77 results on '"Doucey, P."'
Search Results
2. Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis
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Barbara Rewerska, MD, Lawrence D. Sher, MD, Sady Alpizar, MD, Sylvia Pauser, MD, Grazyna Pulka, MD, Neelufar Mozaffarian, MD, PhD, Yacine Salhi, PhD, Camille Martinet, MS, Wafaa Jabert, MS, Girish Gudi, PhD, Vinu CA, MPharm, MSc, Sunitha GN, PhD, Julie Macoin, MSc, Victor Anstett, MS, Riccardo Turrini, PhD, Marie-Agnès Doucey, PhD, Stanislas Blein, PhD, Cyril Konto, MD, and Martina Machkova, MD
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Atopic dermatitis ,anti-OX40 receptor ,humanized monoclonal antibody ,phase 2 ,telazorlimab ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Background: Telazorlimab is a humanized anti-OX40 monoclonal antibody being studied for treatment of T-cell–mediated diseases. Objective: This randomized, placebo-controlled, phase 2b dose-range finding study investigated efficacy, safety, pharmacokinetics, and immunogenicity of telazorlimab in subjects with atopic dermatitis. Methods: In this 2-part study (NCT03568162), adults (≥18 years) with moderate-to-severe disease were randomized to various regimens of subcutaneous telazorlimab or placebo for 16 weeks’ blinded treatment, followed by 38 weeks’ open-label treatment and 12 weeks’ drug-free follow-up. Telazorlimab treatment groups (following a loading dose) in part 1 were 300 mg every 2 weeks; 300 mg every 4 weeks; or 75 mg every 4 weeks. Part 2 evaluated telazorlimab 600 mg every 2 weeks. The primary end point was percentage change from baseline in Eczema Area and Severity Index (EASI) at week 16. Safety assessments included incidence of treatment-emergent adverse events. Results: The study randomized 313 subjects in part 1 and 149 in part 2. At 16 weeks, the least squares mean percentage change from baseline in EASI was significantly greater in subjects receiving telazorlimab 300 mg every 2 weeks (part 1) and 600 mg every 2 weeks (part 2) versus placebo (−54.4% vs −34.2% for part 1 and −59.0% vs −41.8% for part 2, P = .008 for both). Telazorlimab was well tolerated, with similar distribution of adverse events between telazorlimab- and placebo-treated subjects in both part 1 and part 2. Conclusion: Telazorlimab, administered subcutaneously at 300 mg every 2 weeks or 600 mg every 2 weeks following a loading dose, was well tolerated and induced significant and progressive clinical improvement in adults with moderate-to-severe atopic dermatitis.
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- 2024
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3. Systemic Inflammation Causes Microglial Dysfunction With a Vascular AD phenotype
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Praveen Bathini, Isabel Dupanloup, Elena Zenaro, Eleonora Terrabuio, Amrei Fischer, Edona Ballabani, Marie-Agnes Doucey, and Lavinia Alberi
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Inflammation ,PolyI:C ,Brain aging ,Microglia ,Sporadic Alzheimer's disease ,Vascular dementia ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Background: Studies in rodents and humans have indicated that inflammation outside CNS (systemic inflammation) affects brain homeostasis contributing to neurodevelopmental disorders. Itis becoming increasingly evident that such early insults may also belinked to neurodegenerative diseases like late-onset Alzheimer's disease (AD). Importantly, lifestyle and stress, such as viral or bacterial infection causing chronic inflammation, may contribute to neurodegenerative dementia. Systemic inflammatory response triggers a cascade of neuroinflammatory responses, altering brain transcriptome, cell death characteristic of AD, and vascular dementia. Our study aimed to assess the temporal evolution of the pathological impact of systemic inflammation evoked by prenatal and early postnatal peripheral exposure of viral mimetic Polyinosinic:polycytidylic acid (PolyI:C) and compare the hippocampal transcriptomic changes with the profiles of human post-mortem AD and vascular dementia brain specimens. Methods: We have engineered the PolyI:C sterile infection model in wildtype C57BL6 mice to achieve chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months, and 16 months), taking the hippocampus as a reference brain region, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD, and Controls (CTL), in parallel to Vascular dementia (VaD) patients’ specimens. Results: We found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological shifts progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression throughout aging, with a peak in differential expression at 9 months. We show that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD and VaD shows the reproducibility of some gene targets in vascular dementia specimens as compared to AD ones. Conclusions: The PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation causes progressive tau hyperphosphorylation, changes in microglia morphology, astrogliosis and gene reprogramming reflecting increased neuroinflammation, vascular remodeling, and the loss of neuronal functionality seen to some extent in human AD and Vascular dementia suggesting early immune insults could be crucial in neurodegenerative diseases.
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- 2023
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4. P871: ISB 1442, A FIRST-IN-CLASS CD38 AND CD47 BISPECIFIC ANTIBODY INNATE CELL MODULATOR FOR THE TREATMENT OF CD38 POSITIVE HEMATOLOGICAL MALIGNANCIES
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C. Grandclement, C. Estoppey, E. Dheilly, M. Panagopoulou, E. Martini, V. Labanca, S. De Angelis, J. Frei, A. Drake, A. Rubod, G. Gudi, V. Udupa, J. Koch Olsen, R. Giovannini, M. A. Doucey, E. Feldman, C. Konto, A. Srivastava, M. Perro, and S. Sammicheli
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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5. Long-term stability of gentamicin sulfate-ethylenediaminetetraacetic acid disodium salt (EDTA-Na2) solution for catheter locks
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Anne-Sophie Fiolet, Elise Jandot, Pauline Doucey, Coralie Crétet, Célia Brunel, Christine Pivot, Jean-Marc Ghigo, Christophe Beloin, David Lebeaux, and Fabrice Pirot
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Therapeutics. Pharmacology ,RM1-950 - Abstract
A lock solution composed of gentamicin sulfate (5 mg/mL) and ethylenediaminetetraacetic acid disodium salt (EDTA-Na2, 30 mg/mL) could fully eradicate in vivo bacterial biofilms in totally implantable venous access ports (TIVAP). In this study, fabrication, conditioning and sterilization processes of antimicrobial lock solution (ALS) were detailed and completed by a stability study. Stability of ALS was conducted for 12 months in vial (25 °C ± 2 °C, 60% ± 5% relative humidity (RH), and at 40 °C ± 2 °C, RH 75% ± 5%) and for 24 h and 72 h in TIVAP (40 °C ± 2 °C, RH 75% ± 5%). A stability indicating HPLC assay with UV detection for simultaneous quantification of gentamicin sulfate and EDTA-Na2 was developed. ALS was assayed by ion-pairing high performance liquid chromatography (HPLC) needing gentamicin derivatization, EDTA-Na2 metallocomplexation of samples and gradient mobile phase. HPLC methods to separate four gentamicin components and EDTA-Na2 were validated. Efficiency of sterility procedure and conditioning of ALS was confirmed by bacterial endotoxins and sterility tests. Physicochemical stability of ALS was determined by visual inspection, osmolality, pH, and sub-visible particle counting. Results confirmed that the stability of ALS in vials was maintained for 12 months and 24 h and 72 h in TIVAP. Keywords: Gentamicin-EDTA-Na2 loaded antimicrobial lock solution, Pharmaceutical compounding, Stability indicating HPLC assay method, Totally implantable venous access ports
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- 2018
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6. Classifying dementia progression using microbial profiling of saliva
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Praveen Bathini, Sandrine Foucras, Isabelle Dupanloup, Hira Imeri, Amalia Perna, Jean‐Luc Berruex, Marie‐Agnes Doucey, Jean‐Marie Annoni, and Lavinia Auber Alberi
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Alzheimer's disease ,cytokines ,olfaction ,oral microbiome ,Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Introduction There is increasing evidence linking periodontal infections to Alzheimer's disease (AD). Saliva sampling can reveal information about the host and pathogen interactions that can inform about physiological and pathological brain states. Methods A cross‐sectional cohort of age‐matched participants (78) was segmented according to their chemosensory (University of Pennsylvania Smell Identification Test; UPSIT) and cognitive scores (Mini‐Mental State Exam; MMSE and clinical dementia rating; CDR). Mid‐morning saliva was sampled from each participant and processed for microbiome composition and cytokine analysis. Linear discriminant analysis (LDA) was used to unravel specific changes in microbial and immunological signatures and logistic regression analysis (LRA) was employed to identify taxa that varied in abundance among patient groups. Results Using olfaction we distinguish in the cognitively normal population a segment with high chemosensory scores (CNh, 27) and another segment with chemosensory scores (CNr, 16) as low as mild cognitive impairment (MCI, 21) but higher than the AD group (17). We could identify stage‐specific microbial signatures changes but no clearly distinct cytokine profiles. Periodontal pathogen species as Filifactor villosus decline with the increasing severity of AD, whereas opportunistic oral bacteria such as Leptotrichia wadei show a significant enrichment in MCI. Conclusions The salivary microbiome indicates stage‐dependent changes in oral bacteria favoring opportunistic species at the expense of periodontal bacteria, whereas the inflammatory profiles remain mainly unchanged in the sampled population.
