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Xiaojun Li,1 Donghao Cai,2 Chuangchuang Mei,2 Xinghui Huang3 1Department of Nosocomial Infection, Guangdong Provincial Second Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong, 510095, People’s Republic of China; 2Department of Laboratory Medicine, Guangdong Provincial Second Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong, 510095, People’s Republic of China; 3Department of Quality Control, Guangdong Provincial Second Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong, 510095, People’s Republic of ChinaCorrespondence: Xiaojun Li, Department of Nosocomial Infection, Guangdong Provincial Second Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong, 510095, People’s Republic of China, Email jylixiaojun@sina.comPurpose: To develop and validate a predictive model for the risk of death in patients with Acinetobacter baumannii (A. baumannii) bloodstream infection (BSI) for clinical decision-making and patient management.Methods: In this study, we included demographic and clinical data from 206 patients with Acinetobacter baumannii BSI in China between January 2013 and December 2023. Variables were screened by least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression, and prognostic models and nomograms were constructed. The models were evaluated using the area under curve (AUC) of Receiver Operating Characteristic (ROC), decision curve analysis (DCA), and standard curves to evaluate the model.Results: Comorbid septic shock, an elevated neutrophil/lymphocyte ratio (NLR), low hemoglobin (HGB) levels, and low platelet counts (PLT) were found to be independent risk factors for death in patients with A. baumannii BSI. With the models constructed from these four variables, the AUCs of the ROC curves of the test and validation cohorts for the prognostic scenarios at 7, 14, and 28 days were not less than 0.850, and the AUCs of the ROC curves of the risk-of-death prediction model were the highest for both groups at 7 days, at 0.907 and 0.886, respectively. The two sets of calibration curves show that the calibration curves oscillate around a 45° diagonal line at 7, 14, and 28 days, and there is a good correlation between the actual risk and the predicted risk, with a high degree of calibration.The clinical decision curve shows that the model has a strong discriminatory ability when the probability is between 10% and 70%.Conclusion: Septic shock status, NLR, HGB and PLT are independent risk factors for 28-day mortality in patients with A. baumannii BSI. These variables are conveniently and readily available, and in patients with A. baumannii BSI these indicators can be closely monitored in clinical practice and timely interventions can be made to improve prognosis.Keywords: Acinetobacter baumannii, bloodstream infection, predictive model, septic shock

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector.

Lu Liu,1,* Zili Tang,1,* Qian Zeng,1,* Wenchuan Qi,1 Ziyang Zhou,1 Daohong Chen,1 Dingjun Cai,1– 3 Ying Chen,1 Shiqi Sun,1 Siyao Gong,1 Bin He,1 Shuguang Yu,1– 3 Ling Zhao1– 3 1Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, People’s Republic of China; 2Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, Sichuan, People’s Republic of China; 3Key Laboratory of Acupuncture for Senile Disease (Chengdu University of Traditional Chinese Medicine), Ministry of Education, Chengdu City, Sichuan Province, China*These authors contributed equally to this workCorrespondence: Ling Zhao; Shuguang Yu, College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu City, Sichuan Province, 611137, People’s Republic of China, Tel +86 28 6180 0000, Email zhaoling@cdutcm.edu.cn; ysg28588@126.comBackground: Electroacupuncture (EA), with varying stimulation intensities, has demonstrated therapeutic potentials in both animal and clinical studies for the treatment of chronic obstructive pulmonary disease (COPD). However, a comprehensive investigation of the intensity-related effects, particularly 1mA and 3mA of EA, and the underlying mechanisms remains lacking.Methods: A COPD rat model was established by prolonged exposure to cigarette smoke and intermittent intratracheal instillation of lipopolysaccharide. EA treatment was administered at acupoints BL13 (Feishu) and ST36 (Zusanli), 20 minutes daily for 2 weeks, with intensities of 1mA and 3mA. EA effectiveness was evaluated by pulmonary function, histopathological change, serum level of inflammatory cytokines, and level of oxidative stress markers in serum and lung tissues. Transcriptome profiling and weighted gene co-expression network analysis (WGCNA) were performed to reveal gene expression patterns and identify hub genes. Real-time quantitative PCR (RT-qPCR) and Western blot (WB) were performed to detect the mRNA and protein expression levels, respectively.Results: EA at both 1mA and 3mA exerted differing therapeutic effects by improving lung function and reducing inflammation and oxidative stress in COPD rats. Transcriptome analysis revealed distinct expression patterns between the two groups, functionally corresponding to shared and intensity-specific (1mA and 3mA) enriched pathways. Eight candidate genes were identified, including Aqp9, Trem1, Mrc1, and Gpnmb that were downregulated by EA and upregulated in COPD. Notably, Msr1 and Slc26a4 exclusively downregulated in EA-1mA, while Pde3a and Bmp6 upregulated solely in EA-3mA. WGCNA constructed 5 key modules and elucidated the module–trait relationship, with the aforementioned 8 genes being highlighted. Additionally, their mRNA and protein levels were validated by RT-qPCR and WB.Conclusion: Our results demonstrated that 1mA and 3mA intensities induce distinct gene expression patterns at the transcriptional level, associated with shared and 1mA vs 3mA-specific enriched pathways. Genes Mrc1, Gpnmb, Trem1, and Aqp9 emerge as promising targets, and further studies are needed to elucidate their functional consequences in COPD.Keywords: chronic obstructive pulmonary disease, electroacupuncture, intensity, transcriptome profiling, weighted gene co-expression network analysis

