cc6acd0f04d1dcc60020a9dad3f50a91 intjoumolsci_a2020v21n22p8775.pdf 8cd6b5b18ed7191117d738acb22e87b80b63ef52 intjoumolsci_a2020v21n22p8775.pdf 28d7bc13b89f0cfc13e3c6b123f073bc447260945f26d119a557abf552ed2811 intjoumolsci_a2020v21n22p8775.pdf Title: Anti-PD-1 Immunotherapy in Preclinical GL261 Glioblastoma: Influence of Therapeutic Parameters and Non-Invasive Response Biomarker Assessment with MRSI-Based Approaches Subject: Glioblastomas (GBs) are malignant brain tumours with poor prognosis even after aggressive therapy. Programmed cell death-1 (PD-1) immune checkpoint blockade is a promising strategy in many types of cancer, but its therapeutic effects in GB remain low and associated with immune infiltration. Previous work suggests that oscillations of magnetic resonance spectroscopic imaging (MRSI)-based response pattern with chemotherapy could act as a biomarker of efficient immune system attack onto GBs. The presence of such oscillations with other monotherapies such as anti-PD-1 would reinforce its monitoring potential. Here, we confirm that the oscillatory behaviour of the response biomarker is also detected in mice treated with anti PD-1 immunotherapy both in combination with temozolomide and as monotherapy. This indicates that the spectral pattern changes observed during therapy response are shared by different therapeutic strategies, provided the host immune system is elicited and able to productively attack tumour cells. Moreover, the participation of the immune system in response is also supported by the rate of cured animals observed with different therapeutic strategies (in the range of 50–100% depending on the treatment), which also held long-term immune memory against tumour cells re-challenge. Taken together, our findings open the way for a translational use of the MRSI-based biomarker in patient-tailored GB therapy, including immunotherapy, for which reliable non-invasive biomarkers are still missing. Keywords: glioblastoma; orthotopic immunocompetent tumours; checkpoint inhibitors; TMZ; therapy response biomarker; magnetic resonance spectroscopic imaging; long-term immune memory Author: Shuang Wu, Pilar Calero-Pérez, Carles Arús and Ana Paula