Search

Magnetic reconnection is a fundamental process known to play a crucial role in electron acceleration and heating, however, the mechanism of electron energization during reconnection is still not fully understood. This study introduces a novel electron acceleration mechanism in which electrons can be accelerated by secondary reconnection in the separatrix region. The secondary reconnection occurs in a thin current sheet resulted from the shear of the out‐of‐plane Hall magnetic fields of the primary magnetopause reconnection. It results in the intense electron energy fluxes toward the primary X‐line. This mechanism will likely be an important piece in the puzzle of particle acceleration by reconnection. Plain Language Summary: Magnetic reconnection is a fundamental process that plays a critical role in electron acceleration and heating. The separatrix region of magnetic reconnection, which distinguishes the inflow and outflow regions, is a crucial area in the particle acceleration of the reconnection process. However, previous studies mainly focused on the electron acceleration mechanism in the separatrix region under two‐dimensional reconnection, without considering the influence of the three‐dimensional structures. This paper reports, for the first time, the secondary reconnection occurring in the opposite Hall magnetic field in the three‐dimensional separatrix region of magnetopause primary reconnection. This secondary reconnection can accelerate and heat the inflow electrons of the primary reconnection, which provides important clues on how the particles are accelerated and heated by reconnection. Key Points: Secondary reconnection occurs between Hall magnetic fields in the separatrix region of the primary magnetopause reconnectionIntense electron enthalpy fluxes are injected toward the primary X‐line along the separatrixElectrons are accelerated by the secondary reconnection before being injected into the primary X‐line for further energization [ABSTRACT FROM AUTHOR]

Whistler-mode waves have been extensively observed and investigated in terrestrial space. In this study, we present the dynamic response of whistler-mode waves to different solar wind conditions in the dayside terrestrial space based on Magnetospheric Multiscale (MMS) data. Statistical results show that the occurrence rate, amplitudes, and corresponding electron temperature anisotropy of whistler-mode waves increase with P sw in the dayside terrestrial space, which is attributed to the compression of magnetic fields in these magnetosheath and outer magnetosphere. Furthermore, whistler-mode waves under the southward interplanetary magnetic fields (IMFs) show a higher occurrence rate than that under the northward IMFs, mostly corresponding to T e ⊥/ T e ∥ > 1, and have a higher occurrence rate during quasi-radial IMFs. These results present that whistler-mode waves in these magnetosheath and outer magnetosphere are also modulated by the solar wind as clearly as the inner magnetosphere. This work advanced our understanding in the solar–terrestrial interaction. [ABSTRACT FROM AUTHOR]

Zenghua Deng,1,2,* Kanghua Huang,3,* Dongfang Liu,1 Nan Luo,1,2 Tingting Liu,1 Long Han,1 Dexiao Du,1 Dongbo Lian,1,2 Zhaohui Zhong,4 Jirun Peng1,2 1Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China; 2Ninth School of Clinical Medicine, Peking University, Beijing, 100038, People’s Republic of China; 3Department of Radiation Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, People’s Republic of China; 4Department of General Surgery, Peking University People’s Hospital, Beijing, 100044, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jirun Peng; Zhaohui Zhong Email pengjr@medmail.com.cn; pengjr@bjsjth.cn; zhongzhaohui@pkuph.edu.cnBackground: Hepatocellular carcinoma (HCC) is the most common subtype of primary liver cancer, which causes ∼ 800,000 deaths annually world-wide. Immune checkpoint inhibitor (ICI) has reformed cancer therapy and achieved unprecedented results in various malignancies, including HCC. However, the response rate of immunotherapy is very low in HCC. Considereing the complicated and unique immune status in liver, we hypothesize that critical molecules will affect prognosis and correlate with immune context in the tumor microenvironment of HCC.Methods: Using Kaplan–Meier plotter, GEPIA2 and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), survival genes and their prognostic value were estimated in HCC. Based on Tumor Immune Estimation Resource (TIMER), association between survival genes and immune infiltration was examined in HCC. FunRich and STRING were used to analyze gene ontology and protein–protein interaction (PPI) Network, qRT-PCR was used to measure mRNA level of candidates; and a Cell Counting Kit-8 was used to measure proliferation of HCC cell line.Results: Using multiple databases, we identified 36 key prognostic genes highly expressed in HCC and associated with poor survival of patients. Meanwhile, the 36 gene signatures correlated with immune infiltration in HCC. Moreover, these genes were significantly associated with exhausted T cells and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in HCC. Among the 36 key genes, SKA3, SGOL2, SPINDOC, TEDC2, TMCO3 and NUP205 were highly expressed in tumor samples compared with adjacent normal tissues in our HCC cohort (n=22). Additionally, proliferation of SMMC7721 cell line was inhibited when it interfered with SiRNA of each gene.Conclusion: The 36 genes may serve as potential prognostic biomarkers and molecular targets to ameliorate tumor immune microenvironment (TIME) in HCC and therefore represent a novel avenue for individualized immunotherapy in HCC.Keywords: HCC, prognosis, immune infiltrates, exhausted T cell, MDSC

