黎欣白

Hsin-Pai Li (黎欣白)

Title :Assistant Professor

Lab : Tumor Virus and Cancer Research Lab

Highest Degree : Ph.D.

School : University of Southern California/ USA (Department of Microbiology)

Ext:#3593

E-mail:paili@mail.cgu.edu.tw

Location:Rm 0757

MS students (at present): 4

Undergraduate students (at present): 2

 Research Assistant: 2

 Ph D students graduated: 2

MS students graduated: 10

Undergraduate students graduated: 22

2012 Teaching Awards (Medical School-Basic Sciences)

2014 Counseling Awards (Medical School)

Research Focus:

(1) Epstein Barr Virus (Tumor virus)

(2) Cancer Research

(3) DNA Methylation & Gene Expression Regulation in Nasopharyngeal Carcinoma (NPC)

(4) Identify novel differential hypermethylated genes in NPC

- Coding genes

        - Non-coding RNA genes (microRNAs)

Nasopharyngeal carcinoma (NPC) has a high incidence rate in ethnic Chinese population, especially in southeastern Asia, including Taiwan and China, suggesting that genetics and dietary habits may be important cofactors for tumor formation.  The association between NPC and latent Epstein Barr virus (EBV) infection has been well established mainly based on EBV DNA detection in clinical samples and elevated anti-EBV antibody titer in NPC patients’ serology studies.  During EBV latent infection, one of the major viral oncoproteins, latent membrane protein 1, LMP1, is considered to be a key factor in NPC tumor development.  Previously, we demonstrated that LMP1 activates DNA methyltransferase 1 (DNMT1) and causes aberrant cellular DNA hypermethylation leading to inactivation of cell surface adhesion molecule, E-cadherin.  Our results demonstrated that viral protein can manipulate the DNA methylation machinery to silence tumor suppressor genes (TSGs) and promote NPC tumor progression as shown in Fig. 1.

Unlike the genetic changes in the genome, DNA methylation is a reversible process and is catalyzed by three mammalian enzymes, DNA methyltransferases (DNMTs) including DNMT1, DNMT3a and DNMT3b.  These enzymes modify chromatin structure by adding a methyl group to cytosine of CpG dinucleotides.  CpG dinucleotides are gathered in clusters called CpG islands.  There are approximately 29,000 CpG islands in human; and they are unevenly distributed across the genome.  Hypermethylation of CpG islands located within promoter and proximal exon regions leads to recruitment of methyl-CpG binding proteins (MBP) and transcriptional repressors such as histone deacetylases (HDACs).  This, in turn, alters the chromatin structure of the region, making it inaccessible for transcription factors, and results in gene silencing.  Therefore, aberrant methylation, in particular, hypermethylation of TSGs, such as, cell cycle control and DNA repair genes are often detected in various human cancers.  Intriguingly, the most frequent hypermethylated gene loci documented in NPC coincide with the locations of genes for which loss of heterozygosity (LOH) is commonly observed indicating that these genes may be critical for protecting the cell from NPC tumorigenesis.  These hypermethylation and LOH “hot spots” including chromosomes 3p, 9p, 9q, 11q, 12p and 13q are frequently detected in NPC.  The fact that LMP1 activates DNMTs also highlights the importance of a viral factor as an initiator/cofactor to induce epigenetic alterations. 

Fig. 1.  A schematic diagram shows that the EBV oncoprotein, latent membrane protein 1 (LMP1), activates the JNK-AP1 signaling pathway causing transcription activation of the DNA methyltransferases (DNMTs).  Overexpression of DNMTs will lead to aberrant hypermethylation of cellular gene promoter and finally silence these cellular genes.  If these target genes have critical regulation


Fig.2. A schematic diagram indicates how microRNA (miRNA) is regulated by DNA methylation in normal and cancer cells, respectively. Each miRNA will negatively regulate ~800 miRNA-target genes’ translation in normal cells. However, in cancer cells, suppression of miRNA expression via aberrant DNA methylation of miRNA upstream/ promoter region will lead to downregulation of miRNA expression. In the absence of miRNA, the expression of miRNA-targets will be activated or derepressed. Some of these miRNA-targets may have oncogenic potential and therefore overexpression of these oncogenes promote the formation of NPC. (Open circles and black circles represent unmethylated and methylated CpG sites, respectively.)

