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Resume L’imagerie par resonance magnetique (IRM) cardiaque devient un outil essentiel pour le diagnostic des pathologies cardiaques. Cette technique est tres dependante de la qualite de l’electrocardiogramme (ECG) et de la synchronisation des sequences d’acquisition IRM. Notre objectif a ete de developper un capteur ECG « intelligent » totalement compatible avec l’environnement electromagnetique de l’IRM afin de : (1) permettre une synchronisation fiable des sequences IRM en incluant le traitement des troubles du rythme et les patients ayant des ECG de faible amplitude ; et (2) permettre un monitorage continu des patients pour tous types de sequences IRM. Pour atteindre ces objectifs, des capteurs ECG et de mesure de champ magnetique en 3D ont ete developpes en technologie microelectronique, auxquels nous avons associe un capteur pour la mesure des mouvements respiratoires. Ces derniers representent correctement la respiration du patient permettant un meilleur controle de l’acquisition et de la reconstruction en IRM. Les circuits concus sont totalement amagnetiques et peuvent donc etre places directement dans le champ de vue de l’IRM. La creation d’une base de donnees ECG a ete necessaire pour mettre en œuvre et evaluer de nouvelles methodes de traitement de signal comme des techniques de separation de sources, de decomposition en ondelettes et des approches bayesiennes. Grâce a ces methodes, il a ete possible de supprimer la majorite des artefacts sur l’ECG pour un meilleur diagnostic et une tres bonne synchronisation des sequences. En revanche, les methodes de classification des troubles du rythme en IRM n’ont pas encore ete completement developpees.

In addition to their physiologic effects in inflammation and angiogenesis, chemokines are involved in cancer pathology. The aim of this study was to determine whether the chemokine stromal cell–derived factor 1 (SDF-1) induces the growth, migration, and invasion of human hepatoma cells. We show that SDF-1 G protein–coupled receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), and SDF-1 mRNA are expressed in human hepatoma Huh7 cells, which secrete and bind SDF-1. This binding depends on CXCR4 and glycosaminoglycans. SDF-1 associates with CXCR4, and syndecan-4 (SDC-4), a heparan sulfate proteoglycan at the plasma membrane of Huh7 cells, induces the growth of Huh7 cells by promoting their entry into the cell cycle, and inhibits the tumor necrosis factor-α–mediated apoptosis of the cells. SDF-1 also reorganizes Huh7 cytoskeleton and induces tyrosine phosphorylation of focal adhesion kinase. Finally, SDF-1 activates matrix metalloproteinase-9, resulting in increased migration and invasion of Huh7 cells. These biological effects of SDF-1 were strongly inhibited by the CXCR4 antagonist AMD3100, by a glycosaminoglycan, heparin, as well as by β-d-xyloside treatment of the cells, or by c-jun NH2-terminal kinase/stress-activated protein kinase inhibitor. Therefore, the CXCR4, glycosaminoglycans, and the mitogen-activated protein kinase signaling pathways are involved in these events. The fact that reducing SDC-4 expression by RNA interference decreased SDF-1–induced Huh7 hepatoma cell migration and invasion strongly indicates that SDC-4 may be an auxiliary receptor for SDF-1. Finally, the fact that CXCR4 is expressed in hepatocellular carcinoma cells from liver biopsies indicates that the in vitro results reported here could be extended to in vivo conditions. (Mol Cancer Res 2007;5(1):21–33)

The presence of lymph node metastasis is predictive of poor prognosis in solid tumors. Demonstration of specific markers of lymphatic endothelial cells has facilitated the study of the molecular mechanisms of metastasis, particularly lymphangiogenesis. The vascular endothelial growth factor (VEGF)-C/VEGF-D/VEGF receptor (VEGFR)-3 axis has been the most extensively studied, but other molecular pathways are also involved, such as fibroblast growth factor (FGF)-2, platelet-derived growth factor (PDGF)-BB, angiopoietin-1, VEGF-A, hepatocyte growth factor (HGF), insulin-like growth factor (IGF)-1 and -1R, and cyclooxygenase-2. Several strategies are currently being developed to prevent lymphatic metastasis, mainly targeting the VEGF-C/VEGF-D/VEGFR-3 axis: inhibiting maturation and activation of VEGF-C and VEGF-D by successive proteolyses, inhibiting binding of ligands to their receptor, and using tyrosine kinase inhibitors. Many questions remain and will be discussed in this article, particularly the role of lymph node metastasis in the development of visceral metastases, possible toxicities of antilymphangiogenic treatments, and their possible interactions with intratumoral penetration of other anticancer agents.

Neovascularisation is critical for supporting the rapid growth of solid tumours (Folkman, 1990). Tumour angiogenesis appears to be achieved by the overexpression of angiogenic agents within solid tumours that stimulate host vascular endothelial cell mitogenesis and possibly chemotaxis. It is well established now that the induction of vascular endothelial growth factor (VEGF) expression, including via tumour hypoxia (Hlatky et al, 1994), plays a major role in tumour angiogenesis (Dvorak et al, 1991; Millauer et al, 1994; Goldman et al, 1998). In recent years, it has been widely shown that VEGF activity is a key feature during tumour growth and angiogenesis, and that blocking of this signal transduction pathway may inhibit tumour progression (Cheng et al, 1996; Relf et al, 1997). In vivo, VEGFs act as potent mitogenic factors for endothelial cells and as blood vessel permeabilising agents (Senger et al, 1983; Plouet et al, 1989; Klagsbrun and Soker, 1993; Yuan et al, 1996). The VEGF gene family currently includes six members: VEGF-A (prototype VEGF), placenta growth factor (PlGF), VEGF-B, VEGF-C, VEGF-D and VEGF-E, (produced by Orf virus), (reviewed by Veikkola et al, 2000). VEGF is a homodimeric glycoprotein that exists in six isoforms containing 121, 145, 162, 165, 189 and 206 amino-acid residues as a result of alternative splicing from a single gene (Ferrara and Davis-Smith, 1997; Lange et al, 2003). The predominant and the best characterised VEGF species is the heparin-binding 165-amino acid-long form VEGF165 (reviewed by Neufeld et al, 1999).

