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Han Li,1,* Dongsheng Wei,2,* Huimin Cao,2 Yelei Han,1 Luzhen Li,1 Yuting Liu,1 Jiajie Qi,1 Xinyue Wu,1 Zhe Zhang2,3 1The First School of Clinical Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China; 2Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China; 3Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhe Zhang, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, No. 33 Beiling Street, Shenyang, 110032, People’s Republic of China, Tel +86-18102459155, Email pedtrainzhzh7676@163.comPurpose: Myocardial infarction (MI) is a prevalent cardiovascular disorder affecting individuals worldwide. There is a need to identify more effective therapeutic agents to minimize cardiomyocyte damage and enhance cardioprotection. Ginkgo biloba extract is extensively used to treat neurological disorders and peripheral vascular diseases. The aim of this study was to determine the protective effects and mechanisms of ginkgetin on postinfarction cardiomyocytes through bioinformatics and experimental validation.Methods: Bioinformatics analysis was performed to predict the underlying biological mechanisms of ginkgetin in the treatment of MI. Next, we performed further validation through experiments. For in vivo studies, we used coronary ligation to construct an MI rat model. In vitro, oxygen and glucose deprivation (OGD) was performed to simulate ischemia in H9c2 cardiomyocytes.Results: Bioinformatics analysis revealed that the key targets of ginkgetin for MI treatment were MMP2, MMP9, and VEGFA. Immune infiltration analysis revealed that ginkgetin might be involved in immune regulation by acting on the TCR signaling pathway. The results of the GO enrichment analysis revealed that ginkgetin might protect the heart by acting on the cell membrane to alleviate the senescent apoptosis of cardiomyocytes after MI. In vivo studies revealed that ginkgetin ameliorated myocardial pathological damage and cardiac decompensation after MI. It also alleviated the inflammatory infiltration and senescent apoptosis of cardiomyocytes after MI. Additionally, ginkgetin can downregulate the activation signals of the TCR signaling pathway by dephosphorylating CD3 and CD28. In vitro studies revealed that ginkgetin attenuated elevated OGD-induced cytotoxicity, increased cell viability, and alleviated OGD-induced senescent apoptosis, thus protecting cardiomyocytes.Conclusion: Ginkgetin inhibits postinfarction myocardial fibrosis and cardiomyocyte hypertrophy, scavenges oxygen free radicals, decreases postinfarction limbic cell inflammatory infiltration, suppresses activation of the inflammatory-immune pathway, and delays postinfarction peripheral cells from undergoing senescent apoptosis, thus protecting the heart. Keywords: myocardial infarction, ginkgetin, senescence-associated secretory phenotype, immune infiltration, TCR signaling pathway

Jinrong Liu,&ast; Jin Qi,&ast; Jiadi Li,&ast; Tong Zhang, Jianing Ren, Zheyuan Zhang, Xiao Ning, Ran Zhang, Xiaoming Liu, Bing Li, Xiuping Wu Shanxi Medical University School and Hospital of Stomatology; Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Taiyuan, Shanxi, 030001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bing Li; Xiuping Wu, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, 030001, People’s Republic of China, Email libing-1975@163.com; wxp1666@sxmu.edu.cnPurpose: During fixed orthodontic treatment, oral hygiene is difficult to ensure and can easily lead to an imbalance in the oral micro-ecological balance. In this study, based on the adhesive properties of polydopamine (PDA) and the good antimicrobial and remineralization properties of carboxymethyl chitosan (CMC) and xylitol (Xy), new nanocomposites with both antimicrobial and remineralization capabilities were prepared to coat on orthodontic brackets.Methods: Composite carbon dots (CDs) were synthesized using carboxymethyl chitosan and xylitol, we characterized them and the antimicrobial properties of the CMC-Xy-CDs were investigated by co-cultivation with S. mutans in vitro and in vivo. The composite coating was then adhered to the brackets. After the characterization measurements, antibacterial properties against S. mutans and the ability to promote remineralization of isolated teeth were investigated.Results: Biological studies demonstrated that L929 cells co-cultured with CMC-Xy-CDs did not observe significant cytotoxicity and CMC-Xy-CDs have good biocompatibility. In the adhesive action of PDA, various characterizations have proved that CDs are modified on the brackets surface. In the antibacterial experiment, CMC-Xy-CDs and the adhesive coating on the brackets were found to have better antibacterial performance than the control group, with an antibacterial rate of up to 80%. In the animal experiment, the results of CMC-Xy-CDs promoting the healing of S. mutans infection wound models showed that there was a significant difference at 7d (P < 0.001), indicating that the experimental group had good antibacterial effects. The SEM of teeth after CMC-Xy-CDs promoted remineralization showed that the structure of the tooth surface became dense and some precipitation appeared, and the surface hardness measurement was significantly increased (p< 0.0001).Conclusion: Our study revealed that new nanocomposites with both antimicrobial and remineralization capabilities coated on orthodontic brackets provide a good basis for future clinical applications.Keywords: carbon dots, coating, antibacterial, remineralization, orthodontic brackets

Hui Zhang,1,2 Mengli Li,3 Zhiyu Mao,2 Tongtong Yin,2 Jiaying Qi,2 Fangfang Wang,2 Li Wang2 1School of Nursing, Suzhou Vocational Health College, Suzhou, Jiangsu, 215009, People’s Republic of China; 2School of Nursing, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215006, People’s Republic of China; 3School of Nursing, The Hong Kong Polytechnic University, Hong Kong, People’s Republic of ChinaCorrespondence: Li Wang, School of Nursing, Suzhou Medical College of Soochow University, No. 1 Shizi Street, Suzhou, Jiangsu, 215006, People’s Republic of China, Tel +86-512-6522-1499, Fax +86-512-6512-5097, Email li-wang-1@suda.edu.cnBackground: Blood flow restriction training (BFRT) can produce effects similar to high-intensity exercise at lower intensities, making it a potentially more suitable method for older adults with sarcopenia. This study aims to determine the efficacy of the intervention on improving physical fitness in older adults with sarcopenia when blood flow restriction (BFR) and aerobic exercise (AE) are combined (BFR-AE) and to explore the related metabolic and signaling mechanisms.Methods: This is a three-arm, parallel, randomized controlled trial. A total of 171 participants, aged 60 to 90 years, with sarcopenia will be randomly assigned (1:1:1) into one of three groups: a control group, an AE group, and a BFR-AE group. The participants in the control group will maintain their usual diet and activity habits. Those in the AE and BFR-AE groups will undergo a 12-week program of AE and BFR-AE respectively. The primary outcomes will include two long-term indicators: the 6-minutes walking test and 30-s chair stand test. Secondary outcomes will include additional long-term measures (eg, appendicular skeletal muscle mass index, handgrip strength, five-time chair stand test, lower extremity knee extensor and flexor muscle strength, sleep quality, emotion status, serum metabonomic and signal proteins), as well as instantaneous indicators (eg, blood pressure, heart rate, saturation of pulse oxygen, rating of perceived exertion, pain score and blood lactate concentration), adherence to exercise, and adverse events. Outcomes will be assessed at one of or all the time points of baseline, 12 and 24 weeks.Discussion: It is expected that, after 12 weeks of intervention, both exercise groups will show improvements in cardiorespiratory and muscular fitness, with the BFR-AE group demonstrating greater benefits than the AE group alone.Keywords: blood flow restriction, aerobic exercise, sarcopenia, muscular fitness, cardiorespiratory fitness

Mengli Li,1,&ast; Tongtong Yin,1,&ast; Jiaying Qi,1 Minhao Shi,1 Fangfang Wang,1 Zhiyu Mao,1 Hui Zhang,1,2 Li Wang1 1School of Nursing, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2School of Nursing, Suzhou Vocational Health College, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Wang; Hui Zhang, Email li-wang-1@suda.edu.cn; zhanghuichange@sina.comObjective: To explore the cut-off values and health evaluations of upper arm circumference (AC) and calf circumference (CC) on sarcopenia in Chinese community-dwelling older people.Methods: In this cross-sectional study, AC, CC, handgrip strength, muscle mass and gait speed were measured in 1537 Chinese community-dwelling older people in Sub-study 1. Correlation analysis, receiver operator characteristic curve (ROC curve) analysis, and consistency analysis were used for determination of AC and CC cut-off values for sarcopenia diagnosis (sarcopenia-AC and CC). Thereafter, 269 participants accepted additional assessments on physical function, body composition and muscle strength in Sub-study 2. T-test or Mann-Whitney U-test was used to explore the differential effects of sarcopenia-AC and CC on health indicators between sarcopenic and non-sarcopenic participants.Results: In Sub-study 1, the Area Under ROC (AUC) of AC and CC for sarcopenia screening were greater than 0.700 (P< 0.05). The cut-off values, sensitivity and specificity of AC and CC on sarcopenia in males were 25.9 cm (86.0%, 83.6%) and 33.7 cm (90.7%, 81.4%) whereas in females were 26.5 cm (70.8%, 69.7%) and 33.0 cm (86.5%, 69.4%), respectively. In Sub-study 2, the participants with sarcopenia-AC or sarcopenia-CC showed lower muscle strength and lower fat and muscle mass than the ones without (P< 0.05). Additionally, males instead of females with sarcopenia-AC or sarcopenia-CC showed worse performance in time-up and go test and 6-Minute Walk Test (P< 0.05). However, the 30-second chair stand test was not different between participants with and without sarcopenia-AC or sarcopenia-CC in both sexes.Conclusion: We found accurate and Chinese population targeted cut-off values of AC and CC on sarcopenia diagnosis (25.9 cm and 33.7 cm in males; 26.5 cm and 33.0 cm in females) and a good evaluation effect of AC and CC on fat and muscle mass, muscle strength and physical functions in males, not females.Keywords: sarcopenia, upper arm circumference, calf circumference, health assessment

