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Qingru Niu,1– 3,* Chuanmiao Lin,1– 3,* Shuqing Yang,1– 3 Shuxuan Rong,1– 3 Junbin Wei,1– 3 Tingting Zhao,1– 3 Yingying Peng,1– 3 Zhilan Cheng,1– 3 Yunyi Xie,1– 3 Yan Wang1– 3 1Hospital of Stomatology, Guanghua School of Stomatology, Guangzhou, People’s Republic of China; 2Sun Yat-Sen University, Guangzhou, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunyi Xie; Yan Wang, Email xieyy59@mail2.sysu.edu.cn; wang93@mail.sysu.edu.cnPurpose: Periodontitis is a chronic infectious disease characterized by progressive inflammation and alveolar bone loss. Forkhead box O1 (FoxO1), an important regulator, plays a crucial role in maintaining bone homeostasis and regulating macrophage energy metabolism and osteogenic differentiation of mesenchymal stem cells (MSCs). In this study, FoxO1 was overexpressed into small extracellular vesicles (sEV) using engineering technology, and effects of FoxO1-overexpressed sEV on periodontal tissue regeneration as well as the underlying mechanisms were investigated.Methods: Human periodontal ligament stem cell (hPDLSCs)-derived sEV (hPDLSCs-sEV) were isolated using ultracentrifugation. They were then characterized using transmission electron microscopy, Nanosight, and Western blotting analyses. hPDLSCs were treated with hPDLSCs-sEV in vitro after stimulation with lipopolysaccharide, and osteogenesis was evaluated. The effect of hPDLSCs-sEV on the polarization phenotype of THP-1 macrophages was also evaluated. In addition, we measured the reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) production, mitochondrial characteristics, and metabolism of hPDLSCs and THP-1 cells. Experimental periodontitis was established in vivo in mice. HPDLSCs-sEV or phosphate-buffered saline (PBS) were injected into periodontal tissues for four weeks, and the maxillae were collected and assessed by micro-computed tomography, histological staining, and small animal in vivo imaging.Results: In vitro, FoxO1-overexpressed sEV promoted osteogenic differentiation of hPDLSCs in the inflammatory environment and polarized THP-1 cells from the M1 phenotype to the M2 phenotype. Furthermore, FoxO1-overexpressed sEV regulated the ROS level, ATP production, mitochondrial characteristics, and metabolism of hPDLSCs and THP-1 cells in the inflammatory environment. In the in vivo analyses, FoxO1-overexpressed sEV effectively promoted bone formation and inhibited inflammation.Conclusion: FoxO1-overexpressed sEV can regulate osteogenesis and immunomodulation. The ability of FoxO1-overexpressed sEV to regulate inflammation and osteogenesis can pave the way for the establishment of a therapeutic approach for periodontitis. Keywords: periodontal ligament stem cells, small extracellular vesicles, periodontitis, bone homeostasis, mitochondrial function

Kaifei Chu,1,2,* Jie Liu,2,* Xu Zhang,1,2 Minran Wang,1 Wanping Yu,1 Yuyue Chen,1 Lingling Xu,2 Geng Yang,1 Naru Zhang,1 Tiejun Zhao1,2 1Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, People’s Republic of China; 2College of Life Sciences, Zhejiang Normal University, Jinhua, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tiejun Zhao; Naru Zhang, Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, People’s Republic of China, Email tjzhao@hzcu.edu.cn; zhangnr@hzcu.edu.cnAbstract: Plant-derived exosome-like nanovesicles (PDNVs) are small nanoscale vesicles containing lipids, RNAs, proteins and some plant natural products secreted by plant cells. Over the last decade, PDNVs have garnered significant interest due to its exceptional therapeutic benefits in the treatment of various diseases. Herbal medicine, as a medicinal plant, plays an important role in the treatment of diseases including cancer. Especially in recent years, the function of herbal medicine derived exosome-like nanovesicles (HMDNVs) in the treatment of cancer has been widely concerned, and has become a research hotspot of nanomedicine. In this review, the biological characteristics, functions and the therapeutic advantages of PDNVs are reviewed, as well as the recent achievements and research progress of HMDNVs in cancer treatment, demonstrating its enormous promise as a cancer therapy, and new insights are provided for future research and development of anti-tumor drugs.Keywords: herbal medicine, plant-derived exosome-like nanovesicles, extracellular vesicles, cancer treatment, nanomedicine

Jingru Zhou,1 Yanjun Liu,2 Fang Yang,1 Meiling Jing,3 Xiaoli Zhong,1 Yanfen Wang,1 Yan Liu,1 Wenwen Ming,1 Huangyan Li,1 Tianxia Zhao,1 Lin He1 1Department of Nursing, Deyang People’s Hospital, Deyang, Sichuan, 618200, People’s Republic of China; 2Department of Infection, Mianzhu People’s Hospital, Mianzhu, Sichuan, 618000, People’s Republic of China; 3Department of Nursing, West China Hospital, Sichuan University, Chengdu, Sichuan, 610000, People’s Republic of ChinaCorrespondence: Lin He; Xiaoli Zhong, Email 2507148852@qq.com; 20943794@qq.comObjective: Sarcopenia is a common complication of COPD associated with an age-related reduction in skeletal muscle mass associated with decreased muscle strength and / or reduced mobility. The incidence of sarcopenia in patients with COPD is twice that of non-COPD patients and is associated with poor prognosis, this study aimed to investigate the influencing factors of sarcopenia in COPD patients.Methods: Selected studies from PubMed, Embase, Web of Science, Cochrane Library, Wanfang, Wanfang, CNKI, CBM, and Wanfang databases as of November 12023. Patients aged 18 were selected; data were then independently extracted by two reviewers using a standard data collection form.Results: In total, 17 articles reporting on 5408 patients were included. Age (OR = 1.083; 95% CI, 1.024– 1.145), ALB (OR = 0.752; 95% CI, 0.724– 0.780), BMI(OR = 0.701; 95% CI, 0.586– 0.838), smoking (OR = 1.859; 95% CI, 1.037– 3.334), diabetes (OR = 1.361; 95% CI, 1.095– 1.692), qi deficiency (OR = 9.883; 95% CI, 2.052, 47.593), GOLD C (OR =2.232; 95% CI, 1.866, 2.670) and GOLD D (OR = 2.195; 95% CI, 1.826– 2.637) were factors affecting muscle loss in COPD patients.Conclusion: Sarcopenia is more prevalent in patients with COPD. Age, body mass index, smoking, diabetes mellitus, qi deficiency, ALB, and GOLD grade were the contributing factors for sarcopenia in patients with chronic obstructive pulmonary disease. In the future, medical staff should not only pay attention to the early screening of sarcopenia in high-risk groups, but also provide relevant prevention information.Keywords: sarcopenia, chronic obstructive pulmonary disease, prevalence, risk factors, meta-analysis

Di Nie,1,2,&ast; Haozhi Ma,1,2,&ast; Guosheng Huang,1 Tianzeng Zhao,1 Wenxian Li1 1Thoracic Surgery Department, The First Affiliated Hospital of Nanyang Medical College, Nanyang, People’s Republic of China; 2Graduate Division Department, Xinxiang Medical University, Xinxiang, Chian&ast;These authors contributed equally to this workCorrespondence: Wenxian Li, Thoracic Surgery Department, The First Affiliated Hospital of Nanyang Medical College, Nanyang, People’s Republic of China, Tel +86-15565269994, Email 838525809@qq.comPurpose: This study aimed to examine the KAP of physicians regarding targeted drug therapy for lung cancer in China.Methods: This cross-sectional study enrolled physicians working in hospitals in Nanyang. A self-administered questionnaire was developed (Cronbach’s α=0.912) to collect the demographic information and KAP.Results: This study included 191 valid questionnaires. Most participants were male (70.2%) and aged 36– 50 (55.5%). The median knowledge score was 29 (24– 31) (/36, 80.6%), the mean attitude score was 42 (39– 44) (/50, 84.0%), and the mean practice score was 28 (26– 29) (/30, 93.3%), indicating sufficient knowledge, positive attitudes, and proactive practice. The female gender (OR=5.291, 95% CI: 1.426– 19.634, P=0.013), working in non-public tertiary hospitals (OR=0.053, 95% CI: 0.008– 0.360, P=0.003), and working in medical oncology (OR=10.764, 95% CI: 2.638– 43.922, P=0.001) were independently associated with adequate knowledge. Only the knowledge scores (OR=1.121, 95% CI: 1.036– 1.212, P=0.004) were independently associated with a positive attitude. Only the attitude scores (OR=1.895, 95% CI: 1.333– 2.694, P< 0.001) were independently associated with proactive practice.Conclusion: Physicians working in thoracic surgery, respiratory medicine, or medical oncology displayed sufficient knowledge, positive attitude, and proactive practice toward targeted therapy for lung cancer.Keywords: knowledge, attitude, practice, lung cancer, targeted therapy, physician

Yanlei Li,1,&ast; Meng Ge,2,&ast; Jinlong Tian,1,&ast; Jinlei Zhou,1,3 Yao Kang,1 Chen Xia,1 Haiyu Shao,1 Yongguang Wang,4 Yazeng Huang,1 Tingxiao Zhao1 1Center for Plastic & Reconstructive Surgery, Department of Orthopedics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of China; 2Department of Orthopedics, Hospital of Traditional Chinese Medicine of Xiaoshan District, Hangzhou, Zhejiang, People’s Republic of China; 3Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 4Department of Orthopedics, Linping Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tingxiao Zhao; Yazeng Huang, Center for Plastic & Reconstructive Surgery, Department of Orthopedics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Shangtang Road 158&num;, Hangzhou, Zhejiang, People’s Republic of China, Email spinezhaotingxiao@163.com; huangyazeng2007@163.comPurpose: Percutaneous endoscopic transforaminal lumbar interbody fusion (PE-TLIF) has become one of the most popular minimally invasive surgeries today. However, the issue of hidden blood loss (HBL) in this surgery has received little attention. This study aims to examine the HBL in PE-TLIF surgery and the effect of tranexamic acid (TXA) on blood loss.Methods: In our research, We conducted a retrospective analysis of 300 patients who underwent PE-TLIF from September 2019 to August 2023. They were divided into 2 groups based on whether they received intravenous TXA injection before surgery. The variables compared included: demographic data, pre-and postoperative hemoglobin (HB), hematocrit (HCT), platelets (PLT), red blood cells (RBC), total blood loss (TBL), visible blood loss (VBL), HBL, operation time, postoperative hospital stay, inflammatory markers, coagulation parameters, and adverse events.Results: Regarding demographic characteristics, besides the operation time, no significant differences were observed between the two groups. Compared with the control group, the TXA group showed a significant reduction trend in TBL, HBL, and VBL (P < 0.05). On the first day after surgery, there were significant differences in prothrombin (PT), activated partial thromboplastin time (APTT), and D-dimer (D-D) levels between the two groups. Similarly, HCT also found similar results on the third day after surgery. No adverse events occurred in either group.Conclusion: Research has found that there is a significant amount of HBL in patients undergoing PE-TLIF. Intravenous injection of TXA can safely and effectively reduce perioperative HBL and VBL. Additionally, compared to the control group, the TXA group shows a significant reduction in operation time.Keywords: percutaneous endoscopic transforaminal lumbar interbody fusion, tranexamic acid, total blood loss, visible blood loss, hidden blood loss

Hongying Huang, Jinchen Li, Jingyi Shen, Tong Zhao, Rong Xiao, Weiwei Ma School of Public Health, Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, People’s Republic of ChinaCorrespondence: Weiwei Ma, School of Public Health, Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, People’s Republic of China, Tel/Fax +86-10-83911651, Email weiweima@ccmu.edu.cnBackground and Objective: Cognitive dysfunction is highly prevalent in obese people, and food is a key factor in obesity, and dietary inflammatory index (DII) can reflect whether diet has anti-inflammatory or pro-inflammatory potential. In addition, dietary fatty acid consumption is linked to inflammation, obesity, and cognitive impairment. Erythrocyte membrane fatty acids can reflect dietary fatty acid intake. Our hypothesis was that erythrocyte membrane fatty acids might have a significant impact on the relationship between DII and cognition in obese individuals, and we designed experiments to test the hypothesis.Methods: In three villages in Beijing, we collected 579 respondents from individuals 45 to 75 years old and categorized them by body mass index. The Montreal Cognitive Assessment (MoCA) score and DII score was calculated and gas chromatography was used to measure the proportion of erythrocyte membrane fatty acids. The relationship between the DII score and cognition was examined using multiple linear regression and binary logistic regression. Mediation analysis can help to understand the causal chain between variables, deeply explore the internal relationship and mechanism of action between variables. So a multiple chain mediation model was developed to investigate the mediating factors between the DII score and cognitive association.Results: According to adjusted linear regression, higher DII scores were linked to lower MoCA scores in the obese group. The negative correlation between DII score and cognitive function score remains in binary linear regression. We discovered through mediation analysis that erythrocyte membrane fatty acids mediate the detrimental link between DII and cognitive function in obese individuals.Conclusion: We propose that higher DII scores in obese people are associated with a decline in cognitive function. In addition, this effect might be mediated via the fatty acids in the erythrocyte membrane.Keywords: mild cognitive impairment, dietary inflammatory index, obesity, fatty acids, chain mediation effect