Fig. 3.  The ideogram of human chromosomes indicates the results of genome-wide sequence of the enriched methylated DNA in NPC cell line (C666.1).  The red bars represent the differential hypermethylated regions in C666.1 when compared with normal NP cell line (NP69).

 

  Inactivation of the tight junction gene CLDN11 by aberrant hypermethylation modulates tubulins polymerization and promotes cell migration in nasopharyngeal carcinoma

(Journal of Experimental & Clinical Cancer Research 2018 37:102; IF=6.217)

We identified a differentially hypermethylated and downregulated tight junction gene, CLDN11, in NPC cells. The bisulfite sequencing of the CLDN11 promoter and qRT-PCR of CLDN11 mRNA in seven paired NPC clinical samples indicated that methylation percentage of the promoter was conversely correlated with the mRNA expression level. Immunohistochemistry staining of independent NPC clinical samples demonstrated that the CLDN11 protein expression level decreased in seven of nine paired NPC tumor samples. Treatment with a DNA methylation inhibitor, 5’aza, restored CLDN11 RNA expression in NPC cell lines. CLDN11 promoter deletion and site-directed mutation experiments suggested that the −62 to −53 region containing transcription activator GATA1 binding site is responsible for CLDN11 activation. The re-expression of CLDN11 inhibited cell migration and invasion abilities in NPC cells. Through co-immunoprecipitation and LC–MS/MS, we next identified the major components of microtubules, tubulin alpha-1b (TUBA1B) and beta-3 (TUBB3), are the novel CLDN11-interacting proteins. CLDN11 interacts with these two tubulins through its intracellular loop and C-terminus. More importantly these domains are required for CLDN11-mediated cell migration inhibition. The treatment with a tubulin polymerization inhibitor, nocodazole, blocked NPC cell migration. Collectively, our data provided insights that CLDN11 functions as a potential tumor suppressor gene and the inactivation of CLDN11 by DNA hypermethylation promotes NPC progression.



Journal of Experimental & Clinical Cancer Research 2018 37:102
 

Silencing of miRNA-148a by hypermethylation activates the integrin-mediated signaling pathway in nasopharyngeal carcinoma.

(Oncotarget 2014; (5)17:7610-24)

 

MiRNA-148a is downregulated through hypermethylation in NPC biopsies and NPC cell lines compared with adjacent normal and NP cells respectively. Promoter assays demonstrated that upstream stimulatory factor 1 (USF1) is a crucial transcription factor that activates miR-148a promoter activity. EMSA assays confirmed that purified USF1 binds better toward the unmethylated than the methylated CG-containing USF1 consensus probe. The ectopic expression of miR-148a inhibits cell migration in NPC cells through the suppression of integrin-mediated signaling by targeting VAV2, WASL and ROCK1. Furthermore, immunohistochemical staining and Western blotting analysis revealed that the 3 oncogenic targets of miR-148a were overexpressed in NPC biopsies, suggesting that the inactivation of miR-148a caused by DNA methylation promotes NPC progression. Overall, our findings revealed that miR-148a can act as tumor suppressor miRNA for NPC.

 


   

Aberrantly hypermethylated transcription repressor homeobox A2 derepresses metalloproteinase-9 activity through TBP and promotes invasion in nasopharyngeal carcinoma. (Oncotarget 2013; 4:2154-2165)

 

A differential hypermethylated transcription repressor, Homeobox A2 (HOXA2), is identified in NPC tumor, which may render NPC cells invasive and metastaic. Aberrant hypermethylation of HOXA2 led to low RNA expression in NPC tumors and cells. Addition of methylation inhibitor 5’aza restored HOXA2 RNA expression in NPC cells. Methylated HOXA2 promoter reduces the binding affinity of the transcriptional co-activator p300, causing transcriptional repression of HOXA2. In NPC cells, re-expression of ectopic HOXA2 was correlated with decreased invasive ability and reduced metalloproteinase MMP-9 RNA and protein expression. Promoter, ChIP and DNA-pull down assays indicated that HOXA2 competes with the transcription activator, TATA-box binding protein (TBP) for a recognition sequence near the MMP-9 transcription start site, and suppresses MMP-9 transcription. Thus, HOXA2 acts as a suppressor or TBP-antagonist to inhibit MMP-9 expression; while methylation-mediated inactivation of HOXA2 in NPC derepresses MMP-9 production and increases invasion of NPC cells. In NPC plasma samples, increased plasma EBV copy number was correlated with increased in cell-free HOXA2 hypermethylation and elevated MMP-9 levels.


