SCIENTIST EXCHANGES

From Japan:

(1) IBA, Hideo, University of Tokyo
Subject of Research: Functional Analysis of Fos/Jun Family Proteins
Dates: Dec 1996-Jan 1997
Host: H. Hanafusa, Rockefeller University

(2) MORI, Hideki, Gifu University
Subject of Research: Investigation on Mechanisms and Research Methods for Chemo-Prevention of Digestive Organs Carcinogenesis
Dates: Feb 1997
Host: A.H. Conney, Rutgers University

(3) USHIJIMA, Toshikazu, National Cancer Center Research Institute
Subject of Research: Establishment of New-Generation System for Mapping of QTLS in the Rat
Dates: Mar 1997
Host: D.E. Housman, Massachusetts Institute of Technology

(4) NAKAE, Dai, Nara Medical University
Subject of Research: Investigation for Involvement of Oxidative DNA Damage in Carcinogenesis
Dates: Mar 1997
Host: A.P. Grollman, State University of New York at Stony Brook

(5) TATEMATSU, Masae, Aichi Cancer Center Research Institute
Subject of Research: The Clonal Structure of Epithelial Tissue and Carcinogenesis
Dates: Mar 1997
Host: S. Nandi, University of California

(6) TSUBATA, Takeshi, Tokyo Medical & Dental University
Subject of Research: Study on Molecular Mechanisms for Immunological Tolerance
Dates: Mar 1997
Host: R.H. Schwartz, National Institutes of Health

(7) TAKAHASHI, Naoki, Nara Institute of Science & Technology
Subject of Research: Functional Analysis of Homeobox
Dates: Feb 1997
Host: T.M. Jessell, Columbia University

(8) ITOH, Kyogo, Kurume University
Subject of Research: Identification of Genes Encoding Human Tumor-Rejection Antigens and Development of Cancer Vaccine
Dates: Mar 1997
Host: S.A. Rosenberg, National Cancer Institute

(9) KOSUGI, Atsushi, Osaka University
Subject of Research: Mechanism for Modulation of Lymphocyte Development and Activation by TSA-1/Sca-2
Dates: Jan-Feb 1997
Host: A.M. Weissman, National Institutes of Health

(10) TSURUO, Takashi, University of Tokyo
Subject of Research: Information Exchange on New Antitumor Agents, Drug Resistance and Molecular Targets in Cancer Chemotherapy
Dates: Oct 1996
Host: M. Gottesman, National Cancer Institute

(11) SHIKU, Hiroshi, Mie University
Subject of Research: Immuno-Gene Therapy for Cancer
Dates: Mar-Apr 1997
Host: L.J. Old Ludwig Institute for Cancer Research

(12) MITSUDOMI, Tetsuya, Aichi Cancer Center Hospital
Subject of Research: Diagnostic and Therapeutic Application of Molecular Biology of Lung Cancer
Dates: Feb 1997
Host: A.F. Gazdar, University of Texas

(13) MIKI, Yoshio, Japanese Foundation for Cancer Research
Subject of Research: Molecular Genetics and Genetic Testing of Hereditary Breast Cancer
Dates: Oct-Nov 1996
Host: M.H. Skolnick, University of Utah

(14) KIHARA, Masahiro; Kanagawa Cancer Center Research Institute
Subject of Research: Molecular Epidemiology of Genetic Cancer Susceptibility
Dates: Feb 1997
Host: J.K. Wiencke, University of California, San Francisco

(15) HAYASHI, Kenshi, Kyushu University
Subject of Research: Detection and Integration into Database of Human Mutation
Dates: Oct-Nov 1996
Host: S. Pulst, University of California, Los Angeles


(1) Hideo Iba
Department of Gene Regulation Institute of Medical Science University of Tokyo

TITLE: Functional analysis of Fos/Jun family proteins
SPONSOR AND HOST INSTITUTION:
Dr. Hidesaburou Hanafusa, The Rockefeller University, 1230 York Avenue, New York, New York 10021
DATES OF VISIT:
12/27/1996 Tokyo
12/27- 1/3 New York (Rockefeller Univ)
1/3-1/8 Keystone (Keystone Symposium)
1/8-1/12 Santa Fe (Keystone Symposium)
1/12-1/14 Seattle (Fred Hutchinson Cancer Research Center)
1/15/1997 Tokyo

SUMMARY OF ACTIVITIES:
1. Dr. Hidesaburo Hanafusa's lab (The Rockefeller Univ)
We have exchanged information on the endogenous transcriptional factors that are involved in the cellular transformation induced by v-src or v-crk and on the protein kinases such as MAPkinase and JNK which phosphorylate and activate these endogenous transcriptional factors. The discussions concerning the protocols of assay systems for the kinase reaction as well as for cellular transformation of NIH3T3 or CEF were quite useful. Interestingly, Dr. H. Hanafusa's group has recently shown that JNK is activated by v-crk. To examine the biological meanings of JNK activation, we will supply dominant negative mutants of Fos or Jun proteins to them.
2. Keystone Symposium on Growth Control (at Keystone)
This Symposium was organized by Dr. T. Hunter and Dr. C. Sherr and mainly focused on Cell cycle, Signal transduction, Transcriptional factors and Tumor suppresser genes. We presented a paper entitled "Activation mechanisms of endogenous AP-1 in v-src transformed cells". We show here a new pathway for the activation of endogenous AP-1 in v-src transformed cells and in February, 1997, most parts of these results was accepted for publication in Oncogene.
One of the major topic in this Symposium was the signal transduction of TGF-!!!or BMP stimuli. Dr. Masage's group clearly has shown that phosphorylation of Smad family proteins by the receptors is the first step for this pathway. Dr. Eisenman's group has shown the molecular mechanisms involved in the transcriptional suppression by Mad proteins. Mad protein was known to form complex with a co-repressor mSin3 and Dr. Eisenman clearly shown here mSin3 can bind to histon deacetylase, which is expected to change the chromosomal structure in the promoter region.
3. Keystone symposium on Bone, Cartilage and Collagen: Growth and Differentiation (at Santa Fe)
This symposium (organized by Dr. J.T. Potts, Jr., S. Krane, and H. Kronnenberg) covered a broad area including bone or cartilage formation, synthesis or structure of collagen. Biochemists, genetists working on knock out mouse, Drosophilla or C.elegance and developmental biologists using transgenic mouse and chicken embryos gathered here and discussed intensively. We presented two papers entitled "Expression of exogenous Fos gene in chicken limb buds suppresses maturation of chondrocytes and causes cartilage truncation" and "Jun family proteins suppress the maturation process of chondrocytes." The most parts of the former presentation was accepted for publication in Proc.Natl.Acad.Sci.USA. in February, 1997.
4. Dr. A. Dusty Miller's lab (Fred Hutchingson Cancer Research Center, Seattle)
I visited Dr. A. Dusty Miller who is intensively working on human gene therapy by new vector systems using retrovirus, AAV. We exchanged several informations on VSV-G pseudotyped retrovirus vectors with quite high titers (our group) and amphotropic retrovirus vectors (his group) which has affinity on more than two receptor proteins.
ACKNOWLEDGEMENTS:
I greatly appreciate US-JAPAN COOPERATIVE CANCER RESEARCH PROGRAM for giving me the opportunity to introduce our latest works to US Scientists and to learn stimulating results presented by them.



