 Yi Gong,1 Junlan Lu,1 Yuman Zhang,1 Jingmin Ji,1 Zhiqin Zhang,1 Xinli Shi1 1Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 3School of Basic Medical Sciences, Shanxi University of Chinese Medicine, Jinzhong, Shanxi, People’s Republic of ChinaCorrespondence: Xinli Shi, Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, 3 Xingyuan Road, Shijiazhuang, Hebei, 050200, People’s Republic of China, Tel +86-0311-89926237, Email sxlsunshine@sina.comIntroduction: Yes-associated protein 1 (YAP1) is a crucial molecule in the Hippo pathway. The impact of hepatocyte-specific Yap1 knockout (Yap1LKO) on hepatic lipid droplets (LD) and pePLIN2 in metabolic fatty liver has not been reported. This study aims to explore whether Yap1LKO could offer a protective effect in a liver injury model.Methods: Three-week-old Yap1LKO and Yap1Flox mice were given aristolochic acid I (AAI) combined carbon tetrachloride (CCL4) establish liver injury model. Eight-week-old Yap1LKO and Yap1Flox mice were fed with a high-fat diet for 18 weeks to establish obesity-related liver injury model. Further biochemical, histomorphological, immunohistochemical, and lipidomic analyses were performed on serum and liver tissues of these mice to elucidate the effects of hepatocyte-specific Yap1 knockout on hepatic lipid metabolism.Results: Yap1LKO reduced triglyceride (TG) content and PLIN2 expression level in the liver during the intervention of AAI combined CCl4. Moreover, Yap1LKO improved lipid metabolism homeostasis in the liver by increasing the beneficial lipid molecules and reducing the harmful lipid molecules through lipidomics. Finally, Yap1LKO reduced TG content in the serum and liver, hepatic vacuolar degeneration, and hepatic PLIN2 expression level in mice fed with a high-fat diet (HFD).Conclusion: Yap1LKO is protective in regulating liver and blood TG when induced with toxic substances AAI combined CCl4 and a high-fat diet.Keywords: yes-associated protein, hepatocyte-specific Yap1 knockout, perilipin-2, lipidomic, triglyceride

Jidong Zhang, Qiuxiang You, Yutao Wang, Jianwen Ji Center for Neurological Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, People’s Republic of ChinaCorrespondence: Jianwen Ji, Department of Center for Neurological Diseases, The Third Affiliated Hospital of Chongqing Medical University, No. 1 Shuanghu Branch, Yubei District, Chongqing, 401120, People’s Republic of China, Email jijianwen@hospital.cqmu.edu.cnPurpose: The main purpose of this paper is to explore the interaction between GAS5 and miR-135b-5p to understand their function in the metastasis, invasion, and proliferation of glioma. This may provide new ideas for the pathogenesis and treatment of glioma.Patients and Methods: Western blotting assays and RT‑qPCR were employed to investigate the expression of related genes in glioma tissues or cell lines. CCK-8 was used to examine the impact of GAS5 on cell viability. Motile activities were adopted by the transwell and wound healing experiments. A double luciferase experiment was performed to elucidate transcriptional regulation.Results: GAS5 showed low expression in glioma cells and tissues, and up-regulation of GAS5 could depress the invasion, proliferation, and metastasis of glioma. GAS5 negatively regulates miR-135b-5p, which can counteract the cellular effects caused by GAS5. APC was the target of miR-135b-5p, and GAS5 can regulate the expression of APC by sponging miR-135b-5p. APC overexpression reversed the effects of miR-135b-5p promotion on glioma cells, while miR-135b-5p has the opposite function. As a downstream target gene of GAS5, miR-135b-5p was negatively regulated by GAS5. The restoration of miR-135b-5p can remarkably reverse the impact of GAS5 on glioma cells. In addition, GAS5 increased the expression of APC in glioma cells by inhibiting miR-135b-5p.Conclusion: GAS5 increased APC expression by restraining miR-135b-5p and partially blocked the progression of glioma, suggesting that it could be an advantageous therapeutic target for glioma intervention.Keywords: glioma, lncRNA GAS5, miR-135b-5p, APC

Jinrui Ji,1,2,&ast; Xiaoyun Wei,1,2,&ast; Dongyun Wan,1,2,&ast; Lei Wu,1,2,&ast; Guangyao Chen,1,3,&ast; Hengliang Liu1,2,&ast; 1Clinical Medical Department, Faculty of Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, 450000, People’s Republic of China; 2Department of Cardiology, People’s Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, 450000, People’s Republic of China; 3Zhengzhou Institute of Gastroenterology, People’s Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, 450000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hengliang Liu, Henan University of Traditional Chinese Medicine, No. 33, Huanghe Road, Jinshui District, Zhengzhou, Henan Province, 450000, People’s Republic of China, Tel/Fax +86 0371-67077158, Email hnzzjjr@163.comPurpose: This study investigated the influence of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) levels on the degree of atherosclerosis and major adverse cardiovascular and cerebrovascular events (MACCE) in older adults with non-alcoholic fatty liver disease.Methods: The degree of atherosclerosis severity was assessed by the standard Gensini score quartile method. According to the degree of atherosclerosis, patients were divided into mild (0– 24 points; n=84), moderate (25– 53 points; n=86), and severe groups (≥ 54 points; n=84) and then categorized as MACCE (n=30) or non-MACCE (n=224) according to 6-month follow-up data. The patients’ age, sex, smoking history, medical history, and early morning fasting venous blood, for measuring biochemical indexes, were collected. Clinical data were compared between groups and the relationship between Gensini scores and PCSK9 was evaluated.Results: Compared with the mild group, the moderate and severe groups had higher high-sensitivity C-reactive protein(hs-CRP), PCSK9, triglycerides(TG), low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a)[Lp(a)] levels and lower high-density lipoprotein cholesterol(HDL-C) levels (all P< 0.05). Moreover, PCSK9 positively correlated with Gensini scores (r=0.657, P< 0.01). The MACCE and non-MACCE groups had significantly different ages, statin use, Gensini scores, PCSK9, and LDL-C (all P< 0.05). Multi-factorial Cox risk regression analysis showed the Gensini score (HR=1.018, 95% CI: 1.006~1.029) and PCSK9 (HR=1.147, 95% CI: 1.038~1.287) were independent risk factors for MACCE.Conclusion: The Gensini score and PCSK9 levels can be used as predictive indicators for the degree of illness and occurrence of MACCE in older NAFLD patients.Keywords: older adults, non-alcoholic fatty liver disease, proprotein convertase subtilisin/kexin 9, atherosclerosis, major adverse cardiovascular and cerebrovascular events

Jianlin Ji,1,&ast; Liling Yang,2,&ast; Hanlin Yang,1 Chengxi Zeng,1 Wenjuan Tang,2 Qunfeng Lu1,3 1School of Nursing, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Nursing Department, Children’s Hospital of Shanghai, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Nursing, Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qunfeng Lu, Department of Nursing, Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China, Email luluroom2004@163.com Wenjuan Tang, Nursing department, Children’s Hospital of Shanghai, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Email wjtang2014@163.comBackground: Despite the availability of a considerable number of studies on transitional care, few qualitative studies have synthesized physicians’ perspectives on PICU-to-ward transition to develop a comprehensive transitional care curriculum. The aim of this study is to explore physicians’ perceptions and management of the transition of critically ill children from the PICU to the general ward, with the aim of providing an evidence-based curriculum.Methods: A qualitative study was conducted between July and August 2022. The study involved semi-structured interviews with 11 participants, and data analysis was carried out using NVivo 12.0 software through thematic analysis method.Results: Based on the data analysis, three main themes were identified: recognition of professional roles during transition, difficulties during implementation transitional care and suggestions for improving transitional care.Conclusion: The insights of doctors can be valuable in improving transitional care for critically ill children during PICU-to-Ward transition and in developing relevant curricula. It is essential to introduce standardized clinical pathways and strengthen curricula on critical elements, including communication and follow-up.Keywords: pediatric intensive care unit, pediatricians, transitional care, qualitative study

Chenjun Huang,1,&ast; Xiao Xiao,1,&ast; Lin Tong,2,&ast; Zhiyuan Gao,1 Jun Ji,2 Lin Zhou,3 Ya Li,4 Lijuan Liu,5 Huijuan Feng,5 Meng Fang,2 Chunfang Gao1,2 1Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, People’s Republic of China; 2Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, People’s Republic of China; 3Department of Laboratory Medicine, Shanghai Changzheng Hospital, Shanghai, 200003, People’s Republic of China; 4Department of Laboratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of China; 5Department of Laboratory Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunfang Gao, Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, People’s Republic of China, Tel +86-21-65161782-1210, Email gaocf1115@163.com; gaocf1115@shutcm.edu.cnPurpose: Early detection of hepatocellular carcinoma (HCC) through surveillance could reduce this cancer-associated mortality. We aimed to develop and validate algorithms using panel serum biomarkers to identify HCC in a real-world multi-center study in China.Patients and Methods: A total of 10,359 eligible subjects, including HCCs and benign liver diseases (BLDs), were recruited from six Chinese medical centers. The three nomograms were built using logistic regression and their sensitivities and specificities were carefully assessed in training and validation cohorts. HCC patients after surgical resection were followed to determine the prognostic values of these algorithms. Prospective surveillance performance was assessed in a cohort of chronic hepatitis B patients during 144 weeks follow-up.Results: Independent risk factors such as alpha-fetoprotein (AFP), lens cuinaris agglutinin-reactive fraction of AFP (AFP-L3), des-gamma-carboxy prothrombin (DCP), albumin (ALB), and total bilirubin (TBIL) obtained from train cohort were used to construct three nomograms (LAD, C-GALAD, and TAGALAD) using logistic regression. In the training and two validation cohorts, their AUCs were all over 0.900, and the higher AUCs appeared in TAGALAD and C-GALAD. Furthermore, the three nomograms could effectively stratify HCC into two groups with different survival and recurrence outcomes in follow-up validation. Notably, TAGALAD could predict HCC up to 48 weeks (AUC: 0.984) and 24 weeks (AUC: 0.900) before clinical diagnosis.Conclusion: The proposed nomograms generated from real-world Chinese populations are effective and easy-to use for HCC surveillance, diagnosis, as well as prognostic evaluation in various clinical scenarios based on data feasibility.Keywords: hepatocellular carcinoma, real-world data, diagnostic, prognosis, algorithm

Mingxuan Zou,1,2,&ast; Bin Liu,2,&ast; Jing Ji,1 Lei Ren,3,4 Xiuchao Wang,2 Fengzhan Li2 1Public Health School, Shaanxi University of Chinese Medicine, Xianyang, 712046, People’s Republic of China; 2Department of Military Medical Psychology, Air Force Medical University, Xi’ an, 710032, People’s Republic of China; 3Military Psychology Section, Logistics University of PAP, Tianjin, 300309, People’s Republic of China; 4Military Mental Health Services & Research Center, Tianjin, 300309, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fengzhan Li; Xiuchao Wang, Email psyfengzhan@126.com; Wangxiuchao1984@163.comBackground: Military personnel experience prolonged exposure to high-stress environments. Positive coping styles can assist in maintaining their mental and behavioral well-being, whereas negative coping styles cannot. Health behavior change theory specifies that an individual can transition from a negative to a positive coping style. The psychological resilience concept may prove vital in this transition.Methods: In a longitudinal study design, two questionnaires were administered to 233 military personnel twice, the first at T1 in April 2023 and the second at T2 in July 2023. The questionnaire measured individual negative coping style, positive coping style and psychological resilience.Results: The data showed that the negative coping style at T1 negatively predicted the level of psychological resilience at T2 (γ= - 0.26, p < 0.001) and the positive coping style at T2 (γ= - 0.16, p < 0.001). The level of psychological resilience at T1 positively predicted the positive coping style at T2 (γ= 0.22, p < 0.01). Psychological resilience played a mediating role between negative coping style and positive coping style. In addition, there was an interaction between psychological resilience and positive coping style in military personnel at the two time points.Conclusion: The negative coping styles that presently exist among military personnel have the potential to diminish their future positive coping styles by lowering their psychological resilience. This highlights the need to focus on the development and training of psychological resilience for military personnel, as it can effectively counteract negative coping styles and promote positive coping styles.Keywords: military personnel, coping style, resilience, cross-lagged analysis

Background & Aims: Maintenance of abstinence in alcohol-related liver disease (ARLD) is a major unmet therapeutic need. Digital therapeutics can deliver ongoing behavioural therapy, in real-time, for chronic conditions. The aim of this project was to develop and clinically test AlcoChange, a novel digital therapeutic for ARLD. Methods: AlcoChange was developed using validated behaviour change techniques and a digital alcohol breathalyser. This was an open-label, single-centre study. Patients with ARLD, ongoing alcohol use (within 1 month) and possession of a suitable smartphone were eligible. Patients were recruited from inpatient and outpatient settings, and received AlcoChange therapy for 3 months. The primary outcome was reduction in alcohol use from baseline to 3 months, measured by timeline follow-back. Secondary outcomes included: (i) compliance with the AlcoChange app, (ii) alcohol-related and all-cause hospital re-admissions up to 1 year, (iii) qualitative analysis to determine factors associated with compliance. Results: Sixty-five patients were recruited, of whom 41 completed the study per protocol. Patients compliant with the intervention (>60 logins over 3 months) had a significant reduction in alcohol use from baseline compared to non-compliant patients (median [IQR]: -100% [100% to -55.1%] vs. -57.1% [-95.3% to +32.13%], p = 0.029). The proportion attaining abstinence at 3 months was higher in the compliant group (57.1% vs. 22.2%, p = 0.025). The compliant group had a significantly decreased risk of subsequent alcohol-related re-admission up to 12 months (p = 0.008). Qualitative analysis demonstrated that receiving in-app feedback and the presence of a health-related ‘sentinel event’ were predictors of compliance with the intervention. Conclusions: Use of the novel digital therapeutic, AlcoChange, was associated with a significant reduction in alcohol use and an increase in the proportion of patients with ARLD attaining abstinence. Definitive randomised trials are warranted for this intervention. Impact and implications: Alcohol-related liver disease (ARLD) is an increasing health problem worldwide. The main cause of death and disability in ARLD is ongoing alcohol consumption, but few patients receive medications or talking therapy to maintain abstinence. This study demonstrated that a digital therapeutic, linked to a smartphone, may help reduce alcohol consumption and alcohol-related hospital admissions in these patients. If validated in larger, randomised, trials, digital therapeutics may have a role in the primary and secondary prevention of complicatons from ARLD.

