aichi cancer center research instituteit is my pleasure to share with you the 19th scientific report...

Aichi Cancer Center Research Institute

Scientific Report 2004 – 2005

Chikusa-ku, Nagoya 464-8681 Japan

(The Cover) Looking the front entrance and east face of the Main Building of Aichi Cancer Center Research Institute over the drooping cherries in bloom. Published by Dr. Toshitada Takahashi Dr. Kazuo Tajima Director Aichi Cancer Center Research Institute 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan Telephone: 052-762-6111 Facsimile: 052-763-5233 Editorial Committee Dr. Reiji Kannagi, Chief (Division of Molecular Pathology) Dr. Kenji Wakai (Division of Epidemiology and Prevention) Dr. Hirotaka Osada (Division of Molecular Medicine) Dr. Hiroshi Kumimoto (Division of Central Laboratory & Radiation Biology) Dr. Malcolm A. Moore, English Editor Printed by Nagoya University COOP 1 Furoucho, Chikusa-ku, Nagoya 464-0814, Japan

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Contents Preface Takahashi Toshitada 1 Organization of the Aichi Cancer Center Research Institute 2 SCIENTIFIC REPORTS Division of Epidemiology and Prevention

General summary 5 1. Descriptive epidemiologic studies on cancer incidence and mortality Ito, H., Hirose, K., and Tajima, K. 5 2. The hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC) study Hirose, K., Matsuo, K., Wakai, K., Ito, H., Saito, T.,Suzuki, T., Kuriki, K., Yang, C. X., Shinoda, M., Hatooka, S., Kanemitsu, Y., Hirai, T., Kato, T., Toyama, T., Iwata, H., Niwa, Y., Nakanishi, T., Morishima, Y., Nakamura, S., Yatabe, Y., Mitsudomi, T., Sugiura, T., and Tajima, K. 7 3. Nutritional factors and the risk of colorectal cancer: findings from the JACC Study Wakai, K. and the JACC Study Group 11 4. Comparative epidemiological study on increasing cancers focusing on Korea, Japan and China (KOJACH study) Matsuo, K., Wakai, K., Hirose, K., Kuriki, K., Huang, X-E., Yang, C. X., Takezaki, T., Hamajima, N., Gao, C-M., Mo, B-Q., Yoo, K-Y., Ahn, Y-O., Kim, J-S., Zhou, Z-Y., Cao, J., Li, C., Gao, F-C., Li, K., Tokudome, Y., and Tajima, K. 12 5. Ethnoepidemiologic study on virus-related cancer Tajima, K., Matsuo, K., Sonoda, S., Chiba, H., Senoh, H., Tretli, S., and Dobrodeeva, L.K. 12

Division of Oncological Pathology

General summary 14 1. High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylori-infected Mongolian gerbils associated with a shift in mucin production from glandular to surface mucous cells Tatematsu, M., Tsukamoto, T., Mizoshita, T., Kato, S., Cao, X., Hirata, A., and Takasu, S. 15 2. HER2-driven constitutive activation of PI3K-AKT pathway is a new potential molecular target of gefitinib (Iressa) in human gastric cancer liver metastasis Nakanishi, H., Yokoyama, H., Ikehara, Y., Kodera,Y., Ikehara, S. and Tatematsu, M. 15 3. Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotype Tsukamoto, T., Mizoshita, T., Takenaka, Y., Ogasawara, N. and Tatematsu, M. 16

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4. A carbohydrate recognition based drug delivery and controlled release system using intraperitoneal macrophages as a cellular vehicle

Ikehara, Y., Nakanishi, H., Niwa, T., Biao, L., Ikehara, S., Ohashi, N., Kobayashi, T., Simizu, Y., Kojima, N. and Tatematsu, M. 16

5. Colonic and small-intestinal phenotypes in gastric cancers: relationships with clinicopathologic findings Mizoshita, T., Tsukamoto, T., Tanaka, H., Otsuka, T., Hirano, N., and Tatematsu, M. 17

Division of Molecular Oncology

General summary 19 1. EGFR mutation is frequently detected in non-small cell lung cancer with occasional genetic events of second mutation or amplification Yokoyama, T., Kondo, M., Goto, Y., Fukui, T., Sato, N., Taniguchi, T., Kondo, Y., Osada, H., Yokoi, K., T. Shimokata, K., and Sekido, Y. 20 2. The ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features Osada, H., Tatematsu, Y., Yatabe, Y., Horio, Y., and Takahashi, Ta. 20 3. A polycistronic miRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation Hayashita, Y., Osada, H., Tatematsu, Y., Yamada, H., Yanagisawa, K., Tomida, S., Yatabe, Y., Kawahara, K., Sekido, Y., and Takahashi, Ta. 21 4. Establishment and characterization of malignant pleural mesothelioma cell lines from Japanese patients Fukui, T., Taniguchi, T., Usami, N., Yokoyama, T., Hida, T., and Sekido, Y. 21

Division of Molecular Medicine

General summary 24 1. Anti-apoptotic function of API2-MALT1 fusion protein involved in t(11;18)(q21;q21) MALT lymphoma Hosokawa, Y., Suzuki, H. and Seto, M. 24 2. Molecular pathways leading to t(12; 21) TEL-AML1 associated leukemias Tsuzuki, S. and Seto, M. 25 3. Cloning of a translocation partner of t(1;14)(p33;q32) in diffuse large B-cell lymphoma Suzuki, R., Nakamura, S. and Seto, M. 25 4. Comparison of genome profiles for identification of distinct subgroups of diffuse large B-cell lymphoma Tagawa, H., Suguro-Katayama, M., Tsuzuki, S., Morishima, Y. and Seto, M. 26 5. Genome-wide array-based comparative genomic hybridization of natural killer cell lymphoma/leukemia: different genomic alteration patterns of aggressive NK-cell leukemia and extranodal NK/T-cell lymphoma, nasal type Nakashima, Y., Tagawa, H., Suzuki, R., Karnan, S., Karube, K., Ohshima, K., Muta, K., Nawata, H., Morishima, Y., Nakamura, S. and Seto, M. 26

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Division of Immunology General summary 29 1. Identification of an epitope from the epithelial cell adhesion molecule eliciting HLA-A*2402-restricted cytotoxic T lymphocyte responses Tajima, Ko., Demachi-Okamura, A., Ito, Y., Nishida, K., Akatsuka, Y., Tsujimura, K., Kuwano, H., Mitsudomi, T., Takahashi, To. and Kuzushima, K. 30 2. Three immunoproteasome-associated subunits cooperatively generate a CTL epitope of the EBV-LMP2A by overcoming specific structures resistant to epitope liberation Ito, Y., Kondo, E., Demachi-Okamura, A., Akatsuka, Y., Tsujimura, K., Tanimoto, M., Morishima, Y., Takahashi, To. and Kuzushima, K. 30 3. A novel HLA-A*3303-restricted minor histocompatibility antigen encoded by an unconventional open reading frame of the human TMSB4Y gene Torikai, H., Akatsuka, Y., Miyazaki, M., Warren, E.H., Oba, T., Tsujimura, K., Motoyoshi, K., Morishima, Y., Kodera, Y., Kuzushima, K. and Takahashi, To. 31 4. Combination of bortezomib and interferon-γ induces presentation of a newly identified HLA-A24-restricted human papillomavirus type 16 E6-specific cytotoxic T cell epitope Morishima, S., Akatsuka, Y., Nawa, A., Kondo, E., Kiyono, T., Torikai, H., Nakanishi, T., Ito, Y., Tsujimura, K., Iwata, K., Ito, K., Kodera, Y., Morishima, Y., Kuzushima, K. and Takahashi, To. 32 5. Immunity against the mouse thymus-leukemia antigen (TL) protects against development of lymphomas induced by a chemical carcinogenic agent, N-butyl-N-nitrosourea Tsujimura, K., Obata, Y., Matsudaira, Y., Taguchi, O., Nishida, K., Okanami, Y., Akatsuka, Y., Kuzushima, K. and Takahashi, To. 33

Division of Virology

General summary 35 1. Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment Kudoh, A. and Tsurumi, T. 35 2. Architecture of replication compartments formed during Epstein-Barr virus lytic replication Daikoku, T. and Tsurumi, T. 35 3. Activation of ATM DNA damage checkpoint signal transduction elicited by herpes simplex virus infection Shirata, N. and Tsurumi, T. 36 4. Purification of the product of the Epstein-Barr virus BZLF1 gene Nakasu, S. and Tsurumi, T. 37 5. Two Sp1/Sp3 binding sites in the major immediate-early proximal enhancer of human cytomegalovirus genes is necessary for transcriptional activation and viral replication Isomura, H. and Tsurumi, T. 37

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Division of Molecular Pathology General summary 40 1. Mechanism of loss of disialyl Lewis A and induction of sialyl Lewis A expression in early stage human cancers Miyazaki, K. Ohmori, K., Izawa, M., Koike, T. and Kannagi, R. 41 2. Tumor hypoxia augments sialyl Lewis X and sialyl Lewis A expression in locally-advanced human cancers Koike, T., Kimura, N., Miyazaki, K., Chen, G.Y., Yin, J., Kojima, T., Takematsu, H., and Kannagi, R. 42 3. Study on L-selectin ligand mediated homing of naïve T-lymphocytes using gene-disrupted mice Izawa, M., Kimura, N. Uchimura, K., Ohmori, K, Muramatsu, T., Rosen, S.D. and Kannagi, R. 42 4. ATRA-induced apoptosis in the human neuroblastoma cell line, SH-SY5Y,

is accompanied by alteration of ceramide species: Appearance of ceramide containing hydroxy fatty acids Hagiwara, K., Sobue, S., Kyogashima, M., Tamiya-Koizumi, K., Tadano-Aritomi, K., Hara, A., Aoyama, T., Murate, T. and Kannagi, R. 44

5. Rapid demonstration of diversity of sulfatide molecular species from biological materials by MALDI-TOF MS Kyogashima, M., Tamiya-Koizumi, K., Goto, Y., Hara, A., Aoyama, T. and Kannagi, R. 44 6. Expression cloning of a cDNA encoding sialic acid cyclase, which generates cyclic sialic acid containing glycoconjugates, and characterization of the produced enzyme Kanamori, A., Yamaguchi, M., Ishida, H., Kiso, M. and Kannagi, R. 44 7. Immune responses to retinal self-antigens in CD25+CD4+ regulatory T-cell- depleted mice Takeuchi, M., Keino, H., Kezuka, T., Usui, M. and Taguchi, O. 45

Division of Biochemistry

General summary 47 1. Formation of Plk1 and INCENP complexes required for metaphase-anaphase transition Goto, H., Kiyono, T., Tomono, Y., Kawajiri, A., Urano, T., Furukawa, K., Nigg, E.A. and Inagaki, M. 47 2. Phosphorylation by Cdk1 induces Plk1-mediated vimentin phosphorylation

during mitosis Yamaguchi, T., Goto, H., Yokoyama, T., Silljé, H., Hanisch, A., Uldschmid, A., Takai, Y., Oguri, T., Nigg, E.A. and Inagaki, M. 48 3. Mitotic Chk1 phosphorylation at novel sites regulated by cyclin-dependent

kinase 1 (Cdk1) Shiromizu, T., Goto, H., Tomono, Y., Bartek, J., Totsukawa, G., Inoko, A.,

Nakanishi, M., Matsumura, F. and Inagaki, M. 48 4. Functional analysis of the cytoskeleton Izawa, I., Nishizawa, M. and Inagaki, M. 48 5. Characterization and functional analysis of novel keratin filament-binding

proteins, trichoplein and Fbf-1 Inoko, A., Zou, P., Sugimoto, M., Hayashi, Y., Kiyono, T., Izawa, I. and

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Inagaki, M. 49 6. Vimentin-Ser82 as a memory phosphorylation site in astrocytes Oguri, T., Inoko, A., Shima, H., Izawa, I., Arimura, N., Yamaguchi, T., Inagaki, N., Kaibuchi, K., Kikuchi, K. and Inagaki, M. 49

Division of Central Laboratory & Radiation Biology

General summary 51 1. A single nucleotide polymorphism of the MDM2 gene in Japanese esophageal and oral cancer patients Kumimoto, H., Sugimura, T., Furue, H., Shinoda, M., Hatooka, S. and Ishizaki, K. 51 2. DNA repair defects in AT cells and their hypersensitivity to low-dose-rate radiation Nakamura, Hid., Yasui, Y., Saito, N. and Ishizaki, K. 52

Central Service Unit

General summary Nakamura, Hir., Terashima, M., Tokumasu, S., Nishizawa, M., Yamamoto, M., Hagino, M., Mizuno, M. and Nishi, Y. 55 Librarians

Yasuda, T., Teratani, M., Adachi, K. and Ieda, T. 56 Researches Supported by Special Project Programme

1. Defining second-hit genetic abnormalities involved in generation of t(12; 21) TEL-AML1 acute lymphoblastic leukemias by array-based comparative genomic hybridization Tsuzuki, S., Karnan, S., Horibe, K., Matsumoto, K., Kato, K., Inukai, T., Goi, K., Sugita, K., Nakazawa, S., Ueda, R., and Seto, M. 57

Publications

1 Journals 58 2 Reviews and books 80 3. Abstracts for international conferences 83

Records of seminars 88 Records of symposia 90 Author index for research reports and publications 99

From left to right The first row; Dr. M. Tatematsu (Associate Director, and Division chief of Oncological Pathology), Dr. To.Takahashi (Director, and President as of April 2005), and Dr. K. Tajima (Associate Director as of April 2005, and Division chief of Epidemiology and Prevention). The second row; Ms. E. Kaede, Ms. H. Tamaki, and Mrs. M. Hosokawa (Adachi).

Preface _______________________________________________________________________________________

It is my pleasure to share with you the 19th Scientific Report (2004-2005) of the Aichi Cancer Center Research Institute. Since the establishment of the Institute in 1965, Scientific Reports have been published biennially to document major research activities and highlight progress in and contributions to cancer research worldwide. As illustrated on the following page, the organization of the Research Institute was remodeled in 2000 to provide for 9 Divisions, consisting of three study groups: cancer prevention/ epidemiology; preclinical/ experimental therapy; and carcinogenesis/ molecular biology. A total of 60 full-time staff members, 44 researchers and 16 research assistants, as well as 12 research residents, are now conducting a wide range of studies, together with 6 graduate school students affiliated with Nagoya University School of Medicine, Nagoya, and approximately 30 visiting research fellows. The major areas being pursued are as follows: - descriptive and analytical epidemiology of cancers - primary and secondary prevention of cancer - molecular pathogenesis of gastrointestinal cancers - molecular oncology of lung cancer - molecular biology of translocation-junction genes of hemtopoietic tumors - basic studies for cancer immunotherapy - oncogenicity, molecular biology and immunology of DNA tumor viruses - glycobiology of cancer cells in relation to metastasis - molecular mechanisms of cell proliferation and movement - involvement of repair mechanisms in carcinogenesis More detailed descriptions of the research topics of each Division appear in the contents of the report. It is our sincere hope that the activities of the Institute will make a major contribution to elucidation of the mechanisms of carcinogenesis and to development of novel clinical applications in cancer diagnosis, treatment and prevention. Finally, I would like to express my deep appreciation to the Aichi Prefectural Government for the continuous support received, since this Institute was founded in 1964. Granting support from the Ministry of Education, Science, Sports, Culture and Technology, the Ministry of Health, Labor, and Welfare, the Ministry of Economy, Trade and Industry, Japan, and other related organizations is also gratefully acknowledged.

February, 2006

Toshitada Takahashi, M.D., D.Med.Sci. Acting Director of the Research Institute President of the Aichi Cancer Center

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0)rganization ofthe Aichi Cancer Center Research institute

President

R.Ohno

(un宙lMaに h,2005)

To.Takahashi

(as of Ap付:,2005)

Cheif AdministRatOr

M.Ban

tun宙l March,2005)

工 A o k i

( a s o f A p r i l , 2 0 0 5 )

Director

R.Ohno(un付 l DecembeL 2003)

工 Kato(aS Of January9 2004)

Director

To.Takahashi

Associate Directors

M.Tatematsu

K.千封ima

(as of Ap甫12005)

(Chief′Head)

―,Division of Epidemiology and Preventton(K.Taiima)

一 D i v i s i o n o f O n c o l o g i c a l P a t l l o l o g y ( M . T a t e m aほu )

一 DMdon J Mdettlar On∞ ,o9y将柔挺商謎混譜甘拭輪‖憂ぽ畢

M)

一 D i v i s i o n o f M o l e c u l a r M e d i c i n e ( M . S e t O )

一 Division oflmmuno:ogy(K.Kuzushima)

一 DMtton ofVirology tt Tsuttmり

一 Division of Molecular Pathology(R.Kannagi)

―B Division of Blochemisw (M・inagaki)

一 Central Laboratory&Radiatton Biclogy(ェishiZaki)

_Central Service Un忙 (HぃNakamura)

一 Animal Fadnty(M.Tatematsu)

一 Laboratory of Transiational Research

SCIENTIFIC REPORTS

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From left to right First row: Dr. H. Ito, Dr. K. Matsuo, Dr. K. Wakai, Dr. K. Tajima, Dr. K. Hirose, and Ms. T. Saito. Second row: Ms. C. Yoshida, Ms. S. Hiraiwa, Ms. T. Sato, Ms. M. Watanabe, Ms. Y, Yamauchi, and Ms.

M. Nakano. Third row: Dr. T. Suzuki, Dr. K. Kuriki, Ms. M. Sato, Mr. N. Ito, Ms. K. Hasegawa, Ms. K. Mizutani, Ms.

H. Achiwa, and Ms. S. Inui. Inset: Ms. H. Fujikura, Ms. K. Fukaya, Ms. Y. Kamori, Ms. K. Tomita, Ms. T. Nishiwaki, Ms. C. Kanto,

and Ms. K. Suganuma.

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Division of Epidemiology and Prevention ________________________________________________________________________________ Kazuo Tajima, M.D., D.M.Sc., M.P.H. Chief Kenji Wakai, M.D., PhD. Section Head Kaoru Hirose, B.P., D.M.Sc. Senior Researcher Keitaro Matsuo, M.D., PhD., S.M. Researcher Hidemi Ito, M.D., PhD Researcher (As of April 2004) Takeshi Suzuki, M.D. Research Resident (As of April 2005) Toshiko Saito. Research Assistant Visiting Trainees Kiyonori Kuriki, B.P., D.M.Sc. Postdoctoral Fellow (Until March 2005) and Research Resident of Foundation for Promotion of Cancer Research (As of April 2005) Chuanxia Yang, M.D., West China University of Medical School, Chengdu, China (April 2004-March 2005) Takeshi Suzuki, M.D. Nagoya City University Medical School (December 2004- March 2005) Xinen Huang, M.D. Nagoya City University Medical School (Until March 2004) Kosuke Amano, M.Ed. Showa University School of Medicine Sanae Ikehara, Dept. of Epidemiology, Nagoya University Graduate School of Medicine General Summary

The current research activities of the Division of Epidemiology and Prevention cover the fol-lowing four subjects: 1) descriptive epidemiology of cancer incidence and mortality, with special reference to improvement of the Aichi Prefectural Cancer Registry; 2) analytical epidemiology based on the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC) to determine risk and protective factors for main sites of cancer, with a particular focus on gene-environment interactions; 3) a multi-institutional collaborative cohort study on nutritional factors and cancer risk in Japan; 4) a Korea, Japan and China (KOJACH) collaborative study on in-creasing cancers for establishment of future prevention programs in each country; 5) ethnoepidemi-ology of tumor viruses among Mongoloids in the Asian-Pacific area.

Descriptive epidemiologic studies are necessary for nation-wide statistics like “Vital Statis-tics Japan”. With the new model regional cancer registry in Aichi Prefecture established in 1999, a well organized data collection system and a risk evaluation trial of cancer in smokers and/or drink-ers are now in operation. A large-scale HERPACC study was completed for more than 130,000 new outpatients and a third version of HERPACC incorporating the Japan Multi-institutional Collabora-tive Cohort (J-MICC) was started in 2005 to clarify gene-environment interactions for modification of carcinogenicity. In addition to local epidemiologic studies, international collaborative studies in Northeast Asian countries (KOJACH Study) and the North Pole region are ongoing to obtain eth-noepidemiologic evidence of cancer risk among selected Asian populaces. Furthermore, primary prevention trials are being conducted for control of obesity by improvement of dietary habits and promotion of daily exercise.

Cancer prevention is the final goal of our epidemiological studies. Recently, we have been concentrating attention on molecular epidemiology to clarify interactions between host-specific characters and lifestyle exposure to risk factors, particularly with regard to actual functions of metabolic and detoxifying enzymes associated with genetic polymorphisms.

1. Descriptive epidemiological studies on

cancer incidence and mortality

Ito, H., Hirose, K., and Tajima, K.

Impact of habitual smoking on cancer stage at diagnosis based on Aichi cancer registry data: Since 1999, information on smoking habits of can-cer patients has been collected by Aichi Cancer

Registry. The purpose of this study was to examine the risk impact of habitual smoking on cancer stage at diagnosis by site using data registered of the Ai-chi Cancer Registry, Japan. The study subjects were registered cancer cases aged 20 or over and diag-nosed between 1999 and 2003. The relationship between cancer stage at diagnosis (local, regional or metastatic) and smoking history (never or ever) was

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assessed using a simple comparative approach. A total of 66,400 cancer patients with smoking history and cancer stage at diagnosis were registered up un-til 2004. Fifty-six percent were male and 44% were female. The mean age was 64 years. Ever smokers had increased risks of regional (odds ratio (OR), 1.27; 95% confidence interval (CI), 1.21 to 1.32; p<0.001) and metastatic (OR, 1.30; 95% CI, 1.24 to 1.36; p<0.001) disease. The increase in regional disease was most evident for oral & pharynx (OR, 1.38; 95%CI, 1.10-1.73), larynx (OR, 1.66; 95%CI, 1.01-2.73), lung (OR, 1.74; 95%CI, 1.50-2.02), breast (OR, 1.31; 95%CI, 1.12-1.53), and uterus (OR, 1.38; 95%CI, 1.09-1.75) cancers. Increase in metastatic disease was most evident for the lung (OR, 1.46; 95%CI, 1.26-1.69) and breast (OR, 1.80; 95%CI, 1.35-2.40) cancer (Figure 1). The data for smoking status of cancer patients collected by re-gional cancer registration can thus be utilized to

evaluate relationships to cancer stage at diagnosis. Ever smoking appears to be a risk factor for ad-vanced cancers in a wide range of body sites. Trends in cancer mortality in Japan: Cancer mortality statistics in Japan (1950-2003) were cal-culated from the ‘Vital Statistics, Japan’ series. The age-standardized death rate for all sites of can-cer has been stable in males in recent years, and gradually decreasing in females (Figure 2). The mortality rate from stomach cancer has been de-creasing in both sexes, while that from lung cancer has been increasing, becoming stable more recently. In 2003 the numbers of all deaths from malignant neoplasms were 186,912 for men and 122,631 for women. Regarding cancer causing, lung cancer is the most common, accounting for 22.3% of all can-cer deaths for males, followed by stomach cancer with 17.2% and hepatic cancer with 12.5%, while colorectal cancer is the most common for females

Figure 1. Smoking history and risk of metastatic and regional spread of cancer by site.

ORs of smoker group relative to non-smoker group.

Figure 2. Time trends in age-adjusted

mortality rate for cancer in Ja-pan, 1960-2003 (Standard population: 1985 model popu-lation of Japan).

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with 14.6%, followed by stomach cancer with 14.2% and lung cancers with 12.3%. 2. The hospital-based epidemiologic re-

search program at Aichi Cancer Center (HERPACC) study

Hirose, K., Matsuo, K., Wakai, K., Ito. H, Saito, T., Suzuki, T., Kuriki, K., Yang, C. X., Shinoda, M.*1,Hatooka, S.*2, Kanemitsu, Y.*3, Hirai, T.*3, Kato, T.*3, Toyama, T.*4, Iwata, H.*4, Niwa, Y.*5, Nakanishi, T.*5, Morishima Y.*6, Nakamura, S.*7, Yatabe, Y.*8, Mitsudomi, T.*9, Sugiura, T.*10, and Tajima, K.

Molecular epidemiology of folate and gastroin-testinal tract cancer risk: 1) Esophageal cancer: Folate takes part in two bio-logical pathways involved in DNA methylation and synthesis and a potential protective influence against carcinogenicity is now recognized in several sites, including the esophagus. Therefore, functional polymorphisms in encoding genes in folate metabo-lizing enzymes, MTHFR C677T and MTR A2756G, might be suspected of impacting on esophageal cancer risk. To test this hypothesis we conducted a matched case-control study with 165 esophageal cancer cases and 495 non-cancer controls to clarify associations among folate intake, MTHFR C677T and MTR A2756G polymorphisms and cancer risk. Gene-environment interactions between the two polymorphisms and drinking and smoking were also evaluated. Folate consumption and MTHFR 677TT were associated with a non-significant ten-dency for decreased risk while MTR genotypes did not show themselves demonstrate any significant influence; further, when analysis was limited to heavy drinkers, the MTHFR TT genotype signifi-

cantly decreased esophageal cancer risk (odds ratio (OR)=0.27, 95% confidence interval (CI): 0.09-0.76). The OR for the gene-environment in-teraction between heavy drinking and the 677TT genotype with a case-only design was 0.31 (0.10-0.94), indicating risk with heavy drinking to be 69% decreased in individuals harboring the 677TT genotype. We failed to find any significant interaction between either of the polymorphisms and smoking. 2) Colon cancer: One-carbon metabolism, in which folate plays an essential role, is involved in DNA methylation and synthesis and is suspected of im-pacting on colorectal carcinogenesis. Alcohol is well recognized as a risk factor for colorectal cancer (CRC) and interactions with one-carbon metabo-lism have also been suggested. Therefore, func-tional polymorphisms in genes encoding members of this pathway, MTHFR C677T and A1298C, MTR A2756G and TS tandem repeats polymorphisms, have attracted attention. We here conducted a matched case-control study with 257 incident CRC cases and 771 non-cancer controls at Aichi Cancer Center to clarify associations among folate intake and four polymorphisms with reference to CRC risk. Gene-environment interactions between polymor-phisms, drinking and folate consumption were also evaluated. None of the polymorphisms was associ-ated with any significant impact on CRC risk by genotype alone, but when combined with alcohol consumption, the MTHFR 677CC type showed a significantly reduced risk (OR=0.45, 95% confi-dence interval (CI): 0.23-0.86) (p=0.01). MTR GG increased risk only among drinkers (OR=3.35, 1.40-8.05) (p=0.047). The TS polymorphism did not have a significant impact by genotype alone, but

Figure 3. Dietary factors inversely associated with the risk of (a) colon and (b) rectal cancer (Q1-Q4: quartiles 1-4) in the HERPACC II Study.

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interaction with drinking was evident (p=0.028), even after stratification by daily folate consumption and drinking habit. Dietary factors and colorectal cancer risk (Fig-

ure 3): In Japan, the incidence rate for colon cancer has more rapidly increased than that for rectal can-cer. To compare dietary risk factors between colon and rectal cancers, we undertook a case-control study using data from the Hospital-based Epidemi-ologic Research Program at Aichi Cancer Center (HERPACC). Subjects included 507 men and women with newly diagnosed colon (n = 265) and rectal (n = 242) cancers, and 2,535 age- and gen-der-matched, cancer-free outpatients (controls). In-takes of nutrients and food groups were assessed with a food frequency questionnaire, and multivari-ate-adjusted odds ratios (ORs) were estimated using conditional logistic models. We found a decreasing risk of colon cancer with increasing intakes of vi-tamin C and fruit; the ORs across quartiles of intake were 1.00, 0.90, 0.72, and 0.72 (95% CI: 0.47-1.11; trend p = 0.089) for vitamin C, and 1.00, 0.85, 0.67, and 0.68 (95% CI: 0.45-1.03; trend p = 0.036) for fruit. For rectal cancer, higher consumption of meat and green-yellow vegetables was associated with a reduced risk; the ORs for the highest versus lowest quartile were 0.65 (95% CI: 0.42-1.02) and 0.62 (95% CI: 0.39-0.99), respectively. A decreased risk associated with higher intakes of insoluble dietary fiber was observed for colon cancer (OR for the highest quartile: 0.57; 95% CI: 0.37-0.89) but only suggested for rectal cancer. Carbohydrate intake was correlated particularly with the risk of female rectal cancer. In conclusion, differences in secular trends and in international distributions of incidence between the two colorectal sites may partly be at-tributable to variation in dietary risk factors. Colorectal cancer risk and erythrocyte compo-

sition of fatty acids as biomarkers for dietary

habits: Fish consumption rich in n-3 polyunsatu-rated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), is suggested to reduce colorectal can-cer risk through inhibiting the arachidonoic acid (AA) cascade related to tumorigenesis and cell pro-liferation. High intake of saturated fatty acids (SFAs), in contract, appears to increase the risk. To examine associations between colorectal cancer risk and the fatty acid composition of erythrocyte mem-branes, reflecting dietary intake of fish, fat and fatty acids, we conducted a case-control study with 74 incident cases and 221 non-cancer controls (matched by age, sex and season of data collection). Erythrocyte fatty acids were measured by a semi-automatic method using accelerated solvent extraction and gas-liquid chromatography. Colo-rectal cancer incidence risk had no association with dietary intake of meat, fish, fat and fatty acids. However, the risk was inversely associated with erythrocyte compositions of PUFAs, AA and DHA [highest to lowest tertile, odds ratios (ORs) = 0.15, 0.42 and 0.36, 95% confidence intervals (CIs) = 0.05 to 0.46, 0.18 to 0.95 and 0.14 to 0.93, Ptrend <0.05 to 0.005], and positively with those of SFAs, palmitic acid and the ratio of SFAs/PUFAs (ORs = 8.20, 6.46, and 9.45, 95% CIs = 2.86 to 23.52, 2.41 to 17.26, and 2.84 to 31.43, Ptrend <0.005 to 0.0001, Figure 4). We thus demonstrated colorectal cancer risk to be clearly related to fatty acid composition in erythrocyte membranes, but further studies are re-quired to clarify the apparent discrepancy that a high erythrocyte composition of AA may also re-duce risk. Protective and risk factors for hormone related

cancer in women: 1) Soybean products and reduction of breast cancer risk: Components of the Japanese diet which might contribute to the relatively low breast cancer inci-dence rates in Japan, have not been clarified in de-

Figure 4. Decreased (left) and increased (right) risks for colo-rectal cancer according to asso-ciations with fatty acid composi-tions in erythrocytes.

9

tail. Since soybean products are widely consumed in Japan a case-control study taking account of the menopausal status was conducted using data from the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC). In total, 167 breast cancer cases were included and 854 women confirmed as free of cancer were recruited as the control group. Odds ratios (OR) and 95% confi-dence intervals (95%CI) were determined by multi-ple logistic regression analysis. Reduction in risk of breast cancer was associated with high intake of soybean products among premenopausal women, the adjusted OR for the top tertile intake of tofu (soybean curd) being 0.51 (95%CI, 0.26-0.98) compared with women in the lowest tertile. A significant decrease in premenopausal breast cancer risk was also observed for increasing consumption of isoflavones (OR=0.45, 95% CI:0.23-0.89 for highest vs. lowest tertile, p for trend=0.02). The present study found a statistically inverse associa-tion between tofu or isoflavone intake and risk of breast cancer in Japanese premenopausal women while no statistically significant association was evident with the risk among postmenopausal women. 2) Coffee consumption and reduction of endo-metrial cancer risk: Coffee has become a popular beverage worldwide and because it contains large amounts of antioxidants, such as chlorogenic acids, there has been increasing interest in possible bene-ficial health effects. Caffeine, a major ingredient of coffee, has been proposed to modulate circulat-ing estrogen levels and therefore may also be of importance for cancer development. To test this, we examined the relationship between intake of coffee and hormone related cancer risk among Japanese women using data from the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC). In total, 2,122 breast, 539 cervical, 229 endometrial and 166 ovarian cancer cases were included, and 12,425 women, confirmed as free of cancer, were recruited as the control group. A statistically significant inverse associa-tion between risk of endometrial cancer and coffee consumption was noted in our Japanese women, with no clear associations evident for breast, cervi-cal or ovarian cancer risk. The ORs for daily drinking of 1-2 cups and 3 or more cups per day for endometrial cancer were 0.64(95%CI:0.43-0.94) and 0.41 (95%CI:0.20-0.88), respectively, and the linear trend was also statistically significant (p<0.01). The effect of coffee intake on risk of endometrial cancer was most prominent among

leaner women (BMI=<22). In summary, the re-sults of the present study suggested that coffee consumption reduces the risk of endometrial cancer in Japanese, especially in relatively lean women. 3) The CYP19 gene codon39 Trp/Arg polymor-phism increases breast cancer risk in subsets of premenopausal Japanese: The production of estro-gen from androgen via the estrogen biosynthesis pathway is catalyzed by aromatase P450 (CYP19). To assess the association between breast cancer risk and a polymorphism at codon 39 ( Trp to Arg ) of the encoding gene, a case-control study was con-ducted at Aichi Cancer Center Hospital in Japan. Subjects were 248 histologically confirmed breast cancer patients and 603 hospital controls without cancer. Odds ratios (ORs) and 95% confidence intervals (95%CI) were determined by logistic re-gression analysis. The allele frequency among controls was 3.8% for the C allele and the OR of the polymorphism relative to the TT-genotype was 1.21 (95% CI:0.69-2.14) for the TC/CC-genotypes com-bined. There was no association between the CYP19 gene polymorphism and breast cancer risk in the study group as a whole but homozygous and heterozygous carriers of the variant Arg allele showed a significantly increased risk of breast can-cer among premenopausal women with a late age at first-full term pregnancy (OR=7.31, 95%CI: 1.88-28.5) or a high BMI (OR=2.77, 95%CI: 1.12-6.87). Additional larger studies should be performed to confirm that the rare CYP19 variant increases the risk of breast cancer among premeno-pausal Japanese women. Hematopoietic cancer: Recent increase in the in-

cidence of malignant lymphoma (ML) suggests possible involvement of environmental factors in its genesis. Medical conditions could be one potential candidates and their identification may provide clues for future prevention. We focused on peptic ulcer history on ML risk and conducted a case-control study with 645 patients histologically diagnosed as having malignant lymphomas and 3225 non-cancer controls. Plasma H. pylori IgG status was assessed for subgroups for which blood samples were available (116 cases and 114 con-trols). An association with a history of gastric, but not duodenal ulcers was found for gastric lympho-mas [odds ratio (OR) = 5.41, 95% confidence in-terval (CI): 3.12 - 9.39]. On examination according to histological subtype, the Ors were high for both gastric mucous-associated lymphoid tissue (MALT) lymphoma (OR = 5.54, 95% CI: 2.56 - 12.01) and diffuse large B-cell lymphoma (DLBCL) (OR =

10

7.23, 95% CI: 2.62 - 19.90). Further, on subgroup analysis of subjects with H. pylori infection, gastric ulcer history, but not duodenal ulcer history was associated with the risk of gastric lymphoma (OR = 4.15, 95% CI: 1.02 - 16.89). This observation is quite similar to the association between gastric cancer and peptic ulcer history, suggesting a similar mechanism underlying effects on gastric cancer and gastric lymphoma development. Molecular epidemiology of lung cancer: APE1

(apurinic/apyrimidinic endonuclease 1) and XRCC1 (X-ray cross-complementing group 1) are DNA re-pair proteins that play important roles in the base excision repair (BER) pathway. Polymorphisms in their encoding genes are associated with altered DNA repair capacity and thus may impact on can-cer risk. In a case-control study with 178 Japanese incident lung cancer cases and 449 age- and sex- matched controls, we therefore investigated gene-environment interactions among APE1 Asp148Glu, XRCC1 Arg399Gln, and smoking habit in lung cancer risk. The results were analyzed using conditional logistic regression models, adjusted for age, sex and smoking status. The adjusted odds ra-tio for the current smokers with APE1 148Asp/Asp, Asp/Glu and Glu/Glu genotypes as compared with the never smokers with the Asp/Asp genotype were 3.01 (95% CI 1.39-6.51, p= 0.005), 2.73 (1.29-5.77, p=0.008) and 7.33 (2.93-18.3, p<0.001), respec-tively. The gene-environment interaction between current smoking and APE1 148Glu/Glu genotype was statistically significant (OR 3.59, 1.28-10.1, p=0.015). When APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms were evaluated together, the adjusted odds ratios for current smokers with 0-1, 2 and 3-4 of APE1 148Glu or XRCC1 399Gln alleles as compared with never smokers with the rare of these alleles were 2.96 (1.57-5.58, p=0.001), 3.86 (1.85-8.05, p<0.001) and 6.01 (2.25-16.1, p<0.001), respectively. The gene-environment in-teraction between current smoking and 3 or more APE1 148Glu or XRCC1 399Gln alleles was statis-tically significant (OR 2.44, 1.00-9.22, p=0.049). The OR for the gene-environment interaction of the Glu/Glu genotype of the APE1 codon 148 with heavy smoking was 1.04 (0.38-2.90, p=0.936) and that with light smoking was 2.67 (1.00-7.68, p=0.049). These results suggest that APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms might modify the risk of lung cancer attributable to cigarette smoking exposure. Smoking behavior modification:

1) Interleukin 8 (IL8) polymorphisms and smoking

behavior in Japanese: Accumulating evidence in-dicates that the genotype may impact on smoking behavior and a deeper understanding of the mo-lecular basis could lead to more effective strategies for preventing initiation of the habit and for helping smokers to quit. Since individual variation in air-way responsiveness to cigarette smoke might have an important influence, we have focused on asso-ciation between smoking behavior and polymor-phisms affecting the inflammatory cytokine, IL-8. In the present study, 453 Japanese non-cancer out-patients (191 males and 262 females) who visited Aichi Cancer Center Hospital were genotyped for the IL8 -251T/A polymorphism and age- and sex- adjusted odds ratios (aORs) for smoking were esti-mated by a logistic regression model. The aORs for IL8 251-TA and AA combined, genotypes associated with high production of IL-8, were 0.52 (95% CI 0.33-0.82, p=0.004) for being an ever smoker and 0.55 (0.55, 0.33-0.92, p=0.023) for being a current smoker. Our results suggest that the inflamma-tory-prone genotype of IL8 may act to deter initia-tion or characteristics of the smoking habit. 2) Smoking cessation inducement by providing in-formation on the L-myc genotype: To evaluate whether feedback of genetic information regarding an L-myc polymorphism, identified as impacting on tobacco-related cancer risk, has an influence on smoking cessation, an intervention study was con-ducted. We recruited smokers from first-visit outpa-tients at Aichi Cancer Center Hospital. Six hundred and seventeen participated and were allocated into two groups: the biomarker-feedback group (BF) and the follow-up smoking-status group (FS). The sub-jects were asked for their smoking status at enrol-ment and after 3- and 9-months follow-up. BF sub-jects were notified about their L-myc genotype. The smoking cessation rate at 9-months follow-up was essentially the same for both BF and FS cases, at 18.8% and 17.0%, respectively (p=0.798). However, a difference in the rate was evident with non-cancer subjects (12.7% and 8.4%, respectively, p=0.237), especially in females (15.0% and 4.2%, respectively, p=0.024). The non-cancer subjects informed of their genotype were more likely to quit smoking than the FS patients; particularly in those having a risky genotype this was significant (odds ratio: 2.87, p=0.003). Again it was most prominent in females. In conclusion, feedback regarding an L-myc poly-morphism did not impact on smoking cessation overall, but appeared to benefit smokers without cancer. In addition, gender could affect the response to the feedback.

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Introduction of the J-MICC Study: The Japan Multi-Institutional Collaborative Cohort (J-MICC) Study is a new multi-center approach to elucidate environmental and genetic risk factors for cancer and other lifestyle-related diseases. In this project, three types of studies are planned: 1) follow-up to clarify associations between development of disease and lifestyle factors, genotypes, and other bio-markers, or their combinations; 2) search for bio-markers useful for early detection of disease par-ticularly of cancer; and 3) cross-sectional studies relating to lifestyle, genotypes, and biomarkers. Men and women aged 35 to 69 years are to be re-cruited for the study by about ten institutions throughout Japan from the general population, ex-aminees of health check-ups, or hospital patients, with a targeted number of 100,000. The subjects are being requested to complete a questionnaire on life-style and medical factors and also to donate blood samples including buffy coat, plasma, and serum. They will be followed up for death and cancer inci-dence by review of death certificates or medical re-cords, linkage with cancer registries, mail surveys, etc., until March 2025. After hot discussion on the protocol, especially on its ethical issues, the study was launched in October 2005. We, the Division of Epidmiology and Prevention, are taking part in the J-MICC Study as a study center and have been re-cruiting participants of the study together with those of the HERPACC at the Aichi Cancer Center Hos-pital since November 2005. *1 Department of Rehabilitation, Aichi Cancer Center

Hospital *2 Department of Thoracic Surgery, Aichi Cancer Cen-

ter Hospital *3 Department of Gastroenterological Surgery, Aichi

Cancer Center Hospital *4 Department of Breast Oncology, Aichi Cancer Center

Hospital

*5 Department of Gynecologic Oncology, Aichi Cancer Center Hospital

*6 Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital

*7 Department of Pathology, Graduate School of Medi-cal Sciences, Nagoya City University

*8 Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital

*9 Department of Thoracic Surgery, Aichi Cancer Cen-ter Hospital

*10 Department of Thoracic Oncology, Aichi Cancer Center Hospital

3. Nutritional factors and the risk of colo-rectal cancer: findings from the JACC Study

Wakai, K. and the JACC Study Group

The Japan Collaborative Cohort (JACC) Study is a large-scale prospective study conducted in 45 areas throughout Japan. The cohort was established from 1988 to 1990, when 110,792 inhabitants aged 40 to 79 years completed a questionnaire on life-style and medical history. About 35% of the par-ticipants donated blood samples. To elucidate the role of nutritional factors in the etiology of colorec-tal cancer, we analyzed data from the study. Major findings of the analyses are as follows. (a) The as-sociation of serum carotenoid levels with colorectal cancer risk may be modified by sex. In a nested-case control study, a higher level of serum total carotenoids was associated with a decreased risk in men (the odds ratio [OR] for the highest versus the lowest tertile: 0.34; 95% CI: 0.11-1.00; trend P over tertiles: 0.040), whereas its higher level was related to a somewhat increased risk in women (the corresponding OR: 2.47 [95% CI: 0.73-8.34]; trend P: 0.064). (b) Male ex- or current drinkers demonstrated a twofold risk for colon can-cer compared with nondrinkers: the incidence rate ratio (IRR) was 2.01 (95% CI: 1.09-3.68) for ex-drinkers and 1.97 (95% CI: 1.28-3.03) for cur-rent drinkers. (c) An inverse correlation was ob-served between intake of dietary fiber and the risk of colon cancer; the IRRs across quartiles were 1.00, 1.18, 0.50, and 0.68 (95% CI: 0.38-1.21; trend P: 0.049) in men and 1.00, 0.69, 0.67, and 0.59 (95% CI: 0.34-1.01; trend P: 0.061) in women. (d) Intake of fat, particularly that of animal or saturated fat, was associated with an increased risk of colon can-cer. In men, the IRRs over quartiles were 1.00, 1.25, 1.86, and 1.81 (95% CI: 1.05-3.11) for total fat (trend P: 0.015), 1.00, 1.41, 1.75, and 2.06 (95% CI: 1.24-3.41) for animal fat (trend P: 0.003), and 1.00, 1.98, 2.83, and 2.38 (95% CI: 1.35-4.20) for saturated fat (trend P: 0.001). Although we found no significant dose-response relationship for total or saturated fat in women, an increasing trend in colon cancer risk was detected with an increasing intake of animal fat. The IRRs across quartiles of intake were 1.00, 1.08, 1.33, and 1.65 (95% CI: 1.02-2.67; trend P: 0.035).

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4. Comparative epidemiological study on increasing colorectal and breast can-cers focusing on Korea, Japan and China (KOJACH study)

Matsuo, K., Wakai, K., Hirose, K., Kuriki, K., Huang, X-E., Yang, C. X., Takezaki T., Hamajima N., Gao C-M.*1, Yoo K-Y.*2, Ahn Y-O.*2, Cao J.*3, Pan I-M.*4 Li K.*5, Tokudome Y.*6, and Tajima, K.

To establish a basis for cancer prevention in the Asian Pacific region, we started a case-referent study on increasing cancers since 2000, based on a standardized epidemiological approach, in Korea (Seoul), Japan (Nagoya) and China (Nanjing, Chongqing, Benxi and Shantou), the so called KOJACH Study. In Korea they developed their own SQFFQ and we established semi-quantitative food frequency questionnaires (SQFFQs) in the four cit-ies in China. The validity and reproducibility of all SQFFQs established in Korea and China were evaluated for further epidemiologic studies. We have collected lifestyle data by standardized SQFFQs and blood samples for plasma and DNA after obtaining informed consent from more than 1,600 colorectal cancer cases in each area in Korea, Japan and China. The same number of referents matched by age and sex were recruited from hospi-tal patients in Korea and Japan and from the general population in China. A detailed analysis is now ongoing to clarify risk and protective factors for colorectal cancer in each of the three countries and areas of China using data for lifestyle, genetic polymorphisms and interactions. Furthermore, other case-referent studies on breast cancer were also ini-tiated in June 2005. *1 Division of Epidemiology, Cancer Institute of Ji-

angsu Province, Nanjing, China *2 Department of Preventive Medicine, College of

Medicine, Seoul National University, Seoul, Korea *3 Laboratory of Molecular Toxicology, Third Military

Medical University, Chongqing, China *4 Bengan General Hospital, Benxi, China *5 Department of Epidemiology, Shantou University,

Shantou, Chian *6 Life Science, Nagoya Bunri College

5. Ethnoepidemiologic study on virus-related cancer in Mongoloids

Tajima, K., Matsuo, K., Sonoda, S.*1, Chiba, H.*2, Senoh, H.*3, Tretli, S.*4 , and Dobrodeeva, L.K. *5

Human T-cell leukemia virus type 1 (HTLV-1), the main cause of adult T-cell leukemia/lymphoma, is found throughout the world but with micro-geographical clusters of hyperendemicity. Epidemi-ologic studies among Mongoloids showed that HTLV-1 is highly endemic in South Japan (one million carriers) and in the Andes district of South America. In contrast, HTLV-II (also a risk factor for adult T-cell leukemia/lymphoma) is broadly distributed in all of South America, except the An-des line. After sero-epidemiologic studies on HTLV-I antibodies among Tibetan people in China and Sahme people in North Norway in 2001 and 2003 respectively, we conducted field work in the Nenets Autonomous District of the Arkhangelsk Region in northwestern Russia. In total, 105 blood samples from Nenets people of Krasnoe were col-lected in collaboration with Institute of Physiology of Adaptations to Environment, the Ural Branch of the Russian Academy of Sciences. No individuals positive for anti-HTLV-I were detected in the in-digenous Nenets people, in line with the HTLV-I/II clusters among Mongoloids in other areas of the Asian Pacific. *1 Department of Virology, Faculty of Medicine, Ka-

goshima University, Kagoshima, Japan

*2 Department of Laboratory Medicine, Hokkaido University School of Medicine, Sapporo, Japan

*3 Department of Anatomy, Akita University School of Medicine, Akita, Japan,

*4 Institute of Population-based Cancer Research, Oslo, Norway

*5 Department of Ecological Immunology, Institute of Physiology of Adaptations to Environment, the Ural Branch of the Russian Academy of Sciences, Ark-hangelsk, Russia

13

From left to right First row: Dr. T. Mizoshita, Dr. T. Tsukamoto, Dr. M. Tatematsu, Dr. H. Nakanishi and Dr. Y. Ikehara Second row: Mrs. C. Ikedo, Dr. N. Hirano, Dr. Y. Takenaka, Mr. H. Tanaka, Mr. H. Asahara, Mrs. H.

