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Bo Jiang,1 Dong Lu,2 Jiaying Dai,3 Kunfeng Li,4 Qianqian Du,1 Bo Xie,5 Jun Xie,6 Xianhai Zhu,2 Xiang Xie1 1Department of Interventional Ultrasound, The Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China; 2Department of Interventional Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences & Medicine, University of Science & Technology of China, Hefei, 230001, People’s Republic of China; 3Department of Interventional Radiology, Anqing Municipal Hospital, Anqing, Anhui, 246000, People’s Republic of China; 4Department of Radiology, Tongling People’s Hospital, Tongling, Anhui, 244300, People’s Republic of China; 5Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, People’s Republic of China; 6Department of Radiology, Fuyang People’s Hospital, Fuyang, Anhui, 236600, People’s Republic of ChinaCorrespondence: Xiang Xie, Department of Interventional Ultrasound, The Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China, Email 15956922618@163.comObjective: To develop a simple and effective prognostic scoring system to predict the efficacy of drug-eluting bead-transcatheter arterial chemoembolization (DEB-TACE) in the treatment of hepatocellular carcinoma (HCC).Methods: Data were retrospectively collected from 230 patients with HCC who received DEB-TACE treatment at six medical centers between January 2019 and December 2022. We developed a predictive score based on independent risk factors for overall survival (OS), validated the model using a validation cohort, and compared its prognostic accuracy with commonly used HCC staging systems.Results: The number of tumors, albumin-bilirubin levels, alpha-fetoprotein levels, and portal vein thrombus grade were identified as independent factors influencing OS. Based on these factors, we established the DEB-TACE treatment of HCC (DTH) scoring system. The DTH score correlated well with OS, which decreased as the DTH score increased. According to the DTH score, patients were categorized into three risk groups: low-risk (DTH-A, 0– 4 points), medium-risk (DTH-B, 5– 6 points), and high-risk (DTH-A, 7 points). The OS of each risk group was 18.73± 0.62 months, 12.73± 0.10 months, and 6.93± 0.19 months, respectively (p< 0.001). The external cohort validation confirmed the accuracy of the DTH score, demonstrating superior predictive performance compared to other commonly used HCC scoring systems.Conclusion: The DTH-HCC scoring system effectively predicts the outcomes of HCC patients undergoing DEB-TACE as initial treatment. This model can aid in the initial planning and decision-making process for DEB-TACE treatment in HCC patients.Keywords: hepatocellular carcinoma, transcatheter arterial chemoembolization, prognosis prediction model

Wenjie Xie,1,2,&ast; Yixun Zhang,1,2,&ast; Qianfeng Xu,1,2,&ast; Guowei Zhong,1,2 Jundong Lin,2,3 Huichan He,3 Qiuling Du,2 Huijing Tan,1,2 Muqi Chen,1,2 Zhenjie Wu,1– 3 Yulin Deng,1,2 Zhaodong Han,1– 3 Jianming Lu,1,2,4 Jianheng Ye,1,2,4 Fen Zou,1,2 Yangjia Zhuo,1,2 Weide Zhong1– 4 1Department of Urology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China; 2Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China; 3Urology Key Laboratory of Guangdong Province, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510230, People’s Republic of China; 4State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, 999078, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yangjia Zhuo; WeideZhong, Email eyyangjiazhuo@scut.edu.cn; zhongwd2009@live.cnPurpose: Current treatment approaches for Prostate cancer (PCa) often come with debilitating side effects and limited therapeutic outcomes. There is urgent need for an alternative effective and safe treatment for PCa.Methods: We developed a nanoplatform to target prostate cancer cells based on graphdiyne (GDY) and a copper-based metal-organic framework (GDY-CuMOF), that carries the chemotherapy drug doxorubicin (DOX) for cancer treatment. Moreover, to provide GDY-CuMOF@DOX with homotypic targeting capability, we coated the PCa cell membrane (DU145 cell membrane, DCM) onto the surface of GDY-CuMOF@DOX, thus obtaining a biomimetic nanoplatform (DCM@GDY-CuMOF@DOX). The nanoplatform was characterized by using transmission electron microscope, atomic force microscope, X-ray diffraction, etc. Drug release behavior, antitumor effects in vivo and in vitro, and biosafety of the nanoplatform were evaluated.Results: We found that GDY-CuMOF exhibited a remarkable capability to load DOX mainly through π-conjugation and pore adsorption, and it responsively released DOX and generated Cu+ in the presence of glutathione (GSH). In vivo experiments demonstrated that this nanoplatform exhibits remarkable cell-killing efficiency by generating lethal reactive oxygen species (ROS) and mediating cuproptosis. In addition, DCM@GDY-CuMOF@DOX effectively suppresses tumor growth in vivo without causing any apparent side effects.Conclusion: The constructed DCM@GDY-CuMOF@DOX nanoplatform integrates tumor targeting, drug-responsive release and combination with cuproptosis and chemodynamic therapy, offering insights for further biomedical research on efficient PCa treatment. Keywords: graphdiyne, biomimetic nanoplatform, cuproptosis, chemotherapy, prostate cancer