Yudong Ning,1 Hong Yang,2 Sheng Qin,2 Bangrong Cao,3 Zuxian Zhong,4 Chuanshi He,5 Guiquan Zhu6 1Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Department of Pathology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 4Department of Head and Neck Radiotherapy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 5Sichuan Key Laboratory of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, People’s Republic of China; 6Department of Head and Neck Oncology, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Guiquan ZhuDepartment of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Chengdu, Sichuan, 610041, People’s Republic of ChinaEmail zhugq@scu.edu.cnObjective: We aimed to identify new prognostic factors of oral squamous cell carcinoma (OSCC) among platelet-related parameters, establish a survival prediction model to predict the survival status of OSCC patients, and analyze the therapeutic effect of neoadjuvant chemotherapy on OSCC patients on the basis of real-world data.Materials and Methods: The real-world data of patients with OSCC confirmed by pathologic examination at Cancer Hospital from January 2011 to January 2015 and May 2017 to January 2020 were collected. We analyzed clinicopathologic factors using a Cox regression analysis, the Kaplan-Meier method, and propensity score matching (PSM).Results: The multivariate Cox regression analysis of not only validated the traditional prognostic factors such as tumor site, neural invasion, poor differentiation, and tumor-node-metastasis (TNM) stage but also identified a new prognostic factor, preoperative mean platelet volume (MPV) for overall survival (OS, HR, 0.47; 95% CI: 0.25– 0.89, P = 0.020). A nomogram was created to predict the probability of 3-year and 5-year OS. We found that neoadjuvant chemotherapy improved OS in patients with OSCC.Conclusion: Preoperative MPV, being associated with female, neoadjuvant chemotherapy, and advanced stage (Stage III and IV), may be a new prognostic factor for OS of patients with OSCC. The nomograms provided useful prediction for OS in OSCC patients. Neoadjuvant chemotherapy may improve the OS of patients with OSCC.Keywords: oral squamous cell carcinoma, overall survival, nomogram, mean platelet volume, neoadjuvant chemotherapy, induction chemotherapy

Zhanwang Xiang,1,&ast; Zhihui Zhong,2,&ast; Luwen Mu,1 Guohong Li,3 Churen Zhou,1 Haofan Wang,1 Mingsheng Huang1 1Interventional Radiology Program, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People’s Republic of China; Guangdong Provincial Key Lab of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, People’s Republic of China; 2Department of Minimally Invasive Intervention, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China; 3Department of Radiology, Guangdong Second Provincial General Hospital, Guangdong Provincial Emergency Hospital, Guangzhou, 510000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingsheng Huang; Haofan WangInterventional Radiology Program, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People’s Republic of China; Guangdong Provincial Key Lab of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, People’s Republic of ChinaEmail huangmsh@mail.sysu.edu.cn; wanghaof@mail.sysu.edu.cnPurpose: To further evaluate the efficacy and safety of computed tomography (CT)-guided iodine 125 (125I) brachytherapy to treat locally advanced non-small cell lung cancer (NSCLC) after progression of concurrent radiochemotherapy (CCRT).Methods: This study obtained written consent from all patients and was approved by our institution. From January 2006 to June 2018, 210 NSCLC patients (progression of first-line CCRT) were retrospectively recruited and then divided into two groups. A total of 116 patients were given CT-guided 125I brachytherapy and second-line chemotherapy (group A), and 94 were treated with second-line chemotherapy alone (group B).Results: In group A, local response rate (LRR) within 3 years was significantly better (P< 0.05). Mean survival time [progression-free survival time (PFST) and overall survival (OS)] was 15.1± 1.4 months and 21.2± 1.6 months in group A compared with 10.0± 1.4 months and 16.2± 1.7 months in group B (PFST: P< 0.01, HR=1.472, 95% CI 1.097– 1.975; OS: P = 0.036, HR=1.342, 95% CI 1.005– 1.791). Tumor size and No. of first cycle chemotherapy were independent factors that affected survival, ≤ 3cm largest tumor diameter and more than 4 first cycles of chemotherapy showed longer PFST and OS (P< 0.05). Tumor-related clinical symptoms were relieved in group A (P< 0.01). No serious complications occurred in the two groups.Conclusion: 125I brachytherapy is effective and safe in locally advanced NSCLC after progression of CCRT.Keywords: 125I, brachytherapy, NSCLC, concurrent radiochemotherapy, efficacy, safety

