Search

Danyang Fan, Fuqiu Li, Zhe Liu, Zhanhan Tang, Sha Lv Department of Dermatology, The Second Hospital of Jilin University, Changchun, Jilin, 130000, People’s Republic of ChinaCorrespondence: Sha Lv, Department of Dermatology, The second hospital of Jilin University, Changchun, Jilin, 130000, People’s Republic of China, Email lvsha@jlu.edu.cnAbstract: Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare chronic inflammatory disease mainly manifested as skin and osteoarticular lesions. Herein, we describe a female patient with SAPHO syndrome exhibited paradoxical psoriasis and primary palmoplantar pustulosis (PPP) worsened during treatment with adalimumab. We then switched to secukinumab and obtained significant improvement in both skin lesions and osteoarticular pain. These findings suggest that secukinumab might be an appropriate option for patients with SAPHO syndrome who present with TNF-α-inhibitor-induced paradoxical psoriasis.Keywords: SAPHO syndrome, psoriasis, adalimumab, secukinumab

Daopeng Fan,1,* Shuqi Wang,1,* Ran Huang,1,* Xiaoning Liu,1 Hua He,1 Gaiping Zhang1– 3 1College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, People’s Republic of China; 2Longhu Laboratory, Zhengzhou, 450046, People’s Republic of China; 3School of Advanced Agriculture Sciences, Peking University, Beijing, 100871, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hua He, College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, People’s Republic of China, Email hhe@henau.edu.cnBackground: Nanomedicine presents a promising alternative for cancer treatment owing to its outstanding features. However, the therapeutic outcome is still severely compromised by low tumor targeting, loading efficiency, and non-specific drug release.Methods: Light-assisted “nano-neutrophils (NMPC-NPs)”, featuring high drug loading, self-amplified tumor targeting, and light-triggered specific drug release, were developed. NMPC-NPs were composed of neutrophil membrane-camouflaged PLGA nanoparticles (NPs) loaded with a hypoxia-responsive, quinone-modified PTX dimeric prodrug (hQ-PTX2) and photosensitizer (Ce6).Results: hQ-PTX2 significantly enhanced the drug loading of NPs by preventing intermolecular π–π interactions, and neutrophil membrane coating imparted the biological characteristics of neutrophils to NMPC-NPs, thus improving the stability and inflammation-targeting ability of NMPC-NPs. Under light irradiation, extensive NMPC-NPs were recruited to tumor sites based on photodynamic therapy (PDT)-amplified intratumoral inflammatory signals for targeted drug delivery to inflammatory tumors. Besides, PDT could effectively eliminate tumor cells via reactive oxygen species (ROS) generation, while the PDT-aggravated hypoxic environment accelerated hQ-PTX2 degradation to realize the specific release of PTX, thus synergistically combining chemotherapy and PDT to suppress tumor growth and metastasis with minimal adverse effects.Conclusion: This nanoplatform provides a prospective and effective avenue toward enhanced tumor-targeted delivery and synergistic cancer therapy.Keywords: neutrophil, self-amplified tumor targeting, high drug loading, hypoxia-responsive, chemo-photodynamic therapy

Ran Huang,1,* Daopeng Fan,1,* Hanghang Cheng,1 Jian Huo,1 Shuqi Wang,1 Hua He,1 Gaiping Zhang1,2 1College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, People’s Republic of China; 2Longhu Laboratory, Zhengzhou, 450046, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hua He, College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, People’s Republic of China, Email hehua1123@126.com Gaiping Zhang, College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, People’s Republic of China, Email zhanggaip@126.comBackground: Advanced breast cancer is a highly metastatic tumor with high mortality. Simultaneous elimination of primary tumor and inhibition of neutrophil-circulation tumor cells (CTCs) cluster formation are urgent issues for cancer therapy. Unfortunately, the drug delivery efficiency to tumors and anti-metastasis efficacy of nanomedicine are far from satisfactory.Methods: To address these problems, we designed a multi-site attack, neutrophil membrane-camouflaged nanoplatform encapsulating hypoxia-responsive dimeric prodrug hQ-MMAE2 (hQNM-PLGA) for enhanced cancer and anti-metastasis therapy.Results: Encouraged by the natural tendency of neutrophils to inflammatory tumor sites, hQNM-PLGA nanoparticles (NPs) could target delivery of drug to tumor, and the acute hypoxic environment of advanced 4T1 breast tumor promoted hQ-MMAE2 degradation to release MMAE, thus eliminating the primary tumor cells to achieve remarkable anticancer efficacy. Alternatively, NM-PLGA NPs inherited the similar adhesion proteins of neutrophils so that NPs could compete with neutrophils to interrupt the formation of neutrophil-CTC clusters, leading to a reduction in extravasation of CTCs and inhibition of tumor metastasis. The in vivo results further revealed that hQNM-PLGA NPs possessed a perfect safety and ability to inhibit tumor growth and spontaneous lung metastasis.Conclusion: This study demonstrates the multi-site attack strategy provides a prospective avenue with the potential to improve anticancer and anti-metastasis therapeutic efficacy.Keywords: neutrophil membrane, high drug loading, hypoxia-responsive, CTC-neutrophil cluster, cancer and anti-metastasis therapy

