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Wentao Wu,1,* Fei Wen,1,* Jiaxin Hu,1 Leijun Li2 1Department of Psychiatry, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou City, Guangdong Province, People’s Republic of China; 2Department of Psychiatry, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou City, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Leijun Li, Email lljzssyxl@163.comBackground: Anxiety disorders seriously impair patients’ mental health and quality of life, with limited effectiveness of current treatments. Dysregulation of activating transcription factor 4 (ATF4) is involved in various mental diseases, but the research on its potential roles in alleviating anxiety disorders remains limited.Methods: ATF4 was screened out by bioinformatic analysis and its expression was verified in vivo. Mice were treated with 21 d of chronic restraint stress to establish the anxiety mice model. The anxiolytic effect of ATF4 was assessed by a battery of behavior tests and evaluation of hippocampal tissue damage after overexpressing ATF4. Ferroptosis-related indicators were detected by enzyme-linked immunosorbent assay and Western blotting. Then the transforming growth factor beta (TGF-β) signaling pathway was predicted as the downstream regulatory pathway of ATF4 by bioinformatic methods. Western blotting was conducted to detect the protein expression level of TGF-β 1, small mothers against decapentaplegic 3 (Smad3), and phospho-Smad3 (p-Smad3).Results: ATF4 was screened out as a ferroptosis-related anxiolytic gene after bioinformatics analysis and was down-regulated in the anxiety mice model. Mice with ATF4 overexpression spent more time in the open arms in the elevated plus-maze test, appeared more frequently in the central area in the open-field test, and decreased the immobility time in the forced swimming and tail suspension tests. Hippocampal tissue damage was alleviated, ferroptosis was suppressed, and the levels of TGF-β 1 and p-Smad3/Smad3 were increased by AFT4 overexpression.Conclusion: ATF4 overexpression can repress ferroptosis to improve anxiety disorders by activating the TGF-β signaling pathway.Keywords: anxiety disorders, ATF4, ferroptosis, hippocampus, TGF-β signaling pathway

Sandip Patil, Xinye Li, Huirong Mai, Ying Wang, Xue Tang, Sixi Liu, Feiqiu Wen Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of ChinaCorrespondence: Sixi Liu; Feiqiu Wen, Email tigar467@126.com; fwen62@163.comBackground: This case report underscores the intricate challenges in managing paediatric patients with acute myeloid leukaemia (AML) undergoing intensive chemotherapy, particularly when complicated by the emergence of multidrug-resistant pathogens such as Carbapenem-Resistant Pseudomonas aeruginosa (CRPA).Case Presentation: An 11-year-old male with AML presented with skin purpura and persistent cough. Clinical and laboratory assessments revealed a high-risk AML profile with genetic mutations, leading to the initiation of intensive chemotherapy per the C-HUANA-AML-2015 protocol. Despite successful disease remission after initial chemotherapy courses, the patient experienced unexpected complications. Notably, septic shock, bone marrow failure, and the emergence of CRPA were encountered during the clinical course. Septic shock occurred following Course B3 chemotherapy, marked by a fever unresponsive to initial antibiotic therapy. Despite negative blood cultures, meropenem and vancomycin were initiated, successfully normalizing temperature. Subsequent challenges included persistent bone marrow suppression, perianal dermatitis, and the identification of CRPA in stool cultures, leading to altered antibiotic therapy guided by minimum inhibitory concentration (MIC) considerations. Whole-genome sequencing (WGS) of the CRPA strain revealed a highly virulent clone (ST-970) with numerous resistance and virulence genes.Conclusion: This case report offers new insights into the complexities of pediatric AML management, with a focus on the emergence of CRPA. The discovery of a high-risk CRPA clone with detailed genomic data underscores the growing challenge of antimicrobial resistance in pediatric oncology. The persistent presence of CRPA and ongoing bone marrow failure highlight the difficulties in managing these complications. This case calls for a reassessment of treatment strategies and encourages further research to improve outcomes in pediatric AML, emphasizing the need for a multidisciplinary approach to address infectious complications and antimicrobial resistance.Keywords: acute myeloid leukaemia, carbapenem-resistant Pseudomonas aeruginosa, paediatric oncology, antimicrobial resistance, superbugs

Sandip Patil,1,2,* Xinye Li,3,* Pai Liu,1 Yan Dai,3 Xiyi Zhu,3 Junjun Li,3 Sixi Liu,1 Feiqiu Wen1,2 1Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 2Paediatric Research Institute, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 3Department of Paediatrics, the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning City, Guangxi Zhuang Autonomous Region, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feiqiu Wen, Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong, People’s Republic of China, Tel +86-755-83009888, Email fwen62@163.comBackground: Syphilis, a prevalent sexually transmitted infection, poses severe risks, especially during pregnancy. This study aimed to elucidate the trends and impacts of syphilis in Guangxi, China, focusing on prevalence, clinical manifestations, and treatment outcomes in pregnant women and newborns. The objectives included understanding the demographic characteristics of affected pregnant women, analysing the clinical manifestations in newborns, and assessing the effectiveness of the treatment protocol.Methods: Conducted in adherence to ethical guidelines, a retrospective cohort study from January 2013 to December 2023 included 54,048 pregnant women tested for T. pallidum. Diagnosis involved a comprehensive approach, utilizing tests like the Toluidine Red Unheated Serum Test (TRUST) and the Treponema pallidum Particle Agglutination (TPPA) assay. Infant diagnosis and clinical manifestations were evaluated through a decade-long follow-up. Treatment protocols, including Benzathine penicillin, were implemented. Statistical analyses were conducted using SAS version 9.4.Results: Among 54,048 pregnant women, 0.10% were syphilis positive, correlating with a rise in hospitalizations. Newborns exhibited varied clinical manifestations, with neonatal pneumonia and jaundice being prevalent. The treatment protocol, especially with Benzathine penicillin, achieved a remarkable 100% cure success rate. The study noted a significant reduction in mother-to-child transmission. Syphilis in mothers and babies was diagnosed at different clinical stages, including primary, secondary, latent, and tertiary.Conclusion: This study underscores the escalating impact of syphilis on pregnant women and newborns in Guangxi, China. The findings highlight the necessity for robust preventive measures, early diagnosis, and effective treatment strategies. The observed 100% cure success rate with Benzathine penicillin emphasizes the importance of strict treatment protocols in mitigating the adverse effects of congenital syphilis and reducing its transmission.Keywords: congenital syphilis, mother-to-child transmission, diagnosis, antibiotic treatment

Xiaodong Wang,1,2,&ast; Uet Yu,2,&ast; Chao Ding,2,3 Huiying Ye,2 Chunjing Wang,2 Chunlan Yang,2 Yue Li,2 Xiaohui Zhou,2 Qian Zhang,2 Sixi Liu,2 Feiqiu Wen1,2 1Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 2Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 3Discipline of Pediatrics, China Medical University, Shenyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feiqiu Wen, Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China, Email fwen62@163.com Sixi Liu, Department of Hematology and Oncology, Shenzhen Children’s Hospital, 7019 Yitian Road, Futian, Shenzhen, 518038, People’s Republic of China, Email tiger647@126.comBackground: The COVID-19 pandemic presents challenges for healthcare systems globally, especially in vulnerable populations such as pediatric hematopoietic stem cell transplant (HSCT) recipients. This study examines the clinical characteristics and outcomes of COVID-19 infection in pediatric HSCT recipients within one year post-HSCT.Methods: Retrospective analysis was conducted on data from 247 pediatric patients. None of them had received SARS-CoV-2 vaccination or had prior infection. SARS-CoV-2 infection was confirmed using RT-PCR testing. COVID-19 disease severity was categorized according to established guidelines. Demographic, clinical, laboratory, imaging and treatment data were collected.Results: The median age of the cohort was 7± 3.7 years, with thalassemia major as the predominant underlying disease. Allogeneic HSCT was performed in the majority of cases, with haploidentical donors being the most common source of grafts. Nearly half of the patients developed COVID-19, with significantly higher infection rates observed in recipients over 100 days compared to recipients within 100 days post-HSCT (40.1% vs 21.7%, p< 0.05, Fisher’s Exact test). Fever (n=107, 43.2%) and cough (n=88, 35.6%) were the most common symptoms. While most patients had mild disease and did not require specific anti-viral treatment, a significant proportion required hospitalization (n=34, 13.8%). Various treatments were employed hospitalized patients, including Paxlovid (n=19, 55.9%), methylprednisolone (n=7, 20.6%), IL-6 antibody (n=2, 5.9%), mesenchymal stem cells (n=3, 8.8%), and exosomes nebulization therapy (n=2, 5.9%). Despite multidisciplinary approaches, one patient died from severe respiratory failure. However, overall survival of all patients remained high (99.53%; CI 96.72– 99.93%), indicating favorable outcomes in pediatric HSCT recipients with COVID-19.Conclusion: This study provides insights into clinical features, therapeutic measures, and outcomes of pediatric HSCT recipients following COVID-19 infection in a large HSCT center in China. These findings contribute to our understanding of COVID-19 in this population and inform strategies to mitigate the impact the pandemic’s impact on their care.Keywords: COVID-19, SARS-CoV2, hematopoietic stem cell transplantation, pediatrics

Fang Wen,1,&ast; Shantong Jiang,1– 4,&ast; Ping Yuan,1– 5,&ast; Jinbo Liu,1– 4 Xiu Bai,1 Hongwei Zhao,1– 4,6,7 Xin Chen,1– 4,7 Yan-Bing Gong,5 Roland Asmar,8 Hongyu Wang1– 4,6,7 1Department of Vascular Medicine, Peking University Shougang Hospital, Beijing, People’s Republic of China; 2Vascular Health Research Center of Peking University Health Science Center (VHRC-PKUHSC), Beijing, People’s Republic of China; 3Beijing Shijingshan District Key Clinical Specialty of Vascular Medicine, Beijing, People’s Republic of China; 4Heart and Vascular Health Research Center of Peking University Clinical Research Institute (HVHRC-PUCRI), Beijing, People’s Republic of China; 5Department of Scientific Research, Peking University Shougang Hospital, Beijing, People’s Republic of China; 6State Key Laboratory of Vascular Homeostasis and Remodeling, (Peking University), Beijing, People’s Republic of China; 7Heart and Vascular Health Research Center of Chengdu Medical College (HVHRC-CMC), Chengdu, People’s Republic of China; 8Foundation-Medical Research Institutes, Beirut, Lebanon&ast;These authors contributed equally to this workCorrespondence: Hongyu Wang, Department of Vascular Medicine, Peking University Shougang Hospital, Beijing, 100144, People’s Republic of China, Email dr.hongyuwang@foxmail.comAbstract: Cardiovascular disease(CVD) has become a major disease burden affecting people’s health in China. Blood vessels are very important for human health and are the “sentinel” for the development of many cardiovascular and cerebrovascular diseases. The key to effectively preventing fatal, disabling heart, brain and peripheral vascular events lies in controlling traditional and non-traditional risk factors for vascular health from the source, and early assessment and intervention of early vascular lesions. Since 2004, China government promoted the early detection technology of vascular lesions and vascular medicine, and proposed the Beijing Vascular Health Stratification (BVHS) to provide suggestions for the examination, evaluation and management of risk factors, and to provide new ideas for lifelong maintenance of vascular health. This review mainly introduces the establishment and development of the clinical discipline of “vascular medicine” in the past 20 years in China, introduces the indicators for detecting vascular function and structure and the predictive value of vascular events, and carries out intelligent and digital management of vascular health throughout the life cycle of individualized prevention, treatment and rehabilitation for people with different parts or degrees of lesions, effectively reducing the occurrence and development of cardiovascular and cerebrovascular diseases, and the prospect of new technology in maintaining vascular health.Keywords: heart and vascular health, vascular medicine, early assessment, digital, Beijing vascular health stratification

