d4f158cf917d5fdb822db32120039b32 cancers_a2022v14n7p1771.pdf 70a90d30e39cecd4e15222f6d4b46e674b4a4cd9 cancers_a2022v14n7p1771.pdf 5618a3fa59047c1b11a8fa9b270a83bf5ecfa15b12c5fa5431846d3cd8c3d054 cancers_a2022v14n7p1771.pdf Title: Evaluation of the TCR Repertoire as a Predictive and Prognostic Biomarker in Cancer: Diversity or Clonality? Subject: T cells play a vital role in the anti-tumoural response, and the presence of tumour-infiltrating lymphocytes has shown to be directly correlated with a good prognosis in several cancer types. Nevertheless, some patients presenting tumour-infiltrating lymphocytes do not have favourable outcomes. The TCR determines the specificities of T cells, so the analysis of the TCR repertoire has been recently considered to be a potential biomarker for patients’ progression and response to therapies with immune checkpoint inhibitors. The TCR repertoire is one of the multiple elements comprising the immune system and is conditioned by several factors, including tissue type, tumour mutational burden, and patients’ immunogenetics. Its study is crucial to understanding the anti-tumoural response, how to beneficially modulate the immune response with current or new treatments, and how to better predict the prognosis. Here, we present a critical review including essential studies on TCR repertoire conducted in patients with cancer with the aim to draw the current conclusions and try to elucidate whether it is better to encounter higher clonality with few TCRs at higher frequencies, or higher diversity with many different TCRs at lower frequencies. Keywords: clonality; diversity; immune-checkpoint inhibitor; neoantigens; TCR; TILs; tumour-associated antigens Author: Andrea Aran, Laia Garrigós, Giuseppe Curigliano, Javier Cortés and Mercè Martí Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Mar 31 08:49:27 2022 CEST ModDate: Sat Apr 2 06:25:57 2022 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 21 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 878761 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- BGCOJL+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 QUQRRK+VnURWPalladioL Type 1 Custom yes yes no 15 0 DMQPQR+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 DPUTLI+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 UQYTRS+URWPalladioL-Ital Type 1 Custom yes yes no 28 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 DORTIW+EURM10 Type 1 Builtin yes yes no 79 0 MMNAIC+CMSY10 Type 1 Builtin yes yes no 86 0 NNMNNA+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 93 0 NNMNNB+PalatinoLinotype CID TrueType Identity-H yes yes yes 96 0 NNMNNC+PalatinoLinotype TrueType WinAnsi yes yes no 102 0 NNMNNE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 105 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-06-03 02:30:31 CEST RepresentationInformation: cancers_a2022v14n7p1771.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2022-04-04 13:02:16 CEST Size: 878761 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 590 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: T Cell Receptor Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: TCR Assembly and Structure Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: TCR Sequencing and Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: T Cell Response to Different Type of Tumoural Antigens Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Children: Item: Title: Tumour-Associated Antigens Recognition Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Tumour-Specific Antigens Recognition Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: The TCR Repertoire as a Prognostic Biomarker in Cancer Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Children: Item: Title: TCR Repertoire in Patients with Cancer Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Determinant