Bennan Zhao,1,&ast; Qingxiao Liu,2,&ast; Qing Du,3 Jun Kang,1 Rong Tang,4 Yalan Tu,5 Dafeng Liu1 1The First Ward of Internal Medicine, Public Health Clinical Center of Chengdu, Chengdu, People’s Republic of China; 2Department of Neurology, Hospital of Chengdu University of TCM, Chengdu, People’s Republic of China; 3The Second Ward of ICU, Public Health Clinical Center of Chengdu, Chengdu, People’s Republic of China; 4Department of Integrated Chinese and Western Medicine, Public Health Clinical Center of Chengdu, Chengdu, People’s Republic of China; 5Scientific Research and Teaching Department, Public Health Clinical Center of Chengdu, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dafeng Liu, The First Ward of Internal Medicine, Public Health Clinical Center of Chengdu, Chengdu, People’s Republic of China, Tel +86 1 309 449 4836, Email ldf312@126.com Yalan Tu, Scientific Research and Teaching Department, Public Health Clinical Center of Chengdu, Chengdu, People’s Republic of China, Tel +86 1 501 326 6454, Email tyl950330@163.comPurpose: To date, there are few reports about mpox case series in China, and scarce information is available about the in-vivo kinetics of T-cell responses in the early stage of mpox infection. This study aims to investigate the clinical difference among mpox patients with and without human immunodeficiency virus (HIV) infection.Patients and Methods: A total of 56 patients diagnosed with mpox by Chengdu Center for Disease Control and Prevention (CDC) and hospitalized in Public Health Clinical Center of Chengdu were retrospectively included and divided into an HIV-infected group (n=23) and a non-HIV-infected group (n=33). Clinical characteristics and serum chemistry findings of mpox patients were collected in order to analyze the differences between the HIV-infected group and the non-HIV-infected group.Results: Multiple laboratory abnormalities, including elevated C-reactive protein (69.1%), hypocalcemia (50.9%), elevated CD3+CD8+T counts (47.0%) and inverted ratio of CD3+CD4+T to CD3+CD8+T (64.7%) were common in mpox cases. There were statistically significant differences (all P < 0.05) in age, serum calcium levels, CD3+CD4+T counts, the ratio of CD3+CD4+T to CD3+CD8+T, proportion with > 10 rashes, incidence of proctitis anus and time from rash growth to rash scab shedding between HIV-infected group and non-HIV-infected group. In the early stage of mpox infection, the median of CD3+CD8+T counts in the non-HIV-infected group was significantly higher than that in healthy donors (P< 0.001), and the median of CD3+CD4+T/CD3+CD8+T ratio was significantly lower (P< 0.001). The median of CD3+CD4+T counts in mpox patients co-infected with HIV significantly decreased compared to the pre-infection level (p =0.033).Conclusion: Our study indicates that mpox co-infected with HIV patients have longer lasting rash lesions and a higher incidence of proctitis anus. T-cell responses may be different between HIV-infected and non-HIV-infected individuals in the early stage of mpox infection.Keywords: mpox, HIV, clinical characteristics, complication, T-cell response

Jiewei Cui,1,&ast; Yang Li,2,&ast; Qingyan Du,3,&ast; Yuanhui Wei,1 Jinxia Liu,1 Zhixin Liang1 1College of Pulmonary & Critical Care Medicine, 8th Medical Center of Chinese PLA General Hospital, Beijing, 100091, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 3Jiamei Dental Hospital, Beijing, 100143, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhixin Liang, Email liangzhixin301@163.comObjective: Bloodstream infection (BSI) is characterized by high mortality, especially among these increasing super-elderly patients (≥ 85 years), and this study was conducted to understand the species distribution, typical clinical features and risk factors for poor prognosis of super-elderly patients with BSI.Methods: Based on previous work, this retrospective study was performed by reviewing an ongoing prospective medical database in a comprehensive tertiary center in China, and all super-elderly patients with BSI in the past 6 years were enrolled in this study.Results: Out of 5944 adult-patients with BSI, there were totally 431 super-elderly patients (≥ 85 years old) enrolled in this study and age ≥ 90 years accounted for 31.1% (134/431). Among these 431 super-elderly patients with BSI, 40 patients (9.3%) were diagnosed with BSI and the remained 401 super-elderly patients (90.7%) were defined as hospital-acquired BSI. The typical feature of these super-elderly patients with BSI was the high proportion of patients with various comorbidities, such as cardiovascular disease (83.8%), ischemic cerebrovascular disease (63.3%) and pulmonary infection (61.0%). The other typical feature was that most (60.1%) of these patients had been hospitalized for long time (≥ 28 days) prior to the onset of BSI, and most patients had received various invasive treatments, such as indwelling central venous catheter (53.1%) and indwelling urinary catheter (47.1%). Unfortunately, due to these adverse features above, both the 7-day short-term mortality (13.2%, 57/431) and the 30-day long-term mortality (24.8%, 107/431) were high. The multivariate analysis showed that both chronic liver failure (OR 7.9, 95% CI 2.3– 27.8, P=0.001) and indwelling urinary catheter (OR 2.3, 95% CI 1.1– 4.7, P=0.023) were independent risk factors for 7-day short-term mortality, but not for 30-day long-term mortality. In addition, the microbiology results showed that the most common species were associated with nosocomial infection or self-opportunistic infection, such as Staphylococcus hominis (18.3%), Staphylococcus epidermidis (11.8%), Escherichia coli (9.7%), Klebsiella pneumoniae (9.3%) and Candida albicans (8.6%, fungi).Conclusion: Super-elderly patients with BSI had typical features, regardless of the pathogenic species distribution and their drug resistance, or clinical features and their risk factors for poor prognosis. These typical features deserved attention and could be used for the prevention and treatment of BSI among super-elderly patients.Keywords: bloodstream infection, elderly, species, risk factor, mortality, aging, central venous catheter, clinical feature

