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Luohang Ni,* Jianing Xu,* Quanpeng Li, Xianxiu Ge, Fei Wang, Xueting Deng, Lin Miao Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xueting Deng; Lin Miao, Email xtdeng@njmu.edu.cn; linmiao@njmu.edu.cnAbstract: Biliary tract cancer (BTC) represents a challenging malignancy characterized by aggressive behavior, high relapse rates, and poor prognosis. In recent years, immunotherapy has revolutionized the treatment landscape for various cancers, but its efficacy in BTC remains limited. This article provides a comprehensive overview of the advances in preclinical and clinical studies of immunotherapy for BTC. We explore the potential of immune checkpoint inhibitors in reshaping the management of BTC. Despite disappointing results thus far, ongoing clinical trials are investigating the combination of immunotherapy with other treatment modalities. Furthermore, research on the tumor microenvironment has unveiled novel targets for immunotherapeutic interventions. By understanding the current state of immunotherapy in BTC and highlighting future directions, this article aims to fuel further exploration and ultimately improve patient outcomes in this challenging disease.Keywords: biliary tract cancer, cancer immunotherapy, tumor microenvironment, immune checkpoint inhibitors, clinical trials

Yukai Hao,1 Baoling Zhao,1 Dongchao Wu,1 Xuejun Ge,1 Jianmin Han2 1Department of Endodontics, Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, People’s Republic of China; 2Central Laboratory, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, 100081, People’s Republic of ChinaCorrespondence: Xuejun Ge, The Department of Endodontics, Shanxi Medical University School and Hospital ofStomatology, 63 Xinjian South Road, Yingze District, Taiyuan, 030001, People’s Republic of China, Tel +8613834568537, Email gxj19722003@163.com Jianmin Han, Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguan Cun South Street, Beijing, 100081, People’s Republic of China, Tel +8613810459668, Email hanjianmin@bjmu.edu.cnIntroduction: Recombinant humanized collagen, as a novel biomaterial, exhibits multiple excellent biological functions, such as inhibition of inflammation, promotion of cell proliferation and vascular proliferation, and promotion of tissue healing. However, there is a lack of conclusive evidence regarding the specific role of recombinant humanized collagen type 17 (rhCol 17) in oral ulcer healing. This study explored whether rhCol 17 could promote the proliferation of human gingival fibroblasts (HGFs) and inhibit its inflammation, and whether it could promote the healing of oral ulcers in rats by inhibiting inflammation and accelerating tissue healing.Methods: At the cellular level, we investigated the effect of rhCol 17 on the proliferation of (HGFs) by CCK8; HGFs were mixed with lipopolysaccharide (LPS) to investigate the effect of rhCol 17 on HGFs in an inflammatory state. Eighteen adult male Sprague-Dawley rats were randomly distributed into three groups: blank control group, carbomer group (carbomer sprayed only), and rhCol 17 group (carbomer containing rhCol 17 sprayed), 1 time/day. The samples were collected at D3 and D5. At completion, histological staining and PCR were carried out to study its effect on the healing of oral ulcers in rats.Results: Through cellular experiments, we found that rhCol 17 possesses good biocompatibility and anti-inflammatory properties, and can effectively promote the proliferation and migration of HGFs, as well as significantly reduce the inflammation level of the cells. The animal experimental results showed that rhCol 17 could significantly reduce the inflammation level, promote collagen deposition and angiogenesis at the ulcer site, thus effectively accelerating the healing of oral ulcers in rats.Conclusion: In summary, the collagen sprays containing rhCol 17 have excellent anti-inflammatory effects and could accelerate tissue healing and are expected to provide a new effective treatment for patients with recurrent oral ulcers.Keywords: oral ulcer, inflammation, wound healing, recombinant humanized collagen

Jiejie Zhu,1,2 Yumei Wu,1,2 Xiaoyuan Ge,1,2 Xinwen Chen,1,2 Qiao Mei1,2 1Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, People’s Republic of China; 2Key Laboratory of Digestive Diseases of Anhui Province, Hefei, People’s Republic of ChinaCorrespondence: Qiao Mei, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, Anhui Province, 230022, People’s Republic of China, Email meiqiao@hotmail.comBackground: Ulcerative colitis (UC) is a long-lasting idiopathic condition, but its precise mechanisms remain unclear. Meanwhile, evidence has demonstrated that ferroptosis seems to interlock with the progress of UC. This research sought to identify hub genes of UC related to ferroptosis.Methods: First, the relevant profiles for this article were obtained from GEO database. From the FerrDb, 479 genes linked to ferroptosis were retrieved. Using analysis of the difference and WGCNA on colonic samples from GSE73661, the remaining six hub genes linked to ferroptosis and UC were discovered. Through logistic regression analyses, the diagnostic model was constructed and was then evaluated by external validation using dataset GSE92415. Afterwards, the correlation between immune cell filtration in UC and hub genes was examined. Finally, a mice model of colitis was established, and the results were verified using qRT-PCR.Results: We acquired six hub genes linked to ferroptosis and UC. In order to create a diagnostic model for UC, we used logistic regression analysis to screen three of the six ferroptosis related genes (HIF1A, SLC7A11, and LPIN1). The ROC curve showed that the three hub genes had outstanding potential for disease diagnosis (AUC = 0.976), which was subsequently validated in samples from GSE92415 (AUC = 0.962) and blood samples from GSE3365 (AUC = 0.847) and GSE94648 (AUC = 0.769). These genes might be crucial for UC immunity based upon the results on the immune system. Furthermore, mouse samples examined using qRT-PCR also verified our findings.Conclusion: In conclusion, the findings have important implications for ferroptosis and UC, and these hub genes may also offer fresh perspectives on the aetiology and therapeutic approaches of UC.Keywords: ulcerative colitis, ferroptosis, hub genes, immune, bioinformatics analysis

Hang Jin,1,2,* Zhongqiang Yan,3,* Xin Ge,4,* Qi Wang,2 Hui Wang,2 Xinying Du,2 Hongbo Liu,2 Chaojie Yang,2 Ying Xiang,2 Sai Tian,2 Shaofu Qiu,1,2 Yu Zhou5 1School of Public Health, Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Infectious Disease Control and Prevention, Center for Disease Control and Prevention of Chinese PLA, Beijing, People’s Republic of China; 3Department of Disease Prevention and Control, The Second Medical Center of PLA General Hospital, Beijing, People’s Republic of China; 4School of Public Health, Anhui Medical University, Hefei, People’s Republic of China; 5Department of Clinical Laboratory, National Clinical Research Center for Geriatric Diseases, The Second Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaofu Qiu, Center for Disease Control and Prevention of Chinese PLA, Beijing, People’s Republic of China, Email qiushf0613@hotmail.com Yu Zhou, Department of Clinical Laboratory, National Clinical Research Center for Geriatric Diseases, The Second Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China, Email zhouy427@163.comPurpose: This study conducted an phenotypic and whole-genome sequencing analysis with Klebsiella aerogenes to elucidate its clinical epidemiological characteristics, antimicrobial resistance (AMR) phenotype, biofilm formation ability and hemolytic activity testing, AMR genes and phylogenetic relationships, so as to provide a further understanding of the intra-hospital strain transmission.Methods: Samples were collected from a hospital in Beijing between 2020 and 2022. All strains underwent bacterial identification, antimicrobial susceptibility testing (AST) using the VITEK-2 compact system. Biofilm formation ability and hemolytic activity were tested. Second-generation sequencing was applied to all strains, with those carrying the blaKPC gene were selected for third-generation sequencing. Whole-genome analysis identified resistance genes, plasmid types, MLST typing, and phylogenetic relationships. Plasmids were assembled to detect plasmid structures and AMR gene location.Results: Among the 42 K. aerogenes isolates, 21 were carbapenem-resistant K. aerogenes (CRKA). All strains exhibited strong biofilm formation and no hemolytic activity. Most were sourced from sputum (83.3%). CRKA demonstrated extensive resistance to antibiotics, particularly β-lactamase inhibitors and Cefotetan. This resistance pattern was closely associated with the presence of an IncFII(pHN7A8) plasmid, which carried multiple resistance genes, including blaKPC-2, blaCTX-M-65, blaTEM-1, rmtB and a large number of mobile elements. The majority of CRKA strains clustered within the same branch of the phylogenetic tree, exhibiting minimal single nucleotide polymorphism (0– 13 SNPs) differences, and they shared the same sequence type (ST292), resistance genes, and plasmids, originating from different departments, suggesting clonal transmission among the hospital.Conclusion: Our research reveals that the clonal transmission of CRKA occurs across various departments within the hospital. The widespread resistance observed in CRKA, attributed to the presence of blaKPC and ESBLs genes, underscores the need for heightened vigilance to prevent the further dissemination of CRKA within the hospital and, potentially, throughout the wider community.Keywords: Klebsiella aerogenes, carbapenem resistance, blaKPC-2, clonal transmission