Sandip Patil,1,2 Hongyu Chen,3 Yunsheng Chen,3 Shaowei Dong,2 Huirong Mai,1 Bruno Silvester Lopes,4,5 Sixi Liu,1 Feiqiu Wen1,2 1Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 2Paediatric Research Institute, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 3Department of Laboratory Medicine, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 4School of Health and Life Sciences, Teesside University, Middlesbrough, UK; 5National Horizons Centre, Teesside University, Darlington, UKCorrespondence: Feiqiu Wen; Sixi Liu, Department of Haematology and Oncology, Shenzhen Children’s Hospital, 7019 Yitian Road, Futian District, Shenzhen, Guangdong Province, People’s Republic of China, Tel +86-755-83009888, Email fwen62@163.com; tiger647@126.comPurpose: The emergence of multi-drug resistant ESBL-producing E. coli poses a global health problem. In this study, we aimed to investigate the prevalence of E. coli infections and their antibiotic susceptibility profiles in paediatric clinical cases in Shenzhen, China from Jan 1, 2014, to Jan 30, 2019, while also determining temporal trends, identifying ESBL-producing strains, and recommending potential empirical antibiotic therapy options.Methods: We isolated a total of 4148 E. coli from different specimens from a single paediatric healthcare centre. Additionally, we obtained relevant demographic data from the hospital’s electronic health records. Subsequently, we performed antimicrobial susceptibility testing for 8 classes of antibiotics and assessed ESBL production.Results: Out of the 4148 isolates, 2645 were from males. The highest burden of E. coli was observed in the age group of 0– 1 years, which gradually declined over the five-year study period. Antimicrobial susceptibility results indicated that 82% of E. coli isolates were highly resistant to ampicillin, followed by 52.36% resistant to cefazolin and 47.46% resistant to trimethoprim/sulfamethoxazole. Notably, a high prevalence of ESBL production (49.54%) was observed among the E. coli isolates, with 60% of them displaying a multi-drug resistance phenotype. However, it is worth mentioning that a majority of the isolates remained susceptible to ertapenem and imipenem. Our findings also highlighted a decrease in E. coli infections in Shenzhen, primarily among hospitalized patients in the 0– 1 year age group. However, this decline was accompanied by a considerably high rate of ESBL production and increasing resistance to multiple antibiotics.Conclusion: Our study underscores the urgent need for effective strategies to combat multi-drug resistant ESBL-producing E. coli Infections.Keywords: E. coli infections, antibiotic susceptibilities, young children, MDR

Qian Hu,1 Jianle Wu,1 Chengqian Wang,1 Wen Liang,1 Yulei Wang,1 Yuejie Zheng,1 Feiqiu Wen,2 Wenjian Wang,1,&ast; Uet Yu2,&ast; 1Department of Respiratory Diseases, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 2Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Uet Yu, Department of Hematology and Oncology, Shenzhen Children’s Hospital, 7019, Yitian, Road, Shenzhen, 518038, People’s Republic of China, Email cloveringo69@hotmail.com Wenjian Wang, Department of Respiratory Diseases, Shenzhen Children’s Hospital, 7019, Yitian, Road, Shenzhen, 518038, People’s Republic of China, Email wwjxx@126.comBackground: Plastic bronchitis (PB) is a rare and severe lung disease. It can be triggered by influenza virus infection, which is a common respiratory infection in children. Bronchoscopy can aid in the early detection and treatment of PB. However, the outcomes and risk for PB development in pediatric patients with influenza virus infection are not fully understood.Methods: Data from 321 children diagnosed with influenza virus pneumonia who underwent bronchoscopy examinations between 1st January, 2009 and 31st December, 2020 were retrospectively analyzed to assess the outcomes and risk factors associated with PB development.Results: This study included 97 girls and 224 boys with influenza virus pneumonia with a median age of 42 months. Among them, 36 patients (11.2%) were categorized as having PB based on bronchoscopy findings. PB patients had significantly longer fever durations (p=0.010) and higher risks of developing severe conditions including respiratory failure (p< 0.001), acute respiratory distress syndrome (p< 0.001), and air-leak syndrome (p< 0.001) compared to non-PB patients. Conventional treatment including the use of neuraminidase inhibitors and antibiotics did not differ between the PB and non-PB patients, but PB patients required more anti-inflammatory treatment (p=0.019) and ventilator support (p< 0.001). Combined univariate and multivariate analyses suggested that radiographic findings, including mediastinal emphysema (p=0.012) and lung consolidation (p=0.012), as well as increased levels of neutrophils (p=0.026), aspartate aminotransferase (p=0.004), and lactate dehydrogenase (p< 0.001), were identified as risk factors for PB development in patients with influenza virus pneumonia. Although PB patients required more intensive care and had longer hospital stays, they all recovered well after treatment.Conclusion: Influenza virus infection is linked to PB development in children. Identifying risk factors and early intervention such as bronchoscopy can improve the prognosis of children with PB.Keywords: influenza virus, plastic bronchitis, bronchoscopy, pneumonia, pediatric

Sandip Patil,1,2 Shaowei Dong,2 Devender Shrama,3,4 Bruno Silvester Lopes,5,6 Alfizah Hanafiah,7 Xiaowen Chen,2 Feiqiu Wen1,2 1Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 2Paediatric Research Institute, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 3Department of Microbiology, Himachal Dental College, Sundar Nagar, Himachal Pradesh, India; 4School of Biotechnology, Shoolini University, Solan, Himachal Pradesh, India; 5School of Health and Life Sciences, Teesside University, Middlesbrough, TS1 3BA, UK; 6National Horizons Centre, Teesside University, Darlington, DL1 1HG, UK; 7Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, MalaysiaCorrespondence: Feiqiu Wen, Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong, People’s Republic of China, Tel +86-755-83009888, Email fwen62@163.comAim: Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of severe and difficult-to-treat infections in humans and animals. We aimed to identify the predominant lineages of methicillin-resistant S. aureus in Himachal Pradesh, India, to understand the genomic epidemiology along with the genotypic and phenotypic characteristics.Methods: We isolated 250 S. aureus from two district hospitals in Himachal Pradesh, India. Methicillin-Resistant S. aureus (MRSA) isolates were subjected to MLST, SCCmec typing, and resistance as well as virulence determinants were determined by PCR and sequencing. Bio-typing was also performed for source tracking.Results: A 17.6% (44/250) of isolates were classified as MRSA by both the MRSA detection kit and disc diffusion methods. Antimicrobial Susceptibility Testing of MRSA isolates (n = 44) showed high resistance to oxacillin (77.27%), erythromycin (77.27%), tetracycline (75%), cefoxitin (65.9%), and gentamicin (61.36%), while low resistance was observed for teicoplanin (36.36%), vancomycin and levofloxacin (31.81%) and fusidic acid (18.18%). All isolates were sensitive to linezolid, quinupristin-dulfopristin, dalbavancin, and cefazoline. The SCCmec-II was observed in 20.45% of isolates, SCCmec-I in 11.36%, SCCmec-III in 9%, SCCmec-IV in 40.9% and SCCmec-V in 18.18%. The mecA gene was present in all isolates (n = 44) and 50% also had the vanA gene. 35% of isolates had the lukS-PV/lukf-PV toxin gene and 11.36% had the co-existence of mecA, vanA, and lukS-PV/lukf-PV. The major strain was ST398 (39%) followed by ST239 (27%), ST217 (16%), ST121 (11%), and ST338 (7%). The MRSA isolates produced staphylokinase and β-hemolysis but were negative for bovine plasma coagulation tests.In Conclusion: The predominant MRSA clones in Himachal Pradesh, India, were hospital-associated multi-drug resistant-MRSA ST239 with PVL and community-associated MRSA ST398.Keywords: MRSA, molecular epidemiology, antimicrobial resistance, SCCmec, vanA, lukS-PV/lukf-PV

Uet Yu,1 Ke Cao,2 Chunlan Yang,1 Chunjing Wang,1 Yue Li,1 Xiaohui Zhou,1 Qian Zhang,1 Yuanxiang Wang,3 Feiqiu Wen,1 Sixi Liu,1 Xiaodong Wang1 1Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 2Department of Laboratory Medicine, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 3Department of Cardiothoracic Surgery, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of ChinaCorrespondence: Xiaodong Wang; Sixi Liu, Email donlevin@live.cn; tiger647@126.comAbstract: Invasive fungal infections (IFIs) are among the most severe complications in recipients of hematopoietic stem cell transplantation (HSCT) recipients and in patients with hematological malignancies. An increasing number of uncommon fungal infections have been reported in this era of antifungal prophylaxis. Coprinopsis cinerea is a rare pathogen that causes opportunistic infections in the immunocompromised patients, including HSCT recipients and is associated with very high mortality rates. Herein, we present a successfully treated pediatric HSCT patient with breakthrough pulmonary IFI caused by Coprinopsis cinerea despite posaconazole, prophylaxis using multidisciplinary approaches.Keywords: Coprinopsis cinerea, Hormographiella aspergillata, invasive fungal infection, hematopoietic stem cell transplantation, leukemia, case report

Kai Rong, Yi Lang, Yubo Zhou, Liangtao Ni, Lei Wang, Long Wang, Yaowu Zhang, Fengli Wen, Zhan Wang, Pingbo Chen Department of Traumatology, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Wulumuqi, Xinjiang, People’s Republic of ChinaCorrespondence: Pingbo Chen, Department of Traumatology, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, No. 116, Huanghe Street, Wulumuqi, Xinjiang, People’s Republic of China, Tel/Fax +86-13899907800, Email xj.2016@foxmail.comBackground: Osteoporosis (OP) is a common metabolic bone disease characterized by loss of bone mass. IL-10 is considered to be a powerful immune and inflammatory suppressor. This study aimed to assess association between genetic loci in IL-10 and susceptibility to OP.Methods: Association analysis between IL-10 genetic loci and OP risk through SNPStats online software. FPRP analysis (false-positive report probability) verified whether the positive results were noteworthy findings. Linkage disequilibrium (LD) and haplotype analysis were completed by Haploview 4.2 and SNPStats. Multi-factor dimensionality reduction (MDR) was used to assess interaction of SNP–SNP in susceptibility to OP.Results: Allele “G” of IL-10-rs1554286 (OR = 1.21, p = 0.013), allele “C” of IL-10-rs1518111 (OR = 1.22, p = 0.011), allele “C” of IL-10-rs3024490 (OR = 1.20, p = 0.018), and allele “G” of IL-10-rs1800871 (OR = 1.21, p = 0.015) were risk factors for OP. In females, smoking, drinking, or aging ≤ 60 years old participants, the above genetic loci are also significantly associated with the increased risk of OP. FPRP analysis showed that all positive results are noteworthy findings. There are significant differences in serum levels of uric acid, mean hemoglobin concentration, or mean hemoglobin among different genotypes of IL-10 gene loci. MDR showed that four loci model composed rs1554286, rs1518111, rs3021094, and rs1800871 is the best model for predicting OP risk.Conclusion: IL-10-rs1554286, -rs1518111, -rs3021094, and -rs1800871 are risk factors for susceptibility to OP.Keywords: osteoporosis, IL-10, genetic loci, Han population from northwest China

