A5023081248- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Acute Myeloid Leukemia Research
- Platelet Disorders and Treatments
- Chronic Myeloid Leukemia Treatments
- Alzheimer's disease research and treatments
- Cytokine Signaling Pathways and Interactions
- Melanoma and MAPK Pathways
- Inflammatory mediators and NSAID effects
- Peroxisome Proliferator-Activated Receptors
- Eosinophilic Disorders and Syndromes
- Kruppel-like factors research
- Protein Degradation and Inhibitors
- Neuroinflammation and Neurodegeneration Mechanisms
- Protein Structure and Dynamics
- Telomeres, Telomerase, and Senescence
- HER2/EGFR in Cancer Research
- Lipoproteins and Cardiovascular Health
- Cancer Immunotherapy and Biomarkers
- Chronic Lymphocytic Leukemia Research
- Prion Diseases and Protein Misfolding
- Lipid metabolism and disorders
- RNA Interference and Gene Delivery
- Cholinesterase and Neurodegenerative Diseases
- Signaling Pathways in Disease
- Histone Deacetylase Inhibitors Research
de Duve Institute
2020-2025
Ludwig Cancer Research
2020-2025
UCLouvain
2022-2025
Walloon Excellence in Lifesciences and Biotechnology
2022-2023
Karolinska Institutet
2022
Weatherford College
2022
The University of Texas MD Anderson Cancer Center
1997-2012
The University of Texas at Austin
1996
Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted phase II trial imatinib in patients with metastatic expressing at least one these PTKs. Twenty-one whose tumours expressed PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated 400 mg twice daily. One patient acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic...
Lipid metabolism is essential for cellular homeostasis, and its disruption linked to various diseases. Acyl‐coenzyme A synthetase long‐chain family member 4 (ACSL4), a pivotal enzyme in lipid metabolism, has emerged as therapeutic target ferroptosis‐related conditions cancer. Antidiabetic drug rosiglitazone the reference ACSL4 inhibitor. However, potent activity on peroxisome proliferator‐activated receptor gamma (PPARγ), key regulator of represents significant limitation. Here, we report...
Abstract Aging is the main risk factor for Alzheimer’s disease (AD) and other neurodegenerative pathologies, but molecular cellular changes underlying pathological aging of nervous system are poorly understood. AD pathology seems to correlate with appearance cells that become senescent due progressive accumulation insults causing DNA damage. Senescence has also been shown reduce autophagic flux, a mechanism involved in clearing damaged proteins from cell, such impairment linked pathogenesis....
Calreticulin (CALR) frameshift mutations represent the second cause of myeloproliferative neoplasms (MPN). In healthy cells, CALR transiently and non-specifically interacts with immature N-glycosylated proteins through its N-terminal domain. Conversely, mutants turn into rogue cytokines by stably specifically interacting Thrombopoietin Receptor (TpoR), inducing constitutive activation. Here, we identify basis acquired specificity for TpoR define mechanisms which complex formation triggers...
Mutant calreticulin (CALR) proteins resulting from a -1/+2 frameshifting mutation of the CALR exon 9 carry novel C-terminal amino acid sequence and drive development myeloproliferative neoplasms (MPNs). CALRs were shown to interact with activate thrombopoietin receptor (TpoR/MPL) in same cell. We report that mutant are secreted can be found patient plasma at levels up 160 ng/mL, mean 25.64 ng/mL. Plasma is complex soluble transferrin 1 (sTFR1) acts as carrier protein increases half-life....
Lipid metabolism is essential for cellular homeostasis, and its disruption linked to various diseases. Acyl‐coenzyme A synthetase long‐chain family member 4 (ACSL4), a pivotal enzyme in lipid metabolism, has emerged as therapeutic target ferroptosis‐related conditions cancer. Antidiabetic drug rosiglitazone the reference ACSL4 inhibitor. However, potent activity on peroxisome proliferator‐activated receptor gamma (PPARγ), key regulator of represents significant limitation. Here, we report...
Bernard Soulier Syndrome (BSS) is a severe bleeding disorder with moderate to thrombocytopenia, giant platelets, and platelet dysfunction, caused by biallelic mutations in GP1BA, GP1BB, or GP9 genes. We generated induced pluripotent stem cells (iPSC) from BSS patient novel heterozygous GP1BA p.N103D mutation, resulting macrothrombocytopenia. The mutation does not affect megakaryocyte (MK) differentiation GPIb-GPIX complex expression but reduces affinity von Willebrand factor (VWF). It...
