8aae6e5762dd912371386fbb211f53c6  fimmu-16-1692382.pdf
f36245eb3212be056768ab7cc5bd614aa19a8f11  fimmu-16-1692382.pdf
814177cc6f8b2c581ed4dd4ec39e8c27daafc2530d0caf42179e4130b8306616  fimmu-16-1692382.pdf

Title:           Differences in the peripheral blood immune landscape between early-onset and late-onset colorectal cancer
Subject:         Sánchez-Menéndez C, Rodríguez-Pérez J, Fuertes D, Leguizamon V, González-Sanmartín M, Mateos E, Cervero M, San José E, Sanz G, Álvaro E, Ballestero-Pérez A, Martí-Gallostra M, Rueda JA, Hurtado-Caballero E, Pastor C, Balaguer F, Spinelli A, Martínez-Laso J, Torres M, Perea J and Coiras M (2025) Differences in the peripheral blood immune landscape between early-onset and late-onset colorectal cancer. Front. Immunol. 16:1692382. doi: 10.3389/fimmu.2025.1692382
Keywords:        colorectal neoplasms; early diagnosis; immune response; T-cell subsets; cytokine profiling; immune biomarkers
Author:          Clara Sánchez-Menéndez
CreationDate:    Tue Dec  2 04:12:50 2025 CET
ModDate:         Tue Dec  2 04:12:50 2025 CET
Custom Metadata: no
Metadata Stream: yes
Tagged:          no
UserProperties:  no
Suspects:        no
Form:            none
JavaScript:      no
Pages:           21
Encrypted:       no
Page size:       595.389 x 841.663 pts (A4)
Page rot:        0
File size:       4003793 bytes
Optimized:       no
PDF version:     1.4


name                                 type              encoding         emb sub uni object ID
------------------------------------ ----------------- ---------------- --- --- --- ---------
KPLFPA+AdvTTd3a5f740                 Type 1C           WinAnsi          yes yes no     495  0
KPLGAJ+AdvTT2c8ce45a                 Type 1C           WinAnsi          yes yes no     497  0
KPLLKH+AdvTTd168d80a.I               Type 1C           WinAnsi          yes yes no     801  0
KPLFPB+AdvPSA18C                     Type 1C           WinAnsi          yes yes no     802  0
KPLFPC+AdvTTd3a5f740+01              Type 1C           MacRoman         yes yes no     803  0
KPLFPD+AdvTTd3a5f740+20              Type 1C           WinAnsi          yes yes no     804  0
KPLFPE+AdvTT9b12cd41                 Type 1C           WinAnsi          yes yes no     498  0
KPLFPF+AdvPSA323                     Type 1C           WinAnsi          yes yes no     499  0
KPLFPG+AdvTT9b12cd41+01              Type 1C           MacRoman         yes yes no     805  0
KPLGAH+AdvTT9b12cd41+20              Type 1C           WinAnsi          yes yes no     806  0
KPLGAI+AdvTT9b12cd41+fb              Type 1C           Custom           yes yes yes    521  0
KPLMAG+AdvTT2c8ce45a+fb              Type 1C           Custom           yes yes yes    816  0
KPLMAH+AdvOT1ef757c0                 Type 1C           Custom           yes yes yes    492  0
KPLMAI+AdvOT1ef757c0+fb              Type 1C           Custom           yes yes yes    493  0
KPLMAJ+AdvOT1ef757c0+20              Type 1C           WinAnsi          yes yes no     494  0
KPLMEJ+AdvOT7d6df7ab.I               Type 1C           WinAnsi          yes yes no     817  0
KPLMEK+AdvTT58d178b9+03              Type 1C           Custom           yes yes yes    818  0
KPLMEL+AdvOT1ef757c0+01              Type 1C           MacRoman         yes yes no     819  0
KPLMFL+AdvOT1ef757c0+22              Type 1C           Custom           yes yes yes    820  0
KPLMFM+AdvTTd3a5f740+fb              Type 1C           Custom           yes yes yes    520  0
KPLMHN+AdvOT3f84ef53                 Type 1C           WinAnsi          yes yes no     496  0
KPLMNL+AdvOTb65e897d.B               Type 1C           WinAnsi          yes yes no     821  0
LADAAJ+AdvOT7d6df7ab.I+fb            Type 1C           Custom           yes yes yes    838  0


Jhove (Rel. 1.28.0, 2023-05-18)
 Date: 2026-03-04 04:19:25 CET
 RepresentationInformation: fimmu-16-1692382.pdf
  ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16)
  LastModified: 2026-03-03 18:04:00 CET
  Size: 4003793
  Format: PDF
  Version: 1.4
  Status: Well-Formed and valid
  SignatureMatches:
   PDF-hul
  MIMEtype: application/pdf
  PDFMetadata: 
   Objects: 924
   FreeObjects: 1
   IncrementalUpdates: 0
   DocumentCatalog: 
    ViewerPreferences: 
     HideToolbar: false
     HideMenubar: false
     HideWindowUI: false
     FitWindow: false
     CenterWindow: false
     DisplayDocTitle: true
     NonFullScreenPageMode: UseNone
     Direction: L2R
     ViewArea: CropBox
     ViewClip: CropBox
     PrintArea: CropBox
     PageClip: CropBox
    PageLayout: SinglePage
    PageMode: UseOutlines
    Language: en-US
    Outlines: 
     Item: 
      Title: Differences in the peripheral blood immune landscape between early-onset and late-onset colorectal cancer
      Destination: bmark_-207254568
      Children: 
       Item: 
        Title: 1 Introduction
        Destination: s1
       Item: 
        Title: 2 Materials and methods
        Destination: s2
        Children: 
         Item: 
          Title: 2.1 Participants
          Destination: s2_1
         Item: 
          Title: 2.2 Ethical statement
          Destination: s2_2
         Item: 
          Title: 2.3 Sample collection and processing
          Destination: s2_3
         Item: 
          Title: 2.4 Cell lines
          Destination: s2_4
         Item: 