(2)HIDEKI MORI
GIFU UNIVERSITY SCHOOL OF MEDICINE

SPONSOR AND HOST INSTITUTION:
l) DR. ALLAN H. CONNEY, LABORATORY FOR CANCER RESEARCH, COLLEGE OF PHARMACY, NEW JERSEY STATE UNIVERSITY (RUTGERS UNIVERSITY).
2) DR. GARY D. STONER, DIVISION OF ENVIRONMENTAL HEALTH SCIENCES, OHIO STATE UNIVERSITY, SCHOOL OF PUBLIC HEALTH.

SUMMARY OF ACTIVITIES:
l) MAIN OBJECTIVE TO VISIT DR. CONNEY'S LABORATORY WAS To DISCUSS ON THE PHARMACOLOGICAL, BIOLOGICAL OR BIOCHEMICAL PROPERTIES OF CHEMICAL AGENTS SUCH AS PHENOLIC COMPOUNDS, CAROTENOIDS OR ORGANO-SULFUR COMPOUNDS FOR WHICH WE FOUND CHEMOPREVENTIVE ACTIVITIES IN ANIMAL MODELS FOR DIGESTIVE ORGANS CARCINOGENESIS AND TO GET USEFUL INFORMATION TO PURSUE MECHANISTIC ASPECTS OF THESE AGENTS AND FUTURE COLLABORATION IN CHEMOPREVENTION STUDY ON SOME OF THESE AGENTS. DURING THE STAY IN DR. CONNEY'S LABORATORY, I HAD SUFFICIENT DISCUSSION WITH DR. CONNEY AND HIS COWORKERS ON THE TOPICS ON THE MODE OF ACTION AND POSSIVLE MECHANISMS OF CHEMO-PREVENTIVE AGENTS SUCH AS l) NATURAL PHENOLIC COMPOUNDS INCLUDING CURCUMIN, PROTOCATECHUIC ACID OR ELLAGIC ACID, 2) NATURAL ORGANO-SULFUR COMOUNDS INCLUDING S-METHYLMETHANETHIOSULFONATE, 3) CAROTENOIDS INCLUDING ASTAXANTHIN OR CANTHAXANTHIN, 4) OTHERS INCLUDING SYNTHESIZED CHEMICALS, ESPECIALLY ON THE POINTS OF MODIFYING EFFECTS ON METABOLIC ACTIVATION OR DETOXIFICATION, EFFECTS OF ANTIOXIDATIVE PROPERTIES, EFFECTS ON ONCOGENE ACTIVATION OR EFFECTS ON THE CELL PROLIFERATION. ALSO WE HAD DISCUSSION FOR THE SCIENTIFIC PRINCIPLES ON THE POSSIBLE APPLICATION OF THESE CHEMOPREVENTIVE AGENTS INTO CLINICAL TRIALS. WE HAD AN AGREEMENT TO START CHEMOPREVENTION STUDY OF CURCUMIN ON STOMACH CARCINOGENESIS USING MNNG AND NACL IN RATS.

IN THE STUDY, SYNERGISTIC EFFECT OF CURCUMIN WITH VITAMIN D3 AS WELL As CURCUMIN ALONE ON THE CARCINOGENEIS WOULD BE EXAMINED. ALSO, CHEMOPREVENTION STUDY OF CURCUMIN ON HEPATOCARCINOGENESIS (PROBABLY WITH USE OF AFLATOXIN B1) WILL BE VALUABLE CONSIDERING RELATIVELY LOW INCIDENCE OF LIVER CANCERS IN INDIA OR NEIGHBORING COUNTRIES. I HAD A SEMINAR WITH THE TITLE "CANCER CHEMOPREVENTION AND CELL PROLIFERATION" PROVIDING OUR GROUP'S DATA I.E. l) CELL PROLIFERATION GENERATED BY GENOTOXIC CARCINOGENS IN THE INITIATION PHASE IS A KEY ISSUE; 2) EARLY APPEARING APOPTOSIS IS A RELIABLE MARKER FOR THE BLOCKING AGENTS; 3) TELOMERASE ACTIVITY COULD BE A BIOMARKER FOR CELL PROLIFERATION IN THE CHEMOPREVENTION STUDY. WE CAME TO THE CONCLUSION THAT FOR THE APPLICATION OF CANDIDATE CHEMOPREVETIVE AGENTS INTO CLINICAL TRIALS, MECHANISM OF EACH AGENT FOR THE PREVETION POSSIBLY AVAILABLE FROM BASIC RESEARCHES IS MOST IMPORTANT.
2) MAIN OBJECTIVE TO VISIT DR. STONER'S LABORATORY WAS TO DISCUSS ON THE POSSIBILITY THAT CHEMOPREVETIVE AGENTS FOUND BY US IN THE MODELS FOR ORAL, LIVER OR LARGE BOWEL CARCINOGENESIS ARE USEFUL FOR PROMISING AGENTS FOR ESOPHAGEAL CANCERS OR NOT. A PROPOSAL TO USE S-METHYLMETHANETHIOSULFONATE OR PROTOCATECHUIC ACID FOR THE CHEMOPREVENTION STUDY AGAINST PROMOTION-PROGRESSION IN N-NITROSOBENZYLMETHYLAMINE-INDUCED ESOPHAGEAL CARCINOGENESIS WAS DONE BY DR. STONER. WE HAD AN AGREEMENT TO EXCAHNGE TISSUES FROM NEOPLASMS OF THE TONGUE OR ESOPHAGUS FROM 4-NQO OR N-NITROSOBENZYLMETHYLAMINE-INDUCED CARCINOGENESIS IN PREVIOUS OR FUTURE STUDIES. WE ALSO HAD A DISCUSSION ON THE TOPIC OF PREVENTION OF HUMAN ESOPHAGEAL CANCERS ARISING IN THE LOWER PART OF ESOPHAGUS (MOSTLY ADENOCARCINOMA, POSSIBLY RELATED TO BARRETT ESOPHAGUS), AND HAD THE SAME COMMENT THAT FOR THE PREVEN-TION, ANIMAL DATA TO USE SOME MODEL SUCH AS REFLUX ESOPHAGITIS-ASSOCIATED ESOPHAGEAL CANCERS IS USEFUL. I HAD A SEMINAR IN OHIO STATE UNIVERSITY WITH THE TITLE "CHEMOPREVENTION IN ORAL LIVER OR LARGE BOWEL CARCINOGENESIS AND IT'S MODE OF ACTION" PROVIDING A NUMBER OF DATA OBTAINED IN ANIMAL EXPERIMENTS USING 4-NQO. DIETHYLNITROSAMINE OR AZOXYMETHANE-INDUCED CARCINOGENESIS MODELS.