Genetic and cellular heterogeneity is one of mechanisms involved in increasing tumour aggressiveness during neoplastic progression. Development of drug-resistant tumour cell subpopulations is a major problem in clinical oncology. Multi-drug resistant tumour cells survive when exposed to cytotoxic agents. Here, we studied in a three-dimensional (3D) coculture system, called "ex vivo nodules", how drug-resistant and sensitive tumour cells settle down in a 3D space. For this, we cocultured adriamycin-sensitive (MCF-7S) and -resistant (MCF-7R) human breast cancer cells in long term nodules. We showed that both types of cells are able to grow separately or in coculture until five weeks in spheroidal forms. MCF-7R cells did not loose their multi-drug resistance when cultured in nodules as measured by RT-PCR. Curiously, the exterior aspects of mixed (MCF-7S/ MCF-7R) nodules and MCF-7R nodules were similar whereas MCF-7S nodules were completely different. Nevertheless, morphologically these three nodule types were distinct, in particular in their density. Immunostaining showed that in mixed nodules, MCF-7R cells were arranged at the periphery, whereas the MCF-7S cells are in the central part of the nodules. Even if the mechanism of this arrangement remained unclear, this work shows that three-dimensional cell culture is well adapted to the study of the relationships between adhesion mechanisms and drug-resistance.

1. Since the sodium phenylacetate (NaPa) was reported to enhance the inhibitory effect of carboxymethyl benzylamide dextran (CMDB) on the breast cancer growth, we performed the esterification of CMDB with NaPa to obtain a new drug carrying the characteristics of these two components. A new molecule, phenylacetate carboxymethyl benzylamide dextran, was named NaPaC. 2. We investigated in vitro and in vivo the effects of NaPaC on MCF-7ras cell growth as well as its apoptotic and antiangiogenic effects in comparison to NaPa and CMDB. In addition, we assessed in vitro the antiproliferative effects of these drugs on other breast cancer cells, including MDA-MB-231, MDA-MB-435 and MCF-7. 3. In vitro, NaPaC inhibited MCF-7ras cell proliferation by 40% at concentration lower than that of CMDB and NaPa (12 microM vs 73 microM and 10 mM). IC(50)s were 6 and 28 microM for NaPaC and CMDB, respectively. The similar results were obtained for three other breast cancer cell lines. NaPaC reduced the DNA replication and induced cell recruitment in G(0)/G(1) phase more efficiently than its components. Moreover, it induced a cell death at concentration 1000-fold lower than NaPa. 4. In vivo, CMDB (150 mg kg(-1)) and NaPa (40 mg kg(-1)) inhibited the MCF-7ras tumour growth by 37 and 57%, respectively, whereas NaPaC (15 mg kg(-1)) decreased tumour growth by 66% without toxicity. 5. NaPa or CMDB reduced the microvessel number in tumour by 50% after 7 weeks of treatment. NaPaC had the same effect after only 2 weeks. After 7 weeks, it generated a large necrosis area without detectable microvessels. In vitro, NaPaC inhibited human endothelial cell proliferation more efficiently than CMDB or NaPa. NaPaC interacts with vascular endothelial growth factor as observed by affinity electrophoresis. 6. NaPaC acts like NaPa and CMDB but in more potent manner than components used separately. Its antiproliferative, aponecrotic and anti-angiogenic actions make it a good candidate for a new anti-cancer drug.

Sodium phenylacetate (NaPa) and carboxymethyl benzylamide dextran derivative (CMDBLS4) are able to inhibit growth of breast tumour cells. In this study, we explored whether the combination of NaPa and CMDBLS4 may enhance their respective inhibitory effects on the MCF-7ras cell growth in vitro and in vivo. NaPa inhibited MCF-7ras cell proliferation by reducing the DNA replication concomitantly with a recruitment of cells in G0/G1 phase and by inducing apoptosis in a dose- and time-dependent manner. The addition of CMDBLS4 potentiated the NaPa antiproliferative effect in the manner dependent on the ratio of CMDBLS4 and NaPa concentrations. In nude mice, CMDBLS4 (150 mg kg−1) or NaPa (40 mg kg−1) administrated twice a week, for 7 weeks inhibited MCF-7ras xenograft growth by 40% and 60%, respectively. The treatment by both, CMDBLS4 and NaPa, decreased tumour growth by 83% without any toxicity. To better understand the mechanism of NaPa and CMDBLS4 action we assessed their effect on mitogenic activity of MCF-7ras conditioned medium (CM) on BALBC/3T3 fibroblasts. CMDBLS4 added to the CM, inhibited its mitogenic activity whereas NaPa had an anti-mitogenic effect when CM was prepared from MCF-7ras cells pretreated with NaPa. Thus, the antiproliferative effects of NaPa and CMDBLS4 involve 2 different mechanisms explaining, at least in part, the possible synergism between them. Overall, this study points to the potential use of a combination of dextran derivatives with NaPa to inhibit the breast tumour growth. © 2001 Cancer Research Campaignhttp://www.bjcancer.com

Vascular endothelial growth factor (VEGF) binding to the kinase domain receptor (KDR/FLK1 or VEGFR–2) mediates vascularization and tumor-induced angiogenesis. Since there is evidence that KDR plays an important role in tumor angiogenesis, we sought to identify peptides able to block the VEGF–KDR interaction. A phage epitope library was screened by affinity for membrane-expressed KDR or for an anti-VEGF neutralizing monoclonal antibody. Both strategies led to the isolation of peptides binding KDR specifically, but those isolated by KDR binding tended to display lower reactivities. Of the synthetic peptides corresponding to selected clones tested to determine their inhibitory activity, ATWLPPR completely abolished VEGF binding to cell-displayed KDR. In vitro, this effect led to the inhibition of the VEGF-mediated proliferation of human vascular endothelial cells, in a dose-dependent and endothelial cell type-specific manner. Moreover, in vivo, ATWLPPR totally abolished VEGF-induced angiogenesis in a rabbit corneal model. Taken together, these data demonstrate that ATWLPPR is an effective antagonist of VEGF binding, and suggest that this peptide may be a potent inhibitor of tumor angiogenesis and metastasis.

