b18a2f79fce047b84351cb7c2df5c9e3 cancers-14-00830.pdf 255abb88a0faba6c30fc66d3341e0b838bf6b372 cancers-14-00830.pdf 9f0d5220af15e9cef41e75a493e4068a8e5389b9241db712a9150c7a5f196eb6 cancers-14-00830.pdf Title: Dissecting TET2 Regulatory Networks in Blood Differentiation and Cancer Subject: Cytosine methylation (5mC) of CpG is the major epigenetic modification of mammalian DNA, playing essential roles during development and cancer. Although DNA methylation is generally associated with transcriptional repression, its role in gene regulation during cell fate decisions remains poorly understood. DNA demethylation can be either passive or active when initiated by TET dioxygenases. During active demethylation, transcription factors (TFs) recruit TET enzymes (TET1, 2, and 3) to specific gene regulatory regions to first catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and subsequently to higher oxidized cytosine derivatives. Only TET2 is frequently mutated in the hematopoietic system from the three TET family members. These mutations initially lead to the hematopoietic stem cells (HSCs) compartment expansion, eventually evolving to give rise to a wide range of blood malignancies. This review focuses on recent advances in characterizing the main TET2-mediated molecular mechanisms that activate aberrant transcriptional programs in blood cancer onset and development. In addition, we discuss some of the key outstanding questions in the field. Keywords: DNA methylation; TET2; chromatin; transcription factors; gene regulation; blood malignancies Author: Aleksey Lazarenkov and José Luis Sardina Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sun Feb 6 12:28:34 2022 CET ModDate: Sun Feb 6 12:31:12 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1473043 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- DGABBG+URWPalladioL-Bold Type 1 Custom yes yes no 10 0 VYLBUP+URWPalladioL-Roma Type 1 Custom yes yes no 15 0 FQSQLW+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 MNJNJI+URWPalladioL-BoldItal Type 1 Custom yes yes no 23 0 BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes no 27 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 36 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 40 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 44 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 57 0 AOPHAZ+CMSY10 Type 1 Builtin yes yes no 79 0 XXPDQE+EURM10 Type 1 Builtin yes yes no 83 0 OFNJLL+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 93 0 OFNJLM+PalatinoLinotype CID TrueType Identity-H yes yes yes 96 0 OFNJLN+PalatinoLinotype TrueType WinAnsi yes yes no 102 0 OFNJLP+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 105 0 OFNJLL+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 118 0 OFNJLN+PalatinoLinotype TrueType WinAnsi yes yes no 121 0 OFNJLP+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 124 0 OPZDHV+VnURWPalladioL Type 1 Custom yes yes no 146 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-06-30 02:37:09 CEST RepresentationInformation: cancers-14-00830.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-02-06 20:02:13 CET Size: 1473043 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 650 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Mechanisms of TET2 Protein/Enzymatic Regulation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Transcriptional Regulation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Post-Transcriptional Regulation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Post-Translational Regulation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Enzymatic Regulation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Partner-Instructed Tet2 Genomic Recruitment during Development and Cancer Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: During Embryonic Stem Cell Fate Decisions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: During Blood Cell Fate Decisions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: During Myeloid Cell Fate Decisions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Erythroid Lineage Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: B-Cell Lineage Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: T-Cell Lineage Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: In Response to External