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Shiyu Zhang, Fanting Kong, Lei Zheng, Xiaowei Li, Lining Jia, Lixian Yang Department of Breast Surgery, Xingtai People’s Hospital, Xingtai, Hebei, 054000, People’s Republic of ChinaCorrespondence: Lixian Yang, Department of Breast Surgery, Xingtai People’s Hospital, No. 818 Xiangdu District, Xingtai, Hebei, 054000, People’s Republic of China, Email yanglixian@hebmu.edu.cnBackground: The role of Semaphorin 7a (SEMA7A) in the initiation and progression of different types of cancerous lesions has been extensively studied. However, the prognostic significance of SEMA7A, specifically in breast cancer (BC), lacks clarity.Methods: We conducted an evaluation on the relationship between SEMA7A and the prognosis, immune invasion and tumor mutation burden in different types of cancer by analyzing data from The Cancer Genome Atlas database. The present study focused on investigating the expression level, mutation, immune correlation and coexpression of SEMA7A in BC, utilizing various databases such as the University of Alabama at Birmingham Cancer data analysis portal, cBioPortal and tumor immune estimation resource. Survival analysis was carried out using the Kaplan-Meier Plotter. Furthermore, we employed the R software package to generate receiver operating characteristic (ROC) curves and nomograms. Notably, P< 0.05 was considered to indicate statistical significance.Results: Using pancancer analysis, it has been observed that the expression of SEMA7A is elevated in various types of cancer and is strongly correlated with the prognosis of different cancer types. SEMA7A also exhibits a significant association with the tumor mutation burden of diverse types of cancer. Moreover, SEMA7A displays a notable increase in BC cases, and was indicated to have a substantial association with the abundance of immune infiltration. In-depth survival analysis demonstrated that elevated levels of SEMA7A expression are notably linked to shorter overall survival and distant metastasis-free survival among patients with BC. The efficiency of SEMA7A as a reliable prognostic biomarker for BC has been substantiated by the validation of ROC curves and nomograms.Conclusion: SEMA7A has the potential to function as a prognostic indicator for BC, and its correlation with immune infiltration in BC is significant.Keywords: SEMA7A, breast cancer, biomarker, prognosis, methylation, immune infiltration, nomogram, bioinformatics

Jing-Jing Huang,1,&ast; Lin Jia,2,3,&ast; Qiao-Jun Zhang,4 Hao-Hong Li,5 Da-Li Zheng,2 Ming Zheng3 1Second Department of Dental Implant, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350001, People’s Republic of China; 2Fujian Key Laboratory of Oral Diseases, Fujian Biological Materials Engineering and Technology Center of Stomatology, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian, 350004, People’s Republic of China; 3Department of Prosthodontics, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, 350001, People’s Republic of China; 4Zhongshan Hospital Affiliated to Xiamen University, Xiamen, 361000, People’s Republic of China; 5College of Chemistry, Fuzhou University, Fuzhou, Fujian, 350116, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Zheng, Department of Prosthodontics, School and Hospital of Stomatology, Fujian Medical University, 246 Yangqiao Middle Road, Fuzhou, 350001, People’s Republic of China, Tel +86-591-83736431, Email zmdentist@163.com Da-Li Zheng, Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, 88 Jiaotong Road, Fuzhou, 350004, People’s Republic of China, Tel +86-591-83720599, Email dalizheng@fjmu.edu.cnPurpose: To investigate the inhibition of Streptococcus mutans (S.mutans) and its biofilm by AgBr-nanoparticles (NP) @CTMAB (cetyltrimethyl-ammonium bromide) and evaluate the changes in Polymethyl methacrylate (PMMA)’s surface roughness (Ra), microhardness, and flexural strength during prolonged immersion in AgBr-NP@CTMAB for application in the denture cleaning industry.Patients and Methods: The antibacterial activity of AgBr-NP@CTMAB against S.mutans was measured colony formation assay, OD600 and laser confocal microscopy. Changes in the specimens’ values for surface roughness, microhardness, and flexural strength (MPa) were measured after immersion solutions for 180 or 360 days.Results: The AgBr-NP@CTMAB solution exhibited a robust antibacterial effect on planktonic S. mutans, with a minimum bactericidal concentration of 5 μg/mL. The 10 μg/mL AgBr-NP@CTMAB solution efficiently inhibited S. mutans biofilm formation. (2) No significant difference in surface roughness after immersion in AgBr-NP@CTMAB (10 μg/mL and 20 μg/mL) comparing with distilled water (P > 0.05) and Polident had significantly higher than distilled water (P < 0.05). There was a significant decrease in the surface hardness of the PMMA specimens that were immersed in the Polident compared with those in distilled water (P < 0.05). While, no significant differences in surface hardness after immersion in the AgBr-NP@CTMAB (P > 0.05). The result of flexural strength suggested that there was no statistically significant difference (P < 0.05) between AgBr-NP@CTMAB as well as Polident and water.Conclusion: AgBrNP@CTMAB can efficiently inhibit the growth of plankton S.mutans and biofilm formation, without affecting the flexural strength, microhardness, or surface roughness of PMMA. Therefore, AgBrNP@CTMAB holds promise as a new denture cleaning agent.Keywords: AgBr-NP@CTMAB, S.mutans, polymethyl methacrylate, denture cleanser, biofilm

Jiaping Shu,1,&ast; Lili Jia,2,&ast; Pei Zhang,2 Ren Wang,2 Meiqiu Wang,2 Xiaoyi Sun,2 Yingchao Peng,2 Peipei Wang,2 Xiaojie Li,2 Zilu Tang,3 Tingting Han,3 Tao Ju,3 Yaqin Wei,4 Wei Pang,5 Chunlin Gao,2 Zhengkun Xia1 1Department of Pediatrics, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, People’s Republic of China; 2Department of Pediatrics, Jinling Hospital, Nanjing University, Nanjing, Jiangsu, 210093, People’s Republic of China; 3Department of Pediatrics, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210093, People’s Republic of China; 4Department of Pediatrics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510000, People’s Republic of China; 5Department of Military Information, Chinese People’s Liberation Army 31102, Nanjing, Jiangsu, 210000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhengkun Xia, Department of Pediatrics, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, People’s Republic of China, Email njxzk@126.com Chunlin Gao, Department of Pediatrics, Jinling Hospital, Nanjing University, Nanjing, Jiangsu, 210093, People’s Republic of China, Email shuangmu34@163.comIntroduction: The pandemic of SARS-CoV-2 brings great challenge and threats to humans worldwide. Multiple variants of SARS-CoV-2 tend to be epidemic, among which Omicron is highly infectious within China. The aim of this study was to analyze the clinical characteristics of children infected with SARS-CoV-2 variant B.1.1.529 (Omicron) in the Shanghai, China.Methods: We included 9378 pediatric patients diagnosed with Omicron and treated in the Shanghai International Convention and Exhibition Center between April 1, 2022 and May 31, 2022. We recorded and summarized the clinical characteristics, infectious conditions and biological features of the children infected with Omicron.Results: A total of 9355 paediatric patients were treated in isolation since Makeshift became available, including 5564 males (59.48%) and 3791 females (40.52%). More than half (55.56%) of the affected children were identified at premises screening. The number of symptomatic or asymptomatic patients was 4530 (48.42%) and 4825 (51.58%), respectively. Initial signs or symptoms in asymptomatic patients included fatigue (3582, 38.29%), cough (560, 5.99%), fever (242, 2.59%) and other (146, 1.56%). Age and number of vaccinations in paediatric patients were negatively associated with the number of days from positive to negative nucleic acid test results.Conclusion: Age and number of vaccinations were key factors influencing the conversion of nucleic acid test results in paediatric patients. Early childhood vaccination is encouraged to establish a complete immune barrier.Keywords: Omicron variant, COVID-19, child patients, clinical characteristics

In early embryonic development, the cross-regulation of transcription factors and signaling pathways are critical in mediating developmental and physiological processes. Additionally, many studies have shown the importance of post-transcriptional regulation of signaling and network components mediated by microRNAs (miRNAs); however, how miRNAs are transcriptionally regulated is poorly understood. miRNAs are critical fine-tuners of many biological processes and their dysregulation leads to a variety of diseases and developmental defects. Previously, we have shown that miRNAs are dynamically expressed throughout sea urchin development, suggesting that miRNAs are likely to be under transcriptional regulation. Here, we used pharmacological inhibitors, genetic constructs, and loss-of-function reagents to assess the impact of key signaling pathways (Wnt, Nodal, MAPK, Sonic Hedgehog, Delta/Notch, VEGF, and BMP) and transcription factors (Alx1, Ets1/2, and Tbr) on the transcript levels of the evolutionarily conserved miR-1, miR-31, miR-92 and miR-124; the invertebrate-specific miR-71; and the echinoderm-specific miR-2002, miR-2007, and miR-2012. We also used computational methods to identify potential transcription factor binding sites of these miRNAs. Lists of binding motifs for transcription factors (TFs) were acquired from the MEME-Suite Motif Database and used as inputs for the algorithm FIMO (Find Individual Motif Occurrences), which detects short nucleotide motifs within larger sequences. Based on experimental data on miRNA expression in conjunction with bioinformatic predictions, we propose that the transcription factors Tbr, Alx1, and Ets1 regulate SpmiR-1, SpmiR-31, and SpmiR-71, respectively. We additionally observed significant effects on miRNA levels as a result of perturbations to Wnt, Nodal, MAPK, and Sonic Hedgehog signaling pathways, while no significant change on miRNA levels were observed with perturbations to Delta/Notch, VEGF, or BMP signaling pathways. Overall, this study provides insights into the transcriptional regulation of miRNAs by signaling pathways and transcription factors and contribute to our overall understanding of the genetic regulation of developmental processes.