Fei Wu,1– 3,* Jie Chen,4,* Kang Yao,1 Daming Fan,5 Minglei Wang,2 Yongjun Liu,1 Shouhu Xin,1 Zeqiang Sun,1 Shun Li,1 Yang Sun,6 Qingyong Liu1 1Department of Urology, the First Affiliated Hospital of Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250014, People’s Republic of China; 2Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of China; 3Department of Urology, Shandong Provincial Hospital, Shandong First Medical University, Jinan, 250021, People’s Republic of China; 4Department of Urology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250013, People’s Republic of China; 5Department of Pathology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250013, People’s Republic of China; 6Department of Dermatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yang Sun; Qingyong Liu, Email sunyang@qiluhospital.com; liuqingyong@sdhospital.com.cnIntroduction: A primary impediment to the efficacy of immune checkpoint inhibitors is the lack of biomarkers for therapeutic responses and prognosis. Although patients with clear cell renal cell carcinoma (ccRCC) could be precisely selected for targeted therapy based on somatic mutations, it remains controversial to choose the suitable patients with a high response rate to immune checkpoint inhibitors (ICIs). The immune-dependent roles of tumor suppressor PTEN in the formation of tumor immune microenvironment remain elusive.Methods: We comprehensively analyzed the genomic and transcriptomic data from multiple ccRCC datasets, including bulk-RNA sequencing and single-cell RNA sequencing data. In vitro, immunoblotting, qRT-PCR, and RNA sequencing were conducted in ccRCC cell lines upon PTEN depletion. Gene ontology and gene set enrichment analysis were performed to screen the critical pathway and molecules in response to PTEN deletion. Immunohistochemistry staining and further bioinformatic analysis were used to validate our data.Results: Based on multi-omics analysis of public datasets of renal cancer, the frequently mutated or deleted PTEN was found to be correlated with a suppressive tumor immune microenvironment in ccRCC. Furthermore, we depleted PTEN via CRISPR-Cas9 in Caki-1 cells, which led to the upregulation of multiple neutrophil chemokines, particularly CXCL1, CXCL2, CXCL5, CXCL6, and CXCL8. The roles of neutrophil chemokines and neutrophil markers were further validated and investigated for the association with prognosis in vitro, clinical samples, and the publicly available databases. The expression of CXCL1, CXCL8, and neutrophil markers, S100A9 and BCL2A1, were significantly associated with a poor immunotherapy-related prognosis in public dataset of renal cancer patients receiving ICIs treatment.Conclusion: These results add a new layer to understanding the association between PTEN status and the role of neutrophil infiltration in ccRCC. Moreover, our findings propose low expression of PTEN as candidate factor of resistance to anti-PD-1-based immunotherapy in ccRCC.Keywords: PTEN, kidney cancer, CXCL1, renal cancer, prognosis