Luyang Zhang,1 Yan Yin,1 Alison Simons,2 Ngiambudulu M Francisco,3 Feiqiu Wen,1 Sandip Patil1,4 1Division of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 2Post Qualifying Practice Department, Birmingham City University, Birmingham, UK; 3Grupo de Investigação Microbiana e Imunológica, Instituto Nacional de Investigação em Saúde (National Institute for Health Research), Luanda, 3635, Angola; 4Pediatric Research Institute, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of ChinaCorrespondence: Sandip Patil, Division of Haematology and Oncology, Shenzhen Children’s Hospital, 7019 Yitian Road, Futian District, Shenzhen, People’s Republic of China, Tel +86-18813934471, Fax +86-755-83008283, Email sandippatil1309@yahoo.comBackground: Oral mucositis (OM) is a critical condition during chemotherapy in both adult and child cancer patients. Paediatric cancer patients have a higher prevalence of OM than adult cancer patients. Honey is a natural product that has been reported to have the best tissue healing properties. The present mini-review focused on the evaluation of the effectiveness of oral care with honey products in the treatment and prophylaxis of chemotherapy-induced OM in child patients.Methods: A network of electronic English databases including CINAHL, CENTRAL, EMBASE, MEDLINE and PubMed, were used for primary search from April 2010 to April 2020. We have also considered data collected from ClinicalTrials.gov, Web of Science and Google Scholar. PRISMA software was used to build collective data. Controlled trials were included in this review and were critically appraised by Down and Black. The narrative synthesis was performed.Results: A total number of 346 data of children and adolescents with cancer were considered in this short review. All patients were from three randomized controlled trial articles and two were non-randomised controlled trial articles. Based on the evidence so far revealed, honey may show an effect in the treatment and prophylaxis of OM. The analysis of collected data revealed that the probability value P< 0.05. The honey enhanced recovery time and severity of OM were significantly compared with those without honey treatment receiving group of pediatric patients.Conclusion: Honey not only has been shown to have the capability for healing injured tissues but it is also a more economical treatment, and it has fewer side effects compared to synthetic drugs. Honey or honey products can prevent chemotherapy-induced OM (CIOM) and be the best treatment to grade I, II and III CIOM. However, it is disappointing that studies involving children as patients were few, and limited data available so far.Keywords: oral mucositis, honey, pediatric patients, chemotherapy

Hongyu Chen,1 Huirong Mai,2 Bruno Lopes,3 Feiqiu Wen,2 Sandip Patil2,4 1Department of Laboratory Medicine, Shenzhen Children’s Hospital, Shenzhen, Guangdong, 518038, People’s Republic of China; 2Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong, 518038, People’s Republic of China; 3Department of Microbiology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK; 4Paediatric Research Institute, Shenzhen Children’s Hospital, Shenzhen, Guangdong, 518038, People’s Republic of ChinaCorrespondence: Sandip Patil, Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong, 518038, People’s Republic of China, Tel +86-18813934471, Fax +86-755-83008283, Email sandippatil1309@yahoo.com Feiqiu Wen, Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong, 518038, People’s Republic of China, Tel +86-18938690333, Fax +86-755-83009888, Email fwen62@163.comBackground: The rising resistance to carbapenems in Gram-negative bacteria worldwide poses a major clinical and public health risk. This study aimed to characterise carbapenem- and colistin-resistance genes, blaNDM-1 and mcr-1 located on IncX4 plasmid in MDR Pseudomonas aeruginosa, isolated from paediatric patients undergoing chemotherapy as a result of leukaemia.Methods: In this study, six carbapenem-resistant strains of P. aeruginosa were isolated from two paediatric patients under chemotherapy treatment (1.8 years old female and 2.1 years male) from the Shenzhen Hospital, China, in the year 2019. Isolates were screened for conventional antibiotics such as tobramycin, cefepime, imipenem, and ciprofloxacin in additional colistin by using the broth dilution method. Furthermore, resistance determinants: mcr-1, blaNDM-1, blaKPC-1, and blaGES were screened using PCR and sequencing followed by multi-locus sequence typing. The horizontal gene transfer and location of mcr-1 and blaNDM-1 were determined by a liquid mating assay. In addition, Incompatibility type (Inc), PCR-based replicon type, and subgroup (MOB) of plasmid were studied.Results: The screening for conventional antibiotics isolates showed 100% resistance to all the tested antibiotics except tobramycin. All isolates harboured carbapenemase encoding blaNDM-1, of which three also had mcr-1 located on a single IncX4 transferable plasmid. MLST typing revealed that four strains had a novel (new) STs type, while two belonged to ST1966.Conclusion: This study identified for the first time colistin- and carbapenem-resistant MDR P. aeruginosa in paediatric patients with leukaemia in Shenzhen, China. It highlights the need for continuous surveillance in high-risk clones of MDR P. aeruginosa. Prudent use of antibiotics based on local antimicrobial susceptibility and clinical characteristics can help in reducing mortality in immunocompromised patients.Keywords: mcr-1, blaNDM-1, Pseudomonas aeruginosa, leukaemia patients

Sandip Patil,1,2 Xiaorong Liu,2 Hongyu Chen,3 Ngiambudulu M Francisco,4 Feiqiu Wen,1,2 Yixin Chen5,6 1Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong, 518038, People’s Republic of China; 2Paediatric Research Institute, Shenzhen Children’s Hospital, Shenzhen, Guangdong, 518038, People’s Republic of China; 3Department of Laboratory Medicine, Shenzhen Children’s Hospital, Shenzhen, Guangdong, 518038, People’s Republic of China; 4Grupo de Investigação Microbiana e Imunológica, Instituto Nacional de Investigação em Saúde (National Institute for Health Research), Luanda, 3635, Angola; 5Department of Oncology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, Guangdong, 518000, People’s Republic of China; 6Department of Oncology, The First Affiliated Hospital, Southern University of Sciences and Technology, Shenzhen, Guangdong, 518000, People’s Republic of ChinaCorrespondence: Yixin Chen, Department of Oncology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, Guangdong, 518000, People’s Republic of China, Fax +86 755-22942763 Email yixinchen2013@126.comBackground: Since 2015, plasmid-borne mcr-1 has been reported in various bacterial strains in the clinical setting globally. However, the transmission mechanisms of this gene in Salmonella are not well defined. This study aimed to characterize the genomic features of a Salmonella enterica ST34 isolate, which carried a mcr-1, mapped to a carbapenemase and extended spectrum β-lactamase encoding gene located on the IncX4 plasmid.Methods: Salmonella enterica was recovered from a diarrheal paediatric patient in Shenzhen, China. Antimicrobial susceptibility testing was performed by using the VITEK 2 system. Drug resistance genes were identified using targeted primers and Sanger sequencing. The transferability and genome location of mcr-1 was determined by performing conjugation, S1-PFGE and Southern blot hybridization analysis. WGS was performed by Illumina MiSeq sequencing and was assembled using the A5-Miseq pipeline, and gene annotation was performed using RAST 2.0. The database Centre for Genomic Epidemiology’s website was used to identify resistance genes and sequence types (STs).Results: We found that the isolate was extensively drug resistant and belonging to ST34, carrying an IncX4 plasmid with mcr-1, blaKPC-2 and blaCTX-M-15. We also noticed that genes blaPAO, fosA, catB, the mutation in oprD and mexT (MexEF-OprN efflux regulator), and exotoxin-encoding genes (exoS, exoY and exoT) were associated with resistance and virulence in the genome. In addition, heavy metal resistance genes as silP and silE were determined.Conclusion: This study highlights the potential risk of ST34 of Salmonella enterica serotype Typhimurium carrying multiple drug resistance encoding genes in a single IncX4 plasmid.Keywords: Salmonella enterica, MCR-1, KPC-1, CTX-M-15, paediatric patient

Luqi Dai,1,2,&ast; Dan Xu,1,&ast; Chun Wan,1,2 Lian Liu,1 Fuqiang Wen1,2 1Division of Pulmonary Diseases, State Key Laboratory of Biotherapy, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fuqiang Wen; Lian LiuDepartment of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy, Guoxuexiang 37 Road, Chengdu, Sichuan, 610041, People’s Republic of ChinaTel +86 28 8542 2350Fax +86 28 8558 2944Email wenfuqiang@scu.edu.cn; desertfoxliu@hotmail.comPurpose: WNT/β-catenin signal pathway is a potential hope for lung tissue repair. We investigated the levels of Dickkopf‐1 (DKK1), an endogenous inhibitor of WNT/β-catenin signal pathway, in chronic obstructive pulmonary disease (COPD) patients and airway inflammation.Patients and Methods: Collected the demographic and clinical characteristics of 36 healthy controls, 25 stable COPD patients and 10 acute exacerbation of COPD (AECOPD) patients, then performed pulmonary function and detected serum DKK1 levels. After over-expression of DKK1, detect the levels of DDK1, lipoprotein-related protein 6 (LRP6) and inflammatory factors in bronchial epithelial cells stimulated with cigarette smoke extract (CSE).Results: Serum DKK1 were reduced in stable COPD patients compared to healthy controls (3866.72 ± 775.33 pg/mL vs 5317.61 ± 1317.20 pg/mL, p< 0.0001), but there was no significant difference between stable and acutely exacerbated patients (3866.72 ± 775.33 pg/mL vs 3482.10 ± 841.25 pg/mL, p> 0.05). DKK1 was positively correlated with FEV1 (r = 0.570, p< 0.0001), FEV1/FVC (rho = 0.590, p< 0.0001), FEV1/Pre (r = 0.517, p< 0.0001). Multiple linear regression analysis also suggested that FEV1 levels were higher with increasing DKK1. In vitro, elevated IL-6, IL-8, TNF-α and decreased DKK1, LRP6 were found in Beas-2B cells after CSE treatments, and increased LRP6 and decreased inflammatory factors were found after overexpression of DKK1. Andrographolide restored the CSE-induced decrease in DKK1 and increase in IL-6 and IL-8.Conclusion: DKK1 levels were decreased in COPD patients and positively correlated with lung function, overexpression of DKK1 and andrographolide attenuated airway cell inflammation, both suggesting a potential role in pathophysiology and providing a disease-specific biomarker pattern.Keywords: LRP6, lung function, biomarker, andrographolide

Ke Huang,1,2 Kewu Huang,3 Jianying Xu,4 Lan Yang,5 Jianping Zhao,6 Xiangyan Zhang,7 Chunxue Bai,8 Jian Kang,9 Pixin Ran,10 Huahao Shen,11 Fuqiang Wen,12 Yahong Chen,13 Tieying Sun,14 Guangliang Shan,15 Yingxiang Lin,3 Sinan Wu,2,16 Ting Yang,1,2,17 Chen Wang1,2,17,18 1Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 3Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Shanxi Dayi Hospital, Taiyuan, People’s Republic of China; 5Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 6Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 7Department of Pulmonary and Critical Care Medicine, Guizhou Provincial People’s Hospital, Guiyang, People’s Republic of China; 8Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 9Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, People’s Republic of China; 10State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China; 11Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, People’s Republic of China; 12State Key Laboratory of Biotherapy of China and Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, People’s Republic of China; 13Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 14Department of Respiratory and Critical Care Medicine, Beijing Hospital, Beijing, People’s Republic of China; 15Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, People’s Republic of China; 16Institute of Clinical Medical Sciences, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 17Department of Respiratory Medicine, Capital Medical University, Beijing, People’s Republic of China; 18Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Chen Wang; Ting YangDepartment of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Chaoyang District, Beijing, 100029, People’s Republic of ChinaTel +86 10 65105565; +86 10 84206276Email cyh-birm@263.net; dryangting@qq.comPurpose: Anxiety and depression are often underdiagnosed and affect the prognosis of patients with chronic obstructive pulmonary disease (COPD). We analyzed data from the China Pulmonary Health (CPH) study to assess the prevalence of anxiety and depression in COPD patients and their relationship with disease severity.Patients and Methods: A total of 57,779 subjects aged 20 years or older were recruited in the CPH study. All participants were assessed using a standard questionnaire and underwent pulmonary function tests before and after the use of a bronchodilator in local health centers. The Hospital Anxiety and Depression Scale (HADS) questionnaire with a cutoff score of 8 was used to define anxiety and depression. The prevalence of anxiety and depression in patients of COPD were investigated. Multivariate logistic regression was used to investigate the effects of COPD and lung function on anxiety and depression.Results: A total of 49,053 participants (20,661 men and 28,392 women) completed the questionnaire with reliable post-bronchodilator pulmonary function test results and were included in the final analysis, of which 4686 (9.55%) were diagnosed with COPD. Of the patients with COPD, 10.79% had anxiety, 13.65% had depression, and 7.08% had anxiety and depression concomitantly. In the multivariate logistic regression analysis, COPD was not significantly associated with anxiety, depression, or both. After adjusting for confounders in model 1, patients in the GOLD III–IV group had a significantly higher risk of anxiety, depression, and their coincidence. After further adjusting for respiratory symptoms in model 2, lung function impairment in the GOLD III–IV group was only significantly associated with a higher risk of depression or at least one of anxiety and depression.Conclusion: Anxiety and depression are prevalent in patients with COPD in China. More severe lung function impairment is significantly associated with a higher risk of depression.Keywords: anxiety, COPD, depression, Hospital Anxiety and Depression Scale, HADS

Adlay (Coix lacryma-jobi L.), a crop closed related to maize (Zea mays L.) and sorghum (Sorghum bicolor L.), originated in tropical/subtropical regions of Asia and Africa; southwest China primary center of this plant’s origin, evolution and migration. Adlay is a traditional high-value minor crop used for both medicinal and dietary purposes. Adlay has anti-tumor, anti-bacterial, anti-inflammatory, analgesic, blood sugar-lowering, and blood lipid-lowering effects. To clarify the main bioactive components and phytochemical compounds and to fully explore their utility, this review summarizes the research done on the main functional ingredients of adlay, including amino acids and proteins, oils, vitamins and minerals, polysaccharides, and polyphenols. This study also highlighted the application of genome sequencing to tailor nutrient-rich adlay cultivars and nutraceutical product development. Additionally, the acquisition of high-density genomic data combined with next-generation phenotypic analysis will undoubtedly improve our understanding of the potential genetic regulation of adlay nutraceutical traits. This review provides new insights and ideas for the research of adlay in comparison and evolutionary genomics, and a useful reference for molecular breeding and genetic improvement of this important minor crop.