Ailin Zou,1,* Tingting Xiao,1,* Boyu Chi,1,2 Yu Wang,1 Lipeng Mao,1,2 Dabei Cai,1,2 Qingqing Gu,1 Qianwen Chen,1 Qingjie Wang,1 Yuan Ji,1 Ling Sun1,2 1Department of Cardiology, the Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, People’s Republic of China; 2Changzhou Clinical Medical College, Dalian Medical University, Dalian, Liaoning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling Sun; Qingjie Wang, Department of Cardiology, the Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213003, People’s Republic of China, Email sunling85125@hotmail.com; wang-qingjie@hotmail.comBackground: Cardiac repair remains a thorny issue for survivors of acute myocardial infarction (AMI), due to the regenerative inertia of myocardial cells. Cell-free therapies, such as exosome transplantation, have become a potential strategy for myocardial injury. The aim of this study was to investigate the role of engineered exosomes in overexpressing Growth Differentiation Factor-15 (GDF-15) (GDF15-EVs) after myocardial injury, and their molecular mechanisms in cardiac repair.Methods: H9C2 cells were transfected with GDF-15 lentivirus or negative control. The exosomes secreted from H9C2 cells were collected and identified. The cellular apoptosis and autophagy of H2O2-injured H9C2 cells were assessed by Western blotting, TUNEL assay, electron microscopy, CCK-8 and caspase 3/7 assay. A rat model of AMI was constructed by ligating the left anterior descending artery. The anti-apoptotic, pro-angiogenic effects of GDF15-EVs treatment, as well as ensuing functional and histological recovery were evaluated. Then, mRNA sequencing was performed to identify the differentially expressed mRNAs after GDF15-EVs treatment.Results: GDF15-EVs inhibited apoptosis and promoted autophagy in H2O2 injured H9C2 cells. GDF15-EVs effectively decreased the infarct area and enhanced the cardiac function in rats with AMI. Moreover, GDF15-EVs hindered inflammatory cell infiltration, inhibited cell apoptosis, and promoted cardiac angiogenesis in rats with AMI. RNA sequence showed that telomerase reverse transcriptase (TERT) mRNA was upregulated in GDF15-EVs-treated H9C2 cells. AMPK signaling was activated after GDF15-EVs. Silencing TERT impaired the protective effects of GDF15-EVs on H2O2-injured H9C2 cells.Conclusion: GDF15-EVs could fulfil their protective effects against myocardial injury by upregulating the expression of TERT and activating the AMPK signaling pathway. GDF15-EVs might be exploited to design new therapies for AMI.Keywords: exosomes, growth differentiation factor-15, telomerase reverse transcriptase, acute myocardial infarction

Qianwen Chen,1,&ast; Qingqing Gu,1,&ast; Anwen Yin,2,&ast; Dabei Cai,1 Tingting Xiao,1 Yu Wang,1 Yuan Ji,1 Qingjie Wang,1 Jun Wei,3 Ling Sun1 1Department of Cardiology, the Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213000, People’s Republic of China; 2Department of Cardiology, the Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, People’s Republic of China; 3Department of Cardiovascular Surgery, the First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingjie Wang; Ling Sun, Department of Cardiology, the Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, 29 Xinglong Alley, Changzhou, Jiangsu, 213003, People’s Republic of China, Email wang-qingjie@hotmail.com; sunling85125@hotmail.comObjective: This study aimed to explore the association of preoperative neutrophil percentage (NEUT%) with the risk of acute kidney injury (AKI) in patients with acute myocardial infarction (AMI) having undergone coronary interventional therapy.Methods: A single-center, retrospective and observational study was conducted. From December 2012 to June 2021, patients with AMI were enrolled and divided into AKI group and non-AKI group. The NEUT% in the two groups was compared. The association between NEUT% with the risk of post-AMI AKI was analyzed by univariate and multivariable logistic regression. Kaplan-Meier survival curve was drawn to evaluate the prognostic ability of NEUT% for short-term all-cause death following AMI.Results: A total of 3001 consecutive patients were enrolled with an average age of 64.38 years. AKI occurred in 327 (10.9%) patients. The NEUT% was higher in the AKI group than in the non-AKI group ([76.65± 11.43]% versus [73.22± 11.83]%, P< 0.001). NEUT% was also identified as an independent risk factor for AKI in AMI patients after adjustment (OR=1.021, 95% CI: 1.010– 1.033, P < 0.001). Compared with those at the lowest quartile of NEUT%, the patients at quartiles 2– 4 had a higher risk of AKI (P for trend = 0.003). The odds of AKI increased by 29.0% as NEUT% increased by 1 standard deviation (OR=1.290, 95% CI: 1.087– 1.531, P = 0.004). After a median of 35 days follow-up, 93 patients died. Patients with a higher NEUT% presented a higher risk of all-cause death after AMI (Log rank: χ2 =24.753, P< 0.001).Conclusion: In AMI patients, the peripheral blood NEUT% was positively associated with the odds of AKI and short-term all-cause mortality. NEUT% may provide physicians with more information about disease development and prognosis.Keywords: neutrophil percentage, acute kidney injury, acute myocardial infarction

