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Bailong Hou,1,* Ying Zhou,2,* Wei Wang,1 Weifeng Shen,1 Qinlong Yu,1 Minjie Mao,1 Siheng Wang,1 Wenxiu Ai,3 Fangyou Yu,2,3 Pingyang Shao1 1Department of Clinical Laboratory Medicine, The First Hospital of Jiaxing, The Affiliated Hospital of Jiaxing University, Jiaxing, 314000, People’s Republic of China; 2Department of Clinical Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200000, People’s Republic of China; 3Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pingyang Shao, Department of Clinical Laboratory Medicine, The First Hospital of Jiaxing, The Affiliated Hospital of Jiaxing University, Jiaxing, 314000, People’s Republic of China, Email spy202001@163.com Fangyou Yu, Department of Clinical Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200000, People’s Republic of China, Email wzjxyfy@163.comIntroduction: This study aimed to investigate the emergence and characteristics of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains that demonstrate resistance to multiple antibiotics, including aminoglycosides and tigecycline, in a Chinese hospital.Methods: A group of ten CRKP strains were collected from the nine patients in a Chinese hospital. Antimicrobial Susceptibility Testing (AST) and phenotypic inhibition assays precisely assess bacterial antibiotic resistance. Real-time quantitative PCR (RT-qPCR) was used to analyze the mRNA levels of efflux pump genes (acrA/acrB and oqxA/oqxB) and the regulatory gene (ramA). The core-genome tree and PFGE patterns were analyzed to assess the clonal and horizontal transfer expansion of the strains. Whole-genome sequencing was performed on a clinical isolate of K. pneumoniae named Kpn20 to identify key resistance genes and antimicrobial resistance islands (ARI).Results: The CRKP strains showed high resistance to carbapenems, aminoglycosides (CLSI, 2024), and tigecycline (EUCAST, 2024). The mRNA expression levels of efflux pump genes and regulatory genes were detected by RT-qPCR. All 10 isolates had significant differences compared to the control group of ATCC13883. The core-genome tree and PFGE patterns revealed five clusters, indicating clonal and horizontal transfer expansion. Three key resistance genes (blaoxa-232, blaCTX-M-15, and rmtF) were observed in the K. pneumoniae clinical isolate Kpn20. Mobile antibiotic resistance islands were identified containing blaCTX-M-15 and rmtF, with multiple insertion sequences and transposons present. The coexistence of blaoxa-232 and rmtF in a high-risk K. pneumoniae strain was reported. Conjugation assay was utilized to investigate the transferability of blaoxa-232-encoding plasmids horizontally.Conclusion: The study highlights the emergence of ST15-KL112 high-risk CRKP strains with multidrug resistance, including to aminoglycosides and tigecycline. The presence of mobile ARI and clonal and horizontal transfer expansion of strains indicate the threat of transmission of these strains. Future research is needed to assess the prevalence of such isolates and develop effective control measures.Keywords: blaOXA-232, rmtF, Klebsiella pneumoniae, carbapenemase, plasmid

Qiong Wu,1,* Shiying An,1,* RueyJyh Lee,1 Dongwen Gao,2 Yinyifan Zhou,1 Longping Peng,1 Chunrui Hu,1 Lei Yao,3 Chang Zhou,4 Li Zhou,5 Junjie Gao,6 Min Cao,1 Meijiao Mao,1 Guanghao Li,1 Bing Deng,1 Yingjia Xu,4 Youhua Wang1 1Department of Cardiology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Department of Ultrasound, Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Department of Cardiology, Shanghai Fifth People’s Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China; 5Department of Cardiology, Shanghai Jiading Nanxiang Hospital, Shanghai, People’s Republic of China; 6Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingjia Xu, Shanghai Fifth People’s Hospital, Fudan University, Minhang District, 128 Ruili Road, Shanghai, 200240, People’s Republic of China, Tel +862164308151, Email xuyingjia@5thhospital.com Youhua Wang, Department of cardiology, Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Xunhui, 725 South Wan-Ping Road, Shanghai, 200032, People’s Republic of China, Tel +862164385700, Email doctorwyh@163.comBackground: Dilated cardiomyopathy (DCM) is a severe heterogeneous cardiomyopathy characterized by cardiac enlargement and declining