1 A : : 00 Rho G DOCK Rho G Rac1 DOCK GFP FRET Förster resonance energy transfer : Apico - Basal 3 FRET G 3 Rac1 Ras 1 A : :

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1 1 A : 00 9 : 40 SLE RA SLE RA 1 1 SLE RA SLE SLE 1,2,4,11,17 1 synteny SLE SLE 1 SLE RA SLE RA SLE RA 1 A : : 20 L L B L26 Ishii Y, et al. Clin Exp Immunol L26 CD20 L L22 B L22 Takami T, et al. J Immunol L22 L ALOX5 Nagashima T, et al. Am J Pathol ALOX5 Alox5 B T Tfh Tfh T T T Th0 Tfh ALOX5 L ALOX5 B T ALOX5

2 1 A : : 00 Rho G DOCK Rho G Rac1 DOCK GFP FRET Förster resonance energy transfer : Apico - Basal 3 FRET G 3 Rac1 Ras 1 A : : S19 RP S19 RP S19 Lys122 Gln137 RP S19 C5a Ca 2+ /Mg 2+ TRPM p38map RP S19 C5a Ca 2+ /Mg 2+ TRPM p38map A3 G 3 Gln137Asn - RP S19 HL - 60 RP S19 C5a C5a RP S19 C5a C5a RP S19 C5a RP S19 RP S19

3 1 B : : F. tularensis 2001 CDC A HE realtime PCR GenePoint Dako QIAGEN QIAamp FFPE DNA mini kit DanoDrop 0D 260 nm/280 nm 23kDa tul4 Taqman probe primer PCR MX3005 ABI Prism 7900HT : F. tularensis 12 1 : DNA japonica F. tularensis F. tularensis 1 14 : : 35 Pancreatic neoplasms and their different origins Günter Klöppel Department of Pathology, Technical University of Munich, Germany The exact morphological classification of tumors of the pancreas combined with their molecular analysis has broadened our understanding of cancer development and progression in the pancreas. It is evident from these studies that the general phenotypical classification of pancreatic neoplasms into tumors with either ductal, acinar, endocrine, or indeterminate differentiation is associated with distinct molecular profiles that suggest that there are profound differences in the molecular pathways that lead to the various types of pancreatic neoplasms. The molecular pathway of neoplasms with ductal differentiation is characterized by a K - ras mutation, which seems to mark the first step in the development of these cancers. The second step then includes alterations in the tumor suppressor genes p16, p53 and DPC4. Tumors with acinar, endocrine, or indeterminate differentiation, in contrast to ductal tumors, follow molecular pathways that are not initiated by a K - ras mutation. Instead, there is involvement of the APC/ β - catenin pathway, as in acinar cell carcinoma and pancreatoblastoma, the menin/loh 11q pathway, as in neuroendocrine tumors and the β - catenin pathway, as in solid - pseudopapillary tumors. The fact that the various molecular pathways are associated with certain phenotypes of the pancreatic neoplasms suggests that the stem cells from which the tumors originate are already more or less committed to distinct differentiation pathways.

4 : : matricellular RECK 3A 1 S1-1

5 1 S L/day 4 in situ II III ANCA 1 S1-3

6 1 S1-4 tumor necrosis factor - α interleukin6 50% angiotensinii matricellular matricellular, matricellular Tenascin - C 1 S1-5 osteoarthritis=oa II XI OA fibrillation cleft ADAMTS4, 5 MMP - 1, 13 chondrocyte cloning clustering OA chondrocyte cloning 2 RECK reversion - inducing cysteine - rich protein with Kazal motifs OA cloning OA RECK focal adhesion VEGF vascular endothelial growth factor OA VEGFR2-1 VEGF 165 3A cloning OA VEGF 165 3A

7 2 A : 50 9 : 30 β - catenin CTNNB1 CTNNB1 β - catenin β - catenin CTNNB1 CTNNB1 β - catenin 3 liver zonation CTNNB1 30% CTNNB1 β - catenin β - catenin β - catenin zone 3 necrosis β - catenin β - catenin CTNNB1 SLCO1B3 CTNNB1 SLCO1B3 CTNNB1 β - catenin 2 A : : 10 KEAP1 - NRF2 NRF2 KEAP1 E3 KEAP1 NRF2 N DLG ETGE NRF2 CGH KEAP1 KEAP1 Shibata et al, Gastroenterology, 2008, Ohta et al, Cancer Res, 2008 NRF2 Shibata et al, PNAS, 2008, Neoplasia, 2011 in press NRF2 DLG ETGE NRF2 KEAP1 NRF2 NRF2 mtor NRF2 mtor Shibata et al, Cancer Res, 2010 NRF2 NRF2 DeNicola GM et al, Nature, 2011 NRF2 NRF2 KEAP1 NRF2

