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1.
Eur Radiol ; 29(12): 6405-6415, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31119417

ABSTRACT

OBJECTIVES: This study was conducted in order to compare the prevalence of inflammatory posterior arch abnormalities on lumbar spine MRI between axial spondyloarthritis (axSpA) patients and low back pain (LBP) patients. METHODS: Patients-axSpA patients meeting the 2009 ASAS criteria and chronic LBP patients who had a lumbar spine MRI were selected. MRI-STIR and T1 sagittal images up to T8-T9 were reviewed by two experienced rheumatologists blinded to the diagnosis and clinical data to identify inflammatory posterior arch abnormalities. Analyses-The prevalence of inflammatory posterior arch abnormalities between axSpA and LBP patients was compared. Clinical data were compared in the axSpA group depending on whether or not inflammatory posterior arch abnormalities were present. RESULTS: Ninety-five patients were enrolled in each group. The prevalence of all inflammatory posterior arch abnormalities was the same in the axSpA and LBP groups (58% in the SpA group versus 70% in the LBP group, p = 0.1). However, differences in terms of the prevalence of costotransverse joint arthritis, pedicle oedema above L3 and transverse and spinous process oedema were observed between the two groups (axSpA 27% versus LBP 6%, p = 0.0004). Patients with inflammatory posterior arch abnormalities in the axSpA group had a longer disease duration (11 versus 8 years, p = 0.02), higher CRP levels (median 11 versus 3 mg/l, p = 0.0002) and higher prevalence of radiographic sacroiliitis (84 versus 47%, p = 0.001) compared to patients without inflammatory posterior arch abnormalities. CONCLUSIONS: Costotransverse arthritis, pedicle oedema and transverse process oedema are more frequent in axSpA patients than LBP patients, on lumbar spine MRI depicting TH9-S1. KEY POINTS: • MRI pedicle oedema above L3, transverse process oedema, spinous process oedema or costotransverse arthritis is more frequently observed in axial spondyloarthritis (SpA). • SpA patients with at least one MRI inflammatory lesion on the posterior arch had higher clinical activity scores and biological inflammation. • Facet joint arthritis was more common in patients with chronic low back pain.


Subject(s)
Inflammation/diagnostic imaging , Inflammation/physiopathology , Low Back Pain/physiopathology , Magnetic Resonance Imaging/methods , Spondylarthritis/diagnostic imaging , Spondylarthritis/physiopathology , Adult , Case-Control Studies , Edema , Female , Humans , Inflammation/complications , Low Back Pain/complications , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/physiopathology , Male , Middle Aged , Prevalence , Retrospective Studies , Spondylarthritis/complications
2.
Blood ; 125(12): 1936-47, 2015 Mar 19.
Article in English | MEDLINE | ID: mdl-25605370

ABSTRACT

Acute myeloid leukemia (AML) is driven by niche-derived and cell-autonomous stimuli. Although many cell-autonomous disease drivers are known, niche-dependent signaling in the context of the genetic disease heterogeneity has been difficult to investigate. Here, we analyzed the role of Bruton tyrosine kinase (BTK) in AML. BTK was frequently expressed, and its inhibition strongly impaired the proliferation and survival of AML cells also in the presence of bone marrow stroma. By interactome analysis, (phospho)proteomics, and transcriptome sequencing, we characterized BTK signaling networks. We show that BTK-dependent signaling is highly context dependent. In Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive AML, BTK mediates FLT3-ITD-dependent Myc and STAT5 activation, and combined targeting of FLT3-ITD and BTK showed additive effects. In Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-negative AML, BTK couples Toll-like receptor 9 (TLR9) activation to nuclear factor κΒ and STAT5. Both BTK-dependent transcriptional programs were relevant for cell cycle progression and apoptosis regulation. Thus, we identify context-dependent oncogenic driver events that may guide subtype-specific treatment strategies and, for the first time, point to a role of TLR9 in AML. Clinical evaluation of BTK inhibitors in AML seems warranted.


Subject(s)
Leukemia, Myeloid, Acute/immunology , Protein-Tyrosine Kinases/metabolism , Toll-Like Receptor 9/metabolism , fms-Like Tyrosine Kinase 3/metabolism , Adult , Agammaglobulinaemia Tyrosine Kinase , Apoptosis , Bone Marrow Cells/metabolism , Cell Cycle , Cell Line, Tumor , Cell Proliferation , Cell Survival , Enzyme Activation , Gene Expression Regulation, Leukemic , Humans , Immunohistochemistry , Leukemia, Myeloid, Acute/metabolism , Mass Spectrometry , Middle Aged , NF-kappa B/metabolism , Phosphorylation , STAT5 Transcription Factor/metabolism , Signal Transduction , Tumor Suppressor Proteins/metabolism , Tyrosine/chemistry , Young Adult
3.
Mol Cell Proteomics ; 12(6): 1502-12, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23412571

ABSTRACT

Quantitative proteomics is an important tool to study biological processes, but so far it has been challenging to apply to zebrafish. Here, we describe a large scale quantitative analysis of the zebrafish proteome using a combination of stable isotope labeling and liquid chromatography-mass spectrometry (LC-MS). Proteins derived from the fully labeled fish were used as a standard to quantify changes during embryonic heart development. LC-MS-assisted analysis of the proteome of activated leukocyte cell adhesion molecule zebrafish morphants revealed a down-regulation of components of the network required for cell adhesion and maintenance of cell shape as well as secondary changes due to arrest of cellular differentiation. Quantitative proteomics in zebrafish using the stable isotope-labeling technique provides an unprecedented resource to study developmental processes in zebrafish.