heart function, often leading to refractory heart failure and life-threatening outcomes, particularly prevalent in China. The challenge lies in the scarcity of targeted therapies with substantial efficacy for DCM. Additionally, traditional anti-heart failure drugs are constrained due to hypotension propensity or limited symptom improvement. Kuoxin Formula (KXF), internally endorsed at Longhua Hospital, demonstrates clear biological evidence for enhancing cardiac function and myocardial remodeling. Previous clinical studies suggest its potential to enhance patients’ quality of life. This trial aims to further evaluate KXF’s safety and efficacy in managing DCM-related heart failure.Methods: This prospective, randomized, double-blind, placebo-controlled, multicenter trial aims to recruit 230 DCM patients from five centers. Participants will be randomly assigned to either KXF or placebo for 12 weeks, with careful monitoring of key indicators and adverse events. The primary outcome measures the proportion of patients with NT-proBNP reduction exceeding 30%. Secondary outcomes include New York Heart Association functional classification, Traditional Chinese Medicine syndrome scores, 6-minute walk test, Lee’s heart failure score, and Minnesota Heart Failure Quality of Life Scale score. Ventricular remodeling will be assessed using cardiac ultrasound and ELISA. Safety metrics and adverse events will be meticulously recorded.Discussion: This study will be the first multicentered research conducted in China that utilizes a randomized, double-blind, placebo-controlled design to investigate the use of TCM in the treatment of DCM. It seeks to develop new theoretical frameworks and provide solid clinical data to support the integration of TCM and modern medicine in treating heart failure in DCM patients.Trial Registration: China Clinical Trial Registry, ChiCTR2300068937. Registered on March 1, 2023. https://www.chictr.org.cn/bin/project/edit?pid=190926.Keywords: dilated cardiomyopathy, heart failure, Kuoxin Formula, traditional Chinese medicine, clinical trials

Kunlin Guo,* Mingjie Mao,* Susu Zhang, Shiqin Xu, Liping Zhao, Xian Wang, Shanwu Feng Department of Anesthesiology, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xian Wang; Shanwu Feng, Department of Anesthesiology, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, No. 123, Mochou Road, Tianfei Lane, Nanjing, Jiangsu Province, 210004, People’s Republic of China, Tel +86-25-13770723174 ; +86-25-13921426351, Fax +82-25-52226530, Email wangxian2002@126.com; iamfsw@163.comBackground: Allopregnanolone is a kind of neuroactive steroid or neurosteroid in the central nervous system that acts as an endogenenous GABAA receptor positive modulator. However, at present, no comprehensive bibliometric analysis regarding allopregnanolone research is available. In our study, we intend to analyze the research trends and hot spots related to allopregnanolone in the past 20 years.Methods: We searched for allopregnanolone related articles and reviews between 2004 and 2023 from the Web of Science Core Collection database. Then, the bibliometric analysis was conducted using VOSviewer, CiteSpace, Microsoft Excel 2019, as well as the online bibliometric analysis platform (http://bibliometric.com/).Results: A total of 1841 eligible publications were identified. The number of annual publications and citations was generally on the rise. Among countries, the United States ranked first in overall publications, citations, international cooperation, and the number of research institutions. The University of North Carolina was the most active institution, conducting numerous preclinical and clinical work that focusing on allopregnanolone treatment for diverse psychiatric or neurologic disorders. As for authors, Dr. Frye CA, Morrow AL, and Pinna G were identified as the top three prolific scholars due to their great publications and citations. Based on the publication clusters and citation bursts analysis, the keyword co-occurrence network, the strongest citation bursts, and co-cited references analysis, the hot spots in recent years included “depression”, “postpartum depression”, “GABAA receptor”, and so on.Conclusion: Allopregnanolone is still a popular area of research, and the United States leads the way in this area. Dr. Frye CA, Morrow AL, Pinna G, and their teams contributed greatly to the mechanism study and translation study of allopregnanolone. The use of allopregnanolone for the treatment of psychiatric or neurologic disorders, especially postpartum depression, is the current hot spot. However, the underlying mechanisms of anti-depression are still not clear, deserving more in-depth research.Keywords: allopregnanolone, VOSviewer, CiteSpace, bibliometric analysis, research trend