          Title: 2.5 Immune phenotyping and quantification of cytokine production by CD4+ T helper subpopulations
          Destination: s2_5
         Item: 
          Title: 2.6 Immune phenotyping of regulatory T cells
          Destination: s2_6
         Item: 
          Title: 2.7 Characterization of T-cell immune exhaustion and senescence
          Destination: s2_7
         Item: 
          Title: 2.8 Immune phenotyping and quantification of cytokine production by NK and NKT-like cells
          Destination: s2_8
         Item: 
          Title: 2.9 Measurement of capacity for direct cellular cytotoxicity of NK cells
          Destination: s2_9
         Item: 
          Title: 2.10 Measurement of glucose uptake in immune cell populations
          Destination: s2_10
         Item: 
          Title: 2.11 Cytokine and chemokine levels in plasma
          Destination: s2_11
         Item: 
          Title: 2.12 Principal component analysis
          Destination: s2_12
         Item: 
          Title: 2.13 Random forest
          Destination: s2_13
         Item: 
          Title: 2.14 Statistical analysis
          Destination: s2_14
       Item: 
        Title: 3 Results
        Destination: s3
        Children: 
         Item: 
          Title: 3.1 Study population
          Destination: s3_1
         Item: 
          Title: 3.2 Levels of CD4+ T cells and expression of dysfunction markers were similar between cohorts
          Destination: s3_2
         Item: 
          Title: 3.3 Enhanced functionality of CD4+ Th1 and Th2 cells in EOCRC participants
          Destination: s3_3
         Item: 
          Title: 3.4 Enhanced Th9/Th17 cytokine production but reduced Th22 cell levels in EOCRC
          Destination: s3_4
         Item: 
          Title: 3.5 CD8+ T cells from EOCRC showed similar levels to LOCRC but higher LAG-3 expression
          Destination: s3_5
         Item: 
          Title: 3.6 Reduction of CD8+ Tγδ cells in EOCRC with preserved degranulation capacity
          Destination: s3_6
         Item: 
          Title: 3.7 Higher NKT-like cell levels in EOCRC with comparable functionality
          Destination: s3_7
         Item: 
          Title: 3.8 NK cells in EOCRC showed similar phenotypic profiles but reduced cytotoxic capacity
          Destination: s3_8
         Item: 
          Title: 3.9 Higher glucose uptake in EOCRC PBMCs with unchanged GLUT-1 expression
          Destination: s3_9
         Item: 
          Title: 3.10 Increased systemic inflammatory markers IFNγ and IL-8/CXCR8 in EOCRC
          Destination: s3_10
         Item: 
          Title: 3.11 Distinct immunometabolic profiling signatures differentiated EOCRC from LOCRC
          Destination: s3_11
         Item: 
          Title: 3.12 Immunological predictors of risk for EOCRC
          Destination: s3_12
       Item: 
        Title: 4 Discussion
        Destination: s4
       Item: 
        Title: Data availability statement
        Destination: bmark_-1258588262
       Item: 
        Title: Ethics statement
        Destination: bmark_1370551237
       Item: 
        Title: Author contributions
        Destination: bmark_-1208584890
       Item: 
        Title: Group members of the Spanish EOCRC consortium
        Destination: bmark_377734883
       Item: 
        Title: Funding
        Destination: bmark_1865464027
       Item: 
        Title: Acknowledgments
        Destination: bmark_-366698314
       Item: 
        Title: Conflict of interest
        Destination: bmark_1089982005
       Item: 
        Title: Generative AI statement
        Destination: bmark_-1453097031
       Item: 
        Title: Publisher’s note
        Destination: bmark_-1256977648
       Item: 
        Title: Supplementary material
        Destination: bmark_632582120
       Item: 
        Title: References
        Destination: bmark_2090415954
   Info: 
    Title: Differences in the peripheral blood immune landscape between early-onset and late-onset colorectal cancer
    Author: Clara Sánchez-Menéndez
    Subject: Sánchez-Menéndez C, Rodríguez-Pérez J, Fuertes D, Leguizamon V, González-Sanmartín M, Mateos E, Cervero M, San José E, Sanz G, Álvaro E, Ballestero-Pérez A, Martí-Gallostra M, Rueda JA, Hurtado-Caballero E, Pastor C, Balaguer F, Spinelli A, Martínez-Laso J, Torres M, Perea J and Coiras M (2025) Differences in the peripheral blood immune landscape between early-onset and late-onset colorectal cancer. Front. Immunol. 16:1692382. doi: 10.3389/fimmu.2025.1692382
    Keywords: colorectal neoplasms; early diagnosis; immune response; T-cell subsets; cytokine profiling; immune biomarkers
    CreationDate: Tue Dec 02 04:12:50 CET 2025
    ModDate: Tue Dec 02 04:12:50 CET 2025
   ID: 0x1370ef56e5adbe2a33282b2e0fe4e092, 0x986b57ff5f439c89bb6ac51772f07199
   Filters: 
    FilterPipeline: FlateDecode
    FilterPipeline: DCTDecode
   Images: 
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 2919
      ImageHeight: 577
      ColorSpace: CMYK
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 2228
      ImageHeight: 1788
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 2052
      ImageHeight: 1876
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 2052
      ImageHeight: 3116
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 2235
      ImageHeight: 1788