Limin Jia,1 Yanfeng Wang,2 Wenyuan Zhang,3 Yulian Lin,1 Fang Chen,1 Yixiao Wan,1 Xin Fu4,5 1Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, Zhejiang, 317000, People’s Republic of China; 2Department of Geriatrics, Taizhou Central Hospital (Taizhou University Hospital) of Zhejiang, Taizhou, Zhejiang, 318000, People’s Republic of China; 3Department of ICU, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, Zhejiang, 317000, People’s Republic of China; 4Department of Radiology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, Zhejiang, 317000, People’s Republic of China; 5Department of Radiology, Enze Hospital, Taizhou Enze Medical Center (Group), Taizhou, Zhejiang, 318000, People’s Republic of ChinaCorrespondence: Xin Fu, Department of Radiology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, No. 150 Ximen Street, Linhai City, Taizhou, Zhejiang, 317000, People’s Republic of China, Tel + 86-0576-85120120, Email fux005ing@126.comBackground and Purpose: To explore the feasibility of the modified blood collection method in pre-deposit autotransfusion in patients undergoing thoracotomy surgery.Methods: This double-blinded randomised controlled trial enrolled 92 patients from the cardiothoracic surgery department from February 2019 to October 2020.Results: Compared with the conventional blood collection method, the modified blood collection method avoided blood overflow from the oblique plane of the needle (χ2 = 61.986, P < 0.01) and reduced the diameter of the bruising area after 24 hours (χ2 = 24.611, P < 0.01). Furthermore, due to optimising the blood collection method, diastolic blood pressure reduced slightly before and after blood collection (t = 2.036, P < 0.05), and patients in the test group had less pain (based on the numerical rating score) (t = 5.556, P < 0.01). Meanwhile, the time required to collect 400 mL of blood was shortened (t = 17.744, p < 0.01).Conclusion: An improved blood collection method can enhance the blood donation experience, avoid blood spillage, lessen pain and reduce adverse reactions. This may be of great significance in ensuring blood quality and the safety of subsequent transfusions.Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT05539846.Keywords: pre-deposit autotransfusion, extracorporeal circulation, open heart surgery

Abstract Background Tissue injury induces inflammation and the surgical stress response, which are thought to be central to the orchestration of recovery or deterioration after surgery. Enhanced formation of reactive oxygen and nitrogen species accompanies the inflammatory response and triggers separate but integrated reduction/oxidation (redox) pathways that lead to oxidative and/or nitrosative stress (ONS). Quantitative information on ONS in the perioperative period is scarce. This single-centre exploratory study investigated the effects of major surgery on ONS and systemic redox status and their potential associations with postoperative morbidity. Methods Blood was collected from 56 patients at baseline, end of surgery (EoS) and the first postoperative day (day-1). Postoperative morbidity was recorded using the Clavien-Dindo classification and further categorised into minor, moderate and severe. Plasma/serum measures included markers of lipid oxidation (thiobarbituric acid-reactive substances; TBARS, 4-hydroxynonenal; 4-HNE, 8-iso-prostaglandin F2⍺; 8-isoprostanes). Total reducing capacity was measured using total free thiols (TFTs) and ferric-reducing ability of plasma (FRAP). Nitric oxide (NO) formation/metabolism was measured using cyclic guanosine monophosphate (cGMP), nitrite, nitrate and total nitroso-species (RxNO). Interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-⍺) were measured to evaluate inflammation. Results Both oxidative stress (TBARS) and nitrosative stress (total nitroso-species) increased from baseline to EoS (+14%, P = 0.003 and +138%, P < 0.001, respectively), along with an increase in overall reducing capacity (+9%, P = 0.03) at EoS and protein-adjusted total free thiols (+12%, P = 0.001) at day-1 after surgery. Nitrite, nitrate and cGMP concentrations declined concomitantly from baseline to day-1. Baseline nitrate was 60% higher in the minor morbidity group compared to severe (P = 0.003). The increase in intraoperative TBARS was greater in severe compared to minor morbidity (P = 0.01). The decline in intraoperative nitrate was more marked in the minor morbidity group compared to severe (P < 0.001), whereas the cGMP decline was greatest in the severe morbidity group (P = 0.006). Conclusion In patients undergoing major HPB surgery, intraoperative oxidative and nitrosative stress increased, with a concomitant increase in reductive capacity. Baseline nitrate was inversely associated with postoperative morbidity, and the hallmarks of poor postoperative outcome include changes in both oxidative stress and NO metabolism.

Mingyuan Li,1 Meng Li,1 Xinyi Li,1 Wanhui Shao,1 Xiujuan Pei,2 Ruyue Dong,1 Hongmeng Ren,1 Lin Jia,1 Shiqin Li,1 Wenlin Ma,1 Yi Zeng,1 Yun Liu,1 Hua Sun,1 Peng Yu1 1College of Biotechnology/Tianjin Enterprise Key Laboratory for Application Research of Hyaluronic Acid, Tianjin University of Science & Technology, Tianjin, 300457, People’s Republic of China; 2Tianjin Shiji Kangtai Biomedical Engineering Co.,Ltd, Tianjin, 300462, People’s Republic of ChinaCorrespondence: Hua Sun; Peng Yu, Email sunhua@tust.edu.cn; yupeng@tust.edu.cnPurpose: In the present study, we prepared collagen liposomes with the addition of polyol, which is expected to not only increase the solubility of collagen but also improve skin penetration.Methods: Collagen liposomes were prepared by the film dispersion method, and their characteristics, integrity and biosafety were evaluated by Fourier transform infrared spectroscopy (FTIR), UV-VIS spectroscopy, polyacrylamide gel electrophoresis (SDS-PAGE), dynamic light scattering (DLS) and transmission electron microscope (TEM). The transdermal absorption of collagen and collagen liposomes were tested by an ex vivo horizontal Valia-Chien diffusion cell system.Results: We first demonstrated that collagen extracted from bovine Achilles tendon was type I collagen. The results of DLS measurement and TEM observation showed that the collagen liposomes were spherical in shape with average diameter (75.34± 0.93 nm) and maintained high stability at low temperature (4°C) for at least 42 days without toxicity. The encapsulation rate of collagen liposomes was 57.80 ± 0.51%, and SDS-PAGE analysis showed that collagen was intact in liposomes. Finally, permeability studies indicated that the collagen-loaded liposomes more easily penetrated the skin compared to collagen itself.Conclusion: This study proposed a new method to improve the bioavailability and permeability of bovine type I collagen, which improves the applicability of collagen in biomedicine, cosmeceuticals and pharmaceutical industries.Graphical Abstract: Keywords: collagen, liposome, physicochemical properties of collagen, skin penetration, drug delivery

Lili Jia,1 Wenfei Li,1 Yue Liu,1 Longqin Wang2 1Department of Gynaecology and Obstetrics, Binhai County People’s Hospital, Yancheng City, People’s Republic of China; 2Department of Emergency, Binhai County People’s Hospital, Yancheng City, People’s Republic of ChinaCorrespondence: Longqin Wang, Department of Emergency, Binhai County People’s Hospital, 248 Fudong Middle Road, Yancheng City, 224599, People’s Republic of China, Email WLQ_binhai@126.comAbstract: Early pregnancy complications, including miscarriage, ectopic pregnancies, and hyperemesis gravidarum, are common discomforts accounting for about 15% to 20% of all pregnancies. A proportion of women with early pregnancy complications will experience short- and long-term psychologic sequelae in the aftermath of pregnancy complications, including anxiety, depression, and post-traumatic stress disorder (PTSD) which are the most commonly reported psychologic reactions. This review will focus on the course and impact of these psychologic sequelae in early pregnancy complications, and the noninvasive interventions to improve mental health are also briefly discussed.Keywords: miscarriage, ectopic pregnancies, hyperemesis gravidarum, psychologic sequelae

