https://cancerbiologyprogram.med.wayne.edu/pdfs/hallmarks_cancer_article.pdf

Hallmarks of cancer: the next generation.

The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.

/pdf/apoptosis-a-review-of-programmed-cell-death-ly0ozrc0t6.pdf

Apoptosis: A Review of Programmed Cell Death

The terminus of a DNA helix has been called its Achilles' heel. Thus to prevent possible incomplete replication and instability of the termini of linear DNA, eukaryotic chromosomes end in characteristic repetitive DNA sequences within specialized structures called telomeres. In immortal cells, loss of telomeric DNA due to degradation or incomplete replication is apparently balanced by telomere elongation, which may involve de novo synthesis of additional repeats by novel DNA polymerase called telomerase. Such a polymerase has been recently detected in HeLa cells. It has been proposed that the finite doubling capacity of normal mammalian cells is due to a loss of telomeric DNA and eventual deletion of essential sequences. In yeast, the est1 mutation causes gradual loss of telomeric DNA and eventual cell death mimicking senescence in higher eukaryotic cells. Here, we show that the amount and length of telomeric DNA in human fibroblasts does in fact decrease as a function of serial passage during ageing in vitro and possibly in vivo. It is not known whether this loss of DNA has a causal role in senescence.

Telomeres shorten during ageing of human fibroblasts.

Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger gamma-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.

Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase

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

It is often thought that unrepaired or misrepaired complex DNA double‐strand breaks are responsible for cell inactivation and chromosomal aberrations. Here the role of inner‐shell (core) ionizations in DNA atoms is studied. Ultrasoft X‐rays from LURE synchrotron radiation have been used to produce core events which mimic the ones induced by ionizing radiations. By tuning the X‐ray energy below and above the carbon K‐threshold, it is possible to achieve a two‐fold increase of the number of core‐ionizations in DNA for a same dose in cell. Cell survival, DNA double‐strand breaks and chromosomal aberrations have thus been studied, at three energies iso‐attenuated in biological samples:∼ 250, 350 and 800 eV. The relative biological efficiencies of a given dose in cells to induce cell inactivation and chromosome aberrations appear governed by the yields of core events in DNA. On the other hand, the lethal and DNA‐breaking efficiencies of core events in DNA appear strongly correlated.

DNA Breaks, Chromosomal Aberrations And Cell Inactivation Induced By K Ionization Events In DNA

The purpose of RISC RAD integrated project, funded by the European Commission (FP6), is to provide fundamental scientific information needed to test the key assumptions of current radiation protection standards. A key foundation to the project strategy is the knowledge that ionising radiation (at least at high doses) causes genetic damage in somatic cells and that certain of these genetic changes are causally related to the development of cancer. Consortium members believe that a sound understanding of the mechanisms and processes that drive spontaneous and radiation-induced carcinogenesis is needed to understand and quantify radiation cancer risk at low doses (≤100 mSv),. New genes involved in radiosensitivity have been identified. Significant results have been obtained concerning the specific structure of radiation-induced DNA damage ; the processing of complex DSBs by specific proteins like the Artemis endonuclease ; the dose dependence of IR-induced DNA damage response (chromosome aberrations, cell cycle checkpoints, transcriptome and stress response, apoptosis, senescence and emergence, telomere related genome instability) ; the telomeres as sites of DNA repair gene sequestration and drivers of phenomena such as gene amplification, non reciprocal translocations and LOH ; the impact of genetic variation in nonhomologous end joining processes may on the in vivo radiation response of mice ; the development of a number of (transgenic) animal models to provide experimental evidence for genetic risk factors ; the identification of five specific radiation cancer systems for experimentation in the mouse: osteosarcoma, skin basal cell carcinoma, intestinal adenoma, medulloblastoma and myeloid leukaemia. Moreover it has been demonstrated that carcinogenesis can be induced in tissue at distance from the radiation. It is encouraging that within RISC-RAD experimentalists and mathematical modellers are developing close working relationships, particularly for multi-step cancer modelling and for detailed biophysical modelling of chromosome aberration formation after irradiation

/pdf/risc-rad-radiosensitivity-of-individuals-and-susceptibility-4ezkdeq8uk.pdf

RISC-RAD Radiosensitivity of Individuals and Susceptibility to Cancer induced by Ionizing Radiations

Summary R-banded karyotypes were established on fibroblasts from fibrotic tissues derived from experimental fibrosis induced in pigs, either surgically or by 64 Gy of y-rays from iridium-192. No chromosome aberrations were observed in the surgical fibrosis. In radiation-induced fibrosis, the high frequency of abnormal karyotypes and the frequent complexity of the chromosomal rearrangements suggest that the fibroblasts originated either from the 64-Gy area, or from the penumbra, but certainly not from non-irradiated areas. At early passages in vitro, almost all karyotypes were different, demonstrating a multiclonal origin of fibrotic tissue. At late passages (above 24), the situation was quite different, with the persistence of one or two clones only, demonstrating a strong selective pressure occurring in vitro.

Chromosomal anomalies in radiation-induce d fibrosis in the pig

http://rpd.oxfordjournals.org/content/39/1-3/7.full.pdf

Laure Sabatier

Papers

DNA Breaks, Chromosomal Aberrations And Cell Inactivation Induced By K Ionization Events In DNA

RISC-RAD Radiosensitivity of Individuals and Susceptibility to Cancer induced by Ionizing Radiations

Chromosomal anomalies in radiation-induce d fibrosis in the pig

Deterministic Late Effects of Skin Irradiation: In Vitro Studies of Experimental Radiation Fibrosis

European low dose risk research strategy