Although the application of the concept of a threshold to risk assessment is widespread, there remains little experimental evidence for the existence of thresholds for genotoxic compounds, other than aneugens. The clastogenicity of topoisomerase inhibitors is believed to result from the transient stabilization of the topoisomerase enzyme with DNA during the catalytic cycle. This leads to the formation of a stabilized cleavage complex, which, in turn, may result in the formation of a DNA strand break. This indirect mechanism of clastogenicity is the basis for the concept of threshold for this class of drug. Using micronucleus induction in L5178Y mouse lymphoma cells as a genotoxic end-point, a three pronged approach was used to examine whether the concept of a threshold for clastogenicity could be demonstrated for topoisomerase type II inhibitors in vitro. This involved (i) the study of mechanism (TARDIS assay), (ii) hypothesis testing versus estimation (i.e. scoring up to 10,000 cells/treatment at concentrations immediately above and below the NOEL for micronucleus induction) and (iii) statistical modelling of the concentration-response curves for micronucleus induction. Several topoisomerase type II inhibitors were investigated with varying clastogenic potencies (etoposide = doxorubicin < genistein < ciprofloxacin). Pragmatic thresholds for clastogenicity in L5178Y cells were defined at 0.00236 microg/ml for etoposide, 0.00151 microg/ml for doxorubicin, 1 microg/ml for genistein and 50 microg/ml for ciprofloxacin. In addition, it was demonstrated that etoposide-induced clastogenicity was concentration and time dependent. These results, along with mechanistic data showing that all of the compounds induced concentration-dependent increases in the formation of topoisomerase II stabilized cleavage complexes, provide a weight of evidence to support a threshold concept for clastogenicity with topoisomerase II poisons.
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http://dx.doi.org/10.1093/mutage/geg003 | DOI Listing |
Value Health
January 2025
School of Life Course & Population Sciences, Faculty of Life Sciences & Medicine / MPH Student, King's College London, UK, London; Health Economics and Policy Research Unit, Wolfson Institute of Population Health / Lecturer in Health Econmics, Queen Mary University of London, UK, London. Electronic address:
Objectives: To examine recent economic evaluations, whether any type 2 diabetes mellitus (T2DM) screening designs may represent better value for money, and to rate their methodological qualities.
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Sci Robot
January 2025
Biorobotics Laboratory, Soft Robotics Research Center, Institute of Advanced Machines and Design, Department of Mechanical Engineering, Institute of Engineering, Seoul National University, Seoul, Republic of Korea.
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View Article and Find Full Text PDFDisabil Rehabil Assist Technol
January 2025
Centre for Human Movement and Rehabilitation, School of Health & Society, University of Salford, Salford, Greater Manchester, UK.
Purpose: Falls cost the NHS over £2 billion a year, with incidence increasing rapidly with age. Design of indoor walking frames remains limited, often needing to be lifted and not supporting sit-to-stand and turning manoeuvres, which can lead to falling. This study explored aspects of safety and satisfaction and potential for clinical use of a novel prototype walking frame.
View Article and Find Full Text PDFLancet Reg Health West Pac
January 2025
National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing, China.
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View Article and Find Full Text PDFBroadband minimalist wireless base stations without energy-consuming electrical power amplifiers are the rosy scenario of the next-generation wireless communication systems. High-power radio-over-fiber (RoF) links, which are featured by large operation bandwidths, are regarded as the supporting technology for realizing such a vision. Nevertheless, the severe signal-to-noise ratio (SNR) deterioration induced by the second Brillouin scattering in high-power and long-distance RoF links must be first solved.
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