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The central engine that powers gamma-ray bursts (GRBs), the most powerful explosions in the universe, is still not identified. Besides hyper-accreting black holes, rapidly spinning and highly magnetized neutron stars, known as millisecond magnetars, have been suggested to power both long and short GRBs. The presence of a magnetar engine following compact star mergers is of particular interest as it would provide essential constraints on the poorly understood equation of state for neutron stars. Indirect indications of a magnetar engine in these merger sources have been observed in the form of plateau features present in the X-ray afterglow light curves of some short GRBs. Additionally, some X-ray transients lacking gamma-ray bursts (GRB-less) have been identified as potential magnetar candidates originating from compact star mergers. Nevertheless, smoking gun evidence is still lacking for a magnetar engine in short GRBs, and the associated theoretical challenges have been addressed. Here we present a comprehensive analysis of the broad-band prompt emission data of a peculiar, very bright GRB 230307A. Despite its apparently long duration, the prompt emission and host galaxy properties point toward a compact star merger origin, being consistent with its association with a kilonova. More intriguingly, an extended X-ray emission component emerges as the $\gamma$-ray emission dies out, signifying the emergence of a magnetar central engine. We also identify an achromatic temporal break in the high-energy band during the prompt emission phase, which was never observed in previous bursts and reveals a narrow jet with half opening angle of approximately $3.4^\circ$., Comment: 44 pages, 10 figures, 5 tables

Cross-kingdom herbal miRNA was first reported in 2012. Using a modified herbal extraction protocol, we obtained 73,677,287 sequences by RNA-seq from 245 traditional Chinese Medicine (TCM), of which 20,758,257 were unique sequences. We constructed a Bencao (herbal) small RNA (sRNA) Atlas ( http://bencao.bmicc.cn ), annotated the sequences by sequence-based clustering, and created a nomenclature system for Bencao sRNAs. The profiles of 21,757 miRNAs in the Atlas were highly consistent with those of plant miRNAs in miRBase. Using software tools, our results demonstrated that all human genes might be regulated by sRNAs from the Bencao sRNA Atlas, part of the predicted human target genes were experimentally validated, suggesting that Bencao sRNAs might be one of the main bioactive components of herbal medicines. We established roadmaps for oligonucleotide drugs development and optimization of TCM prescriptions. Moreover, the decoctosome, a lipo-nano particle consisting of 0.5%-2.5% of the decoction, demonstrated potent medical effects. We propose a Bencao (herbal) Index, including small-molecule compounds (SM), protein peptides (P), nucleic acid (N), non-nucleic and non-proteinogenic large-molecule compounds (LM) and elements from Mendeleev's periodic table (E), to quantitatively measure the medical effects of botanic medicine. The Bencao sRNA Atlas is a resource for developing gene-targeting oligonucleotide drugs and optimizing botanical medicine, and may provide potential remedies for the theory and practice of one medicine.

Xing-Qi Yin,&ast; Ya-Xin An,&ast; Cai-Guo Yu, Jing Ke, Dong Zhao, Ke Yu Center for Endocrine Metabolism and Immune Diseases, Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ke YuCenter for Endocrine Metabolism and Immune Diseases, Luhe Hospital, Capital Medical University, No. 82, Xinhua South Road, Tongzhou District, Beijing, People’s Republic of China, Tel +86 13811657618, Email yuke@ccmu.edu.cnPurpose: To examine the association of short-chain fatty acids (SCFAs), gut microbiota and obesity in individual twins and to control for genetic and shared environmental effects by studying monozygotic intrapair differences.Patients and Methods: The study recruited 20 pairs of monozygotic twins. Body composition measurements were performed by using the multi-frequency bioelectrical impedance technique. SCFAs were extracted from feces and quantified by gas chromatography-mass spectrometer. Gut microbiota was evaluated by 16S rRNA gene sequencing.Results: Fecal SCFAs were negatively correlated with adiposity parameters including body mass index, visceral adipose tissue and waist circumference (all P < 0.05). Metastat analysis showed that the top 5 relatively abundant bacterial taxa of viscerally obese and non-obese groups were Bacteroides, Collinsella, Eubacterium rectale group, Lachnoclostridium, and Tyzzerella. Participants with visceral obesity had lower abundance of Bacteroides and Collinsella compared to non-obese patients (P < 0.05). Among them, the abundance of Collinsella was positively correlated with acetic acid concentrations (r = 0.63, P = 0.011). There were no significant intrapair differences in each SCFA concentrations between the twins in our study (P > 0.05).Conclusion: Low fecal concentrations of SCFAs were associated with visceral obesity, and the gut microbiota might be involved in the underlying mechanism.Keywords: twins, short-chain fatty acids, gut microbiota, obesity, visceral fat

Jiachan Zhang,1 Changtao Wang,1 Quan An,2 Qianghua Quan,2 Meng Li,2 Dan Zhao1 1Beijing Key Lab of Plant Resource Research and Development, College of chemistry and materials engineering, Beijing Technology and Business University, Beijing, 100048, People’s Republic of China; 2Yunnan Baiyao Group Co., Ltd., Kunming, 650000, People’s Republic of ChinaCorrespondence: Changtao Wang, Beijing Key Lab of Plant Resource Research and Development, College of chemistry and materials engineering, Beijing Technology and Business University, Fucheng Road, Beijing, 100048, People’s Republic of China, Tel +8610-68984917, Email wangct@th.btbu.edu.cn Quan An, Yunnan Baiyao Group Co., Ltd., Kunming, 650000, People’s Republic of China, Email 59304376@qq.comBackground: Pathogenesis and persistence of many skin diseases are related to Staphylococcus aureus (S. aureus) colonization. S. aureus infection can cause varying degrees of changes in cell gene expression, resulting in complex changes in cell phenotype and finally changes in cell life activities.Materials and Methods: The transcriptomes of healthy and Staphylococcus aureus (S. aureus)-infected murine skin tissues were analyzed. We identified 638 differentially expressed genes (DEGs) in the infected tissues compared to the control samples, of which 324 were upregulated and 314 were downregulated, following the criteria of P < 0.01 and |log2FC| > 3. The DEGs were functionally annotated by Gene Ontology (GO), KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway and the protein–protein interaction (PPI) network analyses.Results: The upregulated DEGs were mainly enriched in GO terms, such as response to stimulus, immune system process and signal transduction, as well as in the complement and coagulation cascade pathway. Thus, S. aureus infection likely activates these pathways to limit the influx of neutrophils and prevent skin damage. Four clusters were identified in the PPI network, and the major hubs were mainly related to cell cycle and proliferation, and mostly downregulated. The expression levels of Nox4, Mmrn1, Mcm5, Msx1 and Fgf5 mRNAs were validated by qRT-PCR and found to be consistent with the RNA-Seq data, confirming a strong correlation between the two approaches.Conclusion: The identified genes and pathways are potential drug targets for treating skin inflammation caused by S. aureus and should be investigated further.Keywords: Staphylococcus aureus, inflammation, gene expression profile, transcriptome

Danni Zhao,1 Jonggyu Baek,1 Anne L Hume,2,3 Emily A McPhillips,1 Kate L Lapane1 1Department of Population and Quantitative Health Sciences, UMass Chan Medical School, Worcester, MA, USA; 2Department of Family Medicine, Alpert Medical School, Brown University, Memorial Hospital of Rhode Island, Providence, RI, USA; 3Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, USACorrespondence: Kate L Lapane, Department of Population and Quantitative Health Sciences, UMass Chan Medical School, Worcester, MA, USA, Email kate.lapane@umassmed.eduBackground: Gabapentinoids have been prescribed off-label for almost all types of pain. The geographic variation in the use of gabapentinoids as analgesics remains unknown.Objective: To describe the geographic variation in gabapentinoids, opioids and concurrent use of both for pain by US state and metropolitan statistical area (MSA).Methods: We conducted a cross-sectional study on December 1, 2018, among commercially insured adults aged 18– 64 years without epilepsy or opioid use disorders using IBM® MarketScan® Research Databases. We described the geographic variation in the analgesic regimens (gabapentinoids, opioids and concurrent use of both) by state and MSA, and assessed factors associated with the geographic variation using multilevel logistic regression.Results: We included 9,314,197 beneficiaries; 1.4% had gabapentinoids, 1.5% had opioids and 0.3% had concurrent use of both. The majority of gabapentinoid use lacked an FDA-approved indication. Use of the analgesic regimens varied across states (gabapentinoids (median (interquartile range)): 1.4% (1.2– 1.7%); opioids: 1.5% (1.2– 1.9%); both: 0.3% (0.2– 0.4%)) and MSAs (gabapentinoids: 1.6% (1.3– 2.0%); opioids: 1.8% (1.3– 2.3%); both: 0.3% (0.2– 0.5%)). Demographics explained the largest proportion of the between-state and between-MSA variation. The pattern of the geographic variation in gabapentinoids was similar to that of opioids across states and MSAs.Conclusion: Gabapentinoids were as commonly used as opioids for pain in a commercially insured population (mostly off-label). The geographic variation in gabapentinoids was similar to that of opioids, which suggests that gabapentinoids may be widely used as alternatives or adjuvants to opioids across the US.Keywords: gabapentinoids, opioids, pain, geographic variation

Chunyuan Zheng, Jingjing Meng, Xueling Xiao, Ying Xie, Di Zhao, Honghong Wang Xiangya Nursing School, Central South University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Honghong WangXiangya Nursing School, Central South University, 172 Tongzipo Road, Changsha, Hunan, People’s Republic of ChinaTel +86-731-82650270Fax +86-731-88710136Email honghong_wang@hotmail.comPurpose: People living with HIV (PLWHIV) are susceptible to non-communicable diseases (NCDs) because of aging and infections. This means that the number of non-HIV medications increases, along with issues of polypharmacy and medication-related burden. The purpose of this study was to identify the current situation of polypharmacy and medication-related burden among PLWHIV aged 50 and above, as well as the relation between medication-related burden and antiretroviral therapy (ART) adherence.Patients and Methods: A cross-sectional study was conducted with 185 participants recruited from two HIV clinics in Yuelu District Center for Disease Control (CDC) and Changsha First Hospital in Hunan, China. Participants filled questionnaires about comorbidities, polypharmacy, medication-related burden, ART adherence and sociodemographic characteristics.Results: Among the participants, 40% were receiving polypharmacy, and PLWHIV, who were female (β = 5.946; 95% CI = 1.354, 10.541), had a lower monthly income (β = − 4.777; 95% CI = − 6.923, − 2.632), and took more drugs (β = 2.200; 95% CI = 1.167, 3.233) were more likely to report a higher level of medication-related burden. The score of ART adherence was negatively associated with medication-related burden (rs = − 0.250 p = 0.001).Conclusion: The findings suggest that more attention should be paid to the issues of polypharmacy and targeted interventions should be developed to reduce medication-related burden among older PLWHIV.Keywords: AIDS, aging, comorbidity, potential drug–drug interaction, medication burden, medication adherence

The effective scaling-up of redox flow batteries (RFBs) can be facilitated upon lowering the capital costs. The application of ubiquitous manganese along with hydrogen (known as H2−Mn regenerative fuel cells (RFC)) is seen as an effective solution for this purpose. Here, we aim to evaluate different positive electrodes so as to improve the key performance metrics of the H2/Mn RFC, namely electrolyte utilization, energy efficiency, and peak power densities. Commercially available carbon paper and graphite felt are used to show that the latter provides better key performance indicators (KPIs), which is consistent with the results reported for standard all-vanadium RFBs in the literature. Even better KPIs are obtained when an in-house carbon catalyst layer (CCL) is employed in combination with graphite felt electrodes (e.g., more than 80% energy efficiency, >0.5 W cm−2 peak power density and electrolyte utilization of 20 Ah L−1 for felt and carbon metal fabric (CMF), prepared by means of electrospinning and carbonization, in comparison with about 75% energy efficiency 0.45 W cm−2 peak power density and 11 Ah L−1 electrolyte utilization for felt on its own). It is envisaged that if the electrochemical performance of CCLs can be optimized then it could open up new opportunities for the commercial exploitation of H2−Mn systems.

