48 results on '"Ogier C"'
Search Results
2. Immunotherapy Versus Chemotherapy of Acute Myeloid Leukemia: Response to PHA, Allogeneic Lymphocytes, and Leukemic Myeloblasts of Remission Lymphocytes from Leukemia Patients
- Author
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Reizenstein, P., Ogier, C., Sjögren, A.-M., Allfrey, V. G., editor, Allgöwer, M., editor, Berenblum, I., editor, Bergel, F., editor, Bernard, J., editor, Bernhard, W., editor, Blokhin, N. N., editor, Bock, H. E., editor, Braun, W., editor, Bucalossi, P., editor, Chaklin, A. V., editor, Chorazy, M., editor, Cunningham, G. J., editor, Della Porta, G., editor, Denoix, P., editor, Dulbecco, R., editor, Eagle, H., editor, Eker, R., editor, Good, R. A., editor, Grabar, P., editor, Harris, R. J. C., editor, Hecker, E., editor, Herbeuval, R., editor, Higginson, J., editor, Hueper, W. C., editor, Isliker, H., editor, Kieler, J., editor, Kirsten, W. H., editor, Klein, G., editor, Koprowski, H., editor, Koss, L. G., editor, Macbeth, R. A., editor, Martz, G., editor, Mathé, G., editor, Mühlbock, O., editor, Old, L. J., editor, Potter, V. R., editor, Sabin, A. B., editor, Sachs, L., editor, Saxén, E. A., editor, Schmidt, C. G., editor, Spiegelman, S., editor, Szybalski, W., editor, Tagnon, H., editor, Tissières, A., editor, Uehlinger, E., editor, Wissler, R. W., editor, Rentchnick, P., editor, Senn, H. J., editor, Mathé, Georges, editor, and Muggia, Franco M., editor
- Published
- 1980
- Full Text
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3. Leucocyte Malignancies
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Andrews, R. G., Bernstein, I. D., Torok-Storb, B., Bell, C. G., Biberfeld, P., Christensson, B., Öst, Å., Hast, R., Skoog, L., Andreason, R., Olsson, L., Lagerlöf, B., Reizenstein, P., Boucheix, C., Perrot, J. Y., Mirshahi, M., Fournier, N., Billard, M., Giannoni, F., Bernadou, A., Rosenfeld, C., Chiao, J. W., Wang, C. Y., Del Giacco, G. S., Cengiarotti, L., Di Tucci, A., Broccia, G., Corda, G., Mathieu, A., Indiveri, F., Locci, F., Mantovani, G., Detrick-Hooks, B., Boumsell, L., Bernard, A., Hooks, J. J., Divine, M., Farcet, J. P., Gourdin, M. F., Vasconcelos, A., Tabilio, A., Andre, C., Bouguet, J., Reyes, F., Fontan, S., Zabay, J. M., Garcia, M. C., Pascual-Salcedo, D., Campos, A., de la Concha, E. G., Gordon, J., Åman, P., Mellstedt, H., Klein, G., Habeshaw, J. A., Herrmann, F., Sieber, G., Rühl, H., Lebacq, A. M., Ravoet, A. M., Bazin, H., De Bruyere, M., Rodhain, J., Sokal, G., Losa, G., Maestroni, G., Lucivero, G., Antonaci, S., Stomeo, C., Bonomo, L., Magaud, J. P., Brochier, J., Vu Van, H., El Ansary, M., Gentilhomme, O., Bryon, P. A., Mathé, G., Minowada, J., Ogier, C., Ginsbourg, M., Goutner, A., Knapp, W., Canon, C., Melief, C. J. M., Miedema, F., Rümke, H. C., ten Berge, R. J. M., Terpstra, F. G., v.d. Borne, A. E. G. Kr., Willemze, R., v. Vloten, W., Miljkovic, A. K., Isakovic, K., Jankovic, B. D., Peng, R., Knowles, D. M., Bushkin, Y., Petrányi, G. G., Busch, G., Milford, E., Todd, R., Griffin, J., Reinherz, E., Terhorst, C., Schlossman, St., Carpenter, Ch., Richard, Y., Demeocq, F., Schwarting, R., Thoen, J., Førre, Ø. T., von Fliedner, V., Carrel, S., Heumann, D., Zaech, P., Sekaly, R. P., Girardet, Ch., Mach, J. P., Azzo, W., Worman, C., Mills, K., Brooks, D., Hogg, N., Zola, H., Beverly, P., Cawley, J., Bernard, Alain, editor, Boumsell, Laurence, editor, Dausset, Jean, editor, Milstein, César, editor, and Schlossman, Stuart F., editor
- Published
- 1984
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4. Gestion des eaux pluviales à l’échelle du bassin versant
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Arcos, M., Guyot, S., Perratone, D., OGIER, C., Conseil Général de la Loire, and Brelot, Elodie
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Stratégie ,Bassin versant ,[SDE.IE]Environmental Sciences/Environmental Engineering ,Strategy ,Gouvernance ,Watershed ,Rivières urbaines ,Urban rivers - Abstract
Colloque avec actes et comité de lecture. Internationale.; International audience
- Published
- 2013
5. Effect of treatment with thymustimulin (Tp-1) on T and B cells in lymphoproliferative disorders
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Pontiggia, P., Ogier, C., and Follini, G. D.