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 1547
      ImageHeight: 1158
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 1701
      ImageHeight: 2686
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 1786
      ImageHeight: 3550
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 1526
      ImageHeight: 597
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 2314
      ImageHeight: 3434
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 2098
      ImageHeight: 2438
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
   Fonts: 
    Type1: 
     Font: 
      BaseFont: KPLLKH+AdvTTd168d80a.I
      FontSubset: true
      FirstChar: 46
      LastChar: 117
      FontDescriptor: 
       FontName: KPLLKH+AdvTTd168d80a.I
       Flags: Serif, Nonsymbolic
       FontBBox: -145, -208, 968, 875
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: KPLFPB+AdvPSA18C
      FontSubset: true
      FirstChar: 180
      LastChar: 180
      FontDescriptor: 
       FontName: KPLFPB+AdvPSA18C
       Flags: Nonsymbolic
       FontBBox: -156, -208, 1125, 802
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: KPLFPC+AdvTTd3a5f740+01
      FontSubset: true
      FirstChar: 245
      LastChar: 245
      FontDescriptor: 
       FontName: KPLFPC+AdvTTd3a5f740+01
       Flags: Nonsymbolic
       FontBBox: -52, -208, 947, 885
       FontFile3: true
      Encoding: MacRomanEncoding
     Font: 
      BaseFont: KPLFPD+AdvTTd3a5f740+20
      FontSubset: true
      FirstChar: 134
      LastChar: 146
      FontDescriptor: 
       FontName: KPLFPD+AdvTTd3a5f740+20
       Flags: Nonsymbolic
       FontBBox: -114, -166, 1062, 864
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: KPLFPG+AdvTT9b12cd41+01
      FontSubset: true
      FirstChar: 245
      LastChar: 245
      FontDescriptor: 
       FontName: KPLFPG+AdvTT9b12cd41+01
       Flags: Nonsymbolic
       FontBBox: -52, -208, 958, 875
       FontFile3: true
      Encoding: MacRomanEncoding
     Font: 
      BaseFont: KPLGAH+AdvTT9b12cd41+20
      FontSubset: true
      FirstChar: 134
      LastChar: 146
      FontDescriptor: 
       FontName: KPLGAH+AdvTT9b12cd41+20
       Flags: Nonsymbolic
       FontBBox: -114, -166, 1010, 864
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: LADAAJ+AdvOT7d6df7ab.I+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 1
      FontDescriptor: 
       FontName: LADAAJ+AdvOT7d6df7ab.I+fb
       Flags: Symbolic
       FontBBox: -156, -250, 802, 708
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: KPLMFM+AdvTTd3a5f740+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 3
      FontDescriptor: 
       FontName: KPLMFM+AdvTTd3a5f740+fb
       Flags: Symbolic
       FontBBox: 0, 0, 906, 708
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: KPLGAI+AdvTT9b12cd41+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 3
      FontDescriptor: 
       FontName: KPLGAI+AdvTT9b12cd41+fb
       Flags: Symbolic
       FontBBox: 0, 0, 854, 697
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: KPLMAH+AdvOT1ef757c0
      FontSubset: true
      FirstChar: 2
      LastChar: 252
      FontDescriptor: 
       FontName: KPLMAH+AdvOT1ef757c0
       Flags: Serif, Symbolic
       FontBBox: -20, -250, 947, 854
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: KPLMAI+AdvOT1ef757c0+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 3
      FontDescriptor: 
       FontName: KPLMAI+AdvOT1ef757c0+fb
       Flags: Symbolic
       FontBBox: 0, -10, 781, 708
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: KPLMAJ+AdvOT1ef757c0+20
      FontSubset: true
      FirstChar: 145
      LastChar: 150
      FontDescriptor: 
       FontName: KPLMAJ+AdvOT1ef757c0+20
       Flags: Nonsymbolic
       FontBBox: -135, -187, 1010, 833
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: KPLFPA+AdvTTd3a5f740
      FontSubset: true
      FirstChar: 40
      LastChar: 122
      FontDescriptor: 
       FontName: KPLFPA+AdvTTd3a5f740
       Flags: Serif, Nonsymbolic
       FontBBox: -52, -208, 916, 885
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: KPLMAG+AdvTT2c8ce45a+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 1
      FontDescriptor: 
       FontName: KPLMAG+AdvTT2c8ce45a+fb
       Flags: Symbolic
       FontBBox: 0, 0, 947, 708
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: KPLMHN+AdvOT3f84ef53
      FontSubset: true
      FirstChar: 97
      LastChar: 103
      FontDescriptor: 
       FontName: KPLMHN+AdvOT3f84ef53
       Flags: Nonsymbolic
       FontBBox: -177, -291, 1083, 1000
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: KPLGAJ+AdvTT2c8ce45a
      FontSubset: true
      FirstChar: 40
      LastChar: 121
      FontDescriptor: 
       FontName: KPLGAJ+AdvTT2c8ce45a
       Flags: Nonsymbolic
       FontBBox: -52, -208, 947, 895
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: KPLMEJ+AdvOT7d6df7ab.I
      FontSubset: true
      FirstChar: 38
      LastChar: 121
      FontDescriptor: 
       FontName: KPLMEJ+AdvOT7d6df7ab.I
       Flags: Nonsymbolic
       FontBBox: -135, -250, 1000, 854
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: KPLFPE+AdvTT9b12cd41
      FontSubset: true
      FirstChar: 40
      LastChar: 243
      FontDescriptor: 
       FontName: KPLFPE+AdvTT9b12cd41
       Flags: Serif, Nonsymbolic