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- 2020
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7. PGE2inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function
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Morotti, Matteo, Grimm, Alizee J., Hope, Helen Carrasco, Arnaud, Marion, Desbuisson, Mathieu, Rayroux, Nicolas, Barras, David, Masid, Maria, Murgues, Baptiste, Chap, Bovannak S., Ongaro, Marco, Rota, Ioanna A., Ronet, Catherine, Minasyan, Aspram, Chiffelle, Johanna, Lacher, Sebastian B., Bobisse, Sara, Murgues, Clément, Ghisoni, Eleonora, Ouchen, Khaoula, Bou Mjahed, Ribal, Benedetti, Fabrizio, Abdellaoui, Naoill, Turrini, Riccardo, Gannon, Philippe O., Zaman, Khalil, Mathevet, Patrice, Lelievre, Loic, Crespo, Isaac, Conrad, Marcus, Verdeil, Gregory, Kandalaft, Lana E., Dagher, Julien, Corria-Osorio, Jesus, Doucey, Marie-Agnes, Ho, Ping-Chih, Harari, Alexandre, Vannini, Nicola, Böttcher, Jan P., Dangaj Laniti, Denarda, and Coukos, George
- Abstract
Expansion of antigen-experienced CD8+T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+TILs via the PGE2receptors EP2 and EP4. Mechanistically, PGE2inhibits IL-2 sensing in TILs by downregulating the IL-2Rγcchain, resulting in defective assembly of IL-2Rβ–IL2Rγcmembrane dimers. This results in impaired IL-2–mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
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- 2024
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8. Noninvasive rapid detection of metabolic adaptation in activated human T lymphocytes by hyperpolarized 13C magnetic resonance
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Can, Emine, Mishkovsky, Mor, Yoshihara, Hikari A. I., Kunz, Nicolas, Couturier, Dominique-Laurent, Petrausch, Ulf, Doucey, Marie-Agnès, and Comment, Arnaud
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- 2020
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9. Fine-Tuning of Optimal TCR Signaling in Tumor-Redirected CD8 T Cells by Distinct TCR Affinity-Mediated Mechanisms
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Danilo Presotto, Efe Erdes, Minh Ngoc Duong, Mathilde Allard, Pierre-Olivier Regamey, Manfredo Quadroni, Marie-Agnès Doucey, Nathalie Rufer, and Michael Hebeisen
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cancer immunotherapy ,NY-ESO-1 antigen ,T cell receptor engineering ,T cell receptor-peptide-major histocompatibility complex affinity ,hyporesponsiveness ,CD3ζ ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Redirecting CD8 T cell immunity with self/tumor-specific affinity-matured T cell receptors (TCRs) is a promising approach for clinical adoptive T cell therapy, with the aim to improve treatment efficacy. Despite numerous functional-based studies, little is known about the characteristics of TCR signaling (i.e., intensity, duration, and amplification) and the regulatory mechanisms underlying optimal therapeutic T cell responses. Using a panel of human SUP-T1 and primary CD8 T cells engineered with incremental affinity TCRs against the cancer-testis antigen NY-ESO-1, we found that upon activation, T cells with optimal-affinity TCRs generated intense and sustained proximal (CD3ζ, LCK) signals associated with distal (ERK1/2) amplification-gain and increased function. In contrast, in T cells with very high affinity TCRs, signal initiation was rapid and strong yet only transient, resulting in poor MAPK activation and low proliferation potential even at high antigen stimulation dose. Under resting conditions, the levels of surface TCR/CD3ε, CD8β, and CD28 expression and of CD3ζ phosphorylation were significantly reduced in those hyporesponsive cells, suggesting the presence of TCR affinity-related activation thresholds. We also show that SHP phosphatases were involved along the TCR affinity gradient, but displayed spatially distinct regulatory roles. While PTPN6/SHP-1 phosphatase activity controlled TCR signaling initiation and subsequent amplification by counteracting CD3ζ and ERK1/2 phosphorylation, PTPN11/SHP-2 augmented MAPK activation without affecting proximal TCR signaling. Together, our findings indicate that optimal TCR signaling can be finely tuned by TCR affinity-dependent SHP-1 and SHP-2 activity, and this may readily be determined at the TCR/CD3 complex level. We propose that these TCR affinity-associated regulations represent potential protective mechanisms preventing high affinity TCR-mediated autoimmune diseases.
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- 2017
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10. TIE-2 expressing monocytes in human cancers
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Riccardo Turrini, Angélique Pabois, Ioannis Xenarios, George Coukos, Jean-François Delaloye, and Marie-Agnès Doucey
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human cancer ,monocytes ,tem ,tie-2-expressing monocytes ,tumor microenvironment ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Tumor-associated macrophages (TAM) are well known as a key player in the tumor microenvironment, which support cancer progression. More recently, a lineage of monocytes characterized by the expression of the TIE-2/Tek angiopoietin receptor identified a subset of circulating and tumor-associated monocytes endowed with proangiogenic activity. TIE-2 expressing monocytes (TEM) were found both in humans and mice. Here, we review the phenotypes and functions of TEM reported so far in human cancer and their potential use as markers of cancer progression and metastasis. Finally, we discuss the therapeutic approaches currently used or proposed to target TEM.
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- 2017
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11. Toward a rational design of combination therapy in cancer
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Marie-Agnès Doucey and Ioannis Xenarios
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angiogenesis, monocytes, immune suppression, breast cancer, modeling ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
By merging computational systems modeling and experimental approaches, we have uncovered treatments reprogramming pro-angiogenic monocytes present in breast tumor into immunologically potent cells capable of mediating an anti-tumor immune response. The unraveled pathways and ligands which underlie monocyte pro-angiogenic activity have a strong predictive value for breast cancer patient relapse – free survival.
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- 2015
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12. Angiogenic activity of breast cancer patients' monocytes reverted by combined use of systems modeling and experimental approaches.