Factors of the TCR Repertoire Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: The TCR Repertoire as a Predictive Biomarker of Immune Checkpoint Inhibitor Treatments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Info: Title: Evaluation of the TCR Repertoire as a Predictive and Prognostic Biomarker in Cancer: Diversity or Clonality? Author: Andrea Aran, Laia Garrigós, Giuseppe Curigliano, Javier Cortés and Mercè Martí Subject: T cells play a vital role in the anti-tumoural response, and the presence of tumour-infiltrating lymphocytes has shown to be directly correlated with a good prognosis in several cancer types. Nevertheless, some patients presenting tumour-infiltrating lymphocytes do not have favourable outcomes. The TCR determines the specificities of T cells, so the analysis of the TCR repertoire has been recently considered to be a potential biomarker for patients’ progression and response to therapies with immune checkpoint inhibitors. The TCR repertoire is one of the multiple elements comprising the immune system and is conditioned by several factors, including tissue type, tumour mutational burden, and patients’ immunogenetics. Its study is crucial to understanding the anti-tumoural response, how to beneficially modulate the immune response with current or new treatments, and how to better predict the prognosis. Here, we present a critical review including essential studies on TCR repertoire conducted in patients with cancer with the aim to draw the current conclusions and try to elucidate whether it is better to encounter higher clonality with few TCRs at higher frequencies, or higher diversity with many different TCRs at lower frequencies. Keywords: clonality; diversity; immune-checkpoint inhibitor; neoantigens; TCR; TILs; tumour-associated antigens Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Mar 31 08:49:27 CEST 2022 ModDate: Sat Apr 02 06:25:57 CEST 2022 ID: 0xd5e34e458c49ddfa761a52074c396fc6, 0xd5e34e458c49ddfa761a52074c396fc6 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: DMQPQR+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 121 FontDescriptor: FontName: DMQPQR+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: MMNAIC+CMSY10 FontSubset: true FirstChar: 2 LastChar: 48 FontDescriptor: FontName: MMNAIC+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: DPUTLI+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: DPUTLI+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: BGCOJL+VnURWPalladioL-Bold FontSubset: true FirstChar: 177 LastChar: 226 FontDescriptor: FontName: BGCOJL+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: UQYTRS+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 121 FontDescriptor: FontName: UQYTRS+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: QUQRRK+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: QUQRRK+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: DORTIW+EURM10 FontSubset: true FirstChar: 11 LastChar: 14 FontDescriptor: FontName: DORTIW+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 82, 335, 152, 344 Annotation: Subtype: Link Rect: 34, 324, 113, 332 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: 100, 661, 111, 675 Annotation: Subtype: Link Rect: 297, 661, 308, 675 Annotation: Subtype: Link Rect: 396, 661, 407, 675 Annotation: Subtype: Link Rect: 114, 17, 265, 28 Annotation: Subtype: Link Rect: 410, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 408, 86, 427 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 201, 320, 208, 329 ActionDest: 143 Annotation: Subtype: Link Rect: 208, 320, 215, 329 ActionDest: 143 Annotation: Subtype: Link Rect: 200, 282, 207, 291 ActionDest: 143 Annotation: Subtype: Link Rect: 207, 282, 214, 291 ActionDest: 143 Annotation: Subtype: Link Rect: 434, 282, 441, 291 ActionDest: 143 Annotation: Subtype: Link Rect: 441, 282, 448, 291 ActionDest: 143 Annotation: Subtype: Link Rect: 238, 255, 245, 267 ActionDest: 83 Annotation: Subtype: Link Rect: 535, 144, 542, 153 ActionDest: 143 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 220, 82, 227, 91 ActionDest: 143 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 216, 710, 223, 719 ActionDest: 143 Annotation: Subtype: Link Rect: 351, 685, 363, 694 ActionDest: 143 Annotation: Subtype: Link Rect: 363, 685, 375, 694 ActionDest: 143 Annotation: Subtype: Link Rect: 374, 660, 381, 669 ActionDest: 143 Annotation: Subtype: Link Rect: 544, 572, 556, 581 ActionDest: 143 Annotation: Subtype: Link Rect: 450, 522, 462, 531 ActionDest: 143 Annotation: Subtype: Link Rect: 465, 522, 477, 531 ActionDest: 146 Annotation: Subtype: Link Rect: 192, 509, 203, 518 ActionDest: 146 Annotation: Subtype: Link Rect: 204, 509, 216, 518 ActionDest: 146 Annotation: Subtype: Link Rect: 240, 396, 247, 405 ActionDest: 143 Annotation: Subtype: Link Rect: 247, 396, 259, 405 ActionDest: 146 Annotation: Subtype: Link Rect: 231, 358, 243, 368 ActionDest: 143 Annotation: Subtype: Link Rect: 243, 359, 255, 368 ActionDest: 143 Annotation: Subtype: Link Rect: 460, 346, 472, 355 ActionDest: 146 Annotation: Subtype: Link Rect: 264, 258, 276, 267 ActionDest: 146 Annotation: Subtype: Link Rect: 274, 233, 286, 242 ActionDest: 146 Annotation: Subtype: Link Rect: 321, 221, 333, 229 ActionDest: 143 Annotation: Subtype: Link Rect: 511, 195, 523, 204 ActionDest: 146 Annotation: Subtype: Link Rect: 374, 108, 386, 117 ActionDest: 146 Annotation: Subtype: Link Rect: 389, 108, 401, 117 ActionDest: 146 Annotation: Subtype: Link Rect: 194, 70, 206, 79 ActionDest: 146 Annotation: Subtype: Link Rect: 543, 70, 555, 79 ActionDest: 146 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 336, 710, 348, 719 ActionDest: 146 Annotation: Subtype: Link Rect: 348, 710, 360, 719 ActionDest: 146 Annotation: Subtype: Link Rect: 363, 710, 375, 719 ActionDest: 146 Annotation: Subtype: Link Rect: 198, 509, 210, 519 ActionDest: 146 Annotation: Subtype: Link Rect: 211, 509, 223, 519 ActionDest: 146 Annotation: Subtype: Link Rect: 223, 509, 235, 519 ActionDest: 146 Annotation: Subtype: Link Rect: 545, 497, 557, 506 ActionDest: 146 Annotation: Subtype: Link Rect: 398, 133, 410, 142 ActionDest: 146 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 377, 660, 389, 669 ActionDest: 146 Annotation: Subtype: Link Rect: 389, 660, 401, 669 ActionDest: 146 Annotation: Subtype: Link Rect: 491, 610, 503, 619 ActionDest: 146 Annotation: Subtype: Link Rect: 506, 610, 518, 619 ActionDest: 149 Annotation: Subtype: Link Rect: 359, 597, 371, 606 ActionDest: 146 Annotation: Subtype: Link Rect: 371, 597, 383, 606 ActionDest: 149 Annotation: Subtype: Link Rect: 386, 597, 398, 606 ActionDest: 149 Annotation: Subtype: Link Rect: 520, 572, 531, 581 ActionDest: 146 Annotation: Subtype: Link Rect: 532, 572, 544, 581 ActionDest: 149 Annotation: Subtype: Link Rect: 319, 559, 331, 568 ActionDest: 149 Annotation: Subtype: Link Rect: 332, 559, 344, 568 ActionDest: 149 Annotation: Subtype: Link Rect: 203, 534, 215, 543 ActionDest: 149 Annotation: Subtype: Link Rect: 216, 534, 228, 543 ActionDest: 149 Annotation: Subtype: Link Rect: 453, 484, 465, 493 ActionDest: 146 Annotation: Subtype: Link Rect: 465, 484, 477, 493 ActionDest: 149 Annotation: Subtype: Link Rect: 327, 459, 339, 468 ActionDest: 149 Annotation: Subtype: Link Rect: 350, 434, 362, 443 ActionDest: 149 Annotation: Subtype: Link Rect: 298, 396, 310, 405 ActionDest: 149 Annotation: Subtype: Link Rect: 198, 308, 210, 317 ActionDest: 152 Annotation: Subtype: Link Rect: 524, 283, 536, 292 ActionDest: 146 Annotation: Subtype: Link Rect: 395, 208, 407, 217 ActionDest: 152 Annotation: Subtype: Link Rect: 408, 208, 419, 217 ActionDest: 152 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 