Qianqian Liang,1– 3 Difang Sun,1– 3 Shuyue Xue,1– 3 Xinying Li,1– 3 Xin Liu,1– 3 Qing Du,1– 3 Zhichun Zhang,1– 3 Xiubin Ma,1– 3 Jun Li1– 3 1Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, Shandong, People’s Republic of China; 2State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao, Shandong, People’s Republic of China; 3School of Ophthalmology, Shandong First Medical University, Qingdao, Shandong, People’s Republic of ChinaCorrespondence: Jun Li; Xiubin Ma, Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, 266071, People’s Republic of China, Tel +86-532-85876380, Email doctor_li@126.com; maxiubin2005@126.comPurpose: To compare the effectiveness and safety of adjustable and free postoperative positioning after pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD).Design: Prospective, randomized controlled study.Methods: A total of 94 eyes with RRD were enrolled from April 2020 to April 2023 and monitored postoperatively for at least 3 months. All patients underwent PPV combined with silicone oil injection or gas tamponade and were randomly divided postoperatively into two groups: an adjustable positioning group and a free positioning group. The success of the outcome was based on the retinal reattachment rate, best corrected visual acuity (BCVA), postoperative complications, and ocular biometric parameters such as anterior chamber depth (ACD) and lens thickness (LT).Results: The initial retinal reattachment rate was 97.9% in the adjustable positioning group and 95.7% in the free positioning group, manifesting no statistical difference between the two groups. Similarly, no statistical difference was observed between the two groups in the final BCVA, which was significantly improved compared to the preoperative BCVA. The comparison of the 1-month postoperative ACD and LT with the preoperative values showed no statistically significant differences in the two groups. The rates of complications were not statistically different in the two groups.Conclusion: After treating RRD using PPV, neither the adjustable nor the free postoperative positioning affected the retinal reattachment rate or the incidence of complications. Therefore, our study showed that it is safe and effective to adopt free positioning postoperatively, which may provide more options for patients with RRD undergoing PPV.Keywords: rhegmatogenous retinal detachment, pars plana vitrectomy, adjustable positioning, free positioning

Qiu Du,1,2,&ast; Yingda Lin,3,4,&ast; Changping Ding,5,&ast; Ling Wu,3 Yuan Xu,3 Qingling Feng6 1Department of Neurosurgery, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225012, People’s Republic of China; 2Department of Central Laboratory, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225012, People’s Republic of China; 3Department of Pharmacy, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225012, People’s Republic of China; 4Department of Pharmacy, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, People’s Republic of China; 5Department of Medical Laboratory, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225012, People’s Republic of China; 6Department of Emergency Intensive Care Unit, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225012, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingling Feng, Department of Emergency Intensive Care Unit, the Affiliated Hospital of Yangzhou University, Yangzhou University, 368 Hanjiang Middle Road, Yangzhou, 225012, People’s Republic of China, Email 15216401512@163.com Yuan Xu, Department of Pharmacy, the Affiliated Hospital of Yangzhou University, Yangzhou University, 368 Hanjiang Middle Road, Yangzhou, 225012, People’s Republic of China, Email feebyxuyuan@163.comPurpose: Matrine (Mat), the main active ingredient of traditional Chinese herbal plant Sophora flavescens Ait, has significant antitumor effects, but its pharmacological mechanism on colon cancer (CC) remains unclear. This study aimed to investigate the therapeutic effect of Mat on CC as well as the potential mechanism.Methods: The vasculogenic mimicry (VM) of CC cells was observed by three-dimensional (3D) Matrigel cell culture. Cell proliferation, apoptosis, migration, invasion, and actin filament integrity were detected by CCK8, flow cytometry, wound healing, Transwell and Phalloidin staining assays. qRT-PCR and Western blotting were applied to detect the expression of EMT factors. RNA-sequencing was conducted to screen differentially expressed genes (DEGs), and the GO and KEGG pathway enrichment analyses were performed. Then, the expression of the key MAPK pathway genes and the target gene Claudin-9 (Cldn9) were analyzed. RNA interference was used to silence Cldn9 expression, and the effects of Cldn9 silencing and simultaneous treatment with Mat on VM formation, proliferation, apoptosis, invasion, and migration were investigated. Finally, the expression of EMT factors and MAPK pathway key genes was detected.Results: CT26 cells formed the most typical VM structure. Mat disrupted the VM of CT26 cells, significantly suppressed their proliferation, migration, invasion, actin filament integrity, induced apoptosis, and inhibited EMT process. RNA-sequencing revealed 163 upregulated genes and 333 downregulated genes in Mat-treated CT26 cells, and the DEGs were significantly enriched in cell adhesion molecules and MAPK signaling pathways. Further confirmed that Mat significantly inhibited the phosphorylation levels of JNK and ERK, and the target gene Cldn9 was significantly upregulated in human CC tissues. Silencing Cldn9 markedly inhibited the VM, proliferative activity, invasiveness, and actin filament integrity of CT26 cells, blocked the EMT process, and downregulated the phosphorylation of JNK and ERK, whereas Mat intervention further strengthened the above trends.Conclusion: This study indicated that Mat may synergistically inhibit the EMT process and MAPK signaling pathway through downregulation Cldn9, thereby exerting pharmacological effects on inhibiting VM formation, proliferation, and invasion of CC cells.Keywords: matrine, colon cancer, Cldn9, EMT, MAPK signal pathway

