Biomedical subjects

A Noël

Publications and source records attributed to A Noël.

At least 19 recordsLinked to original sources

PubMed2006

Esophageal cancer: determination of internal target volume for conformal radiotherapy.

BACKGROUND AND PURPOSE: To evaluate esophageal tumor and OAR movement during the respiratory cycle in order to obtain optimal values for ITV and PRV. To correlate tumor motion with chest wall displacement - information of value in the free-breathing gating system. MATERIAL AND METHOD: Inclusion criteria were: histologically proven squamous-cell carcinoma (SCC) or adenocarcinoma at stage T3 - T4 NX or TX N1 M0 according to the UICC 1997 classification. Two spiral scans were performed with breath-hold respiration under spirometric control: one at end expiration (EBH) and the other at end inspiration (IBH). Displacements between exhalation and inhalation were calculated according to ICRU report 42 recommendations. For the correlation study, CT-scan acquisition was performed at the isocenter over a 20 - 40 s period. After Fourier Transform, frequency spectra for amplitude and phase of tumor and chest wall motions were performed for each patient. RESULTS: Cumulative distribution of CTV motion in absolute values showed that 95% of data ranged from 0 to 1 cm. Cumulative distribution of GTV motion in absolute values showed that 95% of data ranged from 0 to 0.8 cm. The correlation study demonstrated no specific relationship between respiratory and esophageal motions. CONCLUSION: The ITV margin for 3D conformal radiotherapy in esophageal cancer was 1 cm when 95% of motions were taken into account in this clinical study involving eight patients. Before using a free-breathing gating system, the correlation between external markers and target displacement during irradiation must be established for each patient.

Adenocarcinoma↗

PubMed2006

Regulation of vimentin by SIP1 in human epithelial breast tumor cells.

The expression of Smad interacting protein-1 (SIP1; ZEB2) and the de novo expression of vimentin are frequently involved in epithelial-to-mesenchymal transitions (EMTs) under both normal and pathological conditions. In the present study, we investigated the potential role of SIP1 in the regulation of vimentin during the EMT associated with breast tumor cell migration and invasion. Examining several breast tumor cell lines displaying various degrees of invasiveness, we found SIP1 and vimentin expression only in invasive cell lines. Also, using a model of cell migration with human mammary MCF10A cells, we showed that SIP1 is induced specifically in vimentin-positive migratory cells. Furthermore, transfection of SIP1 cDNA in MCF10A cells increased their vimentin expression both at the mRNA and protein levels and enhanced their migratory abilities in Boyden Chamber assays. Inversely, inhibition of SIP1 expression by RNAi strategies in BT-549 cells and MCF10A cells decreased vimentin expression. We also showed that SIP1 transfection did not activate the TOP-FLASH reporter system, suggesting that the beta-catenin/TCF pathway is not implicated in the regulation of vimentin by SIP1. Our results therefore implicate SIP1 in the regulation of vimentin observed in the EMT associated with breast tumor cell migration, a pathway that may contribute to the metastatic progression of breast cancer.

Base Sequence↗

PubMed2005

Identification of factors important for the success of suicide gene therapy after a comparative study of Varicella zoster and Herpes simplex viral thymidine kinases efficacy on breast cancer cells.

One of the most frequently studied therapeutic strategies in the field of suicide gene therapy is based on the expression by tumor cells of the Herpes simplex virus thymidine kinase gene (HSVtk) followed by a ganciclovir (GCV) treatment. In order to investigate the potential of other enzyme/prodrug strategies, we studied in vitro and in vivo the ability of the Varicella zoster virus thymidine kinase gene (VZVtk) to act as a suicide gene and to kill non-transduced bystander cells, and compared this activity to that of its HSV counterpart. Four different antiviral compounds were tested as prodrugs. Our comparative study demonstrates the superiority of the HSVtk/GCV system among the different combinations tested and underlines the importance of both the tumor cell type and the prodrug in the success of a prodrug/suicide gene strategy.

Animals↗

PubMed2005

[The metalloproteinases in cancer].

