Cell inactivation by ionizing particles and the shapes of survival curves

Recent experiments concerning the survival of monolayer cells irradiated by different parts of ion Bragg peaks opened a way to a deeper mechanistic understanding of cell inactivation. A new theoretical formula for survival curves has been derived reflecting two basic phases of the given mechanism, i.e. energy transfer to a cell nucleus and subsequent biological effect (depending on the amount of imparted energy). The survival ratio for a given dose has been expressed as a function of inactivation probabilities of individual cells after different numbers of nucleus hits (a given amount of energy being transferred to a cell nucleus in each ion traversal). Having used the experimental data for V79 cells irradiated by protons, deuterons and helium ions in different parts of Bragg peaks preliminary values of these inactivation probabilities for individual cells at different LET values have been established.     

Target theory and survival curves

A general theoretical treatment of cellular radiation damage is presented. The basic assumptions are: (1) the initial damage (“hit”) is not harmful per se, but may be either developed into a biologically significant “lesion” or repaired; (2) each lesion has a certain probability to be lethal, this probability does not depend on the number of lesions per cell; (3) the initial “hits” follow Poisson's distribution. It is shown that under these assumptions the shape of survival curves can be explained. The classical “single-hit” and “multi-hit” curves are obtained as limiting cases.     

The tails of survival curves

This article focuses on the occasional individuals of many species that live longer than is usual for their populations – here called longevity outliers. They appear to be exceptions to the usual patterns of mortality rates that increase with age. There is no model of survivorship that accommodates all of these individuals. They are less vulnerable to the usual causes of death than most in their populations. There are hints of genetically based mechanisms in the form of life-prolonging genes in invertebrates and genetic resistance to fatal diseases in higher organisms. The reasons why longevity outliers ultimately die are not known. Based on well-established trends, I predict that there will be many more humans reaching very old ages in the next century.     

Effects of sampling protocol on the shapes of species richness curves

Aim Scheiner (Journal of Biogeography, 2009, 36 , 2005–2008) criticized several issues regarding the typology and analysis of species richness curves that were brought forward by Dengler (Journal of Biogeography, 2009, 36 , 728–744). In order to test these two sets of views in greater detail, we used a simulation model of ecological communities to demonstrate the effects of different sampling schemes on the shapes of species richness curves and their extrapolation capability. Methods We simulated five random communities with 100 species on a 64 × 64 grid using random fields. Then we sampled species–area relationships (SARs, contiguous plots) as well as species–sampling relationships (SSRs, non‐contiguous plots) from these communities, both for the full extent and the central quarter of the grid. Finally, we fitted different functions (power, quadratic power, logarithmic, Michaelis–Menten, Lomolino) to the obtained data and assessed their goodness‐of‐fit (Akaike weights) and their extrapolation capability (deviation of the predicted value from the true value). Results We found that power functions gave the best fit for SARs, while for SSRs saturation functions performed better. Curves constructed from data of 32² grid cells gave reasonable extrapolations for 64² grid cells for SARs, irrespective of whether samples were gathered from the full extent or the centre only. By contrast, SSRs worked well for extrapolation only in the latter case. Main conclusions SARs and SSRs have fundamentally different curve shapes. Both sampling strategies can be used for extrapolation of species richness to a target area, but only SARs allow for extrapolation to a larger area than that sampled. These results confirm a fundamental difference between SARs and area‐based SSRs and thus support their typological differentiation.     

Bortezomib induces apoptosis of Epstein-Barr virus (EBV)-transformed B cells and prolongs survival of mice inoculated with EBV-transformed B cells

Bortezomib, an inhibitor of the 26S proteasome, is currently approved for treatment of multiple myeloma and is being studied for therapy of non-Hodgkin's lymphoma. We found that Epstein-Barr virus (EBV)-positive B cells with type III latency were more susceptible to killing by bortezomib than those with type I latency. Bortezomib induced apoptosis of EBV lymphoblastoid cell lines (LCLs) by inducing cleavage of caspases 8 and 9; apoptosis was inhibited by pretreatment with a pan-caspase inhibitor. Bortezomib reduced the levels of the p50 and p65 components of the canonical NF-kappaB pathway and reduced the level of p52 in the noncanonical NF-kappaB pathway, which is induced by EBV LMP1. Bortezomib inhibited expression of cIAP-1, cIAP-2, and XIAP, which are regulated by NF-kappaB and function as inhibitors of apoptosis. Bortezomib did not inhibit expression of several other antiapoptotic proteins, including Bcl-2 and Bcl-XL. Finally, bortezomib significantly prolonged the survival of severe combined immunodeficiency mice inoculated with LCLs. These findings suggest that bortezomib may represent a novel strategy for the treatment of certain EBV-associated lymphomas.     

Analysis of mutant frequency curves and survival curves applied to the AL hybrid cell system

A model is presented for the statistical analysis of survival curves and mutant frequency curves for a hybrid cell system. The derivation of the model is given in the Appendix, and depends on simple assumptions about the distribution of insults, their repair, and the loss of a marker that is not rescued. A single formula (5) is found which relates a survival curve to the mutant frequency curve, i. e., the response curve for production of mutants per 10(5) survivors induced by a mutagen. The analysis is applied to loss of the a1 gene in AL-J1 hybrid cells submitted to Cesium gamma-rays. Previous experimental data using X-rays was reported by Waldren et al. (1986: Proc. Natl. Acad. Sci, USA 83, 4839.) Also, a derived formula (10), which predicts the probability that in a surviving cell a marker is lost and not rescued, will form the basis for testing the validity of the model in the future using new experimental data.     

Piecewise exponential survival curves with smooth transitions

Several models of a population survival curve composed of two piecewise exponential distributions are developed. In one formulation the hazard rate changes at a point that is an unobservable random variable that varies between individuals. The population hazard function may decrease with age even when all individuals' hazards are increasing. In a second formulation, the population hazard function is modeled directly. Several models are fit to the survival history of a cohort of 5751 highly inbred male Drosophila melanogaster and the British coal mining disaster data.     

Nonlinear survival curves for cells of solid tumors after large doses of fast neutrons and gamma rays.

We have previously proposed that survival curves for cells of murine NFSa fibrosarcomas after exposure to fast neutrons might demonstrate curvature when the neutron doses reach a level high enough to cure the fibrosarcomas. We report here that this is the case. Murine NFSa fibrosarcomas growing in the hind legs of syngeneic mice were exposed to either gamma rays or fast neutrons. The tumors were removed and retransplanted into fresh recipients to obtain 50% tumor cell doses, from which the dose-cell survival relationship was constructed. Survival curves showed continuous bending down to 10(-7), and were well fitted using the linear-quadratic model. The alpha and beta values for neutrons were larger than those for gamma rays. When the surviving fractions at experimental TCD50 doses were calculated using these values, comparable figures were obtained for neutrons and gamma rays. The RBEs for neutrons were comparable for the TCD50 and TD50 assays. Neutron RBE was independent of dose within a range of 5-28 Gy. The capacity of the tumors to repair the damage caused by large doses of neutrons was identical to that for small doses of neutrons, indicating that cells retained the capacity to repair neutron damage irrespective of the size of the dose.     

Estimation of the probability parameters for a model of radiation inactivation of cells from experimental survival curves

A simple method is proposed for estimation of a and b parameters of the probability model of radiation inactivation of cells with a reference to the experimental survival curves. The examples of such an estimation for bacteria, yeast, and mammalian cells are discussed.