International audience; Zosterin, an apiose-rich pectic polysaccharide, was extracted and purified from the sea grass Zostera marina. Structural studies conducted by gas chromatography and NMR spectroscopy on a purified zosterin fraction (AGU) revealed a typical apiogalacturonan structure comprising an α-1,4-d- galactopyranosyluronan backbone substituted by 1,2-linked apiofuranose oligosaccharides and single apiose residues. The average molecular mass of AGU was estimated to be about 4100 Da with a low polydispersity. AGU inhibited proliferation of A431 human epidermoid carcinoma cells with an approximate IC50 value of 3 μg/mL (0.7 μM). In addition, AGU inhibited A431 cell migration and invasion. Preliminary experiments showed that inhibition of metalloproteases expression could play a role in these antimigration and anti-invasive properties. Autohydrolysis of AGU, which eliminated apiose and oligo-apiose substituents, led to a virtual disappearance of cytotoxic properties, thus suggesting a direct structure-function relationship with the apiose-rich hairy region of AGU.

International audience; Electrocardiogram (ECG) is required during magnetic resonance (MR) examination for monitoring patients under anaesthesia or with heart diseases and for synchronizing image acquisition with heart activity (triggering). Accurate and fast QRS detection is therefore desirable, but this task is complicated by artefacts related to the complex MR environment (high magnetic field, radio-frequency pulses and fast switching magnetic gradients). Specific signal processing has been proposed, whether using specific MR QRS detectors or ECG denoising methods. Most state-of-the-art techniques use a connection to the MR system for achieving their task, which is a major drawback since access to the MR system is often restricted. This paper introduces a new method for on-line ECG signal enhancement, called ICARE, which takes advantage of using multi-lead ECG and does not require any connection to the MR system. It is based on independent component analysis (ICA) and applied in real time. This algorithm yields accurate QRS detection for efficient triggering.

International audience; Due to heart motion, cardiac MRI is made difficult and image acquisitions have to be synchronized with heart activity to suppress cardiac motion artifacts. Electrocardiogram (ECG) is the most accurate tool for this purpose, and Triggering consists in synchronizing MR sequences on the R-waves. The complex MR environment worsens ECG acquisition conditions because of the static magnetic field (Hall Effect), Radio Frequency (RF) and fast switching magnetic field gradients. Many hardware developments have been achieved so as to limit these undesirable effects [1], but gradient artifacts are still a problem and signal processing is required. Two ways of research have been followed; (a) first way consists in building a MR specific QRS detector [2], which is based on the vectocardiogram (VCG) the 3D representation of heart activity. This method does unfortunately not provide a clear ECG and is unable to process patient with low VCG amplitude. (b) Secondly a real-time gradient artifact suppression method has been designed. This method is based on adaptive signal processing [3] and achieves real-time accurate denoising which enables triggering. This method requires gradient signals information, which is a major drawback as the connection to the MR system is rarely available. In this paper a new real-time gradient artifact correction, which does not require any connection to the MR system, is presented. The magnetic field pulse signals will be provided by a new specifically MR designed 3D Hall probe, integrated on a low cost 0.35\μm CMOS technology [4, 5].

The synthesis and biological activity of chloroethyl pyrimidine nucleosides is presented. One of these new nucleosides analogues significantly inhibited cell proliferation, migration and invasion as tested in vitro on the A431 vulvar epidermal carcinoma cell line.

Sodium phenylacetate (NaPa) inhibits breast cancer cell proliferation decreasing prenylation of small G proteins including Ras.Aponecrosis induced by NaPa in MCF-7 and MCF-7ras breast cancer cells was evaluated by measuring Annexin V/PI labelling by flow cytometry. Specific inhibitors of p42/44 (PD 98059), p38 (SB 600125) and JNK (SP 202190) in association with NaPa were also tested. Mitogen-activated kinase (MAPK) activation was measured by immunoprecipitation.NaPa induced cell death more efficiently (80%) in the MCF-7ras cells compared to the MCF-7 cells (60%). NaPa activated ERK 1/2 and its combination with PD 98059 decreased cell death in the MCF-7ras cells in contrast to the MCF-7 cells. Combination of NaPa with specific inhibitors of both JNK and p38 kinases also partly decreased MCF-7ras cell death.NaPa induced cell death differently when ras was overexpressed in breast cancer cells, partly involving p42/44, JNK and p38 pathways.

L'acquisition de l'électrocardiogramme (ECG) pendant un examen IRM est rendue complexe par la présence d'un champ magnétique intense, d'impulsions radiofréquence et de gradients de champ magnétique. Des capteurs spécifiques ont été réalisés afin de minimiser les effets perturbateurs de cet environnement. Néanmoins, ceci n'est pas suffisant et l'ECG reste fortement bruité rendant obligatoire un traitement du signal spécifique. Différentes méthodes de débruitage, basées sur une modélisation des artéfacts à partir des signaux de commande des gradients, ont été proposées. L'inconvénient est que l'accès à ces signaux est restreint. Nous proposons ici une méthode de réduction d'artéfacts qui n'utilise que l'information fournie par les capteurs ECG en appliquant une analyse en composantes indépendantes (ACI).