Lin Zheng,1,&ast; Yusi Yang,2,&ast; Jie Liu,3 Tianliang Zhao,3 Xin Zhang,3 Lihua Chen3 1Department of Vascular Surgery, the Second Hospital, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 2Department of Cardiology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, 030032, People’s Republic of China; 3Department of Cardiac Surgery, the Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lihua Chen, The Second Hospital of Hebei Medical University, 215 Hepingxi Street, Shijiazhuang, 050000, People’s Republic of China, Tel +86 188 4679 1714, Fax +86 0311-87045297, Email lin0928@fjmu.edu.cnPurpose: Immune microenvironment plays an important role in aortic dissection (AD). Therefore, novel immune biomarkers may facilitate AD prevention, diagnosis, and treatment. This study aimed at mining key immune-related genes and relevant mechanisms involved in AD pathogenesis.Patients and Methods: Key immune cells in AD were identified by ssGESA algorithm. Next, genes associated with key immune cells were screened by weighted gene coexpression network analysis (WGCNA). Then hub immune genes were picked from protein-protein interaction network of overlapped genes from differential expression and WGCNA analyses by cytohubba plug-in. Their diagnostic potential was evaluated in two independent cohorts from GEO database. In addition, the expressions of hub immune genes were determined by quantitative RT-PCR, immunohistochemistry, and Western blotting in dissected and normal aortic tissues.Results: Activated B cells, CD56dim natural killer cells, eosinophils, gamma delta T cells, immature B cells, natural killer cells and type 17 T helper cells were identified as key immune cells in AD. Thereafter, a gene module significantly correlated with key immune cells were found by WGCNA method. Subsequently, KDR, IGF1, NOS3, PECAM1, GAPDH, FLT1, DLL4, CDH5, VWF, and TEK were identified as hub immune cell related genes by PPI network analysis, which may be potential diagnostic markers for AD, as evidenced by ROC curves. Moreover, the decreased expression of VWF in AD was validated at both mRNA and protein levels, and its expression was significantly positive correlated with the marker of smooth muscle cells, ACTA2, in AD. Further immunofluorescent results showed that VWF was colocalized with ACTA2 in aortic tissues.Conclusion: We identified key immune cells and hub immune cell-related genes involved in AD. Moreover, we found that VWF was co-expressed with the smooth muscle cell marker ACTA2, indicating the important role of VWF in smooth muscle cell loss in AD pathogenesis.Keywords: aortic dissection, infiltrating immune cells, diagnosis, smooth muscle cells

Boyi Yu,1– 4 Xuanyi Lu,5 Xianglong Feng,1– 4 Ting Zhao,1– 4 Jiaxin Li,1– 4 Yudie Lu,5 Fei Ye,1– 4 Xiongxiong Liu,1– 4 Xiaogang Zheng,1– 4 Zheyu Shen,5 Xiaodong Jin,1– 4 Weiqiang Chen,1– 4 Qiang Li1– 4 1Biomedical Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, People’s Republic of China; 2Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou, People’s Republic of China; 3Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, People’s Republic of China; 4College of Life Sciences, University of Chinese Academy of Sciences, Beijing, People’s Republic of China; 5School of Biomedical Engineering, Southern Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Xiaodong Jin; Weiqiang Chen, Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, Gansu Province, 730000, People’s Republic of China, Tel +86-931-4969316, Fax +86-931-8272100, Email jinxd@impcas.ac.cn; chenwq7315@impcas.ac.cnIntroduction: Radiotherapy is a widely recognized first-line clinical treatment for cancer, but its efficacy may be impeded by the radioresistance of advanced tumors. It is urgent to improve the sensitivity of radioresistant tumors to radiotherapy. In this work, gadolinium oxide nanocrystals (GONs) were utilized as radiosensitizers to enhance the killing effect and reinforce the immune activation of X-ray irradiation on 4T1 breast cancer cells in vitro and in vivo.Methods: 1.0 T small animal MR imaging (MRI) system was employed to trace GONs in vivo, while 225 kVp X-ray irradiation equipment was utilized for investigating the radiosensitization of GONs in 4T1 breast cancer cells in vitro and in vivo. Western blot, quantitative real-time PCR (RT-qPCR), immunohistochemistry, immunofluorescence, clonal survival assay, flow cytometry and reactive oxygen species assay were used to explore the biological mechanism of GON sensitization.Results: GONs exhibited exceptional utility as contrast agents for both in vivo and in vitro MRI imaging. Interestingly, a single dose of 8.0 Gy X-rays together with GONs failed to confer superior therapeutic effects in tumor-bearing mice, while only 3.0 Gy × 3 fractions X-rays combined with GONs exhibited effective tumor growth inhibition. Moreover, fractionated X-ray irradiation with GONs demonstrated a superior capacity to activate the cGAS-STING pathway.Discussion: Fractionated X-ray irradiation in the presence of GONs has demonstrated the most significant activation of the anti-tumor immune response by boosting the cGAS-STING pathway. Keywords: gadolinium oxide nanoparticles, magnetic resonance imaging, radiosensitization, cGAS-STING pathway, 4T1 breast cancer cells

Ting Zhao,1,&ast; Zihao Chen,2,&ast; Wenbo Liu,3 Hongping Ju,4 Fang Li5 1Department of Clinical Pharmacy, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 2Department of Surgical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 3The Third department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 4School of Medicine, Kunming University, Kunming, People’s Republic of China; 5Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fang Li, Email lifang198308@163.comIntroduction: Hub genes related to the development of gastric cancer (GC) were identified based on bioinformatics methods. This study aimed to identify GC hub genes, explore the expression of genes in GC and their correlation with prognosis, so as to provide strategies for GC diagnosis and targeted therapy.Methods: Two messenger RNA (mRNA) microarray datasets were downloaded from GEO database. These data were combined with TCGA database to obtain common DEGs between GC tissues and normal tissues. GO and KEGG pathway enrichment analysis was performed. Visualized PPI network analysis was performed by Cytoscape to further identify hub genes. GEPIA database was used to evaluate the prognostic value of hub genes. The online software Ualcan was applied to analyze the expression of the prognosis-related genes in cancer tissues and normal tissues from different perspectives of primary GC, TNM stage, nodal metastasis status and tumor grade. Immunohistochemical staining of GC tissues and normal tissues was performed to evaluate the expression of signature genes in GC.Results: Eighty-four common differentially expressed genes (DEGs) in GC were identified. These genes were closely related to the P13K-Akt signal pathway and other signaling pathways. Ten hub genes were identified. Collagen type I alpha 1 (COL1A1) and collagen type IV alpha 1 (COL4A1) were significantly associated with poor prognosis of GC and were all positively correlated with T stage, distant metastasis, and TNM stage of GC. Immunohistochemistry revealed that the expression of these 2 genes was upregulated in GC tissues. These 2 genes expression was negatively related with 5-year survival rate of GC patients.Conclusion: Ten highly expressed hub genes in GC tissue were mined by bioinformatics method. COL1A1 and COL4A1 were significantly associated with the prognosis of GC. This study provided a theoretical basis for the pathogenesis, clinical diagnosis and therapeutic targets of GC.Keywords: gastric cancer, bioinformatics analysis, prognosis, differentially expressed genes, immunohistochemical

Fang Chen,&ast; Fan Feng,&ast; Dianping You, Yinghui Guo, Shuo Yang, Tong Zhao, Suzhen Sun,&ast; Le Wang&ast; Institute of Pediatric Research, Children’s Hospital of Hebei Province, Shijiazhuang, 050031, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Le Wang, Institute of Pediatric Research, Children’s Hospital of Hebei Province, 133 Jianhua South Street, Shijiazhuang, Hebei Province, 050031, People’s Republic of China, Tel +86-0311-85911389, Email luka_wl@163.comBackground: Febrile seizures (FS) are a common cause of paediatric emergencies, but research on their aetiology and epidemiology are limited. The aim of this study was to investigate the prevalence of central nervous system (CNS) pathogenic infections in patients with FS-associated hospitalization.Methods: A prospective observational study was conducted in children under 16 years of age with FS-associated hospitalization. Demographic, clinical and laboratory data were recorded. Multiplex-PCR was performed on cerebrospinal fluid (CSF) samples for nine viruses, nine bacteria and one fungus.Results: A total of 119 children were enrolled between June 2021 and June 2022. Of these, 83.2% had a final diagnosis of FS (69.7%) or FS plus (13.4%). In addition, epilepsy and encephalitis/meningitis were also found in 16.8% (20/119). Seven pathogens were identified from 9 CSF samples (7.6%), including viruses (EV, EBV, HHV-6) and bacteria (H. influenzae, S. pneumoniae, M. tuberculosis, S. putrefaciens). There were no significant clinical or laboratory differences between children who tested positive or negative for pathogens in the CSF, except for the presentation of herpes pharyngitis. Children with encephalitis/meningitis had longer hospital stays compared with those diagnosed with FS at discharge; abnormal EEG findings were significantly more common in patients with epilepsy.Conclusion: FS-associated hospitalized children may have viral or bacterial intracranial infections. Pathogen testing of CSF is an important basis for timely antibiotic or antiviral therapy when clinical and laboratory findings make FS indistinguishable from other CNS disorders.Keywords: febrile seizure, children, CSF, infection

Guangxin Hu,1,&ast; Xijuan Qi,1,&ast; Ben Li,1 Ting Ge,1 Xi Li,1 Zhijun Liu,1 Jiaxing Li,1 Xuemei Zhang,1 YinPing Li,1 Shichang Zhang,1 Yajuan Wang,2 Tingting Zhao,3 Botao Zhang,1 Qingbin Xu1 1Department of Cardiology, General Hospital of Ningxia Medical University, Yinchuan, 750002, People’s Republic of China; 2Department of Pharmacy, General Hospital of Ningxia Medical University, Yinchuan, 750002, People’s Republic of China; 3Department of Respiratory Medicine, General Hospital of Ningxia Medical University, Yinchuan, 750002, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangxin Hu, Email hugx8911_ecg@163.comObjective: To assess the effectiveness and safety of an IVUS-guided rotational atherectomy (RA) percutaneous coronary intervention (PCI) in chronic renal patients with complex coronary calcification who are at risk for contrast-related acute kidney injury (AKI).Methods: From October 2018 to October 2021, 48 patients with chronic renal disease who were receiving PCI with RA at the General Hospital of NingXia Medical University were informed for data collection for this research. They were randomly assigned to the IVUS-guided RA group and the Standard RA group, which did not use IVUS. According to a clinical expert consensus document on rotational atherectomy in China, both PCI procedures were performed. The intravascular ultrasound (IVUS) results from the study group were used to describe the morphology of the lesion and to guide the selection of burrs, balloons, and stents. IVUS and angiography were used to evaluate the outcome in the end. IVUS-guided RA PCI and Standard RA PCI groups’ effects and results were contrasted.Results: There were no appreciable differences in the clinical baseline characteristics between the IVUS-guided RA PCI group and the Standard RA PCI group. The average estimated glomerular filtration rate (eGFR) of two groups was (81.42 ± 20.22 vs 82.34 ± 22.19) mL/min/1.73 m2. Most of them (45.8% vs 54.2%) was in stage 60– 90 mL/min/1.73m2. When compared to the standard RA PCI group, RA in IVUS-Guided group was more performed electively (87.5% vs 58.3%; p = 0.02). The IVUS-guided RA PCI group was associated with shorter fluoroscopy time (20.6 ± 8.4 vs 36 ± 22; p< 0.01) and less contrast amount (32 ± 16 vs 184 ± 116mL; p< 0.01) than Standard-RA group. Five patients in the Standard RA PCI group developed contrast-induced nephropathy, which was 5 times than the IVUS-guided RA PCI group (20.8% VS 4.1%; p=0.19).Conclusion: In chronic renal patients with complex coronary calcification, an IVUS-guided RA PCI technique is effective and safe. It can also lower the volume of contrast and perhaps the incidence of contrast-related AKI.Keywords: rotational atherectomy, chronic renal disease, contrast-associated acute kidney injury, intravascular ultrasound