(3) Toshikazu Ushijima
Section Head, Carcinogenesis Division, National Cancer Center Research Institute

SPONSOR AND HOST INSTITUTION:
Dr. David E. Housman, Center for Cancer Research, Massachusetts Institute of Technology; Dr. Alfred G. Knudson, National Cancer Institute
DATE OF VISIT:
March 26, 1997 Genome Center, National Institutes of Health
March 27-28, 1997 US-Japan joint seminar on "cancer and animal genetics" at National Cancer Institute
March 31- April 3, 1997 Massachusetts Institute of Technology

SUMMARY OF ACTIVITIES:
As the human genome project proceeds, mapping of diseases that have a plus-or-minus phenotype and are controlled by a single major gene has almost finished. Subsequently, subtle quantitative traits are getting more important, and polygenes controlling these traits are now to be mapped and cloned. For linkage mapping of quantitative trait loci (QTLs), analysis of a large number of animals is necessary. The exchange scientist is developing a new generation of genetic markers that can be used for genotyping of large number of animals, using a genomic subtraction technique, termed representational difference analysis (RDA).
1) Activities at MIT
The exchange scientist visited Dr. Housman's lab, and made discussion with the professor and other scientists in the lab. Dr. Housman originally developed the interspersed repetitive sequence-representational difference analysis (IRS-RDA) markers using M. spretus and C57Bl mice, and the use of dot-blot analysis in genotyping using the markers. However, he had difficulties in isolating IRS-RDA markers between inbred laboratory strains of mice. On the other hand, the exchange scientist was able to isolate IRS-RDA markers using inbred strains of rats. Detailed protocols for the experiments were exchanged and discussed. It was noted in the discussion that phylogenetic distances among inbred strains of mice and those among inbred strains of rats could be compared by AP-PCR technique and that the plausibility of isolating IRS-RDA markers in the mouse can be estimated.
There was a consensus that the RDA-related markers have a great advantage over microsatellite markers, but that timely preparation is critical for wide use of the markers. Some scientists insisted on IRS-RDA markers using IRS other than the B1 repetitive sequence and combining primers for various IRS. However, others recommended the development of a totally new method to isolate new RDA-related markers. Dr. Housman and the exchange scientist will maintain regular contact to monitor the progress.
The exchange scientist also visited the Whitehead Institute. Information on recent progress in the rat genome project was collected, including the number of available microsatellite markers, the availability of YAC, BAC and PAC libraries, and radiation hybrid panels. The information collected will be provided in Japan.
2) Activities at NCI
The exchange scientist presented mapping of a susceptibility gene to MNNG-induced gastric cancer and new technologies in the genetic markers. Discussion on how to approach polygenic diseases was made. Technical aspects of RDA was questioned by some of the participants, and possible future consultation was established.



(4) Dai Nakae
Department of Oncological Pathology, Cancer Center, Nara Medical University

SPONSOR AND HOST INSTITUTION:
Dr. Arthur P. Grollman, Pharmacological Sciences, State University of New York at Stony Brook
DATE OF VISIT: March 6-21, 1997

SUMMARY OF ACTIVITIES:
The aim of this study was to assess the current status and problems of the investigation for involvement of oxidative DNA damage in carcinogenesis and to discuss its future strategy.
Most investigators use 8-hydroxyguanine (8-OHG) as a parameter chiefly using an electrochemical detection with a high performance liquid chromatography (HPLC-ECD). I agreed with Drs. Fung-Lung Chung (Am. Health Fnd.), Miral Dizdaroglu (Natl. Inst. Standards Tech.), Robert A. Floyd (Oklahoma Med. Res. Fnd.), Krystina Frenkel (New York Univ.) and Grollman that we will have to assess various other types of damage. Dr. Grollman and I also agreed that we have to select plural damage significant in carcinogenesis not by the transient predominance but on by the persistency and resistance against the repair. In terms of the methodology, Drs. Dizdaroglu and Grollman recommended a gas chromatography with a mass spectrometry (GC-MS) since GC-MS can determine plural damage at one time and guarantee their accuracy. Drs. Floyd and Frenkel supported HPLC-ECD because of its ease to handle and less expense. Dr. Floyd is improving HPLC-ECD for the accuracy using a new technology, CouloArray. In the future, various oxidative DNA damage should be at first assessed by HPLC-ECD in numerous institutions and then verified by GC-MS and/or CouloArray by the institutions being able to afford these machines.
An immunohistochemical technique to demonstrate the presence of 8-OHG, being developed by Dr. Regina M. Santella (Columbia Univ.), can visualize the localization of 8-OHG. My collaboration with her is making her antibody possible to use for paraffin-embedded specimens. We have to accumulate data to verify its reliability and develop similar techniques for various other oxidative DNA damage.
Dr. Chung is investigating the formation of exo-cyclic DNA adducts. My collaboration with him has revealed that these damage are not necessarily induced under conditions which induce 8-OHG. We agreed that the relationship between exo-cyclic DNA adducts and various base-altered types of oxidative DNA damage has to be further investigated.
Drs. Vilhelm A. Bohr (Natl. Inst. Aging, NIH) and Grollman are investigating in vitro the mutation pattern of a particular oxidative DNA damage and its influence on the repair system. Although we could not find a concrete strategy, yet, we agreed to look for the future integration of their in vitro and our in vivo works.
The present study gave me directions of our future works. At first, we have to assess the sources of oxidative stress and the nature of radical species in various carcinogenesis cases. Secondly, we have to assess the formation of oxidative DNA damage in relation with the other parameters such as alteration of various transcription/repair factors, signal transduction and mitochondrial functions. Thirdly, we have to accumulate the basic data for the use of oxidative DNA damage as a parameter in the molecular epidemiological works and cancer risk assessments. I would like to express my gratitude to US-Japan (NCI-JSPS) Cooperative Cancer Research Program for giving me this opportunity to meet, discuss with and make relationship with the researchers in this field in the U.S. This experience will be really beneficial for me to our future works.



