Publications by authors named "Dahai Liu"

79 Publications

Functional genomics study of protein inhibitor of activated STAT1 in mouse hippocampal neuronal cells revealed by RNA sequencing.

Aging (Albany NY) 2021 03 24;13(6):9011-9027. Epub 2021 Mar 24.

Foshan Stomatology Hospital, School of Medicine, Foshan University, Foshan 528000, Guangdong, China.

Protein inhibitor of activated STAT1 (PIAS1), a small ubiquitin-like modifier (SUMO) E3 ligase, was considered to be an inhibitor of STAT1 by inhibiting the DNA-binding activity of STAT1 and blocking STAT1-mediated gene transcription in response to cytokine stimulation. PIAS1 has been determined to be involved in modulating several biological processes such as cell proliferation, DNA damage responses, and inflammatory responses, both and . However, the role played by PIAS1 in regulating neurodegenerative diseases, including Alzheimer's disease (AD), has not been determined. In our study, significantly different expression levels of PIAS1 between normal controls and AD patients were detected in four regions of the human brain. Based on a functional analysis of in undifferentiated mouse hippocampal neuronal HT-22 cells, we observed that the expression levels of several AD marker genes could be inhibited by overexpression. Moreover, the proliferation ability of HT-22 cells could be promoted by the overexpression of . Furthermore, we performed RNA sequencing (RNA-seq) to evaluate and quantify the gene expression profiles in response to overexpression in HT-22 cells. As a result, 285 significantly dysregulated genes, including 79 upregulated genes and 206 downregulated genes, were identified by the comparison of /+ cells with WT cells. Among these genes, five overlapping genes, including early growth response 1 (), early growth response 2 (), early growth response 3 (), FBJ osteosarcoma oncogene () and fos-like antigen 1 (), were identified by comparison of the transcription factor binding site (TFBS) prediction results for STAT1, whose expression was evaluated by qPCR. Three cell cycle inhibitors, p53, p18 and p21, were significantly downregulated with the overexpression of . Analysis of functional enrichment and expression levels showed that basic region leucine zipper domain-containing transcription factors including zinc finger C2H2 (zf-C2H2), homeobox and basic/helix-loop-helix (bHLH) in several signaling pathways were significantly involved in PIAS1 regulation in HT-22 cells. A reconstructed regulatory network under PIAS1 overexpression demonstrated that there were 43 related proteins, notably Nr3c2, that directly interacted with PIAS1.
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http://dx.doi.org/10.18632/aging.202749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034905PMC
March 2021

Identification of hub ubiquitin ligase genes affecting Alzheimer's disease by analyzing transcriptome data from multiple brain regions.

Sci Prog 2021 Jan-Mar;104(1):368504211001146

Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.

The ubiquitin-proteasome system (UPS) plays crucial roles in numerous cellular functions. Dysfunction of the UPS shows certain correlations with the pathological changes in Alzheimer's disease (AD). This study aimed to explore the different impairments of the UPS in multiple brain regions and identify hub ubiquitin ligase (E3) genes in AD. The brain transcriptome, blood transcriptome and proteome data of AD were downloaded from a public database. The UPS genes were collected from the Ubiquitin and Ubiquitin-like Conjugation Database. The hub E3 genes were defined as the differentially expressed E3 genes shared by more than three brain regions. E3Miner and UbiBrowser were used to predict the substrate of hub E3. This study shows varied impairment of the UPS in different brain regions in AD. Furthermore, we identify seven hub E3 genes (CUL1, CUL3, EIF3I, NSMCE1, PAFAH1B1, RNF175, and UCHL1) that are downregulated in more than three brain regions. Three of these genes (CUL1, EIF3I, and NSMCE1) showed consistent low expression in blood. Most of these genes have been reported to promote AD, whereas the impact of RNF175 on AD is not yet reported. Further analysis revealed a potential regulatory mechanism by which hub E3 and its substrate genes may affect transcription functions and then exacerbate AD. This study identified seven hub E3 genes and their substrate genes affect transcription functions and then exacerbate AD. These findings may be helpful for the development of diagnostic biomarkers and therapeutic targets for AD.
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http://dx.doi.org/10.1177/00368504211001146DOI Listing
March 2021

Lactobionic acid-modified thymine-chitosan nanoparticles as potential carriers for methotrexate delivery.

Carbohydr Res 2021 Mar 26;501:108275. Epub 2021 Feb 26.

Department of Basic Medicine and Biomedical Engineering, School of Medicine, Foshan University, Foshan, 528000, Guangdong, PR China. Electronic address:

In order to achieve efficient delivery of methotrexate (MTX), thymine-chitosan nanoparticles (Thy-Cs NPs) were prepared, and further decorated with lactobionic acid (LA) to obtain tumor-targeting nanoparticles (LA-Thy-Cs NPs). These nanoparticles possessed a regular spherical structure with the average size about 190-250 nm and narrow size distribution, which were kinetically stable in the physiological environment. Due to electrostatic interactions and multiple hydrogen-bonding interactions between MTX and carriers, MTX was loaded into Thy-Cs NPs with high drug loading content (~20%). MTX release from Thy-Cs NPs was significantly accelerated in the mildly acidic environment due to the destruction of two types of non-covalent interactions. In vitro cell experiments demonstrated that LA-Thy-Cs NPs could be efficiently internalized into hepatoma carcinoma cells, leading to higher cytotoxicity. Moreover, MTX-loaded LA-Thy-Cs NPs performed an enhanced growth inhibition in three-dimensional multicellular tumor spheroids. Thus, the LA decorated thymine-chitosan nanocarriers can be a promising candidate for efficient delivery of MTX.
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http://dx.doi.org/10.1016/j.carres.2021.108275DOI Listing
March 2021

Effect of selenium-enriched kiwifruit on body fat reduction and liver protection in hyperlipidaemic mice.