Subject(s)
Cell Adhesion Molecules/genetics , Fish Proteins/genetics , Gene Expression Regulation, Developmental , Heart/embryology , Morphogenesis/genetics , Proteome/genetics , Zebrafish/genetics , Animals , Cell Adhesion , Cell Adhesion Molecules/metabolism , Cell Shape , Chromatography, Liquid , Fish Proteins/metabolism , Gene Expression Profiling , Isotope Labeling , Leukocytes/cytology , Leukocytes/metabolism , Mass Spectrometry , Proteome/metabolism , Zebrafish/embryology , Zebrafish/metabolism
4.
Blood ; 121(15): 3041-50, 2013 04 11.
Article in English | MEDLINE | ID: mdl-23386126

ABSTRACT

Angiogenesis, defined as blood vessel formation from a preexisting vasculature, is governed by multiple signal cascades including integrin receptors, in particular integrin αVß3. Here we identify the endothelial cell (EC)-secreted factor epidermal growth factor-like protein 7 (EGFL7) as a novel specific ligand of integrin αVß3, thus providing mechanistic insight into its proangiogenic actions in vitro and in vivo. Specifically, EGFL7 attaches to the extracellular matrix and by its interaction with integrin αVß3 increases the motility of EC, which allows EC to move on a sticky underground during vessel remodeling. We provide evidence that the deregulation of EGFL7 in zebrafish embryos leads to a severe integrin-dependent malformation of the caudal venous plexus, pointing toward the significance of EGFL7 in vessel development. In biopsy specimens of patients with neurologic diseases, vascular EGFL7 expression rose with increasing EC proliferation. Further, EGFL7 became upregulated in vessels of the stroke penumbra using a mouse model of reversible middle cerebral artery occlusion. Our data suggest that EGFL7 expression depends on the remodeling state of the existing vasculature rather than on the phenotype of neurologic disease analyzed. In sum, our work sheds a novel light on the molecular mechanism EGFL7 engages to govern physiological and pathological angiogenesis.


Subject(s)
Blood Vessels/metabolism , Endothelial Growth Factors/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , Integrin alphaVbeta3/metabolism , Amino Acid Motifs/genetics , Animals , Calcium-Binding Proteins , Cell Adhesion/genetics , Cell Movement/genetics , EGF Family of Proteins , Embryo, Nonmammalian/blood supply , Embryo, Nonmammalian/metabolism , Endothelial Growth Factors/genetics , Endothelial Growth Factors/pharmacology , Extracellular Matrix/metabolism , Gene Expression , HEK293 Cells , Humans , Immunohistochemistry , Immunoprecipitation , Infarction, Middle Cerebral Artery/genetics , Infarction, Middle Cerebral Artery/metabolism , Integrin alphaVbeta3/genetics , Mice , Mice, Nude , Phosphorylation/drug effects , Protein Binding , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Zebrafish
5.
Genome Res ; 19(11): 2036-51, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19704032

ABSTRACT

Animal genomes possess highly conserved cis-regulatory sequences that are often found near genes that regulate transcription and development. Researchers have proposed that the strong conservation of these sequences may affect the evolution of the surrounding genome, both by repressing rearrangement, and possibly by promoting duplicate gene retention. Conflicting data, however, have made the validity of these propositions unclear. Here, we use a new computational method to identify phylogenetically conserved noncoding elements (PCNEs) in a manner that is not biased by rearrangement and duplication. This method is powerful enough to identify more than a thousand PCNEs that have been conserved between vertebrates and the basal chordate amphioxus. We test 42 of our PCNEs in transgenic zebrafish assays--including examples from vertebrates and amphioxus--and find that the majority are functional enhancers. We find that PCNEs are enriched around genes with ancient synteny conservation, and that this association is strongest for extragenic PCNEs, suggesting that cis-regulatory interdigitation plays a key role in repressing genome rearrangement. Next, we classify mouse and zebrafish genes according to association with PCNEs, synteny conservation, duplication history, and presence in bidirectional promoter pairs, and use these data to cluster gene functions into a series of distinct evolutionary patterns. These results demonstrate that subfunctionalization of conserved cis-regulation has not been the primary determinate of gene duplicate retention in vertebrates. Instead, the data support the gene balance hypothesis, which proposes that duplicate retention has been driven by selection against dosage imbalances in genes with many protein connections.


Subject(s)
Chordata, Nonvertebrate/genetics , Conserved Sequence/genetics , Genome/genetics , Synteny , Animals , Binding Sites/genetics , Chordata, Nonvertebrate/classification , Cluster Analysis , Computational Biology/methods , Embryo, Nonmammalian/embryology , Embryo, Nonmammalian/metabolism , Enhancer Elements, Genetic/genetics , Evolution, Molecular , Gene Duplication , Gene Expression Regulation, Developmental , Genomics/methods , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Mice , Phylogeny , Takifugu/genetics , Transcription Factors/metabolism , Vertebrates/classification , Vertebrates/genetics , Zebrafish/embryology , Zebrafish/genetics
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