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Biomedical subjects

A Noel

Publications and source records attributed to A Noel.

At least 19 recordsLinked to original sources
PubMed2006

Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC).

A Disintegrin and Metalloprotease (ADAM) are transmembrane proteases displaying multiple functions. ADAM with ThromboSpondin-like motifs (ADAMTS) are secreted proteases characterised by thrombospondin (TS) motifs in their C-terminal domain. The aim of this work was to evaluate the expression pattern of ADAMs and ADAMTS in non small cell lung carcinomas (NSCLC) and to investigate the possible correlation between their expression and cancer progression. Reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot and immunohistochemical analyses were performed on NSCLC samples and corresponding nondiseased tissue fragments. Among the ADAMs evaluated (ADAM-8, -9, -10, -12, -15, -17, ADAMTS-1, TS-2 and TS-12), a modulation of ADAM-12 and ADAMTS-1 mRNA expression was observed. Amounts of ADAM-12 mRNA transcripts were increased in tumour tissues as compared to the corresponding controls. In sharp contrast, ADAMTS-1 mRNA levels were significantly lower in tumour tissues when compared to corresponding nondiseased lung. These results were corroborated at the protein level by Western blot and immunohistochemistry. A positive correlation was observed between the mRNA levels of ADAM-12 and those of two vascular endothelial growth factor (VEGF)-A isoforms (VEGF-A(165) and VEGF-A(121)). Taken together, these results providing evidence for an overexpression of ADAM-12 and a lower expression of ADAMTS-1 in non-small-cell lung cancer suggest that these proteases play different functions in cancer progression.

ADAM Proteins↗
PubMed2005

Development of educational image databases and e-books for medical physics training.

Medical physics education and training requires the use of extensive imaging material and specific explanations. These requirements provide an excellent background for application of e-Learning. The EU projects Consortia EMERALD and EMIT developed five volumes of such materials, now used in 65 countries. EMERALD developed e-Learning materials in three areas of medical physics (X-ray diagnostic radiology, nuclear medicine and radiotherapy). EMIT developed e-Learning materials in two further areas: ultrasound and magnetic resonance imaging. This paper describes the development of these e-Learning materials (consisting of e-books and educational image databases). The e-books include tasks helping studying of various equipment and methods. The text of these PDF e-books is hyperlinked with respective images. The e-books are used through the readers' own Internet browser. Each Image Database (IDB) includes a browser, which displays hundreds of images of equipment, block diagrams and graphs, image quality examples, artefacts, etc. Both the e-books and IDB are engraved on five separate CD-ROMs. Demo of these materials can be taken from www.emerald2.net.

Biomedical Engineering↗
PubMed2005

Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) results from persistent vasoconstriction, smooth muscle growth and extracellular matrix (ECM) remodelling of pulmonary arteries (PAs). Matrix metalloproteinases (MMPs) are matrix-degrading enzymes involved in ECM turnover, and in smooth muscle cell (SMC) and endothelial cell migration and proliferation. MMP expression and activity are increased in experimental PAH. Therefore, this study investigated whether similar changes occur in idiopathic PAH (IPAH; formerly known as primary pulmonary hypertension). Both in situ and in vitro studies were performed on PAs from patients undergoing lung transplantation for IPAH and from patients treated by lobectomy for localised lung cancer, who served as controls. In IPAH, MMP-tissue inhibitor of metalloproteinase (TIMP) imbalance was found in cultured PA-SMCs, with increased TIMP-1 and decreased MMP-3. MMP-2 activity was markedly elevated as a result of increases in both total MMP-2 and proportion of active MMP-2. In situ zymography and immunolocalisation showed that MMP-2 was associated with SMCs and elastic fibres, and also confirmed the MMP-3-TIMP-1 imbalance. In conclusion, the findings of this study were consistent with a role for the matrix metalloproteinase-tissue inhibitor of metalloproteinase system in pulmonary vascular remodelling in idiopathic pulmonary arterial hypertension. The matrix metalloproteinase-tissue inhibitor of metalloproteinase imbalance may lead to matrix accumulation, and increased matrix metalloproteinase-2 activity may contribute to smooth muscle cell migration and proliferation. Whether these abnormalities are potential therapeutic targets deserves further investigation.