Jia Ouyang,1 Yu Jiang,2 Chao Deng,2 Zhiyuan Zhong,2 Qing Lan1 1Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, People’s Republic of China; 2Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, People’s Republic of ChinaCorrespondence: Zhiyuan Zhong; Qing Lan Tel/Fax +86-512-65880098Email szlq006@163.com; zyzhong@suda.edu.cnPurpose: Glioblastoma multiforme (GBM) poorly responds to chemotherapy owing to the existence of blood-brain barriers (BBB). It has been a long desire to develop BBB-permeable vehicles to facilitate drug targeting to GBM.Method and Results: Here, we report that doxorubicin hydrochloride loaded in ApoE peptide-functionalized reduction-sensitive polymersomes (ApoE-PS-DOX) induces potent therapy of orthotopic U-87 MG model in nude mice. ApoE-PS-DOX with varying amount of ApoE (10∼ 30 mol%) all had stable DOX loading and small sizes (< 90 nm). As revealed by flow cytometry, confocal microscopy, apoptosis and MTT assays, ApoE-PS-DOX with 20 mol.% ApoE induced the best cellular uptake and inhibitory effect to U-87 MG cells, which were much better than the non-targeted PS-DOX and liposomal doxorubicin (Lipo-DOX) used in the clinic. ApoE-PS-DOX revealed a pharmacokinetic profile comparable to PS-DOX but induced considerably better growth inhibition of orthotopically xenografted U-87 MG tumors in nude mice than PS-DOX and Lipo-DOX, leading to significant survival benefits with a median survival time of 44 days, which was almost doubled relative to the phosphate-buffered saline (PBS) group. Moreover, in contrast to mice treated with Lipo-DOX and PS-DOX, ApoE-PS-DOX group exhibited little body weight loss, signifying that ApoE-PS-DOX not only has low side effects but also can effectively inhibit glioblastoma invasion.Conclusion: This ApoE-docked multifunctional polymersomal doxorubicin induces potent and safe chemotherapy of orthotopic U-87 MG model in nude mice offering an alternative treatment modality for GBM.Keywords: apolipoprotein E, polymersomes, doxorubicin, brain tumor, blood-brain barrier

Liying Zhang,1,* Xinhua Chen,2,* Haili Wang,1 Haipeng Huang,1 Mengyuan Li,1 Lin Yao,1 Shiqi Ma,1 Zhen Zhong,1 Hongmei Yang,3 Hongfeng Wang4 1School of Acupuncture and Massage, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, People’s Republic of China; 2Department of Acupuncture and Moxibustion, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, 130021, People’s Republic of China; 3Jilin Ginseng Academy, Changchun University of Chinese Medicine, Jilin, 130117, People’s Republic of China; 4Northeast Asia Institute of Chinese Medicine, Changchun University of Chinese Medicine, Jilin, 130117, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongmei Yang; Hongfeng WangJilin Ginseng Academy, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, People’s Republic of ChinaTel/Fax +86 431 86763992Email yanghm@mit.eduHongfeng WangNortheast Asia Institute of Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, People’s Republic of ChinaTel/Fax +86 431 89912521Email ccwhf@126.comIntroduction: Traditional Chinese acupuncture has been demonstrated to be beneficial for treatment of type 2 diabetes mellitus (T2DM). The mechanism of acupuncture on T2DM is crucial for their biological activity as well as their usefulness as tools in biology and medicine. However, its mechanism is poorly understood.Methods: In an effort to explore the mechanism, eight db/db mice (a type of spontaneous T2DM mouse) were treated with adjusting internal organs and dredging channel electroacupuncture (AODCEA) for 2 weeks. Another eight db/db mice were fed as T2DM group (T2DMG), and eight db/m mice were set as normal control group (NCG). Lipopolysaccharide (LPS), interleukin-6 (IL-6), and diabetes-related indicators, such as fasting blood glucose (FBG) and triglyceride (TG), were detected by enzyme-linked immune sorbent assay (ELISA). The V4 region of 16S rRNA gene was analyzed by Illumina sequencing to evaluate the effect of AODCEA on intestinal flora. The amount of short-chain fatty acids (SCFAs) in the feces were determined by gas chromatography-mass spectrometry (GC-MS).Results: Our results indicate that AODCEA treatment can reduce diabetes-related indicators. We observed the increased probiotics such as Blautia and Lactobacillus and decreased opportunist pathogens (Alistipes, Helicobacter, Prevotella) by AODCEA interventions. Importantly, the total amount of SCFAs in the feces of T2DM mice was promoted by AODCEA. Finally, obviously alleviated systemic inflammation was exhibited through AODCEA treatment by detection of lipopolysaccharide (LPS) and interleukin-6 (IL-6) in serum.Conclusion: AODCEA can reshape the structure of intestinal flora, which can increase intestinal SCFAs, affect the circulating LPS level, and reduce the inflammatory response.Keywords: gut microbiota, acupuncture, Type 2 diabetes mellitus, short-chain fatty acids, inflammation, insulin resistance