Stimuli Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: TET2 Loss of Function in Blood Malignancies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Children: Item: Title: Preleukemic Conditions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Leukemic Conditions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Summary and Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Info: Title: Dissecting TET2 Regulatory Networks in Blood Differentiation and Cancer Author: Aleksey Lazarenkov and José Luis Sardina Subject: Cytosine methylation (5mC) of CpG is the major epigenetic modification of mammalian DNA, playing essential roles during development and cancer. Although DNA methylation is generally associated with transcriptional repression, its role in gene regulation during cell fate decisions remains poorly understood. DNA demethylation can be either passive or active when initiated by TET dioxygenases. During active demethylation, transcription factors (TFs) recruit TET enzymes (TET1, 2, and 3) to specific gene regulatory regions to first catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and subsequently to higher oxidized cytosine derivatives. Only TET2 is frequently mutated in the hematopoietic system from the three TET family members. These mutations initially lead to the hematopoietic stem cells (HSCs) compartment expansion, eventually evolving to give rise to a wide range of blood malignancies. This review focuses on recent advances in characterizing the main TET2-mediated molecular mechanisms that activate aberrant transcriptional programs in blood cancer onset and development. In addition, we discuss some of the key outstanding questions in the field. Keywords: DNA methylation; TET2; chromatin; transcription factors; gene regulation; blood malignancies Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sun Feb 06 12:28:34 CET 2022 ModDate: Sun Feb 06 12:31:12 CET 2022 ID: 0x2dbeb8d9ac234972126ae94daf0c3872, 0x2dbeb8d9ac234972126ae94daf0c3872 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: OPZDHV+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: OPZDHV+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: FQSQLW+URWPalladioL-Ital FontSubset: true FirstChar: 40 LastChar: 122 FontDescriptor: FontName: FQSQLW+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: XXPDQE+EURM10 FontSubset: true FirstChar: 11 LastChar: 20 FontDescriptor: FontName: XXPDQE+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: MNJNJI+URWPalladioL-BoldItal FontSubset: true FirstChar: 50 LastChar: 116 FontDescriptor: FontName: MNJNJI+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: DGABBG+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: DGABBG+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: BTFGED+VnURWPalladioL-Bold FontSubset: true FirstChar: 178 LastChar: 178 FontDescriptor: FontName: BTFGED+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: VYLBUP+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: VYLBUP+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: AOPHAZ+CMSY10 FontSubset: true FirstChar: 48 LastChar: 48 FontDescriptor: FontName: AOPHAZ+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 34, 323, 152, 332 Annotation: Subtype: Link Rect: 34, 313, 87, 320 Annotation: Subtype: Link Rect: 34, 164, 96, 186 Annotation: Subtype: Link Rect: 126, 90, 154, 99 Annotation: Subtype: Link Rect: 34, 78, 147, 87 Annotation: Subtype: Link Rect: 34, 757, 152, 793 Annotation: Subtype: Link Rect: 515, 757, 560, 793 Annotation: Subtype: Link Rect: 129, 663, 140, 677 Annotation: Subtype: Link Rect: 246, 663, 257, 677 Annotation: Subtype: Link Rect: 207, 206, 214, 215 ActionDest: 143 Annotation: Subtype: Link Rect: 465, 206, 472, 215 ActionDest: 143 Annotation: Subtype: Link Rect: 473, 205, 480, 215 ActionDest: 143 Annotation: Subtype: Link Rect: 365, 181, 372, 189 ActionDest: 143 Annotation: Subtype: Link Rect: 507, 143, 514, 152 ActionDest: 143 Annotation: Subtype: Link Rect: 517, 143, 524, 152 ActionDest: 143 Annotation: Subtype: Link Rect: 345, 105, 352, 114 ActionDest: 143 Annotation: Subtype: Link Rect: 203, 67, 210, 76 ActionDest: 143 Annotation: Subtype: Link Rect: 110, 17, 261, 28 Annotation: Subtype: Link Rect: 410, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 384, 86, 403 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 