Ban

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Division of Oncological Pathology ________________________________________________________________________________ Tatematsu Masae, M.D. Chief Hayao Nakanishi, M.D. Section Head Tetsuya Tsukamoto, M.D. Section Head Yuzuru Ikehara, M.D. Senior Researcher (until Mar, 2006) Tsutomu Mizoshita, M.D. Researcher Harunari Tanaka, B.P., Research Assistant Hisayo Ban, Semi-regular Employee Mikako Asai Semi-regular Employee (until Nov, 2005) Visiting Scientists Malcolm A. Moore, Ph.D. Asian Pacific Organization for Cancer Prevention Kato Kazuo, M.D., Fujita Health University School of Medicine Visiting Trainees Xueyuan Cao, M.D., Dept. of Gastrointestinal Surgery, The University of Tokyo Yoshiharu Takenaka, M.D., Dept. of Gastrointestinal Surgery, The University of Tokyo Takasuke Yamachika, M.D., Kita Hospital Akihiro Hirata, D.V.M. Dept. of Veterinary Pathology, Gifu University Shinji Takasu, D.V.M. Dept. of Veterinary Pathology, Gifu University Yoshiyuki Yokoyama, M.D. Dept. of Surgery II, Nagoya University School of Medicine Norifumi Ohashi, M.D. Dept. of Surgery II, Nagoya University School of Medicine Kenji Tsuboi, M.D. Dept. of Surgery II, Nagoya University School of Medicine Yuichi Ito M.D. Dept. of Surgery II, Nagoya University School of Medicine Sanae Ikehara, Dept. ofEpidemiology, Nagoya University Graduate School of Medicine Toru Niwa, M.D., Dept. of Internal medicine II, Wakayama Medical College Takafumi Otsuka, M.D., Dept. of Internal medicine I, Toho University School of Medicine Naoki Hirano M.D., Dept. of Internal medicine I, Toho University School of Medicine Sousuke Katoh, M.D., Dept. of Internal medicine III, Hokkaido Univesity School of Medicine Naotaka Ogasawara, M.D., Dept. of Internal Medicine and Bioregulation, Nagoya City University of Medicine. Yoshikazu Hirata M.D., Dept. of Internal Medicine and Bioregulation, Nagoya City University of Medicine. Masayasu Hara, M.D., Dept. of Gastroenterological Surgery, Nagoya City University of Medicine. Mistuo Gotoh, D.D.S., School of Dentistry, Aichi-Gakuin University Yasushi Seki, D.D.S., School of Dentistry, Aichi-Gakuin University Fumi Ono, D.D.S., School of Dentistry, Aichi-Gakuin University Atsutaka Kinoshita, D.D.S., School of Dentistry, Aichi-Gakuin University Shinya Satoh, M.D., Aichi Cancer Center Hospital Chihiro Aoki, College of Bioscience and Biotechnology, Chubu University Hisayoshi Asahara, College of Bioscience and Biotechnology, Chubu University General Summary

The responsibility of the Division of Oncological Pathology includes autopsy and research activities. From the establishment of this laboratory in 1965 to the end of 2005, the number of au-topsy cases amounted to 2568. Postmortem examinations are a source of valuable information on the behavior of neoplasms and their response to therapy. Autopsy findings also supply the basis for total evaluation of the course of disease, including the accuracy of clinical diagnosis, effective-ness or failure of drugs, irradiation and surgery, and the appearance of complications such as op-portunistic infection and hemorrhage during treatment.

Main theme of this laboratory is the carcinogenesis and the progression of gastrointestinal malignancies. During 2004-2005, the research activities are divided into the following four main areas. The first deals with the molecular basis and detection of chemical carcinogenesis and initia-tion and promotion activities. In vivo five-week initiation assay model revealed heterocyclic amines, food-derived carcinogen, revealed interference each other. The second concerns gastric cancers and

15

their precancerous lesions along with the mechanisms regulating differentiation of stomach epithe-lium in humans as well as rodent models. High salt diet and younger acquisition of Helicobacter pylori (Hp) exacerbate inflammation and incidence of stomach adenocarcinomas. On the other hand, earlier eradication well suppressed stomach carcinogenesis. Molecular mechanism of intestinal metaplasia, major complication of Hp infection, includes alteration of gastric and intestinal tran-scription factors. The third research area involves basic research on tumor progression and metasta-sis, especially micrometastasis and its clinical application for prevention of recurrent disease after surgery. A new potential molecular therapy targeting to HER2 overexpression using gefitinib in gastric cancer liver metastasis is currently ongoing. In line with this therapeutic strategy, the fourth issue includes the development of a novel drug-delivery system using the carbohydrate-coated li-posomes which are selectively accumulated at a milky spot, a preferential site for intraperitoneal metastasis of gastric cancer.

1. High salt diets dose-dependently pro-

mote gastric chemical carcinogenesis in Helicobacter pylori-infected Mongo-lian gerbils associated with a shift in mucin production from glandular to surface mucous cells

Tatematsu, M., Tsukamoto, T., Mizoshita, T., Kato, S.*1, Cao, X., Hirata, A.*2, and Takasu, S.*2

Intake of salt and salty food is known as a risk factor for gastric carcinogenesis. To examine the dose-dependence and the mechanisms underlying enhancing effects, Mongolian gerbils were treated with N-methyl-N-nitrosourea (MNU), Helicobacter pylori (H. pylori), and food containing various concentrations of salt and sacrificed after 50 weeks. Among gerbils treated with MNU and H. pylori, the incidences of glandular stomach cancers were 15% in the normal diet group and 33%, 36%, and 63% in the 2.5%, 5%, and 10% NaCl diet groups, showing dose-dependent increase (P<0.01). Intermittent intragastric injection of saturated NaCl solution, in contrast, did not promote gastric carcinogenesis. In gerbils infected with H. pylori, a high salt diet was associated with elevation of anti-H. pylori an-tibody titers, serum gastrin levels, and inflamma-tory cell infiltration in a dose-dependent fashion. Ten percent NaCl diet upregulated the amount of surface mucous cell mucin (P<0.05), suitable for H. pylori colonization, despite no increment of MUC5AC mRNA, while H. pylori infection itself had an opposing effect, stimulating transcription of MUC6 and increasing the amount of gland mucous cell mucin. High salt diet, in turn, decreased the amount of gland mucous cell mucin, which acts against H. pylori infection. In conclusion, the present study demonstrated dose-dependent en-hancing effects of salt in gastric chemical carcino-genesis in H. pylori-infected Mongolian gerbils as-sociated with alteration of the mucous microenvi-

ronment. Reduction of salt intake could thus be one of the most important chemopreventive meth-ods for human gastric carcinogenesis. *1 Dept. of Gastroenterology, Hokkaido University

Graduate School of Medicine, Sapporo, Japan *2 Dept. of Veterinary Pathology, Gifu University, Gifu,

Japan 2. HER2-driven constitutive activation of

PI3K-AKT pathway is a new potential molecular target of gefitinib (Iressa) in human gastric cancer liver metastasis

Nakanishi, H., Yokoyama, H. *1, Ikehara, Y., Kodera, Y.*1, Ikehara, S. and Tatematsu, M.

HER2 overexpressing gastric cancer is known to lead to a poor patient outcome, but there is virtually no efficient therapeutic mo-dality. The purpose of the present study is to investigate the possibility of molecular therapy targeting to HER2 overexpression in the gastric cancer patients. We found that gastric cancers metastasized to the liver overexpressed HER2 at significantly higher incidence than primary gastric cancers. We developed three new HER2 overexpressing gastric cancer cell lines (GLM-1, GLM-2, GLM-4) without EGFR mu-tations derived from such liver metastasis, two of which had HER2 gene amplification. Inter-estingly, all these GLM series were highly sen-sitive to gefitinib, a specific inhibitor of epi-dermal growth factor receptor (EGFR) tyrosine kinase (ZD1839, “Iressa”) with IC50 less than 0.1 µM, but not Herceptin, whereas most of HER2-negative counterparts were not (IC50>10 µM). Gefitinib induced strong apop-tosis depending on caspase 3 and exhibited anti-tumor activity against these HER2-overexpressing cancer cell lines both in

16

vitro and in vivo. In GLM-1, GLM-2 and GLM-4 cells, Akt, but not ERK1/2, was con-stitutively phosphorylated without loss of PTEN expression, and gefitinib efficiently in-hibited this HER2-driven Akt phosphorylation. However, gefitinib failed to inhibit constitutive phosphorylation of Akt in HER2-negative gas-tric cancer cell lines. On the other hand, gefit-inib-resistant cells (GLM-1R), exhibited in-creased EGFR expression, followed by consti-tutive activation of MAPK pathway. These re-sults suggest that the anti-tumor effect of gefit-inib is due to the effective inhibition of HER2-driven constitutive activation of PI3K/Akt pathway and that the acquired resis-tance to gefitinib is due to the constitutive acti-vation of Ras/MAPK pathway in compensation for PI3K/Akt pathway. Gastric cancer liver metastasis with HER2-overexpression would be a potential molecular target for gefitinib. *1 Department of Surgery II, Nagoya University School

of Medicine, Tsuruma, Shouwa-ku, Nagoya, Japan

3. Sox2 expression in human stomach adenocarcinomas with gastric and gas-tric-and-intestinal-mixed phenotypes

Tsukamoto. T., Mizoshita, T., Takenaka, Y.*1, Ogasawara, N.*2 and Tatematsu, M.

Aims: Other than ectopic expression of intesti-nal transcription factors, Cdx1 and Cdx2 , molecular mechanisms underlying gastric and intestinal phe-notypes of human stomach adenocarcinomas have yet to be clarified in detail. We have reported that Sox2, an HMG-box gastric transcription factor, is expressed in normal gastric mucosa and down-regulated in intestinal metaplasia. Methods and Results: We analyzed mRNA lev-els of Sox2 and other differentiation markers in fifty surgically resected stomach adenocarcinomas, im-munohistochemically classified into gastric (G), gastric-and-intestinal (GI)-mixed, solely intestinal (I), and null (N) types. Sox2 was found to be transcribed in G and GI-mixed type adenocarcino-mas in accordance with MUC5AC and MUC6 ex-pression, while Cdx1 and Cdx2 were up-regulated in GI-mixed and I types along with the expression of MUC2 and villin. In the N type, both gastric and intestinal transcription factors were suppressed. Immunohistochemistry confirmed expression of Sox2 in MUC5AC positive lesions and Cdx2 local-ization together with MUC2. A stomach adeno-

carcinoma cell line, KATOIII, demonstrated both MUC5AC and Sox2, although MUC5AC mRNA was not detected in the Sox2-positive AGS cell line. Conclusions: Sox2 may play an important role in maintaining a gastric phenotype in stomach can-cers as well as in normal tissue, in cooperation with other cofactor(s). *1 Dept. of Gastrointestinal Surgery, The University of

Tokyo, Tokyo, Japan *2 Dept. of Internal Medicine and Bioregulation, Na-

goya City University of Medicine, Nagoya, Japan. 4. A carbohydrate recognition based drug

delivery and controlled release system using intraperitoneal macrophages as a cellular vehicle

Ikehara, Y., Nakanishi, H., Niwa, T.*1, Biao, L.*2,

Ikehara, S., Ohashi, N.*3, Kobayashi, T. *1, Simizu, Y.*1, Kojima, N. and Tatematsu, M.

We developed a new technology using the car-bohydrate recognition by macrophages that are ap-plied to use as a cellular vehicle in a drug delivery system. The lymphoid tissue in the omentum, called for milky spots, is known as an initial place for dis-seminated cancer cells to develop into solid tu-mours. Intraperitoneal macrophages significantly took up Oligomannose-coated liposomes (OML) that were injected into peritoneal cavity, and then gradually accumulated in the omentum and the other lymphoid tissues within 24 h of intraperito-neal injection of OMLs. When 5-fluorouracil (5-FU) was encapsulated in the OMLs, more than 60% of administered 5-FU accumulated in the omentum. Treatment of macrophages at 39 °C for 30 min led to the release of 5-FU from the macro-phages, suggesting that controlled release from macrophages could be achieved by mild hyperther-mia. We encased magnetic nanoparticles, which are known to convert electromagnetic energy to heat, in the OMLs to achieve in vivo hyperthermia at the site. Using this system in a mouse intraperitoneal metastasis model, we successfully controlled tu-mour development by co-administration of OML-encased 5-FU and OML-encased magnetic nanoparticles, followed by treatment with an alter-nating magnetic field. No apparent reduction was seen in tumour growth with the administration of OML-encased magnetic nanoparticles or OML-encased 5-FU alone. Thus, we have estab-lished the use of intraperitoneal macrophages as a novel drug-delivery system for the control of cancer

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metastatic to milky spots. *1 Department of Applied Biochemistry and The Insti-

tute of Glycotechnology, Tokai University, 1117 Ki-takaname, Hiratsuka-shi, Kanagawa, 259-1292 Japan

*2 EP, *3 Department of Biological Chemistry, College of Bio-

science and Biotechnology, Chubu University 5. Colonic and small-intestinal pheno-

types in gastric cancers: relationships with clinicopathologic findings

Mizoshita, T., Tsukamoto, T., Tanaka, H., Otsuka, T,*1. Hirano, N.*1, and Tatematsu, M.

The clinicopathologic significance of colonic and small-intestinal phenotypes has hitherto re-mained unclear in gastric cancers. In the present study, we therefore examined 86 gastric carcinomas histologically and phenotypically using several phenotypic markers, including colon specific car-bonic anhydrase 1 (CA1) and sucrase as small in-

testine specific. Of 86 gastric cancers, sucrase and CA1 expression was observed in 12 (14.0%) and only 2 (2.3%) cases, respectively, associated with other intestinal markers such as villin and MUC2. In the sucrase cases, expression appeared inde-pendent of the stage. However, CA1 expression was observed only in two advanced cases. No as-sociation was observed between colonic and small-intestinal phenotypes and lymph node metas-tasis and postoperative survival in the advanced gastric cancer cases with intestinal phenotypic ex-pression. Cdx2 appeared linked to upregulation of both CA1 and sucrase. In conclusion, our data suggest that colonic phenotype occur rarely in gas-tric carcinogenesis. Colonic and small intestinal phenotypes appear with expression of several intes-tinal phenotypic markers under the control of Cdx2 and presumably other related transcription factors. *1 Dept. of Internal Medicine I, Toho University School

of Medicine, Tokyo, Japan.

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From left to right Front row: Dr. Y. Kondo, Dr. Y. Sekido, Dr. H. Osada, and Dr. T. Fukui, Second row: Dr. T. Yokoyama, Dr. N. Sato, Dr. T Taniguchi, and Mr. Y. Tatematsu, Inset: Dr. Y. Goto.

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Division of Molecular Oncology ________________________________________________________________________________ Takashi Takahashi, M.D., Ph.D., Chief (until June 2004) Yoshitaka Sekido M.D., Ph.D., Chief (as of April 2005) Hirotaka Osada, M.D., Ph.D., Section Head Kiyoshi Yanagisawa, M.D., Ph.D., Senior Researcher (until June 2004) Yutaka Kondo, M.D., Ph.D., Senior Researcher (as of July 2005) Shuta Tomida, Ph.D., Researcher (until March 2005) Yoshio Tatematsu, B.S., Research Assistant Tomoko Harano, B.S., Research Assistant (until March 2004) Postdoctoral Fellows Toshiyuki Takeuchi, Ph.D. (until June 2004) Research Resident Yoji Hayashita, M.D., (until March 2005) Visiting Trainees Hidemasa Nagai, M.D., Nagoya University School of Medicine (until June 2004) Yoko Karube, M.D., Dokkyou University School of Medicine (until June 2004) Junichi Takamizawa, M.D., Nagoya University School of Medicine (until June 2004) Ken Maeno, M.D., Nagoya City University School of Medicine (until June 2004) Hideki Yamada, M.D., Nagoya University School of Medicine (until June 2004) Hisaaki Tanaka, M.D., Okayama University School of Medicine (until June 2004) Nobuyoshi Sugito, M.D., Nagoya City University School of Medicine (until Sep. 2004) Hiromichi Ebi, M.D., Nagoya City University School of Medicine (until March 2005) Takayuki Fukui, M.D., Nagoya University School of Medicine (as of April 2005) Toshihiko Yokoyama, M.D., Nagoya University School of Medicine (as of April 2005) Naohito Sato, M.D., Nagoya University School of Medicine (as of April 2005) Tetsuo Taniguchi, M.D., Nagoya University School of Medicine (as of May 2005) Yasuhiro Goto, M.D., Nagoya University School of Medicine (as of Aug. 2005) General Summary

Our goal is to determine the genetic lesions giving rise to human solid cancers and use this information for prevention, diagnosis, and treatment of these diseases. Currently, we are focusing on lung cancer, malignant mesothelioma, colon cancer, and hepatomas. Our studies also provide opportunities to dissect biochemical and pathological pathways of malignant phenotypes, related to dysregulated cell growth, differentiation, invasion, and metastasis. Human cancers arise because of genetic mutations in protooncogenes and tumor suppressor genes, and our approach is to focus on candidate genes, systematically analyses of molecular biochemical pathways, and apply microarray analysis of global gene expression and comparative genomic hybridization technique for identifica-tion of chromosomal abnormalities. Epigenetic changes due to DNA methylation and histone modi-fication are also important mechanisms of inactivation of tumor suppressor genes. We also func-tionally analyze candidate genes by transfecting wild type copies into human cancer cells and test-ing for their ability to suppress malignancy in vitro and in vivo as well as characterizing their pro-tein products biochemically. Alternatively, we inactivate their expression using RNA interference (RNAi) in either tumor or normal cells and then study their phenotype. Understanding the func-tions of genes which are mutated and the signaling pathways disrupted is necessary to provide a firm foundation for a translational research approach to human malignancies, from bench to bed-side.

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1. EGFR mutation is frequently detected in non-small cell lung cancer with occa-sional genetic events of second muta-tion or amplification

Yokoyama, T., Kondo, M.*1, Goto, Y., Fukui, T., Sato, N., Taniguchi, T., Kondo, Y., Osada, H., Yokoi, K. *2, T. Shimokata, K.*1, and Sekido, Y.

Non-small cell lung cancer (NSCLC) is one of the leading causes of death from neoplasia in Japan and western countries. As chemotherapy can only marginally prolong survival among patients with advanced disease, molecular target therapy appears the most promising clinical option. The epidermal growth factor receptor (EGFR), one of the ERBB family of receptors, is a particularly promising tar-get, because of its frequent overexpression (range, 40-80%) in NSCLCs and relation to a poor progno-sis. Small molecule tyrosine kinase inhibitors (TKIs) of EGFR such as gefitinib and erlotinib have been shown to have anti-tumor activity and several clinical studies have revealed that Japanese, female, never-smoking patients with adenocarcinoma have a high response rate to gefitinib. We have analyzed mutation and/or amplification of EGFR, HER2, and KRAS, which are involved in EGFR signaling cas-cades, among resected primary NSCLCs from Japanese patients and determined whether there is a correlation with clinicopathological factors. EGFR mutations were found in 102 (29%) of a total of 349 tumors, and 7 tumors had two missense mu-tations. Reverse transcriptase-polymerase chain reaction of EGFR and subsequent subcloning analyses idemonstrated the double mutations in the same allele, since we found both mutations in most mutation-positive cDNA clones. Furthermore, in 202 NSCLCs analyzed by Southern blotting, 11 (5.4%) exhibited amplification of EGFR, with 8 tumors containing an EGFR mutation. Sequence analysis detected only weak or no signals of the wild-type allele in the 8 tumors, strongly suggesting the mutated allele to be selectively amplified. These findings indicate that a dual genetic change of EGFR can occur in the same allele either with a possible second-hit mutation or amplification, which may imply a more selective growth advan-tage in cancer cells. At the same time, HER2 mu-tation and amplification were found in 6 (1.7%) of 349 tumors and 3 (1.5%) of 202 tumors, respec-tively, and KRAS mutations in 21 (6%) of 349 tu-mors. Mutations of the EGFR and HER2 genes were more frequently found in female, never or light smoking patients with adenocarcinomas, and

there were no tumors that had two or more EGFR, HER2, and KRAS mutations. Our study further demonstrated that a double genetic event of EGFR can occasionally occur in lung cancer, thus provid-ing new clues to the understanding of the involve-ment of EGFR signaling cascades in the pathogene-sis of NSCLCs. *1 Department of Respiratory Medicine, Nagoya Uni-

versity Graduate School of Medicine *2 Division of General Thoracic Surgery, Nagoya Uni-

versity Graduate School of Medicine 2. The ASH1 gene is a specific therapeutic

target for lung cancers with neuroen-docrine features

Osada, H., Tatematsu, Y., Yatabe, Y.*1, Horio, Y.*2, and Takahashi, Ta.*3

Lung cancers with neuroendocrine (NE) fea-tures are usually aggressive, although the underly-ing molecular mechanisms largely remain to be de-termined. The basic-helix-loop-helix protein, achaete-scute complex-like 1 (ASCL1)/ achaete-scute homolog 1 (ASH1), is expressed in normal fetal pulmonary NE cells and lung cancers with NE elements, and is suggested to be involved in lung carcinogenesis. We have shown inhibition of ASH1 expression by plasmid-based RNAi to significantly suppress growth of lung cancer cells with ASH1 expression through G2/M-cell cycle ar-rest and accumulation of sub-G1 populations, pos-sibly linked to cleavage of caspase-9 and caspase-7. However, lung cancer cell lines without ASH1 ex-pression and an immortalized normal BEAS-2B bronchial epithelial cells were not affected. The RNAi-resistant mutant ASH1 clearly induced res-cue from G2/M-arrest, suggesting a target-specific effect of RNAi. An ASH1-RNAi adenovirus was also established, and shown to significantly inhibit not only in vitro cell proliferation but also in vivo xenograft growth of ASH1-positive NCI-H460 cells. Elevated levels of apoptosis were also observed in NCI-H460 xenografts with the ASH1-RNAi-adenovirus. Our present studies therefore suggest that ASH1 plays a crucial role in lung cancer development and may be an effective therapeutic target in lung cancers with NE features. *1 Department of Pathology and Molecular Diagnostics,

Aichi Cancer Center Hospital *2 Department of Thoracic Oncology, Aichi Cancer

Center Hospital

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*3 Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya Univer-sity Graduate School of Medicine.

3. A polycistronic miRNA cluster, miR-17-

92, is overexpressed in human lung cancers and enhances cell proliferation

Hayashita, Y.*1, Osada, H., Tatematsu, Y., Yamada, H.*2, Yanagisawa, K.*2, Tomida, S.*2, Yatabe, Y.*3, Kawahara, K.*1, Sekido, Y., and Takahashi Ta.*2.

MicroRNAs (miRNAs) are small, non-coding RNAs, thought to be involved in physiological and developmental processes by negatively regulating expression of target genes. We have previously reported frequent down-regulation of the let-7 miRNA family in lung cancers and in the present study assessed alteration in a panel of 19 lung can-cer cell lines. Using Northern blot and quantita-tive RT-PCR analyses, we found for the first time that the miR-17-92 cluster, which comprises six miRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, miR-92-1) and resides in intron 3 of the C13orf25 gene at 13q31.3, is markedly overex-pressed in lung cancers, especially examples with small cell lung cancer (SCLC) histology. The paralogous clusters, miR-106a-92 (Xq26.2) or miR-106b-25 (7q22), did not show significant alteration of their expression in lung can-cers. Southern blot analysis revealed the presence of in-creased gene copy numbers of the miRNA cluster in a fraction of lung cancer cell lines with overexpression. In addition, we were able to show predominant localiza-tion of C13orf25 transcripts within the nuclei, introduc-tion of the expression con-struct of the miR-17-92 clus-ter, but not the putative open reading frame of C13orf25, enhancing lung cancer cell growth. These findings clearly suggest that marked overexpression of the miR-17-92 cluster with occa-sional gene amplification may play a role in the devel-opment of lung cancers, es-pecially in their most aggres-

sive form, SCLC, and that the C13orf25 gene may well be serving as a vehicle in this regard. *1 Department of Oncological Science (Surgery II),

Oita University Faculty of Medicine *2 Division of Molecular Carcinogenesis, Center for

Neurological Diseases and Cancer, Nagoya Univer-sity Graduate School of Medicine,

*3 Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital.

4. Establishment and characterization of

malignant pleural mesothelioma cell lines from Japanese patients

Fukui, T., Taniguchi, T., Usami, N.*1, Yokoyama, T., Hida, T.*2, and Sekido, Y.

Malignant mesothelioma (MM) is an aggressive neoplasm arising from mesothelial cells, most often occurring in the pleural cavity as malignant pleural mesothelioma (MPM). Owing to the long latency period and the widespread use of asbestos fibers for many years, the incidence of MPM is projected to rise sharply worldwide in the next two decades. In Japan, 500 patients with MM died in 1995, and the number increased to approximately 900 patients in 2003. MM has been demonstrated to be resistant

22

to all of conventional therapy regimens including chemotherapy, radiotherapy and surgery, and the prognosis of patients remains very poor. However, the discrepancy between the rising incidence of MM and the lack of success of new more effective therapeutic strategies seems to be related at least in part to inadequate knowledge of the biological properties of this tumor. It is hoped that a better understanding of MM biology may provide the ra-tionale for new therapeutic strategies. In this re-gard, the development of tumor cell lines has been an important tool in setting up suitable in vitro models for studying the biological properties of many tumors and to assess tumor sensitivity to various drugs or biological response modifiers. However, as opposed to lung cancer for example, where several hundred cell lines have been estab-lished, only a relatively small number of MPM cell lines are available. Furthermore, only a few cell lines have been established from Japanese patients with MPM. We therefore have established four MPM cell lines, ACC-MESO-1, ACC-MESO-4, Y-MESO-8A, and Y-MESO-8D from Japanese patients, with the latter two from the same patient with biphasic-like

characteristics of MPM, showing epithelial and sarcomatous phenotypes in cell culture. Mutation and expression analyses demonstrated that the tu-mor suppressor gene of NF2, which is known to be one of the most frequently mutated in MPMs, is mutated in ACC-MESO-1. We detected homo-zygous deletion of p16 INK4A / p14 ARF in all four MPM cell lines. We also analyzed genetic altera-tions of six other MPM cell lines and confirmed frequent mutations of NF2 and p16 INK4A / p14 ARF. To characterize biological differences between Y-MESO-8A and -8D, we performed cDNA mi-croarray analysis and detected genes that are dif-ferentially expressed in these two cell lines. Thus, our new MPM cell lines seem to be useful as mod-els for studying various aspects of the biology of human MPM as well as materials for development of future therapy. *1 Division of General Thoracic Surgery, Nagoya Uni-

versity School of Medicine *2 Department of Thoracic Oncology, Aichi Cancer

Center Hospital

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First row (from left to right): Dr. Y. Hosokawa, Ms. Y. Kasugai, Dr. M. Sato, Ms. H. Suzuki, Dr. S. Tsuzuki. Second row (from left to right): Dr. Y. Kameoka, Dr. N. Hukuhara, Dr. Y. Nakashima, Dr. A. Oshiro. Third row (from left to right): Dr. H. Tagawa, Dr. R. Suzuki, Dr. M. Nakagawa, Ms. S. Sato, Mr. S. Karnan. Insets (from left to right): Dr. X. Zhang, Dr. K. Mayama, Dr. M. Suguro-Katayama.

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Division of Molecular Medicine ________________________________________________________________________________ Masao Seto, MD., PhD. Chief Yoshitaka Hosokawa, M.D., Ph.D. Section Chief (Until March, 2006) Shinobu Tsuzuki, M.D., Ph.D. Section Chief Ritsuro Suzuki, M.D., Ph.D. Senior Researcher (Until December, 2005) Hiroyuki Tagawa, M.D., Ph.D. Senior Researcher Hiroko Suzuki, B.P. Senior Research Assistant Yumiko Kasugai, B.S. Research Assistant Visiting Trainees Karnan Sivasundaram, Graduate School of Medical Sciences, Nagoya City University Miyuki Suguro-Katayama, MD. The Second Department of Internal Medicine, Mie University School of Medi-cine (Until August, 2004) Koh Mayama, MD. The Third Department of Internal Medicine, Hirosaki University School of Medicine (Until September, 2004) Yoshihiro Kameoka, MD. The Third Department of Internal Medicine, Akita University School of Medicine (Until August, 2005) Masao Nakagawa, MD. The Third Department of Internal Medicine, Hokkaido University School of Medicine (Until September, 2005) Xiaohua Zhang, M.D. Department of Pathology, Yan’an University School of Medicine (Until January, 2004) Yasuhiro Nakashima, MD. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University Aya Oshiro, MD. Second Department of Internal Medicine, University Hospital, University of the Ryukyus Noriko Fukuhara, MD. Department of Rheumatology and Hematology, Tohoku University School of Medicine General Summary

Research in this laboratory is aimed at generating a better understanding of the genetic and molecular bases of human cancer, with eventual application of the acquired knowledge in the field of medical oncology. Our work has been mainly focused on hematologic malignancies, in coopera-tion with physicians of the Department of Hematology and Cell Therapy Aichi Cancer Center Hos-pital (Chief, Dr. Yasuo Morishima). Research on hematologic malignancies have several advantages for exploration of the molecular bases of neoplasia. Chromosomal abnormalities have been ana-lyzed by a large number of researchers and the observed strong association between specific chro-mosome changes and specific hematopoietic tumors provides direct evidence that the resultant gene alterations play a pivotal role in the disease development. Over the last two years, we have concen-trated attention on the following issues.

The function of API2-MALT1 linked to mucosa-associated lymphoid tissue lymphomas is now being studied to identify target genes. An array-CGH (comparative genomic hybridization) that contains 2300 BAC clones on a slide glass that can scan the whole genome every 1.4 MB in aver-age was applied to various kinds of hematopoietic malignancy. Differences in the genome profiles between NK cell leukemias and T/NK cell lymphomas were thereby clarified. Target genes in the 6p21 region amplicon were found to be either CCND3 or BYSL or both. TEL-AML1 leukemias were also analyzed by the array CGH approach and found to also have a characteristic genome pro-file. In vivo oncogenic function of the TEL-AML1 chimeric gene in combination with new onco-genes is being analyzed in a bone marrow transplantation system.

1. Anti-apoptotic action of the API2-

MALT1 fusion protein involved in t(11;18)(q21;q21) MALT lymphomas

Hosokawa, Y., Suzuki, H. and Seto, M.

t(11;18)(q21;q21) is a characteristic chromoso-

mal translocation in the mucosa-associated lym-phoid tissue (MALT) type lymphoma, which results in fusion transcripts of APoptosis Inhibitor 2 (API2), also known as c-IAP2, and Mucosa-Associated Lymphoid Tissue translocation gene 1 (MALT1). Although API2-MALT1 has been shown to enforce

25

activation of NF-κB signaling, the transcriptional target genes of this fusion protein remain to be identified. Our analyses of API2-MALT transfectants have suggested that one target gene may be the apoptotic inhibitor API2 gene. Luciferase reporter assays with deletion and mutational constructs of the API2 promoter and electrophoretic mobility shift assays (EMSA) established that API2-MALT1 induces transcriptional activation of the API2 gene through two NF-κB binding elements. Moreover, super-shift experiments indicated that these elements are recognized by the NF-κB p50/p65 heterodimer. Taken together, our results strongly indicate that API2-MALT1 possesses a novel mechanism of self-activation by up-regulating its own expression in t(11;18)(q21;q21)-carrying MALT lymphomas, highlighting a positive feedback-loop pathway re-sulting in sustained NF-κB activation. We also demonstrated that API2-MALT1 pos-sesses an anti-apoptotic effect, in part through direct interactions with apoptotic regulators. These findings therefore have led us to hypothesize that the anti-apoptotic effect of API2-MALT1 may be mediated by its interaction with apoptotic regulators on the one hand as well as by NF-κB-mediated upregulation of apoptotic inhibitor genes on the other. We have also established that BCL10 and MALT1 shuttle between the nucleus and cytoplasm, and that MALT1 can regulate the subcellular loca-tion of BCL10. It is hoped that further studies will facilitate de-velopment of therapeutic drugs that specifically in-hibit the antigen receptor signaling pathway. CARMA1 and MALT1 represent promising mo-lecular targets, because knock-out mice for these molecules exhibit defects that are exclusively re-stricted to this pathway. Recent studies also indi-cated that self-oligomerization of API2-MALT1 fu-sion proteins results in deregulated ubiquitin ligase activity of MALT1, thereby leading to NF-κB acti-vation. Thus, the development of specific inhibi-tors of API2-MALT1 ubiquitin ligase would be also beneficial for the treatment of MALT lymphoma. Such drugs would be expected to inhibit, with con-trollable side-effects, inappropriate growth and ex-pansion of lymphoma clones. 2. Molecular pathways leading to t(12; 21)

TEL-AML1 associated leukemias Tsuzuki, S. and Seto, M.

The t(12; 21) translocation which generates the

TEL-AML1 (ETV6-RUNX1) fusion gene is the commonest structural chromosome change in childhood cancer and is exclusively associated with the common, B cell progenitor subset of acute lymphoblastic leukemias (ALLs). Evidence sug-gests that the translocation usually occurs in utero during foetal haematopoiesis and most probably constitutes an initiating or “first hit” mutation which is necessary but itself insufficient for the de-velopment of overt, clinical leukemia. In our search for additional “second hit” muta-tions that could be linked to leukemia development, we applied a genome-wide array-CGH technique to 24 TEL-AML1 leukemia samples and two cell lines and found that at least three chromosomal imbal-ances were involved in all samples. The results suggest that, in addition to TEL previously reported as lacking, genes involved in cell cycle regulation (p16INK4a/ARF, BTG1), p53 pathways and apop-tosis are also often deleted. To delineate the roles of deregulated cell cy-cle/p53/apoptosis pathways in leukemia develop-ment, we have developed retroviral vectors to ex-press TEL-AML1 along with a second gene or siRNAs. We are currently investigating the coop-erative roles of the “first” and “second” hits for leukemia development in mice.

3. Cloning of a translocation partner of t(1;14)(p33;q32) in diffuse large B-cell lymphoma

Suzuki, R., Nakamura, S. *1 and Seto, M.

Several oncogenes, such as cyclin D1, BCL2, BCL6, and c-Myc, are activated by the immu-noglobulin heavy chain (IgH) gene in B-cell lym-phomas. We have therefore focused on the translo-cation partner of the IgH gene in t(1;14)(p33;q32) identified as a novel translocation in diffuse large B-cell lymphoma. High molecular weight DNA was extracted from a frozen sample, and long distance inverse PCR technique was employed for cloning. The cloned genomic sequence matched the chro-mosome 1p34 sequence on database search. No known gene existed around the breakpoint on 1p34, but the expression of one EST was highly activated in the tumor sample. Performance of 5’- and 3’-RACE allowed a non-coding RNA spanning more than 20kb to be cloned as the partner. The presence of micro RNA was further investigated, but we could not identify any known or novel micro RNA. Although the mechanism and the significance of expression of non-coding RNA have yet to be

26

fully elucidated, lymphomagenesis by t(1;14)(p33;q32) apparently features a novel and previously unrecognized mechanism, which war-rants further investigation. *1 Department of Pathology and Molecular Diagnostics,

Aichi Cancer Center Hospital, Aichi, Japan 4. Comparison of genome profiles for

identification of distinct subgroups of diffuse large B-cell lymphoma

Tagawa, H., Suguro-Katayama, M., Tsuzuki, S., Morishima, Y. *1 and Seto, M.

Diffuse large B-cell lymphoma (DLBCL) com-prise distinct molecularly subgroups such as acti-vated B-cell-like (ABC) and germinal center B-cell-like (GCB) forms. We previously reported that CD5+ and CD5-CD10+ DLBCL constitute clinically relevant subgroups. To determine whether these two subgroups are related to ABC and GCB DLBCL, we analyzed the genomic imbalance of 99 cases (36 CD5+, 19 CD5-CD10+ and 44 CD5-CD10-) using array-CGH. Some 46 of these cases (22 CD5+, 7 CD5-CD10+ and 17 CD5-CD10-) were subsequently subjected to gene expression profiling, resulting in their division into 28 ABC (19 CD5+ and 9 CD5-CD10-) and 18 GCB (3 CD5+, 7 CD5-CD10+ and 8 CD5-CD10-) types. A com-parison of genome profiles of distinct subgroups of DLBCL demonstrated that: i) the ABC DLBCL is characterized by gain of 3q, 18q and 19q and loss of 6q and 9p21, and the GCB DLBCL by gain of 1q, 2p, 7q and 12q; ii) the genomic imbalances charac-teristic of the CD5+ and CD5-CD10+ groups are similar to those of the ABC and GCB types, respec-tively. These findings suggest that CD5+ and CD5-CD10+ subgroups are included, respectively, in the ABC and GCB types. Finally, on searching for genomic imbalances that affect patients’ prog-nosis, we found that 9p21 loss (p16INK4a locus) marks the most aggressive type of DLBCL. *1 Department of Hematology and Cell Therapy, Aichi

Cancer Center Hospital, Nagoya, Aichi. 5. Genome-wide array-based comparative

genomic hybridization of natural killer cell lymphoma/leukemia: different ge-nomic alteration patterns of aggressive

NK-cell leukemia and extranodal NK/T-cell lymphoma, nasal type

Nakashima, Y., Tagawa, H., Suzuki, R., Karnan, S., Karube, K.*1, Ohshima, K. *1, Muta, K. *2, Nawata, H. *2, Morishima, Y. *3, Nakamura, S. *4 and Seto, M.

Natural killer (NK) cell lymphomas/leukemias are highly aggressive lymphoid malignancies, but little is known about their genomic alterations, and thus there is an urgent need for identification and analysis of NK cell lymphomas/leukemias. Re-cently, we developed our own array-based com-parative genomic hybridization (array CGH) with an average resolution of 1.3 Mb. We performed an array CGH analysis for 27 NK-cell lym-phoma/leukemia cases that were classified into two disease groups based on the World Health Organi-zation Classification (10 aggressive NK-cell leuke-mia cases and 17 extranodal NK/T-cell [NK/T] lymphomas, nasal type). We identified the differ-ences in the genomic alteration patterns of the two groups. The recurrent regions characteristic of the aggressive NK-cell leukemia group compared with those of the extranodal NK/T lymphoma, nasal type group, were gain of 1q and loss of 7p15.1-p22.3 and 17p13.1. In particular, gain of 1q23.1-q24.2 (P= 0.041) and 1q31.3-q44 (P= 0.003-0.047), and loss of 7p15.1-p22.3 (P= 0.012 - 0.041) and 17p13.1 (P= 0.012) occurred significantly more frequently in the former than in the latter group. Recurrent regions characteristic of the extranodal NK/T lymphoma, nasal-type group, compared with those of the other group were gain of 2q, and loss of 6q16.1-q27, 11q22.3-q23.3, 5p14.1-p14.3, 5q34-q35.3, 1p36.23- p36.33, 2p16.1-p16.3, 4q12, and 4q31.3-q32.1. Our results can be expected to provide further insights into the genetic basis of lymphomagenesis and the clinicopathologic features of NK-cell lympho-mas/leukemias. *1 Department of Pathology, School of Medicine, Fu-

kuoka University, Fukuoka, Japan *2 Department of Medicine and Bioregulatory Science,

Graduate School of Medical Sciences, Kyushu Uni-versity, Fukuoka, Japan

*3 Department of Hematology and Chemotherapy, Aichi Cancer Center Hospital, Aichi, Japan

*4 Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Aichi, Japan

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The 11th Aichi Cancer Center International Symposium “Forefront of Cancer Prevention Strategy in Asia,” held on February 5, 2005.

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From left to right First row: Dr. Y. Akatsuka, Dr. K. Kuzushima, Dr. K. Tsujimura, Ms. Y. Matsudaira Second row: Ms. T. Tsuboi, Dr. H. Torikai, Ms. F. Ando, Dr. Demachi-Okamura, Ms. K. Nishida, Dr. Y.

Ito, Dr. T. Kawase, Ms. Y. Nakao, Dr. S. Morishima Insets: Dr. R. Ohta, Dr. M. Miyazaki, Dr. Y. Okanami, Dr. H. Miyauchi, Ms. K. Watanabe, Dr. S. Shi-

mato, Ms. M. Nakayama

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Division of Immunology ________________________________________________________________________________ Kiyotaka Kuzushima, M.D. Chief Yoshiki Akatsuka, M.D. Section Head Kunio Tsujimura, M.D. Section Head Yoshinori Ito, M.D. Senior Researcher Ayako Demachi-Okamura, Ph.D. Research Resident Rieko Ohta, Ph.D. Research Resident (as of August 2004, until June 2005) Yasue Matsudaira, B.S. Senior Research Assistant Keiko Nishida, B.P. Senior Research Assistant Tomiko Tsuboi, Semi-regular Employee Yumi Nakao, Semi-regular Employee Fumiyo Ando, Semi-regular Employee (as of August 2004) Michiyo Nakayama, Semi-regular Employee (as of February 2004) Visiting Scientists Yuichi Obata, Ph.D. Department of Biological Systems, RIKEN BioResource Center Kazuhiro Yoshikawa, B.M.T., M.D. Second Department of Pathology, Aichi Medical University Visiting Trainees Mikinori Miyazaki, M.D. Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences Hiroki Torikai, M.D. Third Department of Internal Medicine, National Defense Medical College Yuko Okanami, M.D. First Department of Surgery, Mie University School of Medicine (until March 2005) Satoko Morishima, M.D. Cancer Genetics, Nagoya University Graduate School of Medicine Takakazu Kawase, M.D. Cancer Genetics, Nagoya University Graduate School of Medicine Hidemasa Miyauchi, M.D. Blood Purification Center, JISHOKAI Health System, Inc. Kazue Watanabe, M.S. Medical & Biological Laboratories Co., Ltd. (as of June 2005) Shinji Shimato, M.D. Department of Neurosurgery, Nagoya University Graduate School of Medicine (as of September 2005) General Summary The object of our research is to characterize and understand T lymphocyte responses to an-tigens expressed on cancer and virus-infected cells. The major projects undertaken over the past two years are summarized below. In the field of human immunology, four projects are continuing with the focus on epitope identification and fine characterization of processing of the epitopes recognized by cancer- and vi-rus-targeting cytotoxic T lymphocyte (CTLs). Firstly, an HLA-A*2402-restricted CTL epitope was determined in the epithelial cell adhesion molecule, which is expressed in almost all carcinomas. Secondly, precise roles of interferon (IFN)-γ inducible immunoproteasome-associated molecules in generation of a CTL epitope derived from Epstein-Barr virus latent membrane protein 2A were elu-cidated. Unequivocal involvement of the immunoproteasome subunit low molecular weight protein 7 and 2 and the proteasome activator 28 α subunit was confirmed by means of RNA interference gene silencing. Thirdly, a novel HLA-A*3303-restricted male-specific minor histocompatibility an-tigen encoded by an unconventional open reading frame of human TMSB4Y gene was identified. Fourthly, an HLA-A*2402-restricted epitope recognized by CTL targeting the HPV-16 protein was characterized. Interestingly, combined treatment with proteasome inhibitors like bortezomib and IFN-γ dramatically augmented CTL-mediated lysis of SiHa cells carrying HPV. Thus, this may provide a novel approach for CTL-based immunotherapy in cervical cancer patients. To understand the roles of specific immunity to tumor progression in vivo, we have been conducting animal experiments employing the mouse thymus-leukemia antigen (TL) as a model. Both cellular and humoral immune responses to chemical carcinogen-induced lymphomas express-ing the TL were extensively studied using T3b-TL transgenic and parental (B6 and C3H) strains.

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1. Identification of an epitope from the epithelial cell adhesion molecule elicit-ing HLA-A*2402-restricted cytotoxic T lymphocyte responses

Tajima, Ko.*1, Demachi-Okamura, A., Ito, Y., Nishida, K., Akatsuka, Y., Tsujimura, K., Kuwano, H.*1, Mitsudomi, T.*2, Takahashi, To.*3 and Kuzushima, K.

Since the epithelial cell adhesion molecule (Ep-CAM) is expressed in almost all carcinomas and human leukocyte antigen (HLA)-A*2402 is the most common allele in many ethnic groups, includ-ing Japanese, identification of peptide sequences which elicit HLA-A*2402-restricted Ep-CAM- specific CTL responses should facilitate specific immunotherapy for various histological types of carcinomas. We have focused on identifying an epitope through the following steps: (a) com-puter-based epitope prediction from the amino acid sequence of Ep-CAM; (b) MHC stabilization assays to determine the affinity of predicted peptides with HLA-A*2402 molecules; (c) stimulation of CD8+ T cells with peptide-pulsed dendritic cells; (d) testing CTL specificity by enzyme-linked immunospot (ELISPOT) assays, CTL assays and MHC/peptide- tetramer staining (Fig. 1). Peripheral CD8+ T cells of 4 of 5 healthy donors after 3 rounds of stimula-tion with the peptide Ep-CAM173-181 (RYQLDPKFI) were found to secrete IFN-γ in ELISPOT assays. A CTL clone specific for one peptide efficiently lysed Ep-CAM-expressing cancer cell lines in an HLA-A*2402-restricted fashion and endogenous

processing and presentation of the peptide in a lung cancer cell line could be confirmed by cold target inhibition assays. The CTL clone was also lytic to normal bronchial epithelial cells but to a lesser ex-tent at low effector : target ratios. All these data suggest that peptide-specific CTL responses may play roles in both anti-cancer and autoimmune reac-tions. Our peptide should prove useful to study anti-Ep-CAM CTL responses among populations possessing HLA-A*2402. *1 Department of Surgery I, Gunma University Faculty

of Medicine *2 Department of Pulmonary Medicine, Aichi Cancer

Center Hospital *3 President, Aichi Cancer Center 2. Three immunoproteasome-associated

subunits cooperatively generate a CTL epitope of the EBV-LMP2A by over-coming specific structures resistant to epitope liberation

Ito, Y., Kondo, E.*1, Demachi-Okamura, A., Akatsuka, Y., Tsujimura, K., Tanimoto, M.*1, Morishima, Y.*2, Takahashi, To.*3 and Kuzushima, K.