Qing-Qing Luo,&ast; Qiao-Nan Li,&ast; Dan Cai, Song Jiang, Shao-Song Liu, Mao-Sheng Liu, Cong Lv, Jin-Ke Wang, Kun-He Zhang, Ting Wang Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology & Hepatology, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ting Wang; Kun-He Zhang, Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology & Hepatology, No. 17, Yongwai Zheng Street, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel +86-13361659001 ; +86-13007202818, Email tingwang@ncu.edu.cn; khzhang@ncu.edu.cnPurpose: The differential diagnosis of atypical hepatocellular carcinoma (aHCC) and atypical benign focal hepatic lesions (aBFHL) usually depends on pathology. This study aimed to develop non-invasive approaches based on conventional blood indicators for the differential diagnosis of aHCC and aBFHL.Patients and Methods: Hospitalized patients with pathologically confirmed focal hepatic lesions and their clinical data were retrospectively collected, in which patients with HCC with serum alpha-fetoprotein (AFP) levels of ≤ 200 ng/mL and atypical imaging features were designated as the aHCC group (n = 224), and patients with benign focal hepatic lesions without typical imaging features were designated as the aBFHL group (n = 178). The performance of indexes (both previously reported and newly constructed) derived from conventional blood indicators by four mathematical operations in distinguishing aHCC and aBFHL was evaluated using the receiver operating characteristic (ROC) curve and diagnostic validity metrics.Results: Among ten previously reported derived indexes related to HCC, the index GPR, the ratio of γ-glutamyltransferase (GGT) to platelet (PLT), showed the best performance in distinguishing aHCC from aBFHL with the area under ROC curve (AUROC) of 0.853 (95% CI 0.814– 0.892), but the other indexes were of little value (AUROCs from 0.531 to 0.700). A new derived index, sAGP [(standardized AFP + standardized GGT)/standardized PLT], was developed and exhibited AUROCs of 0.905, 0.894, 0.891, 0.925, and 0.862 in differentiating overall, BCLC stage 0/A, TNM stage I, small, and AFP-negative aHCC from aBFHL, respectively.Conclusion: The sAGP index is an efficient, simple, and practical metric for the non-invasive differentiation of aHCC from aBFHL.Keywords: atypical hepatocellular carcinoma, differential diagnosis, conventional blood indicator, derived index, sAGP

The nature of dark matter and properties of neutrinos are among the mostpressing issues in contemporary particle physics. The dual-phase xenontime-projection chamber is the leading technology to cover the availableparameter space for Weakly Interacting Massive Particles (WIMPs), whilefeaturing extensive sensitivity to many alternative dark matter candidates.These detectors can also study neutrinos through neutrinoless double-beta decayand through a variety of astrophysical sources. A next-generation xenon-baseddetector will therefore be a true multi-purpose observatory to significantlyadvance particle physics, nuclear physics, astrophysics, solar physics, andcosmology. This review article presents the science cases for such a detector.