Tiantian Liang,1,* Rongtao Zhang,1,* Xianbin Liu,1,* Qian Ding,1 Siqiong Wu,1 Chunhong Li,2 Yan Lin,2 Yun Ye,1 Zhirong Zhong,2 Meiling Zhou1 1Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 2Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Meiling ZhouDepartment of Pharmacy, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, Sichuan, 646000, People’s Republic of ChinaEmail meilzhou@163.comZhirong ZhongDepartment of Pharmaceutical, Sciences School of Pharmacy, Southwest Medical University, No. 319 Zhongshan Road Jiangyang District, Luzhou, Sichuan, 646000, People’s Republic of ChinaEmail zhongzhirong@126.comAbstract: Macrophages have been extensively used in the development of drug delivery systems, as they can prolong the circulation and release of drugs, extend their half-life, increase their stability and targeting ability, and reduce immunogenicity. Moreover, they have good biocompatibility and degradability and offer abundant surface receptors for targeted delivery of a wide variety of drugs. Macrophage-mediated drug delivery systems can be prepared by loading drugs or drug-loaded nanoparticles into macrophages, macrophage membranes or macrophage-derived vesicles. Although such systems can be used to treat inflammation, cancer, HIV infection and other diseases, they require further research and optimization since they have been assembled from diverse sources and therefore can have quite different physical and chemical properties. Moreover, potential cell-drug interactions can limit their application, and the biological activity of membrane proteins might be lost during membrane extraction and storage. In this review, we summarize the recent advances in this field and discuss the preparation of macrophage-mediated drug delivery systems, their advantages over other delivery systems, their potential applications and future lines of research.Keywords: macrophage, macrophage membranes, drug delivery systems, inflammation, tumor, biomimetic

Zhiguo Zhong,1 Yuyun Li,2,3 Yan Chen,2,3 Wen Chen,2 Siyan Li,4 Xiaohua Lv,2 Shiying Luo2 1Traditional Chinese Medicine Department, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524023, People’s Republic of China; 2Department of Pharmacology, School of Pharmacy, Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, 524023, People’s Republic of China; 3Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, 523808, People’s Republic of China; 4School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of ChinaCorrespondence: Shiying LuoDepartment of Pharmacology, School of Pharmacy, Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Biomedical Research Institute, Guangdong Medical University, No. 2 East Wenming Road, Xiashan District, Zhanjiang, 524023, Guangdong, People’s Republic of ChinaTel +86 13763058766Fax +86 7592388588Email luosy76@gdmu.edu.cnBackground: Erzhi Pill (EZP), a traditional Chinese medicine (TCM) prescription, has been widely applied to improve bone metabolism and treat osteoporosis (OP) in China. However, its effective constituents and mechanisms remain unclear.Methods: By combining network pharmacology and zebrafish experiments, an integrative method was employed to address this problem. Firstly, the disease targets of OP were collected from two public gene databases. Secondly, the active compounds and drug targets of EZP were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). Thirdly, a drug-target-disease interaction network was constructed, and the key active components were identified by analyzing the topological characteristics of the network. Finally, these predicted results were tested by zebrafish experiments and compared with those from the literature. Specifically, quercetin as an important representative active component of EZP was applied to wild type and transgenic zebrafish larvae to assess its effects on skull mineralization and osteoplastic differentiation.Results: Our study identified 72 active compounds, 220 targets and 166 signaling pathways probably involved in the prevention and treatment of OP by EZP, wherein quercetin, apigenin, daidzein, luteolin, ursolic acid and kaempferol could be the key compounds, while PI3K-Akt signaling pathway, TNF signaling pathway and IL-17 signaling pathway could be the key signaling pathways. The experiments indicated that quercetin attenuated both the decrease of skull mineralization and the inhibition of skull osteoplastic differentiation in zebrafish larvae trigged by dexamethasone.Conclusion: Our study not only investigated potentially effective constituents and mechanisms of EZP in the prevention and treatment of OP, but also provided a reference for the in-depth research, development and application of TCM.Keywords: Erzhi Pill, osteoporosis, network pharmacology, mechanisms, zebrafish, quercetin

