9bbf53999beef715d825550d0730704b pmc_33291833.pdf 2a2e76ab78256798f0cf97fc0e19230519f60d2f pmc_33291833.pdf f6af6767195026564c9a07b055c4a979a13df65826eecccf558cc87437248913 pmc_33291833.pdf Title: The Biomarker Potential of miRNAs in Myotonic Dystrophy Type I Subject: MicroRNAs (miRNAs) are mostly known for their gene regulation properties, but they also play an important role in intercellular signaling. This means that they can be found in bodily fluids, giving them excellent biomarker potential. Myotonic Dystrophy type I (DM1) is the most frequent autosomal dominant muscle dystrophy in adults, with an estimated prevalence of 1:8000. DM1 symptoms include muscle weakness, myotonia, respiratory failure, cardiac conduction defects, cataracts, and endocrine disturbances. Patients display heterogeneity in both age of onset and disease manifestation. No treatment or cure currently exists for DM1, which shows the necessity for a biomarker that can predict disease progression, providing the opportunity to implement preventative measures before symptoms arise. In the past two decades, extensive research has been conducted in the miRNA expression profiles of DM1 patients and their biomarker potential. Here we review the current state of the field with a tissue-specific focus, given the multi-systemic nature of DM1 and the intracellular signaling role of miRNAs. Keywords: myotonic dystrophies; miRNAs; biomarkers; therapeutics Author: Emma Koehorst, Alfonsina Ballester-Lopez, Virginia Arechavala-Gomeza, Alicia Martínez-Piñeiro and Gisela Nogales-Gadea Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Mon Dec 7 07:41:58 2020 CET ModDate: Mon Dec 7 07:46:56 2020 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: 1211146 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- WLENKM+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 TYUELJ+VnURWPalladioL Type 1 Custom yes yes no 15 0 YXYGMM+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 WMUCYI+URWPalladioL-Bold Type 1 Custom yes yes no 24 0 BJQADR+URWPalladioL-Roma Type 1 Custom yes yes no 28 0 SVVJCD+Rpxr Type 1 Builtin yes yes no 32 0 TRYVMB+Pxsy Type 1 Builtin yes yes no 36 0 XPUSBJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 44 0 BSDWLC+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 47 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 69 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 73 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 77 0 VSHNAE+Rpcxr Type 1 Builtin yes yes no 139 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-07-25 02:33:30 CEST RepresentationInformation: pmc_33291833.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2020-12-28 03:46:40 CET Size: 1211146 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 409 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: miRNAs in Skeletal Muscle Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: miRNAs in the Heart Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: miRNAs in Blood and Serum Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Therapeutic Potential Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Conclusions and Future Perspectives Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Info: Title: The Biomarker Potential of miRNAs in Myotonic Dystrophy Type I Author: Emma Koehorst, Alfonsina Ballester-Lopez, Virginia Arechavala-Gomeza, Alicia Martínez-Piñeiro and Gisela Nogales-Gadea Subject: MicroRNAs (miRNAs) are mostly known for their gene regulation properties, but they also play an important role in