Abstract The Alternative Lengthening of Telomeres (ALT) mechanism enables telomere maintenance, contributing to the immortality certain cancer cells. Disrupting interaction between testis‐specific Y‐encoded‐like protein 5 (TSPYL5) and ubiquitin‐specific protease 7 (USP7) has emerged as a promising strategy target ALT‐dependent cancers. While N‐terminal MATH domain USP7 mediates interaction, regions TSPYL5 involved in binding remain unclear. Here, we present structural analysis TSPYL5–USP7...
8501 Background: BRAF and NRAS mutations (mut) occur in 50-60% 15-20% of melanomas, respectively. As a consequence, MAPK signaling is frequently activated. To correlate clinical benefit MEK inhibitor with the mut status, we performed genomic study using tumors patients (pts) enrolled AZD6244 (a selective inhibitor)-containing combination regimens. Methods: Pts ≥ 18 years age advanced solid WHO performance status 0–1 were phase I trial one 3 drugs 3-week (q3w) treatment cycles: dacarbazine...
Amyloid precursor protein (APP) cleavage by the β-secretase produces C99 transmembrane (TM) protein, which contains three dimerization-inducing Gly-x-x-x-Gly motifs. We demonstrate that dimeric TM orientations regulate precise lines γ-secretase. Of all possible imposed a coiled-coil to domain, dimer containing 33Gly-x-x-x-Gly37 motif in interface promoted Aβ42 processing line and APP intracellular domain-dependent gene transcription, including induction of BACE1 mRNA, enhancing amyloidogenic...
Dimerization of the thrombopoietin receptor (TpoR) is necessary for activation and downstream signaling through activated Janus kinase 2. We have shown previously that different orientations transmembrane (TM) helices within a dimer can lead to outputs. Here we addressed structural basis mutations S505N W515K induce myeloproliferative neoplasms. show using in vivo bone marrow reconstitution experiments ligand-independent TpoR by TM asparagine (Asn) substitutions proportional proximity Asn...
Abstract Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of JAK2 gene, including V617F or several others in exon 12. A 38‐year‐old female had stroke at age 32 and found to have elevated hemoglobin, normal leukocytes, platelets, tested negative for 12 mutations. Next generation sequencing revealed novel mutation: R715T pseudokinase domain (JH2) 47.5%. Its presence her nail DNA confirmed germline origin. Her mother son similarly erythrocytosis mutation....
7528 Background: Imatinib mesylate (Gleevec™), an oral inhibitor of phosphorylation certain tyrosine kinases (TK), is active in gastrointestinal stromal tumors which are chemotherapy resistant. Perhaps MM may respond to Gleevec, especially if the tumor cells or microenvironment express one known TK targets: KIT, PDGF receptors α β, c-abl, ARG. Methods: Tumor biopsies from patients (pts) were screened by immunohistochemistry (IHC) for expression more than 25% cells, as a condition enrollment...
Lipid metabolism affects many cellular processes essential for homeostasis, and its disruption is linked to various diseases. A key enzyme in these processes, acyl-coenzyme synthetase long-chain family member 4 (ACSL4), a promising target treating conditions involving ferroptosis certain cancers. Rosiglitazone (ROSI) known ACSL4 inhibitor but potent activity on peroxisome proliferator-activated receptor gamma (PPARγ), nuclear strongly involved lipid constitutes an important limitation. This...
Most neurodegenerative diseases have the characteristics of proteinopathies, i.e. they cause lesions to appear in vulnerable regions nervous system, corresponding protein aggregates that progressively spread through neuronal network as symptoms progress. Alzheimer's disease is one these proteinopathies. It characterized by two lesions, neurofibrillary tangles (NFTs) and senile plaques, formed essentially amyloid peptides (Aβ). A combination factors ranging from genetic mutations...
Legha, S S; Bedikian, A; Plager, C; Eton, O; Buzaid, Papadopoulos, N; Ross, M Author Information
Abstract Calreticulin (CALR) is a master lectin chaperone that normally guides the proper folding of integral membrane proteins in endoplasmic reticulum. In healthy cells, CALR transiently and non-specifically interacts with thousands immature N-glycosylated through its N-terminal glycan-binding domain. Conversely, frameshift mutants turn into rogue cytokine by acquiring ability to stably specifically interact Thrombopoietin Receptor (TpoR). Strikingly, this interaction induces constitutive...