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Jialu Sun,1 Yijun Shi,1 Yaowei Ding,1 Siqi Wang,1 Lingye Qian,2 Xin Luan,1 Guoge Li,1 Yuxin Chen,1 Xiaotong Li,1 Hong Lv,1,3,4 Guanghui Zheng,1,3,4,&ast; Guojun Zhang1,3,4,&ast; 1Laboratory, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Laboratory, Beijing An Zhen Hospital, Capital Medical University, Beijing, People’s Republic of China; 3NMPA Key Laboratory for Quality Control of in vitro Diagnostics, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Beijing Engineering Research Center of Immunological Reagents Clinical Research, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guanghui Zheng; Guojun Zhang, Beijing Tiantan Hospital, NO. 119 Nansihuan West Road, Fengtai District, Beijing, People’s Republic of China, Tel +86 18600148997 ; +86 13811792425, Email zgh999@yeah.net; guojun.zhang@ccmu.edu.cnBackground: To investigate the factors associated with follow-up CSF cultures (FUCCs) in post-neurosurgical patients with gram-negative bacterial meningitis/encephalitis and the effect of FUCCs on treatment management and patient outcomes.Methods: This single-centered retrospective cohort study enrolled post-neurosurgical patients with gram-negative bacterial meningitis/encephalitis at a tertiary-care university hospital between 2012 and 2022. The risk factors for 28-day mortality were evaluated using multivariate Cox analysis. FUCC-related risk factors were also analyzed.Results: Among the 844 enrolled patients, 504 (59.7%) underwent FUCC, and FUCC was found to be associated with lower rates of both all-cause (hazard ratio (HR) 0.391; 95% confidence interval (CI), 0.235– 0.651; p< 0.001) and attributable mortality (HR 0.463; 95% CI, 0.239– 0.897; p=0.023) in Post-neurosurgical patients diagnosed with Gram-negative bacterial meningitis/encephalitis. Moreover, the results of the study underscored that patients with persistent gram-negative bacterial meningitis/encephalitis had a lower all-cause/attributable short-term survival rate according to 28-day mortality Kaplan–Meier analysis (P=0.001/0.006).Conclusion: Performing FUCC has been demonstrated to lower mortality rates in Post-neurosurgical patients suffering from Gram-negative bacterial meningitis/encephalitis. The higher mortality rate observed in patients with persistent gram-negative bacterial meningitis/encephalitis suggests that performing FUCC is a crucial component of proper patient care and management, and is therefore recommended for use by clinicians as a standard practice. This finding underscores the significance of consistent implementation of FUCC in the management and prognosis of patients with Post-neurosurgical infections.Keywords: gram-negative bacterial meningitis/encephalitis, follow-up cerebrospinal fluid cultures, all-cause 28-day mortality, persistent meningitis/encephalitis, risk factors

Yuxin Sun,&ast; Yizhuo Xie,&ast; Huan Tang, Zhihui Ren, Xue Luan, Yan Zhang, Ming Zhu, Zhe Lv, Han Bao, Yan Li, Rui Liu, Yujia Shen, Yucui Zheng, Jin Pei Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, ChangChun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jin PeiSchool of Pharmaceutical Sciences, Jilin University, 1163 Xinmin Street, ChangChun, 130021, Jilin Province, People’s Republic of ChinaTel +86 431 85619725Email peijin@jlu.edu.cnBackground: Chemotherapy is still the main first-line treatment for advanced metastatic gastric cancer, but it has the limitations of serious side effects and drug resistance. Conventional liposome has been substantially used as drug carriers, but they lack targeting character with lower drug bioavailability in tumor tissues. Based on the above problems, a novel estrogen-targeted PEGylated liposome loaded with oxaliplatin (ES-SSL-OXA) was prepared to further improve the metabolic behavior, the safety profile, and the anti-tumor efficacy of oxaliplatin.Methods: Four kinds of oxaliplatin (OXA) liposomes were prepared by film hydration method. The obtained formulations were characterized in terms of entrapment efficiency (EE), particle size, and so on by HPLC and DLS (dynamic light scanning). The morphology of ES-SSL-OXA was detected by transmission electron microscope (TEM). The in vitro and in vivo targeting effect of ES-SSL-OXA was verified by fluorescence microscopy and in vivo imaging system in gastric cancer cells (SGC-7901) and tumor-bearing athymic mice. The in vitro and in vivo antitumor efficacies of ES-SSL-OXA were investigated on SGC-7901 cells and athymic tumor-bearing mice. Pharmacokinetic, biodistribution, and acute toxicity tests of ES-SSL-OXA were performed on ICR mice.Results: The ES-SSL-OXA exhibited an average particle size of about 153.37 nm with an encapsulation efficiency of 46.20% and low leakage rates at 4°C and 25°C. In vivo and in vitro targeting study confirmed that ES-SSL-OXA could effectively target the tumor site. The antitumor activity demonstrated the strongest inhibition in tumor growth of ES-SSL-OXA. Pharmacokinetics and acute toxicity study showed that ES-SSL-OXA could significantly improve the metabolic behavior and toxicity profile of oxaliplatin.Conclusion: In this study, a novel estrogen-targeted long-acting liposomal formulation of OXA was successfully prepared. ES fragment effectively targeted the delivery system to tumor tissues which highly express estrogen receptor, providing a promising therapeutic method for gastric cancer in clinic.Keywords: estrogen receptors, chemotherapy, long-acting liposomes, targeted drug delivery, pharmacokinetics, antitumor activity