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Nicolas Guex, Isaac Crespo, Sylvian Bron, Assia Ifticene-Treboux, Eveline Faes-Van't Hull, Solange Kharoubi, Robin Liechti, Patricia Werffeli, Mark Ibberson, Francois Majo, Michäel Nicolas, Julien Laurent, Abhishek Garg, Khalil Zaman, Hans-Anton Lehr, Brian J Stevenson, Curzio Rüegg, George Coukos, Jean-François Delaloye, Ioannis Xenarios, and Marie-Agnès Doucey
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Biology (General) ,QH301-705.5 - Abstract
Angiogenesis plays a key role in tumor growth and cancer progression. TIE-2-expressing monocytes (TEM) have been reported to critically account for tumor vascularization and growth in mouse tumor experimental models, but the molecular basis of their pro-angiogenic activity are largely unknown. Moreover, differences in the pro-angiogenic activity between blood circulating and tumor infiltrated TEM in human patients has not been established to date, hindering the identification of specific targets for therapeutic intervention. In this work, we investigated these differences and the phenotypic reversal of breast tumor pro-angiogenic TEM to a weak pro-angiogenic phenotype by combining Boolean modelling and experimental approaches. Firstly, we show that in breast cancer patients the pro-angiogenic activity of TEM increased drastically from blood to tumor, suggesting that the tumor microenvironment shapes the highly pro-angiogenic phenotype of TEM. Secondly, we predicted in silico all minimal perturbations transitioning the highly pro-angiogenic phenotype of tumor TEM to the weak pro-angiogenic phenotype of blood TEM and vice versa. In silico predicted perturbations were validated experimentally using patient TEM. In addition, gene expression profiling of TEM transitioned to a weak pro-angiogenic phenotype confirmed that TEM are plastic cells and can be reverted to immunological potent monocytes. Finally, the relapse-free survival analysis showed a statistically significant difference between patients with tumors with high and low expression values for genes encoding transitioning proteins detected in silico and validated on patient TEM. In conclusion, the inferred TEM regulatory network accurately captured experimental TEM behavior and highlighted crosstalk between specific angiogenic and inflammatory signaling pathways of outstanding importance to control their pro-angiogenic activity. Results showed the successful in vitro reversion of such an activity by perturbation of in silico predicted target genes in tumor derived TEM, and indicated that targeting tumor TEM plasticity may constitute a novel valid therapeutic strategy in breast cancer.
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- 2015
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13. Ne pleure pas sur la Grèce
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Doucey, Bruno and Doucey, Bruno
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" La valise serrée contre ses jambes, il avait laissé ses pensées prendre le large pour apaiser l’angoisse que faisait monter en lui la présence des militaires. Pas un carnet dans la valise, pas un crayon qu’on lui aurait immédiatement confisqué. Non, mais des poèmes par centaines, dans la tête et dans le cœur, que rien ni personne ne parviendrait à lui enlever. Quelle chance, après tout, d’avoir choisi la poésie, et non la peinture ou le piano ! Dans les camps, dans les prisons où on les jette, le peintre privé de toiles et de pigments vit un enfer, le musicien sans piano se voit amputé de la meilleure part de lui-même, mais moi, poète sans stylo, ni papier, de quoi me prive-t-on que je ne puisse trouver en moi ? Les doigts coupés, la langue arrachée, je continuerais à sentir la vibration du poème. Elle est la corde tendue de mes nerfs. Ma résistance." Bruno Doucey a de multiples vies ; toutes le ramènent vers cette histoire qu’il a longtemps portée en lui. L’éditeur a publié six recueils de Ritsos, le poète se nourrit du lyrisme et de l’engagement de son ombre tutélaire, l’homme a trouvé une seconde patrie en Grèce, et l’humaniste abhorre la dictature. Quant au romancier, après avoir redonné vie à Neruda, Lorca, Max Jacob, Marianne Cohn, Victor Jara et Matoub Lounès, il se devait de faire entendre le chant et la révolte de ce frère d’âme.
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- 2021
14. Morbillivirus glycoprotein expression induces ER stress, alters Ca2+ homeostasis and results in the release of vasostatin.
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Jean-Marc Brunner, Philippe Plattet, Marie-Agnès Doucey, Lia Rosso, Thomas Curie, Alexandra Montagner, Riccardo Wittek, Marc Vandelvelde, Andreas Zurbriggen, Harald Hirling, and Béatrice Desvergne
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Medicine ,Science - Abstract
Although the pathology of Morbillivirus in the central nervous system (CNS) is well described, the molecular basis of neurodegenerative events still remains poorly understood. As a model to explore Morbillivirus-mediated CNS dysfunctions, we used canine distemper virus (CDV) that we inoculated into two different cell systems: a monkey cell line (Vero) and rat primary hippocampal neurons. Importantly, the recombinant CDV used in these studies not only efficiently infects both cell types but recapitulates the uncommon, non-cytolytic cell-to-cell spread mediated by virulent CDVs in brain of dogs. Here, we demonstrated that both CDV surface glycoproteins (F and H) markedly accumulated in the endoplasmic reticulum (ER). This accumulation triggered an ER stress, characterized by increased expression of the ER resident chaperon calnexin and the proapoptotic transcription factor CHOP/GADD 153. The expression of calreticulin (CRT), another ER resident chaperon critically involved in the response to misfolded proteins and in Ca(2+) homeostasis, was also upregulated. Transient expression of recombinant CDV F and H surface glycoproteins in Vero cells and primary hippocampal neurons further confirmed a correlation between their accumulation in the ER, CRT upregulation, ER stress and disruption of ER Ca(2+) homeostasis. Furthermore, CDV infection induced CRT fragmentation with re-localisation of a CRT amino-terminal fragment, also known as vasostatin, on the surface of infected and neighbouring non-infected cells. Altogether, these results suggest that ER stress, CRT fragmentation and re-localization on the cell surface may contribute to cytotoxic effects and ensuing cell dysfunctions triggered by Morbillivirus, a mechanism that might potentially be relevant for other neurotropic viruses.
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- 2012
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15. Caveolin-1 interacts with the chaperone complex TCP-1 and modulates its protein folding activity
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Doucey, M. -A., Bender, F. C., Hess, D., Hofsteenge, J., and Bron, C.
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- 2006
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16. Ceux qui se taisent
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Doucey, Bruno and Doucey, Bruno
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« J'en pleure Les quatre points cardinaux ne lui suffisaient pas Il a fallu qu'il en trouve un cinquième et qu'il enferme cinq fois par jour tous les horizons de sa vie dans le corps d'une seule femme vêtue de noir » Quels points communs entre les habitants d'un village de Grèce, un lit d'hôpital où se meurt un ami et la femme d'une cité de banlieue dont le fils a choisi le Coran ? On ne les entend pas, on ne les voit pas. De la Crète à Créteil, de elle à il, le talent de Bruno Doucey est de savoir donner vie à ceux qui sont privés de parole. Sous sa plume, « les mots remontent du silence comme l'odeur de la terre sous une pluie d'été ». Ses poèmes sont autant de chroniques d'une crise violente d'où émergent des noms et des visages : ceux d'un peuple qui ne veut pas vivre à genoux, d'un homme qui combat le crabe entouré des siens, des migrants qui se massent aux portes de l'Europe, d'une mère alliée à d'autres mères. Avec S'il existe un pays (2013), il nous invitait à un voyage autour du monde ; avec Ceux qui se taisent, c'est le monde qui vient à nous. Le livre-témoin d'une époque. Pour Bruno Doucey, poète, éditeur de poètes, la poésie permet de faire entendre ce que les mots ne disent pas, de voir ce que les yeux ne regardent pas, de toucher ce que la main ignore. Avec son dernier recueil paru en 2013, S’il existe un pays (ed.Bruno Doucey), ce sourcier des images nous offrait en partage le fruit de ses voyages autour du monde ; avec Ceux qui se taisent, il donne la parole à ceux qui ne l’ont pas. Et ce sont les silences que sa poésie habite, en témoin engagé de son temps.