Yonghua Ye,1 Yuping Yang,1 Li Yan,1 Li Zhou,2 Shihui Yu,1 Quan Du,3 Xiaoqiao Dong,3 Qiang Yuan,1 Letian Shan,2,4 Le Guo1 1College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Department of Neurosurgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Cell Resource Bank and Integrated Cell Preparation Center of Xiaoshan District, Hangzhou Regional Cell Preparation Center (Shangyu Biotechnology Co., Ltd), Hangzhou, People’s Republic of ChinaCorrespondence: Letian Shan, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China, Tel +15355015568, Email letian.shan@zcmu.edu.cn Le Guo, College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China, Tel +18986648306, Email le.guo@zcmu.edu.cnPurpose: To explore the pharmacological effects and mechanisms of Qinghao Biejia decoction (QBD) against non-small-cell lung cancer (NSCLC) based on network pharmacology and to verify the anticancer effect of artemisinin B (ART B), the active ingredient of QBD, on H1299 cells.Methods: Ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was applied to explore the chemoprofile of QBD. A zebrafish xenograft model was used to determine the anti-cancer efficacy of QBD. Cell counting kit-8 assay, terminal deoxyribonucleotide transferase-mediated-dUTP nick-end labeling assay; immunofluorescence, and flow cytometry were used to evaluate the in vitro anti-proliferative and pro-apoptotic effects of QBD and ART B on H1299 cells. Subsequently, the related targets and action mechanisms of both QBD and ART B predicted by network pharmacological analyses were experimentally validated by real-time PCR and Western blot assays on H1299 cells.Results: UPLC-QTOF-MS/MS identified a total of 69 compounds (such as ART B, mangiferin, and artemisinic acid) in QBD. The in vivo data showed that QBD significantly inhibited the growth of H1299 cells in xenograft larval zebrafish from 125 to 500 μg/mL. The in vitro data showed that QBD induced apoptosis of H1299 cells, accompanied by down-regulating the expression of BCL-2 and up-regulating the expression of BIM, PUMA, BAX, c-PARP, γ-H2A.X, c-CASP3, and c-CASP8. Alike QBD, ART B exerted similar anti-proliferative and pro-apoptotic effects on H1299 cells. Moreover, ART B inhibited expressions of BCL2L1, AKT1, AKT2, MMP-2, and EGFR, and up-regulated ALB expression. Mechanistically, ART B promoted apoptosis of H1299 cells by inhibiting PI3K/Akt signaling pathway.Conclusion: This study revealed the anti-NSCLC efficacy of QBD. ART B, the effective component of QBD, plays an anti-NSCLC role by down-regulating the PI3K-Akt signaling pathway. It suggests that QBD and ART B are promising drug candidates for NSCLC treatment.Graphical Abstract: Keywords: Qinghao Biejia decoction, non-small-cell lung cancer, larval zebrafish, network pharmacology, artemisinin B