Cells, Cultured↗
PubMed2004

Digital detectors for mammography: the technical challenges.

This paper reviews the different techniques available and competing for full-field digital mammography. The detectors are described in their principles: photostimulable storage phosphor plates inserted as a cassette in a conventional mammography unit, dedicated active matrix detectors (i.e., flat-panel, thin-film transistor-based detectors) and scanning systems, using indirect and direct X-ray conversion. The main parameters that characterize the performances of the current systems and influence the quality of digital images are briefly explained: spatial resolution, detective quantum efficiency and modulation transfer function. Overall performances are often the result of compromises in the choice of technology.

Equipment Design↗
PubMed2004

Influence of detector collimation on SNR in four different MDCT scanners using a reconstructed slice thickness of 5 mm.

The purpose of this paper is to compare the influence of detector collimation on the signal-to-noise ratio (SNR) for a 5.0 mm reconstructed slice thickness for four multi-detector row CT (MDCT) units. SNRs were measured on Catphan test phantom images from four MDCT units: a GE LightSpeed QX/I, a Marconi MX 8000, a Toshiba Aquilion and a Siemens Volume Zoom. Five-millimetre-thick reconstructed slices were obtained from acquisitions performed using detector collimations of 2.0-2.5 mm and 5.0 mm, 120 kV, a 360 degrees tube rotation time of 0.5 s, a wide range of mA and pitch values in the range of 0.75-0.85 and 1.25-1.5. For each set of acquisition parameters, a Wiener spectrum was also calculated. Statistical differences in SNR for the different acquisition parameters were evaluated using a Student's t-test (P<0.05). The influence of detector collimation on the SNR for a 5.0-mm reconstructed slice thickness is different for different MDCT scanners. At pitch values lower than unity, the use of a small detector collimation to produce 5.0-mm thick slices is beneficial for one unit and detrimental for another. At pitch values higher than unity, using a small detector collimation is beneficial for two units. One manufacturer uses different reconstruction filters when switching from a 2.5- to a 5.0-mm detector collimation. For a comparable reconstructed slice thickness, using a smaller detector collimation does not always reduce image noise. Thus, the impact of the detector collimation on image noise should be determined by standard deviation calculations, and also by assessing the power spectra of the noise.

Artifacts↗
PubMed2004

Crystal structure of the catalytic domain of MMP-16/MT3-MMP: characterization of MT-MMP specific features.

Membrane-type matrix metalloproteinases (MT-MMPs) have attracted strong attention, because four of them can activate a key player in the tumor scenario, proMMP-2/progelatinase A. In addition to this indirect effect on the cellular environment, these MT-MMPs degrade extracellular matrix proteins, and their overproduction is associated with tumor growth. We have solved the structure of the catalytic domain (cd) of MT3-MMP/MMP-16 in complex with the hydroxamic acid inhibitor batimastat. CdMT3-MMP exhibits a classical MMP-fold with similarity to MT1-MMP. Nevertheless, it also shows unique properties such as a modified MT-specific loop and a closed S1' specificity pocket, which might help to design specific inhibitors. Some MT-MMP-specific features, derived from the crystal structures of MT-1-MMP determined previously and MT3-MMP, and revealed in recent mutagenesis experiments, explain the impaired interaction of the MT-MMPs with TIMP-1. Docking experiments with proMMP-2 show some exposed loops including the MT-loop of cdMT3-MMP involved in the interaction with the proMMP-2 prodomain in the activation encounter complex. This model might help to understand the experimentally proven importance of the MT-loop for the activation of proMMP-2.

Amino Acid Sequence↗
PubMed2004

[Intensity-modulated radiation therapy for head and neck cancers with bilateral irradiation of the neck : preliminary results].

