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THAI NGUYEN UNIVERSITY UNIVERSITY OF AGRICULTURE AND FORESTRY NATIONAL TSING HUA UNIVERSITY THAVISACK MIVONGSACK TITLE: POTENTIAL GENE-NETWORK FOR THE HEALTH EFFECT OF EXPOSURE TO PCB/FS ON HUMAN DIFFUSE LARGE CELL an lu LYMPHOMA n va BACHELOR THESIS ep i gh tn to nl w d oa Study Mode:Full-time an lu Major: Environmental science and management Batch: 2013-2017 oi lm ul nf va Faculty:International Programs Office at nh z z Thai Nguyen, 21/12/2017 l.c gm @ om DOCUMENTATION PAGE WITH ABSTRACT Thai Nguyen University of Agriculture and Forestry Degree Program Bachelor of Environmental Science and Management Student name THAVISACK MIVONGSACK Student ID DNT 1253110103 Thesis Title Potential gene-network for the health effect of exposure to pcb/fs on human diffuse large cell lymphoma Supervisor (s) Prof Chun-Yu Chuang, Associate Prof DRTran Van Dien an lu Abstract: The thesis describes the Lymphoma is the most top cancers in the worldwide, and the n va tn to incidence rises strikingly since the last half of 20thcentury Lymphoma is a cancer ep i gh affecting the immune system; the major risk factor is associated with exposure to occupational or environmental chemicals Polychlorinated biphenyls (PCBS) are a oa nl w class of organic chemicals, known as congeners that have been used in a variety of d commercial products PCBs were used in caulking, electronics, fluorescent light lu va an ballasts and other building materials from the 1950s to the late 1970s Buildings built lm ul nf or renovated during that time may contain PCBs in caulking and other materials PCBare very stable mixtures that are resistant to extreme temperature and pressure oi at nh PCBS were used widely in electrical equipment like capacitors and transformers They z also were used in hydraulic fluids, heat transfer fluids, lubricants, and plasticizers z l.c gm @ i om PCBs have been released into the environment through spills, leaks from electrical and other equipment, and improper disposal and storage It is estimated that more than half of the PCBS produced have been released into the environment Once in the environment, PCBS can be transported long distances and they bind strongly to soil and sediment so they tend to be persistent in the environment They have been found in air, water,soil, and sediments throughoutthe world.PCBs can enter the body through inhalation, ingestion, and dermal routes of exposure They are readily absorbed but are slowly metabolized and excreted In particular, PCBs initially distribute to the liver and muscle tissues, but eventually accumulate in lipid-rich tissues This leads to greater concentrations of PCBS in adipose tissue, breast milk, the liver, and skin The data analysis was subsequently performed using Network Analyst, a standard web an lu browser for network analysis and interactive exploration n va TCDD, Furans, DBLCL, bioinformatics, GEO, Array Keywords Express tn to 59 Number of pages i gh October,2017 ep Date of submission d oa nl w Supervisor’s signature oi lm ul nf va an lu at nh z z l.c gm @ ii om ACKNOWLEDGEMENT First of all, we know that knowledge is just only can be proved by our works, and internship is one of the best opportunity for a student whose can their first project before they find their jobs to enroll in the future Besides that, we are not only improving ourselves by knowledge in company environment, institute or laboratory but also making more friends whose are having many experiences in environment, and it will help us in the near future From my perspective, this internship is absolutely needed, helpful and important Because of that, and be assigned by the International Programs Office and also the allowed of Department of Biomedical Engineering and Environmental Sciences (National TsingHua University, Taiwan) To well done this thesis, I want to express an lu profound gratitude to Advanced Education Program, the school administrators, the n va staffs in Department of Biomedical Engineering and Environmental Sciences, the tn to staffs of YC laboratory, and particularly my supervisor,Associate Prof DRTran Van ep i gh Dien and Prof Chun-Yu Chuang whose were always supporting me every single time nl w I got troubles I would like to send both of supervisors a warmly thanks for the supporting me, and for their sacrifice for education, as same as environmental issues