intercellular signaling. This means that they can be found in bodily fluids, giving them excellent biomarker potential. Myotonic Dystrophy type I (DM1) is the most frequent autosomal dominant muscle dystrophy in adults, with an estimated prevalence of 1:8000. DM1 symptoms include muscle weakness, myotonia, respiratory failure, cardiac conduction defects, cataracts, and endocrine disturbances. Patients display heterogeneity in both age of onset and disease manifestation. No treatment or cure currently exists for DM1, which shows the necessity for a biomarker that can predict disease progression, providing the opportunity to implement preventative measures before symptoms arise. In the past two decades, extensive research has been conducted in the miRNA expression profiles of DM1 patients and their biomarker potential. Here we review the current state of the field with a tissue-specific focus, given the multi-systemic nature of DM1 and the intracellular signaling role of miRNAs. Keywords: myotonic dystrophies; miRNAs; biomarkers; therapeutics Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Mon Dec 07 07:41:58 CET 2020 ModDate: Mon Dec 07 07:46:56 CET 2020 ID: 0x1c80afdb7218cff2f0e9a059151a9dd0, 0x1c80afdb7218cff2f0e9a059151a9dd0 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: SVVJCD+Rpxr FontSubset: true FirstChar: 11 LastChar: 61 FontDescriptor: FontName: SVVJCD+Rpxr Flags: Symbolic FontBBox: -40, -283, 904, 728 FontFile: true Font: BaseFont: YXYGMM+URWPalladioL-Ital FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: YXYGMM+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: TRYVMB+Pxsy FontSubset: true FirstChar: 6 LastChar: 48 FontDescriptor: FontName: TRYVMB+Pxsy Flags: Symbolic FontBBox: -21, -994, 1292, 912 FontFile: true Font: BaseFont: WMUCYI+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 241 FontDescriptor: FontName: WMUCYI+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: WLENKM+VnURWPalladioL-Bold FontSubset: true FirstChar: 189 LastChar: 189 FontDescriptor: FontName: WLENKM+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: VSHNAE+Rpcxr FontSubset: true FirstChar: 169 LastChar: 169 FontDescriptor: FontName: VSHNAE+Rpcxr Flags: Symbolic FontBBox: -212, -286, 1344, 973 FontFile: true Font: BaseFont: BJQADR+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 246 FontDescriptor: FontName: BJQADR+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: TYUELJ+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: TYUELJ+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 75, 757, 217, 793 Annotation: Subtype: Link Rect: 474, 757, 519, 793 Annotation: Subtype: Link Rect: 442, 660, 453, 674 Annotation: Subtype: Link Rect: 340, 647, 351, 660 Annotation: Subtype: Link Rect: 508, 206, 515, 215 ActionDest: 124 Annotation: Subtype: Link Rect: 404, 179, 411, 188 ActionDest: 124 Annotation: Subtype: Link Rect: 355, 165, 362, 175 ActionDest: 124 Annotation: Subtype: Link Rect: 217, 71, 224, 80 ActionDest: 124 Annotation: Subtype: Link Rect: 181, 38, 251, 50 Annotation: Subtype: Link Rect: 418, 38, 519, 50 Annotation: Subtype: Link Rect: 466, 486, 518, 505 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 321, 729, 328, 738 ActionDest: 124 Annotation: Subtype: Link Rect: 508, 702, 515, 711 ActionDest: 124 Annotation: Subtype: Link Rect: 109, 594, 116, 603 ActionDest: 124 Annotation: Subtype: Link Rect: 270, 580, 277, 590 ActionDest: 124 Annotation: Subtype: Link Rect: 326, 580, 333, 590 ActionDest: 124 Annotation: Subtype: Link Rect: 372, 580, 379, 590 ActionDest: 