       FontBBox: -52, -208, 906, 875
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: KPLMEK+AdvTT58d178b9+03
      FontSubset: true
      FirstChar: 0
      LastChar: 0
      FontDescriptor: 
       FontName: KPLMEK+AdvTT58d178b9+03
       Flags: Symbolic
       FontBBox: -645, -354, 916, 895
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: KPLFPF+AdvPSA323
      FontSubset: true
      FirstChar: 180
      LastChar: 180
      FontDescriptor: 
       FontName: KPLFPF+AdvPSA323
       Flags: Nonsymbolic
       FontBBox: -156, -239, 1104, 770
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: KPLMEL+AdvOT1ef757c0+01
      FontSubset: true
      FirstChar: 245
      LastChar: 245
      FontDescriptor: 
       FontName: KPLMEL+AdvOT1ef757c0+01
       Flags: Serif, Nonsymbolic
       FontBBox: -20, -250, 947, 854
       FontFile3: true
      Encoding: MacRomanEncoding
     Font: 
      BaseFont: KPLMFL+AdvOT1ef757c0+22
      FontSubset: true
      FirstChar: 1
      LastChar: 3
      FontDescriptor: 
       FontName: KPLMFL+AdvOT1ef757c0+22
       Flags: Symbolic
       FontBBox: -135, -166, 697, 916
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: KPLMNL+AdvOTb65e897d.B
      FontSubset: true
      FirstChar: 46
      LastChar: 60
      FontDescriptor: 
       FontName: KPLMNL+AdvOTb65e897d.B
       Flags: Nonsymbolic
       FontBBox: -20, -250, 968, 854
       FontFile3: true
      Encoding: WinAnsiEncoding
   XMP: <x:xmpmeta xmlns:x="adobe:ns:meta/" x:xmptk="Adobe XMP Core 9.1-c001 79.2a0d8d9, 2023/03/14-11:19:46        ">
   <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:pdf="http://ns.adobe.com/pdf/1.3/" xmlns:xmpRights="http://ns.adobe.com/xap/1.0/rights/" xmlns:xmp="http://ns.adobe.com/xap/1.0/" xmlns:xmpMM="http://ns.adobe.com/xap/1.0/mm/" rdf:about="">
         <dc:format>application/pdf</dc:format>
         <dc:creator>
            <rdf:Seq>
               <rdf:li>Clara Sánchez-Menéndez</rdf:li>
               <rdf:li>Jaime Rodríguez-Pérez</rdf:li>
               <rdf:li>Daniel Fuertes</rdf:li>
               <rdf:li>Valentina Leguizamon</rdf:li>
               <rdf:li>María González-Sanmartín</rdf:li>
               <rdf:li>Elena Mateos</rdf:li>
               <rdf:li>Miguel Cervero</rdf:li>
               <rdf:li>Esther San José</rdf:li>
               <rdf:li>Gonzalo Sanz</rdf:li>
               <rdf:li>Edurne Álvaro</rdf:li>
               <rdf:li>Araceli Ballestero-Pérez</rdf:li>
               <rdf:li>Marc Martí-Gallostra</rdf:li>
               <rdf:li>José Antonio Rueda</rdf:li>
               <rdf:li>Elena Hurtado-Caballero</rdf:li>
               <rdf:li>Carlos Pastor</rdf:li>
               <rdf:li>Francesc Balaguer</rdf:li>
               <rdf:li>Antonino Spinelli</rdf:li>
               <rdf:li>Jorge Martínez-Laso</rdf:li>
               <rdf:li>Montserrat Torres</rdf:li>
               <rdf:li>José Perea</rdf:li>
               <rdf:li>Mayte Coiras</rdf:li>
            </rdf:Seq>
         </dc:creator>
         <dc:description>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">Sánchez-Menéndez C, Rodríguez-Pérez J, Fuertes D, Leguizamon V, González-Sanmartín M, Mateos E, Cervero M, San José E, Sanz G, Álvaro E, Ballestero-Pérez A, Martí-Gallostra M, Rueda JA, Hurtado-Caballero E, Pastor C, Balaguer F, Spinelli A, Martínez-Laso J, Torres M, Perea J and Coiras M (2025) Differences in the peripheral blood immune landscape between early-onset and late-onset colorectal cancer. Front. Immunol. 16:1692382. doi: 10.3389/fimmu.2025.1692382</rdf:li>
            </rdf:Alt>
         </dc:description>
         <dc:rights>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">Copyright © 2025 Sánchez-Menéndez, Rodríguez-Pérez, Fuertes, Leguizamon, González-Sanmartín, Mateos, Cervero, San José, Sanz, Álvaro, Ballestero-Pérez, Martí-Gallostra, Rueda, Hurtado-Caballero, Pastor, Balaguer, Spinelli, Martínez-Laso, Torres, Perea and Coiras.. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</rdf:li>
            </rdf:Alt>
         </dc:rights>
         <dc:subject>
            <rdf:Bag>
               <rdf:li>colorectal neoplasms</rdf:li>
               <rdf:li>early diagnosis</rdf:li>
               <rdf:li>immune response</rdf:li>
               <rdf:li>T-cell subsets</rdf:li>
               <rdf:li>cytokine profiling</rdf:li>
               <rdf:li>immune biomarkers</rdf:li>
            </rdf:Bag>
         </dc:subject>
         <dc:title>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">Differences in the peripheral blood immune landscape between early-onset and late-onset colorectal cancer</rdf:li>
            </rdf:Alt>
         </dc:title>
         <pdf:Keywords>colorectal neoplasms; early diagnosis; immune response; T-cell subsets; cytokine profiling; immune biomarkers</pdf:Keywords>
         <xmpRights:Marked>True</xmpRights:Marked>
         <xmpRights:WebStatement>https://www.frontiersin.org/legal/copyright-statement</xmpRights:WebStatement>
         <xmp:ModifyDate>2025-12-02T11:12:50+08:00</xmp:ModifyDate>
         <xmp:CreateDate>2025-12-02T11:12:50+08:00</xmp:CreateDate>
         <xmp:MetadataDate>2025-12-02T11:12:50+08:00</xmp:MetadataDate>
         <xmpMM:DocumentID>uuid:01a85121-ad2e-437d-a400-1d93ae8d4067</xmpMM:DocumentID>
         <xmpMM:InstanceID>uuid:b001fc61-404b-4f21-a15e-ff196d46f164</xmpMM:InstanceID>
