References of "De Tullio, Pascal"
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See detailPepsNMR for 1H NMR metabolomic data pre-processing
Martin, Manon; Legat, Benoît; Leenders, Justine ULiege et al

in Analytica Chimica Acta (2018), 1019

In the analysis of biological samples, control over experimental design and data acquisition procedures alone cannot ensure well-conditioned 1H NMR spectra with maximal information recovery for data ... [more ▼]

In the analysis of biological samples, control over experimental design and data acquisition procedures alone cannot ensure well-conditioned 1H NMR spectra with maximal information recovery for data analysis. A third major element affects the accuracy and robustness of results: the data pre-processing/pre-treatment for which not enough attention is usually devoted, in particular in metabolomic studies. The usual approach is to use proprietary software provided by the analytical instruments' manufacturers to conduct the entire pre-processing strategy. This widespread practice has a number of advantages such as a user-friendly interface with graphical facilities, but it involves non-negligible drawbacks: a lack of methodological information and automation, a dependency of subjective human choices, only standard processing possibilities and an absence of objective quality criteria to evaluate pre-processing quality. This paper introduces PepsNMR to meet these needs, an R package dedicated to the whole processing chain prior to multivariate data analysis, including, among other tools, solvent signal suppression, internal calibration, phase, baseline and misalignment corrections, bucketing and normalisation. Methodological aspects are discussed and the package is compared to the gold standard procedure with two metabolomic case studies. The use of PepsNMR on these data shows better information recovery and predictive power based on objective and quantitative quality criteria. Other key assets of the package are workflow processing speed, reproducibility, reporting and flexibility, graphical outputs and documented routines [less ▲]

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See detailNMR-based Metabolomics for New Target Discovery and Personalized Medicine: Application to Age-Related Macular Degeneration (AMD).
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Leenders, Justine ULiege et al

Conference (2018, July 05)

Abstract: Nuclear Magnetic Resonance (NMR) is an indispensable analytical tool for research in the biomedical and pharmaceutical fields. More recently, NMR appeared as one of the major and more powerful ... [more ▼]

Abstract: Nuclear Magnetic Resonance (NMR) is an indispensable analytical tool for research in the biomedical and pharmaceutical fields. More recently, NMR appeared as one of the major and more powerful technological platform for metabolomics approach. Metabolomics is a growing area of the “omics” sciences and is defined as the comprehensive identification and quantification of lowmolecular weight metabolites in biological samples. It provides a unique and direct vision of the functional outcome of organism’s activities that could be correlated to pathologies and/or treatment administration. The links between metabolic changes, patient phenotype, physiological and/or pathological status and treatment are now well established and have opened a new area for the application of metabolomics in new target identification and in personalized medicine. Age-related Macular Degeneration (AMD) is the leading causes of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form, which is characterized by choroidal neovascularization (CNV). Treatment is mainly based on regular intravitreal injection of anti-VEGF to stabilize CNV. Nevertheless, the comprehensive understanding of the pathogenesis and the evolution of this complex multi-factorial disease remain incomplete. Moreover, due to the long-term disease chronicity and to some resistance to treatment, a continuous follow-up of patients, a personalization of treatment and the discovery of new therapeutic approaches are mandatory. In order to study CNV occurrence and evolution and to get new and innovative insights into this pathology, we decided to apply a NMR-based metabolomics approach on both clinical and pre-clinical models (a murine laser-induced CNV model and patient’s cohorts). This approach led us to identify some metabolites linked to CNV developments in both human and murine samples. These molecules could be considered not only as markers of the pathology but also as putative target for a new treatment of AMD. Among those, lactate emerges as a key metabolite in both settings. Mechanistically, we demonstrated that lactate, initially produced in the eyes increases at the systemic level and play a critical role in the onset of the inflammatory and angiogenic phases. For this purpose, we use a combination of NMR measurements (both 1D and 2D) and molecular biology approaches. The control of the systemic concentration of lactate by PDHK inhibition or by LDH modulation decreases significantly CNV development. Based on a metabolomics approach, our data support the innovative concept of lactate as a putative target for a new therapeutic approach of AMD as well as a useful marker for patient’s follow-up during treatment. We highlight also the utility and the efficacy of NMR for metabolomics and metabolites measurement in complex biological samples. [less ▲]