Precise roles of interferon-γ inducible immuno-proteasome-associated molecules in generation of cytotoxic T lymphocyte (CTL) epitopes have yet to be fully elucidated. We describe here a unique epitope derived from the Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) presented by

Fig. 1. Tetramer staining of Ep-CAM pep-tide-specific poly- and monoclonal CTLs.A, Polyclonal CD8+ T cells after stimulation 4times with an Ep-CAM derived peptideRYQLDPKFI (Ep173), were stained withFITC-labeled anti-CD8 antibodies andPE-labeled HLA-A24-tetramers incorporatingEp173 or a control peptide RYLRDQQLL(ENV584), derived from HIV envelope protein.Percentages of tetramer-positive cellsamong total CD8+ T cells are shown at theupper right in each case. B, AnEp173-specific CTL clone was stained as de-scribed above. The percentages oftetramer-positive cells among total CD8+ Tcells are shown at the upper right in eachcase.

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HLA-A*2402 molecules. Generation of the epitope, designated LMP2A222-230, from the full length pro-tein requires the immunoproteasome subunit low molecular weight protein 7 (ip-LMP7) and the pro-teasome activator 28 α subunit, and is accelerated by ip-LMP2, as revealed by gene expression ex-periments using an LMP2A222-230-specific CTL clone as a responder in enzyme-linked immunospot assays. Unequivocal involvement of all three com-ponents was confirmed by means of RNA interfer-ence gene silencing. Interestingly, the LMP2A222-230 epitope could be efficiently generated from incomplete EBV-LMP2A fragments produced by puromycin treatment, or gene-engineered short-ened EBV-LMP2A lacking some of its hydrophobic domains. In addition, epitope generation was in-creased by a single amino acid substitution from leucine to alanine immediately flanking the C-terminus, this being predicted by a web-accessible program to increase the cleavage strength. Taken together, the data indicate that gen-eration of LMP2A222-230 is not only influenced by extrinsic influences such as immunoproteasomes, but also by intrinsic factors such as the length of the EBV-LMP2A protein and proteasomal cleavage strength at specific positions in the source antigen. *1 Department of Internal Medicine II, Okayama Univer-

sity Graduate School of Medicine and Dentistry *2 Department of Hematology and Cell Therapy, Aichi

Cancer Center Hospital *3 President, Aichi Cancer Center

3. A novel HLA-A*3303-restricted minor histocompatibility antigen encoded by an unconventional open reading frame of the human TMSB4Y gene

Torikai, H.*1, Akatsuka, Y., Miyazaki, M.*2, Warren, E.H.*3, Oba, T.*4, Tsujimura, K., Motoyoshi, K.*1, Morishima, Y.*5, Kodera, Y.*4, Kuzushima, K. and Takahashi, To.*6

Minor histocompatibility (H) antigens are MHC (HLA in human)-associated peptides originating mainly from polymorphisms in the genome that trigger T cell responses between MHC identical al-logeneic individuals. Graft-versus-host disease and graft-versus-leukemia/lymphoma (GVL) effects in hematopoietic stem cell transplant recipients are initiated by donor T cell recognition of minor H an-tigens on recipient cells. In the setting of fe-male-to-male hemopoietic stem cell transplantation (HSCT), T cell responses against male-specific mi-

nor H (H-Y) antigens encoded by the Y chromo-some are elicited frequently. All previously identi-fied H-Y antigens have been found to be encoded by conventional open reading frames. We here isolated an HLA-A*3303-restricted CD8+ CTL clone termed 1B6 from a male patient after HSCT from his HLA-identical sister. By ex-amining the lytic patterns of EBV-transformed cell lines carrying various Y chromosome terminal de-letions by clone 1B6, a narrow region containing 5 candidate genes was localized. Further correlation studies between the lytic patterns of the cell lines by 1B6 and mRNA expression levels from genes of the mapped region in these cell lines successfully iden-tified a gene encoding the minor H antigen, TMSB4Y. Minigene transfection and epitope recon-stitution assays allowed determination of an 11-mer peptide, EVLLRPGLHFR, designated TMSB4Y/A33. Surprisingly, its first amino acid was located 405 bp upstream of the TMSB4Y ini-tiation codon (Fig. 2A). Analysis of the precursor frequency of CTL specific for recipient minor H antigens in post-HSCT peripheral blood T cells us-ing limiting dilution methods revealed that a sig-nificant fraction of the total donor CTL response in this patient was directed against the TMSB4Y epi-tope (30% and 10% at days 50 and 146 post-HCT, respectively, Fig. 2B and C). Tetramer analysis continued to detect TMSB4Y/A33-specific CD8+ T cells at least up to 700 days post-HSCT, indicating the TMSB4Y/A33 epitope to indeed be immuno-genic. This finding underscores the in vivo immu-nological relevance of minor H antigen derived from unconventional open reading frame products. Because 1B6 preferentially lysed target cells of hematopoiesis origin, despite relatively ubiquitous expression of TMSB4Y in various tissues, this mi-nor H antigen might be involved in GVL rather than GVHD. *1 Third Department of Internal Medicine, National De-

fense Medical College *2 Department of Internal Medicine and Molecular Sci-

ence, Nagoya City University Graduate School of Medical Sciences

*3 Division of Immunology, Fred Hutchinson Cancer Research Center

*4 Department of Hematology, Japanese Red Cross Na-goya First Hospital

*5 Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital

*6 President, Aichi Cancer Center

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4. Combination of bortezomib and inter-feron-γ induces presentation of a newly identified HLA-A24-restricted human papillomavirus type 16 E6-specific cy-totoxic T cell epitope

Morishima, S.*1, Akatsuka, Y., Nawa, A.*2, Kondo, E.*3, Kiyono, T.*4, Torikai, H.*5, Nakanishi, T.*2, Ito, Y., Tsujimura, K., Iwata, K.*6, Ito, K.*7, Kodera, Y.*8, Morishima, Y.*9, Kuzushima, K. and Takahashi, To.*10

Around 50% of cervical cancers are associated with human papillomavirus type 16 (HPV-16) and since the HPV-16 E6 and E7 oncoproteins are con-stitutively expressed in tumor cells, they are attrac-tive targets for cytotoxic T lymphocyte (CTL)-mediated immunotherapy. Nevertheless, only a limited number of HPV-16 E6 epitopes have so far been identified. Using reverse immunological methods, we have generated a CTL clone against the HPV-16 E649-57 epitope restricted by HLA-A*2402, which is the most common allele in Japan and worldwide. The CTL clone was found able to lyse 293T cells transduced with

HLA-A*2402 and HPV-16 E6, but could not rec-ognize the SiHa cervical cancer cell line positive for HPV-16 and HLA-A*2402. However, SiHa cells transduced with the E6-E7 genes did become sus-ceptible to lysis, suggesting insufficient generation of antigenic peptides in the cell line. Interestingly, combined treatment with proteasome inhibitors, bortezomib or epoxomicin, and interferon (IFN)-γ, fully restored CTL-mediated lysis of SiHa cells. Furthermore, pretreatment of three of four other cervical cancer cell lines expressing HPV-16 E6 and HLA-A*2402 with bortezomib and IFN-γ in-duced cytokine production by specific CTLs. Un-expectedly, HPV-16 E6 levels were found to be de-creased with the combined treatment. These data suggest that impaired presentation of the E649-57 epitope is most likely due to peptide destruction by proteasomes. Thus, combined treatment with a pro-teasome inhibitor and IFN-γ may further provide a novel approach for CTL-based immunotherapy in cervical cancer patients. *1 Cancer Genetics, Nagoya University Graduate School

of Medicine

Fig. 2. A, Genomic organization of TMSB4Y and the relationship with its mRNA. E1 and E2 indicate exons1 and 2, respectively. The conventional ORF is indicated below the mRNA as cORF and the location ofidentified epitope is shown below the 5'UTR of TMSB4Y cDNA. B and C, The proportions of CTL precur-sors specific for the identified TMSB4Y peptide among total CTLp against the recipient minor H antigenswas quantitated using a standard limiting dilution assay. The CTLp frequencies against recipient PHAblasts (open circles) or donor PHA blasts pulsed with TMSB4Y peptide (closed triangles) or unpulsed(open triangles) were calculated with L-Calc software.

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*2 Department of Gynecology and Oncology, Aichi Cancer Center Hospital

*3 Department of Internal Medicine II, Okayama Univer-sity Graduate School of Medicine and Dentistry

*4 Virology Division, National Cancer Center Research Institute

*5 Third Department of Internal Medicine, National De-fense Medical College

*6 Iwata Hospital *7 Sakae Obstetrics and Gynecology Clinic *8 Department of Hematology, Japanese Red Cross Na-

goya First Hospital *9 Department of Hematology and Cell Therapy, Aichi

Cancer Center Hospital *10 President, Aichi Cancer Center 5. Immunity against the mouse thy-

mus-leukemia antigen (TL) protects against development of lymphomas in-duced by a chemical carcinogenic agent, N-butyl-N-nitrosourea

Tsujimura, K., Obata, Y.*1, Matsudaira, Y., Taguchi, O.*2, Nishida, K., Okanami, Y.*3, Akatsuka, Y., Kuzushima, K. and Takahashi, To.*4

Mouse thymus-leukemia antigens (TL) are aberrantly expressed on T lymphomas in C57BL/6 (B6) and C3H/He (C3H) mice, but not on normal T

lymphocytes in these strains. When N-butyl-N-nitrosourea (NBU), a chemical carcino-gen, was administered orally to B6 and C3H strains, lymphoma development was slower than in T3b-TL gene-transduced counterpart strains expressing TL ubiquitously as self-antigens, suggesting that anti-TL immunity may play a protective role. In addition, the development of lymphomas was slightly slower in C3H than in B6, in accordance with the results of skin graft experiments indicating both cellular and humoral immunities against TL to be stronger in the C3H strain. The interesting find-ing that B lymphomas derived from a T3b-TL transgenic strain (C3H background) expressing a very high level of TL were rejected in C3H, but not in H-2Kb transgenic mice (C3H background), raises the possibility that TL-specific effector T cell populations are eliminated and/or anergized to a certain extent by interacting with H-2Kb molecules. *1 Department of Biological Systems, RIKEN BioRe-

source Center *2 Division of Molecular Pathology, Aichi Cancer Center

Research Institute *3 First Department of Surgery, Mie University School

of Medicine *4 President, Aichi Cancer Center

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From left to right First row: Dr. N. Shitara, Dr. S. Iwahori, Mr. K. Ohtake, and Dr. T. Tsurumi. Second row: Mr. J. Ohtsuka, Dr. A. Kudoh, Mr. L. Zhang, Dr. T. Daikoku, Dr. H. Isomura, Dr. S. Nakasu,

and Mr. Y. Nishikawa.

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Division of Virology __________________________________________________________________ Tatsuya Tsurumi, M.D. Chief Shou Nakasu, PhD. Senior Researcher Hiroki Isomura, M.D. Senior Researcher Tohru Daikoku, Ph.D. Senior Researcher (until March 2006) Yutaka Sugaya, PhD. Research Resident (until March 2005) Noriko Shirata, PhD. Research Resident (until March 2006) Satoko Iwahori, PhD. Research Resident (as of April 2005) Yasuhiro Nishikawa. Research Assistant Ayumi Kudoh, Ph.D. Research Fellow of the Japanese Society for the Promotion of Science Visiting Trainees Zhan lumen. M.S. Department of Virology, Nagoya University Graduate School of Medicine General Summary

Approximately 15% of all human cancers have a viral etiology, but only six vi-ruses have actually been implicated in their development. Among these the Ep-stein-Barr virus (EBV) is the object of our own studies. EBV is a ubiquitous gamma herpesvirus associated with several malignant diseases, including Burkitt’s lymphoma, nasopharyngeal lymphoma, a subset of Hodgkin’s lymphomas, some gastric cancers, and B cell lymphomas in immunosuppressed patients. Our research aims are to eluci-date the molecular mechanisms of viral proliferation and oncogenesis of EBV as part of the world-wide effort to combat virus-infected cancers. During the period 2004-2005, our research interest was concentrated on the following issues: 1) Architecture of EBV replication compartments; 2) EBNA1 binding to oriP during EBV latent and lytic rep-lications; 3)Activation of DNA damage checkpoint signal transduction elicited by EBV genome replication; 4)Interaction between p53 and EBV-encoded immediate-early pro-tein BZLF1; 5) Analysis of the human cytomegalovirus major immediate-early enhan-cer and promoter.

1. Epstein-Barr virus lytic replication elic-its ATM checkpoint signal transduction while providing an S-phase-like cellular environment

Kudoh, A. and Tsurumi, T.

When exposed to genotoxic stress, eukaryotic cells demonstrate a DNA damage response with delay or arrest of cell-cycle progression, providing time for DNA repair. We have established that in-duction of the Epstein-Barr virus (EBV) lytic pro-gram elicits a cellular DNA damage response, with activation of the ataxia telangiectasia-mutated (ATM) signal transduction pathway. Activation of the ATM-Rad3-related (ATR) replication check-point pathway, in contrast, is minimal. The DNA damage sensor Mre11-Rad50-Nbs1 (MRN) com-plex and phosphorylated ATM are recruited and re-tained in viral replication compartments, recogniz-ing newly synthesized viral DNAs as abnormal DNA structures. Phosphorylated p53 also becomes

concentrated in replication compartments where it physically interacts with viral BZLF1 protein. De-spite the activation of ATM checkpoint signaling, we found p53-downstream signaling to be blocked, with rather high S-phase CDK activity associated with progression of lytic infection. Therefore, al-though host cells activate ATM checkpoint signal-ing with response to the lytic viral DNA synthesis, we conclude that the virus can skillfully evade this host checkpoint security system and actively pro-mote an S-phase-like environment advantageous for viral lytic replication. 2. Dynamics of Epstein-Barr virus EBNA1

protein binding to the viral genome and the architecture of replication com-partments formed during lytic replica-tion

Daikoku, T. and Tsurumi, T.

Epstein-Barr virus (EBV), a lymphotropic hu-

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man herpesvirus, possesses two life styles; latent and lytic infections. During latent infection, EBV genomes are maintained as double-stranded DNA episomes, and replicated once per cell cycle during the S phase, following the rules of chromosome replication. The viral latent gene product, EBNA1, binds directly to the latent replication origin, oriP, as a homodimer but lacks any activity predicted to be required for replication initiation. Lytic replica-tion differs from the latent amplification state in that multiple rounds of replication are initiated within the lytic replication origin, oriLyt, and the replication process has a greater dependence on seven EBV-encoded lytic replication proteins. A low level of EBNA1 transcripts is still produced during the viral productive cycle. Understanding protein-DNA interactions in vivo at origins of DNA replication throughout the cell cycle and lytic repli-cation may shed further insight on EBNA1 func-tions on replication control. Our focus has therefore been on EBNA1 bind-ing to the EBV genome-wide mapping through la-tent and lytic replication by ChIP assay. We thereby found that EBNA1 binds to the oriP region of the EBV genome throughout the cell cycle. Even after induction of lytic replication EBNA1 still continues to bind to oriP. From confocal microscopy analyses, lytic DNA replication occurs at discrete sites in nu-clei, called replication compartments, where viral replication proteins are clustered. During lytic rep-lication, no chromosomal DNA replication occurs. In latent infection EBNA1 could be shown to be distributed broadly in nuclei as fine punctate dots with weak, diffuse stainig. After induction of lytic replication, EBNA1 was redistributed and clustered to replication compartments with bright granular spots. However, the spots of EBNA1 did not appear to completely coincide with BrdU staining or viral replication proteins, but rather were located side by side with the viral replication proteins and viral progeny DNA. In our study we also performed comprehensive analyses of the architecture of the replication com-partments were EBV productive DNA replication occurs. The BZLF1 oriLyt binding proteins showed a fine, diffuse pattern of distribution throughout the nuclei at immediate-early stages of induction and then became associated with the replicating EBV genome in the replication compartments during lytic infection. The BMRF1 polymerase (Pol) proc-essivity factor showed a homogenous, not dot-like, distribution in the replication compartments, which completely coincided with the newly synthesized

viral DNA. Inhibition of viral DNA replication with phosphonoacetic acid, a viral DNA Pol inhibitor, eliminated the DNA-bound form of the BMRF1 protein, although the protein was sufficiently ex-pressed in the cells. These observations together with the finding that almost all abundantly ex-pressed BMRF1 proteins exist in the DNA-bound form suggest that BMRF1 proteins not only act at viral replication forks as Pol processive factors but also are widely distribute on newly replicated EBV genomic DNA. In contrast, the BALF5 Pol catalytic protein, the BALF2 single-stranded-DNA binding protein, and the BBLF2/3 protein, a component of the helicase-primase complex, were colocalized as distinct dots distributed within replication com-partments, representing viral replication factories. Whereas cellular replication factories are con-structed based on nonchromatin nuclear structures and nuclear matrix, Such viral replication factories could be easily solubilized by DNase I treatment. Thus, compared with cellular DNA replication, EBV lytic DNA replication factories appear simpler so that construction of the replication domain is fa-cilitated. 3. Activation of ATM DNA damage check-

point signal transduction elicited by herpes simplex virus infection

Shirata,N. and Tsurumi, T.

Eukaryotic cells are equipped with machinery to monitor and repair damaged DNA. Herpes simplex virus (HSV) DNA replication occurs at discrete sites in nuclei, considering a replication compart-ment, where viral replication proteins cluster and synthesize large amounts of viral DNA. In our re-cent studies, HSV infection was found to elicit a cellular DNA damage response, with activation of the ATM signal transduction pathway, as observed by autophosphorylation of ATM and phosphoryla-tion of multiple downstream targets including Nbs1, Chk2, and p53, while infection with a UV-inactivated virus or with a replication-defective virus did not. Activated ATM and the DNA damage sensor MRN complex composed of Mre11, Rad50, and Nbs1 were recruited and retained at sites of vi-ral DNA replication, probably due to recognition of newly synthesized viral DNAs as abnormal DNA structures. These events were not observed in ATM-deficient cells, indicating an ATM-dependence for the underlying processes. In Nbs1-deficient cells, HSV infection induced an ATM DNA damage response which was delayed,

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suggesting a functional MRN complex requirement for efficient ATM activation. However, ATM si-lencing had no effect on viral replication in 293T cells. Our data open up the interesting question of how the virus is able to complete its replication, despite host cells activation of ATM checkpoint signaling in response to the HSV infection. 4. Purification of the product of the Ep-

stein-Barr virus BZLF1 gene Nakasu, S. and Tsurumi, T.

The product of the BZLF1 gene (pBZLF1) of the Epstein-Barr virus (EBV) is a nuclear protein which is an activator of the lytic cycle in cells la-tently infected with EBV. pBZLF1 has been sug-gested to play the role as a DNA binding protein specific for the viral lytic origin of DNA replication (ori lyt). In order to understand the contribution of pBZLF1 to induction of the lytic cycle, we focused on purification of the protein and characterization of its biochemical features. We first tried to purify pBZLF1 from insect cells infected with baculovi-ruses which overproduced pBZLF1. But the par-tially purified protein tended to form aggregates and was eluted with a wide range of salt concentrations from ion exchange chromatography columns. The results suggested an abnormal conformation of the pBZLF1 produced in the insect cells so that we next focused on pBZLF1 from B95-8 cells, a cell line latently infected with EBV in which the lytic cycle can be infected. The pBZLF1 could be extracted from the induced cells with high salt buffer (0.6 to 1 M NaCl) and purified more than 100 fold by hy-drophobic, DEAE sephacel, phospho (P) cellulose and hydroxyapatite chromatographies. Most pBZLF1 appeared to be complexed with other pro-teins in low salt buffer (< 0.12 M NaCl) and was eluted from columns with high salt buffer (1.5 M NaCl). The pBZLF1 was further purified with gel filtration and sucrose gradient centrifugation under high salt conditions (1.5 M NaCl) in which it be-haved as a monomer. Though a pBZLF1 sample bound to P cellulose in 0.12 M NaCl buffer was ap-plied to gel filtration and sucrose gradient centrifu-gation, some proportion flowed through P cellulose equilibrated with 0.12 M NaCl buffer after these procedures (FT fraction). The pBZLF1 in the FT fraction bound to DEAE sephacel stronger than be-fore gel filtration and sucrose gradient centrifuga-tion. In addition to these changes in ion exchange chromatographies, the pBZLF1 in the FT fraction

sedimented at a monomer position with sucrose gradient centrifugation under low salt conditions (0.1 M NaCl), indicating existence as a free protein. Starting from 2 l culture, the protein composition of the final fraction (0.2 ml) proved hardly visible by CBB staining of SDS page separation. Therefore a larger scale purification procedure will be required for the further purification. 5. Two Sp1/Sp3 binding sites in the major

immediate-early proximal enhancer of human cytomegalovirus genes are necessary for transcriptional activation and viral replication

Isomura, H. and Tsurumi, T.

HCMV is reactivated under immunosuppressive conditions as with other herpesviruses and progress of medical intensive care has made this virus an important pathogen that causes pneumonitis, hepa-titis, retinitis, and gastrointestinal diseases in im-munocompromized individuals. The molecular mechanisms of HCMV replication, especially in vivo, remain unclear. But it is clear that the major immediate early (IE) genes, IE1 and IE2, are ex-pressed without de novo protein synthesis like other auxiliary IE genes. Furthermore, IE2 is essential. Thus, the cis-elements of the MIE genes are thought to regulate the efficiency for viral replication. We previously reported that replication of re-combinant HCMV was less efficient when the en-hancer was replaced by murine components, even though the human and murine enhancers are posi-tional homologues. Since both have similar ef-fects on the promoter in transient transfection as-says, the results of transfection experiments clearly do not always coincide with expectation of the viral genome. In the present study our goal was to assess the effect of the enhancer and the roles of its individual repeat elements on IE transcription and viral repli-cation in the context of HCMV infection. HCMV has a genome over 200 kbp in length and therefore it is very difficult to make recombi-nant viruses on which specific target genes are mu-tated. However, we recently have developed new genetic engineering in bacteria using homologous recombination. The HCMV genome was cloned into the bacterial artificial chromosome (BAC) in 1999. This has allowed us to construct recombi-nant infectious human CMV DNA containing BAC in vivo in E.coli., whereby mutagenesis can be ma-nipulated. using double-stranded linear fragments

38

amplified by PCR. This is possible because the bacteriophage-encoded recombination proteins exo, beta, and gam efficiently recombine sequences with homologies as short as 35 to 40 bases in the ab-sence of the E.coli RecA protein. We have con-structed recombinant HCMVs featuring either en-tire or partial deletion of the enhancer using this new rapid and reliable technology, and compared the growth of recombinant and parental viruses. As a result, we found that different from the murine CMV case, the HCMV enhancer is essential

for viral replication, and a minimal requirement for viral growth is the SpI binding site in the proximal enhancer between –39 and –67 relative to the tran-scription start site of +1, newly discovered by EMSA and supershift assay with SpI antibodies in the present study. Moreover, infection of NF-kB dominant negative cells with the recombinant vi-ruses revealed that two NF-kB and one CREB or ATF binding sites between –-39 and –173 facilitate transcription from the MIE promoter.

Figure Left panel; Accumulation of DNA damage checkpoint proteins such as ATM and MNR complex at sites of viral replication during EBV lytic infection. Right panel; Model for DNA damage signaling induced by EBV lytic replication.

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From left to right First row: Dr. Keiko Tamiya-Koizumi, Dr. Osamu Taguchi, Dr. Reiji Kannagi, Dr. Akiko Kanamori and

Ms. Yoshiko Goto. Second row: Ms. Naoko Kimura, Ms. Keiko Miyazaki, Dr. Lim Keh-Ti, Ms. Sasako Eguchi, Ms. Mineko

Izawa, Ms. Akiko Nishioka, Mr. Hirokazu Yagi, Ms. Sachiko Kondo, Dr. Guo-Yun Chen, Mr. Jun Yin and Dr. Mamoru Kyogashima.

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Division of Molecular Pathology __________________________________________________________________ Reiji Kannagi, M.D., D.M.Sc., Chief Osamu Taguchi, D.M.Sc., Section Head Mamoru Kyogashima, M.D., D.M.Sc., Senior Researcher (as of April, 2004) Akiko Kanamori, Ph.D., Researcher (until March, 2005), Senior Researcher (as of April 2005) Takaaki Yaomura, M.D., Research Resident (until March, 2005) Masaru Ueda, M.D., Research Resident (until March, 2005) Mineko Izawa, B.A., Research Assistant Yoshiko Goto, D.V.M.S., Research Assistant Sasako Eguchi, Semi-regular Employee Akiko Nishioka, M.T., Semi-regular Employee Visiting Scientists Hiroshi Ikeda, M.D., D.M.Sc., Aichi Medical University Guo-Yun Chen, M.D., D.M.Sc., Japan Science and Technology Agency Keiko Miyazaki, M.T., Japan Science and Technology Agency Lim Keh-Ti, Ph.D., National Institute of Biomedical Innovation Ayako Hashimoto, B.A., Japan Science and Technology Agency (until October, 2005) Fathy Mohamed Mohamed El-Fasakhany, M.D., D.M.Sc., JSPS (until September, 2005) Takashi Murate, M.D., D.M.Sc., Nagoya University School of Health Sciences (as of April, 2004) Keiko Tamiya-Koizumi, Ph.D., Nagoya University School of Health Sciences (as of April, 2004) Visiting Trainees Naoko Kimura, B.P., Nagoya City University Jun Yin, M.T. Nagoya University School of Bioagricultural Sciences Tetsufumi Koike, M.D., Fukushima University School of Medicine Atsushi Akutagawa, M.D., Nagoya University School of Medicine (as of April 2004) Kazumi Hagiwara, M.T., Nagoya University School of Health Sciences (as of April 2004) Sayaka Sobue, M.T., Nagoya University School of Health Sciences (as of April 2005) Hirokazu Yagi, M.P. Nagoya City University (as of April 2005) Sachiko Kondo, M.E. Nagoya City University (as of April 2005) Masaru Ueda, M.D., Kyoto Prefectural University of Medicine (as of April 2005) Akinari Watanabe, M.D., Fukushima University School of Medicine (until March, 2005) Takaaki Hattori, M.D., Tokyo Medical University (until March, 2004) General Summary

Cell adhesion molecules called selectins and their specific carbohydrate ligands, namely sialyl Lewis X and sialyl Lewis A, are involved in hematogenous metastasis of cancers. Expression of sialyl Lewis X and sialyl Lewis A is markedly enhanced on cancer cells compared to normal epithelial cells. During the period 2004-2005, we have succeeded in elucidating the mechanism involved in the cancer-associated induc-tion of sialyl Lewis X and sialyl Lewis A expression in human cancers. We found that normal epithelial cells express carbohydrate determinants that are more complex than the parent ligands. Good examples of such complex determinants are sialyl 6-sulfo Lewis X or disialyl Lewis A, which have additional modifications to sialyl Lewis X or sialyl Lewis A, respectively. Upon malignant transformation, intracellular synthesis of such complex carbohydrate determinants become partially impaired because of transcriptional suppression of some of the genes involved (we call this as "incomplete synthesis"), which results in accumulation of sialyl Lewis X and sialyl Lewis A with relatively simple structures in tumors at early stages. In tumor nests within locally advanced tumors, hypoxia-resistant cancer cells are clonally selected because of the hypoxic environment. Such cancer cells have a strong and sustained expression of a

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transcription factor, hypoxia inducible factor-1α (HIF-1α), which induces expression of various genes which enable cancer cells to cope with or adapt to hypoxia. Included are several genes involved in sialyl Lewis X or sialyl Lewis A synthesis, and our stud-ies have indicated that this further enhances expression of these carbohydrate deter-minants in hypoxia-resistant cancer cells, which selectively grow in advanced stages of cancers undergoing distant hematogenous metastasis. Selectin-mediated cell adhe-sion mediates homing of lymphocytes in healthy individuals, and during the period 2004-2005, we have clarified, using knock out mice, that the sialyl 6-sulfo Lewis X de-terminant contributes as a specific ligand for L-selectin in this normal homing. In these two years we have also concentrated attention on the role of regulatory T-cells in immune responses against self-antigens.

1. Mechanism of loss of disialyl Lewis A and induction of sialyl Lewis A expres-sion in early stage human cancers.

Miyazaki, K. Ohmori, K.*1, Izawa, M., Koike, T. and Kannagi, R.

Expression of sialyl Lewis A, a ligand for E-selectin which mediates hematogenous metastasis, is known to be increased in cancers of digestive or-gans. In contrast, disialyl Lewis A, which has an extra sialic acid attached at the C6-position of the penultimate GlcNAc in sialyl Lewis A, is expressed preferentially on the surface of nonmalignant colo-nic epithelial cells, and is significantly down-regulated on malignant transformation. In-troduction of the gene for a 2-6 sialyltransferase responsible for disialyl Lewis A synthesis into co-lon cancer cells in our laboratory resulted in a marked increase in disialyl Lewis A expression and corresponding decrease in sialyl Lewis A expres-sion. This was accompanied by complete loss of E-selectin binding of the cells. In contrast, trans-fected cells acquired significant binding activity to Siglec-7/p75/AIRM-1, an inhibitory receptor ex-pressed on lymphoid cells (Fig. 1). These findings indicate that the shift in carbohydrate determinants from a disialyl Lewis A-dominant status to a sialyl Lewis A-dominant status on malignant transforma-tion has a dual functional consequence: loss of normal cell-cell recognition between mucosal epithelial cells and lymphoid cells on the one hand and gain of E-selectin binding activity on the other. The transcription of a gene encoding the 2-6 sialyl-transferase was found to be markedly down-regulated in cancer cells compared with nonmalignant epithelial cells, in line with the de-creased expression of disialyl Lewis A and in-creased expression of sialyl Lewis A. Treatment of cancer cells with butyrate or 5-azacytidine strongly induced disialyl Lewis A expression, sug-

gesting that histone deacetylation and/or DNA me-thylation may be involved in the silencing of the gene in cancers. *1 Department of Laboratory Medicine, Kyoto Univer-

sity, School of Medicine.

Fig. 1. Confocal microscopic analyses of epithelial cells expressing disialyl Lewis A and leukocytes expressing Siglec-7 in human colonic mucosa. The distribution of Siglec-7, as detected by polyclonal anti-Siglec-7 antibody, is shown in green, and that of the disialyl Lewis A determi-nant in red. Left panel, low magnification of nonmalignant colonic mucosa, indicating adhe-sion of Siglec-7-expressing lymphoid cells to colonic epithelial cells (arrows). Right panels, higher magnification micrographs showing ad-hesion of Siglec-7-expressing lymphoid cells (green) to nonmalignant colonic epithelial cells expressing the disialyl Lewis A determinant (red) through pseudopodia-like extensions (ar-rowheads). Bars, 10 µm. (Cancer Res., 64: 4498-4505, 2004)

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2. Tumor hypoxia augments sialyl Lewis X and sialyl Lewis A expression in lo-cally-advanced human cancers.

Koike, T., Kimura, N., Miyazaki, K., Chen, G. Y., Yin, J., Kojima, T.*1, Takematsu, H.*2, and Kannagi, R.

Cancer cells undergo distinct metabolic changes to cope with their hypoxic environment, at least partly through the action of transcriptional factors called hypoxia-inducible factor-α and related molecules (HIFs). We have investigated gene ex-pression in human colon cancer cells cultured under hypoxic conditions with special reference to cell-adhesion molecules and carbohydrate determi-nants having cell-adhesive activity using DNA-microarray and RT-PCR techniques. Hy-poxic culture of colon cancer cells induced a marked increase in expression of selectin ligands, the sialyl Lewis X and sialyl Lewis A determinants at the cell surface, which led to a definite increase in cancer cell adhesion to endothelial E-selectin.

The transcription of genes for fucosyltransferase VII (FUT7), sialyltransferase ST3Gal-I (ST3O), and UDP-galactose transporter-1 (UGT1), which are all known to be involved in the synthesis of the carbo-hydrate ligands for E-selectin, was significantly in-duced in cancer cells by hypoxic culture. In addi-tion, remarkable induction was detected for the genes encoding syndecan-4 (SDC4) and α5-integrin (ITGA5) (Fig. 2), cell-adhesion molecules involved in enhanced adhesion of cancer cells to fibronectin. Transcriptional induction by hypoxia was repro-duced in luciferase-reporter assays for these genes, which were significantly suppressed by co-transfection of a dominant-negative form of HIF. These results indicate that the metabolic shifts of cancer cells partly mediated by HIFs significantly enhance their adhesion to vascular endothelial cells, through both selectin- and integrin-mediated path-ways, and suggest that this enhancement further fa-cilitates hematogenous metastasis and tumor an-giogenesis. *1 Department of Medical Technology, Nagoya Univer-

sity School of Health Sciences. *2 Supra-Biomolecular System Research Group, RIKEN

Frontier Research System. 3. Study on L-selectin ligand mediated

homing of naïve T-lymphocytes using gene-disrupted mice.

Izawa, M., Kimura, N. Uchimura, K.*1, Ohmori, K*2, Muramatsu, T.*3, Rosen, S.D.*1 and Kannagi, R.

Selectin-mediated cell adhesion is involved in the routine homing of lymphocytes. Two kinds of carbohydrate ligands for selectin have so far been noted in humans, one is conventional sialyl Lewis X, and the other is sulfated sialyl Lewis X as repre-sented by sialyl 6-sulfo Lewis X. Conventional sialyl Lewis X is preferentially involved in the re-cruitment of leukocytes in inflammation, while sia-lyl 6-sulfo Lewis X primarily mediates routine homing of leukocytes. The sialyl 6-sulfo Lewis X determinant is expressed on the high endothelial venules (HEVs) of peripheral lymph nodes and Peyer's patches, where it mediates L-selectin-dependent homing of lymphocytes, and is synthesized through the sequential action of 6-O-sulfotransferase and fucosyltransferase. Two 6-O-sulfotransferase isoenzymes are proposed to be involved in the synthesis of sialyl 6-sulfo Lewis X in HEV, GlcNAc6ST-1 and -2. Mice with dis-rupted genes for GlcNAc6ST-1 or -2 are known to

Fig. 2. Hypoxia-induced syndecan-4 and α5-integrin expression. Signals includingsyndecan-4 (left panel) and α5-integrin(right panel) in the DNA microarray areshown (white arrows). Cy3-dUTP(normoxia, red) or Cy5-dUTP (hypoxia,1% O2 for 24 h: green) was incorporatedinto cDNA prepared from a human coloncancer cell line, SW480. (Proc. Natl.Acad. Sci. U.S.A., 101: 8132-8137, 2004)

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have impaired lymphocyte homing, indicating both enzymes to be involved in the synthesis of sialyl 6-sulfo Lewis X. Expression of sialyl 6-sulfo Lewis X in HEV of Peyer's patches and mesenteric lymph nodes is decreased in GlcNAc6ST-1 KO mice, while its expression in peripheral lymph node is decreased with GlcNAc6ST-2 KO. In line with this, lymphocyte homing to Peyer's patches is par-tially impaired in the GlcNAc6ST-1 KO case, and that to peripheral lymph node is partially reduced in GlcNAc6ST-2 KO mice. In double-KO mice for both GlcNAc6ST-1 and -2, expression of sialyl 6-sulfo Lewis X in HEV of all lymphoid tissues, including Peyer's patches, peripheral and mesen-teric lymph nodes, is almost completely abrogated (Fig. 3), and marked reduction of lymphocyte homing is observed. These results confirmed our previous finding in humans that sialyl 6-sulfo Lewis X is the major ligand for L-selectin in lymphocyte homing, and indicate that both GlcNAc6ST-1 and -2 are involved in its synthesis.

*1 Department of Anatomy, Program in Immunology, Cardiovascular Research Institute, University of Cali-fornia.

*2 Department of Laboratory Medicine, Kyoto Univer-sity, School of Medicine.

*3 Department of Biochemistry, Nagoya University Graduate School of Medicine.

4. ATRA-induced apoptosis in the human

neuroblastoma cell line, SH-SY5Y, is accompanied by alteration of ceramide species: Appearance of ceramide con-taining hydroxy fatty acids.

Hagiwara, K., Sobue, S., Kyogashima, M., Tamiya-Koizumi, K., Tadano-Aritomi, K.*1, Hara, A.*2, Aoyama, T.*2, Murate, T. and Kannagi, R.

All-trans retinoic acid (ATRA) and its related compounds are regarded as promising reagents for neuroblastoma treatment, but mechanisms of action remain to be clarified. The purpose of our present study was to elucidate the molecular background to

Fig. 3. Sialyl 6-sulfo Lewis X expression in HEVs of wild-type and GlcNAc6ST-deficient lymphoid organs. Cry-ostat-cut sections of peripheral lymph nodes, mesenteric lymph nodes and Peyers' patches from wild-type andGlcNAc6ST-deficient mice were preincubated with sialidase. Sections were then stained with monoclonalantibody AG223, which recognizes 6-sulfo Lewis X. Arrows indicate HEVs lacking sialyl 6-sulfo Lewis Xexpression. Methyl green was used to counterstain the sections. Bars, 40µm. (Nat. Immunol., 6:1105-1113, 2005)

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ATRA-induced cell death in the human neuroblas-toma cell line, SH-SY5Y. ATRA rapidly caused cell death in fetal calf serum-depleted culture, as confirmed to be apoptosis by identification of DNA ladder formation and inhibitory effects of a cas-pase-3 inhibitor. We focused our attention on sphingolipid metabolism as a signaling pathway of apoptosis. Metabolic labeling of sphingolipids with [14C]-serine revealed that ATRA increased ra-dioactivity in the ceramide fraction and decreased that of sphingomyelin. When we measured in vi-tro activities of sphingomyelinase, ceramidase, ser-ine palmitoyltransferase, and synthases of sphin-gomyelin, ceramide and glycolipid, which may be responsible for the increased of radioactive cera-mide, none of the enzymes examined showed dis-tinct ATRA-dependent changes. However, analy-sis of the molecular species of radioactive ceramide by thin-layer chromatography detected ceramide containing hydroxy fatty acid in an ATRA-dependent manner. These results suggest that hydroxy fatty acid in ceramide may play a role in ATRA-induced apoptosis. Further detailed analysis of ceramide species unique to ATRA-induced apoptosis is now in progress using mass spectrometry. *1 Department of Biochemistry, Teikyo University

School of Medicine. *2 Department of Metabolic Regulation, Institute on

Aging and Adaptation, Shinshu University Graduate School of Medicine.

5. Rapid demonstration of diversity of

sulfatide molecular species from bio-logical materials by MALDI-TOF MS

Kyogashima, M., Tamiya-Koizumi, K., Goto, Y., Hara, A.*1, Aoyama, T.*1 and Kannagi, R.

By combining the partition method for enrich-ment of sulfatides without any chromatographic procedures and a preparation method for lysosulfa-tides, we have succeeded in analyzing sulfated gly-cosphingolipids from biological materials by MALDI-TOF MS within a single day. We found SM4s (galactosylsulfatide) to be composed of dif-ferent species. While the exact composition de-pended on the source material, SM4s always con-tained hydroxy fatty acids to various degrees. In addition to the common sphingoid 4-sphingenine (d18:1), uncommon/unusual sphingoids phyto-sphingosine (t18:0), 4-eicosasphinganine (d20:0), 4-eicosasphingenine (d20:1), and sphingadienine

(d18:2) were readily detected. Finally, in addition to SM4s, sulfatide SM3 (sulfated lactosylceramide) and SM2 (sulfated gangliotriaosylceramide) were clearly present in renal tubule cells. The major SM4s was composed of ceramides possessing d18:1 with C22 hydroxy fatty acids (C22:0h), C23:0h, and C24:0h, whereas the major SM3/SM2 forms were composed of ceramides possessing t18:0 with C22 normal fatty acids (C22:0), C23:0, C24:0. Namely, in these two series of sulfatides, either fatty acids or sphingoids were hydroxylated, and chain lengths of these components were exactly the same, conse-quently resulting in a similar polarity of ceramide moieties. These results demonstrate diversity of sulfatide molecular species, not only with respect to sugar- but also to ceramide moieties, which is probably important for specific effective functions in particular microenvironments, such as lipid membrane microdomains. *1 Department of Metabolic Regulation, Institute on

Aging and Adaptation, Shinshu University Graduate School of Medicine.

6. Expression cloning of a cDNA encoding

sialic acid cyclase, which generates cy-clic sialic acid containing glycoconju-gates, and characterization of the pro-duced enzyme.

Kanamori, A., Yamaguchi, M.*1, Ishida, H.*1, Kiso, M.*1 and Kannagi, R.

Recently we have identified a metabolic path-way leading to modification of sialic acid so that a novel ring form named "cyclic sialic acid", lacking its carboxyl group, is generated. By the expres-sion cloning method, we focused on isolating a cDNA encoding a "sialic acid cyclase", which could catalyse this process. For this purpose, HEK-293T cells stably expressing sialyl 6-sulfo Lewis X were used as the recipient cells. Using the G159 mono-clonal antibody recognizing cyclic sialyl 6-sulfo Lewis X antigen as a probe, a cDNA clone (indi-cated as clone A) causing expression of a G159 an-tigen was isolated. Interestingly, in order for the G159 antigen to be produced in recipient cells, an-other two cDNA clones needed to be co-transfected, whose encoded proteins appeared to contribute to the intracellular localization of the clone A product. On the other hand, expression of clone A protein in a HUT-102 derived mutant cell line lacking G159 antigen caused the expression of the latter. The expression levels of sialyl 6-sulfo Lewis X antigen

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found to be in inverse proportion to those of cyclic sialyl 6-sulfo Lewis X detected as the G159 antigen. Sialic acid cyclase activity of the recombinant clone A protein could be assayed by an ELISA method and analysis of the effects of elements which influ-ence its level is now in progress. Our conclusion is that the enzyme protein encoded by clone A in-deed possesses sialic acid cyclase activity. *1 Department of Applied Bioorganic Chemistry, Gifu

University, School of Agriculture. 7. Immune responses to retinal self-anti-

gens in CD25+CD4+ regulatory T-cell- depleted mice.

Takeuchi, M.*1, Keino, H.*1, Kezuka, T.*1, Usui, M.*1 and Taguchi, O.

Prior work has shown that autoimmune uveo-retinitis develops spontaneously in CD25(+)CD4(+) regulatory T-cell-depleted mice (Tr-depleted mice). In our recent studies, the generation of autoanti-bodies and autoreactive T-cells specific to retinal antigens was examined in Tr-depleted mice with uveoretinitis, and the pathogenic and immunogenic abilities of the autoreactive T cells were evaluated. Tr-depletion was achieved in (C57BL/6 x A/J) F1 (B6A) mice by thymectomy on day 3 of life fol-lowed by intraperitoneal injection of an anti-CD25 monoclonal antibody. At 6 months of age,

autoantibodies to the retina were evaluated by indi-rect immunofluorescence, and total IgG2a levels in sera were assessed by ELISA. The pathogenic abili-ties of the splenic T cells were examined after adoptive transfer to syngeneic nu/nu mice, and the proliferation responses and the secretion of granu-locyte-macrophage colony-stimulating factor (GM-CSF), IFN-gamma, and IL-10 on stimulation by retinal self-antigens were also determined. Autoantibodies to the retinal photoreceptor cell layer were detected in Tr-depleted mice, and the titers correlated well with the grades of inflamma-tory lesions. Splenic CD4(+) T cells of Tr-depleted mice induced uveoretinitis in the re-cipients by adoptive transfer and exhibited prolif-erative responses and secretion of IFN-gamma, but not IL-10, by in vitro stimulation with S-Ag and in-terphotoreceptor retinoid-binding protein (IRBP). Moreover, the total IgG2a level in serum was markedly and significantly augmented in Tr-depleted mice. The results suggest that in Tr-depleted mice in which uveoretinitis develops, S-Ag and IRBP-specific T cells are spontaneously sensitized and shifted to a Th1-phenotype. These sensitized T cells may account for the development of autoimmune uveoretinitis. *1 Department of Ophthalmology, Tokyo Medical Uni-

versity, Tokyo.

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From left to right First row: Ms. Y. Takada, Dr. A. Kawajiri, Ms. T. Yuhara, Ms. Y. Hayashi. Second row: Mr. T. Oguri, Dr. P. Zou, Mr. T. Siromizu, Ms. N. Saito, Ms. M. Nishizawa. Third row: Dr. M. Inagaki, Dr. A. Inoko, Dr. H. Goto, Mr. T. Yamaguchi, Dr. I. Izawa. Insets: Dr. K. Nagata, Dr. M. Sugimoto, Dr. T. Yokoyama, Dr. N. Hanai, Mr. M. Inoue.

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Division of Biochemistry __________________________________________________________________ Masaki Inagaki, M.D. Chief Koh-ichi Nagata, M.D. Section Head (until March, 2004) Ichiro Izawa, M.D. Senior Researcher Hidemasa Goto, M.D. Senior Researcher (as of April, 2004) Akihito Inoko, M.D. Researcher Miwako Nishizawa, B.P. Senior Research Assistant (until March, 2004) Yuko Hayashi, Ph.D. Research Assistant (as of April, 2004) Noriko Saito, B.M.T. Research Assistant (until March, 2004) Tomoya Yokoyama, M.D. Research Resident (until June, 2005) Zou Peng, M.D. Research Resident (as of April, 2005) Postdoctoral Fellows Nariko Arimura, Ph.D. (as of April, 2004, until August, 2005) Visiting Trainees Aie Kawajiri, Ph.D. Department of Pathology, Nagoya University School of Medicine (until April, 2004, as of September, 2005) Nobuhiro Hanai, M.D. Department of Otorhinolaryngology, Nagoya City University School of Medicine (until March, 2004) Masahiko Sugimoto, M.D. Department of Ophthalmology, Mie University School of Medicine (until June, 2005) Takashi Oguri, M.S. Department of Cancer Genetics, Nagoya University School of Medicine Takashi Siromizu, M.S. Department of Cancer Genetics, Nagoya University School of Medicine Tomoya Yamaguchi, M.S. Department of Cancer Genetics, Nagoya University School of Medicine (as of April, 2004) Masaki Inoue, Nagoya University School (as of April, 2003, until March, 2004) General Summary

Abnormalities in the cell cycle control and tissue architecture are considered to lead to uncontrolled proliferation, genetic instability, and cell invasion (metastasis), which are the characteristics of cancers. However, the precise processes of carcino-genesis remain largely unknown.