Oncotarget 2013; 4:2154-2165

Publication List 2018

Hsin-Pai Li*, Chen-Ching Peng, Chih-Ching Wu, Chien-Hsun Chen, Meng-Jhe Shih, Mei-Yuan Huang, Yi-Ru Lai, Yung-Li Chen, Ting-Wen Chen, Petrus Tang, Yu-Sun Chang, Kai-Ping Chang and Cheng-Lung Hsu (†Co-first author; *Corresponding)

Inactivation of the tight junction gene CLDN11 by aberrant hypermethylation modulates tubulins polymerization and promotes cell migration in nasopharyngeal carcinoma

Journal of Experimental & Clinical Cancer Research 2018 37:102 (IF=6.217; R/C=33/211=14.86%; ONCOLOGY)

Ting-Wen Chen, Chi-Ching Lee, Hsuan Liu, Chi-Sheng Wu, Curtis R. Pickering , Po-Jung Huang, Jing Wang, Ian Yi-Feng Chang, Yuan-Ming Yeh, Chih-De Chen, Hsin-Pai Li, Ji-Dung Luo, Bertrand Chin-Ming Tan, Timothy En Haw Chan, Chuen Hsueh, Lichieh Julie Chu, Yi-Ting Chen, Bing Zhang, Chia-Yu Yang, Chih-Ching Wu, Chia-Wei Hsu , Lai-Chu See, Petrus Tang, Jau-Song Yu, Wei-Chao Liao, Wei-Fan Chiang, Henry Rodriguez, Jeffrey N. Myers, Kai-Ping Chang & Yu-Sun Chang

APOBEC3A is an oral cancer prognostic biomarker in Taiwanese carriers of an APOBEC deletion polymorphism

Nature Communication 2017; 6;8(1):465 (IF=12.124; R/C=3/64=4.6%; MULTIDISCIPLINARY SCIENCES)

I-Che Chung, Chun-Nan OuYang, Sheng-Ning Yuan, Hsin-Pai Li, Jeng-Ting Chen, Hui-Ru Shieh, Yu-Jen Chen, David M. Ojcius, Ching-Liang Chu, Jau-Song Yu, Yu-Sun Chang & Lih-Chyang Chen

Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis

Scientific Report 2016; 6:36214 (IF=4.847; R/C=7/63=11.1%; MULTIDISCIPLINARY SCIENCES)

Oct 31, 2016

Hung-Ming Wang*, Tung-Liang Lin*, Yung-Chia Kuo, Hsin-Pai Li, Kai-Ping Chang, Chien-Yu Lin, Hsien-Chi Fan, An-Chi Lin, Chia-Hsun Hsieh, Ngan-Ming Tsang, Li-Yu Lee, Sheng-Chieh Chan, Kar-Wai Lui, Yu-Sun Chang, Cheng-Lung Hsu

Correlation between overall survival and differential plasma and tissue tumor marker expression in nasopharyngeal carcinoma patients with different sites of organ metastasis

Oncotarget 2016; (7)33:53217-53229

July 18, 2016

Mei Chao, Chia-Chi Lin, Feng-Ming Lin, Hsin-Pai Li and Shan-Bei Iang

Whole-genome analysis of genetic recombination of hepatitis delta virus: molecular domain in delta antigen determining trans-activating efficiency

Journal of General Virology 2015, 96:3460–3469 (IF=3.192; R/C= 45/163=27.6%; BIOTECHNOLOGY & APPLIED MICROBIOLOGY)

December 2015

Chia-Chi Lin, Chi-Ching Lee, Siao-Han Lin, Po-Jung Huang, Hsin-Pai Li, Yu-Sun Chang, Petrus Tang*, Mei Chao*

RNA recombination in Hepatitis delta virus: Identification of a novel naturally occurring recombinant

Journal of Microbiology, Immunology and Infection (2015) (IF=2.955; R/C= 27/83=32.5%; INFECTIOUS DISEASES)