Shanshan Liu,1,2 Xiaomeng Ge,3 Xizhan Xu,4 Kang Zhang,1 Xinxin Lu1 1Department of Laboratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Infection Management, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People’s Hospital of Lianyungang, Jiangsu, People’s Republic of China; 3Microbial Resources and Big Data Center, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of China; 4Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Xinxin Lu, Department of Laboratory Medicine, Beijing Tongren Hospital, Capital Medical University, No. 1, Dongjiaomin Lane, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +86-13911682566, Fax +8610-65125617, Email luxinxin2009@126.comPurpose: The clinical manifestations of pyogenic liver abscess (PLA) vary between patients with and without diabetes mellitus (DM). However, the relationship between PLA and the gut microbiome remains unknown. This study analyzed the composition of gut microbiota in PLA patients with and without DM and healthy controls (HCs) with the goal of identifying potential reasons for the observed variations in clinical manifestations.Patients and Methods: Using 16S ribosomal RNA(16S rRNA) gene sequencing, we analyzed the compositions of gut microbiota in 32 PLA patients with DM, 32 PLA patients without DM, and 29 matched HCs.Results: In PLA patients with DM, the D-dimer level, fibrinogen degradation products, and thrombin time were significantly higher compared to the PLA patients without DM (P < 0.05). The abundance and diversity of intestinal flora were reduced in both groups of PLA patients compared with the HCs (P < 0.05). Specifically, the PLA patients with DM showed significant decreases in the relative abundances of Bacteroides, Blautia, Prevotella9, and Faecalibacterium, whereas Enterococcus and Escherichia-Shigella were relatively more abundant (P < 0.05). Compared to PLA patients without DM, those with DM had lower relative abundances of Lactobacillus and Klebsiella (P < 0.05) and showed different bacterial flora, including Anaerosporobacter and Megamonas.Conclusion: PLA patients with DM exhibited more severe clinical manifestations of PLA compared to patients without DM. It is important to monitor blood coagulation in PLA patients with DM to prevent the development of thrombotic diseases. Additionally, PLA patients with DM exhibit distinct differences in the composition and diversity of their intestinal flora compared to both PLA patients without DM and HCs.Keywords: Gut microbiota, Pyogenic liver abscess, type 2 diabetes mellitus, 16S rRNA sequencing

Qian Ma,1,&ast; Lei Chang,2,&ast; Wenwen Wang,2,&ast; Lingyi Che,1 Xiaoqin Song,3 Gailing Li,2 Ying Zhang,2 Yibing Chen,1 Zhuoyu Gu,4 Xin Ge5 1Genetics and Prenatal Diagnosis Center, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 2Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 3Physical Examination Center, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 4Department of Thoracic Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 5Department of Breast Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Ge, Department of Breast Surgery, First Affiliated Hospital, Zhengzhou University, 1 Jianshe Road East, Zhengzhou, Henan, 450052, People’s Republic of China, Email Gexin1981@126.com Zhuoyu Gu, Department of Thoracic Surgery, First Affiliated Hospital, Zhengzhou University, 1 Jianshe Road East, Zhengzhou, Henan, 450052, People’s Republic of China, Email guzhuoyu@hotmail.comBackground: It was indicated that tumor intrinsic heterogeneity and the tumor microenvironment (TME) of ovarian cancer (OV) influence immunotherapy efficacy and patient outcomes. Leucyl and cystinyl aminopeptidase (LNPEP) encodes a zinc-dependent aminopeptidase, which has been proved to participant in the vesicle-mediated transport and class I MHC mediated antigen processing and presentation. However, the function of LNPEP in TME of OV and its potential molecular mechanisms have not been determined. Therefore, we aimed to investigate a prognostic biomarker which may be helpful in identifying TME heterogeneity of ovarian cancer.Methods: In this study, bioinformatics databases were used to explore the expression profile and immune infiltration of LNPEP. Bioinformatics analyses of survival data and interactors of LNPEP were conducted to predict the prognostic value of LNPEP in OV. The protein levels of LNPEP were validated by Western blot and immunohistochemistry.Results: Based on the TCGA data, our data displayed that the mRNA expression of LNPEP was markedly down-regulated in ovarian cancer than that in para-cancer tissues, contrary to the protein level. Importantly, high LNPEP expression was associated with poor prognosis in patients with OV. Furthermore, Cox regression analysis showed that LNPEP was an independent prognostic factor in OV. GO and KEGG pathway analyses indicated the co-expressed genes of LNPEP were mainly related to a variety of immune-related pathways, including Th1 and Th2 cell differentiation, Th17 cell differentiation, and immunoregulatory interaction. Our data also demonstrated that the expression of LNPEP was strongly correlated with immune infiltration levels, immunomodulators, chemokines and chemokine receptors.Conclusion: In our study, we identified and established a prognostic signature of immune-related LNPEP in OV, which will be of great value in predicting the prognosis of clinical trials and may become a new therapeutic target for immunological research and potential prognostic biomarker in OV.Keywords: LNPEP, ovarian cancer, prognosis, immune infiltration, tumor microenvironment

Tommy Tsang Cheung,1,&ast; Tu H Mai,2,&ast; Yen Lin Chia,2 Desmond YH Yap,1 Chi-Ho Lee,1 Cecil Chi-Keung Chen,2 Ying Huang,3 Yuwen Jin,3 James Johnston,4 Viktoria Werkström,5 Yuhui Yao,6 Xiaoyun Ge,7 Wenying Zheng8 1Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, People’s Republic of China; 2Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, South San Francisco, CA, USA; 3Clinical Pharmacology, R&D China, AstraZeneca, Shanghai, People’s Republic of China; 4Late-stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; 5Late-Stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 6Respiratory & Immunology, R&D China, AstraZeneca, Shanghai, People’s Republic of China; 7Clinical Safety, R&D China, AstraZeneca, Shanghai, People’s Republic of China; 8Biometrics, R&D China, AstraZeneca, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yen Lin Chia, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, 701 Gateway Blvd, South San Francisco, CA, 9408, USA, Tel +1 425 5272574, Email yenlin@gmail.comPurpose: Biological therapies targeting eosinophils have been shown to be effective in treating patients with severe eosinophilic asthma. Benralizumab (Fasenra®, AstraZeneca) is a humanized monoclonal antibody binding to the alpha subunit of the interleukin-5 receptor, which rapidly depletes eosinophils via antibody-dependent cellular cytotoxicity. The aim of this Phase 1 study was to assess the safety, tolerability, and pharmacokinetics of benralizumab in healthy Chinese individuals.Materials and Methods: In this randomized, single-blind study (NCT03928262), healthy Chinese adult participants aged 18 to 45 years, weighing 50 to 100 kg, were randomized 1:1:1 to receive a single subcutaneous (SC) injection of benralizumab 10 mg, 30 mg, or 100 mg in the upper arms on Day 1. Safety was monitored throughout the study (up to Day 85), and blood samples were taken to determine serum benralizumab concentrations and for detection of anti-drug antibody. A non-compartmental analysis was conducted to estimate the pharmacokinetic parameters.Results: Thirty-six healthy participants were enrolled, 12 in each dose group (mean [SD] age 26 [6] years). Following a single SC injection of benralizumab, 13 adverse events were reported by 10 participants (28%), with one mild injection-site reaction assessed as related. The mean serum benralizumab concentrations increased in a dose proportional manner, followed by exponential decreases. The mean terminal half-lives were 15.1 days for the 10 mg dose, 14.4 days for the 30 mg dose, and 15.4 days for the 100 mg dose. All doses resulted in near-complete depletion of eosinophils on Day 2, which was maintained throughout the study to Day 85.Conclusion: A single SC injection of benralizumab was well tolerated by healthy Chinese participants, with no new or unexpected safety findings. The pharmacokinetics of benralizumab in Chinese participants was dose-proportional and consistent with those of non-Chinese participants observed in previous studies.Clinical Trial Registration: NCT03928262 (https://clinicaltrials.gov/ct2/show/NCT03928262)Keywords: benralizumab, pharmacokinetics, healthy Chinese