Xingqiang Wang,1,2,&ast; Xianna Yang,3,&ast; Shiqi Wang,3,&ast; Xiaofang Tian,1 Jianmei Yin,3 Nian Liu,3 Pengtao Di,1 Jipeng Qi,3 Ya Li,3 Jimin Chen,3,4 Yang Wu,1 Jingjin Wu,1,2 Weiqing Zhao,5 Jiangyun Peng,1,2 Ling Zhang,1,2 Lingli Gu1 1Department of Rheumatology, The No. 1 Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan, 650021, People’s Republic of China; 2Yunnan Provincial Clinical Medicine Research Center of Rheumatism in TCM, Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, Yunnan, 650021, People’s Republic of China; 3The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650021, People’s Republic of China; 4Department of Integrative Internal Medicine, The Lijiang Hospital of Traditional Chinese Medicine, Lijiang, Yunnan, 674100, People’s Republic of China; 5Department of Rheumatology and Immunology, The First People’s Hospital of Yunnan Province and The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650034, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling Zhang; Lingli Gu, Email zebaiyuan@126.com; guyuxin82@126.comAbstract: Glucocorticoids (GC) are crucial in the treatment of rheumatoid arthritis (RA), but discontinuing GC effectively in RA patients poses a significant challenge for rheumatologists. In this two-stage, single-center, non-randomized controlled trial, we investigated the benefits of combining Chinese traditional herbal treatment with csDMARDs to aid GC discontinuation in terms of GC tapering, disease control, and safety. A total of 231 participants were enrolled, of which 150 eligible subjects were included in the first phase and allocated to three groups (control group, treatment group 1, and treatment group 2) based on their willingness to take traditional Chinese medicine and syndrome differentiation, in a 1:1:1 ratio. All groups received basic treatment consisting of methotrexate tablets (10 mg, qw), leflunomide (10 mg, qd), and stratified GC bridging therapy and tapering regimen (The intervention regimen was developed based on rigorous adherence to available evidence). Treatment group 1 received basic treatment combined with Juanbi Granule, while treatment group 2 received basic treatment combined with Yupingfeng Guizhi Decoction Granule. Efficacy was evaluated after a 12-week follow-up, with slightly adjustments to the treatment group based on efficacy and change of syndrome, followed by continued observation until 24 weeks to complete the study. The efficacy evaluation and data analysis were conducted in a blinded manner, including group label concealment, data cleaning, confounder and control regimen analysis, and outcome analysis. This project has received ethical approval from the Ethics Committee of Yunnan Provincial Hospital of Traditional Chinese Medicine (YLZ [2022] Ethical Review No. (006)-01) and has been registered with the China Clinical Trials Registry (Registration number: ChiCTR2300067676, Registered 17 January 2023, https://www.chictr.org.cn/showproj.html?proj=184908). This trial was the first to evaluate the clinical efficacy of combining Chinese herbal medicines with standard Western medicines to facilitate the discontinuation of glucocorticoid (GC) therapy in patients with rheumatoid arthritis (RA).Keywords: rheumatoid arthritis, glucocorticoids tapering, clinical trial, traditional Chinese medicine, Yupingfeng Guizhi Decoction, Juanbi Decoction

Yun Sun,1,&ast; Tongtong Yin,2,&ast; Mengli Li,2,3 Fangfang Wang,2 Jiaying Qi,2 Hui Zhang,2,4 Li Wang,2 Jiehua Zhao,5 Yu Zhang5 1Department of Oncology, Suzhou BenQ Medical Center, Suzhou, Jiangsu, People’s Republic of China; 2School of Nursing, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 3School of Nursing, Hong Kong Polytechnic University, Hongkong, People’s Republic of China; 4School of Nursing, Vocational Health College, Suzhou, Jiangsu, People’s Republic of China; 5Department of Nursing, Suzhou BenQ Medical Center, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Zhang; Jiehua Zhao, Email zhangyu-sz1985@outlook.com; hannah.zhao@benqmedicalcenter.comPurpose: This study aimed to establish equations for estimating muscle mass through anthropometric parameters or together with physical function parameters in the community-dwelling older adults, providing a simple way of muscle mass assessment.Methods: In this cross-sectional descriptive study, a total of 1537 older adults were recruited from the community and accepted the measurements of height, weight, upper arm and calf circumferences, grip strength, and walking speed. Body composition including appendicular skeletal muscle mass (ASM) was measured using bioelectrical impedance analysis (BIA). Participants were randomly divided into the development or validation group. Stepwise multiple linear regression was applied to develop equations in the development group. Thereafter, Pearson correlation coefficients, Bland-Altman plots, paired t-test, intraclass correlation coefficient (ICC) and paired-samples t-tests were used to assess the validity of the equations.Results: All parameters were significantly correlated with ASM (r = 0.195~0.795, P < 0.001) except for the age in the validation group (P = 0.746). The most optimal anthropometric equation was: [adjusted R2 = 0.911, standard error of the estimate (SEE) = 1.311, P < 0.001]. Comparatively speaking, this equation showed high correlation coefficient (r = 0.951, P < 0.001) and ICC (ICC = 0.950, P < 0.001). No significant differences were found between BIA-measured ASM and the estimated ASM. The Bland-Altman plot showed that the mean difference between the estimated ASM and BIA-measured ASM was 0 kg and the limits of agreement of ASM was − 2.70~2.60 kg. Furthermore, inclusion of physical function did not significantly improve the adjusted R2 and SEE.Conclusion: The anthropometric equation offers a practical alternative simple and dependable method for estimating ASM in community-dwelling older adults.Keywords: appendicular muscle mass, anthropometry, physical function, estimation equation, older adults

Huaiyi Cheng,&ast; Yifan Zhao,&ast; Yue Wang,&ast; Yuxi Hou, Ran Zhang, Mingrui Zong, Lingxiang Sun, Yingyu Liu, Jin Qi, Xiuping Wu, Bing Li School and Hospital of Stomatology, Shanxi Medical University, Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bing Li; Xiuping Wu, Email libing1975vip@163.com; 77wxp@163.comBackground: Carbon dots (CDs), a novel nanomaterial, have gained significant attention over the past decade due to their remarkable fluorescence properties, low toxicity, and biocompatibility. These characteristics make them promising in various applications, especially in biomedicine. However, most CDs are currently synthesized using chemical materials, and their biocompatibility falls short of natural compounds. Research on extracting CDs from natural sources is limited, and their potential in biomedicine remains largely unexplored.Methods: We extracted CDs from resveratrol, a natural plant compound, and enhanced their water solubility using citric acid. Characterization of resveratrol-based carbon dots (RES-CDs) was carried out using various techniques, including UV-Vis, SEM, TEM, FTIR, XRD, and fluorescence spectroscopy. Extensive biocompatibility tests, wound healing assays, cell migration studies, and angiogenesis experiments were conducted using human umbilical vein endothelial cells (HUVEC). In addition, we investigated the biocompatibility and wound healing potential of RES-CDs in an in vivo rat model of inflammation.Results: RES-CDs exhibited stable yellow-green fluorescence under 365-nanometer ultraviolet light and demonstrated excellent biocompatibility. In wound healing experiments, RES-CDs outperformed resveratrol in terms of cell scratch healing, migration, and tube formation. In a rat skin defect model, RES-CDs promoted wound healing and stimulated the formation of blood vessels and tissue regeneration near the wound site, as evidenced by increased CD31 and VEGF expression.Conclusion: Resveratrol-derived CDs with enhanced water solubility show superior performance in tissue healing compared to resveratrol. This discovery opens new possibilities for the clinical application of resveratrol-based carbon dots. Keywords: carbon dots, wound healing, resveratrol, fluorescence, bio-imaging, biocompatibility

Xiao-Yan Li,1 Xin-Guang Liu,2 Zhi-Ling Dong,1 Liang-Ting Chai,3 Yan-Jun Liu,4 Jie Qi,3 Jie Zhao1 1Department of Clinical Laboratory, Handan Central Hospital, Handan, Hebei, People’s Republic of China; 2Department of Clinical Laboratory, Children’s Hospital of Hebei, Shijiazhuang, Hebei, People’s Republic of China; 3Department of Clinical Laboratory, Handan First Hospital, Handan, Hebei, People’s Republic of China; 4Department of General Surgery, Handan Central Hospital, Handan, Hebei, People’s Republic of ChinaCorrespondence: Jie Zhao, No. 59 Congtai North Road, Congtai District, Handan City, Hebei Province, 057150, People’s Republic of China, Tel +86-18003205055, Email zjlxy8160@163.comBackground: Drug-resistant Pseudomonas aeruginosa infections rapidly increased and contributed to life-threatening nosocomial infections; however, the distribution, species, drug susceptibility and dynamic trends of P. aeruginosa infection in China remained unclear. This study was conducted to better understand the epidemiological data of increased P. aeruginosa infections from 2016 to 2022 in a hospital in China.Methods: This study involved 3301 patients infected with P. aeruginosa, diagnosed using a nosocomial infection surveillance system in a tertiary hospital between 2016 and 2022. The P. aeruginosa infections from 2016 to 2022 were assessed according to the hospital department and species, and the drug susceptibility was evaluated using 16 antimicrobial agents.Results: The P. aeruginosa infection prevalence in the hospital department was: Neurosurgery (14.30%), Emergency (13.30%), and Critical Care Medicine (11.69%). Samples for P. aeruginosa infection identification were from sputum (72.52%) and other secreta (9.91%). The P. aeruginosa infections demonstrated a greater sensitivity to amikacin (AMK, 91.82%), tobramycin (TOB, 82.79%), and gentamycin (GEN, 82.01%); however, P. aeruginosa infection demonstrated greater resistance to ticarcillin (22.57%), levofloxacin (21.63%), and ciprofloxacin (18.00%).Conclusion: The P. aeruginosa infections were commonly observed in the Neurosurgery, Emergency, and Critical Care Medicine departments and demonstrated greater sensitivity to AMK, TOB, and GEN than the other drugs.Keywords: Pseudomonas aeruginosa, distribution, drug susceptibility, dynamic trend