Xiaoqin Niu, Bolong Hou, Lunyun Yang, Wei Wang, Qinlong Yu, Minjie Mao, Weifeng Shen Department of Clinical Laboratory, The First Hospital of Jiaxing, The Affiliated Hospital of Jiaxing University, Jiaxing, 314000, People’s Republic of ChinaCorrespondence: Weifeng Shen, Department of Clinical Laboratory, The First Hospital of Jiaxing, The Affiliated Hospital of Jiaxing University, No. 1882, Zhonghuan South Road, Nanhu District, Jiaxing, Zhejiang, 314000, People’s Republic of China, Tel +86-18868345828, Email jyzhy526@163.comBackground: Urinary tract infections (UTIs) and the antibiotic resistance of pathogenic bacteria pose severe threats to public health in the current healthcare environment.Objective: The purpose of this study was to assess the frequency distribution of bacterial pathogens causing UTIs as well as the characteristics of antibiotic susceptibility and resistance.Methods: The retrospective study was conducted on 32,391 samples of midstream urine culture from January 1, 2020, to December 31, 2022, in Jiaxing. Bacteria were cultivated on blood agar and identified using MALDI-TOF, and their susceptibility to different antibiotics was assessed using the Kirby-Bauer disk diffusion method and drug sensitivity reaction cards. The SPSS 22 software was used for data analysis. Bivariate logistic regression was used to analyze the risk factors for multidrug resistance.Results: The total number of positive growth samples was 5378 (16.6%), including 3206 females (59.6%) and 2172 males (40.4%). The four most common urinary pathogens were Escherichia coli (39.2%), Enterococcus faecalis (12.4%), Klebsiella pneumoniae (7.6%), and Enterococcus faecium (7.6%). As far as antibiotic resistance was concerned, Escherichia coli had a greater than 50% resistance rate to ampicillin (76.1%), ciprofloxacin (58.6%), and levofloxacin (51.2%). The multidrug resistance rate was high (41.8%). Low levels of resistance were seen to ertapenem (0.1%), imipenem (0.7%), meropenem (0.7%), piperacillin/tazobactam (0.7%), and nitrofurantoin (1.8%). Klebsiella pneumoniae was highly sensitive to ertapenem (100%). The resistance rates to nitrofurantoin, ceftriaxone, and ciprofloxacin were 37.4%, 37.1%, and 35.1%, respectively. Up to 41% of Escherichia coli strains and 26% of Klebsiella pneumoniae strains produced extended-spectrum lactamases (ESBL). Two species of enterococci were highly sensitive to tigecycline and linezolid (100%), and a small number of norvancomycin-resistant strains (0.2%/two strains) were found.Conclusion: Escherichia coli and Enterococcus faecium were the most common urinary pathogens in this study. The isolated pathogens showed different sensitivity patterns. Antibiotics should be selected reasonably according to the sensitivity mode of pathogenic bacteria to effectively treat and prevent urinary tract infections.Keywords: antibiotic resistance, urinary tract infections, pathogenic bacteria, urine culture

Xianyu Zhang, Min Mao, Zhong Zuo Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Zhong Zuo, Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Email zuozhong@hospital.cqmu.edu.cnPurpose: To establish an in vitro lipotoxicity model with mouse cardiomyocytes (MCMs) and investigate the molecular mechanism of the peroxisome proliferator-activated receptors (PPAR) signaling on mitochondrial energy metabolism disorder and cellular injury in diabetic cardiomyopathy (DCM).Methods: Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the differentially expressed genes (DEGs) of DCM. CCK-8 method was used to detect the proliferation inhibition effect of palmitate (PA) on MCMs. Oil red O staining and mRNA levels of CD36 were used to verify intracellular lipid accumulation. DCFH-DA method was used to determine the content of intracellular reactive oxygen species (ROS), and ATP levels were detected by the ATP Detection Kit. Transmission electron