Laihui Luo,1,&ast; Yongzhu He,1,&ast; Guoqing Zhu,1,&ast; Yongqiang Xiao,1 Shengjiang Song,1 Xian Ge,2 Tao Wang,3 Jin Xie,1 Wei Deng,1 Zhigao Hu,1 Renfeng Shan1 1Department of General Surgery, The First Affiliated Hospital of Nanchang, Nanchang, People’s Republic of China; 2Department of Pathology, The First Affiliated Hospital of Nanchang, Nanchang, People’s Republic of China; 3Department of Day Surgery Ward, The First Affiliated Hospital of Nanchang, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Renfeng Shan, Department of General Surgery, The First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, People’s Republic of China, Tel +86 0791-88692522, Email srf1978@126.comPurpose: Conversion therapy gives some patients with initially unresectable hepatocellular carcinoma (HCC) access to surgery. The purpose of this study was to evaluate the safety and efficacy of hepatectomy after conversion therapy and how it differed from those who undergoing direct hepatectomy.Patients and Methods: From January 2018 to April 2022, 745 patients underwent hepatectomy for HCC were enrolled. Among them, 41 patients of unresectable HCC underwent hepatectomy after conversion therapy. A demographically and clinically comparable cohort was created from the remaining patients in a 1:1 ratio using propensity score matching.Results: The median duration of conversion therapy was 108 (42– 298) days, 8 patients achieved complete response (CR) and 33 achieved partial response (PR). Conversion therapy resulted in some degree of myelosuppression, but liver function index remained good. Compared with the direct hepatectomy group, the conversion group had more blood loss (600 mL vs 400 mL, p=0.015), longer operative time (270 min vs 240 min, p=0.02), higher blood transfusion rates, and longer hospital stay (8 days vs 11 days, p< 0.001). Patients in the conversion group had significantly more complications of any grade (82.9% vs 51.2%, p=0.002) and grade 3/4 (26.8% vs 4.9%, p=0.013), and 6 patients developed post-hepatectomy liver failure (PHLF). There were no deaths in either group. All patients achieved R0 resection, 6 (6/41, 14.6%) achieved pathological complete response (pCR), 14 achieved major pathologic responses (MPR). During a median follow-up of 12.8 months, 14 patients in the conversion group experienced recurrence or metastasis, no deaths.Conclusion: Hepatectomy after conversion therapy was more difficult than direct hepatectomy, but accurate preoperative assessment could ensure the safety of the surgery. The damage of liver function after conversion therapy was more severe than expected, PHLF should be prevented and treated. Hepatectomy was effective and necessary, postoperative pathological examination could provide guidance for adjuvant therapy.Keywords: hepatocellular carcinoma, conversion therapy, hepatectomy, post-hepatectomy liver failure, pathological complete response

Huadong Chen,1 Xing’e Xu,1 Jiren Peng,2 Xuan Ge,3 Jing’an Zhang,1 Qianqian Dong,1 Xiunan Jiang,1 Piaopiao Li1 1Department of Pharmacy, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, People’s Republic of China; 2Department of Vasculocardiology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, People’s Republic of China; 3Health Management Center, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, People’s Republic of ChinaCorrespondence: Huadong Chen, Department of Pharmacy, Affiliated Dongyang Hospital of Wenzhou Medical University, 60th Wuning West Road, Dongyang, People’s Republic of China, Email chuadong666@163.comIntroduction: Adherence to warfarin is associated with improved outcome in patients with atrial fibrillation (AF), but the adherence status of patients in rural areas of China is not known.Methods: A questionnaire-based study evaluating warfarin adherence of rural residents with AF was carried out in Dongyang, China. Potentially eligible patients were screened and contacted by telephone, and their demographic characteristics were collected. Illness perception was assessed using the Brief Illness Perception Questionnaire (BIPQ), and warfarin adherence was assessed using a Chinese-version adherence scale. Univariate and multivariate analyses were conducted to identify factors associated with unsatisfactory adherence.Results: A total of 201 patients (male, n=99; mean age, 70.3± 8.12 years) were included, among whom 95 (47.3%) patients showed good adherence and 63 (31.3%) poor adherence. Number of co-dispensed drugs (multivariate analysis: odds ratio [OR]=3.64, 95% confidence interval [CI] 1.35– 9.81, p=0.011) and BIPQ score (OR=1.25, 95% CI 1.17– 1.33, p< 0.001) were identified as factors associated with good adherence.Conclusion: Medical adherence to warfarin needs to improve in rural patients with AF. Efforts that can reduce the number of co-dispensed drugs and increase illness perception may improve warfarin adherence. This study may benefit future management of warfarin administration to rural patients with AF.Keywords: adherence, warfarin, illness perception, polypharmacy, rural

Qingsong Tao,1,&ast; Xin Li,2,&ast; Ting Zhu,1 Xiaoqin Ge,1 Shengping Gong,1 Jianxin Guo,1 Ruishuang Ma1,3 1Department of Radiotherapy and Chemotherapy, Ningbo First Hospital, Ningbo, People’s Republic of China; 2Department of Respiratory Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 3Central Laboratory of the Medical Research Center, Ningbo First Hospital, Ningbo, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianxin Guo; Ruishuang Ma, Department of Radiotherapy and Chemotherapy, Ningbo First Hospital, Ningbo, People’s Republic of China, Email nbdyyygjx@163.com; xiaomisara@163.comPurpose: Lactate, a marker of tumor metabolic reprogramming, maintains the acidic microenvironment and also affects the metabolism and function of immune cells. SLC16A3 is responsible for the extracellular transport of lactate, which is a key component of glycolysis. However, the role of SLC16A3 in immune infiltration and immunosuppression of lung cancer is largely unknown. Our study explored the therapeutic and prognostic value of SLC16A3 in predicting immune infiltration and immune checkpoint efficacy of lung cancer.Methods: SLC16A3 expression was evaluated with TCGA database. Kaplan–Meier analysis was performed for survival rates. GO and KEEG enrichment was conducted to determine predictive signaling pathways. We utilized TIMER and CIBERSORT to analyze the correlation between SLC16A3 and immunocyte infiltration as well as immune checkpoint. Interleukin and HIF-1a expression was measured with ELISA kit and flow cytometry separately.Results: In comparison with normal tissues, SLC16A3 expression was significantly upregulated in both lung adenocarcinoma (LUAD) and squamous carcinoma (LUSC), which was closely related to poor prognosis. GO analysis indicated that SLC16A3 involved in different signal pathways in LUAD and LUSC and linked to HIF-1 signaling in LUAD. High SLC16A3 was correlated with immunosuppressive cells (Treg, Th2 and iDC), immune checkpoint (PD1, PD-L1, PVR, Tim-3, ITGAM) and immunosuppressive factors (foxp3, TGF-β) in LUAD not LUSC. Furthermore, SLC16A3 was identified to tightly interact with IL-8 which may induce microenvironment immune tolerance. Based on the clinical prediction, we performed experiments with LUAD A549 cells and showed reduced IL-8 and HIF-1a when treated with SLC16A3 knockdown. HIF-1a stimulation by dimethyloxalylglycine (DMOG) could restore IL-8 secretion in SLC16A3 downregulated cells.Conclusion: Taken together, our results suggest that SLC16A3 contributes to a worse prognosis in lung cancer and may play an important role in immune microenvironment and evasion through HIF-1a-IL8 axis, which could be a novel therapeutic target for immunotherapy in lung cancer.Keywords: SLC16A3 (MCT4), IL-8, lung cancer, immune evasion, bioinformatics analysis

