The Radial Distribution of Dose around the Path of a Heavy Ion in Liquid Water

Monte Carlo calculations of the radial distribution of dose in liquid water, incorporating energy deposition due to primary excitations and ionizations, have been performed for protons of energy 1, 10, 20, 50, and 100 MeV. By combining these results with earlier semi-empirical formulae used in track structure theory calculations, a corrected analytic formulation has been developed which on radial integration closely reproduces the value of stopping power for protons in the energy range 0.1–1000 MeV. After including a β-dependent ‘effective charge’ formula, this corrected formulation is tested against all published measurements of radial distribution of dose from energetic ions in gaseous media. Though some inconsistencies at the closest and the farthest reaches of the radial distribution of dose remain, the overall agreement is very satisfactory, indicating that the ‘effective charge’ Z*, and Z*2/β2 scaling are phenomenologically valid concepts for describing the radial dose from heavy ions of energies above ~0.5MeV/amu

Inhibition of ERβ Induces Resistance to Cisplatin by Enhancing Rad51–Mediated DNA Repair in Human Medulloblastoma Cell Lines

Cisplatin is one of the most widely used and effective anticancer drugs against solid tumors including cerebellar tumor of the childhood, Medulloblastoma. However, cancer cells often develop resistance to cisplatin, which limits therapeutic effectiveness of this otherwise effective genotoxic drug. In this study, we demonstrate that human medulloblastoma cell lines develop acute resistance to cisplatin in the presence of estrogen receptor (ER) antagonist, ICI182,780. This unexpected finding involves a switch from the G2/M to G1 checkpoint accompanied by decrease in ATM/Chk2 and increase in ATR/Chk1 phosphorylation. We have previously reported that ERβ, which is highly expressed in medulloblastomas, translocates insulin receptor substrate 1 (IRS-1) to the nucleus, and that nuclear IRS-1 binds to Rad51 and attenuates homologous recombination directed DNA repair (HRR). Here, we demonstrate that in the presence of ICI182,780, cisplatin-treated medulloblastoma cells show recruitment of Rad51 to the sites of damaged DNA and increase in HRR activity. This enhanced DNA repair during the S phase preserved also clonogenic potential of medulloblastoma cells treated with cisplatin. In conclusion, inhibition of ERβ considered as a supplemental anticancer therapy, has been found to interfere with cisplatin–induced cytotoxicity in human medulloblastoma cell lines

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Mapping and characterization of structural variation in 17,795 human genomes

A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline1 to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0–11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing

IN MEMORIAM: Robert Katz (1917–2011)

Bob Katz will be well remembered for his enthusiasm and strong personality. In a scientific dispute, few indeed could match his wit or his sense of humor or survive the cutting logic of his arguments. To those who had appreciation for his science and his personality, he was truly a great scientist and a master teacher. There are many people around the world who will remember Bob Katz for what he offered them and for the way he showed them what truth in science is. The Katz Model, developed at that time for solid-state detectors and for cell cultures, relates the action of energetic ions with the radial distribution of dose due to d rays around the ion’s path and is in effect a theory of radiobiological effectiveness (RBE) (3). The model is able to yield quantitative predictions of the response of physical or biological detectors after their irradiation by energetic ions once the parameters characterizing the detector and the ion species and its energy are known. No other radiobiological model has so far been able to match these features. The model, with its fluence-based approach to radiation dosimetry, suggests changes to long-standing paradigms of radiotherapy and radiation protection. The Katz Model brought its author international recognition and respect, controversies notwithstanding. The list of U.S. and international collaborators and friends of Bob Katz is the roster of the world’s experts in microdosimetry, radiation physics, radiation protection and cancer radiotherapy – fields to which the Katz Model has contributed and will very likely contribute in the future

The Response of the Alanine Detector After Charged-Particle and Neutron Irradiations

Radiosensitivity parameters of track structure theory, representing alanine as a one-hit detector, have been fitted for this free-radical amino-acid system on the basis of the available experimental data on the relative effectiveness of alanine after charged particle and neutron irradiations. The experimental data set can be reproduced by theoretical calculations, roughly to within experimental accuracy. A charged-particle “equivalent radiation” is introduced which can mimic the response of alanine to neutron irradiations. Implications of the results of model calculations for alanine on the shape of the radial distribution of δ-ray dose postulated by track theory, are discussed

The Fricke Dosimeter as a 1-Hit Detector

A fit to the experimental data for the response of the Fricke dosimeter to energetic heavy ions is obtained using a calculation of the relative effectiveness of a 1-hit detector, from track theory. We use 2 fitted parameters, the target size, a0, which may be thought to represent a “diffusion length,” and E0, the dose of gamma-rays at which there is an average of one hit per target (the D-37 dose), and a new algorithm for the average radial distribution of dose in liquid water from the passing ion. The G value for ions is then given as the product of the calculated relative effectiveness and the experimental G value for gamma rays

Radiosensitivity Parameters for Neoplastic Transformations in C3H10T1/2 Cells

We have evaluated radiosensitivity parameters for cellular transformation from published experimental data on neoplastic transformations induced in C3H10T1/2 cells by BEVALAC ions. The measured RBE values are well reproduced by a track theory calculation using sets of m-target parameters with either m = 2 or m = 3, suggesting a quadratic or cubic extrapolation to low doses of γ rays. Using track theory one is thus able to predict transformation frequencies in those cells after an arbitrary radiation field, under known or assumed conditions of exposure, in a manner shown earlier for cellular survival. Extension of these calculations to interpret cancer incidence in vivo is also discussed