Qiao Xue,1 Jie Ji,2 Wen-Ge Fan,1 Jian-Peng Pan,3 Mei Wei,1 Hao Ding,1 Jun Zhao1 1Department of Dermatology, Changshu No. 1 People’s Hospital, Changshu Hospital Affiliated to Soochow University, Changshu, Jiangsu Province, 215500, People’s Republic of China; 2Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, 210000, People’s Republic of China; 3Department of Hand Surgery, Changshu No. 2 People’s Hospital, Changshu Hospital Affiliated to Yangzhou University, Changshu, Jiangsu Province, 215500, People’s Republic of ChinaCorrespondence: Jun Zhao, Department of Dermatology, Changshu Hospital Affiliated to Soochow University, Changshu No. 1 People’s Hospital, No. 1 Shuyuan Street, Yushan Town, Changshu, Jiangsu Province, 215500, People’s Republic of China, Tel +86-15051774136, Email zhaojunzhjzzzj@126.comObjective: To understand the situation and risk factors of skin lesions following the eruption of shingles.Methods: We selected 275 patients with shingles who had been diagnosed and treated in the Dermatology Department of Changshu No. 1 People’s Hospital between July 2017 and March 2022. Age, gender, skin lesion site, skin lesion type, prodromal pain, history of diabetes, history of hypertension, history of other immune diseases, as well as other pertinent clinical data, were collected. The severity and pain of patients with severe shingles were evaluated, and their fasting blood sugar and plasma albumin were measured for routine antiviral treatment. They were followed up 6 months—the types of skin lesions and pertinent clinical data were compared, and the risk factors for skin lesions were analyzed.Results: There were no statistically significant differences in gender, age, or site among the different types of skin lesions (P > 0.05). The severity of skin lesions, acute pain, history of diabetes, history of scars, low immune function, combined with hypoproteinemia, squeezing and stripping behavior, and post-herpetic neuralgia (PHN) were significantly associated with skin lesions (P < 0.05). The results of multivariate analysis showed that: age ≥ 60 years old, severe skin injury combined with diabetes, low immune function, scar history, squeezing and stripping were independent risk factors for the development of skin lesions due to shingles.Conclusion: There is no significant difference in age, gender, site, or other characteristics between the types of skin lesions due to shingles. The independent risk factors of skin lesions due to shingles are old age, severe rash, history of scars, diabetes, low immunity, squeezing, and peeling.Keywords: risk factors, skin lesions due to shingles

Wa Cai,1,&ast; Xi-Fang Wei,1,&ast; Chen Hu,1 Jun Ji,2 Hua Shun Cui,1 Wei-Dong Shen1 1Department of Acupuncture, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Department of Acupuncture Literature, Shanghai Research Institute of Acupuncture and Meridian, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei-Dong Shen; Hua Shun Cui, Email shenweidong1018@163.com; cuihuashun@shutcm.edu.cnBackground: Poststroke depression (PSD) is the most frequent neuropsychiatric consequence of stroke. Electroacupuncture (EA) has been found to be an effective therapy for treating PSD. However, the underlying mechanisms of EA’s efficacy remain unclear. This research aimed to investigate the effects of EA on alterations in gut microbiota and fecal metabolome in PSD rats.Methods: Analyses of gut microbiome and fecal metabolome were performed to identify gut microbes and their functional metabolites in a sham group, PSD group, and EA group. We conducted enrichment analysis to identify the differential metabolic pathways in three groups. Correlations between altered gut microbes and differential metabolites after EA treatment were studied.Results: PSD showed decreased species-richness/diversity indices of microbial composition, characterized by an increase in Muribaculaceae, Peptostreptococcaceae, Oscillospiraceae, Ruminococcaceae, and Clostridiaceae and a decrease in Lactobacillaceae, Lachnospiraceae, and Bacteroidaceae. Of these, the abundance of Muribaculaceae, Lactobacillaceae, Lachnospiraceae, Peptostreptococcaceae, and Clostridiaceae were reversed by EA. Furthermore, PSD was associated with 34 differential fecal metabolites, mainly belonging to steroid hormone biosynthesis, that could be regulated by EA.Conclusion: Regulation of gut microbiome and lipid metabolism could be one of the potential mechanisms for EA treatment for alleviating the depressive behaviors of PSD.Keywords: electroacupuncture, gut microbiome, fecal metabolome, metabolic pathways, poststroke depression

Zhigang Liu,1,&ast; Jiahui Liang,1,&ast; Hangzhan Hu,1,&ast; Mengli Wu,1,&ast; Jingjing Ma,1 Ziwei Ma,1 Jianing Ji,1 Hengyi Chen,2 Xiaoquan Li,1 Zhizeng Wang,1,2 Yang Luo2,3 1Joint National Laboratory for Antibody Drug Engineering, Clinical Laboratory of the First Affiliated Hospital, School of Medicine, Henan University, Kaifeng, 475004, People’s Republic of China; 2Center of Smart Laboratory and Molecular Medicine, Jiangjin Hospital, School of Medicine, Chongqing University, Chongqing, 400044, People’s Republic of China; 3College of Life Science and Laboratory Medicine, Kunming Medical University, Kunming, 650500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhizeng Wang, Joint National Laboratory for Antibody Drug Engineering, Clinical Laboratory of the First Affiliated Hospital, School of Medicine, Henan University, Kaifeng, 475004, People’s Republic of China, Tel +86 15093628687, Email wzhzeng@126.com Yang Luo, Center of Smart Laboratory and Molecular Medicine, Jiangjin Hospital, School of Medicine, Chongqing University, Chongqing, 400044, People’s Republic of China, Tel +86 13594088001, Email luoy@cqu.edu.cnIntroduction: Neutralizing antibodies (NAbs) are essential for preventing reinfection with SARS-CoV-2 and the recurrence of COVID-19; nonetheless, the formation of NAbs following vaccination and infection remains enigmatic due to the lack of a practical and effective NAb assay in routine laboratory settings. In this study, we developed a convenient lateral flow assay for the rapid and precise measurement of serum NAb levels within 20 minutes.Methods: Receptor-binding domain-fragment crystallizable (RBD-Fc) and angiotensin-converting enzyme 2-histidine tag (ACE2-His) were expressed by the eukaryotic expression systems of Spodoptera frugiperda clone 9 and human embryonic kidney 293T, respectively. Then, colloidal gold was synthesized and conjugated with ACE2. After optimizing various operating parameters, an NAb lateral flow assay was constructed. Subsequently, its detection limit, specificity, and stability were systematically evaluated, and clinical samples were analyzed to validate its clinical feasibility.Results: RBD-Fc and ACE2-His were obtained with 94.01% and 90.05% purity, respectively. The synthesized colloidal gold had a uniform distribution with an average diameter of 24.15 ± 2.56 nm. With a detection limit of 2 μg/mL, the proposed assay demonstrated a sensitivity of 97.80% and a specificity of 100% in 684 uninfected clinical samples. By evaluating 356 specimens from infected individuals, we observed that the overall concordance rate between the proposed assay and conventional enzyme-linked immunosorbent assay was 95.22%, and we noticed that 16.57% (59/356) of individuals still did not produce NAbs after infection (both by ELISA and the proposed assay). All the above tests by this assay can obtain results within 20 minutes by the naked eye without any additional instruments or equipment.Conclusion: The proposed assay can expediently and reliably detect anti-SARS-CoV-2 NAbs after infection, and the results provide valuable data to facilitate effective prevention and control of SARS-CoV-2.Clinical trial registration: Serum and blood samples were used under approval from the Biomedical Research Ethics Subcommittee of Henan University, and the clinical trial registration number was HUSOM-2022-052. We confirm that this study complies with the Declaration of Helsinki.Keywords: clinical detection, colloidal gold, neutralizing antibody, point-of-care test, SARS-CoV-2

Fanbo Lu,1,&ast; Luwen Zhang,1,&ast; Juanjuan Ji,2 Yuanhong Xu,1 Bo Wang,1 Jinxing Xia1 1Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinxing Xia; Bo Wang, Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, Anhui, People’s Republic of China, Email xiajinxing@ahmu.edu.cn; wangbo8711@126.comObjective: To study the epidemiological and antimicrobial resistant patterns, clinical characteristics and risk factors of critically ill patients infected with carbapenem-resistant Klebsiella pneumoniae (CRKP) from intensive care units (ICUs). The potential molecular mechanisms of antimicrobial resistance and virulence of CRKP were investigated through evaluation of associated genes.Methods: Totally, 201 ICU patients infected with K. pneumoniae were recruited from January 2020 through January 2021. K. pneumoniae strains were collected from diverse clinical specimens and identified by microbial cultures and matrix-assisted laser desorption ionization–time-of-flight mass spectrometry. Antimicrobial resistance was measured through broth micro-dilution or Kirby–Bauer assays. The carbapenemase-, virulence-, and capsular serotype-associated genes of CRKP were individually detected by PCR and sequencing. Demographic and clinical profiles were acquired from hospital databases to evaluate the correlation of CRKP infection incidence with clinical risk factors.Results: Of the 201 K. pneumoniae strains, CRKP accounted for 41.29%. Seasonal bias existed in local prevalence of CRKP infections. CRKP strains mounted significantly strong resistance against major antimicrobial agents except ceftazidime–avibactam, tigecycline and minocycline. Recent exposure to certain antibiotics and prior treatment with invasive interventions were prone to increase CRKP infection risks with worsened infectious outcomes. The local top carbapenemase-encoding and virulence-associated genes of CRKP were blaKPC and irp 2, respectively. Nearly half of CRKP isolates harbored a capsular polysaccharide serotype of K14.K64 (wzi-64) which preferentially emerged in the cohort with worse outcomes of infection.Conclusion: Featured epidemiology and typical clinical characteristics existed extensively in K. pneumoniae infections among ICU patients. The CRKP cohort exhibited substantially high antimicrobial resistance. Distinctive carbapenemase-, virulence-, and serotype-associated genes were intensively involved in the spread and pathogenesis of CRKP. These findings supported careful management of critically ill patients potentially infected with virulent CRKP in the ICUs.Keywords: carbapenem-resistantKlebsiella pneumoniae, epidemiology, clinical features, antimicrobial resistance, virulence, ICU