Jihua Feng,* Jielong Pang,* Dan He,* Zimeng Wu, Qian Li, Pan Ji, Cuiying He, Zhimei Zhong, Hongyuan Li, Jianfeng Zhang Department of Emergency Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianfeng ZhangDepartment of Emergency Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, People’s Republic of ChinaEmail drzhangjf@163.comPurpose: Early diagnosis of sepsis-induced acute respiratory distress syndrome (ARDS) is critical for effective treatment. We aimed to identify early stage biomarkers.Materials and Methods: Differentially expressed genes were identified in whole blood samples from patients with sepsis or ARDS based on the Gene Expression Omnibus (GEO) datasets GSE32707, GSE54514 and GSE10361. Functional enrichment analysis explored the biological characteristics of differentially expressed genes. Genes with high functional connectivity based on a protein-protein interaction network were marked as hub genes, which were validated using the GEO dataset GSE76293, and a gene set variation analysis index (GSVA) was assigned. Diagnostic and predictive ability of the hub genes were assessed by receiver operating characteristic (ROC) curve analysis. DNA methylation levels of hub genes were quantified using the GEO dataset GSE67530.Results: Forty-one differentially expressed genes were shared between sepsis-specific and ARDS-specific datasets. MAP2K2 and IRF7 functional activity was highly connected in sepsis-induced ARDS. Hub genes included RETN, MVP, DEFA4, CTSG, AZU1, FMNL1, RBBP7, POLD4, RIN3, IRF7. ROC curve analysis of the hub gene GSVA index showed good diagnostic ability in sepsis or ARDS. Among genes related to sepsis-induced ARDS, 17 were differentially methylated. Principal component analysis and heatmaps indicated that gene methylation patterns differed significantly between ARDS patients and controls.Conclusion: We identified a genetic profile specific to early-stage sepsis-induced ARDS. The abnormal expression of these genes may be caused by hypomethylation, which may serve as a biomarker for early diagnosis of ARDS.Keywords: acute respiratory distress syndrome, ARDS, sepsis-induced ARDS, hub genes, methylation, gene set variation analysis

OBJECTIVE: Dexmedetomidine has demonstrated potential in preclinical medical research as a protective agent against inflammatory injuries and a provider of neuroprotective benefits. However, its effect on the shortterm prognosis of patients with sepsis-associated encephalopathy remains unclear. This study aims to explore the underlying value of dexmedetomidine in these patients. PATIENTS AND METHODS: This study enrolled patients with sepsis-associated encephalopathy from the Medical Information Mart for Intensive Care (MIMIC)-IV database, and they were divided into two groups based on dexmedetomidine therapy during hospitalization. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were utilized to balance the inter-group baseline differences. Kaplan-Meier (KM) curves with logrank test and subgroup analysis were also employed. The primary outcome was 28-day mortality, and the secondary outcomes were in-hospital mortality, intensive care unit (ICU) stay time, hospital stay time, and the incidence of ventilator-associated pneumonia (VAP). RESULTS: After PSM, 1,075 pairs of patients were matched. In contrast to the non-dexmedetomidine cohort, the dexmedetomidine cohort did not exhibit a shortened ICU [4.65 (3.16, 8.55) vs. 6.14 (3.66, 11.04), p<0.001] and hospital stay duration [10.04 (6.55, 15.93) vs. 12.76 (7.92, 19.95), p<0.001], and there was an elevated incidence of VAP [90 (8.4%) vs. 135 (12.6%), p=0.002]. The log-rank test for the KM curves of dexmedetomidine use and 28-day mortality was statistically significant (p<0.001). The results showed that dexmedetomidine was associated with improved 28-day mortality [hazard ratio (HR) 0.46, 95% confidence interval (CI) 0.35-0.61, p<0.001] and in-hospital mortality (HR 0.50, 95% CI 0.37-0.67, p<0.001) after adjusting for various confounders. In the following subgroup analysis, dexmedetomidine infusion was associated with decreased 28-day mortality in most subgroups. CONCLUSIONS: Dexmedetomidine administration was significantly associated with reduced short-term mortality among patients with sepsis-associated encephalopathy in the ICU. However, it also prolonged ICU and hospital stays and increased the incidence of VAP. [ABSTRACT FROM AUTHOR]

