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2 Vol TEL / FAX henshu@imic.or.jp TEL / FAX

3 % 3 2 1

4 α 3 Boys be ambitious Boys can't be ambitious 2

5 1980 Langer R. Vacanti J.P. ECM ECM

6 N- PIPAAm ECM 4 ( 1) 3 ECM 5 ( 2) 2 1) 2 in vivo µ-ct 6 2) ECM

7 1 3) 8 QOL (Quality of Life) 8 4) endoscopic submucosal dissection: ESD ESD ESD QOL ) 10 QOL 6) 11 7) 5

8 12 8) 3 13 ( 3) mm 19 in vitro in vivo 20 in vivo mmHg 21 ( 4) 3 A: 3 B: 3 C: D: 3 6

9 QOL 1. Langer R, Vacanti JP. Tissue engineering. Science, 260: , Yamada N, Okano T, Sakai H, Karikusa F, Sawasaki Y, Sakurai Y. Thermo-responsive polymeric surfaces; control of attachment and detachment of cultured cells. Die Makromolekulare Chemie, Rapid Communications, 11: , Okano T, Yamada N, Sakai H, Sakurai Y. A novel recovery system for cultured cells using plasmatreated polystyrene dishes grafted with poly(nisopropylacrylamide). J Biomed Mater Res, 27: , Yamato M, et al. Release of adsorbed fibronectin from temperature-responsive culture surfaces requires cellular activity. Biomaterials, 21: , Yang J, et al. Reconstruction of functional tissues with cell sheet engineering. Biomaterials, 28: , Uchiyama H, et al. In vivo 3D analysis with microcomputed tomography of rat calvaria bone regeneration using periosteal cell sheets fabricated on temperature-responsive culture dishes. J Tissue Eng Regen Med, Nishida K, et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med, 351: , Hasegawa M, Yamato M, Kikuchi A, Okano T, Ishikawa I. Human periodontal ligament cell sheets can regenerate periodontal ligament tissue in an athymic rat model. Tissue Eng, 11: , Ohki T, et al. Treatment of oesophageal ulcerations using endoscopic transplantation of tissue-engineered autologous oral mucosal epithelial cell sheets in a canine model. Gut, 55: , Kanzaki M, et al. Functional closure of visceral pleural defects by autologous tissue engineered cell sheets. Eur J Cardiothorac Surg, 34: , Arauchi A, Shimizu T, Yamato M, Obara T, Okano T. Tissue-engineered thyroid cell sheet rescued hypothyroidism in rat models after receiving total thyroidectomy comparing with nontransplantation models. Tissue Eng Part A, 15: , Ohashi K, et al. Engineering functional two- and three-dimensional liver systems in vivo using hepatic tissue sheets. Nat Med, 13: , Shimizu T, Yamato M, Kikuchi A, Okano T. Twodimensional manipulation of cardiac myocyte sheets utilizing temperature-responsive culture dishes augments the pulsatile amplitude. Tissue Eng, 7: , Shimizu T, et al. Fabrication of pulsatile cardiac tissue grafts using a novel 3-dimensional cell sheet manipulation technique and temperatureresponsive cell culture surfaces. Circ Res, 90:e40, Shimizu T, Sekine H, Isoi Y, Yamato M, Kikuchi A, Okano T. Long-term survival and growth of pulsatile myocardial tissue grafts engineered by the layering of cardiomyocyte sheets. Tissue Eng, 12: , Haraguchi Y, Shimizu T, Yamato M, Kikuchi A, Okano T. Electrical coupling of cardiomyocyte sheets occurs rapidly via functional gap junction formation. Biomaterials, 27: , Sekine H, Shimizu T, Kosaka S, Kobayashi E, Okano T. Cardiomyocyte bridging between hearts and bioengineered myocardial tissues with mesenchymal transition of mesothelial cells. J Heart Lung Transplant, 25: , Sekine H, et al. Endothelial cell coculture within 7

Okano T, Yamada N, Sakai H, Sakurai Y. A novel recovery system for cultured cells using plasmatreated polystyrene dishes grafted with poly(nisopropylacrylamide).