Our research aim is to elucidate the mechanisms by which cell cycle (including cell cycle checkpoint) and tissue architecture (including intracellular cytoskeletal net-work) are controlled. Our attention is focused on 2 specific areas. (1) Identification and functional analysis of protein kinases involved in cell cycle control and checkpoint; (2) Regulation of the cytoskeletal protein (especially intermediate filaments) and its asso-ciated protein in the cell adhesion.

1. Complex Formation of Plk1 and INCENP

Required for Metaphase-Anaphase Transition

Goto, H., Kiyono, T.*1, Tomono, Y.*2, Kawajiri, A., Urano, T.*3, Furukawa, K.*3, Nigg, E.A.*4 and Inagaki, M.

Mitotic chromosomal dynamics is regulated by the coordinated activities of many mitotic kinases, such as cyclin-dependent kinase 1 (Cdk1), Aurora-B or Polo-like kinase 1 (Plk1). The abnor-malities in these protein kinases can lead to genetic instability, but its precise regulation remains un-

known. Here we found that Cdk1 phosphorylates Thr59 and Thr388 on inner centromere protein (INCENP), which regulates localization and kinase activity of Aurora-B, from prophase to metaphase. INCENP depletion disrupts Plk1 localization spe-cifically at the kinetochore. This phenotype is res-cued by the exogenous expression of INCENP wild type (WT) and INCENP mutated at Thr59 to Ala (T59A), but not at Thr388 to Ala (T388A). The re-placement of endogenous INCENP with T388A re-sulted in the delay of progression from metaphase to anaphase. These results suggested that INCENP phosphorylation by Cdk1 is necessary for the re-

48

cruitment of Plk1 to the kinetochore, and the com-plex formation of Plk1 and Aurora-B on INCENP may play critical roles in the regulation of chromo-somal dynamics. *1 Virology Division, National Cancer Center Research

Institute *2 Division of Molecular and Cell Biology, Shigei

Medical Research Institute *3 Department of Biochemistry II, Nagoya University

Graduate School of Medicine *4 Department of Cell Biology, Max-Planck Institute for

Biochemistry, Germany. 2. Phosphorylation by Cdk1 induces

Plk1-mediated vimentin phosphoryla-tion during mitosis

Yamaguchi, T., Goto, H., Yokoyama, T., Silljé, H.*1, Hanisch, A.*1, Uldschmid, A. *1, Takai, Y.*2, Oguri, T., Nigg, E.A.*1 and Inagaki, M.

Several kinases phosphorylate vimentin, the most common intermediate filament protein, in mitosis. Aurora-B and Rho-kinase regulate vimentin fila-ment separation through the cleavage fur-row-specific vimentin phosphorylation. Cdk1 also phosphorylates vimentin from prometaphase to metaphase, but its significance has remained un-known. Here we demonstrated a direct interaction between Plk1 and vimentin-Ser55 phosphorylated by Cdk1, an event that led to Plk1 activation and further vimentin phosphorylation. Plk1 phosphory-lated vimentin at ~ 1 mol phosphate/mol substrate, which partly inhibited its filament forming ability, in vitro. Plk1 induced the phosphorylation of vimentin-Ser82, which was elevated from meta-phase and maintained until the end of mitosis. This elevation followed the Cdk1-induced vimentin-Ser55 phosphorylation, and was impaired by Plk1 depletion. Mutational analyses revealed that Plk1-induced vimentin-Ser82 phosphorylation plays an important role in vimentin filaments seg-regation, coordinately with Rho-kinase and Aurora-B. Taken together, these results indicated a novel mechanism that Cdk1 regulated mitotic vimentin phosphorylation via not only a direct en-zyme reaction but also Plk1 recruitment to vimentin. *1 Department of Cell Biology, Max-Planck Institute for

Biochemistry, Germany. *2 Department of Obstetrics and Gynecology, Saitama

Medical Center.

3. Mitotic Chk1 Phosphorylation at Novel

Sites Regulated by Cyclin-dependent kinase 1 (Cdk1)

Shiromizu, T., Goto, H., Tomono, Y.*1, Bartek, J.*2, Totsukawa, G.*3, Inoko, A., Nakanishi, M.*4, Matsumura, F.*3 and Inagaki, M.

Chk1 is phosphorylated at Ser317 and Ser345 by ATR in response to stalled replication and genotoxic stresses. This Chk1 activation is thought to play critical roles in the prevention of premature mitosis. However, the behavior of Chk1 in mitosis remains largely unknown. Here we reported that Chk1 was phosphorylated in mitosis. The reduction of this phosphorylation was observed at the meta-phase-anaphase transition. Two-dimensional phos-phopeptide mapping revealed that Chk1 phos-phorylation sites in vivo were completely over-lapped with the in vitro sites by cyclin-dependent protein kinase (Cdk) 1 or by p38 MAP kinase. Ser286 and Ser301 were identified as novel phos-phorylation sites on Chk1. Treatment with Cdk in-hibitor butyrolactone I induced the reduction of Chk1-S301 phosphorylation, although treatment with p38-specific inhibitor SB203580 or siRNA did not. In addition, ionizing radiation (IR) or ultravio-let (UV) light did not induce Chk1 phosphorylation at Ser317 and Ser345 in nocodazole-arrested mi-totic cells. These observations implied the regula-tion of mitotic Chk1 function through Chk1 phos-phorylation at novel sites by Cdk1. *1 Division of Molecular and Cell Biology, Shigei

Medical Research Institute. *2 Danish Cancer Society, Institute of Cancer Biology,

Department of Cell Cycle and Cancer, Denmark. *3 Department of Molecular Biology and Biochemistry,

Rutgers University, USA. *4 Biochemistry, Nagoya City University Medical

School. 4. Functional analysis of cytoskeleton Izawa, I., Nishizawa, M. and Inagaki, M.

Intermediate filaments (IF) form the structural framework of cytoskeleton. Although the histopa-thological detection of IF proteins are utilized for examining cancer specimens as reliable markers, the molecular mechanisms how IFs are involved in the biology of cancer cells are still unclear. We set out to search for the binding partners with simple epithelial keratin 8/18, and have thus far identified

49

Mrj, TNF receptor type 1-associated death domain protein (TRADD) and trichoplein. Mrj, a DnaJ/Heat shock protein 40 (Hsp40) family protein, directly binds to keratin 18. Mrj may play an important role in the regulation of the keratin 8/18 filament or-ganization as a keratin 18-specific co-chaperone to work together with Hsp/c70. We found a direct as-sociation of keratin 18 with TRADD, an indispen-sable adaptor molecule for TNF receptor type 1 (TNFR1) signaling. Thus, keratin 18 may sequester TRADD to attenuate the interaction of TRADD with activated TNFR1, leading to diminution of TNF-induced apoptosis. These results suggest that simple epithelial keratins may play a role in modu-lating the response to some apoptotic signals. Trichoplein has a domain that shows a low degree of sequence similarity between trichohyalin and plectin, designated as trichohyalin/plectin homol-ogy domain (TPHD). Trichoplein may be involved in the organization of the keratin filament network, possibly affecting cell polarity in simple epithelial cells. The identifications of IF-binding proteins and lessons from transgenic mouse models and human diseases have indicated that IF may affect cell growth, cell death and cell polarity through the in-teractions with a variety of non-structural proteins, including kinases and adaptors for cell signaling. It is hence plausible that IF may play profound roles in cancer development, invasion and metastasis. 5. Characterization and functional analy-

sis of novel keratin filament-binding proteins, trichoplein and Fbf-1

Inoko, A., Zou, P., Sugimoto, M., Hayashi, Y., Kiyono, T.*1, Izawa, I. and Inagaki, M.

As described above, we searched for the binding partners with keratin 8/18 to reveal the function of cytoskeleton especially in the epithelial cells. And, we identified a novel protein of trichoplein and Fbf-1 as keratin filament-binding proteins. Concerned about trichoplein, we newly found that trichoplein localized not only on keratin filament but also at desmosome. This means that the trichoplein of keratin filament-binding protein has potential to participate in the organization of cell-cell contact. Next, to elucidate the function of trichoplein, we executed RNA interfere experiments. The results suggested that the decrease of trichoplein causes morphological changes of cul-tured cells. So, now we are investigating the mo-lecular mechanism of this alteration. Fbf-1 was previously reported as a Fas-binding

protein. But, we newly characterized this protein as a keratin filament-binding protein which mainly concentrated at cell-cell border, and we found that the amino acid sequence of Fbf-1 has similarity to trichoplein because both have TPHD. Subsequently, we are going to clarify the function of Fbf-1 with RNA interfere experiments. *1 Virology Division, National Cancer Center Research

Institute 6. Vimentin-Ser82 as a phosphorylation

site that memorizes the activity of CaMKII in astrocytes

Oguri, T., Inoko, A., Shima, H.*1*2, Izawa, I., Arimura, N., Yamaguchi, T., Inagaki, N.*3, Kaibuchi, K.*4, Kikuchi, K.*1 and Inagaki, M.

In astrocytes, the PGF2α or ionomycin treat-ment induces the phosphorylation at Ser38 and Ser82 of vimentin, a type III intermediate filament, by Ca2+/calmodulin-dependent protein kinase II (CaMKII). We found here that vimentin phos-pho-Ser82 was dephosphorylated much slower than phospho-Ser38. Vimentin phospho-Ser38 was dephosphorylated quickly by purified PP1 catalytic subunit (PP1c) in vitro, whereas phospho-Ser82 was insensitive to PP1c. Because PP1c directly bound to vimentin through a VxF motif (Val83-Asp84-Phe85), the PP1c active site ap-peared to be unable to approach phospho-Ser82, leading to the prolongation of the phosphorylation at Ser-82. In astrocytes, PP1cαwas in vivo associ-ated with vimentin filaments. The repetitive treat-ment by ionomycin at a short interval resulted in the sustained elevation of Ser82 phosphorylation, lead-ing to the marked disassembly of vimentin fila-ments. Taken together, these results suggest that phosphorylation state of vimentin is regulated by PP1c in astrocytes, and vimentin-Ser82 may act as a phosphorylation site that memorizes the activity of CaMKII. *1 Division of Biochemical Oncology and Immunology,

Institute for Genetic Medicine, Hokkaido University *2 Division of Cancer Chemotherapy, Miyagi Cancer

Center Research Institute *3 Division of Signal Transduction, Graduate School of

Biological Science, Nara Institute of Science and Technology

*4 Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University

50

From left to right First row: Dr. H. Furue, Dr. Hid. Nakamura, Ms. N. Saito and Dr. K. Ijichi, Second row: Ms. S. Matsumoto, Dr. K. Ishizaki, Dr. Y. Yasui and Dr. H. Kumimoto

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Division of Central Laboratory & Radiation Biology __________________________________________________________________ Kanji Ishizaki, Ph.D. Chief Hiroshi Kumimoto, Ph.D. Researcher Yoshihiro Yamane, Ph.D. Research Resident (until March 2004) Hideaki Nakamura, Ph.D. Research Resident (as of April 2004) Hiroki Furue, D.D.S. Research Resident (as of April 2005) Yuko Hayashi, Ph.D. Research Assistant (until March 2004) Yoshihiro Yasui, Ph.D. Research Assistant Noriko Saito, Research Assistant (as of April 2004) Visiting Trainees Kei Ijichi, M.D. School of Medicine, Nagoya City University (as of April 2004) Tomotaka Sugimura, D.D.S. School of Medicine, Nagoya University (until March 2005) Makoto Adachi, D.D.S. Asahi University School of Dentistry General Summary One of our main research projects is molecular genetic analysis of human esophageal and oral tumors. We are studying interactions between genetic polymorphisms and life-style factors in development of these tumors to find clues for effective prevention. So far, we have analyzed poly-morphisms in the L-myc, CHK2, CYP1A1, CYP1B1, CYP2E1, XPA, XPC, XPD, XPF, OGG1, XRCC1, ERCC1, STK15, and MDM2 genes and found that specific alleles of the L-myc and STK15 genes are associated with induction of esophageal tumors by smoking and drinking. Poly-morphisms of the CYP2E1, XPA, and ERCCI genes were also shown to be related to oral cancers. Another research project is the study of genetic effects of low-dose-rate radiation on hu-man cells. For this purpose we have established immortal cell lines derived from normal individuals and patients with ataxia telangiectasia (AT), a radiation sensitive genetic disease, by introducing the human telomerase gene. These cell lines are immortal but without any changes in the p53 and other genes that are involved in cellular signal transduction. Using these cell lines we have revealed that cytotoxic effects and mutation induction by low-dose rate radiation in normal cells is much lower than those by high-dose-rate radiation but that AT cell lines exhibit similar radiation sensitivity in-dependent of the dose-rate. Using phosphorylated H2AX foci as indicators of DNA double strand breaks (DSBs), we have demonstrated that AT cells exhibit a partial defect in the repair of DSBs.

1. A single nucleotide polymorphism of

the MDM2 gene in Japanese esophageal and oral cancer patients

Kumimoto, H., Sugimura, T.*1, Furue, H.*1, Shinoda, M.*2, Hatooka, S.*2, and Ishizaki, K.

The human homologue of mouse double min-ute 2 (MDM2) is a key negative regulator of p53. A single nucleotide polymorphism (SNP309) has been identified in the first intron of the MDM2 gene with functional consequences, since the G allele shows higher promoter activity than the T allele. Thus the SNP309 can influence p53 tumor sup-pressorion through its expression level. The G al-lele of the SNP309 showed an increased expression level of the MDM2. And the GG genotype was reported to be associated with high cancer suscepti-bility and an early onset of soft tissue sarcoma de-velopment (G.L. Bond et al., Cell 119 (2004)

591-602). Since mutations of the p53 gene which is a target of the MDM2 protein, and amplification of the MDM2 gene are frequently observed in eso-phageal cancer, and since oral cancer is developed in the same upper digestive tract area, risks with SNP309 for these cancers were analyzed by the po-lymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) approach. Total of 330 Japanese non-cancer outpatients and 165 patients with esophageal cancer at Aichi Can-cer Center Hospital were the subjects. And also PCR-RFLP analysis was performed 122 patients with oral cancer. The genotype distribution fitted with the Hardy-Weinberg equilibrium among non-cancer subjects; 106 with the GG genotype, 165 with the GT genotype and 61 with the TT genotype. While the T allele is dominant in the United States, the G allele was found to be most

52

prevalent, with significance (p<0.001), suggesting that the genotype distribution of the SNP309 may be different among each ethnic group. The risks of esophageal cancer in the GG and TG genotypes compared with the TT genotype were significantly low (OR=0.53 95%CI 0.32-0.88, and OR=0.48 95%CI 0.30-0.77, respectively), which is opposite

to the result in the United States, while the risk of oral cancer did not significantly differ with the genotype (Fig. 1). Interactions with smoking were also analyzed. Smoking and drinking rate did im-pact on esophageal cancer but no genotype differ-ences were significant. Risks of oral cancer, were also significantly influenced by smoking or heavy drinking but again the genotype did not appear to play any role. The average ages of onset of eso-phageal cancer were similar with each genotype and this was also the case for oral cancer (Fig. 2). In conclusion, the genotype distribution of the MDM2 gene among Japanese differ from that among Americans and the risks of upper alimentary tract cancers with the GG genotype are not high com-pared with the TT genotype, suggesting that the contribution of the GG genotype of the MDM2 gene in cancer development might be, if anything, small in Japanese. *1 Nagoya University Graduate School of Medicine, 65

Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550 *2 Department of Thoracic Surgery, Aichi Cancer Cen-

ter Hospital 2. DNA repair defect in AT cells and their

hypersensitivity to low-dose-rate radia-tion

Nakamura, Hid., Yasui, Y., Saito, N. and Ishizaki, K.

To investigate the effects of low-dose-rate ra-diation on ataxia telangiectasia (AT) cells arrested in the G0/G1 phase, AT and normal cells immortal-ized with the human telomerase gene were irradi-ated in non-proliferative condition at high- (2 Gy/min) or low-dose-rate (0.3 mGy/min) radiation. Figure 1 shows the survival curves obtained by colony formation assay with AT (AT1OS/T-n, AT2KY/T-n and AT5KY/T-n) and normal (SuSa/T-n) cells exposed to high- or low-dose-rate radiation. While normal cells showed a higher re-sistance after irradiation at a low-dose rate than a high-dose rate, AT cells showed virtually the same survival after low- and high-dose-rate irradiation. Then, we used the micronucleus assay as a measure of induction of chromosomal aberrations. Although the frequency of micronuclei by low-dose-rate ra-diation showed a large reduction in normal cells, in AT cells it did not exhibit a significant reduction (data not shown). Since recent studies showed a close correlation between the number of γH2AX foci in a nucleus and the number of expected DSBs after irradiation, we determined the number of

0

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esophageal cancer oral cancerGG GT TT GG GT TT

stan

dard

stan

dard

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Fig. 1. Age-sex-adjusted ORs for esophageal or oral cancer according to the genotype of the MDM2 gene. ORs for the GG and GT genotypes in esophageal cancer were significantly low com-pared with the TT genotype. However, no sig-nificant differences risks were found for oral can-cers.

0

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esophageal cancer oral cancerGG GT TT GG GT TT

age

Fig. 2. The average ages of onset of esophageal and oral cancers with each genotype of the MDM2 gene. The average ages of onset of esophageal cancer in each genotype were similar each other. And those of oral cancer were also similar.

53

DSBs and DSB repair activity by analysis of the focus formation of the γH2AX. Figure 2 shows representative focus formations in SuSa/T-n and AT2KY/T-n cells after high- or low-dose-rate irra-diation. The numbers of foci on each nucleus were counted, and the mean numbers of foci induced by each dose of radiation are shown in Fig. 3. The number of γH2AX foci increased in proportion to the dose in both AT and normal cells after high-dose-rate irradiation. Although few γH2AX focus formations were observed by low-dose-rate radiation in normal cells, significant and dose-dependent γH2AX foci were observed in AT cells even after low-dose-rate irradiation, indicating that DNA damage was not completely repaired during low-dose-rate irradiation. These results sug-gest that AT cells might not be able to repair some fraction of DNA damage and are severely affected by low-dose-rate radiation.

0.01

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AT1OS/T-n HDRAT1OS/T-n LDRAT2KY/T-n HDRAT2KY/T-n LDR

AT5KY/T-n HDRAT5KY/T-n LDRSuSa/T-n HDRSuSa/T-n LDR

Surv

ival

Dose (Gy) FIG. 1. Dose-dependent survival curves of AT and normal cells exposed to high- (HDR: open symbol, 2 Gy/min) or low-dose-rate (LDR: closed symbol, 0.3 mGy/min) radiation. Bars indicate standard deviations (n = 3).

FIG. 2. γH2AX foci in SuSa/T-n and AT2KY/T-n cells observed after irradiation at 5 Gy of high- (HDR) or low-dose rate (LDR). Quiescent cells in the SlideFlask were irradiated at high- or low-dose rate and stained with a specific antibody to γH2AX. Nu-clei were also stained with DAPI (blue).

0

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0 1 2 3 4 5 6 7

AT1OS/T-n HDRAT1OS/T-n LDRAT2KY/T-n HDRAT2KY/T-n LDR

AT5KY/T-n HDRAT5KY/T-n LDRSuSa/T-n HDRSuSa/T-n LDR

γH2A

X fo

ci/c

ells

Dose (Gy) FIG. 3. Dose-response curves for γH2AX focus in-duction in AT and normal cells after high- (HDR: open symbol, 2 Gy/min) or low-dose-rate (LDR: closed symbol, 0.3 mGy/min) radiation. For each dose, more than 100 nuclei are scored, and mean values with standard errors were shown.

54

From left to right, First row: Dr, Hir. Nakamura and Mr. Y. Minoura Second row: Ms. M. Mizuno, Ms. M. Nishizawa and Ms. M. Yamamoto

55

Central Service Unit __________________________________________________________________ Hiromu Nakamura, D.M.Sc. Section Head Morio Terashima, B.A. Senior Research Assistant (until March 2004) Sachiko Tokumasu, B.D. Research Assistant (until March 2004) Miwako Nishizawa, B.P. Senior Research Assistant (as of April 2004) Masami Yamamoto, D.V.M. Research Assistant Mikio Hagino Research Assistant (Animal care specialist) Visiting Trainees Yoshimi Nishi, PhD. Nagoya University School of Medicine (until March 2004) General Summary

The Central Service Unit fulfills many functions in assisting the investigations performed by

the Institute and has responsibilities for the maintenance and operation of various instruments for biotechnology research. These are the DNA sequencer (ABI 3100), flow-cytometer (Becton- Dickinson FACS Calibur), imaging analyzers (Fujix BAS-2500Mac, Amersham-Pharmacia ImageMaster-CL and FluorImager-595), X-ray machine (Hitachi MBR-1520R3), electron microscopes (JEOL TEM and Hitachi SEM), confocal laser microscope (Bio-Rad Radiance), real-time PCR equipment (Roche Light Cycler), ultracentrifuges (Beckman and Hitachi), and computer systems for image treatment (Windows and Macintosh systems).

Furthermore, we maintain and manage the radioisotope experimental facilities, SPF and conventional animal rooms, laboratories for translational research and technical photography and hazardous chemical storage, ultra-low temperature freezers, cold rooms, the liquid nitrogen storage room, security systems, air-conditioning, water purifying and waste water treatment systems, as well as the carbon dioxide gas supply, thereby contributing to many other of the Institute’s functions. During the last two years we replaced several instruments such as an ultracentrifuge (Beckman-Coulter Optima LE-80K), a molecular interaction analyzer (Biacore X-system), a flow-cytometer (Becton-Dickinson FACS Calibur) and a real-time PCR (ABI 7500 Fast Real-Time PCR System). Our activities thus provide essential background support for all the research carried out by the Research Institute.

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Librarians ________________________________________________________________________________

From Left to right Librarians, Ms. K. Adachi, Ms. T. Ieda, Ms. M. Teratani, Ms. T. Yasuda, supporting scientific and medical informations.

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Researches Supported by Special Project Programme ________________________________________________________________________________

1. Defining Second-Hit Genetic Abnormali-

ties Involved in Generation of t(12; 21) TEL-AML1 Acute Lymphoblastic Leuke-mias by Array-based Comparative Ge-nomic Hybridization

Tsuzuki, S., Karnan, S., Horibe, K.*1, Matsumoto, K.*2, Kato, K.*2, Inukai, T.*3, Goi, K.*3, Sugita, K.*3, Nakazawa, S.*3, Ueda, R.*4, and Seto, M.

The TEL (ETV6)-AML1 (RUNX1) chimeric gene fusion is the most common genetic abnormality in childhood acute lymphoblastic leukemias (ALL). Evidence suggests that chimeric gene fusion usually occurs in utero during fetal hematopoiesis and most probably constitutes an initiating or first-hit mutation that is necessary but insufficient for the development of overt, clinical leukemia. In our search for additional secondary and postnatal genetic events that could be linked to leukemia development, we applied a genome- wide array- CGH technique to 24 TEL-AML1 leukemia samples and two cell lines (REH, KOPN41) and found that at least three chromosomal imbalances were involved in all patient samples and cell lines. Recurrent regions of chromosomal imbalance (found in > 10% of clinical samples) were gain of chromosomes 10 (17 %) and 21q (25 %) and loss of chromosomes 2p11 (100 %), 12p13.2 (87 %), 9p21.3 (29 %), 9p13.2 (25 %), 12q21.3, (25 %), 3p21 (21 %), 6q21 (17 %), 4q31.23 (17 %),

11q22-q23 (13 %) and 19q13.11-q13.12 (13 %). The two cell lines showed gain of 21q22.12-qter and loss of 2p11.2, 9p21.3, 12p13.2, and 12q21.3. Among these, six regions of loss (2p11, 3p21, 4q31.23, 9p13.2, 12q21.3 and 19q13.12) have not been identified previously by conventional CGH in TEL-AML1 leukemias. Representative genes involved in the regions of loss were Igkappa (2p11), TEL (12p13.2), p16INK4a/ARF (9p21.3), Pax5 (9p13.2), BTG1 (12q21.3), LIMD1 (3p21), AIM1 and BLIMP1 (6q21), NR3C2 (4q31.23), ATM (11q22-q23), and PDCD5 (19q13.11-q13.12), while the region of gain at 21q contained RUNX1. These findings suggest that, in addition to TEL previously reported to be lacking, genes involved in cell cycle regulation, p53 pathways and apoptosis are also often deleted. Our array –CGH obtained data should provide further insights into the molecular basis of TEL-AML1 leukemia development. *1 Clinical Research Center, National Hospital

Organization Nagoya Medical Center *2 Division of Hematology and Oncology, Children's

Medical Center, Japanese Red Cross Nagoya First Hospital

*3 Department of Pediatrics, Faculty of Medicine, University of Yamanashi

*4 Department of Internal Medicine and Molecular Science, Nagoya City University, Graduate School of Medical Sciences

Publications ________________________________________________________________________________

Journals

J001. Abe, T., Takano, K., Suzuki, A., Shimada, Y., Inagaki, M., Sato, N., Obinata, T. and Endo, T.: Myocyte differentiation generates nuclear invaginations traversed by myofibrils associating with sarcomeric protein mRNAs. J.Cell Sci. 117: 6523-6534, 2004. (PMID: 15572409)

J002. Akazawa, T., Masuda, H., Saeki, Y., Matsumoto, M., Takeda, K., Tsujimura, K., Kuzushima, K., Takahashi, To., Azuma, I., Akira, S., Toyoshima, K. and Seya, T.: Adjuvant-mediated tumor regression and tumor-specific cytotoxic response induction are impaired in MyD88-deficient mice. Cancer Res. 64: 757-764, 2004. (PMID: 14744795)

J003. Akiyama, Y., Kuzushima, K., Tsurumi, T. and Yamaguchi, K.: Analysis of HLA-A24- restricted CMVpp65 peptide-specific CTL with HLA-A*2402-CMVpp65 tetramer. Immunol. Lett. 95: 199-205, 2004. (PMID: 15388261)

J004. Anumanthan, G., Halder, SK., Osada, H., Takahashi, Ta., Massion, PP., Carbone, DP., and Datta, PK.: Restoration of TGF-β signalling reduces tumorigenicity in human lung cancer cells. Br. J. Cancer. 93: 1157-1167, 2005. (PMID: 16251876)

J005. Arimura, N., Ménager, C., Kawano, Y., Yoshimura, T., Kawabata, S., Hattori, A., Fukata, Y., Amano, M., Goshima, Y., Inagaki, M., Morone, N., Usukura, J. and Kaibuchi, K.: Phosphorylation by Rho-kinase regulates CRMP-2 activity in growth cones. Mol. Cell. Biol. 25: 9973-9984, 2005. (PMID: 16260611)

J006. Asano, N., Suzuki, R., Kagami, Y., Ishida, F., Kitamura, K., Fukutani, H., Morishima, Y., Takeuchi, K. and Nakamura, S.: Clinicopathologic and prognostic significance of cytotoxic molecule expression in nodal peripheral T-cell lymphoma, unspecified. Am. J. Surg. Pathol., 29:1284-1293, 2005. (PMID: 16160469)

J007. Asaoka, Y., Sakai, H., Takahashi, N., Hirata, A., Tsukamoto, T., Yamamoto, M., Yanai, T., Masegi, T., and Tatematsu, M.: Intraperitoneal injection of D-galactosamine provides a potent cell proliferation stimulus for the detection of initiation

activities of chemicals in rat liver. J Appl Toxicol, 25: 554-561, 2005. (PMID: 16208626)

J008. Azuma, T., Otsuki, T., Kuzushima, K., Froelich, C.J., Fujita, S. and Yasukawa, M.: Myeloma cells are highly sensitive to the granule exocytosis pathway mediated by WT1-specific cytotoxic T lymphocytes. Clin. Cancer Res. 10: 7402-7412, 2004. (PMID: 15534117) J009. Bork, S., Yokoyama, N., Ikehara, Y., Kumar, S., Sugimoto, C. and Igarashi, I.: Growth-inhibitory effect of heparin on Babesia parasites. Antimicrob. Agents Chemother. 48: 236-241, 2004. (PMID: 14693545)

J010. Cao, X., Tsukamoto, T., Nozaki, K., Mizoshita, T., Ogasawara, N., Tanaka, H., Takenaka, Y., Kaminishi, M., and Tatematsu, M.: β-Catenin gene alteration in glandular stomach adenocarcinomas in N-methyl-N-nitrosourea- treated and Helicobacter pylori-infected Mongolian gerbils. Cancer Sci., 95: 487-490, 2004. (PMID: 15182428)

J011. Cao, X., Tsukamoto, T., Nozaki, K., Shimizu, N., Mizoshita, T., Kumagai, T., Kaminishi, M., and Tatematsu, M.: Eradication of Helicobacter pylori induces apoptosis and inhibits proliferation of heterotopic proliferative glands in infected Mongolian gerbils. Cancer Sci, 95: 872-877, 2004. (PMID: 15546504)

J012. Chiba, H., Takezaki, T., Neupani, D., Kim, J., Yoshida, S., Mizoguchi, E., Takeuchi, J., Suzuki, J., Tanaka, Y., Ito, K., Kitamura, T., Kuriki, K., Wakai, K., Samejima, K., Sonoda, S. and Tajima, K.: An epidemiological study of HBV, HCV and HTLV-I in Sherpas of Nepal. Asian Pac J Cancer Prev, 5: 370-373, 2004. (PMID: 15546239)

J013. Chiba, H., Tretli, S., Lund, E., Wakai, K., Takezaki, T., Senoo, H., Sonoda, S. and Tajima, K.: Lack of HTLV-I carriers in the Sami, an ethnic group living in the Arctic area in Norway. Asian Pac J Cancer Prev, 5: 50-53, 2004. (PMID: 15075005)

J014. Daikoku, T., Kudoh, A., Fujita, M., Sugaya, Y., Isomura, H. and Tsurumi, T.: In vivo dynamics of EBNA1-oriP interaction during latent and lytic replication of Epstein-Barr virus. J. Biol. Chem. 279: 54817-54825, 2004. (PMID: 15498777)

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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=PubMed&term=15572409














J015. Daikoku, T., Kudoh, A., Fujita, M., Sugaya, Y., Isomura, H., Shirata, N. and Tsurumi, T.: Architecture of replication compartments formed during Epstein-Barr virus lytic replication. J. Virol. 79: 3409-3418, 2005. (PMID: 15731235)

J016. Daikoku,T., Kudoh, A., Sugaya, Y., Iwahori, S., Shirata, N., Isomura, H. and Tsurumi, T.:Postreplicative Mismatch Repair Factors are recruited to Epstein-Barr Virus Replication Compartments. J. Biol. Chem., in press.

J017. Date, C., Fukui, M., Yamamoto, A., Wakai, K., Ozeki, A., Motohashi, Y., Adachi, C., Okamoto, N., Kurosawa, M., Tokudome, Y., Kurisu, Y., Watanabe, Y., Ozasa, K., Nakagawa, S., Tokui, N., Yoshimura, T. and Tamakoshi, A.: Reproducibility and validity of a self-administered food frequency questionnaire used in the JACC study. J Epidemiol, 15 Suppl 1: S9-23, 2005. (PMID: 15881192)

J018. Dobrodeeva, L. K., Kornienko, E. B., Petrenya, N. N., Lutfalieva, G. T., Schegoleva, L. S., Demeneva, L. V., Duberman, B. L., Tkachev, A. V., Chiba, H., Senoo, H., Ito, K., Mizoguchi, E., Yoshida, S. and Tajima, K.: A unique seroepidemiological pattern of HBV, HCV and HTLV-I in Nenets and Komi in northwestern Russia. Asian Pac J Cancer Prev, 6: 342-345, 2005. (PMID: 16235997)

J019. Duray, P.H., Yin, S.R., Ito, Y., Bezrukov, L., Cox, C., Cho, M.S., Fitzgerald, W., Dorward, D., Zimmerberg, J. and Margolis, L.: Invasion of human tissue ex vivo by Borrelia burgdorferi. J. Infect. Dis. 191: 1747-1754, 2005. (PMID: 15838803)

J020. Dyson, M.H., Thomson, S., Inagaki, M., Goto, H., Arthur, S.J., Nightingale, K., Iborra, F.J. and Mahadevan, L.C.: MAP kinase-mediated phosphorylation of distinct pools of histone H3 at S10 or S28 via mitogen- and stress-activated kinase 1/2. J .Cell Sci. 118: 2247-2259, 2005. (PMID: 15870105)

J021. Endoh, H., Tomida, S., Yatabe, Y., Konishi, H., Osada, H., Tajima, K., Kuwano, H., Takahashi, Ta., and Mitsudomi, T.: Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction. J. Clin. Oncol. 22: 811-819, 2004. (PMID: 14990636)

J022. Fujii, A., Oshima, K., Hamasaki, M., Utsunomiya, H., Okazaki, M., Kagami, Y., Seto,

M., and Kikuchi, M.: Differential expression of cytokines, chemokines and their receptors in follicular lymphoma and reactive follicular hyperplasia: Assessment by complementary DNA microarray. Oncol. Rep., 13: 819-824, 2005. (PMID: 15809744)

J023. Fujii, K., Ishimaru, F., Kozuka, T., Matsuo, K., Nakase, K., Kataoka, I., Tabayashi, T., Shinagawa, K., Ikeda, K., Harada, M. and Tanimoto, M.: Elevation of serum hepatocyte growth factor during granulocyte colony- stimulating factor-induced peripheral blood stem cell mobilization. Br J Haematol, 124: 190-194, 2004. (PMID: 14687029)

J024. Fujita, M., Mizuno, M., Nagasaka, T., Wakabayashi, T., Maeda, K., Ishii, D., Arima, T., Kawajiri, A., Inagaki, M. and Yoshida, J.: Aurora-B dysfunction of multinucleated giant cells in glioma detected by site-specific phosphorylated antibodies. J. Neurosurg. 101: 1012-1017, 2004. (PMID: 15597762)

J025. Fujiwara, K., Fujimoto, N., Tabata, M., Nishii, K., Matsuo, K., Hotta, K., Kozuki, T., Aoe, M., Kiura, K., Ueoka, H. and Tanimoto, M.: Identification of epigenetic aberrant promoter methylation in serum DNA is useful for early detection of lung cancer. Clin Cancer Res, 11: 1219-1225, 2005. (PMID: 15709192)

J026. Fukui, T., Kondo, M., Ito, G., Maeda, O., Sato, N., Yoshioka, H., Yokoi, K., Ueda, Y., Shimokata, K., and Sekido, Y.: Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancer. Oncogene 24: 6323-6327, 2005 (PMID: 16007200)

J027. Fukushima, S., Wanibuchi, H., Morimura, K., Iwai, S., Nakae, D., Kishida, H., Tsuda, H., Uehara, N., Imaida, K., Shirai, T., Tatematsu, M., Tsukamoto, T., Hirose, M., and Furukawa, F.: Existence of a threshold for induction of aberrant crypt foci in the rat colon with low doses of 2-amino-1-methyl-6-phenolimidazo[4,5-b]pyridine. Toxicol Sci., 80: 109-114, 2004. (PMID: 15014208)

J028. Fukushima, S., Wanibuchi, H., Morimura, K., Nakae, D., Tsuda, H., Imaida, K., Shirai, T., Tatematsu, M., Tsukamoto, T., Hirose, M., and Furukawa, F.: Lack of potential of low dose N-nitrosodimethylamine to induce preneoplastic lesions, glutathione S-transferase placental form-positive foci, in rat liver. Cancer Lett., 222:

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11-15, 2005. (PMID: 15837536)

J029. Futamura. N., Nakanishi, H., Hirose, H., Nakamura, S., Tatematsu, M.: The effect of storage on the survival of cancer cells in blood and efficient elimination of contaminating cancer cells by a leukocyte depletion filter. Am Surg. 71:585-90, 2005. (PMID16089124)

J030. Gao, C. M., Takezaki, T., Wu, J. Z., Ding, J. H., Liu, Y. T., Li, S. P., Su, P., Hu, X., Xu, T., Hamajima, N. and Tajima, K.: Methylenetetra hydrofolate reductase genotypes, dietary habits and susceptibility to stomach cancer. Chin J Clin Oncol, 1: 162-166, 2004.

J031. Gao, C. M., Takezaki, T., Wu, J. Z., Liu, Y. T., Ding, J. H., Li, S. P., Su, P., Hu, X., Kai, H. T., Li, Z. Y., Matsuo, K., Hamajima, N., Sugimura, H. and Tajima, K.: Polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase genes and the susceptibility to esophageal and stomach cancer with smoking. Asian Pac J Cancer Prev, 5: 133-138, 2004. (PMID: 15244514)

J032. Gondo, H., Himeji, D., Kamezaki, K., Numata, A., Tanimoto, T., Takase, K., Aoki, K., Henzan, H., Nagafuji, K., Miyamoto, T., Ishikawa, F., Shimoda, K., Inaba, S., Tsukamoto, H., Horiuchi, T., Nakashima, H., Otsuka, T., Kato, K., Kuroiwa, M., Higuchi, M., Shibuya, T., Kamimura, T., Kuzushima, K., Tsurumi, T., Kanda, Y. and Harada, M.: Reconstitution of HLA-A*2402- restricted cytomegalovirus-specific T-cells following stem cell transplantation. Int. J. Hematol. 80: 441-448, 2004. (PMID: 15646657)

J033. Goto, H., Kiyono, T., Tomono, Y., Kawajiri, A., Urano, T., Furukawa, K., Nigg, E.A. and Inagaki, M.: Complex formation of Plk1 and INCENP required for Metaphase-anaphse transition. Nature Cell Biology, in press (PMID: 16378098)

J034. Goto, M., Tsukamoto, T., Inada, K., Mizoshita, T., Ogawa, T., Terada, A., Hyodo, I., Shimozato, K., Hasegawa, Y., and Tatematsu, M.: Loss of p21(WAF1/CIP1) expression in invasive fronts of oral tongue squamous cell carcinomas is correlated with tumor progression and poor prognosis. Oncol. Rep., 14: 837-846, 2005. (PMID: 16142340)

J035. Goto, Y., Hamajima, N., Honda, H., Matsuo, K., Yamamoto, K., Tamakoshi, A., Ando, T. and Goto, H.: Association between Helicobacter pylori seropositivity and NAD(P)H:quinone oxidoreductase 1 (NQO1) C609T polymorphism

observed in outpatients and health checkup examinees. Gastric Cancer, 8: 12-17, 2005. (PMID: 15747169)

J036. Hamajima, N., Atsuta, Y., Goto, Y. and Ito, H.: A pilot study on genotype announcement to induce smoking cessation by Japanese smokers. Asian Pac J Cancer Prev, 5: 409-413, 2004. (PMID: 15546247)

J037. Hamajima, N., Hirose, K. and Tajima, K.: Breast cancer and abortion: collaborative reanalysis of data from 53 epidemiological studies, including 83?000 women with breast cancer from 16 countries. Lancet, 363: 1007-1016, 2004. (PMID: 15051280)

J038. Hanai, N., Nagata, K., Kawajiri, A., Shiromizu, T., Saitoh, N., Hasegawa, Y., Murakami, S. and Inagaki, M.: Biochemical and cell biological characterization of a mammalian septin, Sept11. FEBS Letter, 568: 83-88, 2004. (PMID: 15196925)

J039. Hashimoto, M., Ichihara, M., Watanabe, T., Kawai, K., Koshikawa, K., Yuasa, N., Takahashi Ta., Yatabe, Y., Murakumo, Y., Zhang, JM., Nimura, Y., and Takahashi, M.: Expression of CD109 in human cancer. Oncogene. 23: 3716-3720, 2004. (PMID: 15116102)

J040. Hattori, N., Niimi, T., Sato, S., Achiwa, H., Maeda, H., Oguri, T., Bessho, Y., Ito, H., Shimizu, S. and Ueda, R.: Cytotoxic T-lymphocyte antigen 4 gene polymorphisms in sarcoidosis patients. Sarcoidosis Vasc Diffuse Lung Dis, 22: 27-32, 2005. (PMID: 15881277)

J041. Hayashita, Y., Osada, H., Tatematsu, Y., Yamada, H., Yanagisawa, K., Tomida, S., Yatabe, Y., Kawahara, K., Sekido, Y., and Takahashi, Ta.: A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 65: 9628-9632, 2005. (PMID: 16266980)

J042. He, Y., Rajantie, I., Pajusola, K., Jeltsch, M., Holopainen, T., Yla-Herttuala, S., Harding, T., Jooss, K., Takahashi, Ta., and Alitalo, K.: Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res. 65: 4739-4746, 2005. (PMID: 15930292)

J043. Hirata, A., Inada, K., Tsukamoto, T., Sakai, H., Mizoshita, T., Yanai, T., Masegi, T., Goto, H., Inagaki, M., and Tatematsu, M.:

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Characterization of a monoclonal antibody, HTA28, recognizing a histone H3 phosphorylation site as a useful marker of M-phase cells. J. Histochem. Cytochem., 52: 1503-1509, 2004. (PMID: 15505345)

J044. Hirata, A., Tsukamoto, T., Yamamoto, M., Sakai, H., Yanai, T., Masegi, T., Donehower, L. A., and Tatematsu, M.: Organ-specific susceptibility of p53 knockout mice to N-bis(2-hydroxypropyl) nitrosamine carcinogenesis. Cancer Lett,, 2005. (PMID: 16150539)

J045. Hirata, T., Furukawa, Y., Yang, B.G., Hieshima, K., Fukuda, M., Kannagi, R., Yoshie, O. and Miyasaka, M.: Human PSGL-1 interacts with the skin-associated chemokine CCL27 via sulfated tyrosines at the PSGL-1 amino terminus. J. Biol. Chem., 279: 51775-51782, 2004. (PMID: 15466853)

J046. Hirose, K., Imaeda, N., Tokudome, Y., Goto, C., Wakai, K., Matsuo, K., Ito, H., Toyama, T., Iwata, H., Tokudome, S. and Tajima, K.: Soybean products and reduction of breast cancer risk: a case-control study in Japan. Br J Cancer, 93: 15-22, 2005. (PMID: 15942624)

J047. Hirose, K., Matsuo, K., Toyama, T., Iwata, H., Hamajima, N. and Tajima, K.: The CYP19 gene codon 39 Trp/Arg polymorphism increases breast cancer risk in subsets of premenopausal Japanese. Cancer Epidemiol Biomarkers Prev, 13: 1407-1411, 2004. (PMID: 15298966)

J048. Hishida, A., Matsuo, K., Tajima, K., Ogura, M., Kagami, Y., Taji, H., Morishima, Y., Emi, N., Naoe, T. and Hamajima, N.: Polymorphisms of p53 Arg72Pro, p73 G4C14-to- A4T14 at exon 2 and p21 Ser31Arg and the risk of non-Hodgkin's lymphoma in Japanese. Leuk Lymphoma, 45: 957-964, 2004. (PMID: 15291355)

J049. Hishida, A., Terakura, S., Emi, N., Yamamoto, K., Murata, M., Nishio, K., Sekido, Y., Niwa, T., Hamajima, N., and Naoe, T.: GSTT1 and GSTM1 deletions, NQO1 C609T polymorphism and risk of chronic myelogenous leukemia in Japanese.” Asian Pac. J. Cancer Prev. 6: 251-255, 2005. (PMID: 16235982)

J050. Hosokawa, Y., Suzuki, H., Nakagawa, M., Lee, T.H. and Seto, M.: API2-MALT1 fusion protein induces transcriptional activation of the API2 gene through NF-κB binding elements; evidence for a positive feed-back loop pathway resulting in unremitting NF-κB activation.

Biochem. Biophys. Res. Commun. 334: 51-60, 2005. (PMID: 15982633)

J051. Hosokawa, Y., Suzuki, H., Suzuki, Y., Takahashi, R. and Seto, M.: Anti-apoptotic function of API2-MALT1 fusion protein involved in t(11;18)(q21;q21) MALT lymphoma. Cancer Res., 64: 3452-3457, 2004. (PMID: 15150097)

J052. Hotta, K., Kiura, K., Tabata, M., Harita, S., Gemba, K., Yonei, T., Bessho, A., Maeda, T., Moritaka, T., Shibayama, T., Matsuo, K., Kato, K., Kanehiro, A., Tanimoto, Y., Matsuo, K., Ueoka, H. and Tanimoto, M.: Interstitial lung disease in Japanese patients with non-small cell lung cancer receiving gefitinib: an analysis of risk factors and treatment outcomes in Okayama Lung Cancer Study Group. Cancer J, 11: 417-424, 2005. (PMID: 16259873)

J053. Hotta, K., Matsuo, K., Ueoka, H., Kiura, K., Tabata, M. and Tanimoto, M.: Addition of platinum compounds to a new agent in patients with advanced non-small-cell lung cancer: a literature based meta-analysis of randomised trials. Ann Oncol, 15: 1782-1789, 2004. (PMID: 15550583)

J054. Hotta, K., Matsuo, K., Ueoka, H., Kiura, K., Tabata, M. and Tanimoto, M.: Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol, 22: 3852-3859, 2004. (PMID: 15326195)

J055. Hotta, K., Matsuo, K., Ueoka, H., Kiura, K., Tabata, M. and Tanimoto, M.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol, 22: 3860-3867, 2004. (PMID: 15326194)

J056. Hotta, K., Matsuo, K., Ueoka, H., Kiura, K., Tabata, M., Harita, S., Gemba, K., Yonei, T., Bessho, A. and Tanimoto, M.: Continued gefitinib treatment after disease stabilisation prolongs survival of Japanese patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience. Ann Oncol, 16: 1817-1823, 2005. (PMID: 16157622)

J057. Huang, X. E., Hirose, K., Wakai, K., Matsuo, K., Ito, H., Xiang, J., Takezaki, T. and Tajima, K.: Comparison of lifestyle risk factors by family history for gastric, breast, lung and colorectal cancer. Asian Pac J Cancer Prev, 5: 419-427, 2004. (PMID: 15546249)

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J058. Ichinohe, T., Uchiyama, T., Shimazaki, C., Matsuo, K., Tamaki, S., Hino, M., Watanabe, A., Hamaguchi, M., Adachi, S., Gondo, H., Uoshima, N., Yoshihara, T., Hatanaka, K., Fujii, H., Kawa, K., Kawanishi, K., Oka, K., Kimura, H., Itoh, M., Inukai, T., Maruya, E., Saji, H. and Kodera, Y.: Feasibility of HLA-haploidentical hematopoietic stem cell transplantation between noninherited maternal antigen (NIMA)-mismatched family members linked with long-term fetomaternal microchimerism. Blood, 104: 3821-3828, 2004. (PMID: 15280193)

J059. Iidaka, T., Sakai, H., Tsukamoto, T., Yamamoto, M., Shirai, N., Totsuka, Y., Wakabayashi, K., Yanai, T., Masegi, T., and Tatematsu, M.: Detection of initiating and promoting activity of aminophenylnorharman with a five-week in vivo initiation assay. J. Toxicol. Pathol., 17: 1-5, 2004.