Youwei Wang,1,&ast; Yang Yang,2,&ast; Xiaowei Cao,3 Zhensheng Liu,4 Bing Chen,5 Qiu Du,1,&ast; Xiaoxia Lu6,&ast; 1Department of Neurosurgery, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu Province, People’s Republic of China; 2Department of Clinical Laboratory, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu Province, People’s Republic of China; 3Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu Province, People’s Republic of China; 4Department of Interventional Radiology, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu Province, People’s Republic of China; 5Department of neurosurgery, The Affiliated hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of China; 6Department of Oncology, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoxia Lu, Department of oncology, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu Province, People’s Republic of China, Tel +86 514-82981199, Email luxiaoxia19870318@126.com Qiu Du, Department of neurosurgery, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu Province, People’s Republic of China, Tel +86 514-82981199, Email 092102@yzu.edu.cnPurpose: Circulating tumor DNA (ctDNA) is more representative and accurate than biopsy and is also conducive to dynamic monitoring, facilitating accurate diagnosis and prognosis of glioma. Therefore, the present study aimed to establish and validate a novel amplified method for the detection of IDH1 R132H and BRAF V600E, which were associated with the genetic diagnosis of glioma.Patients and Methods: A dual-signal amplification method based on magnetic aggregation and catalytic hairpin assembly (CHA) was constructed for the simultaneous detection of ctDNAs. When target ctDNAs are present, the CHA reaction is initiated and leads to the assembly of Au-Ag nanoshuttles (Au-Ag NSs) onto magnetic beads (MBs). Further enrichment of MBs under an external magnetic field facilitated the dual-signal amplification of SERS.Results: The limit of detection (LOD) for IDH1 R132H and BRAF V600E in serum was as low as 6.01 aM and 5.48 aM. The reproducibility and selectivity of the proposed SERS analysis platform was satisfactory. Finally, the platform was applied to quantify IDH1 R132H and BRAF V600E in the serum of subcutaneous-tumor‑bearing nude mice, and the results obtained by SERS were consistent with those from quantitative real-time polymerase chain reaction (qRT-PCR).Conclusion: The present study showed that the dual-signal amplification method is a simple and ultrasensitive strategy for gliomas-associated ctDNAs detection, which is crucial for early diagnosis and dynamic monitoring.Keywords: circulating tumor DNA, Au-Ag nanoshuttles, magnetic beads, catalytic hairpin assembly, surface-enhanced Raman spectroscopy

Xiaoyu Wu,1,&ast; Danfei Ji,1,&ast; Zefan Wang,1,&ast; Wenhua Yu,2 Quan Du,2 Wei Hu,3 Yongke Zheng,3 Xiaoqiao Dong,2 Fanghui Chen4 1The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Neurosurgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Department of Intensive Care Unit, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Emergency Department, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoqiao Dong; Fanghui Chen, Email dxqhyy@163.com; wangxiaoleihzsy@163.comBackground: NADPH oxidase 2 (NOX2) is highly expressed in injured brain tissues. We determined serum NOX2 levels of aneurysmal subarachnoid hemorrhage (aSAH) patients and further investigated correlation of serum NOX2 levels with disease severity, delayed cerebral ischemia (DCI) plus prognosis after aSAH.Methods: Serum NOX2 levels were measured in 123 aSAH patients and 123 healthy controls. World Federation of Neurological Surgeons scale (WFNS) score and modified Fisher (mFisher) score were utilized to assess disease severity. Modified Rankin scale (mRS) score was used to evaluate the clinical prognosis at 90 days after aSAH. Relations of serum NOX2 levels to DCI and 90-day poor prognosis (mRS score of 3– 6) were analyzed using multivariate analysis. Receiver operating characteristic curve (ROC) was built to evaluate the prognostic predictive capability.Results: Serum NOX2 levels in aSAH patients, compared with healthy controls, were significantly increased, and were independently correlated with WFNS score, mFisher score and post-stroke 90-day mRS score. Patients with poor prognosis or DCI had significantly higher serum NOX2 levels than other remainders, and serum NOX2 levels independently predicted 90-day poor prognosis and DCI. Serum NOX2 had high prognosis and DCI predictive abilities, and their areas under ROC curve were similar to those of WFNS score and mFisher score.Conclusion: Serum NOX2 levels are significantly associated with hemorrhage severity, poor 90-day prognosis and DCI in aSAH patients. Hence, complement NOX2 may serve as a potential prognostic biomarker after aSAH.Keywords: NADPH oxidase 2, biomarker, aneurysmal subarachnoid hemorrhage, disease severity, delayed cerebral ischemia, prognosis