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See detailCodon-specific translation reprogramming promotes resistance to targeted therapy
Rapino, Francesca ULiege; Delaunay, Sylvain ULiege; Rambow, Florian et al

in Nature (2018), 558

Reprogramming of mRNA translation has a key role in cancer development and drug resistance. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA ... [more ▼]

Reprogramming of mRNA translation has a key role in cancer development and drug resistance. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U34) tRNA (U34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAFV600E oncogene and by resistance to targeted therapy in melanoma. We show that BRAFV600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1α. Together, these results demonstrate that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation. [less ▲]

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See detailEndometriosis: a deep insight into the pathology through metabolomics
Leenders, Justine ULiege; Martin, Manon; NISOLLE, Michelle ULiege et al

Poster (2018, June)

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See detailGUT MICROBIOTA AND FAECAL LEVELS OF SHORT CHAIN FATTY ACIDS DIFFER UPON BLOOD PRESSURE LEVELS IN MAN
HUART, Justine ULiege; Leenders, Justine ULiege; Taminiau, Bernard ULiege et al

in Nephrology Dialysis Transplantation (2018, May 18), 33(Issue suppl_1), 368369

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See detailEndometriosis: deep insight into the pathology through metabolomics
Leenders, Justine ULiege; Martin, Manon; NISOLLE, Michelle ULiege et al

Poster (2018, May)

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See detailNOTA‐PRGD2 and NODAGA‐PRGD2: Bioconjugation, characterization, radiolabelling, and design space
Salvé, Mallory ULiege; Avohou, Tonakpon Hermane ULiege; Monbaliu, Jean-Christophe ULiege et al

in Journal of Labelled Compounds and Radiopharmaceuticals (2018), 61

This work reports on the development of amide bond bioconjugation for the production of ‐NOTA and ‐NODAGA PRGD2 using batch strategy andmicrofluidic reactor technology. The final radiolabelling step was ... [more ▼]

This work reports on the development of amide bond bioconjugation for the production of ‐NOTA and ‐NODAGA PRGD2 using batch strategy andmicrofluidic reactor technology. The final radiolabelling step was fully optimized using Design of Experiments and Design Space approaches, hence targeting robust labelling yields in routine. Optimal labelling conditions were defined insodium acetate buffer as 168 μg/mL peptide concentration, 4.9 pH, 47.5°C temperature, and 12.5‐minute reaction time. Upon optimization, the Gallium‐68 radiolabelling was fully automated. All the work was designed to be compliant to the GMP environment and to support the pharmaceuticalscale‐up. [less ▲]

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See detailA NMR-based metabolomics approach for reducing food losses: the example of minced pork meat
Cauchie, Emilie ULiege; Korsak Koulagenko, Nicolas ULiege; Leenders, Justine ULiege et al

in Proceedings of the First international Conference on "Innovative Food Ingredients and Food safety" (2018)

In Europe, the losses of initial meat production represent 20% and more than half of this occurs at animal production, slaughtering, processing and distribution step. In order to control food waste ... [more ▼]