10 tissue-engineered cardiomyocyte sheets enhances neovascularization and improves cardiac function of ischemic hearts. Circulation, 118(14S):S145- S152, Shimizu T, et al. Polysurgery of cell sheet grafts overcomes diffusion limits to produce thick, vascularized myocardial tissues. FASEB J, 20: , Kubo H, Shimizu T, Yamato M, Fujimoto T, Okano T. Creation of myocardial tubes using cardiomyocyte sheets and an in vitro cell sheetwrapping device. Biomaterials, 28: , Sekine H, Shimizu T, Yang J, Kobayashi E, Okano T. Pulsatile myocardial tubes fabricated with cell sheet engineering. Circulation, 114(1S):I87-93, ( ) 20 8 ( ) 4 4 ( ) ( ) ( ) 14 7 ( ) ( ) ( ) 15 in vitro 8

Creation of myocardial tubes using cardiomyocyte sheets and an in vitro cell sheetwrapping device. Biomaterials, 28:3508-3516, 2007 21. Sekine H, Shimizu T, Yang J, Kobayashi E, Okano T.

11 Morizane Toshio non-inferiority trial z δ 95% δ 2 2 µ1 σ1 µ2 σ2 n1 n2 m1 m2 σ1/ n1 σ2/ n2 m1 m2 2 σ 1 σ n R 110(µ1) 10 σ1 115 µ2 10 σ2 2 n1, n2 30 R n σ1/30 σ2/30 10/30+10/30= R R Enter # > m1 = 110; s1 = 10; m2 = 115; s2 = 10 # > samp.num = 30 # > cyc.num = # 9

115 10 2 30 10 n 2 2 2 1 2 30 10 3 1 2 2 1 2 2 4 σ1/30 σ2/30 10/30+10/30=6.

12 >samp1.30 = replicate(cyc.num, mean(rnorm(samp. num, m1,s1))) >samp2.30 = replicate(cyc.num, mean(rnorm(samp. num, m2,s2))) # 10 >var(samp1.30); var(samp2.30) # [1] [1] > var(samp1.30) + var(samp2.30) #2 [1] > dif = replicate(cyc.num, mean(rnorm(samp. num, m1,s1)) - mean(rnorm(samp.num, m2,s2))) #30 10 > var(dif1.2.30) # 2 1 [1] > mean(dif1.2.30) #30 [1] > mean(samp1.30) - mean(samp2.30) # 30 [1] # > 10*10/ *10/30 # [1] # > hist(dif1.2.30, prob=t) # > lines(density(dif1.2.30, bw=2)) # bw µ1 σ1 µ2 σ2 2 n m1 m2 σ1 2 /n +σ2 2 /n σ 2 1 σ n 1 n 2 2 µ1 µ2 ε=µ2 µ1 H0 H1 H0 ε δ H1 ε δ δ ε µ2 µ1 <µ1 µ2 2 σ n1 n2 x 1 x 2 zα zβ Power 1 β α 0.05 Power 0.8 zα zβ H0 x 1 x 2 δ σ 1 + n 1 1 n 2 > z α α H 0 1 H1 Power=Φ ε δ σ 1 + n 1 1 n 2 z α Power=1-β H σ 2 + σ 2 n 1 n 2 n1, n

005072 > mean(samp1.30) - mean(samp2.30) # 30 [1] -5.002916 # > 10*10/30 + 10*10/30 # [1] 6.666667 # > hist(dif1.2.30, prob=t) # > lines(density(dif1.2.30, bw=2)) # bw µ1 σ1 µ2 σ2 2 n m1 m2 σ1 2 /n +σ2 2 /n σ 2 1 σ 2 + 2 n 1 n 2 2 µ1 µ2 ε=µ2 µ1 H0 H1 H0 ε δ H1 ε δ δ ε µ2 µ1 <µ1 µ2 2 σ n1 n2 x 1 x 2 zα zβ Power 1 β α 0.

13 Power 2 Φ 2 ε δ σ 1 + n 1 z α = z β 1 n 2 n1 n2 1) k δ 0 1 z z z z Z 2 P H1 ε δ zα 3 (z α +z β ) 2 σ 2 (1+1/k) n 1 =kn 2 n 2 = 4 (ε δ) 2 4 Microsoft Excel 2 110(µ1) 10 σ µ 2 10 σ 2 δ margin -2 Power0.8, α δ δ δ n n α m3=108, s3= β 10 z > #H1 > m1=110;s1=10;m2=115;s2=10 > #H0 > m1=110;s1=10;m3=108;s3=10 > cyc= > samp.n=

8, α0.05 26-26 δ δ 115 110 10 δ 2 26-26 n 0.05 0.