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- 2020
17. Optical properties and local atomic order in non hydrogenated amorphous silicon carbonitride films
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Doucey, B., Cuniot, M., Moudni, R., Ténégal, F., Bourée, J. E., Imhoff, D., Rommeluére, M., and Dixmier, J.
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- 2002
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18. New Insight on Bio-sensing by Nano-fabricated Memristors
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Sacchetto, Davide, Doucey, Marie-Agnès, De Micheli, Giovanni, Leblebici, Yusuf, and Carrara, Sandro
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- 2011
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19. Oratorio pour Federico Garcia Lorca
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Doucey, Bruno and Doucey, Bruno
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Oratorio pour Federico Garcia Lorca? Ce long poème, initialement publié dans le recueil S'il existe un pays (Éditions Bruno Doucey, 2013), est dédié au poète espagnol mort en août 1936 sous la mitraille franquiste. Comme il le ferait dans un opéra en trois actes, le poète évoque successivement l'arrestation de Lorca, son exécution dans le barranco de Viznar, et la recherche des preuves qui paraissent aujourd'hui encore se dérober. Dans un entrelacs de mots et de notes, avec un sens inné du dialogue entre les arts, la poésie de Bruno Doucey se mêle à la musique du guitariste de flamenco Pedro Soler, pour ressusciter la figure inoubliable de Federico Garcia Lorca. Parce que le chant des hommes l'emporte sur la barbarie. Depuis qu'il a écrit ses premiers poèmes, Bruno Doucey est épris d'une ville espagnole, Grenade, et du chant de son poète assassiné par les nationalistes. Comme si le sang de Lorca coulait dans ses veines, le poète éditeur de poètes nous transmet sa passion brûlante d'émotion. Il l'a fait une première fois dans un roman, Federico Garcia Lorca, non au franquisme (Actes Sud Junior, 2010). Le voici aujourd'hui qui fait revivre le poète andalou avec le guitariste de flamenco Pedro Soler.
- Published
- 2018
20. Long-term stability of gentamicin sulfate-ethylenediaminetetraacetic acid disodium salt (EDTA-Na2) solution for catheter locks.
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Fiolet, Anne-Sophie, Jandot, Elise, Doucey, Pauline, Crétet, Coralie, Brunel, Célia, Pivot, Christine, Ghigo, Jean-Marc, Beloin, Christophe, Lebeaux, David, and Pirot, Fabrice
- Subjects
SULFATES ,GENTAMICIN ,BIOFILMS ,ETHYLENEDIAMINETETRAACETIC acid ,HUMIDITY ,HIGH performance liquid chromatography - Abstract
Abstract A lock solution composed of gentamicin sulfate (5 mg/mL) and ethylenediaminetetraacetic acid disodium salt (EDTA-Na 2 , 30 mg/mL) could fully eradicate in vivo bacterial biofilms in totally implantable venous access ports (TIVAP). In this study, fabrication, conditioning and sterilization processes of antimicrobial lock solution (ALS) were detailed and completed by a stability study. Stability of ALS was conducted for 12 months in vial (25 °C ± 2 °C, 60% ± 5% relative humidity (RH), and at 40 °C ± 2 °C, RH 75% ± 5%) and for 24 h and 72 h in TIVAP (40 °C ± 2 °C, RH 75% ± 5%). A stability indicating HPLC assay with UV detection for simultaneous quantification of gentamicin sulfate and EDTA-Na 2 was developed. ALS was assayed by ion-pairing high performance liquid chromatography (HPLC) needing gentamicin derivatization, EDTA-Na 2 metallocomplexation of samples and gradient mobile phase. HPLC methods to separate four gentamicin components and EDTA-Na 2 were validated. Efficiency of sterility procedure and conditioning of ALS was confirmed by bacterial endotoxins and sterility tests. Physicochemical stability of ALS was determined by visual inspection, osmolality, pH, and sub-visible particle counting. Results confirmed that the stability of ALS in vials was maintained for 12 months and 24 h and 72 h in TIVAP. [ABSTRACT FROM AUTHOR]
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- 2018
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21. Le carnet retrouvé de monsieur Max
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Doucey, Bruno and Doucey, Bruno
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1943 : Saint-Benoît-sur-Loire. Dans une chambre, un vieux poète juif attend qu'on vienne le chercher. Anticipant son arrestation, Max Jacob noircit les pages d'un petit carnet, racontant avec un humour féroce la folie qui s'est emparée du monde, son inquiétude pour sa soeur déjà déportée, ses angoisses, ses rêves et ses colères. Ce carnet ne le quitte pas en prison et l'accompagne jusqu'à ses dernières heures à Drancy. Il y consigne l'horreur mais aussi l'humanité des rencontres au camp. C'est en poète qu'il vit chaque instant et nous donne à voir un univers où la folie s'est emparée des hommes. Un univers où la poésie se transmet comme seule étincelle de vie contre la barbarie. Ce faux journal résonne avec une justesse bouleversante et nous tient en haleine de bout en bout.
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- 2016
22. S'il existe un pays
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Doucey, Bruno and Doucey, Bruno
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Un recueil qui associe lyrisme et résistance pour faire entendre le chant du monde.
- Published
- 2016
23. Intérêt des nouveaux marqueurs de la dégradation de la fibrine pour le calcul du score ISTH
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Boulay, G., primary, Baudin, F., additional, Floccard, B., additional, Doucey, P., additional, Marcotte, G., additional, Guillaume, C., additional, Rugeri, L., additional, Martin, O., additional, Faure, A., additional, Hengy, B., additional, Malavieille, F., additional, Debord, S., additional, and Rimmelé, T., additional
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- 2014
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24. Systemic Inflammation Causes Microglial Dysfunction With a Vascular AD phenotype
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Bathini, Praveen, Dupanloup, Isabel, Zenaro, Elena, Terrabuio, Eleonora, Fischer, Amrei, Ballabani, Edona, Doucey, Marie-Agnes, and Alberi, Lavinia
- Abstract
Studies in rodents and humans have indicated that inflammation outside CNS (systemic inflammation) affects brain homeostasis contributing to neurodevelopmental disorders. Itis becoming increasingly evident that such early insults may also belinked to neurodegenerative diseases like late-onset Alzheimer's disease (AD). Importantly, lifestyle and stress, such as viral or bacterial infection causing chronic inflammation, may contribute to neurodegenerative dementia. Systemic inflammatory response triggers a cascade of neuroinflammatory responses, altering brain transcriptome, cell death characteristic of AD, and vascular dementia. Our study aimed to assess the temporal evolution of the pathological impact of systemic inflammation evoked by prenatal and early postnatal peripheral exposure of viral mimetic Polyinosinic:polycytidylic acid (PolyI:C) and compare the hippocampal transcriptomic changes with the profiles of human post-mortem AD and vascular dementia brain specimens.