in oa d Taiwan and Vietnam as all countries in the world an lu Finally, I would like to say that I had tried my best to finish this thesis in the nf va lm ul best way, I guess However, to be honest, I partly believe that my thesis still have oi some problems because of the limitation of knowledge and reality experiences, nh at especially in our environmental circumstances these days It is totally happy if I can z z l.c gm @ iii om 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 get feedbacks and comments from you, my Teachers, Professors, and Supervisors, to finish my thesis in a fantastic way, to get the best results Sincerely, Thai Nguyen October, 2017 THAVISACK MIVONGSACK an lu n va ep i gh tn to d oa nl w oi lm ul nf va an lu at nh z z gm @ 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.99 l.c iv om 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 TABLE OF CONTENTS DOCUMENTATION PAGE WITH ABSTRACT i ACKNOWLEDGEMENT iii TABLE OF CONTENTS v LIST OF FIGURES vii ABBRIVIATION ix PART I: INTRODUCTION 1.1 Rationale 1.2 Objectives PART II:LITERATURE REVIEW an lu 2.1 Polychlorinated biphenyls (PCBs) n va 2.1.1 Polychlorinated Biphenyls (PCBs) Toxicity tn to 2.1.2 The industrial production of PCB ep i gh 2.1.3 PCBs and Environment nl w 2.1.4 Health Effects of PCBs 2.2 Lymphoma 12 oa d 2.3 Biological pathway 13 an lu 2.3.1 Diffuse large B cell lymphoma (DLBCL) 15 nf va lm ul 2.4 Gene-network components .17 oi 2.4.1 Gene-network database:Array Express and (GEO) 18 nh at 2.4.2 Statistical analysis .19 z z 3.2 Gene network analysis and Cytoscape for gene-network analysis 24 gm @ 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.99 l.c v om 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 PART IV: RESULTS AND DISCUSSIONS 29 4.1 Genetic datasets 29 4.1.1 Differentially expressed genes .32 4.1.2 Gene-network construction of DLBCL and PCBs 35 4.2 Discussion .38 PART V: CONCLUSION AND RECOMMENDATION 41 5.1 Conclusion 41 5.2 Recommendation 42 REFERENCES 43 an lu n va ep i gh tn to d oa nl w oi lm ul nf va an lu at nh z z gm @ 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.99 l.c vi om 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 LIST OF FIGURES Figure 2.1: Diagram of Polychlorinated Biphenyls (PCBs)(Shoemaker, 2005) .6 Figure2.2: Polychlorinated biphenyls – levels in foods 11 Figure 2.3: Diffuse large Bcell lymphoma 16 Figure 3.1: The flowchart of methodology 24 Figure 3.2: Cytoscape home page(Shannon P, 2003) 26 Figure 4.1: Diagram of Gene-network construction of DLBCL & PBCs Sources: (Rosenwald,2002) 37 Figure 4.2: The potential regulatory pathway of NHL progression in response to PCB exposure Source: (Miller, 2001) 38 an lu n va ep i gh tn to d oa nl w oi lm ul nf va an lu at nh z z gm @ 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.99 l.c vii om 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 LIST OF TABLES Table 4.1: Genetics Datasets of DLBCL 30 Table 4.2: Datasets on Array Express used for PCB analysis 31 Table 4.3: Differentially expressed genes, including –up and down – regulate genes in Diffuse Large B cell lymphoma compared to normal cells 33 Table 4.4: Differentially expressed genes, including up-and down – regulated genes activated by PCB compared to control group 35 an lu n va ep i gh tn to d oa nl w oi lm ul nf va an lu at nh z z gm @ 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.99 l.c viii om 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 ABBRIVIATION ABC Activated B cell AML Acute myeloid leukemia ALL Acute lymphoblastic leukemia B-Cells B-lymphocytes B-NHL Non Hodgkin lymphoma DLBCL Diffuse large B cell lymphoma DMSO Dimethyl sulfoxide DEGS Differentially expressed genes analysis FL Follicular lymphoma FDR False discovery rate GEO (NCBI) Gene expression omnibus National center for Biotechnology information an lu n va Gene Ontology HL Hodgkin lymphoma HIV Human immunodeficiency virus ID Identifier IARC International agency for research on cancer MIAME Minimum ep i gh tn to GO nl w about microarray experiment oa Microarray and Gene Expression Markup d MAGE-ML Language N-acetylneuraminate pyruvate lyase nf va an lu NPL information Non Hodgkin lymphoma PCB Polychlorinated biphenyls RS Reed-Sternberg SNPs Single Nocleotide Polymorphisms T-Cells T-lymphocytes oi lm ul NHL at nh z z gm @ 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.99 l.c ix om 