J060. Iidaka, T., Tsukamoto, T., Totsuka, Y., Hirata, A., Sakai, H., Shirai, N., Yamamoto, M., Wakabayashi, K., Yanai, T., Masegi, T., Donehower, L. A., and Tatematsu, M.: Lack of elevated liver carcinogenicity of aminophenylnorharman in p53-deficient mice. Cancer Lett., 217: 149-159, 2005. (PMID: 15617832)

J061. Ikehara, Y., Ikehara, S. K. and Paulson, J. C.: Negative regulation of T cell receptor signaling by Siglec-7 (p70/AIRM) and Siglec-9. J. Biol. Chem. 279: 43117-43125, 2004. (PMID: 15292262)

J062. Ikehara, Y., Sato, T., Niwa, T., Nakamura, S., Gotoh, M., Ikehara, S., K., Kiyohara, K., Aoki, C., Iwai, T., Nakanishi, H., Hirabayashi, J., Tatematsu, M. and Narimatsu H.: Apical Golgi localization of N,N’-diacetyllactosediamine synthase, β4GalNAc-T3, is responsible for LacdiNAc expression on gastric mucosa. Glycobiology, in press.

J063. Inada, K. I., Mizoshita, T., Tsukamoto, T., Porter, E. M., and Tatematsu, M.: Paneth type gastric cancer cells exhibit expression of human defensin-5. Histopathology, 47: 330-331, 2005. (PMID: 16115240)

J064. Inagaki, H., Nakamura, T., Li, C., Sugiyama, T., Asaka, M., Kodaira, J., Iwano, M., Chiba, T., Okazaki, K., Kato, A., Ueda, R., Eimoto, T., Okamoto, S., Sasaki, N., Uemura, N., Akamatsu, T., Miyabayashi, H., Kawamura, Y., Goto, H., Niwa, Y., Yokoi, T., Seto, M., and Nakamura, S.: Gastric MALT lymphomas are

divided into three groups based on responsiveness to Helicobacter Pylori eradication and detection of API2-MALT1 fusion. Am. J. Surg. Pathol., 28: 1560-1567, 2004. (PMID: 15577674)

J065. Inoue, M., Tsuji, I., Wakai, K., Nagata, C., Mizoue, T., Tanaka, K. and Tsugane, S.: Evaluation based on systematic review of epidemiological evidence among Japanese populations: tobacco smoking and total cancer risk. Jpn J Clin Oncol, 35: 404-411, 2005. (PMID: 15987784)

J066. Ishida, T., Iida, S., Akatsuka, Y., Ishii, T., Miyazaki, M., Komatsu, H., Inagaki, H., Okada, N., Fujita, T., Shitara, K., Akinaga, S., Takahashi, To., Utsunomiya, A. and Ueda, R.: The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-Cell leukemia/lymphoma. Clin Cancer Res., 10: 7529-7539, 2004. (PMID: 15569983)

J067. Ishizaki, K., Hayashi, Y., Nakamura, Hid., Yasui, Y., Komatsu, K. and Tachibana. A.: No induction of p53 phosphorylation and few focus formation of phosphorylated H2AX suggest efficient repair of DNA damage during chronic low-dose-rate irradiation in human cells. J. Radiation Res. 45: 521-525, 2004. (PMID: 15635261)

J068. Isomura, H., Stinski, M.F., Kudoh, A., Daikoku, T., Shirata, N. and Tsurumi, T.: Two Sp1/Sp3 binding sites in the major immediate-early proximal enhancer of human cytomegalovirus have a significant role in viral replication. J. Virol. 79: 9597-9607, 2005. (PMID: 16014922)

J069. Isomura, H., Tsurumi, T. and Stinski, M.F.: Role of the proximal enhancer of the major immediate-early promoter in human cytomegalovirus replication. J. Virol. 78: 12788-12799, 2004. (PMID: 15542631)

J070. Isomura, I., Yasuda, Y., Tsujimura, K., Takahashi, To., Tochikubo, K. and Morita, A.: Recombinant cholera toxin B subunit activates dendritic cells and enhances antitumor immunity. Microbiol. Immunol. 49: 79-87, 2005. (PMID: 15665457)

J071. Itano, N., Sawai, T., Atsumi, F., Miyaishi, O., Taniguchi, S., Kannagi, R., Hamaguchi, M. and Kimata, K.: Selective expression and functional characteristics of three mammalian hyaluronan synthases in oncogenic malignant transformation. J. Biol. Chem., 279: 18679-18687,

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2004. (PMID: 14724275)

J072. Ito, S., Nakanishi, H., Kodera, Y., Mochizuki, Y., Tatematsu, M., and Yamamura, Y.: Prospective validation of quantitative CEA mRNA detection in peritoneal washes in gastric carcinoma patients. Br. J. Cancer, 93 (9):986-92, 2005. (PMID:16205696)

J073. Ito, G., Uchiyama, M., Kondo, M., Mori, S., Usami, N., Maeda, O., Kawabe, T., Hasegawa, Y., Shimokata, K., and Sekido, Y.: Krüppel-Like Factor 6 is frequently down-regulated and induces apoptosis in non-small cell lung cancer cells. Cancer Res. 64: 3838-3843, 2004. (PMID: 15172991)

J074. Ito, H., Inoue, M., Shibata, K. and Tajima, K.: Estimation of cancer incidences in Aichi prefecture: use of a model area with good quality registry data. Asian Pac J Cancer Prev, 5: 320-327, 2004. (PMID: 15373714)

J075. Ito, H., Matsuo, K., Hamajima, N., Mitsudomi, T., Sugiura, T., Saito, T., Yasue, T., Lee, K. M., Kang, D., Yoo, K. Y., Sato, S., Ueda, R. and Tajima, K.: Gene-environment interactions between the smoking habit and polymorphisms in the DNA repair genes, APE1 Asp148Glu and XRCC1 Arg399Gln, in Japanese lung cancer risk. Carcinogenesis, 25: 1395-1401, 2004. (PMID: 15044328)

J076. Ito, H., Matsuo, K., Hamajima, N., Okuma, K., Saito, T. and Tajima, K.: Significant association of interleukin 8 -251T/A polymorphism with smoking behavior in a Japanese population. J Hum Genet, 50: 567-573, 2005. (PMID: 16195815)

J077. Ito, H., Matsuo, K., Wakai, K., Saito, T., Kumimoto, H., Okuma, K., Tajima, K. and Hamajima, N.: An intervention study of smoking cessation with feedback on genetic cancer susceptibility in Japan. Prev Med, 2005. (PMID: 16325899)

J078. Ito, K., Tanaka, Y., Orito, E., Hirashima, N., Ide, T., Hino, T., Kumashiro, R., Kato, A., Nukaya, H., Sakakibara, K., Mukaide, M., Ito, H., Sata, M., Ueda, R. and Mizokami, M.: Predicting relapse after cessation of Lamivudine monotherapy for chronic hepatitis B virus infection. Clin Infect Dis, 38: 490-495, 2004. (PMID: 14765340)

J079. Ito, M., Ito, G., Kondo, M., Uchiyama, M., Fukui, T., Mori, S., Yoshioka, H., Ueda, Y., Shimokata, K., and Sekido, Y.: Frequent inactivation of RASSF1A, BLU, and SEMA3B on

3p21.3 by promoter hypermethylation and allele loss in non-small cell lung cancer. Cancer Letters 225： 131-139, 2005. (PMID: 15922865)

J080. Ito, Y., Grivel, J.C., Chen, S., Kiselyeva, Y., Reichelderfer, P. and Margolis, L.: CXCR4-tropic HIV-1 suppresses replication of CCR5-tropic HIV-1 in human lymphoid tissue by selective induction of CC-chemokines. J. Infect. Dis. 189: 506-514, 2004. (PMID: 14745709)

J081. Ito, Y., Suzuki, K., Tamakoshi, K., Wakai, K., Kojima, M., Ozasa, K., Watanabe, Y., Kawado, M., Hashimoto, S., Suzuki, S., Tokudome, S., Toyoshima, H., Hayakawa, N., Kato, K., Watanabe, M., Ohta, Y., Maruta, M. and Tamakoshi, A.: Colorectal cancer and serum C-reactive protein levels: a case-control study nested in the JACC Study. J Epidemiol, 15 Suppl 2: S185-189, 2005. (PMID: 16127232)

J082. Ito, Y., Wakai, K., Suzuki, K., Ozasa, K., Watanabe, Y., Seki, N., Ando, M., Nishino, Y., Kondo, T., Ohno, Y. and Tamakoshi, A.: Lung cancer mortality and serum levels of carotenoids, retinol, tocopherols, and folic acid in men and women: a case-control study nested in the JACC Study. J Epidemiol, 15 Suppl 2: S140-149, 2005. (PMID: 16127226)

J083. Ivaska, J., Vuoriluoto, K., Huovinen, T., Izawa, I., Inagaki, M. and Parker, P.J.: PKCε-mediated phosphorylation of vimentin controls integrin recycling and motility. EMBO J. 24: 3834-3845, 2005. (PMID: 16270034)

J084. Iwafuchi, H., Mori, N., Takahashi, Ta., and Yatabe, Y.: Phenotypic composition of salivary gland tumors: an application of principal [corrected] component analysis to tissue microarray data. Modern Pathol. 17: 203-210, 2004. (PMID: 15098013)

J085. Iwata, H., Matsuo, K., Hara, S., Takeuchi, K., Aoyama, T., Murashige, N., Kanda, Y., Mori, S., Suzuki, R., Tachibana, S., Yamane, M., Odawara, M., Mutou, Y. and Kami, M.: Usage of HMG-CoA reductase inhibitors is associated with the risk of lymphoid malignancies. Cancer Sci, in press.

J086. Iwata, H., Matsuo, K., Takeuchi, K., Kishi, Y., Murashige, N. and Kami, M.: High incidences of malignant lymphoma in patients infected with hepatitis B or hepatitis C virus. Haematologica, 89: 368-370, 2004. (PMID: 15020283)

J087. Izawa, I. and Inagaki, M.: Regulatory

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mechanisms and functions of intermediate filaments: A study using site- and phosphorylation state-specific antibodies. Cancer Sci, in press.

J088. Jiang, J., Gajalakshmi, V., Wang, J., Kuriki, K., Suzuki, S., Nakamura, S., Akasaka, S., Ishikawa, H. and Tokudome, S.: Influence of the C161T but not Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma on colorectal cancer in an Indian population. Cancer Sci, 96: 507-512, 2005. (PMID: 16108832)

J089. Jiang, J., Suzuki, S., Xiang, J., Kuriki, K., Hosono, A., Arakawa, K., Wang, J., Nagaya, T., Kojima, M., Katsuda, N. and Tokudome, S.: Plasma carotenoid, α-tocopherol and retinol concentrations and risk of colorectal adenomas: A case-control study in Japan. Cancer Lett, 226: 133-141, 2005. (PMID: 15885891)

J090. Jiang, J., Wang, J., Suzuki, S., Gajalakshmi, V., Kuriki, K., Zhao, Y., Nakamura, S., Akasaka, S., Ishikawa, H. and Tokudome, S.: Elevated risk of colorectal cancer associated with the AA genotype of the cyclin D1 A870G polymorphism in an Indian population. J Cancer Res Clin Oncol, 132: 193-199, 2006. (PMID: 16328437)

J091. Kakizaki, I., Kojima, K., Takagaki, K., Endo, M., Kannagi, R., Ito, M., Maruo, Y., Sato, H., Yasuda, T., Mita, S., Kimata, K. and Itano, N.: A novel mechanism for the inhibition of hyaluronan biosynthesis by 4-methylumbelliferone. J. Biol. Chem., 279: 33281-33289, 2004. (PMID: 15190064)

J092. Kameoka, Y., Tagawa, H., Tsuzuki, S., Karnan, S., Ota, A., Suguro, M., Suzuki, R., Yamaguchi, M., Morishima, Y., Nakamura, S. and Seto, M.: Contig array CGH at 3p14.2 points to the FRA3B/FHIT common fragile region as the target gene in diffuse large B-cell lymphoma. Oncogene, 23: 9148-9154, 2004. (PMID: 15480422)

J093. Kamiyama, S., Sasaki, N., Goda, E., Ui-Tei, K., Saigo, K., Narimatsu, H., Jigami, Y., Kannagi, R., Irimura, T., and Nishihara, S.: Molecular cloning and characterization of a novel 3'-phosphoadenosine 5'-phosphosulfate transporter, PAPST2. J. Biol. Chem., in press.

J094. Kanda, H., Tanaka, T., Matsumoto, M., Umemoto, E., Ebisuno, Y., Kinoshita, M., Noda, M., Kannagi, R., Hirata, T., Murai, T., Fukuda, M. and Miyasaka, M.: Endomucin, a sialomucin expressed in high endothelial venules, supports

L-selectin-mediated rolling. Int. Immunol., 16: 1265-1274, 2004. (PMID: 15249540)

J095. Kanda-Akano, Y., Nomura, K., Fujita, Y., Horiike, S., Nishida, K., Nagai, M., Miura, I., Nakamura, S., Seto, M., Iida, S., Ueda, R., and Taniwaki, M.: Molecular-cytogenetic characterization of non-hodgkin's lymphoma with double and cryptic translosations of the immunoglobulin heavy chain gene. Leuk. Lymphoma, 45: 1559-1567, 2004. (PMID: 15370207)

J096. Kaneda, A., Tsukamoto, T., Takamura-Enya, T., Watanabe, N., Kaminishi, M., Sugimura, T., Tatematsu, M., and Ushijima, T.: Frequent hypomethylation in multiple promoter CpG islands is associated with global hypomethylation, but not with frequent promoter hypermethylation. Cancer Sci., 95: 58-64, 2004. (PMID: 14720328)

J097. Kaneda, A., Wakazono, K., Tsukamoto, T., Watanabe, N., Yagi, Y., Tatematsu, M., Kaminishi, M., Sugimura, T., and Ushijima, T.: Lysyl oxidase is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers. Cancer Res., 64: 6410-6415, 2004. (PMID: 15374948)

J098. Kariya, Y., Mulloy, B., Imai, K., Tominaga, A., Kaneko, T., Asari, A., Suzuki, K., Masuda, H., Kyogashima, M. and Ishii, T.: Isolation and partial characterization of fucan sulfates from the body wall of sea cucumber Stichopus japonicus and their ability to inhibit osteoclastogenesis. Carbohydr. Res., 339: 1339-1346, 2004. (PMID: 15113672)

J099. Karnan, S., Tagawa, H., Suzuki, R., Suguro, M., Yamaguchi, M., Okamoto, M., Morishima, Y., Nakamura, S. and Seto, M.: Analysis of Chromosomal Imbalances in de novo CD5-Positive Diffuse Large B-cell Lymphoma Detected by Comparative Genomic Hybridization. Genes, Chromosomes Cancer, 39: 77-81, 2004. (PMID: 14603444)

J100. Karube, Y., Tanaka, H., Osada, H., Tomida, S., Tatematsu, Y., Yanagisawa, K., Yatabe, Y., Takamizawa, J., Miyoshi, S., Mitsudomi, T., and Takahashi, Ta.: Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci. 96: 111-115, 2005. (PMID: 15723655)

J101. Kasugai, Y., Tagawa, H., Kameoka, Y., Morishima, Y., Nakamura, S., and Seto, M.:

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Identification of CCND3 and BYSL as candidate targets for the 6p21 amplification in diffuse large B-cell lymphoma. Clin. Cancer Res., 11:8265-8272, 2005. (PMID: 16322284)

J102. Katagiri, H., Takahashi, M., Wakai, K., Sugiura, H., Kataoka, T. and Nakanishi, K.: Prognostic factors and a scoring system for patients with skeletal metastasis. J Bone Joint Surg Br, 87: 698-703, 2005. (PMID: 15855375)

J103. Kataoka, I., Kami, M., Takahashi, S., Kodera, Y., Miyawaki, S., Hirabayashi, N., Okamoto, S., Matsumoto, N., Miyazaki, Y., Morishita, Y., Asai, O., Maruta, A., Yoshida, T., Imamura, M., Hamajima, N., Matsuo, K., Harada, M. and Mineishi, S.: Clinical impact of graft-versus-host disease against leukemias not in remission at the time of allogeneic hematopoietic stem cell transplantation from related donors. The Japan Society for Hematopoietic Cell Transplantation Working Party. Bone Marrow Transplant, 34: 711-719, 2004. (PMID: 15361916)

J104. Kato, S., Tsukamoto, T., Mizoshita, T., Tanaka, H., Kumagai, T., Ota, H., Katsuyama, T., Asaka, M., and Tatematsu, M.: High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylori-infected Mongolian gerbils associated with a shift in mucin production from glandular to surface mucous cells. Int. J. Cancer, in press.

J105. Kawada, J., Kimura, H., Ito, Y., Ando, Y., Tanaka-Kitajima, N., Hayakawa, M., Nunoi, H., Endo, F. and Morishima, T.: Evaluation of systemic inflammatory responses in neonates with herpes simplex virus infection. J. Infect. Dis. 190: 494-498, 2004. (PMID: 15243922)

J106. Kawada, J., Kimura, H., Ito, Y., Hoshino, Y., Tanaka-Kitajima, N., Ando, Y., Futamura, M. and Morishima, T.: Comparison of real-time and nested PCR assays for detection of herpes simplex virus DNA. Microbiol. Immunol. 48: 411-415, 2004. (PMID: 15215628)

J107. Kida, M., Kawamura, T., Fukuoka, T., Tamakoshi, A., Wakai, K., Ohno, Y. and Toyama, J.: Out-of-hospital cardiac arrest and survival: an epidemiological analysis of emergency service reports in a large city in Japan. Circ J, 68: 603-609, 2004. (PMID: 15226622)

J108. Kim, J., Kim, Y. J., Ahn, Y. O., Paik, H. Y., Ahn, Y., Tokudome, Y., Hamajima, N., Inoue, M. and Tajima, K.: Contribution of specific foods to

fat, fatty acids, and cholesterol in the development of a food frequency questionnaire in Koreans. Asia Pac J Clin Nutr, 13: 265-272, 2004. (PMID: 15331339)

J109. Kimura, H., Hoshino, Y., Hara, S., Sugaya, N., Kawada, J., Shibata, Y., Kojima, S., Nagasaka, T., Kuzushima, K. and Morishima, T.: Differences between T cell-type and natural killer cell-type chronic active Epstein-Barr virus infection. J. Infect. Dis. 191: 531-539, 2005. (PMID: 15655776)

J110. Kimura, H., Ihira, M., Enomoto, Y., Kawada, J., Ito, Y., Morishima, T., Yoshikawa, T. and Asano, Y.: Rapid detection of herpes simplex virus DNA in cerebrospinal fluid: comparison between loop-mediated isothermal amplification and real-time PCR. Med. Microbiol. Immunol. 194: 181-185, 2005. (PMID: 15909202)

J111. Kiselyeva, Y., Ito, Y., Lima, R.G., Grivel, J.C., Das, A.T., Berkhout, B. and Margolis, L.B.: Depletion of CD4 T lymphocytes in human lymphoid tissue infected ex vivo with doxycycline-dependent HIV-1. Virology 328: 1-6, 2004. (PMID: 15380352)

J112. Kitagawa, C., Ando, M., Ando, Y., Sekido, Y., Wakai, K., Imaizumi, K., Shimokata, K. and Hasegawa, Y.: Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics, 15: 35-41, 2005. (PMID: 15864124)

J113. Kodera, Y., Nakanishi, H., Ito, S., Yamamura, Y., Fujiwara, M., Koike, M., Hibi, K., Ito, K., Tatematsu, M., and Nakao, A. Prognostic significance of intraperitoneal cancer cells in gastric carcinoma: detection of cytokeratin 20 mRNA in peritoneal washes, in addition to detection of carcinoembryonic antigen. Gastric Cancer. 8:142-8, 2005. (PMID: 16086116)

J114. Kodera, Y., Nakanishi, H., Ito, S., Tatematsu, M., et al. Prognostic significance of intraperitoneal cancer cells in gastric carcinoma: Analysis of real time RT-PCR after 5 years of follow-up. J Am Coll Surg. 202:231-6, 2006. (PMID:16427547)

J115. Kodera, Y., Nakanishi, H., Ito, S., Mochizuki, Y., Yamamura, Y., Fujiwara, M., Hibi, K., Ito, K., Akiyama, S., Tatematsu, M., and Nakao, A.: Detection of disseminated cancer cells in linitis plastica-type gastric carcinoma. Jpn. J. Clin. Oncol., 34: 525-531, 2004. (PMID:

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15466826)

J116. Koga, T., Horio, Y., Mitsudomi, T., Takahashi, Ta., and Yatabe, Y.: Identification of MGB1 as a marker in the differential diagnosis of lung tumors in patients with a history of breast cancer by analysis of publicly available SAGE data. J. Mol. Diagn. 6: 90-5, 2004. (PMID: 15096563)

J117. Koga, H., Izawa, I., Araki, N., Saya, H., and Mimori, T.: Observation of the intracellular behavior of recombinant Yersinia pseudotuber- culosis invasion protein. Microbiol. Immunol., 49: 297-302, 2005. (PMID: 15840954 )

J118. Koike, T., Kimura, N., Miyazaki, K., Yabuta, T., Kumamoto, K., Takenoshita, S., Chen, J., Kobayashi, M., Hosokawa, M., Taniguchi, A., Kojima, T., Ishida, N., Kawakita, M., Yamamoto, H., Takematsu, H., Kozutsumi, Y., Suzuki, A. and Kannagi, R.: Hypoxia induces adhesion molecules on cancer cells-a missing link between Warburg effect and induction of selectin ligand carbohydrates. Proc. Natl. Acad. Sci. U. S. A., 101: 8132-8137, 2004. (PMID: 15141079)

J119. Kojima, M., Wakai, K., Tamakoshi, K., Tokudome, S., Toyoshima, H., Watanabe, Y., Hayakawa, N., Suzuki, K., Hashimoto, S., Ito, Y. and Tamakoshi, A.: Diet and colorectal cancer mortality: results from the Japan Collaborative Cohort Study. Nutr Cancer, 50: 23-32, 2004. (PMID: 15572294)

J120. Kojima, M., Wakai, K., Tokudome, S., Suzuki, K., Tamakoshi, K., Watanabe, Y., Kawado, M., Hashimoto, S., Hayakawa, N., Ozasa, K., Toyoshima, H., Suzuki, S., Ito, Y. and Tamakoshi, A.: Serum levels of polyunsaturated fatty acids and risk of colorectal cancer: a prospective study. Am J Epidemiol, 161: 462-471, 2005. (PMID: 15718482)

J121. Kojima, M., Wakai, K., Tokudome, S., Tamakoshi, K., Toyoshima, H., Watanabe, Y., Hayakawa, N., Suzuki, K., Hashimoto, S., Ito, Y. and Tamakoshi, A.: Bowel movement frequency and risk of colorectal cancer in a large cohort study of Japanese men and women. Br J Cancer, 90: 1397-1401, 2004. (PMID: 15054462)

J122. Kojima, M., Wakai, K., Tokudome, S., Tamakoshi, K., Toyoshima, H., Watanabe, Y., Hayakawa, N., Suzuki, K., Hashimoto, S., Kawado, M., Suzuki, S., Ito, Y. and Tamakoshi, A.: Perceived psychologic stress and colorectal cancer mortality: findings from the Japan Collaborative Cohort Study. Psychosom Med, 67: 72-77, 2005.

(PMID: 15673627)

J123. Kondo, E., Akatsuka, Y., Kuzushima, K., Tsujimura, K., Asakura, S., Tajima, Ko., Kagami, Y., Kodera, Y., Tanimoto, M., Morishima, Y., and Takahashi, To.: Identification of novel CTL epitopes of CMV-pp65 presented by a variety of HLA alleles. Blood, 103: 630-638, 2004. (PMID: 12947002 )

J124. Kondo, E., Akatsuka, Y., Nawa, A., Kuzushima, K., Tsujimura, K., Tanimoto, M., Kodera, Y., Morishima, Y., Kuzuya, K. and Takahashi, To.: Retroviral vector backbone immunogenicity: identification of cytotoxic T-cell epitopes in retroviral vector-packaging sequences. Gene Ther. 12: 252-258, 2005. (PMID: 15496958)

J125. Kondo, E., Seto, M., Yoshikawa, K., and Yoshino, T.: Highly efficient delivery of p16 antitumor peptide into aggressive leukemia/lymphoma cells using a novel transporter system. Mol. Cancer Ther., 3: 1623-1630, 2004. (PMID: 15634656)

J126. Kondo, M., Yokoyama, T., Fukui, T., Yoshioka, H., Yokoi, K., Nagasaka, T., Imaizumi, K., Kume, H., Hasegawa, Y., Shimokata, K., and Sekido, Y.: Mutations of Epidermal Growth Factor Receptor of non-small cell lung cancer were associated with sensitivity to gefitinib in recurrence after surgery.” Lung Cancer 50: 385-391, 2005 (PMID: 16140420)

J127. Kontani, K., Kajino, K., Huangi, C.L., Fujino, S., Taguchi, O., Yamauchi, A., Yokomisa, H. and Ogasawara, K.: Spontaneous elicitation of potent antitumor immunity and eradication of established tumors by administration of DNA encoding soluble transforming growth factor-β II receptor without active antigen-sensitization. Cancer Immunol. Immunother. 20: 1-9, 2005. (PMID: 16032398)

J128. Kosaka, T., Yatabe, Y., Endoh, H., Kuwano, H., Takahashi, Ta., and Mitsudomi, T.: Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res. 64: 8919-8923, 2004. (PMID: 15604253)

J129. Kozuka, T., Ikeda, K., Teshima, T., Yoshida, C., Shinagawa, K., Kojima, K., Matsuo, K., Bessho, A., Sunami, K., Hiramatsu, Y., Maeda, Y., Noguchi, T., Yamamoto, K., Fujii, N., Imai, T., Kusumoto, K. K., Masuda, K., Takenaka, K., Ishimaru, F., Niiya, K., Koide, N., Tanimoto, M.

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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=PubMed&term=.,







and Harada, M.: Peripheral blood circulating immature cell counts predict CD34+ cell yields in G-CSF-induced PBPC mobilization in healthy donors. Transfusion, 44: 526-532, 2004. (PMID: 15043568)

J130. Kudoh, A., Daikoku, T., Sugaya, Y., Isomura, H., Fujita, M., Kiyono, T., Nishiyama, Y. and Tsurumi, T.: Inhibition of S-phase cyclin-dependent kinase activity blocks expression of Epstein-Barr virus immediate-early and early genes, preventing viral lytic replication. J. Virol. 78: 104-115, 2004. (PMID: 14671092)

J131. Kudoh, A., Fujita, M., Zhang, L., Shirata, N., Daikoku, T., Sugaya, Y., Isomura, H., Nishiyama, Y. and Tsurumi, T.: Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment. J. Biol. Chem. 280: 8156-8163, 2005. (PMID: 15611093)

J132. Kumimoto, H., Yamane, Y., and Ishizaki, K.: Two haplotypes of 5' untranslated region in L-myc gene with different internal ribosome entry site activity. Int. J. Oncol. 26:287-293, 2005.(PMID: 15586251)

J133. Kumimoto, H., Yamane, Y., Nishimoto, Y., Fukami, H., Shinoda, M., Hatooka, S., and Ishizaki, K.: Frequent somatic mutations of mitochondrial DNA in esophageal squamous cell carcinoma. Int. J. Cancer 108:228-231, 2004. (PMID: 14639607)

J134. Kuriki, K., Hamajima, N., Chiba, H., Kanemitsu, Y., Hirai, T., Kato, T., Saito, T., Matsuo, K., Koike, K., Tokudome, S. and Tajima, K.: Increased risk of colorectal cancer due to interactions between meat consumption and the CD36 gene A52C polymorphism among Japanese. Nutr Cancer, 51: 170-177, 2005. (PMID: 15860439)

J135. Kuriki, K., Hamajima, N., Chiba, H., Kanemitsu, Y., Hirai, T., Kato, T., Saito, T., Matsuo, K., Koike, K., Tokudome, S. and Tajima, K.: Relation of the CD36 gene A52C polymorphism to the risk of colorectal cancer among Japanese, with reference to with the aldehyde dehydrogenase 2 gene Glu487Lys polymorphism and drinking habit. Asian Pac J Cancer Prev, 6: 62-68, 2005. (PMID: 15780035)

J136. Kuriki, K., Tokudome, S. and Tajima, K.: Association between type II diabetes and colon cancer among Japanese with reference to changes in

food intake. Asian Pac J Cancer Prev, 5: 28-35, 2004. (PMID: 15075001)

J137. Kusumi, E., Kami, M., Kanda, Y., Murashige, N., Kishi, Y., Suzuki, R., Takeuchi, K., Tanimoto, T.E., Mori, T., Muta, K., Tamaki, T., Tanaka, Y., Ogawa, H., Yamane, T., Taniguchi, S. and Takaue, Y.: Reduced-intensity hematopoietic stem-cell transplantation for malignant lymphoma: A retrospective survey of 112 adult patients in Japan. Bone Marrow Transplant., 36:205-213, 2005. (PMID: 15937505)

J138. Kyogashima, M., Tamiya-Koizumi, K., Ehara, T., Li, G., Hu, R., Hara, A., Aoyama, T., and Kannagi, R.: Rapid demonstration of diversity of sulfatide molecular species from biological materials by MALDI-TOF MS. Glycobiology, in press.

J139. Lee, K. M., Park, S. K., Hamajima, N., Tajima, K., Choi, J. Y., Noh, D. Y., Ahn, S. H., Yoo, K. Y., Hirvonen, A. and Kang, D.: Genetic polymorphisms of interleukin-1 β (IL-1B) and IL-1 receptor antagonist (IL-1RN) and breast cancer risk in Korean women. Breast Cancer Res Treat, 1-6, 2005. (PMID: 16319982)

J140. Li, K., Takezaki, T., Song, FY., Yu, P., Deng, XL. and Tajima, K.: Relative validity of a semi-quantitative food frequency questionnaire versus 3 day weighed diet records in middle-aged inhabitants in Chaoshan area, China. Asian Pac J Cancer Prev, 6: 376-381, 2005. (PMID: 16236003)

J141. Lin, Y., Kikuchi, S., Tamakoshi, A., Wakai, K., Kawamura, T., Iso, H., Ogimoto, I., Yagyu, K., Obata, Y. and Ishibashi, T.: Alcohol consumption and mortality among middle-aged and elderly Japanese men and women. Ann Epidemiol, 15: 590-597, 2005. (PMID: 16118003)

J142. Lin, Y., Kikuchi, S., Tamakoshi, K., Wakai, K., Kondo, T., Niwa, Y., Yatsuya, H., Nishio, K., Suzuki, S., Tokudome, S., Yamamoto, A., Toyoshima, H. and Tamakoshi, A.: Prospective study of alcohol consumption and breast cancer risk in Japanese women. Int J Cancer, 116: 779-783, 2005. (PMID: 15838830)

J143. Lunin, V.V., Li, Y., Linhardt, R.J., Miyazono, H., Kyogashima, M., Kaneko, T., Bell, A.W. and Cygler, M.: High-resolution crystal structure of Arthrobacter aurescens chondroitin AC lyase: an enzyme-substrate complex defines the catalytic mechanism. J. Mol. Biol., 337: 367-386, 2004. (PMID: 15003453)

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J144. Maeda, O., Usami, N., Kondo, M., Takahashi, M., Goto, H., Shimokata, K., Kusugami, K., and Sekido, Y.: Plakoglobin (γ-catenin) has TCF/LEF family-dependent transcriptional activity in β-catenin-deficient cell line. Oncogene 23: 964-972, 2004. (PMID: 14661054)

J145. Maeno, K., Masuda, A., Yanagisawa, K., Konishi, H., Osada, H., Saito, T., Ueda, R., and Takahashi, Ta.: Altered regulation of c-jun and its involvement in anchorage-independent growth of human lung cancers. Oncogene, in press. (PMID: 16158054)

J146. Magari, H., Shimizu, Y., Inada, K. I., Enomoto, S., Tomeki, T., Yanaoka, K., Tamai, H., Arii, K., Nakata, H., Oka, M., Utsunomiya, H., Tsutsumi, Y., Tsukamoto, T., Tatematsu, M., and Ichinose, M.: Inhibitory effect of etodolac, a selective cyclooxygenase-2 inhibitor, on stomach carcinogenesis in Helicobacter pylori-infected Mongolian gerbils. Biochem. Biophys. Res. Commun., 334: 606-612, 2005. (PMID: 16009342)

J147. Marugame, T., Sobue, T., Satoh, H., Komatsu, S., Nishino, Y., Nakatsuka, H., Nakayama, T., Suzuki, T., Takezaki, T., Tajima, K. and Tominaga, S.: Lung cancer death rates by smoking status: comparison of the Three-Prefecture Cohort study in Japan to the Cancer Prevention Study II in the USA. Cancer Sci, 96: 120-126, 2005. (PMID: 15723657)

J148. Matsumoto, K., Mizoshita, T., Tsukamoto, T., Ogasawara, N., Hirata, A., Shimizu, Y., Haneda, M., Yamao, K., and Tatematsu, M.: Cdx2 expression in pancreatic tumors: Relationship with prognosis of invasive ductal carcinomas. Oncol. Rep., 12: 1239-1243, 2004. (PMID: 15547744)

J149. Matsuo, K., Hamajima, N., Suzuki, R., Andoh, M., Nakamura, S., Seto, M., Morishima, Y., and Tajima, K.: Lack of association between DNA base excision repair gene XRCC1 Gln399Arg polymorphism and risk of malignant lymphoma in Japan. Cancer Genet. Cytogenet., 149: 77-80, 2004. (PMID: 15104288)

J150. Matsuo, K., Hamajima, N., Suzuki, R., Ogura, M., Kagami, Y., Taji, H., Yasue, T., Mueller, N. E., Nakamura, S., Seto, M., Morishima, Y. and Tajima, K.: Methylene- tetrahydrofolate reductase gene (MTHFR) polymorphisms and reduced risk of malignant lymphoma. Am J Hematol, 77: 351-357, 2004. (PMID: 15551285)

J151. Matsuo, K., Ito, H., Wakai, K., Hirose, K., Saito, T., Suzuki, T., Kato, T., Hirai, T., Kanemitsu, Y., Hamajima, H. and Tajima, K.: One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan. Carcinogenesis, 26: 2164-2171, 2005. (PMID: 16051637)

J152. Matsuo, K., Kusano, A., Sugumar, A., Nakamura, S., Tajima, K. and Mueller, N. E.: Effect of hepatitis C virus infection on the risk of non-Hodgkin's lymphoma: a meta-analysis of epidemiological studies. Cancer Sci, 95: 745-752, 2004. (PMID: 15471561)

J153. Matsuo, K., Wakai, K., Hirose, K., Ito, H., Saito, T., Suzuki, T., Kato, T., Hirai, T., Kanemitsu, Y., Hamajima, H. and Tajima, K.: A gene-gene interaction between ALDH2 Glu487Lys and ADH2 His47Arg polymorphisms regarding the risk of colorectal cancer in Japan. Carcinogenesis, 27: 1018-1023, 2005. (PMID: 16332725)

J154. Mitsudomi, T., Kosaka, T., Endoh, H., Horio, Y., Hida, T., Mori, S., Hatooka, S., Shinoda, M., Takahashi, Ta., and Yatabe, Y.: Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J. Clin. Oncol. 23: 2513-20, 2005. (PMID: 15738541)

J155. Miyazaki, K., Ohmori, K., Izawa, M., Koike, T., Kumamoto, K., Furukawa, K., Ando, T., Kiso, M., Yamaji, T., Hashimoto, Y., Suzuki, A., Yoshida, A., Takeuchi, M. and Kannagi, R.: Loss of disialyl Lewisa, the ligand for lymphocyte inhibitory receptor Siglec-7, associated with increased sialyl Lewisa expression on human colon cancers. Cancer Res., 64: 4498-4505, 2004. (PMID: 15231659)

J156. Mizoshita, T., Inada, K., Tsukamoto, T., Nozaki, K., Joh, T., Itoh, M., Yamamura, Y., Ushijima, T., Nakamura, S., and Tatematsu, M.: Expression of the intestine-specific transcription factors, Cdx1 and Cdx2, correlates shift to an intestinal phenotype in gastric cancer cells. J. Cancer Res. Clin. Oncol., 130: 29-36, 2004. (PMID: 14615935)

J157. Mizoshita, T., Tsukamoto, T., Cao, X., Otsuka, T., Ito, S., Takahashi, E., Nakamura, S., Nakamura, T., Yamamura, Y., and Tatematsu, M.: Microsatellite instability is linked to loss of hMLH1 expression in advanced gastric cancers: lack of a

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relationship with the histological type and phenotype. Gastric Cancer, 8: 164-172, 2005. (PMID: 16086119)

J158. Mizoshita, T., Tsukamoto, T., Inada, K., Ogasawara, N., Hirata, A., Kato, S., Joh, T., Itoh, M., Yamamura, Y., and Tatematsu, M.: Immunohistochemically detectable Cdx2 is present in intestinal phenotypic elements in early gastric cancers of both differentiated and undifferentiated types, with no correlation to non-neoplastic surrounding mucosa. Pathol. Int., 54: 392-400, 2004. (PMID: 15144397)

J159. Mizoshita, T., Tsukamoto, T., Takenaka, Y., Cao, X., Kato, S., Kaminishi, M., and Tatematsu, M.: Gastric and intestinal phenotypes and histogenesis of advanced glandular stomach cancers in carcinogen-treated, Helicobacter pylori-infected Mongolian gerbils. Cancer Sci., 97: 38-44, 2006. (PMID: 16367919)

J160. Mizoshita, T., Tsukamoto, T., Tanaka, H., Takenaka, Y., Kato, S., Cao, X., Joh, T., and Tatematsu, M.: Colonic and small-intestinal phenotypes in gastric cancers: Relationships with clinicopathological findings. Pathol. Int., 55: 611-618, 2005. (PMID: 16185290)

J161. Mizuno, S., Ito, H., Hamajima, N., Tamakoshi, A., Hirose, K. and Tajima, K.: Association between smoking habits and tryptophan hydroxylase gene C218A polymorphism among the Japanese population. J Epidemiol, 14: 94-99, 2004. (PMID: 15242065)

J162. Mochizuki, Y., Nakanishi, H., Kodera, Y., Ito, S., Yamamura, Y., Kato, T., Hibi, K., Akiyama, S., Nakao, A., and Tatematsu, M.: TNF-α promotes progression of peritoneal metastasis as demonstrated using a green fluorescence protein (GFP)-tagged human gastric cancer cell line. Clin. Exp. Metastasis, 21: 39-47, 2004. (PMID: 15065601)

J163. Mori, S., Ito, G., Usami, N., Yoshioka, H., Ueda, Y., Kodama, Y., Takahashi, M., Fong, K.M., Shimokata, K., and Sekido, Y.: P53 apoptotic pathway molecules are frequently and simultaneously altered in non-small cell lung carcinoma. Cancer 100: 1673-1682, 2004. (PMID: 15073856)

J164. Murashige, N., Kami, M., Iwata, H., Kishi, Y. and Matsuo, K.: No relationship between hepatitis C infection and risk of myeloid malignancy. Haematologica, 90: 572-574, 2005.

(PMID: 15820965)

J165. Murashige, N., Kami, M., Kishi, Y., Kim, S.-W., Takeuchi, M., Matsue, K., Kanda, Y., Hirokawa, M., Kawabata, Y., Matsumura, T., Kusumi, E., Hirabayashi, N., Nagafuji, K., Suzuki, R., Takeuchi, K. and Oshimi, K.: Allogeneic haematopoietic stem cell transplantation as a promising treatment for natural killer-cell neoplasms. Br. J. Haematol., 130:561-567, 2005. (PMID: 16098071)

J166. Murata, K., Miyoshi, E., Ihara, S., Kameyama, M., Ishikawa, O., Doki, Y., Fukuoka, H., Tarui, T., Takada, Y., Kannagi, R., Taniguchi, N. and Imaoka, S.: Attachment of colon cancer cells onto vascular endothelial cells is enhanced by N-acetylglucosaminyltransferase V (GnT-V). Oncology, 66: 492-501, 2004. (PMID: 15452379)

J167. Murata, Y., Itakura, A., Matsuzawa, K., Okumura, A., Wakai, K. and Mizutani, S.: Possible antenatal and perinatal related factors in development of cystic periventricular leukomalacia. Brain Dev, 27: 17-21, 2005. (PMID: 15626536)

J168. Muscat, J. E., Takezaki, T., Tajima, K. and Stellman, S. D.: Charcoal cigarette filters and lung cancer risk in Aichi Prefecture, Japan. Cancer Sci, 96: 283-287, 2005. (PMID: 15904469)

J169. Mutoh, H., Hamajima, N., Tajima, K., Kobayashi, T. and Honda, H.: Exhastive exploring using Artificial Neural Network for identification of ANPSs combination related to Helicobacter pylori infection susceptibility. Chem-Bio Informatics J, 2005.