Jiaxin Qi,1,2,&ast; Xiayu Ren,1,2,&ast; Yanjuan Hou,2 Yaqing Zhang,1,2 Yanru Zhang,1,2 Enxue Tan,1,2 Lihua Wang2 1Second Department of Clinical Medicine, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 2Division of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lihua Wang, Division of Nephrology, The Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, Shanxi, 030000, People’s Republic of China, Tel +8615234166600, Email lihuawang236@126.comPurpose: The triglyceride-glucose (TyG) index is a new index of insulin resistance (IR), and its association with hyperuricemia (HUA) is unclear. The aim of this study was to investigate whether TyG is an independent risk factor for hyperuricemia (HUA) in patients with nonalcoholic fatty liver disease (NAFLD).Patients and Methods: We retrospectively analyzed 461 patients with ultrasound-confirmed NAFLD and calculated the TyG index. Multivariate logistic regression was used to analyze the relationship between the TyG index and HUA in NAFLD patients. The correlation between the TyG index and HUA was further confirmed by a restricted cubic spline. Furthermore, the stability of the association between TyG index and HUA was examined using subgroup analysis. Receiver operating characteristic (ROC) curves were constructed to evaluate the predictive value of the TyG index on HUA. Multivariate linear regression was used to analyze the linear relationship between the TyG index and serum uric acid.Results: A total of 166 HUA patients and 295 non-HUA patients were included in the study. The results of multivariate logistic regression analysis showed that after controlling the confounding risk factors, TyG was still an independent risk factor for HUA (OR = 2.00, 95% CI: 1.38 − 2.91, p < 0.001). Restricted cubic splines showed that HUA risk increased linearly with TyG across the entire TyG range. The ROC curve showed that TyG index was better than triglyceride in predicting HUA in NAFLD patients, with AUC values of 0.62 and 0.59, respectively. Multiple linear regression analysis showed that TyG index was significantly positively correlated with blood uric acid (B = 1.37, 95% CI: 0.67– 2.08, p < 0.001).Conclusion: TyG index is an independent risk factor for HUA in patients with NAFLD. The increase of the TyG index level is closely related to the occurrence and development of HUA in patients with NAFLD.Keywords: triglyceride-glucose index, insulin resistance, non-alcoholic fatty liver disease, hyperuricemia, serum uric acid

IntroductionIn the US, despite the recent decline in breast cancer deaths, a persistent mortality disparity exists between black and white women with breast cancer, with black women having a 41% higher death rate. Several studies are now reporting that racial disparities can exist independent of socioeconomic and standard of care issues, suggesting that biological factors may be involved. Caveolin-1 (Cav1) loss in the tumor stromal compartment is a novel clinical biomarker for predicting poor outcome in breast cancer including triple negative subtype, however the mechanism of Cav1 loss is unknown. We previously identified miR-510-5p as a novel oncomir and propose here that the high levels observed in patients is a novel mechanism leading to stromal Cav1 loss and worse outcomes.MethodsCav1 was identified as a direct target of miR-510-5p through luciferase, western blot and qPCR assays. Stromal cross talk between epithelial cells and fibroblasts was assessed in vitro using transwell co-culture assays and in vivo using xenograft assays.ResultsWe found that Cav1 is a direct target of miR-510-5p and that expression in fibroblasts results in an ‘activated’ phenotype. We propose that this could be important in the context of cancer disparities as we also observed increased levels of circulating miR-510-5p and reduced levels of stromal Cav1 in black women compared to white women with breast cancer. Finally, we observed a significant increase in tumor growth when tumor cells were co-injected with miR-510-5p expressing cancer associated fibroblasts in vivo.ConclusionWe propose that miR-510-5p mediated negative regulation of Cav1 in fibroblasts is a novel mechanism of aggressive tumor growth and may be a driver of breast cancer disparity.

Peiyao Li1,2 &ast;, Jialin Qi3 &ast;, Baishun Zhou,1 Ting Ding,4 Juan Long,5 Heng Xiao1 1Department of Pathology, School of Medicine, Hunan Normal University, Changsha, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, China NHC Key Laboratory of Carcinogenesis, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of Pathology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Department of Endocrinology, Yiyang Central Hospital, Yiyang, People’s Republic of China; 5Department of Dermatology, Hunan Children’s Hospital, Changsha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Heng Xiao, Department of Pathology, School of Medicine, Hunan Normal University, 371 Tongzipo Road, Changsha, Hunan, 410013, People’s Republic of China, Tel +86-731-88912501, Email emmaxiao1988@hotmail.comBackground: Hailey–Hailey disease (HHD) is an autosomal dominant cutaneous disorder that manifests as repeated blisters and erosions on flexural or intertriginous skin areas. The calcium-transporting ATPase type 2C member 1 gene (ATP2C1) encodes the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1), whose deficiency is responsible for HHD. An ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was previously identified in a Han Chinese family with HHD.Methods: In this study, the identified ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was investigated in transfected human embryonic kidney 293 cells to analyze its pathogenic mechanism in HHD patients by using cycloheximide chase assay, CCK8 assay and in silico modeling of SPCA1 mutant.Results: Cycloheximide chase assay showed that the degradation rate of the SPCA1 mutant was not obviously faster than that of the normal SPCA1. CCK8 assay showed that cell proliferation rates in the wild-type, A109_Q120del, and empty vector control groups all decreased in the gradient Mn2+ solutions in a dose-dependent manner. The cell proliferation rate in the wild-type was lower than that in the A109_Q120del and empty vector control (both P < 0.01), indicating overexpression of normal SPCA1 may rather induce Golgi stress, and even cell death. The cell proliferation rate in the A109_Q120del was lower than that in the empty vector control (P < 0.01), indicating that overexpression of the mutated SPCA1 may decrease its detoxification capability. Three-dimensional (3D) structure model of SPCA1 built by SWISS-MODEL and PyMOL showed that absence of the 12 amino acids from p.Ala109 to p.Gln120 in the SPCA1 mutant can cause obviously shortened transmembrane 2, which may affect correct localization of SPCA1 on the Golgi.Conclusion: These results demonstrate that the ATP2C1 mutation (c.325-2A>G, p.Ala109_Gln120del) may cause impaired SPCA1 capability to detoxify Mn2+ and abnormal SPCA1 structure, which reveals a new side for the pathogenesis of HHD.Keywords: ATPase secretory pathway Ca2+ transporting 1, Hailey–Hailey disease, pathogenesis, secretory pathway Ca2+/Mn2+-ATPase 1

Haiyan Cui,1 Baohua Zhang,2 Mei Ruan,3 Chunmei Fang,4 Ning Li,5 Xiaoqin Sun,6 Junmei Qi,1 Rongrong Zuo,1 Shuangshuang Zhang,1 Jiansheng Rong2 1Pathology Department, The Fourth People Hospital of Zibo, Zibo, Shandong, 255067, People’s Republic of China; 2Pathology Department, Zibo Central Hospital, Zibo, Shandong, 255036, People’s Republic of China; 3Oncology Department, The Fourth People Hospital of Zibo, Zibo, Shandong, 255067, People’s Republic of China; 4Gynecology Department, Zibo Lianchi Women & Infants Hospital, Zibo, Shandong, 255000, People’s Republic of China; 5Department of Physical Examination, Zichuan Traditional Chinese Medicine Hospital, Zibo, Shandong, 255100, People’s Republic of China; 6Pathology Department, Zibo Maternal and Child Health Hospital, Zibo, Shandong, 255000, People’s Republic of ChinaCorrespondence: Jiansheng Rong, Pathology Department, Zibo Central Hospital, No. 54 Gongqingtuan West Road, Zibo, Shandong, 255067, People’s Republic of China, Tel/Fax +86 533-2360321, Email rongjiansheng_zbzx@163.comBackground: Human papillomavirus (HPV) is a major cause of cervical cancer (CC) occurrence. This study aimed to explore whether abnormal microRNA (miR)-3653 is associated with HPV infection and to investigate the clinical value of miR-3653 in the diagnosis and prognosis of CC.Methods: Tumor tissues and adjacent non-cancerous tissues were collected from 136 patients with CC. Cervical tissues from 101 patients with uterine fibroids were collected as controls. The expression of miR-3653 was measured by quantitative real-time PCR. The ability of miR-3653 to discriminate between HPV positive (HPV+) and HPV negative (HPV-) CC patients, and to discriminate patients from controls was assessed by receiver operating characteristic analysis. Kaplan–Meier curves and Log rank tests were used to evaluate the relationship of miR-3653 with survival of CC patient. Whether miR-3653 could function as a prognostic indicator was evaluated by univariate and multivariate Cox analyses.Results: miR-3653, highly expressed in CC tissues, was associated with HPV infection, tumor diameter, International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis in CC patients. Additionally, miR-3653 was increased in HPV+ controls, CC patients and CC cells. Moreover, miR-3653 could screen HPV+ controls, screen HPV+ patients and screen CC patients. Furthermore, miR-3653 was associated with the survival of CC patients (log-rank P < 0.001) and could serve as an independent prognostic indicator for CC patients.Conclusion: miR-3653, increased in CC, is related to HPV infection and may serve as a diagnostic and prognostic biomarker for CC patients.Keywords: miR-3653, microRNA, HPV, cervical cancer, diagnosis, prognosis

Qi Chen,1,&ast; Jingqiu Liang,2,&ast; Ling Liang,2 Zhongli Liao,2 Bin Yang,3 Jun Qi2 1Department of Anesthesiology, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 2Chongqing Cancer Multi-Omics Big Data Application Engineering Research Center, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 3Department of Anesthesiology, the First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Yang, Department of Anesthesiology, the First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China, Email yangbin4332@outlook.com Jun Qi, Chongqing Cancer Multi-Omics Big Data Application Engineering Research Center, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China, Email qqyc2005@163.comPurpose: The neutrophil-to-lymphocyte ratio (NLR) is a useful prognostic marker for various diseases and surgery-induced immunosuppression. While opioids are important in general anesthesia, the association between immediate perioperative immune monitoring and opioid consumption for postoperative analgesia after video-assisted thoracoscopic surgery (VATS) is unknown. We aimed to investigate the effect of analgesic techniques on opioid-induced immune perturbation, and the feasibility of NLR as an indicator of opioid-induced immune changes.Patients and Methods: Patients were randomly assigned to two groups: Group P (n=40) or Group C (n=40). Patients in group P received ultrasound-guided paravertebral block (PVB) before surgery, and followed by sufentanil patient-controlled intravenous analgesia (PCIA) after surgery, and group C received sufentanil PCIA only. The total and differential white blood cell counts, including CD4+ T lymphocyte counts, CD8+ T lymphocyte were recorded before surgery and at 24 and 72 hours after surgery. NLR was determined using the frequencies of lymphocyte subpopulations. The cumulative dose of sufentanil were recorded at 24 and 24h after surgery while the 40-item quality of recovery questionnaire (QoR-40) score were assessed at 48h after the surgery.Results: At 24 and 48 hours after surgery, a lower sufentanil consumption, and higher QoR-40 recovery scores were found in group P than in group C (P< 0.05). In biochemical analyses, the values of NLR were lower in group P compared to group C (p< 0.0001) and ratio of CD4/CD8 were higher in group P compared to group C (p< 0.05) on day three after surgery. NLR showed excellent predictive capability for immunosuppression, with an area under the curve (AUC) of 0.92 [95% confidence interval (CI), 0.86– 0.98, P < 0.0001].Conclusion: Opioid-sparing pain management strategies may affect postoperative immunosuppression and NLR could be a reliable indicator of opioid-related immunosuppression. Moreover, opioid-sparing pain management strategies could improve patient’s satisfaction in VATS.Keywords: neutrophil-to-lymphocyte ratio, immunosuppression, paravertebral block, opioid, analgesia

