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Ziyu Li,1,* Qiuyan Zhang,2,* Yuhe Gao,3,* Fang Wan,3 Yincang Wang,3 Bin Hou,2 Wenwen Cui,4,5 Yanan Wang,2 Wei Feng,2 Yunlong Hou4,5 1Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, People’s Republic of China; 2New Drug Evaluation Center, Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, People’s Republic of China; 3Graduate School, Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China; 4National Key Laboratory for Innovation and Transformation of Luobing Theory, Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, People’s Republic of China; 5Key Laboratory of State Administration of TCM (Cardio-Cerebral VesselCollateral Disease), Shijiazhuang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunlong Hou, Email houyunlonghrb@Hotmail.comBackground: The LuoBiTong (LBT) capsule, a novel traditional Chinese medicine formulation, is currently in Phase III clinical trials. Preliminary preclinical and Phase II clinical studies suggest its efficacy and safety in treating rheumatoid arthritis (RA). However, the underlying mechanisms of its action remain to be elucidated.This research aims to explore the effects and mechanisms of LBT in conjunction with a maintenance dose of methotrexate (M-MTX) on RA.Methods: A Collagen-Induced Arthritis (CIA) mouse model was used to evaluate the anti-RA effects of LBT combined with M-MTX. Assessments included foot swelling, arthritis scoring, serum inflammatory factor analysis, and histopathological examination of the foot. These effects were compared with those of high-dose MTX (H-MTX). Network pharmacology was employed to construct a compound-target network for RA, based on drug composition, to predict its potential mechanism of action. Flow cytometry, Western Blot, and immunohistochemical analyses in animal models identified multiple inflammatory pathways targeted by LBT to augment the anti-RA effects of MTX.Results: The study revealed that LBT combined with M-MTX significantly alleviated CIA-induced arthritis without adverse effects. The combination of LBT and M-MTX showed similar or superior efficacy in regulating macrophage polarization, NF-κB, MAPK signaling pathways, and in the suppression of TH-17 expression in proinflammatory cells. These findings suggest that LBT may exert a multi-pathway therapeutic effect in RA treatment. The predicted pharmacological targets and mechanisms align well with this hypothesis.Conclusion: LBT, when combined with MTX, enhances the anti-RA effect by targeting multiple inflammatory pathways, demonstrating significant therapeutic potential.Keywords: rheumatoid arthritis, traditional Chinese medicine, methotrexate, network pharmacology

Geyi Wen,1,&ast; Jinliang Meng,1,&ast; Puxian Peng,2,&ast; Yanyan Xu,1 Ruiqi Wang,1 Wenlong Cui,2 Aihan Wen,2 Guohong Luo,2 Yunhui Zhang,1 Songyuan Tang2 1Department of Pulmonary and Critical Care Medicine, the First People’s Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China; 2Institute of Health Studies, School of Public Health, Kunming Medical University, Kunming, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunhui Zhang, Department of Pulmonary and Critical Care Medicine, the First People’s Hospital of Yunnan Province, No. 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650032, People’s Republic of China, Email yunhuizhang3188@126.com Songyuan Tang, Institute of Health Studies, School of Public Health, Kunming Medical University, 1168 West Chunrong Road, Yuhua Street, Chenggong District, Kunming, Yunnan, 650500, People’s Republic of China, Email tsythailand@hotmail.comPurpose: Chronic obstructive pulmonary disease (COPD) is a significant disease impacting health and quality of life. Yunnan Province, a major tobacco producer, lacks comprehensive COPD studies. The purpose of this study is to describe the epidemic situation of COPD in Yunnan province and explore its influencing factors.Methods: This study is a cross-sectional research conducted in a representative sample of adults aged 20 and older from 13 prefectures and cities in Yunnan Province, China. COPD was diagnosed using post-bronchodilator pulmonary function tests. Demographics were analyzed with descriptive statistics. The influencing factors of COPD were examined by using the multivariate logistic regression models.Results: Our study found that high-risk individuals for COPD accounted for 20.30% of the screened population aged 20 and above, with a COPD prevalence of 27.18% among this high-risk group. Male had a higher prevalence (33.01%) than did female (16.35%; p< 0.001 for sex difference). Additionally, the proportion of severe and extremely severe COPD cases in Yunnan Province was higher than the national average and other provinces. After considering the potential confounding variables, male (OR=2.291, 95% CI: 1.584– 3.313), age (OR=1.501, 95% CI: 1.338– 1.685), underweight (OR=1.747, 95% CI: 1.225– 2.491), previous smoking (OR=1.712, 95% CI: 1.182– 2.478), passive smoking (OR=1.444, 95% CI: 1.159– 1.800), and a history of respiratory system diseases in childhood (OR=2.010, 95% CI: 1.346– 3.001) were significantly associated with an increased risk of COPD. Conversely, being overweight (OR=0.636, 95% CI: 0.489– 0.828), and residing in high-altitude counties (OR=0.445, 95% CI: 0.263– 0.754) were negatively correlated with the risk of COPD.Conclusion: There is significant prevalence of COPD (27.18%) among high-risk population aged 20 and above in Yunnan Province, China. Apart from male, smoking, BMI and other known risk factors for COPD. We found that high-altitude residence had a lower prevalence of COPD. There is no significant difference in COPD prevalence between Han and ethnic minority populations.Keywords: chronic obstructive pulmonary disease, epidemiological characteristics, influencing factors, high-risk population, China

Wenjin Zhang,1 Qiang Song,1 Xiaofei Bi,1 Wei Cui,1 Chengmei Fang,1 Jianya Gao,1 Jinan Li,1 Xiang Wang,1 Kai Qu,1 Xian Qin,1 Xuan An,2,3 Cheng Zhang,1,3 Xianxiang Zhang,1,3 Fang Yan,4 Guicheng Wu1– 3 1Chongqing Municipality Clinical Research Center for Endocrinology and Metabolic Diseases, Chongqing University Three Gorges Hospital, Chongqing, People’s Republic of China; 2Department of Hepatology, Chongqing University Three Gorges Hospital, Chongqing, People’s Republic of China; 3School of Medicine, Chongqing University, Chongqing, People’s Republic of China; 4Geriatric Diseases Institute of Chengdu, Department of Geriatrics, Chengdu Fifth People’s Hospital, Chengdu, People’s Republic of ChinaCorrespondence: Guicheng Wu, Chongqing University Three Gorges Hospital, Xincheng Road 165&num;, Wanzhou District, Chongqing, 404000, People’s Republic of China, Tel +(86) 58103079, Fax +86 23 581045783, Email wuguicheng@cqu.edu.cn Fang Yan, Geriatric Diseases Institute of Chengdu, Department of Geriatrics, Chengdu Fifth People’s Hospital, Mashi Street 33&num;, Wenjiang District, Chengdu, 611130, People’s Republic of China, Tel/Fax +86 28 82661127, Email fangyan@cdutcm.edu.cnPurpose: Pueraria lobata (P. lobata), a dual-purpose food and medicine, displays limited efficacy in alcohol detoxification and liver protection, with previous research primarily focused on puerarin in its dried roots. In this study, we investigated the potential effects and mechanisms of fresh P. lobata root-derived exosome-like nanovesicles (P-ELNs) for mitigating alcoholic intoxication, promoting alcohol metabolism effects and protecting the liver in C57BL/6J mice.Methods: We isolated P-ELNs from fresh P. lobata root using differential centrifugation and characterized them via transmission electron microscopy, nanoscale particle sizing, ζ potential analysis, and biochemical assays. In Acute Alcoholism (AAI) mice pre-treated with P-ELNs, we evaluated their effects on the timing and duration of the loss of the righting reflex (LORR), liver alcohol metabolism enzymes activity, liver and serum alcohol content, and ferroptosis-related markers.Results: P-ELNs, enriched in proteins, lipids, and small RNAs, exhibited an ideal size (150.7 ± 82.8 nm) and negative surface charge (− 31 mV). Pre-treatment with 10 mg/(kg.bw) P-ELNs in both male and female mice significantly prolonged ebriety time, shortened sobriety time, enhanced acetaldehyde dehydrogenase (ALDH) activity while concurrently inhibited alcohol dehydrogenase (ADH) activity, and reduced alcohol content in the liver and serum. Notably, P-ELNs demonstrated more efficacy compared to P-ELNs supernatant fluid (abundant puerarin content), suggesting alternative active components beyond puerarin. Additionally, P-ELNs prevented ferroptosis by inhibiting the reduction of glutathione peroxidase 4 (GPX4) and reduced glutathione (GSH), and suppressing acyl-CoA synthetase long-chain family member 4 (ACSL4) elevation, thereby mitigating pathological liver lipid accumulation.Conclusion: P-ELNs exhibit distinct exosomal characteristics and effectively alleviate alcoholic intoxication, improve alcohol metabolism, suppress ferroptosis, and protect the liver from alcoholic injury. Consequently, P-ELNs hold promise as a therapeutic agent for detoxification, sobriety promotion, and prevention of alcoholic liver injury.Keywords: Pueraria lobata root-derived exosome-like nanovesicles, acute alcoholism, loss of the righting reflex, ethanol metabolism, ferroptosis

Wei Peng, Yin Zhuang, Wei Cui, Wenjin Chen, Rupeng Chu, Zhenzhong Sun, Shujun Zhang Department of Spine Surgery, Wuxi Ninth People’s Hospital Affiliated to Soochow University, Wuxi, Jiangsu, People’s Republic of ChinaCorrespondence: Shujun Zhang, Department of Spine Surgery, Wuxi Ninth People’s Hospital Affiliated to Soochow University, No. 999 Liangqing Road, Binhu District, Wuxi, Jiangsu, People’s Republic of China, Tel +86-13861741839, Email spine_zhang@vip.163.comAbstract: This study describes a patient with an intradural extramedullary (IDEM) tumor removed entirely using the unilateral biportal endoscopic technique (UBE), achieving satisfactory clinical outcomes. A 60-year-old woman had a diagnosis of meningioma with sensations and motor dysfunction in the lower extremities and perineum and gait disturbances for three years, which has worsened over the last month. Preoperative imaging data showed a sizeable IDEM tumor at the T10 level, significantly compressing the thoracic spinal cord to the right side, with 80% intraspinal encroachment. The IDEM tumor was removed entirely by UBE surgery. To the best of our knowledge, this study may be the first to report the application of UBE techniques for IDEM tumor treatment. In this case, UBE provides a magnified and clear surgical field, greater maneuverability, and a less invasive surgical procedure. The procedure objectives were pathological confirmation, spinal cord decompression, and complete tumor removal; all were met. The patient was satisfied with her dramatically improved clinical symptoms. UBE may be an alternative surgical treatment option for benign IDEM tumors presenting with symptomatic, especially the non-giant lateral and posterior tumors.Keywords: unilateral biportal endoscopy, endoscopic spine surgery, intradural extramedullary, tumor, meningioma