PURPOSE: To report preliminary results of a prospective study of intensity-modulated radiotherapy (IMRT) for head and neck squamous cell carcinoma (HNC) with bilateral irradiation of the neck. PATIENTS AND METHODS: At the Alexis Vautrin Cancer Center, 23 patients have been treated with IMRT for HNC since January 2002-August 2003. The first 10 patients with a minimum follow-up of 3 months were analyzed. All tumors were oropharyngeal. There were four females and six males, with a mean age of 50 years (range 39-66). Stages were I-II in eight and III-IV in two. CTV1 was microscopic disease and N0 neck (prescribed dose : 50 Gy) and CTV2 was macroscopic disease and the volume at risk (prescribed dose: 66-70 Gy). PTV were CTV + 5 mm. Patient's immobilization consisted of a five-point head neck shoulder thermoplastic mask. Set-up verifications were done by semi-automatically matching portal images and digitized reconstructed radiographs. IMRT used dynamic multileaf collimation. Five patients (group A) received 50 Gy IMRT (two post-operative and three with a brachytherapy boost with a mean dose: 27.5 Gy), and five patients (group B) received 66-70 Gy IMRT (four post-operative). Acute and late normal tissue effects were graded according to the RTOG-EORTC radiation morbidity scoring criteria. RESULTS: With a median follow-up of 7.4 months (range 3-18.5), no patient died or had loco-regional relapse. The displacements were <4 mm in 98% cases. CTV1 and 2 received 95% of the prescribed dose in 100% of the volume. On average the mean dose to the contralateral parotid was 25.5 Gy for group A vs. 31 Gy for group B (P = 0.09). Mean doses <26 Gy were obtained in three of five patients in group A vs. zero of five patients in group B (P = 0.04). Acute skin toxicities were grade 1 in five patients, grade 2 in four and grade 3 in one. Acute mucositis cases were grade 1 in three patients, grade 2 in five and localized grade 3 in two. At 3 months, 50% of the patients had a grade 0-1 late xerostomia. CONCLUSION: The 26 Gy dose limit constraint to the contralateral parotid was easier to satisfy when IMRT was prescribed at a maximum dose of 50 Gy. Acute toxicity is low. The displacements in the mask indicate that it is possible to define the PTV as CTV + 4 mm. This reduction should decrease the mean dose to the parotids. At 3 months, a 50% rate of grade 0-1 late xerostomia encourages the hope of a very low rate at 2 years.

Adult↗
PubMed2004

Membrane associated proteases and their inhibitors in tumour angiogenesis.

Cell surface proteolysis is an important mechanism for generating biologically active proteins that mediate a range of cellular functions and contribute to biological processes such as angiogenesis. Although most studies have focused on the plasminogen system and matrix metalloproteinases (MMPs), recently there has been an increase in the identification of membrane associated proteases, including serine proteases, ADAMs, and membrane-type MMPs (MT-MMPs). Normally, protease activity is tightly controlled by tissue inhibitors of MMPs (TIMPs) and plasminogen activator inhibitors (PAIs). The balance between active proteases and inhibitors is thought to determine the occurrence of proteolysis in vivo. High concentrations of proteolytic system components correlate with poor prognosis in many cancers. Paradoxically, high (not low) PAI-1 or TIMP concentrations predict poor survival in patients with various cancers. Recent observations indicate a much more complex role for protease inhibitors in tumour progression and angiogenesis than initially expected. As knowledge in the field of protease biology has improved, the unforeseen complexities of cell associated enzymes and their interaction with physiological inhibitors have emerged, often revealing unexpected mechanisms of action.

Cell Membrane↗
PubMed2003

Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis.

The matrix metalloproteinases (MMPs) constitute a multigene family of over 23 secreted and cell-surface associated enzymes that cleave or degrade various pericellular substrates. In addition to virtually all extracellular matrix (ECM) compounds, their targets include other proteinases, chemotactic molecules, latent growth factors, growth factor-binding proteins and cell surface molecules. The MMP activity is controlled by the physiological tissue inhibitors of MMPs (TIMPs). There is much evidence that MMPs and their inhibitors play a key role during extracellular remodeling in physiological situations and in cancer progression. They have other functions that promoting tumor invasion. Indeed, they regulate early stages of tumor progression such as tumor growth and angiogenesis. Membrane type MMPs (MT-MMPs) constitute a new subset of cell surface-associated MMPs. The present review will focus on MT1-MMP which plays a major role at least, in the ECM remodeling, directly by degrading several of its components, and indirectly by activating pro-MMP2. As our knowledge on the field of MT1-MMP biology has grown, the unforeseen complexities of this enzyme and its interaction with its inhibitor TIMP-2 have emerged, often revealing unexpected mechanisms of action.