(5) Masae Tatematsu
Laboratory of Pathology, Aichi Cancer Center Research Institute

SPONSOR AND HOST INSTITUTION:
(1) Prof. Satyabrata Nandi
Cancer Research Laboratory, University of California, Berkeley
(2) Prof. Gerald R. Cunha
Dept. of Anatomy, School of Medicine, University of California, San Francisco
DATES OF VISIT: March 20-29, 1997

SUMMARY OF ACTIVITIES:
Prof. Nandi was my main host scientist of this US-Japan Cooperative Cancer Research Program. I gave a seminar entitled “Monoclonal and polyclonal growth during chimeric mouse carcinogenesis demonstrated by a strain-specific antibody and microsatellite DNA polymorphism patterns” at the Cancer Research Laboratory. It is summarized as follows: The clonality of colon and forestomach epithelial proliferative lesions was immunohistochemically investigated with C3H strain specific antibody (CSA) and microsatellite DNA polymorphism patterns in C3H <—> BALB/c chimeric mice. It revealed that each crypt was entirely composed of either CSA positive of negative cells. The same pattern was found in adenomas as well as in carcinomas. This work proved the clonality of those lesions. Since Professor Nandi’s laboratory has been studying rodent mammary carcinogenesis, they were interested in utilizing the chimeric mice to analyze the clonality of mammary gland structures during normal development as well as during cancer progression. Three quarters of chimera mice have genotypes of XX<—>XY, XY<—>XX, or XY<—>XY and show the male phenotype. For efficient analysis of mammary glands and tumors, they are able to implant estrogen pellets making it possible to use not only female but also male mice to obtain stimulated mammary tissues. They will also supply techniques to induce mammary tumors using mouse mammary tumor virus (MMTV).
They have established techniques for the isolation of mammary epithelial cells (MEC) from mouse or rat mammary glands using collagenase. MEC can be embedded in collagen gel, cultured in vitro in the presence of mitogens such as epidermal growth factor, progesterone and prolactin, or lithium, and treated with the carcinogen, N-methyl-N-nitrosourea. These cells can be subsequently transplanted into mammary fatty tissue in which the epithelial region was removed (cleared mammary fat pad) to reconstitute the entire mammary gland. Furthermore, they have recently established a high titer retrovirus system using a vector with a longer packaging signal and the BOSC23 packaging cell line. Introduction of exogenous cDNAs using this system would be useful for the analysis of the effect of specific oncogenes instead of using carcinogen treatment for neoplastic transformation. We will collaborate to establish a reconstituted colon model using normal or transformed colon epithelial cells such as ones in aberrant crypts, adenoma, or cancer.
We have been collaborating with Prof. Cunha’s laboratory for the analysis of chimera mice. They have investigated urogenital organs such as the prostate gland to reveal clonality of these tissues and this collaborative work will be published in the near future.
They also developed an in vitro tissue reconstitution system utilizing immortalized prostate epithelial cell line in combination with prostate mesenchymal cells from normal, benign part of cancer bearing patient, or cancer. They clarified the importance of mesenchymal factors for the development of prostate cancer. We discussed the possibility of applying this system to our colon model and will set up a collaboration.
COMMENTS FOR THE EXCHANGE PROGRAM:
Overall, I could successfully set up collaborations with both laboratories. This program gave us extraordinary opportunities for international scientific relationships. I truly appreciate this grant and the administrative help of those involved.



(6) Takeshi Tsubata
Medical Research Institute,
Tokyo Medical and Dental University

SPONSOR AND HOST INSTITUTION:
Dr. Ronald H. Schwartz,
NIAID, NIH
DATES OF VISIT: March 23-28, 1997

SUMMARY OF ACTIVITIES:
In this study, I exchanged information with scientists in NIH and American Red Cross to better understand the molecular mechanisms of immunological tolerance. For this purpose, I gave a talk in NIH under the title of “Role of p27Kip1 in cell cycle regulation and apoptosis of B lymphocytes”. In this talk, I presented our work on B lymphocyte apoptosis induced by antigen receptor engagement and discussed the possible role of antigen receptor-mediated apoptosis of mature B lymphocytes in immunological tolerance and the role of signals that block B lymphocyte apoptosis in the course of various antibody responses. I further discussed the molecular mechanisms on antigen receptor-mediated apoptosis, especially the role of p27Kip1 and c-myc in this process.
Next, I made discussions with scientists in NIH and American Red Cross. Dr. Michael Lenardo, Dr. Luciano D’Adamio (NIAID), and Dr. Yufang Shi (American Red Cross) talked to me about antigen receptor-mediated apoptosis in T lymphocytes, and we compared antigen receptor-mediated apoptosis of T lymphocytes to that of B lymphocytes. I also got information on molecular approaches to T lymphocyte tolerance from Dr. Luciano D’Adamio, Dr. Jonathan Powell and Dr. Ronald H. Schwartz (NIAID).
As for B lymphocyte tolerance, I talked with Dr. David Scott (American Red Cross) and members of his laboratory. We discussed function of c-myc and p27Kip1 in antigen receptor-mediated B lymphocyte apoptosis, and signal transduction for apoptosis in B lymphocytes.
Recent studies have revealed that, in natural killer (NK) cells, NK receptors transmit negative signaling, which is supposed to be involved in immunological tolerance. I therefore talked with Dr. Eric Long (NIAID) and got information on signal transduction through NK receptors. Also I made discussion on related subjects such as lymphocyte differentiation and receptor signaling with Dr. B. J. Fowlkes, Dr. Warren Leonard, Dr. Lou Staudt, Dr. Hua Gu (NIAID) and Dr. Larry Samelson (NICHHD).
By these discussions, I exchanged information with scientists working on immunological tolerance in various systems. This exchange of information enhanced understanding of molecular mechanisms for immunological tolerance and left me with a numbers of suggestions to my future work on B lymphocyte tolerance.