Food Funct 2021 Mar;12(5):2044-2057

School of Life Sciences, Anhui University, Hefei 230601, China. and Center for Stem Cell and Translational Medicine, Anhui University, Hefei 230601, China.

This study aimed to investigate the effects and mechanism of selenium-enriched kiwifruit (Se-Kiwi) on lipid-lowering and liver protection in hyperlipidaemic mice induced by consuming a long-term high-fat diet. Selenium-enriched cultivation can significantly improve the contents of vitamins and functional elements in kiwifruits, especially vitamin C, selenium, and manganese, thus enhancing the activity of antioxidant enzymes in Se-Kiwi. Se-Kiwi can significantly improve the activity of antioxidant enzymes in the liver of hyperlipidaemic mice, restore the liver morphology of mice close to normal, reduce the fat content in the liver, and inhibit the accumulation of abdominal fat cells. Meanwhile, the expression levels of inflammation-related factors (TNF-α and NF-κB) and lipid synthesis related genes (SREBP-1c and FAS) are inhibited at the gene transcription and protein expression levels, and the expression levels of energy expenditure related genes (PPAR-α and CPT1) are increased, resulting in lipid reductions and liver protection. In conclusion, our results indicate that the protective mechanism of Se-Kiwi on high-fat diet mice is associated with enhancing the activity of antioxidant enzymes, reducing the degree of the inflammatory reaction, inhibiting the fat synthesis, and accelerating body energy consumption.
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http://dx.doi.org/10.1039/d0fo02410dDOI Listing
March 2021

Phenylboronic acid-conjugated chitosan nanoparticles for high loading and efficient delivery of curcumin.

Carbohydr Polym 2021 Mar 14;256:117497. Epub 2020 Dec 14.

Department of Basic Medicine and Biomedical Engineering, School of Stomatology and Medicine, Foshan University, Foshan, 528000 Guangdong, PR China. Electronic address:

In order to achieve high loading and efficient delivery of curcumin, phenylboronic acid-conjugated chitosan nanoparticles were prepared by a simple desolvation method. These nanoparticles exhibited a regular spherical shape with the average size about 200-230 nm and narrow size distribution, which were kinetically stable under physiological condition. Due to boronate ester formation between curcumin and phenylboronic acid groups in the nanoparticles, and the hydrogen bonding interactions between curcumin and nanocarriers, curcumin was successfully loaded into the nanoparticles with high drug loading content. These curcumin-loaded nanoparticles showed pH and reactive oxygen species (ROS)-triggered drug release behavior. In vitro cell experiments revealed that the blank nanoparticles were completely nontoxic to cultured cells, and the curcumin-loaded nanoparticles exhibited efficient antitumor efficiency against cancer cells. Moreover, the drug-loaded nanoparticles performed an enhanced growth inhibition in three-dimensional multicellular tumor spheroids. Thus, these nanocarriers would be a promising candidate for curcumin delivery in tumor treatment.
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http://dx.doi.org/10.1016/j.carbpol.2020.117497DOI Listing
March 2021

First-Line Immune-Checkpoint Inhibitors in Non-Small Cell Lung Cancer: Current Landscape and Future Progress.

Front Pharmacol 2020 7;11:578091. Epub 2020 Oct 7.

Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China.

Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths worldwide. Most of these patients with non-small cell lung cancer (NSCLC) present with the advanced stage of the disease at the time of diagnosis, and thus decrease the 5-year survival rate to about 5%. Immune checkpoint inhibitors (ICIs) can act on the inhibitory pathway of cancer immune response, thereby restoring and maintaining anti-tumor immunity. There are already ICIs targeting different pathways, including the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) pathway. Since March 2015, the US Food and Drug Administration (FDA) approved nivolumab (anti-PD-1 antibody) as the second-line option for treatment of patients with advanced squamous NSCLC. Additionally, a series of inhibitors related to PD-1/PD-L1 immune-checkpoints have helped in the immunotherapy of NSCLC patients, and modified the original treatment model. However, controversies remain regarding the use of ICIs in a subgroup with targeted oncogene mutations is a problem that we need to solve. On the other hand, there are continuous efforts to find biomarkers that effectively predict the response of ICIs to screen suitable populations. In this review, we have reviewed the history of the continuous developments in cancer immunotherapy, summarized the mechanism of action of the immune-checkpoint pathways. Finally, based on the results of the first-line recent trials, we propose a potential first-line immunotherapeutic strategy for the treatment of the patients with NSCLC.
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http://dx.doi.org/10.3389/fphar.2020.578091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577011PMC
October 2020

Supramolecular nanosubstrate-mediated delivery system enables CRISPR-Cas9 knockin of hemoglobin beta gene for hemoglobinopathies.

Sci Adv 2020 Oct 23;6(43). Epub 2020 Oct 23.

Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging (CIMI), California NanoSystems Institute (CNSI), University of California, Los Angeles, Los Angeles, CA 90095, USA.