J170. Nagata, K., Asano, T., Nozawa, Y. and Inagaki, M.: Biochemical and cell biological analyses of a mammalian septin complex, Sept7/9b/11. J.Biol.Chem. 279: 55895-55904, 2004. (PMID: 15485874)

J171. Nagata, K. and Inagaki, M.: Cytoskeletal modification of Rho guanine nucleotide exchange factor activity: identification of a Rho guanine nucleotide exchange factor as a binding partner for Sept9b, a mammalian septin. Oncogene, 24: 65-76, 2005. (PMID: 15558029 )

J172. Nakagawa, M., Hosokawa, Y., Yonezumi, M., Izumiyama, K., Suzuki, R., Tsuzuki, S., Asaka, M. and Seto, M.: MALT1 contains nuclear export signal and regulates cytoplasmic localization of BCL10. Blood 106, 4210-4216, 2005 . (PMID: 16123224)

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J173. Nakagawa, M., Kameoka, Y. and Suzuki, R.: Nucleophosmin in acute myelogeneous leukemia. N. Engl. J. Med., 352:1819-1820, 2005 (PMID: 15858195)

J174. Nakagawa, T., Hayashita, Y., Maeno, K., Masuda, A., Sugito, N., Osada, H., Yanagisawa, K., Ebi, H., Shimokata, K., and Takahashi, Ta.: Identification of decatenation G2 checkpoint impairment independently of DNA damage G2 checkpoint in human lung cancer cell lines. Cancer Res. 64: 4826-4832, 2004. (PMID: 15256452)

J175. Nakamura, Hid., Fukami, H., Hayashi, Y., Tachibana, A., Nakatsugawa, S., Hamaguchi, M. and Ishizaki, K.: Cytotoxic and mutagenic effects of chronic low-dose-rate irradiation on hTERT-immortalized human cells. Radiation Research 163:283-288, 2005.(PMID: 15733035)

J176. Nakanishi, H., Yasui, K., Ikehara, Y., Yokoyama, H., Munesue, S., Kodera, Y., and Tatematsu, M.: Establishment and characterization of three novel human gastric cancer cell lines with differentiated intestinal phenotype derived from liver metastasis. Clin. Exp. Meta. 22:137-147, 2005. (PMID: 16086234)

J177. Nakashima, Y., Tagawa, H., Suzuki, R., Karnan, S., Karube, K., Ohshima, K., Muta, K., Nawata, H., Morishima, Y., Nakamura, S. and Seto, M.: Genome-wide array-based comparative genomic hybridization of natural killer cell lymphoma/leukemia: different genomic alteration patterns of aggressive NK-cell leukemia and extranodal NK/T-cell lymphoma, nasal type. Genes Chromosomes Cancer. 44: 247-255, 2005. (PMID: 16049916)

J178. Ninomiya, S., Niimi, T., Shimizu, S., Sato, S., Achiwa, H., Ito, H., Akita, K., Maeda, H. and Ueda, R.: Matrix metalloproteinase-1 polymorphism of promoter region in sarcoidosis and tuberculosis patients. Sarcoidosis Vasc Diffuse Lung Dis, 21: 19-24, 2004. (PMID: 15127970)

J179. Nishida, T., Akatsuka, Y., Morishima, Y., Hamajima, N., Tsujimura, K., Kuzushima, K., Kodera, Y. and Takahashi, To.: Clinical relevance of a newly identified HLA-A24-restricted minor histocompatibility antigen epitope derived from BCL2A1, ACC-1, in patients receiving HLA genotypically matched unrelated bone marrow transplant. Br. J. Haematol. 124: 629-635, 2004. (PMID: 14871250)

J180. Nishida, T., Hamaguchi, M., Hirabayashi,

N., Haneda, M., Terakura, S., Atsuta, Y., Imagama, S., Kanie, T., Murata, M., Taji, H., Suzuki, R., Morishita, Y. and Kodera, Y.: Intestinal thrombotic microangiopathy after allogeneic bone marrow transplantation: a clinical imitator of acute enteric graft-versus-host disease. Bone Marrow Transplant., 33:1143-1150, 2004. (PMID: 15077133)

J181. Nishimura, T., Kato, K., Yamaguchi, T., Fukata, Y., Ohno, S. and Kaibuchi, K.: Role of the PAR-3-KIF3 complex in the establishment of neuronal polarity. Nature Cell Biol. 6: 328-334, 2004. (PMID: 15048131)

J182. Nishimura, T., Yamaguchi, T., Kato, K., Yoshizawa, M., Nabeshima, Y., Ohno, S., Hoshino, M. and Kaibuchi, K.: PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nature Cell Biol. 7: 270-277, 2005. (PMID: 15723051)

J183. Nishimura, T., Yamaguchi, T., Tokunaga, A., Hara, A., Hamaguchi, T., Kato, K., Iwamatsu, A., Okano, H. and Kaibuchi, K.: Role of Numb in Dendritic Spine Development with a Cdc42 GEF Intersectin and EphB2. Mol. Biol. Cell. in press. (PMID: 16394100)

J184. Nishizawa, M., Izawa, I., Inoko, A., Hayashi, Y., Nagata, K., Yokoyama, T., Usukura, J. and Inagaki, M.: Identification of trichoplein, a novel keratin filament-binding protein. J.Cell Sci. 118: 1081-1090, 2005. (PMID: 15731013)

J185. Niwa, T., Ikehara, Y., Nakanishi, H., Tanaka, H., Inada, K., Tsukamoto, T., Ichinose, M., and Tatematsu, M.: Mixed gastric- and intestinal-type metaplasia Is formed by cells with dual intestinal and gastric differentiation. J. Histochem. Cytochem., 53: 75-85, 2005. (PMID: 15637340)

J186. Niwa, T., Yamashita, S., Tsukamoto, T., Kuramoto, T., Nomoto, T., Wakazono, K., Fujita, H., Matsushima, T., Tatematsu, M., Sugimura, T., and Ushijima, T.: Whole-genome analyses of loss of heterozygosity and methylation analysis of four tumor-suppressor genes in N-methyl-N'-nitro-N- nitrosoguanidine-induced rat stomach carcinomas. Cancer Sci., 96: 409-413, 2005. (PMID: 16053512)

J187. Niwa, Y., Hamajima, N., Atsuta, Y., Yamamoto, K., Tamakoshi, A., Saito, T., Hirose, K., Nakanishi, T., Nawa, A., Kuzuya, K. and Tajima, K.: Genetic polymorphisms of p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro and

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the risk of cervical cancer in Japanese. Cancer Lett, 205: 55-60, 2004. (PMID: 15036661)

J188. Niwa, Y., Hirose, K., Matsuo, K., Tajima, K., Ikoma, Y., Nakanishi, T., Nawa, A., Kuzuya, K., Tamakoshi, A. and Hamajima, N.: Association of p73 G4C14-to-A4T14 polymorphism at exon 2 and p53 Arg72Pro polymorphism with the risk of endometrial cancer in Japanese subjects. Cancer Lett, 219: 183-190, 2005. (PMID: 15723718)

J189. Niwa, Y., Hirose, K., Matsuo, K., Tajima, K., Ikoma, Y., Nakanishi, T., Nawa, A., Kuzuya, K., Tamakoshi, A. and Hamajima, N.: Lymphotoxin-α polymorphism and the risk of cervical cancer in Japanese subjects. Cancer Lett, 218: 63-68, 2005. (PMID: 15639341)

J190. Niwa, Y., Hirose, K., Nakanishi, T., Nawa, A., Kuzuya, K., Tajima, K. and Hamajima, N.: Association of the NAD(P)H: quinone oxidoreductase C609T polymorphism and the risk of cervical cancer in Japanese subjects. Gynecol Oncol, 96: 423-429, 2005. (PMID: 15661231)

J191. Niwa, Y., Matsuo, K., Ito, H., Hirose, K., Tajima, K., Nakanishi, T., Nawa, A., Kuzuya, K., Tamakoshi, A. and Hamajima, N.: Association of XRCC1 Arg399Gln and OGG1 Ser326Cys polymorphisms with the risk of cervical cancer in Japanese subjects. Gynecol Oncol, 99: 43-49, 2005. (PMID: 15990162)

J192. Niwa, Y., Wakai, K., Suzuki, S., Tamakoshi, K., Lin, Y., Yatsuya, H., Kondo, T., Nishio, K., Yamamoto, A., Tokudome, S., Hamajima, N., Toyoshima, H. and Tamakoshi, A.: Cigarette smoking and the risk of ovarian cancer in the Japanese population: findings from the Japanese Collaborate Cohort study. J Obstet Gynaecol Res, 31: 144-151, 2005. (PMID: 15771641)

J193. Niwa, Y., Yatsuya, H., Tamakoshi, K., Nishio, K., Kondo, T., Lin, Y., Suzuki, S., Wakai, K., Tokudome, S., Yamamoto, A., Hamajima, N., Toyoshima, H. and Tamakoshi, A.: Relationship between body mass index and the risk of ovarian cancer in the Japanese population: findings from the Japanese Collaborate Cohort (JACC) study. J Obstet Gynaecol Res, 31: 452-458, 2005. (PMID: 16176517)

J194. Nozaki, K., Tanaka, H., Ikehara, Y., Cao, X., Nakanishi, H., Azuma, T., Yamazaki, S., Yamaoka, Y., Shimizu, N., Mafune, K., Kaminishi, M. and Tatematsu, M.: Helicobacter pylori- dependent NF-κ B activation in newly established

Mongolian gerbil gastric cancer cell lines. Cancer Sci. 96: 170-175, 2005. (PMID: 15771620)

J195. Ogasawara, N., Tsukamoto, T., Inada, K., Mizoshita, T., Ban, N., Yamao, K., Joh, T., Itoh, M., and Tatematsu, M.: Frequent c-Kit gene mutations not only in gastrointestinal stromal tumors but also in interstitial cells of Cajal in surrounding normal mucosa. Cancer Lett., 230: 199-210, 2005. (PMID: 16297706)

J196. Ohashi, N., Kodera, Y., Nakanishi, H., Yokoyama, H., Fujiwara, M., Koike, M., Hibi, K., Nakao, A., and Tatematsu, M.: Efficacy of intraperitoneal chemotherapy with paclitaxel targeting peritoneal micrometastasis as revealed by GFP-tagged human gastric cancer cell lines in nude mice. Int. J. Oncol. 27:637-44, 2005. (PMID: 16077911)

J197. Ohmori, K., Fukui, F., Kiso, M., Imai, T., Yoshie, O., Hasegawa, H., Matsushima, K. and Kannagi, R.: Identification of cutaneous lymphocyte-associated antigen as sialyl 6-sulfo Lewis x, a selectin ligand expressed on a subset of skin-homing helper memory T cells. Blood, in press. (PMID: 16380447)

J198. Ohyama, I., Ohmiya, N., Niwa, Y., Shirai, K., Taguchi, A., Itoh, A., Hirooka, Y., Wakai, K., Hamajima, N., Mori, N. and Goto, H.: The association between tumour necrosis factor-α gene polymorphism and the susceptibility to rugal hyperplastic gastritis and gastric carcinoma. Eur J Gastroenterol Hepatol, 16: 693-700, 2004. (PMID: 15201584)

J199. Okamura, M., Yokoyama, N., Wickramathilaka, N. P., Takabatake, N., Ikehara, Y. and Igarashi, I.: Babesia caballi and Babesia equi: implications of host sialic acids in erythrocyte infection. Exp. Parasitol. 110: 406-411, 2005. (PMID: 15869756)

J200. Okudela, K., Hayashi, H., Ito, T., Yazawa, T., Suzuki, T., Nakane, Y., Sato, H., Ishi, H., KeQin, X., Masuda, A., Takahashi, Ta., and Kitamura, H.: K-ras gene mutation enhances motility of immortalized airway cells and lung adenocarcinoma cells via Akt activation: possible contribution to non-invasive expansion of lung adenocarcinoma. Am. J. Pathol. 164: 91-100, 2004. (PMID: 14695323)

J201. Okumura, K., Hasegawa, Y., Harada, H., Ishizaki, K. and Murakami, S.: A comparative study of p53 status and clinical response to

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J202. Onizuka, M., Kasai, M., Oba, T., Atsuta, Y., Terakura, S., Suzuki, R., Kitaori, K., Miyamura, K., Hotta, T. and Kodera, Y.: Increased frequency of the angiotensin-converting enzyme gene D-allele is associated with non-infectious pulmonary dysfunction following allogeneic stem cell transplant. Bone Marrow Transplant., 36:617-20, 2005 (PMID: 16044138)

J203. Ono, R., Ihara, M., Nakajima, H., Ozaki, K., Kataoka-Fujiwara, Y., Taki, T., Nagata, K., Inagaki, M., Yoshida, N., Kitamura, T., Hayashi, Y., Kinoshita, M. and Nosaka, T.: Disruption of Sept6, a fusion partner gene of Mixed Lineage Leukemia(MLL), does not affect the ontogeny, leukemogenesis induced by MLL-SEPT6, or the phenotype induced by the loss of Sept4. Mol. Cell. Biol. 25: 10965-10978, 2005. (PMID: 16314519)

J204. Osada, H., Tatematsu, Y., Saito, H., Yatabe, Y., Mitsudomi, T., and Takahashi, Ta.: Reduced expression of class II histone deacetylase genes is associated with poor prognosis in lung cancer patients. Int. J. Cancer. 112: 26-32, 2004. (PMID: 15305372)

J205. Osada, H., Tatematsu, Y., Sugito, N., Horio, Y., and Takahashi, Ta.: Histone modification in the TGFβRII gene promoter and its significance for responsiveness to HDAC inhibitor in lung cancer cell lines. Mol. Carcinog. 44: 233-241, 2005. (PMID: 16163707)

J206. Osada, H., Tatematsu, Y., Yatabe, Y., Horio, Y., and Takahashi, Ta.: ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features. Cancer Res. 65: 10680-10685, 2005. (PMID: 16322211)

J207. Oshimi, K., Kawa, K., Nakamura, S., Suzuki, R., Suzumiya, J., Yamaguchi, M., Kameoka, J., Tagawa, S., Imamura, N., Ohshima, K., Kojya, S., Iwatsuki, K., Tokura, Y., Sato, E. and Sugimori, H.: NK-cell neoplasms in Japan. Hematology, 10:237-245, 2005. (PMID: 16019472)

J208. Oshiro, A., Tagawa, H., Ohshima, K., Karube, K., Uike, N., Tashir,o Y., Utsunomiya, A., Masuda, M., Takasu, N., Nakamura, S., Morishima, Y. and Seto, M.: Identification of subtype specific genomic alteration of agressive type of adult T cell lymphoma/leukemia. Comparison of genome profiles for identification of distinct subtype of diffuse large B-cell lymphoma.

Blood, in press.

J209. Ota, A., Tagawa, H., Karnan, S., Tsuzuki, S., Karpas, A., Kira, S., Yoshida, Y. and Seto, M.: Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. Cancer Res., 64: 3087-3095, 2004. (PMID: 15126345)

J210. Otsubo, N., Ishida, H., Kannagi, R. and Kiso, M.: Design and synthesis of a novel neo-glycolipid containing sialyl Lewis X determinant carried on the mucin GlcNAc β1-6GalNAcα core structure. Tetrahedron Asymmetry, 16: 1321-1327, 2005.

J211. Otsuka, T., Tsukamoto, T., Mizoshita, T., Inada, K., Takenaka, Y., Kato, S., Yamamura, Y., Miki, K., and Tatematsu, M.: Coexistence of gastric- and intestinal-type endocrine cells in gastric and intestinal mixed intestinal metaplasia of the human stomach. Pathol. Int., 55: 170-179, 2005. (PMID: 15826243)

J212. Otsuka, T., Tsukamoto, T., Tanaka, H., Inada, K., Utsunomiya, H., Mizoshita, T., Kumagai, T., Katsuyama, T., Miki, K., and Tatematsu, M.: Suppressive effects of fruit-juice concentrate of Prunus mume Sieb. et Zucc. (Japanese apricot, Ume) on Helicobacter pylori-induced glandular stomach lesions in Mongolian gerbils. Asian Pac. J. Cancer Prev., 6: 337-341, 2005. (PMID: 16235996)

J213. Ozasa, K., Ito, Y., Suzuki, K., Watanabe, Y., Hayashi, K., Mikami, K., Nakao, M., Miki, T., Mori, M., Sakauchi, F., Washio, M., Kubo, T., Wakai, K. and Tamakoshi, A.: Serum carotenoids and other antioxidative substances associated with urothelial cancer risk in a nested case-control study in Japanese men. J Urol, 173: 1502-1506, 2005. (PMID: 15821468)

J214. Ozasa, K., Ito, Y., Suzuki, K., Watanabe, Y., Kojima, M., Suzuki, S., Tokudome, S., Tamakoshi, K., Toyoshima, H., Kawado, M., Hashimoto, S., Hayakawa, N., Wakai, K. and Tamakoshi, A.: Glucose intolerance and colorectal cancer risk in a nested case-control study among Japanese People. J Epidemiol, 15 Suppl 2: S180-184, 2005. (PMID: 16127231)

J215. Ozasa, K., Ito, Y., Suzuki, K., Watanabe, Y., Wakai, K. and Tamakoshi, A.: Association of serum carotenoid concentration and dietary habits among the JACC Study subjects. J Epidemiol, 15 Suppl 2: S220-227, 2005. (PMID: 16127237)

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J216. Ozasa, K., Nakao, M., Watanabe, Y., Hayashi, K., Miki, T., Mikami, K., Mori, M., Sakauchi, F., Washio, M., Ito, Y., Suzuki, K., Kubo, T., Wakai, K. and Tamakoshi, A.: Association of serum phytoestrogen concentration and dietary habits in a sample set of the JACC Study. J Epidemiol, 15 Suppl 2: S196-202, 2005. (PMID: 16127234)

J217. Ozasa, K., Nakao, M., Watanabe, Y., Hayashi, K., Miki, T., Mikami, K., Mori, M., Sakauchi, F., Washio, M., Ito, Y., Suzuki, K., Wakai, K. and Tamakoshi, A.: Serum phytoestrogens and prostate cancer risk in a nested case-control study among Japanese men. Cancer Sci, 95: 65-71, 2004. (PMID: 14720329)

J218. Sakai, H., Eishi, Y., Li, X. L., Akiyama, Y., Miyake, S., Takizawa, T., Konishi, N., Tatematsu, M., Koike, M., and Yuasa, Y.: PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomas. Gut, 53: 323-330, 2004. (PMID: 14960508)

J219. Sakamoto, N., Kono, S., Wakai, K., Fukuda, Y., Satomi, M., Shimoyama, T., Inaba, Y., Miyake, Y., Sasaki, S., Okamoto, K., Kobashi, G., Washio, M., Yokoyama, T., Date, C. and Tanaka, H.: Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in Japan. Inflamm Bowel Dis, 11: 154-163, 2005. (PMID: 15677909)

J220. Sakauchi, F., Mori, M., Washio, M., Watanabe, Y., Ozasa, K., Hayashi, K., Miki, T., Nakao, M., Mikami, K., Ito, Y., Wakai, K. and Tamakoshi, A.: Dietary habits and risk of urothelial cancer death in a large-scale cohort study (JACC Study) in Japan. Nutr Cancer, 50: 33-39, 2004. (PMID: 15572295)

J221. Sakauchi, F., Mori, M., Washio, M., Watanabe, Y., Ozasa, K., Hayashi, K., Miki, T., Nakao, M., Mikami, K., Ito, Y., Wakai, K. and Tamakoshi, A.: Dietary habits and risk of urothelial cancer incidence in the JACC Study. J Epidemiol, 15 Suppl 2: S190-195, 2005. (PMID: 16127233)

J222. Satoh, T., Kanai, Y., Wu, M.H., Yokozeki, H., Kannagi, R., Lowe, J.B. and Nishioka, K.: Synthesis of α(1,3)fucosyltransferases IV- and VII-dependent eosinophil selectin ligand and recruitment to the skin. Am. J. Pathol., 167: 787-796, 2005. (PMID: 16127157)

J223. Sawa, M., Yamamoto, K., Yokozawa, T., Kiyoi, H., Hishida, A., Kajiguchi, T., Seto, M.,

Kohno, A., Kitamura, K., Itoh, Y., Asou, N., Hamajima, N., Emi, N., and Naoe, T.: BMI-1 is highly expressed in M0-Subtype acute myeloid leukemia. Int. J. Hematol., 82:42-47, 2005. (PMID: 16105758)

J224. Shirata, N., Kudoh, A., Daikoku, T., Tatsumi, Y., Fujita, M., Kiyono, T., Sugaya, Y., Isomura, H., Ishizaki, K. and Tsurumi, T.: Activation of ataxia telangiectasia-mutated DNA damage checkpoint signal transduction elicited by herpes simplex virus infection. J. Biol. Chem. 280: 30336-30341, 2005. (PMID: 15964848)

J225. Song, F. Y., Takezaki, T., Li, K., Yu, P., Lin, X. K., Yang, H. L., Deng, X. L., Zhang, Y. Q., Lv, L. W., Huang, X. E. and Tajima, K.: Development of a semi-quantitative food frequency questionnaire for middle-aged inhabitants in the Chaoshan area, China. World J Gastroenterol, 11: 4078-4084, 2005. (PMID: 15996034)

J226. Stefanovic, S., Windsor, M., Nagata, K., Inagaki, M. and Wileman, T.: Vimentin rearrangement during African swine fever virus infection involves retrograde transport along microtubules and phosphorylation of vimentin by calcium calmodulin kinase II. J Virol. 79: 11766-11775, 2005. (PMID: 16140754)

J227. Storek, J., Zhao, Z., Lin, E., Berger, T., McSweeney, P.A., Nash, R.A., Akatsuka, Y., Metcalf, M.D., Lu, H., Kalina, T., Reindl, M., Storb, R., Hansen, J.A., Sullivan, K.M., Kraft, G.H., Furst, D.E. and Maloney, D.G.: Recovery from and consequences of severe iatrogenic lymphopenia (induced to treat autoimmune diseases). Clin. Immunol. 113: 285-298, 2004. (PMID: 15507394)

J228. Sugaya, N., Kimura, H., Hara, S., Hoshino, Y., Kojima, S., Morishima, T., Tsurumi, T. and Kuzushima, K.: Quantitative analysis of Epstein-Barr virus (EBV)-specific CD8+ T cells in patients with chronic active EBV infection. J. Infect. Dis. 190: 985-988, 2004. (PMID: 15295706)

J229. Sugimoto, N., Tatsumi, Y., Tsurumi, T., Matsukage, A., Kiyono, T., Nishitani, H. and Fujita, M.: Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting the binding by geminin. J.Biol.Chem. 279: 19691-19697, 2004. (PMID: 14993212)

J230. Sugimura, T., Kumimoto, H., Tohnai, I., Fukui, T., Matsuo, K., Tsurusako, S., Mitsudo, K.,

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J231. Sugumar, A., Liu, Y. C., Xia, Q., Koh, Y. S. and Matsuo, K.: Insulin-like growth factor (IGF)-I and IGF-binding protein 3 and the risk of premenopausal breast cancer: a meta-analysis of literature. Int J Cancer, 111: 293-297, 2004. (PMID: 15197785)

J232. Suzuki, A., Yoshioka, S., Sekine, M., Yonekawa, H., Takenaka, M. and Kannagi, R.: Core 2 GlcNAc transferase and kidney tubular cell-specific expression. Glycoconj. J., 20: 151-156, 2004. (PMID: 15090728)

J233. Suzuki, K., Ito, Y., Wakai, K., Kawado, M., Hashimoto, S., Toyoshima, H., Kojima, M., Tokudome, S., Hayakawa, N., Watanabe, Y., Tamakoshi, K., Suzuki, S., Ozasa, K. and Tamakoshi, A.: Serum oxidized low-density lipoprotein levels and risk of colorectal cancer: a case-control study nested in the Japan Collaborative Cohort Study. Cancer Epidemiol Biomarkers Prev, 13: 1781-1787, 2004. (PMID: 15533907)

J234. Suzuki, R., Nakamura, S., Suzumiya, J., Ichimura, K., Ichikawa, M., Ogata, K., Kura, Y., Aikawa, K., Teshima, H., Sako, M., Kojima, H., Nishio, M., Yoshino, T., Sugimori, H., Kawa, K., Oshimi, K. and the NK-cell Tumor Study Group: Blastic natural killer cell lymphoma/leukemia (CD56-positive blastic tumor): prognostication and categorization according to anatomic sites of involvement. Cancer, 104:1022-1031, 2005. (PMID: 15999368)

J235. Suzuki, R., Suzumiya, J., Nakamura, S., Aoki, S., Notoya, A., Ozaki, S., Gondo, H., Hino, N., Mori, H., Sugimori, H., Kawa, K., Oshimi, K. and the NK-cell Tumor Study Group: Aggressive natural killer (NK)-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells. Leukemia, 18:763-770, 2004. (PMID: 14961041)

J236. Suzuki, T., Kiyoi, H., Ozeki, K., Tomita, A., Yamaji, S., Suzuki, R., Kodera, Y., Miyawaki, S., Asou, N., Kuriyama, K., Yagasaki, F., Shimazaki, C., Akiyama, H., Nishimura, M., Motoji, T., Shinagawa, K., Takeshita, A., Ueda, R., Kinoshita, T., Emi, N. and Naoe, T.: Clinical characteristics and prognostic implications of NPM1 mutations in

acute myeloid leukemia. Blood, 106:2854-2861, 2005 (PMID: 15994285)

J237. Suzuki, T., Matsuo, K., Ito, H., Hirose, K., Wakai, K., Saito, T., Sato, S., Morishima, Y., Nakamura, S., Ueda, R. and Tajima, K.: A past history of gastric ulcers and Helicobacter pylori infection increase the risk of gastric malignant lymphoma. Carcinogenesis, 2006. (PMID: 16400189)

J238. Tagawa, H. and Seto, M.: A microRNA cluster as a target of genomic amplification in malignant lymphoma. Leukemia Correspondence, 19: 2013-2016, 2005. (PMID: 16167061)

J239. Tagawa, H., Karnan, S., Kasugai, Y., Tsuzuki, S., Suzuki, R., Hosokawa, Y. and Seto, M.: MASL1, a candidate oncogene found in amplification at 8p23.1, is translocated in immuno- blastic B-cell lymphoma cell line OCI-LY8. Oncogene, 23: 2576-2581, 2004. (PMID: 14691450)

J240. Tagawa, H., Karnan, S., Suzuki, R., Matsuo, K., Zhang, X., Ota, A., Morishima, Y., Nakamura, S. and Seto, M.: Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene, 24: 1348-1358, 2005. (PMID: 15608680)

J241. Tagawa, H., Suguro, M., Tsuzuki, S., Matsuo, K., Karnan, S., Ohshima, K., Okamoto, M., Morishima, Y., Nakamura, S. and Seto, M.: Comparison of genome profiles for identification of distinct subgroups of diffuse large B-cell lymphoma. Blood, 106: 1770-1777, 2005. (PMID: 15886317)

J242. Tagawa, H., Tsuzuki, S., Suzuki, R., Karnan, S., Ota, A., Kameoka, Y., Suguro, M., Matsuo, K., Yamaguchi, M., Okamoto, M., Morishima, Y., Nakamura, S. and Seto, M.: Genome-wide array-based comparative genomic hybridization of diffuse large B-cell lymphoma: comparison between CD5-positive and CD5-negative cases. Cancer Res, 64: 5948-5955, 2004. (PMID: 15342373)

J243. Tajima, Ko., Demachi, A., Ito, Y., Nishida, K., Akatsuka, Y., Tsujimura, K., Kuwano, H., Mitsudomi, T., Takahashi, To. and Kuzushima, K.: Identification of an epitope from the epithelial cell adhesion molecule eliciting HLA-A*2402- restricted cytotoxic T-lymphocyte responses. Tissue Antigens 64: 650-659, 2004. (PMID: 15546337)

J244. Tajima, Ko., Ito, Y., Demachi, A., Nishida,

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K., Akatsuka, Y., Tsujimura, K., Hida, T., Morishima, Y., Kuwano, H., Mitsudomi, T., Takahashi, To. and Kuzushima, K.: Interferon-γ differentially regulates susceptibility of lung cancer cells to telomerase-specific cytotoxic T lymphocytes. Int. J. Cancer 110: 403-412, 2004. (PMID: 15095306)

J245. Takami, A., Iwakubo, M., Okada, Y., Kawata, T., Odai, H., Takahashi, N., Shindo, K., Kimura, K., Tagami, Y., Miyake, M., Fukushima, K., Inagaki, M., Amano, M., Kaibuchi, K. and Iijima, H.: Design and synthesis of Pho kinase inhibitors (I). Bioorg. Med. Chem. 12: 2115-2137, 2004. (PMID: 15080913)

J246. Takami, A., Sugimori, C., Feng, X., Yachie, A., Kondo, Y., Nishimura, R., Kuzushima, K., Kotani, T., Asakura, H., Shiobara, S. and Nakao, S.: Expansion and activation of minor histocompatibility antigen HY-specific T cells associated with graft-versus-leukemia response. Bone Marrow Transplant. 34: 703-709, 2004. (PMID: 15322566)

J247. Takamizawa, J., Konishi, H., Yanagisawa, K., Tomida, S., Osada, H., Endoh, H., Harano, T., Yatabe, Y., Nagino, M., Nimura, Y., Mitsudomi, T., and Takahashi, Ta.: Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 64: 3753-3756, 2004. (PMID: 15172979)

J248. Takeuchi, M., Keino, H., Kezuka, T., Usui, M. and Taguchi, O.: Immune responses to retinal self-antigens in CD25+CD4+ regulatory T cell-depleted mice. Invest. Ophthalmol.Vis. Sci., 45: 1879-1886, 2004. (PMID: 15161853)

J249. Tamakoshi, K., Toyoshima, H., Wakai, K., Kojima, M., Suzuki, K., Watanabe, Y., Hayakawa, N., Yatsuya, H., Kondo, T., Tokudome, S., Hashimoto, S., Suzuki, S., Kawado, M., Ozasa, K., Ito, Y. and Tamakoshi, A.: Leptin is associated with an increased female colorectal cancer risk: a nested case-control study in Japan. Oncology, 68: 454-461, 2005. (PMID: 16020976)

J250. Tamakoshi, K., Wakai, K., Kojima, M., Watanabe, Y., Hayakawa, N., Toyoshima, H., Yatsuya, H., Kondo, T., Tokudome, S., Hashimoto, S., Suzuki, K., Ito, Y. and Tamakoshi, A.: A prospective study of body size and colon cancer mortality in Japan: The JACC Study. Int J Obes Relat Metab Disord, 28: 551-558, 2004. (PMID: 14968128)

J251. Tamakoshi, K., Wakai, K., Kojima, M., Watanabe, Y., Hayakawa, N., Toyoshima, H., Yatsuya, H., Kondo, T., Tokudome, S., Hashimoto, S., Suzuki, K., Ito, Y. and Tamakoshi, A.: A prospective study on the possible association between having children and colon cancer risk: findings from the JACC Study. Cancer Sci, 95: 243-247, 2004. (PMID: 15016324)

J252. Tamakoshi, K., Wakai, K., Kojima, M., Watanabe, Y., Hayakawa, N., Toyoshima, H., Yatsuya, H., Kondo, T., Tokudome, S., Hashimoto, S., Suzuki, K., Suzuki, S., Kawado, M., Ozasa, K., Ito, Y. and Tamakoshi, A.: A prospective study of reproductive and menstrual factors and colon cancer risk in Japanese women: findings from the JACC study. Cancer Sci, 95: 602-607, 2004. (PMID: 15245598)

J253. Tamakoshi, K., Yatsuya, H., Wakai, K., Suzuki, S., Nishio, K., Lin, Y., Niwa, Y., Kondo, T., Yamamoto, A., Tokudome, S., Toyoshima, H. and Tamakoshi, A.: Impact of menstrual and reproductive factors on breast cancer risk in Japan: results of the JACC study. Cancer Sci, 96: 57-62, 2005. (PMID: 15649257)

J254. Tanaka, H., Tsukamoto, T., Mizoshita, T., Inada, K., Ogasawara, N., Cao, X., Kato, S., Joh, T., and Tatematsu, M.: Expression of small intestinal and colonic phenotypes in complete intestinal metaplasia of the human stomach. Virchows Arch, 447: 806-815, 2005. (PMID: 16088401)

J255. Terakura, S., Murata, M., Nishida, T., Emi, N., Akatsuka, Y., Riddell, S.R., Morishima, Y., Kodera, Y. and Naoe, T.: A UGT2B17-positive donor is a risk factor for higher transplant-related mortality and lower survival after bone marrow transplantation. Br. J. Haematol. 129: 221-228, 2005. (PMID: 15813850)

J256. Teshima, T., Matsuo, K., Matsue, K., Kawano, F., Taniguchi, S., Hara, M., Hatanaka, K., Tanimoto, M., Harada, M., Nakao, S., Abe, Y., Wake, A., Eto, T., Takemoto, Y., Imamura, M., Takahashi, S., Ishida, Y., Kanda, Y., Kasai, M. and Takaue, Y.: Impact of human leucocyte antigen mismatch on graft-versus-host disease and graft failure after reduced intensity conditioning allogeneic haematopoietic stem cell transplantation from related donors. Br J Haematol, 130: 575-587, 2005. (PMID: 16098073)

J257. Tjew, S.L., Brown, K.L., Kannagi, R. and Johnson, P.: Expression of N-acetylglucosamine

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6-O sulfotransferases (GlcNAc6STs) -1 and -4 in human monocytes: GlcNAc6ST-1 is implicated in the generation of the 6-sulfo N-acetyllactosamine/ Lewis x epitope on CD44 and is induced by TNF-α. Glycobiology, 17: 7C-13C, 2005. (PMID: 15728736)

J258. Togawa, S., Joh, T., Itoh, M., Katsuda, N., Ito, H., Matsuo, K., Tajima, K. and Hamajima, N.: Interleukin-2 gene polymorphisms associated with increased risk of gastric atrophy from Helicobacter pylori infection. Helicobacter, 10: 172-178, 2005. (PMID: 15904474)

J259. Tokudome, S., Kuriki, K., Yamada, N., Ichikawa, H., Miyata, M., Shibata, K., Hoshino, H., Tsuge, S., Tokudome, M., Goto, C., Tokudome, Y., Kobayashi, M., Goto, H., Suzuki, S., Okamoto, Y., Ikeda, M. and Sato, Y.: Anthropometric, lifestyle and biomarker assessment of Japanese non-professional ultra-marathon runners. J Epidemiol, 14: 161-167, 2004. (PMID: 15478671)

J260. Tokudome, S., Soeripto, Triningsih, F. X., Ananta, I., Suzuki, S., Kuriki, K., Akasaka, S., Kosaka, H., Ishikawa, H., Azuma, T. and Moore, M. A.: Rare Helicobacter pylori infection as a factor for the very low stomach cancer incidence in Yogyakarta, Indonesia. Cancer Lett, 219: 57-61, 2005. (PMID: 15770773)

J261. Tokudome, Y., Goto, C., Imaeda, N., Hasegawa, T., Kato, R., Hirose, K., Tajima, K. and Tokudome, S.: Relative validity of a short food frequency questionnaire for assessing nutrient intake versus three-day weighed diet records in middle-aged Japanese. J Epidemiol, 15: 135-145, 2005. (PMID: 16141632)

J262. Tomida, S., Koshikawa, K., Yatabe, Y., Harano, T., Ogura, N., Mitsudomi, T., Some, M., Yanagisawa, K., Takahashi, To., Osada, H., and Takahashi, Ta.: Gene expression-based, individualized outcome prediction for surgically treated lung cancer patients. Oncogene. 23: 5360-5370, 2004. (PMID: 15064725)

J263. Torikai, H., Akatsuka, Y., Miyazaki, M., Warren, E.H., III, Oba, T., Tsujimura, K., Motoyoshi, K., Morishima, Y., Kodera, Y., Kuzushima, K. and Takahashi, To.: A novel HLA-A*3303-restricted minor histocompatibility antigen encoded by an unconventional open reading frame of human TMSB4Y gene. J. Immunol. 173: 7046-7054, 2004. (PMID: 15557202)

J264. Towatari, M., Ciro, M., Ottolenghi, S.,

Tsuzuki, S., and Enver, T.: Involvement of mitogen-activated protein kinase in the cytokine-regulated phosphorylation of transcription factor GATA-1. Hematol. J., 5: 262-272, 2004. (PMID: 15167914)

J265. Towatari, M., Yanada, M., Usui, N., Takeuchi, J., Sugiura, I., Takeuchi, M., Yagasaki, F., Kawai, Y., Miyawaki, S., Ohtake, S., Jinnai, I., Matsuo, K., Naoe, T. and Ohno, R.: Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia. Blood, 104: 3507-3512, 2004. (PMID: 15315963)

J266. Toyooka, S., Tokumo, M., Shigematsu, H., Matsuo, K., Asano, H., Tomii, K., Ichihara, S., Suzuki, M., Aoe, M., Date, H., Gazdar, AF. and Shimizu, N.: Mutational and epigenetic evidence for independent pathways for lung adenocarcinoma arising in smokers and never smokers. Cancer Res, in press.

J267. Tsui, J., Inagaki, M. and Schulman, H.: Calcium/calmodulin-dependent protein kinase II (CaMKII) localization acts in concert with substrate targeting to create spatial restriction for phosphorylation. J. Biol. Chem., 280: 9210-9216, 2005. (PMID: 15582994)

J268. Tsuji, T., Yasukawa, M., Matsuzaki, J., Ohkuri, T., Chamoto, K., Wakita, D., Azuma, T., Niiya, H., Miyoshi, H., Kuzushima, K., Oka, Y., Sugiyama, H., Ikeda, H. and Nishimura, T.: Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes. Blood 106: 470-476, 2005. (PMID: 15790789)

J269. Tsujimura, K., Obata, Y., Matsudaira, Y., Ozeki, S., Taguchi, O., Nishida, K., Okanami, Y., Akatsuka, Y., Kuzushima, K. and Takahashi, To.: Immunity against mouse thymus-leukemia antigen (TL) protects against development of lymphomas induced by a chemical carcinogen, N-butyl-N- nitrosourea. Cancer Sci. 95: 914-919, 2004. (PMID: 15546510)

J270. Tsukamoto, T., Inada, K., Tanaka, H., Mizoshita, T., Mihara, M., Ushijima, T., Yamamura, Y., Nakamura, S., and Tatematsu, M.: Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2: inverse correlation during progression from gastric/

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intestinal-mixed to complete intestinal metaplasia. J. Cancer Res. Clin. Oncol., 130: 135-145, 2004. (PMID: 14655050)

J271. Tsukamoto, T., Mizoshita, T., Mihara, M., Tanaka, H., Takenaka, Y., Yamamura, Y., Nakamura, S., Ushijima, T., and Tatematsu, M.: Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal- mixed phenotypes. Histopathology, 46: 649-658, 2005. (PMID: 15910596)

J272. Tsukamoto, T., Sakai, H., Hirata, A., Fukami, H., and Tatematsu, M.: Three- dimensional analysis of isolated hexosaminidase- altered aberrant crypts from colons of 1,2-dimethylhydrazine-treated rats. Exp. Toxicol. Pathol., 57: 283-289, 2006. (PMID: 16414254)

J273. Tsukamoto, T., Yamamoto, M., Fukami, H., Yoshikawa, A., Sakai, H., Hirata, A., Kusakabe, M., and Tatematsu, M.: Susceptibility to colon carcinogenesis in C3H<-->C57BL/6 chimeric mice reflects both tissue microenvironment and genotype. Cancer Lett., 2005. (PMID: 16168562)

J274. Tsuzuki, S., Greaves, M., Seto, M. and Enver, T.: Modeling first-hit functions of the t(12;21) TEL-AML1 translocation in mice. Proc Natl Acad Sci U S A. 2004 Jun 1;101:8443-8. (PMID: 15155899)

J275. Tsuzuki, S., Kitajima, K., Nakano, T., Glasow, A., Zelent, A. and Enver, T.: Cross talk between retinoic acid signaling and transcription factor GATA-2. Mol Cell Biol. 2004 24:6824-36. (PMID: 15254248)

J276. Uchida, K., Akita, Y., Matsuo, K., Fujiwara, S., Nakagawa, A., Kazaoka, Y., Hachiya, H., Naganawa, Y., Oh-Iwa, I., Ohura, K., Saga, S., Kawai, T., Matsumoto, Y., Shimozato, K. and Kozaki, K.: Identification of specific autoantigens in Sjogren's syndrome by SEREX. Immunology, 116: 53-63, 2005. (PMID: 16108817)

J277. Uchimura, K., Gauguet, J.M., Singer, M.S., Tsay, D., Kannagi, R., Muramatsu, T., Von Andrian, U.H. and Rosen, S.D.: A major class of L-selectin ligands is eliminated in mice deficient in two sulfotransferases expressed in high endothelial venules. Nat. Immun., 6: 1105-1113, 2005. (PMID: 16227986)

J278. Uchimura, K., Kadomatsu, K., El Fasakhany, F.M., Singer, M.S., Izawa, M., Kannagi, R., Takeda, N., Rosen, S.D. and

Muramatsu, T.: N-acetylglucosamine 6-O- sulfotransferase-1 regulates expression of L-selectin ligands and lymphocyte homing. J. Biol. Chem., 279: 35001-35008, 2004. (PMID: 15175329)

J279. Wakai, K., Hirose, K., Takezaki, T., Hamajima, N., Ogura, Y., Nakamura, S., Hayashi, N. and Tajima, K.: Foods and beverages in relation to urothelial cancer: case-control study in Japan. Int J Urol, 11: 11-19, 2004. (PMID: 14678179)

J280. Wakai, K., Ito, Y., Kojima, M., Tokudome, S., Ozasa, K., Inaba, Y., Yagyu, K. and Tamakoshi, A.: Intake frequency of fish and serum levels of long-chain n-3 fatty acids: a cross-sectional study within the Japan Collaborative Cohort Study. J Epidemiol, 15: 211-218, 2005. (PMID: 16276030)

J281. Wakai, K., Kojima, M., Tamakoshi, K., Watanabe, Y., Hayakawa, N., Suzuki, K., Hashimoto, S., Kawado, M., Tokudome, S., Suzuki, S., Ozasa, K., Toyoshima, H., Ito, Y. and Tamakoshi, A.: Alcohol consumption and colorectal cancer risk: findings from the JACC Study. J Epidemiol, 15 Suppl 2: S173-179, 2005. (PMID: 16127230)

J282. Wakai, K., Nakai, S., Kikuchi, K., Iseki, K., Miwa, N., Masakane, I., Wada, A., Shinzato, T., Nagura, Y. and Akiba, T.: Trends in incidence of end-stage renal disease in Japan, 1983-2000: age-adjusted and age-specific rates by gender and cause. Nephrol Dial Transplant, 19: 2044-2052, 2004. (PMID: 15173379)

J283. Wakai, K., Suzuki, K., Ito, Y., Kojima, M., Tamakoshi, K., Watanabe, Y., Toyoshima, H., Hayakawa, N., Hashimoto, S., Tokudome, S., Suzuki, S., Kawado, M., Ozasa, K. and Tamakoshi, A.: Serum carotenoids, retinol, and tocopherols, and colorectal cancer risk in a Japanese cohort: effect modification by sex for carotenoids. Nutr Cancer, 51: 13-24, 2005. (PMID: 15749625)

J284. Wakai, K., Tamakoshi, K., Date, C., Fukui, M., Suzuki, S., Lin, Y., Niwa, Y., Nishio, K., Yatsuya, H., Kondo, T., Tokudome, S., Yamamoto, A., Toyoshima, H. and Tamakoshi, A.: Dietary intakes of fat and fatty acids and risk of breast cancer: a prospective study in Japan. Cancer Sci, 96: 590-599, 2005. (PMID: 16128744)

J285. Wang, L. D., Guo, R. F., Fan, Z. M., He, X., Gao, S. S., Guo, H. Q., Matsuo, K., Yin, L. M. and Li, J. L.: Association of methylenetetrahydrofolate reductase and thymidylate synthase promoter polymorphisms with genetic susceptibility to

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esophageal and cardia cancer in a Chinese high-risk population. Dis Esophagus, 18: 177-184, 2005. (PMID: 16045580)

J286. Washio, M., Mori, M., Sakauchi, F., Watanabe, Y., Ozasa, K., Hayashi, K., Miki, T., Nakao, M., Mikami, K., Ito, Y., Wakai, K. and Tamakoshi, A.: Risk factors for kidney cancer in a Japanese population: findings from the JACC Study. J Epidemiol, 15 Suppl 2: S203-211, 2005. (PMID: 16127235)

J287. Watanabe, N., Kamachi, Y., Koyama, N., Hama, A., Liang, J., Nakamura, Y., Yamamoto, T., Isomura, M., Kudo, K., Kuzushima, K. and Kojima, S.: Expansion of human CMV-specific cytotoxic T lymphocytes to a clinical scale: a simple culture system using tetrameric HLA-peptide complexes. Cytotherapy 6: 514-522, 2004. (PMID: 15512918)

J288. Watanabe, Y., Ozasa, K., Ito, Y., Suzuki, K., Kojima, M., Suzuki, S., Tokudome, S., Tamakoshi, K., Toyoshima, H., Kawado, M., Hashimoto, S., Hayakawa, N., Wakai, K. and Tamakoshi, A.: Medical history of circulatory diseases and colorectal cancer death in the JACC Study. J Epidemiol, 15 Suppl 2: S168-172, 2005. (PMID: 16127229)

J289. Yagi, H., Takahashi, N., Yamaguchi, Y., Kimura, N., Uchimura, K., Kannagi, R. and Kato, K.: Development of structural analysis of sulfated N-glycans by multi-dimensional HPLC mapping methods. Glycobiology, 15: 1051-1060, 2005. (PMID: 15958418)

J290. Yamachika, T., Nakanishi, H., Yasui, K., Ikehara, Y., Niwa, T., Wanibuchi, H., Tatematsu, M., and Fukushima, S.: Establishment and characterization of a human colonic mucinous carcinoma cell line with predominant goblet-cell differentiation from liver metastasis. Pathol. Int., 55:550-7, 2005. (PMID: 16143030)

J291. Yamaguchi, M., Ishida, H., Kanamori, A., Kannagi, R. and Kiso, M.: Synthesis and antigenic property of a novel sialyl 6-O-sulfo Lewis X neo-glycolipid containing lactamized neuraminic acid. J. Carbohydr. Chem., 23: 201-215, 2004. (PMID: 14667701)

J292. Yamaguchi, M., Ishida, H., Kanamori, A., Kannagi, R. and Kiso, M.: 6-O-Sulfo sialylparagloboside and sialyl Lewis X neo-glycolipids containing lactamized neuraminic acid: Synthesis and antigenic reactivity against G159 monoclonal antibody. Glycoconj. J., 22:

95-108, 2005. (PMID: 16133830)

J293. Yamaguchi, T., Goto, H., Yokoyama, T., Silljé, H., Hanisch, A., Uldschmid, A., Takai, Y., Oguri, T., Nigg, E.A. and Inagaki, M.: Phosphorylation by Cdk1 induces Plk1-mediated vimentin phosphorylation during mitosis. J.Cell Biol. 171: 431-436, 2005. (PMID: 16260496)

J294. Yamashita, S., Nomoto, T., Abe, M., Tatematsu, M., Sugimura, T., and Ushijima, T.: Persistence of gene expression changes in stomach mucosae induced by short-term N-methyl-N'-nitro-N-nitrosoguanidine treatment and their presence in stomach cancers. Mutat. Res., 549: 185-193, 2004. (PMID: 15120970)

J295. Yanada, M., Matsuo, K., Emi, N. and Naoe, T.: Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission: a metaanalysis. Cancer, 103: 1652-1658, 2005. (PMID: 15742336)

J296. Yanada, M., Matsuo, K., Suzuki, T., Kiyoi, H. and Naoe, T.: Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia, 19: 1345-1349, 2005. (PMID: 15959528)

J297. Yanada, M., Takeuchi, J., Sugiura, I., Akiyama, H., Usui, N., Yagasaki, F., Kobayashi, T., Ueda, Y., Takeuchi, M., Miyawaki, S., Maruta, A., Emi, N., Miyazaki, Y., Ohtake, S., Jinnai, I., Matsuo, K., Naoe, T. and Ohno, R.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: A phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol, 2005. (PMID: 16344315)

J298. Yang, C. X., Matsuo, K., Ito, H., Hirose, K., Wakai, K., Saito, T., Shinoda, M., Hatooka, S., Mizutani, K. and Tajima, K.: Esophageal cancer risk by ALDH2 and ADH2 polymorphisms and alcohol consumption: exploration of gene-environment and gene-gene interactions. Asian Pac J Cancer Prev, 6: 256-262, 2005. (PMID: 16235983)

J299. Yang, C. X., Matsuo, K., Ito, H., Shinoda, M., Hatooka, S., Hirose, K., Wakai, K., Saito, T., Suzuki, T., Maeda, T. and Tajima, K.: Gene-environment interactions between alcohol drinking and the MTHFR C677T polymorphism

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impact on esophageal cancer risk: results of a case-control study in Japan. Carcinogenesis, 26: 1285-1290, 2005. (PMID: 15790587)

J300. Yang, C. X., Matsuo, K., Wang, Z. M. and Tajima, K.: Phase I/II enzyme gene polymorphisms and esophageal cancer risk: a meta-analysis of the literature. World J Gastroenterol, 11: 2531-2538, 2005. (PMID: 15849806)

J301. Yang, C. X., Wang, H. Y., Wang, Z. M., Du, H. Z., Tao, D. M., Mu, X. Y., Chen, H. G., Lei, Y., Matsuo, K. and Tajima, K.: Risk factors for esophageal cancer: a case-control study in South-western China. Asian Pac J Cancer Prev, 6: 48-53, 2005. (PMID: 15780032)

J302. Yasui, Y., Urano, T., Kawajiri, A., Nagata, K., Tatsuka, M., Saya, H., Furukawa, K., Takahashi, T., Izawa, I. and Inagaki, M.: Autophosphorylation of newly identified site of Aurora-B is indispensable for cytokinesis. J.Biol.Chem. 279: 12997-13003, 2004. (PMID: 14722118)

J303. Yatabe, Y., Koga, T., Mitsudomi, T., and Takahashi, Ta.: CK20 expression, CDX2 expression, K-ras mutation, and goblet cell morphology in a subset of lung adenocarcinomas. J. Pathol., 203: 645-652, 2004. (PMID: 15141379)

J304. Yatabe, Y., Kosaka, T., Takahashi, Ta., and Mitsudomi, T.: EGFR mutation is specific for terminal respiratory unit type adenocarcinoma. Am. J. Surg. Pathol., 29: 633-639, 2005. (PMID: 15832087)

J305. Yatabe, Y., Mitsudomi, T., and Takahashi, Ta.: Maspin expression in normal lung and non-small-cell lung cancers: cellular property- associated expression under the control of promoter DNA methylation. Oncogene, 23: 4041-4049, 2004. (PMID: 15048080)

J306. Yin, J., Hashimoto, A., Izawa, M., Miyazaki, K., Chen, G.Y., Takematsu, H., Kozutsumi, Y., Suzuki, A., Furuhata, K., Cheng, F.-L., Lin, C.-H., Sato, C., Kitajima, K., and Kannagi, R.: Hypoxic culture induces expression of sialin, a sialic acid transporter, and cancer-associated gangliosides containing non-human sialic acid on human cancer cells. Cancer Res., in press.