Diming Zhao,1 Yilin Liu,2 Zhenqiang Xu,3,4 Hechen Shen,1 Shanghao Chen,1 Shijie Zhang,1 Yi Li,1 Haizhou Zhang,3,4 Chengwei Zou,3,4 Xiaochun Ma3,4 1Department of Cardiovascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Ophthalmology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 4Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Xiaochun MaDepartment of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Jinan, 250021, People’s Republic of ChinaTel +8615169196737Email mxcmxc2008@163.comBackground: Hypoplastic left heart syndrome (HLHS) is one of the most complex congenital cardiac malformations, and the molecular mechanism of heart failure (HF) in HLHS is still elusive.Methods: Integrative bioinformatics analysis was performed to unravel the underlying genes and mechanisms involved in HF in HLHS. Microarray dataset GSE23959 was screened out for the differentially expressed genes (DEGs), after which the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were carried out using the Metascape. The protein–protein interaction (PPI) network was generated, and the modules and hub genes were identified with the Cytoscape-plugin. And the integrated network of transcription factor (TF)-DEGs and miRNA-DEGs was constructed, respectively.Results: A total of 210 DEGs were identified, including 135 up-regulated and 75 down-regulated genes. The functional enrichment analysis of DEGs pointed towards the mitochondrial-related biological processes, cellular components, molecular functions and signaling pathways. A PPI network was constructed including 155 nodes as well as 363 edges. And 15 hub genes, such as NDUFB6, UQCRQ, SDHD, ATP5H, were identified based on three topological analysis methods and mitochondrial components and functions were the most relevant. Furthermore, by integrating network interaction construction, 23 TFs (NFKB1, RELA, HIF1A, VHL, GATA1, PPAR-γ, etc.) as well as several miRNAs (hsa-miR-155-5p, hsa-miR-191-5p, hsa-mir-124-3p, hsa-miR-1-3p, etc.) were detected and indicated the possible involvement of NF-κB signaling pathways in mitochondrial dysfunction in HLHS.Conclusion: The present study applied the integrative bioinformatics analysis and revealed the mitochondrial-related key genes, regulatory pathways, TFs and miRNAs underlying the HF in HLHS, which improved the understanding of disease mechanisms and the development of novel therapeutic targets.Keywords: hypoplastic left heart syndrome, differential expression genes, transcription factors, microRNAs, regulatory networks, integrative bioinformatics analysis

Changjuan Li,1,2 Jianwei Mi,1 Fulai Gao,1 Xinying Zhu,1 Miao Su,1 Xiaoli Xie,1 Dongqiang Zhao1 1Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei Province, People’s Republic of China; 2Department of Gastroenterology, The First Hospital of Handan City, Handan, 056002, Hebei Province, People’s Republic of ChinaCorrespondence: Dongqiang ZhaoDepartment of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, He ping West Road, Xinhua District, Shijiazhuang, Hebei Province, 050000, People’s Republic of ChinaTel +86 0311 66636179Email hbzdq1998@163.comPurpose: We aimed to compare the histological and/or cytological diagnostic outcomes of EUS-FNA using 19G and 22G needles for solid pancreatic lesions and to evaluate the feasibility and safety of 19G needle.Patients and Methods: Data from patients with solid pancreatic lesions, who underwent EUS-FNA, were retrospectively retrieved from a single tertiary center from June 2017 to January 2021. The sensitivity, specificity, and accuracy of diagnosis, sample adequacy, number and time of punctures, and adverse events, were compared between the 19G and 22G groups. Univariate and multivariate logistic regression analyses were used to identify optimal factors for a correct histological diagnosis.Results: A total of 186 patients (19G group, n = 90; 22G group, n = 96) were analyzed in the study. The higher sensitivity and accuracy were observed in 19G group than those in the 22G group both in histological evaluation (89.3% vs 76%, p = 0.031; 91.1% vs 79.2%, p = 0.023; respectively) and in the combined histological and cytological evaluations (93.3% vs 81.3%, p = 0.027; 94.4% vs 84.3%, p = 0.027, respectively). However, there were no significant differences in specificity, positive predictive value (PPV), and negative predictive value (NPV). The number of needle passes and the puncture time were significantly lower in the 19G group than that in the 22G group (1.66 ± 0.07 vs 2.25 ± 0.08, p < 0.001; 125.4 ± 4.93s vs 169.0 ± 5.6s p < 0.001; respectively). Only 2 cases were failed in the 19G group and no serious complications occurred. Univariate and multivariate logistic analyses suggested that CA199 levels and needle types are related to the accuracy of the EUS-FNA histological diagnosis.Conclusion: EUS-FNA using a 19G needle is effective and safe for solid pancreatic lesions. Compared with the 22G needle, EUS-FNA with a 19G needle can obtain a better histological diagnostic accuracy of solid pancreatic lesions, and with fewer needle passes and in a shorter time.Keywords: sensitivity, specificity, diagnostic accuracy, histology, cytology

Jiliang Feng,1 Ruidong Zhu,2 Yu Yin,3 Shanshan Wang,1 Lei Zhou,4 Fudong Lv,1 Dawei Zhao5 1Clinical-Pathology Center, Beijing You-An Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 2General Surgical Center, Beijing You-An Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 3Department of Pathology, Anhui Medical University, Hefei, 230032, People’s Republic of China; 4Department of Pathology, First Affiliated Hospital of Bengbu Medical College/Bengbu Medical College, Bengbu, 233004, People’s Republic of China; 5Department of Medical Imaging, Capital Medical University, Beijing, 100069, People’s Republic of ChinaCorrespondence: Jiliang FengClinical-Pathology Center, Beijing You-An Hospital, Capital Medical University, No. 8, Xitoutiao, Youanmenwai Street, FengTai District, Beijing, 100069, People’s Republic of ChinaTel +86-10-83997342Fax +86-10-83997343Email jiliangfeng@ccmu.edu.cnAbstract: The primary epithelial tumors of the liver (PETL) are composed of a series of heterogeneous tumors. Although the classification of PETLs has been updated several times by the World Health Organization, the cellular origins of some tumors in this family remain to be precisely depicted. In addition, certain tumors in different categories have similar histology, molecular phenotypes and biological characteristics, suggesting that they may have the same cellular origin. In this work, a narrative review method was adopted to review the relevant papers. By comparing the expression profiles of biomarkers of liver epithelium at different lineages and stages of differentiation, the cells-of-origin of some major members of the PETL family were reassessed. We propose that 1) hepatic adenomas, hepatocellular carcinomas (HCCs) and pure fetal hepatoblastomas (HBs) share the same spectrum in their cellular origin including the hepatocytic-committed progenitors (HCP) and their differentiated descendants. 2) Bile duct adenomas, peribiliary cysts and intrahepatic cholangiocellular carcinomas (ICCs) can share the same spectrum in their cellular origin including the cholangiocytic-committed progenitors (CCP) and their differentiated descendants. 3) The cells-of-origin of embryonal HBs include liver stem cells (LSCs), hepatoblasts, and transitional cells between them. Embryonal HB with small cell element, small cell undifferentiated HB and small cell neuroendocrine carcinoma of the liver can have the same or similar cells-of-origin from LSC. Embryonal HB lacking the small cell component of the LSC phenotype and presenting both hepatocytic and bile duct/ductule components may originate from actual hepatoblasts/hepatic progenitor cells (HPCs) as the combined HCC-ICC does. 4) Teratoid hepatoblastoma and mixed epithelial/mesenchymal HBs can be derived from the LSCs or even less committed extrahepatic pluripotent stem cell. 5) Many members of the PETLs family, including those derived from LSCs, hepatoblasts/HPCs, early HCPs and CCPs, have neuroendocrine potentiality. Except for those primary hepatic neuroendocrine tumor (PHNET) exhibit hepatocytic and/or cholangiocytic phenotypes, other PHNETs subtype may be derived from the descendants of LSC that differentiate towards the upper digestive tract, pancreas or other lineages.Keywords: HCC, tumor-initiating cell, hepatic progenitor, neuroendocrine tumors, hepatoblastoma

Xiuqin Shi,1,2 Wenjing Cheng,1,3,4 Qian Wang,1 Jiachan Zhang,1,3,4 Changtao Wang,1,3,4 Meng Li,1,3,4 Dan Zhao,1,3,4 Dongdong Wang,1,3,4 Quan An2 1Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, 100048, People’s Republic of China; 2Yunnan Baiyao Group Co., Ltd, Kunming, 650000, People’s Republic of China; 3Beijing Key Lab of Plant Resource Research and Development, Beijing Technology and Business University, Beijing, 100048, People’s Republic of China; 4Institute of Cosmetic Regulatory Science, Beijing Technology and Business University, Beijing, 100048, People’s Republic of ChinaCorrespondence: Jiachan Zhang; Changtao WangCollege of Chemistry and Materials Engineering, Beijing Technology and Business University, 11 Fucheng Road, Haidian District, Beijing, 100048, People’s Republic of ChinaTel +86-13426258535; +86-18910839617Email xiaochan8787@163.com; wangct@th.btbu.edu.cnBackground: Ganoderma lucidum (G. lucidum) is one of China’s traditional medicinal materials. G. lucidum polysaccharide has a wide range of promising pharmacological applications. However, there are many kinds of G. lucidum and they contain different kinds of polysaccharides. The biological mechanism through which Ganoderma lucidum polysaccharides (GLP) is able to protect human skin fibroblasts (HSFs) from H2O2-induced oxidative damage is still unclear.Methods: Six polysaccharides were obtained from G. lucidum to evaluate their free radical scavenging ability (DPPH free radical, ABTS free radical, hydroxyl-free radical, superoxide anion-free radical) in vitro, and their protective and reparative effects on oxidative damage induced by H2O2 in human skin fibroblasts. One polysaccharide was selected to detect oxidative damage markers and gene expression in the Keap1-Nrf2/ARE signaling pathway in HSFs.Results: All six polysaccharides showed the ability to scavenge free radicals and enhance the tolerance of human skin fibroblasts to H2O2 damage. Among them, GLP1 was selected and separated into two components (GLP1I and GLP1II). The results showed that GLP1, GLP1I and GLPII could significantly reduce the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). The protective effect of GLP1II was stronger than that of positive control vitamin C. In addition, GLP1, GLP1I and GLP1II could significantly increase the levels of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). And GLP1I works best in both ways. Meanwhile, Nrf2, a key regulator of keAP1-NRF2/ARE signaling pathway, was activated, while Keap1, a negative regulator, was inhibited, thus promoting the expression of downstream antioxidant enzyme genes (GSTs, GCLs, Nqo1, and Ho-1).Conclusion: The results showed that GLP could protect human skin fibroblasts from oxidative damage caused by H2O2 peroxide by enhancing enzyme activity and activating Keap1-Nrf2/ARE signaling pathway. GLP will act as a natural antioxidant to protect the skin from oxidative stress damage.Keywords: Ganoderma lucidum, polysaccharide, oxidative stress, Keap1-Nrf2/ARE signaling pathway