Leveraging the endogenous homology-directed repair (HDR) pathway, the CRISPR-Cas9 gene-editing system can be applied to knock in a therapeutic gene at a designated site in the genome, offering a general therapeutic solution for treating genetic diseases such as hemoglobinopathies. Here, a combined supramolecular nanoparticle (SMNP)/supramolecular nanosubstrate-mediated delivery (SNSMD) strategy is used to facilitate CRISPR-Cas9 knockin of the hemoglobin beta (HBB) gene into the adeno-associated virus integration site 1 (AAVS1) safe-harbor site of an engineered K562 3.21 cell line harboring the sickle cell disease mutation. Through stepwise treatments of the two SMNP vectors encapsulating a Cas9•single-guide RNA (sgRNA) complex and an HBB/green fluorescent protein (GFP)-encoding plasmid, CRISPR-Cas9 knockin was successfully achieved via HDR. Last, the HBB/GFP-knockin K562 3.21 cells were introduced into mice via intraperitoneal injection to show their in vivo proliferative potential. This proof-of-concept demonstration paves the way for general gene therapeutic solutions for treating hemoglobinopathies.
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http://dx.doi.org/10.1126/sciadv.abb7107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608838PMC
October 2020

REPAIRx, a specific yet highly efficient programmable A > I RNA base editor.

EMBO J 2020 11 15;39(22):e104748. Epub 2020 Oct 15.

School of Life Sciences and Technology, ShanghaiTech University, Shanghai, China.

Programmable A > I RNA editing is a valuable tool for basic research and medicine. A variety of editors have been created, but a genetically encoded editor that is both precise and efficient has not been described to date. The trade-off between precision and efficiency is exemplified in the state of the art editor REPAIR, which comprises the ADAR2 deaminase domain fused to dCas13b. REPAIR is highly efficient, but also causes significant off-target effects. Mutations that weaken the deaminase domain can minimize the undesirable effects, but this comes at the expense of on-target editing efficiency. We have now overcome this dilemma by using a multipronged approach: We have chosen an alternative Cas protein (CasRx), inserted the deaminase domain into the middle of CasRx, and redirected the editor to the nucleus. The new editor created, dubbed REPAIRx, is precise yet highly efficient, outperforming various previous versions on both mRNA and nuclear RNA targets. Thus, REPAIRx markedly expands the RNA editing toolkit and illustrates a novel strategy for base editor optimization.
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http://dx.doi.org/10.15252/embj.2020104748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667880PMC
November 2020

β-catenin regulates myocardial ischemia/reperfusion injury following heterotopic heart transplantation in mice by modulating PTEN pathways.

Am J Transl Res 2020 15;12(8):4757-4771. Epub 2020 Aug 15.

School of Medicine, Guangxi University Nanning, People's Republic of China.

Ischemia reperfusion (I/R) injury, an inevitable event accompanying heart transplantation, is the primary factor leading to organ failure and graft rejection. In order to prevent I/R injury, we established murine heart transplantation model with I/R and cell culture system to determine whether β-catenin is a mediate factor in preventing I/R injury in heart transplantation. After successfully established heterotopic heart transplantation mice model, the I/R injury was induced, and two dynamic temporal were studied during different I/R phases. With the increase of ischemia and reperfusion time, heart damage was more severe. In the initial study, we observed that β-catenin was significantly decreased, while ROCK1 and PTEN increased during the perfusion phase from day 0 to day 1, and remain the same level until 3 days later. The similar pattern that β-catenin was down-regulated while ROCK1 and PTEN were up-regulated was also observed in the dynamic temporal ischemia study. To further investigate the role of β-catenin signaling in I/R injury , β-catenin over-expressing plasmid was transfected into HL-1 cells, a cardiac cell line. We noted that β-catenin over-expressing cardiomyocytes showed decreased ROCK1/PTEN expression both at mRNA and protein levels. In addition, cobalt dichloride (CoCl) -induced oxidative stress model was further established to mimic cardiac I/R injury. We observed that CoCl-induced activation of ROCK1/PTEN signaling pathway were attenuated by transient transfection of a β-catenin over-expressing plasmid. Taken together, our results suggest that cardiac transplant induced IR injury is closely associated with the down-regulation of β-catenin and up-regulation of ROCK1 and PTEN expression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476114PMC
August 2020

Multiscale model for the optimal design of pedestrian queues to mitigate infectious disease spread.

PLoS One 2020 9;15(7):e0235891. Epub 2020 Jul 9.

Computer Science, University of West Florida, Pensacola, Florida, United States of America.

There is direct evidence for the spread of infectious diseases such as influenza, SARS, measles, and norovirus in locations where large groups of people gather at high densities e.g. theme parks, airports, etc. The mixing of susceptible and infectious individuals in these high people density man-made environments involves pedestrian movement which is generally not taken into account in modeling studies of disease dynamics. We address this problem through a multiscale model that combines pedestrian dynamics with stochastic infection spread models. The pedestrian dynamics model is utilized to generate the trajectories of motion and contacts between infected and susceptible individuals. We incorporate this information into a stochastic infection dynamics model with infection probability and contact radius as primary inputs. This generic model is applicable for several directly transmitted diseases by varying the input parameters related to infectivity and transmission mechanisms. Through this multiscale framework, we estimate the aggregate numbers and probabilities of newly infected people for different winding queue configurations. We find that the queue configuration has a significant impact on disease spread for a range of infection radii and transmission probabilities. We quantify the effectiveness of wall separators in suppressing the disease spread compared to rope separators. Further, we find that configurations with short aisles lower the infection spread when rope separators are used.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235891PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347216PMC
September 2020

In situ conversion of defective Treg into SuperTreg cells to treat advanced IPEX-like disorders in mice.

Nat Commun 2020 06 3;11(1):2781. Epub 2020 Jun 3.

School of Life Sciences and Technology, Shanghai Tech University, Shanghai, China.