International audience; The synthesis and biological activity of chloroethyl pyrimidine nucleosides is presented. One of these new nucleosides analogues significantly inhibited cell proliferation, migration and invasion as tested in vitro on the A431 vulvar epidermal carcinoma cell line.

International audience; The synthesis and biological activity of a novel DNA cross-linking antitumor agent is presented. The new alkylating agent significantly inhibited cell proliferation, migration and invasion as tested in vitro on the A431 vulvar epidermal carcinoma cell line.

International audience; Xylans were purified from delignified holocellulose alkaline extracts of Castanea sativa (Spanish chestnut) and Argania spinosa (Argan tree) and their structures analyzed by means of GC of their per-trimethylsilylated methylglycoside derivatives and (1)H NMR spectroscopy. The structures deduced were characteristic of a 4-O-methylglucuronoxylan (MGX) and a homoxylan (HX), respectively, with degrees of polymerization ranging from 182 to 360. In the case of MGX, the regular or random distribution of 4-O-methylglucuronic acid along the xylosyl backbone--determined by MALDI mass spectrometry after autohydrolysis of the polysaccharide--varied and depended both on the botanical source from which they were extracted and on the xylan extraction procedure. The MGX also inhibited in different ways the proliferation as well as the migration and invasion capability of A431 human epidermoid carcinoma cells. These biological properties could be correlated with structural features including values of the degree of polymerization, 4-O-MeGlcA to xylose ratios, and distribution of 4-O-MeGlcA along the xylosyl backbone, giving evidence of a defined structure-activity relationship.

The CC-chemokine regulated on activation, normal T-cell expressed, and presumably secreted (RANTES)/CCL5 mediates its biological activities through activation of G protein–coupled receptors, CCR1, CCR3, or CCR5, and binds to glycosaminoglycans. This study was undertaken to investigate whether this chemokine is involved in hepatoma cell migration or invasion and to modulate these effects in vitro by the use of glycosaminoglycan mimetics. We show that the human hepatoma Huh7 and Hep3B cells express RANTES/CCL5 G protein–coupled receptor CCR1 but not CCR3 nor CCR5. RANTES/CCL5 binding to these cells depends on CCR1 and glycosaminoglycans. Moreover, RANTES/CCL5 strongly stimulates the migration and the invasion of Huh7 cells and to a lesser extent that of Hep3B cells. RANTES/CCL5 also stimulates the tyrosine phosphorylation of focal adhesion kinase and activates matrix metalloproteinase-9 in Huh7 hepatoma cells, resulting in increased invasion of these cells. The fact that RANTES/CCL5-induced migration and invasion of Huh7 cells are both strongly inhibited by anti-CCR1 antibodies and heparin, as well as by β-d-xyloside treatment of the cells, suggests that CCR1 and glycosaminoglycans are involved in these events. We then show by surface plasmon resonance that synthetic glycosaminoglycan mimetics, OTR4120 or OTR4131, directly bind to RANTES/CCL5. The preincubation of the chemokine with each of these mimetics strongly inhibited RANTES-induced migration and invasion of Huh7 cells. Therefore, targeting the RANTES-glycosaminoglycan interaction could be a new therapeutic approach for human hepatocellular carcinoma. [Mol Cancer Ther 2007;6(11):2948–58]

Summary Introduction Investigation of the role of vascular endothelial growth factor-C (VEGF-C) and VEGF receptor-3 (VEGFR-3) in non-small-cell lung cancer (NSCLC) has mainly focused on lymph node (LN) metastasis related to lymphangiogenesis. However, the coexpression of VEGF-C/VEGFR-3 by tumour cells can independently play an important role. The present study was therefore designed to evaluate VEGF-C/VEGFR-3 coexpression in tumour cells from the primary tumour and corresponding LN metastases. Methods VEGF-C and VEGFR-3 expression in cancer cells were evaluated by immunohistochemistry in 92 NSCLC samples and 45 metastatic LNs. Ki67 expression and mitotic index (MI) in tumours and clinicopathological data were analysed concurrently. Results VEGFR-3 and VEGF-C expression were observed in 42% and 74% of tumours, respectively. Concurrent expression of VEGF-C and VEGFR-3, observed in 39% of tumours, was significantly associated with a higher proliferation rate and a higher incidence of LN metastases. VEGF-C expression in tumour cells was observed in 100% of metastatic LN and VEGF-C/VEGFR-3 coexpression was observed in 71% of metastatic LN. Finally, concurrent expression of VEGF-C/VEGFR-3 in the primary tumour was associated with poor disease-free survival on univariate analysis. Conclusion In NSCLC cancer cells, VEGF-C/VEGFR-3 coexpression suggests an autocrine/paracrine loop responsible for a high proliferation rate in tumour cells. As VEGF-C/VEGFR-3 coexpression is very frequent in metastatic LN tumour cells, it can be hypothesised that this coexpression participates in the growth of LN metastasis.

International audience; A glucuronoxylan was purified from a delignified holocellulose alkaline extract of Castanea sativa (Spanish chestnut) and its structure analyzed by means of FT-IR, GC of the per-trimethylsilylated methylglycoside derivatives, and 1H and 13C NMR spectroscopy. The results supported a structure based on a linear polymer of xylopyranose units linked with beta(1-->4) bonds in which, on average, one out of every six units is substituted at C-2 by a 4-O-methylglucuronic acid unit; this structure is typical of a hardwood acidic 4-O-methylglucuronoxylan (MGX) with an estimated degree of polymerization of 200. The MGX from C. sativa inhibited the proliferation of A431 human epidermoid carcinoma cells with an IC50 value of 50 microM. In addition, this xylan inhibited A431 cell migration and invasion. Preliminary experiments showing that secretion of metalloproteinases MMP2 and MMP9 by A431 tumor cells was inhibited by the purified C. sativa MGX strongly suggest that this mechanism of action may play a role in its antimigration and anti-invasive properties.