Pengsheng Li,1,2,&ast; Haiyan Wang,2,3,&ast; Jinping Feng,2 Gengdong Chen,1,2 Zixing Zhou,1,2 Xiaoyan Gou,2,3 Shaoxin Ye,1,2 Dazhi Fan,1,2 Zhengping Liu,1,2 Xiaoling Guo2 1Foshan Fetal Medicine Research Institute, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, People’s Republic of China; 2Department of Obstetrics, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, People’s Republic of China; 3Biobank, Foshan Fetal Medicine Research Institute, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoling GuoDepartment of Obstetrics, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University Email fsguoxl@163.comPurpose: Prenatal depressive symptoms are an important mental health problem during pregnancy. We aimed to explore the moderating role of social support on the association between perceived stress and prenatal depressive symptoms.Materials and Methods: A cross-sectional study was conducted at an obstetrics clinic. A total of 1846 women completed a self-administered questionnaire, with a response rate of 91.8%.Results: Of the 1846 participants, 28.2% reported prenatal depressive symptoms (Edinburgh postnatal depression scale score ≥ 9). After adjusting for demographic characteristics, gestational age, exercise, and passive smoking, both perceived stress (adjusted odds ratio (AOR): 1.210, 95% confidence interval (CI): 1.178– 1.242) and social support (AOR: 0.950, 95% CI: 0.932– 0.968) were associated with prenatal depressive symptoms. Moreover, social support had a moderating effect on the association between perceived stress and prenatal depressive symptoms (p < 0.001), and pregnant women with low social support were more likely to be affected by stress and experience prenatal depressive symptoms.Conclusion: Our study suggests that higher social support reduces the impact of stress on pregnant women, which in turn, decreases the risk of prenatal depressive symptoms. Therefore, interventions aimed at improving social support should be considered for the prevention and treatment of prenatal depressive symptoms.Keywords: prenatal depressive symptoms, stress, social support, moderation

Jiaming Rao,1 Dazhi Fan,1 Zixing Zhou,1 Xin Luo,1 Huiting Ma,1 Yingchun Wan,1 Xiuyin Shen,1 Dongxin Lin,1 Huishan Zhang,1 Yan Liu,2 Zhengping Liu1,2 1Foshan Fetal Medicine Institute, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University (Foshan Maternity & Child Healthcare Hospital), Foshan, Guangdong, 528000, People’s Republic of China; 2Department of Obstetrics, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University (Foshan Maternity & Child Healthcare Hospital), Foshan, Guangdong, 528000, People’s Republic of ChinaCorrespondence: Zhengping Liu; Yan LiuFoshan Fetal Medicine Institute and Department of Obstetrics, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University (Foshan Maternity & Child Healthcare Hospital), Renminxi Road 11, Foshan, Guangdong, 528000, People’s Republic of ChinaTel +86 757 82969878Fax +86 757 82969772Email liuzphlk81@outlook.com; liuyan20102011@163.comBackground: To compare the maternal and neonatal outcomes of placenta previa (PP) with and without coverage of a uterine scar in Foshan, China.Methods: A retrospective cohort study comparing all singleton pregnancies with PP was conducted at a tertiary, university-affiliated medical center from 1 January 2012 to 31 April 2017 in Foshan, China. Demographic, clinical and laboratory data were extracted from electronic medical records (EMRs). Maternal and neonatal outcomes of PP with and without coverage of a uterine scar were compared by statistical method.Results: There were 58,062 deliveries during the study period, of which 726 (1.25%) were complicated PP in singleton pregnancies and were further classified into two groups: the PP with coverage of a uterine scar group (PPCS, n=154) and the PP without coverage of a uterine scar group (Non-PPCS, n=572). Overall, premature birth (< 37 weeks, 67.5% vs 54.8%; P=0.019), cesarean section (100% vs 97.6%; P=0.050), intraoperative blood loss > 1000 mL (77.9% vs 16.0%; P< 0.001) or > 3000mL (29.9% vs 3.0%; P< 0.001), bleeding within 2-24 hours after delivery (168.2± 370.1 ml vs 49.9± 58.4 ml; P< 0.001), postpartum hemorrhage (48.7% vs 15.7%; P< 0.001), transfusion (34.6% vs 16.1%; P< 0.001), hemorrhage shock (7.8% vs 1.9%; P< 0.001), hysterectomy (2.6% vs 0.5%; P=0.019), fetal distress (35.7% vs 12.1%; P< 0.001) and APGAR score at 1 min (15.2% vs 7.1%; P=0.002) had a significant difference between PPCS group and Non-PPCS group. After grouping by whether complicated with placenta accreta spectrum disorders (PASD), we found that PPCS was significant associated with more intraoperative blood loss > 1000mL, intraoperative blood loss > 3000mL, bleeding within 2– 24 hours after delivery and fetal distress than the Non-PPCS group.Conclusion: The PPCS group had poorer maternal and neonatal outcomes than the Non-PPCS group after grouping by whether pregnancies complicated with PASD or with different placental positions.Keywords: placenta previa, placenta accreta spectrum disorders, pregnancy outcomes, uterine scar, hysterectomy, cesarean section

