SUMMARY REPORTS OF EXCHANGE SCIENTISTS

(1) Yukiko Tsunematsu, M.D.
National Children's Hospital, Chief of Hemato-Oncology

Sponsors and Host Institutions:
Louise C. Strong, M.D.
Sue and Radcliffe Killam Professor
Department of Experimental Pediatrics/Genetics
M.D. Anderson Cancer Center
Anna T. Meadows, M.D.
Professor of Pediatrics
University of Pennsylvania School of Medicine
Department of Oncology
The Children's Hospital of Philadelphia
Dates of Visit: January 16, 1989 - February 19, 1989

Summary of Activities
My main objective was to learn methods of genetic cancer epidemiology in the United States. In Japan systematic study of genetic epidemiology has not been carried out yet. First of all, I wanted to learn how to get information and materials from patients or their family members systematically. This objective was achieved by seeing activities of four institutes in the United States.
I would like to point out major differences in getting medical information in Japan as compared with the U.S.A.
1. The problem of informed consent: In the U.S. the first step in getting information from patients is to tell the patients the diagnosis and to obtain a consent to cooperate in clinical studies including family studies. Patients and their families are required to give their information not only when they are at the hospital, but also after their discharge and by the family after death. In Japan it is still not common to tell the patients with cancer the truth. Therefore, it is very difficult to establish a complete follow-up system.
2. The management of medical records: It is essential to establish a complete management system of case records to get information about the patient. Many Japanese hospitals including the National Children's Hospital, still do not have any personnel who take care of medical case records, so that researchers cannot see the charts which are considered to belong to the attending physicians. Therefore a large clinical epidemiological study cannot be carried out under these circumstances.
3. Problems of research collaboration and office assistants: Epidemiologic studies require preparation of protocols, getting funds and such co-workers as clinicians, biostatisticians and basic scientists. Also needed are professional assistants such as interviewers, nurse-practitioners, computer scientists, and medical secretaries. Recently many childhood cancers have been cured. Now the total care system has been established in children's cancer hospitals in which various specialists besides doctors work together; e.g., nurse-practitioners, psychologists, social case-workers, and educational staff. This team works to achieve a better quality of life for patients. In Japan there are very few hospital epidemiologists, and they cannot easily work together because most hospital clinicians have their patients' clinical data personally and want to study clinical epidemiology themselves. Besides, in Japan there is no postgraduate educational programs for specialty nurses training and there is no custom of giving information to trained interviewers by telephone.
At M.D. Anderson Hospital, Dr. Strong and I talked about the possibility of collaboration on a study concerning genetic cell biology of Li-Fraumeni syndrome: to send materials to individuals in affected large Japanese families. We also discussed my data of multiple primary childhood cancer which is considered to occur through the genetic mechanism of loss of heterozygosity. She suggested possibilities for an epidemiological study employing a person-years method for evaluating second malignant tumors in patients with retinoblastoma which have been registered for more than 20 years in Japan.
In the Children's Hospital of Philadelphia, I observed clinical activities and epidemiological studies. I met various persons who work in the Greater Delaware Valley Childhood Cancer Registry, the largest childhood cancer registry in the world. I was very impressed by the educational activities for the young adults who survived childhood cancer.
ANSWERS TO QUESTIONS
1. Has the program assisted you in achieving your research objectives?
Yes it did. I cannot find any suitable word except "seeing is believing" to explain how this program assisted me. I have learned of large differences between the United States and Japan in medical customs and resources pertaining to genetic epidemiology, as mentioned above.
2. How could progress in your research effort be enhanced through this program?
I was encouraged by having the opportunity to discuss difficulties of family studies in Japan with several researchers. I have decided to continue our studies and to make an effort to improve the management system for case records in our hospital as an example.
3. Do you plan to continue your collaboration?
Yes, I do. I would like to continue to collaborate in genetic epidemiological studies with Drs. Strong, Miller and Li, and for study of late effects after treatment with Dr. Anna Meadows.
4. How do you feel your efforts have contributed to the progress of the NCI-JSPS Cancer Program?
In Japan there are very few researchers who study familial cancer systematically. American researchers did not know that in Japan it is very difficult for epidemiologists to get information from hospital records and patients after discharge and that there are many differences in the doctor-patient relationship between the United States and Japan. I feel this visit contributed to a better understanding of fundamental problems of studying genetic epidemiology in Japan.



(2)Kazuyoshi Yanagihara
Research Institute for Nuclear Medicine and Biology, Hiroshima, University

Sponsor and Host Institution:
Robert H. Bassin, Ph.D.
Biochemistry of Oncogenes Section, LTIB, NCI, NIH
Dates of Visit: July 1, 1988 - August 9, 1988 (40 days)