Xinlin Li,1,2,&ast; Baojuan Yang,3,4,&ast; Mengfei Xu,1,2 Fangyi Li,3,4 Zhaoli Geng,1,2 Weiqiang Cui,3,4 Xingfu Sun,3,4 Yanle Li,3,4 Yi Liu1,2 1Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 2Shandong Key Laboratory of Oral Tissue Regeneration, Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, 250012, People’s Republic of China; 3Key Laboratory of High Efficiency and Clean Mechanical Manufacture, Ministry of Education, School of Mechanical Engineering, Shandong University, Jinan, 250061, People’s Republic of China; 4National Demonstration Center for Experimental Mechanical Engineering Education, Shandong University, Jinan, 250061, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Liu, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong, 250012, People’s Republic of China, Tel +86-531-88381630, Email yiliu@sdu.edu.cn Yanle Li, Key Laboratory of High Efficiency and Clean Mechanical Manufacture, Ministry of Education, Shandong University School of Mechanical Engineering, No. 17923, Jingshi Road, Jinan, 250061, People’s Republic of China, Tel +86-531-88392208, Email yanle.li@sdu.edu.cnIntroduction: The lack of osteoinductive, angiogenic and antimicrobial properties of hydroxyapatite coatings (HA) on titanium surfaces severely limits their use in orthopedic and dental implants. Therefore, we doped SiO2, Gd2O3 and CeO2 nanoparticles into HA to fabricate a HASiGdCe coating with a combination of decent antibacterial, angiogenic and osteogenic properties by the plasma spraying technique.Methods: The HASiGdCe coating was analyzed by SEM (EDS), surface roughness tests, contact angle tests, XRD, FTIR spectroscopy, tensile tests and electrochemical dynamic polarization tests. Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PAO-1) were used as representative bacteria to verify the antibacterial properties of the HASiGdCe coating. We evaluated the cytocompatibility and in vitro osteoinductivity of the HASiGdCe coating by investigating its effect on the cell viability and osteogenic differentiation of MC3T3-E1 cells. We assessed the in vitro angiogenic activity of the HASiGdCe coating by migration assay, tube formation assay, and RT‒PCR analysis of angiogenic genes in HUVECs. Finally, we used infected animal femur models to investigate the biosafety, antimicrobial and osteointegration properties of the HASiGdCe coating in vivo.Results: Through various characterization experiments, we demonstrated that the HASiGdCe coating has suitable microscopic morphology, physical phase characteristics, bonding strength and bioactivity to meet the coating criteria for orthopedic implants. The HASiGdCe coating can release Gd3+ and Ce4+, showing strong antibacterial properties against MRSA and PAO-1. The HASiGdCe coating has been shown to have superior osteogenic and angiogenic properties compared to the HA coating in in vitro cellular experiments. Animal implantation experiments have shown that the HASiGdCe coating also has excellent biosafety, antimicrobial and osteogenic properties in vivo.Conclusion: The HASiGdCe coating confers excellent antibacterial, angiogenic and osteogenic properties on titanium implants, which can effectively enhance implant osseointegration and prevent bacterial infections, and it accordingly has promising applications in the treatment of bone defects related to orthopedic and dental sciences.Graphical Abstract: Keywords: hydroxyapatite coatings, SiO2, Gd2O3, CeO2, osseointegration, antibacterial

Changjiang Yu,1,&ast; Wei Guo,1,2,&ast; Zhulai Zhang,1,&ast; Yuting Ma,3,&ast; Xiaobei Cao,1 Na Sun,1 Yingyao Cui,1 Yunshen Wang,1 Wenyu Cui,1 Yongsheng Xu,1 Jianghua Zhan2,4 1Department of Pediatric Respiratory Medicine, Tianjin Children’s Hospital, Tianjin University Children’s Hospital, Tianjin, People’s Republic of China; 2Graduate School of Tianjin Medical University, Tianjin, People’s Republic of China; 3Department of Infection, Tianjin Children’s Hospital, Tianjin University Children’s Hospital, Tianjin, People’s Republic of China; 4Department of Pediatric Surgery, Tianjin Children’s Hospital, Tianjin University Children’s Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongsheng Xu, Department of Pediatric Respiratory Medicine, Tianjin Children’s Hospital, Tianjin University Children’s Hospital, Tianjin, 300134, People’s Republic of China, Email xxyyss@126.com Jianghua Zhan, Graduate School of Tianjin Medical University, Department of Pediatric Surgery, Tianjin Children’s Hospital, Tianjin University Children’s Hospital, Tianjin, 300134, People’s Republic of China, Email zhanjianghuatj@163.comPurpose: Metagenomic next-generation sequencing (mNGS) is an emerging technique for pathogen detection. However, most literature on the clinical application of pediatrics generally comprises case reports or small-scale cohort studies.Patients and Methods: A total of 101 children with community-acquired severe pneumonia admitted to Tianjin Children’s Hospital from November 2021 to February 2022 were included. Pathogens in bronchoalveolar lavage fluid (BALF) specimens were detected using mNGS. The performances of mNGS and conventional tests on pulmonary infection diagnosis and pathogen identification were compared.Results: According to our data, mNGS had a broader spectrum for pathogen detection. The mNGS results of BALF showed that the number of children with severe pneumonia hospitalized for mycoplasma pneumoniae infection was more than that for other bacterial infections during the COVID-19 epidemic. In addition, 43 cases (42.6%) had been identified with mixed infection, including 36 cases (35.6%) of Mycoplasma pneumoniae mixed with other pathogenic bacteria. Analytically, the mNGS exhibited significantly enhanced detection in the BALF as compared with the conventional laboratory pathogenic detection approaches (P < 0.05). The Pearson correlation analysis revealed positive correlation between the time of fever during hospitalization and the number of mycoplasma sequences (P < 0.05).Conclusion: Compared with traditional methods, mNGS has a higher etiological detection rate and can comprehensively detect various pathogens of severe pneumonia. Therefore, mNGS of bronchoalveolar lavage fluid should be performed in children with severe pneumonia, which is of great significance for guiding treatment.Keywords: mNGS, severe pneumonia, pathogen, BALF, children

Aref Smiley,&ast; Te-Yi Tsai,&ast; Ihor Havrylchuk,&ast; Wanting Cui,&ast; Irena Parvanova,&ast; Elena Zakashansky,&ast; Taulant Xhakli,&ast; Hu Cui,&ast; Joseph Finkelstein&ast; Center for Biomedical and Population Health Informatics, Icahn School of Medicine at Mount Sinai, New York, NY, USA&ast;These authors contributed equally to this workCorrespondence: Aref Smiley, Center for Biomedical and Population Health Informatics, Icahn School of Medicine at Mount Sinai, 1770 Madison Avenue, New York, NY, 10035, USA, Tel +1 212-659-9596, Email Aref.smiley@gmail.comPurpose: This paper focuses on developing and testing three versions of interactive bike (iBikE) interfaces for remote monitoring and control of cycling exercise sessions to promote upper and lower limb rehabilitation.Methods: Two versions of the system, which consisted of a portable bike and a tablet PC, were designed to communicate through either Bluetooth low energy (BLE) or Wi-Fi interfaces for real-time monitoring of exercise progress by both the users and their clinical team. The third version of the iBikE system consisted of a motorized bike and a tablet PC. It utilized conventional Bluetooth to implement remote control of the motorized bike’s speed during an exercise session as well as to provide real-time visualization of the exercise progress. We developed three customized tablet PC apps with similar user interfaces but different communication protocols for all the platforms to provide a graphical representation of exercise progress. The same microcontroller unit (MCU), ESP-32, was used in all the systems.Results: Each system was tested in 1-minute exercise sessions at various speeds. To evaluate the accuracy of the measured data, in addition to reading speed values from the iBikE app, the cycling speed of the bikes was measured continuously using a tachometer. The mean differences of averaged RPMs for both data sets were calculated. The calculated values were 0.38 ± 0.03, 0.25 ± 0.27, and 6.7 ± 3.3 for the BLE system, the Wi-Fi system, and the conventional Bluetooth system, respectively.Conclusion: All interfaces provided sufficient accuracy for use in telerehabilitation.Keywords: telerehabilitation, cycling exercise, wireless interface, accuracy

Qiaoyi Xie,1 Xiaote Zhang,2 Wei Cui,1 Yajiao Pang1 1Department of Pediatrics, The Affiliated People’s Hospital of Ningbo University, Ningbo, People’s Republic of China; 2Department of Otolaryngology Head and Neck Surgery, Ningbo Yinzhou No.2 Hospital, Ningbo, People’s Republic of ChinaCorrespondence: Qiaoyi Xie, Department of Pediatrics, The Affiliated People’s Hospital of Ningbo University, No. 251, Baizhang East Road, Ningbo, 315040, People’s Republic of China, Tel + 86 0574-87016888, Email qiaoyi_xie@126.comObjective: The individualized prediction of treatment regimens of macrolide-unresponsive Mycoplasma pneumoniae pneumonia (MUMPP) is scarce. The aim of this study was, therefore, to evaluate the relevant data of patients and construct a nomogram for identifying refractory Mycoplasma pneumoniae pneumonia (RMPP) among children continued to be treated with macrolide after the confirmation of MUMPP, providing a reference for the choice of treatment regimen.Methods: We performed a retrospective study involving 162 children who continued to be treated with macrolide (azithromycin) after the confirmation of MUMPP without antibiotic changes between January 2020 and January 2022. We collected data on clinical feature, hospitalization period, treatments, laboratory data, extrapulmonary symptoms, parapneumonic effusion, and connections with other respiratory pathogens. In addition, the independent risk factors for RMPP were determined through univariate and multivariate analyses, and then a nomogram was constructed and validated.Results: In this study, the multivariate logistic regression analysis showed that age, leukocyte count, neutrophil proportion, serum procalcitonin, and lactate dehydrogenase were independent risk factors for RMPP. Using the five independent associated factors, the nomogram for identification of RMPP was constructed. Moreover, the area under the ROC curve (AUC) was 0.925 (95% CI: 0.882– 0.968) for the nomogram showing excellent discrimination. The calibration curve, close to the 45-degree line, exhibited good calibration of nomogram.Conclusion: We constructed and validated a visual and user-friendly nomogram for individualized prediction of RMPP risk in children who continued to be treated with macrolide after the confirmation of MUMPP based on five variables. According to the nomogram model, continuation of macrolide should be considered rather than second-line antibiotics including tetracyclines (doxycycline or minocycline) and fluoroquinolones for MUMPP children with low predictive values.Keywords: nomogram, refractory, Mycoplasma pneumoniae, pneumonia, children