27 November 2015

Cheng-Lung Hsu, Yung-Chia Kuo, Yenlin Huang, Yin-Cheng Huang, Kar-Wai Lui, Kai-Ping Chang, Tung-Liang Lin, Hsien-Chi Fan, An-Chi Lin, Chia-Hsun Hsieh, Li-Yu Lee, Hung-Ming Wang, Hsin-Pai Li, Yu-Sun Chang

Application of a patient-derived xenograft model in cytolytic viral activation therapy for nasopharyngeal carcinoma

Oncotarget 2015; (6)31: 31323-31334

September 24, 2015

Hsin-Pai Li*, Hsin-Yi Huang, Yi-Ru Lai, Jing-Xuan Huang, Kai-Ping Chang, Chuen Hsueh and Yu-Sun Chang (Co-first author; *Corresponding)

Silencing of miRNA-148a by hypermethylation activates the integrin-mediated signaling pathway in nasopharyngeal carcinoma

Oncotarget 2014; (5)17:7610-24

Ting-Wen Chen†, Hsin-Pai Li†, Chi-Ching Lee, Ruei-Chi Gan, Po-Jung Huang, Timothy H Wu,

Cheng-Yang Lee, Yi-Feng Chang and Petrus Tang* (Co-first author)

ChIPseek, a web-based analysis tool for ChIP data

BMC Genomics 2014, 15:539 (IF=3.867; R/C=26/163=16%; BIOTECHNOLOGY & APPLIED MICROBIOLOGY)

30 June 2014 

I-Che Chung†, Lih-Chyang Chen†, An-Ko Chung, Mei Chao, Hsin-Yi Huang, Chuen Hsueh,Ngan-Ming Tsang, Kai-Ping Chang, Ying Liang, Hsin-Pai Li* and Yu-Sun Chang* (*Co-corresponding)

Matrix metalloproteinase 12 is induced by heterogeneous nuclear ribonucleoprotein K and promotes migration and invasion in nasopharyngeal carcinoma

BMC Cancer 2014, 14:348-361 (IF=3.265; R/C=81/211=38.3%; ONCOLOGY)

20 May 2014, 

Hsin-Pai Li*, Chen-Ching Peng+, I-Che Chung, Mei-Yuan Huang, Shao-Tung Huang, Chia-Chun Chen, Kai-Ping Chang, Cheng-Lung Hsu, Yu-Sun Chang (Co-first author; *Corresponding)

Aberrantly Hypermethylated Homeobox A2 Derepresses Metalloproteinase-9 Through TBP and Promotes Invasion in Nasopharyngeal Carcinoma

Oncotarget 2013; 4: 2154-2165

November 4, 2013 

Wen-I Lee*, Jainn-Jim Lin, Meng-Ying Hsieh, Syh-Jae Lin, Tang-Her Jaing, Shih-Hsiang Chen5, Iou-Jih Hung, Chao-Ping Yang, Chin-Jung Chen, Yhu-Chering Huang, Hsin-Pai Li, Jing-Long Huang*

Immunologic Difference between Hypersensitivity to Mosquito Bite and Hemophagocytic Lymphohistiocytosis Associated with Epstein-Barr Virus Infection

PLoS ONE 2013; Volume 8 | Issue 10 | e76711 (IF=3.057; R/C= 11/63=17.4%, MULTIDISCIPLINARY SCIENCES)

Published October 18, 2013

Cheng-Lung Hsu, Kai-Ping Chang, Chien-Yu Lin, Hsien-Kun Chang, Cheng-Hsu Wang, Tung-Liang Lin, Chun-Ta Liao, Ngan-Ming Tsang, Li-Yu Lee, Sheng-Chieh Chan, Shu-Hang Ng, Hsin-Pai Li, Yu-Sun Chang and Hung-Ming Wang

Plasma EBV DNA Concentration and Clearance Rate as Novel Prognostic Factors for Metastatic Nasopharyngeal Carcinoma

Head & Neck 2012; 1-8 DOI: 10.1002/hed.21890 (IF=2.76; R/C= 3/43= 6.97%, OTORHINOLARYNGOLOGY)