Jihui Lu, Zhijia Wang, Desheng Cai, Xiaoyu Lin, Xuemei Huang, Zhihua Yuan, Yaozhi Zhang, Haimin Lei, Penglong Wang School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of ChinaCorrespondence: Penglong Wang, School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China, Email wpl581@126.com Haimin Lei, School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China, Email hm_lei@126.comBackground: Deaths from bacterial infections have risen year by year. This trend is further aggravated as the overuse antibiotics and the bacterial resistance to all known antibacterial agents. Therefore, new therapeutic alternatives are urgently needed.Methods: Enlightenment the combination usage of traditional herb medicine, one carrier-free binary nanoparticles (GA-BBR NPs) was discovered, which was self-assembled from gallic acid and berberine through electrostatic interaction, π-π stacking and hydrophobic interaction; and it could be successfully prepared by a green, cost-effective and “one-pot” preparation process.Results: The nanoparticles exhibited strong antibacterial activity and biofilm removal ability against multidrug-resistant S. aureus (MRSA) by downregulating mRNA expression of rpsF, rplC, rplN, rplX, rpsC, rpmC and rpsH to block bacterial translation mechanisms in vitro and in vivo, and it had well anti-inflammatory activity and a promising role in promoting angiogenesis to accelerate the wound healing on MRSA-infected wounds model in vivo. Additionally, the nanoparticles displayed well biocompatibility without cytotoxicity, hemolytic activity, and tissue or organ toxicity.Conclusion: GA-BBR NPs originated from the drug combination has potential clinical transformation value, and this study provides a new idea for the design of carrier-free nanomedicine derived from natural herbals.Graphical Abstract: Keywords: carrier-free binary self-assemblies, natural herbal ingredients, antibacterial, wound healing, anti-inflammatory, angiogenesis

Lei Ji,1 Tingting Jiang,1 Xin Zhao,2 Damin Cai,1 Kouzhen Hua,1 Peng Du,1 Yuanyuan Chen,3 Jianping Xie4 1School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 2Department of International Registration, Ustar Biotechnologies (Hangzhou) Ltd, Hangzhou, Zhejiang, People’s Republic of China; 3Tuberculosis Diagnosis and Treatment Center, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, People’s Republic of China; 4Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Ministry of Education Eco-Environment of the Three Gorges Reservoir Region, Ministry of Education, Chongqing Municipal Key Laboratory of Karst Environment, School of Life Sciences, Southwest University, Chongqing, People’s Republic of ChinaCorrespondence: Lei Ji, School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, No. 481 Binwen Road, Hangzhou, Zhejiang, 310053, People’s Republic of China, Tel +86 571 8769 2681, Fax +86 571 8769 2673, Email jilei@hmc.edu.cnPurpose: Fatty acid metabolism plays an important role in the survival and pathogenesis of Mycobacterium tuberculosis. During dormancy, lipids are considered to be the main source of energy. A previous study found that Rv0494 is a starvation-inducible, lipid-responsive transcriptional regulator. However, the role of Rv0494 in bacterial persister survival has not been studied.Methods: We constructed a Rv0494 deletion mutant strain of Mycobacterium tuberculosis H37Rv and evaluated the susceptibility of the mutant strain to antibiotics using a persistence test.Results: We found that mutations in Rv0494 lead to survival defects of persisters, which reflected in increased sensitivity to isoniazid.Conclusion: We conclude that Rv0494 is important for persister survival and may serve as a good target for developing new antibiotics that kill persister bacteria for improved treatment of persistent bacterial infections.Keywords: drug target, drug tolerance, lipids, persisters

Yuhao Zeng,1,&ast; Sha Zhu,1,&ast; Zilin Wang,1 Junru Chen,1 Jindong Dai,1 Zhenhua Liu,1 Guangxi Sun,1 Jiayu Liang,1 Xingming Zhang,1 Zhipeng Wang,1 Jinge Zhao,1 Yuchao Ni,1 Jiyu Yang,1 Minghao Wang,1 Qiang Wei,1 Xiang Li,1 Ni Chen,2 Zhiping Li,3 Xin Wang,3 Yali Shen,3 Jin Yao,4 Rui Huang,5 Jiyan Liu,6 Diming Cai,7 Hao Zeng,1 Pengfei Shen1 1Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 5Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 6Department of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 7Department of Medical Ultrasound, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pengfei Shen; Hao Zeng, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China, Email cdhx510@163.com; kucaizeng@163.comPurpose: Multidisciplinary team (MDT) discussion is a widely used model to manage patients diagnosed with cancer. However, there has been no direct evidence to prove its effect on the prognosis of metastatic renal cell carcinoma (mRCC) patients, so this study explored the impact of MDT discussion on mRCC patient survival.Methods: The clinical data of 269 mRCC patients were retrospectively collected from 2012 to 2021. The cases were grouped into the MDT and non-MDT groups, then subgroup analysis was performed according to different histology types, as well as exploring the role of MDT in patients who have undergone multiple-line therapy. Overall survival (OS) and progression free survival (PFS) were set as the study endpoint.Results: Approximately half (48.0%, 129/269) of the patients were in the MDT group, with univariable survival analyses showing these patients had remarkably longer median OS (MDT group: 73.7 months; non-MDT group: 33.2 months, hazard ratio (HR): 0.423 (0.288, 0.622), p< 0.001) and longer median PFS (MDT group: 16.9 months, non-MDT group: 12.7 months, HR: 0.722 (0.542, 0.962), p=0.026). Furthermore, MDT management resulted in longer survival for both ccRCC and non-ccRCC subgroups. Patients in the MDT group were more likely to receive multi-line therapy (MDT group: 79/129, 61.2% vs non-MDT group: 56/140, 40.0%, p< 0.001), and within this patient group, MDT management still resulted in longer OS (MDT group: 94.0 months; non-MDT group: 43.5 months, p=0.009).Conclusion: MDT is associated with prolonged overall survival in mRCC independent of histology, ensuring that patients receive better management and precise treatment.Keywords: mRCC, MDT, overall survival, prognosis, ccRCC, non-ccRCC, multi-line treatment