Jia Liang,1 Ying Jia,1 Haijing Yan,1 Qingyu Shen,1 Weihua Bian,2 Dongmei Zhao,3 Yong Xu,1 Yongjun Jin,4 Meizi Yang1 1Department of Pharmacology, Binzhou Medical University, Yantai, People’s Republic of China; 2Department of Cell Biology, Binzhou Medical University, Yantai, People’s Republic of China; 3Department of Anatomy, Binzhou Medical University, Yantai, People’s Republic of China; 4Department of Endocrinology, Binzhou Medical University, Yantai, People’s Republic of ChinaCorrespondence: Meizi Yang; Yongjun JinDepartment of Pharmacology, Binzhou Medical University, Yantai, 264003, People’s Republic of ChinaTel +86 535 691 9507Fax +86 535 691 3163Email meizyang@126.com; endojin@126.comPurpose: To investigate resistance to diet-induced obesity (DIO) and monosodium glutamate (MSG)-induced obesity as well as the underlying mechanisms.Methods: Newborn mice were used to construct DIO and MSG-induced obesity models. Obesity indices, such as body weight, body length, Lee index, body temperature, food intake, fat weight, and leptin level, were examined. Mice that did not exhibit obesity were defined as the obesity-resistant group. The morphological changes of white adipose tissue were observed by hematoxylin and eosin staining, and expression levels of PR domain containing 16 (Prdm16) and uncoupling protein-1 (Ucp-1) in white adipose tissue were measured by Western blot.Results: Obesity-resistant mice fed a high-fat diet showed resistance beginning at week 5 along with lower weights and lengths than those in the obesity group from weeks 5 to 12. MSG-induced obesity-resistant mice showed features consistent with resistance to obesity from week 1 along with higher body lengths relative to the obesity group; however, the weight difference was not significant until week 10, when body weights decreased significantly in obesity-resistant mice. The Lee index was lower in obesity-resistant mice than in the obesity group and the normal group, further suggesting obesity resistance. Additionally, obesity-resistant mice showed higher levels of leptin, whereas obese mice induced by a high-fat diet showed leptin resistance. Furthermore, Prdm16 and Ucp-1 levels were both downregulated in the obesity group and upregulated in obesity-resistant mice, showing that white fat browning was highest in obesity-resistant mice.Conclusion: The phenotypes of mice with DIO and MSG-induced obesity differed. Obesity resistance might be related to Prdm16 and Ucp-1-mediated white adipocyte browning.Keywords: obesity resistance, brown adipose tissue, Ucp-1, adipocyte browning

Donglu Zhao, Qi Xing, Hang Song, Yan Zhao, Guiying Guo No. 4 Ward of Hematology Department, Institute of Hematology and Oncology, Harbin First Hospital, Harbin 150010, Heilongjiang Province, People’s Republic of ChinaCorrespondence: Donglu ZhaoNo. 4 Ward of Hematology Department, Institute of Hematology and Oncology, Harbin First Hospital, No. 149 Diduan Street, Daoli District, Harbin 150010, Heilongjiang Province, People’s Republic of ChinaTel +86-13936254716Email zhaodonglu123@163.comBackground: Long noncoding RNA LINC00265 or miR-4500 is involved in the pathogenesis of many cancers. However, their functions in acute lymphoblastic leukemia (ALL) remain unknown. In this study, we investigated how LINC00265 and miR-4500 regulate the malignant characteristics of ALL.Methods: Real-time PCR was used in examining the expression of LINC00265 in ALL cell lines and blood of patients with ALL. Cell proliferation, cell migration, and xenograft tumor assays were performed to verify the function of LINC00265 subjected to overexpressing and silencing experiments. The ceRNA mechanism with LINC00265/miR-4500/STAT3 was investigated through luciferase and RNA pull-down assays. Finally, the function of the LINC00265/miR-4500/STAT3 axis subjected to overexpressing and silencing assays was determined through cell proliferation, cell migration, and xenograft tumor assays.Results: LINC00265 was highly expressed in ALL cell lines and blood of patients with ALL and facilitated the proliferation, migration, invasion, and growth of xenograft tumors of ALL cells. The silencing of LINC00265 expression with LINC00265 siRNA significantly inhibited the malignancy of the ALL cells. RNA pull-down and luciferase assays demonstrated that LINC00265 competitively targeted miR-4500 and enhanced STAT3 expression. Furthermore, miR-4500 inhibitors or overexpressed LINC00265 up-regulated STAT3 expression, and miR-4500 mimics or STAT3 shRNAs eliminated the LINC00265-induced malignancy of the ALL cells.Conclusion: Mechanistically, LncRNA LINC00265 can competitively interact with miR-4500 and thereby up-regulates STAT3 signaling and enhances the malignancy of tumors.Keywords: acute lymphoblastic leukemia, LINC00265, miR-4500, cell proliferation

Dongxing Zhao,1,2 Asghar Abbasi,1 Richard Casaburi,1 Alessandra Adami,3 Nicholas B Tiller,1 Wei Yuan,1,4 Christopher Yee,5 Nicholas G Jendzjowsky,1 David M MacDonald,6,7 Ken M Kunisaki,6,7 William W Stringer,1 Janos Porszasz,1 Barry J Make,8 Russell P Bowler,8 Harry B Rossiter1 On behalf of the COPDGene Investigators1Rehabilitation Clinical Trials Center, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA; 2State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, People’s Republic of China; 3Department of Kinesiology, University of Rhode Island, Kingston, RI, USA; 4Respiratory Medicine Department, Beijing Friendship Hospital Affiliated of Capital Medical University, Beijing, 100050, People’s Republic of China; 5MemorialCare Long Beach Medical Center, Long Beach, CA, USA; 6Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, MN, USA; 7Minneapolis VA Health Care System, Minneapolis, MN, USA; 8National Jewish Health, Denver, CO, USACorrespondence: Harry B Rossiter Email hrossiter@ucla.eduBackground: Slow heart rate recovery (HRR) after exercise is associated with autonomic dysfunction and increased mortality. What HRR criterion at 1-minute after a 6-minute walk test (6MWT) best defines pulmonary impairment?.Study Design and Methods: A total of 5008 phase 2 COPDGene (NCT00608764) participants with smoking history were included. A total of 2127 had COPD and, of these, 385 were followed-up 5-years later. Lung surgery, transplant, bronchiectasis, atrial fibrillation, heart failure and pacemakers were exclusionary. HR was measured from pulse oximetry at end-walk and after 1-min seated recovery. A receiver operator characteristic (ROC) identified optimal HRR cut-off. Generalized linear regression determined HRR association with spirometry, chest CT, symptoms and exacerbations.Results: HRR after 6MWT (bt/min) was categorized in quintiles: ≤ 5 (23.0% of participants), 6– 10 (20.7%), 11– 15 (18.9%), 16– 22 (18.5%) and ≥ 23 (18.9%). Compared to HRR≤ 5, HRR≥ 11 was associated with (p< 0.001): lower pre-walk HR and 1-min post HR; greater end-walk HR; greater 6MWD; greater FEV1%pred; lower airway wall area and wall thickness. HRR was positively associated with FEV1%pred and negatively associated with airway wall thickness. An optimal HRR ≤ 10 bt/min yielded an area under the ROC curve of 0.62 (95% CI 0.58– 0.66) for identifying FEV1< 30%pred. HRR≥ 11 bt/min was the lowest HRR associated with consistently less impairment in 6MWT, spirometry and CT variables. In COPD, HRR≤ 10 bt/min was associated with (p< 0.001): ≥ 2 exacerbations in the previous year (OR=1.76[1.33– 2.34]); CAT≥ 10 (OR=1.42[1.18– 1.71]); mMRC≥ 2 (OR=1.42[1.19– 1.69]); GOLD 4 (OR=1.98[1.44– 2.73]) and GOLD D (OR=1.51[1.18– 1.95]). HRR≤ 10 bt/min was predicted COPD exacerbations at 5-year follow-up (RR=1.83[1.07– 3.12], P=0.027).Conclusion: HRR≤ 10 bt/min after 6MWT in COPD is associated with more severe expiratory flow limitation, airway wall thickening, worse dyspnoea and quality of life, and future exacerbations, suggesting that an abnormal HRR≤ 10 bt/min after a 6MWT may be used in a comprehensive assessment in COPD for risk of severity, symptoms and future exacerbations.Keywords: autonomic dysfunction, chest computed tomography, COPD exacerbation, exercise, spirometry

Jinglong Chen,1,2,&ast; Changbin Jiang,1,&ast; Youlan Zheng,1,&ast; Dongxing Zhao,1,&ast; Fan Wu,1 Zhuxiang Zhao,3 Jun Zhao,2 Qing Li,2 Bing Li,4 Gongyong Peng,1 Yumin Zhou,1 Pixin Ran1 1National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, People’s Republic of China; 2Department of Geriatrics, National Clinical Key Specialty, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou, 510180, People’s Republic of China; 3The Pulmonary Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China; 4GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pixin RanNational Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, People’s Republic of ChinaEmail pxran@gzhmu.edu.cnBackground and Objective: To determine the effects of BSE (biomass smoke exposure) on pulmonary and non-pulmonary changes in patients with COPD compared with normal individuals.Methods: Using a cohort, we recruited 16 healthy individuals with BSE (BSE normal), 19 patients with BSE+COPD, 13 healthy individuals with cigarette smoke exposure (CSE normal), 25 patients with CSE+COPD, and 25 healthy controls. Patients with GOLD stage I and II COPD were included. Baseline data (demographic data, BSE or CSE, lung function, and CT findings) and follow-up lung function data were collected. CT parameters of emphysema, pulmonary small vessels, airway remodeling, pectoralis muscles, and erector spinae muscle were measured.Results: Individuals with BSE were mainly women (32/35, 91.43%). Compared with the CSE+COPD group, the BSE+COPD group demonstrated slower lung function decline, increased lower lung emphysema, narrower airway lumen dimensions and increased airway wall thickening in the moderate and small airways (all P< 0.05). Compared with healthy controls, the CSE normal and BSE normal groups exhibited significant reductions in pulmonary small vessel area and obvious airway remodeling in small airways (P< 0.05). Compared with the BSE normal group, the BSE+COPD group showed significantly more severe emphysema and airway remodeling, as well as reduced left pectoralis major muscle area (all P< 0.05).Conclusion: Healthy individuals with BSE had reduced pulmonary small vessel area and evidence of airway remodeling; patients with BSE and COPD showed more severe emphysema, airway remodeling, and reductions in pectoralis major muscle area.Clinical Trial Registration: ChiCTR-OO-14004264.Keywords: biomass smoke, chronic obstructive pulmonary disease, computed tomography, pulmonary function

Medical data mainly includes various biomedical signals and medical images, and doctors can make judgments on the physical condition of patients through medical data. However, the interpretation of medical data requires a lot of labor costs and may be misjudged, so many scholars use neural networks and deep learning to classify and study medical data, thereby improving doctors' work efficiency and accuracy, achieving early detection of diseases and early diagnosis, so it has a wide range of application prospects. However, traditional neural networks have disadvantages such as high energy consumption and high latency (slow calculation speed). This paper introduces the research on signal classification and disease diagnosis based on the third-generation neural network - pulse neural network in recent years, using medical data, such as electroencephalogram (EEG), electrocardiogram (ECG), electromyography (EMG), magnetic resonance imaging (MRI), etc., summarizes the advantages and disadvantages of pulse neural networks compared with traditional networks, and looks forward to the future development direction., in Chinese language

Qianye Zhao,1,2,&ast; Teng Zhang,2,&ast; Beibei Zhu,1 Ying Bi,3 Shi-Wen Jiang,4 Yifan Zhu,1 Deyu Zhao,1 Feng Liu1 1Department of Respiratory Medicine, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Pediatrics, Lianyungang Maternal and Child Health Care Hospital, Lianyungang, Jiangsu, People’s Republic of China; 3Department of Respiratory Medicine, Xuzhou children’s Hospital, Xuzhou, Jiangsu, People’s Republic of China; 4Research Institute for Reproductive Health and Genetic Diseases, Center of Reproductive Medicine, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Deyu Zhao; Feng LiuDepartment of Respiratory Medicine, Children’s Hospital of Nanjing Medical University, No. 72, Guangzhou Road, Gulou District, Nanjing, Jiangsu, 210008, People’s Republic of ChinaTel +86 189 5176 9559; +86 189 5176 8373Fax +86 025 83117376Email zhaodeyu988@126.com; axsliu@163.comPurpose: It is well known that age is related to the incidence of Mycoplasma pneumoniae pneumonia (MPP), and how age and other factors contribute to MPP remains unclear. In this study, we investigate how age affects the prognosis of MPP.Patients and Methods: A total number of 1875 hospitalized children with pneumonia were enrolled in this study, including 52 children with refractory M. pneumoniae pneumonia (RMPP) and 298 children with non-RMPP. We used multiple logistic regression analysis to further identify the risk factors of RMPP, and found that age and polymorphonuclear neutrophils (PMNs) count were the key independent risk factors for the occurrence of RMPP. In order to improve specificity, 4.5 years old was taken as the cut-off value. Then, according to the cut-off value of age, 76 participants were recruited and divided into four groups: < 4.5y MPP group, ≥ 4.5y MPP group, < 4.5y health control (< 4.5yHC) and ≥ 4.5y HC group. We explored the diverse functions of primary PMNs from children of different ages with MPP at cellular level. Besides, we studied the relationship between lung injury and PMNs in mice model with MPP of different ages.Results: We found that the age and PMNs count of RMPP group were significantly higher than those of the non-RMPP group. Importantly, there is a linear correlation between the age of patients with RMPP and the percentage of PMNs. Further analysis showed that elderly patients infected with M. pneumoniae had more active PMNs function. Meanwhile, proteomics showed that children with M. pneumoniae infection in different age groups have differences in PMNs apoptosis, nicotinamide adenine dinucleotide phosphate, mitochondrial function and oxidative stress. Finally, we found that age is also involved in the pathogenesis of mouse model with MPP.Conclusion: We speculate that age may contribute to the development of RMPP.Keywords: refractory Mycoplasma pneumoniae pneumonia, Mycoplasma pneumoniae, polymorphonuclear neutrophils, reactive oxygen species, neutrophil extracellular traps