Tumor growth and metastatic dissemination are associated to important tissue remodelling involving matrix metalloproteinases (MMPS) acting in a concerted manner with serine proteases. Initially, it was generally accepted that proteases produced by tumor cells promote their invasive capacities by degrading extracellular matrix components. On the opposite, protease inhibitors were viewed as anti-cancer molecules. Recently, new insights into the understanding of peritumoral proteolysis were given by complete human genome sequencing and by improvement in transgenesis leading to the generation of mice deficient for genes of different proteolytic systems. Our work has evidenced the production of proteases and their inhibitors by host cells rather than by tumor cells themselves. It demonstrates the multifunctionality of proteases which can exert different effects by controlling several steps of cancer progression such as tumor growth, angiogenesis and invasion. It identifies these cells, whose genome is more stable than that of cancer cells, as potential therapeutic targets.

Animals↗

PubMed2004

Human chorionic gonadotropin and growth factors at the embryonic-endometrial interface control leukemia inhibitory factor (LIF) and interleukin 6 (IL-6) secretion by human endometrial epithelium.

BACKGROUND: The elucidation of the molecular mechanisms by which the embryo contributes to its implantation is an area of extensive research. The main objective of this study was to investigate the pattern of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) secretion by human endometrial epithelium, and their regulation by human chorionic gonadotropin (hCG) and other growth factors present at the embryonic-endometrial interface. METHODS: Endometrial epithelial cells (EEC) were isolated from biopsies collected at both proliferative and secretory phases of fertile women. RESULTS: HCG (1-50 IU/ml) increased LIF secretion by EEC cultures derived from follicular phase (up to 285+/-75%) or from secretory phase (up to 212+/-16%). In contrast, hCG reduced IL-6 secretion by EEC in both phases. The hCG/LH receptor gene was transcribed by EEC as evidenced by RT-PCR. Insulin-like growth factors 1 and 2 increased LIF secretion by EEC. Transforming growth factor beta1 stimulated LIF and reduced IL-6 secretion. CONCLUSIONS: Through hCG, the blastocyst may be involved in the control of its implantation (via an increase of proimplantatory LIF) and tolerance (via an inhibition of proinflammatory IL-6). Other growth factors present at the embryonic-endometrial interface are also involved in the control of LIF and IL-6 endometrial secretion.

Adolescent↗

PubMed2003

3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo.

In search for new anticancer agents, we have evaluated the antiinvasive and antimigrative properties of recently developed synthetic coumarin derivatives among which two compounds revealed important activity: 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate. Both drugs were able to inhibit cell invasion markedly in a Boyden chamber assay, the bromo derivative being more potent than the reference matrix metalloprotease (MMP) inhibitor GI 129471. In vivo, tumour growth was reduced when nude mice grafted with HT1080 or MDA-MB231 cells were treated i.p. 3 days week(-1) with the bromo coumarin derivative. These effects were not associated with the inhibition of urokinase, plasmin, MMP-2 or MMP-9. The mechanism of action of the drugs remains to be elucidated. However, these two coumarin derivatives may serve as new lead compounds of an original class of antitumour agents.

Animals↗

PubMed2003

Role of plasminogen activator-plasmin system in tumor angiogenesis.

New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and, conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand, genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.

Animals↗

PubMed2003

Effects of a progestogen on normal human breast epithelial cell apoptosis in vitro and in vivo.

Many investigators have reported cyclic proliferation of normal human breast epithelial cells. A delicate balance between proliferation and apoptosis (programmed cell death) ensures breast homeostasis. Both the follicular and luteal phases of the menstrual cycle are characterized by proliferation, whereas apoptosis occurs only at the end of the latter phase. In this study, we observed that the withdrawal of a synthetic progestin (nomegestrol acetate or NOMAC), but not continuous treatment with it, induced apoptosis of normal human breast epithelial cells in vitro and in women who applied NOMAC gel to their breasts. Furthermore, this apoptotic response was specific to normal breast cells, since withdrawal of NOMAC did not induce apoptosis of tumoral T47D cells in vitro or of fibroadenoma cells in women. These observations open up new perspectives in the prevention of hyperplasia and breast cancer.

Adolescent↗

PubMed2003

[Verification of the dose delivered to the patient by means of TLD, SC, PID. What future?].