436, 685, 448, 694 ActionDest: 152 Annotation: Subtype: Link Rect: 500, 670, 507, 682 ActionDest: 121 Annotation: Subtype: Link Rect: 453, 597, 465, 606 ActionDest: 152 Annotation: Subtype: Link Rect: 229, 559, 241, 568 ActionDest: 152 Annotation: Subtype: Link Rect: 407, 522, 419, 531 ActionDest: 152 Annotation: Subtype: Link Rect: 497, 484, 509, 493 ActionDest: 152 Annotation: Subtype: Link Rect: 313, 459, 325, 468 ActionDest: 152 Annotation: Subtype: Link Rect: 361, 434, 373, 443 ActionDest: 152 Annotation: Subtype: Link Rect: 375, 434, 387, 443 ActionDest: 152 Annotation: Subtype: Link Rect: 351, 333, 363, 342 ActionDest: 152 Annotation: Subtype: Link Rect: 487, 333, 499, 342 ActionDest: 152 Annotation: Subtype: Link Rect: 357, 321, 369, 330 ActionDest: 152 Annotation: Subtype: Link Rect: 439, 321, 451, 330 ActionDest: 152 Annotation: Subtype: Link Rect: 233, 308, 245, 317 ActionDest: 152 Annotation: Subtype: Link Rect: 394, 308, 406, 317 ActionDest: 152 Annotation: Subtype: Link Rect: 324, 296, 336, 305 ActionDest: 152 Annotation: Subtype: Link Rect: 377, 296, 388, 305 ActionDest: 152 Annotation: Subtype: Link Rect: 495, 296, 507, 305 ActionDest: 152 Annotation: Subtype: Link Rect: 519, 271, 531, 280 ActionDest: 152 Annotation: Subtype: Link Rect: 531, 271, 543, 280 ActionDest: 152 Annotation: Subtype: Link Rect: 544, 271, 556, 280 ActionDest: 152 Annotation: Subtype: Link Rect: 465, 208, 477, 217 ActionDest: 152 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 447, 723, 459, 732 ActionDest: 152 Annotation: Subtype: Link Rect: 459, 723, 471, 732 ActionDest: 155 Annotation: Subtype: Link Rect: 371, 698, 383, 707 ActionDest: 152 Annotation: Subtype: Link Rect: 531, 581, 541, 589 ActionDest: 152 Annotation: Subtype: Link Rect: 531, 532, 541, 540 ActionDest: 152 Annotation: Subtype: Link Rect: 533, 497, 543, 504 ActionDest: 152 Annotation: Subtype: Link Rect: 524, 434, 534, 442 ActionDest: 152 Annotation: Subtype: Link Rect: 527, 352, 537, 360 ActionDest: 152 Annotation: Subtype: Link Rect: 522, 285, 532, 293 ActionDest: 152 Annotation: Subtype: Link Rect: 527, 240, 537, 248 ActionDest: 152 Annotation: Subtype: Link Rect: 534, 217, 544, 224 ActionDest: 152 Annotation: Subtype: Link Rect: 522, 154, 532, 161 ActionDest: 152 Annotation: Subtype: Link Rect: 528, 79, 538, 87 ActionDest: 152 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 535, 691, 545, 698 ActionDest: 152 Annotation: Subtype: Link Rect: 523, 641, 533, 648 ActionDest: 152 Annotation: Subtype: Link Rect: 529, 582, 539, 589 ActionDest: 152 Annotation: Subtype: Link Rect: 527, 548, 537, 556 ActionDest: 152 Annotation: Subtype: Link Rect: 221, 383, 233, 392 ActionDest: 155 Annotation: Subtype: Link Rect: 514, 370, 526, 379 ActionDest: 155 Annotation: Subtype: Link Rect: 529, 370, 541, 379 ActionDest: 155 Annotation: Subtype: Link Rect: 221, 320, 233, 329 ActionDest: 155 Annotation: Subtype: Link Rect: 209, 194, 221, 203 ActionDest: 155 Annotation: Subtype: Link Rect: 222, 194, 233, 203 ActionDest: 155 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 418, 685, 430, 694 ActionDest: 155 Annotation: Subtype: Link Rect: 260, 622, 272, 631 ActionDest: 155 Annotation: Subtype: Link Rect: 273, 622, 285, 631 ActionDest: 155 Annotation: Subtype: Link Rect: 276, 585, 288, 594 ActionDest: 155 Annotation: Subtype: Link Rect: 291, 585, 308, 594 ActionDest: 155 Annotation: Subtype: Link Rect: 221, 461, 238, 470 ActionDest: 155 Annotation: Subtype: Link Rect: 369, 448, 386, 458 ActionDest: 158 Annotation: Subtype: Link Rect: 539, 436, 556, 445 ActionDest: 158 Annotation: Subtype: Link Rect: 392, 398, 409, 407 ActionDest: 158 Annotation: Subtype: Link Rect: 470, 373, 487, 382 ActionDest: 158 Annotation: Subtype: Link Rect: 497, 298, 514, 307 ActionDest: 158 Annotation: Subtype: Link Rect: 202, 