Bulletin et memoires de l'Academie royale de medecine de Belgique最新文献

Our laboratory studies the Landouzy Dejerine muscular dystrophy or FSHD, a genetic disease which affects 7 in 100,000 individuals. The genetic defect is a deletion on chromosome 4 that decreases the copy number of a repeated DNA element, disturbs chromatin structure and activates the expression of neighbouring genes. The originality of our team has been to identify a gene within the repeated element itself and to show its activation in FSHD muscle cells. This gene expresses DUX4, a transcription factor that targets tens of genes, some of which express other transcription factors which target other genes, leading to a general deregulation. This DUX4-mediated cascade recapitulates by itself the major pathological features of FSHD: muscle atrophy, differentiation defect, oxidative stress... The homologous DUX4c gene located 42 kb from the repeat array expresses a protein that triggers myoblast proliferation. Its high expression level in severe cases of FSHD most probably contributes to the pathology by interfering with myoblast fusion with the muscle fibers at the last steps of muscle regeneration. We are performing global analyses of proteins and metabolites in healthy and FSHD myotubes (collaboration R Wattiez and JM Colet, UMONS) to identify abnormalities and their links with DUX4 or DUX4C.

The appearance of multicellular organisms implicated the development of several mechanisms of communication, which permit the cells to function in coordination. One of the mechanisms found in all tissues of vertebrates is ensured by the proteins of the connexin family. These integral membrane proteins form channels, which allow for the passage ofcytosolic molecules either between adjacent cells or between the cytosol of these cells and the extracellular environment. We have identified connexin 36 (Cx36) as the sole connexin that functionally links ("couples") the beta-cells which produce insulin within pancreatic islets. In vitro and in vivo experiments have shown that Cx36 and/or the intercellular communications to allow play a role in the control of insulin secretion as well as in the resistance of beta-cells against various aggressions, including those induced by the cytokines that are implicated in diabetes. A polymorphism of Cx36 gene is associated to certain forms of human diabetes, opening the possibility that a therapy targeting this protein may be useful in the treatment of diabetic diseases.

The history of the study by our group of the generation, the role and the effects of H2O2 in the thyroid, is summarized. The relations with thyroid diseases are discussed: myxedematous cretinism, thyroiditis, thyroid cancer, congenital hypothyroiddism, are discussed. A new role of H2O2 in the chemorepulsion of bacteria is proposed.

Recent emerging zoonoses (hemorrhagic fevers due to Ebola or Marburg virus, encephalitis due to Nipah virus, severe acute respiratory syndrome due to SRAS virus...) outline the potential of bats as vectors for transmission of infectious disease to humans. Such a potential is already known for rabies encephalitis since seven out of the eight genotypes of Lyssavirus are transmitted by bats. In addition, phylogenetic reconstructions indicate that Lyssavirus have evolved in chiropters before their emergence in carnivores. Nevertheless, carnivores remain the most critical vectors for public health, in particular dogs that are originating 55.000 rabies deaths per year, essentially in developing countries. Rabies control in carnivores by parenteral (dog) or oral (wild carnivores) vaccination is efficacious and campaigns start to be more widely applied. On the other hand, rabies control in bat still remains non realistic, particularly as the pathogenicity of bat Lyssavirus for bats is still under debate, suggesting that a "diplomatic relationship" between partners would have arisen from a long term cohabitation. While comparing the interactions that humans and bats establish with Lyssavirus, scientists try to understand the molecular basis ofpathogenicity in man, a indispensable prerequisite to identify antiviral targets in a perspective of therapy.

Recent technical improvements have allowed to non-invasive cardiac imaging by Multidetector CT. (MDCT). In initial work we compared the value of successive generations of MDCT (4, 16, and 64 slice) for non-invasive imaging of coronary arteries vs. non-invasive magnetic resonance coronary angiography using conventional coronary angiography as gold standard. Our work demonstrated progressive improvement of diagnostic accuracy from 4 to 64 slice MDCT technology. The most recent generation of 64 slice MDCT became more performing than MRI. Since cardiac function is the main predictor of outcome in patients with coronary artery disease, we evaluated whether MDCT can also access left ventricular volumes and ejection fraction, and observed excellent correlation of these parameters estimated by MDCT vs MRI. Subsequently we demonstrated that MDCT can also assess aortic stenosis by direct planimetry of the valve. We also found MDCT to be able of evaluating the severity and mechanism of aortic regurgitation and to evaluate function and mechanism of dysfunction of aortic bioprosthesis. We also demonstrated that MDCT can detect myocardial necrosis and fibrosis, and thus assess myocardial viability using similar mechanisms as MRI. Finally, we demonstrated that combined assessment of non-invasive coronary imaging and assessment of myocardial viability may allow assessing the etiology of ischemic vs non-ischemic heart failure, similarly well as the combination of mri and invasive coronary angiography. We also demonstrated that MDCT might allow avoiding performing systematic invasive coronary angiography in patients prior to valve surgery, by selecting only those patients with suspected coronary artery disease to undergo this test. Thus in summary, we performed work, demonstrating the value of MDCT not only for imaging of coronary arteries, but also for assessment of cardiac and valve function and evaluation of myocardial viability. Such comprehensive cardiac imaging by MDCT might be useful for assessment of patients with valve disease and to evaluate etiology of heart failure.

P53 is 30. Even if the tumor suppressor functions of p53 have long been recognized, the cancer-killing activity of p53 has not yet been exploited selectively and efficiently in the clinic. Recent genetic studies in mice identified MDM2 and MDMX as key regulators of p53 and as such as specific chemotherapeutic targets for treatment of cancer. Specific MDM2 and MDMX antagonists are now being developed as tools to unleash p53 activity in various tumors.

Human tumor metastases are often infiltrated by T lymphocytes that are specific for tumor antigens, but these metastases progress anyway. The spontaneous anti-tumor immune response seems thus to become ineffective, probably because the effector T cells become anergic. This anergy could result from inhibitory mechanisms orchestrated by the tumor cells. We have observed that recently stimulated human cytolytic T cell clones lose transiently their capacity to secrete cytokines. This anergy is correlated with the absence of colocalization of the T cell receptors (TCR) and the CD8 co-receptors. Effector functions' and TCR/CD8 colocalization are recovered by treating cells with galectin-3 ligands, suggesting that exracellular galectin-3 forms glycoprotein-galectin lattices, which decrease the TCR mobility on the surface of anergic T lymphocytes. Galectin-3 is frequently released by tumor cells. This new mechanism of anergy could thus also explain the loss of functions of the tumor-infiltrating lymphocytes, because these lymphocytes recover their effector functions and TCR/CD8 colocalization after ex vivo treatment with galectin-3 ligands. These results could lead to new therapeutical strategies.