J307. Yokoyama, H., Nakanishi, H., Kodera, Y., Ikehara, Y., Ohashi, N., Ito, Y., Koike, M., Fujiwara, M., Tatematsu, M., and Nakao, A.: Biological significance of isolated tumor cells and

micrometastasis in lymph nodes evaluated using a green fluorescent protein (GFP)-tagged human gastric cancer cell line. Clin. Cancer. Res. 12: 361-368, 2006. (PMID: 16428473)

J308. Yokoyama, T., Goto, H., Izawa, I., Mizutani, H. and Inagaki, M.: Aurora-B and Rho-kinase/ROCK, the two cleavage furrow kinases, independently regulate the progression of cytokinesis: Possible existence of a novel cleavage furrow kinase phosphorylates ezrin/radixin/moesin (ERM). Genes Cells 10: 127-137, 2005. (PMID: 15676024)

J309. Yoneda, K., Furukawa, T., Zhengll, Y.J., Momoi, T., Izawa, I., Inagaki, M., Manabe, M. and Inagaki, N.: An autocrine/paracrine loop linking keratin 14 aggregates to tumor necrosis factor α-mediated cytotoxicity in a keratinocyte model of epidermolysis bullosa simplex. J.Biol.Chem. 279: 7296-7303, 2004. (PMID: 14660619)

J310. Yoshida, I., Matsuo, K., Teshima, T., Hashimoto, D., Tanimoto, Y., Harada, M. and Tanimoto, M.: Transient respiratory disturbance by G-CSF administration in healthy donors of allogeneic PBPC transplantation. Transfusion, in press.

J311. Yoshitomi, Y., Nakanishi, H., Kusano, Y., Munesue, S., Oguri, K., Tatematsu, M., Yamashina, I., and Okayama, M.: Inhibition of experimental lung metastases of Lewis lung carcinoma cells by chemically modified heparin with reduced anticoagulant activity. Cancer Lett., 207: 165-174, 2004. (PMID: 15072825)

J312. Zhang, X., Karnan, S., Tagawa, H., Suzuki, R., Tsuzuki, S., Hosokawa, Y., Morishima, Y., Nakamura, S. and Seto, M.: Comparison of genetic aberrations in CD10+ diffused large B-cell lymphoma and follicular lymphoma by comparative genomic hybridization and tissue-fluorescence in situ hybridization. Cancer Sci., 95: 809-814, 2004. (PMID: 15504248)

J313. Zhou, Z. Y., Takezaki, T., Mo, B. Q., Sun, H. M., Wang, W. C., Sun, L. P., Liu, S. X., Ao, L., Cheng, G. H., Wang, Y. M., Cao, J. and Tajima, K.: Development of a semi-quantitative food frequency questionnaire to determine variation in nutrient intakes between urban and rural areas of Chongqing, China. Asia Pac J Clin Nutr, 13: 273-283, 2004. (PMID: 15331340)

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Reviews and Books

R001. Akatsuka, Y. and Ikeda, K.: Macrophage Forum, Minor histocompatibility antigens. Today’s Transplantation 12: 504-514, 2005 [in Japanese].

R002. Akatsuka, Y. and Morishima, Y.: Major and minor histocompatibility antigens in allogeneic hematopoietic stem cell transplantation. Curr. Opin. Organ Transplant. 9: 64-71, 2004.

R003. Akatsuka, Y.: A novel minor histocompatibility antigen gene, BCL2A1, specifically expressed in hematopoietic cells. In: K. Okumura, T. Hirano and S. Sato (eds.), Annual Review Immunology, pp.241-248, Tokyo: Chugai Igakusha, 2005 [in Japanese].

R004. Akatsuka, Y.: Application of minor histocompatibility antigens to immunotherapy. The Medical Frontline (Saishin Igaku) 59: 2472-2478, 2004 [in Japanese].

R005. Akatsuka, Y.: Minor histocompatibility antigens involved in allo-immune response. In: Y. Sakata and K. Ozawa (eds.), Igakuno-ayumi, -state of arts ver.3, pp.274-277, Tokyo: Ishiyaku Shuppan, 2005 [in Japanese].

R006. Akatsuka, Y.: New histocompatibility antigens and GVHD/GVL effects. In: Y. Morishima (ed.) Graft versus Host Disease: Practical manual and its base, pp.137-153, Tokyo: Nankodo, 2005 [in Japanese].

R007. Daikoku, T.: Latent infection and Reactivation of Epstein-Barr virus. Nippon Rinsho. (edited by Nishiyama, Y.) In press.

R008. Goto, H. and Inagaki, M.: Production of site- and phosphorylation state-specific antibodies. In: Protocols for post-translational protein modification (Inagaki, M. ed.), pp. 42-57, Tokyo: Yodosha, 2005 [in Japanese].

R009. Goto, H. and Inagaki, M.: Serine/Threonine kinases. In: Tanpakusitu kagaku illustrated (Takenawa, T. ed.), pp. 94-104, Tokyo: Yodosha, 2005 [in Japanese].

R010. Goto, H.: Identification of in vitro phosphorylation sites using radioactive ATP. In: Protocols for post-translational protein modification (Inagaki, M. ed.), pp. 16-32, Tokyo: Yodosha, 2005 [in Japanese].

R011. Goto, H.: Identification of in vivo

phosphorylation sites using radioactive orthophosphate. In: Protocols for post-translational protein modification (Inagaki, M. ed.), pp. 58-61, Tokyo: Yodosha, 2005 [in Japanese].

R012. Goto, H.: Significance of site- and phosphorylation state-specific antibodies in functional analyses of mitotic protein kinase(s). Jikkenigaku (Tokyo: Yodosha), Vol. 23, pp. 1986-1992, 2005 [in Japanese].

R013. Hirabayashi, Y., Kanamori, A., Nomura, K.H. and Nomura, K.: The acetyl-CoA transporter family SLC33. Pflugers Arch., 447: 760-762, 2004. (PMID: 12739170)

R014. Hirose, K. and Tajima, K.: Evidence in favour of lifestyle intervention for cancer prevention with special reference to colorectal cancer. Environ Health Prev Med, 9: 130-136, 2004.

R015. Hosokawa, Y., and Seto, M.: NF-κB activation and anti-apoptosis in MALT lymphoma. Progress in Hematology Int. J. Heamatol. 80, 215-223, 2004. (PMID: 15540895)

R016. Hosokawa, Y.: Anti-apoptotic action of API2-MALT1 fusion protein involved in t(11;18)(q21;q21) MALT lymphoma. Apoptosis 10, 25-34, 2005. (PMID: 15711920)

R017. Hotta, K., Matsuo, K. and Ueoka, H.: Author reply: Role of adjuvant chemotherapy in patients with resected non-small cell lung cancer: Reappraisal with a metanalysis of randomised controlled trials. J Clin Oncol, 23: 925-926, 2005. (PMID: 15681545)

R018. Hotta, K., Matsuo, K. and Ueoka, H.: Toxicity data in addition to survival data are important in evaluating the applicability of a chemotherapy regimen of advanced non-small-cell lung cancer. Lung Cancer, 49: 277, 2005. (PMID: 15953658)

R019. Inagaki, M. and Yokoyama, T.: Intermediate filaments. In: Wakaru jikkenn igaku series Saiboukokkaku・unndou ga wakaru. (Miki, H. ed.) pp. 73-83, 2004 [in Japanese].

R020. Inagaki, M.: Overview of protocols for protein phosphorylation. In: Protocols for post-translational protein modification (Inagaki, M. ed.), pp. 12-15, Tokyo: Yodosha, 2005 [in Japanese].

R021. Inagaki, M.: Protein phosphorylation controls diverse aspects of biological phenomena.

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Jikkenigaku (Tokyo: Yodosha), Vol. 23, pp. 1982-1985, 2005 [in Japanese].

R022. Inoko, A. and Goto, H.: Intermediate filaments. Tanpakushitsu Kakusan Koso in press [in Japanese].

R023. Isomura, H. and Tsurumi, T.: Tissue tropism for herpesviruses. Nippon Rinsho. (edited by Nishiyama, Y.) in press.

R024. Isomura, H., Kudoh, A. and Tsurumi, T.: Oncogenecity induced by tumor viruses. Experimental Medicine. (edited by Yoshikai Y.) pp. 49-58, Yodosha. 2004.

R025. Izawa, I. and Inagaki, M.: Cleavage furrow kinases and cell division. In: Signal Transduction of Cell Division (Miki, T. ed.) India: Research Signpost, pp. 73-92, 2005.

R026. Izawa, I. and Inagaki, M.: Development of site- and phosphorylation state-specific antibodies. Tanpakushitsu Kakusan Koso 50: 1555-1562, 2005 [in Japanese]. (PMID: 16218456)

R027. Kannagi, R., Goto, Y. and Fukui, F.: In search of the carbohydrate structures on CD44 critical for hyaluronic acid binding - roles of sialylation and sulfation. Trends Glycosci. Glycotechnol., 16: 211-223, 2004.

R028. Kannagi, R., Izawa, M. and Koike, T.: SLX (sialyl SSEA-1, sialyl Lex-i). Nippon Rinsho, 63 Suppl 8: 675-680, 2005 [in Japanese]. (PMID: 16149609)

R029. Kannagi, R., Izawa, M., Koike, T., Miyazaki, K. and Kimura, N.: Carbohydrate- mediated cell adhesion in cancer metastasis and angiogenesis. Cancer Sci., 95: 377-384, 2004. (PMID: 15132763)

R030. Kannagi, R.: Molecular mechanism for cancer-associated induction of sialyl Lewis X and sialyl Lewis A expression - the Warburg effect revisited. Glycoconj. J., 20: 353-364, 2004. (PMID: 15249540)

R031. Kannagi, R.: STN (sialyl Tn antigen). Nippon Rinsho, 63 Suppl 8: 659-662, 2005 [in Japanese]. (PMID: 16149605)

R032. Kawajiri, A. and Inagaki, M. : Approaches to study phosphorylation of intermediate filament proteins using site-specific and phosphorylation state-specific antibodies. Methods in Cell Biol. 78: 353-371, 2004. (PMID: 15646625)

R033. Kudoh, A. and Tsurumi, T.: Classification

and structure of Gammaherpesvirus. Nippon Rinsho. (edited by Nishiyama, Y.) in press.

R034. Kumamoto, K. and Kannagi, R.: BCA225. Nippon Rinsho, 63 Suppl 8: 669-671, 2005 [in Japanese]. (PMID: 16149607)

R035. Kuroishi, T., Hirose, K., Takezaki, T., Tominaga, S., and Tajima, K.: Cancer mortality in Japan (1950-2000). Gann monograph on Cancer Research, 51: 1-93, 2004.

R036. Kuroishi, T., Hirose, K., Takezaki, T., Tominaga, S., Aoki, K. and Tajima, K.: Cancer mortality statistics in 30 ciountries (1953-1997). Gann monograph on Cancer Research, 51: 137-229, 2004.

R037. Kuzushima, K.: Tetramer assay. Cell. Mol. Med. in press [in Japanese].

R038. Kyogashima, M.: The role of sulfatide in thrombogenesis and haemostasis. Arch. Biochem. Biophys., 426: 157-162, 2004. (PMID: 15158666)

R039. Matsuo, K., Hotta, K. and Ueoka, H.: They also serve who only stand and wait: do individual clinical researchers, too? Hoping for individual patient data as public domain. J Clin Oncol, 23: 1334-1335, 2005. (PMID: 15718348)

R040. Matsuo, K., Ikehara, Y., Tajima, K. and Hamajima, N.: Lewis and Secretor status and Helicobacter pylori eradication. Epidemiol Infect, 132: 998-999, 2004. (PMID: 15473165)

R041. Miyazaki, K. and Kannagi, R.: 2-6 Sialyl Lea antigen. Nippon Rinsho, 63 Suppl 8: 663-668, 2005 [in Japanese]. (PMID: 16149606)

R042. Moore, M. A., Sobue, T., Kuriki, K., Tajima, K., Tokudome, S. and Kono, S.: Comparison of Japanese, American-Whites and African-Americans--pointers to risk factors to underlying distribution of tumours in the colorectum. Asian Pac J Cancer Prev, 6: 412-419, 2005. (PMID: 16236010)

R043. Morishima, S. and Akatsuka, Y.: Hematopoietic stem cell transplantation and HLA. Hematology Frontier 14: 1163-1172, 2004 [in Japanese].

R044. Nakajima, H. and Akatsuka, Y.: The Fifth Nagoya International Blood And Marrow Transplantation Symposium: unlimited possibilities of hematopoietic cell transplantation: lessons from the past and prospects for the future. Int. J. Hematol. 79: 200-204, 2004. (PMID: 15005353)

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R045. Nakanishi, H., Ito, S., Mochizuki, Y., Tatematsu, M.: Evaluation of chemosensitivity of micrometastases with green fluorescent protein gene-tagged tumor models in mice.In Blumenthal RD (eds). Chemosensitivity (vol. 2). Methods Mol Med. 111, Humana Press, New Jersey, p351-362, 2005.

R046. Nakanishi, H., Kodera, Y., and Tatematsu, M.: Molecular method to quantitatively detect micrometastases and its clinical significance in gastrointestinal malignancies. Adv Clin Chem, 38: 87-110, 2004. (PMID: 15521189)

R047. Sekido, Y., Fong, K.M., and Minna. J.D.: Molecular biology of lung cancer. In: V.T. DeVita, Jr., S. Hellman, S.A. Rosenberg (ed.), Cancer: Principles and Practice of Oncology, (7th ed.) pp.745-752, Lippincott-Williams & Wilkins 2005.

R048. Seto, M.: Genetic and epigenetic factors involved in B-cell lymphomagenesis. Cancer Sci., 95: 704-710, 2004. (PMID: 15471554)

R049. Shiromizu, T.: Methods for the preparation of activated kinase in the prokaryotic expression system. In: Protocols for post-translational protein modification (Inagaki, M. ed.), pp. 260-265, Tokyo: Yodosha, 2005 [in Japanese].

R050. Suzuki, R.: Leukemia and lymphoma of natural killer cells. J. Clin. Exp. Hematopathol., 45:51-70, 2005

R051. Tatematsu, M., Tsukamoto, T., and Inada, K.: Stem cells and gastric cancer - Role of gastric and intestinal mixed intestinal metaplasia. In: Tsuruo, T., and Kitagawa, T. (eds). Gann Mono- graph on Cancer Research. Cancer Research Front of Japan, 2003, Japan Scientific Societies Press & Karger, Tokyo & Basel, 2004.

R052. Tatematsu, M., Tsukamoto, T., and Mizoshita, T.: Helicobacter pylori and stomach cancer. In: Sundberg, JP., Ichiki, T. (eds). Genetically Engineered Mice Handbook. Taylor & Francis, New York, p. 173-183, 2005.

R053. Tatematsu, M., Tsukamoto, T., and Mizoshita, T.: History of Gastric Carcinoma Research in Japan: Basic Aspects. In: Kaminishi, M., Takubo, K., and Mafune, K. (eds). The Diversity of Gastric Carcinoma, Springer-Verlag, Tokyo, p. 3-28, 2005.

R054. Tatematsu, M., Tsukamoto, T., and Mizoshita, T.: Role of Helicobacter pylori in gastric carcinogenesis: the origin of gastric cancers and

heterotopic proliferative glands in Mongolian gerbils. Helicobacter, 10: 97-106, 2005. (PMID: 15810939)

R055. Tokudome, S., Ichikawa, Y., Okuyama, H., Tokudome, Y., Goto, C., Imaeda, N., Kuriki, K., Suzuki, S., Shibata, K., Jiang, J., Wang, J. and Takeda, E.: The Mediterranean vs the Japanese diet. Eur J Clin Nutr, 58: 1323; author reply 1324-1325, 2004. (PMID: 15054411)

R056. Tokudome, S., Kuriki, K., Suzuki, S., Akasaka, S., Kosaka, H., Ishikawa, H., Yoshimura, T., Azuma, T., Duc Van, D., Cong Khan, N., Sriamporn, S., Wiangnon, S., Soeripto, Triningsih, F. E. and Moore, M. A.: Re: helicobacter pylori infection and gastric cancer: facing the enigmas. Int J Cancer, 112: 166-167; author reply 168-169, 2004. (PMID: 15305392)

R057. Tomida, S., Yatabe, Y., Yanagisawa, K., Mitsudomi, T., and Takahashi, Ta.: Throwing new light on lung cancer pathogenesis: updates on three recent topics. Cancer Sci. 96: 63-68, 2005. Review. (PMID: 15723649)

R058. Tsujimura, K., Obata, Y. and Takahashi, To.: Thymus-leukemia antigen (TL) as a major histocompatibility complex (MHC) class Ib molecule and tumor specific antigen. Cancer Sci. 95: 469-474, 2004. (PMID: 15182425)

R059. Tsukamoto, T., Hirata, A., and Tatematsu, M.: Susceptibility of heterozygous and nullizygous p53 knockout mice to chemical carcinogens: Tissue dependence and role of p53 gene mutations. J. Toxicol. Pathol., 18: 121-134, 2005.

R060. Tsukamoto, T., and Tatematsu, M.: Linkage of tissue dependent susceptibility and p53 gene mutations due to chemical carcinogens in p53 knockout mice. In: Tanaka, T., and Tsuda, H. (eds). Carcinogenesis and Modification of Carcinogenesis, Research Signpost, Kerala, India, 2005.

R061. Tsurumi, T. and Kudoh, A.: Replication of Epstein-Barr virus and host cell response. Seikagaku. 77: 1180-1184, 2005. (PMID: 16241005)

R062. Tsurumi, T., Fujita, M. and Kudoh, A.: Latent and lytic Epstein-Barr virus replication strategies. Rev. Med. Virol. 15: 3-15, 2005. (PMID: 15386591)

R063. Uchida, A., Matsuo, K. and Tanimoto, M.: APL during gefitinib treatment for non-small-cell lung cancer. N Engl J Med, 352: 843, 2005. (PMID:

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15728826)

R064. Utsunomiya, H., Inada, K., Tsukamoto, T., and Tatematsu, M.: Inhibitory effects of "Bainiku-ekisu", Japanese apricot extracts, on motility and growth of Helicobacter pylori. In: Tanaka, T., and Tsuda, H. (eds). Carcinogenesis and Modification of Carcinogenesis, Research Signpost, Kerala, India,2005.

R065. Wakai, K., Ando, M., Ozasa, K., Ito, Y., Suzuki, K., Nishino, Y., Kuriyama, S., Seki, N., Kondo, T., Watanabe, Y., Ohno, Y. and Tamakoshi, A.: Updated information on risk factors for lung cancer: findings from the JACC Study. J Epidemiol, 15 Suppl 2: S134-139, 2005. (PMID: 16127225)

R066. Wakai, K.: The JICA training course, community-based cancer prevention for Asian Pacific countries, 2004 (Epidemiological approach). Asian Pac J Cancer Prev, 5: 231-236, 2004. (PMID: 15460556)

R067. Yokoyama, T.: Methods for the preparation of activated kinase in the insect expression system. In: Protocols for post-translational protein modification (Inagaki, M. ed.), pp. 266-275, Tokyo: Yodosha, 2005 [in Japanese].

Abstracts for international conferences

A001. Akatsuka, Y., Kuzushima, K. and Takahashi, To.: Identification of minor histocompatibility antigens involved in graft-versus-leukemia effect and GVHD following allogeneic hematopoietic cell transplantation. Abstract for US-Japan Cooperative Cancer Research Program, 2005.

A002. Akatsuka, Y.: Identification of two novel minor histocompatibility antigens by linkage analysis and their clinical relevance, Abstract for the 2004 Tandem BMT Meeting (IBMTR/ABMTR and ASBMT), 2004.

A003. Daikoku, T., Kudoh, A. and Tsurumi, T.: Dynamics of Epstein-Barr virus EBNA1 protein binding to viral genome and subcellular redistribution from latent to lytic infection. EBV symposium 2004 The 11th Symposium of the International Association for Research on Epstein-Barr Virus and Associated Diseases. 04.12 Regensburg, Germany. 2004.

A004. Daikoku, T., Kudoh, A. and Tsurumi, T.: Postreplicative mismatch repair factors are recruited to Epstein-Barr virus replication compartments. 5th 3R symposium P47, Awaji Yumebutai, Hyogo. 2005

A005. Fujiwara, K., Fujimoto, N., Tabata, K., Matsuo, K., Kozuki, A., Tokuda, Y., Kiura, K., Nishii, K., Ueoka, H. and Tanimoto, M.: Identification of aberrant promoter methylation in serum DNA for early detection of lung cancer. Proceeding of Annual Meeting 2004, American Association of Cancer Research, 3959, 2004.

A006. Hirose, K., Tajima, K. and Tokudome, S.: Soybean products and reduction of breast cancer risk ： A case-control study in Japan. The 3rd Regional Conference of Asian Pacific Organization for Cancer Control, 26, 2005.

A007. Hotta, K., Matsuo, K., Ueoka, H., Kiura, K., Tabata, M., Harita, S., Gemba, K., Yonei, T., Bessho, A. and Tanimoto, M.: Continued gefitinib treatment after disease stabilization prolongs survival of patients with advanced non-small-cell lung cancer. J Clin Oncol. 23: 642S, 2005.

A008. Ikehara, Y., Kojima, N., Nakanishi, H., Yoshii, T., Biao, L., Niwa, T., and Tatematsu, M.: Intra peritoneal macrophage is activated by uptake

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of Mannose conjugated Liposome. American Society of Glycobiology, Poster, Hawaii, USA, 2004.

A009. Ikehara, Y.,Sato, T., Niwa, T., Nakamura, S., Goto,M. ,Ikehara, K., S., Kiyohara, K., Iwai, T., Hirabayashi, J., Nakanishi, H., Tatematsu, M. and Narimatsu, H.: Apical Golgi localization of N,N'-diacetyllactosediamine synthase β4GalNAc-T3, is responsible for LacdiNAc expression on gastric mucosa. American Society of Glycobiology, Poster, Boston, USA,2005.

A010. Ikehara, Y.: Polymorphisms of two fucosyltransferase genes (Lewis and Secretor genes) involving type I Lewis antigens are associated with the presence of anti-Helicobacter pylori IgG antibody. The 11th Aichi Cancer Center International Symposium, Nagoya, Japan,2005.

A011. Inagaki, M.: Identification and characterization of cleavage fullow kinases. Gordon Research Conference on “Intermediate Filaments”. Oxford, 2004.

A012. Inoko, A., Nishizawa, M., Izawa, I., Nagata, K. and Inagaki, M.: Identification and characterization of a novel keratin binding protein, trichoplein(trichohyalin and plectin like protein), as a desmosomal protein. Gordon Research Conference on “Intermediate Filaments”. Oxford, 2004.

A013. Ishizaki, K.: Effects of low-dose-rate radiation on HTERT-immortalized human cells. 3rd International Workshop on Space Radioration Reserch. NewYork, USA, May 2004.

A014. Isomura , H., Stinski, M.F., Kudoh, A., Daikoku, T., Shirata, N. and Tsurumi, T.: Two SP1/SP3 binding sites in the major immediate-early proximal enhancer of human cytomegalovirus have a significant role in viral replication. 30th Herpesvirus Workshop. 1.42, Turku, Finland. 2005.

A015. Isomura, H., Tsurumi, T. and Stinski, M.F.: The Role of the Proximal Enhancer in human Cytomegalovirus Replication. 29th Herpesvirus Workshop, 1.16, Nevada, USA. 2004.

A016. Ito, H. and Tajima, K.: Comparison of relative risk impact of habitual smoking and drinking for cancer by site based on regional cancer registry data for Aichi prefecture, Japan. The 3rd Regional Conference of Asian Pacific Organization for Cancer Control, 14, 2005.

A017. Ito, H., Hamajima, N., Matsuo, K.,

Mitsudomi, T., Sugiura, T., Sato, S., Ueda, R. and Tajima, K.: Gene-environment interaction between smoking habit and DNA repair genes, APE1 Asp148Glu and XRCC1 Arg399Gln, in lung cancer risk among Japanese. The 6th joint conference of the American Association for Cancer Research and the Japanese Cancer Association, A59, 2004.

A018. Ito, H., Masui, T. and Tajima, K.: Impact of habitual smoking on cancer stage at diagnosis based on regional cancer registry data for Aichi prefecture, Japan. Final program and abstract book of 27th annual meeting of the International Association of Cancer Regisries, 60, 2005

A019. Ito, H., Matsuo, K., Shinoda, M., Hatooka, S., Hirose, K., Saito, T., Wakai, K. and Tajima, K.: Esophageal cancer and polymorphisms of APE1 Asp148Glu and XRCC1 Arg399Gln. The 2nd APOCP General Assembly Conference, 100, 2004.

A020. Iwata, S., Sato, C., Ando, H., Kiso, M., Kannagi, R., and Kitajima, K.: Studies on chemical properties of cyclic sialic acid using their synthetic S- and O-glycosides as model compounds. US/Japan Glyco 2004 (Joint meeting of the Society for Glycobiology and the Japanese Society of Carbohydarate Research, (President, M.E. Etzler) Hawaii, November 17-20, 2004.

A021. Kakizaki, I., Kojima, K., Takagaki, K., Endo, M., Kannagi, R., Yasuda, T., Mita, S., Kimata, K., and Itano, N.: A novel inhibition mechanism of hyaluronan synthesis by 4-methylumbelliferone. US/Japan Glyco 2004 (Joint meeting of the Society for Glycobiology and the Japanese Society of Carbohydrate Research, (President, M.E. Etzler) Hawaii, November 17-20, 2004.

A022. Kannagi, R.: Carbohydrate determinants involved in cell-cell interactions: Transcriptional regulation of their expression. Human Disease Glycomics/Proteome Initiative (HGPI) Workshop "Functional Glycomics in Disease", Chaired by N. Taniguchi, Osaka, Japan, August 23-24, 2004.

A023. Kannagi, R.: Regulation of gene expression in carbohydrate-mediated cell-cell interactions. 2004 Glycolipid and Sphingolipid Biology Gordon Conference, Chaired by Suzuki, A. and Futerman, T., SPring-8, Hyogo, Japan, July 25-30, 2004.

A024. Kannagi, R.: Relationship between enhanced selectin-mediated cell adhesion and hypoxia-induced metabolic shift in human cancers.

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Joint meeting of the Japanese and American Consortia for Glycomics (Chaired by Paulson JC and Taniguchi N), Hawaii, November 21, 2004.

A025. Kannagi, R.: Sialoconjugates involved in cell-cell interactions. Sapporo Sphingolipid Symposium, Chaired by Igarashi, Y., Sapporo, Japan, July 21 - 23, 2004.

A026. Kim, D. H., Ahn, Y. O., Lee, B. H., Whang, D. Y., Kono, S., Wakai, K., Matsuo, K., Hamajima, N. and Tajima, K.: The effect of alcohol and aldehyde dehydrogenase polymophism on the risk of colorectal cancer. Proceedings of 18th Asia Pacific Cancer Conference-Cancer Research and Treatment, 161, 2005.

A027. Kudoh, A. and Tsurumi, T.: Epstein-Barr virus lytic replication evokes ATM checkpoint signal transduction while preventing p53- dounstream signaling. EBV symposium 2004 The 11th Symposium of the International Association for Research on Epstein-Barr Virus and Associated Diseases. 04.18. Regensburg, Germany. 2004.

A028. Kudoh, A., Daikoku, T., Ishimi, Y., Shirata, N., Iwahori, S. and Tsurumi, T.: Phosphorylation of MCM4 at sites inactivating DNA hericase activity of the MCM4-6-7 complex during Epstein-Barr virus productive replication. 5th 3R symposium. P10, Awaji Yumebutai, Hyogo. 2005

A029. Kumimoto, H., and Ishizaki, K.: Frequent somatic mutations in a D-loop region of the mitochondria! DNA in esophageal squamous cell carcinoma. 6th Joint Conference of the American Association for Cancer Research and the Japanese Cancer Association. Advances in Cancer Research. Hawaii, USA, Jan. 2004.

A030. Kumimoto, H. and Ishizaki, K.: Novel polymorphisms in the L-myc 5' UTR showed different risks of smoking of drinking for esophageal cancer. The 9th Japan - Korea Cancer Research Wrokshop -Molecular signature of cancer cells and its application to diagnosis and treatment, pp 82-83, Gyeongju, Korea, Dec 2004.

A031. Kuriki, K., Matsuo, K., Ito, H., Hirose, K., Wakai, K., Saito, T. and Tajima, K.: Colorectal cancer risk according to interactions between meat consumption and genetic polymorphisms of fat metabolism related PPARgamma and CD36 among Japanese. The 3rd Regional Conference of Asian Pacific Organization for Cancer Prevention (APOCP) GI Cancer Control, 17, 2005.

A032. Kyogashima, M., Hara, A., Aoyama, T., Kannagi, R.: Determination of sulfatides and complicated sulfated glycosphingolipids by MALDI-TOF MS. US/Japan Glyco 2004, Joint meeting of the Society for Glycobiology and the Japanese Society of Carbohydrate Research, (President, M.E. Etzler) Hawaii, November 17-20, 2004.

A033. Matsuo, K. Folate metabolizing gene polymorphisms and risk of malignant lymphoma in Japan. Proceedings U.S.-Japan Meeting on Large Cohort Studies for Molecular Epidemiology, 19-20, 2004.

A034. Matsuo, K. and Tajima, K.: Hepatitis C virus infection and risk of non-Hodgkin's lymphoma: Meta-analysis. The 2nd APOCP General Assembly Conference, 87, 2004.

A035. Matsuo, K., Hamajima, N. and Tajima, K.: Risk of esophageal cancer by alcohol drinking is modified by genetic polymorphisms. Proceeding of The fourth Japan-China Joint Conference for Cancer Research, 8-9, 2005.

A036. Matsuo, K., Hamajima, N., Mueller, N. E., Nakamura, S., Seto, M., Morishima, Y. and Tajima, K.: Methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms and reduced risk of malignant lymphoma. The 6th joint conference of the American Association for Cancer Research and the Japanese Cancer Association, A56,2004.

A037. Matsuo, K., Tagawa, H., Tsuzuki, S., Suzuki, R., Morishima, Y., Nakamura, S., Tajima, K. and Seto, M.: Different genomic gain pattern by MTHFR C677T genotypes in diffuse large B-cell lymphoma. Proceeding of Annual Meeting 2005, American Association of Cancer Research, 5793, 2005.

A038. Matsuo, K., Yang, C. X., Ito, H., Hirose, K., Wakai, K., Kuriki, K. and Tajima, K.: Gene-environment interaction between alcohol drinking and MTHFR C677T polymorphism for esophageal cancer risk. The 3rd Regional Conference of Asian Pacific Organization for Cancer Control, 15, 2005.

A039. Matsuo, K.: Challenging strategy of cancer epidemiology in hospital. Aichi Cancer Center International Symposium XI, 6-7, 2005.

A040. Miyazaki, K., Ohmori, K., Izawa, M., Koike, T., Yamaji, T., Hashimoto, Y., Suzuki, A. and Kannagi, R.: Interconversion of carbohydrate ligands for siglecs and selectins on colonic

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epithelial cells upon malignant transformation. Interlec 21, the 21st International Lectin Meeting, Chaired by K. Kasai, Shonan, Kanagawa,Japan, May 23-28, 2004.

A041. Mizoshita, T., Tsukamoto, T., Takenaka, Y., Ogasawara, N., Joh, T., Itoh, M., Ito, S., Nakamura, T., Yamamura, Y., and Tatematsu, M.: Cdx2 Correlates with Intestinal Phenotypic Expression and Prognosis in Advanced Gastric Cancers. 6th International Gastric Cancer Congress, Oral 9, Yokohama, Japan,2005.

A042. Nakanishi, H., Kodera, Y., Ito, S., Yamamura, Y., Jun, Q., Hara, T.,Hirai, T., Kato, T., Tatematsu, M.: Comparison of peritoneal metastasis between gastric cancer and colorectal cancer:Clinical and experimental studies. The 3rd International Conference on Gastroenterological Carcinogenesis, Oral, Sapporo, Japan,2004.

A043. Nakanishi, H., Yokoyama, Y., Ikehara, Y., Kodera, M., tatematsu, M.: Anti-tumor effects of EGFR tyrosine kinase inhibitor, gefitinib, on the HER2-overexpressing human gastric cancer cell lines derived from liver metastasis. International Conference on Tumor Progression and Therapeutic Resistance. Poster, Philadelphia, USA,2004.

A044. Shirata, N. and Tsurumi, T.: Activation of ATM DNA damage checkpoint signal transduction elicited by herpes simplex virus infection. 5th 3R symposium. P103, Awaji Yumebutai, Hyogo. 2005

A045. Suzuki, T., Matsuo, K., Wakai, K., Ito, H., Hirose, K., Sato, S., Nakamura, S., Ueda, R. and Tajima, K.: Past history of gastric ulcer and risk of malignant lymphoma. Proceedings of 18th Asia Pacific Cancer Conference-Cancer Research and Treatment, 1827, 2005.

A046. Tajima, K. Overview of cancer statistics in Asia. Proceeding of The 3rd Asia High-Technology Network, 44, 2005

A047. Tajima, K. UICC programs for cancer prevention in Asia. The 2nd APOCP General Assembly Conference, 24, 2004.

A048. Tajima, K.: A model of hospital-based epidemiologic research program for cancer control in Japan: case-referent studies, cohort study and prevention trial. Proceedings U.S.-Japan Meeting on Large Cohort Studies for Molecular Epidemiology, 9-12, 2004.

A049. Tajima, K.: Cultural determinants for cancer control. Proceeding of the 2nd Regional

APOCP Meeting, 3, 2004.

A050. Tajima, K.: Epidemic patterns and prevention strategies for GI tract cancers in the Asian Pacific. The 3rd Regional Conference of Asian Pacific Organization for Cancer Control, 2, 2005.

A051. Tajima, K.: National cancer control program. Proceedings of 18th Asia Pacific Cancer Conference-Cancer Research and Treatment, 40-41, 2005.

A052. Tajima, K.: Virus related cancers in the Asian Pacific with special reference to ATL. Proceeding of the 36th international symposium of the Princess Takamatsu Cancer Research Foundation Developments in Cancer Epidemiology-Prospects for Cancer Control in the Asian Pacific-Region. 42-43, 2005.

A053. Takematsu, H., Yamamoto, H., Okuno, Y., Kannagi, R., Suzuki, A., Kozutsumi, Y.: DNA Microarray analysis of genes responsible for the expression of carbohydrate epitopes. US/Japan Glyco 2004, Joint meeting of the Society for Glycobiology and the Japanese Society of Carbohydarate Research, (President, M.E. Etzler) Hawaii, November 17-20, 2004.

A054. Tatematsu, M.: Helicobacter pylori and gastric carcinogenesis in Mongolian gerbils. 6th International Gastric Cancer Congress, Symposium 5, Yokohama, Japan,2005.

A055. Terakura, S., Murata, M., Nishida, T., Emi, N., Akatsuka, Y., Riddell, S.R., Morishima, Y., Kodera, Y. and Naoe, T.: Impact of homozygous deletion of UGT2B17 on outcome of allogeneic BMT. Abstract for the 46th Annual Meeting of the American Society of Hematology, 2004. (Abstract#1837)

A056. Terakura, S., Murata, M., Nishida, T., Emi, N., Akatsuka, Y., Riddell, S.R., Morishima, Y., Kodera, Y. and Naoe, T.: Increased risk for treatment-related mortality of bone marrow transplantation in GSTM1-positive recipients. Abstract for the 47th Annual Meeting of the American Society of Hematology, 2005. (Abstract# 1756)

A057. Teshima, T., Matsuo, K., Matsue, K., Kawano, F., Taniguchi, S., Hatanaka, K., Nakao, S., Tanimoto, M., Hara, M., Eto, T., Wake, A., Abe, Y., Ohno, Y., Takemoto, Y., Harada, M., Takahashi, S., Ishida, Y., Kanda, Y., Imamura, M., Kasai, M. and Takaue Y.: Impact of HLA

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Mismatch on the Incidence of Acute GVHD and Rejection after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation (RICT). Blood. 104: 2758, 2004.

A058. Tsukamoto, T., Mizoshita, T., Ito, S., Yamamura, Y., Nakamura, T., Ushijima, T., and Tatematsu, M.: Alteration of gastric and intestinal transcription factors in intestinal metaplasia and adenocarcinomas of the human stomach. 6th International Gastric Cancer Congress, Workshop 2, Yokohama, Japan,2005.

A059. Tsurumi, T. and Kudoh, A.: Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment. The Awaji International Forum on Infection and Immunity, Awaji Yumebutai, Hyogo. 2004.

A060. Tsurumi, T. and Kudoh, A.: Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment. The XIII International congress of Virology, P116, V-22, San Francisco, USA. 2005.

A061. Uchida, A., Tabata, M., Matsuo, K., Ogino, A., Fujiwara, K., Hotta, K., Shinagawa, K., Kiura, K., Ueoka, H. and Tanimoto M.: An increase in incidence of acute promyelocytic leukemia during gefitinib treatment for advanced non-small cell lung cancer. J Clin Oncol. 23: 667S, 2005.

A062. Uchimura, K., Singer, M.S, Tsay, D., Kadomatsu, K., Kannagi, R., Muramatsu, T., and Rosen, S.D.: GlcNAc 6-O-sulfotransferase (GlcNAc6ST)-1 and GlcNAc6ST-2 regulate lymphocyte homing to lymph nodes. US/Japan Glyco 2004, Joint meeting of the Society for Glycobiology and the Japanese Society of Carbohydrate Research, (President, M.E. Etzler) Hawaii, November 17-20, 2004.

A063. Wakai, K. Japan Collaborative Cohort Study. Aichi Cancer Center International Symposium XI, 10-11, 2005.

A064. Wakai, K., Hirose, K., Matsuo, K., Ito, H., Kuriki, K. and Tajima, K.: Dietary factors and colorectal cancer risk in Japan: comparison between colon and rectal cancers. The 2nd APOCP General Assembly Conference, 88, 2004.

A065. Wakai, K., Suzuki, K., Kojima, M., Tamakoshi, K., Toyoshima, H., Watanabe, Y., Hayakawa, N., Hashimoto, S., Tokudome, S., Ito, Y. and Tamakoshi, A. for the JACC Study Group.:

Serum carotenoids, retinol, and tocopherols and colorectal cancer risk: a case-control study nested in the Japan Collaborative Cohort (JACC) Study. The 6th joint conference of the American Association for Cancer Research and the Japanese Cancer Association, C1, 2004.

A066. Wu, P-X., Kimura, N., Kannagi, R., and Sato, T.: Synthesis of sulfated oligosaccharides by sulfotransferase-transfected ECV304 cells using saccharide primer and structure analysis by MALDI-TOF mass spectrometry. US/Japan Glyco 2004, Joint meeting of the Society for Glycobiology and the Japanese Society of Carbohydrate Research, (President, M.E. Etzler) Hawaii, November 17-20, 2004.

A067. Yagi, H., Takahashi, N., Yamaguchi, Y., Kimura, N., Kannagi, R., and Kato, K.: Development and application of multi-dimensional HPLC mapping of N-linked glycans. 2nd Pharmaceutical Sciences World Congress (PSWC2004) Chaired by Sugiyama Y, Kyoto, Japan, May 29-June 2, 2004.

A068. Yagi, H., Takahashi, N., Yamaguchi, Y., Kimura, N., Kannagi, R., and Kato, K.: Development of structural analyses of sulfated N-glycans by mass spectrometry and HPLC mapping. US/Japan Glyco 2004, Joint meeting of the Society for Glycobiology and the Japanese Society of Carbohydrate Research, (President, M.E. Etzler) Hawaii, November 17-20, 2004.

A069. Yanada, M., Emi, N., Usui, N., Takeuchi, J., Sugiura, I., Takeuchi, M., Kobayashi, T., Yagasaki, F., Ohtake, S., Matsuo, K., Naoe, T. and Ohno, R.: Combination of intensive chemotherapy and imatinib (IDEAMOP regimen) for the treatment of newly diagnosed BCR-ABL positive acute lymphoblastic leukemia; excellent efficacy without increasing toxicity. Blood, 2736, 2004.

A070. Yanada, M., Takeuchi, J., Akiyama, H., Usui, N., Yagasaki, F., Emi, N., Miyazaki, Y., Ohtake, S., Jinnai, I., Matsuo, K., Naoe, T. and Ohno R.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL- positive acute lymphoblastic leukemia. Blood. 1827, 2005.

A071. Yang, C. X., Matsuo, K., Wang, Z. M. and Tajima, K.: Phase I/II enzyme gene polymorphisms and esophageal cancer risk: A Meta-analysis. The 2nd APOCP General Assembly Conference, 98, 2004.

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Record of Seminars ___________________________________________________________

Invited Speakers

2004 Mar. 09 Kaneko, R., Kawaguchi, K. and Yashiro K. (Life Science Division, Merk Ltd. Japan) Expression

and solubilization of proteins. April 02 Moore, M. (APPOCP Coordination Director) A practical guide to the use of scientific English. Jun. 22 Henderson, B. (University of Southern California) Inter-continental comparative study on breast

cancer risk among Japanese with special reference to application of a genome wide scan for molecular epidemiology.

Jun. 30 Hanaoka, F. (Institute for Molecular and Cellular Biology, Osaka University) Function of DNA

polymerase eta as a Xeroderma pigmentosum variant responsible gene. July 16 Kanoh H (Department of Science, Tokyo University) Application of Raman spectroscopy for cell

biology and medical science. Oct. 07 Warren, E.H. (University of Washington, Fred Hutchinson Cancer Research Center) Rear-

rangement and proteasome-mediated splicing of non-contiguous peptides encoded by the SP110 gene create a human minor histocompatibility antigen.

2005 Jan. 14 Tsubata, T. (Laboratory of Immunology, School of Biomedical Science, Tokyo Medical and

Dental University) Regulation of the humoral immune response by membrane lectin molecules. Mar. 29 Nomura, T. (Department of Gastrointestinal Surgery, Faculty of Medicine, University of Tokyo)

Polypeptide (TFF2) expressing metaplasia (SPEM): From clonality to bone marrow homing. Jun. 13 Uchimura, K. (Department of Anatomy, University of California, San Francisco, CA, USA)

Regulation of lymphocyte homing to lymph nodes by cell surface sulfated glycoconjugates. Dec. 14 Tauchi, H. (Faculty Science, Ibaragi University) NBS1 controls radiation induced DNA-damage

response and its reapir. Dec. 19 Cheng, A. (Human Cancer Genetics Program, Comprehensive Cancer Centre, Ohio State

University, Columbus, OH, USA) Combinatorial regulation of estrogen signaling.

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Institute Speakers

2004 Jan. 07 Ikehara, Y. (Oncological Pathology) Siglec-7 and Siglec-9 negatively regulate T cell receptor

activation. Mar. 04 Nakamura, Hid. (Central Laboratory & Radiation Biology) Effects of low-dose- rate radiation on

human cells. April 04 Hirose, K. (Epidemiology and Prevention) Risk and protective factors for breast cancer con-

firmed by HERPACC study - Obesity control against breast cancer risk among Japanese postmenopausal women.

Jun. 17 Osada, H. (Molecular Oncology) Novel therapeutic approaches with RNAi targeting ASH1

based on molecular characteristics of lung cancer cells. Sep. 09 Ohta, R. (Immunology) Therapeutic inhibition of a complement regulator enhances antibody

therapy in a model of mammary adenocarcinoma. Nov. 30 Daikoku, T. (Virology) Molecular basis for Epstein-Barr virus genome replication. 2005 Jan. 24 Goto, H. (Biochemistry) Regulation of mitosis through the crosstalk among mitotic protein

kinases. Feb. 10 Adachi, M. (Central Laboratory & Radiation Biology) Molecular mechanisms of cisplatin resis-

tance in human head and neck squamous cell carcinoma cell lines. Mar. 03 Taguchi, O. (Molecular Pathology) Roles of the thymus in recognition of auto-antigens. Mar. 23 Tsukamoto, T. (Oncological Pathology) Stomach cancer and phenotypic differentiation. May 12 Matsuo, K. (Epidemiology and Prevention) Gene-environment interactions of MTHFR gene

polymorphism with habitual drinking for gastrointestinal tract cancer risk. Jun. 09 Ikehara, Y. (Oncological Pathology) A carbohydrate recognition based drug delivery system. Sep. 08 Kondo, Y. (Molecular Oncology) Alterations of DNA methylation and histone modification in

human cancer. Dec. 21 Suzuki, R. (Molecular Medicine) Lymphomagenesis : Translocation, oncogene, microRNA, and

beyond•••. Dec. 27 Shirata, N. (Virology) 1. Interaction between Epstein-Barr virus immediate-early protein, BZLF1,

and p53. 2. Activation of ATM DNA damage checkpoint signal transduction elicited by Herpes simplex virus infection.

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Record of Symposia ___________________________________________________________

The 11th Aichi Cancer Center International Symposium “Forefront of Cancer Prevention Strategy in Asia”

Organizing Committee: Kazuo Tajima (Chairperson), Masae Tatematsu, Shigeo Nakamura, Kenji Wakai,

Hayao Nakanishi, Hirotaka Osada, Kaoru Hirose, Keitaro Matsuo, Hidemi Ito, Hiro-shi Yamaguchi, Takanori Umeda

February 5, 2005, International Conference Hall, Aichi Cancer Center.