Shuyun Chen,1,2,&ast; Xiaochen Li,1,3,&ast; Zihui Wang,1,&ast; Yumin Zhou,1 Dongxing Zhao,1 Zhuxiang Zhao,1,4 Sha Liu,1 Pixin Ran1 1State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Diseases, National Clinical Research Center for Respiratory Disease Guangzhou, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China; 3The People’s Hospital of Hubei Province, Wuhan, Hubei Province, People’s Republic of China; 4The First People’s Hospital of Guangzhou City, Guangzhou, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pixin RanState Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Diseases, National Clinical Research Center for Respiratory Disease Guangzhou, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, No. 195 Dongfeng Xi Road, Guangzhou, 510000, Guangdong Province, People’s Republic of ChinaTel +86 2083205187Email pxran@gzhmu.edu.cnPurpose: The use of simple and affordable screening tools for chronic obstructive pulmonary disease (COPD) is limited. We aimed to assess the validity of a handheld expiratory flowmeter (Vitalograph Ltd., COPD-6®, Ireland) for COPD screening in Chinese primary care settings.Methods: In our cross-sectional study, subjects were randomly selected in eight primary care settings. Tests with the handheld expiratory flowmeter and the conventional spirometry were sequentially performed on all participants. The correlation between the handheld expiratory flowmeter and the conventional spirometry was determined. Validity was determined by the area under the receiver operator characteristic curve (AUC) of the forced expiratory volume in one second (FEV1)/forced expiratory volume in six seconds (FEV6) that used to detect airway obstruction. The sensitivity, specificity, predictive values, and likelihood ratio were calculated according to different FEV1/FEV6 cut-off points.Results: A total of 229 subjects (15.4%) were diagnosed with airflow limitation by conventional spirometry. FEV1, FEV6, and FEV1/FEV6 measured by the handheld expiratory flowmeter were correlated with FEV1, FVC, and FEV1/FVC measured by the conventional spirometry (r=0.889, 0.835 and 0.647, p< 0.001), respectively. AUC of the FEV1/FEV6 to determine airflow obstruction was 0.857 (95% CI: 0.826 to 0.888). No significant difference of AUC was observed between the symptomatic group and the asymptomatic group (AUC=0.869 vs 0.843, P=0.425). A similar phenomenon was found in the AUC of smokers and never-smokers (AUC=0.862 vs 0.840; P=0.515). The cut-off point for FEV1/FEV6 was 0.77 and the corresponding sensitivity and specificity were 71.2% and 89.8%, respectively.Conclusion: The handheld expiratory flowmeter might be used as a screening device for COPD in Chinese primary care settings.Keywords: COPD screening, airflow limitation, FEV1, FEV6, lung function

Building an intelligent dialogue system with the ability to select a proper response according to a multi-turn context is a great challenging task. Existing studies focus on building a context-response matching model with various neural architectures or PLMs and typically learning with a single response prediction task. These approaches overlook many potential training signals contained in dialogue data, which might be beneficial for context understanding and produce better features for response prediction. Besides, the response retrieved from existing dialogue systems supervised by the conventional way still faces some critical challenges, including incoherence and inconsistency. To address these issues, in this paper, we propose learning a context-response matching model with auxiliary self-supervised tasks designed for the dialogue data based on pre-trained language models. Specifically, we introduce four self-supervised tasks including next session prediction, utterance restoration, incoherence detection and consistency discrimination, and jointly train the PLM-based response selection model with these auxiliary tasks in a multi-task manner. By this means, the auxiliary tasks can guide the learning of the matching model to achieve a better local optimum and select a more proper response. Experiment results on two benchmarks indicate that the proposed auxiliary self-supervised tasks bring significant improvement for multi-turn response selection in retrieval-based dialogues, and our model achieves new state-of-the-art results on both datasets., Comment: 10 pages

Saijun Huang1,2 *,* Tao Sun1,2 *,* Yanna Zhu,3 Shanshan Song,1,2 Jie Zhang,4 Linjuan Huang,5 Qiang Chen,6 Guangyang Peng,7 Dongmei Zhao,8 Hong Yu,1,2 Jin Jing3 1Department of Child Healthcare, Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, Guangdong, 528000, People’s Republic of China; 2The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510280, People’s Republic of China; 3Department of Maternal and Child Health, School of Public Health, Sun Yat-Sen University, Guangdong, Guangzhou, 510080, People’s Republic of China; 4Department of Child Healthcare, Xi’an Children’s Hospital, Xi’an, Shaanxi, 710003, People’s Republic of China; 5Health Management Center, Fuzhou Children’s Hospital of Fujian Medical University, Fuzhou, Fujian, 350005, People’s Republic of China; 6Department of Child Psychological Health, Zhuhai Women and Children’s Hospital, Zhuhai, Guangdong, 519001, People’s Republic of China; 7 Department of Child Rehabilitation, Huanggang Ping’an Rehabilitation Hospital, Huanggang, Hubei, 438000, People’s Republic of China; 8Department of Child Healthcare, Jinan Children’s Hospital, Jinan, Shandong, 250022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong Yu; Jin Jing Email yu376@163.com; jingjin@mail.sysu.edu.cnBackground: The COVID-19 pandemic and lockdown will have short-term and long-term psychosocial and mental health implications for children. Children with autism may have some specific needs for support because of their difficulties in social communication, stereotyped behavior patterns, and other specificities brought about by autism.Purpose: The purpose of this study was to investigate the impact of the COVID-19 pandemic on ASD children and their families.Patients and Methods: A total of 406 parents of ASD children completed an online survey investigating basic information; sleep, outdoor activities, and rehabilitation training; ASD children’s frequency of abnormal behaviors; and stress and emotional status of parents.Results: 50.3% of the parents thought their children had sleep problems, and 47.3% of the parents thought their children’s outdoor activity time was reduced. About 40% of parents think that their children have improved cognitive ability, language expression, and understanding. 36.2% of the families reported that their children’s emotional and social performance became worse. 60.8% of parents reported that their children’s training intensity decreased. The most common abnormal behaviors observed in children with ASD were being easily distracted, losing temper, and crying. 81.3% of parents did not have anxiety, but 98% of parents reported that family training was under pressure.Conclusion: The main impact of the COVID-19 pandemic on children with ASD is that they do not have access to professional rehabilitation training. These families need more medical support, especially in family training, to help parents improve the social and emotional control skills of ASD children.Keywords: COVID-19, ASD, child, behavior, rehabilitation training, China

Dizhou Zhao, Jieyu Fang, Wei Xiong, Jun Lin, Wanmei Chen, Chujun Wu Department of Anesthesia, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of ChinaCorrespondence: Jieyu FangDepartment of Anesthesia, The First Affiliated Hospital of Sun Yat-Sen University, No. 56 Zhongshan Road II, Guangzhou, People’s Republic of ChinaTel + 86-13660121136Email fangjy@mail.sysu.edu.cnBackground: Sugammadex has been a revolutionary reversal of neuromuscular blockade. It is known to be highly efficient. However, a change in the coagulation profile is one of the most dangerous potential complications which is a concern for both surgeon and anesthetist. Bleeding may cause hypovolemic shock, hematoma, and so on. To investigate the effects of sugammadex on coagulation profiles in patients with thyroidectomy, we compared patients that were treated with either sugammadex or neostigmine.Patients and Methods: Eighty patients with thyroid neoplasms undergoing thyroidectomy were randomly allocated to sugammadex group (group S) or neostigmine group (group N). Induction of anesthesia was preformed using propofol, sufentanil, and rocuronium. Group S received sugammadex 2.0mg/kg after trachea intubation, similarly Group N received neostigmine 40 μg/kg, for reversal of rocuronium-induced neuromuscular blockade. The intraoperative coagulation profiles were monitored after the rocuronium injection (T0), 10 minutes after reversal (T1) and 30 minutes after reversal (T2) by testing activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (FIB), thrombin time (TT), and TEG-Haemonetics. Amount of bleeding was recorded during perioperative period.Results: There was no significant difference in the thromboelastogram, APTT, PT, FIB, or TT measurements at each time point in Group N. The reaction time (R time) and kinetics time (K time) of Group S in T1 were significantly longer than the corresponding times at T0 and T2, and the R times were significantly longer than those in Group N at the same time points (P< 0.05). Additionally, in Group S, the APTT was prolonged in T1 and returned to normal in T2.Conclusion: The result showed that sugammadex provided transient efficacy in prolonging the coagulation parameters, while neostigmine did not change the coagulation profile.Keywords: sugammadex, neostigmine, TEG-Haemonetics, coagulation, thyroidectomy

Yafeng Pan,1 Xuye Zhao,2 Dean Zhao,1 Junhua Liu1 1Department of Otolaryngology, Xiang’an Hospital of Xiamen University, Xiamen, Fujian, People’s Republic of China; 2Department of Breast and Thyroid Surgery, Xiang’an Hospital of Xiamen University, Xiamen, Fujian, People’s Republic of ChinaCorrespondence: Junhua LiuDepartment of Otolaryngology, Xiang’an Hospital of Xiamen University, Xiamen, Fujian 361101, People’s Republic of ChinaEmail xaherbihou@163.comObjective: To explore the survival value of lymph node dissection (LND) in elderly patients with T3-T4 laryngeal cancer, analyze the risk factors of lymph node metastasis, and construct a preoperative prediction model.Materials and Methods: The study included 996 patients aged ≥ 65 years with laryngectomy confirmed T3-T4 laryngeal cancer queried from Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2017. Propensity score matching (PSM) was applied to balance the effects of confounding factors. Kaplan–Meier (K–M) analysis and competitive risk model were used to compare the overall survival (OS) and cancer-specific survival (CSS) between LND and no-LND (N-LND) group. Combined with risk factors of multivariate logistic regression, a nomogram was built to predict lymph node metastasis preoperatively. The performance was assessed in the training set and the validation set, and internal validation was assessed.Results: Among the cohort, 822 patients underwent LND and 410 patients had positive lymph nodes. The OS and CSS of patients who underwent LND were not better than that of N-LND patients (P> 0.05). The prognosis of patients with lymph node metastases was significantly worse than that of negative patients (P< 0.05). On multivariate logistic regression, supraglottis cancer, tumor size > 5cm and grade 3– 4 classification were associated with significantly greater odds of lymph node metastasis. The nomogram showed favorable predictive efficacy and good calibration (in the training cohort C-index=0.700; in the validation cohort C-index=0.721).Conclusion: For elderly patients with T3-T4 laryngeal cancer, LND did not bring significant survival values. Supraglottis cancer, tumor size > 5cm and grade 3– 4 classification were independent risk factors of lymph node metastasis, which means poor prognosis. The nomogram developed was an easy-to-use tool for lymph node prediction.Keywords: elderly, T3-T4 laryngeal cancer, lymph node dissection, survival, nomogram