Qingwei Li,1 Haiyin Zhang,2 Guozhen Lin,3 Shenxun Shi,4 Yingli Zhang,5 Jianlin Ji,6 Lipeng Yang,7 Jun Yao,1 Wenyuan Wu1 1Department of Psychiatry, Tongji Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 2Clinical Psychology, Shanghai Mental Health Center, Shanghai, People’s Republic of China; 3Department of Psychiatry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Psychiatry Department, Fudan University Affiliated Huashan Hospital, Shanghai, People’s Republic of China; 5Department of Depressive Disorders, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, People’s Republic of China; 6Department of Psychological Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 7Department of Neurology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of ChinaCorrespondence: Wenyuan Wu, Department of Psychiatry, Tongji Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China, Email wuwy@tongji.edu.cnPurpose: To determine the relative safety and efficacy of different doses of tandospirone in treating generalized anxiety disorder (GAD).Patients and Methods: This parallel randomized controlled trial enrolled patients with GAD from eight centers in China. The patients were randomly assigned to 60 mg/day or 30 mg/day tandospirone groups. The primary endpoint was the overall response rate after receiving 6-week treatment. The secondary endpoints included significant response rate, clinical recovery rate, change in the Hamilton Anxiety Scale (HAMA) total score, HAMA subscale score, Hamilton Depression Scale-17 (HAMD-17), Clinical Global Impression-Severity Scale (CGI-S) score, and Impression-Improvement scale (CGI-I) score.Results: No significant difference was found in the overall response rate between the two groups (65.7% vs 58.4%, p = 0.213). A higher significant response rate and change in the HAMA total score were found in the 60 mg/day group. The reduction in the CGI-S score and percentage of patients with a CGI-I score of ≤ 2 were higher in 60 mg/day group. The reduction in HAMA somatic anxiety factor, cardiovascular symptom factor, gastrointestinal symptom factor, and HAMD-17 score were more significant in the 60 mg/day group. The incidence of total adverse events was higher in the 60 mg/day group than in the 30 mg/day group. No significant difference was found in the proportion of withdrawal due to adverse events.Conclusion: Both 60 mg/day and 30 mg/day tandospirone show good efficacy in treating patients with GAD. High doses of tandospirone may have advantages in relieving the somatic symptoms but also present disadvantages due to their high level.Trial Registration: The trial registration no. was NCT01614041.Keywords: generalized anxiety disorder, tandospirone, randomized controlled trial, safety, efficacy

Caili Lou,1,2 Jian Liu,2 Zhibo Ren,2 Jinke Ji,2 Hongbao Ma,2 Hui Dong,3 Linan Wang,2 Xu Zhang,3 Ningkui Niu1 1Department of Spinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China; 2Clinical Medical School, Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China; 3Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of ChinaCorrespondence: Ningkui Niu, Department of Spinal Surgery, General Hospital of Ningxia Medical University, No. 804 Shengli Street, Yinchuan, 750004, People’s Republic of China, Tel +86 13629593280, Email niuningkui6743242@163.com Xu Zhang, Institute of Medical Sciences, General Hospital of Ningxia Medical University, No. 804 Shengli Street, Yinchuan, Ningxia, 750004, People’s Republic of China, Email xuzhang1012@163.comObjective: To investigate the correlation between the expression of lipopolysaccharide-binding protein (LBP) in peripheral blood of spinal tuberculosis and clinical diagnosis and to evaluate its value as a diagnostic marker of spinal tuberculosis.Methods: In the experimental group, clinical history data and peripheral blood were collected from 100 patients with spinal tuberculosis who were admitted to the Department of Spine Surgery, General Hospital of Ningxia Medical University from May 2017 to May 2020, and peripheral blood was collected from 30 healthy volunteers in the control group. Screening of differential LBP expression by proteomics and ELISA to verify its expression in peripheral blood of spinal tuberculosis patients. t-test, Spearman analysis, linear regression and ROC curve were used to evaluate the diagnostic value of LBP in peripheral blood for spinal tuberculosis.Results: The expression of LBP protein in peripheral blood is significantly higher in patients with spinal tuberculosis than in the normal population; LBP assay values were significantly and positively correlated with CRP and ESR values (P < 0.01); the AUC of LBP in the diagnosis of spinal tuberculosis for pathological examination, bacteriological culture, T-cell spot test for tuberculosis infection (T-SPOT), imaging diagnosis, and acid fast bacillus were, respectively, 0.677 (P < 0.01), 0.707 (P < 0.01), 0.751 (P < 0.01), 0.714 (P < 0.01), and 0.656 (P < 0.05), and there was a correlation between LBP and the diagnostic evaluation of spinal tuberculosis.Conclusion: LBP could be a new candidate biomarker for the diagnosis of spinal tuberculosis.Keywords: spinal tuberculosis, proteomics, LBP, biomarker

Jingran Ji, Chongkai Wang, Marwan Fakih Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USACorrespondence: Marwan Fakih, Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Pavillion, Room 3208, 1500 E Duarte St, Duarte, CA, 91010, USA, Tel +1 626-256-4673 extension 83087, Fax +1 626-218-8233, Email mfakih@coh.orgAbstract: Identifying mutations in the KRAS gene has become increasingly important in the treatment of colorectal cancer with many prognostic and therapeutic implications. However, efforts to develop drugs that target KRAS mutations have not been successful until more recently with the introduction of the KRASG12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849). Both agents have demonstrated safety and promising efficacy in preclinical studies and early phase trials, but it appears that not all tumor types harboring the KRASG12C mutation are sensitive to monotherapy approaches. In particular, patients with colorectal cancer (CRC) derive less benefit compared to those with non-small cell lung cancer (NSCLC), likely due to rapid treatment-induced resistance through increased epidermal growth factor receptor (EGFR) signaling. As a result, combination therapy trials with EGFR inhibitors are currently underway. Here, we will review the available clinical trial data on KRASG12C inhibitors in KRASG12C-mutated CRC, possible mechanisms of resistance to monotherapy, the research studying why available agents are proving to be less efficacious in CRC compared to NSCLC, and future directions for these promising new drugs.Keywords: KRASG12C, sotorasib, adagrasib, colorectal cancer, targeted therapy

Junhui Ji,1,&ast; Xiafang Gu,2,&ast; Chengjiao Xiao1 1Anesthesiology Department, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2Anesthesiology Department, The No.2 People’s Hospital of Suzhou Xiangcheng District, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chengjiao XiaoAnesthesiology Department, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Gusu District, Suzhou, 215000, Jiangsu, People’s Republic of ChinaTel +86-13962100544Email xiaocj1646@126.comBackground: Whether intraoperative temperature management can help patients recover quickly in the postanesthesia care unit (PACU) still remains to be investigated. This study aimed to investigate the effect of intraoperative temperature management on the quality of postoperative recovery of patients who underwent pulmonary lobectomy in the PACU.Methods: Totally, 98 patients aged 45– 60 years with a body mass index of 20– 25 kg/m2 who underwent elective thoracoscopic lobectomy were enrolled. Patients were categorized into two groups using a random number table: the conventional group received routine intervention to maintain normothermia (Group C, n = 49) and the aggressive group received integrated interventions (Group A, n = 49). In Group C, normothermic fluid was infused intravenously, the heating blanket was turned on when the intraoperative temperature was < 35.0 °C, and the warming was stopped when the temperature reached 36.5 °C. In Group A, the fluid heated to 37 °C was infused intravenously, and the heating blanket was used intraoperatively. When the body temperature was > 37 °C, the heating blanket was turned off, and when the body temperature was < 36.5 °C, the heating blanket was turned on to continue heating.Results: Steward awakening scores at 1 min and 5 min after extubation and PaO2 levels at 15 min after extubation were higher in Group A than in Group C (P < 0.05); incidence of chills, nausea, and vomiting in the PACU was lower in Group A than in Group C (P < 0.05); and length of stay in the PACU was shorter in Group A than in Group C (P < 0.05).Conclusion: Aggressive intraoperative temperature management of patients undergoing thoracoscopic lobectomy can improve the quality of postoperative recovery in the PACU through a safe and smooth transition compared with routine insulation measures.Keywords: hypothermia, recovery room, thoracoscopy, thoracic surgery

Jianhong Ji,1,&ast; Li Wang,2,&ast; Haiyang Guan,2 Yaqiong Jiang,1 Sanlian Zhou,2 Junhua Sheng,3 Lihua Wang4 1Intensive Care Unit, The Second Affiliated Hospital of Nantong University, Nantong, People’s Republic of China; 2Department of Emergency, The Second Affiliated Hospital of Nantong University, Nantong, People’s Republic of China; 3Department of Medical, The Second Affiliated Hospital of Nantong University, Nantong, People’s Republic of China; 4Department of Nursing, The Second Affiliated Hospital of Nantong University, Nantong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lihua WangDepartment of Nursing, The Second Affiliated Hospital of Nantong University, Nantong, 226001, People’s Republic of ChinaTel +86 13815219995Email lihua_wangdr@outlook.comObjective: This study was designed to verify the effect of group random quality control on the first aid ability of ward doctors and nurses with regard to the resuscitation of patients with in-hospital cardiac arrest (IHCA).Methods: The first aid quality control team of our hospital was established in December 2018, when the number, qualifications, organizational structure, quality control methods, and responsibilities of the team and team members were determined. The baseline data and assessment results of examinees, the rates of return of spontaneous circulation (ROSC), and the discharge survival rate of IHCA patients in 2019 and 2020 were compared.Results: There were no significant differences in the baseline data of examinees at each stage (p > 0.05). As time went on, the results of the four practical examinations were significantly improved (pairwise comparison, p < 0.05). The number of problems in examinations was significantly higher for physicians than for nurses. After guidance in department relearning, the incidence of related problems was significantly reduced, but the mastery of the frequency and depth of extracorporeal cardiac compression were not always up to standard. The proportion of critically ill patients and the incidence of IHCA in the hospital in 2020 was higher than in 2019 (p < 0.05), and the ROSC rate was also significantly higher than it was in 2019 (p < 0.05), but the difference in the survival rate at discharge was not statistically significant (p > 0.05).Conclusion: Group random quality control meets the needs of IHCA emergencies, and it can improve the first aid skills and organizational coordination of doctors and nurses on the ward through continuous discovery and problem solving so that the ultimate goal of improving the success rate of resuscitation can be achieved.Keywords: in-hospital cardiac arrest, cardiopulmonary resuscitation, quality control, patient outcomes, survival, ability

Jianlei Ji,&ast; Qinghai Wang,&ast; Tao Huang, Ziyu Wang, Pingli He, Chen Guo, Weijia Xu, Yanwei Cao, Zhen Dong, Hongyang Wang Department of Kidney Transplantation, the Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhen Dong; Hongyang WangDepartment of Kidney Transplantation, the Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266000, People’s Republic of ChinaTel +8613455263336; +8618661803752Email dong266000@163.com; why19850804@163.comBackground: Trimethoprim/sulfamethoxazole (TMP-SMX) is considered the first-choice treatment for Pneumocystis jirovecii pneumonia (PJP) in recipients of solid organ transplantation. However, this treatment is associated with various severe adverse events that might not be tolerable for some renal transplant recipients, and the optimal dose remains elusive. The present study assessed the efficacy of low-dose TMP-SMX in recipients of a deceased donor kidney.Methods: A total of 37 adult deceased donor kidney recipients who suffered PJP between January 2015 and June 2020 were included. The survival rates of the patients and grafts, the rate of invasive ventilation, and adverse events, including gastrointestinal discomfort, hematologic side effects, hyperkalemia, and renal function impairments, were assessed.Results: The patient and graft survival rates were both 100%. Two patients (5.4%) required invasive ventilation. Eight patients (21.6%) reported gastrointestinal discomfort, but none required dose reduction or discontinued treatment. The frequencies of hematologic side effects, hyperkalemia and impaired kidney function were 5.4% (2/37), 2.7% (1/37), and 2.7% (1/37), respectively.Conclusion: Optimization of TMP-SMX dose may reduce the risk of adverse events without compromising efficacy for the treatment of PJP in deceased donor kidney recipients.Keywords: efficacy, low dose, trimethoprim/sulfamethoxazole, Pneumocystis jirovecii pneumonia, deceased donor kidney recipients