Ying Liu,1,* Xiaojie Li,1,* Shuwen Xiao,1 Xinyi Liu,1 Xuanming Chen,1 Qiyue Xia,1 Song Lei,2 Hongxia Li,1 Zhihui Zhong,3 Kai Xiao1 1National Chengdu Center for Safety Evaluation of Drugs and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 3Laboratory of Non-Human Primate Disease Model Research, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kai Xiao Tel +86-28-83326313Email xiaokaikaixiao@scu.edu.cnBackground: Gold nanoparticles (AuNPs) have shown great promise in various biomedical applications, but their effects on male reproductive function remain to be ascertained. The aim of this study was to investigate the uptake, cytotoxicity and testosterone production inhibition of AuNPs in mouse Leydig cells, as well as their accumulation in the testes of male mice and their effects on male reproductive function.Results: AuNPs (5 nm) were able to be internalized into the endosomes/lysosomes of TM3 Leydig cells, induce the formation of autophagosomes, increase the production of reactive oxygen species (ROS), and disrupt the cell cycle in S phase, resulting in concentration-dependent cytotoxicity and DNA damage. Interestingly, AuNPs significantly reduced testosterone production in TM3 cells by inhibiting the expression of 17α-hydroxylase, an important enzyme in androgen synthesis. After repeated intravenous injection, AuNPs gradually accumulated and retained in the testes of male BALB/c mice in a dose-dependent manner. One week after withdrawal, the level of plasma testosterone in the 0.5 mg/kg AuNPs group was significantly reduced compared to that in the PBS control group, accompanied by the decreased expression of 17α-hydroxylase in the testes. In addition, AuNPs treatment significantly increased the rate of epididymal sperm malformation, but without affecting fertility.Conclusion: Our results suggest that AuNPs can accumulate in the testes and reduce testosterone production in Leydig cells by down-regulating the expression of 17α-hydroxylase, thus affecting the quality of epididymal sperm.Keywords: gold nanoparticles, Leydig cells, testosterone, reproductive toxicity, fertility

In all archetypical reported (001)-oriented perovskite heterostructures, it has been deduced that the preferential occupation of twodimensional electron gases is in-plane dxy state. In sharp contrast to this, the investigated electronic structure of a spinel-perovskite heterostructure γ-Al2O3/SrTiO3 by resonant soft X-ray linear dichroism, demonstrates that the preferential occupation is in out-of-plane dxz/dyz states for interfacial electrons. Moreover, the impact of strain further corroborates that this anomalous orbital structure can be linked to the altered crystal field at the interface and symmetry breaking of the interfacial structural units. Our findings provide another interesting route to engineer emergent quantum states with deterministic orbital symmetry.

The tumor microenvironment (TME) exerts critical pro-tumorigenic effects through cytokines and growth factors that support cancer cell proliferation, survival, motility and invasion. Insulin-like growth factor-1 (IGF-1) and signal transducer and activator of transcription 3 (STAT3) stimulate colorectal cancer development and progression via cell autonomous and microenvironmental effects. Using a unique inhibitor, NT157, which targets both IGF-1 receptor (IGF-1R) and STAT3, we show that these pathways regulate many TME functions associated with sporadic colonic tumorigenesis in CPC-APC mice, in which cancer development is driven by loss of the Apc tumor suppressor gene. NT157 causes a substantial reduction in tumor burden by affecting cancer cells, cancer-associated fibroblasts (CAF) and myeloid cells. Decreased cancer cell proliferation and increased apoptosis were accompanied by inhibition of CAF activation and decreased inflammation. Furthermore, NT157 inhibited expression of pro-tumorigenic cytokines, chemokines and growth factors, including IL-6, IL-11 and IL-23 as well as CCL2, CCL5, CXCL7, CXCL5, ICAM1 and TGFβ; decreased cancer cell migratory activity and reduced their proliferation in the liver. NT157 represents a new class of anti-cancer drugs that affect both the malignant cell and its supportive microenvironment.