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 PSMD10, DNTTIP2, OAT, NSMCE1, TBCB, C14orf119, ACP5, PPM1G, POLR2K, TSG101, PEA15, MRPL49, NIT2, ATIC, PPP2CB, NCBP2, RABAC1, DRG1, NUP107, TCF4, SLC25A19, UFC1, CIB1, BIRC2, NDUFB10, RBBP8, SNX3, SMNDC1, HDHD2, ETF1, RAD23A, MYBL2, SRRM1, TIMMDC1, COX5B, LYRM1, IL18, ARHGAP17, IRF2BPL, NONO, TM2D2, MFAP1, ITGA3, KCTD12, NUPR1, HAT1, AP3S1, MANF,, TMEM14B, CPSF4, PPIH, MIEN1, MTIF2, FAM50A, LRRC47, PAPSS1, GLO1, CCNG1, RPIA, ASNSD1, LYPLA1, WDR83OS, CUTA, DAZAP1, AP1S2, BTBD1, VPS25, BCL11A, MT1E, ZNHIT3, EIF3I, RPL11, S100A8, ANXA2, PPIL3, GLRX, ENOPH1, IER5, CISD1, HAUS1, DRAM1, DDX21, SNRPD3, UBE2L6, TMEM138, RPF2, DUT, GTF3C6, TSPAN13, ITM2A, PPP1R7,PIH1D1, GTF2B, CDK5RAP3, TMEM208, DBF4, GTF3A, RFC4, IER3, YTHDF2, FIBP, TIMM8B, MPLKIP, VPS28, LAGE3, CLIC1, HARS, IMP3, CS, CEBPZ, RFX5, DNAJB1, MRPL16, CSRP1, ORMDL2, PIGP, CDKN1A, NMI, FAM35A, TNFAIP3, PCMT1, EBPL,TUBB6, GBP1, PLOD1, TUBA1C, REEP5, EIF2S1, MRPL1, IMP4, SNRPA, MARCKSL1, DYNLT3, UBE2E2, SCAMP3, POLR3GL, CUEDC2 an lu n va Down- DUSP6, CYTH4, LCP2, SIRPB1, ITGB2, CORO1A, RAB7A, COX7A2L, MEFV, regulated ANPEP, C5AR1, ZYX, DOCK5, STEAP4, GRK6, MSL2, PLXNC1, STK17B, PYGL, genes CD3E, KCNJ15, SCIMP, CAPNS1, GLIPR1, CPPED1, IST1, LILRA1, PRKAR1A, to ARRB2, WDR1, ARHGAP26, DUSP1, WIPF1, MXD1, BSG, CELF2, GNAQ, tn (172) ep i gh ZFAND5, MBOAT7, GABARAP, MBNL1, AOAH, CTSS, DOK3, HIST1H1E, CYP4F3, PTBP3, NCF2, RNASET2, TCP11L2, MAPK1, PIP4K2A, STAT3, DOCK8, nl w TLN1, TGFBR2, SELPLG, PGK1, FPR1, SDHA, SMCHD1, MOB3A, DDX17, TUBB1, GUK1, LYN, CD37, ETS1, CCNI, STK38, ATP6V1B2, CAP1, PDZK1IP1, d oa HBB, EPB41, TREM1, PTAFR, GNAS, FFAR2, RPL18, IL7R, EIF4EBP2, SLC44A2, an lu HLA-DPA1 LITAF ITM2B CXCR2, CYBB, CFL1, LCP1, ALAS2, PTPRC, CSF3R, ARHGDIB, AQP9, DAZAP2, SLC6A6, B2M, SMAP2, BCL2L1, SORL1, RAC2, va nf FBXO7, PSAP, FCN1, ND5, SLC25A37, TNFRSF10C, TMBIM6, CD74, HLA-E, lm ul SLC25A39, DCAF12, CX3CR1, RHOA, CD53, XPO6, TAGLN2, FCGR2A, MSN, LYZ, LAPTM5, MALAT1, TXNIP, ACTB oi at nh z z gm @ 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RPL6, HSP90AA1, RPL3, GZMB, RPL7, RPS7, RPL34, RPL9 an lu n va Molecular biologists have collected considerable data regarding the ep i gh tn to 4.1.2 Gene-network construction of DLBCL and PCBs nl w involvement of genes and microRNAs (miRNAs) in cancer However the underlying mechanisms of cancer with regard to genes and miRNAs remain unclear The first oa d differential expression network that is presented is an experimentally validated an lu nf va network of miRNAs and genes This network presents known biological regulatory lm ul associations among miRNAs and genes in the human body The second network is a oi DLBCL differential expression network Differentially expressed gene and miRNA nh at data regarding DLBCL were collected and, based on the first network and the z z differentially expressed data, the second network was inferred, which demonstrates the gm @ 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37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 irregular regulatory associations that may lead to the occurrence of DLBCL The third network is a DLBCL-associated network This network is comprised of nondifferentially expressed genes and miRNAs that contribute to numerous DLBCL processes The similarities and differences among the three networks were extracted and compared to distinguish key regulatory associations; furthermore, important signaling pathways in DLBCL were identified The present study partially clarified the pathogenesis of DLBCL and provided an improved understanding of the underlying molecular mechanisms, as well as a potential treatment for DLBCL About half of patients with diffuse large B-cell lymphoma (DLBCL) not respond to or relapse soon after the standard chemotherapy, indicating a critical need to better understand the specific pathways perturbed in DLBCL for developing an lu effective therapeutic approaches Mice deficient in the E3 ubiquitin ligase Smurf2 n va spontaneously develop B-cell lymphomas that resemble human DLBCL with tn to molecular features of germinal centre or post-germinal centre B cells Here we show ep i gh that Smurf mediates ubiquitination and degradation of YY1, a key germinal centre nl w transcription factor Smurf2 deficiency enhances YY1-mediated transactivation of cMyc and B-cell proliferation Furthermore, Smurf2 expression