Wei Zhou,1,2,&ast; Yugen Sha,2,&ast; Jingxia Zeng,3,&ast; Xiaoyue Zhang,4 Aihua Zhang,1,2 Xuhua Ge1,3 1Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Pediatric Intensive Care Unit, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 4Department of Chinese Medicine, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuhua GePediatric Intensive Care Unit, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210029, People’s Republic of ChinaEmail gexuhua@njmu.edu.cnAihua ZhangDepartment of Nephrology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210029, People’s Republic of ChinaEmail zhaihua@njmu.edu.cnBackground: Glomerulonephritis is a common urinary system disease among children. Growing evidence suggests that traditional Chinese medicine has potential in treating glomerulonephritis, such as Li-Da-Qian mixture. Although its anti-glomerulonephritis and alleviating hematuria effects have been reported, the exact mechanism of Li-Da-Qian mixture devoting to glomerulonephritis remains unexplored. It was necessary to explore the mechanism of Li-Da-Qian mixture against glomerulonephritis using modern technology, such as Chinese medicine database and molecular biological experiments.Methods: Online databases were used to look up ingredients and predict targets of Li-Da-Qian mixture against glomerulonephritis. The intersecting targets of Li-Da-Qian mixture and glomerulonephritis were selected for enrichment analysis. Cytoscape software was applied to establish network and MCODE analysis. Molecular docking was used for the primary validation. Furthermore, we examined the function of the core compounds analyzed from Li-Da-Qian mixture to rescue LPS-induced inflammation in vivo and vitro. We also explored whether the core compounds can alleviate TGFβ 1-induced renal fibrosis in mouse proximal tubular cells.Results: Network pharmacological analysis of Li-Da-Qian evaluated 20 active ingredients including baicalein, luteolin and quercetin. A total of 113 key targets were screened, including IL6, VEGFA, TP53, EGF, MMP2, etc, and they were enriched in AGE-RAGE signaling pathway in diabetic complications, TNF and IL-17 signaling pathways. Moreover, the core ingredients succeeded in binding to the main targets via molecular docking, further identifying the anti-glomerulonephritis effects and improvement of vascular injury. Western blotting and qPCR also suggested that baicalein and luteolin can improve inflammation and restore disturbance of mesangial cells or kidney induced by LPS. In addition, baicalein and luteolin inhibited renal fibrosis in vitro.Keywords: glomerulonephritis, network pharmacology, Li-Da-Qian mixture, traditional Chinese medicine, molecular docking

Yujing Shi,1 Xiaolin Ge,2 Mengyang Ju,3 Yumeng Zhang,4 Xiaoke Di,2 Liang Liang1 1Jurong People’s Hospital, Zhenjiang, 212400, People’s Republic of China; 2Jiangsu Provincial People’s Hospital, Nanjing, 212000, People’s Republic of China; 3Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, 5650871, Japan; 4Nanjing Medical University, Nanjing, 212000, People’s Republic of ChinaCorrespondence: Liang LiangJurong People’s Hospital, Huayang Town, Jurong City, People’s Republic of ChinaTel +86 511-8730 0705Email lianglvlv@yeah.netAbstract: Esophageal cancer has high incidence and mortality rates and a low five-year survival rate of < 15% owing to its strong capabilities of invasion, relapse and metastasis. The classic view holds that metastasis and diffusion is an advanced event during cancer progression, but recent studies show that distant diffusion of primary cancer cells may actually be an early event. Detection of circulating tumor cells (CTCs) in the circulation may indicate tumor spread, so CTCs are considered to be the key factor of metastatic cascade. In recent years, despite research progress on CTCs, there is a lack of systematic and important evidence to confirm the diagnostic, monitoring and prognostic values of CTCs in esophageal squamous cell carcinoma (ESCC). In this review, we clarify the relationship between CTC values and ESCC and provide more reliable evidence to improve the management and treatment of ESCC.Keywords: esophageal squamous cell carcinoma, circulating tumor cells, diagnostic, prognostic

Jialing Niu,1,2 Jiangtao Liang,3 Qi Feng,2 Mei Wang,2 Luoyu Wang,4 Xiuhong Ge,2 Xiao Wang,5 Zhongxiang Ding2,6 1Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Radiology, Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Hangzhou Universal Medical Imaging Diagnostic Center, Hangzhou, People’s Republic of China; 4Institutes of Psychological Sciences, Hangzhou Normal University, Hangzhou, People’s Republic of China; 5Department of Radiology, Wenrong Hospital of Hengdian, Jinhua, People’s Republic of China; 6Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Xiao Wang; Zhongxiang Ding Email 398043951@qq.com; hangzhoudzx73@126.comIntroduction: Langerhans cell histiocytosis (LCH) is a histiocytic proliferative disease without a well-understood etiology. The aim of our study is to summarize the imaging features of PET/MR in children with LCH and to explore its diagnostic role in LCH.Methods: Retrospective analysis was performed of the pretreatment PET/MR imaging data of 15 children with LCH. Comparison of ADC values was done between lesions and normal tissues.Results: Of the fifteen patients enrolled, five had single-organ or single-system involvement, and ten had multiple-system involvement. Nine patients had varying degrees of bone destruction and increased FDG uptake, whereas thickening and deviation of the pituitary stalk and disappearance of the normal high-signal intensity of T1WI in the neurohypophysis were observed in the pituitary gland in six of them. Splenomegaly with diffuse increased FDG uptake or a normal spleen with increased FDG uptake was found in four cases, liver in three, multiple lymph node enlargement in three, pulmonary lesions in three, and increased metabolism in medullary cavity in two cases. Additionally, two cases involved the skin. Hypermetabolic nodules were detected in muscle in one case, thyroid involvement in one case, and a mediastinal lesion in one case.Conclusion: PET/MR can show well the distribution of the organs, systems, and lesions involved in LCH and is of considerable significance in the systemic evaluation of LCH.Keywords: LCH, PET/MR, fluorodeoxyglucose F18, imaging, histiocytosis, eliminate imaging