Si-Jia Zhao,1 Hong Jia,2 Xiu-Lian Xu,1 Wen-Bo Bu,3 Qian Zhang,3 Xi Chen,4 Juan Ji,2 Jian-Fang Sun1 1Department of Pathology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, People’s Republic of China; 2Department of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, People’s Republic of China; 3Department of Dermatologic Surgery, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, People’s Republic of China; 4Department of Medicine 3, Universitätsklinikum Erlangen, Friedrich Alexander University Erlangen Nuremberg, Erlangen, Bavaria, GermanyCorrespondence: Jian-Fang SunInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, People’s Republic of ChinaTel +86 25 8547 8015Fax +86 25 8541 4477Email JianfangSunPUMC@outlook.comPurpose: Vitiligo is an acquired depigmentation skin disease, which affects an average of 1% of the world’s population. The purpose of this study is to identify the key genes and pathways responsible for vitiligo and find new therapeutic targets.Methods: The datasets GSE65127, GSE53146, and GSE75819 were downloaded from the Gene Expression Omnibus (GEO) database. R language was used to identify the differentially expressed genes (DEGs) between lesional skin of vitiligo and non-lesional skin. Next, the key pathways were obtained by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The protein–protein interaction (PPI) networks were conducted by STRING database and Cytoscape software. Subsequently, module analysis was performed by Cytoscape. Among these results, the Wnt/β-catenin pathway and melanogenesis pathway caught our attention. The expression level of β-catenin, microphthalmia-associated transcription factor (MITF) and tyrosinase (TYR) was detected by immunofluorescence in vitiligo lesions and healthy skin. Moreover, zebrafish was treated with XAV-939, an inhibitor of the Wnt/β-catenin pathway. After that, the area of melanin granules as a percentage of the head area was measured. The mRNA expression of β-catenin, lymphoid-enhancing factor 1(lef1), tyr and mitf were detected by q-PCR (quantitative polymerase chain reaction) in zebrafish (Danio rerio).Results: A total of 2442 DEGs were identified, including 1068 upregulated and 1374 downregulated DEGs. The key pathways were identified by GO and KEGG analyses, such as “NOD-like receptor signaling pathway”, “Wnt signaling pathway”, “Melanogenesis”, “mTOR signaling pathway”, “PI3K-Akt signaling pathway”, “Calcium signaling pathway” and “Rap1 signaling pathway”. The immunofluorescence results showed that the level of β-catenin, MITF and TYR was significantly downregulated in vitiligo lesional skin. In zebrafish, the mean percentage area of melanin granules and the expression of β-catenin, lef1, tyr and mitf were decreased after treated with XAV-939.Conclusion: The present study identified key genes and signaling pathways associated with the pathophysiology of vitiligo. Among them, the Wnt/β-catenin pathway played an essential role in pigmentation and could be a breakthrough point in vitiligo treatment.Keywords: vitiligo, zebrafish, melanogenesis, Wnt/β-catenin, calcium signaling, Rap1

Feifei Yang,1,2,&ast; Chunhong Liu,3,&ast; Jian Ji,3 Wenjun Cao,3 Baixing Ding,1,2 Xiaogang Xu1,2 1Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, People’s Republic of China; 3Department of Clinical Laboratory, Eye and ENT Hospital, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenjun CaoDepartment of Clinical Laboratory, Eye and ENT Hospital, Fudan University, Shanghai, People’s Republic of ChinaEmail wgkjyk@aliyun.comBaixing DingInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaEmail dingbaixing@163.comPurpose: To investigate molecular characteristics, antimicrobial resistance, and biofilm formation ability of Pseudomonas aeruginosa strains isolated from patients with aural infections.Methods: Isolates (n = 199) were collected from ear discharges of patients with aural infections from January 2019 to December 2020. Antimicrobial susceptibility testing was performed according to the Clinical and Laboratory Standards Institute guidelines. All isolates were subjected to multilocus sequence typing (MLST) with amplification and sequencing of seven housekeeping genes. Biofilm formation and eradication were quantitatively assessed in microtiter plates. Genes associated with biofilm formation and the quinolone-resistance-determining region (QRDR) of genes gyrA and parC were investigated using polymerase chain reaction amplification and sequencing.Results: Of the 199 P. aeruginosa strains isolated, 109 (54.77%) were from females and 90 (45.23%) were from males. The isolates exhibited very low rates of resistance to most antibiotics tested, including piperacillin (1.51%), ceftazidime (0.50%), and imipenem (3.52%); however, the quinolones ciprofloxacin (80.40%) and levofloxacin (82.91%) were notable exceptions. The QRDR sequence results of the quinolone-resistant P. aeruginosa isolates showed Thr83Ile (n = 155) was the most common amino acid mutation in gyrA (n = 165), while Ser87Leu (n = 157) was widely detected in parC (n = 165). MLST analysis identified 34 sequence types (STs) with most isolates belonging to ST316 (73.87%). Almost all of the P. aeruginosa isolates (96.98%) produced biofilms and biofilm-forming genes algD (98.49%), pslD (96.98%), and pelF (96.48%) were highly prevalent.Conclusion: The P. aeruginosa strains isolated from aural discharges in this study exhibited very low rates of resistance to most antibiotics tested, except for the resistance rates to quinolones, which were relatively high. The isolates also exhibited a strong biofilm formation ability and low susceptibility to eradication, indicating that more effective drugs and treatment methods are needed to combat these infections.Keywords: Pseudomonas aeruginosa isolate, ear infection, antimicrobial resistance, ST316, biofilm

Qinghai Wang,1 Kai Zhao,2 Chen Guo,1 Hong Li,1 Tao Huang,1 Jianlei Ji,1 Xiaoxia Sun,1 Yanwei Cao,1 Zhen Dong,1 Hongyang Wang1 1Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China; 2Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of ChinaCorrespondence: Zhen Dong; Hongyang WangDepartment of Kidney Transplantation, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266000, People’s Republic of ChinaTel +8613455263336; +8618661803752Email dong266000@163.com; why19850804@163.comObjective: This study aimed to determine the prevalence of antibiotic resistance and virulence genes of Escherichia coli strains among patients with urinary tract infections (UTIs) after kidney transplantation from deceased donors.Methods: Between January 2014 and June 2018, 64 patients who received kidney transplants from deceased donors at our institution developed a UTI due to E. coli. Polymerase chain reaction was used to detect virulence genes in E. coli strains. The Kirby–Bauer method was used to evaluate the antibiotic susceptibility pattern of the isolates.Results: Among the study cohort, 46 (71.9%) UTIs were community-acquired (CA), and 18 (28.1%) were hospital-acquired (HA). The percentages of isolated E. coli strains that showed antibiotic resistance were as follows: 92.2% to ampicillin, 76.6% to cefalotin, 81.3% to carbenicillin, 29.7% to ciprofloxacin, 62.5% to cotrimoxazole, 35.9% to gentamicin, 34.4% to levofloxacin, 28.1% to norfloxacin, 68.8% to pefloxacin, 57.8% to trimethoprim/sulfamethoxazole, and 20.3% to amikacin. HA E. coli showed higher resistance to ciprofloxacin, cotrimoxazole, trimethoprim/sulfamethoxazole and amikacin, compared with CA E. coli (P< 0.05). The most prevalent virulence genes among the E. coli strains were fim (64.1%), followed by irp2 (56.3%), iroN (46.9%), pap GII (45.3%), sfa (31.3%), pap (25%), iuc (23.4%), pap GI (15.6%), pap GIII (14.1%), hly (9.4%), and cnf (4.7%). The irp2 and iroN genes were found more frequently in the HA E. coli than in the CA E. coli (P< 0.05).Conclusion: The E. coli strains, especially HA E. coli, isolated from UTI patients after kidney transplantation from deceased donors showed resistance to multiple antibiotics and harbored numerous virulence genes. These findings provide insight for genetic characterizations and epidemiological studies of E. coli strains causing UTIs in patients after kidney transplantation from deceased donors.Keywords: Escherichia coli, antimicrobial resistance, virulence genes, urinary tract infections, kidney transplantation

Jinyu Zhu,1,2,&ast; Bufu Tang,1,3,&ast; Yang Gao,1,4 Suqin Xu,5 Jianfei Tu,1,4 Yajie Wang,4 Weibin Yang,1,4 Shiji Fang,4 Qiaoyou Weng,4 Zhongwei Zhao,1,4 Min Xu,1,4 Yang Yang,1,4 Minjiang Chen,1,4 Chenying Lu,1,4 Jiansong Ji1,4 1Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People’s Republic of China; 2Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China; 3Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of China; 4Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People’s Republic of China; 5Clinical Laboratory, Fuyuan Hospital of Yiwu, Jinhua, 321000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiansong Ji; Chenying Lu Email jijiansong@zju.edu.cn; luchenying@zju.edu.cnIntroduction: Hepatocellular carcinoma (HCC) is a heterogeneous molecular disease with complex molecular pathogenesis that influences the efficacy of therapies. Exosomes play a crucial role in tumorigenesis and poor disease outcomes in HCC.Objective: The aim of this study was to identify the optimal gene set derived from exosomes in HCC with substantial predictive value to construct models for determining prognosis, recurrence risk and diagnosis and to identify candidates suitable for immunotherapy and chemotherapy, thereby providing new ideas for the individualized treatment of patients and for improving prognosis.Methods: Weighted correlation network analysis (WGCNA) and univariate and multivariate Cox PH regression analyses were applied to identify exosome-related signatures in the TCGA and exoRbase databases associated with clinical relevance, immunogenic features and tumor progression in HCC. Cell experiments were performed to further confirm the oncogenic effect of MYL6B and THOC2.Results: The models for prognosis and recurrence risk prediction were built based on two exosomal genes (MYL6B and THOC2) and were confirmed to be independent predictive factors with superior predictive performance. Patients with high prognostic risk had poorer prognosis than patients with low prognostic risk in all HCC datasets, namely, the TCGA cohort (HR=2.5, P< 0.001), the ICGC cohort (HR=3.15, P< 0.001) and the GSE14520 cohort (HR=1.85, P=0.004). A higher recurrence probability was found in HCC patients with high recurrence risk than in HCC patients with low recurrence risk in the TCGA cohort (HR=2.44, P< 0.001) and the GSE14520 cohort (HR=1.54, P=0.025). High prognostic risk patients had higher expression of immune checkpoint genes, such as PD1, B7H3, B7H5, CTLA4 and TIM3 (P< 0.05). Diagnostic models based on the same two genes were able to accurately distinguish HCC patients from normal individuals and HCC from dysplastic nodules.Conclusion: Our findings lay the foundation for identifying molecular markers to increase the early detection rate of HCC, improve disease outcomes, and determine more effective individualized treatment options for patients.Keywords: exosome, hepatocellular carcinoma, HCC, immune checkpoint, prognosis

Chao Li,1 Zhenchun Shi,2 Jiacui Ji,2 Gengyun Niu,1 Zengxun Liu2 1Department of Psychiatry, Jining Medical University, Jining, 272067, People’s Republic of China; 2Department of Psychiatry, Shandong Mental Health Center, Jinan, 250014, People’s Republic of ChinaCorrespondence: Zengxun LiuDepartment of Psychiatry, Shandong Mental Health Center, No. 49 Wenhua Eastern Road, Jinan, 250014, People’s Republic of ChinaTel +86-13583135343Email zengxunliu@126.comPurpose: Agitation is prevalent among inpatients with schizophrenia. The aim of this study was to investigate whether biochemical parameters are associated with agitation in schizophrenia.Patients and Methods: Agitation was evaluated by the Positive and Negative Syndrome Scale-Excited Component questionnaire (PANSS-EC). Fasting serum levels of C-reactive protein (CRP), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), uric acid (UA), creatinine, glucose and lipids were measured.Results: The analysis included 154 inpatients with schizophrenia (71 with agitation, 83 without agitation) and 75 healthy control subjects. Patients with schizophrenia and agitation had higher serum levels of CRP, FT3, FT4 and UA as well as lower levels of serum TSH and creatinine than patients without agitation (all P < 0.05). Multivariate logistic regression analysis indicated that serum CRP (odds ratio [OR] = 1.470, P = 0.001), FT3 (OR = 13.026, P < 0.001), TSH (OR = 0.758, P = 0.033) and creatinine (OR = 0.965, P = 0.004) were significantly associated with agitation in schizophrenia. CRP, FT3, TSH and creatinine achieved an area under the ROC curve of 0.626, 0.728, 0.620 and 0.663 respectively in discriminating schizophrenia with or without agitation.Conclusion: Increased serum CRP and FT3 levels and decreased serum TSH and creatinine levels are independent risk factors for agitation in hospitalized patients with schizophrenia. Inflammation, thyroid hormones and renal function may be involved in the pathogenesis of agitation in schizophrenia.Keywords: schizophrenia, psychomotor agitation, C-reactive protein, triiodothyronine, thyroid-stimulating hormone, creatinine

Feiyang Jin,1 Di Liu,1 Xiaoling Xu,1 Jiansong Ji,2 Yongzhong Du1 1Institute of Pharmaceutics, College of Pharmaceutics Sciences, Zhejiang University, Hangzhou, 310058, People’s Republic of China; 2Department of Radiology, Lishui Hospital of Zhejiang University, Lishui, 323000, People’s Republic of ChinaCorrespondence: Jiansong JiDepartment of Radiology, Lishui Hospital of Zhejiang University, Lishui, 323000, People’s Republic of ChinaTel +86-578-2285011Email lschrjjs@163.comYongzhong DuInstitute of Pharmaceutics, College of Pharmaceutics Sciences, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou, 310058, People’s Republic of ChinaTel +86-571-88981651Email duyongzhong@zju.edu.cnAbstract: Benefiting from the rapid development of nanotechnology, photodynamic therapy (PDT) is arising as a novel non-invasive clinical treatment for specific cancers, which exerts direct efficacy in destroying primary tumors by generating excessive cytotoxic reactive oxygen species (ROS). Notably, PDT-induced cell death is related to T cell-mediated antitumor immune responses through induction of immunogenic cell death (ICD). However, ICD elicited via PDT is not strong enough and is limited by immunosuppressive tumor microenvironment (ITM). Therefore, it is necessary to improve PDT efficacy through enhancing ICD with the combination of synergistic tumor therapies. Herein, the recent progress of nanomaterials-based PDT combined with chemotherapy, photothermal therapy, radiotherapy, and immunotherapy, employing ICD-boosted treatments is reviewed. An outlook about the future application in clinics of nanomaterials-based PDT strategies is also mentioned.Keywords: photodynamic therapy, immunogenic cell death, antitumor immunity, immunosuppressive tumor environment, nanomedicines