Pengxiang Qu,1,2 Jinpeng Zhao,1,2 Huizhong Hu,1,2 Wenbin Cao,1,2 Yanru Zhang,1,2 Jia Qi,1,2 Bin Meng,1,3 Juan Zhao,2,4 Shuangqing Liu,1 Chong Ding,1,2 Yuqi Wu,1,2 Enqi Liu1,2 1Laboratory Animal Center, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, People’s Republic of China; 2Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an, Shaanxi, People’s Republic of China; 3The Assisted Reproduction Center, Northwest Women’s and Children’s Hospital, Xi’an, People’s Republic of China; 4Department of Hematology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Enqi Liu, Email liuenqi@xjtu.edu.cnBackground: Extracellular vesicles (EVs), as a promising platform for drug delivery, have attracted much attention. Degradation and regeneration of EVs maintain their homeostasis in vivo, but this regeneration is missing in the in vitro culture (IVC) system, which is likely to lead to negative effects. It is particularly concerning that most studies involving the addition of EVs in IVC seem to overlook this point.Methods: We used rabbit embryos and oviduct fluid EVs as a model of embryo development to examine the effect of loss or gain of EV functionality in an IVC system. Embryonic development ratios were determined in each group. Malondialdehyde and ammonium ions in the culture medium were measured. RNA-seq, reactive oxygen species (ROS) staining, immunofluorescence of LC3 and H3K36me3, and qPCR of oxidative stress-related genes and autophagy-related genes of blastocysts in the in vivo group, non-EVs group, con-EVs group, and R-EVsM group was implemented.Results: Incubation of embryos with 9.1× 1011 EV particles/mL had a positive effect at 48 h and 72 h, which disappeared by 96 h, however. EVs at a concentration of 9.1× 1012 particles/mL even showed a negative effect at 96 h. As culture time in the IVC system was increased, the amount of malondialdehyde and ammonium ions in the culture medium was increased, and there was a decrease in embryonic development activity of EVs. Lack of EV renewal in the IVC system impaired embryonic development competence, while replacement of EVs and medium during IVC could sustain embryonic development. Loss or gain of renewal in the IVC system affected EVs’ influence on embryo transcriptome, embryonic ROS, autophagy, epigenetic state and apoptosis.Conclusion: Loss of renewal in the IVC system affected EVs’ role in embryonic development by causing an imbalance in ROS, autophagy, abnormal H3K36me3 levels and apoptosis, while gain of renewal in the IVC system reduced these adverse effects and ensured the beneficial function of EVs.Keywords: extracellular vesicles, hazardous effect, renewal, embryo, in vitro culture

Feng Su,1,&ast; Yong Fang,1,&ast; Jinjie Yu,1 Tian Jiang,1 Siyun Lin,1 Shaoyuan Zhang,1 Lu Lv,2 Tao Long,2 Huiwen Pan,2 Junqing Qi,2 Qiang Zhou,3 Weifeng Tang,4 Guowen Ding,2 Liming Wang,5 Lijie Tan,1 Jun Yin1 1Department of Thoracic Surgery, Zhongshan Hospital of Fudan University, Shanghai, People’s Republic of China; 2Department of Cardiothoracic Surgery, Affiliated People’s Hospital of Jiangsu University, Jiangsu, People’s Republic of China; 3Department of Thoracic Surgery, Sichuan Cancer Hospital & Institute, Sichuan, People’s Republic of China; 4Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Jiangsu, People’s Republic of China; 5Department of Respiratory, Shanghai Xuhui Central Hospital, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Yin; Lijie Tan, Zhongshan Hospital of Fudan University, 180 Fenglin road, Xuhui District, Shanghai, 200032, People’s Republic of China, Email jun_yin@fudan.edu.cn; tan.lijie@zs-hospital.sh.cnBackground: The σ 1A subunit of the adaptor protein 1 (AP1S1) participates in various intracellular transport pathways, especially the maintenance of copper homeostasis, which is pivotal in carcinogenesis. It is therefore rational to presume that AP1S1 might also be involved in carcinogenesis. In this hospital-based case-control study, we investigated the genetic susceptibility to ESCC in relation to SNPs of AP1S1 among Chinese population.Methods: A database containing a total of 1303 controls and 1043 ESCC patients were retrospectively studied. The AP1S1 SNPs were analyzed based on ligation detection reaction (LDR) method. Then, the relationship between ESCC and SNPs of AP1S1 was determined with a significant crude P< 0.05. Then the logistic regression analysis was used for the calculation for adjusted P in the demographic stratification comparison if a significant difference was observed in the previous step.Results: AP1S1 rs77387752 C>T genotype TT was an independent risk factor for ESCC, while rs4729666 C>T genotype TC and rs35208462 C>T genotype TC were associated with a lower risk for ESCC, especially in co-dominant model and allelic test for younger, male subjects who are not alcohol-drinkers nor cigarette smokers.Conclusion: AP1S1 rs77387752, rs4729666 and rs35208462 polymorphisms are associated with susceptibility to ESCC in Chinese individuals. AP1S1 SNPs may exert an important role in esophageal carcinogenesis and could serve as potential diagnostic biomarkers.Keywords: AP1S1, single nucleotide polymorphism, SNP, esophageal squamous cell carcinoma, ESCC

Wei Liu,&ast; Wei Wang,&ast; Jiangmei Liu, Yunning Liu, Shidi Meng, Feixue Wang, Zheng Long, Jinlei Qi, Jinling You, Lin Lin, Lijun Wang, Maigeng Zhou, Peng Yin National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Peng YinNational Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 27 Nanwei Road, Beijing, 100050, People’s Republic of ChinaTel +86 010-63015058Email yinpeng@ncncd.chinacdc.cnBackground: To examine trends in chronic obstructive pulmonary disease (COPD) mortality and years of life lost (YLL) due to COPD for all provinces in China during 2005– 2020.Methods: Data for COPD mortality were derived from China National Mortality Surveillance System (NMSS). We analyzed the numbers and age-standardized rates of death and YLL due to COPD in China, during 2005– 2020. We carried out decomposition analysis to analyze the drivers of change in COPD deaths during the study period.Results: The age-standardized mortality rate of COPD in China decreased significantly from 99.5/100,000 in 2005 to 50.5/100,000 in 2020. Similar trend was seen in the age-standardized YLL rate. The mortality rate increased with age. During 2005– 2020, the age-standardized mortality rate decreased in all provinces (except for Tibet) with the largest decline in Jilin (− 77.8%), Henan (− 68.4%) and Fujian (− 67.1%). The decreased number of deaths was decomposed as population growth (8.5%) and population ageing (69.7%) with offset by decline of age-specific mortality (− 87.5%).Conclusion: COPD remains an important public health problem in China, though significant reductions of COPD mortality and YLL rate were observed. Vigorous prevention and control strategies should be enhanced to improve the quality of life of COPD patients and reduce the premature death caused by COPD in Chinese population.Keywords: COPD, mortality, YLL

Chengxin Li,&ast; Jiejiu Lu,&ast; Siru Zhou, Yinyi Wei, Chunle Lv, Taotao Liu, Yun Wu, Dongni Wu, Jianying Qi, Rongda Cai Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Taotao LiuDepartment of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi Province, People’s Republic of ChinaTel +86 7715356789Email liutaotao@gxmu.edu.cnPurpose: To analyze factors influencing tacrolimus (TAC) trough concentration (C0) in β-thalassemia major (β-TM) pediatric patients after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and to investigate the effects of genotype polymorphism and drug-drug interactions on TAC trough concentration in children with β-TM. Furthermore, to analyze the correlation between TAC C0 and efficacy and adverse reactions.Patients and Methods: Prospectively collection of demographic information and details of combined treatment of patients with β-TM receiving HSCT, and genotypes of CYP3A4, CYP3A5, and ABCB1 (rs1045642, rs1128503, rs2032582) were obtained for each patient. Univariate analysis and multiple linear regression analysis were used to investigate influencing factors on TAC C0. The impact of different genotypes and the co-administration of azole antifungal drugs on β-TM patients receiving TAC were evaluated, together with the correlation between acute graft-versus-host disease (aGVHD), infection, and liver injury of TAC C0.Results: A total of 46 patients with 587 concentration data were included. The multiple linear regression results showed that the patient’s sex, weight, postoperative time, hemoglobin, platelet count, serum cystatin C, and combined voriconazole were independent influencing factors of the infusion trough concentration/daily dose, C0/Div. Age, body surface area, postoperative time, co-administration of voriconazole, and CYP3A4&ast;18B are independent influencing factors of C0/Dpo. Group comparisons showed that voriconazole can affect TAC C0 administered intravenously (IV) and orally in β-TM pediatric patients, while patient genotype can affect TAC C0 during oral administration. TAC C0 does not correlate with aGVHD or liver injury, but infection may be associated with TAC C0.Conclusion: The concentration of TAC should be closely monitored when co-administered with voriconazole. It is worth considering that the influence of genotype on the trough concentration of oral TAC and individualized drug administration warrant investigation. Finally, this study indicated that C0 is not suitable as an indicator of the efficacy of TAC.Keywords: β-thalassemia major, allogeneic hematopoietic stem cell transplantation, tacrolimus, trough concentration