International audience; The capsular polysaccharide produced by the thermophilic blue green alga/cyanobacterium Mastigocladus laminosus was tested for its cytotoxic activity against the A431 human epidermoid carcinoma cell line. This polysaccharide inhibited the proliferation of A431 cells in a dose-dependent manner with an IC (50) value of 50 microg mL (-1). In addition, this polysaccharide strongly inhibited A431 cell migration and invasion. Preliminary experiments showing that secretion of metalloproteinases MMP2 and MMP9 by A431 tumour cells was inhibited by this polysaccharide suggest that this mechanism of action could play a role in its anti-migration and anti-invasive properties. Acid hydrolysis of the polysaccharide produced specific oligosaccharides which conserved - at similar concentrations - their cytotoxic, anti-migration and anti-invasion properties; in this case, the mechanism of action was nevertheless uncorrelated to the decrease of metalloproteinase expression.

The integration of an electrocardiogram (ECG) device into a chip is already well known in the field of implanted devices, such as pacemakers. For noninvasive electrocardiology, this approach has not been used on a broad scale commercially. The extension of electrocardiology to telemetry, home care, and special applications as in magnetic resonance imaging has spawned a new interest in highly miniaturized ECG devices. In our company, we are aiming for using highly integrated devices exactly in these fields. On one hand, the home monitoring market (“eHealth,” “pHealth”) requires small and lightweight devices (“ECG in an electrode”); on the other hand, the use of an ECG device within a hostile environment as in an magnetic resonance imaging machine with strong electromagnetic fields requires small dimensions of the device. Of these 2 fields, the one of home monitoring is the most promising. There is a large population in need of such monitoring (eg, patients with congestive heart failure), and the cost issue in medical care drives the market in this direction. Projects in both fields will be presented as well as the first experiences as a middle-sized manufacturer in trying to produce an integrated ECG “device.”

Bisphosphonates are extensively used in the treatment of patients with metastasis-induced osteolysis. The major drawback in the efficacy of all bisphosphonates lies in their high hydrophilic nature, which results in poor membrane permeability and low availability for soft tissues. A reasonable approach to overcome these problems consists in masking one or more ionizable groups of bisphosphonates, notably by esterification of the hydroxyl functions. We have previously shown that the novel non-nitrogen-containing bisphosphonate BP7033 inhibited angiogenesis and growth of primary tumors in nude mice. The present study focuses on the dimethyl-esterified analog of this compound (Me-BP7033). In-vitro, Me-BP7033 inhibited proliferation of human carcinoma A431 cells as well as their invasive activity based on a transwell invasion assay. in-vivo, administration of Me-BP7033 (0.3 mg/kg) twice a week for 5 weeks inhibited the tumor growth of A431 cells xenografted in nude mice by 65%. Immunostaining of endothelial cells (ECs) in tumor sections revealed that Me-BP7033 inhibited the intratumor ECs density by 60%. The in-vivo anti-angiogenic properties of Me-BP7033 were also demonstrated in an in-vivo angiogenesis assay showing that Me-BP7033 reduced the vascular endothelial growth factor-stimulated infiltration of ECs in a Matrigel plug by 70%. In summary, we demonstrated for the first time that a diesterified bisphosphonate exhibited in vivo both anti-tumoral and anti-angiogenic activities with no apparent sign of toxic effects. These new diesterified compounds, which could display enhanced bioavailability and pharmacokinetics, thus represent interesting candidates for therapeutic applications such as cancer treatment.

There is increasing evidence that bisphosphonates have direct antitumor effects in vivo in addition to their therapeutic antiresorptive properties. Bisphosphonates inhibit proliferation and induce apoptosis of many cancer cell lines. They also exhibit anti-invasive properties in vitro and in vivo. We have previously shown that a novel non-nitrogen-containing bisphosphonate inhibited tumor growth of A431 human epidermoid carcinoma cells. In the present study, we investigated the antitumor properties of three nitrogen-containing bisphosphonates on A431 cells in vitro. We first compared the antiproliferative effects of pamidronate, alendronate and neridronate. Then, by matrigel invasion assay, the effect of alendronate on A431 cell invasiveness was studied. All three bisphosphonates were found to inhibit cell proliferation dose- and time-dependently. The most potent molecule was alendronate. The invasion test demonstrated that alendronate also inhibited cell invasion in a Boyden chamber. These data suggest that alendronate may have beneficial effects in the treatment of carcinomas exhibiting important angiogenesis.

In this paper we present an integrated ECG acquisition system implemented in a standard 0.35 μm CMOS technology. The system mainly consists of amplifiers, filters and an automatic offset compensation module. Composed of comparator, control logic and D/A converter, the compensator is an analog-digital mixed system and designed through a top-down approach. It is an independent module and can be easily reused. A low-pass filter of low cutoff frequency has been realized by using a Gm-C structure with very low bias current. Experimental measurements on the fabricated chip have been done. The results show that the integrated circuit works well with a low noise, a low consumption and a high efficacy of the offset compensator.