Among the different possibilities to check the accuracy of the treatment delivered, only in vivo dosimetry ensures the precision of the dose delivered to the patient during the treatment. In 1970-1980, Ruden assessed the use of thermoluminescent dosimetry to perform in vivo measurements at Radiumemmet in Stockholm. Straightforward in its principle but demanding in its implementation, thermoluminescent dosimetry has largely been used. Today, thanks to the work of Rikner, the use of semiconductor detectors allows the general implementation of in vivo dosimetry. Tomorrow, we will use electronic portal imaging device to verify the geometrical patient setup and the dose delivery at the same time. Its implementation remains complex and will need the development of algorithms to compute exit dose or midplane dose using portal in vivo dosimetry. First clinical results show that portal imaging is an accurate alternative for conventional in vivo dosimetry using diodes.

Algorithms↗

PubMed2002

Murine 5T multiple myeloma cells induce angiogenesis in vitro and in vivo.

Multiple myeloma is a B cell malignancy. Recently, it has been demonstrated that bone marrow samples of patients with multiple myeloma display an enhanced angiogenesis. The mechanisms involved seem to be multiple and complex. We here demonstrate that the murine 5T multiple myeloma models are able to induce angiogenesis in vitro by using a rat aortic ring assay and in vivo by determining the microvessel density. The rat aortic rings cultured in 5T multiple myeloma conditioned medium exhibit a higher number of longer and more branched microvessels than the rings cultured in control medium. In bone marrow samples from 5T multiple myeloma diseased mice, a statistically significant increase of the microvessel density was observed when compared to bone marrow samples from age-matched controls. The angiogenic phenotype of both 5T multiple myeloma cells could be related, at least in part, to their capacity to produce vascular endothelial growth factor. These data clearly demonstrate that the 5T multiple myeloma models are good models to study angiogenesis in multiple myeloma and will allow to unravel the mechanisms of neovascularisation, as well as to test new putative inhibitors of angiogenesis.

Animals↗

PubMed2002

[Digital mammography and computer assisted diagnosis].

Until recently, the film has remained the only medium of information in mammography. The film is used to record, to exploit, to store and to transmit the image. Computerization of images allows to dissociate and to optimize these different functions. Among classical factors of image quality (spatial resolution, contrast, noise), new factors should be added like the detective quantum efficiency and the conversion factor. Radioluminescent screens, then digital sensors for breast stereotactic imaging have been marketed. Manufacturers are now testing full field digital mammographs. Digital imaging allows many applications (computed-aided diagnostic, 3D imaging.) and permits the easy transfer of images for diagnosis and teaching. Three parts are presented in this chapter. The first one describes the different imaging modalities and gives a reminder of the different elements related to image quality. The second one is related to the practical aspects of full field mammography, the reading of mammograms on a review station, ergonomy in full field mammography and to possible changes for screening mammography. The third part is devoted to computed aided diagnosis and its possible application in screening.

Diagnosis, Computer-Assisted↗

PubMed2001

Induction of SPARC by VEGF in human vascular endothelial cells.

SPARC/osteonectin/BM-40 is a matricellular protein that is thought to be involved in angiogenesis and endothelial barrier function. Previously, we have detected high levels of SPARC expression in endothelial cells (ECs) adjacent to carcinomas of kidney and tongue. Although SPARC-derived peptide showed an angiogenic effect, intact SPARC itself inhibited the mitogenic activity of vascular endothelial growth factor (VEGF) for ECs by the inhibiting phosphorylation of flt-1 (VEGF receptor 1) and subsequent ERK activation. Thus, the role of SPARC in tumor angiogenesis, stimulation or inhibition, is still unclear. To clarify the role of SPARC in tumor growth and progression, we determined the effect of VEGF on the expression of SPARC in human microvascular EC line, HMEC-1, and human umbilical vein ECs. VEGF increased the levels of SPARC protein and steady-state levels of SPARC mRNA in serum-starved HMEC-1 cells. Inhibitors (SB202190 and SB203580) of p38, a mitogen-activated protein (MAP) kinase, attenuated VEGF-stimulated SPARC production in ECs. Since intact SPARC inhibits phosphorylation ERK MAP kinase in VEGF signaling, it was suggested that SPARC plays a dual role in the VEGF functions, tumor angiogenesis, and extravasation of tumors mediated by the increased permeability of endothelial barrier function.

