4bab18fc92e361466ec8c73359b1154e pmc_33922979.pdf 13c413f91d9a4d624def1dd6335413f7d26c07f1 pmc_33922979.pdf e9682e2a169abf66dcef0c2f8e5140b73365253275177202f7104e62759d7a68 pmc_33922979.pdf Title: Proteomic Studies on the Management of High-Grade Serous Ovarian Cancer Patients: A Mini-Review Subject: High-grade serous ovarian cancer (HGSC) remains the most common and deadly subtype of ovarian cancer. It is characterized by its late diagnosis and frequent relapse despite standardized treatment with cytoreductive surgery and platinum-based chemotherapy. The past decade has seen significant advances in the clinical management and molecular understanding of HGSC following the publication of the Cancer Genome Atlas (TCGA) researchers and the introduction of targeted therapies with anti-angiogenic drugs and poly(ADP-ribose) polymerase inhibitors in specific subgroups of patients. We provide a comprehensive review of HGSC, focusing on the most important molecular advances aimed at providing a better understanding of the disease and its response to treatment. We emphasize the role that proteomic technologies are now playing in these two aspects of the disease, through the identification of proteins and their post-translational modifications in ovarian cancer tumors. Finally, we highlight how the integration of proteomics with genomics, exemplified by the work performed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC), can guide the development of new biomarkers and therapeutic targets. Keywords: ovarian cancer; mass spectrometry; proteomics; genomics; cancer tissue; biomarker Author: Melissa Bradbury, Eva Borràs, Assumpció Pérez-Benavente, Antonio Gil-Moreno, Anna Santamaria and Eduard Sabidó Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Sun Apr 25 11:29:36 2021 CEST ModDate: Sun Apr 25 11:57:24 2021 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1127983 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MWHIBA+VnURWPalladioL Type 1 Custom yes yes no 10 0 HRAKWX+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 HOUAEF+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 LHKVUD+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 PURWBA+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 37 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 59 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 63 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 67 0 EDJJFC+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 85 0 EDJJFE+PalatinoLinotype TrueType WinAnsi yes yes no 88 0 EDJJFG+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 91 0 EDJKHC+SimSun CID TrueType Identity-H yes yes yes 94 0 EDJJFG+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 106 0 EDJJFC+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 109 0 EDJJFE+PalatinoLinotype TrueType WinAnsi yes yes no 112 0 LWLIVD+EURM10 Type 1 Builtin yes yes no 132 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 03:20:11 CEST RepresentationInformation: pmc_33922979.