Pengsheng Li,1,2,* Haiyan Wang,1,2,* Gengdong Chen,1,2 Jinping Feng,1 Dazhi Fan,1,2 Dongxin Lin,1,2 Jiaming Rao,1,2 Zixing Zhou,1,2 Zhengping Liu,1,2 Xiaoling Guo1 1Department of Obstetrics, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, People’s Republic of China; 2Foshan Fetal Medicine Research Institute, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoling GuoDepartment of Obstetrics, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, People’s Republic of ChinaEmail fsguoxl@163.comPurpose: Nausea and vomiting during pregnancy (NVP) of varying degrees of severity are commonly experienced by pregnant women. This paper explores the association between NVP and poor sleep quality.Patients and Methods: A cross-sectional study was conducted in an obstetrics clinic. A total of 2494 pregnant women (representing a response rate of 92.7%) completed a self-administered questionnaire.Results: Of the 2494 participants, the mean sleep duration was 7.76 hours, and 54.3% of them report poor sleep quality (ie, a Pittsburgh Sleep Quality Index global score > 5). In this study, 49.1%, 49.3% and 1.6% women reported mild, moderate, and severe NVP, respectively. Compare with women with mild NVP, women with moderate or severe NVP were more likely to report poor sleep quality (χ2 = 30.16, p < 0.001). After adjusted for demographics and gestational age, moderate and severe NVP were associated with poor sleep quality (adjusted odds ratio (AOR) = 1.66, 95% confidence interval (CI) = 1.40– 1.96, and AOR = 2.95, 95% CI = 1.44– 6.02, respectively). Moreover, depressive symptoms mediated the association between NVP and poor sleep quality (β = 0.060, p = 0.033, 95% CI = 0.028– 0.180).Conclusion: Our study suggested that moderate and severe NVP increase the risk of poor sleep quality. Further studies are warranted that focus on the mechanisms of the association between NVP and poor sleep quality.Keywords: nausea, vomiting, pregnancy, sleep quality, depressive symptoms

Jianfeng Bao,1,2 Xiangyang Zu,2 Xiao Wang,1 Jinghua Li,2 Dandan Fan,3 Yupeng Shi,1 Qingchun Xia,4 Jingliang Cheng1 1Functional Magnetic Resonance and Molecular Imaging Key Laboratory of Henan Province, Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2College of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, Henan, People’s Republic of China; 3Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 4Henan Key Laboratory of Boron Chemistry and Advanced Energy Materials, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, People’s Republic of ChinaCorrespondence: Jingliang ChengThe First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaTel +86-13603863860Fax +86-37166964992Email cjr.chjl@vip.163.comQingchun XiaHenan Normal University, Xinxiang, Henan, People’s Republic of ChinaTel +86-13353679807Fax +86-3733329030Email xiaqingchun@htu.edu.cnBackground: Recent studies have validated and confirmed the great potential of nanoscale metal-organic framework (NMOF) in the biomedical field, especially in improving the efficiency of cancer diagnosis and therapy. However, most previous studies only utilized either the metal cluster or the organic ligand of the NMOF for cancer treatments and merely reported limited theranostic functions, which may not be optimized. As a highly designable and easily functionalized material, prospective rational design offers a powerful way to extract the maximum benefit from NMOF for cancer theranostic applications.Materials and Methods: A NMOF based on hafnium (Hf) cluster and Mn(III)-porphyrin ligand was rational designed and synthesized as a high-performance multifunctional theranostic agent. The folic acid (FA) was modified on the NMOF surface to enhance the cancer targeting efficacy. The proposed “all-in-one” FA-Hf-Mn-NMOF (fHMNM) was characterized and identified using various analytical techniques. Then, in vitro and in vivo studies were performed to further explore the effects of fHMNM both as the magnetic resonance imaging (MRI)/computed tomography (CT)/photoacoustic imaging (PAI) contrast agent and as the photothermal therapy (PTT)/radiotherapy (RT) agent.Results: A tumour targeting multifunctional fHMNM was successfully synthesized with high performance for MRI/CT/PAI enhancements and image-guided PTT/RT synergistic therapy properties. Compared with the current clinical CT and MR contrast agents, the X-ray attenuation and T1 relaxation rate of this integrated nanosystem increased 1.7-fold and 3– 5-fold, respectively. More importantly, the catalase-like Mn(III)-porphyrin ligand can decompose H2O2 into O2 in tumour microenvironments to improve the synergistic treatment efficiency of PTT and RT. Significant tumour growth inhibition was achieved in mouse cancer models without obvious damage to the other organs.Conclusion: This work highlights the potential of fHMNM as an easily designable material for biomedical applications, could be an effective tool for in vivo detection and subsequent treatment of tumour.Keywords: metal-organic framework, theranostics, multimodality imaging, radiotherapy, photothermal therapy