Qianqian Tian,1 Hui Wang,2 Keneilwe Kenny Kaudimba,1 Shanshan Guo,1 Haixin Zhang,1 Song Gao,1 Ruwen Wang,1 Xin Luan,1 Jason Kai Wei Lee,3– 5 Peijie Chen,1 Tiemin Liu,2 Ru Wang1 1School of Kinesiology, Shanghai University of Sport, Shanghai, People’s Republic of China; 2State Key Laboratory of Genetic Engineering, Department of Endocrinology and Metabolism, Institute of Metabolism and Integrative Biology, Human Phenome Institute, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 4Global Asia Institute, National University of Singapore, Singapore; 5N.1 Institute for Health, National University of Singapore, SingaporeCorrespondence: Tiemin LiuState Key Laboratory of Genetic Engineering, Department of Endocrinology and Metabolism, Institute of Metabolism and Integrative Biology, Human Phenome Institute, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of ChinaTel/Fax +86-21- 31246765Email tiemin_liu@fudan.edu.cnRu WangSchool of Kinesiology, Shanghai University of Sport, Shanghai, People’s Republic of ChinaTel/Fax +86-21-65507351Email wangru@sus.edu.cnPurpose: To (i) describe the characteristics of physical fitness and cardiometabolic risk in Chinese university students with normal-weight obesity (NWO); (ii) assess the association between NWO with physical fitness and cardiometabolic risk.Methods: A total of 249 participants from the 2018 Shanghai University of Sport Alumni Health Cohort Study in China formed the study cohort. NWO was defined as normal body mass index (17.9– 23.9 kg/m2 for males; 17.2– 23.9 kg/m2 for females) but with excess body-fat percentage (≥ 20% for males; ≥ 30% for females). Body composition was assessed by dual-energy X-ray absorptiometry. Physical-fitness scores were calculated from a battery of sex-specific tests. Cardiometabolic risk was calculated using a continuous clustered risk (MetS) score.Results: We found that 16.7% of male and 45.3% of female university students were classified as having NWO. Participants with NWO showed worse cardiorespiratory fitness than those with normal weight (NW) (male NWO (37± 8) vs male NW (41± 6) mL/kg/min, p< 0.01; female NWO (31± 4) vs female NW (33± 6) mL/kg/min, p< 0.01). NWO was associated negatively with the fitness score (OR = 0.853; 95% CI = 0.793– 0.917) and was associated positively with the MetS score (1.280; 1.162– 1.410).Conclusion: University students with NWO were characterized by higher cardiometabolic risk and lower levels of physical fitness. Our findings implied that university students with NWO should be mindful of the potential hidden health risks of excess body fat and participate in exercise to enhance physical fitness.Keywords: body composition, body mass index, body fat distribution, skeletal muscle, public health

Shasha Lin, 1,* Xiaoqian Luan, 1,* Weilei He, 1,* Yiting Ruan, 1 Chengxiang Yuan, 1 Aiyue Fan, 1 Xiachan Chen, 2 Jincai He 1 1Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, People’s Republic of China; 2Department of Neurology, Wenzhou 325000, Zhejiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jincai HeDepartment of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, People’s Republic of ChinaTel/Fax +86 577 5557 9363Email hjc@wmu.edu.cnPurpose: Post-stroke depression (PSD) is a frequent comorbidity in patients presenting with acute ischemic stroke. Impaired kidney function has been associated with depression in non-stroke subjects. We would like to evaluate whether the estimated glomerular filtration rate (eGFR) on admission is associated with the development of PSD.Patients and methods: Total of 268 patients with acute ischemic stroke were recruited and completed 1-month follow-up visit. eGFR was calculated from the serum creatinine value, race, age, and sex by using the chronic kidney disease epidemiology collaboration equation (CKD-EPI creatinine equation). The 17-item Hamilton Depression Scale was used to evaluate depression symptoms. Patients with a depression score of ≥ 7 were evaluated using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition, for diagnosing post-stroke depression at 1 month. Meanwhile, 114 normal control subjects were also recruited.Results: Ninety-three (34.7%) patients were diagnosed as having PSD at 1 month. There was a significant intergroup difference in eGFR levels within 24 hrs after admission (F=13.608, p< 0.001). The levels of eGFR within 24 hrs after admission were significantly lower in both non-PSD patients and PSD patients than in normal controls. In logistic regression, the level of eGFR (< 82mL/min/1.73m 2) was independently associated with increased risk of PSD even after adjusting for confounders (OR=2.328, 95% CI:1.092– 4.965, p=0.029).Conclusion: Reduced eGFR was found to be correlated with the development of PSD and it suggests the need for greater attentions and potential interventions for depression in patients with stroke and with reduced eGFR.Keywords: estimated glomerular filtration rate, eGFR, post-stroke depression, stroke, Depression