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:09:51 CEST Size: 1127983 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 457 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Current Therapeutic Management of High-Grade Serous Ovarian Cancer Patients Destination: section.2 Item: Title: Tumor Mechanisms and Identification of Molecular Therapeutic Targets in HGSC Destination: section.3 Item: Title: Therapy Response and Prognostic Molecular Biomarkers in HGSC Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.5 Info: Title: Proteomic Studies on the Management of High-Grade Serous Ovarian Cancer Patients: A Mini-Review Author: Melissa Bradbury, Eva Borràs, Assumpció Pérez-Benavente, Antonio Gil-Moreno, Anna Santamaria and Eduard Sabidó Subject: High-grade serous ovarian cancer (HGSC) remains the most common and deadly subtype of ovarian cancer. It is characterized by its late diagnosis and frequent relapse despite standardized treatment with cytoreductive surgery and platinum-based chemotherapy. The past decade has seen significant advances in the clinical management and molecular understanding of HGSC following the publication of the Cancer Genome Atlas (TCGA) researchers and the introduction of targeted therapies with anti-angiogenic drugs and poly(ADP-ribose) polymerase inhibitors in specific subgroups of patients. We provide a comprehensive review of HGSC, focusing on the most important molecular advances aimed at providing a better understanding of the disease and its response to treatment. We emphasize the role that proteomic technologies are now playing in these two aspects of the disease, through the identification of proteins and their post-translational modifications in ovarian cancer tumors. Finally, we highlight how the integration of proteomics with genomics, exemplified by the work performed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC), can guide the development of new biomarkers and therapeutic targets. Keywords: ovarian cancer; mass spectrometry; proteomics; genomics; cancer tissue; biomarker Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Sun Apr 25 11:29:36 CEST 2021 ModDate: Sun Apr 25 11:57:24 CEST 2021 ID: 0x1df68040c62eef248c7c27c28814452f, 0x1df68040c62eef248c7c27c28814452f Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: HOUAEF+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 134 FontDescriptor: FontName: HOUAEF+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: LWLIVD+EURM10 FontSubset: true FirstChar: 12 LastChar: 12 FontDescriptor: FontName: LWLIVD+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: LHKVUD+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: LHKVUD+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: MWHIBA+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: MWHIBA+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: PURWBA+VnURWPalladioL-Bold FontSubset: true FirstChar: 160 LastChar: 226 FontDescriptor: FontName: PURWBA+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: HRAKWX+URWPalladioL-Ital FontSubset: true FirstChar: 45 LastChar: 121 FontDescriptor: FontName: HRAKWX+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 35, 759, 153, 795 Annotation: Subtype: Link Rect: 515, 759, 560, 795 Annotation: Subtype: Link Rect: 142, 662, 153, 675 Annotation: Subtype: Link Rect: 485, 662, 497, 675 Annotation: Subtype: Link Rect: 257, 651, 268, 663 Annotation: Subtype: Link Rect: 82, 358, 154, 367 Annotation: Subtype: Link Rect: 35, 347, 114, 355 Annotation: Subtype: Link Rect: 35, 162, 97, 184 Annotation: Subtype: Link Rect: 153, 89, 154, 98 Annotation: Subtype: Link Rect: 35, 77, 147, 86 Annotation: Subtype: Link Rect: 248, 88, 255, 97 ActionDest: 139 Annotation: Subtype: Link Rect: 114, 17, 265, 28 Annotation: Subtype: Link Rect: 408, 17, 558, 28 Annotation: Subtype: Link Rect: 35, 446, 87, 465 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 527, 732, 534, 741 ActionDest: 139 Annotation: Subtype: Link Rect: 421, 518, 428, 527 ActionDest: 139 Annotation: Subtype: Link Rect: 549, 506, 556, 515 ActionDest: 139 Annotation: Subtype: Link Rect: 301, 453, 308, 465 ActionDest: 79 Annotation: Subtype: Link Rect: 424, 430, 431, 439 ActionDest: 139 Annotation: Subtype: Link Rect: 202, 380, 209, 389 ActionDest: 139 Annotation: Subtype: Link Rect: 457, 355, 464, 364 ActionDest: 139 Annotation: Subtype: Link Rect: 194, 317, 201, 326 ActionDest: 139 Annotation: Subtype: Link Rect: 222, 280, 229, 289 ActionDest: 139 Annotation: Subtype: Link Rect: 229, 280, 236, 289 ActionDest: 139 Annotation: Subtype: Link Rect: 372, 217, 379, 226 ActionDest: 139 Annotation: Subtype: Link Rect: 302, 179, 314, 188 ActionDest: 139 Annotation: Subtype: Link Rect: 335, 142, 347, 151 ActionDest: 139 Annotation: Subtype: Link Rect: 327, 114, 334, 126 ActionDest: 79 Annotation: Subtype: Link Rect: 303, 92, 315, 101 ActionDest: 142 Annotation: Subtype: Link Rect: 315, 91, 327, 101 ActionDest: 142 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 508, 745, 520, 754 ActionDest: 142 Annotation: Subtype: Link Rect: 520, 744, 532, 754 ActionDest: 142 Annotation: Subtype: Link Rect: 334, 707, 346, 716 ActionDest: 142 Annotation: Subtype: Link Rect: 458, 657, 470, 666 ActionDest: 142 Annotation: Subtype: Link Rect: 473, 657, 485, 666 ActionDest: 142 Annotation: Subtype: Link Rect: 299, 606, 311, 616 ActionDest: 142 Annotation: Subtype: Link Rect: 436, 581, 448, 590 ActionDest: 142 Annotation: Subtype: Link Rect: 448, 581, 460, 590 ActionDest: 142 Annotation: Subtype: Link Rect: 439, 278, 445, 286 ActionDest: 139 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 334, 732, 341, 741 ActionDest: 139 Annotation: Subtype: Link Rect: 195, 669, 207, 678 ActionDest: 142 Annotation: Subtype: Link Rect: 514, 632, 526, 641 ActionDest: 142 Annotation: Subtype: Link Rect: 529, 632, 541, 641 ActionDest: 142 Annotation: Subtype: Link Rect: 276, 544, 288, 553 ActionDest: 142 Annotation: Subtype: Link Rect: 288, 544, 300, 553 ActionDest: 142 Annotation: Subtype: Link Rect: 453, 493, 465, 503 ActionDest: 142 Annotation: Subtype: Link Rect: 433, 406, 445, 415 ActionDest: 142 Annotation: Subtype: Link Rect: 237, 379, 244, 390 ActionDest: 117 Annotation: Subtype: Link Rect: 251, 380, 263, 390 ActionDest: 142 Annotation: Subtype: Link Rect: 515, 357, 526, 366 ActionDest: 142 Annotation: Subtype: Link Rect: 204, 104, 216, 113 ActionDest: 142 Annotation: Subtype: Link Rect: 217, 104, 229, 113 ActionDest: 146 Annotation: Subtype: Link Rect: 232, 104, 244, 113 ActionDest: 146 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 226, 719, 238, 728 ActionDest: 142 Annotation: Subtype: Link Rect: 363, 694, 375, 703 ActionDest: 146 Annotation: Subtype: Link Rect: 383, 632, 395, 641 ActionDest: 146 Annotation: Subtype: Link Rect: 492, 581, 504, 590 ActionDest: 146 Annotation: Subtype: Link Rect: 201, 531, 213, 540 ActionDest: 146 Annotation: Subtype: Link Rect: 216, 531, 228, 540 ActionDest: 146 Annotation: Subtype: Link Rect: 422, 493, 