We report the phase-connected timing ephemeris, polarization pulse profiles, Faraday rotation measurements, and Rotating-Vector-Model (RVM) fitting results of twelve millisecond pulsars (MSPs) discovered with the Five-hundred-meter Aperture Spherical radio Telescope (FAST) in the Commensal radio Astronomy FAST survey (CRAFTS). The timing campaigns were carried out with FAST and Arecibo over three years. Eleven of the twelve pulsars are in neutron star - white dwarf binary systems, with orbital periods between 2.4 and 100 d. Ten of them have spin periods, companion masses, and orbital eccentricities that are consistent with the theoretical expectations for MSP - Helium white dwarf (He WD) systems. The last binary pulsar (PSR J1912$-$0952) has a significantly smaller spin frequency and a smaller companion mass, the latter could be caused by a low orbital inclination for the system. Its orbital period of 29 days is well within the range of orbital periods where some MSP - He WD systems have shown anomalous eccentricities, however, the eccentricity of PSR J1912$-$0952 is typical of what one finds for the remaining MSP - He WD systems., 11 pages, 5 figures, MNRAS accepted

Dahai Zhao,1,2,* Haijiang Lin,3,* Zhiruo Zhang4 1School of International and Public Affairs, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Shanghai Jiao Tong University-Yale University Joint Center for Health Policy, Shanghai, People’s Republic of China; 3Taizhou City Center for Disease Control and Prevention, Taizhou, Zhejiang Province, People’s Republic of China; 4School of Public Health, Shanghai Jiao Tong University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dahai ZhaoSchool of International and Public Affairs, Shanghai Jiao Tong University, Xinjian Building, No. 1954 Huashan Road, Shanghai 200030, People’s Republic of ChinaTel +86-139-1896-8766Email dahaizhao@sjtu.edu.cnIntroduction: In less than two months, the COVID-19 outbreak in China was controlled through the stringent strategies of screening and isolation. This article aims to use empirical data from all cases from a prefecture-level city of China to introduce and examine the feasibility and efficiency of the screening and isolation strategies and how these were essential in combatting the COVID-19 outbreak.Methods: For this retrospective study, all confirmed COVID-19 patients were recruited from the Taizhou prefecture-level city of Zhejiang province, China.Results: Of the city’s total population, 24% were screened for COVID-19 and isolated at home or designated locations for two weeks. From these, a total of 146 confirmed cases of COVID-19 were analysed. Of all cases, 51% were traced from Wuhan, and 21% of patients were in close contact with confirmed cases from outside of the city. Initially, 13% of all patients reported having no clear symptoms, while 42% of patients presented with fever and/or other symptoms. Compared with local patients, new arrivals to the city had fewer days between their exposure and the development of symptoms of COVID-19 (P< 0.001), and fewer days from the time they developed symptoms to the confirmation of COVID-19 (P< 0.001), respectively.Conclusion: This study has fully confirmed that controlling the COVID-19 outbreak through screening and isolation is effective, efficient, and essential. The evidence-based framework and implementation of China’s strategy to combat COVID-19 can explain how China contained the COVID-19 outbreak in a short time period. This study offers important references and implications for containing the COVID-19 pandemic in the global community.Keywords: COVID-19, pandemic control, screening, isolation, China

Weihua Hu,1,* Minglin Dong,1,* Mengqing Xiong,1,* Dong Zhao,1 Yang Zhao,1 Mengmei Wang,1 Tao Wang,1 Zhenlian Liu,2 Li Lu,3 Ke Hu1 1Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Fever Clinic, The East Campus, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Department of Respiratory Medicine, The East Campus, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ke HuDepartment of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Zhangzhidong Road No. 99, Wuhan 430060, People’s Republic of ChinaTel +86-18971035988Fax +86-027-88042292Email huke-rmhospital@163.comPurpose: In this study, we investigated the acute exacerbation and outcomes of COPD patients during the outbreak of COVID-19 and evaluated the prevalence and mortality of COPD patients with confirmed COVID-19.Methods: A prospectively recruited cohort of 489 COPD patients was retrospectively followed-up for their conditions during the COVID-19 pandemic from December 2019 to March 2020 in Hubei, China. In addition, the features of 821 discharged patients with confirmed COVID-19 were retrospectively analyzed.Results: Of the 489 followed-up enrolled COPD patients, 2 cases were diagnosed as confirmed COVID-19, and 97 cases had exacerbations, 32 cases of which were hospitalized, and 14 cases died. Compared with the 6-month follow-up results collected 1 year ago, in 307 cases of this cohort, the rates of exacerbations and hospitalization of the 489 COPD patients during the last 4 months decreased, while the mortality rate increased significantly (2.86% vs 0.65%, p=0.023). Of the 821 patients with COVID-19, 37 cases (4.5%) had pre-existing COPD. Of 180 confirmed deaths, 19 cases (10.6%) were combined with COPD. Compared to COVID-19 deaths without COPD, COVID-19 deaths with COPD had higher rates of coronary artery disease and/or cerebrovascular diseases. Old age, low BMI and low parameters of lung function were risk factors of all-cause mortality for COVID-19 patients with pre-existing COPD.Conclusion: Our findings imply that acute exacerbations and hospitalizations of COPD patients were infrequent during the COVID-19 pandemic. However, COVID-19 patients with pre-existing COPD had a higher risk of all-cause mortality.Keywords: chronic obstructive pulmonary disease, COPD, exacerbation, mortality, novel coronavirus pneumonia, COVID-19, novel coronavirus, SARS-CoV-2

Yun-jing Hou,1 Xin-xin Yang,1 Rui-qi Liu,2 Di Zhao,1 Chen-xu Guo,1 An-chao Zhu,1 Mei-na Wen,1 Zhao Liu,3 Guo-fan Qu,4 Hong-xue Meng1 1Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 2Department of Radiation Oncology, Sun Yat-Sen University Cancer Hospital, Guangzhou, People’s Republic of China; 3Department of Ultrasound, Harbin Medical University, Harbin, People’s Republic of China; 4Department of Orthopedics, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Hong-xue Meng Department of PathologyHarbin Medical University Cancer Hospital, 150 Haping Road, Harbin, People’s Republic of ChinaTel +86-451-85718261Email menghongxue15@163.comAbstract: The ultimate goal of phototherapy based on nanoparticles, such as photothermal therapy (PTT) which generates heat and photodynamic therapy (PDT) which not only generates reactive oxygen species (ROS) but also induces a variety of anti-tumor immunity, is to kill tumors. In addition, due to strong efficacy in clinical treatment with minimal invasion and negligible side effects, it has received extensive attention and research in recent years. In this paper, the generations of nanomaterials in PTT and PDT are described separately. In clinical application, according to the different combination pathway of nanoparticles, it can be used to treat different diseases such as tumors, melanoma, rheumatoid and so on. In this paper, the mechanism of pathological treatment is described in detail in terms of inducing apoptosis of cancer cells by ROS produced by PDT, immunogenic cell death to provoke the maturation of dendritic cells, which in turn activate production of CD4+ T cells, CD8+T cells and memory T cells, as well as inhibiting heat shock protein (HSPs), STAT3 signal pathway and so on.Keywords: pathological mechanism, nanoparticles, photothermal therapy, PTT, photodynamic therapy, PDT

Hui Zhang,1 Yayun Zhao,1 Yahong Zheng,1 Qinxiang Kong,1,2 Na Lv,1 Yanyan Liu,1,3,4 Dongmei Zhao,5 Jiabin Li,1– 4 Ying Ye1 1Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Infectious Diseases, The Chaohu Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Anhui Center for Surveillance of Bacterial Resistance, Hefei, Anhui, People’s Republic of China; 4Institute of Bacterial Resistance, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 5Department of Infectious Disease, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of ChinaCorrespondence: Ying Ye; Jiabin Li Tel +86-551-62922713Fax +86-551-62922281Email yeying2@139.com; lijiabin@ahmu.edu.cnPurpose: This study aimed to develop and validate a personalized prediction model of death risk in patients with Acinetobacter baumannii (A. baumannii) infection and thus guide clinical research and support clinical decision-making.Patients and Methods: The development group is comprised of 350 patients with A. baumannii infection admitted between January 2013 and December 2015 in The First Affiliated Hospital of Anhui Medical University. Further, 272 patients in the validation group were admitted between January 2016 and December 2018. The univariate and multivariate logistic regression analyses were used to determine the independent risk factors for death with A. baumannii infection. The nomogram prediction model was established based on the regression coefficients. The discrimination of the proposed prediction model was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curves and decision curve analysis (DCA). The calibration diagram was used to evaluate the calibration degree of this model.Results: The infectious source, carbapenem-resistant A. baumannii (CRAB), hypoalbuminemia, Charlson comorbidity index (CCI), and mechanical ventilation (MV) were independent risk factors for death. The AUC of the ROC curve of the two groups was 0.768 and 0.792, respectively. The net income was higher when the probability was between 30% and 80%, showing a strong discrimination capacity of the proposed model. The calibration curve swung around the 45° oblique line, indicating a high degree of calibration.Conclusion: The proposed model helped predict the risk of death from A. baumannii infection, improve the early identification of patients with a higher risk of death, and guide clinical treatment.Keywords: Acinetobacter baumannii, carbapenem resistance, prediction model, risk factors

Dan Zhao, Baomin Zheng, Shaowen Xiao, Weixin Liu, Xiaolong Xu, Huiming Yu, Yan Sun, Weihu Wang Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital Institute, Beijing, People’s Republic of ChinaCorrespondence: Weihu Wang; Yan SunKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Beijing Cancer Hospital & Institute, 52# Fucheng Road, Haidian District, Beijing 100142, People’s Republic of ChinaTel/ Fax +86-10-88196120; +86-10-88196217 Email wangweihu88@163.com; lisaysun@139.comPurpose: This study aimed to retrospectively analyze the failure patterns and clinical outcomes in patients with locally advanced cervical esophageal carcinoma (CEC) after definitive radiotherapy (RT), and illustrate the mapping of regional failures.Patients and Methods: We reviewed 82 patients with CEC confirmed as squamous cell carcinoma who had completed definitive RT from August 2008 to December 2017. Data on clinical characteristics were collected from the medical records system. Patterns of treatment failures and the survival follow-up were analyzed.Results: The median age was 58 (38– 78) years. In 37 patients, the lesions were limited to the cervical esophagus, while in the remaining 45 patients, the disease got beyond the cervical esophagus (pharynx or thoracic esophagus involved). While 10 patients had stage Ⅱ disease, 72 had stage III disease. The completed median dose for 95% PGTV and 95% PTV was 66 Gy and 58 Gy. While the median follow-up was 27.6 months, the median progression-free survival (PFS) and overall survival (OS) was 16.1 and 28.3 months, respectively. The 3-year PFS and OS was 30.3% and 45.3%, respectively. Treatment failures were reported in 55 patients, of which 22, 8, 7, 9, 2, 3, and 4 patients had developed local, regional, distant, local-regional, regional-distant, local-distant and local-regional-distant failure, respectively. Of the 41 relapsed nodal sites, 28 were located “in-field” whereas 1 was “marginal” and 12 were “out-field”. The most frequent regional relapses were at level VIb, IV and the upper-middle mediastinum.Conclusion: Regional recurrences focused on lower neck and upper-middle mediastinum, and mainly “in-field”, after definitive RT in patients with CEC.Keywords: esophageal neoplasms, prognosis, radiotherapy, recurrence, squamous cell carcinoma

Jialin Qu *, Li Wang *, Man Jiang, Deze Zhao, Yuyang Wang, Feng Zhang, Jing Li, Xiaochun Zhang Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaochun Zhang Department of Medical OncologyThe Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiangsu Road, Qingdao 266003, People’s Republic of ChinaTel/ Fax +86 53282913271Email zhangxiaochun9670@126.comAbstract: Lung cancer is currently the malignant tumor with the highest incidence and mortality in the world, while non-small cell lung cancer (NSCLC) is the most common pathological type of lung caner. In the past few decades, the only treatment options available for advanced NSCLC patients have been targeted therapy or chemotherapy, but these therapies are inevitably tolerated by tumors. The discovery of immune checkpints that mediate the immune escape of tumor cells have been promoting a series of immune checkpoint inhibitors to be used in cancer treatment and achieved great results. Among them, pembrolizumab is currently the only PD-1 inhibitor approved for first-line treatment of NSCLC, whether it is monotherapy or combination therapy, for creditable performance in KEYNOTE studies. In this review, we systematically integrate the latest series of clinical trial results, pharmacological mechanisms, adverse events (AEs) and predictive biomarkers in the first-line treatment of NSCLC. We hope pembrolizumab could become a better choice for more clinicians and benefit more patients with advanced NSCLC.Keywords: pembrolizumab, PD-1/PD-L1, KEYNOTE studies, first-line treatment, non-small cell lung cancer, NSCLC