Tianxue Zhao,1 Shaokun Xu,2 Xianfeng Zhang,1 Chenke Xu3 1Department of Endocrinology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Geriatrics, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China; 3Department of Ultrasound, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Chenke Xu, Department of Ultrasound, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310006, People’s Republic of China, Tel +86-571-56005600, Email muerxck@163.comPurpose: To compare the diagnostic performance and unnecessary ultrasound-guided fine-needle aspiration (US-FNA) biopsy rate of the 2015 American Thyroid Association (ATA), 2016 Korean Society of Thyroid Radiology (KSThR), and 2017 American College of Radiology (ACR) guidelines for patients with and without Hashimoto’s thyroiditis (HT).Patients and Methods: This retrospective study included 716 nodules from 696 consecutive patients, which were classified using the categories defined by the three guidelines: ATA, KSThR, and ACR. The malignancy risk in each category was calculated and the diagnostic performance and unnecessary fine-needle aspiration (FNA) rates of the three guidelines were compared.Results: In total, 426 malignant and 290 benign nodules were identified. Patients with malignant nodules had lower total thyroxine levels and higher thyroid-stimulating hormone, thyroid peroxidase antibody, and thyroglobulin antibody levels than those without malignant nodules (all P< 0.01). The margin difference was significant in non-HT patients (P< 0.01), but comparable in HT patients (P=0.55). The calculated malignancy risks of high and intermediate suspicion nodules in the ATA and KSThR guidelines and moderately suspicious nodules in the ACR guidelines were significantly lower in non-HT patients compared with HT patients (P< 0.05). The ACR guidelines showed the lowest sensitivity, highest specificity, and lowest unnecessary FNA rates in patients with and without HT. Compared to non-HT patients, HT patients had significantly lower unnecessary FNA rates (P< 0.01).Conclusion: HT was associated with a higher malignancy rate of thyroid nodules with intermediate suspicion according to the ATA, KSThR, and ACR guidelines. The three guidelines, especially ACR, were likely to be more effective and could allow a greater reduction in the percentage of benign nodules biopsied in patients with HT.Keywords: ultrasound-based malignant risk stratification system, Hashimoto’s thyroiditis, thyroid nodules, diagnostic value, papillary thyroid cancer

Songzhi Kong,1 Lijiao Lv,1 Jiaqi Guo,1 Xiaohong Yang,1 Mingneng Liao,1 Tianyang Zhao,1 Haiyang Sun,1 Shuqun Zhang,1 Wenjie Li2 1School of Chemistry and Environmental Science, Guangdong Ocean University, Zhanjiang, 524088, People’s Republic of China; 2Department of Hematology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524001, People’s Republic of ChinaCorrespondence: Songzhi Kong, School of Chemistry and Environmental Science, Guangdong Ocean University, 1 Haida Road, Mazhang District, Zhanjiang, 524088, People’s Republic of China, Tel +86-759-238-3679, Email kongsongzhi@gdou.edu.cn Wenjie Li, Department of Hematology, Affiliated Hospital of Guangdong Medical University, People’s Avenue, Xiashan District, Zhanjiang, 524001, People’s Republic of China, Email dglwj.135@163.comBackground: Photoaging decreases quality of life and increases the risk of skin cancer, underscoring the urgent need to explore natural, high-efficacy, anti-skin photoaging (SP) active substances.Methods: In this study, a gel (CS/CSCPs/β-GP gel) was prepared using chitosan (CS) and sodium β-glycerophosphate (β-GP) through crosslinking with small molecular CSCPs as the carried drug. We evaluated its structural characteristics and properties. The effect of CS/CSCPs/β-GP gel on the degree of ultraviolet (UV)-induced skin aging of mice was investigated through comparative analysis of skin damage, the integrity of collagen tissues and elastic fibers, levels of reactive oxygen species (ROS) and key inflammatory factors (tumor necrosis factor [TNF]-α and interleukin [IL]-1β, IL-6, and IL-10), and tissue expression of matrix metalloproteinase-3 (MMP-3) after repeated UV irradiation in a nude mice SP model.Results: The results showed that CS/CSCPs/β-GP gel was successfully prepared and had the desired characteristics. Compared with CSCPs alone, the CS/CSCPs/β-GP gel more evidently improved typical photoaging characteristics on mouse dorsal skin. It also increased the moisture content, causing the skin to become glossy and elastic. Pathological skin analysis revealed that this peptide-carrying gel can effectively inhibit epidermal thickening, reduce tissue inflammatory infiltration, suppress collagen fiber degradation, increase the collagen content, alleviate structural elastic fiber damage, and significantly inhibit abnormal MMP-3 expression. In addition, biochemical analysis showed that the CS/CSCPs/β-GP gel can effectively inhibit the elevated expressions of ROS and key proinflammatory factors (TNF-α, IL-1β, IL-6) in photoaging skin tissues and promote expression of the anti-inflammatory factor IL-10.Conclusion: SP can cause many clinical skin diseases, such as solar freckle-like nevus, solar keratosis, cutaneous melanoma, and squamous cell carcinoma. CSCPs are a high-efficacy anti-SP natural active substance and CS/CSCPs/β-GP gel can synergistically enhance the CSCPs’ anti-SP effect. The mechanism is likely related to the inhibited activation of ROS/nuclear transcription factor-κB signaling and the expression of downstream inflammatory factors.Graphical Abstract: Keywords: cod skin collagen peptides, temperature-sensitive gel, chitosan, skin photoaging, ROS/NF-κB

Huijuan Wang,1 Yinmin Shi,2 Jiying Ma,1 Wenxia Wang,2 Jianrong Gao,3 Lili Zhao,1 Ting Zhao,2 Guifeng Ding4 1The National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, Shaanxi, 710069, People’s Republic of China; 2Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, Shaanxi, 710069, People’s Republic of China; 3Department of Obstetrics, Xi’an International Medical Center Hospital, Xi’an, Shaanxi, 710018, People’s Republic of China; 4Department of Obstetrics and Gynecology, Urumqi Maternal and Child Health Care Hospital, Urumqi, Xinjiang, 830001, People’s Republic of ChinaCorrespondence: Guifeng Ding, Department of Obstetrics and Gynecology, Urumqi Maternal and Child Health Care Hospital, No. 344 Jiefang South Road, Urumqi, Xinjiang, People’s Republic of China, Tel +86 1 331 988 0258, Fax + 86 991-8554656, Email dingguifeng123@126.comBackground: Preeclampsia (PE) is a multi-system disorder of pregnancy that poses a serious threat to maternal and perinatal health worldwide. This study aims to evaluate the global alterations of protein expression and N-glycosylations that are crucial for PE pathogenesis. Here, tandem mass tag labeling combined with LC-MS/MS was employed to determine the global expression of all proteins and intact glycopeptide in placentas from three healthy pregnant women, three patients with early-onset severe PE, and three patients with late-onset severe PE.Results: A total of 2260 proteins were quantified across 9 placental tissues, of which 37 and 23 were differentially expressed in the early-onset and late-onset PE groups, compared to the controls. A total of 789 glycopeptides were accurately quantified, which were derived from 204 glycosylated sites in 159 glycoproteins and were modified by 59 N-Linked glycans. A total of 123 differently expressed glycopeptides, which were from 47 glycoproteins were identified among three groups. Through a combined analysis of proteomic and glycoproteomic data, it was found that the changes in 10 glycoproteins were caused by the difference in glycosylation level but not in the protein abundance level.Conclusion: This is the first study to conduct an integrated proteomic and glycoproteomic characterization of placental tissues of PE patients. Our findings suggest that glycosylation modification may affect the molecular function of proteins through changes in the glycosylation structure or the occupancy of glycosylation, which will provide new insights to help elucidating the pathogenic mechanism of PE.Keywords: preeclampsia, placenta, proteomics, glycoproteomics, glycosylation

Hao Tian,1,&ast; Tingting Zhao,1,&ast; Yanling Li,1,&ast; Na Sun,1 Dandan Ma,1 Qiyun Shi,1 Guozhi Zhang,1 Qingqiu Chen,1 Kongyong Zhang,1 Ceshi Chen,2,&ast; Yi Zhang,1 Xiaowei Qi1 1Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, People’s Republic of China; 2Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaowei Qi; Yi Zhang, Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Gaotanyan Street 29, Chongqing, 400038, People’s Republic of China, Tel/Fax +86-23-68754160, Email qxw9908@foxmail.com; zhangyi1489@sina.comBackground: Epigenetic modification of chromatin is an important step in the regulation of gene expression. The chromobox family proteins (CBXs), as epigenetic modifier, may play a vital role in tumorigenesis and cancer progression. Herein we explored the correlation between CBXs and breast cancer (BC) via the bioinformatics approach and qRT-PCR validation.Methods: Several databases, including GEPIA, TCGA, GEO, K-M plotter, STRING, DAVID, cBioPortal, CIBERSORT, and HPA were employed to analyze the expression levels of CBXs and the correlations between CBXs and prognosis (overall and recurrence-free survival) in BC. We analyzed molecular functions, genetic variations, transcription factors of CBXs, and immune cell infiltration status. ROC curve analysis was performed to determine the predictive value of CBXs. RNA extracted from 11 human BC and paired adjacent normal tissues were subjected to qRT-PCR.Results: The mRNA expression level of CBX1– 5 was significantly upregulated, while that of CBX7 was significantly downregulated in BC; no expression disparities were observed in CBX6/8 expression. Further, high mRNA expression of CBX1/2/3/4/8 correlated with advanced BC, whereas high mRNA expression of CBX6/7 correlated with early BC. High mRNA expressions of CBX1/2/3/5 predict poor OS and RFS, while higher mRNA expressions of CBX6/7 predict better OS and RFS in patients with BC. ROC curve analysis revealed that CBX3 showed excellent discriminatory ability. Gene ontology enrichment analysis showed that CBXs primarily participated in SUMOylation and post-/transcriptional regulation. Moreover, they presented varying degrees of amplification in BC tissues and were related to the infiltration of various immune cells.Conclusion: CBXs can serve as putative biomarkers for BC. Further studies are warranted to determine the exact molecular mechanisms underlying the action of CBXs in BC, particularly CBX1/2/3/5/7.Keywords: chromobox family proteins, breast cancer, prognosis, bioinformatics, qRT-PCR

Yanlei Li,1,2,&ast; Jinlong Tian,1,2,&ast; Meng Ge,1,2,&ast; Lichen Ji,1,3 Yao Kang,1 Chen Xia,1 Jun Zhang,1,2 Yazeng Huang,1,2 Fabo Feng,1 Tingxiao Zhao,1,2 Haiyu Shao1 1Center for Plastic & Reconstructive Surgery, Department of Orthopedics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, People’s Republic of China; 2Bengbu Medical College, Bengbu, People’s Republic of China; 3Wenzhou Medical University, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiyu Shao; Tingxiao Zhao, Center for Plastic & Reconstructive Surgery, Department of Orthopedics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Shangtang Road 158#, Hangzhou, 310014, People’s Republic of China, Email shaohaiyu@163.com; spinezhaotingxiao@163.comBackground: With the aging population growth in the world, the prevalence of osteoporotic vertebral compression fracture (OVCF) is rapidly increasing and receiving widespread attention. Although there are numerous articles on the topic, the research status and hotspot analysis are unclear.Objective: The goal of this study is to identify trends in the OVCF field and to analyze the most highly cited original articles published in the Web of Science Index on OVCF using bibliometric analysis.Methods: All OVCF data were obtained from the Web of Science Core Collection, and the number of citations, institutions, journals, countries, and years of publication in this field were visually analyzed using VOSviewer, the bibliometrics online analysis platform, and Excel software. Simultaneously, the top 100 most cited articles were extracted and analyzed.Results: A total of 756 publications were related to OVCF were included from 1900 to 2022. In recent years, the number of articles on OVCF significantly increased. They are mainly from 41 countries/regions and 202 journals, led by China and the United States. Among all countries, China had the most significant contribution on OVCF (n = 363), and it also was cited most often (n = 3337). The institution with the most articles was Soochow University (n = 40). Osteoporosis International was the journal with most studies and has published 50 on this field. The journal of Spine was cited most often (n = 1968). The most productive periods were from 2016 to 2020, which received 294 articles and 4868 citations. After the analysis, the “vertebroplasty” and “kyphoplasty” of OVCF have been the most common research hotspots.Conclusion: This study represents an updated bibliometric analysis of OVCF. The aim is to identify current research hotspots and future trends to guide clinicians and researchers in this field.Keywords: osteoporotic vertebral compression fracture, OVCF, bibliometric analysis, VOSviewer, Web of Science, research trends