434, 503 ActionDest: 146 Annotation: Subtype: Link Rect: 435, 493, 447, 503 ActionDest: 146 Annotation: Subtype: Link Rect: 373, 468, 385, 477 ActionDest: 146 Annotation: Subtype: Link Rect: 329, 443, 341, 452 ActionDest: 146 Annotation: Subtype: Link Rect: 344, 443, 356, 452 ActionDest: 146 Annotation: Subtype: Link Rect: 199, 418, 211, 427 ActionDest: 146 Annotation: Subtype: Link Rect: 211, 418, 223, 427 ActionDest: 146 Annotation: Subtype: Link Rect: 346, 406, 358, 415 ActionDest: 146 Annotation: Subtype: Link Rect: 339, 343, 351, 352 ActionDest: 146 Annotation: Subtype: Link Rect: 544, 179, 556, 188 ActionDest: 139 Annotation: Subtype: Link Rect: 407, 154, 419, 163 ActionDest: 139 Annotation: Subtype: Link Rect: 419, 142, 431, 151 ActionDest: 139 Annotation: Subtype: Link Rect: 510, 117, 522, 126 ActionDest: 149 Annotation: Subtype: Link Rect: 522, 117, 534, 126 ActionDest: 149 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 388, 744, 400, 754 ActionDest: 139 Annotation: Subtype: Link Rect: 286, 719, 298, 728 ActionDest: 139 Annotation: Subtype: Link Rect: 281, 694, 293, 703 ActionDest: 149 Annotation: Subtype: Link Rect: 528, 644, 540, 653 ActionDest: 149 Annotation: Subtype: Link Rect: 514, 619, 526, 628 ActionDest: 149 Annotation: Subtype: Link Rect: 256, 581, 267, 590 ActionDest: 149 Annotation: Subtype: Link Rect: 516, 468, 528, 477 ActionDest: 149 Annotation: Subtype: Link Rect: 223, 418, 235, 427 ActionDest: 149 Annotation: Subtype: Link Rect: 235, 418, 247, 427 ActionDest: 149 Annotation: Subtype: Link Rect: 544, 393, 556, 402 ActionDest: 149 Annotation: Subtype: Link Rect: 346, 355, 358, 364 ActionDest: 149 Annotation: Subtype: Link Rect: 359, 355, 371, 364 ActionDest: 149 Annotation: Subtype: Link Rect: 437, 305, 449, 314 ActionDest: 149 Annotation: Subtype: Link Rect: 452, 305, 464, 314 ActionDest: 149 Annotation: Subtype: Link Rect: 403, 280, 415, 289 ActionDest: 149 Annotation: Subtype: Link Rect: 457, 242, 469, 251 ActionDest: 149 Annotation: Subtype: Link Rect: 425, 205, 437, 214 ActionDest: 149 Annotation: Subtype: Link Rect: 438, 205, 450, 214 ActionDest: 149 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 529, 732, 541, 741 ActionDest: 149 Annotation: Subtype: Link Rect: 544, 732, 556, 741 ActionDest: 149 Annotation: Subtype: Link Rect: 457, 682, 469, 691 ActionDest: 149 Annotation: Subtype: Link Rect: 282, 644, 294, 653 ActionDest: 149 Annotation: Subtype: Link Rect: 261, 607, 273, 616 ActionDest: 149 Annotation: Subtype: Link Rect: 454, 594, 466, 603 ActionDest: 149 Annotation: Subtype: Link Rect: 455, 443, 467, 452 ActionDest: 149 Annotation: Subtype: Link Rect: 467, 443, 479, 452 ActionDest: 149 Annotation: Subtype: Link Rect: 479, 443, 491, 452 ActionDest: 149 Annotation: Subtype: Link Rect: 492, 443, 504, 452 ActionDest: 152 Annotation: Subtype: Link Rect: 504, 406, 516, 415 ActionDest: 149 Annotation: Subtype: Link Rect: 447, 330, 459, 339 ActionDest: 149 Annotation: Subtype: Link Rect: 307, 280, 319, 289 ActionDest: 152 Annotation: Subtype: Link Rect: 495, 217, 507, 226 ActionDest: 152 Annotation: Subtype: Link Rect: 519, 180, 531, 189 ActionDest: 152 Annotation: Subtype: Link Rect: 484, 104, 496, 113 ActionDest: 152 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 472, 553, 479, 565 ActionDest: 117 Annotation: Subtype: Link Rect: 