Mutations disrupting regulatory T (Treg) cell function can cause IPEX and IPEX-related disorders, but whether established disease can be reversed by correcting these mutations is unclear. Treg-specific deletion of the chromatin remodeling factor Brg1 impairs Treg cell activation and causes fatal autoimmunity in mice. Here, we show with a reversible knockout model that re-expression of Brg1, in conjunction with the severe endogenous proinflammatory environment, can convert defective Treg cells into powerful, super-activated Treg cells (SuperTreg cells) that can resolve advanced autoimmunity,  with  Brg1 re-expression in a minor fraction of Treg cells sufficient for the resolution in some cases. SuperTreg cells have enhanced trafficking and regulatory capabilities, but become deactivated as the inflammation subsides, thus avoiding excessive immune suppression. We propose a simple, robust yet safe gene-editing-based therapy for IPEX and IPEX-related disorders that exploits the defective Treg cells and the inflammatory environment pre-existing in the patients.
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http://dx.doi.org/10.1038/s41467-020-15836-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271236PMC
June 2020

Fuel shortages during hurricanes: Epidemiological modeling and optimal control.

PLoS One 2020 1;15(4):e0229957. Epub 2020 Apr 1.

Department of Graduate Studies, Embry-Riddle Aeronautical University, Daytona Beach, Florida, United States of America.

Hurricanes are powerful agents of destruction with significant socioeconomic impacts. A persistent problem due to the large-scale evacuations during hurricanes in the southeastern United States is the fuel shortages during the evacuation. Computational models can aid in emergency preparedness and help mitigate the impacts of hurricanes. In this paper, we model the hurricane fuel shortages using the SIR epidemic model. We utilize the crowd-sourced data corresponding to Hurricane Irma and Florence to parametrize the model. An estimation technique based on Unscented Kalman filter (UKF) is employed to evaluate the SIR dynamic parameters. Finally, an optimal control approach for refueling based on a vaccination analogue is presented to effectively reduce the fuel shortages under a resource constraint. We find the basic reproduction number corresponding to fuel shortages in Miami during Hurricane Irma to be 3.98. Using the control model we estimated the level of intervention needed to mitigate the fuel-shortage epidemic. For example, our results indicate that for Naples- Fort Myers affected by Hurricane Irma, a per capita refueling rate of 0.1 for 2.2 days would have reduced the peak fuel shortage from 55% to 48% and a refueling rate of 0.75 for half a day before landfall would have reduced to 37%.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229957PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112216PMC
July 2020

Yolk-shell nanovesicles endow glutathione-responsive concurrent drug release and T MRI activation for cancer theranostics.

Biomaterials 2020 06 16;244:119979. Epub 2020 Mar 16.

Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, 20892, United States. Electronic address:

The effort of incorporating therapeutic drugs with imaging agents has been one of the mainstreams of nanomedicine, which holds great promise in cancer treatment in terms of monitoring therapeutic drug activity and evaluating prognostic index. However, it is still technically challenging to develop nanomedicine endowing a spatiotemporally controllable mechanism of drug release and activatable imaging capability. Here, we developed a yolk-shell type of GSH-responsive nanovesicles (NVs) in which therapeutic drug (Doxorubicin, DOX) and magnetic resonance imaging (MRI) contrast agent (ultrasmall paramagnetic iron oxide nanoparticles, USPIO NPs) formed complexes (denoted as USD) and were encapsulated inside the NVs. The formation of USD complexes is mediated by both the electrostatic adsorption between DOX and poly(acrylic acid) (PAA) polymers and the DOX-iron coordination effect on USPIO NPs. The obtained USD NVs showed a unique yolk-shell structure with restrained drug activity and quenched T MRI contrast ability which, on the other hand, can respond to glutathione (GSH) and lead to drug release and T contrast activation in a spatiotemporally concurrent manner. Furthermore, the USD NVs exhibited great potential to kill HCT116 cancer cells in vitro and effectively inhibit the tumor growth in vivo. This study may shed light on the design of sophisticated nanotheranostics in precision nanomedicine.
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http://dx.doi.org/10.1016/j.biomaterials.2020.119979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138217PMC
June 2020

Erratum to: Bisphenol S triggers the malignancy of hemangioma cells via regulation of basic fibroblast growth factor [Chemico-Biological Interactions 315 (2020)].

Chem Biol Interact 2020 Jan;315:108982

Department of Obstetrics and Gynecology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China.

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http://dx.doi.org/10.1016/j.cbi.2020.108982DOI Listing
January 2020

Germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors.

J Hum Genet 2020 Jul 7;65(7):577-587. Epub 2020 Feb 7.

Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.

Genetic testing for BRCA1/2 mutations has become the standard clinical practice. Recent findings suggest the clinical significance of multigene panel testing of BRCA1/2 and other cancer-related genes. However, the clinical features of patients with breast cancer with germline mutations identified using multigene panels remain unclear. In this study, DNA samples from 583 Chinese women with breast cancer were subjected to target sequencing for 54 cancer-related genes using a pre-capture pooling method followed by next-generation sequencing. We identified 79 pathogenic germline mutations in 21 cancer-related genes. Forty-five patients (7.7%) harbored BRCA1/2 mutations, and 38 patients (6.5%) carried pathogenic mutations in the remaining 19 genes. PALB2 was the most commonly (1.2%) mutated gene other than BRCA1/2. Most of the identified pathogenic mutations were novel, suggesting mutation screening by using multigene panel testing is important particularly for non-European populations. Mutations in BRCA1/2 and the other cancer-related genes were differentially associated with clinical features. BRCA1 mutation carriers were strongly associated with triple-negative breast cancer (TNBC), whereas BRCA2 mutation carriers were not. Tumors in BRCA1-mutation carriers had a high histological grade. Patients with BRCA2-mutated breast cancers were likely to develop E-cadherin-negative tumors with bone metastases. Furthermore, mutations in PALB2 were strongly associated with TNBC. We demonstrated the usefulness of multigene panel testing and observed that a substantial proportion of patients with breast cancer had hereditary risk factors. Identifying differential associations between mutation status and clinical features will advance our understanding regarding the pathologies of this heterogeneous disease.
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http://dx.doi.org/10.1038/s10038-020-0729-7DOI Listing
July 2020

Ethanol extract of suppresses liver cancer cell proliferation and migration.