Yanzheng Zou,1,* Ming Yue,2,* Linna Jia,1 Yidi Wang,1 Hongbo Chen,3 Yifan Wang,3 Meiling Zhang,3 Yue Feng,4 Rongbin Yu,1 Sheng Yang,5 Peng Huang1 1Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Infectious Disease, Jurong Hospital Affiliated to Jiangsu University, Jurong, People’s Republic of China; 4Faculty of Life Science and Technology, Kunming University of Science and Technology, Yunnan, People’s Republic of China; 5Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng Huang, Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China, Email huangpeng@njmu.edu.cn Sheng Yang, Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China, Email yangsheng@njmu.edu.cnPurpose: It is unclear whether and how the long-term risk of hepatocellular carcinoma (HCC) will change in hepatitis C virus (HCV) infected patients who have reached sustained virologic response (SVR) with direct-acting antivirals (DAA). In this study, we assessed the long-term risk of HCC up to 10 years after SVR using fibrosis 4 score (FIB-4) and its dynamic changes.Patients and Methods: A total of 701 DAA-treated patients who achieved SVR between January 2012 to October 2020 were enrolled in the study. The FIB-4 score of each patient was measured at the date of SVR and each follow-up visit annually. Patients were followed until December 31, 2021, with the longest follow-up time being 9.82 years.Results: Following SVR, 27 cases of HCC were observed. The annual incidence rate of HCC remained stable with no obvious downward trend. Patients with a FIB-4 > 3.25 at baseline or anytime during follow-up were at a higher risk of developing HCC than those whose FIB-4 remained below 3.25. Patients with cirrhosis and patients with no cirrhosis but a FIB-4 > 3.25 were at higher risk of developing HCC than patients with no cirrhosis and a FIB-4 ≦3.25.Conclusion: FIB-4 > 3.25 measured at SVR or any time post-SVR was associated with HCC risks. The repeated measurement of FIB-4 revealed a better predictive ability of HCC risks than the simple measurement of FIB-4 at baseline. The additional stratification of patients by combining FIB-4 and cirrhosis leads to more accurately identifying high-risk patients. Surveillance of HCC is recommended for virologically cured patients with a FIB-4 > 3.25 at SVR or anytime afterward and patients diagnosed with cirrhosis.Keywords: chronic hepatitis C, sustained virologic response, direct-acting antivirals, serum biomarker, hepatocellular carcinoma

Mingliang Su,&ast; Yukun Chen,&ast; Lijun Jia, Zhanxia Zhang Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lijun Jia; Zhanxia Zhang, Email ljjia@shutcm.edu.cn; zhanxiazhang@shutcm.edu.cnIntroduction: Camptothecin (CPT) is a cytotoxic quinolone alkaloid (isolated from a traditional Chinese medicine Camptotheca acuminata), used for the treatment of various malignancies, which inhibits DNA topoisomerase I (Topo I). However, its drawbacks, such as poor water solubility, stability, and highly toxic side effects, limit its clinical application. Therefore, CPT needs to be prepared as a nanomedicine to improve solubility, reduce side effects, and synergize with other therapies to improve efficacy.Methods: In this work, we constructed CPT NPs (nanoparticles), which were CPT-loaded and manganese dioxide (MnO2)-coated polydopamine (PDA) nanomedicine. In vitro, we explored the antitumor effect including CPT NPs-induced cell proliferation inhibition, apoptosis and ferroptosis for tumor cell lines. In vivo, we established LLC tumor-bearing mice model to evaluate their tumor imaging and anticancer effects.Results: CPT NPs improve the water solubility and stability of CPT and reduce its toxic effects. It has good biocompatibility, excellent photothermal conversion ability for photothermal therapy (PTT) and pH release in the tumor microenvironment. It can inhibit tumor cell proliferation, induce apoptosis and result in ferroptosis of tumor cells. More significantly, this nanomedicine can provide information for the location and diagnosis of tumors via magnetic resonance imaging. In general, the nanomedicine integrated with diagnosis and treatment has excellent anticancer effect.Discussion: Altogether, this nanomedicine possesses the ability to diagnose and therapy through magnetic resonance imaging and chemo-photothermal therapy, respectively. In addition, the integrated diagnosis and treatment nanomedicine has potential clinical application prospects through treating lung cancer with high efficiency and low side effect. It can support the construction of related nano-delivery systems.Graphical Abstarct: Keywords: photothermal therapy, ferroptosis, NMR imaging, pH response, camptothecin

Yan Zhang,1 Wenjie Li,1 Xiaomin Tian,1 Ruanyang Sun,1 Shidan Zhou,2 Ling Jia,1 Jian Sun,1,3,4 Xiao-Ping Liao,1,3,4 Ya-Hong Liu,1,3,4 Yang Yu1,3,4 1Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, People’s Republic of China; 2Intensive Care Unit, Huizhou Municipal Central Hospital, Huizhou, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Microbial Safety and Health, Guangdong Institute of Microbiology, Guangdong Academy of Science, Guangzhou, People’s Republic of China; 4Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, People’s Republic of ChinaCorrespondence: Yang Yu, Email graceyyu@scau.edu.cnObjective: Carbapenem-resistant Enterobacteriaceae (CRE) have become an increasingly common cause of healthcare-related infections and present a serious challenge to clinical treatment. This study examined the phenotypic, genotypic characterization, clinical, and microbiological data of CRE in the Huizhou Municipal Central Hospital.Methods: We conducted a phenotypic susceptibility evaluation and whole genome sequence analysis for 52 CRE strains isolated from 37 patients and 2 medical device-related samples during 2013– 2017 to characterize risk factors, antimicrobial resistance profiles, dominant clones and hospital transmission.Results: Long-term hospitalization, treatment time with antibiotics and use of invasive devices were linked to the risk of CRE infection. The carbapenem resistance genes (CRGs) we found included blaNDM (82.7%), blaIMP (19.2%) and blaKPC (3.8%), Escherichia coli (44.2%) and Klebsiella pneumoniae (44.2%) were the dominant species we identified, and the type of CRG carried by isolates was highly correlated with species. The coexistence of CRGs with a variety of other antibiotic resistance genes leads to an increased prevalence of high resistance levels for CRE to β-lactams and other antibiotic classes such as aminoglycosides and fluoroquinolones. These isolates were sensitive only to colistin and tigecycline. In addition to this, we observed significantly genomic diversity of CRE isolates in this hospital. Importantly, we found that long-term transmission of multiple CRE clones had occurred at this hospital between various wards.Conclusion: Evaluating and improving the current infection control strategies may be necessary, and reducing nosocomial transmission remains the primary control element for CRE infections in China.Keywords: carbapenem-resistant Enterobacteriaceae, bacteremia, carbapenem resistance genes, nosocomial transmission

Qi Qiao,1 Zhenzhen Qu,1 Shuang Tian,2 Huifang Cao,3 Yange Zhang,4 Can Sun,5 Lijing Jia,1,&ast; Weiping Wang1,&ast; 1The Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2The Department of Neurology, Shijiazhuang People’s Hospital, Shijiazhuang, People’s Republic of China; 3The Department of Rehabilitation, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 4The Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 5The Department of Neurology, The Third Hospital of Peking University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weiping Wang; Lijing Jia, The Department of Neurology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, People’s Republic of China, Email weip_wanghb2@163.com; jialijing_sjz@outlook.comBackground: The ketogenic diet (KD) is a proven therapy for refractory epilepsy. Although the anti-seizure properties of this diet are understood to a certain extent, the exploration of its neuroprotective effects and underlying mechanisms is still in its infancy. Tissue acidosis is a common feature of epileptogenic foci. Interestingly, the activation of acid-sensing ion channel 1a (ASIC1a), which mediates Ca2+-dependent neuronal injury during acidosis, has been found to be inhibited by ketone bodies in vitro. This prompted us to investigate whether the neuroprotective effects induced by the KD occur via ASIC1a and interconnected downstream mechanisms in a rat model of temporal lobe epilepsy.Methods: Male Sprague-Dawley rats were fed either the KD or a normal diet for four weeks after undergoing pilocarpine-induced status epilepticus (SE). The effects of KD on epileptogenesis, cognitive impairment and hippocampal neuron injury in the epileptic rats were subsequently evaluated by video electroencephalogram, Morris water maze test and Nissl staining, respectively. The expression of ASIC1a and cleaved caspase-3 in the hippocampus were determined using Western blot analysis during the chronic period following SE. Moreover, the intracellular Ca2+ concentration, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mROS) and cell apoptosis of hippocampal cells were detected by flow cytometry.Results: We found that the KD treatment strongly attenuated the spontaneous recurrent seizures, ameliorated learning and memory impairments and prevented hippocampal neuronal injury and apoptosis. The KD was also shown to inhibit the upregulation of ASIC1a and the ensuing intracellular Ca2+ overload in the hippocampus of the epileptic rats. Furthermore, the seizure-induced structure disruption of neuronal mitochondria, loss of MMP and accumulation of mROS were reversed by the KD treatment, suggesting that it has protective effects on mitochondria. Finally, the activation of caspase-3 was also inhibited by the KD.Conclusion: These findings indicate that the KD suppresses mitochondria-mediated apoptosis possibly by regulating ASIC1a to exert neuroprotective effects. This may provide a mechanistic explanation of the therapeutic effects of KD.Keywords: ketogenic diet, temporal lobe epilepsy, acid-sensing ion channel 1a, mitochondrial pathway, neuroprotection

Lingying Jia, Yan Hu School of Nursing, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Yan Hu, School of Nursing, Fudan University, Shanghai, People’s Republic of China, Tel +86 21 6443 1273, Fax +86 21 6416 1784, Email huyan@fudan.edu.cnObjective: This study aims to describe the experience and connotations of self-management about adjuvant therapy (AT) in Chinese breast cancer survivors (BCS) and explore possible factors that affect their self-management level.Methods: Semi-structured interviews were conducted in postoperative BCS undergoing AT using a qualitative description method. The conceptual structure and connotations were extracted after researchers collected and coded interview transcripts.Results: After interviewing 29 patients, the conceptual framework of self-management in BCS during AT was optimized with three major themes: medical-related, emotion, and role management. Medical-related management includes AT-related adverse reactions; medical cooperation and knowledge acquisition; recovery and protection of affected limb; medical compliance; body image; sexual function and fertility; healthy lifestyle; catheter daily protection; and AT-related financial burdens. Emotion management includes recognition, prevention, and regulation of negative emotions. Role management consists of three aspects: family role, social role, and work role.Conclusion: The conceptual structure and connotations formed in this study can help researchers to evaluate and intervene in the self-management ability of BCS during AT, so as to formulate the best model of care to improve their quality of life and clinical outcomes.Keywords: breast neoplasm, adjuvant therapy, self-management, survivorship