Yawen Jiang, Dan Cai, Si Shi School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, People’s Republic of ChinaCorrespondence: Yawen Jiang, School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, NO. 66 Gongchang Road, Guangming District, Shenzhen, Guangdong, People’s Republic of China, Tel +86 13266737281, Email jiangyw26@mail.sysu.edu.cnIntroduction: Advanced hepatocellular carcinoma (HCC) represents a major public health threat. Several emerging combination therapies have shown promising results for the first-line treatment of advanced HCC. The present study compared the efficacy of atezolizumab plus bevacizumab (AB) with lenvatinib plus pembrolizumab (LP), which were two of the leading combination therapies.Methods: The outcomes of the present analysis were overall survival (OS) time and progression-free survival (PFS) time. Two matching-adjusted indirect comparisons (MAICs) were first conducted using the individual-level patient data (IPD) of the sorafenib arm from a previous clinical trial and the aggregate data (AgD) of the AB and LP arms from the corresponding published trials. From the MAICs, the hazard ratios (HRs) of AB and LP vs sorafenib were estimated by conducting weighted Cox regressions. The HRs from the two MAICs were then pooled to conduct a second-order indirect comparison of AB vs LP.Results: In the MAIC analyses, AB had better efficacy on both OS (HR: 0.58, 95% CI: 0.42– 0.79) and PFS (HR: 0.59, 95% CI: 0.47– 0.76) than sorafenib, whereas LP had significantly better efficacy on PFS (HR: 0.62, 95% CI: 0.41– 0.94) but not OS (HR: 0.83, 95% CI: 0.52– 1.32). In the second-order comparison, AB was insignificantly more efficacious on OS (HR: 0.71, 95% CI: 0.42– 1.23) than and similarly efficacious on PFS (HR: 0.95, 95% CI: 0.60– 1.51) as the LP regimen.Conclusion: LP regimen may be a potential first-line immunotherapy option for advanced HCC given its comparative effectiveness in relation to AB.Keywords: matching, adjusted, overall, progression-free, survival, PD-1, PD-L1, balancing, first-line, unresectable

Bing Xu, Mengmeng Yan, Fei Zhou, Desheng Cai, Wenbo Guo, Xiaohui Jia, Runping Liu, Tao Ma, Tong Li, Feng Gao, Penglong Wang, Haimin Lei School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of ChinaCorrespondence: Penglong Wang; Haimin Lei Email wpl581@126.com; hm_lei@126.comBackground: The clinical utility of camptothecin (CPT) is restricted by poor aqueous solubility, high lipophilicity, active lactone ring instability, and off-targeted toxicities. We report here a prostate-specific membrane antigen (PSMA) and esterase dual responsive self-assembled nanoparticles (CPT-WT-H NPs) for highly efficient CPT delivery and effective cancer therapy.Methods and Results: In this study, smart self-assembled nanoparticles CPT-WT-H NPs were elaborately designed and synthesized by combing hydrophobic CPT with hydrophilic PSMA-responsive penta-peptide via a cleavable ester bond. This dual responsive nanoparticle with negatively charged surface first respond to the extracellular PSMA and then to the intracellular esterase, achieving a programmable release of CPT at the tumor site and producing the byproducts of biocompatible glutamic acid and aspartic acid. Our data demonstrated that CPT-WT-H NPs exhibited greatly improved water solubility and stability. Results from MTT and flow cytometry showed CPT-WT-H NPs exhibited significantly higher cytotoxicity as well as apoptosis-inducing activity against PSMA-expressing LNCaP-FGC cells than the non-PSMA-expressing cancer cells, showing excellent cytotoxic selectivity. Moreover, the unique nanostructure provided the efficient transportation of CPT to tumor site, which resulted in the effective inhibition of tumor growth and low systemic toxicity in vivo.Conclusion: CPT-WT-H NPs exhibited excellent in vitro PSMA-response ability and in vivo antitumor activity and safety, holding the promise to become a new and potent anticancer drug. The current research presents a promising strategy for efficient drug delivery.Keywords: CPT prodrug, dual responsive, sequential drug release, prostate-specific membrane antigen, self-assembly