Chunhong Liu,1,2,* Baixing Ding,3,* Jian Ji,1 Zhujian Wang,1 Huiwen Chen,1 Wenjun Cao1,2 1Clinical Laboratory, Eye & ENT Hospital, Fudan University, Shanghai, People’s Republic of China; 2Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, People’s Republic of China; 3Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenjun Cao Email wgkjyk@aliyun.comPurpose: To report antibiotic resistance rates and trends of common ocular isolates collected over a 15-year period.Methods: We collected 3533 isolates from July 1, 2005 to July 31, 2020. Antibiotic sensitivity was determined according to the guidelines of the Clinical and Laboratory Standards Institute. Chi-squared (χ2) test was used to analyze changes in antibiotic susceptibility over 15 years.Results: Among the 3533 isolates, the predominant pathogens were the staphylococcal species. Methicillin resistance was observed in 381 Staphylococcus aureus (S. aureus) isolates (46.4%) and 1888 coagulase-negative staphylococci (CoNS) isolates (61.1%), and methicillin-resistant (MR) isolates had a high probability of concurrent resistance to fluoroquinolones and aminoglycosides. The mean percentage of resistance in staphylococcal isolates did not reach statistical significance across patient age groups (P = 0.87). Methicillin resistance did not increase in the CoNS (P = 0.546) isolates, and resistance to methicillin slightly decreased among S. aureus (P = 0.04) isolates over 15 years. Additional exploratory analysis revealed a small decrease in resistance to tobramycin (P = 0.01) and chloramphenicol (P < 0.001) among the CoNS isolates. All staphylococcal isolates were susceptible to vancomycin.Conclusion: Staphylococci were the most common microorganisms responsible for causing ocular infections. Antibiotic resistance was high among staphylococci, with nearly half of these isolates were resistant to methicillin and these had a high probability of concurrent resistance among MR staphylococci to other antibiotics. Overall, ocular resistance did not significantly change during the 15-year study period. We conclude that continued surveillance of antibiotic resistance provides critical data to guide antibiotic selection.Keywords: methicillin, antibiotic resistance, ocular isolate, staphylococci

Qian Xu,1,2,* Ying Fu,3,* Jingshu Ji,3 Xiaoxing Du,1,2 Yunsong Yu1,2 1Department of Infectious Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310016, People’s Republic of China; 2Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang Province, 310016, People’s Republic of China; 3Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunsong Yu Qingchun East Road No. 3, Hangzhou City, Zhejiang Province, 310016, People’s Republic of ChinaTel/Fax +86-571-86006142Email yvys119@zju.edu.cnIntroduction: Antibiotics for treating infectious diseases caused by carbapenem-resistant Gram-negative pathogens (CR-GNOs) are very limited in clinical practice. We aim to provide supportive evidence by revealing the combined effect of aztreonam (ATM) and amoxicillin/clavulanic acid (AMC) against GNOs with carbapenem resistance mediated by metallo-β-lactamase (MBL).Methods: All isolates were identified by the VITEK system and EDTA inhibitory assays. PCR followed by sequencing was conducted to confirm the genotypes of MBL and extended spectrum β-lactamase (ESBL). Time kill assay was performed to clarify the bactericidal effect of drug combination.Results: A total of 59 MBL-producing CR-GNOs (33 Enterobacteriaceae spp. isolates and 26 Pseudomonadales isolates) were identified and there found three MBL genes, namely, blaIMP, blaNDM and blaVIM, with ratios of 76.2%, 11.8% and 11.8%, respectively. The Enterobacteriaceae spp. isolates were commonly positive for the ESBL genes, including blaTEM (18 isolates), blaSHV (20 isolates) and blaCTX-M-1 (8 isolates), while the P. aeruginosa isolates were positive for blaOXA-10 (11 isolates). The checkerboard microdilution assay was used to detect combination effect of ATM and AMC, which showed synergy (97.0%) and partial synergy (3.0%) in Enterobacteriaceae spp. isolates, and partial synergy (42.3%) and indifference (34.6%) in the Pseudomonadales isolates. Four Enterobacteriaceae spp. isolates were selected for a time-kill assay, and rapid bactericidal effects were observed in the combination groups compared to the control and mono-ATM groups; these effects began in the first hour and continued to the sixth hour, yielding a 5- to 7-fold reduction in Log10 CFU/mL.Discussion: The combination of ATM and AMC would be an available option to control infections caused by MBL-producing CR-GNOs, especially Enterobacteriaceae spp. isolates that coproduce ESBLs, and exhibit significant synergic effects in vitro.Keywords: gram-negative pathogens, carbapenem resistance, metallo-β-lactamase, extended spectrum β-lactamase, aztreonam, amoxicillin/clavulanic acid, combination

Meihong Sheng,1 Juan Ji,1 Chenying Zhang,1 Zirui Zhang,1 Shenchu Gong,1 Yihua Lu2 1Department of Radiology, Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong, Jiangsu, 226001, People’s Republic of China; 2Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, 226019, Jiangsu, People’s Republic of ChinaCorrespondence: Shenchu Gong Email gongshenchu@msn.comBackground: Full-field digital mammography (FFDM) and digital breast tomosynthesis (DBT) are used separately or in combination to identify small breast lesions. The dose of the examination depends on the density of the breast and the imaging (FFDM or DBT) performed. We have performed a retrospective review of FFDM and DBT in women with denser breasts in order to demonstrate how varying the combination of FFDM and DBT in CC and MLO views affects lesion detection and the average gland dose.Methods: Eighty-one patients with dense breast received both full-field digital mammography (FFDM) and DBT bilateral screening. The recorded data included the display rates for small lesions or other positive lesions, the type of breast gland, the average gland dose (AGD), and the compression thickness of different collection methods. ANOVA was used to compare the AGD among different collection combinations, and t-test was used to perform pairwise comparison between groups with the same gland type. The relationship between AGD and compression thickness was analyzed by Pearson linear correlation, and the lesion display rates were compared using Chi-square test.Results: We found that AGDs were significantly different among the 6 collection methods (F = 119.06, p< 0.01), but were not obviously different between groups with the same gland type (F = 0.848, p> 0.05). The types of dense glands were correlated with compression thickness, and the thickness was moderately to strongly correlated with AGD (r=0.596– 0.736). The combination of single-view DBT(CC-DBT) and FFDM showed significantly higher mass display rates than the two-view FFDM (p< 0.05), while the display rates for other positive lesions were similar (p> 0.05).Conclusion: Our study showed that in opportunistic screening of patients with small breast masses that can be easily detected by ultrasound, MLO-FFDM+CC-DBT or CC-FFDM+MLO-DBT combinations can better balance the individual average gland dose and detection accuracy. The study result cannot be applied to the detection of non-mass lesions as the numbers are too small.Keywords: breast, breast tomography, screening, digital mammography, average gland dose

Zining Liu,* Yinkui Wang,* Fei Shan, Xiangji Ying, Yan Zhang, Shuangxi Li, Yongning Jia, Ziyu Li, Jiafu Ji Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziyu LiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaEmail ziyu_li@hsc.pku.edu.cnBackground: The duration and the optimal time to adjuvant chemotherapy (TAC) in locally advanced gastric cancer (LAGC) have net not been sufficiently demonstrated. Sequential adjuvant chemotherapy (AC) after neoadjuvant chemotherapy plus gastrectomy is increasingly utilized, making the question more complicated.Patients and Methods: Data were collected from patients with LAGC who underwent 5-Fu-based doublet regimens as adjuvant treatment after gastrectomy in a single-center database. TAC and duration (cycles) were used to evaluate survival outcomes.Results: A total of 816 patients were included. Patients received over six cycles and TAC less than 42 days significantly correlated with better survival (log-rank Ptrend< 0.001). The analysis of TAC and number cycles were separately applied in perioperative chemotherapy (PEC) and postoperative chemotherapy (POC) group using Cox regression. The number of cycles revealed a statistical significance improving OS rate both in POC (HR=0.904, 95% CI=0.836– 0.977, P=0.011) and PEC (HR=0.887, 95% CI=0.798– 0.986, P=0.026), while only in POC did the TAC show an increasing trend of risk with borderline significance (OS: HR=1.008, 95% CI=0.999– 1.018, P=0.094; PFS: HR=1.009, 95% CI=1.000– 1.018, P=0.055). A spline model demonstrates the less improvement in survival after cycles of chemotherapy reaching six.Conclusion: Our findings suggest that TAC is more likely to downregulate the survival benefit in POC rather than PEC, while overall survival is susceptible to cumulative cycles of chemotherapy in both groups. Furthermore, six cycles of chemotherapy tended to reach the maximum survival benefits. Prospective confirmation is required.Keywords: gastric cancer, chemotherapy, time to initiation, duration, restricted cubic spline

Yuanyuan Wang,1 Jingjing Chen,1 Wei Chen,2 Ling Liu,2 Mei Dong,2 Juan Ji,2 Die Hu,3 Nianzhi Zhang2 1Graduate School, Anhui University of Chinese Medicine, Anhui, Hefei 230012, People’s Republic of China; 2Department of Respiratory Medicine, The First Affiliated Hospital of Anhui University of Chinese Medicine, Anhui, Hefei, 230031, People’s Republic of China; 3Department of Scientific Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Anhui, Hefei 230031, People’s Republic of ChinaCorrespondence: Nianzhi Zhang Tel +86 551-62850057Email dczhangnz@126.comBackground: Chronic obstructive pulmonary disease (COPD) is the third cause of disease-related death and brings a heavy burden to human health. Long non-coding RNA (lncRNA) was revealed to participate in COPD pathogenesis. This study aims to establish the effects and regulatory mechanism of lncRNA long intergenic non-coding 00987 (LINC00987) in lipopolysaccharide (LPS)-induced apoptosis, oxidative stress, inflammation and autophagy in BEAS-2B cells.Methods: The expression levels of LINC00987 and let-7b-5p were detected by real-time quantitativepolymerase chain reaction (RT-qPCR). The expression of apoptosis-associated proteins, oxidative stress (ROS)-related proteins, autophagy-related proteins and sirtuin1 (SIRT1) protein was determined by Western blot. Cell viability was illustrated by cell counting kit-8 (CCK-8) assay. Cell apoptosis was investigated by caspase3 activity and apoptosis analysis assays. ROS, inflammation and autophagy were demonstrated by detecting reactive ROS level and superoxide dismutase (SOD) activity, enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, respectively. The binding sites between let-7b-5p and LINC00987 or SIRT1 were predicted by lncBase or miRWalk online database, and identified by dual-luciferase reporter assay.Results: LINC00987 expression was strikingly downregulated and let-7b-5p expression was obviously upregulated in COPD tissues and LPS-induced BEAS-2B cells compared with control groups. LINC00987 overexpression promoted BEAS-2B cells against LPS-mediated viability, apoptosis, oxidative stress, inflammation and autophagy, whereas these effects were attenuated by let-7b-5p mimic or SIRT1 knockdown. Furthermore, LINC00987 sponged let-7b-5p and let-7b-5p bound to SIRT1.Conclusion: LINC00987 ameliorated COPD through modulating LPS-induced cell apoptosis, oxidative stress, inflammation and autophagy via sponging let-7b-5p to associate with SIRT1. This finding will provide a theoretical basis for the research of LncRNA-mediated treatment in COPD.Keywords: COPD, LINC00987, let-7b-5p, SIRT1, LPS

Qiang Yu,1,2 Liwei Wu,2 Jie Ji,2 Jiao Feng,2 Weiqi Dai,1– 3 Jingjing Li,1,2 Jianye Wu,1 Chuanyong Guo1,2 1Department of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai 200060, People’s Republic of China; 2Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China; 3Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200336, People’s Republic of ChinaCorrespondence: Jianye Wu; Chuanyong GuoDepartment of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai 200060, People’s Republic of ChinaEmail wjymail@163.com; guochuanyong@hotmail.comAbstract: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. HCC incidence rate is sixth and mortality is fourth worldwide. However, HCC pathogenesis and molecular mechanisms remain unclear. The incidence of HCC is associated with genetic, environmental, and metabolic factors. The role of gut microbiota in the pathogenesis of HCC has attracted researchers’ attention because of anatomical and functional interactions between liver and intestine. Studies have demonstrated the involvement of gut microbiota in the development of HCC and chronic liver diseases, such as alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and liver cirrhosis. Peroxisome proliferator-activated receptors (PPARs) are a group of receptors with diverse biological functions. Natural and synthetic PPAR agonists show potential for treatment of NAFLD, liver fibrosis, and HCC. Recent studies have demonstrated that PPARs take part in gut microbiota inhabitation and adaptation. This manuscript reviews the role of gut microbiota in the development of HCC and precancerous diseases, the role of PPARs in modulation of gut microbiota and HCC, and potential of gut microbiota for HCC diagnosis and treatment.Keywords: gut microbiota, hepatocellular carcinoma, PPARs, carcinogenesis