Animals↗
PubMed2003

Pathogenic role of matrix metalloproteases and their inhibitors in asthma and chronic obstructive pulmonary disease and therapeutic relevance of matrix metalloproteases inhibitors.

Matrix metalloproteinases (MMPs) are an at least 23 member family of calcium and zinc dependent enzymes implicated in many physiological and pathological processes. Asthma, chronic obstructive pulmonary disease (COPD) and emphysema are diseases associated with an inflammation of the airways and lung parenchyma. In this review, we focus on the role played by MMPs in the pathogenesis of inflammation, airway remodelling and alveolar destruction, depicting the observational studies in humans and the experimental studies in animal models. During the course of asthma, MMP-2,-8,-9 and TIMP-1 are expressed at baseline and the allergen exposure or exacerbations of the disease lead to an increase of MMP-9 secretion being at this time much higher than that of TIMP-1, allowing temporarily a matrix damage, possibly followed by abnormal repair. Animal models suggest a predominant role for MMP-9 and MMP-12 in the pathogenesis of pulmonary inflammation and link an absence of MMP-2 to an increased parenchymal inflammation. In COPD and emphysema, human studies indicate an over-secretion of MMP-2,-8,-9 and animal models pointout MMP-1 and MMP-12 as being key players in the pathogenesis of emphysema. Taken together, these data identify specific MMP inhibition as appropriate target for therapeutic intervention in asthma or COPD/emphysema They also strongly argue against the widespread use of large spectrum non specific inhibitors that could be detrimental.

Animals↗
PubMed2002

MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression.

Membrane type 1 metalloprotease (MT1-MMP) is a transmembrane metalloprotease that plays a major role in the extracellular matrix remodeling, directly by degrading several of its components and indirectly by activating pro-MMP2. We investigated the effects of MT1-MMP overexpression on in vitro and in vivo properties of human breast adenocarcinoma MCF7 cells, which do not express MT1-MMP or MMP-2. MT1-MMP and MMP-2 cDNAs were either transfected alone or cotransfected. All clones overexpressing MT1-MMP 1) were able to activate endogenous or exogenous pro-MMP-2, 2) displayed an enhanced in vitro invasiveness through matrigel-coated filters independent of MMP-2 transfection, 3) induced the rapid development of highly vascularized tumors when injected subcutaneously in nude mice, and 4) promoted blood vessels sprouting in the rat aortic ring assay. These effects were observed in all clones overexpressing MT1-MMP regardless of MMP-2 expression levels, suggesting that the production of MMP-2 by tumor cells themselves does not play a critical role in these events. The angiogenic phenotype of MT1-MMP-producing cells was associated with an up-regulation of VEGF expression. These results emphasize the importance of MT1-MMP during tumor angiogenesis and open new opportunities for the development of anti-angiogenic strategies combining inhibitors of MT1-MMP and VEGF antagonists.

Animals↗
PubMed2001

Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf-/-). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf-/- mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf-/- mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.

Animals↗
PubMed2001

Down-Regulation of MT1-MMP expression by the alpha3 chain of type IV collagen inhibits bronchial tumor cell line invasion.

The basement membrane (BM) is the first barrier encountered by tumor cells when they become invasive. Moreover, some invasive tumor clusters are surrounded by a remnant or neosynthetized BM material. We have previously reported the presence of a particular alpha chain of type IV collagen, the alpha3(IV) chain, in bronchopulmonary carcinomas. This chain was not detected in the normal bronchial epithelium, but was found around some invasive tumor cluster BM. In the present study, we examined the effects of the alpha3(IV) chain on the invasive properties of bronchial tumor cell lines, with special emphasis on their expression of matrix metalloproteinase-2 (MMP-2) and its activator, membrane type 1-matrix metalloproteinase (MT1-MMP), which is largely involved in tumor progression. Two epithelial bronchial cell lines (16HBE14o- and BZR), showing different invasive abilities, were evaluated. Using the Boyden chamber invasion assay, we demonstrated that the alpha3(IV) chain inhibits the invasive properties of BZR cells and modifies their morphology by inducing an epithelial cell shape. In the presence of the recombinant NC1 domain of the alpha3(IV) chain, the expression of MMP-2 and tissue inhibitor of metalloproteinase-2 (TIMP-2) was not modified in either cell line. The NC1 alpha3(IV) domain did not modulate the MT1-MMP expression of noninvasive 16HBE14o- cells, whereas a 50% decrease of MT1-MMP mRNA was observed in invasive BZR cells. Accordingly, Western blot analyses showed a disappearance of the 45-kd MT1-MMP form when BZR cells were treated with the recombinant NC1 alpha3(IV) domain. These findings suggest that the alpha3 chain of type IV collagen may play a role in tumor invasion, at least by decreasing the expression and synthesis of MT1-MMP.