Bing Han,1,* Yue Yang,1,2,* Jinglin Chen,1 Huan Tang,1 Yuxin Sun,1 Zheng Zhang,1 Zeng Wang,1 Yan Li,1 Yao Li,1 Xue Luan,1 Qianwen Li,1 Zhihui Ren,1 Xiaowei Zhou,1 Dengli Cong,1 Zhiyi Liu,1 Qin Meng,1 Fei Sun,1 Jin Pei1 1Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, ChangChun, People’s Republic of China; 2Department of Pharmacy, Ministry of Health Service, Chinese PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jin Pei Tel +86 431 85619725Email peijin@jlu.edu.cnBackground: Breast cancer is the leading cause of cancer death in women. Chemotherapy to inhibit the proliferation of cancer cells is considered to be the most important therapeutic strategy. The development of long-circulating PEG and targeting liposomes is a major advance in drug delivery. However, the techniques used in liposome preparation mainly involve conventional liposomes, which have a short half-life, high concentrations in the liver and spleen reticuloendothelial system, and no active targeting.Methods: Four kinds of paclitaxel liposomes were prepared and characterized by various analytical techniques. The long-term targeting effect of liposomes was verified by fluorescence detection methods in vivo and in vitro. Pharmacokinetic and acute toxicity tests were conducted in ICR mice to evaluate the safety of different paclitaxel preparations. The antitumor activity of ES-SSL-PTX was investigated in detail using in vitro and in vivo human breast cancer MCF-7 cell models.Results: ER-targeting liposomes had a particle size of 137.93± 1.22 nm and an acceptable encapsulation efficiency of 88.07± 1.25%. The liposome preparation is best stored at 4°C, and is stable for up to 48 hrs. Cytotoxicity test on MCF-7 cells demonstrated the stronger cytotoxic activity of liposomes in comparison to free paclitaxel. We used the near-infrared fluorescence imaging technique to confirm that ES-SSL-PTX was effectively targeted and could quickly and specifically identify the tumor site. Pharmacokinetics and acute toxicity in vivo experiments were carried out. The results showed that ES-SSL-PTX could significantly prolong the half-life of the drug, increase its circulation time in vivo, improve its bioavailability and reduce its toxicity and side effects. ES-SSL-PTX can significantly improve the pharmacokinetic properties of paclitaxel, avoid allergic reaction of the original solvent, increase antitumor efficacy and reduce drug toxicity and side effects.Conclusion: ES-SSL-PTX has great potential for improving the treatment of breast cancer, thereby improving patient prognosis and quality of life.Keywords: breast cancer, estrogen receptors, paclitaxel, long-acting liposomes, targeted drug delivery

Huiping Shen,1,2,* Xinjie Tu,1,* Xiaoqian Luan,1 Yaying Zeng,1,2 Jincai He,1 Wenjie Tang21Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People’s Republic of China; 2First School of Clinical Medicie, Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China*These authors contributed equally to this work Purpose: Post-stroke depression (PSD) is a psychiatric complication after stroke that leads to poorer stroke outcomes. Recent observational studies have indicated that lipid profiles were associated with a higher risk of stroke and depression. This study aims to further explore the possible relationship between serum lipid profiles and the development of PSD.Methods: A total of 373 acute ischemic stroke patients were examined. Serum lipid profiles including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), total cholesterol (TC), apolipoprotein A1 (Apo A1) and apolipoprotein B (Apo B) were measured within 24 hrs of admission. Depression symptoms were assessed by the 17-item Hamilton Depression Scale (HAMD-17) at the one-month follow-up, and HAMD scores ≥7 indicated a diagnosis of PSD.Results: A total of 114 patients were diagnosed with PSD at the one-month follow-up, for a percentage of 30.6%. There were significant differences in HDL-C levels (P