We previously reported a simple and efficient one-pot procedure for synthesis of 1-hydroxymethylene-1,1-bisphosphonic acids (HMBP). According to this method, we synthesized a series of new aromatic HMBP and investigated structure-activity relationships by evaluating their anti-proliferative activity against A431 human tumor cell line. Our results showed that the introduction of an extra methylene group in a pyridyl-containing R2 side chain increased 100-fold the anti-proliferative activity of the HMBP. In contrast, this chemical modification did not modify the anti-proliferative activity of compounds substituted with a phenyl-containing R2 side chain. Para-substitution of the phenyl ring with various groups markedly influenced the HMBP activity, the order of potency (brominechlorinefluorine = none) closely matching the atomic volume of the substituted group. Moreover, changes in the substitution position of the bromine group also affected the anti-proliferative activity, the more potent activity being obtained with para-substitution of the phenyl ring. In conclusion, this structure-activity study led us to identify the new aromatic HMBP [(4-Bromo-phenyl)-hydroxy-phosphono-methyl]-phosphonic acid as a potent in vitro anti-proliferative molecule against tumor cell lines (IC50 value of 9.5 x 10(-5) M). Interestingly, this compound can be further easily esterified on its phosphonic acid functions according to our chemical method and, thus, represents a potential candidate for the development of new esterified HMBP with enhanced pharmacokinetics.

Electrocardiogram (ECG) acquisition is still a challenge as gradient artefacts superimposed on the electrophysiological signal can only be partially removed. The signal shape of theses artefacts can be similar to the QRS-complex, causing possible misinterpretation during patient monitoring and false triggering/gating of the MRI. For their real-time suppression, an adaptive filter is proposed. The adaptive filter is based on the noise-canceller configuration with LMS coefficient updates. The references of the noise canceller are the three gradient signals that are acquired simultaneously with the noisy ECG. Tests were done on patients, on volunteers and using an MR-safe ECG simulator. The noise canceller's performance was measured offline, simulating real-time processing by point-by-point operations. To create worst-case scenarios, clinical sequences with strong- and fast-switching gradients have been chosen. The noise-cancelling filter reduces the gradient artefacts' peak amplitudes by 80-99% after adaptation, without changing the desired ECG signal shape. The estimated reduction of total average power of the MR gradient artefacts is 62-98%. The proposed filter is capable of reducing artefacts due to strong- and fast-switching gradients in real-time applications and worst-case situations. The quality of the ECG is sufficiently high that a standard one-lead QRS-detector can be used for gating/triggering the MRI. For permanent patient monitoring, further improvements are needed.

Bisphosphonates (BP) are powerful inhibitors of bone resorption and are widely used in the treatment of patients with metastasis-induced osteolysis. In the present study, we show that a novel non-nitrogen-containing BP (BP7033) that exhibits antitumor activity is a potent inhibitor of both in vivo and in vitro angiogenesis. When administered to mice, BP7033 inhibited tumoral angiogenesis (65% at 0.06mg/injection) as well as tumor growth (65% at 0.006mg/injection) in a tumor model of A431 cells xenografted in nude mice, with no sign of toxicity. Additionally, in vivo angiogenesis induced by vascular endothelial growth factor-containing Matrigel implants was reduced by 90% in the presence of BP7033 (0.6mg/plug). In vitro, BP7033 inhibited proliferation of human umbilical vein endothelial cells (HUVEC) (IC(50) value 3x10(-4) M) and completely prevented the formation of capillary-like tubules by HUVEC in Matrigel. Moreover, treatment of A431 cells by BP7033 induced an inhibition of Ras processing and a decrease in the secretion of both vascular endothelial growth factor and matrix metalloproteinase-2, two well-known stimulators of the proliferation and migration of endothelial cells. These findings indicate that this new BP compound has marked antiangiogenic properties and thus represents a promising candidate for treatment of malignant diseases with an angiogenic component.

We investigated the effect of a new dextran derivative, phenylacetate carboxymethyl benzylamide dextran (NaPaC), on epidermoid carcinoma A431 cells secreting a large quantity of angiogenic factor, vascular endothelial growth factor (VEGF). In vitro, NaPaC inhibited the proliferation of A431 cells (IC(50)=5 micro M). Also, NaPaC decreased the binding of radiolabelled VEGF(165) to endothelial cells (IC(50)=0.2 micro M). In vivo, we explored the effects of NaPaC (15 mg kg(-1)) on A431 xenograft growth starting the drug administration at the time of tumour cell inoculation (early treatment) and 1 week later, when tumours were well established (late treatment). Early treatment was more efficient on tumour inhibition (70% vs control) than late treatment (50% vs control). Early and late NaPaC-treatment increased the aponecrosis in tumour by 70 and 30%, respectively. Whatever treatment, NaPaC inhibited the intratumour endothelial cell density in the same manner. In contrast, vessel area was decreased only when NaPaC was injected early (35%). These results show that NaPaC has a potent inhibitory effect, dependent on treatment outset, on epidermoid carcinoma growth associated with an intratumour microvascular network diminution and an aponecrosis increase. As this drug is nontoxic at efficient dose, it offers interesting perspectives for the therapy of malignant lesions.

In this work, the tumor suppressor gene p16 was efficiently transferred into FR cells isolated from a patient with malignant mesothelioma using cationic liposomes prepared from trimethyl aminoethane carbamoyl cholesterol (TMAEC-Chol) and triethyl aminopropane carbamoyl cholesterol (TEAPC-Chol). This transfer was performed after preliminary assays were undertaken to find the optimal transfection conditions. Results showed that an efficient transfer of plasmids containing the reporter gene pCMV-β galactosidase vectorized by TMAEC-Chol/DOPE and TEAPC-Chol/DOPE liposomes into mesothelioma FR cells was obtained as assessed by luminometric measurements of β-galactosidase activity. Cytotoxicity studied by MTT test showed that at concentrations used for this study, the cationic liposomes have no effect on cell growth. Transfer into mesothelioma FR cells of a plasmid construct containing the tumor suppressor gene p16 was carried out with these liposomes. Western blotting and immunofluorescence showed the presence of p16 in treated cells. An inhibition of cell growth was observed, indicating that efficient tumor suppressor gene transfer can be performed by using cationic liposomes.

