Kinetics of mouse jejunum radiosensitization by 2',2'-difluorodeoxycytidine (gemcitabine) and its relationship with pharmacodynamics of DNA synthesis inhibition and cell cycle redistribution in crypt cells.

Gemcitabine (dFdC), a deoxycitidine nucleoside analogue, inhibits DNA synthesis and repair of radiation-induced chromosome breaks in vitro, radiosensitizes various human and mouse cells in vitro and shows clinical activity in several tumours. Limited data are however available on the effect of dFdC on normal tissue radiotolerance and on factors associated with dFdC's radiosensitization in vivo. The purpose of this study was to determine the effect of dFdC on mouse jejunum radiosensitization and to investigate the kinetics of DNA synthesis inhibition and cell cycle redistribution in the jejunal crypts as surrogates of radiosensitization in vivo. For assessment of jejunum tolerance, the mice were irradiated on the whole body with 60Co gamma rays (3.5-18 Gy single dose) with or without prior administration of dFdC (150 mg kg-1). Jejunum tolerance was evaluated by the number of regenerated crypts per circumference at 86 h after irradiation. For pharmacodynamic studies, dFdC (150 or 600 mg kg-1) was given i.p. and jejunum was harvested at various times (0-48 h), preceded by a pulse BrdUrd labelling. Labelled cells were detected by immunohistochemistry on paraffin-embedded sections. DNA synthesis was inhibited within 3 h after dFdC administration. After an early wave of apoptosis (3-6 h), DNA synthesis recovered by 6 h, and crypt cells became synchronized. At 48 h, the labelling index returned almost to background level. At a level of 40 regenerated crypts, radiosensitization was observed for a 3 h time interval (dose modification factor of 1.3) and was associated with DNA synthesis inhibition, whereas a slight radioprotection was observed for a 48-h time interval (dose modification factor of 0.9) when DNA synthesis has reinitiated. In conclusion, dFdC altered the radioresponse of the mouse jejunum in a schedule-dependent fashion. Our data tend to support the hypothesis that DNA synthesis inhibition and cell cycle redistribution are surrogates for radiosensitization. More data points are however required before a definite conclusion can be drawn

Queueing Theory an Index Factor for Production Inventory Control in Automotive Industry—A Review

In this paper, various approaches to inventory control within the automotive industry were reviewed using queueing theory. Different models used in past literature were stated and the model considered to be most effective in this review is dock management modeling. This model was used to analyze inventory control and how effectively automotive industries can minimize inventory by getting the component needed in the assembly line just in time, this helps to reduce additional costs for warehouse maintenance and capital tied down in form of excess inventory. Analytical and simulation models are the mathematical models that are considered in this review as they are used in several papers by different authors

A symbolic-numeric method to analyse nonlinear differential equations in Fourier domain.

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Implémentation de l'analyse harmonique symbolique des oscillateurs à quartz.

National audienc

Early Exposure to Nanoparticles: A Risk Factor to Develop Chronic Obstructive Pulmonary Disease?

International audienceRATIONALE OF THE STUDY Chronic obstructive pulmonary disease (COPD) is a disease ofincreasing incidence characterized by progressive airflow limitation and inflammation. COPD riskis strongly related to tobacco smoking, but environmental and genetic factors are also involved inits pathogenesis. There is increasing evidence that adverse exposures (cigarette smoke,pollution, nanoparticles (NP)) occurring during foetal and early infant life can impair thedevelopment of the lungs and may finally increase risks of COPD at adulthood. Using a mousemodel, we have recently shown that respiratory exposure of pregnant mice to metal NP leads toalterations in lung morphology in pups, with a persistent alveolar airspace enlargement. In orderto determine if such modifications represent a susceptibility factor to develop a COPD-likephenotype in later life, we exposed the progeny to cigarette smoke and analysed the morphologyof the lungs. METHODS Three metal nanoparticles were used in the study: Cerium oxide, Silverand Gold (diameter 15 to 30 nm). We performed weekly non-surgical intratracheal instillation of100µg nanoparticles on C57BL/6 pregnant mice during the entire course of gestation. At the ageof two months, the progeny was exposed to cigarette smoke for 7 and 12 weeks. The lungmorphology was analysed at different stages of alveolar development (E17.5, P23 and P60) andafter cigarette smoke exposure. RESULTS The number of pups per pregnant mother, as well astheir weight was similar between the 4 experimental groups. Respiratory exposure of pregnantmice to metal nanoparticles induce persistent lung morphological abnormalities in the progeny,demonstrated by enlargement of the alveolar airspace already at P23 and which remains at P60.The mean linear intercept (MLI), of 151.3 +/- 7.2 µm in controls lungs, is increased to 171.8 +/- 8.2µm with Silver, 166.0 +/-3.9 with Cerium and 166.4 +/-3.9 with Gold NP (p<0.005). Cigarettesmoke exposure induces an alveolar enlargement in control lungs (MLI = 172.8 +/- 9.3 µm),which is increased in all the NP groups, with MLI of 191.7 +/- 6.5 with Silver, 190.9 +/- 5.8 withCerium and 191.3 +/- 7.6 with Gold NP (p<0.005). The biological mechanisms underlying theseeffects are currently under investigation. CONCLUSIONS These findings suggest that earlyexposure to metal nanoparticles during the critical time-window of pregnancy could represent arisk factor to develop COPD in adultho

Radiosensitization of mouse sarcoma cells by fludarabine (F-ara-A) or gemcitabine (dFdC), two nucleoside analogues, is not mediated by an increased induction or a repair inhibition of DNA double-strand breaks as measured by pulsed-field gel electrophoresis.

PURPOSE: To investigate the effect of fludarabine (F-ara-A) and gemcitabine (dFdC), two radiosensitizing nucleoside analogues, on the induction and repair of DNA dsb after ionizing radiation. MATERIALS AND METHODS: Radiosensitization of mouse sarcoma SA-NH and FSA cells was studied using a clonogenic assay. Cell survival curves were fitted with the linear-quadratic model. DNA dsbs were detected by pulsed-field gel electrophoresis under neutral conditions. RESULTS: F-ara-A (100 micromol dm(-3) for 1 h prior to irradiation) induced a substantial radiosensitization in SA-NH cells with a dose modification factor of 2.0 for a surviving fraction of 0.5. In a FSA mouse sarcoma cell line, dFdC (5 micromol dm(-3) for 3 h prior to irradiation) induced a modest radiosensitization with a DMF of 1.2 for a surviving fraction of 0.5. Under similar experimental conditions, neither F-ara-A nor dFdC altered the yield of radiation-induced DNA dsbs in the dose range of 0-40 Gy. After a single dose of 25 Gy (SA-NH cells) or 40 Gy (FSA cells), neither the kinetics of repair nor the amount of residual damage was affected by F-ara-A or dFdC. CONCLUSIONS: For experimental conditions under which radiosensitization was observed, neither the induction nor the repair of DNA dsbs after ionizing radiation were affected by F-ara-A or dFdC