Sandip Patil,1– 3 Hongyu Chen,4 Chunna Guo,4 Xiaoli Zhang,3 Pei-Gen Ren,1 Ngiambudulu M Francisco,5 Feiqiu Wen2,3 1Shenzhen Institute of Advanced Technology, Shenzhen University Town, Shenzhen, Guangdong Province, People’s Republic of China; 2Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 3Paediatric Research Institute, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 4Department of Laboratory Medicine, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 5Grupo de Investigação Microbiana e Imunológica, Instituto Nacional de Investigação em Saúde (National Institute for Health Research), Luanda, AngolaCorrespondence: Feiqiu WenDepartment of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of ChinaTel +86 18938690333Fax +86-755 83009888Email fwen62@163.comAim: We investigated the clonal diversity of carbapenemase-producing Klebsiella pneumoniae isolates from the Shenzhen Children’s Hospital, China, and drew conclusions on the clinical and public health impact of these isolates as multidrug-resistant.Methods: From January 2014 to December 2018, a total number of 36 unique carbapenemase-producing clinical isolates of Klebsiella pneumoniae were collected out of 900 clinical isolates in paediatric patients from the Shenzhen Children’s Hospital, China. After carbapenemase production confirmation, antimicrobial susceptibility, resistance determinants and phylogenetic relationship were determined.Results: The isolates showed resistance to ceftazidime, ertapenem, ampicillin, cefazolin, ceftriaxone, cefotetan, ticarcillin, cefaclor, cefpodoxime, azlocillin, cefcapene, mezlocillin and ampicillin-sulbactam. Of the 36 Klebsiella pneumoniae carbapenemase genes coding isolates, blaNDM was the mostly detected 50% (n=18) followed by blaKPC and blaIMP 19% (n=7), blaVIM 17% (n=6), blaOXA-48-like 8% (n=3) and blaSME 5% (n=2), whereas extended-spectrum β-lactamase (blaSHV) was predominantly detected 92% (n=33) followed by blaCTX-M 53% (n=19) and blaCMY 28% (n=10). Pulsed-field gel electrophoresis typing showed eight different patterns, and twenty-five distinct sequences types were observed with ST307 being predominantly identified 11% (n=4), followed by ST2407 8% (n=3). Plasmid replicon typing results indicated that IncFIS, IncHI2, IncFIC and IncFIA plasmids carry blaCTX-M, blaSHV and blaNDM genes.Conclusion: This study reports on the occurrence and spread of carbapenemase and extended-spectrum β-lactamase encoding genes co-existence in sporadic Klebsiella pneumoniae ST307 in paediatric patients from the Shenzhen Children’s Hospital, China.Keywords: Klebsiella pneumoniae, carbapenemase, ESBLs, antimicrobial susceptibility, molecular characterization

Mei Yang,&ast; Ting Yang,&ast; Xiaoou Li,&ast; Diandian Li, Zenglin Liao, Yongchun Shen, Dan Xu, Lei Chen, Fuqiang Wen Department of Respiratory and Critical Care Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lei Chen; Fuqiang WenDepartment of Respiratory and Critical Care Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of ChinaEmail lchens@126.com; wenfuqiang@scu.edu.cnPurpose: Elevated blood eosinophils have been implicated in chronic obstructive pulmonary disease (COPD) progression and exacerbation. We aim to investigate clinical predictors of high blood eosinophils in a Chinese COPD cohort.Patients and Methods: We conducted a retrospective cohort study in Sichuan province, a Southwest province with high prevalence of COPD in China. All patients in this cohort were extracted from the Chinese Pulmonary Health study, a large cross-sectional study on COPD epidemiology in China. Demographics, personal and family history, living condition, spirometry and blood eosinophil counts were obtained. Univariate and multiple linear regression analyses were performed to determine predictors of high blood eosinophils.Results: A total of 375 COPD patients were included in this cohort. The median absolute blood eosinophil count was 138.8 cells/μL, and the prevalence of COPD with high blood eosinophils was 66.7% and 14.7% when using the thresholds of 100 cells/μL and 300 cells/μL, respectively. Univariate analyses indicated that male gender, lower body mass index, high-density lipoprotein (HDL), lower family income, raising pets and biomass use were significantly associated with high blood eosinophils (p < 0.05). Multiple linear regression model further revealed male gender (unstandardized coefficient (B)=66.125, 95% confidence intervals (CI) 16.350 to 115.900, p=0.009), age (B=2.819, 95% CI 0.639 to 5.000, p=0.012) predicted high blood eosinophil level, whereas HDL (B=− 64.682, 95% CI − 123.451 to − 5.914, p=0.031) was a negative predictor for high blood eosinophils.Conclusion: This retrospective cohort study suggests male gender, oldness and lower HDL could be clinical predictors of high blood eosinophils in Chinese COPD patients.Keywords: chronic obstructive pulmonary disease, blood eosinophil count, high-density lipoprotein, predictor, retrospective study

Zhongze Cui,&ast; Yangyang Li,&ast; Shuang He, Feifei Wen, Xiaoyang Xu, Lizhen Lu, Shuhua Wu Department of Pathology, Binzhou Medical University Hospital, Binzhou, Shandong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuhua Wu Email wushuhua6108@163.comBackground: Colon adenocarcinoma (COAD) is one of the most common malignancies. To identify candidate genes that may be involved in colon adenocarcinoma development and progression, weighted gene co-expression network analysis (WGCNA) was used to construct gene co-expression networks to explore associations between gene sets and clinical features and to identify candidate biomarkers. Moreover, we intend to make a preliminary exploration on it.Methods: Gene expression profiles and clinical information were collected from The Cancer Genome Atlas COAD database for analysis. The gene expression profiles of GSE106582 and GSE110224 were screened from the Gene Expression Omnibus database for verification. WGCNA analysis, functional pathway enrichment analysis, and prognosis analysis were performed on three databases. Target genes were selected from the key genes for experimental verification and research.Results: Key genes obtained by WGCNA analysis were mainly enriched in key functions and pathways such as drug metabolism, steroid hormones, and retinol metabolism. A total of four prognostic genes were screened out: SELENBP1, NAT2, VSIG2, and CES2. VSIG2 was selected as the target gene for experimental verification, and its encoded protein was found to be mainly expressed in immune cells. Its expression was positively correlated with immune infiltration.Conclusions: VSIG2 was shown to be associated with immune invasion and antigen presentation in COAD, suggesting it plays an important role in COAD development and progression. It could be used as a potential biomarker or therapeutic target for COAD.Keywords: prognosis, WGCNA, immune-related gene, molecular biomarkers, The Cancer Genome Atlas, Gene Expression Omnibus

Chenye Feng,1 Mingtao Xu,1 Jian Kang,1 Fuqiang Wen,2 Yahong Chen,3 Jing Zhang,4 Wei Xiao,5 Zhonghe Zhang,6 Lan Yang,7 Jianmin Huo,8 Jie Cao,9 Li Zhao,10 Shuyue Xia,11 Yan Yin,1 Wei Wang1 1Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Disease, State Key Laboratory of Biotherapy of China, Chengdu, Sichuan, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Peking University, Third Hospital, Beijing, People’s Republic of China; 4Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 5Department of Pulmonary Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, People’s Republic of China; 6Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaonign, People’s Republic of China; 7Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shanxi, People’s Republic of China; 8Department of Respiratory, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; 9Respiratory Department, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 10Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China; 11Department of Pulmonary Medicine, Central Hospital Affiliated with Shenyang Medical College, Shenyang, People’s Republic of ChinaCorrespondence: Jian KangDepartment of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of ChinaTel +86-024-83282530Fax +86-024-83282002Email kangjian58@163.comPurpose: The proportion of atypical pathogens in patient with AECOPD within mainland China is unknown. The objectives of this study were to determine the distribution of atypical pathogens among Chinese patients with AECOPD, to evaluate the clinical characteristics of different atypical pathogen infections, and to compare different detection methods for atypical pathogens.Patients and Methods: Specimens were collected from patients with AECOPD from March 2016 to November 2018 at eleven medical institutions in eight cities in China. Double serum, sputum, and urine samples were obtained from 145 patients. Serological and nucleic acid tests were used to assess for Mycoplasma pneumonia and Chlamydia pneumoniae; serological, urinary antigen, and nucleic acid tests were applied to detect Legionella pneumophila. The clinical characteristics of atypical pathogen-positive and -negative groups were also compared.Results: The overall positivity rate for Mycoplasma pneumoniae was 20.69% (30/145), with the highest rate being 20.00% (29/145) when determined by passive agglutination.The overall positive rates for Chlamydia pneumoniae and Legionella pneumophila were 29.66% (43/145) and 10.34% (15/145), respectively. The most common serotype of Legionella pneumophila was type 6. The maximum hospitalized body temperature, ratio of eosinophils, C-reactive protein (CRP) level, and procalcitonin (PCT) level of the Mycoplasma pneumoniae-positive group were significantly higher than those of the Mycoplasma pneumoniae-negative group. Patients in the Chlamydia pneumoniae-positive group smoked more, had higher proportions of comorbidities and frequent aggravations in the previous two years than those in the Chlamydia pneumoniae-negative group. Furthermore, the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) ratio assessment of lung function was higher, and the concentration of arterial blood bicarbonate (HCO3−) was lower in the Legionella pneumophila-positive group than in the Legionella pneumophila-negative group.Conclusion: Overall, atypical pathogens play an important role in AECOPD. Regarding the testing method, serological testing is a superior method to nucleic acid testing.Keywords: COPD, exacerbations, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila

Wen-Jie Huang,1,* Shuai Ruan,1,* Fang Wen,2 Xiao-na Lu,1 Su-ping Gu,2 Xiao-xue Chen,1 Miao Liu,3 Peng Shu1 1Oncology Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 3Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Peng ShuOncology Department, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, Jiangsu Province, People’s Republic of ChinaEmail shupengsp@163.comMiao LiuDepartment of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USAEmail mliu0@bwh.harvard.eduAbstract: Chemotherapy is the main clinical treatment method of gastric cancer. Multidrug resistance (MDR) has become a common phenomenon with the development of tumors, which alleviates the effect of chemotherapy and makes it difficult to break the bottleneck of survival rate of advanced gastric cancer. Therefore, the exploration of MDR reversal agents for gastric cancer is the focus and also the difficulty of current treatment. Currently, the researches on the mechanisms of drug resistance in gastric cancer have been continuously deepened, which reveal different pathways and targets of MDR, laying a solid foundation for studying reversal agents. As a kind of natural medicine, traditional Chinese medicine (TCM) owns the characteristics of low toxicity, high safety and effectiveness. It can inhibit the occurrence, growth and metastasis of tumors, and reverse MDR via multiple pathways and mechanisms, the pathological function of which has become a research hotspot in recent years. TCM reversers are mainly divided into Chinese medicine monomers, Chinese patent medicines, and Chinese herbal compounds. With certain quantity and advantage, TCM reversers for MDR play an important role in the clinical treatment and show great potential in gastric cancer.Keywords: gastric cancer, multidrug resistance, MDR, mechanisms, traditional Chinese medicine, TCM, review

Yanqiu Wu,1,2 Jiangyue Qin,1,2 Junyun He,3 Yongchun Shen,1,2 Hao Wang,1,2 Yanping Li,4 Qianglin Zeng,5 Jiajia Dong,1,2 Yunfei An,6 Shuguang Xiong,7 Mei Feng,2 Fuqiang Wen1,2 1Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Hospital of Chengdu Office of People’s Government of Tibetan Autonomous Region, Chengdu, Sichuan, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Third People’s Hospital of Chengdu, Sichuan, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Chengdu University, Chengdu, Sichuan, People’s Republic of China; 6Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 7Department of Respiratory and Critical Care Medicine, 416 Hospital of Nuclear Industry, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Fuqiang WenDivision of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, People’s Republic of ChinaTel +86-28-8542 2350Email wenfuqiang@scu.edu.cnBackgrounds and Aims: It is well known that angiogenesis contributes to the progression of chronic obstructive pulmonary disease (COPD) by initiating the remodeling of bronchial vasculature. However, the specific molecular mechanisms are incompletely understood. This research aimed to explore whether endostatin, a member of endogenous antiangiogenic proteins, is a biomarker in COPD and plays a role in the angiogenesis of COPD.Methods: 100 stable COPD patients, 130 patients with acute exacerbation (AECOPD) and 68 healthy volunteers were recruited in this research. Lung function test was conducted in the healthy people and stable COPD patients. Serum endostatin, C-reactive protein (CRP) and vascular endothelial growth factor (VEGF) of all the subjects were measured by Human Magnetic Luminex Screening Assay.Results: Serum endostatin level was significantly higher in stable COPD compared with healthy control and even more in AECOPD patients (P< 0.001). Besides, stable COPD patients with frequent exacerbation (≥ 2 exacerbations per year) in the last 1 year had a higher concentration of endostatin in the circulation compared to the patients with less exacerbation (P=0.037). Furthermore, circulatory endostatin was negatively associated with forced expiratory volume in 1 s % predicted (FEV1%pre), an index of lung function in the stable COPD group (P=0.009). Finally, endostatin was positively correlated to serum CRP in COPD group (including stable and AECOPD) (P=0.005) and all the subjects (P< 0.001), but only associated with VEGF in the total participants (P=0.002), not in the COPD group.Conclusion: These results suggested that endostatin is a biomarker for COPD and associated with lower lung function, exacerbation, and systemic inflammation. Endostatin potentially contributes to the pathogenesis of COPD.Keywords: chronic obstructive pulmonary disease, endostatin, lung function, angiogenesis, inflammation

Sandip Patil,1,2 Hongyu Chen,2 Xiaoli Zhang,2 Ma Lian,2 Pei-Gen Ren,1 Feiqiu Wen2 1Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, People’s Republic of China; 2Shenzhen Children’s Hospital, Futian District, Shenzhen, Guangdong Province, People’s Republic of ChinaCorrespondence: Feiqiu WenShenzhen Children’s Hospital, 7019 Yitian Road, Futian District, Shenzhen, Guangdong Province 518038, People’s Republic of ChinaTel +86 18938690333Fax +86-755 83009888Email fwen62@163.comIntroduction: The emergence of multi-drug-resistant Gram-negative bacteria (GNB) is a concern in China and globally. This study investigated antimicrobial resistance traits and resistance determinant detection in GNB isolates from paediatric patients in China.Methods: In the present study, a total of 170 isolates of GNB including the most prevalent Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii were collected from Shenzhen Children’s Hospital, China. ESBLs production was confirmed by using the combination disc diffusion method, and carbapenemase production was confirmed by using a carbapenem inactivation method followed by antimicrobial susceptibility. In addition, β-lactamase-encoding genes and co-existence of plasmid-borne colistin resistance mcr-1 gene were determined by PCR and sequencing.Results: Overall, 170 etiological agents (GNB) were recovered from 158 paediatric patients. The most prevalent species was E. coli 40% (n=68), followed by K. pneumoniae 17.64% (n=30), and Enterobacter cloacae 14.11% (n=24). Of 170 GNB, 71.76% (n=122) were multi-drug-resistant, 12.35% (n=21) extreme-drug resistant, and 7.64% (n=13) single-drug-resistant, while 8.23% (n=14) were sensitive to all of the studied antibiotics. The prevalence of ESBLs and carbapenemase producers were 60% and 17%, respectively. blaCTX-M was the most prevalent resistance gene (59.42%), followed by blaTEM (41.17%), blaSHV (34.270%), blaKPC (34.11%), blaOXA-48 (18.82%) and blaNDM-1 (17.64%).Conclusion: The present study provides insights into the linkage between the resistance patterns of GNB to commonly used antibiotics and their uses in China. The findings are useful for understanding the genetics of resistance traits and difficulty in tackling of GNB in paediatric patients.Keywords: Gram-negative bacteria, antimicrobial susceptibility, ESBLs, carbapenemase, molecular characterization

Diandian Li,1,* Yanqiu Wu,1,* Shujin Guo,2,* Jiangyue Qin,1 Mei Feng,1 Yunfei An,3 Junlong Zhang,3 Yanping Li,4 Shuguang Xiong,5 Hui Zhou,6 Qianglin Zeng,6 Lei Chen,1 Fuqiang Wen11Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu 610041, People’s Republic of China; 2Department of Internal Medicine, Sichuan Provincial People’s Hospital and Sichuan Academy of Medical Science, Chengdu 610072, People’s Republic of China; 3Department of Laboratorial Medicine, West China Hospital of Sichuan University, Chengdu 610041, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, The 3rd People’s Hospital of Chengdu, Chengdu 610031, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, 416 Hospital, Chengdu 610051, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Chengdu University, Chengdu 610081, People’s Republic of ChinaCorrespondence: Lei Chen; Fuqiang WenDepartment of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu 610041, People’s Republic of ChinaTel +86 288 542 2350Fax +86 288 558 2944Email lchens@126.com; wenfuqiang.scu@gmail.com*These authors contributed equally to this workIntroduction: Patients with COPD often show increased systemic inflammation which is associated with lower functional status, greater exacerbation risk, and worse clinical outcomes. Syndecans (SDCs), a family of transmembrane heparan sulfate proteoglycans (HSPGs), have been found to involve in inflammatory processes in many chronic inflammatory diseases. The aim of this preliminary clinical study was to investigate the possible association between two SDCs, SDC-1 and SDC-4, with lung function, systemic inflammation, and risk of exacerbations in COPD patients.Method: Serum SDC-1 and SDC-4 levels were measured in 101 COPD patients and 57 health controls. Correlations between SDCs and other parameters were analyzed using Spearsman’s rho. Receiver operating curve (ROC) analysis was used to evaluate the threshold value in differentiating disease status.Results: Although both serum SDC-1 and SDC-4 showed a downward trend in COPD patients, only SDC-1 levels were correlated positively with the ratio of FEV1/FVC and parameters of small airway obstruction. Besides, SDC-1 but not SDC-4, was negatively correlated with C-reactive protein (CRP) in COPD patients and downregulated in frequent exacerbators (FEs) of COPD. Using a cutoff value of 2.08 ng/mL, the sensitivity and specificity of SDC-1 to differentiate FE were 44% and 93.4%, respectively.Conclusion: In conclusion, circulating SDC-1 may be a novel inflammatory biomarker associated with lung function and systemic inflammation in patients with COPD, which could also be useful to identify the risk of COPD exacerbation. Further studies should be performed to clarify the influences of SDC-1 on the pathogenesis and outcomes of COPD.Keywords: syndecan, chronic obstructive pulmonary disease, systemic inflammation, exacerbation, biomarker

Drop-on-demand (DOD) bioprinting has been widely used in tissue engineering due to its high-throughput efficiency and cost effectiveness. However, this type of bioprinting involves challenges such as satellite generation, too-large droplet generation, and too-low droplet speed. These challenges reduce the stability and precision of DOD printing, disorder cell arrays, and hence generate further structural errors. In this paper, a multi-objective optimization (MOO) design method for DOD printing parameters through fully connected neural networks (FCNNs) is proposed in order to solve these challenges. The MOO problem comprises two objective functions: to develop the satellite formation model with FCNNs; and to decrease droplet diameter and increase droplet speed. A hybrid multi-subgradient descent bundle method with an adaptive learning rate algorithm (HMSGDBA), which combines the multi-subgradient descent bundle (MSGDB) method with Adam algorithm, is introduced in order to search for the Pareto-optimal set for the MOO problem. The superiority of HMSGDBA is demonstrated through comparative studies with the MSGDB method. The experimental results show that a single droplet can be printed stably and the droplet speed can be increased from 0.88 to 2.08 m·s−1 after optimization with the proposed method. The proposed method can improve both printing precision and stability, and is useful in realizing precise cell arrays and complex biological functions. Furthermore, it can be used to obtain guidelines for the setup of cell-printing experimental platforms. Keywords: Drop-on-demand printing, Inkjet printing, Gradient descent multi-objective optimization, Fully connected neural networks

Sandip Patil,1,2 Xiaowen Chen,1,2 Ma Lian,2 Feiqiu Wen1,21Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province 518038, People’s Republic of China; 2Paediatric Research Institute, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province 518038, People’s Republic of ChinaAims and Objectives: The emergence and spread of extended-spectrum β-lactamases (ESBLs) particularly CTX-M producing multi-drug-resistant (MDR) Escherichia coli (E. coli) is one of the greatest challenges for community health globally. The study investigated the phenotypic and genotypic characteristics of ESBLs-producing E. coli recovered from pediatric patients from Shenzhen Children’s Hospital, China.Materials and methods: Present study, a total of 2,670 isolates of E. coli were collected from Shenzhen Children’s Hospital, China of which 950 were ESBLs producer. ESBLs production was confirmed by using the combination disc diffusion method, and antimicrobial susceptibility test was detected. In addition, β-lactamase-producing genes and co-existence of carbapenem/colistin resistance genes were determined by PCR assay and sequencing. The diversity and phylogenetic relationship were determined by multi-locus sequence typing method.Results: Thirty-five percent (n=950) prevalence of ESBLs-producing E. coli we reported in Shenzhen, China of which 50 ESBLs producing E. coli were randomly selected for a further characterization. All 50 ESBLs- producing E. coli isolates revealed MDR phenotype and 100% were resistant to Ampicillin/sulbactam, Ampicillin, Cefazolin, and Ceftriaxone. All 50 ESBLs producers harbored at least one type of β-lactamase gene particular blaCTX-M. The PCR and sequencing revealed the most common CTX-M subtype was blaCTX-M-15 (n=18), followed by blaCTX-M-14 (n=16), blaCTX-M-90 (n=9), blaCTX-M-55 (n=3), blaCTX-M-27, blaCTX-M-101, and blaCTX-M-211 each (n=1). Co-existence of blaCTX-M with blaTEM, blaSHV, blaGES, and blaVEB was detected in few isolates. Among identified sequence types, ST131 (12%) was more dominant in ESBLs-producing E. coli. Phylogenetic group A was the most prominent group among the ESBLs-producing E. coli based on multiplex PCR.Conclusion: Our study shows the prevalence of blaCTX-M gene in ESBLs-producing E. coli in pediatric patients in Shenzhen, China. We highlight the importance to monitor the emergence and trends of ESBLs-producing isolates in a pediatric healthcare setting.Keywords: Antimicrobial resistance, molecular characterization, MLST, ESBLs, Escherichia coli