8 2 A : : 50 divergent pathway 3 1 ALKBH ALKBH DNA 8 ALKBH - 3, 8 dysplasia grade ALKBH - 3, 8 ROS ALKBH - ROS - key signal ROS 2 Mitogen activated protein MAP MAP / MAP c - jun NH2 terminal kinase JNK MMP9 VEGF JNK JNK MAP kinase phosphatase MKP - 1 JNK JNK MKP CD138 plasmacytoid variant plasma cell marker CD138 CD138 CD138 sirna CD138 CD138 ALKBH CD138 JNK ROS A : : 30 blood - brain barrier : BBB BBB BBB BBB BBB BBB BBB mrna cdna BBB P - BBB P - Aβ Aβ LDL LDL CD36 P - CD36 BBB Aβ BBB matrix metalloproteinase MMP MMP - 1,2,3,9 MMP - 13 Hif - 1α T Hif - 1α T T Hif - 1α BBB Aβ MMP Hif - 1α Aβ

9 2 A : : : : 20 IgG4 : Institute of Liver Studies, King s College Hospital, London IgG4 : IgG4 IgG4 IgG4 IgG 40% IgG4 IgG4 Küttner : IgG4 IgG % 9% : IgG4 4 : Th2 IL - 4 IL - 5 IL - 13 Th2 mrna T IL - 10 TGF - β Th2 IgE IgG4 Th2 : IgG GIST

10 2 S2-1 2 S2-2 : GIST 1,2 1 2 K - ras EGFR HER - 2 MammaPrint Pathwork Tissue of Origin Test FDA EML4 - ALK BRAF K - ras 2,000 2 EGFR HER - 2 FISH FDA Home Brew Test Oncotype Dx Mammaprint TAILORx MINDACT Companion Diagnostics GIST c - kit c - kit KIT c - kit KIT PDGFRα GIST c - kit PDGFRα GIST MIB - 1 Ki - 67 /PNET /PNET VAC VDC/IE GIST /PNET

11 2 S2-3 2 S2-4 EGFR ALK 60% EGFR 5% ALK EGFR ALK EML4 - ALK ALK EGFR BAC hobnail BAC hobnail EGFR ALK cribriform pattern ALK FISH RT - PCR iaep TP53 - TP oncogene - addiction KIT imatinib Glivec RNA : molecular taxonomy prognostic signature ER HER2 intrinsic subtype Luminal A, Luminal B, HER2, Basal - like, claudin - low, molecular apocrine MammaPrint, OncotypeDx, Theros, MapQuantDx GGI Intrinsic subtype PAM50 stem cell signature, fibroblast signature ER PgR HER2 Ki - 67 ER /HER2 ER PgR HER2 ER /HER2 Pertuzumab T - DM1 Neratinib p95her2 HER3 HER2 ER/HER2 PARP1 BRCA1 AR ERα33 ERβ1

12 2 S2-5 VEGF EGF EGF HER2 EGF DNA K - RAS K - RAS EGF K - RAS HER2 IHC3+IHC2+ FISH/DISH K - RAS B : : 45 HCA 90%, HCA 1 Hepatocyte nuclear factor 1α HNF1α 2 β - catenin 3 Inflammatory HCA IHCA 3 1 liver fatty acid binding protein LFABP 2 Glutamine synthetase GS 3 serum amyloid A SAA HCA HCA HCA 19 M/F=10/9, 40.8±15.0 LFABP GS SAA HCA 19 HNF1α % ; M/ F=0/2 40.5±4.9 β - catenin % ; M/F=1/1 28.5±3.5 IHCA % ; M/F=8/3 45.8± % ; M/F=1/3 33.5± IHCA 8 M/F=6/ % 36% 50% % 50% HCA % HCA 4.0±1.4 cm 17.5±2.1 cm 3.0±2.6 cm 4.4±2.6 cm β - catenin 1 HCA HNF1α IHCA

13 : : core needle biopsy : CNB vacuum associated biopsy : VAB OSNA HER2 1. ER PgR HER : : A. CIN CIN HPV p16 INK4a Ki - 67 CIN1 CIN2 HPV B. p63 CK5/6 2. A. ER p16 INK4a B. p16 INK4a WHO glandular dysplasia de novo C.

日本消化器外科学会雑誌第29巻第9号

日本消化器外科学会雑誌第29巻第9号 Table 1 Oligonucleotide primers used for RT-PCR and internal probes used for Southern blot hybridization Cytokine Primer Sequence (5'-3') 5' 3' Internal probe s' 3' Internal probe 5' 3' Internal probe