Mo Chen,1 Yanhua Li,1 Shu Li,2 Wenqiang Cui,2 Yonghui Zhou,3 Qianwei Qu,1 Ruixiang Che,4 Lu Li,5 Shuguang Yuan,2 Xin Liu3 1College of Veterinary Medicine, Northeast Agricultural University, Harbin, People’s Republic of China; 2Research Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Shenzhen, People’s Republic of China; 3College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, People’s Republic of China; 4College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, People’s Republic of China; 5College of Life Sciences, Northeast Agricultural University, Harbin, People’s Republic of ChinaCorrespondence: Shuguang Yuan, Research Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Shenzhen, People’s Republic of China, Tel +86-150-0209-0670, Email shuguang.yuan@siat.ac.cn Xin Liu, College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, People’s Republic of China, Tel +86-188-8605-6643, Email 1046977102@qq.comPurpose: Drug resistance presents an ever-increasing global public health threat that involves all major microbial pathogens and antimicrobial drugs. Strains that are resistant to multiple drugs pose severe clinical problems and cost lives. However, systematic studies on cross-resistance of Staphylococcus xylosus have been missing.Methods: Here, we investigated various mutations in the sequence of ribosomal proteins involved in cross-resistance. To understand this effect on a molecular basis and to further elucidate the role of cross-resistance, we computationally constructed the 3D model of the large ribosomal subunit from S. xylosus as well as its complexes with both tylosin and florfenicol. Meanwhile, all-atom molecular dynamics simulations was used. In addition, the regulation of protein networks also played an essential role in the development of cross-resistance in S. xylosus.Results: We discovered that the minimum inhibitory concentration against both tylosin and florfenicol of the mutant strain containing the insertion L22 97KRTSAIN98 changed dramatically. Further, we found that unique structural changes in the β-hairpin of L22 played a central role in this variant in the development of antibiotic resistance in S. xylosus. The regulation of protein networks also played an essential role in the development of cross-resistance in S. xylosus.Conclusion: Our work provides insightful views into the mechanism of S. xylosus resistance that could be useful for the development of the next generation of antibiotics.Keywords: antimicrobial resistance, Staphylococcus xylosus, cross-resistance evolution, ribosomal protein L22

Yuan Zhang,1,&ast; Hongli Yue,1,&ast; Yirui Qin,1 Jiajing Wang,1 Chenyang Zhao,1 Miao Cheng,1 Bo Han,2 Ruquan Han,1 Weihua Cui1,&ast; 1Department of Anesthesiology, Beijing Tian Tan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ruquan Han; Weihua Cui, Department of Anesthesiology, Beijing Tian Tan Hospital, Capital Medical University, No. 119, Nan Si Huan Xi Lu, Fengtai District, Beijing, 100070, People’s Republic of China, Tel +8613701285393 ; Tel +8613701285393, Fax +861059976658, Email ruquan.han@ccmu.edu.cn; weihuacui@ccmu.edu.cnPurpose: Patients undergoing intraspinal tumor resection usually experience severe postoperative pain. Inadequate postoperative analgesia usually leads to severe postsurgical pain, which could cause patients to suffer from many other related complications. Recently, an increasing number of studies have found that gabapentin can relieve hyperalgesia, postoperative pain, and postoperative inflammation. However, there have been no reports on the use of gabapentin combined with sufentanil preoperatively for acute pain following intraspinal tumor resection.Study Design and Methods: This is a protocol for a randomized, placebo-controlled, and double-blinded trial. One-hundred and sixty-eight participants with chronic pain related to the intraspinal tumor will be randomized into the gabapentin and placebo groups in a 1:1 ratio. In the gabapentin group, patients will be given 300 mg gabapentin orally 36 h, 24 h, and 12 h before surgery; the placebo group will receive a placebo orally at the same time points preoperatively. To estimate the efficacy and safety endpoints, all the researchers and patients will be blinded until the completion of this study. The primary outcome will be the consumption of sufentanil within 48 h postoperatively. The secondary outcomes include the visual analog scale pain score and Von Frey mechanical pain threshold 36 h and 24 h before and 24 h and 48 h after surgery, the incidence of postoperative nausea, vomiting, and drowsiness, the length of hospital stay and medical expenses.Discussion: This trial is to evaluate the efficacy and safety of gabapentin combined with sufentanil for postoperative analgesia in patients who complain of pain before intraspinal tumor resection. The findings will provide a new strategy for multimode perioperative analgesia management in these patients.Keywords: gabapentin, intraspinal tumor resection, multimode perioperative analgesia, opiates

Cluster number count is a major cosmological probe for the next generation of cosmological large scale-structure surveys like the one expected from the Euclid satellite mission. Cosmological constraints will be mainly limited by the understanding of the selection function (SF), which characterize the probability of detecting a cluster of a given mass and redshift. The SF can be estimated by injecting realistic simulated clusters into the survey and re-applying the detection procedure. In this paper, we use the galaxy clusters from The Three Hundred project to study this effect with their member galaxies. We further study possible resolution effects by comparing low and high resolution simulations. Finally, we present the density profiles of the member galaxies and discuss their evolution with cluster mass and redshift.

Our study introduces a new machine learning algorithm for estimating 3D cumulative radial profiles of total and gas mass in galaxy clusters from thermal Sunyaev-Zel’dovich (SZ) effect maps. We generate mock images from 2522 simulated clusters, employing an autoencoder and random forest in our approach. Notably, our model makes no prior assumptions about hydrostatic equilibrium. Our results indicate that the model successfully reconstructs unbiased total and gas mass profiles, with a scatter of approximately 10%. We analyse clusters in various dynamical states and mass ranges, finding that our method’s accuracy and precision are consistent. We verify the capabilities of our model by comparing it with the hydrostatic equilibrium technique, showing that it accurately recovers total mass profiles without any bias.

The new generation of upcoming deep photometric and spectroscopic surveys will allow us to measure the astrophysical properties of faint galaxies in massive clusters. This would demand to produce simulations of galaxy clusters with better mass resolution than the ones available today if we want to make comparisons between the upcoming observations and predictions of cosmological models. But producing full-physics hydrodynamical simulations of the most massive clusters is not an easy task. This would involve billions of computational elements to reliably resolve low mass galaxies similar to those measured in observations. On the other hand, dark matter only simulations of cluster size halos can be done with much larger mass resolution but at the cost of having to apply a model that populate galaxies within each of the subhalos in these simulations. In this paper we present the results of a new set of dark matter only simulations with different mass resolutions within the The Three Hundred project. We have generated catalogs of galaxies with stellar and luminosity properties by applying the Sage Semi-Analytical Model of galaxy formation. To obtain the catalogs consistent with the results from hydrodynamical simulations, the internal physical parameters of Sage were calibrated with the Particle Swarm Optimization method using a subset of full-physics runs with the same mass resolution than the dark matter only ones.

The study of the morphology of 2D projected maps of galaxy clusters is a suitable approach to infer, from real data, the dynamical state of those systems. We recently developed a new method to recover the morphological features in galaxy cluster maps which consists of an analytical modelling through the Zernike polynomials. The validation of this approach was done on a set of high-resolution mock maps of the Compton parameter y. These maps are from hydrodynamically simulated galaxy clusters in The Three Hundred project. After this step, we apply the Zernike modelling on y-maps of local (z < 0.1) galaxy clusters observed by the Planck satellite. With a single parameter collecting the main information of the Zernike modelling, we classify their morphology. A set of mock Planck-like y-maps, generated from The Three Hundred clusters, is also used to validate our indicator with a proper dynamical state classification. This approach allows us to test the efficiency of the Zernike morphological modelling in evaluating the dynamical population in the real Planck sample.

Galaxy clusters and their filamentary outskirts reveal useful laboratories to test cosmological models and investigate Universe composition and evolution. Their environment, in particular the filaments of the Cosmic Web to which they are connected, plays an important role in shaping the properties of galaxy clusters. In this project, we analyse the gas filamentary structures present in 324 regions of The Three Hundred hydrodynamical simulation extracted with the DisPerSE filament finder. We estimate the number of gas filaments globally connected to several galaxy clusters, i.e. the connectivity k, with a mass range of 1013 ≤ M200 h−1 M⊙ ≤ 1015 at redshift z = 0. We study the positive correlation between the connectivity and mass of galaxy clusters. Moreover, we explore the impact of filaments on the dynamical state of clusters, quantified by the degree of relaxation parameter χ.

The abundance of galaxy clusters with mass and redshift is a wellknown cosmological probe. The cluster mass is a key parameter for studies that aim to constrain cosmological parameters using galaxy clusters, making it critical to understand and properly account for the errors in its estimates. Subsequently, it becomes important to correctly calibrate scaling relations between observables like the integrated Compton parameter and the mass of the cluster. The NIKA2 Sunyaev-Zeldovich Large program (LPSZ) enables one to map the intracluster medium profiles in the mm–wavelength band with great details (resolution of 11 & 17″ at 1.2 & 2 mm, respectively) and hence, to estimate the cluster hydrostatic mass more precisely than previous SZ observations. However, there are certain systematic effects which can only be accounted for with the use of simulations. For this purpose, we employ The Three Hundred simulations which have been modelled with a range of physics modules to simulate galaxy clusters. The so-called twin samples are constructed by picking synthetic clusters of galaxies with properties close to the observational targets of the LPSZ. In particular, we use the Compton parameter maps and projected total mass maps of these twin samples along 29 different lines of sight. We investigate the scatter that projection induces on the total masses. Eventually, we consider the statistical values along different lines of sight to construct a kind of 3D scaling law between the integrated Compton parameter, total mass, and overdensity of the galaxy clusters to determine the overdensity that is least impacted by the projection effect.

