Hermann J. Muller (1890–1967)
Krishna Dronamraju in A Century of Geneticists, 2018
With Julian Huxley’s help, Muller obtained a temporary position at the Institute for Animal Genetics at Edinburgh University. He was then 50 years old. Muller attracted several students during that period, including some who became well-known geneticists in their own right, such as Charlotte Auerbach, Guido Pontecorvo, and S.P. Ray Chaudhury. With Pontecorvo, Muller worked out the breakage–fusion–bridge cycle (dicentric chromosome formation), independently of Barbara McClintock, and used it to explain the curious dominant lethals he had observed in large numbers since his X-ray work in 1927. The dicentric chromosomes led to cell death and aborted embryos (Pontecorvo and Muller 1942). With his student S.P. Ray Chaudhury, Muller extended his radiation studies to chronic and acute doses. Another finding was that, for gene mutations, it made no difference whether a dose of 400 R was administered in a few minutes or drawn out over a month-long period. In either case, the mutation rate was the same, confirming Muller’s belief that gene mutations were punctiform events (Muller and Chaudhury 1939). The same observation got him embroiled in a dispute with British radiologists who considered it inappropriate it to extrapolate from flies to humans and that Muller’s view might unnecessarily alarm the public about the uses of radiation.
A Brief Review of Cancer
C.S. Sureka, C. Armpilia in Radiation Biology for Medical Physicists, 2017
Aberrant activation of CDKs, regulatory proteins, and p53 proteins (>50%) leads to irregularities in the cell cycle. Further, activation of telomerase (~90% contribution) triggers the cell to achieve an infinite life (referred to as immortalization). This also happens when the cell repairs its dicentric chromosome using a non-homologous end-joining mechanism (discussed in Chapter 3). Hence, a normal cell is transformed into a malignant cell due to its irregular cell cycle, failure in apoptosis, and cell immortalization.
Cell death after irradiation: How, when and why cells die
Michael C. Joiner, Albert J. van der Kogel in Basic Clinical Radiobiology, 2018
Why does irradiation cause proliferating cells to undergo mitotic catastrophe and cell death? This appears to result from the fact that although DDR pathways remove much of the initial damage caused by irradiation, they are unable to prevent some cells with DNA breaks or DNA rearrangements from entering mitosis. The consequences of incomplete or improper DNA repair become readily visible as chromosomes condense in metaphase as a series of different types of chromosome aberrations. The fate of cells harbouring chromosome aberrations is largely determined by the nature of the chromosome aberration itself (Figure 3.3) (1). Studies have demonstrated approximately equal numbers of reciprocal translocations and non-reciprocal translocations (a dicentric chromosome + acentric fragment) are formed after irradiation. Both of these types of aberrations result from misrepair in which chromosome ends are incorrectly ligated together in a largely stochastic process. However, whereas cells with dicentrics and acentric fragments all die, those with reciprocal translocations often survive. The presence of two centromeres in dicentric chromosomes prevents their separation at metaphase, and consequently leads to mitotic catastrophe and eventually cell death. Some cells with dicentric chromosomes may manage to complete mitosis, however, loss of genetic material present in the acentric fragment (which forms a ‘micronuclei’) in subsequent mitosis may lead to subsequent death at a later time. This explains the good correlation which has been observed between the formation of dicentric chromosomes or micronuclei formation and cell survival. Reciprocal translocations do not cause problems at metaphase, and thus do not cause mitotic catastrophe or cell death. In fact, these types of aberrations can be found in cells from people exposed to irradiation many years later.
Construction and evaluation of an α-particle-irradiation exposure apparatus
Published in International Journal of Radiation Biology, 2021
Zacharenia Nikitaki, Evangelia Choulilitsa, Spyridon A. Kalospyros, Sofia Kaisaridi, Georgia I. Terzoudi, Mike Kokkoris, Alexandros G. Georgakilas
The dicentric chromosome is the aberration type that is most frequently used in biological dosimetry. Dicentric chromosome is called an aberrant chromosome bearing two centromeres derived from the misrepair of two broken chromosomes (IAEA 2011). The International Organization for Standardization (ISO), in 2004, accepted the Dicentric Chromosome Analysis (DCA) as an International Standard for laboratories performing radiation biological dosimetry by cytogenetics. The DCA technique is particularly useful when it comes to the evaluation of cases of suspected or verified radiation exposure as well as for dose estimation in the absence of physical dosimetry (IOfS 2004). Although radiation induces many types of chromosomal changes in addition to dicentric chromosomes, dicentric analysis is considered the “gold standard” for assessing radiation dose. Finally, this analysis is both specific and sensitive to radiation exposure even at low doses. Dicentric analysis has been performed by McNally et al to compare α-particle irradiation with X-rays, concluding that their levels are proved to be similar to that of 6 Gy for X-rays, 24 h upon irradiation with 2 Gy of alpha particles – (Manti 1997).
Reexamining the role of tissue inflammation in radiation carcinogenesis: a hypothesis to explain an earlier onset of cancer
Published in International Journal of Radiation Biology, 2021
Cells bearing unstable-type chromosome aberrations would remain quiescent and may not affect the microenvironment until they undergo their first post-exposure mitosis where a dicentric chromosome causes a mechanical problem during the separation of the two daughter nuclei by forming an inter-nucleus chromosome bridge, which may lead to either cell death or polyploidization. Likewise, cells bearing an acentric chromosome fragment may result in a release of free chromatin or DNA (uncoated with nuclear membrane) into the cytoplasm after a cell division, which triggers the activation of IFN-I, MAPK, and NF-κB (Emming and Schroder 2019), or may be detected by the cGAS (cyclic GMP-AMP synthetase)-STING (stimulator of interferon genes) system, which leads to an induction of inflammatory responses (Dou et al. 2017; Emming and Schroder 2019).
Evaluation of the premature chromosome condensation scoring protocol after proton and X-ray irradiation of human peripheral blood lymphocytes at high doses range
Published in International Journal of Radiation Biology, 2018
K. Rawojć, J. Miszczyk, A. Możdżeń, J. Swakoń, A. Sowa-Staszczak
The number of PCC cells in different cells stage scored during the analysis of the excess fragments in high dose range is still under investigation. The number differs within the published results: some authors present 1076 G2/M scoring for non-irradiated cells and 259 for cells exposed to 20.0 Gy (Wang et al. 2009), while others report using a constant number of 100 cells for each applied dose (Romero et al. 2013). Flegal et al. proposed another approach of a semi-automated dicentric chromosome scoring by using QuickScan Device. Authors showed that their approach may be appropriate in dose estimating with a sensitivity of 0.1 Gy. Flegal et al. showed that instead of scoring 1,000 metaphases, only 200 metaphase cells might be analyzed (Flegal et al. 2012). However, in case of high doses exposure (as presented in our study 5.0–20.0 Gy) PCC assay is a method of choice. Due to the cells inability to reach mitosis, the DCA is typically used to assess doses lower than 4.0 Gy.
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