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Leuven, Belgium

Degryse S.,Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease | Degryse S.,Katholieke University Leuven Center for Human Genetics | De Bock C.E.,Vlaams Instituut voor Biotechnologie Center for the Biology of the Disease | De Bock C.E.,Katholieke University Leuven Center for Human Genetics | And 21 more authors.
Blood | Year: 2014

JAK3 is a tyrosine kinase that associates with the common g chain of cytokine receptors and is recurrently mutated in T-cell acute lymphoblastic leukemia (T-ALL). We tested the transforming propertiesofJAK3 pseudokinase and kinase domain mutants usinginvitro and in vivo assays. Most, but not all, JAK3 mutants transformed cytokine-dependent Ba/F3 or MOHITO cell lines to cytokine-independent proliferation. JAK3 pseudokinase mutants were dependent on Jak1 kinase activity for cellular transformation, whereas the JAK3 kinase domain mutant could transform cellsinaJak1 kinase-independent manner. Reconstitution of the IL7 receptor signaling complex in 293T cells showed that JAK3 mutants required receptor bindingtomediate downstream STAT5 phosphorylation. Mice transplanted with bone marrow progenitor cells expressing JAK3 mutants developed a long-latency transplantable T-ALL-like disease, characterized by an accumulation of immature CD8+ T cells. In vivo treatment of leukemic mice with the JAK3 selective inhibitor tofacitinib reduced the white blood cell count and caused leukemic cell apoptosis. Our data show that JAK3 mutations are drivers of T-ALL and require the cytokine receptor complex for transformation. These results warrant further investigation of JAK1/JAK3 inhibitors for the treatment of T-ALL. © 2014 by The American Society of Hematology. Source


Van Gool H.,University Ziekenhuizen | Peers K.,Catholic University of Leuven | Peers K.,Universitair Sportmedisch Adviescentrum te Leuven
Sport en Geneeskunde | Year: 2012

Aims: Development of a research protocol based on the best available literature involving diagnostic and therapeutic approaches for osteochondritis dissecans of the elbow. Methods: literature review of PubMed, EMBAsE.com and SPORTDISCUS. Results: 43 articles were included. Conclusion: When an osteochondral lesion of the elbow is suspected, imaging should be performed to confirm the diagnosis. While radiography may be the initial screening modality, magnetic resonance imaging is the preferred diagnostic study. In addition, the choice of conservative versus surgical treatment should be based on the radiological findings, such as the stability of the lesion and the status of the growth plate. There will be a shift depending on the clinical findings. Source


Ottoni C.,University of Rome Tor Vergata | Ottoni C.,University Ziekenhuizen | Ottoni C.,Catholic University of Leuven | Ottoni C.,University of Perugia | And 8 more authors.
PLoS ONE | Year: 2010

The Tuareg of the Fezzan region (Libya) are characterized by an extremely high frequency (61%) of haplogroup H1, a mitochondrial DNA (mtDNA) haplogroup that is common in all Western European populations. To define how and when H1 spread from Europe to North Africa up to the Central Sahara, in Fezzan, we investigated the complete mitochondrial genomes of eleven Libyan Tuareg belonging to H1. Coalescence time estimates suggest an arrival of the European H1 mtDNAs at about 8,000-9,000 years ago, while phylogenetic analyses reveal three novel H1 branches, termed H1v, H1w and H1x, which appear to be specific for North African populations, but whose frequencies can be extremely different even in relatively close Tuareg villages. Overall, these findings support the scenario of an arrival of haplogroup H1 in North Africa from Iberia at the beginning of the Holocene, as a consequence of the improvement in climate conditions after the Younger Dryas cold snap, followed by in situ formation of local H1 sub-haplogroups. This process of autochthonous differentiation continues in the Libyan Tuareg who, probably due to isolation and recent founder events, are characterized by village- specific maternal mtDNA lineages. © 2010 Ottoni et al. Source


Boyer D.S.,Retina Vitreous Associates | Goldbaum M.,University of Sao Paulo | Leys A.M.,University Ziekenhuizen | Starita C.,Pfizer
British Journal of Ophthalmology | Year: 2014

Objective: To assess the rate of pegaptanib-associated sustained intraocular pressure (IOP) elevation. Methods: A posthoc analysis was conducted on all IOP measurements, except the immediate 30-min postinjection, from all subjects randomised to pegaptanib 0.3 mg or sham injections continuously in the first 2 years of the Vascular endothelial growth factor Inhibition Study in Ocular Neovascularisation (V.I.S.I.O.N.) study. Measurements were taken with Goldmann applanation tonometer or Tonopen, except at baseline and in cases of an IOP reading >30 mm Hg when a Goldmann applanation tonometer was mandatory. Results: Of 221 subjects, IOP measurements ≥22 mm Hg were seen in 28/114 and 23/107 subjects of the pegaptanib and sham subgroups, respectively (p=0.6338) and measurements ≥24 mm Hg were observed in eight and eight subjects in the pegaptanib and sham groups, respectively. More than two measurements ≥22 mm Hg occurred in six and 10 subjects (p=0.3025), and more than two measurements ≥24 mm Hg were observed in one and four subjects in the pegaptanib and sham groups, respectively. One patient with sustained IOP elevation in the pegaptanib study group, and four in the sham group, had IOP lowering medication added during the course of the study. No subject required glaucoma surgery. Conclusions: In V.I.S.I.O.N., after 2 years, there was no evidence of sustained IOP elevation associated with pegaptanib 0.3 mg use. Source


Savige J.,Royal Melbourne Hospital | Savige J.,University of Melbourne | Sheth S.,Royal Childrens Hospital | Leys A.,University Ziekenhuizen | And 3 more authors.
Clinical Journal of the American Society of Nephrology | Year: 2015

Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Mutations in the COL4A5 (X-linked), or COL4A3 and COL4A4 (autosomal recessive) genes result in absence of the collagen IVα3α4α5 network from the basement membranes of the cornea, lens capsule, and retina and are associated with corneal opacities, anterior lenticonus, fleck retinopathy, and temporal retinal thinning. Typically, these features do not affect vision or, in the case of lenticonus, are correctable. In contrast, the rarer ophthalmic complications of posterior polymorphous corneal dystrophy, giant macular hole, andmaculopathy all produce visual loss. Many of the ocular features of Alport syndrome are common, easily recognizable, and thus, helpful diagnostically, and in identifying the likelihood of early-onset renal failure. Lenticonus and central fleck retinopathy strongly suggest the diagnosis ofAlport syndrome and are associated with renal failure before the age of 30 years, in males with X-linked disease. Sometimes, ophthalmic features suggest the mode of inheritance. A peripheral retinopathy in the mother of a male with hematuria suggests X-linked inheritance, and central retinopathy or lenticonus in a female means that recessive disease is likely. Ocular examination, retinal photography, and optical coherence tomography are widely available, safe, fast, inexpensive, and acceptable to patients. Ocular examination is particularly helpful in the diagnosis of Alport syndrome when genetic testing is not readily available or the results are inconclusive. It also detects complications, such as macular hole, for which new treatments are emerging. © 2015 by the American Society of Nephrology. Source

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