Hongli Yue,1,&ast; Man Zhou,2,&ast; Yingzi Chong,1 Miao Cheng,1 Hui Qiao,3 Yu Lu,1 Weihua Cui1 1Department of Anesthesiology, Beijing Tian Tan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Anesthesiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 3Department of Neurophysiology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Lu; Weihua CuiDepartment of Anesthesiology, Beijing Tian Tan Hospital, Capital Medical University, No. 119, Nan Si Huan Xi Lu, Fengtai District, Beijing, 100070, People’s Republic of China, Tel +8613661067447; +8613651315600, Fax +861059976658, Email luyutiantan@163.com; weihuacui@ccmu.edu.cnPurpose: At present, it is believed that intravenous (IV) infusion of lidocaine can inhibit hyperalgesia, relieve postoperative acute and chronic pain, and accelerate the rehabilitation of patients. However, studies of its effects on necessary electrophysiological monitoring during neurosurgery are few, and the results are controversial. This study assumes that the propofol-remifentanil based anaesthesia combined with lidocaine in patients undergoing intraspinal tumour resection will not have adverse effects on motor-evoked potentials (MEPs) or somatosensory-evoked potentials (SEPs).Study Design and Methods: This is a prospective, randomized, placebo-controlled double-blind trial. A total of 96 patients undergoing intraspinal tumour resection will be randomly allocated to lidocaine and placebo group. The lidocaine group will receive IV lidocaine during anaesthesia, while the placebo group will receive the same dose of normal saline with the same infusion rate and infusion time, and the anaesthesia procedures of the two groups will be the same. All patients will be monitored the MEPs and SEPs of all four limbs during operation. The primary outcome will be the MEP amplitudes of both upper limbs at the end of operation. The secondary outcome measures will be the other electrophysiological parameters at the end of operation, the incidence of alert events for all four limbs, and the incidence of false positive events.Discussion: The purpose of this study is to evaluate the effects of IV infusion of lidocaine on SEPs and MEPs during intraspinal tumour resection to determine whether electrophysiological monitoring can accurately reflect the integrity of nerve functions while infusing lidocaine and to explore the possibility of lidocaine use during intraspinal tumour resection as an anaesthesia option.Keywords: motor-evoked potentials, somatosensory-evoked potentials, intraspinal tumour resection, lidocaine

Yuqian Wang,1,&ast; Zhilong Zhao,2,&ast; Chenlu Liu,3 Miao Hao,1 Chenfei Kong,1 Xiaoming Zhao,1 Yiyao Gao,1 Yucheng Zhang,1 Wanxing Cui,4 Congxiao Zhang,2 Jinlan Jiang1 1Scientific Research Center, China-Japan Union Hospital, Jilin University, Changchun, 130031, People’s Republic of China; 2Department of Stomatology, The First Hospital of Jilin University, Changchun, 130031, People’s Republic of China; 3Biobank, China-Japan Union Hospital, Jilin University, Changchun, 130031, People’s Republic of China; 4Medstar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC, 20007, USA&ast;These authors contributed equally to this workCorrespondence: Congxiao Zhang; Jinlan Jiang, Email zhangcongxiao@jlu.edu.cn; jiangjinlan@jlu.edu.cnIntroduction: Coating of nanomedicine with cell membranes has attracted increasing attention as it can boost biocompatibility and improve the efficiency of treatment. Herein, we prepared innovative tumor cell-membrane-coated vesicles based on photodynamic therapy (PDT) drug indocyanine green (ICG) and explore the effect on melanoma in vitro and in vivo.Methods: ICG was coated with B16 cell membranes (I@BM NVs) by sonication and extrusion, and the morphological characteristics of I@BM NVs were evaluated by transmission electron microscopy (TEM) and NP-tracking analysis. Homologous cellular uptake was evaluated by flow cytometry (FCM) after staining by DiD dye. Cellular cytotoxicity was evaluated by cell counting kit-8 assay and the anti-tumor effect in vitro was assessed by FCM and western blotting. The anti-tumor effect in vivo was evaluated in a B16 xenograft model in mice. The tumor micro-environment was investigated by FCM and real-time PCR.Results: The vesicles are stable and uniform in nature, and show strong homologous targeting in vivo and in vitro. The vesicles can generate reactive oxygen species to induce apoptosis of B16 cells under near-infrared irradiation. Furthermore, the I@BM NVs induce a significant anti-tumor response in vivo, and perform better with respect to both tumor growth inhibition and lifespan extension. Analysis of immunocytes in the tumor microenvironment showed significant reductions in numbers of myeloid-derived suppressor cells and tumor-associated M2 macrophages in mice in the I@BM NVs group. This was accompanied by significant increases in numbers of M1 macrophages and proliferative CD4+/CD8+ T cells. Expression levels of IFN-γ and IL-2 increased in the I@BM NVs group, while expression of TGF-β and IL-10 decreased.Conclusion: The results show that the I@BM NVs are feasible drugs for the treatment of melanoma by inducing cell apoptosis under NIR and shifting the immunosuppressive tumor microenvironment in vivo.Graphical Abstract: Keywords: melanoma, vesicles, tumor microenvironment, photodynamic therapy, immunotherapy

Wenqiang Cui,1,&ast; Jiwei Zhang,2,&ast; Fei Xu,3 Hongwei Zhi,1 Haitao Li,1 Baopeng Li,4 Sishuo Zhang,1 Wei Peng,1 Hongyun Wu1 1Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 2College of Acumox and Tuina, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 3Department of Geriatric Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 4Department of Medical Imaging, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongyun Wu; Wei PengAffiliated Hospital of Shandong University of Traditional Chinese Medicine, 16769 Jingshi Road, Jinan, Shandong, People’s Republic of ChinaTel +86 13853148590; +86 13953187058Email whylzhangonly@126.com; pengwei0625@163.comObjective: To evaluate whether migraine without aura (MwoA) can be partly attributed to abnormalities of vision-related brain networks (VBN) and whether these specific regional abnormalities affect the patients’ quality of life (QoL).Methods: A total of 40 participants, including 20 MwoA patients and 20 healthy control volunteers, were enrolled. There were no significant differences in sex, age, educational qualifications and dominant hand between the two groups. Headache intensity and QoL were assessed by the Pain Number Evaluation Scale (NRS) and the Migraine-Specific Quality of Life Questionnaire (MSQ 2.1), respectively. Resting state functional magnetic resonance imaging (rs-fMRI) and independent component analysis (ICA) were performed to determine and evaluate the VBN.Results: Three components were identified as consistent with the VBN in the template and recorded as N1, N2 and N3, respectively. The functional activity of the left primary visual cortex (N1), left culmen of cerebellum (N1), left lingual gyrus (N2), superior frontal gyrus (N2) and left posterior lateral prefrontal cortex (N3) in the MwoA group enhanced compared with the healthy control group. However, the functional activity of right middle occipital gyrus, left fusiform gyrus, right lingual gyrus, and right primary motor cortex in the N3 network weakened. Pearson correlation analysis showed that decline of attention to work and life (MSQ5) was positively associated with the functional activity of left primary visual cortex and left lingual gyrus. Canceling from work and daily life (MSQ8) was inversely associated with the functional activity of right primary motor cortex. The burden of feeling like others (MSQ13) and the overall decrease in QoL were both positively associated with the functional activity of right lingual gyrus.Conclusion: MwoA patients showed abnormal VBN function, which was moderately correlated with decreased QoL. This study provides evidence for the precise prevention and treatment of migraine by neural regulation.Keywords: migraine, rs-fMRI, neural regulation, vision-related brain networks, quality of life

Ying Zhang,1– 3,&ast; Li-Si Zeng,4,&ast; Juan Wang,5,&ast; Wen-Qi Cai,2,3 Weiwen Cui,6 Tong-Jun Song,7 Xiao-Chun Peng,2,8 Zhaowu Ma,2,3 Ying Xiang,2,3 Shu-Zhong Cui,4 Hong-Wu Xin2,3 1Department of Gastroenterology, Chun’an County First People’s Hospital (Zhejiang Provincial People’s Hospital Chun’an Branch), Hangzhou, Zhejiang Province, 311700, People’s Republic of China; 2Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, 434023, People’s Republic of China; 3Department of Molecular Biology and Biochemistry, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, 434023, People’s Republic of China; 4State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, People’s Republic of China; 5Department of Obstetrics and Gynecology, Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China; 6Department of Bioengineering, University of California, Berkeley, CA, 94720, USA; 7Department of Neurosurgery, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong Province, 518104, People’s Republic of China; 8Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, 434023, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong-Wu Xin; Ying XiangLaboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, 1 Nanhuan Road, Jingzhou, Hubei, 434023, People’s Republic of ChinaTel +86 13311055391; +86 15107212530Fax +0716-8062633Email hongwu_xin@126.com; xying316@163.comAbstract: Herpes simplex viruses (HSVs) often cause latent infection for a lifetime, leading to repeated recurrence. HSVs have been engineered as oncolytic HSVs. The mechanism of the latent infection and recurrence remains largely unknown, which brings great challenges and limitations to eliminate HSVs in clinic and engineer safe oHSVs. Here, we systematically reviewed the latest development of the multi-step complex process of HSV latency and reactivation. Significantly, we first summarized the three HSV latent infection pathways, analyzed the structure and expression of the LAT1 and LAT2 of HSV-1 and HSV-2, proposed the regulation of LAT expression by four pathways, and dissected the function of LAT mediated by five LAT products of miRNAs, sRNAs, lncRNAs, sncRNAs and ORFs. We further analyzed that application of HSV LAT deletion mutants in HSV vaccines and oHSVs. Our review showed that deleting LAT significantly reduced the latency and reactivation of HSV, providing new ideas for the future development of safe and effective HSV therapeutics, vaccines and oHSVs. In addition, we proposed that RNA silencing or RNA interference may play an important role in HSV latency and reactivation, which is worth validating in future.Keywords: non-coding RNA, small RNA, oncolytic virus, herpes simplex virus, HSV, latent infection, latency-associated transcripts, LATs