microscope (TEM) was used to observe the mitochondrial structure. Western blot was used to detect the expression levels of PPARα, PPARγ, P-mTOR, mTOR, PGC-1α, UCP2, and BNP. In addition, the expression of PPARγ was also detected by cellular immunofluorescence staining. BNP levels were detected by qRT-PCR and the ELISA Kit.Results: KEGG pathway analysis combined with GO analysis has shown that PPAR signaling played a significant regulatory role in mitochondrial biogenesis and fatty acid metabolism in DCM. Then, MCMs stimulated with PA for 24 h were selected as an in vitro lipotoxicity model. PA decreased cell viability, cell membrane shrinkage, and lipid accumulation. Meanwhile, PA-induced increase in cellular ROS led to ATP generation reduction and mitochondrial damage. Furthermore, the expression levels of p-mTOR- PPARα/γ were decreased, and the expressions of PGC-1α and UCP2 were increased. The levels of BNP were elevated, demonstrating PA impaired cardiomyocytes.Conclusion: Mitochondrial energy metabolism obstacle and cell injury appeared in cardiac lipotoxicity of DCM, associated with lipid accumulation and increased ROS, indicating a crosstalk with the PPAR pathway mediated mechanism.Keywords: diabetic cardiomyopathy, lipotoxicity, mitochondrial energy metabolism, cell damage, PPAR

Jing Ding,1 Xudong Li,1 Jun Ge,1 Yuanqian Gong,1 Ya Zhou,1 Juan Xiao,1 Qin Yang,2 Jing Chen,1 Mian Mao3 1Department of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China; 2Department of Oncology, Bazhong Central Hospital, Bazhong, Sichuan, People’s Republic of China; 3Department of Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Mian Mao, Tel/Fax +86-28-85420311, Email maokefei_0703@163.comPurpose: We aimed to investigate the clinicopathological characteristics and survival risk factors in small cell lung cancer (SCLC) patients with preexisting type 2 diabetes mellitus (preDM).Patients and Methods: All patients with SCLC admitted to our hospital between January 2013 and August 2018 were followed up until August 2020 and retrospectively analyzed. Clinical characteristics of SCLC patients with and without preDM were extracted. Cox proportional hazards models were conducted to identify potential independent prognostic factors.Results: Of 628 eligible individuals, 88 individuals had preDM. preDM was independently significantly associated with distant metastasis in all SCLC patients (p =0.016, OR=1.80, 95% CI 1.11– 2.91), while preDM did not affect the outcome of SCLC patients (p=0.803, HR=1.04, 95% CI 0.79– 1.36) by multivariate analysis. In the preDM group, the median overall survival (OS) was shorter in the insulin group than in the non insulin group (13.93 months versus 21.77 months, p=0.024). Multivariate analysis identified that insulin treatment was an independent unfavorable factor associated with OS (p =0.009, HR=2.10, 95% CI 1.19– 3.64). In addition, poorer performance status (PS) and liver metastasis were also independent unfavorable prognostic factors (all p< 0.01), while thoracic therapy significantly improved OS and decreased mortality risk in diabetic patients with SCLC (p< 0.05).Conclusion: preDM may promote distant metastasis of SCLC while it is insulin therapy and not preDM which adversely affects the prognosis of SCLC patients. These findings indicate that enhancing blood glucose control and reducing insulin analog use may be essential to the improvement of the long-term survival of the diabetic population with SCLC.Keywords: type 2 diabetes mellitus, small cell lung cancer, distant metastasis, insulin, overall survival

Long Liang,1,&ast; Taiyu Chen,2,&ast; Tao Ren,3 Mian Mao,4 Keli Wang,5 Chunhan Tang,2 Juan Xiao,1 Hongyuan Jia,1 Wenli Chen,1 Qifeng Wang,1 Tao Li1 1Department of Radiation Oncology, Sichuan Cancer Hospital and Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Radiation Oncology Key Laboratory of Sichuan Province, Chengdu, People’s Republic of China; 2Clinical Medical College of Chengdu Medical College, Chengdu, 610500, People’s Republic of China; 3Oncology Department, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, People’s Republic of China; 4Department of Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 5Clinical Medical College of Southwest Medical University, Luzhou, 646000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Li