Epub 2011 Nov 

Chia-Chen Hsu, Hsin-Pai Li, Yu-Hung Hung , Yu-Wei Leu , Wu-Hsiung Wu, Feng-Sheng Wang , Kuan-Der Lee , Pey-Jium Chang , Chi-Sheng Wu, Yen-Jung Lu , Tim H.-M. Huang, Yu-Sun Chang, Shu-Huei Hsiao (Co-first author)

Targeted Methylation of CMV and E1A viral promoters

Biochemical and Biophysical Research Communications 2010; 402: 228–234 (IF=2.371; R/C= 41/73, BIOPHYSICS)

Yen-Jung Lu, Chi-Sheng Wu, Hsin-Pai Li*, Hao-Ping Liu, Chang-Yi Lu, Yu-Wei Leu, Chia-Siu Wang, Lih-Chyang Chen, Kwang-Huei Lin, and Yu-Sun Chang* (*Co-corresponding)

Aberrant Methylation Impairs Low Density Lipoprotein Receptor-Related Protein 1B (LRP1B) Tumor Suppressor Function in Gastric Cancer.

GENES CHROMOSOMES & CANCER 2010; 49(5):412-24. (IF=3.96; R/C= 39/167; GENETICS & HEREDITY)

Chi-Sheng Wu†, Yen-Jung Lu†, Hsin-Pai Li, Chuen Hsueh, Chang-Yi Lu, Yu-Wei Leu, Hao-Ping Liu, Kwang-Huei Lin, Tim Hui-Ming Huang and Yu-Sun Chang (†Co-first author)

Glutamate receptor, ionotropic, kainate 2 silencing by DNA hypermethylation possesses tumor suppressor function in gastric cancer.

International Journal of Cancer 2010; 126(11):2542-52. (IF=5.531; R/C= 31/211; Oncology)

Hsin-Pai Li, Mei Chao, Su-Jen Chen, Yu-Sun Chang

Human Oncogenic Viruses: Epstein-Barr Virus and Its Oncogenesis (Invited Chapter)

p. 209-267

ISBN: 978-981-283-346-4

World Scientific 2010, Editors: Jing-Hsiung James Ou and T. S. Benedict Yen

Lih-Chyang Chen, Hao-Ping Liu, Hsin-Pai Li, Chuen Hsueh, Jau-Song Yu, Ying Liang, Yu-Sun Chang

Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells.

Oncogene 2009;1-12. (IF=7.932; R/C= 13/211; Oncology)

Wei-Chun Tai, Hsin-Pai Li,Tze-Yi. Chen-Yuan. Lin, and Meng-Tse Wu

Response of extranodal NK/T-cell lymphoma, nasal type, to interferon-a, corticosteroid, and narrowband ultraviolet B phototherapy.

Clinical and Experimental Dermatology 2009 Dec;34(8):e927-30. (IF=1.315; R/C= 45/63; dERMATology)

Wen-I Lee, MD, Shih-Hsiang Chen, Iou-Jih Hung, Chao-Ping Yang, Tang-Her Jaing, Chih-Jung Chen, Hsin-Pai Li, and Jing-Long Huang

Clinical Aspects, Immunologic Assessment, and Genetic Analysis in Taiwanese Children With Hemophagocytic Lymphohistiocytosis

Pediatric Infectious Disease Journal 2009 January; 28 (1):30-34 (IF=2.587; R/C= 19/120; PEDIATRICS) ISSN 0891-3668

Ka-Po Tse, Nang-Ming Tsang, Kung-Den Chen, Hsin-Pai Li*, Ying Liang, Chuen Hsueh, Kai-Ping Chang, Jau-Song Yu, Sheng-Po Hao, Ling-Ling Hsieh, and Yu-Sun Chang

MCP-1 Promoter Polymorphism at -2518 is Associated with Metastasis of Nasopharyngeal Carcinoma after Treatment.

Clinical Cancer Research 2007; 13:6320-6326. (IF=8.738; R/C= 12/211; ONCOLOGY)

Chia-Lung Tsai, Hsin-Pai Li, Chuen Hsueh, Ying Liang, Chi-Long Chen, Sai Wah Tsao, Ka-Po Tse, Yen-Jung Lu, Jau-Song Yu and Yu-Sun Chang ( Co-first author)

Activation of DNA methyltransferase 1 by Epstein-Barr Virus LMP1 involves JNK signaling.