Qing Ye,1,* Qiqiang Zhang,1,* Huijuan Yao,1,* Ajing Xu,1 Yan Liu,1 Jia Qi,1 Hai Zhang,2 Jian Zhang1 1Department of Pharmacy, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People’s Republic of China; 2Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian ZhangDepartment of Pharmacy, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, People’s Republic of ChinaTel/Fax +86 21-25077150Email zhangjian@xinhuamed.com.cnHai ZhangDepartment of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, 2699 High Tech West Road, Pudong New Area, Shanghai, 201204, People’s Republic of ChinaTel/Fax +86 21-20261401Email zhxdks2005@126.comBackground: Shegan Mixture (SGM) is a traditional Chinese medicine that has anti-inflammatory and therapeutic effects on asthma. However, its active ingredients and combined action mechanism have not been fully elucidated so far. The purpose of this study was to screen the effective ingredients and targets and elucidate the synergistic action mechanism of SGM in asthma mice using the network pharmacological approach.Methods: A mouse model of asthma model was used in this study. Mice were orally administered SGM at three doses for 4 weeks and the effect of SGM on asthma was evaluated. The active ingredients and their targets of SGM were identified by searching databases, such as Traditional Chinese Medicine Systems Pharmacology Database (TCMSP). The main active ingredients were selected with parameters OB and DL. The synergistic action mechanisms of SGM in asthma were studied through key active ingredient-target interaction network and verified using surface plasmon resonance assay (SPR).Results: SGM exerts anti-asthmatic effects by reducing lung tissue damage and inflammatory factors (IFN-γ, IL-4, IL-5, and IL-13) in asthmatic mice. Twenty ingredients and 45 related proteins were selected as potential nodes using enrichment analysis and network analysis. Inflammation and smooth muscle regulation-related pathways were considered to be the main pharmacological mechanisms of SGM in the treatment of asthma. Especially, 5 molecule-target pairs (including 3 ingredients and 4 proteins) were well docked with each other and the SPR assay revealed that glabridin-PTGS2 had good binding with 44.5 μM Kd value.Conclusion: SGM exerts the synergistic anti-asthma effects by virtue of reducing lung-tissue damage and inflammatory factors in asthmatic mice, which explains the theoretical basis for the traditional Chinese medicine, SGM, to treat asthma. Our study thus sheds light on a variety of options including Chinese medicine that could potentially be used in the clinical treatment of asthma.Keywords: Shegan mixture, asthma, network pharmacology, surface plasmon resonance, traditional Chinese medicine

Ting Yang,1,2 Wen-Juan Wu,1 Li-Ming Tian,3 Deng-Feng Zhang,4 Xiao-Yan Yang,1 Jue Qi,1 Ying Tu,1 Li He1 1Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650023, People’s Republic of China; 2Department of Dermatology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, 435000, People’s Republic of China; 3Department of Dermatology, First Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People’s Republic of China; 4Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, People’s Republic of ChinaCorrespondence: Li HeDepartment of Dermatology, First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Wuhua District, Kunming, Yunnan, 650023, People’s Republic of ChinaTel/Fax +86 0871-65317895Email lihe_4785@163.comObjective: Androgens acting through the androgen receptor play a crucial role in the pathogenesis of acne. This study aimed to identify whether two key genes (CYP21A2 and CYP19A1) involved in the synthesis and metabolism of androgens were associated with Pillsbury III-IV severe acne vulgaris.Methods: We carried out a standard questionnaire survey about acne and enlisted 600 Pillsbury III-IV severe acne vulgaris patients and 652 healthy controls of Han Chinese descent from Yunnan, China in the study. Twenty-two single nucleotide polymorphisms (SNPs) were genotyped by SNaPshot assay and analyzed for association with severe acne.Results: There was no significant difference in gender between the two groups (P = 0.085), and the age of the acne case group was significantly lower than that of the control group (P < 0.001). Our results revealed that only two SNPs, rs6474 (p.Arg102Lys) (P = 0.001) and rs6465 (P = 0.025) of the CYP21A2 gene were significantly associated with severe acne among the Han Chinese. When subjects were divided into males and females, significant associations were observed only in male patients with severe acne vulgaris for four variants: CYP21A2 rs6474 (p.Arg102Lys) (P = 0.002); CYP21A2 rs6465 (P = 0.012); CYP19A1 rs8023263 (P = 0.037); and CYP19A1 rs2470152 (P = 0.007). Haplotype analyses showed that the distribution of CYP21A2 haplotypes was significantly associated with male patients, while no association of CYP19A1 haplotypes was observed. The structure of the human CYP21A2 consists of two substrate binding sites and one substrate access channel.Conclusion: This study shed a light on a potentially important effect of CYP21A2 and CYP19A1 genes in severe acne vulgaris in the Han Chinese, especially for male patients. Future studies using independently verified datasets from a broader geographical spectrum will be valuable in identifying the causal and functional variants responsible for severe acne vulgaris within the CYP19A1 and CYP21A2 genes.Keywords: androgen receptor, severe acne, synthesis, metabolism, genetic risk

Jing Qi, Feiyang Jin, Xiaoling Xu, Yongzhong Du Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, People’s Republic of ChinaCorrespondence: Yongzhong Du 866 Yu-Hang-Tang Road, Hangzhou, 310058, People’s Republic of ChinaTel +86-571-88208435Email duyongzhong@zju.edu.cnAbstract: Cancer immunotherapy is a promising treatment strategy that aims to strengthen immune responses against cancer. However, the low immunogenicity of tumor cells and inhibition of effector T cells in the tumor immunosuppressive microenvironment remain two major challenges. Immunogenic cell death (ICD) inducers not only directly kill cancer cells but also increase the tumor immunogenicity and induce antitumor immune responses. Immune checkpoint inhibitors can alleviate the inhibition of immune cells. Significantly, the combination of ICD inducers and immune checkpoint inhibitors elicits a remarkable antitumor effect. Nanoparticles confer the ability to modulate systemic biodistribution and achieve targeted accumulation of administered therapeutic agents, thereby facilitating the clinical translation of immunotherapies based on ICD inducers in a safe and effective manner. In this review, we summarize the nanoparticle-based chemical and physical cues that induce effective tumor ICD and elicit an antitumor immune response. In particular, combination of ICD inducers with immune checkpoint inhibitors can further reverse immunosuppression and prevent tumor metastasis and recurrence. An overview of the future challenges and prospects is also provided.Keywords: tumor immunotherapy, immunogenic cell death, nanoparticles, immune checkpoint inhibitors

Jianming Gong,* Xiangdong Kong,* Jinhui Qi, Jiangkun Lu, Shaofeng Yuan, Ming Wu Department of Surgery, Tinglin Hospital of Jinshan District, Shanghai 201505, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ming WuDepartment of Surgery, Tinglin Hospital of Jinshan District, No. 80 Siping North Road, Jinshan District, Shanghai 201505, People’s Republic of ChinaTel + 86-18121367005Email wum7005@126.comBackground: Thyroid cancer is one of the most common cancers with rising incidence worldwide, and papillary thyroid carcinoma (PTC) accounts for 80– 85% of thyroid malignancy. Although it has been reported that many genes relate to the carcinogenesis of PTC, the molecular mechanisms remain mostly unclear.Methods: QRT-PCR assay was performed to detect circRNA_104565, miR-134 and ELF2 expression. CCK8 assay was exercised to examine cell proliferation. Western blot was used to detect ELF2 expression.Results: We found that circRNA_104565 was highly expressed in PTC tissue and cell and promoted cell proliferation in vitro and in vivo. In addition, circRNA_104565 promoted cell proliferation in PTC by regulating the miR-134/ELF2 axis.Conclusion: Hence, revealing the function of circRNA_104565 in PTC is important for understanding the molecular mechanism of carcinogenesis and providing new biomarkers or therapeutic targets for PTC.Keywords: circRNA_104565, cell proliferation, PTC, miR-134, ELF2

Hong Lu,1,2 Jongphil Kim,3 Jin Qi,1,2 Qian Li,1 Ying Liu,1 Matthew B Schabath,4 Zhaoxiang Ye,1 Robert J Gillies,2 Yoganand Balagurunathan2,5 1Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China; 2Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 3Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 4Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 5Department of Machine Language, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USACorrespondence: Yoganand Balagurunathan; Robert J GilliesH. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USAEmail Yoganand.Balagurunathan@moffitt.org; Robert.Gillies@moffitt.orgRationale and Objectives: Evaluate ability of radiological semantic traits assessed on multi-window computed tomography (CT) to predict lung cancer risk.Materials and Methods: A total of 199 participants were investigated, including 60 incident lung cancers and 139 benign positive controls. Twenty lung window features and 2 mediastinal window features were extracted and scored on a point scale in three screening rounds. Multivariate logistic regression analysis was used to explore the association of these radiological traits with the risk of developing lung cancer. The areas under the receiver operating characteristic curve (AUROC), sensitivity, specificity, and positive predictive value (PPV) were computed to evaluate the best predictive model.Results: Combining mediastinal window-specific features with the lung window features-based model significantly improves performance compared to individual window features. Model performance is consistent both at baseline and the first follow-up scan, with an AUROC increased from 0.822 to 0.871 (p = 0.009) and from 0.877 to 0.917 (p = 0.008), respectively, for single to multi-window feature models. We also find that the multi-window CT based model showed better specificity and PPV, with PPV at the second follow-up scan improved to 0.953.Conclusion: We find combining window semantic features improves model performance in identifying cancerous nodules. We also find that lung window features are more informative compared to mediastinal features in predicting malignancy.Keywords: multi-window, radiological, CT, lung cancer, screening