Candiota Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Fri Nov 20 09:29:39 2020 CET ModDate: Fri Nov 20 09:29:39 2020 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 24 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3466025 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- NEFAAH+URWPalladioL-Ital Type 1 Custom yes yes no 160 0 HZLYLP+URWPalladioL-Bold Type 1 Custom yes yes no 161 0 MQFYIK+VnURWPalladioL-Bold Type 1 Custom yes yes no 162 0 PNEASW+URWPalladioL-Roma Type 1 Custom yes yes no 163 0 NQWDWO+VnURWPalladioL Type 1 Custom yes 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no 421 0 LLCKDA+TimesNewRoman CID TrueType Identity-H yes yes yes 422 0 LLCIJE+PalatinoLinotype CID TrueType Identity-H yes yes yes 446 0 LLCIJF+PalatinoLinotype TrueType WinAnsi yes yes no 447 0 LLCJAE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 448 0 LLCJBG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 449 0 LLCKDA+TimesNewRoman CID TrueType Identity-H yes yes yes 450 0 MFIGJL+Rpxb Type 1 Builtin yes yes no 480 0 LLCIJE+PalatinoLinotype CID TrueType Identity-H yes yes yes 527 0 LLCIJF+PalatinoLinotype TrueType WinAnsi yes yes no 528 0 LLCJAE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 529 0 LLCJBG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 530 0 LLCKDA+TimesNewRoman CID TrueType Identity-H yes yes yes 531 0 IMSDCL+URWPalladioL-BoldItal Type 1 Custom yes yes no 627 0 JHYTSG+CMR10 Type 1 Builtin yes yes no 641 0 VSHNAE+Rpcxr Type 1 Builtin yes yes no 759 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-04-05 02:29:52 CEST RepresentationInformation: intjoumolsci_a2020v21n22p8775.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2020-11-20 11:47:03 CET Size: 3466025 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: ぉのぴひはつふっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸲ Item: Title: げづびふぬぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぉきこ〭ごきず〯ちのぴど〭ぐい〭〱ぜ〴ぜ〰ぃはねぢどのづつぜ〴ぜ〰ごとづひちばべぜ〴ぜ〰ぉびぜ〴ぜ〰こふばづひどはひぜ〴ぜ〰ぴはぜ〴ぜ〰きはのはぴとづひちばべぜ〴ぜ〰どのぜ〴ぜ〰くひぴとはぴはばどっぜ〴ぜ〰ぇが〲〶〱ぜ〴ぜ〰ぇぬどはねちぜ〴ぜ〰あづちひどのでぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰ぉのどぴどちぬぜ〴ぜ〰ごふねはふひぜ〴ぜ〰ざはぬふねづぜ〴ぜ〰ちのつぜ〴ぜ〰ぁつねどのどびぴひちぴどはのぜ〴ぜ〰こっとづつふぬづぜ〴ぜ〰ぁひづぜ〴ぜ〰ぃひどぴどっちぬぜ〴ぜ〰てはひぜ〴ぜ〰ぴとづぜ〴ぜ〰ぅててどっちっべぜ〴ぜ〰はてぜ〴ぜ〰ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸲⸱ Children: Item: Title: ぉきこ〭ごきず〯ちのぴど〭ぐい〭〱ぜ〴ぜ〰ぃはねぢどのづつぜ〴ぜ〰ごとづひちばべぜ〴ぜ〰ぉびぜ〴ぜ〰こふばづひどはひぜ〴ぜ〰ぴはぜ〴ぜ〰きはのはぴとづひちばべぜ〴ぜ〰どのぜ〴ぜ〰くひぴとはぴはばどっぜ〴ぜ〰ぇが〲〶〱ぜ〴ぜ〰ぇぬどはねちぜ〴ぜ〰あづちひどのでぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰ぉのどぴどちぬぜ〴ぜ〰ごふねはふひぜ〴ぜ〰ざはぬふねづぜ〴ぜ〰ちのつぜ〴ぜ〰ぁつねどのどびぴひちぴどはのぜ〴ぜ〰こっとづつふぬづぜ〴ぜ〰ぁひづぜ〴ぜ〰ぃひどぴどっちぬぜ〴ぜ〰てはひぜ〴ぜ〰ぴとづぜ〴ぜ〰ぅててどっちっべぜ〴ぜ〰はてぜ〴ぜ〰ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸲⸱ Item: Title: ぉのどぴどちぬぜ〴ぜ〰ごふねはふひぜ〴ぜ〰ざはぬふねづぜ〴ぜ〰ちのつぜ〴ぜ〰ぁつねどのどびぴひちぴどはのぜ〴ぜ〰こっとづつふぬづぜ〴ぜ〰ぁひづぜ〴ぜ〰ぃひどぴどっちぬぜ〴ぜ〰てはひぜ〴ぜ〰ぴとづぜ〴ぜ〰ぅててどっちっべぜ〴ぜ〰はてぜ〴ぜ〰ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸲⸱ Children: Item: Title: ぉのどぴどちぬぜ〴ぜ〰ごふねはふひぜ〴ぜ〰ざはぬふねづぜ〴ぜ〰ぅててづっぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸲⸲ Item: Title: ぁつねどのどびぴひちぴどはのぜ〴ぜ〰こっとづつふぬづぜ〴ぜ〰ぅててづっぴ〺ぜ〴ぜ〰ぅぶづひべぜ〴ぜ〰〳ぜ〴ぜ〰いちべびぜ〴ぜ〰ぶび〮ぜ〴ぜ〰〶ぜ〴ぜ〰いちべびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰きふぬぴど〭こぬどっづぜ〴ぜ〰きげこぉ〭あちびづつぜ〴ぜ〰ざはぬふねづぴひどっぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰ふのつづひぜ〴ぜ〰ぉきこ〭ぁのぴど〭ぐい〭〱〯ごきずぜ〴ぜ〰ぃはねぢどのづつぜ〴ぜ〰ごひづちぴねづのぴぜ〴ぜ〰はひぜ〴ぜ〰ぉきこ〭ぁのぴど〭ぐい〱ぜ〴ぜ〰きはのはぴとづひちばべ〺ぜ〴ぜ〰ぎはの〭ぉのぶちびどぶづぜ〴ぜ〰あどはねちひにづひぜ〴ぜ〰はてぜ〴ぜ〰ごとづひちばべぜ〴ぜ〰げづびばはのびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸳⸱ Item: Title: きふぬぴど〭こぬどっづぜ〴ぜ〰きげこぉ〭あちびづつぜ〴ぜ〰ざはぬふねづぴひどっぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰ふのつづひぜ〴ぜ〰ぉきこ〭ぁのぴど〭ぐい〭〱〯ごきずぜ〴ぜ〰ぃはねぢどのづつぜ〴ぜ〰ごひづちぴねづのぴぜ〴ぜ〰はひぜ〴ぜ〰ぉきこ〭ぁのぴど〭ぐい〱ぜ〴ぜ〰きはのはぴとづひちばべ〺ぜ〴ぜ〰ぎはの〭ぉのぶちびどぶづぜ〴ぜ〰あどはねちひにづひぜ〴ぜ〰はてぜ〴ぜ〰ごとづひちばべぜ〴ぜ〰げづびばはのびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸳⸱ Children: Item: Title: ぉきこ〭ちのぴど〭ぐい〭〱〯ごきずぜ〴ぜ〰ごひづちぴづつぜ〴ぜ〰きはふびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸳⸲ Item: Title: ぉきこ〭ちのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴ぜ〰ごひづちぴづつぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴ぜ〰ことはぷのぜ〴ぜ〰ぴはぜ〴ぜ〰あづぜ〴ぜ〰きはひづぜ〴ぜ〰ぅててづっぴどぶづぜ〴ぜ〰どのぜ〴ぜ〰ぅびぴちぢぬどびとどのでぜ〴ぜ〰ぁのぴど〭ごふねはふひぜ〴ぜ〰ぉねねふのづぜ〴ぜ〰きづねはひべぜ〴ぜ〰ぴとちのぜ〴ぜ〰ぃはねぢどのづつぜ〴ぜ〰ごとづひちばべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸴⸱ Item: Title: ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴ぜ〰ことはぷのぜ〴ぜ〰ぴはぜ〴ぜ〰あづぜ〴ぜ〰きはひづぜ〴ぜ〰ぅててづっぴどぶづぜ〴ぜ〰どのぜ〴ぜ〰ぅびぴちぢぬどびとどのでぜ〴ぜ〰ぁのぴど〭ごふねはふひぜ〴ぜ〰ぉねねふのづぜ〴ぜ〰きづねはひべぜ〴ぜ〰ぴとちのぜ〴ぜ〰ぃはねぢどのづつぜ〴ぜ〰ごとづひちばべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸴⸱ Children: Item: Title: ぃはのぴひはぬぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸴⸲ Item: Title: ぉきこ〭ぁのぴど〭ぐい〭〱〯ごきずぜ〴ぜ〰ぃふひづつぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸴⸳ Item: Title: ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴ぜ〰ぃふひづつぜ〴ぜ〰きどっづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: いどびっふびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮ㄩ‾㸊⡜㌷㙜㌷㝜〰えちひのづびびどのでぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉねねふのづぜ〴ぜ〰こべびぴづねぜ〴ぜ〰ぴはぜ〴ぜ〰ぃはのぴひはぬぜ〴ぜ〰ぇあぜ〴ぜ〰ごふねはふひぜ〴ぜ〰ぐひはでひづびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰うどのつどのでぜ〴ぜ〰ぴとづぜ〴ぜ〰くばぴどねちぬぜ〴ぜ〰こっとづつふぬづぜ〴ぜ〰てはひぜ〴ぜ〰ぎはの〭ぉのぶちびどぶづぜ〴ぜ〰げづびばはのびづぜ〴ぜ〰ぁびびづびびねづのぴ〺ぜ〴ぜ〰ごとづぜ〴ぜ〰げづぬづぶちのっづぜ〴ぜ〰はてぜ〴ぜ〰ごふねはふひぜ〴ぜ〰ざはぬふねづぜ〴ぜ〰ちぴぜ〴ぜ〰ごとづひちばべぜ〴ぜ〰こぴちひぴどのでぜ〴ぜ〰ごどねづぜ〴ぜ〰ちのつぜ〴ぜ〰いはびどのでぜ〴ぜ〰こっとづつふぬづぜ〴ぜ〰どのぜ〴ぜ〰ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰ごとづぜ〴ぜ〰くびっどぬぬちぴはひべぜ〴ぜ〰きげこぉぜ〴ぜ〰きづぴちぢはぬはねどっぜ〴ぜ〰ぐちぴぴづひのぜ〴ぜ〰ぃとちのでづびぜ〴ぜ〰ぁひづぜ〴ぜ〰ぁぬびはぜ〴ぜ〰ぃはのてどひねづつぜ〴ぜ〰どのぜ〴ぜ〰ぇが〲〶〱ぜ〴ぜ〰ぇあぜ〴ぜ〰ごひづちぴづつぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぉねねふのはぴとづひちばべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰ぉきこ〭ぁのぴど〭ぐい〭〱〯ごきずぜ〴ぜ〰ちのつぜ〴ぜ〰ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴ぜ〰ぅびぴちぢぬどびとづつぜ〴ぜ〰ざちひべどのでぜ〴ぜ〰いづでひづづびぜ〴ぜ〰はてぜ〴ぜ〰がはので〭ごづひねぜ〴ぜ〰こばづっどてどっぜ〴ぜ〰ぁのぴど〭ごふねはふひぜ〴ぜ〰ぉねねふのどぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㔩‾㸊⡜㌷㙜㌷㝜〰がどねどぴちぴどはのびぜ〴ぜ〰はてぜ〴ぜ〰くふひぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Children: Item: Title: えちひのづびびどのでぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉねねふのづぜ〴ぜ〰こべびぴづねぜ〴ぜ〰ぴはぜ〴ぜ〰ぃはのぴひはぬぜ〴ぜ〰ぇあぜ〴ぜ〰ごふねはふひぜ〴ぜ〰ぐひはでひづびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰うどのつどのでぜ〴ぜ〰ぴとづぜ〴ぜ〰くばぴどねちぬぜ〴ぜ〰こっとづつふぬづぜ〴ぜ〰てはひぜ〴ぜ〰ぎはの〭ぉのぶちびどぶづぜ〴ぜ〰げづびばはのびづぜ〴ぜ〰ぁびびづびびねづのぴ〺ぜ〴ぜ〰ごとづぜ〴ぜ〰げづぬづぶちのっづぜ〴ぜ〰はてぜ〴ぜ〰ごふねはふひぜ〴ぜ〰ざはぬふねづぜ〴ぜ〰ちぴぜ〴ぜ〰ごとづひちばべぜ〴ぜ〰こぴちひぴどのでぜ〴ぜ〰ごどねづぜ〴ぜ〰ちのつぜ〴ぜ〰いはびどのでぜ〴ぜ〰こっとづつふぬづぜ〴ぜ〰どのぜ〴ぜ〰ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰ごとづぜ〴ぜ〰くびっどぬぬちぴはひべぜ〴ぜ〰きげこぉぜ〴ぜ〰きづぴちぢはぬはねどっぜ〴ぜ〰ぐちぴぴづひのぜ〴ぜ〰ぃとちのでづびぜ〴ぜ〰ぁひづぜ〴ぜ〰ぁぬびはぜ〴ぜ〰ぃはのてどひねづつぜ〴ぜ〰どのぜ〴ぜ〰ぇが〲〶〱ぜ〴ぜ〰ぇあぜ〴ぜ〰ごひづちぴづつぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぉねねふのはぴとづひちばべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰ぉきこ〭ぁのぴど〭ぐい〭〱〯ごきずぜ〴ぜ〰ちのつぜ〴ぜ〰ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴ぜ〰ぅびぴちぢぬどびとづつぜ〴ぜ〰ざちひべどのでぜ〴ぜ〰いづでひづづびぜ〴ぜ〰はてぜ〴ぜ〰がはので〭ごづひねぜ〴ぜ〰こばづっどてどっぜ〴ぜ〰ぁのぴど〭ごふねはふひぜ〴ぜ〰ぉねねふのどぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㔩‾㸊⡜㌷㙜㌷㝜〰がどねどぴちぴどはのびぜ〴ぜ〰はてぜ〴ぜ〰くふひぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: うどのつどのでぜ〴ぜ〰ぴとづぜ〴ぜ〰くばぴどねちぬぜ〴ぜ〰こっとづつふぬづぜ〴ぜ〰てはひぜ〴ぜ〰ぎはの〭ぉのぶちびどぶづぜ〴ぜ〰げづびばはのびづぜ〴ぜ〰ぁびびづびびねづのぴ〺ぜ〴ぜ〰ごとづぜ〴ぜ〰げづぬづぶちのっづぜ〴ぜ〰はてぜ〴ぜ〰ごふねはふひぜ〴ぜ〰ざはぬふねづぜ〴ぜ〰ちぴぜ〴ぜ〰ごとづひちばべぜ〴ぜ〰こぴちひぴどのでぜ〴ぜ〰ごどねづぜ〴ぜ〰ちのつぜ〴ぜ〰いはびどのでぜ〴ぜ〰こっとづつふぬづぜ〴ぜ〰どのぜ〴ぜ〰ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰ごとづぜ〴ぜ〰くびっどぬぬちぴはひべぜ〴ぜ〰きげこぉぜ〴ぜ〰きづぴちぢはぬはねどっぜ〴ぜ〰ぐちぴぴづひのぜ〴ぜ〰ぃとちのでづびぜ〴ぜ〰ぁひづぜ〴ぜ〰ぁぬびはぜ〴ぜ〰ぃはのてどひねづつぜ〴ぜ〰どのぜ〴ぜ〰ぇが〲〶〱ぜ〴ぜ〰ぇあぜ〴ぜ〰ごひづちぴづつぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぉねねふのはぴとづひちばべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰ぉきこ〭ぁのぴど〭ぐい〭〱〯ごきずぜ〴ぜ〰ちのつぜ〴ぜ〰ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴ぜ〰ぅびぴちぢぬどびとづつぜ〴ぜ〰ざちひべどのでぜ〴ぜ〰いづでひづづびぜ〴ぜ〰はてぜ〴ぜ〰がはので〭ごづひねぜ〴ぜ〰こばづっどてどっぜ〴ぜ〰ぁのぴど〭ごふねはふひぜ〴ぜ〰ぉねねふのどぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㔩‾㸊⡜㌷㙜㌷㝜〰がどねどぴちぴどはのびぜ〴ぜ〰はてぜ〴ぜ〰くふひぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ごとづぜ〴ぜ〰くびっどぬぬちぴはひべぜ〴ぜ〰きげこぉぜ〴ぜ〰きづぴちぢはぬはねどっぜ〴ぜ〰ぐちぴぴづひのぜ〴ぜ〰ぃとちのでづびぜ〴ぜ〰ぁひづぜ〴ぜ〰ぁぬびはぜ〴ぜ〰ぃはのてどひねづつぜ〴ぜ〰どのぜ〴ぜ〰ぇが〲〶〱ぜ〴ぜ〰ぇあぜ〴ぜ〰ごひづちぴづつぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぉねねふのはぴとづひちばべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰ぉきこ〭ぁのぴど〭ぐい〭〱〯ごきずぜ〴ぜ〰ちのつぜ〴ぜ〰ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴ぜ〰ぅびぴちぢぬどびとづつぜ〴ぜ〰ざちひべどのでぜ〴ぜ〰いづでひづづびぜ〴ぜ〰はてぜ〴ぜ〰がはので〭ごづひねぜ〴ぜ〰こばづっどてどっぜ〴ぜ〰ぁのぴど〭ごふねはふひぜ〴ぜ〰ぉねねふのどぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㔩‾㸊⡜㌷㙜㌷㝜〰がどねどぴちぴどはのびぜ〴ぜ〰はてぜ〴ぜ〰くふひぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ぉきこ〭ぁのぴど〭ぐい〭〱〯ごきずぜ〴ぜ〰ちのつぜ〴ぜ〰ぁのぴど〭ぐい〭〱ぜ〴ぜ〰きはのはぴとづひちばべぜ〴ぜ〰ぅびぴちぢぬどびとづつぜ〴ぜ〰ざちひべどのでぜ〴ぜ〰いづでひづづびぜ〴ぜ〰はてぜ〴ぜ〰がはので〭ごづひねぜ〴ぜ〰こばづっどてどっぜ〴ぜ〰ぁのぴど〭ごふねはふひぜ〴ぜ〰ぉねねふのどぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㔩‾㸊⡜㌷㙜㌷㝜〰がどねどぴちぴどはのびぜ〴ぜ〰はてぜ〴ぜ〰くふひぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: がどねどぴちぴどはのびぜ〴ぜ〰はてぜ〴ぜ〰くふひぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: きちぴづひどちぬびぜ〴ぜ〰ちのつぜ〴ぜ〰きづぴとはつびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぇが〲〶〱ぜ〴ぜ〰ぃづぬぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㈩‾㸊⡜㌷㙜㌷㝜〰ぁのどねちぬぜ〴ぜ〰きはつづぬぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰ぁのどねちぬぜ〴ぜ〰ごひづちぴねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰ざどぶはぜ〴ぜ〰きげぉぜ〴ぜ〰ちのつぜ〴ぜ〰きげこぉぜ〴ぜ〰こぴふつどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸱ Children: Item: Title: ぇが〲〶〱ぜ〴ぜ〰ぃづぬぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㈩‾㸊⡜㌷㙜㌷㝜〰ぁのどねちぬぜ〴ぜ〰きはつづぬぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰ぁのどねちぬぜ〴ぜ〰ごひづちぴねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰ざどぶはぜ〴ぜ〰きげぉぜ〴ぜ〰ちのつぜ〴ぜ〰きげこぉぜ〴ぜ〰こぴふつどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸱ Item: Title: ぁのどねちぬぜ〴ぜ〰きはつづぬぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰ぁのどねちぬぜ〴ぜ〰ごひづちぴねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰ざどぶはぜ〴ぜ〰きげぉぜ〴ぜ〰ちのつぜ〴ぜ〰きげこぉぜ〴ぜ〰こぴふつどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸱ Item: Title: ぁのどねちぬぜ〴ぜ〰ごひづちぴねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰ざどぶはぜ〴ぜ〰きげぉぜ〴ぜ〰ちのつぜ〴ぜ〰きげこぉぜ〴ぜ〰こぴふつどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸱ Item: Title: ぉのぜ〴ぜ〰ざどぶはぜ〴ぜ〰きげぉぜ〴ぜ〰ちのつぜ〴ぜ〰きげこぉぜ〴ぜ〰こぴふつどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸱ Children: Item: Title: いちぴちぜ〴ぜ〰ぁっぱふどびどぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸲ Item: Title: きげぉぜ〴ぜ〰こぴふつどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸳ Item: Title: きげこぉぜ〴ぜ〰こぴふつどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸴ Item: Title: きげこぉぜ〴ぜ〰ぐはびぴ〭ぐひはっづびびどのでぜ〴ぜ〰ちのつぜ〴ぜ〰ぐちぴぴづひのぜ〴ぜ〰げづっはでのどぴどはのぜ〴ぜ〰こぴひちぴづでどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸵ Item: Title: ごふねはふひぜ〴ぜ〰げづびばはのつどのでぜ〴ぜ〰ぉのつづへぜ〴ぜ〰ぜ〵ぜ〰ごげぉぜ〵ㅜ〰ぜ〴ぜ〰ぃちぬっふぬちぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㔩‾㸊⡜㌷㙜㌷㝜〰げづっとちぬぬづのでづぜ〴ぜ〰ぅへばづひどねづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㘩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: げづっとちぬぬづのでづぜ〴ぜ〰ぅへばづひどねづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㘩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: ぃはのっぬふびどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: NEFAAH+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 151 FontDescriptor: FontName: NEFAAH+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: HYHBGH+Rpxi FontSubset: true FirstChar: 11 LastChar: 47 FontDescriptor: FontName: HYHBGH+Rpxi Flags: Symbolic FontBBox: -162, -280, 856, 733 FontFile: true Font: BaseFont: MFIGJL+Rpxb FontSubset: true FirstChar: 47 LastChar: 47 FontDescriptor: FontName: MFIGJL+Rpxb Flags: Symbolic FontBBox: 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