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- 2023
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25. Édito
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Edwige Chirouter and Agnès Perrin-Doucey
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Education ,Special aspects of education ,LC8-6691 - Full Text
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26. Preclinical characterization of ISB 1342, a CD38 × CD3 T-cell engager for relapsed/refractory multiple myeloma
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Pouleau, Blandine, Estoppey, Carole, Suere, Perrine, Nallet, Emilie, Laurendon, Amélie, Monney, Thierry, Pais, Daniela, Drake, Adam, Carretero-Iglesia, Laura, Macoin, Julie, Berret, Jérémy, Pihlgren, Maria, Doucey, Marie-Agnès, Gudi, Girish S., Menon, Vinu, Udupa, Venkatesha, Maiti, Abhishek, Borthakur, Gautam, Srivastava, Ankita, Blein, Stanislas, Mbow, M. Lamine, Matthes, Thomas, Kaya, Zeynep, Edwards, Claire M., Edwards, James R., Menoret, Emmanuelle, Kervoëlen, Charlotte, Pellat-Deceunynck, Catherine, Moreau, Philippe, Zhukovsky, Eugene, Perro, Mario, and Chimen, Myriam
- Abstract
•ISB 1342 exhibits potent killing of primary MM cells and MM cell lines with low sensitivity to daratumumab.•ISB 1342 induced complete MM tumor eradication in 2 in vivo mouse models.
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- 2023
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27. Angiogenic Activity of Breast Cancer Patients’ Monocytes Reverted by Combined Use of Systems Modeling and Experimental Approaches
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Guex, Nicolas, Crespo, Isaac, Bron, Sylvian, Ifticene-Treboux, Assia, Faes-van’t Hull, Eveline, Kharoubi, Solange, Liechti, Robin, Werffeli, Patricia, Ibberson, Mark, Majo, Francois, Nicolas, Michäel, Laurent, Julien, Garg, Abhishek, Zaman, Khalil, Lehr, Hans-Anton, Stevenson, Brian J., Rüegg, Curzio, Coukos, George, Delaloye, Jean-François, Xenarios, Ioannis, and Doucey, Marie-Agnès
- Abstract
Angiogenesis plays a key role in tumor growth and cancer progression. TIE-2-expressing monocytes (TEM) have been reported to critically account for tumor vascularization and growth in mouse tumor experimental models, but the molecular basis of their pro-angiogenic activity are largely unknown. Moreover, differences in the pro-angiogenic activity between blood circulating and tumor infiltrated TEM in human patients has not been established to date, hindering the identification of specific targets for therapeutic intervention. In this work, we investigated these differences and the phenotypic reversal of breast tumor pro-angiogenic TEM to a weak pro-angiogenic phenotype by combining Boolean modelling and experimental approaches. Firstly, we show that in breast cancer patients the pro-angiogenic activity of TEM increased drastically from blood to tumor, suggesting that the tumor microenvironment shapes the highly pro-angiogenic phenotype of TEM. Secondly, we predicted in silico all minimal perturbations transitioning the highly pro-angiogenic phenotype of tumor TEM to the weak pro-angiogenic phenotype of blood TEM and vice versa. In silico predicted perturbations were validated experimentally using patient TEM. In addition, gene expression profiling of TEM transitioned to a weak pro-angiogenic phenotype confirmed that TEM are plastic cells and can be reverted to immunological potent monocytes. Finally, the relapse-free survival analysis showed a statistically significant difference between patients with tumors with high and low expression values for genes encoding transitioning proteins detected in silico and validated on patient TEM. In conclusion, the inferred TEM regulatory network accurately captured experimental TEM behavior and highlighted crosstalk between specific angiogenic and inflammatory signaling pathways of outstanding importance to control their pro-angiogenic activity. Results showed the successful in vitro reversion of such an activity by perturbation of in silico predicted target genes in tumor derived TEM, and indicated that targeting tumor TEM plasticity may constitute a novel valid therapeutic strategy in breast cancer.
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- 2015
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28. Spectroscopic and protein chemical analyses demonstrate the presence of C-mannosylated tryptophan...
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Loffler, Andreas and Doucey, Marie-Agnes
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- 1996
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29. ISB 1442, a First-in-Class CD38 and CD47 Bispecific Antibody Innate Cell Modulator for the Treatment of Relapsed Refractory Multiple Myeloma
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Stefano, Sammicheli, Grandclement, Camille, Dehilly, Elie, Panagopoulou, Maria, Martini, Evangelia, Castillo, Rosa, Suere, Perrine, Pouleau, Blandine, Estoppey, Carole, Frei, Julia, Loyau, Jeremy, Monney, Thierry, Wood, Rebecca, Croset, Amelie, Rubod, Alain, Gudi, Girish, Udupa, Venkatesha, Gn, Sunitha, Menon, Vinu, Rasmussen, Daniel, Olsen, Jeppe Koch, Giovannini, Roberto, Chakrapani, Aravind, Blein, Stanislas, Doucey, Marie-Agnes, Drake, Adam, Riva, Alessandro, Konto, Cyril, Perro, Mario, and Mbow, Lamine
- Abstract
ISB 1442 is a bispecific antibody (BsAb) using Ichnos' proprietary Bispecific Engagement by Antibodies based on the T-cell receptor (BEAT ®) platform. A fully human BsAb with anti-CD38 and CD47 binding arms, ISB 1442 was developed for the treatment of relapsed/refractory multiple myeloma (rrMM). The CD38 binding arm consists of two bi-paratopic Fabs that strongly bind to CD38 through avidity-induced interactions. The anti-CD47 arm comprises a single Fab arm designed to block the interaction between CD47 and the signal-regulatory protein alpha (SIRPα) receptor present on phagocytes (including macrophages, monocytes and dendritic cells). With this design, the CD38 Fab arm preferentially drives binding to tumor cells and enables blocking of proximal CD47 receptors on the same cell via avidity-induced binding. Hence, ISB 1442 is anticipated to induce minimal unintended effects on red blood cell (RBC) hemagglutination compared to benchmark anti-CD47 monoclonal antibodies (mAb) magrolimab. The Fc portion of ISB 1442 is engineered to enhance antibody dependent cell phagocytosis (ADCP), antibody dependent cell cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). ISB 1442 is the first-in-class with these unique molecular attributes, which are designed to overcome mechanisms of resistance to daratumumab in rrMM patients.
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- 2021
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30. c-Cbl expression levels regulate the functional responses of human central and effector memory CD4 T cells
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Brembilla, Nicolò C., Weber, Johann, Rimoldi, Donata, Pradervand, Sylvain, Schütz, Frédéric, Pantaleo, Giuseppe, Rüegg, Curzio, Quadroni, Manfredo, Harshman, Keith, and Doucey, Marie-Agnès
- Abstract
The biochemical mechanisms controlling the diverse functional outcomes of human central memory (CM) and effector memory (EM) T-cell responses triggered through the T-cell receptor (TCR) remain poorly understood. We implemented reverse phase protein arrays to profile TCR signaling components in human CD8 and CD4 memory T-cell subsets isolated ex vivo. As compared with CD4 CM cells, EM cells express statistically significant increased amounts of SLP-76 and reduced levels of c-Cbl, Syk, Fyn, and LAT. Moreover, in EM cells reduced expression of negative regulator c-Cbl correlates with expression of c-Cbl kinases (Syk and Fyn), PI3K, and LAT. Importantly, consistent with reduced expression of c-Cbl, EM cells display a lower functional threshold than CM cells. Increasing c-Cbl content of EM cells to the same level as that of CM cells using cytosolic transduction, we impaired their proliferation and cytokine production. This regulatory mechanism depends primarily on c-Cbl E3 ubiquitin ligase activity as evidenced by the weaker impact of enzymatically deficient c-Cbl C381A mutant on EM cell functions. Our study reports c-Cbl as a critical regulator of the functional responses of memory T cell subsets and identifies for the first time in humans a mechanism controlling the functional heterogeneity of memory CD4 cells.