(7)NAOKI TAKAHASHI
NARA INSTITUTE OF SCIENCE AND TECHNOLOGY

SPONSOR AND HOST INSTITUTION:
PROF. TOMAS M. JESSELL
(COLUMBIA UNIVERSITY)
DATE OF VISIT: FROM FEBRUARY 9, 1997 TO FEBRUARY 23, 1997

SUMMARY OF ACTIVITIES:
1. T. Jessell(Columbia University)
We have isolated a novel homeobox gene family Dbx in mouse, which consists of Dbx and Dbx2(Shoji et al., Mech. Dev. 56, 25-39(1996)). In the spinal cord, both Dbx and Dbx2 are expressed at the boundary of the alar and basal plates. Dr. Jessell’s group has been worked on the role of Sonic Headgehog and BMPs in the induction and patterning of ventral and dorsal meural cell types(Yamada et al., Cell 73, 673-686(1993) and Liem et al., Cell 82, 969-979(1995)). Since I and Dr. Jessell are interested in the patterning of cell types along the dorsoventral axis of the neural tube, we collaborate in the research. We discussed this collaborative research when I visited Dr. Jessell’s Lab. Dr. Jessell’s group analysed the expression patterns of Dbx and Dbx2 in the background of wild-type and Pax6 mutant mice. The expression domain of Dbx in the mutant mice was different from that in the wild-type mice. This result suggests that the Pax6 regulates Dbx gene expression in the develpping mouse spinal cord. To analyse expression patterns of the Dbx and Dbx2 genes under the influence of Headgehog and BMPs, we cloned chicken Dbx and Dbx2 genes for the explant experiments. We are making DbxlDbx2 knockout mice as a joint experiment.
2. R. Behringer(The University of Texas)
We have generated Hoxc-4 mutant mice by gene targeting(Saegusa et al., Dev. Biol. 174, 55-64(1996)). Dr. R. Behringer’s group has generated Hoxa-4, b-4 and d-4 knockout mice(Horan et al., Genes Dev. 9, 1667- 16777(1995)). To investigate the function of paralogous group 4 Hox genes in vivo, we are trying to make Hoxa-4, b-4, c-4 and d-4 knockout mice as a joint experiment. We have isolated several Hox tardeh genes by immunopurification (Tomotsune et al., Nature 365, 69-72(1993)). We are planning to analyse the expression patterns of these target genes in the background of Hox mutant mice.



(8) KYOGO ITOH, M.D.
DEPARTMENT OF IMMUNOLOGY
KURUME UNIVERSITY SCHOOL OF MEDICINE.
67 ASAHI MACHI, KURUME 830, JAPAN
TEL;81-942-31-7551. FAX;81-942-31-7699

SUBJECT OF RESEARCH :
IDENTIFICATIONOFGENES ENCODING TUMOR-REJECTION ANTIGENS AND DEVELOPMENT OF CANCER VACCINE.
PERIOD OF STAY : 12 DAYS FROM MARCH 18 TO MARCH 29, 1997.
MAIN HOST SCIENTIST :
STEVEN A ROSENBERG, M.D., PHD. CHIEF OF SURGICAL BRANCH, NATIONAL CANCER INSTITUTE, NIH, USA.

ITINERARY :
1. May 18 and 19, 1997. I visited City of Hope National Medical Center, and saw Dr. Charles. M. Balch (President) and scientists in the following list for the discussion on the current progress of tumor immunology and vaccine therapy for cancer patients; Drs. Theodore Krontiris (Chair, Molecular Metlicine), Authur Riggs (Director, Biology), Akira Yoshida (Director, Biochemical Genetics), John Rossi (Director, Molecular Biology), John Shively (Chair, Immunology), John Zaia (Director, Virology and Infectious Disease), and several other scientists. I had the lecture at the Center, and the title of the talk is “A bicistronic human gene encoding tumor-antigen shared by squamous cell carcinoma and adenocarcinoma”.
2. May 21 and 24, 1997. I visited M.D. Anderson Cancer Center and saw Dr. Margaret L Kripke (Chairman of Dep. Immunology) and the scientists at the Cancer Center for the discussion on the current progress of tumor immunology and vaccine therapy for cancer patients. The scientists I met were Drs. M. L. Kripke, H. Ananthaswamy (Professor, Immunology), I. J. Fidler (Chairman, Cell Biology), I. Ioannides (Associate Professor, Gynecology), E. Grimm (Professor, Tumor Biology), J. Roth (Chaiman, Thoracic Surgery). I also had the lecture at the M.D. Anderson Cancer Center.
3. May 26, 1997. I visited National Cancer Institute, and saw Dr. Steven A Rosenberg (Chief of the Surgical Branch), and scientists at the Branch for the discussion on the current progress of cloning of genes encoding tumor-rejection antigens and vaccine therapy for cancer patients. Main scientists I met were Drs. R. A. Rosenberg, Y. Kawakami, N.P. Restifo, F. Marancola, S. Topalian, J. C. Yang, P. Hwu, and M.I.Nishimura. I also had the lecture at the Surgical Branch.
4. May 27, 1997. I talked with Dr. David R Parkinson (ex-Chief of the CTEP, presently Research Director for Novartis USA) on the telephone with regard to the current progress of cancer therapy in USA, in particular, vaccine therapy for cancer patients.
RESULTS:
1). I could grasp the update information on the research in the field of tumor immunology. The direction of the research of tumor immunology seemed to understand molecular mechanisms underlying T cell-mediated tumor cell recognition. In particular, the identification of genes encoding tumor-rejection antigens and antigenic peptides is currently pivotal for this field. There are several new information on genes encoding melanoma rejection antigens. However, there is no new information on tumor-rejection antigens of human squamous cell carcinoma or adenocarcinoma. Therefore, our research (a new gene from squamous cell carcinoma) was highly evaluated by the scientists I met in this trip.
2). I could get the update information on the ongoing clinical trials of vaccine therapy for HLA-A2 positive melanoma patients in the Surgical Branch. Peptides (HLA-A2 binding MART-1 or gp100 peptides) seemed to be more potent than viral-vector-encoding antigens for in vivo induction of HLA-A2-restricted CTL recognizing tumor antigens. This tendency was opposite in the animal models. There were almost no clinical toxicity in the peptide vaccines. With regard to clinical responses, peptides alone (plus incomplete Freund’s adjuvant) seemed too weak to induce major tumor regression in the advanced stages of metastatic melanoma patients who had bulky tumors. This tendency was different from the vaccine trials with MAGE-3 peptide where three of 12 melanoma patients had PR (Int. J. Cancer. 1995). There were several patients who had PR in response to the peptide plus IL-2, peptide plus IL-12, or peptide plus GM-CSF. In contrast, clinical trials with viral-vector-encoding tumor antigens seemed to have no objective clinical responses. These results were the evaluation at the early phase of clinical trials, and thus needed to have more patients.
3) I also got the update information on gene therapy for cancer patients in USA. The most of gene therapies for cancer patients, altought on the way, seemed to face the several problems. One of them was a poor delivery system of the genes to cancer cells. One of the few exemption seemed the local injection of wild p53 gene into lung cancer mass directed by Dr. J. Roth at M.D.Anderson Cancer Center.
4). Except for tumor immunology, there are many excellent ongoing research projects on tumor suppressor genes, in particular p53 genes.