124 Annotation: Subtype: Link Rect: 192, 567, 204, 576 ActionDest: 127 Annotation: Subtype: Link Rect: 204, 567, 216, 576 ActionDest: 127 Annotation: Subtype: Link Rect: 368, 540, 380, 549 ActionDest: 127 Annotation: Subtype: Link Rect: 423, 459, 435, 468 ActionDest: 127 Annotation: Subtype: Link Rect: 503, 418, 515, 427 ActionDest: 127 Annotation: Subtype: Link Rect: 503, 364, 515, 373 ActionDest: 127 Annotation: Subtype: Link Rect: 437, 324, 449, 333 ActionDest: 127 Annotation: Subtype: Link Rect: 449, 324, 461, 333 ActionDest: 127 Annotation: Subtype: Link Rect: 256, 297, 268, 306 ActionDest: 127 Annotation: Subtype: Link Rect: 392, 175, 404, 184 ActionDest: 127 Annotation: Subtype: Link Rect: 405, 175, 417, 184 ActionDest: 127 Annotation: Subtype: Link Rect: 435, 135, 447, 144 ActionDest: 127 Annotation: Subtype: Link Rect: 448, 135, 460, 144 ActionDest: 127 Annotation: Subtype: Link Rect: 326, 108, 338, 117 ActionDest: 127 Annotation: Subtype: Link Rect: 339, 107, 351, 117 ActionDest: 127 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 305, 729, 317, 738 ActionDest: 127 Annotation: Subtype: Link Rect: 455, 715, 467, 725 ActionDest: 127 Annotation: Subtype: Link Rect: 483, 675, 495, 684 ActionDest: 127 Annotation: Subtype: Link Rect: 498, 675, 510, 684 ActionDest: 127 Annotation: Subtype: Link Rect: 190, 621, 201, 630 ActionDest: 127 Annotation: Subtype: Link Rect: 425, 553, 436, 562 ActionDest: 127 Annotation: Subtype: Link Rect: 147, 540, 159, 549 ActionDest: 127 Annotation: Subtype: Link Rect: 144, 526, 155, 535 ActionDest: 130 Annotation: Subtype: Link Rect: 341, 486, 353, 495 ActionDest: 130 Annotation: Subtype: Link Rect: 353, 486, 364, 495 ActionDest: 130 Annotation: Subtype: Link Rect: 257, 432, 268, 441 ActionDest: 130 Annotation: Subtype: Link Rect: 262, 405, 274, 414 ActionDest: 130 Annotation: Subtype: Link Rect: 441, 240, 453, 250 ActionDest: 130 Annotation: Subtype: Link Rect: 192, 200, 204, 209 ActionDest: 130 Annotation: Subtype: Link Rect: 273, 186, 285, 196 ActionDest: 130 Annotation: Subtype: Link Rect: 288, 173, 300, 182 ActionDest: 130 Annotation: Subtype: Link Rect: 311, 159, 323, 169 ActionDest: 130 Annotation: Subtype: Link Rect: 394, 119, 406, 128 ActionDest: 130 Annotation: Subtype: Link Rect: 205, 92, 217, 101 ActionDest: 130 Annotation: Subtype: Link Rect: 417, 78, 429, 87 ActionDest: 130 Annotation: Subtype: Link Rect: 432, 78, 444, 87 ActionDest: 130 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 170, 713, 177, 725 ActionDest: 87 Annotation: Subtype: Link Rect: 206, 713, 213, 725 ActionDest: 93 Annotation: Subtype: Link Rect: 439, 715, 451, 725 ActionDest: 130 Annotation: Subtype: Link Rect: 195, 688, 207, 698 ActionDest: 130 Annotation: Subtype: Link Rect: 126, 621, 138, 630 ActionDest: 130 Annotation: Subtype: Link Rect: 249, 580, 261, 590 ActionDest: 130 Annotation: Subtype: Link Rect: 504, 526, 516, 535 ActionDest: 133 Annotation: Subtype: Link Rect: 503, 405, 515, 414 ActionDest: 130 Annotation: Subtype: Link Rect: 235, 118, 297, 131 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 171, 448, 182, 456 ActionDest: 130 Annotation: Subtype: Link Rect: 165, 399, 176, 407 ActionDest: 133 Annotation: Subtype: Link Rect: 177, 274, 188, 282 ActionDest: 133 Annotation: Subtype: Link Rect: 165, 220, 176, 228 ActionDest: 133 Annotation: Subtype: Link Rect: 164, 186, 175, 194 ActionDest: 133 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 261, 742, 273, 752 ActionDest: 133 Annotation: Subtype: Link Rect: 458, 567, 470, 576 ActionDest: 133 