UnlabelledThis study was to determine if antibody against sclerostin (Scl-Ab) could prevent glucocorticoid (GC)-induced osteoporosis in mice. We found that Scl-Ab prevented GC-induced reduction in bone mass and bone strength and that the anabolic effects of Scl-Ab might be partially achieved through the preservation of osteoblast activity through autophagy.IntroductionGlucocorticoids (GCs) inhibit bone formation by altering osteoblast and osteocyte cell activity and lifespan. A monoclonal antibody against sclerostin, Scl-Ab, increased bone mass in both preclinical animal and clinical studies in subjects with low bone mass. The objectives of this study were to determine if treatment with the Scl-Ab could prevent loss of bone mass and strength in a mouse model of GC excess and to elucidate if Scl-Ab modulated bone cell activity through autophagy.MethodsWe generated reporter mice that globally expressed dsRed fused to LC3, a protein marker for autophagosomes, and evaluated the dose-dependent effects of GCs (0, 0.8, 2.8, and 4 mg/kg/day) and Scl-Ab on autophagic osteoblasts, bone mass, and bone strength.ResultsGC treatment at 2.8 and 4 mg/kg/day of methylprednisolone significantly lowered trabecular bone volume (Tb-BV/TV) at the lumbar vertebrae and distal femurs, cortical bone mass at the mid-shaft femur (FS), and cortical bone strength compared to placebo (PL). In mice treated with GC and Scl-Ab, Tb-BV/TV increased by 60-125 %, apparent bone strength of the lumbar vertebrae by 30-70 %, FS-BV by 10-18 %, and FS-apparent strength by 13-15 %, as compared to GC vehicle-treated mice. GC treatment at 4 mg/kg/day reduced the number of autophagic osteoblasts by 70 % on the vertebral trabecular bone surface compared to the placebo group (PL, GC 0 mg), and GC + Scl-Ab treatment.ConclusionsTreatment with Scl-Ab prevented GC-induced reduction in both trabecular and cortical bone mass and strength and appeared to maintain osteoblast activity through autophagy.

Jiamin Li,1,2 Zhenchao Zhong,1,2 Lei Mo1,2 1Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangzhou 510631, People’s Republic of China; 2School of Psychology, Center for Studies of Psychological Application, Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, People’s Republic of ChinaCorrespondence: Lei MoSchool of Psychology, Center for Studies of Psychological Application, Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou 510631, People’s Republic of ChinaEmail molei@m.scnu.edu.cnBackground: Recently, a study revealed that people liked others significantly more than they estimated that others liked them. Thus, the study found that people tended to underestimate how much others liked them, a phenomenon the authors called the Liking Gap. However, the logic and testing of the study existed unclear nature. In order to show whether people underestimate the positivity of impression they left on others, we directly compare the estimate of the impression we left on others with others’ actual impression of us, which make the logic clear. Besides, we explored the new findings with regard to the mechanism of the effect.Methods: Based on this idea, in study 1, we explored whether there is indeed a negative deviation effect in the estimate of the impression people left on others in short interpersonal communication. In study 2, we investigated the potential psychological mechanisms of that effect.Results: In Study 1, the results revealed that people estimated that others liked them significantly less than others actually liked them. That is, a negative deviation effect did occur, and even if people were clear about their liking for others, the effect still existed. In Study 2, we provided evidence that a negative deviation effect existed not just because people are too focused on their own-negative thoughts in conversational performance but rather because people had a psychological defense towards others in their first communication.Conclusion: People significantly underestimate how much they are liked and its reason is that their psychological defense towards others in their initial communication. The results of the study are beneficial for people in social interaction and provide them with new ways of thinking in interpersonal communication and mutual contact.Keywords: impression, negative deviation, negative thoughts, psychological defense

Lin-lin Pei,1,* Wen-zhu Yang,1,* Jing-yuan Fu,1,* Meng-xi Liu,1 Ting-ting Zhang,1 Dong-bo Li,1 Ruo-yue Huang,1 Li Zhang,1 Guang-neng Peng,1 Gang Shu,1 Zhi-xiang Yuan,2 Ju-chun Lin,1 Wei Zhang,1 Zhi-jun Zhong,1 Ling Zhao,1 Hua-lin Fu1 1Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, People’s Republic of China; 2College of Pharmacy, Southwest Minzu University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hua-lin FuDepartment of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, People’s Republic of ChinaTel +86 028-86291162Email fuhl2005@sohu.comIntroduction: Enrofloxacin is used in the treatment of a wide variety of bacterial infections in mammals. However, its poor solubility limits the clinical use.Methods: In order to improve the solubility of enrofloxacin, the enrofloxacin mesylate (EM) were obtained by a chemical synthesis method. The characterization of EM was carried out using ultraviolet scan (UV), synchronous thermal analysis (SDT), fourier transform infrared spectrometer (FTIR) and mass spectrometry (MS), nuclear magnetic resonance (NMR) and X-ray powder diffraction analysis (XRPD). Acute toxicity of EM in Kunming mice was studied. Besides, pharmacokinetic studies were performed in New Zealand rabbits at a single oral dose of 10 mg/kg, and the antibacterial activity of EM was also evaluated.Results: EM was successfully synthesized and purified. The stoichiometric ratio of mesylate to enrofloxacin was 1:1 and the aqueous solubility of EM was 483.01± 4.06 mg/mL, the solubility of EM was about 2000 times higher than enrofloxacin. The oral lethal dose (LD50) of EM was 1168.364 mg/kg, and the pharmacokinetics indicated that the oral relative bioavailability of EM was about 1.79 times and 1.48 times higher than that of enrofloxacin and enrofloxacin hydrochloride, respectively. In addition, the in vitro antibacterial activity of EM was not significantly changed compared with enrofloxacin and enrofloxacin hydrochloride.Conclusion: EM has higher solubility, low toxicity for oral use, and increases the oral bioavailability in rabbit. This study may be of benefit for the development of new enrofloxacin drugs.Keywords: enrofloxacin mesylate, characterization, antibacterial effect, acute toxicity, pharmacokinetics