Jing Xu,1 Wei Zhang,2 Wei Song,1 Jiaqi Cui,1 Yanni Tian,1 Huan Chen,1 Pan Huang,1 Shujun Yang,1 Lu Wang,1 Xin He,3 Lin Wang,4 Bingyin Shi,5 Wei Cui1 1Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China; 2Department of Breast Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China; 3Department of Endocrinology, Xi’an Aerospace General Hospital, Xi’an, Shaanxi, 710000, People’s Republic of China; 4Department of Endocrinology, Xi’an Gaoxin Hospital, Xi’an, Shaanxi, 710075, People’s Republic of China; 5Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of ChinaCorrespondence: Wei CuiThe First Affiliated Hospital of Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, 710061, Shaanxi, People’s Republic of ChinaEmail doctorweiwei.cui@126.comBingyin ShiThe First Affiliated Hospital of Xi’an Jiaotong University, #277 Yanta West Road, Xi’an, Shaanxi, 710061, People’s Republic of ChinaEmail xjtougao@126.comPurpose: This study aimed to explore the relationship between KCNQ1 polymorphism and type 2 diabetes mellitus (T2DM) risk in the population of Northwest China.Patients and Methods: Case-control strategy was used to reveal the correlation between KCNQ1 polymorphism and T2DM risk, and MDR analysis clarified the influence of KCNQ1 polymorphism interaction on T2DM risk. The related proteins, functions, and signal pathways of KCNQ1 were further explored through bioinformatics methods. PCR was used to explore the relative expression of KCNQ1 in T2DM patients and the controls.Results: Studies showed that rs163177, rs163184, rs2237895 and rs2283228 on the KCNQ1 gene are closely related to the risk of T2DM in Northwest China. MDR results showed that the three-locus model is the best model for T2DM risk assessment, which increases the risk of T2DM. The bioinformatics results showed that KCNQ1 closely-acted proteins are mainly involved in signal pathways such as gastric acid secretion and renin secretion. The PCR results showed that, compared with the controls, the expression of KCNQ1 was up-regulated in T2DM patients.Conclusion: The results revealed that KCNQ1 polymorphism is related to the risk of T2DM in the population of Northwest China and provide a scientific basis for the early screening and prevention of T2DM high-risk populations.Keywords: KCNQ1, polymorphism, type 2 diabetes, case-control strategy, MDR analysis

Xin Chen,1,2,&ast; Zhicheng Yu,1,3,&ast; Jianhua Wang,1 Wenjing Cui,1 Can Cui,1 Yajie Wang,1 Yongkang Liu,1 Hao Zhou,1 Cheng Wang,4 Zhongqiu Wang,1 Xiao Chen1 1Department of Radiology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China; 2Department of Radiology, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai, 200233, People’s Republic of China; 3Department of Radiology, Jiading Central Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, 201800, People’s Republic of China; 4Department of Radiology, Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhongqiu Wang; Xiao ChenDepartment of Radiology, The Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210029, People’s Republic of ChinaTel +86-025-86619843Email zhqwang001@126.com; chxwin@163.comPurpose: The purpose of this study was to analyze the prevalence of and risk factors for incidental pancreatic cystic lesions (PCLs) in the Chinese general population. Furthermore, the association between baseline imaging findings and PCL progression was also investigated.Patients and Methods: A total of 9826 individuals who underwent computed tomography (CT) examinations for lung cancer screening between January 1, 2018 and January 1, 2019 were included in this study. The participants’ CT imaging findings and biochemical biomarker levels were reviewed and analyzed. PCLs detected during the screening were followed up for 12 months. Associations between imaging findings and clinical factors with PCL progression were explored.Results: PCLs were observed in 172 of the 9826 participants. The crude prevalence of PCLs in total population was 1.75%. In subjects aged > 60 years, the prevalence of PCLs was 3.2% (102/3151). The occurrence of PCLs was significantly increased with an increase of age in both men and women (p < 0.001). High-risk PCLsL commonly located in pancreatic head showed extrapancreatic growth, and had high urea levels (p = 0.005, p = 0.015, p = 0.002, respectively) compared with low-risk PCLs. Location in the pancreatic head (odds ratio (OR) = 6.286, 95% confidence interval (CI): 1.842– 21.452) and extrapancreatic growth (OR = 4.049, 95% CI: 1.235– 13.333) were risk factors for PCL progression.Conclusion: PCLs are not uncommon in the Chinese general population. Location in the pancreatic head and extrapancreatic growth are the independent predictors of high-risk of PCLs and PCL progression.Keywords: pancreatic cystic lesion, computed tomography, prevalence, progression, Chinese population

Yi-Qun Che,1,2 Yue Zhang,1 Han-Bing Li,1 Di Shen,1 Wei Cui1 1Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 2Center for Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of ChinaCorrespondence: Wei CuiDepartment of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People’s Republic of ChinaTel/Fax +86-10-87788448Email wendycuiwei@sina.cnPurpose: With the advancement of minimally invasive surgery and catheters for hepatocellular carcinoma (HCC), it is becoming more and more inconvenient to get tissues or the tissues gained are insufficient for testing. Screening of blood-derived markers is of great significance for prognosis assessment.Patients and Methods: Data-independent acquisition (DIA) and parallel reaction monitoring (PRM) were implemented to identify valuable prognostic HCC biomarkers in 48 patients with different prognosis. The potential candidate biomarkers were examined in 205 HCC patients using enzyme-linked immunosorbent assay (ELISA) and then validated in The Cancer Genome Atlas (TCGA) HCC cohort.Results: DIA screened 86 significantly differentially regulated proteins between patients with poor prognosis and those with good prognosis. Eight proteins from the DIA proteomic analyses were quantified by PRM, and six of them (KLKB1, IGFBP3, SHBG, SAA1, C7, and CD44) presented consistent expression trends between DIA and PRM. Then, the results of ELISA indicated that KLKB1 was abnormally expressed in HCC patients, and the serum level of KLKB1 also exhibited significant changes before and after treatment (P = 0.016). Patients with higher KLKB1 serum levels had significantly superior overall survival (P = 0.035) and progression-free survival (P = 0.027) than those with lower KLKB1 expression. In the TCGA-HCC cohort, Cox regression analysis suggested that KLKB1 was an independent prognostic factor for overall survival (P = 0.032) of HCC patients.Conclusion: Aberrant expression of KLKB1 was strongly associated with the prognosis of HCC patients. KLKB1 may be used to evaluate the prognosis and guide the treatment for HCC.Keywords: KLKB1, hepatocellular carcinoma, prognostic, data-independent acquisition, parallel reaction monitoring

Jintao Zhang,1,&ast; Zihan Wang,1,&ast; Dong Zhang,1 Yun Pan,1 Xiaofei Liu,1 Xinrui Qiao,1 Wenjing Cui,1 Liang Dong1,2 1Department of Respiratory, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, The First Affiliated Hospital of Shandong First Medical University, Shandong Institute of Respiratory Diseases, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liang DongDepartment of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, The First Affiliated Hospital of Shandong First Medical University, Shandong Institute of Respiratory Diseases, Jinan, People’s Republic of ChinaEmail dl5506@126.comBackground: During asthma progression, the intricate molecular networks, including microRNA (miRNA) transcriptional regulation in airway epithelium, remain largely undefined. The abnormal expression of miRNAs in asthmatic airway epithelium is a recent and fast-growing area in developing diagnostic and therapeutic targets for asthma.Material and Methods: Analyses were conducted to compare airway epithelial miRNAs and gene expression between patients with asthma and healthy subjects from three datasets (two for miRNAs expression profiles and one for gene expression profile). The interactions network between differentially expressed (DE)-miRNAs and mRNAs was further identified for functional analysis. To verify the involvement and functions of all the identified miRNAs in asthma, we constructed two cellular models of asthma. The most promising causal miRNA candidate, miR-1246, was examined in an in vitro system to explore its targets and roles in asthma pathophysiology.Results: Through integrative analysis, we obtained six miRNAs with 31 validated target genes in airway epithelium associated with asthma. Next, we confirmed that these miRNAs were all associated with asthma progression by in vitro functional experiments. They may participate in eosinophilic inflammation (miR-92b-3p, miR-1246, miR-197-3p, and miR-124-5p) or remodeling (miR-197-3p, miR-193a-5p, miR-1246, and miR-92b-3p). Additionally, some other non-screened valuable miRNAs were also examined and identified (miR-21-5p and miR-19b-3p), and some detected in blood correlated with the disease status. Furthermore, we found that miR-1246 could directly target POSTN and influence epithelial-to-mesenchymal transition and fibrosis in airway epithelial cells.Conclusion: We constructed a preliminary epithelial regulatory network in asthma based on six identified miRNAs and their valuable target genes. Candidate factors in the biological miRNA-mRNA network in airway epithelium may provide further information on the pathogenesis of asthma. Strikingly, among all screened miRNAs, miR-1246, which could interact with POSTN may have multifunctional effects in the course of asthma and be a promising agent for asthma treatment and molecular subtyping.Keywords: asthma, miRNA, regulatory network, biomarkers, molecular subtyping

Fengqi Liu,1,2,&ast; Li Zhong,1,2,&ast; Feifei Zhou,3,&ast; Cheng Zheng,1,4 Kai Zhang,1 Jiachang Cai,5 Hongwei Zhou,5 Kankai Tang,2 Zhaohui Dong,2 Wei Cui,1 Gensheng Zhang1 1Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China; 2Department of Critical Care Medicine, First Affiliated Hospital, Huzhou Teachers College, The First People’s Hospital of Huzhou, Huzhou, 313000, Zhejiang, People’s Republic of China; 3Department of Critical Care Medicine, Ningbo Medical Center, Li Huili Hospital, Ningbo, Zhejiang, 315040, People’s Republic of China; 4Department of Critical Care Medicine, Taizhou Municipal Hospital, Taizhou, Zhejiang, 318000, People’s Republic of China; 5Department of Clinical Microbiology Laboratory, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gensheng Zhang; Wei CuiDepartment of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, cc88 Jiefang Road, Hangzhou, 310009, People’s Republic of ChinaTel +86-571-8778-3636; +86-571-8778-3551Fax +86-571- 87022776Email genshengzhang@zju.edu.cn; zricu@zju.edu.cnPurpose: Candida albicans (C. albicans) candidemia has been well reported in previous studies, while research on non-albicans Candida (NAC) bloodstream infections remains poorly explored. Therefore, the present study aimed to investigate the clinical characteristics and outcomes of patients with NAC candidemia.Patients and Methods: We recruited inpatients with candidemia from January 2013 to June 2020 in a tertiary hospital for this retrospective observational study.Results: A total of 301 patients with candidemia were recruited in the current study, including 161 (53.5%) patients with NAC candidemia. The main pathogens in NAC candidemia were Candida tropicalis (C. tropicalis) (23.9%), Candida parapsilosis (15.6%) and Candida glabrata (10.3%). Patients with NAC candidemia had more medical admissions (P=0.034), a higher percentage of hematological malignancies (P=0.007), a higher frequency of antifungal exposure (P=0.012), and more indwelling peripherally inserted central catheters (P=0.002) than those with C. albicans candidemia. In a multivariable analysis, prior antifungal exposure was independently related to NAC candidemia (adjusted odds ratio [aOR], 0.312; 95% confidence interval [CI], 0.113– 0.859). Additionally, NAC was obviously resistant to azoles, especially C. tropicalis had a high cross-resistance to azoles. However, no significant differences were noted in the mortality rates at 14 days, 28 days and 60 days between these two groups.Conclusion: NAC is dominant in candidemia, and prior antifungal exposure is an independent risk factor. Of note, although the outcomes of NAC and C. albicans candidemia are similar, drug resistance to specific azoles as well as cross-resistance frequently occurs in patients with NAC candidemia, and this drug resistance deserves attention in clinical practice and further in-depth investigation.Keywords: non-albicans candidemia, clinical features, risk factor, cross-resistance