Jingjing Yan,1 Dahai Zhao1,2 1School of International and Public Affairs, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Shanghai Jiao Tong University-Yale University Joint Center for Health Policy, Shanghai, People’s Republic of ChinaCorrespondence: Dahai ZhaoSchool of International and Public Affairs, Shanghai Jiao Tong University, No. 1954 Huashan Road, Shanghai 200030, People’s Republic of ChinaTel +86 139-1896-8766Email dahaizhao@sjtu.edu.cnIntroduction: From December 2019 to January 2020, a novel coronavirus disease (officially COVID-19) was reported in Wuhan and continued to spread all China. This study describes the administrative mechanism of joint participation and cooperation during the early stages of the COVID-19 outbreak in Wuhan and the rest of the country by health practitioners and administrative authorities.Methods: This study adopted a qualitative design. An analytical framework based on the theory of policy participation that included stimulus, setting, and position of policy participation was constructed. Qualitative data of policy participation by health practitioners and administrative authorities consisted of publicly available data.Results: Early during the outbreak, from December 2019 to January 2020, three main stages occurred according to the containment situation. The first stage was characterized by limited knowledge of the transmission dynamics of the virus and a consequently weak response. In the second stage, the disease spreads rapidly because of travel during a national festival. In the third stage, particularly when top Chinese leaders delivered instructions to intensify containment efforts, diverse departments initiated joint prevention and control measures to combat COVID-19.Conclusion: The administrative mechanism of joint participation and cooperation was instrumental in avoiding a substantial increase in both cases and fatalities in the initial stage of the outbreak. This joint participation provides valuable experience and initiatives for major public health emergency preparedness, and the new empirical evidence further highlights the importance of policy participation theory in epidemic prevention in other countries.Keywords: joint administration, coronavirus disease 2019, public health emergency, policy participation

Qiang Wang,1,2,* Xinyu Hu,1,* Mingyu Du,1,* Zhiwei Lu,2 Keshi Yan,3 Dingliang Zhao,4 Ning Jiang,1 Yi Peng,1 Xia He,1 Li Yin1 1The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, People’s Republic of China; 2Department of Radiation Oncology, Xuzhou Cancer Hospital, Xuzhou, Jiangsu, People’s Republic of China; 3Department of Anesthesiology, Clinical Medical School of Yangzhou University, Subei People’s Hospital of Jiangsu Province, Yangzhou, People’s Republic of China; 4Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xia He; Li YinThe Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Bai Zi Ting Road, Nanjing, Jiangsu, People’s Republic of China, Email hexiabm@163.com; yinli_2012@126.comBackground: Long noncoding RNAs (lncRNAs) are known as key regulators in many cancer types, but their biological functions in nasopharyngeal carcinoma (NPC) remain largely unknown. In the present study, we aim to explore the role of the lncRNA ZNRD1-AS1 in NPC tumor development.Methods: The role of ZNRD1-AS1 in NPC tissues and cells was explored by using quantitative real-time PCR assay. Cellular behavioral experiments were used in testing NPC cell proliferation, invasion, and migration. Luciferase reporter assay, RNA-binding protein immunoprecipitation, and Western blot analysis were used in estimating the associations among ZNRD1-AS1, miR-335, and ROCK1.Results: ZNRD1-AS1 expression was elevated in the NPC tissues and cells, and ZNRD1-AS1 overexpression was positively correlated with advanced TNM stage and the presence of lymph node metastasis. Our biological experiments indicated that ZNRD1-AS1 knockdown reduces NPC cell invasion and metastasis. Further analyses revealed that ZNRD1-AS1 as a ceRNA promotes the migration and invasion of NPC cells by sponging miR-335. We provided evidence that ZNRD1-AS1 facilitates the invasion and metastasis of NPC cells via the miR-335–ROCK1 axis.Conclusion: Our data shed light on the oncogenic role of ZNRD1-AS1 in NPC tumor development, and a promising therapeutic target for NPC was identified.Keywords: nasopharyngeal carcinoma, ZNRD1-AS1, miR-335

Dingyun Zhao,1,* Fan Tang,1,* Li Min,1 Minxun Lu,1 Jie Wang,1 Yuqi Zhang,1 Kun Zhao,1,2 Yong Zhou,1 Yi Luo,1 Chongqi Tu1 1Department of Orthopeadics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China; 2Department of Orthopeadics, Tianjin Fifth Central Hospital, Tianjin 300450, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chongqi TuDepartment of Orthopedics, West China Hospital of Sichuan University, No. 37 Guo Xue Xiang, Chengdu, Sichuan 610041, People’s Republic of ChinaTel +86-189-8060-1387Fax +86-28-8542-2246Email tcqbonetumor@163.comPurpose: This study aimed to evaluate the early stability, limb function, and mechanical complications of 3D-printed porous prosthetic reconstruction for “ultra-critical sized bone defects” following intercalary tibial tumor resections.Methods: This study defined an “ultra-critical sized bone defect” in thetibia when the length of segmental defect in thetibiawas> 15.0 cm or > 60% of thefull tibia and the length of theresidual fragment in proximal or distal tibia was between 0.5 cm and 4.0 cm. Thus, five patients with “ultra-critical sized bone defects” following an intercalary tibial malignant tumor resection treated with 3D-printed porous prosthesis between June 2014 and June 2018 were retrospectively reviewed. Patient information, implants design and fabrication, surgical procedures, and early clinical outcome data were collected and evaluated.Results: Among the five patients, three were male and two were female, with an average age of 30.2 years. Pathological diagnoses were two osteosarcomas, one Ewing sarcoma, one pseudo-myogenic hemangioendothelioma, and one undifferentiated pleomorphic sarcoma . The average length of the bone defects following tumor resection was 22.8cm, and the average length of ultra-short residual bone was 2.65cm (range=0.6cm– 3.8cm). The mean follow-up time was 27.6 months (range=14.0– 62.0 months). Early biological fixation was achieved in all five patients. The average time of clinical osseointegration at the bone–porous interface was 3.2 months. All patients were reported to be pain free and have no limitations in their walking distance. No prosthetic mechanical complications were observed.Conclusion: Reconstruction of the “ultra-critical sized bone defect” after an intercalary tibial tumor resection using 3D-printed porous prosthesis achieved satisfactory overall early biological fixation and limb function. Excellent primary stability and the following rigid biological fixation were key factors for success. The outcomes of this study were supposed to support further clinical application and evaluation of 3D-printed porous prosthetic reconstruction for “ultra-critical sized bone defects” in thetibia.Keywords: 3D-printed porous, prosthetic reconstruction, intercalary tibial resection, critical sized bone defect

Dehua Zhao,1 Jing Chen,1 Mingming Chu,2 Xiaoqing Long,1 Jisheng Wang1 1Department of Clinical Pharmacy, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang 621000, People’s Republic of China; 2Department of Clinical Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, People’s Republic of ChinaCorrespondence: Jisheng Wang; Dehua Zhao Email wangjishengyaoshi@163.com; zhaodehua1000@163.comAbstract: Anaplastic lymphoma kinase (ALK) inhibitors are important treatment options for non-small-cell lung cancer (NSCLC), associated with ALK gene rearrangement. Patients with ALK gene rearrangement show sensitivity to and benefit clinically from treatment with ALK tyrosine kinase inhibitors (ALK-TKIs). To date, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and entrectinib have received approval from the US Food and Drug Administration and/or the European Medicines Agency for use during the treatment of ALK-gene-rearrangement forms of NSCLC. Although the oral route of administration is convenientand results in good compliance among patients, oral administration can be affected by many factors, such as food, intragastric pH, cytochrome P450 enzymes, transporters, and p-glycoprotein. These factors can result in increased risks for serious adverse events or can lead to reduced therapeutic effects of ALK-TKIs. This review characterizes and summarizes the pharmacokinetic parameters and drug–-drug interactions associated with ALK-TKIs to provide specific recommendations for oncologists and clinical pharmacists when prescribing ALK-TKIs.Keywords: ALK, TKIs, NSCLC, PK, drug–drug interactions

Longyan Yang,1,* Yan Wang,1,* Rongxin Sun,1,* Yuanyuan Zhang,1 Ying Fu,1 Zhaohui Zheng,1 Zhili Ji,2 Dong Zhao1 1Beijing Key Laboratory of Diabetes Research and Care, Center for Endocrine Metabolism and Immune Diseases, Luhe Hospital Capital Medical University, Beijing 101149, People’s Republic of China; 2Department of General Surgery, Luhe Hospital Capital Medical University, Beijing 101149, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dong Zhao; Zhili Ji Tel +86-10-69543901Fax +86-10-69531069Email zhaodong@ccm.edu.cn; lhyyjzl@163.comPurpose: Although papillary thyroid carcinoma (PTC) is associated with a generally favorable prognosis, about 15% of patients present recurrence and distant metastasis in the next decade leading to death. Angiopoietin-like 4 (ANGPTL4) is secreted to circulation and belongs to the angiopoietin-like proteins. The expression of ANGPTL4 was increased in several solid tumor tissues compared to corresponding paracancerous tissues. ANGPTL4 was identified as pro-tumorigenic protein, including stimulating tumor cell growth, promoting tumor metastasis. However, the clinical significance and biological function of ANGPTL4 in PTC is still unclear. Hence, the purpose of this study was to evaluate the role of ANGPTL4 in PTC, investigating the possibility of whether ANGPTL4 could become a novel target for PTC therapy.Methods: We investigated the expression level of ANGPTL4 and pAKT in PTC and paracancerous tissue by immunohistochemistry. We determined the effect of ANGPTL4 in PTC cell proliferation through cell counting kit-8 (CCK-8) and cell cycle by flow cytometry analysis. Furthermore, the correlation between ANGPTL4 expression levels and PTC cell proliferation from the TCGA data set was analyzed by GSEA. We explored the role of ANGPTL4 on the phosphorylation of AKT and proliferation in PTC cells via overexpression or knockdown assays and AKT inhibitor assay.Results: In the present study, we found that ANGPTL4 was highly expressed in both protein and mRNA level in PTC compared with adjacent noncancerous tissues or benign nodule. ANGPTL4 expression increased according to thyroid tumor progression. ANGPTL4 level was positively correlated with the size of PTC. ANGPTL4 increased cell proliferation and decreased cell cycle arrest of PTC. Knockdown of ANGPTL4 inhibited the phosphorylation of AKT. ANGPTL4 regulated PTC cell proliferation through AKT signaling pathway.Conclusion: Our findings suggested that ANGPTL4 was increased in PTC compared with adjacent noncancerous tissues, and ANGPTL4 increased cell proliferation and inhibited cell cycle arrest in PTC cells via promoting AKT phosphorylation. The study may provide fundamental information to suggest its suitability as a target for the treatment of PTC.Keywords: papillary thyroid carcinoma, angiopoietin-like 4, AKT, proliferation