Yukun Chen,1 Zhenzhi Wang,2 Xiaofan Wang,3 Mingliang Su,1 Fan Xu,1 Lian Yang,1 Lijun Jia,1 Zhanxia Zhang1 1Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China; 2Shaanxi University of Chinese Medicine, Xianyang, 712046, People’s Republic of China; 3Department of Oncology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078, People’s Republic of ChinaCorrespondence: Lijun Jia; Zhanxia Zhang, Email ljjia@shutcm.edu.cn; zhanxiazhang@shutcm.edu.cnAbstract: 10-Hydroxycamptothecin (HCPT) is a natural plant alkaloid from Camptotheca that shows potent antitumor activity by targeting intracellular topoisomerase I. However, factors such as instability of the lactone ring and insolubility in water have limited the clinical application of this drug. In recent years, unprecedented advances in biomedical nanotechnology have facilitated the development of nano drug delivery systems. It has been found that nanomedicine can significantly improve the stability and water solubility of HCPT. NanoMedicines with different diagnostic and therapeutic functions have been developed to significantly improve the anticancer effect of HCPT. In this paper, we collected reports on HCPT nanomedicines against tumors in the past decade. Based on current research advances, we dissected the current status and limitations of HCPT nanomedicines development and looked forward to future research directions.Keywords: 10-hydroxycamptothecin, antitumor, nanomedicine, nano-drug delivery systems

Xiao-nan Gao,1 Xu-yang Nie,1 Jing-lin Gao,1 Tian-fang Heng,2 Yu-qi Zhang,2 Li Hua,1 Ya-qi Sun,1 Zhang-ying Feng,1 Ming-xia Wang,1 Li Jia2 1Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of ChinaCorrespondence: Ming-xia Wang, Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, People’s Republic of China, Tel +86 311-66696233, Email mxia_wang@163.com Li Jia, Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, People’s Republic of China, Email 281575038@qq.comPurpose: This study aimed to characterize the pharmacokinetics of nalbuphine in patients undergoing general anesthesia with varying degrees of liver dysfunction.Patients and Methods: Twenty-four patients were enrolled and divided into three cohorts based on liver function: normal liver function (n = 13), mild liver dysfunction (n = 5), and moderate/severe liver dysfunction (n = 6). During the induction of anesthesia, they received 15 mg of nalbuphine intravenously. Venous blood samples were collected from each patient. The plasma concentration of nalbuphine was determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of nalbuphine were calculated by non-compartmental analysis (NCA) using Phoenix WinNonlin software.Results: Compared with the normal liver function group, the plasma elimination half-life (T1/2) of nalbuphine was increased by approximately 33% in the moderate/severe liver dysfunction group (2.66 h vs 3.54 h, P< 0.05), and the volume of distribution (Vd) increased by approximately 85% (100.08 L vs 184.95 L, P< 0.05). Multivariate analysis revealed that weight and platelet were associated with clearance (CL); total bilirubin as an independent factor was associated with T1/2, and weight associated with area under the curve (AUC(0→∞)) independently.Conclusion: The T1/2, mean residence time, and Vd of nalbuphine in patients with moderate/severe liver dysfunction were prolonged or increased significantly compared with those in the normal liver function group. These data suggest that it may need to be used with caution when nalbuphine is administered to patients with moderate or severe liver dysfunction.Keywords: nalbuphine, intravenous, liver dysfunction, UPLC-MS/MS, pharmacokinetics

Xiaoling Zhang,1,2,&ast; Xiaoyu Wang,3,&ast; Liting Jia,4 Yang Yang,5 Fan Yang,3 Shengjun Xiao2,3,6 1Department of Physiology, Faculty of Basic Medical Science, Guilin Medical University, Guilin, People’s Republic of China; 2Key Laboratory of Tumor Immunology and Microenvironmental Regulation of Guangxi, Guilin Medical University, Guilin, People’s Republic of China; 3Department of Pathology, the Second Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China; 4Department of Pathology, Affiliated Hospital of Hebei Engineering University, Handan, People’s Republic of China; 5Department of Pathology, General Hospital of Central Theater Command, Wuhan, People’s Republic of China; 6Department of Pathology, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, the Second Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shengjun Xiao, Department of Pathology, The Second Affiliated Hospital, Guilin Medical University, No. 212, Renmin Road, Guilin, Guangxi Province, 541199, People’s Republic of China, Email xiaoshengjun@glmc.edu.cn Xiaoling Zhang, Department of Physiology, Faculty of Basic Medical Science, Guilin Medical University, No. 1, Zhiyuan Road, Guilin, Guangxi Province, 541100, People’s Republic of China, Email rose2006@glmc.edu.cnBackground: Sarcomatoid hepatocellular carcinoma (sHCC), a highly aggressive subtype of hepatocellular carcinoma (HCC), mostly transforms from classical hepatocellular carcinoma (cHCC). The study intended to explore the role of C-terminal binding protein 1 (CtBP1) in sarcomatoid transformation of hepatocellular carcinoma.Methods: Western blotting and/or immunohistochemistry were used to confirm the expression of CtBP1 and other proteins in HCC cells, xenografts and clinical tissue samples. CtBP1 shRNA-expressing lentivirus was used to infect HepG2 cells to construct CtBP1 knockdown cells. Cell migration was determined by scratch wound assays and Transwell assays. Immunofluorescence was used to label the a-tubulin cytoskeleton to evaluate cell morphology. HepG2 cells were inoculated subcutaneously in nude mice to construct xenografts and beneath the liver capsule to evaluate in vivo metastasis.Results: Compared to that in the cHCC area, CtBP1 expression was significantly upregulated in the sHCC area, as shown by immunohistochemistry. HE staining showed that cells in the sHCC area were spindle-shaped, while those in the cHCC area were polygonal. Immunohistochemically, the epithelial markers pancytokeratin (CK) and E-cadherin were partially or completely lost, while the expression of the mesenchymal marker vimentin was upregulated in the sHCC area. Moreover, HepG2, an HCC cell line with high expression of CtBP1, autonomously underwent sarcomatoid transformation, showing a sarcomatoid morphology and phenotype. HIF1a expression was upregulated in epithelial cells adjacent to the sHCC area. Hypoxia upregulated CtBP1 protein expression and induced an EMT phenotype with increased migration and a spindle-shaped morphology in HepG2 cells. Knockdown of CtBP1 partially reversed the EMT phenotype induced by hypoxia. Silencing CtBP1 completely blocked the sarcomatoid transformation of subcutaneous xenografts and decreased lung metastasis in subcapsular xenografts of the liver in nude mice.Conclusion: CtBP1 plays a key role in hypoxia-induced EMT and sarcomatoid transformation in HCC and could be a candidate target for the management of sHCC.Graphical Abstract: Keywords: C-terminal binding protein 1, sarcomatoid hepatocellular carcinoma, hypoxia, sarcomatoid transformation, epithelial-to-mesenchymal transition

Dongdong Xue,1 Jingzhao Han,1 Ze Liang,1 Lin Jia,1 Yifan Liu,1,2 Hongfang Tuo,1 Yanhui Peng1 1Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 2Department of Graduate School, Hebei Medical University, Shijiazhuang, People’s Republic of ChinaCorrespondence: Yanhui Peng, Department of Hepatobiliary Surgery, Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang, 050051, Hebei Province, People’s Republic of China, Tel/Fax +86-311-859 8321, Email yhpeng@hebmu.edu.cnAbstract: As a common malignant tumor worldwide, the prognosis of hepatocellular carcinoma (HCC) remains unsatisfactory, even though treatment methods have improved. Despite the developments in traditional chemotherapy and emerging targeted immunotherapy, the problem of recurrence and metastasis of HCC and adverse effects on survival and prognosis are still serious. Drug resistance is a daunting challenge that impedes HCC treatment. Exosomes, a class of extracellular vesicles ranging in size from 30 to 100 nm, have been the focus of recent studies. Exosomes can activate various signaling pathways and regulate the tumor microenvironment with their cargo, which includes functional lipids, proteins, and nucleic acids. Thus, they change the phenotype of recipient cells via exosome-mediated communication. Exosomes secreted by tumors or stromal cells can also transfer drug-resistant traits to other tumor cells. However, their effects on drug resistance in HCC are not completely understood. In this review, we summarize and discuss the underlying relationship between exosomes and drug resistance in HCC. In addition, we also show that exosomes may act as candidate biomarkers for predicting and monitoring drug responses and as potential targets or vectors to reverse the drug resistance of HCC.Keywords: hepatocellular carcinoma, exosome, tumor microenvironment, targeted therapy