491, 723, 498, 732 ActionDest: 143 Annotation: Subtype: Link Rect: 501, 723, 513, 732 ActionDest: 151 Annotation: Subtype: Link Rect: 229, 698, 241, 707 ActionDest: 151 Annotation: Subtype: Link Rect: 244, 698, 256, 707 ActionDest: 151 Annotation: Subtype: Link Rect: 288, 673, 300, 682 ActionDest: 151 Annotation: Subtype: Link Rect: 300, 673, 312, 682 ActionDest: 151 Annotation: Subtype: Link Rect: 313, 673, 324, 682 ActionDest: 151 Annotation: Subtype: Link Rect: 262, 648, 274, 657 ActionDest: 151 Annotation: Subtype: Link Rect: 275, 647, 287, 657 ActionDest: 151 Annotation: Subtype: Link Rect: 544, 471, 556, 480 ActionDest: 151 Annotation: Subtype: Link Rect: 188, 446, 200, 455 ActionDest: 151 Annotation: Subtype: Link Rect: 544, 421, 556, 430 ActionDest: 151 Annotation: Subtype: Link Rect: 506, 396, 518, 405 ActionDest: 151 Annotation: Subtype: Link Rect: 460, 371, 472, 380 ActionDest: 143 Annotation: Subtype: Link Rect: 543, 358, 555, 367 ActionDest: 151 Annotation: Subtype: Link Rect: 348, 346, 360, 355 ActionDest: 143 Annotation: Subtype: Link Rect: 253, 321, 265, 330 ActionDest: 151 Annotation: Subtype: Link Rect: 357, 295, 369, 305 ActionDest: 151 Annotation: Subtype: Link Rect: 240, 195, 252, 204 ActionDest: 151 Annotation: Subtype: Link Rect: 515, 170, 527, 179 ActionDest: 151 Annotation: Subtype: Link Rect: 199, 130, 214, 141 ActionDest: 76 Annotation: Subtype: Link Rect: 221, 132, 233, 141 ActionDest: 151 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 291, 710, 303, 719 ActionDest: 151 Annotation: Subtype: Link Rect: 358, 698, 370, 707 ActionDest: 151 Annotation: Subtype: Link Rect: 363, 660, 375, 669 ActionDest: 151 Annotation: Subtype: Link Rect: 184, 622, 196, 631 ActionDest: 151 Annotation: Subtype: Link Rect: 196, 622, 208, 631 ActionDest: 154 Annotation: Subtype: Link Rect: 211, 622, 223, 631 ActionDest: 154 Annotation: Subtype: Link Rect: 262, 620, 269, 632 ActionDest: 87 Annotation: Subtype: Link Rect: 545, 585, 556, 594 ActionDest: 154 Annotation: Subtype: Link Rect: 199, 570, 206, 582 ActionDest: 87 Annotation: Subtype: Link Rect: 439, 547, 451, 556 ActionDest: 154 Annotation: Subtype: Link Rect: 489, 544, 496, 556 ActionDest: 87 Annotation: Subtype: Link Rect: 516, 535, 528, 544 ActionDest: 154 Annotation: Subtype: Link Rect: 528, 535, 540, 544 ActionDest: 154 Annotation: Subtype: Link Rect: 543, 535, 555, 544 ActionDest: 154 Annotation: Subtype: Link Rect: 487, 509, 499, 519 ActionDest: 154 Annotation: Subtype: Link Rect: 201, 472, 213, 481 ActionDest: 154 Annotation: Subtype: Link Rect: 281, 170, 292, 178 ActionDest: 154 Annotation: Subtype: Link Rect: 293, 170, 304, 178 ActionDest: 154 Annotation: Subtype: Link Rect: 304, 170, 315, 178 ActionDest: 154 Annotation: Subtype: Link Rect: 315, 170, 326, 178 ActionDest: 154 Annotation: Subtype: Link Rect: 326, 170, 337, 178 ActionDest: 154 Annotation: Subtype: Link Rect: 439, 116, 559, 127 Annotation: Subtype: Link Rect: 284, 106, 295, 114 ActionDest: 154 Annotation: Subtype: Link Rect: 296, 106, 306, 114 ActionDest: 154 Annotation: Subtype: Link Rect: 544, 59, 556, 69 ActionDest: 151 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 544, 723, 556, 732 ActionDest: 151 Annotation: Subtype: Link Rect: 411, 685, 423, 694 ActionDest: 154 Annotation: Subtype: Link Rect: 280, 635, 292, 644 ActionDest: 154 Annotation: Subtype: Link Rect: 458, 622, 470, 631 ActionDest: 154 Annotation: Subtype: Link Rect: 194, 597, 206, 606 ActionDest: 154 Annotation: Subtype: Link Rect: 381, 572, 393, 581 ActionDest: 154 Annotation: Subtype: Link Rect: 418, 560, 430, 569 ActionDest: 154 Annotation: Subtype: Link Rect: 334, 459, 346, 468 ActionDest: 154 Annotation: Subtype: Link Rect: 349, 459, 361, 468 ActionDest: 154 Annotation: Subtype: Link Rect: 379, 434, 391, 443 ActionDest: 154 Annotation: Subtype: Link Rect: 299, 409, 311, 418 ActionDest: 154 Annotation: Subtype: Link Rect: 312, 409, 324, 418 ActionDest: 154 Annotation: Subtype: Link Rect: 334, 396, 346, 405 ActionDest: 154 Annotation: Subtype: Link Rect: 544, 371, 556, 380 ActionDest: 154 Annotation: Subtype: Link Rect: 244, 333, 256, 342 ActionDest: 151 Annotation: Subtype: Link Rect: 256, 333, 268, 342 ActionDest: 154 Annotation: Subtype: Link Rect: 544, 321, 556, 330 ActionDest: 154 Annotation: Subtype: Link Rect: 248, 283, 260, 