Ruofeng Yin,1 Junzhi Liu,2 Dongxu Zhao,1 Fei Wang1 1Department of Orthopedics, China-Japan Union Hospital Jilin University, Changchun, Jilin 130033, People’s Republic of China; 2Department of Quality Control, China-Japan Union Hospital Jilin University, Changchun, Jilin 130033, People’s Republic of ChinaCorrespondence: Fei WangDepartment of Orthopedics, China-Japan Union Hospital Jilin University, No. 126, Xiantai Road, Changchun, Jilin 130033, People’s Republic of ChinaEmail wangfei_king@163.comPurpose: ASB16 antisense RNA 1 (ASB16-AS1) is a cancer-associated long non-coding RNA that contributes to tumorigenesis and tumor development. Nevertheless, to the best of our knowledge, whether and how ASB16-AS1 is implicated in osteosarcoma (OS) malignancy remains unclear and therefore warrants exploration. Our current study focused on making in-depth investigation of ASB16-AS1 in OS. In the present study, the expression pattern of ASB16-AS1 in OS tissues and cell lines was analyzed. In addition, we examined the clinical value of ASB16-AS1 for OS patients. Furthermore, we explored the impacts of ASB16-AS1 on the malignant phenotype of OS cells in vitro and in vivo as well as the underlying mechanism.Methods: ASB16-AS1, microRNA-760 (miR-760) and hepatoma-derived growth factor (HDGF) expressions were measured using reverse transcription-quantitative PCR. Cell proliferation and apoptosis were evaluated using CCK-8 and flow cytometry analyses, respectively, and cell migration and invasion were determined via cell migration and invasion assays.Results: ASB16-AS1 expression was significantly elevated in OS tissues and cell lines, and increased ASB16-AS1 expression was related to patients’ tumor size, TNM stage, and distant metastasis. The overall survival rate of OS patients presenting high ASB16-AS1 expression was shorter than that of patients presenting low ASB16-AS1 expression. Reduced ASB16-AS1 expression inhibited OS cell proliferation, migration, and invasion; promoted cell apoptosis; and impaired tumor growth in vivo. Mechanistically, ASB16-AS1 served as a sponge for miR-760 and positively modulated the expression of its target HDGF. Finally, inhibiting miR-760 and restoring HDGF expression abolished the impacts of ASB16-AS1 knockdown on the malignant characteristics of OS cells.Conclusion: ASB16-AS1 is a novel oncogenic lncRNA in OS cells. ASB16-AS1 increased HDGF expression by sponging miR-760, thereby conferring cancer-promoting roles in OS. ASB16-AS1 is a potential early diagnostic and therapeutic target in OS.Keywords: osteosarcoma therapy, ASB16-AS1, hepatoma-derived growth factor, microRNA-760

Danyang Zhao,1,* Hui Zhang,2,* Jianxiong Long,3 Mujun Li1 1Department of Reproductive Center, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, People’s Republic of China; 2Department of Obstetrics, Chongzuo People’s Hospital, Chongzuo, Guangxi Province, People’s Republic of China; 3School of Public Health of Guangxi Medical University, Nanning, Guangxi Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianxiong LongSchool of Public Health of Guangxi Medical University, No. 22 Shuangyong Road, Nanning 530021, Guangxi Province, People’s Republic of ChinaTel +86-158 0771 4732Email longjx12345@163.comMujun LiDepartment of Reproductive Center, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, Guangxi Province, People’s Republic of ChinaTel +86-182 9010 8786Email sciencecid@126.comBackground: Long non-coding RNA (LncRNA) SNHG7 is involved in the development of multiple cancers. However, its role in cervical cancer (CC) has not been elucidated. This study aimed to explore the function of SNHG7 in CC progression and the underlying mechanisms.Materials and Methods: The expression levels of SNHG7 and miR-485-5p in CC tissues and cell lines were measured by qPCR. Functional experiments including CCK-8 assay, wound healing assay, transwell assay, flow cytometry, Western blot, luciferases reporter assay and immunoprecipitation (RIP) were performed to explore the SNHG7/miR-485-5p/JUND pathway. Additionally, in vivo study was carried out by establishing tumor xenograft models.Results: We found that SNHG7 was markedly enhanced in CC tissues and cell lines, and associated with poor clinical characteristics. In vitro, knockdown of SNHG7 inhibited CC cell proliferation, migration and invasion, as well as aggravated cell apoptosis. As to mechanism investigation, rescue experiments revealed that miR-485-5p inhibitor could partially reverse the effects on CC cells induced by SNHG7 knockdown. SNHG7 upregulated JUND expression via miR-485-5p. Moreover, tumor xenograft models were established to confirm the findings in vivo.Conclusion: SNHG7 promoted CC progression through miR-485-5p/JUND axis. The SNHG7/miR-485-5p/JUND pathway might provide a novel therapeutic target for CC treatment.Keywords: lncRNA SNHG7, cervical cancer, CC, miR-485-5p, JUND, cell proliferation

8th World Conference on Photovoltaic Energy Conversion; 1579-1584, Battery energy storage plays a vital role in the renewable energy system. Battery as the only dynamic element in a PV system, the current, voltage, resistivity, etc. are varying during charging and discharging. With an accurate and efficient battery model, the designer can predict and optimize battery runtime and performance during different working scenarios. However, low-complexity state-of-the-art models are too weak on the transient behavior. The primary purpose of this study is to provide an efficient dynamic battery model for the simulation of stand-alone PV applications. In this study, an enhanced and comprehensive electrical battery model has been proposed and implemented in the SPICE environment. The proposed model accounts for battery non-linear open-circuit voltage and non-linear capacity effect, which are essential for renewable energy storage applications. The proposed model consists of kinetic based runtime estimation model and transient response model. The proposed model was validated with experimental data on Li-ion batteries. The results show that the proposed model can accurately predict the battery runtime and I–V performance with acceptable execution time overhead. Moreover, the proposed model can also be easily extended to other batteries.

The microstructure evolution and impact toughness of the coarse grain heat-affected zone (CGHAZ) of TiNbV microalloyed steels were investigated by using a thermal simulation test. The samples were treated with various simulated welding thermal cycles. The phase constituents and grain sizes were analyzed by using electron backscatter diffraction analysis. The microstructure of the CGHAZ of the treated samples consisted of ferrite, acicular ferrite, pearlite, and bainite. The samples have a higher impact toughness under a lower welding heat input. This is because the microstructure of the CGHAZ is dominated by the higher volume fraction of the high-angle grain boundaries of acicular ferrites. The presence of bainite and coarsening grains are two key factors deteriorating the toughness of the CGHAZ of TiNbV microalloyed steels. The volume fraction of bainite sharply increased as the welding heat input increased, leading to a decrease in the impact toughness of the CGHAZ. For a higher welding heat input, both the severe coarsening of the grain size and a higher bainite content would result in poor impact toughness.

Paediatric cataract is an opacity of the normally transparent lens in the eye, which occurs at birth (congenital) or develops during childhood. It is a leading cause of irreversible blindness in children. Up to 30% of paediatric cataracts are inherited. Although hundreds of cataract-related genes and loci have been found, genetic aetiology can not be identified in at least 40% of patients with inherited cataracts. Paediatric cataract is a highly heterogeneous disease with variable severity observed in affected individuals with the same causative mutation within a family. Several studies have suggested the involvement of modifier genes in paediatric cataract formation, but such genes have not been identified. This project consists of two studies and the overall aim is to identify causative and modifier genes for paediatric cataract. The first study assessed the biological function of a novel candidate causative gene previously identified in a family with paediatric cataract. The HTR1F gene was knocked out in F0 zebrafish using CRISPR-Cas9 ribonucleoprotein complexes. There was no significant difference in cataract formation between the htrlfknockout group and the control group. Therefore we concluded that knocking out HTRJF in the zebrafish models does not provide evidence for it being a cataract causative gene. Further investigations are warranted to obtain additional evidence. The second study investigated the potential for modifier genes in two extended families (family CRCH13 and family CSA91/110) with autosomal dominant paediatric cataract. The clinical phenotype information for each participant was updated and a high degree of variability for age of diagnosis and age of surgery within each family was noted. Genome-wide multipoint parametric linkage analyses of the affection status of cataract combined with whole-genome sequencing validated the previously reported causative genes. In addition, linkage analysis also indicated the existence of potential modifier genes through the presence of several suggestive linkage peaks. Further study of genes that modify the disease severity was conducted in these two extended paediatric cataract families. Genome-wide multipoint variance components linkage analysis of disease severity classified by age of diagnosis and age of surgery revealed one significant linkage region and two suggestive linkage regions likely containing modifier variants in family CRCH13, but failed to detect any linkage regions in CSA91/110 likely due to limited statistical power. In summary, we evaluated the function of a novel candidate cataract­ causing gene in zebrafish models. In addition, we developed an approach for rapid and highly efficient evaluation of cataract candidate genes in FO zebrafish using CRISPR-Cas9 ribonucleoprotein complexes. Zebrafish cataract assessment criteria were also generated, which to our knowledge, is the first systematic, definitive cataract assessment criteria for the zebrafish model. We confirmed the causative genes in two large paediatric cataract families and identified candidate linkage intervals for genetic modifiers in one of the families. The findings and novel strategies generated from this project can benefit the understanding of the pathogenesis of paediatric cataract and contribute to the identification of novel cataract-causing genes and modifier genes.

One set of horizontal target elements of the Test Divertor Units (TDU), retrieved from the Wendelstein 7-X (W7-X) vessel after the end of second divertor Operation Phase (OP1.2B) in Hydrogen (H), were investigated by picosecond Laser-Induced Breakdown Spectroscopy (ps-LIBS). The Boron (B) distribution, H pattern and the material erosion/deposition pattern on these target elements were analyzed with high depth resolution and mapped in the poloidal direction of W7-X. From the spectroscopic analysis, B, H, Carbon (C) and Molybdenum (Mo) were clearly identified. A non-uniformly distributed B pattern on these divertor target elements was determined by the combination of B layer deposition during the three boronizations and W7-X plasma operation with multiple erosion and deposition steps of B. Like the TDU, the analyzed target elements are made of fine grain graphite, but have two marker layers which allow us to determine the material migration via the ps-LIBS technique. Two net erosion zones including one main erosion zone with a peak erosion depth of 6.5 μm and one weak erosion with a peak erosion of 1.3 μm were determined. Between two net erosion zones, a net deposition zone with width of 135 mm and a thickness up to 3.5 μm at the peak deposition location was determined by the ps-LIBS technique. The B distributions are correlated with the erosion/deposition pattern and the operational time in standard magnetic configuration of W7-X in the phases after the boronizations. The thickness of the containing B layer on these target elements also correlates with the erosion/deposition depth, in which the thickness of the containing B layer varies spatially in poloidal direction between 0.1 μm and 6 μm. Complementary, Focused Ion Beam combined with Scanning Electron Microscopy (FIB-SEM) was employed also to verify and investigate the deposition layer thicknesses at typical net erosion and net deposition zones as well as to identify the three boronizations in depth.

Peer reviewed: True, The effective scaling-up of redox flow batteries (RFBs) can be facilitated upon lowering the capital costs. The application of ubiquitous manganese along with hydrogen (known as H2−Mn regenerative fuel cells (RFC)) is seen as an effective solution for this purpose. Here, we aim to evaluate different positive electrodes so as to improve the key performance metrics of the H2/Mn RFC, namely electrolyte utilization, energy efficiency, and peak power densities. Commercially available carbon paper and graphite felt are used to show that the latter provides better key performance indicators (KPIs), which is consistent with the results reported for standard all-vanadium RFBs in the literature. Even better KPIs are obtained when an in-house carbon catalyst layer (CCL) is employed in combination with graphite felt electrodes (e.g., more than 80% energy efficiency, >0.5 W cm−2 peak power density and electrolyte utilization of 20 Ah L−1 for felt and carbon metal fabric (CMF), prepared by means of electrospinning and carbonization, in comparison with about 75% energy efficiency 0.45 W cm−2 peak power density and 11 Ah L−1 electrolyte utilization for felt on its own). It is envisaged that if the electrochemical performance of CCLs can be optimized then it could open up new opportunities for the commercial exploitation of H2−Mn systems.