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- 2008
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31. CD3 delta establishes a functional link between the T cell receptor and CD8.
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Doucey, Marie-Agnès, Goffin, Laurence, Naeher, Dieter, Michielin, Olivier, Baumgärtner, Petra, Guillaume, Philippe, Palmer, Ed, and Luescher, Immanuel F
- Abstract
T cells expressing T cell receptor (TCR) complexes that lack CD3 delta, either due to deletion of the CD3 delta gene, or by replacement of the connecting peptide of the TCR alpha chain, exhibit severely impaired positive selection and TCR-mediated activation of CD8 single-positive T cells. Because the same defects have been observed in mice expressing no CD8 beta or tailless CD8 beta, we examined whether CD3 delta serves to couple TCR.CD3 with CD8. To this end we used T cell hybridomas and transgenic mice expressing the T1 TCR, which recognizes a photoreactive derivative of the PbCS 252-260 peptide in the context of H-2K(d). We report that, in thymocytes and hybridomas expressing the T1 TCR.CD3 complex, CD8 alpha beta associates with the TCR. This association was not observed on T1 hybridomas expressing only CD8 alpha alpha or a CD3 delta(-) variant of the T1 TCR. CD3 delta was selectively co-immunoprecipitated with anti-CD8 antibodies, indicating an avid association of CD8 with CD3 delta. Because CD8 alpha beta is a raft constituent, due to this association a fraction of TCR.CD3 is raft-associated. Cross-linking of these TCR-CD8 adducts results in extensive TCR aggregate formation and intracellular calcium mobilization. Thus, CD3 delta couples TCR.CD3 with raft-associated CD8, which is required for effective activation and positive selection of CD8(+) T cells.
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- 2003
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32. Surface properties of silicon nitride powders
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Cerovic, L. S., Milonjic, S. K., Bahloul-Hourlier, D., and Doucey, B.
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- 2002
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33. SiCN Nanocomposites : Powder Synthesis, Materials Processing and Ductility Assessment
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Doucey, B., Bahloul-Hourlier, Dj., Besson, J.L., and Goursat, Paul
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Not Available
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- 2001
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34. Investigations on thermal reactivity of Si/C/N nanopowders produced by laser aerosol or gas interactions
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BahloulHourlier, Djamila, Doucey, Benoît, Laborde, Etienne, and Goursat, Paul
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Ultrafine SiCN particles with various compositions, synthesised by laser pyrolysis in interaction either with gaseous or liquid reactant, were heat treated at temperatures between 300 and1773 K. Thermogravimetric measurements performed under inert (helium) atmosphere, showed that the best thermal stability was exhibited by nanopowders prepared from gaseous precursors (SiH4, CH3NH2, NH3). Mass spectrometry analysis data revealed that nanopowders derived from a mixture with ammonia and hexamethyldisilazane (HMDS) contained more NH and CN groups than those obtained without ammonia. The loss of hydrogen clearly dominated amongst the observed losses in all the examined samples at all temperatures. This study indicates that thermal degradation of such silicon based systems is not a single reaction but the net result of a number of reactions.
- Published
- 2001
35. CTL activation is induced by cross‐linking of TCR/MHC‐peptide‐CD8/p56lckadducts in rafts
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Doucey, Marie‐Agnès, Legler, Daniel F., Boucheron, Nicole, Cerottini, Jean‐Charles, Bron, Claude, and Luescher, Immanuel F.
- Abstract
To investigate the role of the coreceptor CD8 and lipid rafts in cytotoxic T lymphocyte (CTL) activation, we used soluble mono‐and multimeric H‐2Kd‐peptide complexes and cloned S14 CTL specific for a photoreactive derivative of the Plasmodium bergheicircumsporozoite (PbCS) peptide 252–260 [PbCS(ABA)]. We report that activation of CTL in suspension requires multimeric Kd‐PbCS(ABA) complexes co‐engaging TCR and CD8. Using TCR ligand photo‐cross‐linking, we find that monomeric Kd‐PbCS(ABA) complexes promote association of TCR/CD3 with CD8/p56lck. Dimerization of these adducts results in activation of p56lckin lipid rafts, where phosphatases are excluded. Additional cross‐linking further increases p56lckkinase activity, induces translocation of TCR/CD3 and other signaling molecules to lipid rafts and intracellular calcium mobilization. These events are prevented by blocking Src kinases or CD8 binding to TCR‐associated Kdmolecules, indicating that CTL activation is initiated by cross‐linking of CD8‐associated p56lck. They are also inhibited by methyl‐β‐cyclodextrin, which disrupts rafts and by dipalmitoyl phosphatidylethanolamine, which interferes with TCR signaling. Because efficient association of CD8 and p56lcktakes place in rafts, both reagents, though in different ways, impair coupling of p56lckto TCR, thereby inhibiting the initial and essential activation of p56lckinduced by cross‐linking of engaged TCR.
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- 2001
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36. Requirement of the Lec35 gene for all known classes of monosaccharide-P-dolichol-dependent glycosyltransferase reactions in mammals.
- Author
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M, Anand, S, Rush J, S, Ray, A, Doucey M, J, Weik, E, Ware F, J, Hofsteenge, J, Waechter C, and A, Lehrman M
- Abstract
The Lec35 gene product (Lec35p) is required for utilization of the mannose donor mannose-P-dolichol (MPD) in synthesis of both lipid-linked oligosaccharides (LLOs) and glycosylphosphatidylinositols, which are important for functions such as protein folding and membrane anchoring, respectively. The hamster Lec35 gene is shown to encode the previously identified cDNA SL15, which corrects the Lec35 mutant phenotype and predicts a novel endoplasmic reticulum membrane protein. The mutant hamster alleles Lec35.1 and Lec35.2 are characterized, and the human Lec35 gene (mannose-P-dolichol utilization defect 1) was mapped to 17p12-13. To determine whether Lec35p was required only for MPD-dependent mannosylation of LLO and glycosylphosphatidylinositol intermediates, two additional lipid-mediated reactions were investigated: MPD-dependent C-mannosylation of tryptophanyl residues, and glucose-P-dolichol (GPD)-dependent glucosylation of LLO. Both were found to require Lec35p. In addition, the SL15-encoded protein was selective for MPD compared with GPD, suggesting that an additional GPD-selective Lec35 gene product remains to be identified. The predicted amino acid sequence of Lec35p does not suggest an obvious function or mechanism. By testing the water-soluble MPD analog mannose-beta-1-P-citronellol in an in vitro system in which the MPD utilization defect was preserved by permeabilization with streptolysin-O, it was determined that Lec35p is not directly required for the enzymatic transfer of mannose from the donor to the acceptor substrate. These results show that Lec35p has an essential role for all known classes of monosaccharide-P-dolichol-dependent reactions in mammals. The in vitro data suggest that Lec35p controls an aspect of MPD orientation in the endoplasmic reticulum membrane that is crucial for its activity as a donor substrate.
- Published
- 2001
37. Requirement of the Lec35 Gene for All Known Classes of Monosaccharide-P-Dolichol-dependent Glycosyltransferase Reactions in Mammals
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Anand, Monika, Rush, Jeffrey S., Ray, Sutapa, Doucey, Marie-Agnes, Weik, Jennifer, Ware, Felecia E., Hofsteenge, Jan, Waechter, Charles J., and Lehrman, Mark A.