Yanan Dong,1–3 Rongzhan Fu,1–3 Jing Yang,1–3 Pei Ma,1–3 Lihua Liang,2 Yu Mi,1–3 Daidi Fan1–31Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi 710069, People’s Republic of China; 2Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi 710069, People’s Republic of China; 3Biotech & Biomed Research Institute, Northwest University, Xi’an, Shaanxi 710069, People’s Republic of ChinaCorrespondence: Yu Mi; Daidi FanShaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an, Shaanxi 710069, People’s Republic of ChinaEmail mi_yu@nwu.edu.cn; fandaidi@nwu.edu.cnBackground and purpose: Ginsenoside Rg5 (Rg5), a triterpene saponin, extracted from the natural herbal plant ginseng, is one of the most potent anticancer drugs against various carcinoma cells. However, the therapeutic potential of Rg5 is limited by its low solubility in water, poor bioavailability, and nontargeted delivery. Therefore, we prepared folic acid (FA)-modified bovine serum albumin (BSA) nanoparticles (FA-Rg5-BSA NPs) to improve the therapeutic efficacy and tumor targetability of Rg5.Methods: Various aspects of the FA-Rg5-BSA NPs were characterized, including size, polydispersity, zeta potential, morphology, entrapment efficiency (EE), drug loading (DL), in vitro drug release, thermal stability, in vitro cytotoxicity, cell apoptosis, cellular uptake, in vivo antitumor effects and in vivo biodistribution imaging.Results: The FA-Rg5-BSA NPs showed a particle size of 201.4 nm with a polydispersity index of 0.081, uniform spherical shape, and drug loading of 12.64±4.02%. The aqueous solution of FA-Rg5-BSA NPs had favorable stability for 8 weeks at 4°C. The FA-Rg5-BSA NPs dissolved under acidic conditions. Moreover, the Rg5-BSA NPs and FA-Rg5-BSA NPs had advanced anticancer activity compared with Rg5 in MCF-7 cells, while poor cytotoxicity was observed in L929 cells. The FA-Rg5-BSA NPs facilitated cellular uptake and induced apoptosis in MCF-7 cells. In addition, in an MCF-7 xenograft mouse model, the in vivo antitumor evaluation revealed that FA-Rg5-BSA NPs were more effective in inhibiting tumor growth than Rg5 and Rg5-BSA NPs. The in vivo real-time bioimaging study showed that the FA-Rg5-BSA NPs exhibited superior tumor accumulation ability.Conclusion: The results suggested that FA-Rg5-BSA NPs could serve as a promising system to improve the antitumor effect of Rg5.Keywords: ginsenoside Rg5, drug delivery, nanoparticles, antitumor activity, human MCF-7 breast cancer cells