Jing Liu,1,&ast; Xianglu Sun,2,&ast; Qianyu Du,3 Jinghao Yao,1,4 Mengfen Dai,1 Qianqian Cheng,1 Han Xu,5 Yawei Li,6 Xiuli Liu,7 Mingliang Zhang,8 Yongchun Zhou,2 Yan Yang1 1Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233004, People’s Republic of China; 2Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233004, People’s Republic of China; 3Department of Medical Oncology, Suzhou Municipal Hospital, Suzhou, Anhui, 234000, People’s Republic of China; 4Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230000, People’s Republic of China; 5Department of Medical Oncology, The Third People’s Hospital of Bengbu, Bengbu, Anhui, 233000, People’s Republic of China; 6Department of Medical Oncology, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233040, People’s Republic of China; 7Department of Oncology, The Fifth People’s Hospital of Fuyang, Fuyang, Anhui, 236000, People’s Republic of China; 8Department of Oncology Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Yang, Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233004, People’s Republic of China, Tel/Fax +86 552 3086178, Email qiannianhupo@163.com Yongchun Zhou, Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233004, People’s Republic of China, Tel/Fax +86 552 3086845, Email zhouyongchun_1@hotmail.comPurpose: To explore the efficacy, safety, and potential factors influencing efficacy and outcome of pyrotinib-based therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) in complex clinical practice.Methods: Real-world data for HER2-positive MBC patients treated with pyrotinib-based regimens from 6 hospitals in Northern Anhui, China, from September 2018 to February 2022, were retrospectively collected, and clinicopathological features, efficacy, prognosis, and safety were analyzed. Potential influencing factors including baseline serum vascular endothelial growth factor-A (VEGF-A) for evaluating pyrotinib’s treatment response and outcome were also explored.Results: A total of 169 patients with HER2-positive MBC were enrolled. The objective response rate (ORR), disease control rate (DCR), and median progression-free survival (mPFS) of the overall cohort were 65.1%, 87.6%, and 12.4 months, respectively. Pyrotinib is highly beneficial as different treatment lines and appears to be a feasible strategy both in combination with chemotherapeutic drugs and alone. The mPFS values were 16.5 months, 12.4 months, and 9.3 months in the first, second, and third-or-higher lines of anti-HER2 therapy, respectively (P=0.027). The most common adverse event (AE) was diarrhea (88.2%), and patients with < grade 3 diarrhea achieved a longer mPFS than patients with ≥ grade 3 diarrhea (13.3 months vs 6.9 months, P=0.007). Among the patients with available baseline VEGF-A data, the ORR was 43.5% in patients with a high level of VEGF-A, compared to 81.5% in patients with a low level of VEGF-A (P=0.005). Moreover, patients in the VEGF-A-high group exhibited a shorter mPFS time than those in the VEGF-A-low group (7.8 months vs 19.1 months, P=0.004). Further analysis demonstrated AE of diarrhea and VEGF-A at baseline to be independent prognostic factors for PFS.Conclusion: Pyrotinib-based regimens showed promising efficacy, with manageable tolerance, and AE occurrence of severe diarrhea and baseline level of serum VEGF-A are helpful in predicting the treatment outcome of pyrotinib in HER2-positive MBC.Keywords: breast cancer, HER2, pyrotinib, efficacy, prognostic factor, vascular endothelial growth factor A

Luting Yang, Chuhui Wang, Yijing Zhang, Quanfang Wang, Yulan Qiu, Sihan Li, Bo Yang, Qian Du, Jiaojiao Chen, Mengmeng Teng, Taotao Wang, Yalin Dong Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of ChinaCorrespondence: Yalin Dong; Taotao Wang, Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China, Tel +86-29-85323241 ; Tel/Fax +86-29-85323243, Fax +86-29-85323240, Email dongyalin@mail.xjtu.edu.cn; wangtaotao1989@mail.xjtu.edu.cnPurpose: Voriconazole (VRC) is an antifungal agent which is used for treatment and prophylaxis of invasive fungal infections. The common clinical adverse reactions mainly include central nervous system (CNS) toxicity and abnormal liver function. These adverse reactions limit the clinical use of voriconazole to a certain extent. Therefore, the aim of this study was to analyze the risk factors of voriconazole neurotoxic side effects and to determine the plasma trough concentration (Cmin) threshold of voriconazole-induced CNS toxicity, so as to improve the safety of voriconazole treatment.Patients and Methods: This study retrospectively collected the clinical data of 165 patients who received voriconazole and underwent therapeutic drug monitoring (TDM). CNS toxicity was defined using the National Cancer Institute (NCI) criteria, logistic regression was used to analyze the risk factors of CNS toxicity, classification and Regression tree (CART) model was used to determine the Cmin threshold for CNS toxicity.Results: Voriconazole-related CNS toxicity occurred during treatment in 34 of 165 patients (20.6%) and the median time from administration to onset of CNS toxicity was 6 days (range, 2– 19 days). The overall incidence of CNS toxicity was 20.6% (34/165), including visual disturbances in 4.8% (8/165) and nervous system disorders in 15.8% (26/165). Cmin significantly affects the occurrence of CNS toxicity and the threshold of Cmin for voriconazole CNS toxicity was determined to be 4.85 mg/L, when Cmin > 4.85 mg/L and ≤ 4.85 mg/L, the incidence of CNS was 32.9% and 11.6%, respectively.Conclusion: Voriconazole trough concentration of Cmin is an independent risk factor for CNS toxicity, and the threshold of Cmin for CNS toxicity is 4.85mg/L. TDM should be routinely performed in patients with clinical use of voriconazole to reduce the occurrence of CNS toxicity of voriconazole.Keywords: voriconazole, TDM, Cmin, CNS toxicity, cohort study