Da Wang,1,&ast; Chao Chen,1,&ast; Xiaoxu Ge,1,2 Qi Yang,2 Yuhuai Huang,1 Tianyi Ling,1 Tian Jin,1 Shaojun Yu,1 Jian Wang,1 Lifeng Sun1 1Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China; 2Department of Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Da Wang; Lifeng SunDepartment of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of ChinaTel +86-571-87784720; +86-571-87783586Email wangda0618@zju.edu.cn; sunlifeng@zju.edu.cnPurpose: This study aimed to analyze clinicopathological, survival, prognostic factors, as well as the timing of brain metastases (BM) in colorectal cancer (CRC) using data from a Chinese center.Patients and Methods: Data of 65 consecutive CRC patients with BM were collected from a single institution in China. The time from primary tumor surgery to the occurrence of BM was calculated. Kaplan-Meier analysis was used to evaluate cumulative survival of patients. Factors associated with prognosis of overall survival (OS) were explored using Cox’s proportional hazard regression models.Results: The median time interval from CRC surgery to the diagnosis of BM was 24 months. After diagnosis of BM, median OS values for patients were 11 months. Extracranial metastases occurred in 45 cases (69.2%) when BM was diagnosed, and 58.5% of these patients with lung metastases Time of BMs (P=0.018), presence of extracranial metastases (P=0.033), treatment (P=0.003), CA199 (P=0.034), CA125 (P< 0.001), CA242 (P=0.018), and CA211 (P=0.012) were associated with OS of patients through univariate analysis. Multivariate analysis using a Cox regression model showed that only treatment was an independent predictor for OS (conservative treatment; HR=1.861, 95% CI=1.077– 3.441; P=0.048).Conclusion: Surgical treatment of metastatic lesions may be an alternative choice for CRC patients with BM. Identifying the timing of brain metastases can help to detect this disease early, leading to a better survival outcome.Keywords: colorectal cancer, brain metastases, prognosis factors, surgery

Yajie Zhu,1 Xiaoli Ge,1 Di Xie,1 Shangyuan Wang,1 Feng Chen,2 Shuming Pan1 1Department of Emergency Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of China; 2Division of Medical Microbiology, Department of Clinical Laboratory, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of ChinaCorrespondence: Shuming PanDepartment of Emergency Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, People’s Republic of ChinaTel +862125076045Fax +862165030840Email panshuming@xinhuamed.com.cnFeng ChenDivision of Medical Microbiology, Department of Clinical Laboratory, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, People’s Republic of ChinaTel +862125078999Fax +862165030840Email chenfeng@xinhuamed.com.cnBackground: Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are most often caused by bacterial pneumonia and characterized by severe dyspnea and high mortality. Knowledge about the lung injury effects of current clinical bacterial strains is lacking. The aim of this study was to investigate the ability of representative pathogenic bacteria isolated from patients to cause ALI/ARDS in mice and identify the major virulence factor.Methods: Seven major bacterial species were isolated from clinical sputum and unilaterally instilled into the mouse airway. A histology study was performed to determine the lung injury effect. Virulence genes were examined by PCR. Sequence types of P. aeruginosa strains were identified by MLST. LC-MS/MS was used to analysis the bacterial exoproducts proteome. LasB was purified through a DEAE-cellulose column, and its toxicity was tested both in vitro and in vivo.Results: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus agalactiae, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli were randomly separated and tested 3 times. Among them, gram-negative bacteria have much more potential to cause acute lung injury than gram-positive bacteria. However, P. aeruginosa is the only pathogen that induces diffuse alveolar damage, hemorrhage and hyaline membranes in the lungs of mice. The lung injury effect is associated with the excreted LasB elastase. Purified LasB recapitulated lung injury similar to P. aeruginosa infection in vivo. We found that this was due to the powerful degradation effect of LasB on the extracellular matrix of the lung and key proteins in the coagulation cascade without inducing obvious cellular apoptosis. We also report for the first time that LasB could induce DIC-like coagulopathy in vitro.Conclusion: P. aeruginosa strains are most capable of inducing ALI/ARDS in mice among major clinical pathogenic bacteria tested, and this ability is specifically attributed to their LasB production.Keywords: unilateral lung injury, LasB elastase, Pseudomonas aeruginosa, ALI/ARDS

Baize Zhang,1 Junhui Wang,1 Zhifei Zhou,2 Xin Ge,1 Geng Cheng,3 Yujiang Chen,1 Xiaojing Wang1 1State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Pediatric Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of China; 2Department of Stomatology, The General Hospital of Tibetan Military Region, Lasha, 850000, People’s Republic of China; 3State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Endodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of ChinaCorrespondence: Xiaojing WangDepartment of Pediatric Dentistry, School of Stomatology, The Fourth Military Medical University, 145 West Changle Road, Xi’an, Shaanxi, 710032, People’s Republic of ChinaTel/Fax +86-29-84776239Email wxjingpd@hotmail.comAbstract: Currently, the common treatment for pulpitis and periapical diseases is root canal treatment. However, the complex variations of root canal system often affect the effect of root canal treatment and even lead to treatment failure. Therefore, it is of great significance for dentists to emphasize the diversity of root canal morphology and to be familiar with the anatomical morphology of root canal to improve the success rate of clinical diagnosis and treatment. We reported a case of an eight-year-old female patient of type V root canal in a young maxillary middle incisor. The young maxillary central incisor was diagnosed with irreversible pulpitis by radiography and CBCT examination. The present case report described the entire treatment procedure of a young maxillary central incisor after trauma, including successive apical examination, CBCT examination and multiple root canal filling, and finally the treatment was completed with the aid of microscope. The root canals were filled with the vertical compression technique. Z350 composite resin was used to repair the tooth. The patient was followed-up at three, six, and 12 months after endodontic treatment. All of the examinations were normal. Finding the anatomical configuration of root canal by various ways will help to improve the success rate of root canal therapy.Keywords: cone-beam computed tomography, CBCT, one root with two root canals, root canal microscope, young maxillary central incisor

Danxu Ma,1 Huili Li,1 Rong Shi,1 Yinan Yang,1 Haoda Liu,2 Xiaodong Ge1 1Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Anesthesiology, Beijing Huairou Maternal and Child Health Care Hospital, Beijing, People’s Republic of ChinaCorrespondence: Xiaodong GeDepartment of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Gongtinan Road, Chaoyang District, Beijing 100020, People’s Republic of ChinaEmail xiaodongge2005@163.comBackground: Persistent or recurring radicular pain after lumbar surgery is a clinical condition of failed back surgery syndrome (FBSS) that seriously affects the life quality of patients. Conventional medication and physiotherapy do not fully relieve this pain. A simpler, safer, and less invasive option is lumbar selective nerve root block or paravertebral block. Here, we share our experience regarding lumbar paravertebral block for a patient with FBSS, which successfully alleviated radicular pain after lumbar surgery.Case Presentation: An 80-year-old man with left lower limb radicular pain diagnosed as L4-5, L5-S1 intervertebral disc protrusion, spinal canal stenosis, and degenerative scoliosis underwent lumbar surgery. Four months after surgery, he experienced left lower limb radicular pain. After designing the puncture route based on X-ray film, we performed a combined ultrasound-guided L4 and L5 paravertebral block. With his improved pain control, his functional status and ability to perform daily activities also markedly improved.Conclusion: Real-time ultrasound-guided lumbar paravertebral block performed with a pre-designed route on X-ray film can provide a simple and safe way to relieve radicular pain in FBSS.Keywords: lumbar paravertebral block, failed back surgery syndrome, ultrasound-guided, pre-designed route