(9) Atsushi Kosugi
School of Allied Health Sciences, Faculty of Medicine Osaka University

SPONSOR AND HOST INSTITUTION:
Ailan M. Weissman M. D. , National Institutes of Health
DATES OF VISIT: From January 27 To February 7

SUMMARY OF ACTIVITIES
Semaphorin family members are thought to be involved in axon guidance during neural network formation. We have isolated a novel member of this family, mouse-semaphorin G (M-Sema G). M-Sema G was strongly expressed in lymphoid tissues, especially in thymus as well as in the nervous system. Our results provided the first evidence that semaphorin is expressed on lymphocytes, and suggest that semaphorin may play an important role in the immune system as well as in the nervous system. However, the functional role of M-Sema G in lymphocytes remains to be elucidated.
One of the powerful technique for investigating a role of proteins which function has not yet identified is generating a gene-targeting mice. Dr. Weissman was working on generating a gene-targeting mice of a ubiquitin protein ligase. I inspected experimental procedures and discussed with Dr. Weissman for the development of “knock-out” mice. Experimental procedures which I had learned during my stay were; (a) the analysis of genomic DNA; (b) the method for making a targeting construct; (c) the method for the culture of ES cells; (d) the screening method of ES cells transfected with a targeting construct; (e) the method for the micro-injection of ES cells into blastocysts; and (f) the method for the transplantation of blastocysts into founder mice, etc. Especially, Dr. Kuehn who is the collaborator of Dr. Weissman screened ES cells when I visited NIH, and I was able to learn the details of ES cell screening.
The knowledge and experience that I have got during my visit should contribute to our work regarding the elucidation of functional role of semaphorins in lymphocytes.



(10) Takashi TSURUO
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan.

SPONSOR AND HOST INSTITUTION:
Dr. M. Gottesman: NCI, NIH
Dr. E. Sausville: NCI, NIH
Dr. B. A. Chabner: Massachusetts General Hospital Cancer Center
Dr. R. Mayer: Dana-Farber Cancer Institute
Dr. J. Bertino: Memorial Sloan-Ketering Cancer Center
Dr. S. Larson: Memorial Sloan-Ketering Cancer Center
DATES OF VISIT:
Oct. 19-23: Dr. M. Gottesman, Dr. E. Sausville (NCI, NIH)
Oct. 24-28: Dr. B. A. Chabner (MGH Cancer Center)
Dr. R. Mayer (Dana-Farber Cancer Institute)
Oct. 29-Nov. 1: Dr. J. Bertino, Dr. S. Larson (Memorial Sloan-Ketering Cancer Center)

SUMMARY OF ACTIVITIES:
Recent advances in cancer biology have revealed various targets in cancer chemotherapy. These include oncogene products, signal transduction pathway, growth factors and receptors, transcriptinal factors, DNA replication and repair pathways, cell cycle components cytoskeletal components, drug susceptible and resistance factors, cytokines, metastasis factors, apoptosis factors and so on.
The objectives of the project this time is to exchange and discuss our recent research progresses on these molecular targets in cancer chemotherapy, especially on drug resistance factors, metastasis factors, and new antitumor agents targeting new molecular targets. The achievements of this exchange are as follows.
1. NCI, NIH
1) Dr. M. Gottesman
The information exchange and discussion on drug resistance and gene therapy were carried out. Especially valuable information exchange was carried out on the functions of P-glycoprotein as revealed by genetic site-mutation studies and by gene targeting technique.
2) Dr. Ira Pastan
The information exchange and discussion on immunotoxin and apoptosis were carried out. Especially the information related to the new CAS(cellular apoptosis susceptibility) was obtained. CAS is an interesting molecule to be examined in our system in future in Japan.
3) Dr. W. Stetler-Stevenson
The information exchange and discussion on metastasis were carried out. Inhibitors of MMP(matrix metalloprotease) can be used for metastasis inhibition.
2. Massachusetts General Hospital(MGH) and Dana-Farber Cancer Institute
Dr. B. A. Chabner(MGH) and Dr. R. Mayer(Dana-Farber)
The information exchange and discussion were carried out on drug resistance, apoptosis resistance, and new antitumor agents. The information of the analytical method of new antitumor agent was discussed. Also our future cooperation between US and Japan on the development of new antitumor agents was discussed.
3. Memorial Sloan-Kettering Cancer Center(MSKCC)
Dr. J. Bertino, Dr. S. Larson, Dr. K. Scott
The information exchange and discussion on drug resistance and it’s revesing agents, apoptosis, and nuclear imaging of drug resistance with MRK-16 were carried out. Possible clinical applications of the new Japanese MDR revesing agent and the MRK-16 in patients were discussed.
This exchange was successfully carried out in science and also in personal relationship. Several future collaborative works have ben suggested.



(11)SHIKU HIROSHI, M.D.
2nd Department of Internal Medicine
Mie University School of Medicine

SPONSOR AND HOST INSTITUTION:
LLOYD J. OLD, M.D.
Ludwig Institute for Cancer Research Director
DATES OF VISIT: from March 28, 1997 to April 13, 1997

SUMMARY OF ACTIVITIES:
In this cooperative program, I visited five distinguished institutes in the United States in order to exchange ideas on new developments of immuno-gene therapy for cancer. I visited all these five institutes as scheduled. In each institute, I have discussed various aspects of immuno-gene therapy with host and other researchers, as follows:
1) Fred Hutchison Cancer Research Center
I met Dr. Hansen and his associates in order to mainly discuss on hematopoietic stem cell transplantation for hematological malignancies. In particular, we discussed on donor lymphocyte infusion as therapy for relapsed leukemia after allogeneic bone marrow transplantation. It seems to be very enchanting and promising to establish leukemia specific CTL clones derived from donor lymphocytes. Dr. Hansen’s group has recently established a new technology which enables us to grow CTL in extremely high numbers. Here, I have had an occasion to learn technical details of establishing human CTL clones.
2) Ludwig Institute for Cancer Research
At this institute, I have had an opportunity to meet more than ten researchers, including my host researcher Dr. Old. We have, in particular, discussed the possibility of peptide vaccination of cancer patients. Early clinical trials of peptide vaccination with peptides derived from MAGE or tyrosinase genes have been ongoing in the U.S. Since we have been analyzing tumor rejection activity of HER2 derived peptides for some time, we discussed the possibility of utilizing them in the treatment of patients whose tumor present amplified expression of HER2 gene. I have also had a chance to learn technical details of SEREX - a newly developed molecular biological approach to define tumor derived molecules which are immunogenic in cancer patients.
3) Tufts University
At this university, I have discussed with Dr. Feig the possibility of developing gene therapy by targeting various molecules involved in the intracellular signal transduction pathway.
4) Pittsburgh Cancer Institute
Here, I have discussed with Dr. Lotze and his associates, in particular, the use of bone marrow derived dendritic cells in the development of powerful peptide vaccines. Since bone marrow derived dendritic cells are the best antigen presenting cells for unprimed lymphocytes, manipulation of these cells has become a central technical issue in development of cancer vaccines. In their laboratory, I was also able to learn technical details of preparation of bone marrow derived dendritic cells.
5) MD Anderson Cancer Center
At this center, Dr. Roth and his associates have been conducting clinical trials of gene therapy with a wild type p53 gene. Since we consider to perform a similar approach in Japan, the discussion with Dr. Roth and his associates on the entire procedure of gene therapy, and its clinical outcome was extremely meaningful.
To conclude, my visit to the five above mentioned institutes was enlightening and meaningful for the future development of immuno-gene therapy trials in our group, as well as giving me new opportunities to start joint studies with several institutes.