1. Since the sodium phenylacetate (NaPa) was reported to enhance the inhibitory effect of carboxymethyl benzylamide dextran (CMDB) on the breast cancer growth, we performed the esterification of CMDB with NaPa to obtain a new drug carrying the characteristics of these two components. A new molecule, phenylacetate carboxymethyl benzylamide dextran, was named NaPaC. 2. We investigated in vitro and in vivo the effects of NaPaC on MCF-7ras cell growth as well as its apoptotic and antiangiogenic effects in comparison to NaPa and CMDB. In addition, we assessed in vitro the antiproliferative effects of these drugs on other breast cancer cells, including MDA-MB-231, MDA-MB-435 and MCF-7. 3. In vitro, NaPaC inhibited MCF-7ras cell proliferation by 40% at concentration lower than that of CMDB and NaPa (12 microM vs 73 microM and 10 mM). IC(50)s were 6 and 28 microM for NaPaC and CMDB, respectively. The similar results were obtained for three other breast cancer cell lines. NaPaC reduced the DNA replication and induced cell recruitment in G(0)/G(1) phase more efficiently than its components. Moreover, it induced a cell death at concentration 1000-fold lower than NaPa. 4. In vivo, CMDB (150 mg kg(-1)) and NaPa (40 mg kg(-1)) inhibited the MCF-7ras tumour growth by 37 and 57%, respectively, whereas NaPaC (15 mg kg(-1)) decreased tumour growth by 66% without toxicity. 5. NaPa or CMDB reduced the microvessel number in tumour by 50% after 7 weeks of treatment. NaPaC had the same effect after only 2 weeks. After 7 weeks, it generated a large necrosis area without detectable microvessels. In vitro, NaPaC inhibited human endothelial cell proliferation more efficiently than CMDB or NaPa. NaPaC interacts with vascular endothelial growth factor as observed by affinity electrophoresis. 6. NaPaC acts like NaPa and CMDB but in more potent manner than components used separately. Its antiproliferative, aponecrotic and anti-angiogenic actions make it a good candidate for a new anti-cancer drug.

This study examines the effect of varying several factors, both extrinsic and technology-dependent, on the reconstruction of human sperm trajectories and the derived kinematic measurements using videotapes and the Motion Analysis Celltrak/S instrument. In semen samples from normal healthy men, curvilinear (VCL) and straight line velocities (VSL) were found to increase 1.5-fold, and linearity (LIN) of trajectories and amplitude of lateral head displacement (ALH) increased 1.25-fold when the temperature of analysis was raised from 24 to 37 degrees C. Only VCL and VSL were found to increase significantly between 24 and 37 degrees C for sperm samples selected by Percoll gradient and incubated in a capacitating medium. An analysis chamber of 20 microm depth was found to be adequate for seminal sperm samples while for Percoll-selected sperm samples the analysis in a 50 microm depth provided the highest proportions of spermatozoa with the highest VCL and the largest ALH. The grey level detection threshold required careful adjustment: using a threshold lower than the optimal threshold produced spurious sperm trajectories for seminal sperm samples and rejected some trajectories for Percoll-selected sperm samples. Definition of the appropriate frame rate and maximum burst speed was critical for valid trajectory reconstruction and therefore adequate derived kinematic measurements. Optimal values of these parameters were found to be 30 Hz and 400 microm/s for seminal spermatozoa and 60 Hz and 700 microm/s for selected spermatozoa. The optimal values of 'ALH path-smoothing factor' used to calculate average path and ALH were 5-10 points for seminal spermatozoa analysed at 30 Hz and 15-20 points for selected spermatozoa analysed at 60 Hz. We propose a set of standard conditions for reliable kinematic analysis of human spermatozoa using the Celltrak/S system.

Immunolocalization of desmin in fetal rat livers shows that on day 12 of gestation a high number of liver cells express desmin. This number decreases from day 14 onward. On day 20 about the same density of desmin-containing cells is found in fetal rat livers as is found in adult rat livers. Desmin-containing cells show two types of labeling patterns, especially on days 12 and 13 of gestation: (a) a basketlike network of intermediate filaments throughout the whole cell, similar to the labeling pattern of cytokeratin in hepatocytes; and (b) more strongly labeled intermediate filaments developing long and slender processes between adjacent cells, close to the labeling pattern of Ito cells in adult rats. From day 14 of gestation, the first type becomes rare, and from day 18 only the second type remains. Double-labeling experiments show that coexpression of desmin and cytokeratin is found in cells of the first type on days 12, 13 and 14 of gestation. Cells containing desmin with the labeling pattern of the second type never express cytokeratin. Coexpression of vimentin and cytokeratin is never found in fetal hepatocytes, even on day 12 of gestation. Numerous nonhepatocyte cells coexpress desmin and vimentin, but some cells contain vimentin or desmin alone. In desmincontaining cells the labeling pattern is of the first type (basketlike network). These results suggest that in early stages of fetal liver development, desmin is found in two different types of liver cells. Cells of the first type contain cytokeratin and desmin, and those of the second type contain desmin and vimentin, as Ito cells in adult liver tissue. Cells of the first type might represent a particular type of fetal hepatocyte. The existence of these two types of desmin immunolocalization is in convergence with electron microscopic data showing numerous lipid droplets both in fetal hepatocytes and in perisinusoidal cells. It is generally admitted that fetal liver differentiation is the result of the close association between endodermal and mesenchymal cells. Among the latter, desmin-containing cells (fetal Ito cells) might play a crucial role, especially because they are known to contain vitamin A and to express a hepatocyte growth factor in the normal adult liver. (HEPATOLOGY 1993;17:293–300.)