Xueling Ge,1 Wei Jiang,2 Yujie Jiang,1 Xiao Lv,1 Xin Liu,1 Xin Wang1 1Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, People’s Republic of China; 2Information Center, Shandong Mental Health Center, Jinan, Shandong 250014, People’s Republic of ChinaCorrespondence: Xin WangDepartment of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, People’s Republic of ChinaTel +86-13156012606Fax +86-531-87068707Email xinw007@126.comObjective:: TMED2 is a member of the transmembrane emp24 domain (Tmed)/p24 protein family, which is significantly upregulated in breast cancer, ovarian cancer and other tumour tissues. The purpose of this study was to investigate the expression of TMED2 in MM cell lines and its effect on the biological behaviour of MM cell lines.Methods: Real-time quantitative PCR (RT-qPCR) was used to detect the expression of TMED2 in MM cell lines, including MM.1S and RPMI 8226 cells, and lentivirus vector-mediated TMED2 gene silencing was used to further study the effect of the downregulation of TMED2 expression on cell viability, the cell cycle, and apoptosis.Results: Based on the RT-qPCR results, the expression of the TMED2 mRNA was increased in the MM cell lines MM.1S and RPMI 8226 compared with endogenous control GAPDH. The expression of the TMED2 mRNA was substantially reduced after transfection of the shRNA targeting TMED2 (shTMED2) in both MM cell lines. The CCK-8 assay showed significant decreases in the viability of MM.1S and RPMI 8226 cells, suggesting that the TMED2 gene plays an important role in the proliferation of these two cell lines. The cell cycle of MM.1S and RPMI 8226 cells was substantially altered by shTMED2, as evidenced by the increased number of cells in G1 phase and decreased number of cells in S and G2/M phases. The FACS analysis revealed a significant increase in the apoptosis of MM.1S and RPMI 8226 cells due to the increased activity of Caspase 3/7, suggesting that the TMED2 gene is significantly related to the apoptosis of these two cell lines.Conclusion: Based on these results, TMED2 may play an important role in the pathogenesis of MM. This novel study may contribute to further investigations of useful biomarkers and potential therapeutic targets in patients with MM.Keywords: multiple myeloma, TMED2, FACS, shRNA

Chao Chen,1,* Jian Wang,1,* Yamei Zhao,1 Xiaoxu Ge,1,2 Zhanhuai Wang,1 Shaojun Yu,1 Yongmao Song,1 Kefeng Ding,1 Suzhan Zhang,1,2 Shu Zheng,1,2 Lifeng Sun1 1Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China; 2Department of Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lifeng SunThe Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang 310009, People’s Republic of ChinaTel +86-571-87783586Email sunlifeng@zju.edu.cnPurpose: To analysis factors prognostic for peritoneal metastases (PM) from colorectal cancer (CRC) treated with surgery using data from two sources and investigate the origin and effective treatment of ovarian metastases (OM).Patients and Methods: Data from CRC patients with PM who had undergone surgery were collected from the Surveillance, Epidemiology, and End Results (SEER) database (n = 639) and a single Chinese institution (n = 60). Cumulative survival was evaluated by Kaplan–Meier analysis. Factors associated with overall survival (OS) and progression-free survival (PFS) prognosis were assessed using Cox’s proportional hazard regression models.Results: Median OS values for patients who underwent surgery were 19 and 32 months in the SEER database and Chinese center, respectively. Age was an independent predictor of OS in both datasets. Signet-ring cell cancer and perineural invasion were independent predictors of inferior OS only in the SEER dataset, while completeness of cytoreduction (CC) and peritoneal carcinomatosis index were independent predictors for OS and PFS only in the Chinese center. Median OS was 24 months in CRC patients with PM alone and 36 months in those with both PM and OM (p = 0.181). Further, median PSF in patients with PM alone was 10 months, while that in individuals with both PM and OM was 20 months (p = 0.181).Conclusion: Surgical treatment of the primary and metastatic sites is effective and safe for CRC patients with PM. CC-0 is recommended for improved prognosis. Moreover, OM should be recognized as a feature of PM, and cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is beneficial for CRC patients with OM.Keywords: ovarian metastases, prognosis factors, cytoreductive surgery, hyperthermic intraperitoneal chemotherapy

Hao Wang,1,2,* Xuhui Ge,1,3,* Huiheng Qu,1,2,* Ning Wang,1,2 Jiawen Zhou,4 Wenjing Xu,1,2 Jingjing Xie,1,2 Yongping Zhou,1,2 Liqing Shi,1 Zhongke Qin,1 Zhuang Jiang,1,2 Wenjie Yin,1 Jiazeng Xia1,2 1Department of General Surgery and Translational Medicine Center, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, Wuxi 214002, Jiangsu, People’s Republic of China; 2Department of General Surgery, Wuxi Clinical College Affiliated to Nantong University, Wuxi 214002, Jiangsu, People’s Republic of China; 3Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People’s Republic of China; 4The State Key Laboratory of Reproductive Medicine; Key Laboratory for Aging & Disease, Research Centre for Bone and Stem Cells, Department of Human Anatomy, Nanjing Medical University, Nanjing 211166, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiazeng XiaDepartment of General Surgery and Translational Medicine Center, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, 68, Zhong Shan Road, Wuxi 214002, Jiangsu, People’s Republic of ChinaEmail jiazengxia@yahoo.comPurpose: Glycyrrhizic acid (GA) is the main active ingredient extracted from Chinese herb licorice root, and it shows anti-tumor effects in many cancer types, while its role in gastric cancer (GC) is still unknown. In this study, we evaluated the effects of GA on GC cells and explored the underlying mechanisms.Methods: The anti-proliferation effect of GA on GC cells was assessed by CCK-8, colony formation, and EdU assay. The effects of GA on cell cycle and apoptosis were detected by flow cytometer. Western blotting was performed to explore the underlying mechanisms.Results: Our results showed that GA had a time- and dose-dependent inhibitory effect on proliferation of GC cells. Flow cytometer analysis demonstrated that GA would lead to G1/S-phase arrest and apoptosis. GA treatment down-regulated the levels of G1 phase-related proteins, including cyclin D1, D2, D3, E1, and E2. In terms of apoptosis, GA treatment up-regulated the levels of Bax, cleaved PARP, and pro-caspase-3, -8, -9, but did not influence their cleavage patterns. The expression of Bcl-2, survivin and p65 was attenuated after treatment. Besides, GA would down-regulate the phosphorylation of PI3K/AKT pathway.Conclusion: This study focused on inhibitory effect of GA on GC cells by inducing cell cycle arrest and apoptosis. Several important cyclins- and apoptosis-related proteins were involved in the regulation of GA to GC cells, and phosphorylated PI3K and AKT were attenuated. The results of this study indicated that GA is a potential and promising anti-cancer drug for GC.Keywords: glycyrrhizic acid, gastric cancer, cell cycle, apoptosis, PI3K/AKT pathway

Ni Wang,1,* Yang Cao,2,* Xianxiu Ge,1,* Junjie Nie,1 Yang Yu,1 Quanpeng Li,1 Fei Wang,1 Lin Miao11Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China; 2Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of ChinaCorrespondence: Lin MiaoDepartment of Gastroenterology, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiangjiayuan, Nanjing, Jiangsu Province 210011, People’s Republic of ChinaEmail linmiao@njmu.edu.cn*These authors contributed equally to this workPurpose: MicroRNA-195 is dysregulated in different kinds of cancers and plays a pivotal role in tumorigenesis. It may function as a prognostic biomarker for cancers. However, the results from articles were not consistent. This study was designed to validate the prognostic value of microRNA-195 in human tumors.Methods: We conducted a detailed search on PubMed until December 31, 2018. The quality of these publications was assessed on the basis of a list of key reviews presented by PRISMA statement. The pooled hazard ratios (HR) and pooled odds ratios (OR) of each 95% confidence interval (95% CI) were calculated to assess the effect.Results: This meta-analysis included 12 studies involving 940 cancer patients to assess the prognostic value of miR-195 in different solid tumors. The results showed that patients with high expression of miR-195 had favorable tumor-node-metastasis (late vs early: pooled OR =0.16, 95% CI: 0.11–0.22, P

