NOTE The report of the Committee without its annexes appears as Official Records of the General Assembly, Sixty-third Session, Supplement No. 46. The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. The country names used in this document are, in most cases, those that were in use at the time the data were collected or the text prepared. In other cases, however, the names have been updated, where this was possible and appropriate, to reflect political changes. Scientific Annexes Annex A. Medical radiation exposures Annex B. Exposures of the public and workers from various sources of radiation INTROdUCTION 1. In the course of the research and development for and the application of atomic energy and nuclear technologies, a number of radiation accidents have occurred. Some of these accidents have resulted in significant health effects and occasionally in fatal outcomes. The application of technologies that make use of radiation is increasingly widespread around the world. Millions of people have occupations related to the use of radiation, and hundreds of millions of individuals benefit from these uses. Facilities using intense radiation sources for energy production and for purposes such as radiotherapy, sterilization of products, preservation of foodstuffs and gamma radiography require special care in the design and operation of equipment to avoid radiation injury to workers or to the public. Experience has shown that such technology is generally used safely, but on occasion controls have been circumvented and serious radiation accidents have ensued. 2. Reviews of radiation exposures from accidents have been presented in previous UNSCEAR reports. The last report containing an exclusive chapter on exposures from accidents was the UNSCEAR 1993 Report [U6]. 3. This annex is aimed at providing a sound basis for conclusions regarding the number of significant radiation accidents that have occurred, the corresponding levels of radiation exposures and numbers of deaths and injuries, and the general trends for various practices. Its conclusions are to be seen in the context of the Committee's overall evaluations of the levels and effects of exposure to ionizing radiation. 4. The Committee's evaluations of public, occupational and medical diagnostic exposures are mostly concerned with chronic exposures of …

sources and effects of ionizing radiation

During malignant transformation, cancer cells acquire genetic mutations that override the normal mechanisms controlling cellular proliferation. Primary rodent cells are efficiently converted into tumorigenic cells by the coexpression of cooperating oncogenes1,2. However, similar experiments with human cells have consistently failed to yield tumorigenic transformants3,4,5, indicating a fundamental difference in the biology of human and rodent cells. The few reported successes in the creation of human tumour cells have depended on the use of chemical or physical agents to achieve immortalization6, the selection of rare, spontaneously arising immortalized cells7,8,9,10, or the use of an entire viral genome11. We show here that the ectopic expression of the telomerase catalytic subunit (hTERT)12 in combination with two oncogenes (the simian virus 40 large-T oncoprotein and an oncogenic allele of H-ras) results in direct tumorigenic conversion of normal human epithelial and fibroblast cells. These results demonstrate that disruption of the intracellular pathways regulated by large-T, oncogenic ras and telomerase suffices to create a human tumor cell.

Creation of human tumour cells with defined genetic elements

http://www.columbia.edu/itc/biology/pollack/w4065/client_edit/readings/9912a.pdf

Clonally Derived Human Embryonic Stem Cell Lines Maintain Pluripotency and Proliferative Potential for Prolonged Periods of Culture

A number of genetic mutations have been identified in human breast cancers, yet the specific combinations of mutations required in concert to form breast carcinoma cells remain unknown. One approach to identifying the genetic and biochemical alterations required for this process involves the transformation of primary human mammary epithelial cells (HMECs) to carcinoma cells through the introduction of specific genes. Here we show that introduction of three genes encoding the SV40 large-T antigen, the telomerase catalytic subunit, and an H-Ras oncoprotein into primary HMECs results in cells that form tumors when transplanted subcutaneously or into the mammary glands of immunocompromised mice. The tumorigenicity of these transformed cells was dependent on the level of ras oncogene expression. Interestingly, transformation of HMECs but not two other human cell types was associated with amplifications of the c-myc oncogene, which occurred during the in vitro growth of the cells. Tumors derived from the transformed HMECs were poorly differentiated carcinomas that infiltrated through adjacent tissue. When these cells were injected subcutaneously, tumors formed in only half of the injections and with an average latency of 7.5 weeks. Mixing the epithelial tumor cells with Matrigel or primary human mammary fibroblasts substantially increased the efficiency of tumor formation and decreased the latency of tumor formation, demonstrating a significant influence of the stromal microenvironment on tumorigenicity. Thus, these observations establish an experimental system for elucidating both the genetic and cell biological requirements for the development of breast cancer.

http://genesdev.cshlp.org/content/15/1/50.full.pdf

Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells

Molecular Biology of Aging

Expression of the human telomerase catalytic component, hTERT, in normal human somatic cells can reconstitute telomerase activity and extend their replicative lifespan We report here that at twice the normal number of population doublings, telomerase-expressing human skin fibroblasts (BJ-hTERT) and retinal pigment epithelial cells (RPE-hTERT) retain normal growth control in response to serum deprivation, high cell density, G1 or G2 phase blockers and spindle inhibitors In addition, we observed no cell growth in soft agar and detected no tumour formation in vivo Thus, we find that telomerase expression in normal cells does not appear to induce changes associated with a malignant phenotype

Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype

It has been discovered that increasing telomerase activity in cells surrounding a wound has a variety of effects that enhance wound healing. Replication capacity is enhanced, and the mobility of the epithelial cells can be increased by 3-fold or more. Some aspects of the invention relate to agents that increase telomerase activity in cells at the site of the wound, promoting cells to move to the site and restore an epithelial layer and the underlying stratum. Other aspects of the invention relate to compositions comprising epithelial cells in which telomerase activity has been increased, useful as grafts for the treatment of wounds.

Treatment for wounds

Overexpression of telomerase reverse transcriptase (hTERT) can immortalize some primary human mesenchymal cells. We investigated whether retrovirally-mediated expression of hTERT in CD34+ umbilical cord blood (UCB) cells can extend the replicative lifespan of human hematopoietic progenitor cells. Overexpression of hTERT did not immortalize these cells but did lead to enhanced survival of mature hematopoietic cells.

Enhanced long-term survival, but no increase in replicative capacity, following retroviral transduction of human cord blood CD34+ cells with human telomerase reverse transcriptase.

On a constate que l'augmentation de l'activite de la telomerase dans les cellules situees autour d'une blessure induisait une variete d'effets ameliorant la guerison de la blessure. Par l'augmentation de cette activite, on ameliore la capacite de replication; en outre, la mobilite des cellules epitheliales peut etre multipliee par trois ou plus. Selon certains aspects, l'invention concerne des agents qui augmentent l'activite de la telomerase dans les cellules situees sur le site de la blessure, incitant les cellules a se deplacer vers le site proprement dit et a retablir a la fois une couche epitheliale et la couche sous-jacente. Selon d'autres aspects, l'invention concerne des compositions qui renferment des cellules epitheliales dans lesquelles l'activite de la telomerase a ete augmentee: lesdites compositions sont utiles comme greffes pour le traitement des blessures.

Xu-Rong Jiang

Papers

Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype

Treatment for wounds

Enhanced long-term survival, but no increase in replicative capacity, following retroviral transduction of human cord blood CD34+ cells with human telomerase reverse transcriptase.

Traitement pour blessures