Annotation: Subtype: Link Rect: 295, 472, 302, 481 ActionDest: 124 Annotation: Subtype: Link Rect: 176, 270, 187, 279 ActionDest: 133 Annotation: Subtype: Link Rect: 225, 229, 237, 238 ActionDest: 133 Annotation: Subtype: Link Rect: 266, 215, 278, 225 ActionDest: 130 Annotation: Subtype: Link Rect: 296, 188, 308, 198 ActionDest: 130 Annotation: Subtype: Link Rect: 153, 161, 165, 171 ActionDest: 133 Annotation: Subtype: Link Rect: 390, 161, 401, 171 ActionDest: 133 Annotation: Subtype: Link Rect: 368, 148, 380, 157 ActionDest: 133 Annotation: Subtype: Link Rect: 450, 121, 462, 130 ActionDest: 133 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 383, 729, 394, 738 ActionDest: 133 Annotation: Subtype: Link Rect: 504, 729, 516, 738 ActionDest: 130 Annotation: Subtype: Link Rect: 301, 702, 313, 711 ActionDest: 133 Annotation: Subtype: Link Rect: 273, 688, 285, 698 ActionDest: 130 Annotation: Subtype: Link Rect: 184, 494, 191, 506 ActionDest: 87 Annotation: Subtype: Link Rect: 217, 494, 224, 506 ActionDest: 102 Annotation: Subtype: Link Rect: 319, 497, 330, 506 ActionDest: 133 Annotation: Subtype: Link Rect: 503, 429, 515, 439 ActionDest: 133 Annotation: Subtype: Link Rect: 244, 308, 256, 317 ActionDest: 133 Annotation: Subtype: Link Rect: 504, 294, 515, 304 ActionDest: 133 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 172, 454, 183, 462 ActionDest: 133 Annotation: Subtype: Link Rect: 181, 334, 192, 342 ActionDest: 133 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 306, 680, 313, 692 ActionDest: 87 Annotation: Subtype: Link Rect: 342, 680, 349, 692 ActionDest: 108 Annotation: Subtype: Link Rect: 503, 642, 515, 651 ActionDest: 130 Annotation: Subtype: Link Rect: 442, 493, 454, 502 ActionDest: 130 Annotation: Subtype: Link Rect: 183, 453, 195, 462 ActionDest: 130 Annotation: Subtype: Link Rect: 455, 412, 467, 421 ActionDest: 130 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 189, 428, 200, 436 ActionDest: 130 Annotation: Subtype: Link Rect: 201, 369, 212, 377 ActionDest: 130 Annotation: Subtype: Link Rect: 189, 316, 200, 324 ActionDest: 133 Annotation: Subtype: Link Rect: 201, 228, 212, 235 ActionDest: 133 Annotation: Subtype: Link Rect: 192, 159, 203, 167 ActionDest: 133 Annotation: Subtype: Link Rect: 192, 125, 203, 133 ActionDest: 133 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 477, 742, 489, 752 ActionDest: 133 Annotation: Subtype: Link Rect: 389, 729, 401, 738 ActionDest: 130 Annotation: Subtype: Link Rect: 255, 553, 267, 562 ActionDest: 130 Annotation: Subtype: Link Rect: 254, 526, 266, 535 ActionDest: 133 Annotation: Subtype: Link Rect: 425, 513, 437, 522 ActionDest: 130 Annotation: Subtype: Link Rect: 198, 378, 210, 387 ActionDest: 133 Annotation: Subtype: Link Rect: 314, 364, 326, 373 ActionDest: 133 Annotation: Subtype: Link Rect: 314, 310, 326, 319 ActionDest: 133 Annotation: Subtype: Link Rect: 504, 229, 515, 238 ActionDest: 133 Annotation: Subtype: Link Rect: 503, 121, 515, 130 ActionDest: 133 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 422, 715, 434, 725 ActionDest: 133 Annotation: Subtype: Link Rect: 434, 715, 446, 725 ActionDest: 133 Annotation: Subtype: Link Rect: 446, 715, 458, 725 ActionDest: 133 Annotation: Subtype: Link Rect: 425, 688, 437, 698 ActionDest: 133 Annotation: Subtype: Link Rect: 437, 688, 449, 698 ActionDest: 133 Annotation: Subtype: Link Rect: 243, 648, 255, 657 ActionDest: 130 Annotation: Subtype: Link Rect: 255, 648, 267, 657 ActionDest: 133 Annotation: Subtype: Link Rect: 361, 634, 372, 644 ActionDest: 130 Annotation: Subtype: Link Rect: 373, 634, 384, 644 ActionDest: 133 Annotation: Subtype: Link Rect: 314, 621, 326, 630 ActionDest: 133 Annotation: Subtype: Link Rect: 485, 607, 496, 617 ActionDest: 133 Annotation: Subtype: Link Rect: 160, 594, 171, 603 ActionDest: 133 Annotation: Subtype: Link Rect: 405, 540, 417, 549 ActionDest: 133 Annotation: Subtype: Link Rect: 490, 418, 502, 427 ActionDest: 127 Annotation: Subtype: Link Rect: 503, 418, 515, 427 ActionDest: 133 Annotation: Subtype: Link Rect: 332, 324, 344, 333 ActionDest: 133 Annotation: Subtype: Link Rect: 344, 324, 356, 333 ActionDest: 133 Annotation: Subtype: Link Rect: 234, 238, 241, 250 ActionDest: 118 Annotation: Subtype: Link Rect: 456, 159, 468, 169 ActionDest: 133 Annotation: Subtype: Link Rect: 288, 78, 300, 87 ActionDest: 136 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 503, 729, 515, 738 ActionDest: 136 Annotation: Subtype: Link Rect: 196, 675, 208, 684 ActionDest: 136 Annotation: Subtype: Link Rect: 205, 621, 217, 630 ActionDest: 136 Annotation: Subtype: Link Rect: 150, 192, 212, 204 Annotation: Subtype: Link Rect: 390, 145, 401, 154 ActionDest: 136 Annotation: Subtype: Link Rect: 503, 118, 515, 127 ActionDest: 133 Annotation: Subtype: Link Rect: 117, 77, 128, 87 ActionDest: 133 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 503, 742, 515, 752 ActionDest: 136 Annotation: Subtype: Link Rect: 344, 632, 351, 641 ActionDest: 124 Annotation: Subtype: Link Rect: 456, 538, 468, 547 ActionDest: 136 Annotation: Subtype: Link Rect: 288, 301, 326, 312 Annotation: Subtype: Link Rect: 438, 275, 475, 286 Annotation: Subtype: Link Rect: 145, 250, 183, 260 Annotation: Subtype: Link Rect: 189, 250, 225, 260 Annotation: Subtype: Link Rect: 214, 211, 252, 222 Annotation: Subtype: Link Rect: 258, 211, 294, 222 Annotation: Subtype: Link Rect: 204, 172, 242, 183 Annotation: Subtype: Link Rect: 248, 172, 284, 183 Annotation: Subtype: Link Rect: 391, 146, 429, 157 Annotation: Subtype: Link Rect: 361, 108, 398, 118 Annotation: Subtype: Link Rect: 405, 108, 441, 118 Annotation: Subtype: Link Rect: 332, 82, 369, 93 Annotation: Subtype: Link Rect: 455, 69, 492, 80 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 349, 727, 387, 738 Annotation: Subtype: Link Rect: 332, 701, 370, 712 Annotation: Subtype: Link Rect: 376, 701, 412, 712 Annotation: Subtype: Link Rect: 309, 663, 346, 673 Annotation: Subtype: Link Rect: 353, 663, 389, 673 Annotation: Subtype: Link Rect: 266, 625, 304, 635 Annotation: Subtype: Link Rect: 310, 625, 346, 635 Annotation: Subtype: Link Rect: 136, 573, 174, 583 Annotation: Subtype: Link Rect: 180, 573, 216, 583 Annotation: Subtype: Link Rect: 327, 546, 364, 557 Annotation: Subtype: Link Rect: 481, 521, 516, 531 Annotation: Subtype: Link Rect: 279, 482, 316, 493 Annotation: Subtype: Link Rect: 437, 456, 475, 467 Annotation: Subtype: Link Rect: 231, 417, 268, 428 Annotation: Subtype: Link Rect: 407, 391, 444, 402 Annotation: Subtype: Link Rect: 211, 353, 248, 364 Annotation: Subtype: Link Rect: 440, 327, 476, 338 Annotation: Subtype: Link Rect: 482, 327, 516, 338 Annotation: Subtype: Link Rect: 368, 288, 406, 299 Annotation: Subtype: Link Rect: 425, 262, 462, 273 Annotation: Subtype: Link Rect: 468, 262, 503, 273 Annotation: Subtype: Link Rect: 172, 237, 210, 247 Annotation: Subtype: Link Rect: 216, 237, 252, 247 Annotation: Subtype: Link Rect: 337, 198, 375, 209 Annotation: Subtype: Link Rect: 381, 198, 417, 209 Annotation: Subtype: Link Rect: 281, 160, 319, 170 Annotation: Subtype: Link Rect: 476, 120, 513, 131 