Zhiying Shen,1 Guolin Tan,2 Zhuqing Zhong,1 Siqing Ding,1 Fang Wang2 1Nursing Department, Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Department of Otolaryngology Head Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Fang WangDepartment of Otolaryngology Head Neck Surgery, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, People’s Republic of ChinaTel/Fax +86 731-88618624Email wangfang_xy3yy@163.comBackground: Allergic rhinitis (AR) is a common chronic inflammatory disease of nasal mucosa worldwide, and its symptoms seriously affect the lives of patients. Subcutaneous immunotherapy (SCIT) is an effective treatment for AR, but it is also associated with low patient compliance and difficulties in fully achieving therapeutic effects.Objective: In this prospective randomized controlled study, we verified the effects of an interactive network platform named “U breath” in improving patient compliance and the efficacy of SCIT in patients with AR.Methods: A total of 148 patients who received SCIT were recruited as participants and randomly assigned to either the standardized management (SM) or the interactive network platform management (INP) group. The SM group experienced the standard management SCIT process. The INP group experienced a new management approach based on an interactive network platform called “U breath”. The compliance rate, combined symptom and medication score (CSMS), visual analogue scale score and the rhinoconjunctivitis quality of life questionnaire (RQLQ) results were evaluated at baseline and 1-year postintervention for the two groups.Results: Within the first year of treatment, the INP group had a higher compliance rate than did the SM group, with a statistically significant difference (P

Feili Yan,1,* Hui Li,1,* Zhirong Zhong,1,* Meiling Zhou,2 Yan Lin,1 Can Tang,1 Chunhong Li1 1Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, People’s Republic of China; 2Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Can Tang; Chunhong LiDepartment of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, 3-319 Zhongshan Road, Luzhou, Sichuan 646000, People’s Republic of ChinaTel +86 18982455783; +86 13679696586Fax +86 08306302050Email 2291691527@qq.com; lispringhong@126.comBackground: Prednisolone (PD) is extremely effective for treating rheumatoid arthritis (RA). However, it distributes nonspecifically throughout the body and its use is associated with serious side effects, which promoted us to compound it into a phytomedicine for greater efficacy and safety.Methods: We combined PD with curcumin (CU), an effective monomer from traditional Chinese medicine, and human serum albumin (HSA) in a nanoparticulate system (N-PD/CU) to compensate for the poor bioavailability of PD and CU. N-PD/CU was prepared by high-pressure homogenization, and its characteristics were evaluated in vitro. Next, we investigated its toxicity and mechanism of anti-inflammatory to macrophages. Finally, its pharmacokinetics, biodistribution and therapeutic efficacy were assessed in rats with adjuvant-induced arthritis (AIA).Results: N-PD/CU showed a narrow size distribution around 150.4 ± 2.4 nm, a polydispersity index of 0.22 ± 0.02 and drug loading efficiency (DLE) of 88.75 ± 1.82% for PD and 85.79 ± 1.43% for CU. N-PD/CU showed sustained release of both drugs in vitro. N-PD/CU had no toxicity to macrophages in vitro on concentrations between 0.1 and 1.2 μmol/mL. In activated macrophages, N-PD decreased levels of pro-inflammatory cytokines, while N-CU increased levels of anti-inflammatory IL-10, and N-PD/CU exhibited best therapeutic effect in vitro, suggesting co-delivery of PD and CU may synergistically control the course of RA. In AIA rats, N-PD/CU accumulated in inflamed joints through the effect of extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS effect) in inflammatory lesion and showed higher therapeutic efficacy than single-loaded nanoparticles, either free drug on its own, or a simple mixture of the two drugs.Conclusion: This codelivery system based on HSA is a promising platform for combination chemotherapy in RA.Keywords: co-delivery, prednisolone, curcumin, human serum albumin, rheumatoid arthritis

Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis. Zhang et al. report p16INK4a as a downstream integrator of diverse signals, such as inherited genetic risk, age, and intraocular pressure, in the pathogenesis of glaucoma. They demonstrate that upregulation of SIX6 upon stress directly increases p16INK4a, leading to retinal ganglion cell senescence and death.