Chin Med 2020 31;15:11. Epub 2020 Jan 31.

1Department of Basic Medicine and Biomedical Engineering, School of Stomatology and Medicine, Foshan University, Foshan, People's Republic of China.

Background: belonging to the genus (Rubiaceae), is distributed throughout tropical and subtropical Asia. In this study, we evaluated for the first time the anti-proliferation and anti-migration effects of ethanol extract of (OPE) on HepG2 and SMMC-7721 cells, and explored the related mechanism.

Methods: OPE was prepared by percolation with 95% ethanol and its main compounds were analyzed by HPLC-MS. The anti-proliferation effect of OPE was evaluated by the CCK-8 assay and colony formation assay. Cell cycle distribution, apoptosis, and reactive oxygen species (ROS) level were detected by flow cytometry. Migration and invasion abilities were detected by Transwell migration/invasion assays. The expression of correlated proteins was determined using western blotting.

Results: A total of 5 tentative compounds were identified from OPE, including pumiloside, deoxypumiloside, camptothecin, aknadinine, and β-stigmasterol. OPE displayed strong cytostatic effects on HepG2 and SMMC-7721 cells. OPE induced G2/M phase cell cycle arrest, increased apoptosis, and augmented ROS production in these cell lines. In addition, OPE possessed a significant inhibition on cell migration and invasion by reduction of MMP-9 and MMP-2 expression. Moreover, OPE significantly suppressed the phosphorylation of p65.

Conclusions: Our data showed that OPE suppresses liver cancer cell proliferation and migration, which is possibly involved with the inhibition of the NF-κB pathway.
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http://dx.doi.org/10.1186/s13020-020-0291-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995237PMC
January 2020

Prognostic model based on circular RNA circPDK1 for resected lung squamous cell carcinoma.

Transl Lung Cancer Res 2019 Dec;8(6):907-919

Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao 266003, China.

Background: Circular RNA has been revealed as a potential biomarker in multiple malignancies. However, few studies have focused on its potential to be prognostic markers in lung squamous cell carcinoma (LSCC). In this work, we aimed to build a prognostic model of resected LSCC based on circular RNA pyruvate dehydrogenase kinase 1 (circPDK1) and other clinicopathological factors.

Methods: circPDK1 was identified via next-generation sequencing. Three hundred two cases of LSCC tissue and their adjacent normal lung tissues were obtained from multiple medical centers and divided into study cohort (n=232) and validation cohort (n=70). The expression of circPDK1 was detected for analyzing its potential prognostic value for recurrence-free survival (RFS) and overall survival (OS) in LSCC. Finally, combined with circPDK1, T staging, lymph nodes (LN) metastasis status, age, and serum squamous cell Carcinoma Antigen (SCCAg), we built a prognostic model by nomograms method and confirmed it in the validation cohort.

Results: CircPDK1 was identified to be overexpressed (P<0.01) in LSCC. Through analysis in study cohort, circPDK1 patients (less than the mean expression, n=124) showed more lymph nodes metastasis (P=0.025), more vascular invasion (VI) (P=0.047), more visceral pleural invasion (VPI) (P=0.015) and poorer prognosis (P=0.003) than circPDK1 ones (n=108). Univariate and multivariate analysis showed that circPDK1, T staging, LN status, age, and SCCAg were significant prognostic factors for RFS and OS. The prognostic model based on these factors showed the concordance index (C-index) of 0.8214 and 0.8359 for predicting 5-year RFS and OS, respectively. Finally, the calibration curves were performed in the study cohort and a validation cohort to evaluate the model's efficiency.

Conclusions: circPDK1 was identified as a potential biomarker of resected LSCC. The prognostic model including circPDK1, T staging, LN status, age, and SCCAg could effectively predict prognosis of resected LSCC.
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http://dx.doi.org/10.21037/tlcr.2019.11.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976365PMC
December 2019

Fibrinogen, Neutrophil-to-Lymphocyte Rate and Platelet-to-Neutrophil Rate as Novel Acute Phase Indicators in Patients with Thromboangiitis Obliterans.

Ann Vasc Surg 2020 May 16;65:137-144. Epub 2019 Nov 16.

Department of the Lymphatic and Vascular Surgery, China-Japan Union Hospital of Jilin University, Changchun, China. Electronic address:

Background/objectives: The acute exacerbations and progressive deterioration seen in thromboangiitis obliterans (TAO) have been related to poor clinical outcomes. Here, we have studied the association of laboratory biomarkers with the acute phase of TAO (AP-TAO).

Methods/results: We conducted a retrospective case-control study on 112 patients with TAO and 98 healthy controls; comparing the neutrophil-to-lymphocyte rate (NLR), lymphocyte-to-monocyte rate (LMR), platelet-to-neutrophil rate (PNR), fibrinogen (FIB), and apolipoprotein A-I (ApoA-I). Significantly higher NLR level, as well as lower LMR, PNR, and ApoA-I levels were observed in patients with TAO, particularly the acute phase. Significantly increased FIB was only observed in AP-TAO. A positive correlation was found between NLR and with C-reactive protein (CRP) in the acute phase (r = 0.817, P < 0.001). Moreover, NLR, PNR, and FIB levels of 3.38, 45.12, and 3.69 were shown to be the predictive cut-off values for the AP-TAO (sensitivity 72.5, 82,4, and 66,7%, specificity 92.2, 78.4, and 96.1%; area under the curve [AUC] 0.875, 0.855, and 0.872), respectively. The FIB level was independently associated with the AP-TAO (OR = 11.420, P = 0.007).