Bronchi↗
PubMed2001

New functions of stromal proteases and their inhibitors in tumor progression.

Acquisition of invasive metastatic potential through protease expression is a key event in tumor progression. In carcinomas, the production of metalloproteinases and serine proteinases is regulated by a cross talk between stromal cells and cancer cells. Paradoxically, high rather than low levels of their inhibitors predict poor survival of patients suffering from a variety of cancers. Recent observations suggest a much more complex role of these inhibitors in tumor progression than expected initially.

Disease Progression↗
PubMed2000

In vivo gene transfer of endothelial nitric oxide synthase to carotid arteries from hypercholesterolemic rabbits enhances endothelium-dependent relaxations.

BACKGROUND AND PURPOSE: Hypercholesterolemia is associated with abnormal endothelium-dependent vasorelaxation due to decreased nitric oxide bioavailability. Our aim was to examine the effect of adenovirus-mediated gene transfer of endothelial nitric oxide synthase (eNOS) to the hypercholesterolemic rabbit carotid artery in vivo. In addition, we examined whether adenovirus-mediated gene transfer was associated with vascular dysfunction. METHODS: Rabbits were fed a 1% cholesterol diet for 4 weeks followed by a 0.5% cholesterol diet for 6 weeks. Vascular reactivity was assessed in nontransduced carotid arteries from chow- and cholesterol-fed animals. In addition, carotid arteries were surgically isolated, and 2 separate doses of adenoviral vectors encoding eNOS or beta-galactosidase (AdbetaGal) on the contralateral side were delivered to the lumen (1x10(10) and 5x10(10) pfu/mL). RESULTS: Abnormal acetylcholine-mediated endothelium-dependent vasorelaxation was detected in the carotid artery from cholesterol-fed animals, whereas responses to calcium ionophore A23187 and diethylamine NONOate were normal. Vascular reactivity was similar in nontransduced and AdbetaGal-transduced hypercholesterolemic vessels. In vessels transduced with eNOS, transgene expression was demonstrated by immunostaining in both the endothelium and the adventitia and by Western blot analysis. High-dose but not low-dose eNOS gene transfer enhanced endothelium-dependent relaxation in vessels from cholesterol-fed rabbits. CONCLUSIONS: Adenovirus-mediated gene transfer of eNOS to carotid arteries of cholesterol-fed animals improves endothelium-dependent relaxation when an optimal viral titer is administered.

Animals↗
PubMed1999

Cyclooxygenase dependent release of heme from microsomal hemeproteins correlates with induction of heme oxygenase 1 transcription in human fibroblasts.

Induction of heme oxygenase 1 transcription and enzymatic activity is a common response after exposure of cells to various forms of oxidative stress including ultraviolet A radiation (UVA) and hydrogen peroxide. We now show that UVA irradiation or hydrogen peroxide treatment of human skin fibroblasts leads to an immediate release of the heme oxygenase substrate, heme, from microsomal hemeproteins. The release of heme by UVA apparently involves cyclooxygenase activity because it is inhibited by the cyclooxygenase inhibitor indomethacin. We also demonstrate a high degree of correlation between the amount of heme released and the degree of subsequent induction of heme oxygenase 1 transcription following UVA and hydrogen peroxide treatment. We propose that release of heme from microsomal hemeproteins determines the degree of induction of heme oxygenase 1 transcription in human fibroblasts after oxidative stress.

Butylated Hydroxytoluene↗