- Abstract
The Lec35 gene product (Lec35p) is required for utilization of the mannose donor mannose-P-dolichol (MPD) in synthesis of both lipid-linked oligosaccharides (LLOs) and glycosylphosphatidylinositols, which are important for functions such as protein folding and membrane anchoring, respectively. The hamster Lec35 gene is shown to encode the previously identified cDNA SL15, which corrects the Lec35 mutant phenotype and predicts a novel endoplasmic reticulum membrane protein. The mutant hamster alleles Lec35.1 and Lec35.2 are characterized, and the human Lec35 gene (mannose-P-dolichol utilization defect 1) was mapped to 17p12-13. To determine whether Lec35p was required only for MPD-dependent mannosylation of LLO and glycosylphosphatidylinositol intermediates, two additional lipid-mediated reactions were investigated: MPD-dependent C-mannosylation of tryptophanyl residues, and glucose-P-dolichol (GPD)-dependent glucosylation of LLO. Both were found to require Lec35p. In addition, the SL15-encoded protein was selective for MPD compared with GPD, suggesting that an additional GPD-selective Lec35 gene product remains to be identified. The predicted amino acid sequence of Lec35p does not suggest an obvious function or mechanism. By testing the water-soluble MPD analog mannose-β-1-P-citronellol in an in vitro system in which the MPD utilization defect was preserved by permeabilization with streptolysin-O, it was determined that Lec35p is not directly required for the enzymatic transfer of mannose from the donor to the acceptor substrate. These results show that Lec35p has an essential role for all known classes of monosaccharide-P-dolichol-dependent reactions in mammals. The in vitro data suggest that Lec35p controls an aspect of MPD orientation in the endoplasmic reticulum membrane that is crucial for its activity as a donor substrate.
- Published
- 2001
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38. SiCN nanocomposite: creep behaviour
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Besson, J. L., Doucey, B., Lucas, S., Bahloul-Hourlier, D., and Goursat, P.
- Published
- 2001
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39. Structural determination of sintered Si3N4/SiC nanocomposite using the XPS differential charge effect
- Author
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Tenegal, F., Rocque, Gheorghiu de la, A., Dufour, G., Senemaud, C., Doucey, B., Bahloul-Hourlier, D., Goursat, P., Mayne, M., and Cauchetier, M.
- Published
- 2000
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40. A study of the Li/Li^+ couple in DMC and PC solvents. Part 1: Characterization of LiAsF~6/DMC and LiAsF~6/PC solutions
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Doucey, L., Revault, M., Lautie, A., Chausse, A., and Messina, R.
- Published
- 1999
- Full Text
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41. Recombinant human interleukin-12 is the second example of a C-mannosylated protein.
- Author
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Doucey, M A, Hess, D, Blommers, M J, and Hofsteenge, J
- Abstract
The beta-chain of human interleukin 12 (IL-12) contains at position 319-322, the sequence Trp-x-x-Trp. In human RNase 2 this is the recognition motif for a new, recently discovered posttranslational modification, i.e., the C-glycosidic attachment of a mannosyl residue to the side chain of tryptophan. Analysis of C-terminal peptides of recombinant IL-12 (rHuIL-12) by mass spectrometry and NMR spectroscopy revealed that Trp-319beta is (partially) C-mannosylated. This finding was extended by in vitro mannosylation experiments, using a synthetic peptide derived from the same region of the protein as an acceptor. Furthermore, human B-lymphoblastoid cells, which secrete IL-12, were found to contain an enzyme that carries out the C-mannosylation reaction. This shows that nonrecombinant IL-12 is potentially C-mannosylated as well. This is only the second report on a C-mannosylated protein. However, the occurrence of the C-mannosyltransferase activity in a variety of cells and tissues, and the presence of the recognition motif in many proteins indicate that more C-mannosylated proteins may be found.
- Published
- 1999
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42. Protein C-mannosylation is enzyme-catalysed and uses dolichyl-phosphate-mannose as a precursor.
- Author
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A, Doucey M, D, Hess, R, Cacan, and J, Hofsteenge
- Abstract
C-mannosylation of Trp-7 in human ribonuclease 2 (RNase 2) is a novel kind of protein glycosylation that differs fundamentally from N- and O-glycosylation in the protein-sugar linkage. Previously, we established that the specificity determinant of the acceptor substrate (RNase 2) consists of the sequence -x-x-W, where the first Trp becomes C-mannosylated. Here we investigated the reaction with respect to the mannosyl donor and the involvement of a glycosyltransferase. C-mannosylation of Trp-7 was reduced 10-fold in CHO (Chinese hamster ovary) Lec15 cells, which are deficient in dolichyl-phosphate-mannose (Dol-P-Man) synthase activity, compared with wild-type cells. This was not a result of a decrease in C-mannosyltransferase activity. Rat liver microsomes were used to C-mannosylate the N-terminal dodecapeptide from RNase 2 in vitro, with Dol-P-Man as the donor. This microsomal transferase activity was destroyed by heat and protease treatment, and displayed the same acceptor substrate specificity as the in vivo reaction studied previously. The C-C linkage between the indole and the mannosyl moiety was demonstrated by tandem electrospray mass spectrometry analysis of the product. GDP-Man, in the presence of Dol-P, functioned as a precursor in vitro with membranes from wild-type but not CHO Lec15 cells. In contrast, with Dol-P-Man both membrane preparations were equally active. It is concluded that a microsomal transferase catalyses C-mannosylation of Trp-7, and that the minimal biosynthetic pathway can be defined as: Man -> -> GDP-Man -> Dol-P-Man -> (C2-Man-)Trp.
- Published
- 1998
43. C-Mannosylation of human RNase 2 is an intracellular process performed by a variety of cultured cells.
- Author
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Krieg, J, Gläsner, W, Vicentini, A, Doucey, M A, Löffler, A, Hess, D, and Hofsteenge, J
- Abstract
C2-alpha-Mannosyltryptophan was discovered in RNase 2 from human urine, representing a novel way of attaching carbohydrate to a protein. Here, we have addressed two questions related to the biosynthesis of this modification: (i) is C-mannosylation part of the normal intracellular biosynthetic route, and (ii) how general is it, i.e. which organisms perform this kind of glycosylation? To answer the first question, RNase 2, which is identical to the eosinophil-derived neurotoxin, was isolated from intracellular stores of cultured human HL-60 cells. The enzyme was C-mannosylated at Trp-7, showing that the modification occurs intracellularly, before secretion of the protein. The second question was investigated by immunological and chemical analysis of RNase 2 purified from the supernatant of transiently transformed cells from different organisms. This revealed that C-mannosylation occurs in cells from man, green monkey, pig, mouse, and hamster. The observation that pig kidney cells contain the machinery for C-mannosylation of Trp-7 of human RNase 2 but that the homologous RNase from porcine kidney is not a substrate, since it does not contain a tryptophan at position 7, strongly suggests that C-mannosylated proteins other than RNase 2 exist. Recombinant RNase 2 isolated from insect cells, plant protoplasts, and Escherichia coli was not C-mannosylated. These results not only form the basis for further studies on the biochemical aspects of C-mannosylation but also have implications for the choice of cells for production of recombinant glycoproteins.
- Published
- 1997
44. Thermal behaviour of SiCN nanopowders issued from laser pyrolysis
- Author
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Mayne, M., Bahloul-Hourlier, D., Doucey, B., Goursat, P., Cauchetier, M., and Herlin, N.
