Search

Malgré une grande hétérogénéité des situations cliniques, la définition de l'insuffisance rénale aiguë (IRA) est unique et son diagnostic repose essentiellement sur l'augmentation de la créatininémie et/ou la diminution de la diurèse. À l'inverse de l'évolution sur les marqueurs biologiques de l'infarctus du myocarde observée depuis plus de 50 ans, c'est toujours la créatinine "marqueur fonctionnel" qui sert de gold standard biologique pour le diagnostic de l'IRA. Cependant, sous le terme d'IRA, sont regroupées des situations cliniques très hétérogènes d'un point de vue étioIogique, physiopathologique, de durée, d'évolution et d'éventuelles complications associées. Depuis une quinzaine d'années des nouveaux biomarqueurs potentiels sont étudiés et semblent prometteurs. Contrairement à la troponine qui est augmentée dans tous les types d'infarctus du myocarde, ces nouveaux biomarqueurs présentent des sensibilités et spécificités différentes en fonction du type d'IRA, ce qui explique possiblement leur sous-utilisation en pratique courante. Despite a great heterogeneity of clinical situations, the definition of acute kidney injury (AKI) is unique and its diagnosis includes an increase in serum creatinine and/or a decrease in diuresis. Contrary to the evolution of the biological markers of myocardial infarction observed for more than 50 years, it is always the "functional marker" creatinine which serves as the biological gold standard for the diagnosis of AKI. However, under the term of acute renal failure, very heterogeneous clinical situations are grouped together from an etiological, pathophysiological mechanisms, duration, evolution and associated complications. For fifteen/twenty years, new potential biomarkers have been studied and seem promising. Unlike troponin, which is increased in all types of myocardial infarction, these new biomarkers have different sensitivities and specificities depending on the type of AKI, which possibly explains their under-use in current practice. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Previous studies have shown that microRNA-95-3p (miR-95-3p) plays a crucial role in multiple human cancers except for prostatic cancer (PCa). Therefore, the function of miR-95-3p was investigated in PCa in the present work. PATIENTS AND METHODS: The expression of miR-95-3p was measured by Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) assay. Western blot assay was used to examine the protein expression of epithelial-mesenchymal transition (EMT) markers. In addition, the function of miR-95-3p was detected through MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and transwell assays. Dual Luciferase assay was applied to confirm the relationship between miR-95-3p and dickkopf-3 (DKK3). The tumor growth was observed through xenograft tumor formation assay. RESULTS: The upregulation of miR-95-3p was detected in PCa tissues and cell lines, which predicted poor prognosis of PCa patients. Moreover, miR-95-3p promoted cell proliferation, migration and invasion in PCa by targeting DKK3 and activating the Wnt/β-catenin pathway. MiR-95-3p also promoted the tumor growth of PCa in vivo. Besides that, downregulation of DKK3 was identified in PCa and low DKK3 expression predicted poor prognosis of PCa patients. CONCLUSIONS: MiR-95-3p promoted the development of PCa via targeting DKK3 and activating the Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

This study is to explore the mechanism of KDM1A-regulated hepatoblastoma (HB) development. Cancerous and paracancer tissues of 30 HB patients were collected for detection of KDM1A and DKK3 expression. HuH-6 and HepG2 cells were subjected to assays of cellular activities after treatment with sh-KDM1A, sh-DKK3, and/or XAV-939 (an inhibitor of the Wnt/β-catenin pathway). Chromatin immunoprecipitation was used to determine the interaction of KDM1A with DKK3. Nude mice were injected with HuH-6 cells in which KDM1A was knocked down. KDM1A was highly expressed and DKK3 was lowly expressed in HB patients. Knockdown of KDM1A reduced the proliferative and invasive capabilities of HepG2 and HuH-6 cells and accelerated the cell apoptosis; these influences were nullified by knockdown of DKK3. KDM1A inhibited DKK3 transcription by reducing H3 methylation. XAV-939 treatment inhibited the development of HepG2 and HuH-6 cells in which KDM1A and DKK3 were both knocked down. Knockdown of KDM1A reduced the tumor mass, inactivated the Wnt/β-catenin signaling, and increased the expression of DKK3 in nude mice. KDM1A stimulates HB development by activating the Wnt/β-catenin pathway through inhibition of DKK3 transcription. • KDM1A is upregulated and DKK3 is downregulated in HB patients. • Knockdown of KDM1A inhibits the development of HB. • KDM1A inhibits DKK3 transcription by reducing H3 methylation. • KDM1A activates the Wnt/β-catenin pathway by regulating DKK3. • KDM1A affects HB development by regulating the DKK3/Wnt/β-catenin axis. [ABSTRACT FROM AUTHOR]

