Biomedical subjects
Publications and source records attributed to S Ménard.
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This paper mainly aims at presenting the measurements and the results obtained with the electronic personal neutron dosemeter Saphydose-N at different facilities. Three campaigns were led in the frame of the European contract EVIDOS ('Evaluation of Individual Dosimetry in Mixed Neutron and Photon Radiation Fields'). The first one consisted in the measurements at the IRSN French research laboratory in reference neutron fields generated by a thermal facility (SIGMA), radionuclide ISO sources ((241)AmBe; (252)Cf; (252)Cf(D(2)O)\Cd) and a realistic spectrum (CANEL/T400). The second one was performed at the Krümmel Nuclear Power Plant (Germany) close to the boiling water reactor and to a spent fuel transport cask. The third one was realised at Mol (Belgium), at the VENUS Research Reactor and at Belgonucléaire, a fuel processing factory.
The QUADOS EU cost shared action conducted an intercomparison on the usage of numerical methods in radiation protection and dosimetry. The eight problems proposed were intended to test the usage of Monte Carlo and deterministic methods by assessing the accuracy with which the codes are applied and also the methods used to evaluate uncertainty in the answer gained through these methods. The overall objective was to spread good practice through the community and give users information on how to assess the uncertainties associated with their calculated results.
'QUADOS', a concerted action of the European Commission, has promoted an intercomparison aimed at evaluating the use of computational codes for dosimetry in radiation protection and medical physics. This intercomparison was open to all users of radiation transport codes. Eight problems were selected for their relevance to the radiation dosimetry community, five of which involved photon and proton transport. This paper focuses on a discussion of lessons learned from the participation in solving the photon and charged particle problems. The lessons learned from the participation in solving the neutron problems are presented in a companion paper (in this issue).
A splice variant of the human gene HER2, lacking exon-16 (DeltaHER2) which encodes a small extracellular region, has been described. This altered receptor forms disulfide bond-stabilized homodimers. We report here that the DeltaHER2 splice variant represents about 9% of the HER2 mRNA obtained from most of the 46 breast carcinoma samples with HER2 expression levels ranging from 3+ to 0 by HercepTest. Analysis of human cells transfected with DeltaHER2 or wild-type (WT) cDNA revealed no growth of WT cells in nude mice, whereas clones expressing 10-fold less DeltaHER2 were tumorigenic. Unlike WT transfectants, DeltaHER2-expressing cells showed low sensitivity to two new therapeutic drugs targeting receptors of the HER family (ZD1839 and Trastuzumab), whereas an inhibitor of the HER2 tyrosine kinase domain (Emodin) blocked activation of both DeltaHER2 and WT transfectants. Taken together, our findings indicate that the DeltaHER2 transcript encodes the transforming form of the oncoprotein. It is plausible that malignant transformation arises when a critical threshold of DeltaHER2 is reached in HER2-overexpressing tumors. Specific inhibitors of HER2 catalytic activity represent a promising approach to therapy of HER2-overexpressing tumors.
QUADOS, a Concerted Action of the European Commission, has promoted an intercomparison aimed at evaluating the use of computational codes for dosimetry in radiation protection and medical physics. This intercomparison was open to all users of radiation transport codes. Eight problems were selected for their relevance to the radiation dosimetry community, five of which involved photon and proton transport. This paper focuses on the analysis of the photon and charged particle problems. The neutron problems were presented in a paper at the NEUDOS9 conference.
In recent years IRSN has developed tissue-equivalent proportional counters (TEPCs) for neutron monitoring. A detector with a multi-element geometry was studied for personal dosimetry purposes. The determination of the personal dose equivalent using a multi-element TEPC requires to calculate the mean chord length of the charged particles in the counter gas. This paper presents the results of the simulations using the MCNPX code and explains the influence of the gas parameters on the mean chord length and the consequences on the dose equivalent response.