Cancer Research 2006; 66:11668-11674. (IF= 8.556; R/C= 13/184; cELL BIology)

Lee YN, Chen LK, Ma HC, Yang HH, Li HP*, Lo SY

Thermal aggregation of SARS-CoV membrane protein

J Virological Methods 2005 Jul; 129:152-161 (IF= 1.508; R/C= 93/163; BIOTECHNOLOGY & APPLIED MICROBIOLOGY)

Li HP, Leu YW, Chang YS.

Epigenetic changes in virus-associated human cancers

Cell Research 2005 Apr; 15(4):262-271 (IF= 14.812; R/C= 13/184; cELL BIology) 

Li HP, Chang YS.
Epstein-Barr virus latent membrane protein 1: structure and functions.

J Biomed Sci 2003 Sep-Oct; 10:490–504 (IF=2.935; R/C= 50/123; MEDICINE, RESEARCH & EXPERIMENTAL)

Yu JS, Tsai HC, Wu CC, Weng LP, Li HP, Chung PJ, Chang YS.
Induction of inducible nitric oxide synthase by Epstein-Barr virus B95-8-derived LMP1 in Balb/3T3 cells promotes stress-induced cell death and impairs LMP1-mediated transformation.

Oncogene, 2002 Nov 14;21(52):8047-61 (IF=7.932; R/C= 13/211; Oncology)

Shi ST, Huang P, Li HP, Lai MM.
Heterogeneous nuclear ribonucleoprotein A1 regulates RNA synthesis of a cytoplasmic virus.

EMBO J 2000 Sep 1;19(17):4701-11 (IF=9.643; R/C= 11/290; BIOCHEMISTRY & MOLECULAR BIOLOGY)

Zhang X, Li HP, Xue W, Lai MM.
Formation of a ribonucleoprotein complex of mouse hepatitis virus involving heterogeneous nuclear ribonucleoprotein A1 and transcription-regulatory elements of viral RNA.

Virology 1999 Nov 10;264(1):115-24 (IF=3.2; R/C= 13/33; VIROLOGY)

Li HP, Huang P, Park S, Lai MM.
Polypyrimidine tract-binding protein binds to the leader RNA of mouse hepatitis virus and serves as a regulator of viral transcription.

J Virol 1999 Jan;73(1):772-7 (IF=4.606; R/C= 7/33; VIROLOGY)

Zhang X, Li HP, Xue W, Lai MM.

Cellular protein hnRNP-A1 interacts with the 3'-end and the intergenic sequence of mouse hepatitis virus negative-strand RNA to form a ribonucleoprotein complex.

Adv Exp Med Biol 1998;440:227-34 (IF=1.953; R/C=25/85 ; BIOLOGY)

Kraeft SK, Chen DS, Li HP, Chen LB, Lai MM.
Mouse hepatitis virus infection induces an early, transient calcium influx in mouse astrocytoma cells.

Exp Cell Res 1997 Nov 25;237(1):55-62  (IF=3.378; R/C= 86/211; ONCOLOGY)

Li HP, Zhang X, Duncan R, Comai L, Lai MM.
Heterogeneous nuclear ribonucleoprotein A1 binds to the transcription-regulatory region of mouse hepatitis virus RNA.

Proc Natl Acad Sci U S A 1997 Sep 2;94(18):9544-9 (IF=9.423; R/C= 4/57; MULTIDISCIPLINARY SCIENCES)

Chen DS, Asanaka M, Yokomori K, Wang F, Hwang SB, Li HP, Lai MM.

A pregnancy-specific glycoprotein is expressed in the brain and serves as a receptor for mouse hepatitis virus.

Proc Natl Acad Sci U S A 1995 Dec 19;92(26):12095-9  (IF=9.423; R/C= 4/57; MULTIDISCIPLINARY SCIENCES)

Lai MY, Chang HC, Li HP, Ku CK, Chen P J, Sheu J C, Huang G T, Lee PH, Chen DC.

Splicing mutations of the p53 gene in human hepatocellular carcinoma.

Can Res 1993 Apr 1;53(7): 1653-6 (IF= 8.556; R/C= 13/184; cELL BIology)

HPL Lab Photos

  


                                                                       



                   

  
       

 

           

   


 

 

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