Liyun Zheng,1,2,* Shiji Fang,1,2,* Junguo Hui,3 Vinothkumar Rajamanickam,2 Minjiang Chen,2 Qiaoyou Weng,2 Xulu Wu,2 Zhongwei Zhao,1 Jiansong Ji1– 3 1Interventional Diagnosis and Treatment Center, Lishui Hospital of Zhejiang University, Lishui, Zhejiang 323000, People’s Republic of China; 2Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital of Zhejiang University, Lishui, Zhejiang 323000, People’s Republic of China; 3Department of Radiology, Lishui Hospital of Zhejiang University, Lishui, Zhejiang 323000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiansong JiLishui Hospital of Zhejiang University, Lishui, Zhejiang 323000, People’s Republic of ChinaTel +86-13648782878Fax +86-578-2133457Email lschrjjs@163.comBackground: Osteosarcoma (OS) is the most common primary malignancy arise from bone and is one of the causes of cancer-related deaths. Triptonide (TN), a diterpenoid epoxide presented in Tripterygium wilfordii, is shown to possess a broad spectrum of biological properties.Methods: In this study, we investigate the growth inhibitory effect of TN against human OS cells and its underlying molecular mechanism of action.Results: Findings of our in vitro study revealed that TN exhibited a dose-dependent cytotoxic effect in MG63 and U-2OS cells. ROS-mediated cytotoxic effect was achieved in OS cells treated with TN which was reversed upon NAC treatment. Significantly, increased expression of PERK, p-EIF2, GRP78, ATF4 and CHOP in TN-treated OS cells unfolds the molecular mechanism of TN targets ER stress-mediated apoptosis. Modulation of ERK MAPK pathway was also observed as evidenced by the increased phosphorylation of ERK (p-ERK) and p-p38 in TN-treated OS cells.Conclusion: Altogether, the outcome of the study for the first time revealed that TN exhibited its potential chemotherapeutic effects through ROS-mediated ER stress-induced apoptosis via p38 and ERK MAPK signaling pathways.Keywords: osteosarcoma, triptonide, ER stress, apoptosis, MAPK signaling

Shiwei Liu,1 Exian Mou,1 Shiyan Zeng,1 Lu Wang,2 Hao Dong,3 Juan Ji,3 Hong Yang,3 Junjie Li,1 Hao Wang,1 Hui Li,1 Jia Xu1 1Department of Breast Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, People’s Republic of China; 2Department of Operating Room, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, People’s Republic of China; 3Department of Pathology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, People’s Republic of ChinaCorrespondence: Hui Li; Jia XuDepartment of Breast Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, No. 55, Section 4, South Renmin Road, Chengdu, Sichuan Province, People’s Republic of ChinaTel/Fax +86-02885420456Email zlyy_lh@163.com; scszlyyxujia@sohu.comPurpose: The aim of the present study was to investigate the effect of trastuzumab on the pathological complete response (pCR) rate and event-free survival (EFS) in neoadjuvant-treated HER2-positive breast cancer with a low infiltrating level of tumor-infiltrating lymphocytes (TILs).Patients and Methods: The infiltrating level of TILs was evaluated in hematoxylin and eosin-stained slides from diagnostic needle biopsies, and a low infiltrating level of TILs was defined as TILs < 10%. Data of 179 HER2-positive patients with a low infiltrating level of TILs were retrospectively reviewed and compared according to whether trastuzumab was administered or not. The associations of clinicopathological characteristics with pCR or EFS were assessed in univariate and multivariate analyses. EFS was estimated by the Kaplan–Meier method and compared by the log rank test.Results: Of 179 patients, the overall pCR rate was 20.1%, and 74 patients (41.3%) received trastuzumab. Patients treated with trastuzumab showed a pCR rate of 20.3% compared with 20.0% for those without trastuzumab (P = 0.965). Trastuzumab administration was not associated with pCR in univariate (P = 0.965) and multivariate (P = 0.994) analyses. Negative status of hormone receptor (HR) (P < 0.001) and histological grade 3 (P = 0.007) were independent predictors for pCR in multivariate analyses. Trastuzumab usage had no significant impact on EFS in univariate (P = 0.916) and multivariate (P = 0.431) analyses, and pCR was the only independent predictor for favorable EFS (P = 0.012) in multivariate analyses.Conclusion: In neoadjuvant-treated HER2-positive breast cancer with a low infiltrating level of TILs, additional trastuzumab had no significant influence on the pCR rate and EFS. HR-negative status and histological grade 3 were independently associated with higher pCR rates, and pCR was the only independent predictor for improved survival. Our findings may help identify patients who are resistant to trastuzumab, thereby guiding the de-escalating choice of anti-HER2 therapy.Keywords: HER2, trastuzumab, tumor-infiltrating lymphocytes, pathological complete response, event-free survival

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

Yuzhu Hu, 1–3 Yihong He, 1–3 Jianrui Ji, 1 Songping Zheng, 1–3 Yongzhong Cheng 1–3 1Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, People’s Republic of China; 2Department of Medical Oncology, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People’s Republic of China; 3Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People’s Republic of ChinaCorrespondence: Songping Zheng; Yongzhong ChengDepartment of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People’s Republic of ChinaTel +86 28 8516 4063Email 13618088051@163.com; chengyz@scu.edu.cnIntroduction: Curcumin (Cur) is a natural extract of Asian spice Curcumin longa, showing multi-targeting capability and low toxicity in anti-tumor activities. The low bioavailability restricts its application as a therapeutic agent. Folate (FA) receptors are highly expressed in many malignant tumors while low expressed in normal tissue. Herein, we developed a self-assembled FA modified MPEG-PCL micelle to incorporate Cur (FA/Nano-Cur) and applied it for colorectal cancer therapy.Methods: We prepared FA/Nano-Cur micelles and identified their characteristics. The drug release behavior, pharmacokinetics and in vitro anti-tumor activities of FA/Nano-Cur were studied. Furthermore, the in vivo anti-tumor ability assessment and anti-tumor mechanisms investigation were carried out in murine colorectal cancer model.Results: FA/Nano-Cur micelles had an average particle size of 30.47 nm. Elongated T 1/2 and larger AUC were found in FA/Nano-Cur group than that in the Free Cur group. MTT assay and apoptotic study indicated the growth inhibitory effect and pro-apoptotic effect of FA/Nano-Cur were the most significant among all treatments. Moreover, the in vivo study demonstrated that FA/Nano-Cur micelles exhibited a much stronger effect to suppress tumor growth, promote tumor apoptosis and attenuate tumor angiogenesis than Free Cur and Nano-Cur micelles.Conclusion: The present study demonstrated FA/Nano-Cur micelles might be a promising therapeutic agent in colorectal cancer treatment with distinctive advantages of improved bioavailability, sustained drug release, tumor-targeted delivery and low toxicity.Keywords: curcumin, colorectal cancer, folate, nanoformulation, apoptosis, angiogenesis

Tong Liu, 1–3,* Sainan Li, 2,* Liwei Wu, 2 Qiang Yu, 2, 4 Jingjing Li, 1 Jiao Feng, 2 Jie Zhang, 2, 4 Jiaojiao Chen, 2, 4 Yuting Zhou, 2, 4 Jie Ji, 2 Kan Chen, 2 Yuqing Mao, 5 Fan Wang, 6 Weiqi Dai, 7 Xiaoming Fan, 8 Jianye Wu, 1 Chuanyong Guo 1, 2 1Department of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai 200060, People’s Republic of China; 2Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China; 3Department of Gastroenterology, Shandong Provincial Hospital of Shandong University, Ji’nan 250000, People’s Republic of China; 4Department of Gastroenterology, Shanghai Tenth People’s Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai 200072, People’s Republic of China; 5Department of Gerontology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China; 6Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China; 7Department of Gastroenterology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, People’s Republic of China; 8Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai 201508, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianye WuDepartment of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai 200060, People’s Republic of ChinaEmail wjymail@163.comChuanyong GuoDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of ChinaEmail guochuanyong@hotmail.comObjective: Shikonin is a natural product with many activities, including anti-cancer effects. Pyruvate kinase type M2 (PKM2) plays a crucial role in the growth of tumor cells. However, the effect of shikonin on PKM2 in hepatocellular carcinoma (HCC) is unclear.Methods: Cell viability, apoptosis level, glucose uptake, and lactate production were detected in HCC cells. Lentivirus-overexpressed and –shRNA of PKM2 were used to verify the key target of shikonin. A xenograft mouse model was used to detect the efficacy of shikonin and its combination with sorafenib in vivo.Results: Shikonin inhibited proliferation and glycolysis and induced apoptosis in HCC cells. Either PKM2-overexpressed or PKM2-shRNA alleviated or enhanced this effect. The results of CCK-8 showed that shikonin significantly inhibited cell viability of HCC cells. The levels of glucose uptake and lactate production were dramatically decreased by shikonin-treated. Results of flow cytometry and Western blot showed that the levels of apoptosis of HCC cells were significantly increased in a dose-dependent manner after shikonin treatment. In addition, shikonin enhanced the anti-cancer effect of sorafenib in vitro and in vivo. Our results showed that SK combined with sorafenib markedly inhibits tumor growth in HCC-transplanted nude mice compared to SK or sorafenib alone.Conclusion: By inhibiting PKM2, shikonin inhibited proliferation and glycolysis and induced cell apoptosis in HCC cells. The effect of shikonin on tumor cell proliferation, apoptosis and glycolsis will make it promising drug for HCC patients.Keywords: shikonin, PKM2, glycolysis, apoptosis, proliferation, hepatocellular carcinoma

Ming Sun,1,2 Youxin Wang,2 Jan Sundquist,1,3,4 Kristina Sundquist,1,3,4 Jianguang Ji1 1Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden; 2Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, People’s Republic of China; 3Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4Center for Community-Based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Shimane, JapanCorrespondence: Jianguang JiCenter for Primary Health Care Research, Jan Waldenströms Gata 35, Skåne University Hospital, Malmö 205 02, SwedenTel +46 40391382Fax +46 40391370Email Jianguang.ji@med.lu.seYouxin WangBeijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, 10 Youanmen Xitoutiao, Beijing 100069, People’s Republic of ChinaTel +86 10 8391 1779Fax +86 10 8391 1501Email wangy@ccmu.edu.cnPurpose: The incidence of colorectal cancer (CRC) varies by age, sex, and anatomical subsite. Few studies have examined the temporal trends of age-specific sex disparity in incidence and survival by age at diagnosis and anatomical site.Patients and Methods: The study was performed on all incident cases of CRC, using data derived from the nationwide Swedish Cancer Register between 1960 and 2014, including right-sided colon cancer (RCC), left-sided colon cancer (LCC), and rectal cancer. Male-to-female age-standardized incidence rate ratio (IRR) and male-to-female five-year survival rate ratio (SRR) were calculated as the main indicators. Furthermore, we performed joinpoint regression analyses to estimate average annual percentage change.Results: The overall male-to-female IRR was 1.05 for RCC, 1.31 for LCC, and 1.66 for rectal cancer. Male-to-female IRR increased steadily for RCC by an average of 0.4% per year until the mid-1990s and then decreased gradually by an average of 1.0% per year. LCC patients showed an increase of 0.6% per year since the mid-1970s. For rectal cancer, a non-significant random fluctuation was noted during the study period. The temporal trends of male-to-female IRR varied by age at diagnosis. The male-to-female SRR was 0.87 for RCC, 0.88 for LCC, and 0.86 for rectal cancer, which remained relatively stable during the study period.Conclusion: Sex disparity of CRC is age-, period-, and anatomical subsite-dependent. Further studies are needed to investigate the underlying contributing factors.Keywords: colorectal cancer, sex disparity, incidence, survival, temporal trend