      </rdf:Description>
   </rdf:RDF>
</x:xmpmeta>
   Pages: 
    Page: 
     Label: 1
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 221, 695, 496, 716
      Annotation: 
       Subtype: Link
       Rect: 221, 670, 467, 691
      Annotation: 
       Subtype: Link
       Rect: 221, 645, 470, 666
      Annotation: 
       Subtype: Link
       Rect: 221, 620, 496, 641
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
      Annotation: 
       Subtype: Link
       Rect: 49, 700, 125, 715
      Annotation: 
       Subtype: Link
       Rect: 60, 547, 112, 554
      Annotation: 
       Subtype: Link
       Rect: 60, 527, 140, 534
      Annotation: 
       Subtype: Link
       Rect: 49, 328, 159, 334
      Annotation: 
       Subtype: Link
       Rect: 89, 242, 182, 248
      Annotation: 
       Subtype: Link
       Rect: 49, 233, 99, 240
      Annotation: 
       Subtype: Link
       Rect: 450, 802, 506, 809
      Annotation: 
       Subtype: Link
       Rect: 466, 793, 529, 800
      Annotation: 
       Subtype: Link
       Rect: 446, 783, 540, 790
      Annotation: 
       Subtype: Link
       Rect: 49, 789, 233, 806
    Page: 
     Label: 2
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 199, 313, 204, 322
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 143, 275, 147, 284
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 152, 275, 156, 284
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 139, 225, 143, 234
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 234, 213, 238, 222
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 52, 163, 57, 172
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 86, 125, 90, 134
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 95, 125, 99, 134
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 346, 388, 350, 397
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 355, 388, 359, 397
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 307, 375, 312, 384
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 515, 375, 523, 384
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 424, 363, 432, 372
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 428, 350, 432, 359
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 437, 350, 446, 359
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 451, 350, 460, 359
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 308, 313, 317, 322
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 325, 313, 334, 322
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 460, 262, 464, 272
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 468, 262, 473, 272
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 518, 225, 526, 234
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 532, 225, 540, 234
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 417, 162, 426, 172
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 430, 162, 439, 172
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 481, 125, 490, 134
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 494, 125, 502, 134
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 3
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 52, 750, 61, 759
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 157, 285, 166, 294
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 262, 123, 271, 132
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 491, 110, 499, 119
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 4
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 201, 575, 290, 584
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 65, 562, 70, 571
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 49, 200, 136, 209
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 462, 575, 543, 584
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 304, 550, 386, 559
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 380, 462, 388, 471
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 324, 450, 333, 459
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 517, 262, 525, 271
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 304, 162, 391, 171
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 5
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 149, 600, 157, 609
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 175, 575, 183, 584
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 279, 575, 287, 584
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 185, 562, 194, 571
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 255, 512, 263, 521
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 176, 450, 185, 459
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 53, 338, 62, 346
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 69, 338, 79, 346
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 185, 313, 194, 321
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 420, 687, 428, 696
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 486, 687, 494, 696
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 500, 687, 509, 696
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 532, 675, 540, 684
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 500, 537, 528, 546
       Destination: 38
      Annotation: 
       Subtype: Link
       Rect: 408, 525, 494, 534