Jinbao Chen,1,&ast; Wentao Wu,1,&ast; Xue He,1 Linlin Jia,1 Jiahua Yang,1 Xianke Si,1 Kun Yu,1 Sen Li,1 Yanyan Qiu,1 Ke Xu,2 Peihao Yin,1,3 Yijun Cao,1 Qiong Li,4 Wei Li1 1Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Institute of Translational Medicine, Shanghai University, Shanghai, People’s Republic of China; 3Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei LiDepartment of General Surgery, Putuo Hospital, Shanghai University of Traditional, Chinese Medicine, Shanghai, 200062, People’s Republic of ChinaEmail liwei1511972@163.comQiong LiDepartment of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201100, People’s Republic of ChinaEmail 1030190686@qq.comPurpose: As rapidly dividing cells are usually the target of anticancer chemotherapy, it is inevitable that rapidly dividing normal cells become damaged, with myelosuppressive effects being a serious side effect of this therapy. Many recent studies have found that exosomal microRNAs (miRNAs) are related to the occurrence of some diseases.Patients and Methods: Small RNA sequencing was used to investigate differential exosomal miRNAs with the same expression trend between groups after chemotherapy: MildA (before chemotherapy in patients with mild myelosuppression) and MildB (after chemotherapy in patients with mild myelosuppression); SevereA (before chemotherapy in patients with severe myelosuppression) and SevereB (after chemotherapy in patients with severe myelosuppression). A Venn diagram was generated to screen exosomal miRNAs related to chemotherapy. Small RNA sequencing was also used to investigate differentially expressed exosomal miRNAs among these groups, and exosomal miRNAs related to myelosuppression after chemotherapy was explored using a Venn diagram. RT-qPCR was applied to further verify the sequencing results. We performed target gene prediction and functional analysis for candidate exosomal miRNAs.Results: Compared with that in the MildA or SevereA group, an increase in exosomal miR-122-5p was found in the MildB or SevereB group, and the expression level was lower in the SevereB group than in the MildB group. However, we found no notable difference in its expression level between the MildA and SevereA groups. Similar results were not obtained for the remaining miRNAs. RT-qPCR confirmed the screening results. Further analyses indicated that exosomal miR-122-5p targets CDK4 to inhibit the cell cycle.Conclusion: The expression level of exosomal miR-122-5p in the serum of patients with colorectal cancer correlates with the severity of myelosuppression caused by chemotherapy, and miR-122-5p targets CDK4 to inhibit cell cycle progression.Keywords: colorectal cancer, chemotherapy, myelosuppression, miR-122-5p

Qian Liang,1– 3,* Haofei Hu,4,* Han Wu,1– 3 Xuan Chen,1– 3 Wei Wang,1– 3 Ying Le,1– 3 Shufen Yang,1– 3 Lijing Jia1– 3 1Department of Endocrinology, Shenzhen People’s Hospital, Shenzhen, 518020, Guangdong Province, People’s Republic of China; 2Department of Endocrinology, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518020, Guangdong Province, People’s Republic of China; 3Department of Endocrinology, The Second Affiliated Hospital of Jinan University, Shenzhen, 518020, Guangdong Province, People’s Republic of China; 4Department of Nephrology, Shenzhen Second People’s Hospital, Shenzhen, 518000, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lijing JiaDepartment of Endocrinology, Shenzhen People’s Hospital, 1017 Dongmen North Road, Luohu District, Shenzhen, Guangdong Province, People’s Republic of ChinaEmail srmyynfmk@126.comBackground: Diabetic kidney disease often presents as increased urine albumin to creatinine ratio (UACR). 25-hydroxyvitamin D (25(OH)D) is considered as the best indicator of vitamin D status. Previous studies have shown that 25(OH)D is related to the UACR. However, evidence concerning the connection between 25(OH)D and UACR is still limited in the Chinese population.Materials and Methods: A total of 549 participants with type 2 diabetes were enrolled in the study from Shenzhen People’s Hospital, China. The participants were grouped by the tertiles of 25(OH)D level. The association between 25(OH)D and UACR was examined by multiple linear regression. A generalized additive model (GAM) was used to verify a non-linear relationship. We conducted a subgroup analysis to evaluate the robustness of the results.Results: After adjusting for relevant variables, 25(OH)D was negatively correlated with UACR (β = − 8.7, 95% CI (− 12.0, − 5.4)). A non-linear relationship was discovered between 25(OH)D and UACR, and the 25(OH)D threshold was 67. The effect sizes and confidence intervals on the left and right sides of the inflection point were − 13.9 (− 18.2, − 9.6) and 8.9 (− 1.1, 18.9), respectively. Subgroup analysis showed a stronger correlation could be detected in males. The same trend also could be found in patients older than 70 years old, those with using ACEI/ARB, with history of hypertension, with SBP ≥ 140 mmHg and eGFR < 60 mL/min/1.73m2.Conclusion: The relationship between 25(OH)D and UACR is non-linear. 25(OH)D was negatively related to UACR when 25(OH)D is less than 67 nmol/L.Keywords: 25-hydroxyvitamin D, urine albumin to creatinine ratio, nonlinearity

Most patients with end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) choose hemodialysis as their treatment of choice. Thus, upper-extremity veins provide a functioning arteriovenous access to reduce dependence on central venous catheters. However, it is unknown whether CKD reprograms the transcriptome of veins and primes them for arteriovenous fistula (AVF) failure. To examine this, we performed transcriptomic analyses of bulk RNA sequencing data of veins isolated from 48 CKD patients and 20 non-CKD controls and made the following findings: (1) CKD converts veins into immune organs by upregulating 13 cytokine and chemokine genes, and over 50 canonical and noncanonical secretome genes; (2) CKD increases innate immune responses by upregulating 12 innate immune response genes and 18 cell membrane protein genes for increased intercellular communication, such as CX3CR1 chemokine signaling; (3) CKD upregulates five endoplasmic reticulum protein-coding genes and three mitochondrial genes, impairing mitochondrial bioenergetics and inducing immunometabolic reprogramming; (4) CKD reprograms fibrogenic processes in veins by upregulating 20 fibroblast genes and 6 fibrogenic factors, priming the vein for AVF failure; (5) CKD reprograms numerous cell death and survival programs; (6) CKD reprograms protein kinase signal transduction pathways and upregulates SRPK3 and CHKB; and (7) CKD reprograms vein transcriptomes and upregulates MYCN, AP1, and 11 other transcription factors for embryonic organ development, positive regulation of developmental growth, and muscle structure development in veins. These results provide novel insights on the roles of veins as immune endocrine organs and the effect of CKD in upregulating secretomes and driving immune and vascular cell differentiation.

It has been our pleasure to have been able to develop two special issues within the International Journal of Molecular Sciences: (1) Renin-Angiotensin-Aldosterone System in Pathologies and (2) Renin-Angiotensin-Aldosterone System in Metabolism & Disease [...]

Microfibers are key components in construction of fiber-based materials, biomimetic materials, microsensors, and other fiber-based microstructures. Due to the scaling law, the adhesion forces such as van der Waals force or electrostatic force in the micro world play a more dominant role than the gravity, causing difficulties in precise pick-and-place of the micro objects. In this paper, we propose a capillary force-based pick-and-place method for handling microfibers. The method combines the typical robotic transportation technique and capillary gripping method to achieve fast and accurate pick-and-place of microfibers. We quantitatively analyzed the critical conditions for capillary pick-up and placement of microfibers and validated the technique experimentally. The theoretical analysis indicates that both pick-up and the placement of microfibers are largely dependent on the contact length on the fiber or the contact angle of the meniscus on the substrate. The experimental results show that the microfibers can be reliably picked up from and placed on the substrate of different materials including paper tissue, glass, silicon, stainless steel, copper with droplet volume of 0.1 nL and 0.3 nL. We further applied the method to the placement of the microfibers on super hydrophilic-super hydrophobic grooves and studied its placement speed and accuracy. We demonstrated that microfiber can be placed in such grooves in less than 0.1 seconds, with linear placement accuracy of $10~\mu \text{m}$ and angular placement accuracy of 0.5°. The proposed method is fast and simple, and it is especially suitable for handling fragile and flexible micro sized objects and construction of fiber-based materials.

Yanping Shi,1 Li Jia,2 Hongli Wen2 1Department of Gynaecology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, Henan 450003, People’s Republic of China; 2Department of Gynaecology, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, People’s Republic of ChinaCorrespondence: Li Jia Tel +86 17784307991Email jerney1985@163.comBackground: Endometrial cancer (EC) is one of the most common gynecological malignancies. Circular RNAs (circRNAs) play crucial roles in the occurrence and development of tumors. This research aimed to explore the function and potential mechanism of human serum albumin (hsa)_circ_0109046 in EC.Materials and Methods: The abundance of circ_0109046, microRNA-136 (miR-136) and high-mobility group AT-hook 2 (HMGA2) was detected by quantitative real-time polymerase chain reaction or Western blot. Cell counting kit-8 (CCK-8) and colony formation assays were employed to assess cell proliferation. Transwell assay was used to measure cell migration and invasion. The levels of E-cadherin, Vimentin and N-cadherin were examined by Western blot. The binding association among circ_0109046, miR-136 and HMGA2 was verified by dual-luciferase reporter assay, RNA pull-down assay and RNA immunoprecipitation assay. Xenograft assay was performed to test tumor growth in vivo.Results: Circ_0109046 and HMGA2 were up-regulated, and miR-136 was down-regulated in EC tissues and cells. Knockdown of circ_0109046 impeded the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of EC cells. Moreover, miR-136 knockdown reversed the suppression of circ_0109046 silencing on EC development. HMGA2 overexpression abolished the inhibition of miR-136 on EC progression. Besides, depletion of circ_0109046 inhibited EC growth in vivo.Conclusion: Circ_0109046 accelerated EC progression via modulating miR-136/HMGA2 axis, indicating that circ_0109046 might be a promising therapeutic target for EC.Keywords: circ_0109046, miR-136, HMGA2, endometrial cancer