Conclusions: NLR, PNR, and FIB may be useful markers for the identification of inflammation and the AP-TAO. FIB may be an independent risk factor for the acute phase.
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http://dx.doi.org/10.1016/j.avsg.2019.11.020DOI Listing
May 2020

Exploration of intermediate-sized INDELs by next-generation multigene panel testing in Han Chinese patients with breast cancer.

Hum Genome Var 2019 29;6:51. Epub 2019 Oct 29.

3Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China.

Multigene panel testing via next-generation sequencing focuses on the detection of small-sized mutations, such as single nucleotide variants and short insertions and deletions (INDELs). However, intermediate-sized INDELs have not been fully explored due to technical difficulties. Here, we performed bioinformatics analyses to identify intermediate-sized INDELs in 54 cancer-related genes from 583 Han Chinese patients with breast cancer. We detected a novel deletion-insertion in a translational variant of (also known as ) in one patient.
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http://dx.doi.org/10.1038/s41439-019-0080-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820797PMC
October 2019

WITHDRAWN: Bisphenol S triggers the malignancy of hemangioma cells via regulation of basic fibroblast growth factor.

Chem Biol Interact 2020 01 24;315:108866. Epub 2019 Oct 24.

Lymph and Vascular Surgery Department, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China. Electronic address:

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http://dx.doi.org/10.1016/j.cbi.2019.108866DOI Listing
January 2020

A transcriptomic study of selenium against liver injury induced by beta-cypermethrin in mice by RNA-seq.

Funct Integr Genomics 2020 May 28;20(3):343-353. Epub 2019 Oct 28.

Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei City, 230601, Anhui Province, China.

Evidence from biochemical liver function index and histopathology analysis suggested that selenium could effectively repair the liver injury caused by beta-cypermethrin (β-CYP). However, the molecular mechanism of selenium against liver injury induced by β-CYP remains unclear. In the present study, dynamic changes in gene expression profiles before and after the treatment of NaSeO in liver injury mice were analyzed by using RNA sequencing. As a result, several essential genes and pathways were identified to be significantly associated with this process. In particular, ten genes including Cyp2j11, Cyp2b10, Cyp3a13, Dhrs9, Socs2, Stat4, Gm13305, Cyp3a44, Retsat, and Cyp26b1 were significantly enriched in the functional categories related to retinol metabolism, linoleic acid metabolism, and Jak-STAT signaling pathway. Among them, the expression patterns of nine genes were validated by qRT-PCR, except for Cyp3a44. Furthermore, we have constructed the associated regulatory network based on the identified targets revealed by high throughput screening. Our study may provide insight into the molecular mechanism underlying the protective effect of selenium against liver injury induced by β-CYP in mammals.
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http://dx.doi.org/10.1007/s10142-019-00719-7DOI Listing
May 2020

Integrated analysis of 10 lymphoma datasets identifies E2F8 as a key regulator in Burkitt's lymphoma and mantle cell lymphoma.

Am J Transl Res 2019 15;11(7):4382-4396. Epub 2019 Jul 15.

Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences Kunming 650223, Yunnan, China.

Burkitt's lymphoma (BURK), diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are three main types of B-cell lymphomas. This study aimed to compare the differences of affected biological functions and pathways, as well as to explore the possible regulatory mechanisms and the potential therapeutic targets in BURK, DLBCL and MCL. We performed an integrated analysis of 10 lymphoma datasets including 352 BURK patients, 880 DLBCL patients, 216 MCL patients, and 33 controls. Our results showed that signaling pathways, amino acid metabolism and several lipid metabolism pathways varies considerably among these three types of lymphoma. Furthermore, we identified several key transcription factors (TFs) and their target genes that may promote these diseases by influencing multiple carcinogenic pathways. Among these TFs, we reported first that E2F8 displayed the most significant effects in BURK and MCL. Our results demonstrate that over-expression of E2F8 activates target genes that may promote cell cycle, mitosis, immune and other cancer related functions in BURK and MCL. Therefore, we suggest that E2F8 could be used as a biomarker and potential therapeutic target for BURK and MCL. These findings would be helpful in the study of pathogenesis, and drug discovery and also in the prognosis of B cell lymphomas.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684893PMC
July 2019

Mono (2-ethylhexyl) phthalate (MEHP) triggers the proliferation of hemangioma-derived endothelial cells via YAP signals.

Chem Biol Interact 2019 Sep 24;311:108773. Epub 2019 Jul 24.

Lymph and Vascular Surgery Department, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China. Electronic address:

Hemangioma (HA) is tumor formed by hyper-proliferation of vascular endothelial cells. However, the potential effects of mono-(2-ethylhexyl) phthalate (MEHP) on the progression of HA are not well illustrated. Our present study revealed that MEHP exposure can significantly increase the in vitro proliferation of hemangioma-derived endothelial cells (HemECs). MEHP treatment can activate yes-associated protein (YAP), a key effector of Hippo pathway, by inhibiting its phosphorylation. The dephosphorylation of YAP induced by MEHP can promote the nuclear accumulation of YAP. Knockdown of YAP or its inhibitor can block MEHP triggered cell proliferation. MEHP can increase the levels of precursor and mature mRNA of YAP in HemECs. As well, MEHP extended the half-life of YAP protein. Mechanistically, MEHP can decrease the phosphorylation of YAP via suppressing the activity of large tumor suppressor kinase 1/2 (LATS1/2) to inhibit it induced degradation of YAP. Further, MEHP increased the expression of interferon regulatory factor 1 (IRF1), which can bind to the promoter of YAP to initiate its transcription. Collectively, we revealed that Hippo-YAP signal is involved in MEHP-induced proliferation of HA cells.
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http://dx.doi.org/10.1016/j.cbi.2019.108773DOI Listing
September 2019

Combination of cetuximab with met inhibitor in control of cetuximab-resistant oral squamous cell carcinoma.