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 447, 112, 531, 122
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 6
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 181, 673, 223, 682
       Destination: 39
      Annotation: 
       Subtype: Link
       Rect: 245, 635, 280, 644
       Destination: 39
      Annotation: 
       Subtype: Link
       Rect: 159, 548, 194, 557
       Destination: 40
      Annotation: 
       Subtype: Link
       Rect: 70, 523, 106, 532
       Destination: 40
      Annotation: 
       Subtype: Link
       Rect: 52, 485, 88, 494
       Destination: 40
      Annotation: 
       Subtype: Link
       Rect: 81, 460, 114, 469
       Destination: 40
      Annotation: 
       Subtype: Link
       Rect: 133, 448, 166, 457
       Destination: 40
      Annotation: 
       Subtype: Link
       Rect: 206, 398, 242, 407
       Destination: 40
      Annotation: 
       Subtype: Link
       Rect: 80, 348, 174, 357
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 84, 323, 179, 332
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 175, 310, 265, 319
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 159, 214, 195, 223
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 252, 189, 288, 198
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 78, 152, 115, 161
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 81, 127, 116, 136
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 52, 89, 87, 98
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 501, 102, 543, 111
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 7
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 252, 332, 288, 341
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 52, 282, 89, 291
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 245, 232, 288, 241
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 79, 170, 169, 179
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 84, 145, 171, 154
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 159, 95, 249, 104
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 349, 268, 386, 277
       Destination: 42
      Annotation: 
       Subtype: Link
       Rect: 350, 218, 385, 226
       Destination: 42
      Annotation: 
       Subtype: Link
       Rect: 396, 120, 432, 129
       Destination: 43
      Annotation: 
       Subtype: Link
       Rect: 348, 95, 383, 104
       Destination: 43
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 8
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 145, 251, 185, 260
       Destination: 44
      Annotation: 
       Subtype: Link
       Rect: 52, 226, 89, 235
       Destination: 44
      Annotation: 
       Subtype: Link
       Rect: 111, 214, 146, 223
       Destination: 44
      Annotation: 
       Subtype: Link
       Rect: 115, 114, 152, 123
       Destination: 45
      Annotation: 
       Subtype: Link
       Rect: 157, 89, 192, 98
       Destination: 45
      Annotation: 
       Subtype: Link
       Rect: 307, 279, 342, 288
       Destination: 45
      Annotation: 
       Subtype: Link
       Rect: 499, 254, 534, 263
       Destination: 45
      Annotation: 
       Subtype: Link
       Rect: 307, 216, 394, 225
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 406, 114, 445, 123
       Destination: 46
      Annotation: 
       Subtype: Link
       Rect: 350, 89, 386, 98
       Destination: 46
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 9
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 10
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 197, 268, 227, 277
       Destination: 47
      Annotation: 
       Subtype: Link
       Rect: 52, 156, 94, 165
       Destination: 48
      Annotation: 
       Subtype: Link
       Rect: 371, 296, 412, 305
       Destination: 48
      Annotation: 
       Subtype: Link
       Rect: 381, 271, 422, 280
       Destination: 48
      Annotation: 
       Subtype: Link
       Rect: 499, 233, 540, 242
       Destination: 48
      Annotation: 
       Subtype: Link
       Rect: 308, 93, 398, 102
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 11
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 162, 282, 171, 291
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 176, 282, 184, 291
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 238, 232, 247, 241
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 466, 232, 475, 241
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 480, 232, 489, 241
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 12
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 13
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 14
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 253, 463, 262, 472
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 202, 413, 210, 422
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 152, 375, 161, 384
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 167, 375, 176, 384
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 179, 338, 188, 347
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 192, 338, 201, 347
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 165, 313, 174, 322
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 221, 275, 230, 284
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 147, 163, 156, 172
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 135, 100, 144, 109