Jinjie Yu,1,* Yunpeng Dong,1,* Weifeng Tang,2 Huiwen Pan,2 Lu Lv,2 Tao Long,2 Qiang Zhou,2 Junqing Qi,2 Jianchao Liu,2 Guowen Ding,2 Jun Yin,1 Lijie Tan1 1Department of Thoracic Surgery, Zhongshan Hospital of Fudan University, Shanghai, People’s Republic of China; 2Department of Cardiothoracic Surgery, Affiliated People’s Hospital of Jiangsu University, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Yin; Lijie TanDepartment of Thoracic Surgery, Zhongshan Hospital of Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, People’s Republic of ChinaTel +86 13917483128; +86 13681972151Email yin.jun2@zs-hospital.sh.cn; tan.lijie@zs-hospital.sh.cnBackground: The TGF-β signal pathways play a key role in the development and promotion of squamous cell carcinoma (SCC). The pathway is mediated by the SMAD family proteins that include SMAD3 and SMAD6. Our study aimed to evaluate the relationship between single nucleotide polymorphism (SNP) of SMAD3/SMAD6 and susceptibility to esophageal squamous cell carcinoma (ESCC) in the Chinese population.Patients and Methods: This was a hospital-based case–control study compromised of 1043 ESCC patients and 1315 non-cancer patients. Seven SMAD3/SMAD6 (rs8028147, rs3743343, rs3743342, rs8025774, rs8031440, rs803167, and rs34643453) SNPs were selected and used to evaluate their correlation with ESCC susceptibility. Genetic model tests, stratified analyses, linkage disequilibrium analyses, and haplotype analyses were performed in our study.Results: Participants with SMAD3 rs3743342 C>T, rs8025774 C>T, rs8031440 G>A or rs8031627 G>A had a significantly higher risk of ESCC. This was more evident in males, older patients (> 63 years), smokers, and non-alcohol drinking participants. Linkage disequilibrium analyses further revealed that there were strong correlations between SMAD3 rs3743342 C>T, rs8025774 C>T, rs8031440 G>A, and rs8031627 G>A. In the same line, haplotype analyses revealed that SMAD3 ACCCGGSMAD6A and SMAD3AGCCGGSMAD6A were associated with less susceptibility to ESCC while SMAD3ATTTAASMAD6A was associated with a higher risk of ESCC.Conclusion: SNPs of SMAD3 were related to higher susceptibility to ESCC. As such, they may contribute to the development of viable strategies for early diagnosis and treatment of ESCC. However, more detailed association mechanisms between SMAD3/SMAD6 SNPs and ESCC need further experiments to prove.Keywords: SMAD, single nucleotide polymorphism, esophageal squamous cell carcinoma

Fei Yang,* Rigao Chen,* Dangwei Gu, Qingqing Ye, Wei Liu, Jianhua Qi, Kai Xu, Xiaohong Fan Department of Spine Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaohong Fan Email 173787798@qq.comPurpose: Although lumbar spinal stenosis (LSS) is the most common spinal disease in the elderly, there is still a confusion about the appropriate surgical treatment strategy. The aim of this study was to compare the safety and efficacy of full-endoscopic and microscopic unilateral laminotomy for bilateral decompression (ULBD) for LSS in elderly patients.Patients and Methods: A retrospective analysis of 61 consecutive elderly patients with LSS who underwent either full-endoscopic (FE group) or microscopic (Micro group) unilateral laminotomy for bilateral decompression was performed. Clinical data were assessed before 2 weeks, 3 months, 6 months and 12 months after surgery using the Visual Analog Scale (VAS), the Oswestry Disability Index (ODI) and the modified MacNab criteria.Results: There are no significant differences in VAS (back and leg) and ODI between the two groups. However, the VAS back pain in the FE group was significantly improved compared to the Micro group at 2 weeks. The rate of excellent or good outcomes was 87.88% and 85.71% in the FE and Micro group, respectively (P> 0.05). The hospital stay and early ambulation in FE group were shorter than those in Micro group, but the operation time was longer (P< 0.05). The complications between the FE group (18.18%) and the Micro group (17.86%) were minor (P> 0.05).Conclusion: Both full-endoscopic and microscopic decompression have achieved favorable clinical results in treating elderly lumbar spinal stenosis, and the complications are minor. Full-endoscopic decompression has the advantages of small incision and rapid recovery, which can be used as an alternative for the treatment of lumbar spinal stenosis, especially the elderly with comorbidities.Keywords: central stenosis, minimally invasive spinal surgery, MISS, comorbidity, complication

Hua Li,1,* Limei Lv,2,* Chunyan Wu,3 Jisheng Qi,4 Baolin Shi5 1Department of Neurology, Anqiu People’s Hospital, Anqiu 262100, Shandong, People’s Republic of China; 2Department of Neurology, Traditional Chinese Medical Hospital of Anqiu, Anqiu 262100, People’s Republic of China; 3Department of Neurology, Affiliated Hospital of Weifang Medical College, Weifang 261031, Shandong, People’s Republic of China; 4Department of Rehabilitation Medicine, Shandong Rongjun General Hospital, Jinan 250000, Shandong, People’s Republic of China; 5Department of Neurology, Weifang People’s Hospital, Weifang 261031, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Baolin ShiDepartment of Neurology, Weifang People’s Hospital, No. 151 Guangwen Street, Kuiwen District, Weifang 261031, Shandong, People’s Republic of ChinaTel +86-15965096500Email cengbohuan58112@163.comBackground: β-Amyloid (Aβ) induces oxidative stress and inflammation of microglial cells, thus leading to Alzheimer’s disease. Methyl jasmonate (MeJA) is reported to have anti-inflammatory and anti-oxidant effects. However, the potential roles of MeJA in Aβ-induced cell activities and the underlying mechanism are unclear.Methods: Microglial cell line BV-2 was stimulated by 20 μM Aβ and/or 20 μM MeJA and then divided into four groups (control, Aβ, MeJA, and Aβ+MeJA). Cell viability was detected by MTT assay. MDA, SOD activity, and ROS were detected by fluorescence spectrophotometry and immunofluorescence assay. Nrf2 and HO-1 were detected by qRT-PCR and Western blot. Furthermore, inflammatory cytokines (p-NFκB, TLR4, TNF-α, IL-1β, and IL-6) and apoptosis factors (Bcl-2, Bax, and cl-casp-3) were detected by Western blot. TUNEL assay was applied to investigate apoptosis rate. Moreover, the mechanism of how MeJA played anti-oxidative stress and anti-inflammatory roles was investigated by silencing of Nrf2 via siRNA.Results: The result of MTT assay showed that MeJA improved the decreased viability of BV-2 cells induced by Aβ. The detection of MDA, SOD activity, and ROS showed the oxidative stress levels were decreased in Aβ+MeJA group compared with Aβ group. Nrf2, HO-1, and SOD were significantly up-regulated in Aβ+MeJA group compared with Aβ group (p< 0.01). In contrast, inflammatory cytokines were significantly down-regulated in Aβ+MeJA group compared with Aβ group (p< 0.05). Similarly, the expressions of apoptosis cytokines and TUNEL assay suggested a decreased apoptosis rate in Aβ+MeJA group compared to Aβ group (p< 0.01). Finally, results of Nrf2 knockdown experiment showed down-regulations of anti-oxidative stress factors (Nrf2, HO-1 and SOD), up-regulations of inflammatory cytokines, and increased ratio of Bax to Bcl in Aβ+MeJA+si-Nrf2 group compared with Aβ+MeJA group (p< 0.01).Conclusion: MeJA could relieve Aβ-induced oxidative stress and inflammatory response in microglial cells by activating Nrf2/HO-1 pathway.Keywords: methyl jasmonate, Nrf2-dependent HO-1 pathway, β-amyloid, oxidative stress, inflammatory cytokines

Hailong Liu,* Jie Ding,* Yanyuan Wu, Di Wu, Jun Qi Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun QiDepartment of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, People’s Republic of ChinaEmail qijun@xinhuamed.com.cnBackground: Although circulating tumor cells (CTCs) are considered as a surrogate marker in monitoring disease progression and treatment response in late stage prostate cancer (PCa), its clinical impact in localized PCa remains unclear, indicating the limitation that is simply based on cell count. This perspective observational study aimed to detect the epithelial-to-mesenchymal transition (EMT) subtypes of CTCs in localized PCa and analyze their clinical relevance and application in predicting PCa stages before surgery compared with the Partin table.Patients and Methods: Between August 2017 and April 2019, 80 newly diagnosed localized PCa patients were enrolled in the study. Peripheral blood samples (5 mL) were collected prior to surgery. The CanPatrolTM CTC enrichment technique, a size-based isolation method, was used to detect the EMT CTCs. Clinical relevance of the CTCs was analyzed with Spearman’s rank correlation test. Models to predict pathological were built with multivariate logistic regression. Receiver operating characteristic (ROC) curve and area under the curve (AUC) analysis were performed to evaluate the accuracy of the prediction model.Results: CTCs were detected in 55% of all patients. The biophenotypic CTCs were most valuable and closely correlated with PSA, Gleason score, D’Amico risk classification, and pathological stage in localized PCa. The mesenchymal subtype was rare in this population but associated with seminal vesicle invasion, while the epithelial subtype had limited clinical significance. In addition, the biophenotypic CTCs combined with traditional clinical variables were analyzed by multivariate logistic regression to predict organ-confined disease before surgery, of which the AUC reached 0.818 and was superior to the Partin table 2017 in our cohort.Conclusion: This study highlights the clinical impact of the biophenotypic CTCs in localized PCa, which was most closely related to clinical variables and could help to predict pathology outcomes before surgery.Keywords: circulating tumor cells, localized prostate cancer, EMT