Cells, Cultured↗

PubMed2001

Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2: effect on in vivo mammary tumor growth and angiogenesis.

The tissue inhibitor of metalloproteinases-2 (TIMP-2) has at least two independent functions, i.e., regulation of matrix metalloproteinases and growth promoting activity. We investigated the effects of TIMP-2 overexpression, induced by retroviral mediated gene transfer, on the in vivo development of mammary tumors in syngeneic mice inoculated with EF43.fgf-4 cells. The EF43.fgf-4 cells established by stably infecting the normal mouse mammary EF43 cells with a retroviral expression vector for the fgf-4 oncogene, are highly tumorigenic and overproduce vascular endothelial growth factor (VEGF). Despite a promotion of the in vitro growth rate of EF43.fgf-4 cells overexpressing timp-2, the in vivo tumor growth was delayed. At day 17 post-cell injection, the volume of tumor derived from TIMP-2-overexpressing cells was reduced by 80% as compared with that obtained with control cells. Overexpression of TIMP-2 was associated with a down-regulation of VEGF expression in vitro and in vivo, a reduction of vessel size, density, and blood supply in the induced tumors. In addition, TIMP-2 completely inhibited the angiogenic activity of EF43.fgf-4 cell-conditioned medium in vitro using a rat aortic ring model. Our findings suggest that overexpression of TIMP-2 delays growth and angiogenesis of mammary carcinoma in vivo and that down-regulation of VEGF expression may play an important role in this TIMP-2-mediated antitumoral and antiangiogenic effects. Finally the in vivo delivery of TIMP-2, as assessed by i.v. injection of recombinant adenoviruses vectors, significantly reduced the growth of the EF43.fgf-4-induced tumors. This effect of TIMP-2 was shown to be equally comparable with that of angiostatin, a known potent inhibitor of angiogenesis.

Adenoviridae↗

PubMed2001

The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies.

The plasminogen (Plg)/plasminogen activator (PA) system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumor cell migration. Consequently, urokinase-type PA (uPA)/plasmin antagonists are currently being developed for suppression of tumor growth and angiogenesis. Paradoxically, however, high levels of PA inhibitor 1 (PAI-1) are predictive of a poor prognosis for survival of patients with cancer. We demonstrated previously that PAI-1 promoted tumor angiogenesis, but by an unresolved mechanism. We anticipated that PAI-1 facilitated endothelial cell migration via its known interaction with vitronectin (VN) and integrins. However, using adenoviral gene transfer of PAI-1 mutants, we observed that PAI-1 promoted tumor angiogenesis, not by interacting with VN, but rather by inhibiting proteolytic activity, suggesting that excessive plasmin proteolysis prevents assembly of tumor vessels. Single deficiency of uPA, tissue-type PA (tPA), uPA receptor, or VN, as well as combined deficiencies of uPA and tPA did not impair tumor angiogenesis, whereas lack of Plg reduced it. Overall, these data indicate that plasmin proteolysis, even though essential, must be tightly controlled during tumor angiogenesis, probably to allow vessel stabilization and maturation. These data provide insights into the clinical paradox whereby PAI-1 promotes tumor progression and warrant against the uncontrolled use of uPA/plasmin antagonists as tumor angiogenesis inhibitors.

Angiogenesis Inhibitors↗

PubMed2001

Improved quantification of angiogenesis in the rat aortic ring assay.

In vitro angiogenesis assays are essential for the identification of potential angiogenic agents and screening for pharmacological inhibitors. Among these assays, the rat aortic ring model developed by Nicosia bridges the gap between in vivo and in vitro models. The quantification of angiogenesis on this system must be applicable to characterise vascular networks of various states of complexity. We present here an improved computer-assisted image analysis which allows: (1) the determination of the aortic ring area and its factor shape; (2) the number of microvessels, the total number of branchings, the maximal microvessel length and the microvessel distribution; (3) the total number of isolated fibroblast-like cells and their distribution. We show that this method is suitable to quantify spontaneous angiogenesis as well as to analyse a complex microvascular network induced by various concentrations of vascular endothelial growth factor (VEGF). In addition, by evaluating a new parameter, the fibroblast-like cell distribution, our results show that: (1) during spontaneous angiogenic response, maximal fibroblast-like cell migration delimits microvascular outgrowth; and (2) the known angiogenic inhibitor Batimastat prevents endothelial cell sprouting without completely blocking fibroblast-like cell migration. Finally, this new method of quantification is of great interest to better understand angiogenesis and to test pro- or anti-angiogenic agents.