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 467, 500, 475, 509
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 481, 500, 489, 509
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 494, 500, 503, 509
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 364, 463, 373, 472
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 338, 450, 347, 459
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 507, 413, 516, 422
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 449, 313, 457, 322
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 337, 175, 346, 184
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 307, 163, 316, 172
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 321, 163, 330, 172
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 338, 150, 347, 159
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 494, 138, 502, 147
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 431, 88, 440, 97
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 447, 75, 456, 84
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 15
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 16
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 115, 204, 123, 213
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 271, 167, 279, 176
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 179, 104, 188, 113
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 243, 92, 252, 101
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 308, 229, 317, 238
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 480, 129, 489, 138
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 17
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 166, 687, 175, 696
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 185, 612, 194, 621
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 180, 537, 188, 546
       Destination: 52
      Annotation: 
       Subtype: Link
       Rect: 195, 537, 203, 546
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 249, 450, 257, 459
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 263, 450, 271, 459
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 277, 450, 285, 459
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 121, 387, 130, 396
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 136, 387, 145, 396
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 257, 313, 266, 321
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 413, 662, 421, 671
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 428, 662, 436, 671
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 465, 650, 473, 659
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 366, 612, 375, 621
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 18
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 102, 620, 191, 629
       Destination: 51
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 19
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 315, 347, 545, 356
      Annotation: 
       Subtype: Link
       Rect: 304, 335, 403, 344
      Annotation: 
       Subtype: Link
       Rect: 238, 244, 290, 251
      Annotation: 
       Subtype: Link
       Rect: 62, 217, 135, 224
      Annotation: 
       Subtype: Link
       Rect: 106, 198, 290, 205
      Annotation: 
       Subtype: Link
       Rect: 49, 190, 170, 197
      Annotation: 
       Subtype: Link
       Rect: 62, 155, 114, 162
      Annotation: 
       Subtype: Link
       Rect: 225, 136, 278, 143
      Annotation: 
       Subtype: Link
       Rect: 97, 109, 176, 116
      Annotation: 
       Subtype: Link
       Rect: 192, 82, 271, 89
      Annotation: 
       Subtype: Link
       Rect: 387, 244, 446, 251
      Annotation: 
       Subtype: Link
       Rect: 317, 217, 384, 224
      Annotation: 
       Subtype: Link
       Rect: 518, 190, 545, 197
      Annotation: 
       Subtype: Link
       Rect: 304, 182, 359, 189
      Annotation: 
       Subtype: Link
       Rect: 521, 163, 545, 170
      Annotation: 
       Subtype: Link
       Rect: 304, 155, 335, 162
      Annotation: 
       Subtype: Link
       Rect: 371, 128, 437, 135
      Annotation: 
       Subtype: Link
       Rect: 449, 101, 503, 108
      Annotation: 
       Subtype: Link
       Rect: 426, 82, 505, 89
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 20
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 124, 744, 184, 751
      Annotation: 
       Subtype: Link
       Rect: 264, 717, 290, 724
      Annotation: 
       Subtype: Link
       Rect: 49, 709, 96, 716
      Annotation: 
       Subtype: Link
       Rect: 184, 682, 255, 689
      Annotation: 
       Subtype: Link
       Rect: 215, 655, 282, 662
      Annotation: 
       Subtype: Link
       Rect: 62, 620, 146, 627
      Annotation: 
       Subtype: Link
       Rect: 266, 593, 290, 600
      Annotation: 
       Subtype: Link
       Rect: 49, 585, 117, 592
      Annotation: 
       Subtype: Link
       Rect: 222, 550, 290, 557
      Annotation: 
       Subtype: Link
       Rect: 49, 542, 69, 549
      Annotation: 
       Subtype: Link
       Rect: 62, 507, 117, 514
      Annotation: 
       Subtype: Link
       Rect: 118, 480, 208, 487
      Annotation: 
       Subtype: Link
       Rect: 62, 445, 141, 452
      Annotation: 
       Subtype: Link
       Rect: 98, 418, 165, 425