Jing Qi, 1 Xiuzhi Guo, 1 Aihua Li 2 1Department of Respiration Medicine, Tai’an Central Hospital, Tai’an; 2Department of Respiration Medicine, Yankuang Group General Hospital, Jining, ChinaCorrespondence: Aihua LiDepartment of Respiration Medicine, Yankuang Group General Hospital, 560 Kuangjian East Road, Jining, Shandong 273500, ChinaTel +86 537 536 7018Fax +86 537 536 7017Email lahykjtzyy@sohu.comBackground: Several published meta-analyses have confirmed that single-agent maintenance therapy in advanced non-small-cell lung cancer (NSCLC) can prolong time to disease progression and potentially increase overall survival (OS) in comparison to placebo. However, whether doublet maintenance therapy can improve the survival of advanced NSCLC remains undetermined.Methods: We searched several databases for relevant trials. Prospective randomized controlled trials comparing doublet vs single-agent maintenance therapy in NSCLC patients were included for analysis. Outcomes of interest were OS, progression-free survival (PFS), and incidence of grade 3/4 toxicities.Results: A total of 1,950 advanced-NSCLC patients from six trials were included for analysis. Our results showed that doublet maintenance therapy in NSCLC patients significantly improved PFS (HR 0.74, 95% CI 0.59– 0.93; P=0.010), but not for OS (HR 0.95, 95% CI 0.85– 1.07; P=0.40) in comparison with single-agent maintenance therapy. Subgroup analysis by maintenance regimen showed that pemetrexed plus bevacizumab maintenance therapy significantly improved PFS, but not OS. In addition, there was no significant risk difference between doublet and single-agent maintenance therapy in terms of grade 3/4 hematologic and nonhematologic toxicities.Conclusion: Our study suggests that doublet maintenance therapy in advanced-NSCLC patients demonstrates PFS benefits, but not OS benefits, in comparison with single-agent maintenance therapy. Future trials are suggested to assess the long-term clinical benefit of doublet maintenance treatment in NSCLC patients and its impact on health-related quality of life.Keywords: targeted agents, maintenance therapy, doublet, single agent, meta-analysis

Jialin Qi,1,2,* Zhenmin Hu,1,2,* Heng Xiao,3 Ruijie Liu,2 Wei Guo,4 Zhichun Yang,5 Kewen Ma,2 Shitong Su,2 Ping Tang,1 Xunjian Zhou,2 Jianhua Zhou,1,2 Kuansong Wang1,2 1Department of Pathology, School of Basic Medical Science, Central South University, Changsha 410013, People’s Republic of China; 2Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, People’s Republic of China; 3Department of Pathology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 4Department of Pathology, Hunan Provincial People’s Hospital, Changsha, Hunan 410005, People’s Republic of China; 5Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kuansong Wang; Jianhua Zhou Email 13787146109@126.com; zhoujh15@163.comIntroduction: Differential diagnosis of metaplastic squamous cell carcinoma of breast (MSCCB) is difficult. In particular, in terms of metastatic MSCCB, because of the low speciality of traditional markers such as mammaglobin, gross cystic disease fluid protein-15 (GCDFP-15) and GATA binding protein 3 (GATA3), the most common problem is differentiating the spread of MSCCB to the lung from a primary lung squamous cell carcinoma. It is urgently required to explore a novel marker to aid in differential diagnosis.Aim: The aim of this study is to explore a novel marker to aid in the differential diagnosis of MSCCB from other squamous cell carcinomas (SCC) in other organs.Methods: We tested the expression of SOX10 in 375 human SCC specimens with immunohistochemistry (IHC).Results: In a series of 20 MSCCB, 9 (45%) were positive for SOX10. All of them were triple-negative MSCCB. Conversely, SOX10 was totally negative in another 205 SCC originating from lung, skin, cervix, oral mucosa, and esophagus. In a series of 150 triple-negative breast cancer and their metastatic foci, SOX10 labeling in the primary tumor and metastasis was 78% and 79.3%, respectively, and the agreement rate was 97.3% (P> 0.05).Conclusion: Our findings demonstrate that SOX10 was recommended for differentiating MSCCB from non-mammary metastasis to the breast, as well as for distinguishing primary SCC from metastatic MSCCB, and SOX10 may be valuable in the pathological diagnosis of breast-derived metaplastic squamous cell carcinoma.Keywords: SOX10, squamous cell carcinoma, breast, lung, differential diagnosis

Congyan Shu,1 Pengyan Sun,2 Hanghang Xie,3 Weiwei Huang,3 Jialong Qi,3 Yanbing Ma3 1Sichuan Institute for Food and Drug Control, Chengdu, 611731, People’s Republic of China; 2Yunnan Center for Disease Control and Prevention, Kunming 650022, People’s Republic of China; 3Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming 650118, People’s Republic of ChinaCorrespondence: Yanbing MaLaboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, People’s Republic of ChinaTel +86 871 68339287Fax +86 871 68334483Email yanbingma@126.comBackground: Fibroblast growth factor (FGF)-2 is overexpressed in various tumor tissues. It affects tumor cell proliferation, invasion and survival, promotes tumor angiogenesis and is tightly involved in the development of systemic and local immunosuppressive tumor mechanisms.Purpose: This study aimed to develop an effective vaccine against FGF-2 and to investigate the effects of anti-FGF-2 immunization on tumor growth and antitumor immune responses.Methods: A set of thirteen synthesized overlapping peptides covering all possible linear B-cell epitopes of murine FGF-2 and a recombinant FGF-2 protein were conjugated to virus-like particles (VLPs) of recombinant hepatitis B core antigen (HBcAg). The VLPs were immunized through a preventive or therapeutic strategy in a TC-1 or 4T1 grafted tumor model.Results: Immunization with FGF-2 peptides or full-length protein-coupled VLPs produced FGF-2-specific antibodies with a high titer. Peptide 12, which is located in the heparin-binding site of FGF-2, or protein-conjugated VLPs presented the most significant effects on the suppression of TC-1 tumor growth. The levels of IFN-γ-expressing splenocytes and serum IFN-γ were significantly elevated; further, the immune effector cells CD8+ IFN-γ+ cytotoxic T lymphocytes (CTLs) and CD4+ IFN-γ+ Th1 cells were significantly increased, whereas the immunosuppressive cells CD4+ CD25+ FOXP3+ Treg cells and Gr-1+ CD11b+ myeloid-derived suppressor cells (MDSCs) were decreased in the immunized mice. In addition, VLP immunization significantly suppressed tumor vascularization and promoted tumor cell apoptosis. In mice bearing 4T1 breast tumor, preventive immunization with FGF-2-conjugated VLPs suppressed tumor growth and lung metastasis, and increased effector cell responses.Conclusion: Active immunization against FGF-2 is a new possible strategy for tumor immunotherapy.Keywords: fibroblast growth factor-2, virus-like particle, VLP, anticytokine active immunization, tumor, immune response

Peng Li,1 Ruihua Luo,1 Lanwei Guo,2 Wenlu Li,3 Jinxing Qi1 1Department of Head Neck and Thyroid Surgery, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Office for Cancer Control and Research, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Oral and Maxillofacial Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Peng LiDepartment of Head Neck and Thyroid Surgery, Affiliated Cancer Hospital of Zhengzhou University, 127 Dongming Road, Jinshui District, Zhengzhou 450008, Henan, People’s Republic of ChinaEmail zlyylipeng2383@zzu.edu.cnObjective: To investigate the effects of different values of the body mass index (BMI) on postoperative hemorrhage (PH) in thyroid cancer (TC) and its clinical management.Methods: This retrospective cohort study selected 43 patients with hemorrhage after TC surgery in 7413 cases. Patients were divided based on the BMI (kg/m2) into normal (24), overweight group (24 ≤BMl< 28) and obese (≥ 28) groups. Clinical and pathologic data, bleeding cause, bleeding site, treatment and prognosis were assessed.Results: BMI (P=0.038) is an independent risk factor for PH of TC, related to hypertension (P=0.004) and coronary heart disease (P=0.001) in the three groups. Preoperative weight loss was not noted (P=0.477). Hemorrhage in 60.47% of patients occurred between 4 h and 8 h after surgery. The higher the BMI, the longer was the operative time (≥ 1 h, 65.12%) (P=0.017), which resulted in greater intraoperative blood loss (≥ 20 mL, 74.42%) (P=0.025), postoperative hypoparathyroidism (P=0.015) and the probability of injury to the recurrent laryngeal nerve (P=0.026). The main causes of bleeding were incomplete vascular ligation (30.23%), severe postoperative cervical activity (16.28%) and long-term use of anticoagulant drugs (11.63%). Overall survival at 5 years in the obese group was poor (P=0.015). Forty patients (93.02%) underwent surgical exploration and hemostasis and two patients (4.65%) underwent tracheotomy. All PH complications disappeared completely after active postoperative treatment, and all patients were discharged from hospital.Conclusion: Obesity is closely associated with PH in TC patients. Therefore, in obese patients, active prevention preoperatively, complete hemostasis intraoperatively, early detection and timely treatment postoperatively are the key factors to reduce PH risk.Keywords: body mass index, thyroid cancer, hemorrhage

Jing Qi, Liming Xu, Jian Sun, Xin Wang, Lujun Zhao Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin′s Clinical Research Center for Cancer, Tianjin 300060, People’s Republic of ChinaCorrespondence: Lujun ZhaoTianjin Medical University Cancer Institute and Hospital, Huanhu West Street, Tianjin 300060, People’s Republic of ChinaEmail zhaolujun@tjmuch.comPurpose: Thoracic radiotherapy (TRT) is the recommended therapeutic regimen for extensive-stage small cell lung cancer (ES-SCLC). Little is known about TRT benefits in elderly populations. The aim of this study was to evaluate TRT effects on the prognosis of elderly patients with ES-SCLC.Patients and methods: This retrospective analysis reviewed the records of patients over 65 years of age with metastatic ES-SCLC treated between 2010 and 2016. Enrolled patients received standard chemotherapy regimens (etoposide plus cisplatin or carboplatin). A total of 93 eligible patients were subjected to propensity score matching, which led to 40 patients being assigned to the TRT group and 40 to the no thoracic radiotherapy (noTRT) group. The cohort of 80 patients (67 males) had the median age of 69 years (range, 65–85 years), with a median of 4 chemotherapy cycle (range, 1–8 cycles), and a median chest irradiation dose of 50 Gy (range, 30–60 Gy). We analyzed overall survival (OS), progression-free survival (PFS), and local recurrence-free survival (LRFS) as endpoints; survival rates were determined by the Kaplan–Meier method and compared across groups with log-rank tests. Multivariate prognostic analysis was performed with Cox regression modeling, and categorical variables were analyzed with Chi-square tests.Results: In all patients, the 1-year OS, PFS, and LRFS rates were 38.3%, 16%, and 17.9%, respectively. The TRT group had superior survival outcomes compared to the noTRT group: their 1-year OS, PFS, and LRFS rates were 55% vs. 25% (P < 0.001), 32.1% vs. 0% (P < 0.001), and 31% vs. 2.6% (P < 0.001), respectively. TRT did not increase the incidence of adverse reactions (P = 0.431).Conclusion: TRT can improve chest tumor control and survival time in elderly ES-SCLC patients. Large-scale studies to further assess the benefits of TRT are warranted.Keywords: chemotherapy, radiotherapy, prognosis, elderly, small cell lung cancer

