L'inhibition de l'activité transcriptionnelle de PRDM6 diminue la migration et l'invasion de cellules de cancer ovarien épithélial

La base moléculaire de la progression du cancer ovarien épithélial (COE) est encore peu comprise. Lors d’une étude antérieure, nous avons déterminé PRDM6 comme gène potentiellement hypométhylé dans les tumeurs de cancer ovarien de haut stade et grade comparés à des tissus normaux. L’hypométhylation n’a pas pu être confirmée, mais la surexpression de ce gène dans les tumeurs de COE laisse croire que PRDM6 peut avoir une implication dans ce cancer. L’expression de PRDM6 fut diminuée dans la lignée COE SKOV3 par la technique de l’interférence à l’ARN et des études fonctionnelles furent effectuées. La diminution de l’expression de PRDM6 entraine la diminution significative de la migration, l’invasion et la formation de colonie qui sont des facteurs nécessaires à la carcinogénèse. De plus, une analyse de l’expression génique a permis de confirmer la sousexpression de gènes associés au développement du cancer dans les lignées dont l’expression de PRDM6 est diminuée.The molecular base of the progression of epithelial ovarian cancer (EOC) is still poorly understood. In a previous study, we identified the gene PRDM6 as potentially hypomethylated in high grade and stage EOC tumors compared to normal tissue. The hypomethylation could not be confirmed, but the overexpression of this gene in EOC tumors suggests that PRDM6 might have some implications in this type of cancer. Using RNA interference, PRDM6 expression was decreased in the EOC cell line SKOV3 and functional studies were performed. Decreased expression of PRDM6 induced a significant decrease in migration, invasion and colony formation factors that are necessary for carcinogenesis. In addition, an analysis of gene expression confirmed the underexpression of genes associated with the development of cancer in cell lines whose PRDM6 expression was decreased

The increased synthesis of inducible nitric oxide inhibits IL-1ra synthesis by human articular chondrocytes: possible role in osteoarthritic cartilage degradation

SummaryThe degradation of osteoarthritic (OA) cartilage is likely related to the synthesis and the release of catabolic factors by chondrocytes. Nitric oxide (NO) has recently been suggested as playing a role in cartilage degradation. Since NO production is largely dependent on stimulation by IL-1, its effects on factors regulating the IL-1 biological activity, such as IL-1ra, are of the utmost importance. This study examined and compared the level of NO production by normal and OA cartilage and chondrocytes, as well as studied the effect of IL-1-induced NO production on the synthesis and steady-state mRNA of interleukin-1 receptor antagonist (IL-1ra).The NO baseline production by normal cartilage explants was undetectable but inducible by rhIL-1β. OA cartilage spontaneously produced NO. About a two-fold increase in NO production was found in OA rhIL-1β-stimulated (0.5–100 units/ml) cartilage as compared with the similarly stimulated normal cartilage. On chondrocytes rhIL-1β-stimulation (0.5–100 units/ml) produced a dose-dependent enhancement of both NO production and IL-1ra synthesis. Treatment with 200 μm Ng-monomethyl-L-arginine (L-NMA), a well known NO synthase inhibitor, induced over 70% inhibition of the NO production and a marked increased IL-1ra synthesis (average of 84%) and expression (mRNA level). Inhibition of prostaglandin synthesis by indomethacin had no effect on both the NO production or the IL-1ra level.In the present study, we demonstrated the capacity of OA cartilage to produce a larger amount of NO than the normal controls, both in spontaneous and IL-1-stimulated conditions. These data support the notion that, in vivo, OA chondrocytes are stimulated by factors, possibly IL-1, which in turn may induce the expression of NO synthase, thus the synthesis of NO itself. Importantly, our results showed that the elevation of NO production may be an important factor in the pathophysiology of OA since it can reduce IL-1ra synthesis by chondrocytes. As such, an increased level of IL-1, associated with a decreased IL-1ra level, may be responsible for the stimulation of OA chondrocytes by this cytokine, leading to an enhancement of cartilage matrix degradation

The mining industry in Canada north of the 55th parallel : a maritime traffic generator?

This paper reviews and assesses the state of the mining industry in Canada north of the 55th parallel. It aims to describe and monitor to what extent the development of mining projects in the Canadian Arctic are likely to trigger and expand commercial shipping in Canadian Arctic waters. Based on a literature and statistical review of publicly available information, the results show that only 3 actives mines out of 10 rely on a shipping logistics through Canadian Arctic waters to export raw materials. Once active and in operation, seven other mining projects will likely increase commercial shipping activities through Canadian Arctic waters, while it remains difficult to quantify precisely. However, this paper argues that the viability of northern mineral development is related to a wide variety of conditions including access to capital and foreign direct investment for the development and construction of infrastructure, international market conditions, and shifting demand which largely determines commodity prices and the profitability of a project, harsh environmental conditions, and high operating costs in northern latitudes. In this context, there is no Arctic mining rush and all these factors contribute to increasing the cost of doing business in the north

Knee meniscal extrusion in a largely non-osteoarthritic cohort: association with greater loss of cartilage volume