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- 1983
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6. The MMP/TIMP system in the nervous system
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Rivera, S., Jourquin, J., Ogier, C., Bernard, A., Charton, G., Tremblay, E., Khrestchatisky, Michel, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)
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[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2004
7. Remission with high erythrocyte sedimentation rates in acute myeloid leukemia is of short duration
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Brizzi, A., Ogier, C., and Reizenstein, P.
- Published
- 1985
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8. Genetic Variability of Some Biological and Morphological Characters in Lixophaga diatraeae (Diptera: Tachinidae)
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Pintureau, B., primary, Grenier, S., additional, Paris, A., additional, and Ogier, C., additional
- Published
- 1995
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9. Genetic Variability of Some Biological and Morphological Characters in Lixophaga diatraeae(Diptera: Tachinidae)
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Pintureau, B., Grenier, S., Paris, A., and Ogier, C.
- Abstract
Genetic variability was compared in a laboratory strain of Lixophaga diatraeaeand a newly collected strain from Cuba. Five characteristics were analyzed: larval and pupal developmental durations and pupal length, diameter, and weight. The comparison of the within- and between-family variances by variance analyses showed that the Cuban strain was generally more variable than the laboratory strain. Thus, the latter strain shows a lower genetic variability probably proceeding from a genetic drift or bottlenecks. Heritability computations by the parent-child regression method also revealed some differences in the genetic variability of the two strains. Pupal length was selected in a Cuban strain for eight generations. An obvious differentiation was obtained between the low and the high selected lines. Such a selection could be used to improve biological control results.
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- 1995
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10. Observations sur une ponte fertile d'ouvrieres d'Acromyrmex octospinosus (REICH) (Hymenoptera - Formicidae)
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Febvay, Gérard, Ogier, C., Unité de recherche Productions végétales (CRAG ANT PROD V), Institut National de la Recherche Agronomique (INRA), Laboratoire de biologie appliquée, and ProdInra, Migration
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[SDV] Life Sciences [q-bio] ,INSECTE ,[SDV]Life Sciences [q-bio] ,REPRODUCTION SEXUEE - Published
- 1984
11. Age-Related Effect of High-Dose IgG Infusion in Autoimmune Thrombocytopenia (ATP).
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Ogier, C. and Ballerini, G.
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- 1984
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12. Contes espagnols
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Contamine de Latour, Emmanuel, n. 1858, trad, Foulché-Delbosc, R, trad, Ogier, C, il, Arana, Vicente de, Arana, Vicente de Arana, Contamine de Latour, Emmanuel, n. 1858, trad, Foulché-Delbosc, R, trad, Ogier, C, il, Arana, Vicente de, and Arana, Vicente de Arana
- Published
- 1889
13. [Splenectomy in idiopathic thrombopenic purpura and in myelofibrosis. A retrospective study of platelet increase, hemorrhagic complications and mortality]
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Per Hellstrom, Ogier C, Askergren J, Sundblad R, and Reizenstein P
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Adult ,Male ,Platelet Count ,Hemorrhage ,Middle Aged ,Prognosis ,Postoperative Complications ,Purpura, Thrombocytopenic ,Primary Myelofibrosis ,Splenectomy ,Humans ,Female ,Intraoperative Complications ,Aged ,Follow-Up Studies ,Retrospective Studies - Abstract
In a retrospective study of 39 splenectomies, patients with increased blood cell breakdown (13 cases of idiopathic thrombocytopenic purpura (ITP), 5 cases of hereditary spherocytosis, 2 of Felty's syndrome and 2 of autoimmune hemolytic anemia) were compared with those patients also presenting decreased blood cell production [14 cases of myelofibrosis (MF) with splenomegaly and 3 cases of advanced chronic myelogeneous leukemia (CML)]. Platelet regeneration post-operatively was significantly (p less than 0.01) more rapid in the ITP than in the MF group. Only 1/22 patients in the ITP group had major post-operative complications as compared to 10/17 in the MF group. None of the patients in the ITP group died within 25 days of operation as compared to 5/17 in the MF group. Only 3/22 patients in the ITP group lost more than 800 ml of blood during the operation as compared to 8/17 with MF. No statistically significant higher blood loss was found in patients with less than 30 x 10(9) platelets/l preoperatively, compared to those with higher platelet counts. However, correlation between the splenic weights and amount of blood loss was statistically significant (p less than 0.01). Thus, splenectomy seems much better tolerated in patients with ITP, even if platelets are low, than in patients with myelofibrosis.