Runzhi Guo,1 Yiping Huang,1 Hao Liu,1 Yunfei Zheng,1 Lingfei Jia,2 Weiran Li1,3 1Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, People’s Republic of China; 2Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, People’s Republic of China; 3National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing 100081, People’s Republic of ChinaCorrespondence: Yiping Huang Department of OrthodonticsPeking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, People’s Republic of ChinaTel/ Fax +86-10-82195775Email hyp891213@163.comWeiran LiDepartment of Orthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing 100081, People’s Republic of ChinaTel/ Fax +86-10-82195332Email weiranli@bjmu.edu.cnPurpose: Periodontitis is the leading cause of tooth loss. The role of long non-coding RNA (lncRNA) in periodontal inflammation remains unclear. The aim of this study was to investigate the role of lncRNA H19 in periodontitis and its possible regulation of autophagy in periodontitis.Material and Methods: Inflammation level was determined by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) in periodontal ligament cells (PDLCs). Western blotting, flow cytometric analysis, and immunofluorescence staining were used to detect the autophagy flux. Overexpression or knockdown of H19 was used to confirm its function. Ligature-induced periodontitis model in mice and periodontitis-affected human gingival tissue were used in vivo. RNA sequencing was performed to determine the differentially expressed genes.Results: Autophagy was significantly increased in PDLCs after inflammatory stimulation as well as in a ligature-induced periodontitis model in mice and periodontitis-affected human gingival tissue. During the inflammatory process, H19 expression was also significantly upregulated. Further, the levels of autophagic markers were significantly upregulated after overexpressing H19 in PDLCs, and the increased autophagic activity induced by inflammatory stimulation was reversed by H19 knockdown. RNA sequencing showed that the expression profiles of mRNAs were significantly altered after H19 overexpression, and the differentially expressed genes were enriched in the PI3K/AKT signaling pathway, which was confirmed by the decreased p-AKT protein expression in the H19 overexpression group.Conclusion: Periodontal inflammation activates autophagy flux, and H19 mediates the activation of autophagy via AKT pathway in periodontitis. This study expands our understanding of molecular regulation in periodontitis.Keywords: autophagy, periodontitis, long non-coding RNA

Suoyi Feng,1,2 Longzhu Ju,1 Ziqi Shao,1,3 Mark Grzanna,2 Lu Jia,4 Ming Liu5 1College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province 150030, People’s Republic of China; 2Science Department, The John Carroll School, Bel Air, Maryland, USA; 3College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei Province 430070, People’s Republic of China; 4School of Basic Medical Science, Shanxi University of Traditional Chinese Medicine, Jinzhong, Shanxi Province 030619, People’s Republic of China; 5State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang Province 150069, People’s Republic of ChinaCorrespondence: Suoyi FengScience Department, The John Carroll School, 703 E Churchville Road, Bel Air, Maryland 21014, USAEmail fengsuoyi2001@hotmail.comMing LiuState Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, 678 Haping Road, Harbin, Heilongjiang Province 150069, People’s Republic of ChinaEmail liuming04@126.comObjective and Design: Allergic rhinitis (AR) is an immunoglobulin E (IgE)-mediated inflammatory respiratory hypersensitivity characterized by elevated Th2 cytokines and infiltration of inflammatory cells to nasal tissues. BX471 is a small-molecule C-C chemokine receptor type 1 (CCR1) antagonist involved in suppression of inflammation via blocking of primary ligands. In this study, we examined the anti-inflammatory effect of BX471 on ovalbumin (OVA)-induced AR mice model.Materials and Methods: Levels of OVA-specific IgE and Th1 cytokines were determined by enzyme-linked immunosorbent assay (ELISA). Nasal expression of proinflammatory mediators was assessed by real-time polymerase chain reaction (RT-qPCR). Nasal-cavity sections were stained with hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) to study eosinophil infiltration and goblet cell metaplasia. Relative protein levels of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB), Toll-like Receptor 4 (TLR4) and Toll-like-receptor 2 (TLR2) were assessed by Western Blot. Percentage of CD4+CD25+Foxp3+ T regulatory cells (Treg) was measured by flow cytometry.Results: Mice treated with BX471 showed significantly relieved sneezing and nasal-rubbing behaviors. The expression of nasal proinflammatory factors was significantly downregulated by BX471, and protein levels of tumor necrosis factor alpha (TNF- α) and NF-kB were suppressed. Blockade of CCR1 ligands inhibited eosinophil recruitment in nasal cavity. In addition, Treg cells population were upregulated in BX471-treated mice.Conclusion: BX471 exerts anti-inflammatory effects in a mouse model of AR by inhibiting CCR1-mediated TNF-α production, which subsequently suppresses NF-kB activation in inflammatory cells, leading to a decrease in Th2 cytokines, IL-1β, VCAM-1, GM-CSF, RANTES, and MIP-1α expression levels, thus inhibiting eosinophil recruitment to nasal mucosa. In addition, BX-471 exhibits anti-allergic effect by increasing Treg cell population. Overall, BX471 represents a promising therapeutic strategy against AR.Keywords: allergic rhinitis (AR), inflammation, C-C chemokine receptor type 1 antagonist, cytokines, chemokines

Jing Wang,1 Guangxiao Ni,2 Yanming Liu,3 Ying Han,4 Lin Jia,5 Yali Wang1,6 1Department of Chinese Medicine Diagnostics, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, People’s Republic of China; 2Department of Rehabilitation Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People’s Republic of China; 3College of Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, People’s Republic of China; 4Department of Chinese Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, People’s Republic of China; 5Department of Respiratory Diseases, Hebei Province Hospital of Traditional Chinese Medicine, Shijiazhuang, Hebei 050000, People’s Republic of China; 6College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, People’s Republic of ChinaCorrespondence: Yali WangDepartment of Chinese Medicine Diagnostics, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, Hebei 050200, People’s Republic of ChinaEmail lvyihongni1988@163.comPurpose: The aim of this study was to evaluate the neuroprotective effect of tanshinone IIA (TSA) on focal cerebral ischemia in rats and to investigate whether it was associated with Nogo-A/NgR1/RhoA/Rho-associated protein kinase 2 (ROCKII)/myosin light chain (MLC) signaling.Methods: In this study, focal cerebral ischemia animal model was used. Neurological deficit scores and infarction volume were investigated to evaluate the neuroprotection of TSA. Hematoxylin-eosin staining, Nissl staining, and immunofluorescence staining were conducted to detect ischemic changes in brain tissue and changes in neurofilament protein 200 (NF200) and growth-associated protein-43 (GAP-43) expression, respectively. Western blotting and qRT-PCR analyses were used to detect the expression levels of NF200, GAP-43 and Nogo-A/NgR1/RhoA/ROCKII/MLC pathway-related signaling molecules.Results: TSA treatment can improve the survival rate of rats, reduce the neurological score and infarct volume, and reduce neuron damage. In addition, TSA also increased axon length and enhanced expression of NF200 and GAP-43. Importantly, TSA significantly attenuated the expression of Nogo-A, NgR1, RhoA, ROCKII, and p-MLC, and thus inhibiting the activation of this signaling pathway.Conclusion: TSA promoted axonal regeneration by inhibiting the Nogo-A/NgR1/RhoA/ROCKII/MLC signaling pathway, thereby exerting neuroprotective effects in cerebral ischemia rats, which provided support for the clinical application of TSA in stroke treatment.Keywords: tanshinone IIA, cerebral ischemia, axonal regeneration, neuroprotective effect, neurite outgrowth inhibitor-A, Nogo receptor, Rho-associated protein kinase

Contrary to public perception, hypertension remains one of the most important public health problems in the United States, affecting 46% of adults with increased risk for heart attack, stroke, and kidney diseases. The mechanisms underlying poorly controlled hypertension remain incompletely understood. Recent development in the Cre/LoxP approach to study gain or loss of function of a particular gene has significantly helped advance our new insights into the role of proximal tubule angiotensin II (Ang II) and its AT1 (AT1a) receptors in basal blood pressure control and the development of Ang II-induced hypertension. This novel approach has provided us and others with an important tool to generate novel mouse models with proximal tubule-specific loss (deletion) or gain of the function (overexpression). The objective of this invited review article is to review and discuss recent findings using novel genetically modifying proximal tubule-specific mouse models. These new studies have consistently demonstrated that deletion of AT1 (AT1a) receptors or its direct downstream target Na+/H+ exchanger 3 (NHE3) selectively in the proximal tubules of the kidney lowers basal blood pressure, increases the pressure-natriuresis response, and induces natriuretic responses, whereas overexpression of an intracellular Ang II fusion protein or AT1 (AT1a) receptors selectively in the proximal tubules increases proximal tubule Na+ reabsorption, impairs the pressure-natriuresis response, and elevates blood pressure. Furthermore, the development of Ang II-induced hypertension by systemic Ang II infusion or by proximal tubule-specific overexpression of an intracellular Ang II fusion protein was attenuated in mutant mice with proximal tubule-specific deletion of AT1 (AT1a) receptors or NHE3. Thus, these recent studies provide evidence for and new insights into the important roles of intratubular Ang II via AT1 (AT1a) receptors and NHE3 in the proximal tubules in maintaining basal blood pressure homeostasis and the development of Ang II-induced hypertension.