Xiaoshuai Zhang,1 Fang Tang,2 Jiadong Ji,1 Wenting Han,3 Peng Lu3 1School of Statistics, Shandong University of Finance and Economics, Jinan, People’s Republic of China; 2Center for Data Science in Health and Medicine, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, People’s Republic of China; 3Department of Preventive Medicine, School of Public Health and Management, Binzhou Medical University, Yantai, People’s Republic of ChinaCorrespondence: Xiaoshuai ZhangSchool of Statistics, Shandong University of Finance and Economics, Jinan 250014, People’s Republic of ChinaTel +86 13589896463Email zhxiaoshuai@gmail.comObjective: Dyslipidemia has been recognized as a major risk factor of several diseases, and early prevention and management of dyslipidemia is effective in the primary prevention of cardiovascular events. The present study aims to develop risk models for predicting dyslipidemia using Random Survival Forest (RSF), which take the complex relationship between the variables into account.Methods: We used data from 6328 participants aged between 19 and 90 years free of dyslipidemia at baseline with a maximum follow-up of 5 years. RSF was applied to develop gender-specific risk model for predicting dyslipidemia using variables from anthropometric and laboratory test in the cohort. Cox regression was also adopted in comparison with the RSF model, and Harrell’s concordance statistic with 10-fold cross-validation was used to validate the models.Results: The incidence density of dyslipidemia was 101/1000 in total and subgroup incidence densities were 121/1000 for men and 69/1000 for women. Twenty-four predictors were identified in the prediction model of males and 23 in females. The C-statistics of the prediction models for males and females were 0.731 and 0.801, respectively. The RSF model shows better discriminative performance than CPH model (0.719 for males and 0.787 for females). Moreover, some predictors were observed to have a nonlinear effect on dyslipidemia.Conclusion: The RSF model is a promising method in identifying high-risk individuals for the prevention of dyslipidemia and related diseases.Keywords: random survival forest, Cox proportional hazard model, dyslipidemia, risk prediction

Xihui Ying,1 Jianfei Tu,1 Wenxian Wang,2 Xingliang Li,3 Chunwei Xu,4 Jiansong Ji1 1Department of Radiology, Lishui Central Hospital/Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Lishui, Zhejiang 323000, People’s Republic of China; 2Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, People’s Republic of China; 3Department of Thoracic Disease Diagnosis and Treatment Center, Zhejiang Rongjun Hospital, Jiaxing, Zhejiang 314000, People’s Republic of China; 4Department of Pathology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, People’s Republic of ChinaCorrespondence: Jiansong JiDepartment of Radiology, Lishui Central Hospital/Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Lishui, Zhejiang 323000, People’s Republic of ChinaEmail lschrjjs@163.comAbstract: Fibroblast growth factor receptor (FGFR) family includes four highly conserved receptor tyrosine kinases. Particularly, FGFR2 has been identified as a potential target for tyrosine kinase inhibitor (TKI) treatment. Except for immunohistochemistry and fluorescence in situ hybridization, next-generation sequencing (NGS) technology represents a novel tool for FGFR2 detection that covers a wide range of fusion genes. In the present work, we present a case of cholangiocarcinoma who had FGFR2-BICC1 rearrangement detected by NGS. A 76-year-old female diagnosed with cholangiocarcinoma underwent four cycles of chemotherapy. The NGS assay showed that the tumor had a FGFR2-BICC1 rearrangement. The patient had a favorable tumor response to sorafenib. Herein, we report the first case with cholangiocarcinoma harboring FGFR2-BICC1 who is sensitive to sorafenib therapy.Keywords: cholangiocarcinoma, NGS, FGFR2 rearrangement

Lin Wang,1,2 Xianzi Wen,1 Fengming Luan,1 Tao Fu,2 Chao Gao,2 Hong Du,1 Ting Guo,1 Jing Han,1 Longtao Huangfu,1 Xiaojing Cheng,1 Jiafu Ji1,21Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 2Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of ChinaCorrespondence: Xiaojing ChengKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaTel +86 108 819 6760Email chengli@bjmu.edu.cnJiafu JiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaTel +86 108 819 6048Email jijiafu@hsc.pku.edu.cnPurpose: Eukaryotic translation initiation factor (EIF) plays a vital role in protein synthesis. EIF3B is a core subunit of the EIF3 family, and is overexpressed in many tumors. EIF3B is associated with an unfavorable prognosis, as well as the genesis and development of tumors. However, the potential role of EIF3B in gastric cancer (GC) remains unknown. In the current study, we explored the clinical significance and the possible mechanism of EIF3B in the progression of GC.Methods: EIF3B expression was analyzed in 78 GC tissue samples through quantitative PCR and in 94 GC tissue samples through immunohistochemistry (IHC) staining. The correlation between EIF3B and clinicopathological features was analyzed in GC tissues. The role of EIF3B in GC progression was investigated through in vitro and in vivo assays.Results: EIF3B expression was upregulated in GC tissues (73.4%, IHC). High expression of EIF3B was significantly correlated with the depth of tumor invasion, lymph node metastasis and TNM stage (P=0.000, 0.000 and 0.000, respectively). Multivariate analysis indicated that GC patients with high EIF3B expression suffered a poorer 5-year survival. EIF3B promoted GC cell proliferation and was strongly associated with proliferating cell nuclear antigen (PCNA) expression in GC samples (P=0.009). It also enhanced tumor cell migration and invasion, which were affected through epithelial-mesenchymal transition (EMT) and the Stat3 signaling pathway. Knockdown of EIF3B in GC cells suppressed the growth of xenograft tumors and lung metastatic colonization in vivo. Furthermore, gene set enrichment analysis (GSEA) and Western blot results demonstrated that EIF3B activated the PI3K/AKT/mTOR signaling pathway.Conclusion: Our results suggest that EIF3B plays an oncogenic role in GC progression and serves as an independent prognostic factor for GC patients.Keywords: EIF3B, gastric cancer, prognosis, PI3K/AKT/mTOR pathway

Chen Huang,1,2 Qingyi Shi,1 Beiwen Zheng,1 Jinru Ji,1 Chaoqun Ying,1 Xiao Yu,1 Hui Wang,2 Yonghong Xiao11State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Respiratory Medicine, Lihuili Hospital, Ningbo Medical Center, Ningbo, People’s Republic of ChinaObjectives: Monte Carlo simulation (MCS) was used to evaluate optimal dosage for cefepime (FEP), moxalactam (MOX), and cefperazone/sulbactam (CFZ/SBT) against extended-spectrum β-lactamase (ESBL) producers isolated from the Blood Bacterial Resistant Investigation Collaborative System.Methods: Minimum inhibitory concentration (MIC) was tested by agar dilution, and ESBL producers were identified by modified Clinical and Laboratory Standards Institute tests. Pharmacokinetic parameters were derived from data on healthy individuals, and probability of target attainment (PTA) and cumulative fraction of response (CFR) %fT >MIC values were estimated by MCS.Results: A total of 2032 Escherichia coli (875 ESBL-producing) and Klebsiella pneumoniae (157 ESBL-producing) strains, and 371 other Enterobacteriaceae strains, were isolated from patients with bloodstream infections (BSIs). MIC90 values for FEP, MOX, and CFZ/SBT against ESBL-producing E. coli and K. pneumoniae were 64/64 mg/L, 2/32 mg/L, and 64/128 mg/L, respectively. Conventional MOX and CFZ/SBT doses failed to reach 90% PTA against isolates with MICs ≥8 mg/L and ≥4 mg/L, respectively. Against ESBL producers, neither FEP nor CFZ/SBT achieved ≥90% CFR, while CFRs for MOX (1 g iv q6h, 2 g iv q12h, and 2 g iv q8h) exceeded 90% against ESBL-producing E. coli. Simulated CFRs for FEP and MOX were similar (>90%) against non-ESBL-producing Enterobacteriaceae, and higher than CFRs for CFZ/SBT.Conclusion: ESBL producers from BSIs were highly susceptible to MOX, and PTA values were generally higher for MOX than FEP or CFZ/SBT for conventional dosing regimens. This large MCS analysis shows that MOX but not FEP or CFZ/SBT can be used empirically to treat BSIs caused by ESBL-producing E. coli strains.Keywords: Monte Carlo simulation, Enterobacteriaceae, extended-spectrum β-lactamase, moxalactam, cefperazone/sulbactam, cefepime

Jiali Ji,1 Xiaolan Dai,2 Sai-Ching Jim Yeung,3 Xuexin He11Department of Medical Oncology, The 2nd Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Pharmacy, School of Medicine, Shantou University, Shantou, Guangdong, People’s Republic of China; 3Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USAAbstract: Long non-coding RNAs (lncRNAs) have shown potential as a biomarker in the diagnosis and prognosis in multiple cancers. LncRNAs are dysregulated in various cancers, playing either oncogenic or tumor suppressive roles. Emerging evidences have proved that the growth arrest-specific 5 (GAS5) lncRNA can function as a tumor suppressor in several cancers. LncRNA GAS5 is downregulated in many types of cancer, regulating cellular processes such as cell proliferation, apoptosis and invasion. The low level of GAS5 expression often elevates capacity of proliferation and predicts poorer prognosis in some cancers. This review aims to summarize the recent published literature on the biogenesis, regulation mechanism and function of GAS5 in different types of cancers and explore its potential for cancer diagnosis, prognosis and treatment.Keywords: lncRNA, GAS5, tumor suppressor, tumor

Zhong-Guo Fan,1 Wen-Ling Zhang,2 Bing Xu,1 Jun Ji,1 Nai-Liang Tian,3 Sheng-Hu He1 1Department of Cardiology, Subei People’s Hospital of Jiangsu Province, Yangzhou University, Yangzhou, Jiangsu, China; 2Department of Geriatric Gastroenterology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China; 3Department of Cardiology, Nanjing First Hospital, Nanjing Heart Center, Nanjing Medical University, Nanjing, Jiangsu, China Background: The efficacy and safety of ticagrelor following percutaneous coronary intervention for patients with acute coronary syndrome remains unclear. This study sought to evaluate clinical outcomes of ticagrelor as part of dual-antiplatelet treatment for these patients. Methods: PubMed, MEDLINE, Embase, and other Internet sources were searched for eligible citations. The primary end point was major adverse cardiovascular and cerebrovascular events, consisting of cardiovascular death, myocardial infarction, and stroke. The secondary end point was the occurrence of definite/probable stent thrombosis (ST). The risk of bleeding was chosen to be the safety end point. Results: Eleven clinical trials – six randomized trials and five observational trials – were finally analyzed. A tendency toward reduction in the risk of major adverse cardiovascular and cerebrovascular events was observed only with respect to ticagrelor (OR 0.83, 95% CI 0.66–1.03; P=0.091), which might have resulted from the lower risk of cardiovascular death (OR 0.78, 95% CI 0.68–0.89; P

Benquan Liu,1 Jiemei Ji,1 Qing Feng,1 Xi Luo,1 Xiurong Yan,1 Yuxia Ni,2 Yajun He,1 Zhongxuan Mao,1 Jingchen Liu1 1Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China; 2Department of Anesthesiology, Langdong Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China Background: Local anesthetics in spinal anesthesia have neurotoxic effects, resulting in severe neurological complications. Intrathecal monosialoganglioside (GM1) administration has a therapeutic effect on bupivacaine-induced neurotoxicity. The aim of this study was to determine the underlying mechanisms of bupivacaine-induced neurotoxicity and the potential neuroprotective role of GM1.Materials and methods: A rat spinal cord neurotoxicity model was established by injecting bupivacaine (5%, 0.12 µL/g) intrathecally. The protective effect of GM1 (30 mg/kg) was evaluated by pretreating the animals with it prior to the bupivacaine regimen. The neurological and locomotor functions were assessed using standard tests. The histomorphological changes, neuron degeneration and apoptosis, and endoplasmic reticulum stress (ERS) relevant markers were analyzed using immunofluorescence, quantitative real-time PCR, and Western blotting.Results: Bupivacaine resulted in significant neurotoxicity in the form of aberrant neurolocomoter functions and spinal cord histomorphology and neuronal apoptosis. Furthermore, the ERS specific markers were significantly upregulated during bupivacaine-induced neurotoxicity. These neurotoxic effects were ameliorated by GM1.Conclusion: Pretreatment with GM1 protects against bupivacaine-induced neurotoxicity via the inhibition of the GRP78/PERK/eIF2α/ATF4-mediated ERS. Keywords: bupivacaine, GM1 ganglioside, ERS, neurotoxicity