In Europe, the losses of initial meat production represent 20% and more than half of this occurs at animal production, slaughtering, processing and distribution step. In order to control food waste, studies have highlighted the importance of monitoring the microbial diversity of food products because spoilage by bacteria that contaminate the food matrix is a major issue. As such, the combination of metabolomics data with other complementary approaches (classical microbiology and quality parameters) can gives the opportunity to gain deeper insights into and have a better comprehension of the spoilage mechanisms. The aim of the current study was to assess meat spoilage through the evolution of bacterial counts and changes in the metabolic profile of minced pork meat using Nuclear Magnetic Resonance (NMR) based metabolomics. Microbiological assessment, pH measurements, gas composition and metabolomics analysis were carried out in meat samples stored under food wrap and under modified atmosphere packaging (70% O2 – 30% CO2) at 4, 8 and 12°C during 13 days. All samples were irradiated and then inoculated separately with three dominant bacterial species: Brochothrix thermosphacta, Leuconostoc gelidum and Pseudomonas fragi. For all conditions, non-inoculated samples were also stored. Analysis were carried out at day 0 and at day 13 for metabolomics analysis, and each day for all others measurements. The multivariate analysis (PLS-DA) reveals a clear discrimination between: (i) the non-inoculated product at day 0 and at day 13, (ii) the inoculated and non-inoculated samples, (iii) the type of bacterium, and (iv) the packaging conditions. It can be observed that the type of bacterium inoculated had a higher impact on the metabolome than that the packaging conditions. Moreover, some metabolites are significantly increased: acetate and glycerol for B. thermosphacta, betaine and lactate for L. gelidum, threonine and glycine for P. fragi. Exploration of the correlations of NMR-based metabolomics results with others microbial parameters suggested their use as possible spoilage tool to provide information on minced pork meat spoilage and to follow intrinsically the evolution of the metabolomics pattern linked to a specific bacterium in a complex bacterial ecosystem. [less ▲]

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See detailCXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury.
Yakulov, Toma A.; Todkar, Abhijeet P.; Slanchev, Krasimir et al

in Nature Communications (2018), 9(1), 3660

Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos ... [more ▼]

Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis. [less ▲]

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See detailRadiotherapy-activated cancer-associated fibroblasts promote tumor progression through paracrine IGF-1R activation.
Tommelein, Joke; De Vlieghere, Elly; Verset, Laurine et al

in Cancer Research (2018)

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer (RC), a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAF are ... [more ▼]

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer (RC), a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAF are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer (CRC) cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell cycle arrest, and secretion of paracrine mediators including insulin-like growth factor-1 (IGF-1). Subsequently, RT-activated CAF promoted survival of CRC cells as well as a metabolic switch favoring glutamine consumption through IGF-1 receptor (IGF-1R) activation. RT followed by IGF-1R neutralization in orthotopic CRC models reduced the number of mice with organ metastases. Activation of the downstream IGF-1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from RC patients after neoadjuvant chemoRT. Taken together, our data support the notion that paracrine IGF-1/IGF-1R signaling initiated by RT-activated CAF worsen CRC progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival. [less ▲]

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See detail7‐Phenoxy-Substituted 3,4-Dihydro‐2H‐1,2,4-benzothiadiazine 1,1- Dioxides as Positive Allosteric Modulators of α‐Amino-3-hydroxy-5- methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency
Goffin, Eric ULiege; Drapier, Thomas ULiege; Probst Larsen, Anja et al

in Journal of Medicinal Chemistry (2018), 61

We report here the synthesis of 7-phenoxy- substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of ... [more ▼]

We report here the synthesis of 7-phenoxy- substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4- cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-ben- zothiadiazine 1,1-dioxide, EC50 = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11m per dimer interface, contrary to most benzothiadiazine dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first benzothiadiazine dioxide AMPApam to reach the nanomolar range. [less ▲]

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See detailFrom Metabolomics Study of Age-Related Macular Degeneration (AMD) to the Development of New Pyruvate Dehydrogenase Kinase Inhibitors (PDK)
Arslan, Deniz ULiege; Schoumacher, Matthieu ULiege; Pirotte, Bernard ULiege et al

Poster (2017, September 14)

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small part of ... [more ▼]

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small part of the retina specialized for the high-acuity vision. Exudative AMD, called “wet”, is characterized by the formation of new blood vessels growing under the retina according to a process named choroidal neovascularization (CNV). Currently, the aetiology and pathogenesis of AMD remain unclear. Nevertheless, a recent metabolomics study performed on the serum of “wet” AMD patients and on a CNV murine model, that mimics the effect of “wet” AMD, have demonstrated that lactate level is clearly involved in the severity of the pathology as well as the relationship between lactate, CNV and AMD [1]. According to this result, we suggest a new therapeutic approach of AMD based on the normalization of blood lactate level. The modulation of the lactate plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase (PDK) inhibitors significantly decrease the CNV. PDK and its four isoforms (PDK1-4) regulate the activity of the pyruvate dehydrogenase complex (PDH), a mitochondrial enzyme that plays a major role in the metabolic pathway of glucose, by reversible phosphorylation. Starting from these results, development of new PDK inhibitors could open the way to innovative treatment opportunities in AMD disease. Different analogues of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (fig.1) have been already synthetized and pharmacological evaluation is currently in progress. According to the results obtained, various pharmacomodulations will be investigated. [less ▲]