Danfeng Cai,1,2,* Lian Zhu,3,* Wuke Zhang,2,4 Hao Ding,2,4 Ailian Wang,5 Yao Lu,1 Jia Jin5 1College of Science & Technology, Ningbo University, Ningbo, People’s Republic of China; 2Academy of Neuroeconomics and Neuromanagement at Ningbo University, Ningbo, People’s Republic of China; 3School of Journalism and Communication, Shanghai International Studies University, Shanghai, People’s Republic of China; 4Business School, Ningbo University, Ningbo, People’s Republic of China; 5Laboratory of Applied Brain and Cognitive Sciences, School of Business and Management, Shanghai International Studies University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jia Jin Email jinjia.163@163.comPurpose: Social crowding refers to the extent of social presence and proximity to others. A large number of studies have explored the effect of social crowding on consumers’ feelings and behaviours in real shopping scenes, whereas few studies have examined the potential marketing effect of social crowding on online mobile consumption behaviour despite mobile commerce’s increasing popularity in recent years. The current intends to explore the effect of social crowding on online mobile purchase and its underlying neural basis.Methods: The current study employed a questionnaire survey and an implicit panic buying experiment, in which the participants were asked to press the button as soon as possible to buy the showed product. A 2-level social crowding (low vs high) × 2-level feedback of panic buying (success vs fail) design was employed to test the negative impact of social crowding on consumers’ online mobile purchase intention by using electroencephalogram (EEG) recordings.Results: Behaviorally, participants showed higher purchase intention in low social crowding environment compared with the high crowding condition. The event-related potentials (ERPs) results indicated that consumers had a higher affective/motivational evaluation (reflected in a smaller feedback-related negativity (FRN) amplitude) regarding the successful rather than the failing feedback in the low social crowding condition. However, this difference was not detected in the high social crowding condition. Meanwhile, more attentional resources (reflected in a greater P300 amplitude) were directed toward processing the feedback outcomes in the low rather than the high social crowding condition.Conclusion: The current study provided neurophysiological response that social crowding negatively influences consumers’ online purchase intention. Some implications for theory and practice were also discussed.Keywords: social crowding, online purchase intention, ERP, FRN, P300

Yang Luo,1,* Sisi Li,2,* Jingting He,1 Dan Cai,3 Yi Dai,3 Lijuan Feng,1 Chengqin Sun,1 Xiaoping Zhu4 1Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Nursing Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4Nursing Department, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jingting HeDepartment of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan 430022, People’s Republic of ChinaTel +8615007122833Fax +862785871829Email hejingting@hust.edu.cnPurpose: This study aimed to obtain a translation and validation of the Fear of Pain Questionnaire 9 Items (FOP-9) into simplified Chinese.Methods: The questionnaire was translated following the forward-backward method. The final version was filled out by (n = 300) patients. Cronbach’s coefficient was calculated to test the internal consistency of simplified Chinese version of FOP-9 (sc-FOP-9), and 50 painless patients completed the sc-FOP-9 questionnaire within a 2-weeks interval to evaluate test–retest reliability. To verify the construct validity, exploratory factor analysis was used to explore the factor structure, and confirmatory factor analysis was conducted to evaluate the goodness fit of models.Results: Satisfactory psychometric qualities were obtained (Cronbach’s α of the total score was 0.873 and intraclass correlation coefficient was 0.975). Three first-order models were tested and all show a good model fit and the 3-factor structure may be better due to its higher factor loading.Conclusion: The sc-FOP-9 is a reliable and valid instrument to evaluate the fear of pain among Chinese patients with or without pain. Fear of pain may have an important effect on perioperative pain and chronic pain, and this tool is a good complement to the measurement in mainland China.Keywords: fear of pain, reliability, validity, Chinese, pain-related fear

