57920a9b057e25c33b62a5e8af0a476a 302796.pdf 71969a3ab4733867a979318b50591487d661b7cd 302796.pdf a9289feb046ee51911d607a759b41039079ec4ff28061c872ce9eee3746c126b 302796.pdf Title: Using Small Non-Coding RNAs in Extracellular Vesicles of Semen as Biomarkers of Male Reproductive System Health: Opportunities and Challenges Subject: Reproductive dysfunction and urogenital malignancies represent a serious health concern in men. This is in part as a result of the absence of reliable non-invasive tests of diagnosis/prognosis. Optimizing diagnosis and predicting the patient’s prognosis will affect the choice of the most appropriate treatment and therefore increase the chances of success and the result of therapy, that is, it will lead to a more personalized treatment of the patient. This review aims firstly to critically summarize the current knowledge of the reproductive roles played by extracellular vesicle small RNA components, which are typically altered in diseases affecting the male reproductive tract. Secondly, it aims to describe the use of semen extracellular vesicles as a non-invasive source of sncRNA-based biomarkers for urogenital diseases. Keywords: urogenital diseases; male infertility; prostate cancer; semen; extracellular vesicles; sncRNAs; non-invasive biomarker; diagnosis Author: Sara Larriba, Francesc Vigués and Lluís Bassas Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Mar 13 07:09:17 2023 CET ModDate: Mon Mar 13 07:13:29 2023 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1144337 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- YSPQJI+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 OPZDHV+VnURWPalladioL Type 1 Custom yes yes no 15 0 SUIQBZ+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 LIBEFG+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 YCYTKA+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 46 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 49 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 79 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 83 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 87 0 ArialMT TrueType WinAnsi no no no 91 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 116 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 120 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 124 0 BCDHEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 128 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-11-12 02:45:17 CET RepresentationInformation: 302796.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-11-11 09:47:46 CET Size: 1144337 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 403 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Semen Extracellular Vesicles Destination: section.2 Children: Item: Title: Semen sEVs and Fertility Destination: subsection.2.1 Item: Title: Semen sEVs and Prostate Cancer Destination: subsection.2.2 Item: Title: sncRNA EV Content as a Biomarker Destination: section.3 Item: Title: The Small RNA Population Signature Is Different between the Organs of the Reproductive Tract Destination: section.4 Children: Item: Title: Profile of Small RNA Populations in Human Testis Destination: subsection.4.1 Item: Title: Epididymis Destination: subsection.4.2 Item: Title: Prostate Destination: subsection.4.3 Item: Title: Scenarios of Urogenital Pathology for the Study of the Content of Extracellular Vesicle sncRNAs in Semen Destination: section.5 Children: Item: Title: Male Infertility Due to Poor Semen Quality Destination: subsection.5.1 Item: Title: Unexplained Male Infertility Destination: subsection.5.2 Item: Title: Prostate Cancer Destination: subsection.5.3 Item: Title: Technical Issues to Consider for a Proper Interpretation of Results on Semen sEVs Destination: section.6 Children: Item: Title: Impact of Surgical Procedures for Contraception Destination: subsection.6.1 Item: Title: Impact of Extracellular Vesicle Isolation Methods and Preclinical Variables