408, 455, 420, 465 ActionDest: 149 Annotation: Subtype: Link Rect: 421, 455, 433, 465 ActionDest: 149 Annotation: Subtype: Link Rect: 433, 455, 445, 465 ActionDest: 152 Annotation: Subtype: Link Rect: 544, 430, 556, 439 ActionDest: 152 Annotation: Subtype: Link Rect: 478, 405, 490, 414 ActionDest: 149 Annotation: Subtype: Link Rect: 264, 355, 276, 364 ActionDest: 149 Annotation: Subtype: Link Rect: 522, 305, 534, 314 ActionDest: 152 Annotation: Subtype: Link Rect: 228, 242, 240, 251 ActionDest: 152 Annotation: Subtype: Link Rect: 240, 242, 252, 251 ActionDest: 152 Annotation: Subtype: Link Rect: 272, 217, 284, 226 ActionDest: 152 Annotation: Subtype: Link Rect: 285, 217, 296, 226 ActionDest: 152 Annotation: Subtype: Link Rect: 369, 192, 381, 201 ActionDest: 149 Annotation: Subtype: Link Rect: 381, 192, 393, 201 ActionDest: 152 Annotation: Subtype: Link Rect: 290, 167, 302, 176 ActionDest: 152 Annotation: Subtype: Link Rect: 305, 167, 317, 176 ActionDest: 152 Annotation: Subtype: Link Rect: 262, 117, 274, 126 ActionDest: 152 Annotation: Subtype: Link Rect: 277, 117, 289, 126 ActionDest: 155 Annotation: Subtype: Link Rect: 376, 104, 388, 113 ActionDest: 155 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 387, 732, 398, 741 ActionDest: 155 Annotation: Subtype: Link Rect: 401, 732, 418, 741 ActionDest: 155 Annotation: Subtype: Link Rect: 194, 669, 206, 678 ActionDest: 149 Annotation: Subtype: Link Rect: 544, 657, 556, 666 ActionDest: 149 Annotation: Subtype: Link Rect: 408, 619, 425, 628 ActionDest: 155 Annotation: Subtype: Link Rect: 288, 569, 305, 578 ActionDest: 155 Annotation: Subtype: Link Rect: 189, 506, 206, 515 ActionDest: 155 Annotation: Subtype: Link Rect: 403, 481, 420, 490 ActionDest: 155 Annotation: Subtype: Link Rect: 420, 481, 437, 490 ActionDest: 155 Annotation: Subtype: Link Rect: 478, 468, 485, 477 ActionDest: 139 Annotation: Subtype: Link Rect: 485, 468, 492, 477 ActionDest: 139 Annotation: Subtype: Link Rect: 208, 393, 225, 402 ActionDest: 155 Annotation: Subtype: Link Rect: 405, 368, 421, 377 ActionDest: 155 Annotation: Subtype: Link Rect: 368, 343, 385, 352 ActionDest: 155 Annotation: Subtype: Link Rect: 398, 305, 415, 314 ActionDest: 155 Annotation: Subtype: Link Rect: 418, 305, 435, 314 ActionDest: 155 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 469, 343, 506, 354 Annotation: Subtype: Link Rect: 274, 319, 311, 330 Annotation: Subtype: Link Rect: 254, 296, 291, 307 Annotation: Subtype: Link Rect: 291, 274, 329, 284 Annotation: Subtype: Link Rect: 237, 250, 274, 261 Annotation: Subtype: Link Rect: 86, 217, 124, 227 Annotation: Subtype: Link Rect: 282, 148, 319, 158 Annotation: Subtype: Link Rect: 326, 148, 362, 158 Annotation: Subtype: Link Rect: 449, 124, 486, 135 Annotation: Subtype: Link Rect: 95, 102, 133, 112 Annotation: Subtype: Link Rect: 139, 102, 175, 112 Annotation: Subtype: Link Rect: 95, 79, 132, 89 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 104, 709, 141, 719 Annotation: Subtype: Link Rect: 148, 709, 184, 719 Annotation: Subtype: Link Rect: 394, 685, 431, 696 Annotation: Subtype: Link Rect: 441, 662, 478, 673 Annotation: Subtype: Link Rect: 484, 662, 520, 673 Annotation: Subtype: Link Rect: 168, 628, 205, 638 Annotation: Subtype: Link Rect: 211, 628, 248, 638 Annotation: Subtype: Link Rect: 368, 593, 405, 604 Annotation: Subtype: Link Rect: 193, 547, 231, 558 Annotation: Subtype: Link Rect: 122, 501, 160, 512 Annotation: Subtype: Link Rect: 356, 478, 393, 489 Annotation: Subtype: Link Rect: 95, 444, 133, 454 Annotation: Subtype: Link Rect: 139, 444, 175, 454 Annotation: Subtype: Link Rect: 341, 408, 379, 419 Annotation: Subtype: Link Rect: 377, 375, 415, 385 Annotation: Subtype: Link Rect: 408, 339, 444, 350 Annotation: Subtype: Link Rect: 392, 305, 430, 316 Annotation: Subtype: Link Rect: 436, 305, 472, 316 Annotation: Subtype: Link Rect: 479, 270, 516, 281 Annotation: Subtype: Link Rect: 521, 270, 557, 281 Annotation: Subtype: Link Rect: 156, 236, 194, 247 Annotation: Subtype: Link Rect: 118, 191, 155, 201 Annotation: Subtype: Link Rect: 290, 156, 328, 166 Annotation: Subtype: Link Rect: 195, 122, 232, 132 Annotation: Subtype: Link Rect: 255, 98, 293, 109 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 439, 719, 477, 730 Annotation: Subtype: Link Rect: 348, 685, 386, 696 Annotation: Subtype: Link Rect: 392, 685, 428, 696 Annotation: Subtype: Link Rect: 118, 639, 155, 650 Annotation: Subtype: Link Rect: 162, 639, 198, 650 Annotation: Subtype: Link Rect: 302, 604, 340, 615 Annotation: Subtype: Link Rect: 451, 581, 488, 592 Annotation: Subtype: Link Rect: 122, 547, 160, 558 Annotation: Subtype: Link Rect: 122, 513, 160, 523 Annotation: Subtype: Link Rect: 166, 513, 202, 523 Annotation: Subtype: Link Rect: 196, 478, 233, 489 Annotation: Subtype: Link Rect: 122, 444, 160, 454 Annotation: Subtype: Link Rect: 117, 398, 155, 408 Annotation: Subtype: Link Rect: 104, 363, 142, 373 Annotation: Subtype: Link Rect: 148, 363, 184, 373 Annotation: Subtype: Link Rect: 420, 328, 457, 339 Annotation: Subtype: Link Rect: 104, 294, 142, 304 Annotation: Subtype: Link Rect: 148, 294, 184, 304 Annotation: Subtype: Link Rect: 118, 260, 155, 270 Annotation: Subtype: Link Rect: 486, 236, 523, 247 Annotation: Subtype: Link Rect: 223, 214, 261, 224 Annotation: Subtype: Link Rect: 122, 179, 160, 189 Annotation: Subtype: Link Rect: 113, 145, 151, 155 Annotation: Subtype: Link Rect: 113, 110, 150, 120 Annotation: Subtype: Link Rect: 330, 86, 368, 97 Annotation: Subtype: Link Rect: 374, 86, 410, 97 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 95, 732, 133, 742 Annotation: Subtype: Link Rect: 139, 732, 175, 742 Annotation: Subtype: Link Rect: 390, 696, 428, 707 Annotation: Subtype: Link Rect: 434, 696, 470, 707 Annotation: Subtype: Link Rect: 95, 662, 133, 673 Annotation: Subtype: Link Rect: 139, 662, 175, 673 Annotation: Subtype: Link Rect: 256, 628, 293, 638 Annotation: Subtype: Link Rect: 299, 628, 335, 638 Annotation: Subtype: Link Rect: 520, 605, 557, 615 Annotation: Subtype: Link Rect: 275, 581, 313, 592 Annotation: Subtype: Link Rect: 471, 558, 509, 569 Annotation: Subtype: Link Rect: 282, 524, 320, 535 Annotation: Subtype: Link Rect: 95, 501, 133, 512 Annotation: Subtype: Link Rect: 139, 501, 175, 512 Annotation: Subtype: Link Rect: 322, 478, 359, 489 Annotation: Subtype: Link Rect: 365, 478, 401, 489 Annotation: Subtype: Link Rect: 109, 455, 146, 466 Annotation: Subtype: Link Rect: 401, 431, 438, 442 Annotation: Subtype: Link Rect: 450, 408, 487, 419 Annotation: Subtype: Link Rect: 494, 408, 530, 419 Annotation: Subtype: Link Rect: 427, 385, 465, 396 Annotation: Subtype: Link Rect: 471, 385, 507, 