Program of symposium Opening Remarks: Ryuzo Ohno (Aichi Cancer Center) Comprehensive epidemiologic studies in hospital: A Challenging strategy of cancer epidemiology in hospital. Keitaro Matsuo (Aichi Cancer Center) Diet and risk in Mediterranean countries Carlo La Vecchia (Istituto di Ricerche Farmacologiche, Milan, Italy) Cohort study and cancer risk assessment in Asia: The Japan Collaborative Cohort (JACC) Study. Kenji Wakai (Aichi Cancer Center) Korean Multi-center Cancer Cohort Studies for Genomic Epidemiology: Current Status and Perspectives Keun-Young Yoo（Seoul National University） The Self Defense Forces Cohort Study Suminori Kono (Kyushu University) A population-based prospective study on cancer and major chronic diseases: the JPHC Study Shoichiro Tsugane (National Cancer Center) Infection and cancer prevention: Polymorphisms of two fucosyltransferase genes (Lewis and Secretor genes) involving type I Lewis antigens are associated with the presence of anti-Helicobacter pylori IgG antibodies. Yuzuru Ikehara (Aichi Cancer Center) Study of the Association of Human Papillomavirus Infection and Cervical Cancer in China Wang Yixun (Liaoning province Tumor Hospital and Institute, Liaoning, P. R China) Hepatitis virus and heapatocellular carcinoma Hideo Tanaka (Osaka Medical Center for Cancer and Cardiovascular Diseases) Liver flukes and Cholangiocarcinoma Petcharin Srivatanakul (National Cancer Institute, Bangkok, Thailand) Forefront strategy of cancer prevetion: New strategies of individualized cancer prevention Nobuyuki Hamajima (Nagoya University) Breast cancer susceptibility and chemoprevention T.Rajkumar (Cancer institute, Chennai, India) Natural immunological host defense and cancer prevention Kei Nakachi (Radiation Effects Research Foundation) Forefront of cancer prevention in Asia Robert Burton (Strategic Leader, UICC, Melbourne, Australia) Concluding Remarks: Toshitada Takahashi (Aichi Cancer Center)

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Abstracts A challenging strategy for cancer epidemi-

ology in hospital. Keitaro Matsuo

Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan

Population-based approaches have been the gold standard of analytical epidemiologic study in the field of cancer, however, but are not practical in certain conditions; e.g., where there is a low inci-dence or a requirement for biomarkers. In such conditions, hospital-based efforts are advantageous. We have developed a comprehensive cancer epidemiology study system called HERPACC (Hospital-based Epidemiologic Research Program at Aichi Cancer Center), the first version (HER-PACC-I) which was started in 1988. Every first visit outpatient was systematically requested to en-roll in the program and fill out a common ques-tionnaire covering lifestyle factors. Case status was identified via hospital-based cancer registration. Until 2000, data for 12,500 cancer patients and 83,000 non-cancer outpatients were pooled in HERPACC-I. In a second version of HERPACC, started in 2001, we added a protocol for obtaining blood samples and semi-quantitative food fre-quency questionnaire, and this is ongoing. We are now planning to conduct a cohort study using non-cancer subject enrolled in HERPACC. Direct comparison of results of case-control studies and cohort study using same HERPACC population is a unique and challenging approach for cancer epidemiology. In this presentation, several results of HER-PACC-based epidemiological studies will be intro-duced. Diet and risk in Mediterranean countries Carlo La Vecchia

Istituto di Ricerche Farmacologiche“Mario Negri”- Mi-lano and Istituto di Statistica Medica e Biometria, Uni-versita di Milano - Milano, Italy

Various aspects of the Mediterranean diet are considered favourable not only cardiovascular dis-ease, but also on several common epithelial cancers. These include frequent consumption of vegeta-bles and fruit, which was analyzed using data from a series of case-control studies conducted in North-

ern Italy on over 12,000 cases of 20 cancer sites and 10,000 controls. For most epithelial cancers, the risk decreased with increasing vegetable and fruit consumption, with relative risks (RR) between 0.3 and 0.7 for the highest versus the lowest tertile. For digestive tract cancers, the population attributable risks for low intake of vegetables and fruit ranged between 15 and 40%. A number of antioxidants (including carotenoids, lycopene and flavonoids) and other micronutrients showed an inverse relation with cancer risk, but the main components respon-sible for the favourable effect of a diet rich in vege-tables and fruit remain undefined. Fish, and conse-quently a diet rich in n-3 fatty acids, tended to be another favourable diet indicator. In contrast, sub-jects reporting frequent red meat intake showed RRs above unity for several common neoplasms. Whole grain food (and hence possibly fiber) intake was related to reduced risk of several cancers, par-ticularly of the upper digestive tract. In contrast, re-fined grain intake and, consequently, glycemic load and glycemic index were associated to increased risk of different types of cancers. In conclusion, a low risk diet for cancer in the Mediterranean would imply increasing fruit and vegetables as well as avoiding increasing meat and refined carbohydrate consumption. Olive oil and other unsaturated fats, which are also typical as-pects of the Mediterranean diet, should also be pre-ferred to saturated ones. The Japan Collaborative Cohort (JACC)

Study Kenji Wakai

Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan

The Japan Collaborative Cohort Study (JACC Study; Chairman of the study group: Akiko Tama-koshi at Nagoya University Graduate School of Medicine) is a nationwide, multicenter cohort study, with 24 participating research institutions. The study started in 1988 to 1990, when 110,792 in-habitants aged 40 to 79 years completed a baseline questionnaire. They were enrolled from 45 study areas throughout Japan. The baseline questionnaire covered lifestyle factors including smoking and drinking habits, physical activity, and dietary habits, as well as

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medical history, education, family history of cancer, height and weight, and occupation. In addition to completing the questionnaire survey, 39,242 par-ticipants donated peripheral blood samples at health screening check-ups. The serum samples were stored at -80. until analyzed for nested case-control studies. For 61,557 subjects (55.6% of the total) in selected areas, we ascertained the incidence of can-cer by means of linkage with the records of popula-tion-based cancer registries, supplemented by a re-view of medical records. The vital and residential status of subjects was determined using resident registration records, and causes of death were iden-tified from death certificates. During the follow-up through 1999 for death and through 1997 for cancer incidence, 4,528 cancer deaths (in all study areas) and 3,437 incident cases of cancer (in the selected areas) were documented. Members of the JACC Study Group have exten-sively examined associations of lifestyle or other factors and serum components with the risk of can-cer incidence and death. More than forty original articles have been published from the study includ-ing papers from nested case-control studies utilizing the stored sera. The follow-up of subjects and the analysis of data and serum samples are still on go-ing. The JACC Study has generated a significant body of information for primary cancer prevention in Asia. It also may provide a good model for na-tionwide or international multicenter cohort studies, in which individual participating institutions are independent and maintain their originality in re-search but all contribute to one large cohort. Korean Multi-center Cancer Cohort Studies

for Genomic Epidemiology: Current Status and Perspectives

Keun-Young Yoo

Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.

Human genome epidemiology is the systematic application of the epidemiologic method to the ge-nome to assess the impact of genetic variation on health and disease. Cohort studies are the ultimate application of human genome epidemiology. The Korean Multi-center Cancer Cohort (KMCC) is a multi-center prospective cohort to meet the re-quirement of genome epidemiological studies on cancer etiology, which had been conducted since 1993. Data on general lifestyle, physical activity,

diet, reproductive factors, and agricultural expo-sures were obtained through direct interview using a structured questionnaire. Anthropometric meas-urements and some clinical laboratory findings have also been collected and stored in the web-based da-tabase system. A biological materials bank with blood (serum, plasma, buffy coat, packed erythro-cytes) stored at -70. and urine at -20. has been es-tablished for the genome epidemiological studies on the cancer etiology. DNA yield study revealed the PCR products for β-globin from nearly all of the samples (98%) from the long term-stored buffy coat specimen in the KMCC. Follow-up for the cancer occurrence has been commencing based on an ac-tive surveillance system by health personnel in each district, and a passive surveillance system through record linkages between the central cancer registry, the national death certificate, and the national health insurance claim databases in Korea. As of August 2004, total number of observation for the cohort with biologic specimen was 20,342. Until Decem-ber 2002, total 382 incident cancer cases have been identified by the passive surveillance and total number of follow-up was 64,999 person-years. Five leading sites of cancer incidence were stomach, lung, liver, colorectum, esophagus in men, and uterine cervix and breast in women. A fundamental question about genomic cohort is how large should it be in order to estimate the main effect of a SNP or haplotype and to detect gene-environmental and gene-gene interactions. On this purpose, the Korean Genomic Epidemiology Society has recently been founded, and a few of new genomic cancer cohorts, i.e. KOEX, KCDC, KNCC, etc., have been launched under the supervision of the Society. The recruitment goal and the design of each cohort will briefly be introduced. Along with other cancer co-horts in Japan, the Korean Genomic Cancer Cohort could provide more convincing evidence on new etiologies of cancer and on the cancer prevention strategy in the Asian-Pacific region. The Self Defense Forces Cohort Study Suminori Kono

Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan

Taking into account the advantage of the com-prehensive medical examination for retiring self-defense officials at the Self Defense Forces (SDF) hospitals, the author initiated the SDF Health Study at the SDF Fukuoka Hospital in October of

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the year 1986, when he was a part-time physician there. Sigmoidoscopy, abdominal ultrasonography, and a 75-g oral glucose tolerance test were included as a procedures in the preretirement health exami-nation during a 5-day admission. This health ex-amination was not mandatory, but was received by almost all retiring officials. A lifestyle question-naire was introduced to inquire about smoking, al-cohol use, physical activity, and habitual consump-tion of limited items of foods and beverages. At the time of the inception of the SDF Health Study, much interest had been focused on increased risk of colon or colorectal cancer associated with low blood cholesterol levels observed in prospective studies. Thus the first cancer-related study was to examine the relation between serum lipids and co-lorectal adenomas, and the outcome was no material relation with serum total cholesterol. The SDF Health Study was once deployed at four SDF hos-pitals across the nation. A series of studies have revealed increased risk of colorectal adenomas associated with cigarette smoking, alcohol use, physical inactivity, abdomi-nal obesity, and non-insulin dependent diabetes mellitus. Total colonoscopy was introduced as a routine procedure in the year 1995; at that time the study had retreated to Kyushu. This approach estab-lished that cigarette smoking and alcohol use were associated with a greater risk of adenomas in the distal segment of the colorectum while diabetes mellitus was more markedly related to an increased risk of proximal colon adenomas. It was also found that the association between cigarette smoking and colorectal adenomas did not vary with genetic polymorphisms of CYP1A1, GSTM1, and GSTT1, which are key enzymes in the metabolism of to-bacco-related carcinogens. The SDF Health Study evolved to a prospective cohort study in April of the year 2004. Informed consent was obtained as re-gards the follow-up health survey as well as for do-nation of venous blood for genetic analysis. Details of the design of the cohort study and conduct of the baseline survey will be discussed. A population-based prospective study on

cancer and major chronic diseases: the JPHC Study

Shoichiro Tsugane

Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan

Lifestyle is closely related to occurrence of cancer and other chronic diseases. Biological specimens such as plasma and white blood cells are expected to provide useful information on expo-sure-disease relations considering genetic suscepti-bility using recent biochemical and molecular tech-niques. To investigate factors associated with can-cer and other chronic diseases in Japan where the disease profile (coronary heart disease is a minor cause of death and the stomach continues to be the most frequent cancer site) and diet are substantially different from Western countries, we launched a population-based prospective study in 1990. Ap-proximately 140,000 men and women aged 40-69 years were selected based on resident registration in 29 communities covered by 11 public health center areas nationwide. At the baseline survey, a self-administered questionnaire including items on simple food frequency, blood (3 aliquots of plasma and 1 buffy coat) and health check-up data (an-thropometric measures, blood pressure, biochemical measures such as lipids and liver function test) were collected from 110,000 (80%), 49,000 (35%) and 48,000 (34%) persons, respectively. At year six, a follow-up survey (same survey items as those at baseline plus a semiquantitative food frequency questionnaire with validity information compared with 4 season 7 day diet records) was conducted, and 100,000 questionnaires, 35,000 blood samples and 33,000 health check-up reports were collected. Further at year eleven, the self-administered ques-tionnaire used at year six was repeated and col-lected from 97,000 persons. Mortality and immigra-tion, as well as disease incidence (cancer, cere-brovascular disease, ischemic heart disease, diabe-tes, etc.), were treated as endpoints. Among all co-hort subjects, 10,500 deaths, 8,900 cancers, 2,900 strokes and 600 myocardial infarctions were docu-mented as of October 2004. Several findings from the JPHC study will be presented. Polymorphisms of two fucosyltransferase

genes (Lewis and Secretor genes) in-volving type I Lewis antigens are asso-ciated with the presence of anti- Helicobacter pylori IgG antibodies

Yuzuru Ikehara

Division of Oncological Pathology, Aichi Cancer Center Research Institute Nagoya, Japan

Recent progress in the molecular analysis of H. pylori infection has revealed that the bacteria attach

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to the gastric mucosa through the blood group anti-gen-binding adhesin, BabA and a clinical relevance has been shown for the babA2 gene encoding BabA adhesin with regard to H. pylori-related diseases. BabA binds to both Leb [Gal (α 1.2Fuc)β1.3 GlcNAc(α1.4Fuc)-R] and H type I blood group carbohydrate structures [H type I structures; Gal (α1.2Fuc)β1.3GlcNAc-R] expressed on the foveo-lar epithelium of the gastric mucosa. We have been studying Lewis blood type anti-gens using biochemical and molecular biological methods and have obtained the following results concerning type I Le antigen synthesis. Individuals homozygous for nonfunctional alleles of Le gene (le/le) fail to express type I Le antigen (so called Le negative). In the human fucosyltransferase family, only the Le enzyme (FUT3, Fuc-T III) exhibits fucose transfer activity toward a type I precursor (Galβ1.3GlcNAc-R) or H type I structure with β1.4 linkage. The Se enzyme (FUT2, Fuc-T II) exhibits fucose transfer activity toward the type I precursor with α1.2 linkage and is responsible for Leb expres-sion on erythrocytes, solely determining the secre-tor status, and making a marked contribution to Leb expression in colorectal tissues. Individuals homozygous for nonfunctional al-leles of the Se gene fail to express ABH blood an-tigens in secreted fluids (so called for non-secretors), whereas those very rare individuals homozygous for nonfunctional alleles of the H gene (h/h) fail to express ABH blood antigens on eryth-rocytes. Considering the type I Le antigen synthetic pathway, it is possible that the type I precursor structure for acceptor substrate is used by Se and Le enzymes, with some competition between the two. The present study was performed to investigate the possibility that Se and Le gene polymorphisms alter the risk of H. pylori infection. Two hundred and thirty-nine participants were genotyped for Se and Le and tested for the presence of anti-H. pylori IgG antibodies. Using the normal gastric mucosa from 60 gastric cancer patients, we further assessed immunohistochemically whether type I Le antigen expression depended on the Se and Le genotypes. The H. pylori infection rate was positively as-sociated with the number of Se alleles (se/se group, 45.1%; Se/se group, 64.6%; and Se/Se group, 73.3%) and negatively associated with the number of Le alleles (le/le group, 76.4%; Le/le group, 68.3%; and Le/Le group, 55.6%). When the subjects were classified into three groups [low risk, (se/se, Le/Le) genotype; high risk, (Se/Se, le/le), (Se/Se, Le/le), and (Se/se, le/le) geno-

types;moderate risk, other than low- or highrisk group], the odds ratio relative to the low-risk group was 3.30 (95% confidence interval, 1.40-7.78) for the moderate-risk group and 10.33 (95% confidence interval, 3.16-33.8) for the high-risk group (Figure 2). Immunohistochemical analysis supported the finding that Se and Le genotypes affected the ex-pression of H. pylori adhesin ligands. We conclude that Se and Le genotypes impact on susceptibility to H. pylori infection. Study of the Association of Human Papil-

lomavirus Infection and Cervical Cancer in China

Wang Yixun

GYN Oncology Department, Liaoning province Tumor Hospital and Institute, Liaoning, P. R China

It was in 1980s, the relationship of cervical cancer to HPV started to be elucidated. HPV type 16 and 18 were first isolated directly from cervical cancer in 1983. From that time the strong associa-tion between HPV and cervical neoplasms has been reported worldwide. HPV DNA can be detected from 99.7% of cervical cancer specimens. Ap-proximately 90 types of HPV have been identified, some of which are oncogenic or high risk types. In order to investigate Human Papilloma virus infection prevalence in China, The study of associa-tion between HPV infection and cervical cancer was conducted in a high incidence area of cervical cancer -Shanxi province. It was found that for women from 35- 50, the high risk HPV infection rate was 24%, which is much higher than 5%-10% reported from the world. For a group of 1997 mar-ried women aged 35-45 : exfoliated cells were col-lected from cervix (by clinician) and from vagina (by subject herself), Hybrid capture 2 assay, which could detect 13 types HPV DNA of high risk, was carried out. HPV DNA detection rate was 20.8%. The infection rate increased with progression of cervical lesions. (X2=444.04,P=0.000). Comparison of 2 groups of aged 35-39 and 40- 45, there was no significant difference of infection rate (20.9%; 20.6%, X2=0.03, P=0.86). While compared with normal subjects: the risk odds ratio HPV infection with cervical cancer/high grade CIN and low grade CIN were 254.2 and 26.4 respectively, with attribu-tive risk percentage (ARP) of 98.1% and 83.6%. The sensitivity of the assay for high risk HPV DNA from clinician collected sample was 98%, which was higher than self collected samples of

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84%(X2=5.92 P=0.015. No significant difference can be seen in specificity. (86%:85%, X2=0.00, P=0.997). We conclude that high risk HPV infec-tion in female genital tract was the major risk factor of cervical cancer and CINs in this area of China. Hepatitis virus and hepatocellular carci-

noma Hideo Tanaka

Department of Cancer Control and Statistics, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan

Chronic hepatitis B virus (HBV) infection is a major risk factor of hepatocellular carcinoma (HCC) in Asia. Immunization with HBV vaccine is a most effective weapon against HBV infection and its consequences, although the modality differs among Asian countries. A recent cohort study in Japanese blood donors showed coinfection with HBV and hepatitis C virus (HCV) carried a super-additive risk for HCC. HCV is a blood-borne virus which causes a wide spectrum of liver diseases, ranging from acute hepatitis to HCC. Parenteral infection through blood transfusion, intravenous drug abuse (IVDU) and tattooing, as well as occupational exposure to blood, have been well defined as determinants of HCV transmission. Recently, the incidence of HCV infection among Japanese blood donors was esti-mated as 2-5 per 105 person-years. Approximately 60% of persons infected with HCV become HCV carriers and about 75% of Japanese with HCC cases are associated with chronic HCV infection. Life time risk of developing HCC among HCV carriers has been estimated as 30% for males and 6% for females, based on data for the age and sex specific incidence rates of HCC among HCV carriers in Osaka. An older age, being male, duration of HCV infection, type Ib infection, co-infection with HBV, having a high serum transaminase level, having a low platelet count, and heavy drinking and smoking are independent fac-tors associated with the development of HCC among HCV carriers. Cohort studies have demon-strated that interferon therapy can significantly lower the incidence of HCC among patients with chronic hepatitis C who showed normalization of the serum transaminase level after completion of the therapy. In Japan, a nationwide community-based anti-HCV and HBsAg screening system targeting

the age group of 40-70 years has been under the process of development by local municipal gov-ernments since 2002. The effectiveness of this screening system for preventing HCC will be evaluated in the future. Liver flukes and Cholangiocarcinoma Petcharin Srivatanakul

Cancer Control Unit, National Cancer Institute, Bang-kok,Thailand

The liver flukes, Opisthorchis viverrini, Opist-horchis felineus and Clonorchis sinensis, are bio-logically similar, food-borne trematodes which chronically infect the bile ducts and, more rarely, the pancreatic duct and gall-bladder of human be-ings and other mammals. Infection is acquired by eating raw or undercooked freshwater fish which contain the infective stage (metacercaria) of flukes. Immature flukes migrate up through the ampulla of Vater to the biliary tree, mature in the small intra-hepatic ducts and produce eggs, which are passed in the faeces. If the eggs reach a water body and are consumed by an appropriate species of snail, they hatch and undergo asexual multiplication to pro-duce free-swimming larvae, which can penetrate freshwater fish and become encysted metacercariae. Infection with Opisthorchis viverrini is car-cinogenic to humans (Group 1). Infection with O. felineus is not classifiable as to its carcinogenicity to humans (Group 3). Infection with C. sinensis is probably carcinogenic to humans (Group 2A). Primary cancers of the liver in adults are of two main histological types: hepatocellular carcinoma which is derived from hepatocytes, and cholangio-carcinoma, (CCA) which is derived from the epithelial lining of the intrahepatic bile ducts. About 560,000 new cases of liver cancer, usually hepatocellular carcinoma, occur annually, and con-tribute significantly to cancer mortality worldwide. CCA is a relatively rare tumour in most popula-tions but second among primary malignant liver tumours; about 15% of liver cancers are estimated to be CCA. The geographic distribution worldwide coincides with endemic areas of the liver flukes O. viverrini and C. sinensis. The interaction between genes and the environment and the interplay of en-vironmental factors, which include diet and lifestyle, illustrate the complexity in understanding the sus-ceptibility to environmental exposures. The highest incidence of CCA is found in areas of Laos and North and Northeast Thailand suffering

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from endemic infection with the liver fluke, O. viverrini. In Khon Kaen (the Northeast Thailand) , 86.5% of liver cancer cases are CCA. In both en-demic and non-endemic areas, there have been no significant changes in the incidence of CCA in re-cent years. It is less than 10 years since O. viverrini drug therapy was initiated;since it probably takes 30 years for CCA development after the infection, the trends of CCA are probably not likely to change in the next decade. Patients with CCA are elderly, with no clear sex differences. CCA occurs at rather older ages than hepatocellular carcinoma in most clinical series. C. sinensis parasitizes the bile ducts of millions of individuals in the Far East, particularly China and Korea. In the C. sinensis endemic area in Ko-rea , there is also a high incidence of liver cancer. About 20% of liver cancers in Pusan , Korea are CCA. Chronic infection with the liver fluke, O. viver-rini is the major risk factor for the development of CCA. Carcinogenesis of CCA is probably related to the length and severity of infection, the host's im-mune response, and other variables such as inges-tion of dietary carcinogens, for example nitrosa-mines. In northeast Thailand, several carcinogenic N-nitroso compounds and their precursors exist at low levels in the daily diet. In addition, endogenous nitrosamine formation by liver fluke infection has been reported. Increased levels of urinary nitrates and salivary nitrites are found in O. viverrini in-fected individuals. The subjects living in high-risk areas for fluke infection who had antibodies to O. viverrini had a 10-fold greater potential for en-dogenous nitrosation, measured on the basis of uri-nary levels of N-nitrosoproline after praline inges-tion, than individuals who did not have antibodies. Vitamin C is found to be effective inhibitor for prevention of the formation of endogenous nitrosa-tion. In several studies in hamsters infected with O. viverrini and treated with various carcinogenic Nni-trosamines, induction of cholangiocarcinomas and of hepatocellular nodules was enhanced. These re-sults suggest that the interaction between chemical carcinogens, especially nitrosamines, and OV in-festation may play role in the development of CCA in Thailand. Both exogeneous and in situ nitrosa-mine formation may lead to DNA alkylation and deamination. It seems that the presence of parasites induces DNA damage and mutations as a conse-quence of the formation of carcinogens/free radicals and of cellular proliferation of the intrahepatic bile duct epithelium.

New strategies of individualized cancer pre-vention

Nobuyuki Hamajima

Department of Preventive Medicine / Biostatistics and Medical Decision Making, Nagoya University Graduate School of Medicine, Nagoya, Japan

Generally, health information based on the in-dividuals' background allows a stronger message to induce behavior changes in lifestyle, supplement intake, health checkup motivation, and medical fa-cility visits. The background for each individual is made up of past exposure experiences, disease his-tory, current biomarker conditions, and genetic traits, as evidenced by a family history. In order to provide attractive cancer prevention methods for individuals, links to such individual background information are becoming important. To date, several individualized cancer preven-tion models have been introduced in practice. Pre-ventive measures to block mother-to-child trans-mission of hepatitis B virus and thus liver cancer is provided for carrier mothers. Preventive mastec-tomy against breast cancer is conducted for BRCA1 abnormal gene carriers. Intensive checkup and counseling against colorectal cancer are provided for those with FAP and HNPCC related genes. These specific cancer prevention models for carriers are accepted in several societies. Recent biomarker studies on the most common cancers indicate possible new strategies. Eradica-tion of Helicobacter pylori seems effective to pre-vent gastric cancer for individual with heavy infec-tion. Health services not covered by health insur-ance started in Japan for those who seek the test and medication for the eradication. Reported gene-environment interactions between genotypes and interventions also provide new models for indi-vidualized cancer prevention. For example, the in-teraction between aspirin use and an A316G poly-morphism of the ornithine decarboxylase gene sug-gests a possibility to recommend aspirin intake more strongly for A-allele-possessing patients at risk of colorectal adenoma/carcinoma. Genotype announcement may be a new strategy to induce behavior changes to a less risky lifestyle. Awareness of susceptible genotypes or enhanced health consciousness through genotyping could provide opportunities to correct high risk behavior, e.g., smoking and drinking. Concerning smoking, the cessation rate was found to be higher for the announced group in some studies, although not in all cases.

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Undoubtedly, the increasing number of avail-able biomarkers will contribute to the establishment of new modes of individualized cancer prevention. Breast cancer susceptibility and chemo-

prevention T. Rajkumar

Department of Molecular Oncology, Cancer institute (WIA), Adyar, Chennai, India

Breast cancer is the second most common can-cer among Indian women. The incidence of breast cancer has shown a trend towards gradual increase in the Chennai Metropolitan area over the past two decades, with the current CIR of 19.9 /100,000. While hereditary breast cancers account for 5-10%, the vast majority is sporadic. BRCA1 and BRCA2 are the major breast cancer susceptibility genes identified to date. However, contrary to the initial predictions, they account for only 15-20% of hereditary cancers. In our series of 61 patients of Hereditary breast &/or ovarian can-cers, 8 deleterious mutations were detected. Of the 24 Hereditary breast cancer families tested, four were found to have a deleterious mutation (16%). Only one of the thirteen families with Hereditary breast and ovarian families were detected to have a deleterious mutation in our series. Two out of 20, of the early onset breast cancers (<35 years of age) tested were found to have a disease causing muta-tion. Apart from the high-risk genes several low risk genes could also contribute to the development of breast cancer. These low susceptibility genes in-clude those that are involved in carcinogen activa-tion and inactivation, estrogen metabolism, growth factors and their receptors etc. Single nucleotide polymorphisms in these genes could contribute to changes in their functional efficiency. Examples of these include Cyp19 (Trp39Arg), Cyp17 (T-34C) GSTP1 (Ile462Val), GSTM1 (Present/Null), TGFβ (Leu10Pro) and c-erbB2 (Ile655Val). Chemo-prevention is likely to contribute sig-nificantly in the prevention of several cancers in-cluding that of breast cancer. Tamoxifen for exam-ple has been shown to reduce the risk of contralat-eral breast cancers. The trials evaluating the role of steroidal and non-steroidal aromatase inhibitors are already underway and should provide the critical answers to the efficacy of this approach in the high-risk group.

Natural immunological host defense and cancer prevention

Kei Nakachi

Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima, Ja-pan

The concept of multi-stage carcinogenesis im-plies that cancer prevention with different strategies is feasible for each stage. Recently emphasis has been placed on defense mechanisms existing in dif-ferent stages of carcinogenesis, with the immune system as the body's last line of defense against cancer development. Cancer immunosurveil-lance-routinely eliminating nascent transformed cells in the body-needs to be proven through inves-tigations of general populations. We previously reported an elevated incidence of cancer among individuals showing low levels of NK activity in peripheral blood lymphocytes, as compared to medium or high levels, based on a prospective cohort study of a Japanese general population. Large differences were found among individuals in NK activity, and lifestyle factors seemed to explain only a part of these, so we inves-tigated the genetic factors underlying individually variation in NK activity. From the cohort members, we selected two groups with low and high NK ac-tivity, each of which consisted of gender-and age-matched individuals who had not experienced any cancer. Next, a phenotype-genotype association analysis was carried out, comparing these two groups in terms of HLA class I genotypes and SNPs in the NKG2D gene. We found that specific HLA-B and C genotypes were associated with NK activity, implying a role of HLA class I molecules in maintaining a stable repertoire of NK cells; furthermore we succeeded in identifying two haplotype blocks in the NKG2D gene region, each of which generated two major haplotype alleles closely related to low and high NK activity (P<0.0001). In addition, these haplo-types were found to be significantly associated with cancer risk, in terms of a case-control study within this cohort. We previously found that selected life-style factors known as good health practices were associated with high NK activity. In our study, we are looking for further evidence of “individualized immuno-prevention of cancer”: NK activ-ity-enhancing effects of lifestyle may differ among individuals with different NKG2D haplotypes.

98

Forefront of cancer prevention in Asia Robert Burton

International Union Against Cancer, Geneva, Switzer-land, National Cancer Control Initiative, Melbourne, Australia

Only primary prevention and early detection and removal of pre-malignant lesions can reduce cancer incidence, although early detection of many cancers and effective treatment can cure the major-ity of cancer patients. The World Health Organiza-tion has estimated that failure to implement effec-tive cancer prevention programs will result in the global burden of cancer increasing from 10 million new cases in the year 2000, to 15 million in 2020 with about 10 million cancer deaths in that year. About 85 percent of cancer is caused by environ-mental exposure, most of which are due to non-communicable diseases (NCD), and about 20 per-cent to communicable diseases. About half of the 10 million new cases of cancer in the year 2000 were preventable, using our current knowledge. In Asia, NCD are now the commonest causes of

death and disability, and cancer is either the second or third commonest cause of death in most Asian countries. The major risk factors for NCD in Asia are tobacco use, unhealthy nutrition, physical inac-tivity and alcohol abuse. In some Asian countries more than half of all adult males use tobacco, and overweight/obesity is a rapidly developing problem in many countries. Therefore integrated NCD pre-vention programs are being developed and imple-mented in a number of Asian countries, of which the Philippines is the leading example. Vaccination (immunisation) is the great hope for prevention of the infectious cancers, and hepati-tis B vaccination of newborn children has been progressively introduced in Asia since the early 1980's. Finally, cervical screening and removal of premalignant lesions, using low technology screen-ing tests and simple surgical procedures preformed by trained health workers, has great potential to dramatically decrease cervical cancer mortality, which is the second commonest cancer of women in Asia.

99

Author index for research reports and publications ________________________________________________________________________________

Adachi, K. 56

Akatsuka, Y. 30, 31, 32, 33, J066, J123, J124, J179, J227, J243, J244, J255, J263, J269, R001, R002, R003, R004, R005, R006, R043, R044, A001, A002, A055, A056

Akazawa, T. J002

Aoki, K. R036

Arimura, N. 49, J005

Cao, X. 15, J010, J011, J157, J159, J160, J194, J254

Chen, G.Y. 42, J306

Daikoku, T. 35, J014, J015, J068, J130, J131, J224, R007, A003, A004, A014, A028

Demachi-Okamura, A. 30, J243, J244

Fujii, K. J023

Fujita, M. J014, J015, J024, J130, J131, J224, J229, R062

Fukami, H. J133, J175, J272, J273

Fukui, F. J197, R027

Fukui, T. 20, 21, J026, J079, J126, J230

Gao, C. J030, J031

Goto, H. 47, 48, J020, J033, J035, J043, J064, J144, J198, J259, J293, J308, R008, R009, R010, R011, R012, R022

Goto, M. J034

Goto, Y. 20, 44, J035, J036, R027

Gotoh, M. J062

Hagino, M. 55

Hagiwara, K. 44

Hamajima, N. 12, J030, J031, J035, J036, J037, J047, J048, J049, J075, J076, J077, J103, J108, J134, J135, J139, J149, J150, J161, J169, J179, J187, J188, J189, J190, J191, J192, J193, J198, J223, J258, J279, R040, A017, A026, A035, A036

Hara, M. J256, A057

Harada, H. J201

Harano, T. J247, J262

Hasegawa, Y. J034, J038, J073, J112, J126, J201

Hashimoto, A. J306

Hatooka, S. 7, 51, J133, J154, J298, J299, A019

Hayashi, N. J279

Hayashi, Y. 49, J067, J175, J184, J203

Hayashita, Y. 21, J041, J174

Hida, T. 21, J154, J244

Hirai, T. 7, J134, J135, J151, J153, A042

Hirata, A. 15, J007, J043, J044, J060, J148, J158, J272, J273, R059

Hirose, K. 5, 7, 12, J037, J046, J047, J057, J151, J153, J161, J187, J188, J189, J190, J191, J237, J261, J279, J298, J299, R014, R035, R036, A006, A019, A031, A038, A045, A064

Hishida, A. J048, J049, J223

Horio, Y. 20, J116, J154, J205, J206

Hoshino, Y. J106, J109, J228

Hosokawa, Y. 24, J050, J051, J172, J239, J312, R015, R016

Huang, X-E. 12, J057, J225

Ichinose, M. J146, J185

Ieda, T. 56

Iidaka, T. J059, J060

Ikehara, S. 15, 16, J061, J062

Ikehara, Y. 15, 16, J009, J061, J062, J176, J185, J194, J199, J290, J307, R040, A008, A009, A010, A043

Imai, T. J129

Inada, K. J034, J043, J063, J146, J156, J158, J185, J195, J211, J212, J254, J270, R051, R064

Inagaki, M. 47, 48, 49, J001, J005, J020, J024, J033, J038, J043, J083, J087, J170,

100

J171, J184, J203, J226, J245, J267, J293, J302, J308, J309, R008, R009, R019, R020, R021, R025, R026, R032, A011, A012

Inagaki, N. 49, J309

Inoko, A. 48, 49, J184, R022, A012

Inoue, M. J065, J074, J108

Ishida, H. 44, J291, J292

Ishida, T. J066

Ishizaki, K. 51, 52, J067, J132, J133, J175, J201, J224, J230, A013, A029, A030

Isomura, H. 37, J014, J015, J016, J068, J069, J130, J131, J224, R023, R024, A015

Ito, H. 5, 7, J036, J040, J046, J057, J074, J075, J076, J077, J078, J151, J153, J161, J178, J191, J237, J258, J298, J299, A016, A017, A018, A019, A031, A038, A045, A064

Ito, S. J072, J113, J114, J115, J157, J162, R045, A041, A042, A058

Ito, Y. 30, 32, J019, J080, J105, J106, J110, J111, J243, J244,

Iwata, H. 7, J046, J047, J085, J086, J164

Izawa, I. 48, 49, J083, J087, J117, J184, J302, J308, J309, R025, R026, A012

Izawa, M. 41, 42, J155, J278, J306, R028, R029, A040

Joh, T. J156, J158, J160, J195, J254, J258, A041

Kagami, Y. J006, J022, J048, J123, J150

Kameoka, Y. J092, J101, J173, J242

Kanamori, A. 44, J291, J292, R013

Kanemitsu, Y. 7, J134, J135, J151, J153

Kannagi, R. 41, 42, 44, J045, J071, J091, J093, J094, J118, J138, J155, J166, J197, J210, J222, J232, J257, J277, J278, J289, J291, J292, J306, R027, R028, R029, R030, R031, R034, R041, A020, A021, A022, A023, A024, A025, A032, A040, A053, A062, A066, A067, A068

Karnan, S. 26, 57, J092, J099, J177, J209, J239, J240, J241, J242, J312

Kasugai, Y. J101, J239

Kato, K. 57, J052, J081, J181, J182, J183

Kato, S. 15, J104, J158, J159, J160, J211, J254

Kato, T. 7, J134, J135, J151, J153, J162, A042

Kawajiri, A. 47, J024, J033, J038, J302, R032

Kimura, N. 42, J118, J289, R029, A066, A067, A068

Kitamura, T. J012, J203

Kiyono, T. 32, 47, 49, J033, J130, J224, J229

Kobayashi, T. 16, J169, J297, A069

Kodera, Y. 31, 32, J058, J072, J103, J113, J114, J115, J123, J124, J162, J176, J179, J180, J196, J202, J236, J255, J263, J307, R046, A042, A055, A056

Koike, K. J134, J135

Koike, T. 41, 42, J118, J155, R028, R029, A040

Kojima, N. 16, A008

Kondo, E. 30, 32, J123, J124, J125

Kondo, M. 20, J026, J073, J079, J126, J144

Kondo, Y. 20

Konishi, H. J021, J145, J247

Kontani, K. J127

Koshikawa, K. J039, J262

Kozaki, K. J276

Kudoh, A. 35, J014, J015, J016, J068, J130, J131, J224, R024, R033, R061, R062, A003, A004, A014, A027, A028, A059, A060

Kumamoto, K. J118, J155, R034

Kumimoto, H. 51, J077, J132, J133, J230, A029, A030

Kuriki, K. 7, 12, J012, J088, J089, J090, J134, J135, J136, J259, J260, R042, R055, R056, A031, A038, A064

Kuroishi, T. R035, R036

101

Kuzushima, K. 30, 31, 32, 33, J002, J003, J008, J032, J109, J123, J124, J179, J228, J243, J244, J246, J263, J268, J269, J287, R037, A001

Kuzuya, K. J124, J187, J188, J189, J190, J191

Kyogashima, M. 44, J098, J138, J143, R038, A032

Maeda, Y. J129

Maeno, K. J145, J174

Masuda, A. J145, J174, J200

Masui, T. A018

Matsudaira, Y. 33, J269

Matsukage, A. J229

Matsuo, K. 7, 12, J023, J025, J031, J035, J046, J047, J048, J052, J053, J054, J055, J056, J057, J058, J075, J076, J077, J085, J086, J103, J129, J134, J135, J149, J150, J151, J152, J153, J164, J188, J189, J191, J230, J231, J237, J240, J241, J242, J256, J258, J265, J266, J276, J285, J295, J296, J297, J298, J299, J300, J301, J310, R017, R018, R039, R040, R063, A005, A007, A017, A019, A026, A031, A033, A034, A035, A036, A037, A038, A039, A045, A057, A061, A064, A069, A070, A071

Matsuzawa, K. J167

Mitsudomi, T. 7, 30, J021, J075, J100, J116, J128, J154, J204, J243, J244, J247, J262, J303, J304, J305, R057, A017

Miyazaki, K. 41, 42, J118, J155, J306, R029, R041, A040

Miyazaki, M. 31, J066, J263

Mizoshita, T. 15, 16, 17, J010, J011, J034, J043, J063, J104, J148, J156, J157, J158, J159, J160, J195, J211, J212, J254, J270, J271, R052, R053, R054, A041, A058

Mizuno, M. 55

Mizutani, K. J298

Mochizuki, Y. J072, J115, J162, R045

Moore, M. J260, R042, R056

Morishima, S. 32, R043

Morishima, Y. 7, 26, 30, 31, 32, J006, J048, J092, J099, J101, J123, J124, J149, J150, J177, J179, J208, J237, J240, J241, J242, J244, J255, J263, J312, R002, A036, A037, A055, A056

Murate, T. 44

Nagata, K. J038, J170, J171, J184, J203, J226, J302, A012

Nakagawa, M. J050, J172, J173

Nakagawa, T. J174

Nakamura, Hir. 55

Nakamura, Hid. 52, J067, J175

Nakamura, S. 7, 25, 26, J006, J029, J062, J064, J088, J090, J092, J095, J099, J101, J149, J150, J152, J156, J157, J177, J207, J208, J234, J235, J237, J240, J241, J242, J270, J271, J279, J312, A009, A036, A037, A045

Nakamura, T. 25, J064, J157, A041, A058

Nakanishi, H. 15, 16, J029, J062, J072, J113, J114, J115, J162, J176, J185, J194, J196, J290, J307, J311, R045, R046, A008, A009, A042, A043

Nakanishi, T. 7, 32, J187, J188, J189, J190, J191

Nakashima, Y. 26, J177

Nakasu, S. 37

Nawa, A. 32, J124, J187, J188, J189, J190, J191

Nishi, Y. 55

Nishida, K. 30, 33, J095, J243, J244, J269

Nishida, T. J179, J180, J255, A055, A056

Nishimoto, Y. J133

Nishio, M. J234

Nishizawa, M. 48, 55, J184, A012

Niwa, T. 16, J049, J062, J185, J186, J290, A008, A009

Nozaki, K. J010, J011, J156, J194

Obata, Y. 33, J141, J269, R058

Ogasawara, N. 16, J010, J148, J158, J195, J254, A041

Ogura, M. J048, J150

102

Oguri, T. 48, 49, J040, J293

Ohashi, N. 16, J196, J307

Okada, Y. J245

Okanami, Y. 33, J269

Okuma, K. J076, J077

Osada, H. 20, 21, J004, J021, J041, J100, J145, J174, J204, J205, J206, J247, J262

Oshiro, A. J208

Ota, A. J092, J209, J240, J242

Otsuka, T. 17, J157, J211, J212

Ozeki, S. J269

Saito, H. J204

Saito, N. 52

Saito, T. 7, J075, J076, J077, J134, J135, J145, J151, J153, J187, J237, J298, J299, A019, A031

Sakai, H. J007, J043, J044, J059, J060, J218, J272, J273

Sato, N. 20, J001, J026

Sekido, Y. 20, 21, J026, J041, J049, J073, J079, J112, J126, J144, J163, R047

Seto, M. 24, 25, 26, 57, J022, J050, J051, J064, J092, J095, J099, J101, J125, J208, J238, J239, J149, J150, J172, J177, J209, J223, J240, J241, J242, J274, J312, R015, R048, A036, A037

Shima, H. 49

Shimizu, N. J011, J194, J266

Shimizu, S. J040, J178

Shinoda, M. 7, 51, J133, J154, J298, J299, A019

Shirai, N. J059, J060

Shirata, N. 36, J015, J016, J068, J131, J224, A014, A028, A044

Shiromizu, T. 48, J038, R049

Sobue, S. 44

Sugaya, N. J109, J228

Sugaya, Y. J014, J015, J016, J130, J131, J224

Sugimoto, M. 49

Sugiura, T. 7, J075, A017

Suguro-Katayama, M. 26, J092, J099, J241, J242

Suzuki, H. 24, J050, J051

Suzuki, R. 25, 26, J006, J085, J092, J099, J137, J149, J150, J165, J172, J173, J177, J180, J202, J207, J234, J235, J236, J239, J240, J242, J312, R050, A037

Suzuki, S. J081, J088, J089, J090, J120, J122, J142, J192, J193, J214, J233, J249, J252, J253, J259, J260, J281, J283, J284, J288, R055, R056

Suzuki, T. 7, J147, J151, J153, J200, J236, J237, J296, J299, A045

Tagawa, H. 26, J092, J099, J101, J177, J208, J209, J238, J239, J240, J241, J242, J312, A037

Taguchi, O. 33, 45, J127, J248, J269

Taji, H. J048, J150, J180

Tajima, Ka. 5, 7, 12, J012, J013, J018, J030, J031, J037, J046, J047, J048, J057, J074, J075, J076, J077, J108, J134, J135, J136, J139, J140, J147, J149, J150, J151, J152, J153, J161, J168, J169, J187, J188, J189, J190, J191, J225, J230, J237, J258, J261, J279, J298, J299, J300, J301, J313, , R014, R035, R040, R042, R036, A006, A016, A017, A018, A019, A026, A031, A034, A035, A036, A037, A038, A045, A046, A047, A048, A049, A050, A051, A052, A064, A071

Tajima, Ko. 30, J021, J123, J243, J244

Takahashi, M. J039, J102, J144, J163

Takahashi, Ta. 20, 21, J004, J021, J041, J042, J084, J100, J116, J128, J145, J154, J174, J200, J204, J205, J206, J247, J262, J303, J304, J305, R057

Takahashi, To. 30, 31, 32, 33, J002, J066, J070, J123, J124, J179, J243, J244, J262, J263, J269, R058, A001

Takenaka, Y. 16, J010, J159, J160, J211, J271, A041

103

Takezaki, T. 12, J012, J013, J030, J031, J057, J140, J147, J168, J225, J279, J313, , R035, R036

Tamiya-Koizumi, K. 44, J138

Tanaka, H. 17, J010, J100, J104, J160, J185, J194, J212, J219, J254, J270, J271

Taniguchi, T. 20, 21

Tatematsu, M. 15, 16, 17, J007, J010, J011, J027, J028, J029, J034, J043, J044, J059, J060, J062, J063, J072, J096, J097, J104, J113, J114, J115, J146, J148, J156, J157, J158, J159, J160, J162, J176, J185, J186, J194, J195, J196, J211, J212, J218, J254, J270, J271, J272, J273, J290, J294, J307, J311, R045, R046, R051, R052, R053, R054, R059, R060, R064, A008, A009, A041, A042, A054, A058

Tatematsu, Y. 20, 21, J041, J100, J204, J205, J206

Terashima, M. 55

Teratani, M. 56

Tokumasu, S. 55

Tomida, S. 21, J021, J041, J100, J247, J262, R057

Tominaga, S. J147, R035, R036

Torikai, H. 31, 32, J263

Tsujimura, K. 30, 31, 32, 33, J002, J070, J123, J124, J179, J243, J244, J263, J269, R058

Tsukamoto, T. 15, 16, 17, J007, J010, J011, J027, J028, J034, J043, J044, J059, J060, J063, J096, J097, J104, J146, J148, J156, J157, J158, J159, J160, J185, J186, J195, J211, J212, J254, J270, J271, J272, J273, R051, R052, R053, R054, R059, R060, R064, A041, A058

Tsurumi, T. 35, 36, 37, J003, J014, J015, J016, J032, J068, J069, J130, J131, J224, J228, J229, R023, R024, R033, R061, R062, A003, A004, A014, A015, A027, A028, A044, A059, A060

Tsuzuki, S. 25, 26, 57, J092, J172, J209, J239, J241, J242, J264, J274, J275, J312,

A037

Uchida, K. J276

Ueda, R. 57, J040, J064, J066, J075, J078, J095, J145, J178, J236, J237, A017, A045

Wakai, K. 7, 11, 12, J012, J013, J017, J046, J057, J065, J077, J081, J082, J102, J107, J112, J119, J120, J121, J122, J141, J142, J151, J153, J167, J192, J193, J198, J213, J214, J215, J216, J217, J219, J220, J221, J233, J237, J249, J250, J251, J252, J253, J279, J280, J281, J282, J283, J284, J286, J288, J298, J299, R065, R066, A019, A026, A031, A038, A045, A063, A064, A065

Watanabe, A. J058

Yabuta, T. J118

Yamachika, T. J290

Yamada, N. J259

Yamaguchi, M. 44, J092, J099, J207, J242, J291, J292

Yamaguchi, T. 48, 49, J181, J182, J183, J293

Yamamoto, M. 55, J007, J044, J059, J060, J273

Yamamura, Y. J072, J113, J115, J156, J157, J158, J162, J211, J270, J271, A041, A042, A058

Yamane, Y. J132, J133

Yanagisawa, K. 21, J041, J100, J145, J174, J247, J262, R057

Yang, C. X. 7, 12, J298, J299, J300, J301, A038, A071

Yasuda, T. 56

Yasui, K. J176, J290

Yasui, Y. 52, J067, J302

Yatabe, Y. 7, 20, 21, J021, J039, J041, J084, J100, J116, J128, J154, J204, J206, J247, J262, J303, J304, J305, R057

Yin, J. 42, J306

Yokoyama, N. J009, J199

Yokoyama, T. 20, 21, 48, J126, J184, J219, J293, J308, R019, R067

104

Yokoyama, Y. A043

Yonezumi, M. J172

Yoshida, T. J103

Yoshikawa, A. J273

Yoshikawa, K. J125

Zhang, X. J312

Zou, P. 49

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