Tingyao Zhao,1,&ast; Xinting Wang,2,&ast; Qian Liu,2 Tianshu Yang,1 Huiyan Qu,1 Hua Zhou2 1Department of Cardiovascular Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hua Zhou; Huiyan Qu, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No. 528, Zhangheng Road, Pudong New Area, Shanghai, 201203, People’s Republic of China, Email zhouhua@shutcm.edu.cn; 1520043084@qq.comAbstract: Purpose: This study aimed to elucidate the potential molecular mechanisms by which GSRd improves cardiac inflammation and immune environment after MI.Materials and Methods: The potential target genes of GSRd were predicted using the STITCH database. In vivo, MI mice models were established by left anterior descending ligation and were divided into the sham group, MI + Vehicle group, and MI + GSRd group. DMSO, DMSO, and GSRd 50 μL/day were intraperitoneally injected, respectively. After 28 days, echocardiography, Masson staining, immunofluorescence staining, flow cytometry, RT-PCR, and Western blot were performed. Mice peritoneal macrophages were extracted in vitro, and Western blot was performed after GSRd and/or Akt inhibitor MK2206 intervention.Results: GSRd significantly improved mouse myocardial function, attenuated cardiac fibrosis, and inhibited inflammation and apoptosis in myocardial tissues after myocardial infarction. Meanwhile, GSRd increased non-classical Ly6Clow Mos/Mps while reduced of classical Ly6Chigh Mos/Mps at the same time in myocardial tissues. In addition, GSRd significantly reversed the activity of p-Akt and p-mTOR in the heart Mos/Mps after MI. In vitro studies showed that the activity of p-Akt and p-mTOR in peritoneal macrophages were significantly increased in a dose-dependent manner after GSRd treatment. Furthermore, the AKT inhibitor MK2206 was found to block the enhanced activity of p-Akt and p-mTOR induced by GSRd in peritoneal macrophages.Conclusion: GSRd can enhance the transformation of Ly6Chigh Mos/Mps to Ly6Clow Mos/Mps in mice after MI by activating the Akt/mTOR signaling pathway, inhibiting cardiac dysfunction and promoting cardiac repair.Keywords: myocardial infarction, ginsenoside rd, monocytes/macrophages, Akt/mTOR

Yanping Tong,1,2 Jie Liu,3 Tao Yang,1,2 Jingwen Wang,4 Tianyou Zhao,4 Yuezhi Kang,1,2 Yongping Fan1,2 1Department of Traditional Chinese Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China; 2Beijing Integrative Medicine on Encephalopathy Research Institution, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China; 3Department of Respiratory Medicine, Beijing First Hospital of Integrated Chinese and Western Medicine, Beijing, 100026, People’s Republic of China; 4Department of Neurology, Beijing Miyun District Hospital of Traditional Chinese Medicine, Beijing, 101599, People’s Republic of ChinaCorrespondence: Yongping Fan, Email yongpingf@hotmail.comObjective: To investigate the association of pain with plasma C5a levels and other related inflammatory cytokines in neuromyelitis optica spectrum disorders (NMOSD) patients during remission.Participants and Methods: NMOSD patients (n = 87) and healthy controls (HC; n = 44) were consecutively recruited between January 2017 and April 2018. Plasma complement 5 (C5), C5a, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β levels were detected. Visual Analogue Scale (VAS), ID pain scale, 24-item Hamilton Depression Scale (HAMD), Multiple Sclerosis Impact Scale (MSIS-29), and Kurtzke Expanded Disability Status Scale (EDSS) were used to evaluate the degree and types of pain, the existence of depression and anxiety, and the life quality and disability status of patients. Binary logistic regression equation was used to assess the association of pain with plasma C5a levels.Results: Among the 87 NMOSD patients, 40 complained of pain that in 67.5% (27/40) of cases had a neuropathic component (ID pain ≥ 2). Plasma C5a, IL-6, TNF-α, and IL-1β levels were significantly elevated in NMOSD patients than in HC. Plasma C5 levels were negatively correlated with the time from sampling to the last relapse or disease onset. NMOSD patients with pain had higher plasma C5a levels, and they suffered from a higher disability, more anxiety, and worse life quality compared to those patients without pain. In NMOSD patients with pain, there were not significant differences between plasma levels of C5, C5a, IL-6, TNF-α, or IL-1β, regardless of neuropathic pain or not. Binary logistic regression showed that the OR of plasma C5a level was 1.002, with gender and EDSS score were identified as independent factors associated with pain in NMOSD.Conclusion: NMOSD patients during remission had elevated C5a and related inflammatory cytokines levels in peripheral blood. Elevated C5a may have a unique role in the pathogenesis of pain in NMOSD patients.Keywords: neuromyelitis optica spectrum disorders, remission, pain, C5a

Xiaofei Mo,1 Tianyun Zhao,1 Jinghui Chen,1 Xiang Li,1 Jun Liu,2 Cuiyi Xu,1 Xingrong Song1 1Department of Anesthesiology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Medical Records, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of ChinaCorrespondence: Xingrong Song; Tianyun Zhao, Department of Anesthesiology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, 9 Jinsui Road, Tianhe District, Guangzhou, 510623, People’s Republic of China, Tel +86 13922416303 ; +86 18198907639, Fax +86 20 38076243, Email sxjess@163.com; wenyan_404@tom.comPurpose: Programmed intermittent epidural bolus (PIEB) was reported to provide superior maintenance of labour analgesia with better pain relief and less motor block than continuous epidural infusion (CEI). Whether this is also evident for uterine contraction pain relief after cesarean section remains unknown.Patients and Methods: Parturients scheduled for cesarean section were recruited for the study. At the end of the surgery, after a similar epidural loading dose given, patients received either PIEB (6 mL·h− 1) or CEI (6 mL·h− 1) of 0.1% ropivacaine. The primary outcome was the uterine contraction pain assessed with visual analog scale (VAS-U) at the postoperative 36 h. Secondary outcomes included incision pain at the rest (VAS-R) and in the movement-evoked (VAS-P), and lower extremity motor block (defined as Bromage score > 0). The whole profile of VAS scores between groups was analyzed using linear mixed model. When significant differences were found, the pairwise comparison was done with the Mann Whitney U-test followed by Bonferroni correction.Results: One hundred and twenty parturients were studied (PIEB, 60; CEI, 60). VAS-U at the postoperative 36 h in the PIEB group was lower than in the CEI group (Bonferroni-adjusted P < 0.01). The linear mixed model indicated that VAS-U, VAS-R and VAS-P were lower in the PIEB group compared with the CEI group (all P < 0.01). Motor block was higher in the CEI group than in the PIEB group during the study period except 2 h (all P < 0.05). No differences of adverse events such as hypotension and urinary retention were observed between the two groups.Conclusion: Programmed intermittent epidural bolus provides more effective uterine contraction and incision pain relief and less motor block after cesarean section than continuous epidural infusion without an increased risk of urinary retention and blood pressure instability.Keywords: cesarean section, epidural, pain, postoperative analgesia, uterine contraction

Han-yu Jiang,1,&ast; Hui-min Zheng,1,&ast; Cheng Xia,1 Xiang Li,1 Gang Wang,1 Tong Zhao,1 Xiao-nan Cui,2 Ruo-yu Wang,1,3 Ying Liu1,3 1Department of Oncology, The Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, People’s Republic of China; 2Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 3The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Liu, Department of Oncology, The Affiliated Zhongshan Hospital of Dalian University, Dalian, People’s Republic of China, Tel +8615942653462, Fax +86 411-62893555 Email ly_janet198862@sina.com Ruo-yu Wang, Department of Oncology, The Affiliated Zhongshan Hospital of Dalian University, No. 6, Liberation Street, Zhongshan District, Dalian, 116001, People’s Republic of China, Tel +86071762897187, Fax +86 411-62893555, Email wangruoyu1963@163.comAbstract: Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world with a five-year survival rate of less than 20%. Nonetheless, selecting an appropriate therapeutic agent to inhibit the development of hepatoma cells is still a challenge. Bufalin, a component of the traditional Chinese medicine Chansu, has been shown to inhibit the proliferation, invasion and metastasis of HCC through various signaling pathways. In addition, bufalin and sorafenib demonstrate a synergistic effect in cancer therapeutics. This review highlighted on several focal signaling pathways involved in the inhibitory effects of bufalin on HCC and its synergistic mechanisms with sorafenib. The immunotherapy effect of bufalin has also been discussed as a novel property.Keywords: bufalin, cancer, therapy, signaling pathways, immunotherapy effect

Meng Ge,1,2,&ast; Yuan Zhang,2,3,&ast; Yanlei Li,1,2,&ast; Chenchen Feng,1,2,&ast; Jinlong Tian,1,2 Yazeng Huang,1,2 Tingxiao Zhao1 1Center for Plastic & Reconstructive Surgery, Department of Orthopedics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, People’s Republic of China; 2Bengbu Medical College, Bengbu, People’s Republic of China; 3Center for General Practice Medicine, Department of Rheumatology and Immunology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tingxiao Zhao; Yazeng Huang, Center for Plastic & Reconstructive Surgery, Department of Orthopedics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Shangtang Road 158#, Hangzhou, Zhejiang, 310014, People’s Republic of China, Email spinezhaotingxiao@163.com; huangyazeng2007@163.comBackground: In recent years, the research on subacromial impingement syndrome (SIS) has gradually increased. Although the research directions are diverse, the overall research status and trend are not clear.Objective: The aim of our study was to use bibliometric analysis to identify the trends in SIS-related research and to analyze the most highly cited scientific publications on SIS.Methods: All data were retrieved from the Web of Science Core Collection database, and the year of publications, countries, journals, institutions and total number of citations were extracted and analyzed. The results related to countries, institutions and keywords were then analyzed using VOSviewer software and bibliometrics online analysis platform. And, we also identified the 100 most cited articles on SIS.Results: A total of 548 articles related to AIS were identified. The frequency of publication on SIS has increased substantially over time. Among all countries, Turkey has contributed the most publications on SIS (n=118). The institution with the most articles was Istanbul University (n=17). Journal of Shoulder and Elbow Surgery topped the list of journals and has published 19 SIS-related publications. The hotspot of research changed from the former arthroscopic surgery to physical therapy and rehabilitation.Conclusion: The scientific research on SIS has rapidly expanded in recent years. This study represents the first bibliometric analysis of SIS, gives us a systematic and comprehensive summary into the development of SIS.Keywords: subacromial impingement syndrome, SIS, bibliometric analysis, research trends, VOSviewer, Web of Science

Fu Shi, Yanjie Chen, Hongtao Li, Yang Zhang, Tonghang Zhao Department of Anesthesiology, Liaocheng People’s Hospital, Liaocheng, 252000, People’s Republic of ChinaCorrespondence: Tonghang Zhao Email zthlymz@163.comIntroduction: The best candidate intravenous anesthetic agent for patients with liver cirrhosis undergoing endoscopic variceal ligation (EVL) remains unclear. Remimazolam tosilate (RT) is a new type of benzodiazepine with quick onset, rapid recovery, and no accumulation. Here, we investigated the efficacy and safety of RT for general anesthesia in cirrhotic patients undergoing EVL.Methods: Patients undergoing EVL were randomly classified into the remimazolam tosilate (group R) and the propofol group (group P). RT was administered as a slow bolus of 0.2 mg/kg for induction and followed by 1.0– 2.0 mg/kg/h for maintenance of general anesthesia. Propofol was started at 2 mg/kg, followed by 4– 10 mg/kg/h until the end of surgery. Flumazenil was routinely administered to group R and the same volume of saline was given to group P immediately after surgery. The efficacy and safety of RT for general anesthesia during EVL were compared with propofol.Results: All patients in the two groups had satisfactory anesthetic effects and the efficacy rates were 100%. The time to loss of consciousness (LoC) was longer in group R than in group P (P > 0.05). The return of consciousness (RoC) time, extubation time, and transfer time in group R were significantly shorter than that in group P (P < 0.05). The incidence of intraoperative hypotension and postoperative low SpO2 in group R were lower than that in the group P (P < 0.05). There were no significant differences between the two groups with respect to the satisfaction degree of patients and operators (P > 0.05).Conclusion: Remimazolam tosilate can provide satisfactory anesthetic effects for surgery. Group R patients recovered faster and had a shorter PACU stay time than group P patients. Moreover, RT decreased the incidence of hypotension and low SpO2. RT was a safer and more effective alternative for general anesthesia in cirrhotic patients undergoing EVL than propofol.Keywords: remimazolam tosilate, propofol, general anesthesia, endoscopic variceal ligation, liver cirrhosis