396 Annotation: Subtype: Link Rect: 337, 351, 375, 362 Annotation: Subtype: Link Rect: 381, 351, 417, 362 Annotation: Subtype: Link Rect: 175, 306, 213, 316 Annotation: Subtype: Link Rect: 219, 306, 255, 316 Annotation: Subtype: Link Rect: 308, 270, 346, 281 Annotation: Subtype: Link Rect: 402, 236, 440, 247 Annotation: Subtype: Link Rect: 370, 213, 408, 224 Annotation: Subtype: Link Rect: 156, 179, 194, 189 Annotation: Subtype: Link Rect: 200, 179, 236, 189 Annotation: Subtype: Link Rect: 235, 145, 272, 155 Annotation: Subtype: Link Rect: 415, 121, 452, 132 Annotation: Subtype: Link Rect: 515, 98, 553, 109 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 95, 720, 133, 730 Annotation: Subtype: Link Rect: 139, 720, 175, 730 Annotation: Subtype: Link Rect: 117, 685, 155, 696 Annotation: Subtype: Link Rect: 140, 662, 178, 673 Annotation: Subtype: Link Rect: 184, 662, 220, 673 Annotation: Subtype: Link Rect: 95, 628, 132, 638 Annotation: Subtype: Link Rect: 139, 628, 175, 638 Annotation: Subtype: Link Rect: 104, 593, 142, 604 Annotation: Subtype: Link Rect: 113, 559, 150, 569 Annotation: Subtype: Link Rect: 157, 559, 193, 569 Annotation: Subtype: Link Rect: 412, 524, 450, 535 Annotation: Subtype: Link Rect: 104, 490, 142, 500 Annotation: Subtype: Link Rect: 148, 490, 184, 500 Annotation: Subtype: Link Rect: 118, 455, 155, 466 Annotation: Subtype: Link Rect: 492, 431, 530, 442 Annotation: Subtype: Link Rect: 255, 397, 292, 408 Annotation: Subtype: Link Rect: 501, 351, 538, 362 Annotation: Subtype: Link Rect: 171, 317, 209, 327 Annotation: Subtype: Link Rect: 167, 283, 204, 293 Annotation: Subtype: Link Rect: 210, 283, 246, 293 Annotation: Subtype: Link Rect: 376, 259, 414, 270 Annotation: Subtype: Link Rect: 104, 225, 141, 235 Annotation: Subtype: Link Rect: 148, 225, 184, 235 Annotation: Subtype: Link Rect: 104, 191, 142, 201 Annotation: Subtype: Link Rect: 148, 191, 184, 201 Annotation: Subtype: Link Rect: 172, 156, 210, 166 Annotation: Subtype: Link Rect: 216, 156, 252, 166 Annotation: Subtype: Link Rect: 104, 122, 142, 132 Annotation: Subtype: Link Rect: 148, 122, 184, 132 Annotation: Subtype: Link Rect: 481, 98, 519, 109 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 243, 719, 281, 730 Annotation: Subtype: Link Rect: 95, 685, 132, 696 Annotation: Subtype: Link Rect: 519, 662, 557, 673 Annotation: Subtype: Link Rect: 118, 628, 155, 638 Annotation: Subtype: Link Rect: 159, 593, 197, 604 Annotation: Subtype: Link Rect: 262, 570, 300, 581 Annotation: Subtype: Link Rect: 459, 547, 497, 558 Annotation: Subtype: Link Rect: 503, 547, 539, 558 Annotation: Subtype: Link Rect: 514, 524, 552, 535 Annotation: Subtype: Link Rect: 456, 501, 494, 512 Annotation: Subtype: Link Rect: 500, 501, 536, 512 Annotation: Subtype: Link Rect: 147, 444, 184, 454 Annotation: Subtype: Link Rect: 191, 444, 227, 454 Annotation: Subtype: Link Rect: 247, 409, 283, 419 Annotation: Subtype: Link Rect: 373, 339, 411, 350 Annotation: Subtype: Link Rect: 95, 306, 133, 316 Annotation: Subtype: Link Rect: 139, 306, 175, 316 Annotation: Subtype: Link Rect: 177, 271, 214, 281 Checksum: c69843e7 Type: CRC32 Checksum: 4bab18fc92e361466ec8c73359b1154e Type: MD5 Checksum: 13c413f91d9a4d624def1dd6335413f7d26c07f1 Type: SHA-1 Checksum: e9682e2a169abf66dcef0c2f8e5140b73365253275177202f7104e62759d7a68 Type: SHA-256