Am J Transl Res 2019 15;11(4):2370-2381. Epub 2019 Apr 15.

Department of Basic Medicine and Biomedical Engineering, School of Stomatology and Medicine, Foshan University Foshan 528000, Guangdong, China.

To investigate the underlying molecular mechanisms contributing to oral squamous cell carcinoma (OSCC) cell resistance to the epidermal growth factor receptor (EGFR) inhibitor. OSCC cell lines HSC-2 and HSC-3 were assessed for drug treatment, cell viability, and gene expression and the online gene expression in OSCC tissues was analyzed for association with OSCC prognosis. HSC-2 and HSC-3 cells expressed high EGFR levels, but hepatocyte growth factor (HGF) treatment induced cetuximab resistance, whereas the Met inhibitor PHA-665752 as well as Met siRNA was able to restore OSCC cell sensitivity to cetuximab. HGF treatment induced tumor cells to express p-Akt and p-ERK1/2. In contrast, the activity of Akt and ERK1/2 was suppressed by treatment with PHA-665752, Met siRNA, or their combination. Furthermore, Met was highly expressed in OSCC tissues and associated with a poor patient survival, while Met/HGF-activated Akt also was associated with a poor patient survival. This study demonstrates that Met/HGF expression results in OSCC resistance to cetuximab and tumor recurrence after cetuximab therapy; thus, inhibition of Met/HGF activity could restore OSCC sensitivity to cetuximab.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511799PMC
April 2019

Bryostatin-1 inhibits cell proliferation of hepatocarcinoma and induces cell cycle arrest by activation of GSK3β.

Biochem Biophys Res Commun 2019 05 20;512(3):473-478. Epub 2019 Mar 20.

Department of Vascular Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China. Electronic address:

Bryostatin-1, a macrolide lactone derived from marine organism Bugula neritina, has been shown to inhibit carcinogenesis in several prospective clinical trials. In the current study, the therapeutic potential of bryostatin-1 in inhibiting proliferation of hepatocarcinoma was evaluated by in vitro and in vivo studies. The mechanisms of action of bryostatin-1 were predicted by in silico assay and further validated by surface plasmon resonance and western blot assay. Our results show that bryostatin-1 (100, 200 nM) treatment can suppress cell proliferation and induce G1 cell cycle arrest in PLC/PRF/5 and SMCC7721 cell. We also found a significant inhibitory action of bryostatin-1 (100, 200 nM) on CyclinD1 activity in PLC/PRF/5 cells, and bryostatin-1 can promote ubiquitination-dependent protein degradation of CyclinD1 in PLC/PRF/5 cells. Western blot results confirmed that the active form phospho-GSK3β Tyr216 expression was increased significantly after bryostatin-1 treatment. Activation of GSK3β might be responsible for bryostatin-1 induced cyclinD1 degradation and cell cycle arrest. Taken together, bryostatin-1 may inhibit HCC cells proliferation by promoting cyclinD1 proteolysis and inducing cell cycle arrest.
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http://dx.doi.org/10.1016/j.bbrc.2019.03.014DOI Listing
May 2019

Long noncoding RNA TUG1 promotes proliferation and inhibits apoptosis in multiple myeloma by inhibiting miR-29b-3p.

Biosci Rep 2019 03 22;39(3). Epub 2019 Mar 22.

Department of Ultrasonography, China-Japan Union Hospital of Jilin University, Changchun 130033, PR China

: Long non-coding RNA taurine up-regulated gene 1 (TUG1) was reportedly involved in initiation and development of several cancers. However, its function and molecular mechanisms in multiple myeloma (MM) are still unclear. The present study aimed to determine the expression status, biological function, and potential mechanisms of TUG1 in the progression of MM. The expression levels of TUG1 were examined in MM samples and cell lines by real-time quantitative PCR. The effects of TUG1 on MM cells proliferation and apoptosis were assessed using Cell Counting Kit-8 assay and flow cytometry respectively. MiRNAs-targeted sites in TUG1 were screened by Starbase2.0 and were identified by RNA immunoprecipitation assay combined with luciferase reporter assay.: The expression levels of TUG1 were markedly increased in MM samples and cell lines. Knockdown of TUG1 significantly suppressed the proliferation, induced cell cycle arrest at G1/G0 phase, and promoted apoptosis of MM cells. In exploring the regulatory mechanism, miR-29b-3p was confirmed to be a direct target of TUG1, and repression of miR-29b-3p could partially rescue the effect TUG1 knockdown on MM cell proliferation, cycle, and apoptosis. In addition, TUG1 positively modulated histone deacetylases 4 (HDAC4, a target of miR-29b-3p) expression through sponging of miR-29b-3p in MM cells.: These findings suggested that TUG1 exerted an oncogenic role in MM by acting as a competing endogenous RNA of miR-29b-3p, and implied the potential application of TUG1 in treatment for MM.
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http://dx.doi.org/10.1042/BSR20182489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430741PMC
March 2019

Use of a modified bacterial ghost lysis system for the construction of an inactivated avian pathogenic Escherichia coli vaccine candidate.