The association between expression of the 67 kDa laminin receptor (67LR) and tumor aggressiveness has been convincingly demonstrated although the exact function of this molecule in the metastatic process has remained unclear. In this study, we tested whether the laminin-1, upon interaction with 67LR, promotes tumor cell aggressiveness; the investigation was based on: (i) the previous demonstration that soluble 67LR, as well as a 20-amino-acid peptide corresponding to the 67LR laminin binding site, changes the conformation of laminin upon interaction with this adhesion molecule and (ii) the known relevance of microenvironment remodeling by the tumor, leading to structural modification of extracellular matrix components in tumor progression. MDAMB231 breast carcinoma cells plated on peptide G-treated laminin-1 exhibited a polygonal array of actin filament bundles compared with cells seeded on native laminin-1 which presented the actin bundles organized as multiple cables parallel to margins. Furthermore, in cells seeded on peptide G-treated laminin-1, 67LR was distinct from the alpha6 integrin subunit in filopodia protrusions in addition to colocalizing with this integrin in focal adhesion plaques as it occurs when cells are plated on native laminin-1. In addition to differences in tumor cell adhesion and migration found in cells exposed to peptide G-treated vs native laminin-1, breast carcinoma cells seeded on modified laminin-1 showed a 6-fold increase in invasion capability compared with cells seeded on unmodified laminin-1. Alterations in actin organization as well as adhesion, migration and especially invasion observed in MDAMB231 cells in the presence of peptide G-treated laminin-1 were even found in MDAMB231 cells that, after selection for 67LR high expression, were seeded on native laminin-1. As the 67LR shedding is proportional to its expression level, these findings indicate a role for 67LR in changing laminin structure. Expression analysis of 97 genes encoding proteins that mediate cell matrix interactions, revealed significant differences between cells exposed to modified vs unmodified laminin-1 in 19 genes, 17 of which--including those encoding alpha3 integrin, extracellular matrix protein 1, proteolytic enzymes (such as MT1-MMP, stromelysin-3 and cathepsin L) and their inhibitors--were up-modulated in cells treated with modified laminin-1. Zymogram analysis clearly indicated a significant increase in the activity of the gelatinolytic enzyme MMP-2 in the culture supernatant from cells exposed to modified laminin-1, without an increase in mRNA abundance as observed in microarray analysis. Invasiveness of tumor cells conditioned by modified laminin-1, evaluated as the capability to cross Matrigel basement, was significantly more inhibited by MMPinhibitor TIMP-2 than invasiveness induced by native laminin-1. Taken together, our findings indicate that the role of 67LR in tumor aggressiveness rests in its ability to modify laminin-1 thereby activating proteolytic enzymes that promote tumor cell invasion through extracellular matrix degradation.
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HER2 (human epidermal growth factor receptor-2; also known as erbB2) and its relatives HER1 (epidermal growth factor receptor; EGFR), HER3 and HER4 belong to the HER family of receptor tyrosine kinases. In normal cells, activation of this receptor tyrosine kinase family triggers a rich network of signaling pathways that control normal cell growth, differentiation, motility and adhesion in several cell lineages. The first tumor studied for an alteration of the HER2 oncogene is breast carcinoma, and so far the majority of studies have been performed on this oncotype. Although involvement of HER2 as a cause of human cell transformation needs to be further investigated, overexpression of the HER2 oncogene in human breast carcinomas has been associated with a more aggressive course of disease. It has been suggested that this association depends on HER2-driven proliferation, vessel formation and/or invasiveness; however, poor prognosis may not be directly related to the presence of the oncoprotein on the cell membrane but instead to the breast carcinoma subset identified by HER2 overexpression and characterized by a peculiar gene expression profile, as recently identified. HER2-positive tumors were recently shown to benefit from anthracyclin treatment and to be resistant to endocrine therapy. Despite the fact that many pathways interacting with HER2 are still not fully understood, this tyrosine kinase receptor is, to date, a promising molecule for targeted therapy.
The study was conducted to investigate the effects of a novel therapeutic approach, i.e. the combination of chemotherapy and immunotherapy, against a human prostate carcinoma xenograft. A topoisomerase I inhibitor, topotecan, and CpG-containing oligodeoxynucleotides (CpG-ODN) were combined. Athymic mice bearing the PC-3 human prostate carcinoma were treated with the maximum tolerated dose (MTD) of topotecan (3 weekly treatments) and with repeated treatments of CpG-ODN (40 and 20 microg/mouse); tumour growth and lethal toxicity were monitored. Topotecan effect on CpG-ODN-induced production of interleukin (IL) 12, interferon (IFN)-gamma and tumour necrosis factor-alpha was also assessed. Since topotecan pretreatment differentially influenced CpG-ODN-induced production of IL-12 and IFN-gamma, the antitumour effects of the two therapies were investigated in a sequential (full topotecan regimen followed by CpG-ODN) or in an alternating sequence (starting with CpG-ODN). Topotecan inhibited PC-3 tumour growth, inducing 95% tumour volume inhibition. All combined treatments resulted in a significant delay in tumour growth, compared to the effects in topotecan-treated mice (P<0.01, by analysis of tumour growth curves). The combination regimens were well tolerated, except for the alternating sequence of 40 microg CpG-ODN and topotecan, which resulted in three out of eight toxic deaths. This alternating sequence was highly toxic even when another cytotoxic drug (doxorubicin) was used in healthy mice. In conclusion, the combination of topotecan and CpG-ODN increased antitumour effects over chemotherapy alone in the growth of a human prostate carcinoma xenograft. Administration sequence was critical to the combination toxicity: the complete regimen of the cytotoxic drug followed by repeated administrations of the immunomodulator seemed the most promising for further investigations.