Ying Fei Li,1 Chengyue Zhang,1 Simon Zhou,1 Miao He,2 Huixia Zhang,2 Nianhang Chen,1 Feng Li,2 Xin Luan,2 Manjunath Pai,3 Hebao Yuan,2 Duxin Sun,2 Yan Li1 1Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ 07901, USA; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; 3Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA Background: Paclitaxel (PTX) products currently approved by the Food and Drug Administration include Kolliphor EL-paclitaxel micelles (KoEL-paclitaxel, Taxol) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane). Despite containing the same cytotoxic agent, different PTX formulations have distinct pharmacological responses and indications in patients with cancer. Several novel PTX delivery vehicles that have shown superior efficacy to Taxol in animal models failed to demonstrate efficacy in Phase II/III human clinical trials. Materials and methods: A 10 mg/kg IV dose of KoEL-paclitaxel or nab-paclitaxel was administered to mice, and the pharmacokinetics (PK) profile of PTX in mice was then compared with the human PK profile from clinical studies. Population PK model and simulation was used to delineate the distribution and elimination characteristics in each species. In addition, tumor shrinkage was measured after weekly administration of both formulations in mouse xenograft model. Results: Our pharmacokinetic modeling results suggested that elimination predominates over distribution in driving PTX disposition in mice, hence restricting the PTX tissue accumulation. Moreover, the rapid elimination of PTX in mice minimized the different formulation effects on PTX tissue distribution, which is believed to link to the superior efficacy of nab-paclitaxel over KoEL-paclitaxel seen in human. In contrast to mice, PTX distribution predominates over elimination in human, and the decline in plasma PTX concentration reflected the deeper tissue distribution by nab-paclitaxel.Conclusion: This species difference in PTX distribution and elimination hinders a simple direct extrapolation from animals to humans. Therefore, species difference in drug distribution and elimination should be carefully assessed during translational drug development. Keywords: paclitaxel, pharmacokinetics, tissue distribution, drug elimination, disposition, species difference

Xiuran Niu,1,* Zhihui Gao,1,* Shanshan Qi,1 Linjia Su,1 Nan Yang,1 Xiuli Luan,1 Jia Li,1 Qing Zhang,2 Yingli An,3 Sihe Zhang1 1Department of Cell Biology, School of Medicine, Nankai University, Tianjin, People’s Republic of China; 2Department of Clinical Laboratory, Cancer Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 3State Key Laboratory of Medicinal Chemical Biology and Institute of Polymer Chemistry, Nankai University, Tianjin, People’s Republic of China *These authors contributed equally to this work Background: Successful implementation of gene therapy heavily relies on efficiently delivering genetic materials and specific targeting into cells. Oncogene-driven endocytosis stimulates nutrient uptake and also develops an endocytosis-mediated defense against therapeutic agents. Cell-penetrating peptides, typically HIV-Tat, are well known for efficient delivery of nucleic acid drugs but lack targeting specificity. Various passive targeting strategies were pursued to enhance the tumor targeting efficiency; however, they are still limited by complicated cellular endocytosis routes and the heterogeneity of cancer types. Methods: Tat/pDNA complexes were noncovalently compacted and their physiochemical properties were determined. The siRNA pool and pLV-RNAi-GFP lentivirus were used to knock down dbl oncogene (originally isolated from diffuse B-cell lymphoma) expression, and its overexpression was performed by plasmid transient transfection. The cellular uptake of fluorescent ligands was quantified by confocal imaging and flow cytometry analysis. The transgene efficiency was determined by the Luciferase expression assay. Rho GTPase activation was checked by the GST-Rho GTPase-binding domain pull-down assay. Results: pGL3 plasmid DNA was noncovalently compacted with the Tat peptide into nano-size complexes at high N/P ratios. Macropinocytosis, a clathrin- and caveolin-independent endocytosis process, was shown to contribute to the uptake of middle-sized (~600 nm) Tat/pGL3 complexes. Cell-type-specific variation in macropinocytosis was essentially controlled by the action of the Dbl oncogene. Onco-Dbl presentation constantly induced a high level of macropinocytosis activity in ovarian cancer cells. Onco-Dbl overexpression hyperstimulated macropinocytosis enhancement in cells mainly through actin cytoskeleton reorganization mediated by the PH domain and Rac1 activation. The Dbl-driven Rho GTPase signaling collectively determined the cell-type-specific macropinocytosis phenotype. Conclusion: Such an aspect can be exploited to selectively confer targeted delivery of Tat/pDNA nano-complexes into ovarian cancer cells. Our work provides a novel alternative for targeted delivery of cell-penetrating peptide-based nucleic acid drugs into certain tumor types if specific endocytosis pathways are used. Keywords: onco-Dbl, macropinocytosis, Rac1, Tat/pDNA complex, targeting delivery