Tel/Fax +86 2885420173Email litaoxmf@126.comAbstract: Pulmonary carcinosarcoma (PC) is a rare and highly malignant type of non-small cell lung cancer (NSCLC) that is insensitive to radiotherapy and chemotherapy and has a poor prognosis. Here, we report a case of an 88-year-old patient with inoperable PC and a history of cerebral infarction who was treated with first-line anlotinib combined with stereotactic body radiation therapy (SBRT). The therapeutic response has sustained for 10 months. Our work suggests that SBRT combined with anlotinib may be a safe and effective treatment strategy for octogenarians with PC.Keywords: pulmonary carcinosarcoma, SBRT, anlotini

Long Liang,1 Mian Mao,2 Lei Wu,1 Taiyu Chen,3 Jiahua Lyu,1 Qifeng Wang,1 Tao Li1 1Department of Radiation Oncology, Sichuan Cancer Hospital and Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Radiation Oncology Key Laboratory of Sichuan Province, Chengdu, People’s Republic of China; 2Department of Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Centre, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Clinical Medical College of Chengdu Medical College, Chengdu, 610500, People’s Republic of ChinaCorrespondence: Tao LiDepartment of Radiation Oncology, Sichuan Cancer Hospital Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, No. 55, 4th Section of Renmin South Road, Chengdu, People’s Republic of ChinaEmail litaoxmf@126.comAbstract: EML4-ALK rearrangement is common in lung adenocarcinoma. The ALK inhibitors remarkably inhibit lung adenocarcinoma and reveal long-term beneficial effects in several patients. Advanced genetic testing technology reveals that EML4-ALK rearrangement has been observed in patients with lung squamous cell carcinoma. In the present study, we report a case of a 53-year-old patient with EML4-ALK rearranged in lung squamous carcinoma; PET/CT scan revealed brain and multiple bone metastases. First-line ALK-TKI combined with local stereotactic body radiation therapy indicated progression-free survival of 9 months. After progressive disease, treatment was switched to lorlatinib, with little efficacy and a total overall survival of 11 months. The emergence of drug resistance revealed that the genetic test result was EML4-ALK fusion (V3a/b variants), indicating a poor prognosis. In this study, we analyzed the treatment efficacy of ALK inhibitors and provided a research basis for the treatment of EML4-ALK rearranged in lung squamous cell carcinoma patients.Keywords: lung squamous cell carcinoma, EML4-ALK rearrangement, alectinib, lorlatinib, SBRT

Mengying Mao,1– 3 Wenjie Zhang,2– 4 Zhengwei Huang,1– 3 Jing Huang,1– 3 Jia Wang,1– 3 Weiping Li,1– 3 Shensheng Gu1– 3 1Department of Endodontics, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2National Clinical Research Center for Oral Diseases, Shanghai, People’s Republic of China; 3Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, People’s Republic of China; 4Department of Prosthodontics, Oral Bioengineering and Regenerative Medicine Lab, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Shensheng GuDepartment of Endodontics, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, People’s Republic of ChinaEmail gss2m9h@163.comWeiping LiShanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, People’s Republic of ChinaEmail wp_li95814@163.comIntroduction: Dental caries is a biofilm-dependent disease that largely relies on the ability of Streptococcus mutans to synthesize exopolysaccharide matrix. Graphene oxide-based metal nanomaterials, as the derivatives of graphene, are potent agents against pathogens by their impressive antibacterial and anti-biofilm biofunctions. Previously, we fabricated the novel graphene oxide-copper nanocomposites (GO-Cu), maintaining a long-term release of copper nanoparticles. Here, the biofunctionalization of GO-Cu nanocomposites against cariogenic S. mutans is investigated.Methods: Growth curve observation and colony forming units counting were applied to detect the antibacterial effect of GO-Cu nanocomposites on S. mutans. Scanning electron microscopy and the crystal violet assay were used to detect nanocomposite effects on biofilm forming ability. The production and distribution of exopolysaccharides within biofilm was analyzed and the expression of genes required for biofilm formation was