(12) Tetsuya Mitsudomi, MD
Department of Thoracic Surgery
Aichi Cancer Center Hospital
1-1 Kanokoden, Chikusa-ku, Nagoya 464, Japan

SPONSOR AND HOST INSTITUTION:
Adi F. Gazdar, MD
The W.Ray Wallace Distinguished Chair in Molecular Oncology Research,
Hamon Center for Therapeutic Oncology Research and Department of Pathology
University of Texas, Southwestern Medical Center at Dallas 5323 Harry Hines Blvd., Dallas, Texas 75235-8593, USA
DATE OF VISIT
FROM: February 9, 1997
TO: February 23, 1997

SUMMARY OF ACTIVITIES:
The US - Japan (NCI-JSPS) Cooperative Cancer Research Program for Scientist Exchange Program made it possible for me to visit four distinguished laboratories in the US.
1. Hamon Center for Therapeutic Oncology Research,
University of Texas, Southwestern Medical Center
Adi Gazdar and John Minna
The first laboratory I visited in the US was that of Dr. Gazdar, who has been studying on relationship between histopathology of solid tumor especially lung cancer and molecular genetic abnormalities, using microdissection strategy. I was able to learn the microdissection technique and multiplex PCR, which facilitated quick allelotyping of the dissected samples. It was intriguing to learn that Dr. Gazdar’s group found that loss of heterozygosity was detectable in “normal” bronchial epithelium of smokers but not of non-smokers. Dr. Gazdar proposed a collaborative study on micorsatellite analysis of lung cancer of non-smoking women and on telomerase activity of atypical adenomatous hyperplasia.
The laboratory of Dr. Minna in the same center has been concentrating on isolation of putative tumor suppressor gene on chromosome 3p. They have isolated some 30 genes from the homozygously deleted region at 3p21 in a lung cancer cell line. Mutation search were vigorously being performed. Dr. Minna proposed a collaborative study on clinical significance of this putative gene, when it is isolated.
For these two laboratories, I gave a an hour-talk entitled “Translational Research in Lung Cancer using the p53 gene as a diagnostic tool”, in which I presented our data concerning p53 gene mutation and prognosis of lung cancer, p53 gene mutation as a clonal marker of multiple primary lung cancer, and anti-p53 auto-antibody in lung cancer patients.
2. Vanderbilt Cancer Center, Vanderbilt University, Nashville, Texas David Carbone
Next, I visited Dr. Carbone’s laboratory, where they were trying to develop immunotherapy using mutated p53 gene or ras gene as a target of cytotoxic T lymphocytes (CTL). Especially, they were interested in dendritic cells (DC) for more efficient antigen presentation. I was able to learn experimental protocol for isolation of DC from cord blood and peripheral blood. Dr. Carbone’s group has recently found that vascular endothelial growth factor inhibited differentiation of DC. They were trying to prove involvement of NF-kB system in this inhibition. I presented our data concerning p53 gene mutation and prognosis of lung cancer, p53 gene mutation as a clonal marker of multiple primary lung cancer, and anti-p53 auto-antibody in lung cancer patients. The audience at VCC positively responded to the plan for p53 based adjuvant chemotherapy trial for non-small cell lung cancer.
On the last day of my visit at VCC, I was able to attend the Vanderbilt Cancer Center Affiliated Network meeting. I was impressed to see that clinical trials as well as innovative therapeutic trials were being planned or actively performed, involving neighboring affiliated hospitals.
3. Surgery Branch, NCI, Bethesda, MD
Yutaka Kawakami
Dr. Kawakami is a Research Associate of Dr. Rosenberg’s laboratory, which is one of the leading laboratory of cancer immunotherapy. I was able to talk to him on clinical trial of immunotherapy for melanoma. He also gave me a comment on strategies of immunotherpies for various cancers utilizing oncogenes or tumor suppressor gene products a tumor antigens. He criticized current enthusiasm for this approach, stating that cytotoxic lymphocytes obtained by peptide pulse tend to fail to kill original tumor cells. These comments were helpful for me to search for new direction of our laboratory.
4. Surgical Oncology, Brigham and Women’s Hospital
Timothy Eberlein
Finally I stopped by Dr. Eberlein’s laboratory at Brigham and Women’s Hospital. He and his associates were busy making CTLs from ovarian cancer patients. I could learn methods for isolating tumor cells and lymphocytes, for stimulation of T lymphocytes using solid phase anti CD3 antibody , and for assay of cytotoxicity, etc.
It was a really a fruitful tour for me, because I was able to talk to many scientists including many other reseachers not mentioned above and to exchange valuable information on cancer research. Lastly, I would like to express my sincere gratitude to this program as well as many people to whom this tour.was concerned.



(13) YOSHIO MIKI
JAPANESE FOUNDATION FOR CANCER RESEARCH

SPONSOR AND HOST INSTITUTION:
DR. MARK H. SKOLNICK
UNIVERSITY OF UTAH(USA)
DATE OF VISIT: OCTOBER 29, 1996 - NOVEMBER 14, 1996 (17 DAYS)