14 > dif.alt=replicate(cyc,mean(rnorm(samp.n,m2,s2))- mean(rnorm(samp.n,m1,s1))) > dif.null=replicate(cyc,mean(rnorm(samp.n,m3,s3))- mean(rnorm(samp.n,m1,s1))) > quantile(dif.alt,0.2) 20% > quantile(dif.null,0.95) 95% > min(dif.alt) [1] > max(dif.alt) [1] > min(dif.null) [1] > max(dif.null) [1] > hist(dif.alt,seq(-14,17,1),prob=t) > hist(dif.null,prob=t,add=t) > lines(density(dif.alt,bw=1)) > lines(density(dif.null,bw=1)) >2.61 α 0.05 Power 0.8 > m1=110;s1=10;m2=115;s2=10;m3=108;s3=10 > cyc= > samp.num=25 >dif.alt=replicate(cyc,mean(rnorm(samp.num,m2, s2))-mean(rnorm(samp.num,m1,s1))) >dif.null=replicate(cyc,mean(rnorm(samp.num,m3, s3))-mean(rnorm(samp.num,m1,s1))) > quantile(dif.alt,0.2) 20% > quantile(dif.null,0.95) 95% > hist(dif.alt,seq(-15,18,1),prob=t) > hist(dif.null,seq(-15,18,1),prob=t,add=t) > lines(density(dif.alt,bw=1)) > lines(density(dif.null,bw=1)) < Power 0.8 α P<0.05 P>

alt,seq(-14,17,1),prob=t) > hist(dif.null,prob=t,add=t) > lines(density(dif.alt,bw=1)) > lines(density(dif.null,bw=1)) 25 25 2.61 0.8 2.67 0.05 2.67>2.61 α 0.05 Power 0.

15 equality trial H0 ε=0 H1 ε 0 µ1 µ2 ε=µ2 µ n1 n2 δ=0 zα/2 6 7 H0:ε=0 x 1 x 2 > z α/2 σ 1 n n2 H0:ε 0 ε Power=Φ z α/2 +Φ σ 1 n n 2 ε σ 1 + n 1 z α/2 1 n 2 (z n 1 =kn α +z β ) 2 σ 2 (1+1/k) 2 n 2 = ε 2 α H 0 σ 1 + n 1 8 Microsoft Excel 5 63 ε σ 1 + n 1 ε 5 z α/2 1 n 2 z α/2 1 n 2 = 6 z β α0.05 Power >3.48 α0.05 Power0.8 > m1=110;s1=10;m2=115;s2=10 > cyc= > samp.num=63 >dif.alt=replicate(cyc,mean(rnorm(samp.num,m2, s2))-mean(rnorm(samp.num,m1,s1))) >dif.null=replicate(cyc,mean(rnorm(samp.num,m1, s1))-mean(rnorm(samp.num,m1,s1))) > quantile(dif.alt,0.2);quantile(dif.null,0.975) 20% % > min(dif.null);max(dif.alt) [1] [1] > hist(dif.null,seq(-8,14,1),prob=true) > lines(density(dif.null,bw=0.4)) > hist(dif.alt,seq(-8,14,1),prob=true,add=true) > lines(density(dif.alt,bw=0.4)) α Power 5 13

num=63 >dif.alt=replicate(cyc,mean(rnorm(samp.num,m2, s2))-mean(rnorm(samp.num,m1,s1))) >dif.null=replicate(cyc,mean(rnorm(samp.num,m1, s1))-mean(rnorm(samp.num,m1,s1))) > quantile(dif.alt,0.

16 α β Power analysis 2 6 µ0µ1 7 µ0µ1 1) Chow SC, Shao J, Wang H: Sample size calculations in clinical research.2003, CRC Press Taylor & Francis Group, Boca Raton, FL, USA. 14

17 Shigeaki Yamazaki 1889 Johns Hopkins Index Medicus(1879 ) John Shaw Billings (scientific medicine) 1893 Johns Hopkins 4 William H. Welch William S. Halsted William Osler Howard A. Kelly Welch The Four Doctors (by John Singer Sargent) Osler Principles and Practice of Medicine 1893 Kelly Dictionary of American Medical Biography Walter L. Burrage Welch ) EBM 2) publication bias positive-outcome bias 3) EBM PubMed/Medline MeSH publication bias Major ProCite MeSH Welch Johns Hopkins "The Four Doctors" JAMA MeSH

Kelly Welch The Four Doctors (by John Singer Sargent) Osler Principles and Practice of Medicine 1893 Kelly Dictionary of American Medical Biography