- Published
- 1997
- Full Text
- View/download PDF
45. Protein C-Mannosylation Is Enzyme-catalysed and Uses Dolichyl-Phosphate-Mannose as a Precursor
- Author
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Doucey, Marie-Agnès, Hess, Daniel, Cacan, René, and Hofsteenge, Jan
- Abstract
C-mannosylation of Trp-7 in human ribonuclease 2 (RNase 2) is a novel kind of protein glycosylation that differs fundamentally from N- and O-glycosylation in the protein-sugar linkage. Previously, we established that the specificity determinant of the acceptor substrate (RNase 2) consists of the sequence W-x-x-W, where the first Trp becomesC-mannosylated. Here we investigated the reaction with respect to the mannosyl donor and the involvement of a glycosyltransferase. C-mannosylation of Trp-7 was reduced 10-fold in CHO (Chinese hamster ovary) Lec15 cells, which are deficient in dolichyl-phosphate-mannose (Dol-P-Man) synthase activity, compared with wild-type cells. This was not a result of a decrease inC-mannosyltransferase activity. Rat liver microsomes were used to C-mannosylate the N-terminal dodecapeptide from RNase 2 in vitro, with Dol-P-Man as the donor. This microsomal transferase activity was destroyed by heat and protease treatment, and displayed the same acceptor substrate specificity as the in vivo reaction studied previously. The C-C linkage between the indole and the mannosyl moiety was demonstrated by tandem electrospray mass spectrometry analysis of the product. GDP-Man, in the presence of Dol-P, functioned as a precursor in vitro with membranes from wild-type but not CHO Lec15 cells. In contrast, with Dol-P-Man both membrane preparations were equally active. It is concluded that a microsomal transferase catalyses C-mannosylation of Trp-7, and that the minimal biosynthetic pathway can be defined as: Man –> –> GDP-Man –> Dol-P-Man –> (C2-Man-)Trp.
- Published
- 1998
- Full Text
- View/download PDF
46. P2‐248: CLASSIFYING DEMENTIA PROGRESSION USING INFLAMMATORY AND MICROBIAL PROFILING OF SALIVA.
- Author
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Auber, Lavinia Alberi, Bathini, Praveen, Perna, Amalia, Foucras, Sandrine, Doucey, Marie-Agnes, and Annoni, Jean Marie
- Published
- 2019
- Full Text
- View/download PDF
47. Selective inhibition of CTL activation by a dipalmitoyl‐phospholipid that prevents the recruitment of signaling molecules to lipid rafts
- Author
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Legler, Daniel F., Doucey, Marie-Agnès, Cerottini, Jean-Charles, Bron, Claude, and Luescher, Immanuel F.
- Abstract
Antigen‐specific T‐cell activation implicates a redistribution of plasma membrane‐bound molecules in lipid rafts, such as the coreceptors CD8 and CD4, the Src kinases Lck and Fyn, and the linker for activation of T cells (LAT), that results in the formation of signaling complexes. These molecules partition in lipid rafts because of palmitoylation of cytoplasmic, membrane proximal cysteines, which is essential for their functional integrity in T‐cell activation. Here, we show that exogenous dipalmitoyl‐phosphatidylethanolamine (DPPE), but not the related unsaturated dioleoyl‐phosphatidylethanolamine (DOPE), partitions in lipid rafts. DPPE inhibits activation of CD8+T lymphocytes by sensitized syngeneic antigen‐presenting cells or specific major histocompatibility complex (MHC) peptide tetramers, as indicated by esterase release and intracellular calcium mobilization. Cytotoxic T lymphocyte (CTL)‐target cell conjugate formation is not affected by DPPE, indicating that engagement of the T‐cell receptor by its cognate ligand is intact in lipid‐treated cells. In contrast to other agents known to block raft‐dependent signaling, DPPE efficiently inhibits the MHC peptide‐induced recruitment of palmitoylated signaling molecules to lipid rafts and CTL activation without affecting cell viability or lipid raft integrity.
- Published
- 2001
- Full Text
- View/download PDF
48. TIE-2 expressing monocytes in human cancers
- Author
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Turrini, Riccardo, Pabois, Angélique, Xenarios, Ioannis, Coukos, George, Delaloye, Jean-François, and Doucey, Marie-Agnès
- Abstract
ABSTRACTTumor-associated macrophages (TAM) are well known as a key player in the tumor microenvironment, which support cancer progression. More recently, a lineage of monocytes characterized by the expression of the TIE-2/Tek angiopoietin receptor identified a subset of circulating and tumor-associated monocytes endowed with proangiogenic activity. TIE-2 expressing monocytes (TEM) were found both in humans and mice. Here, we review the phenotypes and functions of TEM reported so far in human cancer and their potential use as markers of cancer progression and metastasis. Finally, we discuss the therapeutic approaches currently used or proposed to target TEM.
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- 2017
- Full Text
- View/download PDF
49. TIE-2-expressing monocytes are lymphangiogenic and associate specifically with lymphatics of human breast cancer
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Bron, Sylvian, Henry, Luc, Faes-van't Hull, Eveline, Turrini, Riccardo, Vanhecke, Dominique, Guex, Nicolas, Ifticene-Treboux, Assia, Marina Iancu, Emanuela, Semilietof, Aikaterini, Rufer, Nathalie, Lehr, Hans-Anton, Xenarios, Ioannis, Coukos, George, Delaloye, Jean-François, and Doucey, Marie-Agnès
- Abstract
ABSTRACTIn experimental mouse models of cancer, increasingly compelling evidence point toward a contribution of tumor associated macrophages (TAM) to tumor lymphangiogenesis. Corresponding experimental observations in human cancer remain scarce although lymphatic metastasis is widely recognized as a predominant route for tumor spread. We previously showed that, in malignant tumors of untreated breast cancer (BC) patients, TIE-2-expressing monocytes (TEM) are highly proangiogenic immunosuppressive cells and that TIE-2 and VEGFR signaling pathways drive TEM immunosuppressive function. We report here that, in human BC, TEM express the canonical lymphatic markers LYVE-1, Podoplanin, VEGFR-3 and PROX-1. Critically, both TEM acquisition of lymphatic markers and insertion into lymphatic vessels were observed in tumors but not in adjacent non-neoplastic tissues, suggesting that the tumor microenvironment shapes both TEM phenotype and spatial distribution. We assessed the lymphangiogenic activity of TEM isolated from dissociated primary breast tumors in vitroand in vivousing endothelial cells (EC) sprouting assay and corneal vascularization assay, respectively. We show that, in addition to their known hemangiogenic function, TEM isolated from breast tumor display a lymphangiogenic activity. Importantly, TIE-2 and VEGFR pathways display variable contributions to TEM angiogenic and lymphangiogenic activities across BC patients; however, combination of TIE-2 and VEGFR kinase inhibitors abrogated these activities and overcame inter-patient variability. These results highlight the direct contribution of tumor TEM to the breast tumor lymphatic network and suggest a combined use of TIE-2 and VEGFR kinase inhibitors as a therapeutic approach to block hem- and lymphangiogenesis in BC.
- Published
- 2016
- Full Text
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50. Toward a rational design of combination therapy in cancer
- Author
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Doucey, Marie-Agnès and Xenarios, Ioannis
- Abstract
By merging computational systems modeling and experimental approaches, we have uncovered treatments reprogramming pro-angiogenic monocytes present in breast tumor into immunologically potent cells capable of mediating an anti-tumor immune response. The unraveled pathways and ligands which underlie monocyte pro-angiogenic activity have a strong predictive value for breast cancer patient relapse – free survival.
- Published
- 2015
- Full Text
- View/download PDF
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