on Downstream sncRNA Analysis in Semen Destination: subsection.6.2 Item: Title: Impact of Profiling Methods for Biomarker Testing Destination: subsection.6.3 Item: Title: Future Perspectives of Study Destination: section.7 Item: Title: Conclusions Destination: section.8 Item: Title: References Destination: section.8 Info: Title: Using Small Non-Coding RNAs in Extracellular Vesicles of Semen as Biomarkers of Male Reproductive System Health: Opportunities and Challenges Author: Sara Larriba, Francesc Vigués and Lluís Bassas Subject: Reproductive dysfunction and urogenital malignancies represent a serious health concern in men. This is in part as a result of the absence of reliable non-invasive tests of diagnosis/prognosis. Optimizing diagnosis and predicting the patient’s prognosis will affect the choice of the most appropriate treatment and therefore increase the chances of success and the result of therapy, that is, it will lead to a more personalized treatment of the patient. This review aims firstly to critically summarize the current knowledge of the reproductive roles played by extracellular vesicle small RNA components, which are typically altered in diseases affecting the male reproductive tract. Secondly, it aims to describe the use of semen extracellular vesicles as a non-invasive source of sncRNA-based biomarkers for urogenital diseases. Keywords: urogenital diseases; male infertility; prostate cancer; semen; extracellular vesicles; sncRNAs; non-invasive biomarker; diagnosis Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Mar 13 07:09:17 CET 2023 ModDate: Mon Mar 13 07:13:29 CET 2023 ID: 0x72e427c73b476f833a7e4fc44bd4d2b4, 0x72e427c73b476f833a7e4fc44bd4d2b4 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: SUIQBZ+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 121 FontDescriptor: FontName: SUIQBZ+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: LIBEFG+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: LIBEFG+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: YSPQJI+VnURWPalladioL-Bold FontSubset: true FirstChar: 178 LastChar: 189 FontDescriptor: FontName: YSPQJI+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: YCYTKA+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 121 FontDescriptor: FontName: YCYTKA+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true 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 Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 110, 279, 152, 288 Annotation: Subtype: Link Rect: 34, 267, 130, 276 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, 756, 180, 792 Annotation: Subtype: Link Rect: 515, 756, 560, 792 Annotation: Subtype: Link Rect: 103, 642, 114, 655 Annotation: Subtype: Link Rect: 277, 310, 284, 319 ActionDest: 140 Annotation: Subtype: Link Rect: 523, 298, 530, 307 ActionDest: 140 Annotation: Subtype: Link Rect: 476, 122, 483, 131 ActionDest: 140 Annotation: Subtype: Link Rect: 484, 122, 491, 131 ActionDest: 140 Annotation: Subtype: Link Rect: 380, 97, 387, 106 ActionDest: 140 Annotation: Subtype: Link Rect: 139, 17, 278, 28 Annotation: Subtype: Link Rect: 422, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 365, 87, 384 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 245, 685, 251, 694 ActionDest: 140 Annotation: Subtype: Link Rect: 428, 673, 435, 682 ActionDest: 140 Annotation: Subtype: Link Rect: 519, 547, 526, 556 ActionDest: 140 Annotation: Subtype: Link Rect: 283, 421, 290, 430 ActionDest: 140 Annotation: Subtype: Link Rect: 199, 396, 206, 405 ActionDest: 140 Annotation: Subtype: Link Rect: 207, 396, 218, 405 ActionDest: 140 Annotation: Subtype: Link Rect: 354, 333, 361, 342 ActionDest: 140 Annotation: Subtype: Link Rect: 486, 333, 498, 342 ActionDest: 140 Annotation: Subtype: Link Rect: 472, 308, 484, 317 ActionDest: 140 Annotation: Subtype: Link Rect: 543, 270, 555, 279 ActionDest: 140 Annotation: Subtype: Link Rect: 226, 258, 238, 267 ActionDest: 140 Annotation: Subtype: Link Rect: 238, 258, 250, 267 ActionDest: 140 Annotation: Subtype: Link Rect: 342, 200, 354, 210 ActionDest: 140 Annotation: Subtype: Link Rect: 252, 188, 264, 197 ActionDest: 140 Annotation: Subtype: Link Rect: 417, 188, 429, 197 ActionDest: 140 Annotation: Subtype: Link Rect: 429, 188, 441, 197 ActionDest: 140 Annotation: Subtype: Link Rect: 419, 125, 431, 134 ActionDest: 140 Annotation: Subtype: Link Rect: 260, 100, 272, 109 ActionDest: 143 Annotation: Subtype: Link Rect: 329, 88, 341, 97 ActionDest: 143 Annotation: Subtype: Link Rect: 482, 75, 493, 84 ActionDest: 143 Annotation: Subtype: Link Rect: 494, 75, 506, 84 ActionDest: 143 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 417, 710, 429, 719 ActionDest: 143 Annotation: Subtype: Link Rect: 417, 698, 429, 707 ActionDest: 143 Annotation: Subtype: Link Rect: 543, 698, 555, 707 ActionDest: 143 Annotation: Subtype: Link Rect: 292, 685, 304, 694 ActionDest: 143 Annotation: Subtype: Link Rect: 270, 635, 277, 644 ActionDest: 140 Annotation: Subtype: Link Rect: 277, 635, 289, 644 ActionDest: 140 Annotation: Subtype: Link Rect: 244, 547, 256, 556 ActionDest: 143 Annotation: Subtype: Link Rect: 494, 547, 506, 556 ActionDest: 143 Annotation: Subtype: Link Rect: 400, 459, 407, 468 ActionDest: 140 Annotation: Subtype: Link Rect: 407, 459, 414, 468 ActionDest: 140 Annotation: Subtype: Link Rect: 549, 446, 556, 455 ActionDest: 140 Annotation: Subtype: Link Rect: 199, 431, 206, 443 ActionDest: 71 Annotation: Subtype: Link Rect: 475, 130, 487, 139 ActionDest: 143 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 228, 735, 240, 744 ActionDest: 143 Annotation: Subtype: Link Rect: 256, 723, 263, 732 ActionDest: 140 Annotation: Subtype: Link Rect: 303, 720, 310, 732 ActionDest: 108 Annotation: Subtype: Link Rect: 412, 710, 419, 719 ActionDest: 140 Annotation: Subtype: Link Rect: 454, 484, 466, 493 ActionDest: 143 Annotation: Subtype: Link Rect: 540, 421, 547, 433 ActionDest: 108 Annotation: Subtype: Link Rect: 393, 373, 404, 382 ActionDest: 143 Annotation: Subtype: Link Rect: 544, 373, 556, 382 ActionDest: 143 Annotation: Subtype: Link Rect: 496, 345, 503, 357 ActionDest: 108 Annotation: Subtype: Link Rect: 324, 197, 336, 206 ActionDest: 143 Annotation: Subtype: Link Rect: 339, 197, 351, 206 ActionDest: 143 Annotation: Subtype: Link Rect: 470, 185, 482, 194 ActionDest: 143 Annotation: Subtype: Link Rect: 482, 185, 494, 194 ActionDest: 143 Annotation: Subtype: Link Rect: 495, 185, 507, 194 ActionDest: 143 Annotation: Subtype: Link Rect: 224, 160, 236, 169 ActionDest: 143 Annotation: Subtype: Link Rect: 384, 147, 396, 156 ActionDest: 143 Annotation: Subtype: Link Rect: 399, 147, 411, 156 ActionDest: 143 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 498, 735, 510, 744 ActionDest: 143 Annotation: Subtype: Link Rect: 513, 735, 525, 744 ActionDest: 143 Annotation: Subtype: Link Rect: 343, 673, 355, 682 ActionDest: 143 Annotation: Subtype: Link Rect: 453, 673, 464, 682 ActionDest: 143 Annotation: Subtype: Link Rect: 463, 610, 475, 619 ActionDest: 147 Annotation: Subtype: Link Rect: 263, 572, 275, 581 ActionDest: 143 Annotation: Subtype: Link Rect: 275, 572, 287, 581 ActionDest: 143 Annotation: Subtype: Link Rect: 288, 572, 300, 581 ActionDest: 147 Annotation: Subtype: Link Rect: 251, 522, 263, 531 ActionDest: 147 Annotation: Subtype: Link Rect: 266, 522, 278, 531 ActionDest: 147 Annotation: Subtype: Link Rect: 531, 497, 543, 506 ActionDest: 147 Annotation: Subtype: Link Rect: 543, 497, 555, 506 ActionDest: 147 Annotation: Subtype: Link Rect: 486, 409, 498, 418 ActionDest: 147 Annotation: Subtype: Link Rect: 263, 295, 270, 307 ActionDest: 108 Annotation: Subtype: Link Rect: 544, 247, 556, 256 ActionDest: 147 Annotation: Subtype: Link Rect: 410, 222, 422, 231 ActionDest: 147 Annotation: Subtype: Link Rect: 229, 209, 241, 218 ActionDest: 147 Annotation: Subtype: Link Rect: 420, 172, 432, 181 ActionDest: 143 Annotation: Subtype: Link