292 ActionDest: 157 Annotation: Subtype: Link Rect: 213, 208, 225, 217 ActionDest: 151 Annotation: Subtype: Link Rect: 394, 167, 401, 179 ActionDest: 112 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 189, 270, 200, 278 ActionDest: 157 Annotation: Subtype: Link Rect: 200, 270, 211, 278 ActionDest: 157 Annotation: Subtype: Link Rect: 395, 197, 407, 207 ActionDest: 143 Annotation: Subtype: Link Rect: 407, 197, 419, 207 ActionDest: 157 Annotation: Subtype: Link Rect: 422, 197, 434, 207 ActionDest: 157 Annotation: Subtype: Link Rect: 197, 185, 209, 194 ActionDest: 157 Annotation: Subtype: Link Rect: 212, 185, 224, 194 ActionDest: 157 Annotation: Subtype: Link Rect: 265, 172, 277, 181 ActionDest: 157 Annotation: Subtype: Link Rect: 278, 172, 290, 181 ActionDest: 157 Annotation: Subtype: Link Rect: 424, 172, 436, 181 ActionDest: 157 Annotation: Subtype: Link Rect: 437, 173, 449, 181 ActionDest: 157 Annotation: Subtype: Link Rect: 421, 122, 433, 131 ActionDest: 157 Annotation: Subtype: Link Rect: 453, 110, 465, 119 ActionDest: 157 Annotation: Subtype: Link Rect: 465, 110, 477, 119 ActionDest: 157 Annotation: Subtype: Link Rect: 193, 85, 205, 94 ActionDest: 157 Annotation: Subtype: Link Rect: 273, 85, 285, 94 ActionDest: 157 Annotation: Subtype: Link Rect: 544, 60, 556, 69 ActionDest: 157 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 224, 698, 236, 707 ActionDest: 157 Annotation: Subtype: Link Rect: 424, 647, 436, 657 ActionDest: 151 Annotation: Subtype: Link Rect: 527, 647, 539, 657 ActionDest: 151 Annotation: Subtype: Link Rect: 416, 597, 428, 606 ActionDest: 157 Annotation: Subtype: Link Rect: 503, 585, 515, 594 ActionDest: 157 Annotation: Subtype: Link Rect: 515, 585, 527, 594 ActionDest: 157 Annotation: Subtype: Link Rect: 224, 547, 236, 556 ActionDest: 157 Annotation: Subtype: Link Rect: 234, 497, 246, 506 ActionDest: 157 Annotation: Subtype: Link Rect: 247, 497, 259, 506 ActionDest: 157 Annotation: Subtype: Link Rect: 259, 497, 271, 506 ActionDest: 157 Annotation: Subtype: Link Rect: 293, 472, 305, 481 ActionDest: 143 Annotation: Subtype: Link Rect: 202, 434, 213, 443 ActionDest: 157 Annotation: Subtype: Link Rect: 544, 270, 556, 279 ActionDest: 157 Annotation: Subtype: Link Rect: 440, 245, 452, 254 ActionDest: 160 Annotation: Subtype: Link Rect: 320, 233, 332, 242 ActionDest: 151 Annotation: Subtype: Link Rect: 446, 208, 458, 217 ActionDest: 143 Annotation: Subtype: Link Rect: 516, 195, 528, 204 ActionDest: 160 Annotation: Subtype: Link Rect: 210, 157, 222, 166 ActionDest: 160 Annotation: Subtype: Link Rect: 504, 145, 516, 154 ActionDest: 151 Annotation: Subtype: Link Rect: 347, 132, 359, 141 ActionDest: 160 Annotation: Subtype: Link Rect: 194, 107, 206, 116 ActionDest: 160 Annotation: Subtype: Link Rect: 207, 107, 219, 116 ActionDest: 160 Annotation: Subtype: Link Rect: 342, 82, 354, 91 ActionDest: 160 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 233, 723, 245, 732 ActionDest: 160 Annotation: Subtype: Link Rect: 345, 673, 357, 682 ActionDest: 160 Annotation: Subtype: Link Rect: 376, 635, 388, 644 ActionDest: 160 Annotation: Subtype: Link Rect: 215, 585, 227, 594 ActionDest: 160 Annotation: Subtype: Link Rect: 544, 534, 556, 543 ActionDest: 160 Annotation: Subtype: Link Rect: 295, 497, 307, 506 ActionDest: 154 Annotation: Subtype: Link Rect: 446, 446, 458, 455 ActionDest: 160 Annotation: Subtype: Link Rect: 483, 433, 495, 443 ActionDest: 160 Annotation: Subtype: Link Rect: 275, 408, 287, 417 ActionDest: 160 Annotation: Subtype: Link Rect: 290, 408, 302, 417 ActionDest: 160 Annotation: Subtype: Link Rect: 252, 358, 263, 367 ActionDest: 160 Annotation: Subtype: Link Rect: 544, 333, 556, 342 ActionDest: 151 Annotation: Subtype: Link Rect: 420, 308, 432, 317 ActionDest: 151 Annotation: Subtype: Link Rect: 364, 232, 376, 241 ActionDest: 160 Annotation: Subtype: Link Rect: 379, 232, 391, 241 ActionDest: 160 Annotation: Subtype: Link Rect: 544, 169, 556, 178 ActionDest: 154 Annotation: Subtype: Link Rect: 360, 94, 372, 103 ActionDest: 160 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 537, 710, 554, 719 ActionDest: 160 Annotation: Subtype: Link Rect: 189, 660, 206, 669 ActionDest: 160 Annotation: Subtype: Link Rect: 209, 660, 226, 669 ActionDest: 163 Annotation: Subtype: Link Rect: 310, 635, 322, 644 ActionDest: 151 Annotation: Subtype: Link Rect: 322, 635, 334, 644 ActionDest: 151 Annotation: Subtype: Link Rect: 335, 635, 352, 644 ActionDest: 163 Annotation: Subtype: Link Rect: 386, 632, 393, 644 ActionDest: 134 Annotation: Subtype: Link Rect: 519, 622, 535, 631 ActionDest: 163 Annotation: Subtype: Link Rect: 538, 622, 555, 631 ActionDest: 163 Annotation: Subtype: Link Rect: 470, 594, 478, 606 ActionDest: 134 Annotation: Subtype: Link Rect: 236, 481, 358, 492 Annotation: Subtype: Link Rect: 482, 483, 493, 492 ActionDest: 154 Annotation: Subtype: Link Rect: 494, 483, 504, 492 ActionDest: 154 Annotation: Subtype: Link Rect: 242, 470, 257, 479 ActionDest: 163 Annotation: Subtype: Link Rect: 257, 470, 273, 479 ActionDest: 163 Annotation: Subtype: Link Rect: 275, 471, 291, 479 ActionDest: 163 Annotation: Subtype: Link Rect: 526, 368, 541, 376 ActionDest: 163 Annotation: Subtype: Link Rect: 526, 357, 541, 365 ActionDest: 163 Annotation: Subtype: Link Rect: 526, 346, 541, 354 ActionDest: 163 Annotation: Subtype: Link Rect: 528, 313, 539, 321 ActionDest: 151 Annotation: Subtype: Link Rect: 523, 302, 538, 310 ActionDest: 163 Annotation: Subtype: Link Rect: 521, 242, 536, 251 ActionDest: 163 Annotation: Subtype: Link Rect: 521, 231, 536, 240 ActionDest: 163 Annotation: Subtype: Link Rect: 521, 220, 536, 229 ActionDest: 163 Annotation: Subtype: Link Rect: 521, 209, 536, 218 ActionDest: 163 Annotation: Subtype: Link Rect: 521, 198, 536, 207 ActionDest: 163 Annotation: Subtype: Link Rect: 523, 188, 538, 196 ActionDest: 163 Annotation: Subtype: Link Rect: 521, 176, 536, 185 ActionDest: 163 Annotation: Subtype: Link Rect: 523, 144, 538, 152 ActionDest: 163 Annotation: Subtype: Link Rect: 521, 133, 536, 141 ActionDest: 163 Annotation: Subtype: Link Rect: 523, 122, 538, 130 ActionDest: 163 Annotation: Subtype: Link Rect: 525, 111, 536, 119 ActionDest: 154 Annotation: Subtype: Link Rect: 525, 100, 536, 108 ActionDest: 154 Annotation: Subtype: Link Rect: 525, 89, 536, 97 ActionDest: 154 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 521, 676, 536, 684 ActionDest: 163 Annotation: Subtype: Link Rect: 523, 588, 538, 596 ActionDest: 163 Annotation: Subtype: Link Rect: 240, 481, 256, 490 ActionDest: 163 Annotation: Subtype: Link Rect: 301, 456, 313, 465 ActionDest: 151 Annotation: Subtype: Link Rect: 313, 456, 330, 465 ActionDest: 163 Annotation: Subtype: Link Rect: 333, 456, 350, 465 ActionDest: 166 Annotation: Subtype: Link Rect: 473, 431, 485, 440 ActionDest: 154 Annotation: Subtype: Link Rect: 485, 431, 497, 440 ActionDest: 154 Annotation: Subtype: Link Rect: 498, 431, 515, 440 ActionDest: 166 Annotation: Subtype: Link Rect: 518, 431, 535, 440 ActionDest: 166 Annotation: Subtype: Link Rect: 272, 406, 289, 415 ActionDest: 166 Annotation: Subtype: Link Rect: 337, 381, 354, 390 ActionDest: 166 Annotation: Subtype: Link Rect: 354, 381, 371, 390 ActionDest: 166 Annotation: Subtype: Link Rect: 445, 368, 457, 377 ActionDest: 160 Annotation: Subtype: Link Rect: 276, 252, 283, 264 ActionDest: 134 Annotation: Subtype: Link Rect: 300, 242, 312, 251 ActionDest: 151 Annotation: Subtype: Link Rect: 312, 242, 329, 251 ActionDest: 166 Annotation: Subtype: Link Rect: 398, 230, 409, 239 ActionDest: 154 Annotation: Subtype: Link Rect: 410, 230, 427, 239 ActionDest: 163 Annotation: Subtype: Link Rect: 374, 205, 386, 214 ActionDest: 151 Annotation: Subtype: Link Rect: 386, 205, 403, 214 ActionDest: 166 Annotation: Subtype: Link Rect: 436, 202, 443, 214 ActionDest: 134 Annotation: Subtype: Link Rect: 465, 179, 482, 189 ActionDest: 166 Annotation: Subtype: Link Rect: 249, 129, 266, 138 ActionDest: 163 Annotation: Subtype: Link Rect: 395, 104, 407, 113 ActionDest: 154 Annotation: Subtype: Link Rect: 407, 104, 424, 113 ActionDest: 166 Annotation: Subtype: Link Rect: 382, 89, 397, 101 ActionDest: 109 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 282, 723, 294, 732 ActionDest: 151 Annotation: Subtype: Link Rect: 294, 723, 306, 732 ActionDest: 160 Annotation: Subtype: Link Rect: 307, 723, 324, 732 ActionDest: 166 Annotation: Subtype: Link Rect: 387, 710, 399, 719 ActionDest: 160 Annotation: Subtype: Link Rect: 400, 710, 417, 719 ActionDest: 166 Annotation: Subtype: Link Rect: 410, 685, 422, 694 ActionDest: 154 Annotation: Subtype: Link Rect: 423, 685, 435, 694 ActionDest: 154 Annotation: Subtype: Link Rect: 