Danyang Zhao,1,* Wenban Qin,2,* Chuanxiang Zhao,3 Jianxiong Long,4 Mujun Li1 1Department of Reproductive Center, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China; 2Department of Oncology, Chongzuo People’s Hospital, Nanning 530021, Guangxi Province, People’s Republic of China; 3Department of General Surgery, The Second People’s Hospital of Shenzhen, Nanning 530021, Guangxi Province, People’s Republic of China; 4School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianxiong LongSchool of Public Health, Guangxi Medical University, No. 22 Shuangyong Road, Nanning 530021, Guangxi Province, People’s Republic of ChinaEmail longjx12345@163.comMujun LiDepartment of Reproductive Center, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi 530021, People’s Republic of ChinaEmail sciencecid@126.comPurpose: Recent studies indicate that CXC chemokine receptor type 7 (CXCR7) is associated with tumorigenesis, progression, and metastasis of various cancers, but its roles and molecular mechanisms of action in cervical squamous cell carcinoma (CSCC) remain unclear. Our purpose was to explore the expression patterns of CXCR7 and epidermal growth factor receptor (EGFR) in CSCC and to identify possible correlations with clinical characteristics. We also tested whether CXCR7 can be a screening index for treatment options for CSCC stages IB1 and IIA1.Methods: Expression of CXCR7 and EGFR in tumors from 165 patients with CSCC was evaluated by immunohistochemistry and compared with the clinical data including survival.Results: Patients at CSCC stages IB1 and IIA1 received different treatment options, including radical hysterectomy, pelvic lymph node dissection, and para-aortic lymph node sampling (RH group, 67 patients) or pelvic external-beam radiation therapy with brachytherapy (EBRT group, 34 patients). Disease-free survival (DFS) and overall survival (OS) were compared between two groups at different CXCR7 expression levels. Immunohistochemical staining showed that CXCR7, EGFR, phospho-ERK, and phospho-AKT amounts increased from normal cervical epithelia and cervical intraepithelial neoplasia to CSCC, and CXCR7 was associated with the disease stage, lymph node metastasis, tumor size ≥40 mm, and EGFR expression. Kaplan–Meier analysis revealed that CXCR7 and EGFR expression was associated with shorter DFS and OS. Multivariate analysis suggested that CXCR7 was independently associated with DFS and OS. Prevalence of recurrence and distant metastasis was significantly lower in the EBRT group than in the RH group during CXCR7 expression. Besides, CXCR7 knockdown significantly decreased the proliferation and invasion of CSCC cells.Conclusion: CXCR7 is coexpressed with EGFR, which may be involved in ERK or AKT pathway activation. CXCR7 may be a screening index for treatment options at CSCC stages IB1 and IIA1.Keywords: CXC chemokine receptor type 7, cervical cancer, cancer treatment protocol

Fluctuating superconductivity—vestigial Cooper pairing in the resistive state of a material—is usually associated with low dimensionality, strong disorder, or low carrier density. Here, we report single-particle spectroscopic, thermodynamic and magnetic evidence for persistent superconducting fluctuations in the heavily hole-doped cuprate superconductor () despite the high carrier density. With a sign-problem-free quantum MonteCarlo calculation, we show how a partially flat band at can help enhance superconducting phase fluctuations. Finally, we discuss the implications of an anisotropic band structure on the phase-coherence-limited superconductivity in overdoped cuprates and other superconductors.

Abbe error is an important factor affecting high-precision machine tools, and the traditional modeling method does not consider Abbe error. Aiming at this problem, based on the traditional error model of machine tools and the formation mechanism of Abbe error, this paper establishes a machine tool spatial error model that considers Abbe error. Then combined with a specific machine tool, based on the measurement of 21 geometric errors of the machine tool to obtain relevant error data, through the combination of qualitative and quantitative accuracy evaluation methods, two models of traditional error model and error model considering Abbe error are analyzed. The accuracy of the machine tool is compared, and the comparison of the compensation effects of the two error models after compensation is also analyzed. The example verification shows that the machine tool spatial error model considering Abbe error is effective and feasible, and the compensation effect is better. It provides an important modeling method for improving the machining accuracy of precision machine tools.

RNA polymerase II (Pol II)-mediated transcription in metazoan requires precise regulation. RNA polymerase II-associated protein 2 (RPAP2) was previously identified to transport Pol II from cytoplasm to nucleus and dephosphorylates Pol II C-terminal domain (CTD). We found that RPAP2 binds hypo/hyper-phosphorylated Pol II with undetectable phosphatase activity. Structure of RPAP2-Pol II shows mutually exclusive assembly of RPAP2-Pol II and pre-initiation complex (PIC) due to three steric clashes. RPAP2 prevents/disrupts Pol II-TFIIF interaction and impairs in vitro transcription initiation, suggesting a function in prohibiting PIC assembly. Loss of RPAP2 in cells leads to global accumulation of TFIIF and Pol II at promoters, indicating critical role of RPAP2 in inhibiting PIC assembly independent of its putative phosphatase activity. Our study indicates that RPAP2 functions as a gatekeeper to prohibit PIC assembly and transcription initiation and suggests a novel transcription checkpoint.

Yuxing Jin, Huikang Xie, Liang Duan, Deping Zhao, Jiaan Ding, Gening Jiang Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People’s Republic of ChinaCorrespondence: Gening JiangDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People’s Republic of ChinaEmail jiang15736@sina.comBackground: The long noncoding RNA cancer susceptibility 9 (CASC9) has been recognized as an important modulator of cell growth and metastasis in many cancers. However, its detailed roles in lung cancer remain unclear. In this study, we aimed to investigate its functions and molecular mechanism in lung cancer progression.Methods: Expression of CASC9 was determined in lung cancer tissues and cell lines by real-time PCR. CCK-8, colony formation, wound healing and transwell assays were done to evaluate the cell proliferation, migration and invasion capacities in vitro. Real-time PCR, Western blot and RNA immunoprecipitation (RIP) assays were performed to dissect the mechanisms.Results: CASC9 was overexpressed in lung cancer specimens and cell lines. Knockdown of CASC9 inhibited cell proliferation, migration, invasion and EMT in lung cancer cells. While overexpression of CASC9 in normal lung epithelial cells did the opposite. CASC9 interacted with HIF-1α and enhanced its protein stability. They formed a positive feedback loop by reciprocally inducing each other expression and regulated cell proliferation and metastasis.Conclusion: Our findings demonstrated a novel regulatory signaling pathway, namely the CASC9/HIF-1α axis, which was involved in lung cancer progression. These findings can provide valuable insights on the potential therapy application for lung cancer.Keywords: CASC9, HIF-1α, cell proliferation, metastasis, lung cancer

Seong Yong Lim1,*, Di Zhao2,*, Eliseo Guallar2, Yoosoo Chang3, Seungho Ryu3, Juhee Cho4, Jung Yeon Shim5 1Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea; 2Department of Epidemiology and Medicine, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; 3Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, South Korea; 4Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea; 5Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea*These authors contributed equally to this workCorrespondence: Jung Yeon ShimDepartment of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunanro, Jongro-ku, Seoul 03181, South KoreaTel +82 22 001 2200Fax +82 22 001 1922Email jy7.shim@samsung.comPurpose: Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation. We investigated whether elevated baseline serum C-reactive protein (CRP) levels in healthy individuals are associated with the risk of incident COPD by smoking status.Patients and methods: This was a cohort study of 63,260 adult men and women who were older than 40years, free of COPD at baseline, and underwent health screening from 2002 to 2016 with at least one follow-up visit through December 2016. We investigated the association between baseline high-sensitivity CRP (hsCRP) levels and incident COPD by smoking status, using flexible parametric proportional hazards models and pooled logistic regression analyses.Results: The multivariable-adjusted hazard ratio (95% confidence interval) comparing participants in the 90th to those in the 10th percentile of hsCRP was 1.19 (1.08, 1.31). The corresponding hazard ratio in never, former, and current smokers were 1.07 (0.89, 1.29), 1.22 (1.05, 1.42), and 1.22 (1.05, 1.41), respectively. The association between hsCRP levels and incident COPD had a similar dose–response pattern in former and current smokers, but not in never smokers.Conclusion: Higher baseline hsCRP is associated with an increased risk to develop COPD in ever smokers but not in never smokers.Keywords: smokers, C-reactive protein, systemic inflammation, COPD, cohort studies

Xin-Yu Liao,1,* Yang Lei,2,* Song-Feng Chen,2 Jing Cheng,3 Dan Zhao,4 Zhi-Feng Zhang,2 Xin Han,5 Ya Zhang,2 Hua-Bao Liao,2 Yang Zhuang,2 Juan Chen,6 Hai-Bing Zhou,5 Qi Wan,7 Ying-Ying Zou,11Department of Pathology and Pathophysiology, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming 650500, People’s Republic of China; 2Department of Physiology, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan 430071, People’s Republic of China; 3Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, People’s Republic of China; 4Department of Physiology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, People’s Republic of China; 5School of Pharmacy, Wuhan University, Wuhan 430071, People’s Republic of China; 6Department of Neurology, The Central Hospital of Wuhan, Tongji Medical College of Huazhong University of Science & Technology, Wuhan 430013, People’s Republic of China; 7Institute of Neuroregeneration & Neurorehabilitation, Collaborative Innovation Center for Brain Science, Department of Neurosurgery of the Affiliated Hospital, Qingdao University, Qingdao 266071, People’s Republic of China*These authors contributed equally to this work Background: The authors have recently designed a new compound bisperoxovandium (pyridin-2-squaramide) [bpV(pis)] and verified that bpV(pis) confers neuroprotection through suppressing PTEN and activating ERK1/2, respectively. Intracerebral hemorrhage (ICH) is the second most common cause of stroke and has severe clinical outcome. In this study, we investigate the effect of bpV(pis) in ICH model both in vivo and in vitro.Materials and methods: The novel drug bpV(pis) was synthesized in the Faculty of Pharmacy, Wuhan University School of Medicine. An ICH model was generated on both SD rats and cells. bpV(pis) was injected into intracerebroventricular or culture media. Western blotting was applied to test the signal pathway. To determine the effect of bpV(pis) on PTEN inhibition and ERK1/2 activation, we measured the phosphorylation level of AKT (a direct downstream target of PTEN that negatively regulates AKT) and ERK1/2. FJC, MTT, and LDH were applied to measure the cell viability. Neurobehavioral tests were performed to measure the effect of bpV(pis).Results: The in vivo results showed that intracerebroventricular administration of bpV(pis) significantly alleviates hematoma, the damage of brain–blood barrier and brain edema. The in vitro results demonstrated that bpV(pis) treatment reduces ICH-induced neuronal injury. Western blotting results identified that bpV(pis) exerts a neuroprotective effect by significantly increasing the phosphorylation level of AKT and ERK1/2 after experimental ICH. Neurobehavioral tests indicate that bpV(pis) promotes functional recovery in ICH animals.Conclusion: This study provides first and direct evidence for a potential role of bpV(pis) in ICH therapy.Keywords: bpV(pis), intracerebral hemorrhage, PTEN, AKT, ERK1/2, neuroprotection

Dehua Zhao,1 Jing Chen,1 Mingming Chu,2 Jisheng Wang11Department of Clinical Pharmacy, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang 621000, People’s Republic of China; 2Department of Clinical Pharmacy, The Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, People’s Republic of ChinaBackground: The present standard dose of gemcitabine (Gem), a pyrimidine antimetabolite, is 1,000–1,250 mg/m2, and the infusion time is 30min. However, pharmacological studies have demonstrated that Gem with prolonged infusion could attain a better accumulation rate of Gem triphosphate (active metabolites of Gem), indicating that Gem with prolonged infusion is superior to 30-min infusion. Thus, this systematic review aims to provide some references for Gem administered as a prolonged infusion.Methods: We searched electronic databases, including PubMed, EMBASE, Cochrane Library, and CNKI, for trials. Keywords were “Gem,” “prolonged infusion,” and “low-dose.” In addition, we used the Cochrane Handbook V5.1.0 and methodological index for non-randomized studies to evaluate the quality of randomized controlled trials (RCTs) and non-RCTs, respectively. Furthermore, Cochrane Collaboration guidelines and the PRISMA statement were adopted.Results: We systematically reviewed 19 studies (5 RCTs and 14 non-RCTs). All studies assessed the efficacy and safety of Gem administered as a prolonged low-dose infusion (P-LDI) and reported that Gem administered as P-LDI was effective and well tolerated.Conclusion: Gem administered as P-LDI is effective, safe, and economical, especially suited for patients with poor performance status or without good economic condition.Keywords: gemcitabine, low dose, prolonged infusion, pharmacokinetics