Tian Yan,1 Ze-Fan Wang,1 Xiao-Yu Wu,1 Quan Du,2 Wen-Hua Yu,2 Wei Hu,3 Yong-Ke Zheng,3 Ke-Yi Wang,4 Xiao-Qiao Dong2 1The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Neurosurgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Department of Intensive Care Unit, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Clinical Laboratory Center, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Xiao-Qiao Dong, Department of Neurosurgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China, Email dxqhyy@163.comObjective: SIRT3 may act as a brain-protective factor. We measured the plasma SIRT3 levels of patients with intracerebral hemorrhage (ICH) and further determined the relationship between plasma SIRT3 and clinical outcome plus severity of ICH.Methods: In this prospective cohort study, we quantified plasma SIRT3 levels in 105 ICH patients and 72 healthy controls. Glasgow Coma Scale (GCS) score and hematoma volume were used to assess severity. Poor prognosis was defined as a Glasgow Outcome Scale (GOS) score of 1– 3 at 90 days after ICH.Results: Plasma SIRT3 levels were markedly lower in patients than in controls (median, 10.19 versus 13.17 ng/mL; P< 0.001). Among all patients, plasma SIRT3 levels were independently correlated with hematoma volume (beta, − 0.098; 95% confidence interval, − 0.158--0.039; t, − 3.282; P=0.001) and GCS score (beta, 0.465; 95% confidence interval, 0.107– 0.823; t, 2.576; P=0.011). A total of 46 cases had a poor prognosis at post-stroke 90 days. The plasma levels of SIRT3 significantly decreased in patients with a poor prognosis, compared with those with a good prognosis (median, 6.1 versus 11.2 ng/mL; P< 0.001). Plasma SIRT3 was an independent predictor for 90-day poor prognosis of patients (odds ratio, 0.837; 95% confidence interval, 0.708– 0.990; P=0.038). Plasma SIRT3 levels distinguished the development of poor prognosis with area under receiver operating characteristic curve at 0.801 (95% confidence interval, 0.711– 0.872) and plasma SIRT3 levels ≤ 7.38 ng/mL predicted poor prognosis with 63.04% sensitivity and 93.22% specificity.Conclusion: Declined plasma SIRT3 levels are highly associated with hemorrhagic severity and poor 90-day outcome, thus suggesting that plasma SIRT3 may serve as a potential prognostic biomarker for ICH.Keywords: intracerebral hemorrhage, prognosis, severity, SIRT3, outcome

Dan He,1 Wan Dan,1 Qing Du,1 Bing-Bing Shen,1 Lin Chen,1 Liang-zi Fang,1 Jian-Jun Kuang,1 Chun-yu Tang,2 Ping Cai,1 Rong Yu,1,3 Shui-han Zhang,1 Jian-hua Huang1,3 1Hunan Academy of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410013, People’s Republic of China; 2Hunan Times Sunshine Pharmaceutical Co., Ltd., Changsha, Hunan, 425007, People’s Republic of China; 3Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine Hunan, Changsha, Hunan, 410208, People’s Republic of ChinaCorrespondence: Shui-han Zhang; Jian-hua Huang, Hunan Academy of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410013, People’s Republic of China, Tel +86 13637400650 ; +86 18692265317, Email zhangshuihan0220@126.com; huangjianhua1985@163.comPurpose: This study aimed to reveal the multicomponent synergy mechanisms of SWP based on network pharmacology and metabolomics for exploring the relationships of active ingredients, biological targets, and crucial metabolic pathways.Materials: Network pharmacology, including TRRUST, GO, and KEGG, enrichment was used to discover the active ingredients and potential regulation mechanisms of SWP. LC-MS and multivariate data analysis method were further applied to analyze serum metabolomics profiling for discovering the potential metabolic mechanisms of SWP on AA induced by Cyclophosphamide (CTX) and 1-Acetyl-2-phenylhydrazine (APH).Results: A total of 27 important bioactive ingredients meeting the ADME (absorption, distribution, metabolism, and excretion) screening criteria from SWP were selected. Interaction networks were constructed and validated based on the 10 associated ingredients with the relevant targets. A total of 125 biomarkers were found by Metabolomics approach, which associated with the development of AA, mainly involved in amino acid metabolism and lipid metabolism. While SWP can reverse the above 12 metabolites changed by AA. Network analysis revealed the synergistic effects of SWP through the 43 crucial pathways, including Sphingolipid signaling pathway, Sphingolipid metabolism, Arginine and proline metabolism, VEGF signaling pathway, Estrogen signaling pathway.Conclusion: The study suggested that SWP is a useful alternative for the treatment of AA induced by CTX + APH. Its potential mechanisms are to improve hematopoietic microenvironment and promote bone marrow hematopoiesis therapies.Keywords: aplastic anemia, Siwu Paste, network pharmacology, metabolomics, integration analysis

Yingda Lin,1,2,&ast; Fuming He,2 Ling Wu,1 Yuan Xu,1 Qiu Du3,4,&ast; 1Department of Pharmacy, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225012, People’s Republic of China; 2Medical College, Yangzhou University, Yangzhou, 225001, People’s Republic of China; 3Department of Neurosurgery, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225012, People’s Republic of China; 4Department of Central Laboratory, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225012, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiu Du, Department of Neurosurgery, the Affiliated Hospital of Yangzhou University, Yangzhou University, 368 Hanjiang Middle Road, Yangzhou, 225012, People’s Republic of China, Email 092102@yzu.edu.cn Yuan Xu, Department of pharmacy, the Affiliated Hospital of Yangzhou University, Yangzhou University, 368 Hanjiang Middle Road, Yangzhou, 225012, People’s Republic of China, Email feebyxuyuan@163.comAbstract: As The main effective monomer of the traditional Chinese medicine Sophora flavescens Ait, matrine has a broad scope of pharmacological activities such as anti-tumor, anti-inflammatory, analgesic, anti-fibrotic, anti-viral, anti-arrhythmia, and improving immune function. These actions explain its therapeutic effects in various types of tumors, cardiopathy, encephalomyelitis, allergic asthma, rheumatoid arthritis (RA), osteoporosis, and central nervous system (CNS) inflammation. Evidence has shown that the mechanism responsible for the pharmacological actions of matrine may be via the activation or inhibition of certain key molecules in several cellular signaling pathways including the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), transforming growth factor-β/mothers against decapentaplegic homolog (TGF-β/Smad), nuclear factor kappa B (NF-κB), Wnt (wingless/ integration 1)/β-catenin, mitogen-activated protein kinases (MAPKs), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. This review comprehensively summarizes recent studies on the pharmacological mechanisms of matrine to provide a theoretical basis for molecular targeted therapies and further development and utilization of matrine.Keywords: matrine, pharmacological effects, signaling pathways, review