      Annotation: 
       Subtype: Link
       Rect: 265, 391, 290, 398
      Annotation: 
       Subtype: Link
       Rect: 49, 383, 95, 390
      Annotation: 
       Subtype: Link
       Rect: 111, 364, 168, 371
      Annotation: 
       Subtype: Link
       Rect: 106, 345, 209, 352
      Annotation: 
       Subtype: Link
       Rect: 266, 326, 290, 333
      Annotation: 
       Subtype: Link
       Rect: 49, 318, 103, 325
      Annotation: 
       Subtype: Link
       Rect: 84, 272, 149, 279
      Annotation: 
       Subtype: Link
       Rect: 265, 261, 290, 268
      Annotation: 
       Subtype: Link
       Rect: 49, 253, 99, 260
      Annotation: 
       Subtype: Link
       Rect: 158, 226, 244, 233
      Annotation: 
       Subtype: Link
       Rect: 101, 199, 172, 206
      Annotation: 
       Subtype: Link
       Rect: 158, 180, 244, 187
      Annotation: 
       Subtype: Link
       Rect: 49, 153, 133, 160
      Annotation: 
       Subtype: Link
       Rect: 153, 134, 221, 141
      Annotation: 
       Subtype: Link
       Rect: 104, 115, 160, 122
      Annotation: 
       Subtype: Link
       Rect: 101, 80, 170, 87
      Annotation: 
       Subtype: Link
       Rect: 317, 736, 394, 743
      Annotation: 
       Subtype: Link
       Rect: 317, 717, 382, 724
      Annotation: 
       Subtype: Link
       Rect: 317, 682, 391, 689
      Annotation: 
       Subtype: Link
       Rect: 399, 663, 476, 670
      Annotation: 
       Subtype: Link
       Rect: 349, 636, 427, 643
      Annotation: 
       Subtype: Link
       Rect: 317, 609, 380, 616
      Annotation: 
       Subtype: Link
       Rect: 433, 555, 507, 562
      Annotation: 
       Subtype: Link
       Rect: 452, 528, 537, 535
      Annotation: 
       Subtype: Link
       Rect: 317, 493, 411, 500
      Annotation: 
       Subtype: Link
       Rect: 441, 466, 535, 473
      Annotation: 
       Subtype: Link
       Rect: 373, 439, 444, 446
      Annotation: 
       Subtype: Link
       Rect: 349, 412, 403, 419
      Annotation: 
       Subtype: Link
       Rect: 436, 377, 513, 384
      Annotation: 
       Subtype: Link
       Rect: 487, 358, 545, 365
      Annotation: 
       Subtype: Link
       Rect: 304, 350, 324, 357
      Annotation: 
       Subtype: Link
       Rect: 371, 323, 433, 330
      Annotation: 
       Subtype: Link
       Rect: 353, 296, 431, 303
      Annotation: 
       Subtype: Link
       Rect: 349, 269, 430, 276
      Annotation: 
       Subtype: Link
       Rect: 317, 242, 394, 249
      Annotation: 
       Subtype: Link
       Rect: 522, 223, 545, 230
      Annotation: 
       Subtype: Link
       Rect: 304, 215, 345, 222
      Annotation: 
       Subtype: Link
       Rect: 347, 180, 439, 187
      Annotation: 
       Subtype: Link
       Rect: 402, 153, 476, 160
      Annotation: 
       Subtype: Link
       Rect: 522, 124, 545, 131
      Annotation: 
       Subtype: Link
       Rect: 304, 116, 349, 123
      Annotation: 
       Subtype: Link
       Rect: 317, 79, 400, 86
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 21
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 139, 736, 224, 743
      Annotation: 
       Subtype: Link
       Rect: 236, 708, 288, 715
      Annotation: 
       Subtype: Link
       Rect: 266, 680, 290, 687
      Annotation: 
       Subtype: Link
       Rect: 49, 672, 88, 679
      Annotation: 
       Subtype: Link
       Rect: 263, 653, 290, 660
      Annotation: 
       Subtype: Link
       Rect: 49, 645, 96, 652
      Annotation: 
       Subtype: Link
       Rect: 97, 618, 167, 625
      Annotation: 
       Subtype: Link
       Rect: 264, 599, 290, 606
      Annotation: 
       Subtype: Link
       Rect: 49, 591, 110, 598
      Annotation: 
       Subtype: Link
       Rect: 146, 564, 221, 571
      Annotation: 
       Subtype: Link
       Rect: 224, 537, 270, 544
      Annotation: 
       Subtype: Link
       Rect: 266, 510, 290, 517
      Annotation: 
       Subtype: Link
       Rect: 49, 502, 106, 509
      Annotation: 
       Subtype: Link
       Rect: 521, 752, 545, 759
      Annotation: 
       Subtype: Link
       Rect: 304, 744, 375, 751
      Annotation: 
       Subtype: Link
       Rect: 522, 717, 545, 724
      Annotation: 
       Subtype: Link
       Rect: 304, 709, 365, 716
      Annotation: 
       Subtype: Link
       Rect: 414, 682, 501, 689
      Annotation: 
       Subtype: Link
       Rect: 522, 655, 545, 662
      Annotation: 
       Subtype: Link
       Rect: 304, 647, 358, 654
      Annotation: 
       Subtype: Link
       Rect: 422, 620, 498, 627
      Annotation: 
       Subtype: Link
       Rect: 317, 585, 388, 592
      Annotation: 
       Subtype: Link
       Rect: 432, 566, 502, 573
      Annotation: 
       Subtype: Link
       Rect: 469, 547, 524, 554
      Annotation: 
       Subtype: Link
       Rect: 376, 520, 446, 527
      Annotation: 
       Subtype: Link
       Rect: 428, 485, 521, 492
      Annotation: 
       Subtype: Link
       Rect: 449, 791, 545, 798
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
  Checksum: 44112dac
   Type: CRC32
  Checksum: 8aae6e5762dd912371386fbb211f53c6
   Type: MD5
  Checksum: f36245eb3212be056768ab7cc5bd614aa19a8f11
   Type: SHA-1
  Checksum: 814177cc6f8b2c581ed4dd4ec39e8c27daafc2530d0caf42179e4130b8306616
   Type: SHA-256