Wanli Yang,1,* Jiaojiao Ma,1,* Wei Zhou,1,* Zichao Li,2 Xin Zhou,2 Bo Cao,2 Yujie Zhang,1 Jinqiang Liu,1 Zhiping Yang,1 Hongwei Zhang,3 Qingchuan Zhao,3 Liu Hong,1 Daiming Fan1 1State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China; 2The First Brigade of Student, Air Force Military Medical University, Xi’an, China; 3Department of Digestive Surgery, Xijing Hospital, Air Force Military Medical University, Xi’an, China *These authors contributed equally to this work Background: Colon cancer is one of the leading malignant neoplasms worldwide. Until now, the concrete mechanisms of colonic cancerogenesis are largely unknown; identification of driven genes and pathways is, therefore, of great importance for monitoring and conquering this disease. This study aims to explore the potential biomarkers and therapeutic targets for colon cancer treatment. Methods: The gene expression profile of GSE44076 from Gene Expression Omnibus database, including 98 primary colon cancers and 98 normal distant colon mucosa, was deeply analyzed. GEO2R tool was used to screen the differentially expressed genes (DEGs) between colon cancer tissues and normal samples. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed for screening DEGs using Database for Annotation, Visualization and Integrated Discovery database and Panther database. Moreover, Search Tool for the Retrieval of Interacting Genes, Cytoscape software, and Molecular Complex Detection plug-in were used to visualize the protein–protein interaction of these DEGs. Results: A total of 497 DEGs were obtained, including 129 upregulated genes mainly enriched in Hippo signaling pathway, Wnt signaling pathway, and cytokine–cytokine receptor interaction and 368 downregulated genes enriched in retinol metabolism, steroid hormone biosynthesis, drug metabolism, and chemical carcinogenesis. Using Molecular Complex Detection software, three important modules were selected from the protein–protein interaction network. Moreover, 20 hub genes with high degree of connectivity were selected, including COL1A1, CXCL5, GNG4, TIMP1, and so on. The Kaplan–Meier analysis for overall survival and correlation analysis were applied among the hub genes. Conclusion: Taken together, DEGs, especially the hub genes such as COL1A1, might be the driven genes in colon cancer progression. More importantly, they might be the novel biomarkers for diagnosis and guiding therapeutic strategies of colon cancer. Keywords: colon cancer, protein–protein interaction, bioinformatics analysis, diagnosis, prognosis

Lina Tang,1,* Chunling Zhang,2,* Hairong He,3 Zhenyu Pan,3,4 Di Fan,1 Yinli He,1 Haisheng You,1 Yuanjie Li5 1Department of Pharmacy, The First Affiliated Hospital, Xi’an Jiao Tong University, Xi’an, China; 2Department of Pharmacy, Hong-Hui Hospital, Xi’an Jiao Tong University College of Medicine, Xi’an, China; 3Clinical Research Center, The First Affiliated Hospital, Xi’an Jiao Tong University, Xi’an, China; 4Department of Pharmacy, Xi’an Jiao Tong University Affiliated Children’s Hospital, Xi’an, China; 5Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi’an Jiao Tong University Health Science Center, Xi’an, China *These authors contributed equally to this work Background: Gefitinib is frequently used to treat patients with non-small cell lung cancer (NSCLC) and is excreted out from cells via the ATP-binding cassette transporter ABCG2. ABCG2 gene polymorphisms have been suggested to be associated with ABCG2 protein expression and function and may influence the risk of gefitinib toxicity in NSCLC patients. Previous studies on the associations between ABCG2 gene polymorphisms and the toxicity of gefitinib in NSCLC patients have produced conflicting results. The aim of this meta-analysis was to determine whether ABCG2 gene polymorphisms are associated with the risk of gefitinib-induced toxicity in NSCLC patients.Methods: The PubMed and EMBASE databases were searched systematically for all eligible studies. A relative risk with corresponding 95% CI was calculated to evaluate the associations between ABCG2 gene polymorphisms and gefitinib-induced toxicity.Results: Data were finally extracted from seven studies and 515 patients were found to meet the inclusion criteria of the meta-analysis. A dominant model showed that there was no significant association between the ABCG2 C421A polymorphism and the risk of gefitinib-induced toxicity, while the ABCG2 G34A polymorphism might be associated with an increased risk of skin toxicity in gefitinib therapy (relative risk =1.54, 95% CI 1.08–2.21, P=0.02). However, more reliable data are required to confirm the associations between the ABCG2 C421A and ABCG2 G34A polymorphisms and the toxicity of gefitinib in NSCLC patients.Conclusion: While the ABCG2 C421A polymorphism might not be a reliable marker of gefitinib-related toxicity, the ABCG2 G34A genotype may be predictive of the skin toxicity of gefitinib in NSCLC patients. These conclusions need to be verified in further large-scale studies. Keywords: gefitinib, ABCG2, meta-analysis, polymorphism, toxicity, NSCLC