explored. Moreover, the regulatory landscape of GO-Cu nanocomposites on S. mutans pathogenicity was probed.Results: It has been found that GO-Gu nanocomposites were antibacterial to S. mutans and 10 μg/mL GO-Cu nanocomposites could inhibit the bacteria bioactivity instead of killing them. The biomass of S. mutans biofilm was significantly reduced when treated with 10 μg/mL GO-Cu nanocomposites. Also, 10 μg/mL GO-Cu nanocomposites could alter the biofilm architecture and impair exopolysaccharides production and distribution, and dysregulated the expression of exopolysaccharide-associated genes.Conclusion: In all, we found low-dose GO-Cu nanocomposites could disrupt exopolysaccharide matrix assembly and further impair optimal biofilm development with minimal cytotoxicity. Therefore, GO-Cu nanocomposites can open up a new avenue for the development of alternative anti-caries biomaterials.Keywords: graphene oxide-copper nanocomposites, anti-biofilm, Streptococcus mutans, exopolysaccharides, dental caries

Zhenhui Zhou,1,&ast; Meng Mao,2,&ast; Xuechun Cai,1 Wei Zhu,1 Jie Sun3 1Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Anesthesiology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 3Department of Anesthesiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie SunDepartment of Anesthesiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, People’s Republic of ChinaTel +8615895971012Email dgsunjie@hotmail.comWei ZhuDepartment of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210009, People’s Republic of ChinaTel +8618905182820Email zhuweijsph@163.comPurpose: The mechanisms of remifentanil-induced postoperative hyperalgesia (RIPH) remain unclear. Store-operated calcium channels (SOCCs) are mainly comprised of stromal interaction molecules 1 (STIM1) and pore-forming subunits (Orai1). They were found to take a pivotal part in Ca2+-dependent procedures and involved in the development of central sensitization and pain. Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα), regulated by Ca2+/calmodulin complex, has been shown to have a crucial role in RIPH. This study aims to determine whether SOCCs contribute to RIPH via activating CaMKIIα.Materials and Methods: Intra-operative infusion of remifentanil (1.0 μg kg− 1 min− 1, 60 min) was used to establish a RIPH rat model. The SOCCs blocker (YM-58483) was applied intrathecally to confirm the results. Animal behavioral tests including paw withdrawal thermal latency (PWTL) and paw withdrawal mechanical threshold (PWMT) were performed at − 24, 2, 6, 24, 48 h after incision and remifentanil treatments. The protein expression of STIM1, Orai1, CaMKIIα, and p-CaMKIIα was assayed with Western blot, and the number of STIM1 and Orai1 positive cells was shown by immunofluorescence.Results: Remifentanil administration significantly induced postoperative mechanical and thermal hyperalgesia, as well as increased STIM1 and Orai1 protein expression in the spinal dorsal horn. Furthermore, the intrathecal administration of YM-58483 effectively alleviated remifentanil-induced postoperative mechanical and thermal hyperalgesia according to the behavioral tests. In addition, YM-58483 suppressed the phosphorylation of CaMKIIα but had no effect on the expression of STIM1 and Orai1.Conclusion: Our study demonstrated that SOCCs are involved in RIPH. The over-expressed STIM1 and Orai1 in the spinal cord contribute to RIPH via mediating the phosphorylation of CaMKIIα. Blockade of SOCCs may provide an effective therapeutic approach for RIPH.Keywords: remifentanil, hyperalgesia, SOCCs, CaMKII&#x03B1

Lin Zhang,1,2,* Juan Ye,2– 4,* Qiuyun Luo,2 Miaohuan Kuang,1 Minjie Mao,1 Shuqin Dai,1 Xueping Wang1 1Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, People’s Republic of China; 2Department of Experimental Research, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China; 3Department of Infectious Diseases, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of China; 4Department of Oncology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xueping Wang; Shuqin Dai Tel/ Fax +86 20 8734 3438Email wangxuep@sysucc.org.cn; daishq@sysucc.org.cnBackground and Objective: Tools for the non-invasive assessment of colorectal cancer (CRC) prognosis have profound significance. Although plasma coagulation tests have been investigated in a variety of