Jun Zhang,1,* Feng Zhou,2,* Xiaoxiang Ge,3 Xu Ran,4 Yeping Li,4 Si Chen,5 Xiaotong Dai,5 Dafang Chen,5 Baoguo Jiang6 1Department of Neurology, Peking University People’s Hospital, Beijing, China; 2Department of Data Science, Tsinghua University, Beijing, China; 3Office of Academic Affairs, Army Military Medical University, Chongqing, China; 4Department of Research and Development, Chongqing Hospital Management Limited Company (Doctor-Patient Experience Research Base, National Health and Family Planning Commission of the People’s Republic of China), Chongqing, China; 5Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; 6Department of Orthopedics, Peking University People’s Hospital, Beijing, China *These authors contributed equally to this work Background and aims: Patient satisfaction is one of the important ways to measure the results of treatment and the quality of medical services. The purpose of the present study was to verify the reliability and validity of the indicator system for evaluating satisfaction of outpatients and inpatients in Chinese hospitals.Methods: The study was based on the satisfaction questionnaire program of the national doctor–patient experience research center with data from 99,802 outpatients and 229,215 inpatients, collected in China between 2016 and 2017. We adopted exploratory factor analysis for validity analysis and the method of split-half reliability and Cronbach’s α coefficient for reliability analysis.Results: In the validity analysis of the indicator system for outpatients, the factor loading was between 0.438 and 0.919, and the reliability was excellent. In the validity analysis of the indicator system for nonsurgical inpatients, the factor loading of the secondary indicators was between 0.417 and 0.75, and the reliability was excellent. In the validity analysis of the indicator system for surgical inpatients satisfaction, the factor loading of the secondary indicators range was 0.391–0.751, and the reliability was excellent.Conclusion: The indicator systems for evaluating satisfaction of outpatients, surgical inpatients and nonsurgical inpatients all have excellent reliability and good validity. They can be widely used for an outpatient and inpatient satisfaction questionnaire in Chinese hospitals. Keywords: patient satisfaction questionnaire, reliability, validity, evaluation

Feimin Yang,1 Qian Zhang,1 Wei Kong,1 Hongdan Shen,1 Jing Lu,1 Xiaolong Ge,1 Yiyu Zhuang2 1Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China; 2Nursing Department, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China Objective: The aim of this study is to investigate the attitudes of hospitalized patients with gastrointestinal cancer toward being informed of the truth and to provide references for informing patients of their gastrointestinal cancer diagnosis.Methods: Nine patients with gastrointestinal cancer were selected for this study by using a purposive sampling technique from a general surgery ward in a tertiary-level general hospital in Zhejiang Province from June 2016 to October 2016. Semi-structured, in-depth interviews were conducted, and the descriptive phenomenological method (developed by Amedeo Giorgi) was used to analyze the interview data.Results: Five themes were developed through reading, analysis, reflection, and classification of the data: Theme 1, guessing the diagnosis of gastrointestinal cancer before being informed of the truth; Theme 2, eagerness to know the diagnosis results; Theme 3, expectations related to beginning treatment for cancer; Theme 4, stress and anxiety during treatment; and Theme 5, providing patients with hope and optimism at the early diagnosis stage.Conclusion: Patients have a strong desire to survive and can confidently confront their gastrointestinal cancer diagnosis. Medical staff should carefully select the appropriate time to inform patients of their diagnosis by evaluating their attitudes toward being informed, thereby actively meeting patients’ needs for information and treatment. Keywords: patient with gastrointestinal cancer, disclosure of diagnosis, qualitative study

Ice storm is a major form of extreme climatic event and may occur more frequently in the future under a changing climate. The 2008 Chinese ice storm provided a natural laboratory to study ecosystem responses and feedbacks to climate variability and extreme events. Four typical subtropical forests (Chinese fir plantation, pine plantation, moso bamboo plantation, and secondary mixed broadleaved forest) were selected to assess the damage caused by the ice storm. The ice damage rate of typical subtropical forests varied between 25% and 81%. The secondary broadleaved forest had most extensive damage while the Chinese fir plantation experienced the most severe damage. Exotic pine species (Pinus elliottii Engelm. and Pinus taeda Linn.) were more severely damaged than the native species, Pinus massoniana Lamb. Ice damage was also affected by tree/culm size, age, stand density, site altitude, and management practices. Large-sized trees/culms were more vulnerable to stem breakage, decapitation, and uprooting, while small-sized trees/culms were more vulnerable to bending and leaning. Younger trees/culms had the highest damage rate, and were more susceptible to bending damage. Ice damage rate increased linearly with the stand density, and higher altitude led to a significant increase of stem breakage. Oleoresin tapping aggravated the damage to pine trees. Resistance of trees to ice damage is an emergent consequence of tree attributes, species origin, site conditions, and human disturbance. Forest silviculture and management practices can play significant roles in controlling forest susceptibility to extreme events. Inappropriate utilization of non-timber forest products can reduce trees’ resistance to extreme events. For sustainable forest development, balance needs to be achieved between the high productivity of introduced exotic tree species and the resistance of native species to extreme climatic events.

Liping Xu,* Xi Yang,* Jiayan Chen, Xiaolin Ge, Qin Qin, Hongcheng Zhu, Chi Zhang, Xinchen Sun Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Objective: Statins are widely used lipid-lowering drugs, which have pleiotropic effects, such as anti-inflammation, and vascular protection. In our study, we investigated the radioprotective potential of simvastatin (SIM) in a murine model of radiation-induced salivary gland dysfunction. Design: Ninety-six Institute of Cancer Research mice were randomly divided into four groups: solvent + sham irradiation (IR) (Group I), SIM + sham IR (Group II), IR + solvent (Group III), and IR + SIM (Group IV). SIM (10 mg/kg body weight, three times per week) was administered intraperitoneally 1 week prior to IR through to the end of the experiment. Saliva and submandibular gland tissues were obtained for biochemical, morphological (hematoxylin and eosin staining and Masson’s trichrome), and Western blot analysis at 8 hours, 24 hours, and 4 weeks after head and neck IR. Results: IR caused a significant reduction of salivary secretion and amylase activity but elevation of malondialdehyde. SIM remitted the reduction of saliva secretion and restored salivary amylase activity. The protective benefits of SIM may be attributed to scavenging malondialdehyde, remitting collagen deposition, and reducing and delaying the elevation of transforming growth factor β1 expression induced by radiation. Conclusion: SIM may be clinically useful to alleviate side effects of radiotherapy on salivary gland. Keywords: simvastatin, radiation protection, submandibular gland, transforming growth factor-β1, mice

Xiangting Ge,1,2,* Zhiguo Feng,1,* Tingting Xu,2 Beibei Wu,3 Hongjin Chen,1 Fengli Xu,3 Lili Fu,1 Xiaoou Shan,3 Yuanrong Dai,2 Yali Zhang,1 Guang Liang11Chemical Biology Research Center, School of Pharmaceutical Sciences, 2Department of Pulmonary Medicine, The 2nd Affiliated Hospital, 3Department of Pediatrics, The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, People’s Republic of China*These authors contributed equally to this workAbstract: Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs to treat sepsis in the clinic are lacking. In this study, we found a novel imidazopyridine derivative, X22, which has powerful anti-inflammatory activity. X22 dose-dependently inhibited lipopolysaccharide (LPS)-induced proinflammatory cytokine production in mouse primary peritoneal macrophages and RAW 264.7 macrophages. X22 also downregulated the LPS-induced proinflammatory gene expression in vitro. In vivo, X22 exhibited a significant protection against LPS-induced death. Pretreatment or treatment with X22 attenuated the sepsis-induced lung and liver injury by inhibiting the inflammatory response. In addition, X22 showed protection against LPS-induced acute lung injury. We additionally found that pretreatment with X22 reduced the inflammatory pain in the acetic acid and formalin models and reduced the dimethylbenzene-induced ear swelling and acetic acid-increased vascular permeability. Together, these data confirmed that X22 has multiple anti-inflammatory effects and may be a potential therapeutic option in the treatment of inflammatory diseases.Keywords: LPS, imidazopyridine derivative, sepsis, acute lung injury, inflammation

In this work, we successfully applied the Fray-Farthing-Chen Cambridge electro-reduction process on the preparation of chromium from chromium oxide, and for the first time, the synthesis of ferrochromium alloy from chromium oxide and iron oxide mixture and the chromite ore in molten calcium chloride. The present work systematically investigated the influences of sintered temperature of the solid precursor, electrochemical potential, electrolysis temperature and time on the products by using a set of advanced characterization techniques, including XRD and SEM/EDS analyses. In particular, our results show that this process is energy-friendly and technically-feasible for the direct extraction of ferrochromium alloy from chromite ore. Our findings thus provide useful insights for designing a novel green process to produce ferrochromium alloy from low-grade chromite ore or stainless steel slag.