Objectives: The generation of transgenic mice expressing green fluorescent proteins (GFPs) has greatly aided our understanding of the development of connective tissues such as bone and cartilage. Perturbation of a biological system such as the temporomandibular joint (TMJ) within its adaptive remodeling capacity is particularly useful in analyzing cellular lineage progression. The objectives of this study were to determine: (i) if GFP reporters expressed in the TMJ indicate the different stages of cell maturation in fibrocartilage and (ii) how mechanical loading affects cellular response in different regions of the cartilage.Design/methods: Four-week-old transgenic mice harboring combinations of fluorescent reporters (Dkk3-eGFP, Col1a1(3.6 kb)-GFPcyan, Col1a1(3.6 kb)-GFPtpz, Col2a1-GFPcyan, and Col10a1-RFPcherry) were used to analyze the expression pattern of transgenes in the mandibular condylar cartilage (MCC). To study the effect of TMJ loading, animals were subjected to forced mouth opening with custom springs exerting 50 g force for 1 h/day for 5 days. Dynamic mineralization and cellular proliferation (EdU-labeling) were assessed in loaded vs control mice.Results: Dkk3 expression was seen in the superficial zone of the MCC, followed by Col1 in the cartilage zone, Col2 in the prehypertrophic zone, and Col10 in the hypertrophic zone at and below the tidemark. TMJ loading increased expression of the GFP reporters and EdU-labeling of cells in the cartilage, resulting in a thickness increase of all layers of the cartilage. In addition, mineral apposition increased resulting in Col10 expression by unmineralized cells above the tidemark.Conclusion: The TMJ responded to static loading by forming thicker cartilage through adaptive remodeling. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the expression of DKK3 protein and its target, beta-catenin, in uterine cervical squamous cell carcinoma and to determine potential clinical correlations.Six carcinoma in-situ (CIS) tissues and 88 invasive cervical cancer tissues were included in the study. Twenty-two normal cervical tissues and one gastric cancer tissue were used as controls. The expression of DKK3 and beta-catenin proteins was evaluated by immunohistochemical analysis. Clinical and pathological parameters were obtained from medical records. Survival data were estimated using Kaplan-Meier estimates and compared with a log-rank test. Multivariate analysis was performed using the Cox regression method.DKK3 was predominantly present in the cytoplasm. Beta-catenin was observed only on the cellular membrane of both normal and cancer cells in contrast to earlier reports, in which beta-catenin was localized to the cytoplasm and nucleus of cancer cells. The expressions of beta-catenin and DKK3 were not correlated. Three of 6 CIS (50%) and 57 of 88 invasive cancer specimens (64.8%) had lower DKK3 expression than normal controls. DKK3 expression was decreased in a stage-dependent manner (P = 0.021). The patients with low expression of DKK3 were older than those with high expression of DKK3 (P < 0.01). Moreover, the patients with low DKK3 expression had a significantly lower 5-year disease-free survival rate than those with high DKK3 expression (P = 0.026). A multivariate analysis showed that International Federation of Gynecology and Obstetrics clinical stage and parametrial involvement were independent prognostic factors.Decreased DKK3 expression was associated with advanced International Federation of Gynecology and Obstetrics clinical stages and was predictive of lower disease-free survival in patients with cervical squamous cell carcinoma. DKK3 may be implicated in cervical carcinogenesis through a beta-catenin-independent mechanism. [ABSTRACT FROM AUTHOR]

The Dickkopf (Dkk) family is composed of four main members (Dkk1–4), which typically regulate Wnt/β-catenin signaling. An exception is Dkk3, which does not affect Wnt/β-catenin signaling and whose function is poorly characterized. Here, we describe the Xenopus dkk3 homolog and characterize its expression and function during embryogenesis. Dkk3 is maternally expressed and zygotically in the cement gland, head mesenchyme, and heart. We show that depletion of Dkk3 in Xenopus embryos by Morpholino antisense oligonucleotides induces axial defects as a result of Spemann organizer and mesoderm inhibition. Dkk3 depletion leads to down-regulation of Activin/Nodal signaling by reducing levels of Smad4 protein. Dkk3 overexpression can rescue phenotypic effects resulting from overexpression of the Smad4 ubiquitin ligase Ectodermin. Furthermore, depletion of Dkk3 up-regulates FGF signaling, while Dkk3 overexpression reduces it. These results indicate that Dkk3 modulates FGF and Activin/Nodal signaling to regulate mesoderm induction during early Xenopus development. [ABSTRACT FROM AUTHOR]

Objectives Ninety percent of patients with esophageal adenocarcinoma ultimately die of their disease, highlighting the need for novel therapeutic targets. The goal of this study was to define the functional significance of overexpression of Dickkopf-3 (DKK3) in esophageal adenocarcinoma. Methods DKK3 expression was analyzed by real-time polymerase chain reaction in 95 chemonaive and 21 chemoresistant esophageal adenocarcinomas. The esophageal adenocarcinoma cell line OE33 was stably transfected with DKK3 (OE33/DKK3) and evaluated using WST-1 (Roche, Basel, Switzerland), Matrigel (BD Biosciences, San Jose, Calif), endothelial tube formation, and chemosensitivity assays. Tumorigenesis was evaluated by injecting 1 × 10 6 OE33/DKK3 and vector cells in NOD/SCIDγ mice. Results DKK3 was overexpressed (>2-fold) in 75.8% (72/95) of esophageal adenocarcinomas. DKK3 protein was present at moderate to high levels in 46.8% (29/62) of esophageal adenocarcinomas on tissue microarray. Stable transfection of DKK3 significantly increased proliferation ( P < .05) and Matrigel invasion ( P < .001). Levels of SMAD4, a key mediator of the transforming growth factor-ß pathway, increased after activin treatment of OE33/DKK3, and siSMAD4 significantly decreased Matrigel invasion, suggesting that DKK3 acts through the transforming growth factor-β pathway. OE33/DKK3 cells increased endothelial tube formation and were significantly more resistant to 5-fluorouracil and cisplatin, and DKK3 expression was significantly higher in chemoresistant esophageal adenocarcinomas ( P < .005). In NOD/SCIDγ mice, OE33/DKK3 cells resulted in tumors at all sites (8/8), whereas vector cells grew in only 1 of 8 sites. Nodal metastases were also significantly increased in patients with esophageal adenocarcinomas highly overexpressing DKK3 , 28 of 32 (88%) versus 42 of 63 (68%) ( P < .05). Conclusions These findings suggest that DKK3 may be important in mediating invasion in esophageal adenocarcinoma and could be a novel target in the treatment and prevention of metastatic disease. [ABSTRACT FROM AUTHOR]