Tong Zhao, Dongdong Zhang, Yiming Liu, Mingming Feng, Ze Xu, Haoyue Huang, Luoya Zhang, Wenjie Li, Xing Li Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, People’s Republic of ChinaCorrespondence: Xing LiDepartment of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People’s Republic of ChinaTel +86 371 6778 1305Email lixing530@zzu.edu.cnBackground: GC (group-specific component globulin) encoding VDBP (Vitamin D binding protein) polymorphisms have been associated with susceptibility to some diseases such as diabetes, obesity, osteoporosis, and polycystic ovary syndrome, but the evidence for metabolic syndrome (MetS) in the Chinese rural population is inconclusive. Therefore, we investigated the relationship between GC variants (rs7041, rs4588, rs2282679, and rs705117) and MetS risk as well as VDBP levels in the Chinese rural population.Patients and Methods: The participants (range of age: 20– 90 years) of this case–control study were recruited from the northern Chinese Han rural population. We matched 445 MetS cases with non-MetS controls in a 1:1 ratio by sex, age (within 5 years). Real-time PCR technology was carried out by TaqMan assays to examine the four variants of rs7041, rs4588, rs2282679, and rs705117 within the GC gene. To identify the association of GC gene polymorphisms with MetS, we calculated ORs using a conditional logistic regression model adjusted for potential confounding factors.Results: We observed inverse associations of CA and AA genotypes of rs4588 with risk of MetS (OR = 0.678, 95% CI 0.505– 0.910, P = 0.010; 0.603, 95% CI 0.373– 0.973, P = 0.039, respectively) compared with carriers of CC genotype. A similar relationship was also found between rs2282679 and MetS, showing that carrying AC genotype of rs2282679 can decrease the risk of MetS (OR = 0.683, 95% CI 0.509– 0.917, P = 0.011) compared with carriers of AA genotype. The results of correlation analysis between MetS components and GC polymorphisms showed that the ORs of AA genotype of rs4588 with high level of TG (triglycerides) and low level of HDL-C (high-density lipoprotein cholesterol) were 0.473 (95% CI 0.245– 0.911, P = 0.025) and 0.268 (95% CI 0.117– 0.615, P = 0.002), respectively; the ORs of CC genotype of rs2282679 with high level of TG and low level of HDL-C were 0.428 (95% CI 0.217– 0.842, P = 0.014) and 0.263 (95% CI 0.110– 0.628, P = 0.003), respectively. However, there was no significant association between the concentration of VDBP and MetS risk.Conclusion: Among the Chinese rural population, GC polymorphism was associated with lower metabolic syndrome susceptibility, which might be through affecting blood lipid levels (TG and HDL-C).Keywords: GC, polymorphism, metabolic syndrome, rural population

Yu Liu,1 Ying Liang,1 Min Gao,1 Yingchun Li,1 Tingting Zhao,2 Yani Zhao1 1Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, Shanxi, 030032, People’s Republic of China; 2Shaanxi University of Traditional Chinese Medicine, Xi’an, Shaanxi, 712046, People’s Republic of ChinaCorrespondence: Ying LiangThird Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, No. 99, Longcheng Street, Xiaodian District, Taiyuan, Shanxi, 030032, People’s Republic of ChinaTel +86-13934225687Email sx.liangying@126.comAbstract: Complex regional pain syndrome (CRPS) is a chronic pain disorder characterized by spontaneous or evoked regionally-confined pain which is out of proportion to the initial trauma event. The disease can seriously affect the quality of the patients’ life, increase the psychological burden, and cause various degrees of disability. Despite the awareness of CRPS among medical practitioners for over a century, its pathogenesis remains unclear, and the available treatment is still unsatisfactory. Effective animal models are the foundation of disease research, which is helpful in understanding the pathogenesis and an in-depth exploration of the appropriate therapeutic approaches. Currently, researchers have established a series of animal models of the disease. There are four main CRPSI animal models: chronic post-ischemic pain (CPIP) model, tibial fracture/cast immobilization model, passive transfer-trauma model, and the needlestick-nerve-injury (NNI) model. The modeling methods of these models are constantly improving over time. In preclinical studies, the interpretation of experimental results and the horizontal comparison between similar studies may be affected by the nature of the experimental animal breeds, sex, diet, and psychology. There is need to facilitate the choice of appropriate animal models and avoid the interference of the factors influencing animal models on the interpretation of research results. The review will provide a basic overview of the influencing factors, modeling methods, and the characteristics of CRPSI animal models.Keywords: CRPS, reflex sympathetic dystrophy, animal model, mouse, rat, sex, diet, psychology

Xianwen Liu,1 Baofeng Ding,2 Fu Shi,1 Yang Zhang,1 Lei Liu,1 Yongwei Sha,3 Tonghang Zhao1 1Department of Anaesthesiology, Liaocheng People’s Hospital, Liaocheng, Shandong, People’s Republic of China; 2Department of Anaesthesiology, Liaocheng Second People’s Hospital, Liaocheng, Shandong, People’s Republic of China; 3Department of Anaesthesiology, Guanxian Central Hospital, Liaocheng, Shandong, People’s Republic of ChinaCorrespondence: Tonghang Zhao Email lbzthgn@163.comObjective: The optimal sedation regime during endoscopy remains controversial, especially for elderly outpatients. In this study, we compared the efficacy and safety between remimazolam tosilate (RT) and etomidate-propofol (EP) in elderly outpatients undergoing colonoscopy.Methods: A total of 260 elderly outpatients undergoing sedative colonoscopy were randomized into two groups. Patients in the RT group received a 0.075-mg/kg maintenance dose of remimazolam following an initial dose of 0.15 mg/kg, whereas patients in the EP group (10 mL:20 mg etomidate plus 10 mL:100 mg propofol) received a 0.05-mL/kg maintenance dose following an initial dose of 0.1 mL/kg to maintain a Modified Observer’s Assessment of Alertness/Sedation score of ≤ 3 during the procedure. The primary endpoint was the success of the procedure. Secondary endpoints included time metrics, hemodynamics, consumption of fentanyl, etomidate, propofol, and remimazolam, intraoperative body movement, patient and endoscopist satisfaction scores, supplemental dose of sedative and fentanyl, and incidence and severity of adverse events.Results: The procedure success rate was 96.52% in the RT group and 100% in the EP group. The difference in procedure success rate between the RT and EP groups was − 3.48% (95% confidence interval: − 6.81%, − 0.15%). Four patients in the RT group required rescue midazolam. Compared with patients in the RT group, the onset time of the EP group was significantly lower (p < 0.05), whereas time to fully alert (p = 0.001), ready for discharge (p = 0.001), and hospital discharge (p = 0.002) were all significantly higher in the EP group. However, there were no significant differences in procedure time (p = 0.846) or cecal intubation time (p = 0.320) between the two groups. Although the frequency of intraoperative body movement was higher in the RT group, the difference was not significant (p = 0.508). There were no significant differences in patients’ demographic and baseline characteristics, supplemental doses of sedative and fentanyl, or patient and endoscopist satisfaction scores (p > 0.05). Muscular tremor and pain on injection were recorded more frequently in the EP group (p < 0.05). However, there were no significant differences in hypoxia, respiratory depression, or incidence of postoperative nausea and vomiting. The severity of adverse events was all mild (grade 1) across both groups.Conclusion: RT may have non-inferior efficacy and a higher safety profile than EP in elderly outpatients undergoing colonoscopy, which suggests that RT may be more suitable for elderly outpatients undergoing colonoscopy.Keywords: remimazolam tosilate, etomidate, propofol, elderly outpatients, colonoscopy

Yue Zhuang, Tiantian Zhao, Xuanrong Shao School of Safety Science and Emergency Management, Wuhan University of Technology, Wuhan City, Hubei Province, People’s Republic of ChinaCorrespondence: Tiantian ZhaoSchool of Safety Science and Emergency Management, Wuhan University of Technology, 122 Luoshi Road, Wuhan City, Hubei Province, People’s Republic of ChinaEmail ztt220@whut.edu.cnPurpose: Taking COVID-19 as an example, this paper explores the mechanism of WeChat’s impact on risk information transmission in social media and builds a model of WeChat’s impact on public risk perception based on risk communication.Methods: Research primarily utilised the questionnaire survey method to collect and analyse public attitudes towards COVID-19 to achieve the research goals. We checked the adequacy of measurements and tested the hypotheses with regression analysis based on 801 participants in China.Results: The results indicated that the levels of the public WeChat COVID-19 risk information attention and trust had a significant positive impact on the public’s risk perception and willingness of pandemic prevention. The improved public risk perception of COVID-19 as a mediator enhanced the public pandemic prevention ability, which allowed WeChat to play a more effective role in major disaster emergency.Keywords: COVID-19, WeChat, public risk perception, pandemic prevention

Liangyan Lin,1 Dongdong Zhang,1 Qingsong Jin,1 Yaqin Teng,1 Xiaoyan Yao,1 Tiantian Zhao,1 Xinmiao Xu,2 Yongjun Jin1 1Department of Endocrinology and Metabolism, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, People’s Republic of China; 2Department of Endocrinology, Yantai Yeda Hospital, Yantai, Shandong, People’s Republic of ChinaCorrespondence: Yongjun JinDepartment of Endocrinology and Metabolism, Yantai Affiliated Hospital of Binzhou Medical University, Jinbu Street No. 717, Yantai, 264100, People’s Republic of ChinaTel/Fax +86 535-4770613Email jinyj0001@sina.comObjective: Previous studies showed that variants in mitochondrial DNA (mtDNA) are associated with type 2 diabetes mellitus (T2DM). However, the relationships between mitochondrial tRNA (mt-tRNA) variants and T2DM remain poorly understood.Methods: In this study, we performed a mutational screening of 22 mt-tRNA genes in a cohort of 200 Han Chinese subjects with T2DM and 200 control subjects through PCR–Sanger sequencing. The identified mt-tRNA variants were assessed for their pathogenicity via the phylogenetic approach, structural and functional analysis. Furthermore, two Han Chinese pedigrees with maternally inherited diabetes and deafness (MIDD) were reported by clinical and genetic assessments.Results: A total of 49 genetic variants in mt-tRNA genes were identified; among them, 31 variants (17 pathogenic/likely pathogenic) were absent in controls, located at extremely conserved nucleotides, may have potential structural and functional significance, thereby considered to be T2DM-associated variants. In addition, sequence analysis of entire mitochondrial genomes of the matrilineal relatives from two MIDD pedigrees revealed the occurrence of tRNALeu(UUR) A3243G and T3290C mutations, as well as sets of polymorphisms belonging to mitochondrial haplogroups F2 and D4. However, the lack of any functional variants in connexin 26 gene (GJB2) and tRNA 5-methylaminomethyl-2-thiouridylate (TRMU) suggested that nuclear genes may not play active roles in clinical expression of MIDD in these pedigrees.Conclusion: Our data indicated that mt-tRNA variants were associated with T2DM, screening for mt-tRNA pathogenic mutations was recommended for early detection and prevention of mitochondrial diabetes.Keywords: type 2 diabetes mellitus, mitochondrial tRNA, variants, Chinese population

Duo Liu,1,2,&ast; Jingjing Zhu,2,&ast; Tianying Zhao,2,3,&ast; Sodbo Sharapov,4 Evgeny Tiys,4 Lang Wu2 1Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 2Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA; 3Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI, USA; 4Laboratory of Glycogenomics, Institute of Cytology and Genetics, Novosibirsk, Russia&ast;These authors contributed equally to this workCorrespondence: Lang WuCancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USATel +1 808 564-5965Email lwu@cc.hawaii.eduBackground: Previous studies suggest a potential link between glycosylation and prostate cancer. To better characterize the relationship between the two, we performed a study to comprehensively evaluate the associations between genetically predicted blood plasma N-glycan levels and prostate cancer risk.Methods: Using genetic variants associated with N-glycan levels as instruments, we evaluated the associations between levels of 138 plasma N-glycans and prostate cancer risk. We analyzed data of 79,194 cases and 61,112 controls of European ancestry included in the consortia of BPC3, CAPS, CRUK, PEGASUS, and PRACTICAL.Results: We identified three N-glycans with genetically predicted levels in plasma to be associated with prostate cancer risk after Bonferroni correction. The estimated odds ratios (95% confidence intervals) were 1.29 (1.20– 1.40), 0.80 (0.74– 0.88), and 0.79 (0.72– 0.87) for PGP18, PGP33, and PGP109, respectively, per every one standard deviation increase in genetically predicted levels of N-glycan. However, the instruments for these N-glycans only involved one to two variants. The proportions of variations that can be explained by the instruments range from 1.58% to 2.95% for these three N-glycans.Conclusion: We observed associations between genetically predicted levels of three N-glycans PGP18, PGP33, and PGP109 and prostate cancer risk. Given the correlated nature of the N-glycans and that many N-glycans share genetic loci, pleiotropy is a major concern. Future work is warranted to better characterize the relationship between N-glycans and prostate cancer.Keywords: plasma N-glycans, prostate cancer, risk