223, 218, 232 ActionDest: 158 Annotation: Subtype: Link Rect: 221, 222, 238, 232 ActionDest: 158 Annotation: Subtype: Link Rect: 314, 183, 321, 194 ActionDest: 130 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 781, 440, 794, 447 ActionDest: 158 Annotation: Subtype: Link Rect: 772, 395, 786, 403 ActionDest: 158 Annotation: Subtype: Link Rect: 777, 342, 790, 350 ActionDest: 158 Annotation: Subtype: Link Rect: 780, 291, 794, 299 ActionDest: 158 Annotation: Subtype: Link Rect: 778, 255, 792, 262 ActionDest: 158 Annotation: Subtype: Link Rect: 776, 231, 790, 239 ActionDest: 158 Annotation: Subtype: Link Rect: 776, 202, 790, 210 ActionDest: 158 Annotation: Subtype: Link Rect: 779, 174, 793, 182 ActionDest: 158 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 780, 428, 794, 436 ActionDest: 158 Annotation: Subtype: Link Rect: 778, 372, 792, 380 ActionDest: 158 Annotation: Subtype: Link Rect: 770, 325, 784, 332 ActionDest: 158 Annotation: Subtype: Link Rect: 772, 291, 786, 299 ActionDest: 158 Annotation: Subtype: Link Rect: 775, 241, 789, 249 ActionDest: 158 Annotation: Subtype: Link Rect: 777, 197, 791, 204 ActionDest: 158 Annotation: Subtype: Link Rect: 777, 173, 791, 181 ActionDest: 161 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 773, 415, 787, 422 ActionDest: 161 Annotation: Subtype: Link Rect: 774, 359, 784, 367 ActionDest: 155 Annotation: Subtype: Link Rect: 775, 329, 789, 337 ActionDest: 161 Annotation: Subtype: Link Rect: 779, 306, 793, 313 ActionDest: 161 Annotation: Subtype: Link Rect: 779, 282, 789, 290 ActionDest: 155 Annotation: Subtype: Link Rect: 781, 258, 795, 266 ActionDest: 161 Annotation: Subtype: Link Rect: 775, 232, 789, 240 ActionDest: 161 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 492, 743, 508, 752 ActionDest: 158 Annotation: Subtype: Link Rect: 508, 744, 524, 752 ActionDest: 158 Annotation: Subtype: Link Rect: 524, 744, 540, 752 ActionDest: 158 Annotation: Subtype: Link Rect: 540, 743, 556, 752 ActionDest: 161 Annotation: Subtype: Link Rect: 204, 718, 221, 727 ActionDest: 158 Annotation: Subtype: Link Rect: 221, 718, 238, 727 ActionDest: 158 Annotation: Subtype: Link Rect: 347, 693, 364, 702 ActionDest: 158 Annotation: Subtype: Link Rect: 367, 693, 384, 702 ActionDest: 158 Annotation: Subtype: Link Rect: 384, 693, 401, 702 ActionDest: 158 Annotation: Subtype: Link Rect: 402, 693, 419, 702 ActionDest: 158 Annotation: Subtype: Link Rect: 419, 693, 436, 702 ActionDest: 161 Annotation: Subtype: Link Rect: 409, 668, 426, 677 ActionDest: 158 Annotation: Subtype: Link Rect: 427, 668, 444, 677 ActionDest: 158 Annotation: Subtype: Link Rect: 444, 668, 461, 677 ActionDest: 158 Annotation: Subtype: Link Rect: 538, 668, 555, 677 ActionDest: 161 Annotation: Subtype: Link Rect: 414, 655, 431, 665 ActionDest: 158 Annotation: Subtype: Link Rect: 461, 630, 478, 639 ActionDest: 161 Annotation: Subtype: Link Rect: 516, 593, 533, 602 ActionDest: 161 Annotation: Subtype: Link Rect: 536, 593, 553, 602 ActionDest: 161 Annotation: Subtype: Link Rect: 336, 542, 353, 552 ActionDest: 158 Annotation: Subtype: Link Rect: 354, 543, 371, 552 ActionDest: 158 Annotation: Subtype: Link Rect: 371, 543, 388, 552 ActionDest: 158 Annotation: Subtype: Link Rect: 388, 542, 405, 552 ActionDest: 161 Annotation: Subtype: Link Rect: 234, 517, 251, 526 ActionDest: 158 Annotation: Subtype: Link Rect: 251, 517, 268, 526 ActionDest: 158 Annotation: Subtype: Link Rect: 432, 505, 449, 514 ActionDest: 158 Annotation: Subtype: Link Rect: 413, 442, 430, 451 ActionDest: 158 Annotation: Subtype: Link Rect: 490, 442, 506, 451 ActionDest: 161 Annotation: Subtype: Link Rect: 238, 430, 255, 439 ActionDest: 158 Annotation: Subtype: Link Rect: 376, 430, 393, 439 ActionDest: 161 Annotation: Subtype: Link Rect: 417, 404, 434, 414 ActionDest: 158 Annotation: Subtype: Link Rect: 325, 392, 342, 