Jian Liu,1,2 Doudou Zhang,1,2 Shu Lian,1,2 Junxia Zheng,1,2 Bifei Li,1,2 Tao Li,1,2 Lee Jia1,2 1Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis, State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou 350002, China; 2Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou 350002, China Background: Gefitinib (Gef), an important epidermal growth factor receptor (EGFR), is used to treat lung cancer, but low water solubility and poor bioavailability severely limit its application in cancer therapy.Methods: In this study, nano-graphene oxide (NGO) was decorated with hyaluronic acid (HA) by a linker cystamine dihydrochloride containing disulfide bonds (-SS-), followed by the incorporation of gefitinib, thus, constructing a HA-functionalized GO-based gefitinib delivery system (NGO-SS-HA-Gef). Subsequently, studies of biological experiments in vitro and in vivo were performed to investigate the therapeutic effect of the system in lung cancer.Results: The HA-grafted GO nanosheets possessed enhanced physiological stability, admirable biocompatibility, and no obvious side effects in mice and could act as a nanocarrier for the delivery of gefitinib to tumor. Cellular uptake and intracellular cargo release assays showed that the uptake of NGO-SS-HA by A549 cells was facilitated via CD44 receptor-mediated endocytosis, and that more drug was released from NGO-SS-HA in the presence of GSH than in the absence of GSH. The target-specific binding of NGO-SS-HA to cancer cells with redox-responsive cargo release significantly enhanced the abilities of gefitinib-loaded GO nanosheets to induce cell apoptosis, suppress cell proliferation, and inhibit tumor growth in lung cancer cell-bearing mice.Conclusion: The results demonstrated the potential utility of NGO-SS-HA-Gef for therapeutic applications in the treatment of lung cancer. Keywords: nano-graphene oxide, gefitinib, hyaluronic acid, CD44, redox-responsive

Lijun Shen,1,2* Miao Mo,2,3* Leon Jia,4 Huixun Jia,2,3 Qingguo Li,2,5 Lei Liang,2,5 Debing Shi,2,5 Zhen Zhang,1,2 Sanjun Cai,2,5 Xinxiang Li,2,5 Ji Zhu1,2 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; 3Department of Cancer Prevention, Fudan University Shanghai Cancer Center, Shanghai, China; 4Virginia Commonwealth University, Richmond, VA, USA; 5Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China *These authors contributed equally to this work Purpose: To investigate the association of age and sex on survival in non-metastatic colorectal cancer (CRC) patients and to identify groups at high risk for poor outcomes.Materials and methods: We performed a retrospective analysis of 5,047 non-metastatic CRC patients from 2008 to 2013. Data regarding age at diagnosis; gender; tumor site; tumor stage; differentiation; lymphatic, neural or vascular invasion; and survival outcomes were collected. Patients were stratified into 10-year age groups (≤35, 36–45, 46–55, 56–65, 66–75, >75) and then further analyzed in three age groups (≤35, 36–75, >75). Disease-free survival (DFS) and overall survival (OS) were evaluated using univariate and multivariate Cox regression models.Results: Of the 5,047 eligible patients, 41.3% were female. The tumor stages were balanced between the genders. In the female patients, the tumor stages were similarly distributed among the different age groups, while younger male patients were diagnosed with more advanced disease (P75 had shorter DFS than patients between 36 and 75 years old (HR=1.57 [1.03–2.38] and HR=1.51 [1.11–2.05, respectively]), while there was no difference in DFS between females ≤35 and those >75. For male patients, older age was associated with poorer OS after the same adjustment.Conclusion: Young female CRC patients (≤35 years old) had the poorest DFS and quite poor OS compared to the other age groups. This emphasizes the need for health care providers to have a heightened awareness and to conduct further research when caring for young female CRC patients. Keywords: colorectal cancer, young female, prognosis, China

Li Kang,1,2 Peipei Han,2 Jiazhong Wang,2 Yixuan Ma,2 Liye Jia,2 Liyuan Fu,2 Hairui Yu,2 Xiaoyu Chen,2 Kaijun Niu,3,4 Qi Guo1,2 1Department of Rehabilitation Medicine, Tianjin Economic-Technological Development Area International Cardiovascular Hospital, Cardiovascular Clinical College of Tianjin Medical University, 2Department of Rehabilitation Medicine, 3Nutritional Epidemiology Institute, 4School of Public Health, Tianjin Medical University, Tianjin, China Purpose: Falling is a major health problem in community-dwelling elderly individuals. The aim of the present study was to conduct a prospective investigation to evaluate the accuracy of the Timed Up and Go Test (TUGT), 4-meter walking test, and grip strength test to screen for the risk of falls and to determine a cutoff point to be used clinically.Patients and methods: This was a prospective study that included 541 participants. The fall data were obtained via face-to-face interview, and the date, site, and circumstances of any falls were recorded. TUGTs were recorded as part of a comprehensive geriatric assessment. We collected the same data at baseline and after follow-up via comprehensive geriatric assessment.Results: The incidence of falls of our study subjects was 20.8%. The recurrent-fall group had a fall rate of 6.8% during the follow-up year. The standard area under the curve (AUC) of our screening tool was >0.70, and hence our tool can be used for clinical purposes. After adjusting for age and gender, the AUC of TUGT became 0.642, so it cannot be used as a predictive tool for measuring any types of falls. However, when recurrent falls were adjusted for age and gender, the TUGT’s AUC improved to 0.733 and a score of 15.96 seconds is used as a cut-point to screen recurrent falls in community-dwelling elderly Chinese individuals.Conclusion: Future falls were best predicted by TUGT in recurrent fallers at baseline. A score of 15.96 seconds is used as a cut-point to screen recurrent falls in community-dwelling elderly Chinese individuals. Keywords: community dwelling, elderly, fall, TUGT

Zhi-xiang Yuan,1,* Lu Jia,2,* Lee Yong Lim,3 Ju-chun Lin,1 Gang Shu,1 Ling Zhao,1 Gang Ye,1 Xiao-xia Liang,1 Hongming Ji,2 Hua-lin Fu1 1Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, 2Department of Neurosurgery, Shanxi Provincial People’ Hospital, Taiyuan, China; 3Pharmacy, Centre for Optimization of Medicines, School of Allied Health, The University of Western Australia, Crawley, Australia *These authors contributed equally to this work Abstract: Previously, 3,5-dipentadecyloxybenzamidine hydrochloride (TRX-20)-modified liposomes were reported to specifically target mesangial cells (MCs) in glomeruli. To further gain a better understanding of the characteristics and potential application for glomerular diseases of TRX-20-modified liposomes, we synthesized TRX-20 and prepared TRX-20-modified liposomes (TRX-LPs) with different molar ratios – 6% (6%-TRX-LP), 11% (11%-TRX-LP), and 14% (14%-TRX-LP) – of TRX-20 to total lipid in the present study. All TRX-LPs exhibited concentration-dependent toxicity against the MCs at a lipid concentration ranging from 0.01 to 1.0 mg/mL with IC50 values of 3.45, 1.13, and 0.55 mg/mL, respectively. Comparison of the cell viability of TRX-LPs indicated that high levels of TRX-20 caused severe cell mortality, with 11%-TRX-LP showing the higher cytoplasmic accumulation in the MCs. Triptolide (TP) as a model drug was first loaded into 11%-TRX-LP and the liposomes were further modified with PEG5000 (PEG-TRX-TP-LP) in an attempt to prolong their circulation in blood and enhance TP-mediated immune suppression. Due to specific binding to MCs, PEG-TRX-TP-LP undoubtedly showed better anti-inflammatory action in vitro, evidenced by the inhibition of release of nitric oxide (NO) and tumor necrosis factor-α from lipopolysaccharide-stimulated MCs, compared with free TP at the same dose. In vivo, the PEG-TRX-TP-LP effectively attenuated the symptoms of membranous nephropathic (MN) rats and improved biochemical markers including proteinuria, serum cholesterol, and albumin. Therefore, it can be concluded that the TRX-modified liposome is an effective platform to target the delivery of TP to glomeruli for the treatment of MN. Keywords: triptolide, pegylated liposomes, TRX-20, renal targeting, mesangial cells

Yan Di,1 Ting Li,1 Zhihong Zhu,1 Fen Chen,2 Lianqun Jia,2 Wenbing Liu,3 Xiumei Gai,1 Yingying Wang,1 Weisan Pan,1 Xinggang Yang1 1Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 2Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, 3Key Laboratory of Structure-Based Drug Design & Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang, China Abstract: The aim of this study was to simultaneously introduce pH sensitivity and folic acid (FA) targeting into a micelle system to achieve quick drug release and to enhance its accumulation in tumor cells. Paclitaxel-(+)-α-tocopherol (PTX-VE)-loaded mixed micelles (PHIS/FA/PM) fabricated by poly(ethylene glycol) methyl ether-poly(histidine) (MPEG-PHIS) and folic acid-poly(ethylene glycol)-(+)-α-tocopherol (FA-PEG-VE) were characterized by dynamic light scattering and transmission electron microscopy (TEM). The mixed micelles had a spherical morphology with an average diameter of 137.0±6.70 nm and a zeta potential of -48.7±4.25 mV. The drug encapsulation and loading efficiencies were 91.06%±2.45% and 5.28%±0.30%, respectively. The pH sensitivity was confirmed by changes in particle size, critical micelle concentration, and transmittance as a function of pH. MTT assay showed that PHIS/FA/PM had higher cytotoxicity at pH 6.0 than at pH 7.4, and lower cytotoxicity in the presence of free FA. Confocal laser scanning microscope images demonstrated a time-dependent and FA-inhibited cellular uptake. In vivo imaging confirmed that the mixed micelles targeted accumulation at tumor sites and the tumor inhibition rate was 85.97%. The results proved that the mixed micelle system fabricated by MPEG-PHIS and FA-PEG-VE is a promising approach to improve antitumor efficacy. Keywords: pH sensitive, folic acid targeting, mixed micelles, drug delivery, in vivo antitumor activity