18 International Congress on Peer Review in Biomedical Publication JAMA 1989 PubMed 1986 Journal of Clinical Oncology (Vol.4: ) RJ Simes "Publication bias: the case for an international" Source:PubMed 11 Aug 2010, MeSH Major Heading:publication bias (N=576) 10 3 Chalmers Dickersin BMJ 2-4 MeSH PubMed 1 10 MeSH 3 4 Major MeSH Major MeSH 3 clinical trials randomized controlled trials53 2 periodicals 3 metaanalysis 4 conflict of interest 7 drug industry 1 16

Heading:publication bias (N=576) 10 3 Chalmers Dickersin 2-3 2 10 4 3 2 1 1 BMJ 2-4 MeSH PubMed 1 10 MeSH 3 4 Major MeSH Major

19 6 peer review URM (Uniform Requirements for Manuscripts Submitted to Biomedical Journals) IIIA: Obligation to publish negative studies 4) URM ) Obligation to register clinical trials(iii-j) MeSH 1994 URM 4 PubMed publication bias Simes ) International Cancer Research Data Bank(ICRDB) JAMA Council of Biology Editors(CBE 1991 ) Peer Review in Scientific Publishing Dickersin 7) 2 3 MeSH 17

trials(iii-j) MeSH 1994 URM 4 PubMed publication bias Simes 1986 6) International Cancer Research Data

20 1980 Evaluation Education Smith 1959 Journal of American Statistical Association Sterling Chalmers 8) 2005 JAMA EBM Good Publication Practice 10 1 Fleming D. William H. Welch and the Rise of Modern Medicine. Baltimore: Johns Hopkins University Press, 1987, p EBM Medline 1998; 19(4): Ioannou A. Publication Bias: A Threat to the Objective Report of Research Results. 2009, [accessed ] In p ; 214: Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol 1986; 4(10): Dickersin K. The existence of publication bias and risk factors for its occurrence. JAMA 1990; 263(10): Chalmers TC, Frank CS, Reitman D. Minimizing the three stages of publication bias. JAMA 1990; 263(10): Moses H 3rd, Dorsey ER, Matheson DH, Thier SO. Financial anatomy of biomedical research. JAMA 2005; 294(11): Jones AH, McLellan F. Ethical Issues in Biomedical Publication. Baltimore: Johns Hopkins University Press, 2000, p

Publication Bias: A Threat to the Objective Report of Research Results. 2009, http://www.eric.ed.gov/pdfs/ed504425.pdf [accessed 2010-09-01] 4 2008 10 In p.2-23. 5 2005; 214: 958-9. 6 Simes RJ.

21 TTAGGG DNA DNA Profile

22 DNA DNA 1 ADP- TRF1 2 (ADP- ) 1) 3 (ADP- ) Cancer Cell 1) OK

23 TRF1 (ADP- ) TRF1 A A TRF1 A 2) TRF1 TRF1 (ADP- ) 4 6 3,4) 1) Seimiya H, Muramatsu Y, Ohishi T, Tsuruo T. Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics. Cancer Cell, 7: 25-37, ) Ohishi T, Hirota T, Tsuruo T, Seimiya H. TRF1 mediates mitotic abnormalities induced by Aurora- A overexpression. Cancer Res, 70: , ) Mashima T, Okabe S, Seimiya H. Pharmacological targeting of constitutively active truncated androgen receptor by nigericin and suppression of hormone-refractory prostate cancer cell growth. Mol Pharmacol, 278: , ) Mashima T, Sato S, Sugimoto Y, Tsuruo T, Seimiya H. Promotion of glioma cell survival by acyl-coa synthetase 5 under extracellular acidosis conditions. Oncogene, 28: 9-19, NY 4 memorable 21

24 22 IT IMIC 4 Web IT I-dis ASP SELIMIC Web Selimic Web IMIC

25 23 WEB MMWR NCI info IMIC 4 IMIC IMIC IMIC

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PubMed 1. CD-ROM MEDLINE MeSH PubMed 2. Automatic Term Mapping MeSH 3. Related Article 1 1. 2. MeSH Browser MeSH PreMEDLINE MeSH -2-

PubMed 1. CD-ROM MEDLINE MeSH PubMed 2. Automatic Term Mapping MeSH 3. Related Article 1 1. 2. MeSH Browser MeSH PreMEDLINE MeSH -2- PubMed MEDLINE NLM 1879 Index Medicus 1960 MEDLARS Medical Literature Analysis and Retrieval System 1970 MEDLINE MEDlars online 1966 70 4,000 170 PubMed MEDLINE NLM National Center for Biotechnology Information