401 ActionDest: 161 Annotation: Subtype: Link Rect: 448, 291, 460, 301 ActionDest: 155 Annotation: Subtype: Link Rect: 460, 292, 477, 301 ActionDest: 158 Annotation: Subtype: Link Rect: 478, 292, 495, 301 ActionDest: 161 Annotation: Subtype: Link Rect: 321, 266, 338, 275 ActionDest: 161 Annotation: Subtype: Link Rect: 518, 254, 535, 263 ActionDest: 161 Annotation: Subtype: Link Rect: 535, 254, 552, 263 ActionDest: 161 Annotation: Subtype: Link Rect: 213, 216, 230, 225 ActionDest: 158 Annotation: Subtype: Link Rect: 383, 216, 400, 225 ActionDest: 158 Annotation: Subtype: Link Rect: 400, 216, 417, 225 ActionDest: 158 Annotation: Subtype: Link Rect: 527, 166, 544, 175 ActionDest: 161 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 95, 401, 132, 411 Annotation: Subtype: Link Rect: 161, 378, 199, 388 Annotation: Subtype: Link Rect: 59, 355, 96, 365 Annotation: Subtype: Link Rect: 102, 355, 138, 365 Annotation: Subtype: Link Rect: 162, 320, 200, 330 Annotation: Subtype: Link Rect: 304, 296, 342, 307 Annotation: Subtype: Link Rect: 189, 274, 227, 284 Annotation: Subtype: Link Rect: 235, 250, 273, 261 Annotation: Subtype: Link Rect: 187, 227, 225, 238 Annotation: Subtype: Link Rect: 59, 205, 96, 215 Annotation: Subtype: Link Rect: 104, 171, 141, 181 Annotation: Subtype: Link Rect: 104, 148, 142, 158 Annotation: Subtype: Link Rect: 432, 124, 470, 135 Annotation: Subtype: Link Rect: 257, 101, 295, 112 Annotation: Subtype: Link Rect: 95, 78, 133, 89 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 261, 724, 299, 735 Annotation: Subtype: Link Rect: 172, 690, 210, 700 Annotation: Subtype: Link Rect: 427, 666, 464, 677 Annotation: Subtype: Link Rect: 137, 644, 175, 654 Annotation: Subtype: Link Rect: 468, 620, 505, 631 Annotation: Subtype: Link Rect: 59, 598, 96, 608 Annotation: Subtype: Link Rect: 59, 575, 96, 585 Annotation: Subtype: Link Rect: 102, 575, 138, 585 Annotation: Subtype: Link Rect: 210, 551, 248, 562 Annotation: Subtype: Link Rect: 254, 551, 290, 562 Annotation: Subtype: Link Rect: 59, 517, 96, 527 Annotation: Subtype: Link Rect: 102, 517, 138, 527 Annotation: Subtype: Link Rect: 261, 493, 299, 504 Annotation: Subtype: Link Rect: 258, 460, 295, 470 Annotation: Subtype: Link Rect: 301, 460, 337, 470 Annotation: Subtype: Link Rect: 259, 436, 297, 447 Annotation: Subtype: Link Rect: 59, 402, 96, 412 Annotation: Subtype: Link Rect: 135, 368, 173, 378 Annotation: Subtype: Link Rect: 86, 333, 124, 343 Annotation: Subtype: Link Rect: 130, 333, 166, 343 Annotation: Subtype: Link Rect: 59, 299, 96, 309 Annotation: Subtype: Link Rect: 136, 264, 173, 274 Annotation: Subtype: Link Rect: 425, 240, 463, 251 Annotation: Subtype: Link Rect: 469, 240, 505, 251 Annotation: Subtype: Link Rect: 235, 217, 273, 228 Annotation: Subtype: Link Rect: 519, 206, 557, 217 Annotation: Subtype: Link Rect: 59, 195, 95, 205 Annotation: Subtype: Link Rect: 234, 172, 272, 182 Annotation: Subtype: Link Rect: 278, 172, 314, 182 Annotation: Subtype: Link Rect: 407, 148, 445, 159 Annotation: Subtype: Link Rect: 451, 148, 487, 159 Annotation: Subtype: Link Rect: 226, 114, 263, 125 Annotation: Subtype: Link Rect: 59, 80, 96, 90 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 420, 712, 457, 723 Annotation: Subtype: Link Rect: 464, 712, 500, 723 Annotation: Subtype: Link Rect: 303, 689, 341, 700 Annotation: Subtype: Link Rect: 347, 689, 383, 700 Annotation: Subtype: Link Rect: 478, 666, 515, 677 Annotation: Subtype: Link Rect: 521, 666, 557, 677 Annotation: Subtype: Link Rect: 407, 643, 444, 654 Annotation: Subtype: Link Rect: 250, 609, 287, 619 Annotation: Subtype: Link Rect: 293, 609, 330, 619 Annotation: Subtype: Link Rect: 158, 575, 194, 585 Annotation: Subtype: Link Rect: 95, 540, 133, 550 Annotation: Subtype: Link Rect: 139, 540, 175, 550 Annotation: Subtype: Link Rect: 59, 506, 96, 516 