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See detailMetabolomics approaches of endometriosis
Leenders, Justine ULiege; Munaut, Carine ULiege; NISOLLE, Michelle ULiege et al

Conference (2017, September 12)

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See detailDevelopment of an HPTLC method for determination of hypoglycin A in aqueous extracts of seedlings and samaras of Acer species.
Habyarimana, Jean Belt Adélite ULiege; Baise, Etienne; Douny, Caroline ULiege et al

E-print/Working paper (2017)

Hypoglycin A (HGA) is a toxin contained in seeds of the sycamore maple tree (Acer pseudoplatanus). Ingestion of this amino acid causes equine atypical myopathy (AM) in Europe. Another variety, A. negundo ... [more ▼]

Hypoglycin A (HGA) is a toxin contained in seeds of the sycamore maple tree (Acer pseudoplatanus). Ingestion of this amino acid causes equine atypical myopathy (AM) in Europe. Another variety, A. negundo, is claimed to be present where AM cases were reported in the US. For unknown reasons, occurrence of this disease has increased. It is important to define environmental key factors that may influence toxicity of samaras from Acer species. In addition, the content of HGA in seedlings needs to be determined since AM outbreaks, during autumn period when the seeds fall but also during spring when seeds are germinating. The present study aims to validate a reliable method using high performance thin layer chromatography for determination and comparison of HGA in samaras and seedlings. The working range of the method was between 20 μg HGA to 408 μg HGA per ml water, corresponding to 12 - 244 mg/kg fresh weight or 40 - 816 mg/kg dry weight, taking into account of an arbitrary average dry matter content of 30%. Instrumental limit of detection and limit of quantification were of 10 µg HGA/ml and 20 µg HGA/ml water, respectively. Instrumental precision was 4% (RSD on 20 repeated measurements) while instrumental accuracy ranged between 86% and 121% of expected value. The HGA recovery of the analytical method estimated from spiked samaras and seedlings samples ranged between 63 and 103%. The method was applied to 9 samples of samaras from Acer pseudoplatanus, A. platanoides and A. campestre and 5 seedlings samples from A. pseudoplatanus. The results confirm detection of HGA in samaras from A. pseudoplatanus and the absence of detection in samaras of other tested species. They also suggest that detected levels of HGA are highly variable. This confirmed the suitability of the method for HGA detection in samaras or seedling. [less ▲]

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See detailDiscovery and Characterization of R/S-N-3-Cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea, a New Histone Deacetylase Class III Inhibitor Exerting Antiproliferative Activity against Cancer Cell Lines
Schnekenburger, M; Goffin, Eric ULiege; Lee, J-Y et al

in Journal of Medicinal Chemistry (2017), 60(11), 4714-4733

A new series of N-aryl-N'-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting ... [more ▼]

A new series of N-aryl-N'-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells. On the basis of computational docking combined to in vitro sirtuin 1/2 inhibition assays, we selected compound 18 [R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea] which displays a potent antiproliferative activity on various glioma cell types, assessed by quantitative videomicroscopy, eventually triggering senescence. The impact on normal glial cells was lower with a selectivity index of >10. Furthermore, human U373 and Hs683 glioblastoma cell lines served to demonstrate the inhibitory activity of 18 against histone deacetylase (HDAC) class III sirtuins 1 and 2 (SIRT1/2) by quantifying acetylation levels of histone and non-histone proteins. The translational potential of 18 was validated by an NCI-60 cell line screen and validation of growth inhibition of drug resistant cancer cell models. Eventually, the anticancer potential of 18 was validated in 3D glioblastoma spheroids and in vivo by zebrafish xenografts. In summary, compound 18 is the first representative of a new class of SIRT inhibitors opening new perspectives in the medicinal chemistry of HDAC inhibitors. [less ▲]

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