is significantly oa d decreased in primary human DLBCL samples, and low levels of Smurf expression an lu correlate with inferior survival in DLBCL patients The Smurf2-YY1-c-Myc nf va lm ul regulatory axis represents a novel pathway perturbed in DLBCL that suppresses B-cell oi proliferation and lymphomagenesis, suggesting pharmaceutical targeting of Smurf2 as at nh a new therapeutic paradigm for DLBCL z z gm @ 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.99 l.c 36 om 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 Figure 4.1: Diagram of Gene-network construction of DLBCL & PBCs an lu Sources: (Rosenwald,2002) n va 4.1.3 Sub- network and potential pathways for DLBCL and PCB exposure i gh tn to To identify the gene regulatory sub-network between DLBCL and PCB modules, the gene ontological networks via the analysis of ClueGo plug-in were ep nl w further conducted into Cluepedia plug-in The above two ontological networks, NHL d oa and PCB exposure, were plugged into clupedia These two modules were integrated to an lu perform a union gene-gene regulatory network of PCB exposure relevant to NHL nf va Gene in this integrated regulatory network was selected with highly gene connectivity lm ul and the significance within each network Red lines represented the regulatory oi pathway of PCB exposure only Yellow lines displayed the regulatory pathway of nh at NHL; while black lines performed the colarbory pathway of PCB exposure and NHL z z NFKB1(purple circle) was the only one gene that interacted with red, blue and gm @ 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.99 l.c 37 om 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 blacklines This study chose NFKB1 as a middle point to explore its Up-stream (PCB only) and down-stream (intersection of PCB and NHL) genes Of NFKB1, CTNNB1 and NFKB1 were considered as initiator genes of PCB exposure Down- stream genes of NFKB1, AR, IGF1 and TWIST1 were regarded as carcinogenic genes of NHL progression after PCB exposure The final carcinogenic pathway related to NHL progression corresponding to PCB exposure was shown in figure… Eventually, this study focused on the CTNNB1-NFKB1-AR-IGF1-TWIST1 pathway as a potential pathway of NHL progression in response to PCB exposure an lu n va ep i gh tn to nl w d oa Figure 4.2: The potential regulatory pathway of NHL progression in response to lm ul 4.2 Discussion Source: (Miller, 2001) nf va an lu PCB exposure oi The impact of chemical on human health, especially PCB leading to DLBCL in nh at this study was examined based on gene-network construction In fact, gene network z z gm @ was created by the interaction of most obvious differentially expressed genes, which 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37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 were activated by any kinds of chemical or human disease In the study, the most different expressed genes of PCB/Furan and DLBCL compared to control and normal groups respectively were selected in order to construct gene network that can stimulate the biological pathway including these kind of gene According to the result of this study, the potential pathway underlying cause of PCB/ Furan to DLBCL disease can be easily to find out, especially through protein interaction network The main biological pathways involved in this merge network including cell proliferation, DNA and histone modification, cell response to hypoxia, angiogenesis, xenobiotic stimulus, tumor necrosis factor production and NIK/NF-kB signaling might be generally relate to carcinogenesis (Hu et at., 2006) Figure also indicated that PCB mainly effects human body by response to hypoxia (green zone) while Furans mainly an lu cause the alteration of DNA, histone modification and cell division (blue zone) n va 4.3 Inhibition of cancer cell apoptosis and tumorigenesis factor inDLBCL tn to TWIST1isawell–knownproteinassociatedwithtumorgenesis,angiogenesis,cell ep i gh proliferation and cell differentiation and an important target for cancer treatment Twist1 is a nl w member of Twist protein group, and a previous study has revealed that the expression of TWIST1 protein is higher than B-NHL tissues and it can be connected with B-NHL oa d progression (Jiaet al., 2014) Twist can promote tumor cell growth throughexpression and an lu hence both of them can induce tumor progression, cell growth and oncogenesis in