Current antiviral therapy can not cure chronic hepatitis B virus (HBV) infection or eliminate the risk of hepatocellular carcinoma. The licensed epidermal growth factor receptor (EGFR) inhibitors have found to inhibit hepatitis C virus replication via downregulation of signal transducers and activators of transcription 3 (STAT3) phosphorylation. Since STAT3 is also involved in HBV replication, we further studied the anti-HBV efficacy of the EGFR inhibitors in this study. HBV-transfected HepG2.2.15 cells and HBV-infected HepG2-NTCP cells were used as cell models, and HBV replication, the syntheses of viral antigens and the magnitude of the covalently closed circular DNA (cccDNA) reservoir were used as indictors to test the anti-HBV effects of EGFR inhibitors erlotinib and gefitinib. Erlotinib inhibited HBV replication with a half-maximal inhibitory concentration of 1.05 μM. It also reduced the syntheses of viral antigens at concentrations of 2.5 μM or higher. The underlying mechanism was possibly correlated with its inhibition on STAT3 phosphorylation via up-regulation of suppressor of cytokine signaling 3. Gefitinib also inhibited HBV replication and antigen syntheses. Compared with the commonest antiviral drug entecavir, these EGFR inhibitors additionally reduced hepatitis B e antigen and erlotinib also marginally affected the cccDNA reservoir in HBV-infected HepG2-NTCP cells. Interestingly, these promising anti-HBV effects were significantly enhanced by extension of treatment duration. In conclusion, EGFR inhibitors demonstrated a comprehensive anti-HBV potential, highlighting a new strategy to cure HBV infection and suggesting animal model-related studies or clinical try in the future.

Luqi Dai,1,2,* Junyun He,3,* Jun Chen,1,2 Tao Wang,1,2 Lian Liu,1,2 Yongchun Shen,2 Lei Chen,2 Fuqiang Wen1,2 1Division of Pulmonary Diseases, State Key Laboratory of Biotherapy, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, China; 2Department of Respiratory and Critical Care Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, China; 3Department of Respiratory Medicine, Hospital of Chengdu Office of People’s Government of Tibetan Autonomous Region of China, Chengdu, Sichuan 610041, China *These authors contributed equally to this work Background: Endocan is thought to be a novel inflammatory marker that is associated with a variety of inflammatory diseases. However, its role in the pathogenesis of COPD remains unclear. This study aims to explore the potential role of endocan in COPD. Methods: In total, 27 healthy volunteers, 55 COPD patients and 36 acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients were included in the study. Basic demographic characteristics, clinical features and blood samples were collected. Magnetic luminex screening assays were used to detect the concentration of endocan, Fas and Fas ligand (Fas-L) in plasma. Differences between groups were compared using an Independent sample t-test, Welch’s t-test, chi-squared test and Wilcoxon rank sum test. The correlations of plasma endocan with lung function parameters, Fas and Fas-L were analyzed by Pearson’s partial correlation test (adjusted for age, gender, body mass index and smoking history) and multiple linear regression. Results: Plasma endocan levels in COPD patients were significantly higher than those in healthy volunteers (509.7±18.25 pg/mL vs 434.8±18.98 pg/mL (P=0.0124)), and AECOPD patients had the highest levels of endocan (524.7±27.18 pg/mL). Correlation analysis showed that circulating endocan had a negative correlation to FEV1/FVC, FEV1/ predictive and FVC (adjusted r=-0.213, P=0.03; adjusted r=-0.209, P=0.034; and adjusted r=-0.300, P=0.002, respectively), and had a positive correlation to Fas (adjusted r=0.280, P=0.004). Conclusion: Our study shows that elevated circulating endocan levels are associated with reduced lung ventilation function in COPD and AECOPD patients. In addition, endocan may influence apoptosis in COPD, suggesting that endocan may play a role in COPD pathogenesis. Keywords: endocan, COPD, lung function, apoptosis

Jiaxing Huang,1,2,* Weiting Liao,1,2,* Jing Zhou,1,2 Pengfei Zhang,1,2 Feng Wen,1,2 Xinyuan Wang,1,2 Mengxi Zhang,1,2 Kexun Zhou,1,2 Qiuji Wu,1,2 Qiu Li1,2 1Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; 2West China Biomedical Big Data Center, Sichuan University, Chengdu 610041, China *These authors contributed equally to this work Background: The effectiveness of gemcitabine plus capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer has been evaluated in the ESPAC-4 trial. We aimed to assess the cost-effectiveness of these adjuvant regimens on resected pancreatic cancer. Methods: A Markov model was established to simulate the disease process of resected pancreatic cancer (relapse-free survival, progressive disease, and death). The efficacy and toxicity profiles were collected from the ESPAC-4 trial. Transition probabilities were calculated based on survival in each group. Cost data were calculated from the perspective of the Chinese healthcare payer. The primary endpoint in the analysis was the incremental cost-effectiveness ratio (ICER), and model uncertainties were explored by one-way sensitivity analysis and probabilistic sensitivity analysis. Results: Our results demonstrated that gemcitabine monotherapy cost $36,028.45 and yielded a survival of 1.02 quality-adjusted life year (QALY), while gemcitabine plus capecitabine cost $46,095.05 and yielded a survival of 1.23 QALY. Therefore, the incremental cost-effectiveness ratio of gemcitabine plus capecitabine vs gemcitabine monotherapy was $45,191.23 which surpassed the willingness-to-pay threshold of $29,291.42 per QALY in China. Conclusion: The gemcitabine monotherapy regimen is more cost-effective compared with gemcitabine plus capecitabine regimen for the patients with postoperative pancreatic cancer from the Chinese societal perspective. Keywords: cost-effectiveness, Markov model, gemcitabine, capecitabine, resected pancreatic cancer

Yuting Peng, Xiongze Zhang, Miaoling Li, Bing Liu, Lan Mi, Chengguo Zuo, Feng Wen State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China Introduction: To evaluate the functional and morphological outcomes of intravitreal conbercept monotherapy in patients with polypoidal choroidal vasculopathy (PCV). Materials and methods: In this retrospective, observational case series study, we reviewed medical records of 48 eyes (48 patients) with naive PCV that were treated with a series of 3 monthly intravitreal injections of 0.5 mg of conbercept followed by as-needed injections (3+pro re nata). All patients completed at least 6 months of monthly follow-up. Changes in the best-corrected visual acuity, optical coherence tomography, and indocyanine green angiography were retrospectively evaluated. Results: At 6 months, the mean best-corrected visual acuity significantly improved from 0.89±0.35 (20/160 in Snellen equivalent) at baseline to 0.58±0.26 (Snellen equivalent of 20/80; P

Yongchun Shen,1 Shaoguang Huang,2 Jian Kang,3 Jiangtao Lin,4 Kefang Lai,5 Yongchang Sun,6 Wei Xiao,7 Lan Yang,8 Wanzhen Yao,6 Shaoxi Cai,9 Kewu Huang,10 Fuqiang Wen1 1Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, 2Department of Pulmonary Disease, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 3Department of Respiratory Medicine, Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 4Department of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, 5State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 6Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, 7Department of Respiratory Medicine, Qilu Hospital of Shandong University, Jinan, 8Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 9Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 10Division of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China Abstract: Airway mucus hypersecretion is one of the most important characteristics of chronic airway inflammatory diseases. Evaluating and managing airway mucus hypersecretion is of great importance for patients with chronic airway inflammatory diseases. This consensus statement describes the pathogenesis, clinical features, and the management of airway mucus hypersecretion in patients with chronic airway inflammatory diseases in the People’s Republic of China. The statement has been written particularly for respiratory researchers, pulmonary physicians, and patients. Keywords: mucus, COPD, asthma, bronchiectasis, cystic fibrosis, treatment

Hao Wang,1,* Caishuang Pang,2,* Ni Zeng,1 Chun Wan,1 Yongchun Shen,1 Fuqiang Wen1 1Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, China; 2Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing, China *These authors contributed equally to this work Background: The gene polymorphism of interleukin-6 (IL-6) has been shown to be implicated in tuberculosis susceptibility in many studies, but with conflicting results. This study aimed to provide more accurate estimation of the relationship between IL-6 gene polymorphism and tuberculosis risk through a meta-analysis Method: A literature search was performed in PubMed, EMBASE, and other databases. Data were retrieved, and pooled odds ratio (OR) with 95% CI were calculated. Statistical analyses were performed by using STATA 12.0. Results: Twelve publications with 2635 cases and 3049 controls were included. The pooled analysis demonstrated significant evidence of association between IL-6 (-174G/C) and low risk of tuberculosis in dominant model (CC+GC vs GG: OR =0.693, 95% CI 0.581–0.826, p

Hao Wang,1,2,* Ting Yang,1,2,* Diandian Li,1,2 Yanqiu Wu,1,2 Xue Zhang,1,2 Caishuang Pang,1,2 Junlong Zhang,3 Binwu Ying,3 Tao Wang,1,2 Fuqiang Wen1,2 1Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China *These authors contributed equally to this work Background: Plasminogen activator inhibitor-1 (PAI-1) and soluble urokinase-type plasminogen activator receptor (suPAR) participate in inflammation and tissue remolding in various diseases, but their roles in chronic obstructive pulmonary disease (COPD) are not yet clear. This study aimed to investigate if PAI-1 and suPAR were involved in systemic inflammation and small airway obstruction (SAO) in COPD. Methods: Demographic and clinical characteristics, spirometry examination, and blood samples were obtained from 84 COPD patients and 51 healthy volunteers. Serum concentrations of PAI-1, suPAR, tissue inhibitor of metalloproteinase-1 (TIMP-1), Matrix metalloproteinase-9 (MMP-9), and C-reactive protein (CRP) were detected with Magnetic Luminex Screening Assay. Differences between groups were statistically analyzed using one-way analysis of variance or chi-square test. Pearson’s partial correlation test (adjusted for age, sex, body mass index, cigarette status, and passive smoke exposure) and multivariable linear analysis were used to explore the relationships between circulating PAI-1 and indicators of COPD. Results: First, we found that serum PAI-1 levels but not suPAR levels were significantly increased in COPD patients compared with healthy volunteers (125.56±51.74 ng/mL versus 102.98±36.62 ng/mL, P=0.007). Then, the correlation analysis showed that circulating PAI-1 was inversely correlated with pulmonary function parameters including the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC), FEV1/Pre (justified r=-0.308, P

