32 research outputs found
Deterministic mathematical modelling for cancer chronotherapeutics: cell population dynamics and treatment optimisation
Chronotherapeutics has been designed and used for more than twenty years as an effective treatment against cancer by a few teams around the world, among whom one of the first is Francis LĂ©vi's at Paul-Brousse hospital (Villejuif, France), in application of circadian clock physiology to determine best infusion times within the 24-hour span for anticancer drug delivery. Mathematical models have been called in the last ten years to give a rational basis to such optimised treatments, for use in the laboratory and ultimately in the clinic. While actual clinical applications of the theoretical optimisation principles found have remained elusive so far to improve chronotherapeutic treatments in use, mathematical models provide proofs of concepts and tracks to be explored experimentally, to progress from theory to bedside. Starting from a simple ordinary differential equation model that allowed setting and numerically solving a drug delivery optimisation problem with toxicity constraints, this modelling enterprise has been extended to represent the division cycle in proliferating cell populations with different molecular targets, to allow for the representation of anticancer drug combinations that are used in clinical oncology. The main point to be made precise in such a therapeutic optimisation problem is to establish, here in the frame of circadian chronobiology, physiologically based differences between healthy and cancer cell populations in their responses to drugs. To this aim, clear biological evidence at the molecular level is still lacking, so that, starting from indirect observations at the experimental and clinical levels and from theoretical considerations on the model, speculations have been made, that will be exposed in this review of cancer chronotherapeutics models with the corresponding optimisation problems and their numerical solutions, to represent these differences between the two cell populations, with regard to circadian clock control
Recommended from our members
Size distribution of autotrophy and microheterotrophy in reservoirs: implications for foodweb structure
Particle size is a primary determinant of resources available to consumers and of the efficiency of energy transfer through planktonic food chains. Dual radioisotopic labeling (with /sup 14/C-bicarbonate and /sup 3/H-acetate) and size fractionation of naturally-occurring phytoplankton-bacterioplankton assemblages were employed to examine the particle size distributions of planktonic autotrophy and microheterotrophy in four limnologically-dissimilar US reservoirs (Lake Mead, Arizona-Nevada, oligo-mesotrophic; Broken Bow Lake, Oklahoma, mesotrophic; Lake Texoma, Oklahoma-Texas, eutrophic; and Normandy Lake, Tennessee, eutrophic). Small nano- and ultraphytoplankton (< 8.0 ..mu..m) and free-living bacteria (< 3.0 ..mu..m) were primarly responsible for planktonic autotrophy and microheterotrophy, respecitvely, even in eutrophic conditions. Zooplankton grazing experiments indicated that (1) most grazing pressure occurs on 3.0 to 8.0 ..mu..m particles, (2) grazer limitation of the occurrence of attached bacteria amd microbial-detrital aggregates is unlikely, and (3) free-living bacteria are inefficiently harvested, relative to algae, by most reservoir zooplankton. Relative to autorophy, the microheterotrophic conversion of allochthonous dissolved organic matter and algal excretion products to bacterial biomass appears unlikely to be a significant source of organic carbon for planktonic grazers in most reservoirs
Recommended from our members
Regulatory compliance issues related to the White Oak Creek Embayment time-critical removal action
In September 1990, Martin Marietta Energy Systems (Energy Systems) discovered high levels of Cesium-137 ({sup 137}Cs) in surface sedimenus near the mouth of White Oak Creek Embayment (WOCE). White Oak Creek (WOC) receives surface water drainage from Oak Ridge National Laboratory. Since this discovery, the Department of Energy (DOE) and Energy Systems have pursued actions designed to stabilize the contaminated WOCE sediments under provisions of the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA), and the implementing regulations in the National Contingency Plan (NCP) (40 CFR Part 300), as a time-critical removal action. By definition, a time-critical removal is an action where onsite activities are initiated within six months of the determination that a removal action is appropriate. Time-critical removal actions allow comparatively rapid mobilization to protect human health and the environment without going through the lengthy and extensive CERCLA Remedial Investigation/Feasibility Study/Record of Decision process. Many aspects of the project, in terms of compliance with the substantive requirements of the NCP and ARARs, have exceeded the regulatory requirements, despite the fact that there is no apparent authority on conducting removal actions at Federal facilities. Much of the interpretation of the NCP was groundbreaking in nature for both EPA and DOE. 4 refs., 2 figs