Pengcheng Zhang,1– 4 Boyi Yu,1,2 Xiaodong Jin,1,2 Ting Zhao,1 Fei Ye,1,2 Xiongxiong Liu,1,2 Ping Li,1,2 Xiaogang Zheng,1 Weiqiang Chen,1,2 Qiang Li1,2 1Institute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China; 2University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China; 3The First Hospital of Lanzhou University, Lanzhou, 730000, People’s Republic of China; 4Department of Radiation Oncology, The First Hospital of Lanzhou University, Lanzhou, 730000, People’s Republic of ChinaCorrespondence: Weiqiang Chen; Qiang LiInstitute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of ChinaEmail chenwq7315@impcas.ac.cn; liqiang@impcas.ac.cnPurpose: Gold nanoparticles (AuNPs) are widely studied as radiosensitizers, but their radiosensitization in carbon ion radiotherapy is unsatisfactory. There is a lack of in vivo data on the radiosensitization of AuNPs under carbon ion irradiation. This study focused on the radiosensitization effect of AuNPs in the mouse melanoma cell line B16-F10 in vitro and in vivo.Materials and Methods: 11-mercaptoundecanoic acid (11-MUA)-coated gold (Au) nanoparticles (mAuNPs) formulations were prepared and characterized. To verify the radiosensitization effect of mAuNPs, hydroxyl radicals were generated in aqueous solution, and the detection of intracellular reactive oxygen species (ROS) and clone survival were carried out in vitro. The tumor growth rate (TGR) and survival of mice were analyzed to verify the radiosensitization effect of mAuNPs in vivo. The apoptosis of tumor cells was detected, and the expression of key proteins in the apoptosis pathway was verified by immunohistochemistry.Results: The intracellular ROS level in B16-F10 cells was enhanced by mAuNPs under carbon ion irradiation. The sensitization rate of mAuNPs was 1.22 with a 10% cell survival rate. Compared with irradiation alone, the inhibitory effect of mAuNPs combined with carbon ion irradiation on tumor growth was 1.94-fold higher, the survival time of mice was prolonged by 1.75-fold, and the number of apoptotic cells was increased by 1.43-fold. The ratio of key proteins Bax and Bcl2 in the apoptosis pathway was up-regulated, and the expression of caspase-3, a key executor of the apoptosis pathway, was up-regulated.Conclusion: In in vivo and in vitro experiments, mAuNPs showed radiosensitivity to carbon ion irradiation. The sensitization effect of mAuNPs on mice tumor may be achieved by activating the mitochondrial apoptosis pathway and increasing tumor tissue apoptosis. To our best knowledge, the present study is the first in vivo evidence for radiosensitization of mAuNPs in tumor-bearing mice exposed to carbon ion irradiation.Keywords: gold nanoparticles, radiosentization, carbon ion irradiation, tumor-bearing mice, apoptosis

Yunfang Luo,1,* Fang Yu,1,* Xianjing Feng,1 Di Liao,1 Yuanlin Ying,1 Xi Li,1 Qin Huang,1 Zeyu Liu,1 Minping Wei,1 Tingting Zhao,1 Lin Zhang,1 Ruxin Tu,1 Jian Xia1– 3 1Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Clinical Research Center for Cerebrovascular Disease of Hunan Province, Central South University, Changsha, Hunan, People’s Republic of China; 3National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian XiaDepartment of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of ChinaTel +86 731 84327216Fax +86 731 84327401. Email xjian1216@csu.edu.cnPurpose: Previous studies have shown a rising incidence of early-onset symptomatic intracranial atherosclerosis (sICAS), which has brought a severe economic burden to social development. This study aimed to evaluate the molecular biomarkers associated with early-onset sICAS and to seek possible intervention strategies for early prevention.Patients and Methods: We consecutively recruited patients with sICAS and divided them into two groups based on age: early-onset sICAS group as age ≤ 60 years old and late-onset sICAS group as age > 60 years old. We collected and compared the demographic data and laboratory results of each group. A bivariate logistic regression model was applied to evaluate the independent molecular biomarkers of early-onset sICAS.Results: A total of 1007 subjects with sICAS were enrolled in this study, comprising 519 patients in the early-onset sICAS group and 488 patients in the late-onset sICAS group. Bivariate logistic regression analysis demonstrated an increased level of white blood cell, platelet, albumin globulin ratio, free triiodothyronine, and a decreased level of total bile acid, urea nitrogen, high-density lipoprotein, homocysteine, and fibrinogen in the early-onset sICAS group when compared to the late-onset group.Conclusion: Our study showed the relevance between early sICAS and circulating levels of different molecular biomarkers. Detection of these related molecular biomarkers may provide a simple way for early sICAS preventions in the future.Keywords: ischemic stroke, symptomatic intracranial atherosclerosis, molecular biomarkers

Tingting Zhao,1,* Jing Guo,1,* Yafang Song,2 Hao Chen,2 Mengzhu Sun,1 Lu Chen,3 Hao Geng,3 Lixia Pei,3 Jianhua Sun3 1Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China; 2Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China; 3Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianhua Sun; Lixia PeiDepartment of Acupuncture Rehabilitation, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, People’s Republic of ChinaEmail 377201634@qq.com; 11801758@qq.comBackground: Migraine is the second-leading cause of disability worldwide. It is often characterized by attacks of severe, mostly unilateral, pulsating headache associated with symptoms such as photophobia, phonophobia, nausea, vomiting, and cutaneous allodynia. Acupuncture therapy has been used worldwide for the treatment of migraine. However, no visual bibliometric analysis has been conducted on the effects of acupuncture on migraine over the past 20 years. Therefore, this study aimed to explore the current status and trends on the use of acupuncture in the treatment of migraine from 2000 to 2020.Purpose: The objective of this study is to identify the current status and emerging trends of the global use of acupuncture on migraine from 2000 to 2020 using CiteSpace and VOSviewer.Methods: Web of Science databases were searched for publications related to acupuncture therapy for treating migraine between 2000 and 2020. CiteSpace and VOSviewer were used to analyze the number of publications per year, countries, institutions, authors, journals, references, and keywords.Results: A total of 572 publications were included in the final analysis. The total number of publications has continued to increase with some fluctuations over the past 20 years. The most productive country and institution in this field were the USA, and Chengdu University of Traditional Chinese Medicine, respectively. The most active and cited authors were Liang FR and Linde K, respectively. Cephalalgia was the most productive, cited, and co-cited journal. The Linde K (2005) had the highest co-citation, citation number and centrality. The keywords “migraine” ranked first in frequency. The common type of migraine (tension-type headache), research method (randomized controlled trial, multicenter, double-blind), acupuncture’s role (prophylactic, quality of life, pain), and evaluation (meta-analysis, systematic review) were the hotspots and frontier trends of acupuncture therapy on migraine between 2000 and 2020.Conclusion: The present study examined the research-related trend in acupuncture therapy on migraine using bibliometric methods and identified the statement and research frontiers over the past two decades. This may help researchers to identify potential hotspots and new directions for future research in this field.Keywords: acupuncture, migraine, bibliometric analysis, CiteSpace, VOSviewer, network

Tong Zhao,1 Yuqin Tian,2 Xinjia Ding,3 Lin Liu,4 Bowen Tan,5 Bin Yang,5 Jianlin Wu,5 Ting Lei,6 Ruoyu Wang,2 Yan Ding5,7 1Department of Oncology, The Affiliated Zhongshan Hospital of Dalian University, Dalian, People’s Republic of China; 2Department of Care Operations, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 3Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China; 4Navy Qingdao Special Care Center, Qingdao, 266071, People’s Republic of China; 5The Institute for Translational Medicine, The Affiliated Zhongshan Hospital of Dalian University, Dalian, People’s Republic of China; 6Department of Thoracic Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China; 7Department of Pediatrics, Children’s Hospital of Boston, Harvard Medical School, Boston, MA, 02115, USACorrespondence: Yan Ding; Ruoyu Wang Email yan.ding@childrens.harvard.edu; wangruoyu1963@163.comAbstract: Multiple primary cancers (MPC) occurring in the same individual is considered rare but being increasingly recognized owing to the longer cancer survival nowadays. Despite of accumulating experience in diagnosis, effective treatment remains to be problematic in many scenarios. Genetic testing-based targeted therapy could be an invaluable option for both diagnosis and treatment of such patients. Here we present a 74-year-old male with triple primary cancers including kidney, prostate, and lung with metastatic tumor on the costal bones. The patient visited the hospital for persistent cough and hemoptysis, and a diagnosis of squamous cell carcinoma of the left lung was made by bioptic fiberoptic bronchoscopy. A previous history included renal cancer controlled by Sorafenib and prostate cancer controlled by Goserelin. Radiotherapy and platinum-based chemotherapy failed to help the patient and the tumor size increased over a period of 6 months. In order to seek better therapeutical options, we performed targeted sequencing using the cancerous tissues from his lung, kidney, and prostate cancers. Briefly, the results identified VHL, EGFR, PIK3CA, TP53, and AKT1 mutations in lung cancer, AKT1, FGFR2, and TP53 mutations in renal cancer, and FGFR2 mutations in prostate cancer. A combined medication targeting PIK3CA and AKT1 signaling was recommended and the patient was given BKM120 (PIK3CA, Phase III clinical trial) and MK2206 (AKT, phase III clinical trial). Revisit chest CTs after 4 months and 9 months showed a significant shrinkage of tumor size by 40% and 80%, respectively. Our experience demonstrated a good example that genetic analysis could be valuable to diagnose and precisely treat multiple primary cancers.Keywords: multiple primary cancers, next generation sequencing, targeted therapy, Buparlisib, BKM120, MK2206

Xin Jiang,1,* Wenqi Zhao,1,* Tiantian Zhao,2,* Mei Yang,1 Hongbin Yuan,1 Jun Qian,2 Zhenghua Xiang3 1Department of Anesthesiology, Changzheng Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of General Surgery, Affiliated Xinchang Hospital of Shaoxing University, Zhejiang, People’s Republic of China; 3Department of Neurobiology, Key Laboratory of Molecular Neurobiology, Ministry of Education, Naval Medical University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenghua XiangDepartment of Neurobiology, Key Laboratory of Molecular Neurobiology, Ministry of Education, Naval Medical University, No. 800 Xiangyin Road, Shanghai, 200433, People’s Republic of ChinaTel +86 21 81871044Fax +86 21 81885822Email xiang-zhenghua@163.comJun QianDepartment of General Surgery, Affiliated Xinchang Hospital of Shaoxing University, No. 117 Middle Gushan Road, Xinchang, Zhejiang, 312500, People’s Republic of ChinaTel +86 575 8638079Email qianj001@163.comPurpose: To detect the spatio-temporal expression of S100A4 in a spinal nerve ligation (SNL) rat model. Also to figure out which other molecules directly interact with S100A4 to explore the possible mechanisms which might be involved in neuropathic pain.Methods: Seven-week-old male SD rats were used for the SNL model construction. Immunofluorescence and Western blotting were used to detect the spatio-temporal expression of S100A4 in the model. S100A4 was co-labeled with a number of related molecules and marker molecules that can distinguish between cell types. After intrathecal injection of S100A4 neutralizing antibody, the behavioral changes of SNL rats were recorded, and molecular changes compared. The direct interaction between S100A4 and other related molecules was verified by co-immunoprecipitation (co-IP) to explore its possible mechanism.Results: After spinal nerve ligation, the content of S100A4 in the dorsal root ganglion (DRG) and spinal dorsal horn increased significantly. Intrathecal injection of S100A4 neutralizing antibody could effectively relieve the mechanical pain in rats. co-IP revealed a direct interaction between S100A4 and RAGE.Conclusion: The content of S100A4 in the DRG and spinal dorsal horn of SNL rats increased, compared with that of the control group. Intrathecal injection of S100A4 neutralizing antibody could effectively relieve the mechanical pain in SNL rats. S100A4 may be involved in the production of neuropathic pain through RAGE or other ways, but the specific mechanism needs to be further studied.Keywords: neuropathic pain, S100 calcium binding protein A4, receptor for advanced glycation end products, spinal nerve ligation model