Jin Tao,1 Yang Zhang,2 Ao Shen,3 Yunxu Yang,1 Lu Diao,4 Luye Wang,1 Danwei Cai,4 Ying Hu1,4 1School of Pharmaceutical Sciences, Zhejiang Pharmaceutical College, Ningbo, Zhejiang, People’s Republic of China; 2Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, People’s Republic of China; 3School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia; 4School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Ying HuZhejiang Pharmaceutical College, No. 888, East Section, Yinxian Main Road, The Zone of Higher Education, Ningbo, Zhejiang 315100, People’s Republic of ChinaTel +86 574 8822 2707Fax +86 574 8822 3023Email pharmhawk@126.comPurpose: Osteomyelitis, particularly chronic osteomyelitis, remains a major challenge for orthopedic surgeons. The traditional treatment for osteomyelitis, which involves antibiotics and debridement, does not provide a complete solution for infection and bone repair. Antibiotics such as vancomycin (VCM) are commonly used to treat osteomyelitis in clinical settings. VCM use is limited by a lack of effective delivery methods that provide sustained, high doses to entirely fill irregular bone tissue to treat infections.Methods: We engineered a chitosan (CS)-based thermosensitive hydrogel to produce a VCM-nanoparticle (NPs)/Gel local drug delivery system. The VCM-NPs were formed with quaternary ammonium chitosan and carboxylated chitosan nanoparticles (VCM-NPs) by positive and negative charge adsorption to enhance the encapsulation efficiency and drug loading of VCM, with the aim of simultaneously preventing infection and repairing broken bones. This hydrogel was evaluated in a rabbit osteomyelitis model.Results: The VCM-NPs had high encapsulation efficiency and drug loading, with values of 60.1± 2.1% and 24.1± 0.84%, respectively. When embedded in CS-Gel, the VCM-NPs maintained their particle size and morphology, and the injectability and thermosensitivity of the hydrogel, which were evaluated by injectability test and rheological measurement, were retained. The VCM-NPs/Gel exhibited sustained release of VCM over 26 days. In vitro tests revealed that the VCM-NPs/Gel promoted osteoblast proliferation and activity against Staphylococcus aureus. In vivo, VCM-NPs/Gel (with 10 mg vancomycin per rabbit) was used to treat rabbits with osteomyelitis. The VCM-NPs/Gel showed excellent anti-infection properties and accelerating bone repair under osteomyelitis conditions.Conclusion: The reported multifunctional NPs hydrogel system for local antibiotic delivery (VCM-NPs/Gel) showed bone regeneration promotion and anti-infection properties, demonstrating significant potential as a scaffold for effective treatment of osteomyelitis.Keywords: vancomycin, chitosan, nanoparticles, injectable hydrogel, osteomyelitis

Rong Shi, Zheyun Niu, Birong Wu, Taotao Zhang, Dujie Cai, Hui Sun, Yuhong Hu, Ruohui Mo, Fan Hu School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Fan HuSchool of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaTel +8613585828140Fax +862151322466Email joyking2003@163.comPurpose: This study aimed to develop a diabetic nephropathy (DN) or diabetic retinopathy (DR) incidence risk nomogram in China’s population with type 2 diabetes mellitus (T2DM) based on a community-based sample.Methods: We carried out questionnaire evaluations, physical examinations and biochemical tests among 4219 T2DM patients in Shanghai. According to the incidence of DN and DR, 4219 patients in our study were divided into groups of T2DM patients with DN or DR, patients with both, and patients without any complications. We successively used least absolute shrinkage and selection operator regression analysis and logistic regression analysis to optimize the feature selection for DN and DR. To ensure the accuracy of the results, we carried out multivariable logistic regression analysis of the above significant risk factors on the sample data for both DN and DR. The selected features were included to establish a prediction model. The C-index, calibration plot, curve analysis and internal validation were used to validate the distinction, calibration, and clinical practicality of the model.Results: The predictors in the prediction model included disease course, body mass index (BMI), total triglycerides (TGs), systolic blood pressure (SBP), postprandial blood glucose (PBG), haemoglobin A1C (HbA1c) and blood urea nitrogen (BUN). The model displayed moderate predictive power with a C-index of 0.807 and an area under the receiver operating characteristic curve of 0.807. In internal verification, the C-index reached 0.804. The risk threshold was 16– 75% according to the analysis of the decision curve, and the nomogram could be applied in clinical practice.Conclusion: This DN or DR incidence risk nomogram incorporating disease course, BMI, TGs, SBP, PBG, HbA1c and BUN can be used to predict DN or DR incidence risk in T2DM patients. The research team has developed an online app based on a clinical prediction model incorporating risk factors for rapid and simple prediction.Keywords: diabetic nephropathy, diabetic retinopathy, predictors, nomogram, type 2 diabetes mellitus

Abstract Recent modeling studies of future vegetation change suggest the potential for large-scale forest die-off in the tropics. Taken together with observational evidence of increasing tree mortality in numerous ecosystem types, there is clearly a need for projections of vegetation change. To that end, the authors have performed an ensemble of climate–vegetation experiments with the National Science Foundation–DOE Community Atmosphere Model (CAM) coupled to the Community Land Model (CAM–CLM-CN) with its dynamic vegetation model enabled (CAM–CLM-CNDV). To overcome the limitations of using a single model, the authors employ the sea surface temperature (SST) warming patterns simulated by eight different models from the Coupled Model Intercomparison Program phase 3 (CMIP3) as boundary conditions. Since the SST warming pattern in part dictates how precipitation may change in the future, in this way a range of future vegetation–climate trajectories can be produced. On an annual average basis, this study’s CAM–CLM-CN simulations do not produce as large a spread in projected precipitation as the original CMIP3 archive. These differences are due to the tendency of CAM–CLM-CN to increase tropical precipitation under a global warming scenario, although this response is modulated by the SST warming patterns imposed. However, the CAM–CLM-CN simulations reproduce the enhanced dry season in the tropics simulated by CMIP3. These simulations show longer fire seasons and increases in fractional area burned. In one ensemble member, extreme droughts over tropical South America lead to fires that remove vegetation cover in the eastern Amazon, suggesting that large-scale die-offs are an unlikely but still possible event.