435, 685, 452, 694 ActionDest: 166 Annotation: Subtype: Link Rect: 455, 685, 472, 694 ActionDest: 166 Annotation: Subtype: Link Rect: 460, 647, 476, 657 ActionDest: 166 Annotation: Subtype: Link Rect: 479, 647, 496, 657 ActionDest: 166 Annotation: Subtype: Link Rect: 374, 622, 386, 631 ActionDest: 160 Annotation: Subtype: Link Rect: 387, 622, 404, 631 ActionDest: 166 Annotation: Subtype: Link Rect: 404, 623, 421, 631 ActionDest: 166 Annotation: Subtype: Link Rect: 319, 572, 336, 581 ActionDest: 166 Annotation: Subtype: Link Rect: 539, 535, 556, 544 ActionDest: 163 Annotation: Subtype: Link Rect: 515, 447, 532, 456 ActionDest: 163 Annotation: Subtype: Link Rect: 533, 447, 550, 456 ActionDest: 163 Annotation: Subtype: Link Rect: 433, 331, 440, 343 ActionDest: 87 Annotation: Subtype: Link Rect: 423, 306, 430, 318 ActionDest: 112 Annotation: Subtype: Link Rect: 439, 283, 451, 292 ActionDest: 143 Annotation: Subtype: Link Rect: 320, 233, 332, 242 ActionDest: 151 Annotation: Subtype: Link Rect: 222, 208, 234, 217 ActionDest: 151 Annotation: Subtype: Link Rect: 316, 180, 323, 192 ActionDest: 87 Annotation: Subtype: Link Rect: 233, 133, 244, 142 ActionDest: 151 Annotation: Subtype: Link Rect: 245, 133, 257, 142 ActionDest: 154 Annotation: Subtype: Link Rect: 260, 133, 272, 142 ActionDest: 154 Annotation: Subtype: Link Rect: 272, 133, 284, 142 ActionDest: 154 Annotation: Subtype: Link Rect: 285, 133, 297, 142 ActionDest: 154 Annotation: Subtype: Link Rect: 335, 130, 342, 142 ActionDest: 87 Annotation: Subtype: Link Rect: 384, 95, 396, 104 ActionDest: 154 Annotation: Subtype: Link Rect: 396, 95, 408, 104 ActionDest: 154 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 222, 735, 234, 744 ActionDest: 154 Annotation: Subtype: Link Rect: 234, 735, 246, 744 ActionDest: 160 Annotation: Subtype: Link Rect: 247, 735, 264, 744 ActionDest: 166 Annotation: Subtype: Link Rect: 264, 735, 281, 744 ActionDest: 166 Annotation: Subtype: Link Rect: 211, 710, 228, 719 ActionDest: 166 Annotation: Subtype: Link Rect: 205, 582, 212, 594 ActionDest: 87 Annotation: Subtype: Link Rect: 235, 582, 242, 594 ActionDest: 112 Annotation: Subtype: Link Rect: 515, 535, 532, 544 ActionDest: 169 Annotation: Subtype: Link Rect: 532, 535, 549, 544 ActionDest: 169 Annotation: Subtype: Link Rect: 401, 376, 438, 387 Annotation: Subtype: Link Rect: 444, 376, 480, 387 Annotation: Subtype: Link Rect: 108, 354, 146, 364 Annotation: Subtype: Link Rect: 152, 354, 188, 364 Annotation: Subtype: Link Rect: 59, 331, 96, 341 Annotation: Subtype: Link Rect: 95, 308, 133, 318 Annotation: Subtype: Link Rect: 139, 308, 175, 318 Annotation: Subtype: Link Rect: 95, 273, 133, 283 Annotation: Subtype: Link Rect: 356, 249, 394, 260 Annotation: Subtype: Link Rect: 344, 226, 381, 237 Annotation: Subtype: Link Rect: 520, 203, 557, 214 Annotation: Subtype: Link Rect: 322, 180, 359, 191 Annotation: Subtype: Link Rect: 106, 147, 144, 157 Annotation: Subtype: Link Rect: 192, 124, 229, 134 Annotation: Subtype: Link Rect: 236, 124, 272, 134 Annotation: Subtype: Link Rect: 421, 100, 458, 111 Annotation: Subtype: Link Rect: 465, 100, 501, 111 Annotation: Subtype: Link Rect: 478, 77, 515, 88 Annotation: Subtype: Link Rect: 521, 77, 557, 88 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 59, 711, 96, 721 Annotation: Subtype: Link Rect: 102, 711, 138, 721 Annotation: Subtype: Link Rect: 427, 687, 465, 698 Annotation: Subtype: Link Rect: 104, 653, 141, 664 Annotation: Subtype: Link Rect: 108, 619, 146, 629 Annotation: Subtype: Link Rect: 59, 584, 96, 594 Annotation: Subtype: Link Rect: 357, 549, 395, 560 Annotation: Subtype: Link Rect: 401, 549, 437, 560 Annotation: Subtype: Link Rect: 196, 526, 233, 537 Annotation: Subtype: Link Rect: 334, 503, 372, 514 Annotation: Subtype: Link Rect: 104, 469, 141, 479 Annotation: Subtype: Link Rect: 147, 469, 183, 479 Annotation: Subtype: Link Rect: 59, 435, 96, 445 Annotation: Subtype: Link Rect: 102, 435, 138, 445 Annotation: Subtype: Link Rect: 164, 400, 201, 410 Annotation: Subtype: Link Rect: 207, 400, 243, 410 Annotation: Subtype: Link Rect: 519, 376, 557, 387 Annotation: Subtype: Link Rect: 59, 366, 95, 376 Annotation: Subtype: Link Rect: 59, 331, 96, 341 Annotation: Subtype: Link Rect: 102, 331, 138, 341 Annotation: Subtype: Link Rect: 197, 297, 235, 307 Annotation: Subtype: Link