Animals↗

PubMed2001

Matrix metalloproteinases and TIMP-1 production by peripheral blood granulocytes from COPD patients and asthmatics.

Both asthmatic and COPD patients were found to have increased amounts of granulocytes and matrix metalloproteinase-9 (MMP-9) in their sputum. The present study was conducted to investigate whether the elevated amounts of MMP-9 and TIMP-1 found in such patients' airways may be linked to an enhanced secretion by granulocytes. Blood granulocytes from asthmatics (n = 10), COPD patients (n = 11), and healthy controls (n = 11) were isolated and cultured under basal conditions or after stimulation by phorbol 12-myristate 13-acetate (PMA) or N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). MMP-9 activity was detected by zymography while MMP-8 and TIMP-1 levels were measured by ELISA. In zymography, pro- and activated forms of MMP-9 were present in each group (healthy subjects, asthmatics, and COPD patients). Spontaneous release was not different between the three groups. Stimulation by fMLP and PMA increased to a similar extent the release of MMP-9 by granulocytes in all the three groups. TIMP-1 levels were also increased after stimulation by PMA and fMLP only in healthy subjects and COPD patients. MMP-8 levels were barely detectable. We conclude that circulating granulocytes from COPD patients and asthmatics do not display an abnormal secretion of MMP-9, and that granulocytes from asthmatics have an impaired ability to release TIMP-1 upon stimulation.

Adult↗

PubMed2001

Influence of plasminogen activator inhibitor type 1 on choroidal neovascularization.

High levels of the plasminogen activators, but also their inhibitor, plasminogen activator inhibitor 1 (PAI-1), have been documented in neovascularization of severe ocular pathologies such as diabetic retinopathy or age-related macular degeneration (AMD). AMD is the primary cause of irreversible photoreceptors loss, and current therapies are limited. PAI-1 has recently been shown to be essential for tumoral angiogenesis. We report here that deficient PAI-1 expression in mice prevented the development of subretinal choroidal angiogenesis induced by laser photocoagulation. When systemic and local PAI-1 expression was achieved by intravenous injection of a replication-defective adenoviral vector expressing human PAI-1 cDNA, the wild-type pattern of choroidal angiogenesis was restored. These observations demonstrate the proangiogenic activity of PAI-1 not only in tumoral models, but also in choroidal experimental neovascularization sharing similarities with human AMD. They identify therefore PAI-1 as a potential target for therapeutic ocular anti-angiogenic strategies.

Adenoviridae↗

PubMed2001

Presence of oestrogen receptor type beta in human retina.

BACKGROUND/AIMS: Recent studies have demonstrated the existence of two oestrogen receptor subtypes alpha (ORalpha) and beta (ORbeta) with significant differences of expression among organs. Since important pathologies of human eye could be linked to hormonal status, the expression of ORbeta in ocular posterior segment was sought. METHODS: Immunohistochemical localisation of ORbeta and ORalpha protein and detection of OR mRNAs by reverse transcription-polymerase chain reaction (RT-PCR) were performed in macular and extramacular regions of the retina and in the choroid on male and female donors eyes. RESULTS: ORbeta protein was localised in the ganglion cell layer and in the choroid. At the transcriptional level, mRNA for ORbeta and for ORalpha were both present. Local differences in the expression level were observed, however, suggesting the possibility of variation in the ratio of ORalpha v ORbeta. CONCLUSIONS: The coexistence of two oestrogen receptor subtypes in the human ocular posterior segment raises acute questions about their potential physiological role, but offers a perspective for preferential targeting of a specific receptor subtype.

Aged↗