Ning Wang,1,* Yanqi Peng,1,* Lu Wang,1 Lin Song,2 Bo Sun,2 Junxiang Wei,3 Ting Wang,4 Yang Mi,3 Wei Cui1 1Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, People’s Republic of China; 3The Second Department of Obstetrics, Northwest Women and Children’s Hospital, Xi’an, People’s Republic of China; 4Department of Respiratory Medicine, Xi’an No.4 Hospital, Xi’an, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yang MiThe Second Department of Obstetrics, Northwest Women and Children’s Hospital, 1616 Yanxiang Road, Xi’an, Shaanxi, 710065, People’s Republic of ChinaTel +86-13700222172Email miyangmm@163.comWei CuiDepartment of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, Shaanxi, 710061, People’s Republic of ChinaTel +86-13609281695Email doctorweiweixjtu@126.comPurpose: To study the risk factors of gestational diabetes mellitus (GDM) heterogeneity, and to evaluate the correlation between the risk factors and obesity.Methods: We performed a case–control study of 452 women with GDM and 516 women with normal glucose tolerance (NGT) at the first and second trimester. We defined GDM women as GDM-resistance subtype, GDM-dysfunction subtype, and GDM-mixed subtype, according to their simultaneous insulin-release test with predominant insulin-sensitivity defect, insulin-secretion defect, or both defects.Results: We found that higher maternal age, family history of diabetes, the elevated level of fasting blood glucose in the first trimester (≥ 5.1 mmol/L) were risk factors of all GDM subtypes. Pre-pregnancy overweight/obesity and the increased gestational weight gain (GWG) in the first-trimester are risk factors of the GDM-resistance subtype. Indicators including younger age at first menstruation, the elevated levels of alanine aminotransferase (ALT), total bile acid (TBA), triglyceride (TG), and the decreased level of high-density lipoprotein cholesterol (HDL-C) are risk factors of the GDM-resistance subtype. However, the associations between those risk factors and GDM-resistance subtype attenuated after adjusted by pre-pregnancy body mass index (pre-BMI) and gestational weight gain (GWG) in the first trimester. Nonalcoholic fatty liver disease (NAFLD) and the improved level of TG are independent risk factors for the GDM-resistance subtype and the GDM-mixed subtype, respectively.Conclusion: Women with GDM exhibited heterogeneity based on glycemic physiology and their risk factors are not all the same. Some obesity-related risk factors are specific to the GDM-resistance subtype, which are mediated by pre-pregnancy overweight/obesity and the elevated GWG the first-trimester.Keywords: pregnancy, pre-pregnancy BMI, gestational weight gain, obesity, insulin resistance, insulin secretion

Xin Chen,1 Chuangen Guo,2 Wenjing Cui,1 Ke Sun,3 Zhongqiu Wang,1 Xiao Chen1 1Department of Radiology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 2100029, People’s Republic of China; 2Department of Radiology, The First Affiliated Hospital, College of Medicine Zhejiang University, Hangzhou 310003, People’s Republic of China; 3Department of Pathology, The First Affiliated Hospital, College of Medicine Zhejiang University, Hangzhou 310003, People’s Republic of ChinaCorrespondence: Zhongqiu Wang; Xiao Chen Tel +086-025-86619843; +086-025-86617141Email zhqwang001@126.com; chxwin@163.comPurpose: CD56 is a neural cell adhesion molecule that plays a role in the cohesiveness of neuroendocrine cells. The aim of this study was to explore the biological values of CD56 expression in pancreatic neuroendocrine neoplasms (PNENs) and its role in predicting PNENs grades.Patients and Methods: A total of 138 patients with histological-proven PNENs was included (66 G1, 46 G2 and 26 G3). The clinicopathological characteristics, including mitosis count, ki67 index, chromogranin A (CgA), synaptophysin (Syn) and CD56 expression, were evaluated. We assessed the diagnostic performance of markers in predicting PNEN G3 and the association between CD56 expression and risk of G3 or organs invasion.Results: Lack of CD56 immunoreaction (CD56-) was more common in PNEN G3 than G1/G2 (31% vs 0– 2%, p < 0.01). The sizes of CD56- tumors were larger than CD56 positive tumors in PNEN G3 (p < 0.01). The odds ratio (OR) of CD56- expression was 13.6 [95% confidence interval (CI): 2.1– 88.1] in predicting PNEN G3. The OR of CD56- expression was 6.5 (95% CI: 1.1– 38.6) and 31.9 (95% CI: 1.09– 938.3) in predicting organs invasion and neuroendocrine carcinoma in PNEN G3, respectively. Tumor size (area under the curve [AUC] = 0.77 and size+CD56- expression [AUC = 0.84]) had acceptable performance in predicating PNEN G3.Conclusion: Lack of CD56 immunoreaction may be a predictor and biological behavior marker for PNEN G3.Keywords: pancreatic neuroendocrine neoplasm, grade, pancreatic neuroendocrine carcinoma, CD56

Hongli Yue,* Man Zhou,* Yu Lu, Liang Chen, Weihua Cui Department of Anesthesiology, Beijing Tian Tan Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weihua CuiDepartment of Anesthesiology, Beijing Tian Tan Hospital, Capital Medical University, No. 119, Nan Si Huan Xi Lu, Fengtai District, Beijing 100070, People’s Republic of ChinaTel +8613651315600Fax +861059976658Email weihuacui@ccmu.edu.cnPurpose: Patients undergoing intraspinal tumor resection usually experience severe acute pain, delaying postoperative rehabilitation, and increasing incidence of chronic pain. Recently, an increasing number of studies have found that low-dose intravenous lidocaine infusion during and/or after surgery can reduce opioid usage and the incidence of related side effects, inhibit hyperalgesia and promote recovery. Thus far, no studies have evaluated the analgesic effect and safety of perioperative intravenous lidocaine infusion for intraspinal tumor resection, especially the long-term analgesic effects of patient-controlled analgesia (PCA) with lidocaine during the first postoperative 48 hours. This study tests the hypothesis that intra- and postoperative systemic lidocaine infusion for patients undergoing intraspinal tumor resection can relieve postoperative acute or chronic pain and reduce the opioid dosage and incidence of related side effects without other problems.Study Design and Methods: This is a prospective, randomized, placebo-controlled, and double-blinded study. In total, 180 participants scheduled for intraspinal tumor resection will be randomly divided into lidocaine and placebo groups. The lidocaine group will be administered lidocaine intravenously during anesthesia and postoperative pain management during the first 48 postoperative hours; the placebo group will be administered normal saline at the same volume, infusion rate, and timing. The primary outcome will be the postoperative visual analog scale (VAS) score. Secondary outcomes will be postoperative cumulative sufentanil consumption, indicators of postoperative recovery, and the incidence of perioperative adverse events.Discussion: This study investigates the effect of continuous intravenous lidocaine infusion on postoperative sufentanil consumption and VAS scores. The findings will provide a new strategy of anesthesia and analgesia management for intraspinal tumor resection.Keywords: postoperative pain, intraspinal tumor resection, lidocaine, opiates

Cheng Zheng,1,2,* Jiachang Cai,3,* Haizhou Liu,1,4,* Shufang Zhang,5 Li Zhong,1,6 Nanxia Xuan,1 Hongwei Zhou,3 Kai Zhang,1 Yesong Wang,1 Xijiang Zhang,2 Baoping Tian,1 Zhaocai Zhang,1 Changming Wang,2 Wei Cui,1 Gensheng Zhang1 1Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People’s Republic of China; 2Department of Critical Care Medicine, Taizhou Municipal Hospital, Taizhou, Zhejiang, People’s Republic of China; 3Clinical Microbiology Laboratory, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People’s Republic of China; 4Department of Critical Care Medicine, Zhejiang Rehabilitation Hospital, Hangzhou, Zhejiang, People’s Republic of China; 5Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, People’s Republic of China; 6Department of Critical Care Medicine, Huzhou First People’s Hospital, Huzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gensheng ZhangDepartment of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People’s Republic of ChinaTel +86-571-8778-3636Fax +86-571- 87022776Email genshengzhang@zju.edu.cnPurpose: Although the enterococcal bloodstream infections (EBSI) are often observed in clinic, the mixed-EBSI are few reported. The aim of this study was to investigate the clinical characteristics and risk factors of mixed-EBSI in comparison with monomicrobial EBSI (mono-EBSI).Methods: A single-center retrospective observational study was performed between Jan 1, 2013 and Dec 31, 2018 in a tertiary hospital. All patients with EBSI were enrolled, and their data were collected by reviewing electronic medical records.Results: A total of 451 patients with EBSI were enrolled including 157 cases (34.8%) with mixed-EBSI. The most common co-pathogens were Coagulase-negative Staphylococcus (26.86%), followed by Acinetobacter baumannii (23.43%) and Klebsiella pneumoniae (8.57%). In multivariable analysis, burn injury (adjusted odds ratio [aOR], 7.39; 95% confidence interval [CI], 2.69–20.28), and length of prior hospital stay (aOR, 1.01; 95% CI, 1.00–1.02) were associated with mixed-EBSI. Patients with mixed-EBSI developed with more proportion of septic shock (19% vs. 31.8%, p=0.002), prolonged length of intensive care unit (ICU) stay [9(0,25) vs. 15(2.5,36), p