Rect: 241, 297, 277, 307 Annotation: Subtype: Link Rect: 346, 273, 383, 284 Annotation: Subtype: Link Rect: 170, 238, 208, 249 Annotation: Subtype: Link Rect: 472, 215, 510, 226 Annotation: Subtype: Link Rect: 318, 182, 356, 192 Annotation: Subtype: Link Rect: 106, 147, 144, 157 Annotation: Subtype: Link Rect: 150, 147, 186, 157 Annotation: Subtype: Link Rect: 514, 123, 552, 134 Annotation: Subtype: Link Rect: 434, 112, 471, 123 Annotation: Subtype: Link Rect: 477, 112, 513, 123 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 499, 722, 537, 733 Annotation: Subtype: Link Rect: 122, 688, 159, 698 Annotation: Subtype: Link Rect: 166, 688, 202, 698 Annotation: Subtype: Link Rect: 285, 652, 323, 664 Annotation: Subtype: Link Rect: 329, 652, 365, 664 Annotation: Subtype: Link Rect: 519, 629, 557, 640 Annotation: Subtype: Link Rect: 59, 619, 95, 629 Annotation: Subtype: Link Rect: 131, 584, 168, 594 Annotation: Subtype: Link Rect: 175, 584, 211, 594 Annotation: Subtype: Link Rect: 108, 550, 146, 560 Annotation: Subtype: Link Rect: 113, 527, 150, 537 Annotation: Subtype: Link Rect: 258, 491, 295, 502 Annotation: Subtype: Link Rect: 503, 468, 540, 479 Annotation: Subtype: Link Rect: 395, 445, 432, 456 Annotation: Subtype: Link Rect: 520, 422, 557, 433 Annotation: Subtype: Link Rect: 59, 412, 95, 422 Annotation: Subtype: Link Rect: 95, 377, 133, 387 Annotation: Subtype: Link Rect: 139, 377, 175, 387 Annotation: Subtype: Link Rect: 309, 342, 346, 353 Annotation: Subtype: Link Rect: 99, 308, 137, 318 Annotation: Subtype: Link Rect: 143, 308, 179, 318 Annotation: Subtype: Link Rect: 235, 274, 273, 284 Annotation: Subtype: Link Rect: 520, 250, 557, 261 Annotation: Subtype: Link Rect: 520, 227, 557, 238 Annotation: Subtype: Link Rect: 59, 216, 95, 226 Annotation: Subtype: Link Rect: 329, 181, 366, 192 Annotation: Subtype: Link Rect: 183, 147, 221, 157 Annotation: Subtype: Link Rect: 227, 147, 263, 157 Annotation: Subtype: Link Rect: 167, 113, 205, 123 Annotation: Subtype: Link Rect: 468, 89, 506, 100 Annotation: Subtype: Link Rect: 512, 89, 548, 100 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 59, 711, 96, 721 Annotation: Subtype: Link Rect: 102, 711, 138, 721 Annotation: Subtype: Link Rect: 491, 687, 529, 698 Annotation: Subtype: Link Rect: 250, 653, 287, 664 Annotation: Subtype: Link Rect: 210, 619, 247, 629 Annotation: Subtype: Link Rect: 500, 595, 538, 606 Annotation: Subtype: Link Rect: 156, 561, 194, 571 Annotation: Subtype: Link Rect: 200, 561, 236, 571 Annotation: Subtype: Link Rect: 479, 537, 516, 548 Annotation: Subtype: Link Rect: 521, 537, 557, 548 Annotation: Subtype: Link Rect: 95, 504, 133, 514 Annotation: Subtype: Link Rect: 139, 504, 175, 514 Annotation: Subtype: Link Rect: 520, 480, 557, 491 Annotation: Subtype: Link Rect: 467, 457, 505, 468 Annotation: Subtype: Link Rect: 511, 457, 547, 468 Annotation: Subtype: Link Rect: 290, 434, 328, 445 Annotation: Subtype: Link Rect: 95, 400, 133, 410 Annotation: Subtype: Link Rect: 483, 376, 520, 387 Annotation: Subtype: Link Rect: 95, 343, 133, 353 Annotation: Subtype: Link Rect: 95, 308, 133, 318 Annotation: Subtype: Link Rect: 95, 274, 133, 284 Annotation: Subtype: Link Rect: 139, 274, 175, 284 Annotation: Subtype: Link Rect: 519, 250, 557, 261 Annotation: Subtype: Link Rect: 59, 239, 95, 249 Annotation: Subtype: Link Rect: 381, 204, 419, 215 Annotation: Subtype: Link Rect: 425, 204, 461, 215 Annotation: Subtype: Link Rect: 166, 169, 204, 180 Annotation: Subtype: Link Rect: 210, 169, 246, 180 Annotation: Subtype: Link Rect: 458, 146, 496, 157 Annotation: Subtype: Link Rect: 470, 123, 508, 134 Annotation: Subtype: Link Rect: 422, 100, 460, 111 Annotation: Subtype: Link Rect: 109, 67, 146, 77 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 338, 710, 376, 721 Annotation: Subtype: Link Rect: 155, 676, 193, 687 Annotation: Subtype: Link Rect: 199, 676, 235, 687 Annotation: Subtype: Link Rect: 434, 652, 471, 664 Annotation: Subtype: Link Rect: 477, 652, 513, 664 Annotation: Subtype: Link Rect: 154, 618, 192, 629 Annotation: Subtype: Link Rect: 232, 596, 269, 606 Annotation: Subtype: Link Rect: 324, 560, 362, 571 Annotation: Subtype: Link Rect: 320, 526, 358, 537 Annotation: Subtype: Link Rect: 156, 492, 194, 502 Annotation: Subtype: Link Rect: 200, 492, 236, 502 Annotation: Subtype: Link Rect: 