Jialong Qi,1 Ruiyu Gao,1 Cunbao Liu,1 Bin Shan,2 Fulan Gao,1 Jinrong He,1 Mingcui Yuan,1 Hanghang Xie,1 Shumei Jin,3 Yanbing Ma1 1Department of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China; 2Department of Clinical Lab, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 3Yunnan Institute of Materia Medica, Kunming, People’s Republic of ChinaCorrespondence: Yanbing MaInstitute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, NO935#, Jiaoling Road, Kunming, People’s Republic of ChinaTel +86 6 833 9287Email yanbingma@126.comBackground: Tachyplesin III, an antimicrobial peptide (AMP), provides protection against multidrug-resistant (MDR) bacterial infections and shows cytotoxicity to mammalian cells. Mixed bacterial infections, of which P. aeruginosa plus A. baumannii is the most common and dangerous combination, are critical contributors to the morbidity and mortality of long-term in-hospital respiratory medicine patients. Therefore, the development of effective therapeutic approaches to mixed bacterial infections is urgently needed.Methods and results: In this study, we demonstrated that compared with individual infections, mixed infections with MDR bacteria P. aeruginosa and A. baumannii cause more serious diseases, with increased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and chemokines (MCP-1/MIP-2) and reduced mouse survival. In vitro treatment with Tachyplesin III enhanced phagocytosis in a mouse alveolar macrophage cell line (MH-S). Strikingly, in vivo, Tachyplesin III demonstrated a potential role against mixed-MDR bacterial coinfection. The bacterial burden in bronchoalveolar lavage fluid (BALF) was significantly reduced in the Tachyplesin III-treated group. In addition, a systemic reduction in pro-inflammatory cytokines and decreased lung injury occurred with Tachyplesin III therapy.Conclusion: Therefore, our study demonstrated that Tachyplesin III represents a potential therapeutic treatment against mixed-MDR bacterial infection in vivo, which sheds light on the development of therapeutic strategies against mixed-MDR bacterial infections.Keywords: Tachyplesin III, antimicrobial peptides, multidrug-resistant bacterial, coinfection, phagocytosis

Kang Wang,1,* Zhengyang Zhang,1,* Ming Wang,1 Xiongfeng Cao,1 Jianchen Qi,1 Dongqing Wang,1,2 Aihua Gong,3 Haitao Zhu1,21Central Laboratory of Medical Imaging, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, People’s Republic of China; 2Department of Radiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, People’s Republic of China; 3School of Medicine, Jiangsu University, Zhenjiang 212013, People’s Republic of China*These authors contributed equally to this workObjective: To investigate the exact role of GRP78 in artesunate-induced ferroptosis in KRAS mutant pancreatic cancer cells.Methods: Artesunate-induced KRAS mutant human pancreatic cancer cells (AsPC-1 and PaTU8988) ferroptosis was confirmed by fluorescent staining experiments and CCK8. Western blot and short-hairpin RNA-based knockdown assays were conducted to detect GRP78 activity and its role in artesunate-induced ferroptosis.Results: Artesunate induced AsPC-1 and PaTU8988 cell death in ferroptosis manner, rather than necrosis or apoptosis. In addition, artesunate increased the mRNA and protein levels of GRP78 in a concentration-dependent manner in AsPC-1 and PaTU8988 cells. Knockdown GRP78 enhanced artesunate-induced ferroptosis of pancreatic cancer cells in vitro and in vivo.Conclusion: Combining artesunate with GRP78 inhibition may be a novel maneuver for effective killing of KRAS mutant pancreatic ductal adenocarcinoma cells.Keywords: ferroptosis, GRP78, artesunate, pancreatic cancer

Xiao Li,1,2 Bang An,3 Qi Zhao,1,2 Jianni Qi,2,4 Wenwen Wang,1,2 Di Zhang,1,2 Zhen Li,1,2 Chengyong Qin1,2,5 1Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China; 2Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan 250021, Shandong, China; 3Department of Cardiology, Central Hospital of Zibo, Zibo 255036, Shandong, China; 4Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China; 5Health Commission of Shandong Province, Jinan 250021, Shandong, China Purpose: The aim of this study was to investigate the clinical significance of the combined fibrinogen and neutrophil–lymphocyte ratio (F-NLR) in patients with resectable colorectal cancer (CRC). Patients and methods: We retrospectively recruited 693 patients with stage I–III CRC following curative surgery. Cutoff values of the preoperative fibrinogen and neutrophil–lymphocyte ratio (NLR) were determined with the receiver operating characteristic analysis. Patients were divided into three groups based on the F-NLR value and were further divided into the chemotherapy and nonchemotherapy groups. The overall survival (OS) and disease-free survival (DFS) were evaluated with the Kaplan–Meier survival method, the log-rank test, univariate and multivariate Cox proportional hazards models, and subgroup analyses. Results: The Kaplan–Meier survival curves revealed that the 5-year OS rates in the F-NLR 0, 1, and 2 groups were 78.4%, 52%, 42.6%, respectively (P

Xiao Li,1,2 Qi Zhao,1,2 Bang An,3 Jianni Qi,2,4 Wenwen Wang,1,2 Di Zhang,1,2 Zhen Li,1,2 Chengyong Qin1,2 1Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, People’s Republic of China; 2Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan 250021, Shandong Province, People’s Republic of China; 3Department of Cardiology, Central Hospital of Zibo, Zibo, People’s Republic of China; 4Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, People’s Republic of China Purpose: The purpose of this study was to determine whether macroscopic growth patterns had an impact on the prognosis of colorectal cancer (CRC) patients with different tumor–node–metastasis (TNM) stages and responses to chemotherapy in stage III patients. Patients and methods: We retrospectively recruited 4,080 stage I–III CRC patients who underwent curative resection at Shandong Provincial Hospital affiliated to Shandong University. All patients were grouped by macroscopic growth patterns (expansive, infiltrative and ulcerative subtypes), and stage III patients were further divided into chemotherapy and nonchemotherapy groups. Kaplan–Meier methods, univariate and multivariate analyses and subset analyses were performed to assess the overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). Results: Kaplan–Meier survival curves and univariate analyses revealed better OS (HR=0.731; 95% CI=0.584–0.916), CSS (HR=0.714; 95% CI=0.548–0.932) and DFS (HR=0.722; 95% CI=0.602–0.864) in the expansive subtype and worse OS (HR=2.121; 95% CI=1.457–3.088), CSS (HR=2.499; 95% CI=1.664–3.753) and DFS (HR=2.360; 95% CI=1.756–3.170) in the infiltrative subtype. Subset analyses based on the tumor–node–metastasis stage showed that the infiltrative subtype was associated with inferior DFS in stage II (HR=2.357; 95% CI=1.210–4.595) and stage III patients (HR=1.941; 95% CI=1.394–2.702) and inferior OS and CSS in stage III patients (HR=1.805; 95% CI=1.210–2.693 and HR=1.981, 95% CI=1.280–3.065, respectively). In addition, multivariate Cox proportional hazard regression models revealed similar results. Furthermore, in stage III patients, the OS, CSS and DFS in both the expansive and ulcerative subtypes were significantly extended after the administration of chemotherapy (all, P

Jie Qi,1,* Huang Zhang,2,* Yingzhou Wang,3 Mohan Prasath Mani,4 Saravana Kumar Jaganathan5–7 1Department of Orthopedics, Shaanxi Provincial People’s Hospital, 2Department of Orthopedics, Han Zhong People’s Hospital, Han Zhong, Shaanxi Province, 3Beijing Meinuoyikang Health Food Co., Ltd, Beijing, People’s Republic of China; 4Faculty of Biosciences and Medical Engineering, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia; 5Department for Management of Science and Technology Development, 6Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam; 7IJN-UTM Cardiovascular Engineering Centre, Department of Clinical Sciences, Faculty of Biosciences and Medical Engineering, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia *These authors contributed equally to this work Introduction: Currently, the design of extracellular matrix (ECM) with nanoscale properties in bone tissue engineering is challenging. For bone tissue engineering, the ECM must have certain properties such as being nontoxic, highly porous, and should not cause foreign body reactions. Materials and methods: In this study, the hybrid scaffold based on polyvinyl alcohol (PVA) blended with metallocene polyethylene (mPE) and plectranthus amboinicus (PA) was fabricated for bone tissue engineering via electrospinning. The fabricated hybrid nanocomposites were characterized by scanning electron microscopy (SEM), Fourier transform and infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), contact angle measurement, and atomic force microscopy (AFM). Furthermore, activated partial thromboplastin time (APTT), prothrombin time (PT), and hemolytic assays were used to investigate the blood compatibility of the prepared hybrid nanocomposites. Results: The prepared hybrid nanocomposites showed reduced fiber diameter (238±45 nm) and also increased porosity (87%) with decreased pore diameter (340±86 nm) compared with pure PVA. The interactions between PVA, mPE, and PA were identified by the formation of the additional peaks as revealed in FTIR. Furthermore, the prepared hybrid nanocomposites showed a decreased contact angle of 51°±1.32° indicating a hydrophilic nature and exhibited lower thermal stability compared to pristine PVA. Moreover, the mechanical results revealed that the electrospun scaffold showed an improved tensile strength of 3.55±0.29 MPa compared with the pristine PVA (1.8±0.52 MPa). The prepared hybrid nanocomposites showed delayed blood clotting as noted in APTT and PT assays indicating better blood compatibility. Moreover, the hemolysis assay revealed that the hybrid nanocomposites exhibited a low hemolytic index of 0.6% compared with pure PVA, which was 1.6% suggesting the safety of the developed nanocomposite to red blood cells (RBCs). Conclusion: The prepared nanocomposites exhibited better physico-chemical properties, sufficient porosity, mechanical strength, and blood compatibility, which favors it as a valuable candidate in bone tissue engineering for repairing the bone defects. Keywords: scaffold, electrospinning, bone tissue engineering, physico-chemical characterization, blood compatibility