tumours, the prognostic value of the prothrombin time (PT) and activated partial thromboplastin time (APTT) in CRC has not been discussed. Our study objective was to explore the prognostic significance of preoperative PT and APTT in CRC patients.Patients and Methods: A retrospective analysis of preoperative coagulation indexes including PT, PTA, INR, APTT, FIB, TT, PLT, NLR and PLR in 250 patients with CRC was performed. Kaplan–Meier and multivariate Cox regression analysis were used to demonstrate the prognostic value of these preoperative coagulation indexes.Results: The overall survival (OS, p< 0.05) and disease-free survival (DFS, p< 0.05) of CRC patients with lower PT and APTT levels were significantly prolonged. Based on univariate analysis, PT levels (p< 0.001, p< 0.001), PTA levels (p=0.001, p=0.001), APTT levels (p=0.001, p< 0.001), INR levels (p< 0.001, p< 0.001), fibrinogen levels (p=0.032, p=0.036), tumour status (p=0.005, p=0.003), nodal status (p< 0.001, p< 0.001), metastasis status (p< 0.001, p< 0.001) and TNM stages (p< 0.001, p< 0.001) were remarkably associated with DFS and OS. Multivariate Cox regression analysis suggested that the levels of PT (HR: 2.699, p=0.006) and APTT (HR: 1.942, p=0.015), metastasis status (HR: 2.091, p= 0.015) and TNM stage (HR: 7.086, p=0.006) were independent predictors of survival in CRC. In the whole cohort, the enrolled patients were then divided into three groups according to their PT and APTT levels. The OS and DFS differed notably among the low-risk (PT< 11.85 sec and APTT< 25.85 sec), medium-risk (PT≥ 11.85 sec or APTT≥ 25.85 sec), and high-risk (PT≥ 11.85 sec and APTT≥ 25.85 sec) groups.Conclusion: Elevated levels of preoperative PT and APTT were predictors of poor outcomes in CRC patients. Moreover, the combination of preoperative PT and APTT can be a new prognostic stratification approach for more precise clinical staging of CRC.Keywords: PT, APTT, CRC, prognosis

Xiaojiao Zheng, Kejun Xu, Linyan Zhu, Meiya Mao, Fubin Zhang, Lining Cui Department of Obstetrics and Gynecology, Ningbo First Hospital, Ningbo, Zhejiang 315035, People’s Republic of ChinaCorrespondence: Lining CuiDepartment of Obstetrics and Gynecology, Ningbo First Hospital, 59 Liuting Street, Haishu District, Ningbo, Zhejiang 315035, People’s Republic of ChinaEmail 1935148739@qq.comBackground: miRNA expression acts as a potential biomarker in many diseases including endometrial carcinoma (EC). miR-486-5p dysregulation is observed in several tumor types, but the roles of miR-486-5p in EC are hardly ever studied.Objective: This study aimed to analyze the expression profile of miR-486-5p in tumor tissues and serum samples of patients with EC and explore the target prediction, function analysis and validation in immortal cell lines.Patients and Methods: A total of 42 freshly paired EC tissues, the corresponding adjacent non-neoplastic tissues and serum samples were also collected from patients with EC, and 42 matched normal serum samples were included as control group. The level of miR-486-5p expression was tested by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was determined by colony formation assay and CCK-8 assay. Furthermore, functional evaluation of miR-486-5p on migration was performed by wound-healing assay and invasion was estimated by transwell invasion assay. qRT-PCR, luciferase reporter assay and Western blotting (WB) were performed to verify the targeting of MARK1 by miR-486-5p.Results: miR-486-5p was significantly up-regulated in EC tissues and serum samples, promoting the proliferation, migration and invasive activities of EC cells by targeting MARK1.Conclusion: These data indicated miR-486-5p as a novel molecular biomarker for diagnosing and treating EC, and MARK1 might act as a critical and functional target of miR-486-5p with the implications on cell proliferation, migration and invasiveness of EC tumor cells.Keywords: endometrial carcinoma, miR-486-5p, MARK1, proliferation, migration, invasion