Si Zeng,1,* Hui Qiao,2,* Xue-wen Lv,1 Dan Fan,1 Tong Liu,1 Dongli Xie1 1Department of Anesthesiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, 2Department of Anesthesiology, The Eye and ENT Hospital of Fudan University, Shanghai, China *These authors contributed equally to this work Abstract: Prolonged administration of an excessive dose of corticosteroids proved to be harmful for patients with acute lung injury (ALI). A previous study has found that repeated administration of an excessive dose of methylprednisolone reduced alveolar macrophages (AMs) in bronchoalveolar lavage fluid (BALF) with an unknown mechanism. This study aimed to investigate the effect of excessive use of dexamethasone (Dex) on BALF AMs in vitro. Transmission electron microscopy and DNA fragmentation analysis demonstrated that 10–4 and 10–5 M Dex induced lipopolysaccharide-stimulated rat AMs apoptosis with downregulation of tumor necrosis factor-α, interleukin (IL)-12 and upregulation of IL-10, transforming growth factor-β. These results indicated that apoptosis might be a novel contribution involved in the detrimental effect of excessive dose of Dex clinically used to treat ALI. Keywords: dexamethasone, alveolar macrophage, lipopolysaccharide, acute lung injury, apoptosis, inflammatory cytokines

Zhengquan Feng,1,2 Wanrong Hao,3 Xiaoyang Lin,3 Daping Fan,4 Juhua Zhou5 1Department of Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China; 2Department of Oncology, Guang An Men Hospital, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China; 3Department of Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China; 4Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC, USA; 5Institute for Tumor Immunology, Ludong University College of Life Sciences, Yantai, Shandong, People's Republic of China Objective: To determine the antitumor activity of Radix tetrastigmae flavonoids and their inhibitory effect on regulatory T cells (Tregs) in mice. Materials and methods: Total flavonoids were isolated from Radix tetrastigmae, the root of Tetrastigma hemsleyanum Diels et Gilg, and administered to C57BL/6 mice by oral gavage after inoculation with Lewis lung carcinoma (LLC) cells. The effects of total flavonoids on tumor growth in vivo were examined. Flow cytometry was used to study the effects on Tregs, and enzyme-linked immunosorbent assay was used to analyze the changes in the serum levels of transforming growth factor ß, prostaglandin E2, and cyclooxygenase 2 after tumor inoculation and flavonoid administration. Results: Total flavonoids from T. hemsleyanum Diels et Gilg significantly inhibited tumor growth in C57BL/6 mice inoculated with LLCs. These flavonoids dramatically suppressed regulatory T-cell development in tumor-bearing mice. Further studies revealed that total flavonoids significantly decreased the serum levels of transforming growth factor β, prostaglandin E2, and cyclooxygenase 2 in tumor-bearing mice, which may be responsible for the inhibition of Tregs. Conclusion: The antitumor activity of total flavonoids from T. hemsleyanum Diels et Gilg is associated with the inhibition of Tregs in a mouse tumor model. Total flavonoids from T. hemsleyanum Diels et Gilg may be used as antitumor agents in cancer prevention and treatment. Keywords: flavonoids, radix tetrastigmae, regulatory T cells, tumor growth, TGF-β1

Yanzhi Song,1 Qingjing Tian,1 Zhenjun Huang,1 Di Fan,1 Zhennan She,1 Xinrong Liu,1 Xiaobo Cheng,1 Bin Yu,2 Yihui Deng11College of Pharmacy, Shenyang Pharmaceutical University, 2Liaoning Medical Device Test Institute, Shenyang, People’s Republic of ChinaAbstract: Despite being one of the most promising amphiphilic block copolymers, use of Pluronic F68 in drug delivery is limited due to its high critical micelle concentration (CMC). In this study, we developed a novel F68 derivative, cholesterol-coupled F68 (F68-CHMC). This new derivative has a CMC of 10 µg/mL, which is 400-fold lower than that of F68. The drug-loading capacity of F68-CHMC was investigated by encapsulating cabazitaxel, a novel antitumor drug. Drug-loaded micelles were fabricated by a self-assembly method with simple dilution. The optimum particle size of the micelles was 17.5±2.1 nm, with an entrapment efficiency of 98.1% and a drug loading efficiency of 3.16%. In vitro release studies demonstrated that cabazitaxel-loaded F68-CHMC micelles had delayed and sustained-release properties. A cytotoxicity assay of S180 cells showed that blank F68-CHMC was noncytotoxic with a cell viability of nearly 100%, even at a concentration of 1,000 µg/mL. The IC50 revealed that cabazitaxel-loaded F68-CHMC micelles were more cytotoxic than Tween 80-based cabazitaxel solution and free cabazitaxel. In vivo antitumor activity against S180 cells also indicated better tumor inhibition by the micelles (79.2%) than by Tween 80 solution (56.2%, P

By analyzing the convergence of the retrieved effective electromagnetic parameters, we presented that one wavelength of the propagating wave in the nanostructure is the minimum thickness requirement for effectively characterizing a finite thickness nanostructure. This thickness condition has been separately validated in a photonic crystal with negative refraction and in a typical fishnet metamaterial which has been investigated theoretically and experimentally before.