Baiyang Chen,1,&ast; Yang Gu,2,&ast; Hui Shen,3 Qiangsheng Liu,4 Hongbo Wang,1 Yabo Li,1 Xifan Liu,1 Yu Liu,1 Qinghao Du,1 Huapeng Sun,1 Xiaofeng Liao1 1Department of General Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, People’s Republic of China; 2Department of Hepatobiliary and Pancreas, The First People’s Hospital of Jingmen, Jingmen, Hubei, People’s Republic of China; 3Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, People’s Republic of China; 4Department of Anesthesiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaofeng Liao; Huapeng Sun, Department of General Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, People’s Republic of China, Email liaoxiaofeng66@163.com; sunhuapeng1@163.comBackground and Aims: Hepatocellular carcinoma (HCC) is a common malignant disease with high morbidity and mortality throughout the world. While Borealin is a putative oncogene that is dysregulated in multiple tumors, its exact role in HCC remains less investigated.Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) assays were employed to examine the relative amount of Borealin. Gene set enrichment analysis (GSEA) and other bioinformatic analyses were implemented to probe into the potential functions of Borealin. The biological roles and mechanisms of Borealin in the tumorigenesis and development of HCC were further evaluated using a battery of functional assays in vivo and in vitro.Results: Borealin was enhanced in the HCC tissue samples and hepatoma cells when compared with the nontumor tissues and normal liver cells. Higher Borealin expression was positively linked with advanced pathological phenotypes and inferior overall survival. The overexpression of Borealin promoted the cells’ abilities on proliferation, invasion and epithelial–mesenchymal transition (EMT) in vitro, facilitated tumor growth and lung metastasis in vivo, whereas the silencing of Borealin inhibited these capabilities in vitro. Furthermore, Borealin interacted with β-catenin and further activated the Wnt/β-catenin signaling pathway, which endowed HCC cells with highly aggressive and metastatic capabilities.Conclusion: Borealin was identified as an oncogene that could promote HCC growth and metastasis by activating the WNT/β-catenin signaling pathway. These findings extended the understanding of Borealin in HCC tumorigenesis and development and highlighted the significance of Borealin in HCC diagnosis and treatment.Keywords: hepatocellular carcinoma, Borealin, epithelial mesenchymal transition, Wnt/β-catenin

In order to determine the most suitable turbulence model for studying the aerodynamic performance of bus, the effects of different turbulence models on the aerodynamic characteristics of bus were investigated. A comparative analysis was conducted on five turbulence models (IDDES, DDES, DES, LES, URANS). The pressure distribution on the cross section at x=0 and y=0 is also analyzed for each model. The results reveal that IDDES accurately captures the negative pressure at the rear of the bus and predicts the pressure gradients more effectively than other models. IDDES also captures more vortices at the head of the bus and predicts the wake flow more widely than other models. DDES has obvious shedding phenomenon in the wake flow, while IDDES provides a relatively smooth airflow trajectory, but its prediction of airflow trajectory at a distance is less clear. Through quantitative and qualitative analyses of the aerodynamic characteristics of bus under different turbulence models, it can be concluded that IDDES is the most suitable turbulence model to study the aerodynamic characteristics of bus. [ABSTRACT FROM AUTHOR]

Both educational data mining and learning analytics aim to understand learners and optimise learning processes of educational settings like Moodle, a learning management system (LMS). Analytics in an LMS covers many different aspects: finding students at risk of abandoning a course or identifying students with difficulties before the assessments. Thus, there are multiple prediction models that can be explored. The prediction models can target at the course also. For instance, will this activity assessment engage learners? To ease the evaluation and usage of prediction models in Moodle, we abstract out the most relevant elements of prediction models and develop an analytics framework for Moodle. Apart from the software framework, we also present a case study model which uses variables based on assessments to predict students at risk of dropping out of a massive open online course that has been offered eight times from 2013 to 2018, including a total of 46,895 students. A neural network is trained with data from past courses and the framework generates insights about students at risk in ongoing courses. Predictions are then generated after the first, the second, and the third quarters of the course. The average accuracy that we achieve is 88.81% with a 0.9337 F1 score and a 73.12% of the area under the ROC curve.