Vet Microbiol 2019 Feb 17;229:48-58. Epub 2018 Dec 17.

Shanghai Veterinary Research Institute, the Chinese Academy of Agricultural Sciences (CAAS), 518 Ziyue Road, Shanghai, 200241, PR China. Electronic address:

Vaccination is an effective strategy to prevent avian colibacillosis. Bacterial ghosts (BGs) are prepared by the controlled expression of the phiX174 gene E, which mediates the lysis of Gram-negative bacteria. Staphylococcal nuclease A may be used to produce BGs for further inactivation of host bacteria and elimination of residual genetic material. In this study, the double promoter lysis plasmid (pUC19-ΔcI857-E-rrnB-pL-SN) was successfully constructed and BGs were prepared at 37 °C. The cleavage efficiency of Escherichia coli BGs was 99.9%. Furthermore, to evaluate the immunological effects of the BG vaccines in chickens, a BG vaccine was prepared using the serotype O2 avian pathogenic Escherichia coli deletion strain (DE17ΔluxSΔaroA). The results showed that the BG vaccine was able to achieve over 90% immune protection against virulent challenge using the same serotype O2 strain (DE17 or CE35), while it showed poor cross-protection against serotypes O1 and O78 (data not shown). The enzyme-linked immunosorbent assay results showed that the antibody levels in the immunized groups were higher than in the control group (p < 0.05), with the BG group being the highest. The cytokine tests showed that the levels of interferon-γ in the BG immune group were higher than in the phosphate-buffered saline (PBS) control group (non-immune) (p < 0.01) and the formalin-inactivated vaccine immune group (p < 0.05), and the levels of tumor necrosis factor-α in the BG group were higher than in the formalin-inactivated vaccine (p > 0.05) and the PBS control groups (p < 0.05). In addition, pathological analysis revealed that the PBS control group showed typical fibrinous pericarditis and perihepatitis, whereas the immune group showed no obvious pathological changes. In summary, our findings provide a new strategy for the prevention and control of avian colibacillosis.
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http://dx.doi.org/10.1016/j.vetmic.2018.12.020DOI Listing
February 2019

Effects of PKM2 on global metabolic changes and prognosis in hepatocellular carcinoma: from gene expression to drug discovery.

BMC Cancer 2018 Nov 21;18(1):1150. Epub 2018 Nov 21.

Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China.

Background: Hepatocellular carcinoma (HCC) is a malignant tumor that threatens global human health. High PKM2 expression is widely reported in multiple cancers, especially in HCC. This study aimed to explore the effects of PKM2 on global gene expression, metabolic damages, patient prognosis, and multiple transcriptional regulation relationships, as well as to identify several key metabolic genes and screen some small-molecule drugs.

Methods: Transcriptome and clinical HCC data were downloaded from the NIH-GDC repository. Information regarding the metabolic genes and subsystems was collected from the Recon 2 human metabolic model. Drug-protein interaction data were obtained from the DrugBank and UniProt databases. We defined patients with PKM2 expression levels ≥11.25 as the high-PKM2 group, and those with low PKM2 expression (< 11.25) were defined as the low-PKM2 group.

Results: The results showed that the global metabolic gene expression levels were obviously divided into the high- or low-PKM2 groups. In addition, a greater number of affected metabolic subsystems were observed in the high-PKM2 group. Furthermore, we identified 98 PKM2-correlated deregulated metabolic genes that were associated with poor overall patient survival. Together, these findings suggest more comprehensive influences of PKM2 on HCC. In addition, we screened several small-molecule drugs that target these metabolic enzymes, some of which have been used in antitumor clinical studies.

Conclusions: HCC patients with high PKM2 expression showed more severe metabolic damage, transcriptional regulation imbalance and poor prognosis than low-PKM2 individuals. We believe that our study provides valuable information for pathology research and drug development for HCC.
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http://dx.doi.org/10.1186/s12885-018-5023-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249977PMC
November 2018

Molecular cloning and expression study on Toll-like receptor 5M in turbot, Scophthalmus maximus.

Dev Comp Immunol 2018 08 3;85:44-50. Epub 2018 Apr 3.

College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China; Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China. Electronic address:

Toll-like receptor 5 (TLR5) is responsible for the recognition of bacterial flagellin in mammals and play an important role in innate immunity. In the present study, a TLR5M gene was cloned from turbot, Scophthalmus maximus, and its immune responsive expression was subsequently studied in vivo. The Scophthalmus maximus (Sm)TLR5M gene is 4268 bp in length, consists of four exons and three introns and encodes a peptide of 892 amino acids (aa). The deduced protein possesses a signal peptide sequence, a leucine-rich repeat (LRR) domain composed of 23 LRR motifs, a transmembrane (TM) domain and a Toll/interleukin-1 receptor (TIR) domain. Phylogenetic analysis grouped SmTLR5M with other teleost TLR5Ms. A number of binding sites for transcription factors involved in immune response regulation were predicted in the 5'-flanking region of SmTLR5M. Quantitative real-time PCR (qPCR) analysis demonstrated that SmTLR5M mRNA was expressed ubiquitously with higher levels in head kidney and spleen. Its expression following stimulation with flagellin and lipopolysaccharide (LPS) was further tested in gills, spleen, head kidney and muscle. The maximum increases of SmTLR5M transcript levels ranged from 1.3 to 6.8-fold and appeared at 3 h to 5 day post-injection depending on different organs and stimuli. These findings suggest that SmTLR5M may play an important role in immune responses to infections with bacterial pathogens.
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http://dx.doi.org/10.1016/j.dci.2018.03.020DOI Listing
August 2018