We previously showed that sodium phenylacetate (NaPa) and carboxymethyl benzylamide dextran (CMDB) are both able to block the tumor growth of the breast cancer cell line MCF-7ras in athymic mice. In this study, we studied the effect of a new molecule: a CMDB esterified by phenylacetic acid (NaPaC). In vitro, NaPaC can inhibit threefold to fourfold more MCF-7ras proliferation than NaPa alone. Furthermore, we showed that the antiproliferative activity of NaPaC was dependent on phenylacetate substitution. In vivo studies showed that a very low dose of NaPaC (15 mg/kg) inhibited the MCF-7ras tumor growth of 60% without animal toxicity. The inhibition of tumor growth was concomitant with a reduction in angiogenesis and an increase in necrosis. Moreover, we demonstrated that NaPaC inhibited the paracrine mitogenic effect of MCF-7ras conditioned medium (CM) on fibroblasts and endothelial cells proliferation.

In this paper we present a novel approach of simulating urban growth by utilising the computation power of modern GPUs. The simulation results can be used in urban policy modelling to reduce turnaround times in the policy cycle. We use a state-of-the-art agent-based simulation model that consists of rules to describe human behaviour. The simulation incorporates geospatial information such as land-use, current population density and road network data. In order to simulate the phenomena of urbanisation, in our model citizens more likely settle near roads or existing settlements/cities. In this paper we present our implementation that is based on the FLAME GPU framework. Each agent on the GPU represents a group of citizens at a specific location. In order to evaluate our approach we present a practical use case. We measure the performance of our implementation and compare it with a Java-based solution. Finally, we discuss our approach and show opportunities for agile and interactive urban policy modelling. INTRODUCTION AND MOTIVATION The term “urban sprawl” describes the problem of modern cities growing quickly resulting in wide-spread developments with a very low density. This often has negative effects on environment and therefore on people’s health: more land is covered with buildings or streets; public transport in suburbs is often not sufficiently developed and so citizens have to use the car to get to their job or to the city centre which effectively leads to a higher air pollution. Besides, urban sprawl may also affect the cultural life and family life. People living in suburbs sometimes participate less in cultural events than people living near the city centre. Long travels to work and back to home reduce the time an employee can spend with his or her family. Urban planning and policy modelling therefore aim for creating more compact but at the same time sustainable and healthy cities. This development requires infrastructure changes that have to be well thought out. So, urban planners more and more involve citizens in the discussion about urban development plans in order to create a city that is well received by everyone. They make use of simulations based on geospatial information. Innovative techniques such as 3D visualisation help urban planners to present the simulation results to decision makers and to the public. Modern urban policy modelling deploys a so-called policy cycle (see Kramer et al., 2013). Simulations and 3D visualisations are used to gain feedback from decision makers and citizens. This feedback can then be incorporated in new simulations which are presented to the public again. This loop repeats until a general agreement on the planning has been found. The shorter the feedback cycle is, the faster a final decision can be made. Creating such simulations is currently a timeconsuming task that may take several hours or even days with existing solutions (see section “Performance” below). Urban planners often make use of modern satellite imagery to improve their calculations. For example, satellite images or LIDAR data spanning several years allow urban planners to calculate urban growth and hence to estimate future trends. The ongoing development of sensor technology leads to more accurate data sets which may be exploited to achieve better simulation results. However, at the same time the volume of data to process becomes larger and larger which makes them harder to process with standard geospatial information systems (GIS). Nonetheless, quickly creating simulations based on such data sets is a crucial part for the urban policy feedback cycle. Modern computer architectures with multi-core CPUs and GPUs allow for creating high performance applications (cf. Owens et al., 2007). However, current GIS solutions do not fully take advantage of this yet. In practice, urban planners process raster data or point clouds such as satellite images or LIDAR data respectively with software tailored to simple workstations. In recent years these workstations have evolved and already include sophisticated graphics hardware. With this hardware it now becomes possible to not only create high performance 3D visualisations but also to make use of the thousands Proceedings 27th European Conference on Modelling and Simulation ©ECMS Webjorn Rekdalsbakken, Robin T. Bye, Houxiang Zhang (Editors) ISBN: 978-0-9564944-6-7 / ISBN: 978-0-9564944-7-4 (CD) and millions of cores offered by a modern GPU to create geospatial simulations. Modelling the behaviour of citizens in an urban environment can be rather complex in that it is non-linear and possibly chaotic. A lot of individual factors have to be taken into account that make the model large and hard to comprehend. Agent-based modelling (ABM) attempts to simplify such problems. Agents are autonomous units that act on their own, just like citizens. Modelling urban life becomes a lot easier by considering only one citizen or a group of similar citizens and by representing them as individual agents. Modern graphics hardware allows agent-based simulations to run on the GPU. So, it is possible to create high-performance simulations modelling urban life on the graphics card. To summarise, in order to create sustainable, compact cities, urban planners deploy a feedback cycle that is based on geospatial simulations. The shorter this cycle is, the faster decisions can be made. However, geospatial data—which provides the basis for such simulations— becomes larger and larger and so simulations take more and more time with current GIS technology. In this paper we therefore present a new approach of interactively simulating urban development with modern GPU hardware. We use agents to model real urban life. We describe our implementation and evaluate its performance compared to a pure Java application. We conclude with a final discussion on the applicability of our approach to a practical use case, and we show opportunities for agile urban policy modelling.

International audience; Acquisition of an Electrocardiogram (ECG) during MRI is challenging. Applications of magnetic field gradients induces artifacts on ECG signals, so that patient monitoring or sequence triggering remain complicated. Signal processing is required to accurately detect QRS. To overcome this issue, specific QRS detector based on vectocardiogram were designed [1] or artifact suppression methods were proposed [2, 3, 4] using information of the gradient signals as input. Here we propose a new method for artifact reduction applying Independent Component Analysis (ICA) [5] avoiding the connection to the gradient cabinet.