409, 468, 446, 479 Annotation: Subtype: Link Rect: 225, 434, 263, 445 Annotation: Subtype: Link Rect: 95, 400, 133, 410 Annotation: Subtype: Link Rect: 90, 366, 128, 376 Annotation: Subtype: Link Rect: 134, 366, 170, 376 Annotation: Subtype: Link Rect: 167, 343, 204, 353 Annotation: Subtype: Link Rect: 211, 343, 247, 353 Annotation: Subtype: Link Rect: 403, 319, 440, 330 Annotation: Subtype: Link Rect: 447, 319, 483, 330 Annotation: Subtype: Link Rect: 249, 284, 287, 295 Annotation: Subtype: Link Rect: 293, 284, 329, 295 Annotation: Subtype: Link Rect: 520, 261, 557, 272 Annotation: Subtype: Link Rect: 410, 238, 447, 249 Annotation: Subtype: Link Rect: 279, 204, 317, 215 Annotation: Subtype: Link Rect: 341, 181, 378, 192 Annotation: Subtype: Link Rect: 419, 158, 456, 169 Annotation: Subtype: Link Rect: 520, 135, 557, 146 Annotation: Subtype: Link Rect: 519, 112, 557, 123 Annotation: Subtype: Link Rect: 59, 101, 95, 111 Annotation: Subtype: Link Rect: 150, 67, 188, 77 Annotation: Subtype: Link Rect: 194, 67, 230, 77 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 238, 710, 275, 721 Annotation: Subtype: Link Rect: 122, 676, 160, 687 Annotation: Subtype: Link Rect: 59, 642, 96, 652 Annotation: Subtype: Link Rect: 270, 606, 308, 617 Annotation: Subtype: Link Rect: 314, 606, 350, 617 Annotation: Subtype: Link Rect: 59, 573, 96, 583 Annotation: Subtype: Link Rect: 86, 550, 124, 560 Annotation: Subtype: Link Rect: 465, 526, 502, 537 Annotation: Subtype: Link Rect: 268, 491, 306, 502 Annotation: Subtype: Link Rect: 460, 457, 498, 468 Annotation: Subtype: Link Rect: 504, 457, 540, 468 Annotation: Subtype: Link Rect: 178, 423, 215, 433 Annotation: Subtype: Link Rect: 222, 423, 258, 433 Annotation: Subtype: Link Rect: 164, 389, 201, 399 Annotation: Subtype: Link Rect: 207, 389, 243, 399 Annotation: Subtype: Link Rect: 365, 365, 402, 376 Annotation: Subtype: Link Rect: 409, 365, 445, 376 Annotation: Subtype: Link Rect: 59, 331, 96, 341 Annotation: Subtype: Link Rect: 104, 297, 141, 307 Annotation: Subtype: Link Rect: 147, 297, 183, 307 Annotation: Subtype: Link Rect: 122, 262, 159, 272 Annotation: Subtype: Link Rect: 127, 228, 164, 238 Annotation: Subtype: Link Rect: 461, 192, 499, 203 Annotation: Subtype: Link Rect: 375, 158, 413, 169 Annotation: Subtype: Link Rect: 167, 124, 204, 134 Annotation: Subtype: Link Rect: 408, 100, 446, 111 Annotation: Subtype: Link Rect: 452, 100, 488, 111 Annotation: Subtype: Link Rect: 59, 67, 96, 77 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 135, 711, 173, 721 Annotation: Subtype: Link Rect: 104, 676, 141, 687 Annotation: Subtype: Link Rect: 147, 676, 183, 687 Annotation: Subtype: Link Rect: 479, 652, 516, 664 Annotation: Subtype: Link Rect: 521, 652, 557, 664 Annotation: Subtype: Link Rect: 507, 629, 544, 640 Annotation: Subtype: Link Rect: 131, 596, 168, 606 Annotation: Subtype: Link Rect: 196, 561, 233, 571 Annotation: Subtype: Link Rect: 173, 538, 211, 548 Annotation: Subtype: Link Rect: 487, 514, 524, 525 Annotation: Subtype: Link Rect: 59, 481, 96, 491 Annotation: Subtype: Link Rect: 102, 481, 138, 491 Annotation: Subtype: Link Rect: 144, 446, 182, 456 Annotation: Subtype: Link Rect: 161, 411, 199, 422 Annotation: Subtype: Link Rect: 81, 377, 119, 387 Annotation: Subtype: Link Rect: 125, 377, 161, 387 Annotation: Subtype: Link Rect: 520, 353, 557, 364 Annotation: Subtype: Link Rect: 59, 343, 95, 353 Annotation: Subtype: Link Rect: 195, 308, 233, 318 Annotation: Subtype: Link Rect: 59, 274, 96, 284 Annotation: Subtype: Link Rect: 185, 239, 223, 249 Annotation: Subtype: Link Rect: 218, 205, 256, 215 Annotation: Subtype: Link Rect: 131, 170, 168, 180 Annotation: Subtype: Link Rect: 175, 170, 211, 180 Annotation: Subtype: Link Rect: 240, 136, 277, 146 Annotation: Subtype: Link Rect: 284, 136, 320, 146 Annotation: Subtype: Link Rect: 356, 112, 393, 123 Annotation: Subtype: Link Rect: 399, 112, 435, 123 Annotation: Subtype: Link Rect: 520, 89, 557, 100 Annotation: Subtype: Link Rect: 485, 66, 522, 77 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 256, 710, 294, 721 Annotation: Subtype: Link Rect: 160, 676, 197, 687 Annotation: Subtype: Link Rect: 204, 676, 240, 687 Checksum: 04f3c0a9 Type: CRC32 Checksum: b18a2f79fce047b84351cb7c2df5c9e3 Type: MD5 Checksum: 255abb88a0faba6c30fc66d3341e0b838bf6b372 Type: SHA-1