Shun Chen,1,2,* Xuemei Ge,2,* Yinghui Chen,3,* Nan Lv,2 Zhenguo Liu,1 Weien Yuan2 1Department of Neurology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, 2School of Pharmacy, Shanghai Jiaotong University, Shanghai, 3Department of Neurology, Jinshan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this workAbstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized clinically by memory and cognitive dysfunction. Unfortunately, there is no effective therapeutic method for AD treatment or ways to halt disease progression. Many mechanisms are involved in the disease, including genes mutation and protein dysfunction. RNA interference (RNAi) technology may potentially be able to control AD. It can inhibit the protein expression of specific genes by activating a sequence-specific RNA degradation process. This is a powerful tool with which to study gene function, investigate the mechanism of the disease, and validate drug targets. In this review, we highlight the advances in RNAi technology in the investigation and treatment of AD.Keywords: RNAi, β-amyloid, tau, amyloid precursor protein

Shi-Yue Duan, Xue-Mei Ge, Nan Lu, Fei Wu, Weien Yuan, Tuo JinSchool of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of ChinaAbstract: A chemically dynamic spermine-based polymer: polyspermine imidazole-4, 5-amide (PSIA, Mw > 7 kDa) was designed, synthesized, and evaluated in terms of its ability to deliver nucleic acids. This polymer was made from an endogenous monomer professionally condensing genes in sperms, spermine, and a known safety drug metabolite, imidazole-4, 5-dicarboxylic acid, through a bis-amide bond conjugated with the imidazole ring. This polymer can condense pDNA at a W/W ratio above 10 to form polyplexes (100–200 nm in diameter), which is consistent with the observation by transmission electron microscopy (TEM), and the zeta potential was in the range of 10–20 mV. The pDNA packaged polymer was stable in phosphate buffer solution (PBS) at pH 7.4 (simulated body fluid) while the polyplexes were releasing pDNA into the solution at pH 5.8 (simulated endo-lysosomes) due to the degradation of the bis-amide linkages in response to changes in pH values. PSIA-polyplexes were able to achieve efficient cellular uptake and luciferase gene silencing by co-transfection of pDNA and siRNA in COS-7 cells and HepG2 cells with negligible cytotoxicity. Biodistribution of Rhodamine B-labeled PSIA-polyplexes after being systemically injected in BALB/c nude-mice showed that the polyplexes circulated throughout the body, accumulated mainly in the kidney at 4 hours of sample administration, and moved to the liver and spleen after 24 hours. All the results suggested that PSIA offered a promising example to balance the transfection efficiency and toxicity of a synthetic carrier system for the delivery of therapeutic nucleic acids.Keywords: gene delivery, polyspermine, cytotoxicity, transfection efficiency, biodistribution

Background and purposeFractional flow measured on 3D-TOF-MRA was proposed to quantify cerebral hemodynamic changes in patients with artery stenosis. We investigated the association between fractional flow and cerebral perfusion changes in patients with symptomatic MCA stenosis.Materials and methodsThis prospective study was approved by the institutional review board, and all participants provided written informed consent. From June 2015 to May 2018, four hundred twenty-nine patients with symptomatic intracranial arterial stenosis were consecutively recruited and underwent conventional brain MR imaging, 3D-TOF-MRA, and brain CTP. A total of 91 patients with unilateral M1 segment stenosis of the MCA and a stenosis degree of 50%∼99% were included in the analysis. Fractional flow was measured by comparing distal and proximal signal intensity changes across the stenosis on 3D-TOF-MRA. The cutoff value for fractional flow for discriminating between normal perfusion and hypoperfusion was obtained from the receiver operating characteristic curve. Associations between fractional flow and hypoperfusion were assessed using univariate and multivariate analyses.ResultsThe receiver operating characteristic curve showed a significant fractional flow threshold value at 0.90 (sensitivity, 70.1%; 95% CI, 55.9%-81.2%; specificity, 69.6%; 95% CI, 47.6%-84.1%). Participants with a fractional flow of ≤0.90 were independently associated with cerebral hypoperfusion downstream from the stenosis site (adjusted OR, 3.68; 95% CI, 1.63-11.62; P = .027).ConclusionsFractional flow measured on 3D-TOF-MRA may serve as a noninvasive and practical tool for determining the cerebral hypoperfusion in patents with symptomatic MCA stenosis.

INTRODUCTION: Elective surgical hubs focusing on high-volume routine surgery using protected facilities and ringfenced resources are key to NHS England's elective recovery strategy. In May 2021, the Getting It Right First Time initiative introduced the high-volume low-complexity programme to coordinate new and existing hubs nationally, and to provide a framework for delivery. This paper presents results from the first national survey to identify their prevalence, location and configuration, the provision of care offered and the contextual setting within healthcare providers in order to provide a strong foundation for future research. METHODS: NHS regional leads were invited to participate in a survey conducted in March 2022 and disseminated by NHS England. RESULTS: A total of 87 elective surgical hubs were identified across 64 acute NHS trusts in England. London, the Midlands and the South East had the greatest concentration of hubs per trust. The contextual setting of hubs within healthcare providers varied widely. Two-fifths (43%) were configured as stand-alone, 34% as integrated and 23% as ringfenced hubs. Half (49%) were established before 2019. Seventy-six per cent catered for patients attending for either day-case or inpatient surgery. The majority (72%) covered multiple specialties, with 80% specialising in trauma and orthopaedic surgery. Two-fifths (43%) provided enhanced care. CONCLUSIONS: Elective surgical hubs are widespread across NHS regions in England. There is wide variation in hub configuration and capacity as well as in the provision of care offered and their contextual setting within healthcare providers, suggesting that the optimal hub model has not been established. Further research into the efficacy of elective hubs is required to aid their potential role in reducing waiting lists and improving quality of care. [ABSTRACT FROM AUTHOR]

This study evaluated the effectiveness of two bioswales eight years after construction in Davis, California. The treatment bioswale measured 9 m × 1 m × 1 m (L × W × D). Engineered soil mix (75% native lava rock and 25% loam soil) replaced the native loam soil. Four Red Tip Photinia (Photinia × fraseri Dress) trees and two Blueberry Muffin Hawthorn (Rhaphiolepis umbellata (Thunb.) Makino) shrubs were planted in the bioswale. Runoff flowed into the bioswale from an adjacent 171 m2 panel of turf grass. An identically sized control bioswale consisting of non-disturbed native soil was located adjacent to the treatment bioswale. Surface runoff quantity and quality were measured during three experiments with different pollutant loads. When compared to the control, the treatment bioswale reduced surface runoff by 99.4%, and reduced nitrogen, phosphate, and total organic carbon loading by 99.1%, 99.5%, and 99.4%, respectively. After eight years, tree growth characteristics were similar across both sites.