Nannan Gao,1 Chunhou Li,2 Jiadong Ji,3 Yanli Yang,1 Shaoting Wang,1 Xinlun Tian,1 Kai-Feng Xu1 1Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China; 2Office of Medical Insurance, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China; 3School of Statistics, Shandong University of Finance and Economics, Jinan, China Purpose: Evidence between air pollution and COPD admissions is inconsistent and limited in China. In this study, we aimed to explore the effects of air pollutants on COPD admissions in Beijing, China.Patients and methods: Daily COPD hospital admission visits derived from tertiary and secondary hospitals in Beijing were retrieved from January 2013 to February 2017. Air pollutant levels and meteorological data over the same periods were also achieved. Generalized additive model was applied to estimate the percentage changes with 95% CIs in daily admissions corresponding to 10 µg/m3 increases in pollutants levels [1 mg/m3 in carbon monoxide (CO)], stratified by age, gender, and season.Results: Seventy-three thousand seventy-six COPD hospital admission visits were included with mean daily visits of 48 (21). Cumulative lag effect with per 10 µg/m3 increase in air pollutant levels was largest for nitrogen dioxide (NO2) with 3.03% (95% CI: 1.82%–4.26%) at lag 06, for sulfur dioxide (SO2) with 2.07% (95% CI: 1.00%–3.15%) at lag 01, for particulate matter ≤10 µm in aerodynamic diameter (PM10) with 0.92% (95% CI: 0.55%–1.30%) at lag 07, and for particulate matter ≤2.5 µm in aerodynamic diameter (PM2.5) with 0.82% (95% CI: 0.38%–1.26%) at lag 06, respectively. Percentage increase for each 1 mg/m3 increase in CO was 5.99% (95% CI: 2.74%–9.34%) at lag 06. Further, stronger effects on COPD admissions were found in warm seasons than in cold seasons.Conclusion: Short-term exposures to PM2.5, PM10, NO2, SO2, and CO had adverse effects on COPD hospitalizations in Beijing with different magnitudes and lag days. Keywords: adverse effects, air pollution, COPD, time series analysis, hospital visits

Wenbin Lu,1,* JingJing Ji,1,* Genshan Ma,1 Qiming Dai,1 Lijuan Chen,1 Pengfei Zuo,1 Yuanjin Zhao2 1Department of Cardiology, ZhongDa Hospital Affiliated with Southeast University, Nanjing, China; 2State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China *These authors contributed equally to this work Background: The two-dimensional incubation method is now the most commonly method for mesenchymal stem cell (MSC) production. however, gene expression and secretion of growth factors are relatively low; thus, the transplanted cells cannot be effectively utilized for potential clinical applications after acute myocardial infarction (AMI).Objectives: We aimed to investigate whether our newly made substrates of inverse opal with specific surface microstructures for MSC culturing can increase the viability of the cells and can contributes to decreased myocardial remodeling after transplanted to AMI mice. Methods: The inverse opal structure is fabricated by the convenient bottom-up approach of the self-assembly of colloidal nanoparticles. Mouse-derived MSCs were then cultured on the substrates when expanded at different times to investigate the cell growth status including morphology. Then the inverse opal substrates loaded MSCs were transplanted to AMI mice, cardiomyocyte apoptosis and LV remodeling were further compared. To explore the possible mechanisms of curation, the secretions and viability of MSCs on substrates were determined using mice ELISA kits and JC-1 mitochondrial membrane potential assay kits respectively at normal and hypoxic conditions. Results: 6 times expanded inverse opals allowed greatly the orderly growth of MSCs as compared to four (34% ± 10.6%) and two (20%±7.2%) times expanded as well as unexpanded (13%±4.1%) (P

Lena Palmberg,* Britt-Marie Sundblad,* Jie Ji, Jakob Karén, Kjell Larsson Work Environment Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden *These authors contributed equally to this work Background: Exposure in a pig barn induces airway inflammation that has similarities with the response observed in acute exacerbations in COPD. Methods: A total of 15 smokers with COPD and 15 healthy non-smokers were exposed for 2 hours in a pig barn (in vivo exposure). Symptoms were assessed, lung function measured, and blood and sputum samples taken before and after exposure. Blood neutrophils were isolated and stimulated ex vivo with dust from a pig barn and acetylcholine, and inflammatory markers were analyzed. Results: In vivo exposure caused more symptoms and greater lung function fall in COPD patients than in controls. Baseline concentrations of MMP9, TIMP1, IL6, CXCL8, in sputum and neutrophil blood count were higher in COPD patients than in controls. In vivo exposure increased MMP9, TIMP1, IL6, CXCL8, TNFα, and LTB4 in sputum and MMP9 and IL6 in blood, with no difference between the groups, and serum CRP increased more in COPD subjects. Expression of choline acetyltransferase and acetylcholinesterase on sputum and blood cells was similar in the groups and uninfluenced by in vivo exposure. Dust exposure ex vivo increased choline acetyltransferase expression in neutrophils, but the dust and acetylcholine response did not differ between the groups before and after in vivo exposure. Conclusion: COPD patients exposed in a pig barn experience symptoms similar to those in acute exacerbations and lung function deterioration that is unrelated to bronchial responsiveness. Cholinergic mechanisms are involved in the inflammatory response to dust, with no difference between COPD and non-smokers. Keywords: organic dust, airway inflammation, chronic obstructive pulmonary disease, COPD, pig barn

Chenfei Zhou,1,* Xiaojing Feng,2,* Fei Yuan,3 Jun Ji,4 Min Shi,1 Yingyan Yu,4 Zhenggang Zhu,1,4 Jun Zhang1 1Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Clinical Laboratory, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Objective: The aim of this study was to compare the molecular profiling, including somatic mutation and somatic copy number variation (SCNV), between human epidermal growth factor receptor 2 (HER2)-positive (HER2+) and HER2-negative (HER2–) gastric cancer patients.Patients and methods: Tumor samples were collected from 15 gastric cancer patients, including 10 HER2+ samples and five HER2– samples, which were diagnosed by immunohistochemistry. Whole-genome sequencing was performed by Illumina HiSeq PE150 instrument, along with somatic single nucleotide variant (SNV), somatic structural variation (SV) and SCNV analyses.Results: The average number of somatic SNVs and mutation spectrum were similar between HER2+ and HER2– samples. Transition of C>T was the main type of mutation. For somatic SV, number of intrachromosomal translocation (2,850.3±1,260.4 vs 1,157±586.6, P=0.015) and insertion of large fragment (1,125.6±457.4 vs 500±138.9, P=0.002) in HER2+ samples were higher than those in HER2– samples. For all samples, lysine methyltransferase 2C (KMT2C), ZNF91, TAF1 and MAP4 genes were identified as new significant mutated driver genes. KMT2C gene mutations were mainly detected in HER2+ samples (7/10), which were correlated with the lysine degradation pathway. SERF2 gene mutations were more common in HER2– samples (3/5) than in HER2+ samples (1/10). Copy number gain was the major type of SCNV in both groups, and the average number of SCNVs was similar. In the HER2+ samples, by using the GISTIC algorithm, amplification of known driver genes cyclin-dependent kinase 12 (CDK12, 6/10) and RARA (5/10) was mainly observed, and other amplifications including JUP, GJD3, KRT39, CDC6, RAPGEFL1, WIPF2, FAM65C, KLF5, DACH1 and PIBF1 genes were also observed. Amplifications of solute carrier family 12 member 7 (SLC12A7, 5/5), TTC40 (4/5) and GALNT9 (4/5) genes were mainly detected in HER2– samples.Conclusion: Differences in genomic landscape between HER2+ and HER2– gastric cancer samples were revealed in this study. KMT2C mutation and CDK12 amplification were mainly detected in HER2+ gastric cancer, whereas SERF2 mutation and SLC12A7 amplification were detected in HER2– gastric cancer. Keywords: gastric cancer, HER2, whole-genome sequencing, gene mutation, gene amplification

Yafei Cui,1–3,* Lin Li,2,4,* Ling Xia,1,* Qian Zhao,2 Shengnan Chen,2 Ting Fu,1 Juan Ji,1 Zhifeng Gu1 1Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, China; 2School of Nursing, Nantong University, Nantong, China; 3Department of Nursing, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; 4Department of Nursing, Changzhou 2nd People’s Affiliated Hospital of Nanjing Medical University, Changzhou, China *These authors contributed equally to this work Objective: The primary purpose of the present study was to survey the quality of life (QoL) in primary Sjögren’s syndrome (pSS) and to analyze the relationships between disease activity, anxiety/depression, fatigue, pain, age, oral disorders, impaired swallowing, sicca symptoms, and QoL.Patients and methods: A survey was conducted on 185 pSS patients and 168 healthy individuals using the Short Form 36 health survey for QoL. Disease activity was assessed using the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index. We examined these data using independent samples t-tests, Mann–Whitney U test, chi squared analysis, and linear regression.Results: The result for each domain in Short Form 36 health survey was lower in pSS patients than in healthy controls, especially the score in the dimension of role physical function. In the bivariate analysis, age, pain, fatigue, disease activity, disease complication, anxiety/depression, oral disorders, and impaired swallowing correlated with QoL. Also, in the linear regression model, pain, fatigue, disease activity, impaired swallowing, and anxiety/depression remained the main predictors of QoL.Conclusion: pSS patients had a considerably impaired QoL compared to the controls, and pSS could negatively affect the QoL of patients. Measuring QoL should be considered as a vital part of the comprehensive evaluation of the health status of pSS patients, which could contribute some valuable clues in improving the management of disease and treatment decisions. Keywords: primary Sjögren’s syndrome, quality of life, disease activity, depression

Chen Li,1,* Wei Li,2,* Yanli Zhang,3 Xin Zhang,2 Tong Liu,1 Yi Zhang,2 Yongmei Yang,2 Lili Wang,2 Hongwei Pan,2 Jian Ji,2 Chuanxin Wang1 1Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, China; 2Department of Clinical Laboratory, Qilu Hospital, Shandong University, Jinan, 250012, China; 3Department of Clinical Laboratory, Shandong Provincial Third Hospital, Jinan, 250031, China *These authors contributed equally to this work Purpose: Colorectal cancer (CRC) is a leading cause of cancer-associated mortality worldwide. Natural antisense transcripts (NATs) are pervasively expressed in human genome and have been confirmed to contribute to cancer progression. In our study, we aimed to investigate the expression and clinical pertinence of serine peptidase inhibitor, Kunitz type 1 antisense RNA1 (SPINT1-AS1) in CRC. Materials and methods: The expression levels of SPINT1-AS1 and the corresponding sense transcript SPINT1 mRNA were analyzed in 150 pairs of CRC tissues and adjacent normal (AN) tissues, along with 45 pairs of preoperative and postoperative serum exosome samples by the strand-specific real-time quantitative polymerase chain reaction. Results: Compared with AN tissues, the expression of SPINT1-AS1 was increased (P

Chang-Liang Luo,1,* Zhi-Gao Xu,2,* Hao Chen,2 Jia Ji,1 Yu-Hui Wang,1 Wei Hu,1 Kun Wang,3 Wu-Wen Zhang,1 Chun-Hui Yuan,4 Fu-Bing Wang1 1Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China; 2Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, China; 3Department of Laboratory Medicine, Hubei Cancer Hospital, Wuhan, China; 4Department of Laboratory Medicine, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China *These authors contributed equally to this work Background: Tissue biopsy-based cancer diagnosis has limitations because of the fact that tumor tissues are in constant evolution and extremely heterogeneous. The current study was aimed to examine whether tumor-educated blood platelets (TEPs) might be a potential all-in-one source for blood-based cancer diagnostics to overcome the limitations of conventional cancer biopsy.Methods: In the present study, we evaluated the expression pattern of MAGI2 antisense RNA 3 (MAGI2-AS3) and ZNFX1 antisense RNA 1 (ZFAS1) in both plasma and platelets of 101 non-small-cell lung cancer (NSCLC) patients. Receiver operating characteristic (ROC) curve was generated to evaluate their diagnostic potential. In addition, epidermal growth factor receptor (EGFR) mutations were detected in DNA and RNA samples of platelets for companion diagnostics.Results: Our results showed that the levels of MAGI2-AS3 and ZFAS1 in both plasma and platelets of NSCLC patients were significantly downregulated than those in healthy controls. A positive correlation of long noncoding RNA expression was observed between platelets and plasma (r=0.738 for MAGI2-AS3, r=0.751 for ZFAS1, respectively). By ROC analysis, we found that molecular interrogation of MAGI2-AS3 and ZFAS1 in TEPs and plasma can offer valuable diagnostic performance for NSCLC patients (area under the ROC curve [AUC]MAGI2-AS3=0.853/0.892, and AUCZFAS1=0.780/0.744 for diagnosing adenocarcinoma and squamous cell carcinoma cases from controls, respectively). Clinicopathologic characteristic analysis further revealed that MAGI2-AS3 level significantly correlated with tumor–node–metastasis (TNM) stage (p=0.001 in TEPs, p=0.003 in plasma), lymph-node metastasis (p=0.016 in TEPs, p=0.023 in plasma), and distant metastasis (p=0.045 in TEPs, p=0.045 in plasma), while ZFAS1 level was only correlated with TNM stage (p=0.005 in TEPs, p=0.044 in plasma). Furthermore, EGFRvIII RNA existed in both TEPs and plasma, but EGFR intracellular mutations cannot be detected in DNA of TEPs isolated from NSCLC.Conclusion: Our data suggested that TEP is a promising source for NSCLC diagnosis and companion diagnostics. Keywords: tumor-educated platelets, lncRNA-MAGI2-AS3, lncRNA-ZFAS1, EGFR mutations, NSCLC