Xiaoou Li,1–3 Tao Wang,1,2 Ting Yang,1,2 Yongchun Shen,1,2 Jing An,1,2 Lian Liu,1,2 Jiajia Dong,1,2 Lingli Guo,1,2 Diandian Li,1,2 Xue Zhang,1,2 Lei Chen,1,2 Dan Xu,1,2 Fuqiang Wen1,2 1Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Rationale: Pigment epithelium-derived factor (PEDF) is a 50 kD small secreting glycoprotein that participates in multiple physiological and pathological processes. Recent studies have reported that PEDF plays an important role in inflammatory responses in several diseases. However, the role of PEDF in the pathogenesis of chronic obstructive pulmonary disease (COPD) remains unclear.Objective: The aim of the present study is to explore the potential relationship between PEDF and COPD.Methods: We used differential proteomics – stable isotope labeling with amino acids in cell culture – to investigate protein expression profile changes in cigarette smoke extract-treated pulmonary cells and found that the neurotrophic and antiangiogenic protein PEDF was abnormally expressed. Furthermore, Western blotting was used to detect the expression of PEDF in the lung tissue of rats that were exposed to cigarette smoke. Eighty subjects between the ages of 40–90 years, including 20 healthy nonsmokers, ten smoking volunteers, and 50 COPD patients, were recruited from September 2012 until August 2013 in Sichuan Province, People’s Republic of China. We measured the plasma PEDF concentration and classic proinflammatory cytokines by multiplex enzyme-linked immunosorbent assay. In addition, we performed a spirometry examination to diagnose COPD patients and we also analyzed the correlation between PEDF and lung function.Results: First, we found that the expression of PEDF in cigarette smoke extract-treated cells increased 16.2-fold when compared with the control group. Next, we confirmed that 4 weeks’ exposure to cigarette smoke can upregulate PEDF levels in rat lung tissues. We also discovered that plasma PEDF in COPD patients was significantly increased when compared with either healthy nonsmoking or smoking subjects. Furthermore, circulating PEDF was correlated with inflammatory cytokine and blood neutrophil numbers, but it was reversely associated with a decline in forced expiratory volume in 1 second percent predicted.Conclusion: Our findings provide a novel link between PEDF and COPD. Elevated PEDF levels may be involved in promoting the development of COPD by performing proinflammatory functions. Keywords: chronic obstructive pulmonary disease, pigment epithelium-derived factor, cigarette smoke, inflammation

Ye Wang,1,# Yongchun Shen,1,# Qiunan Zuo,2 Li Zhao,3 Chun Wan,1 Panwen Tian,1 Lei Chen,1 Fuqiang Wen11Department of Respiratory Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, People’s Republic of China; 2Department of Geriatrics, Sichuan Provincial People’s Hospital, Chengdu, People’s Republic of China; 3Department of Respiratory Medicine, Guizhou People’s Hospital, Guizhou, People’s Republic of China#These authors contributed equally to this work and share joint first authorshipBackground: Appetite reduction is a major cause of cachexia in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). This study tested the correlation of appetite and circulating levels of acylated ghrelin in patients with AECOPD.Methods: Thirty-six patients with AECOPD and 23 healthy adults were enrolled in this study. Circulating total ghrelin, acylated ghrelin, and obestatin levels, Simplified Nutritional Appetite Questionnaire (SNAQ) score, and caloric intake were compared in patients and healthy controls. Additionally, the above parameters were compared between admission and discharge in the patients with AECOPD.Results: Compared with healthy controls, SNAQ scores and caloric intake were significantly lower in patients with AECOPD, but there were no significant differences in total ghrelin, acyl ghrelin, or obestatin levels. In patients with AECOPD, the total ghrelin level was significantly higher at admission than on discharge, the SNAQ score and caloric intake were significantly increased at discharge when compared with admission, and there was no significant difference in acylated ghrelin level between admission and discharge.Conclusion: We demonstrated lower appetite scores and caloric intake in patients with AECOPD, but could not confirm that these effects were caused by insufficient levels of the orexigenic peptide, acyl ghrelin. Further studies are needed to confirm our findings and to determine the mechanism regulating appetite in patients with AECOPD.Keywords: ghrelin, appetite, pulmonary disease, chronic obstructive, malnutrition, comorbidities

Abstract Background Harsh parenting has been recognized as a risk factor for adolescent anxiety; however, the underlying mechanisms of this relationship remain unclear, and it is unknown whether this relationship is influenced by different parental roles and living arrangements. This study aimed to investigate the mediating mechanisms between harsh parenting and adolescent anxiety symptoms using a multiple mediation model and to further compare specific roles of harsh parenting and distinguish between the living arrangements. Methods A total of 3505 adolescents completed this survey, and 3295 adolescents (54.7% girls, Mage = 14.97 years) were included in the study. Participants completed self-assessments measuring harsh parenting, self-efficacy, school connectedness, Internet addiction, sleep problems, and anxiety. They were categorized into three groups based on living arrangements: living with both parents, only with the mother, or only with the father. Results Correlational analyses revealed that both maternal and paternal harsh parenting were associated with increased anxiety symptoms. Structural equation modeling (SEM) mediation analyses and multigroup analyses showed that the independent mediating effects of school connectedness, Internet addiction, and sleep problems, as well as the sequential mediating pathways involving self-efficacy → school connectedness, self-efficacy → Internet addiction, and self-efficacy → sleep problems, vary across the adolescents’ living arrangements in the association between maternal and paternal harsh parenting and adolescent anxiety symptoms. Conclusions This study elucidated the mechanisms linking harsh parenting to adolescent anxiety symptoms and validated the effects of different parental roles and living arrangements. The findings provide important insights for developing targeted interventions to address anxiety symptoms in adolescents exposed to harsh parenting.

The high thermal conductivity of graphene shows great potential in the thermal management of electronic systems. Spherical Al2O3 was modified by polydiallyl dimethyl ammonium chloride （PDDA） to make the surface of Al2O3 positively charged， and then combined with negatively charged graphene oxide through electrostatic assembly. After high temperature thermal reduction， rGO@Al2O3 hybrid filler was obtained， and the hybrid filler was filled into the two-component silicone rubber. The thermal silicon gel enhanced by rGO@Al2O3 was further prepared. Then， the morphology and structure of the material during the preparation process were characterized by AFM， SEM， Raman， XRD， etc.， and the thermal conductivity and mechanical properties of thermal silicon gel were tested and analyzed. The thermal conductivity of thermal silicon gel which filled with rGO@Al2O3 prepared by 2% （mass fraction）GO is 0.817 W/（m·K）. Compared with the thermal conductive silicon gel filled with pure Al2O3， the thermal conductivity of rGO@Al2O3 silicon gel has been greatly improved.

Abstract Despite recent advances, severe acute pancreatitis (SAP) remains a lethal inflammation with limited treatment options. Here, we provide compelling evidence of GV-971 (sodium oligomannate), an anti-Alzheimer’s medication, as being a protective agent in various male mouse SAP models. Microbiome sequencing, along with intestinal microbiota transplantation and mass cytometry technology, unveil that GV-971 reshapes the gut microbiota, increasing Faecalibacterium populations and modulating both peripheral and intestinal immune systems. A metabolomics analysis of cecal contents from GV-971–treated SAP mice further identifies short-chain fatty acids, including propionate and butyrate, as key metabolites in inhibiting macrophage M1 polarization and subsequent lethal inflammation by blocking the MAPK pathway. These findings suggest GV-971 as a promising therapeutic for SAP by targeting the microbiota metabolic immune axis.

Abstract Background The aim of this research is to prospectively investigate the diagnostic performance of intravoxel incoherent motion (IVIM) using the integrated slice-specific dynamic shimming (iShim) technique in staging primary esophageal squamous cell carcinoma (ESCC) and predicting presence of lymph node metastases from ESCC. Methods Sixty-three patients with ESCC were prospectively enrolled from April 2016 to April 2019. MR and IVIM using iShim technique (b = 0, 25, 50, 75, 100, 200, 400, 600, 800 s/mm2) were performed on 3.0T MRI system before operation. Primary tumour apparent diffusion coefficient (ADC) and IVIM parameters, including true diffusion coefficient (D), pseudodiffusion coefficient (D*), pseudodiffusion fraction (f) were measured by two independent radiologists. The differences in D, D*, f and ADC values of different T and N stages were assessed. Intraclass correlation coefficients (ICCs) were calculated to evaluate the interobserver agreement between two readers. The diagnostic performances of D, D*, f and ADC values in primary tumour staging and prediction of lymph node metastasis of ESCC were determined using receiver operating characteristic (ROC) curve analysis. Results The inter-observer consensus was excellent for IVIM parameters and ADC (D: ICC = 0.922; D*: ICC = 0.892; f: ICC = 0.948; ADC: ICC = 0.958). The ADC, D, D* and f values of group T1 + T2 were significantly higher than those of group T3 + T4a [ADC: (2.55 ± 0.43) ×10− 3 mm2/s vs. (2.27 ± 0.40) ×10− 3 mm2/s, t = 2.670, P = 0.010; D: (1.82 ± 0.39) ×10− 3 mm2/s vs. (1.53 ± 0.33) ×10− 3 mm2/s, t = 3.189, P = 0.002; D*: 46.45 (30.30,55.53) ×10− 3 mm2/s vs. 32.30 (18.60,40.95) ×10− 3 mm2/s, z=-2.408, P = 0.016; f: 0.45 ± 0.12 vs. 0.37 ± 0.12, t = 2.538, P = 0.014]. The ADC, D and f values of the lymph nodes-positive (N+) group were significantly lower than those of lymph nodes-negative (N0) group [ADC: (2.10 ± 0.33) ×10− 3 mm2/s vs. (2.55 ± 0.40) ×10− 3 mm2/s, t=-4.564, P

Abstract Faults play a crucial role in shaping the formation and damage patterns of landslides in the mountainous region, particularly in Qinling-Daba (Qinba) area in China. On 6 October 2022, following a 4-day rainfall event totaling 221.5 mm, a landslide occurred in Hanwang Town, Shaanxi Province. The left boundary of the landslide coincided with a fault, which influence the formation and movement development of the landslide. To further understand and quantified the formation process and damage mechanism of the landslide, a comprehensive study was conducted, incorporating field investigations, local rainfall data, and various methods including unmanned aerial vehicles (UAVs), numerical simulations, and laboratory test. The results indicate that fault dictate the formation of the Lijiaping landslide by influencing the mechanical strength of the rock mass and the catchment topography in the landslide area. Due to fault, the rock mass in the landslide area is high fragmentation, with a softening coefficient of about 0.52. Weathering resulted in numerous residual and slope sediments in the landslide area, providing ample material for the landslide. Meanwhile, the fault activity led to a wedge-shaped topography in the landslide area, with an average Terrain Wetness Index (TWI) of 3.43, significantly higher than the Hanwang Township average of 1.47. This creates a hydrogeological structure favorable for landslides. Numerical simulations revealed that the maximum velocity of the landslide reached 5.05 m/s and the maximum displacement was 53.18 m, both occurring in the central part of the landslide. These findings offer crucial scientific insights for understanding and preventing similar geological hazards.

Abstract Gaining a comprehensive understanding of the role played by the oral microbiome in moderate to severe plaque psoriasis and its potential implications for disease management and development holds significant importance. With the objective of exploring correlations between the oral microbiota and severe psoriasis, this study involved 72 severe psoriasis patients and 16 healthy individuals, whose clinical manifestations and living habits were carefully recorded. Cutting-edge techniques such as 16S rRNA gene sequencing and bioinformatics analysis were employed to compare the microbial flora, investigating dynamic changes among severe plaque psoriasis patients, psoriatic arthritis patients and healthy individuals. The findings revealed noteworthy patterns including increased levels of Aggregatibacter in the psoriatic arthritis group, accompanied by a decrease in the level of Prevotella. Moreover, the enrichment o Capnocytandophaga (P = 0.009), Campylobacter (P = 0.0022), and Acetobacter (P = 0.0292) was notably more substantial in the psoriasis group compared to the control group, whereas certain bacterial species such as Bacteroides (P = 0.0049), Muribaculaceae (P = 0.0048) demonstrated decreased enrichment. Additionally, the psoriatic arthritis group exhibited significantly higher levels of Ralstonia, Bifidobacterium and Micromonospora. Based on these findings, it can be inferred that individuals with lower levels of Prevotella and higher levels of Corynebacterium may be more susceptible to psoriasis exacerbation.