Yingying Qi, Lina Guo, Yanchao Liu, Tonghang Zhao, Xianwen Liu, Yang Zhang Department of Anesthesiology, Liaocheng People’s Hospital, Liaocheng, Shandong, People’s Republic of ChinaCorrespondence: Yang ZhangDepartment of Anesthesiology, Liaocheng People’s Hospital, No. 67, Dongchang West Road, Liaocheng, 252000, Shandong, People’s Republic of ChinaTel +86-0635-8276414Email zhangyang3309@163.comPurpose: Sevoflurane (SEV) is a frequently used volatile anesthetic in cancer surgery. Sevoflurane treatment has been shown to suppress the migration and invasion of several human cancer cells. However, the effect of sevoflurane on glioma remains largely unclear.Methods: Glioma cell lines (U251 and U343) were treated by various concentrations of sevoflurane. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), flow cytometry assay, and transwell assay were performed to detect the cell viability, apoptosis, migration and invasion. Western blot assay was employed to detect the protein levels of β-catenin, c-Myc, CyclinD1, β-catenin, N-cadherin, vimentin, and DEK. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine the expression level of miR-218-5p. The target interaction between miR-218-5p and DEK was predicted through bioinformatics analysis and verified by dual-luciferase reporter assay system.Results: We found that sevoflurane aberrantly inhibited the abilities on viability, migration, invasion, EMT and β-catenin signaling and promoted cell apoptosis in U251 and U343 cells in a dose-dependent manner. MiR-218-5p strikingly suppressed the abilities of proliferation, migration, invasion rather than apoptosis and activation of β-catenin signaling. Sevoflurane could facilitate the miR-218-5p expression, and its suppressing effects on glioma cells were reversed by pre-treatment with miR-218-5p inhibitors or pcDNA3.1/DEK in vitro and in vivo. Silencing of miR-218-5p reverted sh-DEK and sevoflurane-induced repression on proliferation, migration, invasion, and β-catenin signaling, and promotion on apoptosis in the glioma cells.Conclusion: Our data showed that sevoflurane inhibited the proliferation, migration, invasion, and enhanced the apoptosis in glioma cells through regulating miR-218-5p/DEK/β-catenin axis.Keywords: glioma, sevoflurane, miR-218-5p, DEK, β-catenin signaling pathway

Wei Zhou,1,2 Shuang-long Li,3 Ti Zhao,3 Le Li,3 Wen-bin Xing,3 Xiang-jun Qiu,3 Wei Zhang1 1The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of China; 2Nanyang City Central Hospital, Nanyang 473009, People’s Republic of China; 3School of Basic Medicine, Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaCorrespondence: Wei ZhangThe First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of ChinaEmail zhangw571012@126.comXiang-jun QiuSchool of Basic Medicine, Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaEmail lyxiangjun@126.comObjective: We developed and validated a sensitive and reliable UPLC-MS/MS method for simultaneous determination of dezocine (DEZ), midazolam (MDZ) and its metabolite 1-hydroxymidazolam (1-OH-MDZ) in beagle plasma and investigated the effect of dexmedetomidine (DEX) on the pharmacokinetics of DEZ, MDZ and 1-OH-MDZ in beagles.Materials and Methods: Diazepam was used as the internal standard (IS); the three analytes and IS were extracted by acetonitrile precipitation and separated on an Acquity UPLC BEH C18 column using acetonitrile-0.1% formic acid as mobile phase in gradient mode. In positive ion mode, the three analytes and IS were monitored by multiple reaction monitoring (MRM). Six beagles were designed as a double cycle self-control experiment with 0.15 mg/kg in the first cycle (Group A). After a 1-week washout period, the same six beagles were slowly injected intravenously with 2 μg/kg DEX in the second cycle (Group B), with continuous injection for 7 days. On the seventh day, 0.5 hr after intravenous injection of 2 μg/kg DEX, the six beagles were intramuscularly given with DEZ 0.33 mg/kg and MDZ 0.15 mg/kg.Results: Under the conditions of this experiment, this method exhibited a good linearity for each analyte. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect and stability have also met the requirements.Conclusion: The developed UPLC-MS/MS method for simultaneous determination of DEZ, MDZ and 1-OH-MDZ in beagles plasma was accurate, reproducible, specific, and suitable. DEX could inhibit the metabolism of DEZ and MDZ and increase the exposure of DEZ and MDZ in beagles. Therefore, the change of therapeutic effect and the occurrence of adverse reactions caused by drug–drug interaction should be paid attention to when the drugs were used in combination.Keywords: dexmedetomidine, dezocine, midazolam, 1-hydroxymidazolam, pharmacokinetics, drug–drug interactions

Wenli Mao,1,* Heng Yin,2,* Wenya Chen,1,* Tingxiu Zhao,1 Shaofeng Wu,3 He Jin,1 Biaoyan Du,1 Yuhui Tan,2 Ren Zhang,2,3 Yanli He1,3 1Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China; 2Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China; 3Research Center for Integrative Medicine of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanli He; Ren Zhang Tel +86 20-39358015; +86 20-39358007 Fax +86 20-39358020Email blhhh@gzucm.edu.cn; zren@gzucm.edu.cnPurpose: Dioscin, a natural glycoside derived from many plants, has been proved to exert anti-cancer activity. Several studies have found that it reverses TGF-β 1-induced epithelial–mesenchymal transition (EMT). Whether dioscin can reverse EMT by pathways other than TGF-β is still unknown.Methods: We used network-based pharmacological methods to systematically explore the potential mechanisms by which dioscin acts on lung cancer. Cell Counting Kit-8 assay, scratch healing, Transwell assay, Matrigel invasion assay, immunofluorescence assay, and Western blotting were employed to confirm the prediction of key targets and the effects of dioscin on EMT.Results: Here, using network-based pharmacological methods, we found 42 possible lung cancer-related targets of dioscin, which were assigned to 98 KEGG pathways. Among the 20 with the lowest p-values, the PI3K-AKT signaling pathway is involved and significantly related to EMT. AKT1 and mTOR, with high degrees (reflecting higher connectivity) in the compound-target analysis, participate in the PI3K-AKT signaling pathway. Molecular docking indicated the occurrence of dioscin-AKT1 and dioscin-mTOR binding. Functional experiments demonstrated that dioscin suppressed the proliferation, migration, invasion, and EMT of human lung adenocarcinoma cells in a dose-dependent manner, without TGF-β stimulation. Furthermore, we determined that dioscin downregulated p-AKT, p-mTOR and p-GSK3β in human lung adenocarcinoma cells without affecting their total protein levels. The PI3K inhibitor LY294002 augmented these changes.Conclusion: Dioscin suppressed proliferation, invasion and EMT of lung adenocarcinoma cells via the inactivation of AKT/mTOR/GSK3β signaling, probably by binding to AKT and mTOR, and inhibiting their phosphorylation.Keywords: dioscin, lung adenocarcinoma, epithelial–mesenchymal transition, network-based pharmacology

Junpeng Ma,1 Wei Chen,2 Ke Wang,1 Kaibing Tian,1 Qi Li,3 Tianna Zhao,4 Liwei Zhang,1,3,5,6 Liang Wang,1,5,6 Zhen Wu,1,3,5,6 Junting Zhang1,5,6 1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People’s Republic of China; 3China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China; 4Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 5Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, People’s Republic of China; 6Beijing Key Laboratory of Brian Tumor, Beijing, People’s Republic of ChinaCorrespondence: Junting Zhang; Liang WangBeijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, People’s Republic of ChinaTel +86-10-59978431Fax +86-10-59971377Email zhangjunting2003@aliyun.com; saintage7@126.comPurpose: The roles of T (brachyury) isoforms in chordomas remain unclear. This study aimed to investigate the different roles and mechanisms of them in chordomas.Patients and methods: The expression of T isoforms mRNAs in 57 chordomas was assessed, and a prognosis analysis was conducted. Cell apoptosis, proliferation and cell cycle assays were performed after specific T isoform mRNA knockdown. Whole-transcriptome sequencing, Gene Set Enrichment Analysis, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis and competing endogenous RNA (ceRNA) analysis were conducted.Results: As revealed in this study, the T-long isoform was a significant risk factor (hazard ratio [HR], 1.09; P=0.018) and the T-short isoform was a protective factor (HR, 0.24; P=0.012) associated with tumor recurrence. After T-long isoform knockdown, the cell cycle was arrested at G0/G1 phase and cell proliferation was significantly inhibited. A bioinformatic analysis revealed that the upregulation of H19, P21 and GADD45B; downregulation of SKP2 and CDK2; and accompanying changes in the P53 signaling pathway consistently contributed to G0/G1 arrest. After T-short isoform knockdown, the cell cycle was arrested at G2/M phase and cell apoptosis tended to increase slightly (P=0.067). The upregulation of YWHAZ and downregulation of E2F1 and its target genes might contribute to cell cycle arrest in G2/M phase and apoptosis. In addition, the ceRNA network, consisting of long noncoding RNAs, mRNAs and microRNAs, was established.Conclusion: The T-long isoform was a risk factor and the T-short isoform was a protective factor for chordoma recurrence. In addition, the cell cycle was the main target of T isoforms knockdown, and the changes in the downstream transcriptome may contribute to the different effects of specific T isoform knockdown on the changes in the cell cycle distributions and apoptosis and proliferation of chordoma cells.Keywords: brachyury, ceRNA, cell cycle, chordoma, prognosis, whole-transcriptome sequencing

Nai-Li Wei,1,2,* Zi-Fang Quan,3,4,* Tong Zhao,1,* Xu-Dong Yu,4 Qiang Xie,1 Jun Zeng,1 Fu-Kai Ma,1 Fan Wang,1 Qi-Sheng Tang,1 Heng Wu,3 Jian-Hong Zhu11Fudan University Huashan Hospital, Department of Neurosurgery, State Key Laboratory for Medical neurobiology, Institutes of Brain Science, Shanghai Medical College-Fudan University, Shanghai, 20040, People’s Republic of China; 2Department of Neurosurgery, The Second Hospital of Lanzhou University, Lanzhou Gansu China, 730030, People’s Republic of China; 3Department of Neurology, The First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, People’s Republic of China; 4Institute of Neuroscience, Medical College, University of South China, Hengyang, Hunan, 421001, People’s Republic of China *These authors contributed equally to this workBackground: Stress-related obesity might be related to the suppression of the hypothalamic-pituitary- adrenocortical axis and dysregulation of the metabolic system. Chronic stress also induces the dysregulation of the reward system and increases the risk of food addiction, according to recent clinical findings. However, few studies have tested the effect of chronic stress on food addiction in animal models.Purpose: The objective of this study was to identify whether chronic stress promotes food addiction or not and explore the possible mechanisms.Method: We applied adaily 2 hrsflashing LED irradiation stress to mice fed chow or palatable food to mimic the effect of chronic stress on feeding. After 1 month of chronic stress exposure, we tested their binge eating behaviors, cravings for palatable food, responses for palatable food, and compulsive eating behaviors to evaluate the effect of chronic stress on food addiction-like behaviors. We detected changes in the levels of various genes and proteins in the nucleus accumbens (NAc), ventral tegmental area (VTA) and lateral hypothalamus using qPCR and immunofluorescence staining, respectively.Results: Behaviors results indicated chronic stress obviously increased food addiction score (FAS) in the palatable food feeding mice. Moreover, the FAS had astrong relationship with the extent of the increase in body weight. Chronic stress increased the expression of corticotropin-releasing factor receptor 1(CRFR1) was increased in the NAc shell and core but decreased in the VTA of the mice fed with palatable food. Chronic stress also increased expression of both dopamine receptor 2 (DR2) and mu-opioid receptor (MOR) in the NAc.Conclusion: Chronic stress aggravates the FAS and contributed to the development of stress-related obesity. Chronic stress drives the dysregulation of the CRF signaling pathway in the reward system and increases the expression of DR2 and MOR in the nucleus accumbens.Keywords: chronic stress, obesity, food addiction, dopamine receptor 2, mu-opioid receptor, nucleus accumbens

Fangping Ren,1,* Tian Zhao,2,* Bing Liu,3 Lei Pan11Department of Respiratory, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, People’s Republic of China; 2Department of Clinical Laboratory, The 161st Hospital of PLA, Wuhan, 430010, People’s Republic of China; 3Department of Disease Control and Prevention, PLA Rocket Force Characteristic Medical Center, Beijing, People’s Republic of China*These authors contributed equally to this workPurpose: The aim of this study was to identify the prognostic value of blood neutrophil–lymphocyte ratio (NLR) in patients with advanced non-small-cell lung cancer (NSCLC) who received immune checkpoint blockade (ICB) therapy.Materials and methods: 147 advanced NSCLC patients were enrolled in this study from June 30, 2013, to August 30, 2017. Survival analysis used the Kaplan and Meier methodology. The mean follow-up time was 2.6 years. The phenotypic T cells subtypes were evaluated by flow cytometry.Results: Of these patients, receiver operating characteristic (ROC) curves analysis were used to confirm the cut-off value, and patients were stratified into NLR>2.5 (n=88) and NLR≤2.5 (n=59) groups. Survival analysis showed that patients with NLR≤2.5 had significantly favorable overall survival (OS) and progression-free survival (PFS) compared with patients with NLR>2.5. After stratified with the tumor mutational burden (TMB), we further found that patients with NLR≤2.5 had significantly favorable OS and PFS compared with patients with NLR>2.5 in the group of patients with TMB>10, while in group patients with TMB≤10, patients with NLR≤2.5 had no significantly favorable OS and PFS compared with patients with NLR>2.5. The CD3+ and CD8+/CD28+ T cell subsets were significantly increased in patients with NLR≤2.5 (P