SUMMARY OF ACTIVITIES:
I attended the 46th Annual Meeting of American Society of Human Genetics in San Francisco in October 29 - November 2, 1996. I presented on Mutations of the BRCA1 gene in primary breast cancers. During the meeting I discussed molecular genetics of hereditary breast cancer. A plenty of reports was informative to consider application of genetic testing for hereditary breast cancer and a lot of new data on molecular genetics of breast cancer also were presented.
From November 3 - 7, 1996, I visited University of Utah and Myriad Genetics Inc., based in Salt Lake City, Utah. Myriad Genetics Inc. is a gene discovery and genetic testing company focused on the characterization and commercialization of genes involved in major common diseases, including cancer, cardiovascular disease, and metabolic and respiratory disorders. A group of Myriad Genetics scientists led the teams that discovered the complete sequences of both BRCA1 and BRCA2 genes. They offer full-sequence analysis of the BRCA1 and BRCA2 genes for susceptibility to breast and ovarian cancer. I investigated their system and policy of genetic testing. I gave a seminar entitled Mutations of BRCA1 and BRCA2 genes in Japanese breast cancer families. Our data of germline mutations of BRCA1 and BRCA2 in Japanese families were different from those in USA or Europe. I organized a joint study on hereditary breast cancer.
From October 8 - 10, 1996, I visited Kimmel Cancer Institute in Philadelphia to see research activity in molecular oncology. I saw a high activity in Dr. C. M.Croce’s laboratory. They studied leukemia to isolate responsible genes and investigate genes’ functions. They studied also solid tumors including breast cancer, prostate cancer and renal cancer.
From October 11 - 13, 1996, I visited Columbia University in New York. They studied Apoptosis in Dr. T. Sato’s laboratory. The novel protein, that binds to Fas, FAP(Fas associated protein) was isolated by Two Hybrid Method in this laboratory. I will send a researcher to Dr. Sato’s lab to learn the techniques of Two Hybrid System. Dr. R. Parsons in the Dept. of Pathology showed me the data that candidate region for breast cancer suppressor gene(s) was detected on chromosome 10 by representative difference analysis(RDA).
My activities in the meeting of American Society of Human Genetics and other three institutes were useful to learn the advances in hereditary and sporadic breast cancers. Two research projects for hereditary breast cancer and new technology were successfully organized in collaboration with Myriad and Columbia University. I greatly appreciate the US-JAPAN COOPERATIVE CANCER RESEARCH PROGRAM for my successful trip to organize the collaboration study on hereditary breast cancer.
Publication
1) Katagiri, T., Nakamura, Y. and Miki, Y. Frequent missense mutations of BRCA1 and BRCA2 genes in Japanese breast cancer families. (submitted)




(14) Masahiro Kihara, M.D., Ph.D.
Department of Epidemiology, Kanagawa Cancer Center research Institute
1-1-2 Nakao, Asahiku, Yokohama 241

SPONSOR AND HOST INSTITUTION:
John.K.Wiencke, Ph.D.
Associate Professor, Director, Laboratory for Molecular Epidemiology,
Dept. of Epidemiology and Biostatistics, School of Medicine
University of California, San Francisco
MU-420 West, Box0560, School ofMedicine, UCSF, San Francisco, CA94143-0560, USA
DATE OF VISIT: February 4, 1997 to February 24, 1997

SUMMARY OF ACTIVITIES:
(1) Seminars
I held seminars upon request as follwos;
Title: “CYP1A1 and GSTM1 gene polymorphisms and the susceptibility to smoking related cancers in Japanese”
Place: Genetic Epidemiology Branch(Dr.Caporaso), National Cancer Institute(NCI), Rockville
Lab. of Human Carcinogenesis(Dr.Shields), NCI, Bethesda
Lab. of Biochemical Cancer Risk(Dr.Bell), National Institute of Environmental Health Science, Research Triangle
(2)Symposium
I attended the following symposium and learned the most advance topics in molecular epidemilogy of cancer;
“Molecular advances in cancer epidemiology and prevention”
Program chair: Dr.J.K.Wiencke,
Date/Place: Feb.20-22, San Francisco
Program:
1)From basic Research to Cancer Prevention(D.Sidransky)
2)Epidemiology of prostate cancer and PSA testing(A.S.Whittemore)
3)Molecular epidemiology of papilloma virus and cervical cancer (M.Manos)
4)p53 gene alterations and cancer etiology(J.A.Taylor)
5)p53 gene alterations: Correlations with survival and therapeutic response (K.T.Kelsey)
6)Epidemiology of ductal in situ carcinoma of the breast(V.L.Ernster)
7)Molecular analysis of pre-malignant breast disease(J.Simpson)
8)Genetic markers and screening in familial colon cancer(N.W.Toribara)
9)Genetic markers of susceptibility to breast cancer(D.J.Hunter)
10)Emerging technologies for genetic analysis: Applications of the GeneChip System to the p53 gene(S.Dee)
11)Genetic testing for cancer risk:clinical and ethical considerations (P . R. Billings)
12)Methodologic issues in biomarkers studies of gene-environment interactions (R.C.Millikans)
13)Lung cancer and polymorphisms of genes encoding carcinogen-metabolizing enzymes(S.J.London)
14)Molecular markers in occupational epidemiology and leukemia (N.Rothman)
(3)Record of laboratory visits
National Cancer Institute: At Genetic Epidemiology Branch, I discussed with Dr.Caporaso and his colleagues. Of particular interest was to find that we were sharing the similar findings that some drug-metabolizing enzyme gene polymorphisms may affect the smoking behavior as well as the susceptibility to cancer. It was very encouraging to hear that Japan has a great advantage in the research of molecular epidemiology since Japanese population is genetically homogenous compared to US where people are genetically mixed up. It was also very stimulating to be able to touch the topic of diet and genetic susceptibility which will become a new field for epidemiology of chronic diseases. Potential future cooperation was discussed. At the Lab. of Human Carcinogenesis, Dr.Shields and his colleagues explaned me a recent progress in p53 research as well as the technical aspect of DNA adduct measurement. Also explained was a outline of prospective Tamoxifen study to evaluate its potential carcinogenic activity.
National Institute of Environmental Health Science: At the Laboratory of Biochemical Risk Analysis, Dr.Bell explained their recent work on the relationship between colon and bladder cancers and genetic polymorphisms of GST and NAT(N-acetyl transferase), Detailed technical protocol for PCR determination of GST Pi polymorphism was kindly provided by Dr.Bell. We also met with Dr.J.A.Taylor, epidemiologist, he explained his work on the ethnic variations in the p53 mutation profile. It was very interesting that its profile is different between whites and blacks, which suggested the carcinogenic pathways potentially diverse by ethnic groups. Future cooperation on this topic was discussed.
Cincinnati University: At the Department of Environmental Medicine, I communicated Dr.Nebert, a world specialist for cytochrome P450s research, with our recent findings on the relationships of CYP1A1 and GSTM1 gene polymorphisms with lung and bladder cancers. He suggested a potential link of CYP1A1 polymorphism with other CYP genes, which could be a potential topic in our future research.
National Institute for Occupational Safety and Health: Dr.Shulte and his colleagues explained methodological issues of molecular epidemiology such as design and quality control as well as its potential social and ethical impacts.
California University San Francisco: Dr.Wiencke explained his previous works on in vitro cellular response to carcinogens using human lymphocytes and their ongoing study on genetic-environmental interactions in population-based studies. Discussions at the occasion of the symposium “Molecular advances in cancer epidemiology and prevention” was most fruitful.