With the soaring generation of hazardous waste (HW) during industrialization and urbanization, HW illegal dumping continues to be an intractable global issue. Particularly in developing regions with lax regulations, it has become a major source of soil and groundwater contamination. One dominant challenge for HW illegal dumping supervision is the invisibility of dumping sites, which makes HW illegal dumping difficult to be found, thereby causing a long-term adverse impact on the environment. How to utilize the limited historic supervision records to screen the potential dumping sites in the whole region is a key challenge to be addressed. In this study, a novel machine learning model based on the positive-unlabeled (PU) learning algorithm was proposed to resolve this problem through the ensemble method which could iteratively mine the features of limited historic cases. Validation of the random forest-based PU model showed that the predicted top 30% of high-risk areas could cover 68.1% of newly reported cases in the studied region, indicating the reliability of the model prediction. This novel framework will also be promising in other environmental management scenarios to deal with numerous unknown samples based on limited prior experience.

Abstract Background Angiostrongyliasis is a zoonotic parasitic disease caused by the rat lungworm Angiostrongylus cantonensis. The intermediate hosts of A. cantonensis are gastropods, and snail species such as Pomacea canaliculata play a key role in the transmission of human angiostrongyliasis. Detecting A. cantonensis infection in snails is an important component of epidemiological surveillance and the control of angiostrongyliasis. Methods In this study, a new method for diagnosing A. cantonensis infection in gastropods was developed by recovering larvae from the buccal cavity of three snail species. The entire buccal cavity of a snail was extracted, and the tissue was pressed between two microscope slides to observe whether A. cantonensis larvae were present. Our new method was compared with traditional pathogenic detection methods of lung microscopy, tissue homogenization, and artificial digestion. We artificially infected 160 P. canaliculata, 160 Cipangopaludina chinensis, and 160 Bellamya aeruginosa snails with A. cantonensis. Then, the four different detection methods were used to diagnose infection in each snail species at 7, 14, 21, and 28 days post exposure. Results We found no significant difference in the percentages of infected P. canaliculata snails using the four methods to detect A. cantonensis larvae. The radula pressing method had a mean detection rate of 80%, while the lung microscopy (81.3%), tissue homogenization (83.8%), and artificial digestion (85%) methods had slightly greater detection rates. Similarly, the percentages of infected C. chinensis snails that were detected using the radula pressing (80%), tissue homogenization (82.1%), and artificial digestion (83.8%) methods were not significantly different. Finally, the percentages of infected B. aeruginosa snails that were detected using the radula pressing (81.3%), tissue homogenization (81.9%), and artificial digestion (81.4%) methods were not significantly different. These results showed that the radula pressing method had a similar detection rate to traditional lung microscopy, tissue homogenization, or artificial digestion methods. Conclusions This study demonstrates a new method for the qualitative screening of gastropods that act as intermediate hosts of A. cantonensis (and other Angiostrongylus species), provides technical support for the control of human angiostrongyliasis, and furthers research on A. cantonensis. Graphical Abstract

Abstract Background The potential involvement of circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification in the progression of Wilms tumor (WT) has not been fully elucidated. This study investigates the regulatory mechanisms and clinical significance of m6A-modified circMARK2 and its role in WT progression. Methods We identified dysregulated circRNAs through deep sequencing and validated their expression by qRT-PCR in WT tissues. The biological functions of circMARK2 were assessed using clone formation, transwell migration, and orthotopic animal models. To dissect the underlying mechanisms, we employed RNA immunoprecipitation, RNA pull-down, dual-luciferase reporter assays, Western blotting, and immunofluorescence and immunohistochemical staining. Results CircMARK2, upregulated in WT tissues, was found to be m6A-modified and promoted cytoplasmic export. It facilitated WT progression by stabilizing LIN28B mRNA through the circMARK2/IGF2BP2 interaction. In vitro and in vivo studies demonstrated that circMARK2 enhances the malignant behavior of WT cells. Clinically, higher circMARK2 levels in tumor tissues of WT patients were linked to increased tumor aggressiveness and reduced survival rates. Conclusions Our study provides the first comprehensive evidence that m6A-modified circMARK2 contributes to WT progression by enhancing LIN28B mRNA stability, promoting cellular aggressiveness. CircMARK2 emerges as a potential biomarker for prognosis and a promising target for therapeutic intervention in WT, underscoring the clinical relevance of m6A modification in pediatric renal cancer.

Abstract Background Pancreatic cancer (PC) is one of the most malignant cancers with highly aggressiveness and poor prognosis. N6-methyladenosine (m6A) have been indicated to be involved in PC development. Glucan Branching Enzyme 1 (GBE1) is mainly involved in cell glycogen metabolism. However, the function of GBE1 and Whether GBE1 occurs m6A modification in PC progression remains to be illustrated. Methods The clinical prognosis of GBE1 was analyzed through online platform. The expression of GBE1 was obtained from online platform and then verified in normal and PC cell lines. Lentivirus was used to generated GBE1 stable-overexpression or knockdown PC cells. Cell Counting Kit (CCK-8), colony formation assay, sphere formation assay and flow cytometry assay were conducted to analyze cell proliferation and stemness ability in vitro. Subcutaneous and orthotopic mouse models were used to verify the function of GBE1 in vivo. RNA immunoprecipitation (RIP) assay, RNA stability experiment and western blots were conducted to explore the molecular regulation of GBE1 in PC. Results GBE1 was significantly upregulated in PC and associated with poor prognosis of PC patients. Functionally, GBE1 overexpression facilitated PC cell proliferation and stemness-like properties, while knockdown of GBE1 attenuated the malignancy of PC cells. Importantly, we found the m6A modification of GBE1 RNA, and WTAP and IGF2BP3 was revealed as the m6A regulators to increase GBE1 mRNA stability and expression. Furthermore, c-Myc was discovered as a downstream gene of GBE1 and functional rescue experiments showed that overexpression of c-Myc could rescue GBE1 knockdown-induced PC cell growth inhibition. Conclusions Our study uncovered the oncogenic role of GBE1/c-Myc axis in PC progression and revealed WTAP/IGF2BP3-mediated m6A modification of GBE1, which highlight the potential application of GBE1 in the targeted therapy of PC.

Abstract Background Wilms tumor is the most prevalent embryonal kidney malignancy in children worldwide. Previous genome-wide association study (GWAS) identified that LIM domain only 1 (LMO1) gene polymorphisms affected the susceptibility to develop certain tumor types. Apart from LMO1, the LMO gene family members also include LMO2-4, each of which has oncogenic potential. Methods We conducted this five-center case‒control study to assess the correlations between single nucleotide polymorphisms in LMO family genes and Wilms tumor susceptibility. Odds ratios and 95% confidence intervals were calculated to evaluate the strength of the association. Results We found LMO1 rs2168101 G > T and rs11603024 C > T as well as LMO2 rs7933499 G > A were significantly associated with Wilms tumor risk. Stratified analysis demonstrated a protective role of rs2168101 GT/TT genotypes against Wilms tumor in the subgroups of age ≤ 18 months, males and clinical stages I/II compared to the rs2168101 GG genotype. Nevertheless, carriers with the rs11603024 TT genotype were more likely to have an increased risk of Wilms tumor than those with rs11603024 CC/CT genotypes in age > 18 months. And the rs11603024 was identified as a protective polymorphism for reducing the risk of Wilms tumor in the sex- and gender- subgroup. Likewise, carriers with the rs7933499 GA/AA genotypes were at significantly elevated risk of Wilms tumor in age ≤ 18 months and clinical stages I/II. Conclusion Overall, our study identified the importance of LMO family gene polymorphisms on Wilms tumor susceptibility in Chinese children. Further investigations are needed to validate our conclusions. Graphical Abstract

Abstract Industrial enterprises are major sources of contaminants, making their regulation vital for sustainable development. Tracking contaminant generation at the firm-level is challenging due to enterprise heterogeneity and the lack of a universal estimation method. This study addresses the issue by focusing on hazardous waste (HW), which is difficult to monitor automatically. We developed a data-driven methodology to predict HW generation using wastewater big data which is grounded in the availability of this data with widespread application of automatic sensors and the logical assumption that a correlation exists between wastewater and HW generation. We created a generic framework that used representative variables from diverse sectors, exploited a data-balance algorithm to address long-tail data distribution, and incorporated causal discovery to screen features and improve computation efficiency. Our method was tested on 1024 enterprises across 10 sectors in Jiangsu, China, demonstrating high fidelity (R² = 0.87) in predicting HW generation with 4,260,593 daily wastewater data.

Abstract Background Long noncoding RNAs (lncRNAs) are implicated in the initiation and progression of diffuse large B-cell lymphoma (DLBCL). Small nucleolar RNA host gene 20 (SNHG20) has been recognized as a critical lncRNA in multiple human cancers. However, the role of SNHG20 and its underlying mechanism in DLBCL are still unclear. Methods The expression levels of SNHG20, c-MYC, β-catenin, and ubiquitin-specific peptidase 14 (USP14) were measured by reverse transcription-quantitative polymerase chain reaction (RT‒qPCR) and immunoblotting. Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2′-deoxyuridine (EdU) incorporation, and flow cytometry assays were used to assess the proliferation and apoptosis of DLBCL cells. The transcriptional regulation of SNHG20 by c-MYC was confirmed by a luciferase reporter assay and RNA immunoprecipitation. The interaction between USP14 and β-catenin was demonstrated using coimmunoprecipitation. A subcutaneous xenograft model was constructed to determine the role of SNHG20 in vivo. Results In the present study, we found that SNHG20 expression was upregulated in DLBCL cell lines and tissues compared to their normal counterparts. SNHG20 knockdown prominently reduced the proliferation and induced the apoptosis of U2932 and OCI-LY3 cells. However, SNHG20 overexpression increased the proliferation and apoptosis resistance of DLBCL cells. Mechanistically, the expression of SNHG20 was positively regulated by c-MYC in DLBCL cells. C-MYC directly bound to the promoter of SNHG20 to activate its transcription. SNHG20 was expressed mainly in the cytosol in DLBCL cells. SNHG20 silencing did not impact USP14 expression but markedly decreased the level of β-catenin, the substrate of USP14, in DLBCL cells. USP14 overexpression increased the β-catenin level, and this increase was attenuated by SNHG20 knockdown. Treatment with the proteasome inhibitor MG132 abolished SNHG20 knockdown-induced β-catenin downregulation. Moreover, SNHG20 silencing reduced the half-life but increased the ubiquitination of β-catenin in DLBCL cells. SNHG20 knockdown weakened the interaction between both endogenous and exogenous USP14 and β-catenin. In turn, SNHG20 overexpression increased the c-MYC level, and this increase was attenuated by β-catenin knockdown. Importantly, β-catenin knockdown attenuated the SNHG20-mediated increase in DLBCL cell proliferation in vitro and tumour growth in vivo. Conclusions Taken together, our results suggested that c-MYC-activated SNHG20 accelerated the proliferation and increased the apoptosis resistance of DLBCL cells via USP14-mediated deubiquitination of β-catenin. The c-MYC/SNHG20 positive feedback loop may be a new target for anti-DLBCL treatment.

Abstract To improve the understanding of potential pathological mechanisms of macular edema (ME), we try to discover biomarker candidates related to ME caused by diabetic retinopathy (DR) and retinal vein occlusion (RVO) in spectral-domain optical coherence tomography images by means of deep learning (DL). 32 eyes of 26 subjects with non-proliferative DR (NPDR), 77 eyes of 61 subjects with proliferative DR (PDR), 120 eyes of 116 subjects with branch RVO (BRVO), and 17 eyes of 15 subjects with central RVO (CRVO) were collected. A DL model was implemented to guide biomarker candidate discovery. The disorganization of the retinal outer layers (DROL), i.e., the gray value of the retinal tissues between the external limiting membrane (ELM) and retinal pigment epithelium (RPE), the disrupted and obscured rate of the ELM, ellipsoid zone (EZ), and RPE, was measured. In addition, the occurrence, number, volume, and projected area of hyperreflective foci (HRF) were recorded. ELM, EZ, and RPE are more likely to be obscured in RVO group and HRFs are observed more frequently in DR group (all P ≤ 0.001). In conclusion, the features of DROL and HRF can be possible biomarkers related to ME caused by DR and RVO in OCT modality.