many cases nf va lm ul of cancer (Shiotaet al., 2008) In addition, up – regulated protein TWIST1 has ability to oi activate lymph angiogenesis, which has a general role in tumorsdevelopment, nh at invasionandmetastatic.Infact,somelymphomastudieshaveshown that several markers of z z gm @ 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.99 l.c 39 om 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 angiogenesis have a correlation with outcome oflymphoma development and progression (Ganjooet al., 2007) Persistent activation of NF-KB has been reported to play an essential role in the growth and survival of specific cancer cell types, including adult T-cell leukemia, lymphoma, melanoma, and prostate cancer cells The NF-KB family of transcription factors, NFKB1 and NFKB2, are compelling mediators of MYC’s response in B cells, which are key regulators of B cell developments an lu n va ep i gh tn to d oa nl w oi lm ul nf va an lu at nh z z gm @ 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.99 l.c 40 om 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stimulus, regulation of lymphocyte proliferation, regulation of intrinsicapoptoticsignalingpathway,regulationofangiogenesis, NIF/NFkappasignaling, regulationoffibroblastproliferation,regulationoftransitionofmitoticcellcycle, B cell an lu proliferation, intracellular signaling pathway, tumor necrosis factor production, cell n va death in response to hydrogen peroxide DNA modification and regulation of histone Thirdly, the pathway of dioxins entering human body via the receptor In gene- ep i gh tn to modification nl w network analysis, this study identified five target genes of PCB exposure (CTNNB1, NFKB1, AR, IGF1 and TWIST1) underlying NHL progression (Figure 7), in this oa d pathway CTNNB1 is a downstream effectors of canonical wnt signaling with the an lu oi lm ul nf va ability to induce cell-cell adhesion, cell adhesion, cell differentiation and cell growth at nh z z gm @ 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37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 Thereforeconcludedthatallresearchobjectiveshavebeenachievedgiventhese results, and the research has provided the information on the effect of exposure onPCBs/ Furans in DLBCL development This research, however, still has some limitations, for instance,thelackofknowledgeongeneticandpracticalexperienceinthisfieldareneeded to be fulfilled in order to complete the research since it was only carried out during the period of three months for a preliminaryresearch Itishencesuggestedthatfurtherstudiescanconcentratedonexploringtheeffectof chemicals on human body by the advanced application of bioinformatics, especially the effect of dioxins coming from various sources Apart from contribution to technical development in lymphoma treatment, the results of this study could be implemented for further studies or research relating to exposure dioxins in order to an lu explore the long-term impact of this chemical remaining from the American War in n va Vietnam in 20thcentury We continue to survey the synthesis of a gene-network analysis to identify ep i gh tn to 5.2 Recommendation nl w potential pathway and target genes of NHL carcinogenesis in response to PCB exposure with different conditions to induce CTNNB1 expression to increase oa d downstream genes NFKB1, AR, IGF1 and TWIST1 expression to initiate NHL an lu nf va progressionfor powerful and useful processing in the future lm ul The research experimental is very important to explore new scientific ideas for oi improve and develop the previous ideas as very necessary to identify potential at nh pathway and target genes z z gm @ 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.99 l.c 42 om 37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.2237.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.66 REFERENCES 1) AidongZang (2006) Theadvance analysis of gene expression microarray data, world scientific connecting great minds, J.Neurooncol, doi: 10: 1007/s 11060017-2680-9 2) Jennifer Amengual, MD (2017)Lymphoma research fundation Diffuse Large BCell Lymphoma J Clin Oncol, 10; 35 (20): 2260-2267 3) The Non-Hodgkin's Lymphoma Classification Project National Cancer Institute Sponsored Study of Classifications of non-Hodgkin's Lymphomas Summary and description of Working Formulation for Clinical 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