Rect: 360, 109, 372, 118 ActionDest: 147 Annotation: Subtype: Link Rect: 372, 109, 384, 118 ActionDest: 147 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 415, 635, 427, 644 ActionDest: 143 Annotation: Subtype: Link Rect: 217, 447, 229, 456 ActionDest: 143 Annotation: Subtype: Link Rect: 413, 447, 425, 456 ActionDest: 147 Annotation: Subtype: Link Rect: 425, 447, 437, 456 ActionDest: 147 Annotation: Subtype: Link Rect: 396, 384, 408, 393 ActionDest: 147 Annotation: Subtype: Link Rect: 198, 220, 210, 229 ActionDest: 147 Annotation: Subtype: Link Rect: 446, 220, 458, 229 ActionDest: 147 Annotation: Subtype: Link Rect: 544, 158, 556, 167 ActionDest: 147 Annotation: Subtype: Link Rect: 311, 145, 323, 154 ActionDest: 147 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 437, 522, 449, 531 ActionDest: 147 Annotation: Subtype: Link Rect: 209, 471, 221, 481 ActionDest: 147 Annotation: Subtype: Link Rect: 483, 371, 495, 380 ActionDest: 147 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 193, 341, 204, 349 ActionDest: 143 Annotation: Subtype: Link Rect: 204, 341, 215, 349 ActionDest: 147 Annotation: Subtype: Link Rect: 216, 341, 227, 349 ActionDest: 147 Annotation: Subtype: Link Rect: 229, 341, 240, 349 ActionDest: 147 Annotation: Subtype: Link Rect: 240, 341, 251, 349 ActionDest: 147 Annotation: Subtype: Link Rect: 254, 341, 265, 349 ActionDest: 147 Annotation: Subtype: Link Rect: 255, 223, 267, 232 ActionDest: 147 Annotation: Subtype: Link Rect: 246, 124, 258, 133 ActionDest: 147 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 352, 534, 364, 543 ActionDest: 147 Annotation: Subtype: Link Rect: 364, 534, 376, 543 ActionDest: 147 Annotation: Subtype: Link Rect: 531, 346, 543, 355 ActionDest: 147 Annotation: Subtype: Link Rect: 543, 346, 555, 355 ActionDest: 150 Annotation: Subtype: Link Rect: 290, 308, 302, 317 ActionDest: 150 Annotation: Subtype: Link Rect: 497, 283, 509, 292 ActionDest: 150 Annotation: Subtype: Link Rect: 544, 270, 556, 279 ActionDest: 150 Annotation: Subtype: Link Rect: 343, 245, 355, 254 ActionDest: 150 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 433, 514, 470, 525 Annotation: Subtype: Link Rect: 422, 502, 460, 513 Annotation: Subtype: Link Rect: 398, 479, 436, 490 Annotation: Subtype: Link Rect: 442, 479, 478, 490 Annotation: Subtype: Link Rect: 211, 456, 249, 467 Annotation: Subtype: Link Rect: 109, 434, 146, 444 Annotation: Subtype: Link Rect: 95, 411, 133, 421 Annotation: Subtype: Link Rect: 161, 388, 198, 398 Annotation: Subtype: Link Rect: 180, 354, 218, 364 Annotation: Subtype: Link Rect: 475, 330, 513, 341 Annotation: Subtype: Link Rect: 113, 308, 151, 318 Annotation: Subtype: Link Rect: 157, 308, 193, 318 Annotation: Subtype: Link Rect: 171, 285, 209, 295 Annotation: Subtype: Link Rect: 131, 262, 168, 272 Annotation: Subtype: Link Rect: 59, 239, 96, 249 Annotation: Subtype: Link Rect: 190, 215, 228, 226 Annotation: Subtype: Link Rect: 234, 215, 270, 226 Annotation: Subtype: Link Rect: 468, 192, 505, 203 Annotation: Subtype: Link Rect: 161, 170, 199, 180 Annotation: Subtype: Link Rect: 319, 146, 356, 157 Annotation: Subtype: Link Rect: 363, 146, 399, 157 Annotation: Subtype: Link Rect: 267, 123, 304, 134 Annotation: Subtype: Link Rect: 294, 100, 332, 111 Annotation: Subtype: Link Rect: 338, 100, 374, 111 Annotation: Subtype: Link Rect: 358, 77, 396, 88 Annotation: Subtype: Link Rect: 402, 77, 438, 88 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 139, 722, 176, 733 Annotation: Subtype: Link Rect: 183, 722, 219, 733 Annotation: Subtype: Link Rect: 186, 699, 224, 710 Annotation: Subtype: Link Rect: 230, 699, 266, 710 Annotation: Subtype: Link Rect: 357, 676, 395, 687 Annotation: Subtype: Link Rect: 267, 653, 304, 664 Annotation: Subtype: Link Rect: 398, 629, 435, 640 Annotation: Subtype: Link Rect: 157, 607, 194, 617 Annotation: Subtype: Link Rect: 201, 607, 237, 617 Annotation: Subtype: Link Rect: 473, 583, 510, 594 Annotation: Subtype: Link Rect: 59, 550, 96, 560 Annotation: Subtype: Link Rect: 59, 515, 96, 525 Annotation: Subtype: Link Rect: 102, 515, 138, 525 Annotation: Subtype: Link Rect: 506, 503, 544, 514 Annotation: Subtype: Link Rect: 59, 481, 96, 491 Annotation: Subtype: Link Rect: 59, 446, 96, 456 Annotation: Subtype: Link Rect: 102, 446, 138, 456 Annotation: Subtype: Link Rect: 412, 422, 449, 433 Annotation: Subtype: Link Rect: 455, 422, 491, 433 Annotation: Subtype: Link Rect: 406, 399, 443, 410 Annotation: Subtype: Link Rect: 372, 388, 409, 399 Annotation: Subtype: Link Rect: 474, 376, 512, 387 Annotation: Subtype: Link Rect: 518, 376, 554, 387 Annotation: Subtype: Link Rect: 139, 343, 176, 353 Annotation: Subtype: Link Rect: 285, 319, 322, 330 Annotation: Subtype: Link Rect: 329, 319, 365, 330 Annotation: Subtype: Link Rect: 424, 296, 461, 307 Annotation: Subtype: Link Rect: 388, 273, 426, 284 Annotation: Subtype: Link Rect: 432, 273, 468, 284 Annotation: Subtype: Link Rect: 201, 250, 238, 261 Annotation: Subtype: Link Rect: 244, 250, 280, 261 Annotation: Subtype: Link Rect: 59, 228, 96, 238 Annotation: Subtype: Link Rect: 59, 193, 96, 203 Annotation: Subtype: Link Rect: 419, 169, 457, 180 Annotation: Subtype: Link Rect: 462, 146, 499, 157 Annotation: Subtype: Link Rect: 505, 146, 541, 157 Annotation: Subtype: Link Rect: 379, 123, 416, 134 Annotation: Subtype: Link Rect: 59, 90, 96, 100 Annotation: Subtype: Link Rect: 161, 66, 199, 77 Annotation: Subtype: Link Rect: 205, 66, 241, 77 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 107, 722, 145, 733 Annotation: Subtype: Link Rect: 401, 699, 439, 710 Annotation: Subtype: Link Rect: 445, 699, 481, 710 Annotation: Subtype: Link Rect: 311, 676, 348, 687 Annotation: Subtype: Link Rect: 346, 652, 383, 664 Annotation: Subtype: Link Rect: 390, 652, 426, 664 Annotation: Subtype: Link Rect: 113, 619, 151, 629 Annotation: Subtype: Link Rect: 157, 619, 193, 629 Annotation: Subtype: Link Rect: 334, 595, 372, 606 Annotation: Subtype: Link Rect: 364, 572, 401, 583 Annotation: Subtype: Link Rect: 59, 538, 95, 548 Annotation: Subtype: Link Rect: 104, 504, 141, 514 Annotation: Subtype: Link Rect: 147, 504, 183, 514 Annotation: Subtype: Link Rect: 155, 469, 193, 479 Annotation: Subtype: Link Rect: 199, 469, 235, 479 Annotation: Subtype: Link Rect: 320, 445, 358, 456 Annotation: Subtype: Link Rect: 364, 445, 400, 456 Annotation: Subtype: Link Rect: 188, 411, 226, 422 Annotation: Subtype: Link Rect: 232, 411, 268, 422 Annotation: Subtype: Link Rect: 519, 388, 557, 399 Annotation: Subtype: Link Rect: 59, 377, 95, 387 Annotation: Subtype: Link Rect: 348, 342, 386, 353 Annotation: Subtype: Link Rect: 392, 342, 428, 353 Annotation: Subtype: Link Rect: 432, 319, 470, 330 Annotation: Subtype: Link Rect: 317, 296, 354, 307 Annotation: Subtype: Link Rect: 492, 273, 529, 284 Annotation: Subtype: Link Rect: 519, 250, 557, 261 Annotation: Subtype: Link Rect: 59, 239, 95, 249 Annotation: Subtype: Link Rect: 479, 215, 515, 226 Annotation: Subtype: Link Rect: 521, 215, 557, 226 Annotation: Subtype: Link Rect: 275, 192, 313, 203 Annotation: Subtype: Link Rect: 82, 159, 119, 169 Annotation: Subtype: Link Rect: 131, 124, 168, 134 Annotation: Subtype: Link Rect: 519, 100, 557, 111 Annotation: Subtype: Link Rect: 59, 90, 95, 100 Annotation: Subtype: Link Rect: 468, 77, 506, 88 Annotation: Subtype: Link Rect: 512, 77, 548, 88 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 465, 722, 502, 733 Annotation: Subtype: Link Rect: 509, 722, 545, 733 Annotation: Subtype: Link Rect: 268, 699, 306, 710 Annotation: Subtype: Link Rect: 170, 664, 208, 675 Annotation: Subtype: Link Rect: 280, 641, 318, 652 Annotation: Subtype: Link Rect: 86, 607, 124, 617 Checksum: 1ec19c13 Type: CRC32 Checksum: 57920a9b057e25c33b62a5e8af0a476a Type: MD5 Checksum: 71969a3ab4733867a979318b50591487d661b7cd Type: SHA-1 Checksum: a9289feb046ee51911d607a759b41039079ec4ff28061c872ce9eee3746c126b Type: SHA-256