Summary of Activities:
Our previous studies on the mechanism of transformation by retroviral oncogenes have indicated that there are fundamental differences in monovalent cation amino acid transport in NIH/3T3 cells and other cell lines following transformation by the oncogene ras (Cancer Res., 48, 2483-2491, 1988). These differences are "corrected" in flat revertant cells that resist transformation by ras and certain other oncogenes. The proline analog 4-Cis-hydroxyproline (CHP) is less toxic for normal cells than for transformed (revertant) cells from populations of ras transformed cells.
Morphologic flay revertants of Kirsten murine sarcoma virus (Ki-MuSV)-transformed NIH/3T3 cells were isolated using CHP as a selective agent that preferentially kills transformed cells. These revertants, which appear to be cellular variants resistant to transformation by the Ki-MuSV oncogene (V-Ki-ras), contain Ki-MuSV-specific DNA, elevated levels of the V-Ki-ras gene product p21, and rescuable transforming virus. Somatic cell hybridization studies indicated that the revertant phenotype is dominant in hybrids between revertant cells and transformed cells by Ki-MuSV or the closely related Harvey MuSV and BALB MuSV. These revertants were also resistant to retransformation by v-Ha-ras, bas, v-mos, v-raf, v-fos, but could be retransformed by the v-src, v-abl, v-fgr, v-fas, v-fms and v-sis. This differential sensitivity of the revertants to retransformation by various oncogenes suggests the existence of a limited number of biochemical pathways for transformation.
These revertants may be useful for detecting relationships among oncogenes, for identifying and classifying oncogenes, for isolating the anti-oncogene(s), and for characterizing the cellular constituents with which the products of oncogenes interact.
Publications:
YANAGIHARA, K., and BASSIN, R.H.: Isolation of new class of revertants from ras-transformed NIH/3T3 cells using 4-Cis-hydroxyproline as the selective agent. (preparation of manuscript)
1. I was very pleased to have the support of the NCI-JSPS cooperative cancer research program for our collaborative work.
2. We confirmed several preliminary experimental results. Moreover, we isolated two new classes of cellular revertants from transformed cells by v-Ki-ras. We will continue our collaboration.
3. The isolation of a collection of revertants from cells transformed by different oncogenes constitutes a potentially valuable approach to identify cellular pathways of transformation, to define points at which various oncogenes activate these pathways, to establish a functional relationship among oncogenes, and to dissect the mechanisms of cell transformation. Therefore, we have isolated a new class of cellular revertants from a population of ras-transformed cells. We believe that it is useful model for analysis of mechanisms of retroviral transformation.



(3) Shigeru Tsuiki
Research Institute for Tuberculosis and Cancer
Tohoku University
Sendai 980, Japan

Sponsor and Host Institution:
Dr. Joseph Larner
Professor and Chairman of Pharmacology
University of Virginia School of Medicine
Charlottesville, Virginia 22908
Dates of Visit: November 12-25, 1988
Itinerary:
From November 12, 1988 to November 17, 1988:
Department of Pharmacology
University of Virginia School of Medicine
Charlottesville, Virginia 22908
From November 17, 1988 to November 20, 1988: Department of Nutrition Science University of Alabama at Birmingham Birmingham, Alabama 35294
From November 20, 1988 to November 23, 1988:
The Wistar Institute of Anatomy and Biology
36th Street at Spruce
Philadelphia, Pennsylvania 19104-4268

Summary of Activities
I first visited the University of Virginia School of Medicine, where I talked mainly with Drs. J. Larner and K. R. Lynch about cDNA cloning of protein phosphatase IA (2C). This is the research project we have been working on together. We also talked of readying our manuscript for publication. (This paper, entitled "Molecular cloning of rat type 2C 91A) protein phosphatase mRNA" has been published recently in Proc. Natl. Acad. Sci. USA [vol. 86, pp. 1796-1800, 1989].)
On November 14, I gave a lecture at the University of Virginia on my work on protein phosphatases and cancer. The seminar was jointly sponsored by the Diabetic Research Center and the Cancer Center of the University. In that lecture, I stressed the vital importance of protein phosphatase as an anti-cancer agent since many of the known oncogenes encode protein kinases. My conclusion was that one serine protein phosphatase, phosphatase IA and one tyrosine protein phosphatase, PtPP-3, appear to counteract cellular oncogenes, raf and src, respectively, which play a critical role in hepatocarcinogenesis.
The remaining time at the University of Virginia was mostly spent in discussing with Dr. Larner future plans for cooperative studies on protein phosphatases. I also talked with Drs. M. Weber and S. Persons on p60^src and its monoclonal antibody, and with L. Huang on insulin mediator. Dr. T. Sturgill and I considered the possibility of working together to study tyrosine protein phosphatases.
During my stay in Virginia, I visited NIH and discussed with people there the methodology of studying cancer metastases biochemically.
Next, I went to Birmingham. Alabama, where I spent three days as a guest of Professor Tunenobu Tamura. There I visited the Department of Nutrition Sciences, University of Alabama, and consulted with Dr. Tamura on his work as to how malnutrition influences the efficiency of hepatocarcinogenesis. The rate of tyrosine protein phosphorylation may be useful as an indicator of the efficiency.
I next flew to Philadelphia, Pennsylvania, and visited the Wistar Institute, where Professor Leonard Warren was the host scientist. I talked with him about neoplastic alterations of cell membranes and also the possibility of alterations of protein phosphorylation being involved in membrane alterations. As Dr. Warren is the man who first found hypersialylation in cancer cell membranes, the behavior of sialic acid upon cancer was the major topic of our discussion. At the Institute, I gave a lecture entitled "Rat liver sialyltransferases and sialidases and their neoplastic alterations". In that lecture, I introduced our finding that rat tissues contain at least four types of sialidase, which differ from one another in subcellular distribution and substrate specificity and probably in function. I then moved to our more recent finding that upon hepatocarcinogenesis, sialyltransferases and sialidases are altered so as to induce hypersialylation.
In Philadelphia, I also visited Children's Hospital of Philadelphia to meet with Dr. Mary Catherine Glick, who has been working on the relation of sialyltransferase activity and oncogene expression in NIH 3T3 cells. I also talked with Dr. Stephan Roth, Pennsylvania University School of Science, about neoplastic alterations of glycosyltransferases in general.
General Comments and Conclusion:
Scientifically, it was a truly memorable trip. I obtained many new friends and valuable information, and these are certainly profitable for further extension of our studies on protein phosphatases and cancer. In conclusion, I would like to sincerely thank the Japan Society for the Promotion of Science for permitting me to make this valuable trip.