Li Zhou,1 Lianlian Liu,2 Wei Chai,1 Ting Zhao,1 Xin Jin,3 Xinxin Guo,1 Liying Han,2 Chunli Yuan1 1Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun 130021, China; 2Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun 130041, China; 3Department of Obstetrics and Gynecology, Dalian Municipal Women and Children’s Medical Center, Dalian 130041, China Background: Metabolic reprogramming is a characteristic of tumor cells and is considered a potential therapeutic target. Even under aerobic conditions, tumor cells use glycolysis to produce energy, a phenomenon called the “Warburg effect”. Pyruvate dehydrogenase kinase 1 (PDK1) is a key factor linking glycolysis and the tricarboxylic acid cycle. Dichloroacetic acid (DCA) reverses the Warburg effect by inhibition of PDK1 to switch cytoplasmic glucose metabolism to mitochondrial oxidative phosphorylation (OXPHOS).Methods: Cell viability was examined using a standard MTT assay. Glucose consumption and L-lactate production were measured using commercial colorimetric kits, and intracellular lactate dehydrogenase (LDH) activity was evaluated using cell lysates and an LDH Quantification Kit. Real-time PCR was used to detect the expression of related genes. The production of total ROS was evaluated by staining with dichlorofluorescin diacetate.Results: Comparison of various aspects of glucose metabolism, such as expression of key enzymes in glycolysis, lactate production, glucose consumption, mitochondrial oxygen consumption rate, and citric acid production, revealed that A2780/DDP cells were primarily dependent on glycolysis whereas A2780 cells were primarily dependent on mitochondrial OXPHOS. Mitochondrial uncoupling protein 2 (UCP2) protects against mitochondrial ROS while allowing energy metabolism to switch to glycolysis. Treatment of A2780 cells with various concentrations of DCA resulted in decreased expression of UCP2, a metabolic switch from glycolysis to mitochondrial OXPHOS, and an increase in oxidative stress induced by ROS. These effects were not observed in A2780/DDP cells with higher UCP2 expression suggesting that UCP2 might induce changes in mitochondrial functions that result in different sensitivities to DCA.Conclusion: Our results show that a drug targeting tumor metabolic changes affects almost the entire process of glucose metabolism. Thus, it is necessary to comprehensively determine tumor metabolic functions to facilitate individualized antitumor therapy. Keywords: DCA, glycolysis, mitochondrial function, glucose, metabolism

Clusters of topologically connected calorimeter cells around cells with large absolute signal-to-noise ratio (topo-clusters) are the basis for calorimeter signal reconstruction in the ATLAS experiment. Topological cell clustering has proven performant in LHC Runs 1 and 2. It is, however, susceptible to out-of-time pile-up of signals from soft collisions outside the 25 ns proton-bunch-crossing window associated with the event’s hard collision. To reduce this effect, a calorimeter-cell timing criterion was added to the signal-to-noise ratio requirement in the clustering algorithm. Multiple versions of this criterion were tested by reconstructing hadronic signals in simulated events and Run 2 ATLAS data. The preferred version is found to reduce the out-of-time pile-up jet multiplicity by ∼50% for jet pT∼20 GeV and by ∼80% for jet pT≳50 GeV, while not disrupting the reconstruction of hadronic signals of interest, and improving the jet energy resolution by up to 5% for 20

Lin Feng,1,2 Xiaozhe Yang,1,2 Yanfeng Shi,1,2 Shuang Liang,1,2 Tong Zhao,1,2 Junchao Duan,1,2 Zhiwei Sun1,2 1Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; 2Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China Background: The harmful effects following the release of nanomaterials into environment are of great concern today. Purpose: In this study, subacute effect due to co-exposure to low-dose silica nanoparticles (SiNPs) and lead acetate (Pb) on cardiovascular system was detected in Sprague Dawley male rats. Materials and Methods: Histopathological and ultrastructural changes of heart, aortic arch and abdominal aorta were detected. Blood routine and blood biochemistry examinations were used to show the changes of blood components. The fibrinolytic and plasmin factors, inflammation-related factors and myocardial-related enzyme in serum were analysised by ELISA and Western blot assay. Results: Histopathological and ultrastructural examination of heart, aortic arch, and abdominal aorta showed that serious damage occurred in co-exposure group (n=6/group). Blood routine examination showed that leukocytosis and thrombocytopenia increased markedly, while changes in the erythrocyte count were not obvious in the co-exposure group. The expression of alanine transaminase (ALT) decreased obviously in co-exposure group, while no significant changes were noted in the expression of aspartate aminotransferase (AST), cholesterol (CHO), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) in the co-exposure group on blood biochemistry analysis. In addition, data from ELISA analysis showed that the levels of fibrinolytic and plasmin factors, including thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), tissue-type plasminogen activator (t-PA), tissue factor pathway inhibitor (TFPI), and antithrombin III (AT III), were decreased, while those of human fibrinogen (FIB) and D-dimer (D2D) increased significantly in the co-exposure group. Moreover, the myocardial-related enzyme in serum, tested by ELISA, and cardiovascular-related protein expression of atrial natriuretic peptide and brain natriuretic peptide, tested by Western blot assay, was increased in the heart. Furthermore, the expression of inflammation factors such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) was increased in heart tissue subjected to combined exposure, which was manifested by Western blot assay, while the protein levels of angiotensin II (ANG II) and endothelin 1 were (ET-1) elevated in blood vessels in the co-exposure group. Conclusion: In conclusion, the major interactions involved in subacute toxicity due to co-exposure to low doses of SiNPs and Pb on cardiovascular system were expected to be additive and synergistic in nature. Co-exposure to SiNPs and Pb could aggravate the cardiovascular toxicity via endothelial damage, hypercoagulation, and cardiac injury in vivo. Keywords: SiNPs, Pb, combined exposure, cardiovascular toxicity, in vivo

Yanyan Wei,* Feng Dai,* Tianhui Zhao, Chen Tao, Lili Wang, Wei Ye, Wei Zhao Liver Disease Department, The Second Hospital of Nanjing, Medical School of Southeast University, Nanjing, China *These authors contributed equally to this work Background: The prognosis of massive hepatocellular carcinomas (MHCCs; ≥10 cm) remains worse. Purpose: The aim of this study was to evaluate the clinical benefits of transcatheter arterial chemoembolization (TACE) or TACE combined with percutaneous microwave coagulation therapy (PMCT) and the long-term survival rate of MHCC patients treated with these techniques. Patients and methods: A retrospective study was performed using data involving 102 MHCC patients admitted to the Second Hospital of Nanjing from September 2010 to August 2015. The median interval between treatments and overall survival (OS) was hierarchically analyzed using log-rank tests. Multivariate analysis was done using Cox regression model analysis. Results: The median survival time of MHCC patients was 3 months (range, 1–10 months) in the palliative group, 3 months (range, 1–39 months) in the TACE group, and 7.5 months (range, 3–30 months) in the TACE–PMCT group (P=0.038). The 6-, 12-, and 18-month OS rates for MHCC patients were 15%, 0%, and 0% in the palliative group, 30%, 25.63%, and 17.97% in the TACE group, and 50%, 41.67%, and 16.67% in the TACE–PMCT group, respectively (P=0.0467). In addition, TACE sessions had positive correlation with the survival time of MHCC patients (rho = 0.462, P

Chunliu Ning,1 Tengfei Zhao,1 Zechen Wang,1 Delong Li,1 Yurong Kou,2 Shaohui Huang1 1Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning, People’s Republic of China; 2Department of Oral Biology, School of Stomatology, China Medical University, Shenyang, Liaoning, People’s Republic of China Background: The purpose of this research was to determine whether neck dissection is necessary for the adenoid cystic carcinoma (ACC) of head and neck. Materials and methods: This article screened the abstract and full-text papers that investigated salivary gland primary ACC of head and neck. Two independent reviewers searched for articles published before October 2017 in three databases (Web of Science, PubMed, and Ovid), having no limits in date and language. Statistical data were analyzed statistically by Review Manager 5.3. Results: In total, 18 studies involving 2993 patients were included in the analysis. Of the 2993 patients, 473 patients had cervical lymph node metastasis, with a merge frequency of 16% (95% CI: 13–19). Among included articles, only 4 involved cervical lymph node occult metastases, with a merge frequency of 14% (95% CI: 9–20). There were 5 articles containing minor salivary glands (MiSGs) involving 370 patients of which 92 patients had cervical lymph node metastases and the merge frequency was 25% (95% CI: 11–38). Moreover, there were 4 studies on major salivary glands involving 904 patients of which 158 patients had cervical lymph node metastases and the merge frequency was 17% (95% CI: 15–20). Conclusion: Elective neck dissection is unnecessary for all patients with salivary gland ACC of head and neck. Moreover, compared with major salivary glands, MiSGs have a higher cervical lymph node metastases rate in ACC. The overall cervical lymph node metastases rate of MiSGs is 25%, which is enough to attract our attention. Therefore, we suggest that neck dissection might be applied to ACC of MiSGs. Keywords: adenoid cystic carcinoma, rates of cervical metastases and occult metastases, elective neck dissection, meta-analysis

Yurong Kou,1,* Tengfei Zhao,2,* Shaohui Huang,2 Jie Liu,3 Weiyi Duan,2 Yunjing Wang,2 Zechen Wang,2 Delong Li,2 Chunliu Ning,2 Changfu Sun2 1Department of Oral Biology, School of Stomatology, China Medical University, Shenyang, Liaoning, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning, People’s Republic of China; 3Centre of Science Experiment, China Medical University, Shenyang, Liaoning, People’s Republic of China *These authors contributed equally to this work Purpose: The aim of this study was to clarify whether level IIb dissection should be performed or avoided in the treatment of oral squamous cell carcinoma by meta-analysis.Materials and methods: Articles that were published before June 2017 were searched electronically in four databases (Web of Science, PubMed, Ovid and China National Knowledge Infrastructure) without any date or language restrictions by two independent reviewers. Abstracts and full-text papers which investigated the cervical metastases to level IIb from primary head and neck cancers and were deemed potentially relevant were screened. Data were analyzed using RevMan 5.3.Results: Four hundred and fifty-five abstracts and 129 full-text papers were screened, and 22 studies were included in the analysis. Among the 2001 patients included, 112 patients had level IIb metastases, the pooled frequency of which was 6% (95% confidence interval [CI]: 4.0–7.0). Among the 400 patients with tongue squamous cell carcinoma from 12 studies, 37 patients had level IIb metastases, the pooled incidence of which was 7% (95% CI: 5.0–10.0). Metastases to level IIb always went together with level IIa, and only three patients were found to have isolated level IIb metastases without involving the other levels.Conclusion: Due to the low frequency of level IIb nodal metastases in oral squamous cell carcinoma patients and rare occurrence of isolated level IIb, level IIb dissection could be avoided when the primary lesions were in early stages (T1 and T2), with the exception of tongue cancer. It is recommended to dissect level IIb tongue cancers without considering the stages of primary lesions and the lymph nodes status. It is also suggested that level IIb dissection should be performed in patients preoperatively or intraoperatively found with multilevel neck metastasis, especially level IIa metastasis. Keywords: level IIb, meta-analysis, neck dissection, oral squamous cell carcinoma, submuscular recess

Lisha Xie,1,* Tiancen Zhao,1,2,* Jing Cai,1 You Su,1 Zehua Wang,1 Weihong Dong1 1Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 2Department of Obstetrics and Gynecology, Central Hospital of Wuhan, Wuhan, China *These authors contributed equally to this work Objective: The objective of this study was to investigate the mechanism of sensitivity to methotrexate (MTX) in human choriocarcinoma cells regarding DNA damage response. Methods: Two choriocarcinoma cancer cell lines, JAR and JEG-3, were utilized in this study. An MTX-sensitive osteosarcoma cell line MG63, an MTX-resistant epithelial ovarian cancer cell line A2780 and an MTX-resistant cervical adenocarcinoma cell line Hela served as controls. Cell viability assay was carried out to assess MTX sensitivity of cell lines. MTX-induced DNA damage was evaluated by comet assay. Quantitative reverse transcription polymerase chain reaction was used to detect the mRNA levels of BRCA1, BRCA2, RAD51 and RAD52. The protein levels of γH2AX, RAD 51 and p53 were analyzed by Western blot. Results: Remarkable DNA strand breaks were observed in MTX-sensitive cell lines (JAR, JEG-3 and MG63) but not in MTX-resistant cancer cells (A2780 and Hela) after 48 h of MTX treatment. Only in the choriocarcinoma cells, the expression of homologous recombination (HR) repair gene RAD51 was dramatically suppressed by MTX in a dose- and time-dependent manner, accompanied with the increase in p53. Conclusion: The MTX-induced DNA strand breaks accompanied by deficiencies in HR repair may contribute to the hypersensitivity to chemotherapy in choriocarcinoma. Keywords: choriocarcinoma, chemotherapy hypersensitivity, DNA double-strand break, RAD51, p53