Annotation: Subtype: Link Rect: 102, 506, 138, 516 Annotation: Subtype: Link Rect: 461, 482, 499, 493 Annotation: Subtype: Link Rect: 505, 482, 541, 493 Annotation: Subtype: Link Rect: 109, 448, 146, 458 Annotation: Subtype: Link Rect: 152, 448, 188, 458 Annotation: Subtype: Link Rect: 283, 390, 321, 401 Annotation: Subtype: Link Rect: 327, 390, 363, 401 Annotation: Subtype: Link Rect: 360, 367, 398, 378 Annotation: Subtype: Link Rect: 404, 367, 440, 378 Annotation: Subtype: Link Rect: 59, 345, 96, 355 Annotation: Subtype: Link Rect: 102, 345, 138, 355 Annotation: Subtype: Link Rect: 439, 332, 477, 343 Annotation: Subtype: Link Rect: 273, 309, 310, 320 Annotation: Subtype: Link Rect: 316, 309, 352, 320 Annotation: Subtype: Link Rect: 59, 276, 96, 286 Annotation: Subtype: Link Rect: 316, 240, 353, 251 Annotation: Subtype: Link Rect: 360, 240, 396, 251 Annotation: Subtype: Link Rect: 104, 207, 142, 217 Annotation: Subtype: Link Rect: 148, 207, 184, 217 Annotation: Subtype: Link Rect: 519, 183, 557, 194 Annotation: Subtype: Link Rect: 59, 172, 95, 182 Annotation: Subtype: Link Rect: 95, 149, 133, 159 Annotation: Subtype: Link Rect: 59, 126, 96, 136 Annotation: Subtype: Link Rect: 102, 126, 138, 136 Annotation: Subtype: Link Rect: 59, 92, 96, 102 Annotation: Subtype: Link Rect: 102, 92, 138, 102 Annotation: Subtype: Link Rect: 512, 79, 548, 90 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 217, 724, 255, 735 Annotation: Subtype: Link Rect: 188, 701, 225, 712 Annotation: Subtype: Link Rect: 193, 678, 231, 689 Annotation: Subtype: Link Rect: 520, 654, 557, 665 Annotation: Subtype: Link Rect: 59, 621, 96, 631 Annotation: Subtype: Link Rect: 194, 586, 231, 596 Annotation: Subtype: Link Rect: 91, 552, 128, 562 Annotation: Subtype: Link Rect: 228, 517, 266, 527 Annotation: Subtype: Link Rect: 95, 483, 133, 493 Annotation: Subtype: Link Rect: 139, 483, 175, 493 Annotation: Subtype: Link Rect: 304, 447, 341, 458 Annotation: Subtype: Link Rect: 348, 447, 384, 458 Annotation: Subtype: Link Rect: 432, 424, 470, 435 Annotation: Subtype: Link Rect: 476, 424, 512, 435 Annotation: Subtype: Link Rect: 509, 390, 547, 401 Annotation: Subtype: Link Rect: 59, 356, 96, 366 Annotation: Subtype: Link Rect: 59, 322, 96, 332 Annotation: Subtype: Link Rect: 498, 298, 536, 309 Annotation: Subtype: Link Rect: 148, 263, 185, 274 Annotation: Subtype: Link Rect: 95, 230, 133, 240 Annotation: Subtype: Link Rect: 141, 195, 179, 205 Annotation: Subtype: Link Rect: 475, 171, 512, 182 Annotation: Subtype: Link Rect: 519, 171, 555, 182 Annotation: Subtype: Link Rect: 481, 137, 518, 148 Annotation: Subtype: Link Rect: 185, 103, 223, 113 Annotation: Subtype: Link Rect: 229, 103, 265, 113 Annotation: Subtype: Link Rect: 171, 69, 209, 79 Annotation: Subtype: Link Rect: 215, 69, 251, 79 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 59, 713, 96, 723 Annotation: Subtype: Link Rect: 102, 713, 138, 723 Annotation: Subtype: Link Rect: 321, 689, 359, 700 Annotation: Subtype: Link Rect: 365, 689, 401, 700 Annotation: Subtype: Link Rect: 292, 666, 329, 677 Annotation: Subtype: Link Rect: 299, 644, 336, 654 Annotation: Subtype: Link Rect: 227, 609, 265, 619 Annotation: Subtype: Link Rect: 357, 574, 395, 585 Annotation: Subtype: Link Rect: 519, 551, 557, 562 Annotation: Subtype: Link Rect: 59, 540, 95, 550 Annotation: Subtype: Link Rect: 442, 516, 480, 527 Annotation: Subtype: Link Rect: 486, 516, 522, 527 Annotation: Subtype: Link Rect: 472, 505, 509, 516 Annotation: Subtype: Link Rect: 515, 505, 551, 516 Annotation: Subtype: Link Rect: 241, 471, 279, 481 Annotation: Subtype: Link Rect: 285, 471, 321, 481 Annotation: Subtype: Link Rect: 59, 437, 96, 447 Annotation: Subtype: Link Rect: 243, 402, 281, 412 Annotation: Subtype: Link Rect: 59, 356, 96, 366 Annotation: Subtype: Link Rect: 518, 332, 556, 343 Annotation: Subtype: Link Rect: 441, 298, 478, 309 Annotation: Subtype: Link Rect: 507, 275, 544, 286 Annotation: Subtype: Link Rect: 369, 240, 406, 251 Annotation: Subtype: Link Rect: 259, 218, 296, 228 Annotation: Subtype: Link Rect: 230, 183, 267, 194 Annotation: Subtype: Link Rect: 273, 183, 309, 194 Annotation: Subtype: Link Rect: 171, 149, 209, 159 Annotation: Subtype: Link Rect: 215, 149, 251, 159 Annotation: Subtype: Link Rect: 479, 125, 516, 136 Annotation: Subtype: Link Rect: 521, 125, 557, 136 Annotation: Subtype: Link Rect: 262, 91, 299, 102 Annotation: Subtype: Link Rect: 306, 91, 342, 102 Annotation: Subtype: Link Rect: 472, 79, 509, 90 Annotation: Subtype: Link Rect: 516, 79, 552, 90 Page: Sequence: 20 Annotations: Annotation: Subtype: Link Rect: 224, 724, 262, 735 Annotation: Subtype: Link Rect: 324, 666, 361, 677 Annotation: Subtype: Link Rect: 283, 643, 321, 654 Annotation: Subtype: Link Rect: 327, 643, 363, 654 Annotation: Subtype: Link Rect: 322, 620, 360, 631 Annotation: Subtype: Link Rect: 366, 620, 402, 631 Annotation: Subtype: Link Rect: 59, 586, 96, 596 Annotation: Subtype: Link Rect: 102, 586, 138, 596 Annotation: Subtype: Link Rect: 59, 552, 96, 562 Annotation: Subtype: Link Rect: 102, 552, 138, 562 Annotation: Subtype: Link Rect: 358, 528, 395, 539 Annotation: Subtype: Link Rect: 402, 528, 438, 539 Annotation: Subtype: Link Rect: 59, 494, 96, 504 Annotation: Subtype: Link Rect: 102, 494, 138, 504 Annotation: Subtype: Link Rect: 386, 471, 423, 481 Annotation: Subtype: Link Rect: 280, 436, 317, 447 Annotation: Subtype: Link Rect: 324, 436, 360, 447 Annotation: Subtype: Link Rect: 164, 401, 202, 412 Annotation: Subtype: Link Rect: 208, 401, 244, 412 Annotation: Subtype: Link Rect: 132, 368, 169, 378 Annotation: Subtype: Link Rect: 478, 344, 515, 355 Annotation: Subtype: Link Rect: 521, 344, 557, 355 Annotation: Subtype: Link Rect: 189, 309, 227, 320 Annotation: Subtype: Link Rect: 233, 309, 269, 320 Annotation: Subtype: Link Rect: 214, 276, 251, 286 Annotation: Subtype: Link Rect: 257, 276, 293, 286 Annotation: Subtype: Link Rect: 131, 241, 168, 251 Annotation: Subtype: Link Rect: 175, 241, 211, 251 Annotation: Subtype: Link Rect: 406, 217, 443, 228 Annotation: Subtype: Link Rect: 449, 217, 486, 228 Annotation: Subtype: Link Rect: 59, 184, 96, 194 Annotation: Subtype: Link Rect: 102, 184, 138, 194 Annotation: Subtype: Link Rect: 208, 149, 245, 159 Annotation: Subtype: Link Rect: 519, 125, 557, 136 Annotation: Subtype: Link Rect: 59, 115, 95, 125 Annotation: Subtype: Link Rect: 228, 80, 266, 90 Annotation: Subtype: Link Rect: 272, 80, 308, 90 Page: Sequence: 21 Annotations: Annotation: Subtype: Link Rect: 364, 712, 401, 723 Annotation: Subtype: Link Rect: 407, 712, 443, 723 Annotation: Subtype: Link Rect: 208, 678, 245, 689 Annotation: Subtype: Link Rect: 251, 678, 287, 689 Annotation: Subtype: Link Rect: 357, 643, 394, 654 Annotation: Subtype: Link Rect: 401, 643, 437, 654 Annotation: Subtype: Link Rect: 229, 609, 267, 619 Annotation: Subtype: Link Rect: 273, 609, 309, 619 Annotation: Subtype: Link Rect: 408, 575, 446, 585 Annotation: Subtype: Link Rect: 268, 540, 306, 550 Annotation: Subtype: Link Rect: 312, 540, 348, 550 Annotation: Subtype: Link Rect: 426, 516, 464, 527 Annotation: Subtype: Link Rect: 470, 516, 506, 527 Annotation: Subtype: Link Rect: 177, 494, 215, 504 Annotation: Subtype: Link Rect: 473, 482, 511, 493 Annotation: Subtype: Link Rect: 461, 470, 560, 481 Annotation: Subtype: Link Rect: 56, 460, 195, 470 Annotation: Subtype: Link Rect: 256, 425, 294, 435 Annotation: Subtype: Link Rect: 430, 401, 467, 412 Annotation: Subtype: Link Rect: 491, 344, 528, 355 Annotation: Subtype: Link Rect: 456, 321, 494, 332 Checksum: 5e716c31 Type: CRC32 Checksum: d4f158cf917d5fdb822db32120039b32 Type: MD5 Checksum: 70a90d30e39cecd4e15222f6d4b46e674b4a4cd9 Type: SHA-1