Shuai Ren,1 Xiao Chen,1 Wenjing Cui,1 Rong Chen,2 Kai Guo,1 Huifeng Zhang,1 Shuai Chen,1 Zhongqiu Wang11Department of Radiology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province 210029, People’s Republic of China; 2Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USACorrespondence: Zhongqiu WangDepartment of Radiology, The Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Nanjing, Jiangsu Province 210029, People’s Republic of ChinaTel +86 258 086 1278Email zhqwang001@126.comPurpose: Both chronic mass-forming pancreatitis (CMFP) and pancreatic ductal adenocarcinoma (PDAC) are focal pancreatic lesions and share very similar clinical symptoms and imaging performance. There is great clinical value in preoperative differentiation of those two lesions. The purpose of this study was to investigate the value of computed tomography (CT) features in discriminating CMFP from PDAC.Patients and methods: Forty-seven patients with pathologically confirmed PDAC and 21 patients with CMFP were included in this study. Demographic and CT features, including tumor location, size, margin, pancreatic or bile duct dilatation, vascular invasion, cystic necrosis, pancreatic atrophy, calcification, and tumor contrast enhancement, were retrospectively analyzed and compared. Multivariate logistic regression analyses were adopted to identify relevant CT imaging features to discriminate CMFP from PDAC.Results: There were significant differences between CMFP and PDAC with respect to main pancreatic duct dilatation, vascular invasion, cystic necrosis, pancreatic atrophy, calcification, and tumor contrast enhancement. Delayed contrast enhancement (>70.5 Hounsfield units) showed high sensitivity and specificity of 84.2% and 84.7%. The areas under the curve (AUCs) of the predicting models based on qualitative and quantitative variables were 0.770 (95% CI: 0.660–0.880) and 0.943 (95% CI: 0.888–0.999), respectively. When all significant variables were used in combination to build a predicting model, the AUC was 0.969 (95% CI: 0.930–1.000) with 84.2% sensitivity and 94.7% specificity.Conclusion: Main pancreatic duct dilatation, vascular invasion, cystic necrosis, pancreatic atrophy, calcification, tumor size, and tumor contrast enhancement were shown to be useful CT imaging features in discriminating CMFP from PDAC.Keywords: pancreas, adenocarcinoma, pancreatitis, computed tomography

Yushan Liang,1,2 Guofei Feng,1,2 Liang Wu,3 Suhua Zhong,1,2 Xiaoyu Gao,1,2 Yan Tong,1,2 Wanmeng Cui,1 Yongying Qin,1 WenQing Xu,1 Xue Xiao,1,2 Zhe Zhang,1,2 Guangwu Huang,1,2 Xiaoying Zhou1,41Key laboratory of High-Incidence-Tumor Prevention & Treatment, Ministry of Education, Guangxi Medical University, Nanning, People’s Republic of China; 2Department of Otolaryngology Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 3Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, People’s Republic of China; 4Life Science Institute, Guangxi Medical University, Nanning, People’s Republic of ChinaPurpose: Caffeic acid phenethyl ester (CAPE) is the main polyphenol extracted from honeybee propolis, which inhibits the growth of several kinds of tumor. This study aimed to assess the inhibitory effect of CAPE in nasopharyngeal carcinoma (NPC), evaluate the synergistic action of CAPE in radiotherapy sensitivity of NPC cell lines and further elucidate the possible molecular mechanism involved.Materials and methods: CCK-8 assay was used to analyze cell proliferation ability. Colony formation assay was used to evaluate the clonogenic ability and radio-sensitiveness of NPC cells by CAPE treatment. Wound-healing and transwell assay were used to assess the motility of cells. The expression of key molecules of the epithelial–mesenchymal transition (EMT) was determined by western blot analysis and changes in radiation sensitivity were measured by colony-formation assay. cDNA microarray analysis was used to determine differentially expressed genes with and without CAPE treatment, with Gene Ontology enrichment of gene function and KEGG pathways determined. Cell cycle and apoptosis were detected by flow cytometry and western blot analysis.Results: CAPE suppressed the viability of NPC cell lines time- and dose-dependently. It induced apoptosis in NPC cells along with decreased expression of Bcl-XL and increased cleavage of PARP and expression of Bax. G1 phase arrest was induced by CAPE with ower expression of CDK4, CDK6, Rb and p-Rb. The migratory and invasive ability of NPC cells was decreased by the EMT pathway. The irradiation sensitivity of NPC cells was enhanced with CAPE treatment. CAPE specifically inhibited nuclear factor κB (NF-κB) signaling pathway by suppressing p65 subunit translocation from cytoplasm to nucleus. CAPE treatment was synergistic with chemotherapy and radiotherapy.Conclusion: CAPE may inhibit the proliferation and metastasis of NPC cells but enhance radiosensitivity in NPC therapy by inhibiting the NF-κB pathway. CAPE could be a potential therapeutic compound for NPC therapy.Keywords: nasopharyngeal carcinoma, CAPE, proliferation, metastasis, NF-κB pathway

Cluster number count is a major cosmological probe for the next generation of cosmological large scale-structure surveys like the one expected from the Euclid satellite mission. Cosmological constraints will be mainly limited by the understanding of the selection function (SF), which characterize the probability of detecting a cluster of a given mass and redshift. The SF can be estimated by injecting realistic simulated clusters into the survey and re-applying the detection procedure. For this purpose we intend to use The Three Hundreds project, a 324 cluster sample simulated with full-physics hydrodynamical re-simulations. In this paper we concentrate on the study of the distribution of member galaxies in the cluster sample. First, we study possible resolution effects by comparing low and high resolution simulations. Finally, accounting for the latter we derive the density profiles of the member galaxies and discuss their evolution with cluster mass and redshift.

The simulation database of The Three Hundred Project has been used to pick synthetic clusters of galaxies with properties close to the observational targets of the NIKA2 camera Sunyaev–Zeldovich (SZ) Large Program. Cross–matching of cluster parameters such as mass and redshift of the cluster in the two databases has been implemented to generate the so–called twin samples for the Large Program. This SZ Large Program is observing a selection of galaxy clusters at intermediate and high redshift (0:5 < z < 0:9), covering one order of magnitude in mass. These are SZ–selected clusters from the Planck and Atacama Cosmology Telescope catalogs, wherein the selection is based on their integrated Compton parameter values, Y500: the value of the parameter within the characteristics radius R500. The Three Hundred hydrodynamical simulations provide us with hundreds of clusters satisfying these redshift, mass, and Y500 requirements. In addition to the standard post-processing analysis of the simulation, mock observational maps are available mimicking X–ray, optical, gravitational lensing, radio, and SZ observations of galaxy clusters. The primary goal of employing the twin samples is to compare different cluster mass proxies from synthetic X–ray, SZ effect and optical maps (via the velocity dispersion of member galaxies and lensing κ-maps) of the clusters. Eventually, scaling laws between different mass proxies and the cluster mass will be cross–correlated to reduce the scatter on the inferred mass and the mass bias will be related to various physical parameters.

Wenli Qiu,1 Rong Chen,2 Xiao Chen,3 Huifeng Zhang,1 Lina Song,3 Wenjing Cui,3 Jingjing Zhang,1 Dandan Ye,1 Yifen Zhang,4 Zhongqiu Wang3 1The First Clinical Medical School, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; 3Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 4Department of Pathology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China Purpose: Early diagnosis and therapy are critical to improve the prognosis of patients with pancreatic cancer. However, conventional imaging does not significantly increase the capability to detect early stage disease. In this study, we developed a multifunctional theranostic nanoplatform for accurate diagnosis and effective treatment of pancreatic cancer.Methods: We developed a theranostic nanoparticle (NP) based on gold nanocages (AuNCs) modified with hyaluronic acid (HA) and conjugated with anti-Glypican-1 (anti-GPC1) antibody, oridonin (ORI), gadolinium (Gd), and Cy7 dye. We assessed the characteristics of GPC1-Gd-ORI@HAuNCs-Cy7 NPs (ORI-GPC1-NPs) including morphology, hydrodynamic size, stability, and surface chemicals. We measured the drug loading and release efficiency in vitro. Near-infrared fluorescence (NIRF)/magnetic resonance imaging (MRI) and therapeutic capabilities were tested in vitro and in vivo.Results: ORI-GPC1-NPs demonstrated long-time stability and fluorescent/MRI properties. Bio-transmission electron microscopy (bio-TEM) imaging showed that ORI-GPC1-NPs were endocytosed into PANC-1 and BXPC-3 (overexpression GPC1) but not in 293 T cells (GPC1-negative). Compared with ORI and ORI-NPs, ORI-GPC1-NPs significantly inhibited the viability and enhanced the apoptosis of pancreatic cancer cells in vitro. Moreover, blood tests suggested that ORI-GPC1-NPs showed negligible toxicity. In vivo studies showed that ORI-GPC1-NPs enabled multimodal imaging and targeted therapy in pancreatic tumor xenografted mice.Conclusion: ORI-GPC1-NP is a promising theranostic platform for the simultaneous diagnosis and effective treatment of pancreatic cancer. Keywords: pancreatic cancer, GPC1, ORI, theranostic

Yi Guo, Feng Chen, Wei Cui State Key Laboratory of Molecular Oncology, Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China Purpose: To investigate the usefulness of plasma D-dimer level for monitoring the development of distant organ metastasis in colorectal cancer (CRC) patients after curative resection. Patients and methods: One hundred and seventy-eight CRC patients after curative resection were enrolled in the study. Ninety-two patients developed distant organ metastasis during follow-up (metachronous metastasis), and blood was collected on the day metastasis was confirmed. Eighty-six patients had no evidence of metastasis yet, and their blood samples were evaluated at last return visit. The levels of D-dimer, carcinoembryonic antigen (CEA), and lactate dehydrogenase (LDH) between two patient groups were compared. The agreement between D-dimer and CEA (or LDH) was examined. The receiver operator characteristic (ROC) curve was used to evaluate the performance of D-dimer, CEA, LDH, and their combination in detection of distant organ metastasis. Results: The level of D-dimer in CRC patients with metachronous metastasis was higher than that in non-metastasis patients (P

Shanshan Wang,1,* Weihua Cui,1,* Min Zeng,1 Yi Ren,1 Song Han,2 Junfa Li2 1Department of Anesthesiology, Beijing Tian Tan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neurobiology, Beijing Institute for Neuroscience, Capital Medical University, Beijing, People’s Republic of China *These authors contributed equally to this work Background: Studies have confirmed that activation of the neurons of primary somatosensory cortex (S1) is involved in the process of remifentanil (Remi)-induced hyperalgesia (RIH), which can be suppressed by lidocaine (Lido). A total intravenous anesthesia model of rats mimicking clinical Remi-based anesthesia was set up to explore the release of amino acid neurotransmitters of S1 cortex in RIH and its inhibition by Lido in this study. Materials and methods: Sprague Dawley rats were randomly divided into the following four groups: propofol (Pro), Remi, Remi combined Lido, and Lido groups. Mechanical hyperalgesia was evaluated by von Frey test; the amino acid neurotransmitters in the microdialysates of S1 area were detected by high-performance liquid chromatography (HPLC)-fluorescence, and conventional protein kinase C (cPKC)γ levels in the whole-cell lysates and membrane lipid rafts (MLRs) were determined by Western blotting. Results: The von Frey test showed that co-administration of Lido significantly inhibited a Remi-induced decrease in the threshold of the paw withdrawal response in Remi group at 2 h postinfusion. Meanwhile, the Remi-induced increases in both the excitatory and inhibitory amino acid releases in S1 were suppressed by co-administrating Lido within 5 h postinfusion. Western blotting showed that the increased cPKCγ level in the membrane lipid rafts (MLR) induced by Remi was also inhibited by Lido. Conclusion: The increased release of amino acid neurotransmitters and the translocation of cPKCγ in MLR suggest the activation of S1 neurons, which may be one of the mechanisms underlying RIH. Lido reduces the release of amino acid neurotransmitters in S1 neurons and the translocation of cPKCγ in MLRs after stopping Remi, which may be one of its antihyperalgesic mechanisms. Keywords: hyperalgesia, remifentanil, lidocaine, amino acid neurotransmitter, protein kinase C