He Chen,1 Min Mao,2 Jing Jiang,1 Daling Zhu,2 Peiling Li11Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, People’s Republic of China; 2Department of Biopharmaceutical Sciences, Harbin Medical University, Daqing 163319, People’s Republic of ChinaBackground and objectives: Ovarian cancer is the most fatal primary malignancy among gynecological cancers. Circular RNAs (circRNAs) play an important role in the development of various cancers, but the functions of circRNAs in ovarian cancer development have not been studied. We aim to explore the function and mechanism of CDR1as in the progression of ovarian cancer and to provide a new target for the diagnosis and treatment of ovarian cancer.Methods: Ovarian cancer cell proliferation was assessed according to proliferating cell nuclear antigen (PCNA) and Ki67 protein expression levels and MTT and CCK8 assays. The migration ability of cells was detected by scratch-wound assays, and the invasion ability of the cells was determined by Transwell® assays. qRT-PCR and Western blotting were used to verify miRNA and protein expression.Results: CDR1as expression in ovarian tissues was significantly lower in ovarian cancer patients than in patients without ovarian cancer. CDR1as overexpression inhibited the proliferation, invasion and migration of ovarian cancer cells. Silencing CDR1as increased the expression of miR-135b-5p and decreased the expression of hypoxia-inducible factor 1-alpha inhibitor (HIF1AN), thus increasing the proliferation capacity of ovarian cancer cells.Conclusions: CDR1as, acting as a sponge of miR-135b-5p, promotes the expression of HIF1AN and therefore plays a role in tumor inhibition.Keywords: circular RNAs, CDR1as, ovarian cancer, miR-135b-5p, HIF1AN

Cong Chen,1,2 Shumin Huang,3 Aihua Huang,1,2 Yunlu Jia,1,2 Ji Wang,1,2 Misha Mao,1,2 Jichun Zhou,1,2 Linbo Wang1,2 1Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; 2Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China; 3Department of Pediatric Health Care, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China Background: Despite the considerable experience gained thus far using endoscopic technologies, the role of total endoscopic thyroidectomy (ET) for papillary thyroid cancer (PTC) remains controversial. We conducted a systematic review and meta-analysis to investigate the safety and effectiveness of total ET compared with conventional open thyroidectomy (OT) in PTC. Methods: A systematic search was conducted using the PubMed, Embase and Cochrane Library electronic databases up to March 2018. The quality of included studies was evaluated using the Newcastle–Ottawa Scale. Review Manager software version 5.3 was used for the meta-analysis. Results: Twelve studies including 2,672 patients were ultimately included in the systematic review and meta-analysis. ET was associated with longer operative time (P

Cong Chen,1,2 Shumin Huang,3 Aihua Huang,2,4 Yunlu Jia,1,2 Ji Wang,1,2 Zeqin Zhang,1,2 Misha Mao,1,2 Linbo Wang,1,2 Jichun Zhou1,2 1Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; 2Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China; 3The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China; 4Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China Background: Ductal carcinoma in situ with microinvasion (DCISM) represents ~1% of all breast cancer cases. Risk factors for lymph node (LN) metastasis and appropriate adjuvant therapy for DCISM are still widely debated. Methods: We retrieved DCISM data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results registry database (1998–2013). Chi-squared tests and logistic regression models were applied to investigate the potential risks of LN metastasis. Univariate and multivariate Cox proportional hazards regressions were performed to estimate the prognostic factors of DCISM. Survival outcomes were estimated using the Kaplan–Meier method. A 1:1 propensity score matching was used to minimize potential bias. Results: Overall, 6,219 patients with DCISM met our inclusion criteria. Younger age and higher grade disease were identified as risk factors for LN metastasis. In the multivariable analysis, LN metastasis and chemotherapy were prognostic factors for worse overall survival and breast cancer-specific survival. Furthermore, propensity score matching and subgroup analysis showed that chemotherapy may not be effective for DCISM patients. Conclusion: Younger patients with high-grade disease tend to have LN involved in DCISM. Adjuvant chemotherapy might not be necessary for patients with DCISM. Keywords: SEER database, breast cancer, ductal carcinoma in situ with microinvasion, adjuvant chemotherapy, lymphatic metastasis