Noise in timing and precision of gene activities in a genetic cascade

Biological developmental pathways require proper timing of gene expression. We investigated timing variations of defined steps along the lytic cascade of bacteriophage λ. Gene expression was followed in individual lysogenic cells, after induction with a pulse of UV irradiation. At low UV doses, some cells undergo partial induction and eventually divide, whereas others follow the lytic pathway. The timing of events in cells committed to lysis is independent of the level of activation of the SOS response, suggesting that the lambda network proceeds autonomously after induction. An increased loss of temporal coherence of specific events from prophage induction to lysis is observed, even though the coefficient of variation of timing fluctuations decreases. The observed temporal variations are not due to cell factors uniformly dilating the timing of execution of the cascade. This behavior is reproduced by a simple model composed of independent stages, which for a given mean duration predicts higher temporal precision, when a cascade consists of a large number of steps. Evidence for the independence of regulatory modules in the network is presented

20. Setting the pace for strengthening radiotherapy in Europe: the estro esquire project

In most medical specialties the success rate and outcome of treatment coincide and can be measured immediately. This is not the case for radiotherapy where debilitating of even lethal side effects may show up as late as 18 years after treatment. To determine the outcome or therapeutic ratio of radiotherapy, it is therefore necessary to link tumour control closely to the actuarial long-term disease free survival of the patient.The therapeutic window for radiotherapy is narrow. In walking the tightrope between cure and complications, radiotherapy can put the odds at its side. As a precautionary measure, strict quality assurance measures including the monitoring of side effects need to be put in place. Recent studies have demonstrated that every gain in the accuracy of the beam output and treatment delivery is translated into important gains in the uncomplicated cure probability, thus sparing the lives of thousands of patients every year. QA will become all the more mandatory now that new technological developments allow much more precision in the delivery of the intended dose to the intended target volume, thus making an escalation of the dose and hence the improvement of the cancer cure rata possible.Europe has only half the number of treatment units of America and Japan. However, it has also its own strengths. These are exactly in the field of quality assurance and education. ESTRO has become a world leader in the provision of teaching in the field of radiotherapy. The ESTRO teaching programme commands the admiration and even the envy of the International radiation oncology community. We need to capitalise on this achievement and keep it at the cutting edge of scientific and technological progress to offset, through the development of the human potential and optima) use of capital-intensive infrastructural resources, at least partially the shortage in capital investment and the past shortfall in spending for research.For this reason ESTRO is embarking on an ambitious new project called ESQUIRE (Education, Science and Quality Assurance In Radiotherapy in Europe) which it hopes to realise with the support of EU funding. The aim of this project is to increase the confidence level of clinicians for embracing optimised RT treatment regimes by making sure they can be introduced without an increase in severe side effects. Actions proposed for this purpose: monitoring the accuracy of the dose (Talk 1:E∼UAL) and the side effects (Task 2: REACT), by stepping up education for the implementation of new technology (Task 3: EDRO,) by developing quality assurance procedures for optimised RT (Task 5: QUASIMODO) and brachytherapy (Task 6: BRAPHY∼S), and establishing a procedure-based surveillance of quality in treatment and research (Task 4:EPOQART)

33. Last results and lessons of the Estro European Network on Quality Assurance in Radiotherapy

State of the ArtThe EQUAL Dosimetry audit service, set-up by the ESTRO in 1998aaThe present ESTRO-EQUAL Project (MORQA) has been funded by an EU contract., is wellknown through large numbers of TL-dosimeters sent to hospitals to be irradiated in clinically relevant conditions, and read at the EQUAL Measuring Laboratory, IGR, Villejuif.All European countries have now applied to participate (404 centres out of 880) for photon and electron beams. In relation with the IAEA, this service has been extended to 27 centres of 7 countries from Eastern and Central Europe, and the Mediterranean Basin. 757 photon beams and 277 electron beams have been checked according to the “on the beam axis” procedure.Results and outcome–Reference beam output results demonstrating improvements with respect to the former EC Network, and good reliability of the procedure: mean ratios of measured to stated dose of 0.997 (SD 1.8%) for photon beams, and 1.003 (SD 2.1%) for electron beams.–Useful service detecting 7% of the photon beams presenting at least one check point with a deviation > 5% (2% for electron beams, but 3 times more deviations between 3 and 5%).–Re-checks and on-site visits in 8 centres reveal inaccuracies in TPS algorithms or input data and/or in local measurements (wedge factors, collimator aperture factors, PDD's, beams calibrations).ConclusionA number of dosimetric problems are still observed, even on the beam axis. Improvements should be introduced and checked before considering more sophisticated treatment techniques

Comparison of distribution and activity of nanoparticles with short interfering DNA (Dbait) in various living systems

Introducing small DNA molecules (Dbait) impairs the repair of damaged chromosomes and provides a new method for enhancing the efficiency of radiotherapy in radio-resistant tumors. The radiosensitizing activity is dependent upon the efficient delivery of Dbait molecules into the tumor cells. Different strategies have been compared, to improve this key step. We developed a pipeline of assays to select the most efficient nanoparticles and administration protocols before preclinical assays: (i) molecular analyses of complexes formed with Dbait molecules, (ii) cellular tests for Dbait uptake and activity, (iii) live zebrafish embryo confocal microscopy monitoring for in vivo distribution and biological activity of the nanoparticles and (iv) tumor growth and survival measurement on mice with xenografted tumors. Two classes of nanoparticles were compared, polycationic polymers with linear or branched polyethylenimine (PEI) and covalently attached cholesterol (coDbait). The most efficient Dbait transfection was observed with linear PEI complexes, in vitro and in vivo. Doses of coDbait ten-fold higher than PEI/Dbait nanoparticles, and pretreatment with chloroquine, were required to obtain the same antitumoral effect on xenografted melanoma. However, with a 22-fold lower ‘efficacy dose/toxicity dose' ratio as compared with Dbait/PEI, coDbait was selected for clinical trials

Interplay between edge states and simple bulk defects in graphene nanoribbons

We study the interplay between the edge states and a single impurity in a zigzag graphene nanoribbon. We use tight-binding exact diagonalization techniques, as well as density functional theory calculations to obtain the eigenvalue spectrum, the eigenfunctions, as well the dependence of the local density of states (LDOS) on energy and position. We note that roughly half of the unperturbed eigenstates in the spectrum of the finite-size ribbon hybridize with the impurity state, and the corresponding eigenvalues are shifted with respect to their unperturbed values. The maximum shift and hybridization occur for a state whose energy is inverse proportional to the impurity potential; this energy is that of the impurity peak in the DOS spectrum. We find that the interference between the impurity and the edge gives rise to peculiar modifications of the LDOS of the nanoribbon, in particular to oscillations of the edge LDOS. These effects depend on the size of the system, and decay with the distance between the edge and the impurity.Comment: 10 pages, 15 figures, revtex