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 172, 715, 210, 725 Annotation: Subtype: Link Rect: 216, 715, 252, 725 Annotation: Subtype: Link Rect: 429, 688, 466, 699 Annotation: Subtype: Link Rect: 472, 688, 507, 699 Annotation: Subtype: Link Rect: 290, 650, 328, 661 Annotation: Subtype: Link Rect: 334, 650, 370, 661 Annotation: Subtype: Link Rect: 347, 611, 385, 622 Annotation: Subtype: Link Rect: 391, 611, 427, 622 Annotation: Subtype: Link Rect: 481, 585, 516, 596 Annotation: Subtype: Link Rect: 186, 547, 223, 557 Annotation: Subtype: Link Rect: 229, 547, 265, 557 Annotation: Subtype: Link Rect: 123, 508, 160, 519 Annotation: Subtype: Link Rect: 167, 508, 203, 519 Annotation: Subtype: Link Rect: 253, 470, 290, 480 Annotation: Subtype: Link Rect: 464, 443, 501, 454 Annotation: Subtype: Link Rect: 313, 418, 350, 428 Annotation: Subtype: Link Rect: 208, 379, 246, 389 Annotation: Subtype: Link Rect: 252, 379, 288, 389 Annotation: Subtype: Link Rect: 206, 341, 243, 351 Annotation: Subtype: Link Rect: 405, 314, 442, 325 Annotation: Subtype: Link Rect: 448, 314, 483, 325 Annotation: Subtype: Link Rect: 149, 276, 187, 286 Annotation: Subtype: Link Rect: 436, 236, 473, 247 Annotation: Subtype: Link Rect: 299, 199, 337, 209 Annotation: Subtype: Link Rect: 167, 160, 205, 170 Annotation: Subtype: Link Rect: 305, 133, 343, 144 Annotation: Subtype: Link Rect: 329, 94, 367, 105 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 141, 715, 178, 725 Annotation: Subtype: Link Rect: 150, 663, 187, 673 Annotation: Subtype: Link Rect: 193, 663, 229, 673 Annotation: Subtype: Link Rect: 293, 637, 330, 648 Annotation: Subtype: Link Rect: 336, 637, 372, 648 Annotation: Subtype: Link Rect: 439, 611, 475, 622 Annotation: Subtype: Link Rect: 481, 611, 516, 622 Annotation: Subtype: Link Rect: 260, 573, 298, 583 Annotation: Subtype: Link Rect: 304, 573, 340, 583 Annotation: Subtype: Link Rect: 203, 533, 241, 544 Annotation: Subtype: Link Rect: 247, 533, 283, 544 Annotation: Subtype: Link Rect: 364, 508, 402, 519 Annotation: Subtype: Link Rect: 159, 470, 196, 480 Annotation: Subtype: Link Rect: 202, 470, 238, 480 Annotation: Subtype: Link Rect: 145, 418, 183, 428 Annotation: Subtype: Link Rect: 226, 366, 263, 376 Annotation: Subtype: Link Rect: 307, 327, 344, 338 Annotation: Subtype: Link Rect: 270, 289, 308, 299 Annotation: Subtype: Link Rect: 314, 289, 350, 299 Annotation: Subtype: Link Rect: 334, 262, 371, 273 Annotation: Subtype: Link Rect: 378, 262, 414, 273 Annotation: Subtype: Link Rect: 136, 224, 174, 234 Annotation: Subtype: Link Rect: 180, 224, 216, 234 Annotation: Subtype: Link Rect: 344, 198, 382, 209 Annotation: Subtype: Link Rect: 388, 198, 424, 209 Annotation: Subtype: Link Rect: 175, 160, 212, 170 Annotation: Subtype: Link Rect: 314, 121, 352, 131 Annotation: Subtype: Link Rect: 470, 82, 506, 92 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 191, 715, 229, 725 Annotation: Subtype: Link Rect: 377, 675, 414, 686 Annotation: Subtype: Link Rect: 195, 638, 232, 648 Annotation: Subtype: Link Rect: 437, 611, 472, 622 Annotation: Subtype: Link Rect: 478, 611, 512, 622 Annotation: Subtype: Link Rect: 440, 585, 476, 596 Annotation: Subtype: Link Rect: 482, 585, 516, 596 Annotation: Subtype: Link Rect: 145, 560, 182, 570 Annotation: Subtype: Link Rect: 189, 560, 225, 570 Annotation: Subtype: Link Rect: 76, 487, 166, 518 Annotation: Subtype: Link Rect: 234, 482, 407, 493 Checksum: 80c47cf1 Type: CRC32 Checksum: 9bbf53999beef715d825550d0730704b Type: MD5 Checksum: 2a2e76ab78256798f0cf97fc0e19230519f60d2f Type: SHA-1