Haijuan Hu, Jidong Zhang, Yan Wang, Zejun Tian, Demin Liu, Guangming Zhang, Guoqiang Gu, Hongmei Zheng, Ruiqin Xie, Wei Cui Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China Background: The objective of the study was to investigate the relationship between baseline blood pressure (BP) and the magnitude of BP reduction in patients with essential hypertension treated with nifedipine gastrointestinal therapeutic system (NGTS).Methods and patients: One hundred and thirty-eight patients with essential hypertension were enrolled in this prospective, single-arm, open-label study. NGTS was administered for 24 weeks to achieve target BP of 140/90 mmHg. The dose could be uptitrated to 60 mg/d in case of unsatisfactory BP reduction after 4-week treatment. Home blood pressure measurement was recorded through the initial 1–14 days, and office BP and heart rate were evaluated at 2, 4, 8, 12, and 24 weeks.Results: One hundred and seventeen patients (84.8%) completed the study, and their average BP decreased by 19.0/11.3 mmHg after 24 weeks. The reduction of either systolic or diastolic BP was positively correlated with baseline BP at weeks 2, 4, or 24 after treatment (r=0.603–0.762, all p

Yuan Ding,1,* Wei Cui,2,* Dan Sun,1 Gui-Ling Wang,1 Yu Hei,1 Shuai Meng,1 Jian-Hua Chen,3 Ying Xie,1 Zhi-Qiang Wang4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, 2School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 3School of Medicine, Jianghan University, Wuhan, People’s Republic of China; 4Department of Chemistry and Biochemistry, Kent State University Geauga, Burton, OH, USA *These authors contributed equally to this work Abstract: In vivo evaluation of drug delivery vectors is essential for clinical translation. In BALB/c nude mice bearing human breast cancer tumors, we investigated the biocompatibility, pharmacokinetics, and pharmacodynamics of doxorubicin (DOX)-loaded novel cell-penetrating peptide (CPP)-modified pH-sensitive liposomes (CPPL) (referred to as CPPL(DOX)) with an optimal CPP density of 4%. In CPPL, a polyethylene glycol (PEG) derivative formed by conjugating PEG with stearate via acid-degradable hydrazone bond (PEG2000-Hz-stearate) was inserted into the surface of liposomes, and CPP was directly attached to liposome surfaces via coupling with stearate to simultaneously achieve long circulation time in blood and improve the selectivity and efficacy of CPP for tumor targeting. Compared to PEGylated liposomes, CPPL enhanced DOX accumulation in tumors up to 1.9-fold (p

Jidong Zhang, Yan Wang, Haijuan Hu, Xiaohong Yang, Zejun Tian, Demin Liu, Guoqiang Gu, Hongmei Zheng, Ruiqin Xie, Wei Cui Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China Background: Nifedipine gastrointestinal therapeutic system (GITS) is used to treat angina and hypertension. The authors aimed to study the early intervention impact on arterial stiffness and pulse wave velocity (PWV) independent of its blood-pressure-(BP) lowering effect in mild hypertensive patients.Methods: This single-center, single-arm, open-label, prospective, Phase IV study recruited patients with mild hypertension and increased PWV from December 2013 to December 2014 (N=138; age, 18–75 years; systolic blood pressure, 140–160 mmHg; diastolic BP, 90–100 mmHg; increased brachial–ankle pulse wave velocity [baPWV, ≥12 m/s]). Nifedipine GITS (30 mg/d) was administered for 24 weeks to achieve target BP of 0.05). There were no other drug-related serious adverse events.Conclusion: Nifedipine GITS was considerably effective in reducing baPWV and BP, indicating improvement in arterial stiffness as early as 4 weeks. Keywords: nifedipine, gastrointestinal therapeutic system, calcium channel blockers, brachial–ankle pulse wave velocity, hypertension

Shao-Hui Lin,1 Wei Cui,2 Gui-Ling Wang,1 Shuai Meng,1 Ying-Chun Liu,3 Hong-Wei Jin,4 Liang-Ren Zhang,4 Ying Xie1,4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, 2School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 3Soft Matter Research Center, Department of Chemistry, Zhejiang University, Hangzhou, 4State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People’s Republic of China Abstract: Albumin-based nanoparticles (NPs) are a promising technology for developing drug-carrier systems, with improved deposition and retention profiles in lungs. Improved understanding of these drug–carrier interactions could lead to better drug-delivery systems. The present study combines computational and experimental methods to gain insights into the mechanism of binding of albuterol sulfate (AS) to bovine serum albumin (BSA) on the molecular level. Molecular dynamics simulation and surface plasmon resonance spectroscopy were used to determine that there are two binding sites on BSA for AS: the first of which is a high-affinity site corresponding to AS1 and the second of which appears to represent the integrated functions of several low-affinity sites corresponding to AS2, AS3, and AS8. AS1 was the strongest binding site, established via electrostatic interaction with Glu243 and Asp255 residues in a hydrophobic pocket. Hydrogen bonds and salt bridges played a main role in the critical binding of AS1 to BSA, and water bridges served a supporting role. Based upon the interaction mechanism, BSA NPs loaded with AS were prepared, and their drug-loading efficiency, morphology, and -release profiles were evaluated. Successful clinical development of AS-BSA-NPs may improve therapy and prevention of bronchospasm in patients with reversible obstructive airway disease, and thus provide a solid basis for expanding the role of NPs in the design of new drug-delivery systems. Keywords: molecular dynamics, surface plasmon resonance, interaction mechanism, BSA nanoparticles, drug delivery systems

Liang Zhao,1,* Rongjian Su,2,* Wenyu Cui,3 Yijie Shi,1 Liwei Liu,1 Chang Su4 1School of Pharmacy, Liaoning Medical University, Jinzhou, People's Republic of China; 2Central Laboratory of Liaoning Medical University, Jinzhou, People’s Republic of China; 3National Vaccine and Serum Institute, Beijing, People’s Republic of China; 4School of Veterinary Medicine, Liaoning Medical University, Jinzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Heat-labile enterotoxin subunit B (LTB) is a non-catalytic protein from a pentameric subunit of Escherichia coli. Based on its function of binding specifically to ganglioside GM1 on the surface of cells, a novel nanoparticle (NP) composed of a mixture of bovine serum albumin (BSA) and LTB was designed for targeted delivery of 5-fluorouracil to tumor cells. BSA-LTB NPs were characterized by determination of their particle size, polydispersity, morphology, drug encapsulation efficiency, and drug release behavior in vitro. The internalization of fluorescein isothiocyanate-labeled BSA-LTB NPs into cells was observed using fluorescent imaging. Results showed that BSA-LTB NPs presented a narrow size distribution with an average hydrodynamic diameter of approximately 254±19 nm and a mean zeta potential of approximately -19.95±0.94 mV. In addition, approximately 80.1% of drug was encapsulated in NPs and released in the biphasic pattern. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that BSA-LTB NPs exhibited higher cytotoxic activity than non-targeted NPs (BSA NPs) in SMMC-7721 cells. Fluorescent imaging results proved that, compared with BSA NPs, BSA-LTB NPs could greatly enhance cellular uptake. Hence, the results indicate that BSA-LTB NPs could be a potential nanocarrier to improve targeted delivery of 5-fluorouracil to tumor cells via mediation of LTB. Keywords: heat-labile enterotoxin subunit B, nanoparticle, bovine serum albumin, 5-fluorouracil

Song Zhao,1,* Jingwen Zhao,3,* Shikui Dong,1 Xiaoqiao Huangfu,1 Bin Li,2,3 Huilin Yang,2,3 Jinzhong Zhao,1 Wenguo Cui2,31Department of Arthroscopic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 2Orthopedic Institute, Soochow University, Suzhou, Jiangsu, 3Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China *These authors contributed equally to this work Abstract: Clinically, rotator cuff tear (RCT) is among the most common shoulder pathologies. Despite significant advances in surgical techniques, the re-tear rate after rotator cuff (RC) repair remains high. Insufficient healing capacity is likely the main factor for reconstruction failure. This study reports on a basic fibroblast growth factor (bFGF)-loaded electrospun poly(lactide-co-glycolide) (PLGA) fibrous membrane for repairing RCT. Implantable biodegradable bFGF–PLGA fibrous membranes were successfully fabricated using emulsion electrospinning technology and then characterized and evaluated with in vitro and in vivo cell proliferation assays and repairs of rat chronic RCTs. Emulsion electrospinning fabricated ultrafine fibers with a core-sheath structure which secured the bioactivity of bFGF in a sustained manner for 3 weeks. Histological observations showed that electrospun fibrous membranes have excellent biocompatibility and biodegradability. At 2, 4, and 8 weeks after in vivo RCT repair surgery, electrospun fibrous membranes significantly increased the area of glycosaminoglycan staining at the tendon–bone interface compared with the control group, and bFGF–PLGA significantly improved collagen organization, as measured by birefringence under polarized light at the healing enthesis compared with the control and PLGA groups. Biomechanical testing showed that the electrospun fibrous membrane groups had a greater ultimate load-to-failure and stiffness than the control group at 4 and 8 weeks. The bFGF–PLGA membranes had the highest ultimate load-to-failure, stiffness, and stress of the healing enthesis, and their superiority compared to PLGA alone was significant. These results demonstrated that electrospun fibrous membranes aid in cell attachment and proliferation, as well as accelerating tendon–bone remodeling, and bFGF-loaded PLGA fibrous membranes have a more pronounced effect on tendon–bone healing. Therefore, augmentation using bFGF–PLGA electrospun fibrous membranes is a promising treatment for RCT. Keywords: rotator cuff tear, bFGF, electrospinning, PLGA, rat model