The optical path lengths travelled by rays across a wavefront essentially determine the resulting phase front irrespective of the shape of a medium according to the principle of equal optical path. Thereupon we propose a method for the transformation between two arbitrary wavefronts by a slab, i.e. the profile of the spatial separation between the two wavefronts is taken to be transformed to a plane surface. Interestingly, for the mutual conversion between planar and curved wavefronts, the method reduce to an inverse transformation method in which it is the reversed shape of the desired wavefront that is converted to a planar one. As an application, three kinds of phase transformation are realized and it is found that the transformation on phase is able to realize some important properties such as phase reversal or compensation, focusing, and expanding or compressing beams, which are further confirmed by numerical simulations. The slab can be applied to realizing compact electromagnetic devices for which the values of the refractive index or the permittivity and permeability can be high or low, positive or negative, or near zero, depending on the choice of coordinate transformations.

Modelling long-time convective flows in the interiors of stars is extremely challenging using conventional compressible hydrodynamics codes due to the acoustic timestep limitation. Many of these flows are in the low Mach number regime, which allows us to exploit the relationship between acoustic and advective time scales to develop a more computationally efficient approach. MAESTROeX is an open source low Mach number stellar hydrodynamics code that allows much larger timesteps to be taken, therefore enabling systems to be modelled for much longer periods of time. This is particularly important for the problem of convection in the cores of rotating massive stars prior to core collapse. To fully capture the dynamics, it is necessary to model these systems in three dimensions at high resolution over many rotational periods. We present an overview of MAESTROeX's current capabilities, describe ongoing work to incorporate the effects of rotation and discuss how we are optimising the code to run on GPUs.

We present MAESTROeX, a massively parallel solver for low Mach number astrophysical flows. The underlying low Mach number equation set allows for efficient, long-time integration for highly subsonic flows compared to compressible approaches. MAESTROeX is suitable for modeling full spherical stars as well as well as planar simulations of dynamics within localized regions of a star, and can robustly handle several orders of magnitude of density and pressure stratification. Previously, we have described the development of the predecessor of MAESTROeX, called MAESTRO, in a series of papers. Here, we present a new, greatly simplified temporal integration scheme that retains the same order of accuracy as our previous approaches. We also explore the use of alternative spatial mapping of the one-dimensional base state onto the full Cartesian grid. The code leverages the new AMReX software framework for block-structured adaptive mesh refinement (AMR) applications, allowing for scalability to large fractions of leadership-class machines. Using our previous studies on the convective phase of single-degenerate progenitor models of SNe Ia as a guide, we characterize the performance of the code and validate the new algorithmic features. Like MAESTRO, MAESTROeX is fully open source.

This paper describes the second data release (DR2) of the Beijing-Arizona Sky Survey (BASS). BASS is an imaging survey covering a 5400 deg2 footprint in the g and r bands using the 2.3 m Bok telescope. DR2 includes the observations through 2017 July obtained by BASS and by the Mayall z-band Legacy Survey (MzLS), which used the 4 m Mayall telescope to observe the same footprint. BASS and MzLS have completed 72% and 76% of their observations. The two surveys will be served for the spectroscopic targeting of the upcoming Dark Energy Spectroscopic Instrument. Both BASS and MzLS data are reduced by the same pipeline. We have updated the basic data reduction and photometric calibrations in DR2. In particular, source detections are performed on stacked images, and photometric measurements are co-added from single-epoch images based on these sources. The median 5σ point-source depths after Galactic extinction corrections are 24.05, 23.61, and 23.10 mag for the g, r, and z bands, respectively. The DR2 data products include stacked images, co-added catalogs, and single-epoch images and catalogs. The BASS website (http://batc.bao.ac.cn/BASS/) provides detailed information and links to download the data.