Since 1993, the Institute for Radiological Protection and Nuclear Safety (IRSN) has lead, in association with Electricité de France (EDF), a R&D study of a neutron personal electronic dosemeter. This dosemeter, called 'Saphydose-N', is manufactured by the SAPHYMO company. This paper presents first the optimisation of some detector components using Monte Carlo calculations, and second the test of the manufactured Saphydose-N under radiation following the IEC 1323 standard's recommendations for active personal neutron dosemeters. The measurements with the manufactured dosemeter were performed on the one hand at PTB (Physikalisch-Technische Bundesanstalt) in mono-energetic neutron fields and, on the other hand at IRSN in neutron fields generated by a thermal facility (SIGMA), radionuclide ISO sources and a realistic spectrum (CANEL/T400). The manufactured dosemeter Saphydose-N was also tested during measurement campaigns of the European programme EVIDOS ('Evaluation of Individual Dosimetry in Mixed Neutron and Photon Radiation Fields') at different nuclear workplaces. The study showed that Saphydose-N complies with the recommendations of standard IEC 1323 and can be used at any workplace with no previous knowledge of the neutron field characteristics.
Tissue-equivalent proportional counters (TEPC) allow the measurements of the absorbed dose and the ambient dose equivalent for neutron fields. A device based on this approach, called NAUSICAA((1,2)), has already been developed by IRSN to be used in high energy neutron fields for space applications. The response of this detector underestimates significantly the dose equivalent at low energies (several hundred keV) which represent the major component of neutron fields at workplaces in the nuclear industry. A counter with a similar geometry (cylindrical detector) and a lower gas pressure was studied in order to simulate a 1 microm biological site. In 2003, the performance of the device was further improved by adding a small amount of 3He to the tissue-equivalent gas (propane based) in order to increase the response for the lower energies of neutrons. Three amplification circuits were used to cover lineal energy range from 10(-1) to 10(4) keV microm(-1). Tests were performed in monoenergetic neutron and source fields. This paper presents the experimental results obtained with this change.
'QUADOS', a Concerted Action of the European Commission, has run an intercomparison aimed at evaluating the use of computational codes for dosimetry in radiation protection and medical physics. This intercomparison was open to all users of Monte Carlo, analytic and semi-analytic codes or deterministic methods. Its main aim was to provide a snapshot of the methods and codes currently in use. It also intended to furnish information on the methods used to assess the reliability of computational results and disseminate 'good practice' throughout the radiation dosimetry community. Eight problems were selected for their relevance to the radiation dosimetry community, three of which involve neutron transport. This paper focuses on the analysis of the neutron problems.
BACKGROUND: Probiotic bacteria have a beneficial effect on intestinal inflammation. In this study, we have examined the effect of lactic acid and commensal Gram positive (+) bacteria conditioned media (CM) on tumour necrosis factor alpha (TNF-alpha) release and the mechanisms involved. METHODS: Lipopolysaccharide (LPS) induced TNF-alpha secretion by peripheral blood mononuclear cells or the THP-1 cell line was monitored in the presence or absence of bacteria CM obtained from two probiotic strains, Bifidobacterium breve (Bb) and Streptococcus thermophilus (St), and three commensal bacterial strains (Bifidobacterium bifidum, Ruminococcus gnavus, and unidentified Streptococcus). Bb and St bacteria CM were allowed to cross filter grown intestinal epithelial cell monolayers (HT29-19A) to assess intestinal transport of active bacterial products. These products were characterised and their effect on LPS binding to THP-1 cells and nuclear factor kappa B (NF kappa B) activation assessed. RESULTS: Dose dependent inhibition of LPS induced TNF-alpha secretion was noted for both probiotic bacteria CM (64% and 71% inhibition for Bb and St, respectively) and to a lesser extent commensal bacteria CM (21-32% inhibition). Active products from Bb and St were resistant to digestive enzymes and had a molecular mass <3000 Da. Their inhibitory effect was preserved after transepithelial transport across intestinal cell monolayers, mainly in inflammatory conditions. LPS-FITC binding to THP-1 cells and NF kappa B activation were significantly inhibited by Bb and St CM. CONCLUSION: B breve and S thermophilus release metabolites exerting an anti-TNF-alpha effect capable of crossing the intestinal barrier. Commensal bacteria also display a TNF-alpha inhibitory capacity but to a lesser extent. These results underline the beneficial effect of commensal bacteria in intestinal homeostasis and may explain the role of some probiotic bacteria in alleviating digestive inflammation.
Examination of parity, age at menarche and at menopause by HER2 status in a large series of breast carcinomas showed a statistically significant increased-frequency of HER2-positive tumours in lower risk subgroups. The findings suggest a difference in the protective role of hormone-related risk factors between HER2-positive and -negative tumours.
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The innate immune response, which depends on so-called pattern-recognition receptors (PRRs) is an evolutionarily old immune response able to elicit a defensive response against a vast array of pathogens. The purpose of this review is to revisit the role of innate immunity in breast carcinoma from the oldest therapeutic approach using bacillus Calmette-Guerin to the recent findings on the manipulation of the PRR pathways with unmethylated cytosine-guanosine dinucleotides (CpG motifs). Encouraging results have been obtained in prevention and local treatment of murine mammary tumors using tumor cells engineered to express stably mycobacterial antigens or directly using CpG-containing oligonucleotides. The experimental findings raise the possibility of successful anti-tumor management through stimulation of innate immunity in women at high risk of developing breast cancer and in breast cancer patients with reasonable immunological performance and low tumor load.