The urban three-dimensional (3-D) model, which can truly and vividly express the 3-D spatial information of ground objects, was an essential link in the process of smart city construction. The backpack 3-D laser scanning systems had gradually become an important technical means to build urban 3-D models because of their high efficiency and high fineness. In this paper, the error source of backpack point cloud data was analysed based on the composition of backpack 3-D laser scanning system. The distribution of point cloud error was statistically analysed by designing experiments. It was found that there was a systematic error in the backpack 3-D laser scanning point cloud. There were many factors influencing the system errors and they were superimposed on each other. In order to solve this problem, an error compensation model with additional system parameters based on a multiple linear regression algorithm was constructed. The results showed that this model can weaken the influence of system errors on the backpack point cloud, effectively improve the accuracy of the backpack point cloud, and provide reliable point cloud data for subsequent processing of the building point cloud. [ABSTRACT FROM AUTHOR]

Abstract Rapid and broad-scale forest mortality associated with recent droughts, rising temperature, and insect outbreaks has been observed over western North America (NA). Climate models project additional future warming and increasing drought and water stress for this region. To assess future potential changes in vegetation distributions in western NA, the Community Earth System Model (CESM) coupled with its Dynamic Global Vegetation Model (DGVM) was used under the future A2 emissions scenario. To better span uncertainties in future climate, eight sea surface temperature (SST) projections provided by phase 3 of the Coupled Model Intercomparison Project (CMIP3) were employed as boundary conditions. There is a broad consensus among the simulations, despite differences in the simulated climate trajectories across the ensemble, that about half of the needleleaf evergreen tree coverage (from 24% to 11%) will disappear, coincident with a 14% (from 11% to 25%) increase in shrubs and grasses by the end of the twenty-first century in western NA, with most of the change occurring over the latter half of the twenty-first century. The net impact is a ~6 GtC or about 50% decrease in projected ecosystem carbon storage in this region. The findings suggest a potential for a widespread shift from tree-dominated landscapes to shrub and grass-dominated landscapes in western NA because of future warming and consequent increases in water deficits. These results highlight the need for improved process-based understanding of vegetation dynamics, particularly including mortality and the subsequent incorporation of these mechanisms into earth system models to better quantify the vulnerability of western NA forests under climate change.

Rui-Min Long,1,2,* Qing-Lei Dai,1,* Xia Zhou,1,* Duan-Hua Cai,1 Ya-Zhen Hong,1–3 Shi-Bin Wang,1–4 Yuan-Gang Liu1–3 1College of Chemical Engineering, Huaqiao University, Xiamen 361021, China; 2Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen 361021, China; 3Institute of Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, China; 4Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China *These authors contributed equally to this work Abstract: In recent times, co-delivery of therapeutics has emerged as a promising strategy for treating dreadful diseases such as cancer.Materials and methods: In this study, we developed a novel nanocarrier based on bacterial magnetosomes (BMs) that co-loaded with siRNA and doxorubicin (DOX) using polyethyleneimine (PEI) as a cross-linker (BMs/DP/siRNA). The delivery efficiency of siRNA as well as the pH-responsive release of DOX, and synergistic efficacy of these therapeutics in vitro were systematically investigated.Results: The structure of DOX–PEI (DP) conjugates that synthesized via hydrazone bond formation was confirmed by 1H nuclear magnetic resonance (NMR). The in vitro release experiments showed that the DP conjugate (DOX-loading efficiency – 5.77%±0.08%) exhibited the long-term release behavior. Furthermore, the optimal BMs/DP/siRNA particle size of 107.2 nm and the zeta potential value of 31.1±1.0 mV facilitated enhanced cellular internalization efficiency. Moreover, the agarose gel electrophoresis showed that the co-delivery system could protect siRNA from degradation in serum and RNase A. In addition, the cytotoxicity assay showed that BMs/DP/siRNA could achieve an excellent synergistic effect compared to that of siRNA delivery alone. The acridine orange (AO)/ethidium bromide (EB) double staining assay also showed that BMs/DP/siRNA complex could induce cells in a stage of late apoptosis and nanocomplex located in the proximity of the nucleus.Conclusion: The combination of gene and chemotherapeutic drug using BMs is highly efficient, and the BMs/DP/siRNA would be a promising therapeutic strategy for the future therapeutics. Keywords: bacterial magnetosomes, co-delivery, gene therapy, pH-responsive release