We conducted a longitudinal study (duration 2 years), including 294 individuals (mean age 45 years, 58% female), in order to examine associations between meniscal extrusion, knee structure, radiographic changes and risk factors for osteoarthritis (OA) in a largely non-osteoarthritic cohort. Meniscal extrusion, tibiofemoral cartilage defect score and cartilage volume, and tibial plateau bone area were determined using T1-weighted fat-saturated magnetic resonance imaging. At baseline the presence of medial meniscal extrusion was significantly associated with body mass index (odds ratio [OR] per kg/m2 = 1.13, 95% confidence interval [CI] = 1.02–1.25), past knee injury (positive versus negative history: OR = 3.73, 95% CI = 1.16–11.97), medial tibial bone area (OR per cm2 = 1.37, 95% CI = 1.02–1.85), and osteophytes (OR per grade = 4.89, 95% CI = 1.59–15.02). Two-year longitudinal data revealed that medial meniscal extrusion at baseline was associated with a greater rate of loss of medial tibiofemoral cartilage volume (extrusion versus no extrusion: -1.4%/year; P < 0.05) and greater risk for increased medial femoral cartilage defects (OR = 2.59, 95% CI = 1.14–5.86) and lateral tibial cartilage defects (OR = 2.64, 95% CI = 1.03–6.76). However, the latter two associations became nonsignificant after adjustment for tibial bone area and osteophytes. This study suggests that increasing body mass index and bone size, past knee injury, and osteophytes may be causally related to meniscal extrusion. Most importantly, meniscal extrusion at baseline is associated with greater loss of knee cartilage over 2 years, and this seems to be mediated mostly by subchondral bone changes, suggesting extrusion represents one pathway between bone expansion and cartilage loss

Degradation of small leucine-rich repeat proteoglycans by matrix metalloprotease-13: identification of a new biglycan cleavage site

A major and early feature of cartilage degeneration is proteoglycan breakdown. Matrix metalloprotease (MMP)-13 plays an important role in cartilage degradation in osteoarthritis (OA). This MMP, in addition to initiating collagen fibre cleavage, acts on several proteoglycans. One of the proteoglycan families, termed small leucine-rich proteoglycans (SLRPs), was found to be involved in collagen fibril formation/interaction, with some members playing a role in the OA process. We investigated the ability of MMP-13 to cleave members of two classes of SLRPs: biglycan and decorin; and fibromodulin and lumican. SLRPs were isolated from human normal and OA cartilage using guanidinium chloride (4 mol/l) extraction. Digestion products were examined using Western blotting. The identities of the MMP-13 degradation products of biglycan and decorin (using specific substrates) were determined following electrophoresis and microsequencing. We found that the SLRPs studied were cleaved to differing extents by human MMP-13. Although only minimal cleavage of decorin and lumican was observed, cleavage of fibromodulin and biglycan was extensive, suggesting that both molecules are preferential substrates. In contrast to biglycan, decorin and lumican, which yielded a degradation pattern similar for both normal and OA cartilage, fibromodulin had a higher level of degradation with increased cartilage damage. Microsequencing revealed a novel major cleavage site (... G(177)/V(178)) for biglycan and a potential cleavage site for decorin upon exposure to MMP-13. We showed, for the first time, that MMP-13 can degrade members from two classes of the SLRP family, and identified the site at which biglycan is cleaved by MMP-13. MMP-13 induced SLRP degradation may represent an early critical event, which may in turn affect the collagen network by exposing the MMP-13 cleavage site in this macromolecule. Awareness of SLRP degradation products, especially those of biglycan and fibromodulin, may assist in early detection of OA cartilage degradation

Effect of IL-13 on cytokines, cytokine receptors and inhibitors on human osteoarthritis synovium and synovial fibroblasts

AbstractObjective: In this study we investigated the effect of interleukin-13 (IL-13), an anti-inflammatory cytokine, for potential therapeutic use in osteoarthritis (OA).Design: We examined the effect of IL-13 on the synthesis and expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-1 receptor antagonist (IL-1Ra) and stromelysin-1 on human OA synovial membrane inex vivocultures. In addition, we explored the effect of IL-13 on both the IL-1 receptor (IL-1R) and TNF-receptor (TNF-R) systems on OA synovial fibroblasts. This included determination of the levels of IL-1β and TNF-α receptor binding, IL-1Ra and TNF-soluble receptors 55 and 75 (TNF-sR55 and TNF-sR75).Results: In OA synovial membrane treated with LPS, IL-13 inhibited the synthesis of IL-1β, TNF-α and stromelysin-1, but increased IL-1Ra production. In addition, IL-13 reduced the level of IL-1β mRNA and stimulated the level of IL-1Ra mRNA. In synovial fibroblasts, IL-13 decreased the level of IL-1 binding, an effect related to the increased production of IL-1Ra. Although IL-13 had no effect on the TNF-R level, this cytokine markedly decreased the shedding of TNF-R75.Conclusion: These experiments suggest that IL-13 is potentially useful in the therapeutic treatment of OA, as it could regulate the major pathological process of this disease by reducing the production of proinflammatory cytokines and metalloproteases, and favoring the production of IL-1Ra

Montluçon – Les Hauts de Buffon

Identifiant de l'opération archéologique : 2005/304 - 2006/126 et 133 Date de l'opération : 2006 (EX) Le diagnostic réalisé en juin 2006 sur l’emprise du projet de lotissement « Les Hauts de Buffon » a révélé, dans un contexte sédimentaire peu dilaté, la présence de deux phases d’occupation, l’une datée du Magdalénien et l’autre de l’époque gallo-romaine. Un dépôt isolé d’une céramique se rapporte quant à lui à l’âge du Bronze. Le premier site, conservé s..