Compatible taper and volume models were created for Quercus variabilis Blume (cork oak) forests in North China. 174 trees were felled to obtain stem analysis data. Linear mixed effects analyses were used in modelling. Firstly, a bark thickness model was built. Then diameter at breast height over bark (DBHob) for the inner layers of the 174 trees could be calculated, based on which a total volume model was built. The estimated volume and a specific parameter restriction were then substituted into a polynomial taper model, finally the taper model was fitted and compatible taper and volume models were obtained. Four sets of models based on different data sets were separately built and compared through coefficients of determination (R2), root mean square error (RMSE), value of Akaike’s information criterion (AIC), residuals plots and histograms of residuals. Models based on data of the analyzed stems without ramicorns and simultaneously with relative diameter under 1.5 were chosen as the most precise. Further testing of the chosen models using the jackknife method for the bark thickness and total volume models and a validation data set for the taper model verified that those models can be used to predict bark thickness, diameter at a specific point along the stem, merchantable volume and total stem volume of cork oak forests in North China within specific tree diameter at breast height and height ranges.

Linpei Jia,1–3 Weiguang Zhang,2,3 Xiangmei Chen1–3 1Department of Nephrology, Second Hospital of Jilin University, Changchun, Jilin Province, 2Department of Nephrology, Chinese People’s Liberation Army General Hospital, Beijing, 3State Key Laboratory of Kidney Disease, Chinese People’s Liberation Army General Hospital, Beijing, People’s Republic of China Abstract: At present, no single indicator could be used as a golden index to estimate aging process. The biological age (BA), which combines several important biomarkers with mathematical modeling, has been proposed for >50 years as an aging estimation method to replace chronological age (CA). The common methods used for BA estimation include the multiple linear regression (MLR), the principal component analysis (PCA), the Hochschild’s method, and the Klemera and Doubal’s method (KDM). The fundamental differences in these four methods are the roles of CA and the selection criteria of aging biomarkers. In MLR and PCA, CA is treated as the selection criterion and an independent index. The Hochschild’s method and KDM share a similar concept, making CA an independent variable. Previous studies have either simply constructed the BA model by one or compared the four methods together. However, reviews have yet to illustrate and compare the four methods systematically. Since the BA model is a potential estimation of aging for clinical use, such as predicting onset and prognosis of diseases, improving the elderly’s living qualities, and realizing successful aging, here we summarize previous BA studies, illustrate the basic statistical steps, and thoroughly discuss the comparisons among the four common BA estimation methods. Keywords: chronological age, statistical method, aging biomarker, statistical model

See Article Kemp et al

Tao Zhou,1 Lei Jia,1 Yi-Feng Luo,2 Jun Xu,1 Ru-Hua Chen,2 Zhi-Jun Ge,2 Tie-Liang Ma,2 Hong Chen,2 Tao-Feng Zhu2 1Department of Physics and Chemistry, Henan Polytechnic University, Jiaozuo, Henan, 2The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, People’s Republic of China Abstract: A novel multifunctional halloysite nanotube (HNT)-based Fe3O4@HNT-polyethyleneimine-Tip-Eu(dibenzoylmethane)3 nanocomposite (Fe-HNT-Eu NC) with both photoluminescent and magnetic properties was fabricated by a simple one-step hydrothermal process combined with the coupling grafting method, which exhibited high suspension stability and excellent photophysical behavior. The as-prepared multifunctional Fe-HNT-Eu NC was characterized using various techniques. The results of cell viability assay, cell morphological observation, and in vivo toxicity assay indicated that the NC exhibited excellent biocompatibility over the studied concentration range, suggesting that the obtained Fe-HNT-Eu NC was a suitable material for bioimaging and biological applications in human hepatic adenocarcinoma cells. Furthermore, the biocompatible Fe-HNT-Eu NC displayed superparamagnetic behavior with high saturation magnetization and also functioned as a magnetic resonance imaging (MRI) contrast agent in vitro and in vivo. The results of the MRI tests indicated that the Fe-HNT-Eu NC can significantly decrease the T2 signal intensity values of the normal liver tissue and thus make the boundary between the normal liver and transplanted cancer more distinct, thus effectively improving the diagnosis effect of cancers. Keywords: halloysite nanotube, lanthanide complex, iron oxide, luminescence, contrast agent

Feihu Wang1, Yuxuan Chen2, Dianrui Zhang1, Qiang Zhang3, Dandan Zheng1, Leilei Hao1, Yue Liu1, Cunxian Duan1, Lejiao Jia1, Guangpu Liu11Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan, People’s Republic of China; 2Department of Pharmacy, Shenzhou Hospital, Shenyang, People’s Republic of China; 3State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of ChinaBackground: A critical disadvantage for successful chemotherapy with paclitaxel (PTX) is its nontargeting nature to cancer cells. Folic acid has been employed as a targeting ligand of various anticancer agents to increase their cellular uptake within target cells since the folate receptor is overexpressed on the surface of such tumor cells. In this study, a novel biodegradable deoxycholic acid-O-carboxymethylated chitosan–folic acid conjugate (DOMC-FA) was used to form micelles for encapsulating the anticancer drug PTX.Methods and results: The drug-loading efficiency, encapsulation efficiency, in vitro drug release and physicochemical properties of PTX-loaded micelles were investigated in detail. In vitro cell culture studies were carried out in MCF-7 cells, a human breast carcinoma cell line, with folate receptor overexpressed on its surface. An increased level of uptake of folate-conjugated micelles compared to plain micelles in MCF-7 cells was observed, and the enhanced uptake of folate-micelles mainly on account of the effective process of folate receptor-mediated endocytosis. The MTT assay, morphological changes, and apoptosis test implied that the folate-conjugated micelles enhanced the cell death by folate-mediated active internalization, and the cytotoxicity of the FA-micellar PTX (DOMC-FA/PTX) to cancer cells was much higher than micelles without folate (DOMC/PTX) or the commercially available injectable preparation of PTX (Taxol).Conclusion: Results indicate that the PTX-loaded DOMC-FA micelle is a successful anticancer-targeted drug-delivery system for effective cancer chemotherapy.Keywords: paclitaxel, folate, polymeric micelles, targeted delivery

Drug induced liver injury (DILI) is an idiosyncratic adverse drug reaction leading to severe liver damage. Kupffer cells (KC) sense hepatic tissue stress/damage and therefore could be a tool for the estimation of consequent effects associated with DILI. Aim of the present study was to establish a human in vitro liver model for the investigation of immune-mediated signaling in the pathogenesis of DILI. Hepatocytes and KC were isolated from human liver specimens. The isolated KC yield was 1.2±0.9×106 cells/g liver tissue with a purity of >80%. KC activation was investigated by the measurement of reactive oxygen intermediates (ROI, DCF assay) and cell activity (XTT assay). The initial KC activation levels showed broad donor variability. Additional activation of KC using supernatants of hepatocytes treated with hepatotoxic drugs increased KC activity and led to donor-dependent changes in the formation of ROI compared to KC incubated with supernatants from untreated hepatocytes. Additionally, a compound- and donor-dependent increase in proinflammatory cytokines or in anti-inflammatory cytokines was detected. In conclusion, KC related immune signaling in hepatotoxicity was successfully determined in a newly established in vitro liver model. KC were able to detect hepatocyte stress/damage and to transmit a donor- and compound-dependent immune response via cytokine production.

The renin-angiotensin system (RAS) is well recognized as one of the oldest and most important regulators of arterial blood pressure, cardiovascular and renal function. New frontiers have recently emerged in the RAS research well beyond its classic paradigm as a potent vasoconstrictor, an aldosterone release stimulator, or a sodium-retaining hormone. First, two new members of the RAS have been uncovered, which include the renin/(Pro)renin receptor (PRR) and angiotensin-converting enzyme 2 (ACE2). Recent studies suggest that prorenin may act on the PRR independent of the classical ACE/ANG II/AT1 receptor axis, whereas ACE2 may degrade ANG II to generate ANG (1-7), which activates the Mas receptor. Second, there is increasing evidence that ANG II may function as an intracellular peptide to activate intracellular and/or nuclear receptors. Third, currently there is a debate on the relative contribution of systemic versus intrarenal RAS to the physiological regulation of blood pressure and the development of hypertension. The objectives of this article are to review and discuss the new insights and perspectives derived from recent studies using novel transgenic mice that either overexpress or are deficient of one key enzyme, ANG peptide, or receptor of the RAS. This information may help us better understand how ANG II acts, both independently or through interactions with other members of the system, to regulate the kidney function and blood pressure in health and disease.