14. HEME-MEDIATED MODULATION OF ALPHA-GLOBIN CHAIN BIOSYNTHESIS IN PORPHYRIA CUTANEA-TARDA ASSOCIATED WITH HETEROZYGOUS BETA-THALASSEMIA
- Author
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Gambari, R., Buzzoni, D., Barbieri, R., Carla Perrotta, Piva, R., Conconi, F., Delsenno, L., and Ogier, C.
15. Biological response to minimal residual disease
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Reizenstein, P., primary, Ogier, C., additional, and Hast, R.L., additional
- Published
- 1986
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16. Stockage et mobilisation de la tyrosine chez une larve de lépidoptère :dosages de la tyrosine, de son glucoside et d'autres acides aminés chez Spodoptera littoralis — lépidoptère ; noctuidae
- Author
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RAHBÉ, Y., primary, DELOBEL, B., additional, BONNOT, G., additional, OGIER, C., additional, and GUILLAUD, J., additional
- Published
- 1984
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17. Astrocyte reactivity to Fas activation is attenuated in TIMP-1 deficient mice, an in vitro study
- Author
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Khrestchatisky Michel, Soloway Paul D, Boucraut José, Creidy Rita, Ogier Crystel, and Rivera Santiago
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
Abstract Background Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional secreted protein with pleiotropic actions, including the inhibition of matrix metalloproteinases (MMPs), cell death/survival and growth promoting activities. After inflammatory challenge, the levels of TIMP-1 are highly and selectively upregulated in astrocytes among glial cells, but little is know about its role in these neural cells. We investigated the influence of TIMP-1 null mutation in the reactivity of cultured astrocytes to pro-inflammatory stimuli with TNF-α and anti-Fas antibody. Results When compared to WT, mutant astrocytes displayed an overall increased constitutive gelatinase expression and were less responsive to Fas-mediated upregulation of MMP-9, of monocyte chemoattractant protein-1 (MCP-1) and of intercellular cell adhesion molecule-1 (ICAM-1), all markers of astrocyte inflammatory response. In contrast, TNF-α treatment induced all these factors similarly regardless of the astrocyte genotype. The incorporation of 3H-thymidin, a marker of cell proliferation, increased in wild-type (WT) astrocytes after treatment with anti-Fas antibody or recombinant TIMP-1 but not in mutant astrocytes. Finally, lymphocyte chemotaxis was differentially regulated by TNF-α in WT and TIMP-1 deficient astrocytes. Conclusion We provide evidence that the alteration of the MMP/TIMP balance in astrocytes influences their reactivity to pro-inflammatory stimuli and that Fas activation modulates the expression of members of the MMP/TIMP axis. We hypothesise that the Fas/FasL transduction pathway and the MMP/TIMP system interact in astrocytes to modulate their inflammatory response to environmental stimuli.
- Published
- 2005
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18. Netrin G1 Ligand is a new stromal immunomodulator that promotes pancreatic cancer.
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Vendramini-Costa DB, Francescone R, Franco-Barraza J, Luong T, Graves M, de Aquino AM, Steele N, Gardiner JC, Dos Santos SAA, Ogier C, Malloy E, Borghaei L, Martinez E, Zhigarev DI, Tan Y, Lee H, Zhou Y, Cai KQ, Klein-Szanto AJ, Wang H, Andrake M, Dunbrack RL, Campbell K, and Cukierman E
- Abstract
Understanding pancreatic cancer biology is fundamental for identifying new targets and for developing more effective therapies. In particular, the contribution of the stromal microenvironment to pancreatic cancer tumorigenesis requires further exploration. Here, we report the stromal roles of the synaptic protein Netrin G1 Ligand (NGL-1) in pancreatic cancer, uncovering its pro-tumor functions in cancer-associated fibroblasts and in immune cells. We observed that the stromal expression of NGL-1 inversely correlated with patients' overall survival. Moreover, germline knockout (KO) mice for NGL-1 presented decreased tumor burden, with a microenvironment that is less supportive of tumor growth. Of note, tumors from NGL-1 KO mice produced less immunosuppressive cytokines and displayed an increased percentage of CD8
+ T cells than those from control mice, while preserving the physical structure of the tumor microenvironment. These effects were shown to be mediated by NGL-1 in both immune cells and in the local stroma, in a TGF-β-dependent manner. While myeloid cells lacking NGL-1 decreased the production of immunosuppressive cytokines, NGL-1 KO T cells showed increased proliferation rates and overall polyfunctionality compared to control T cells. CAFs lacking NGL-1 were less immunosuppressive than controls, with overall decreased production of pro-tumor cytokines and compromised ability to inhibit CD8+ T cells activation. Mechanistically, these CAFs downregulated components of the TGF-β pathway, AP-1 and NFAT transcription factor families, resulting in a less tumor-supportive phenotype. Finally, targeting NGL-1 genetically or using a functionally antagonistic small peptide phenocopied the effects of chemotherapy, while modulating the immunosuppressive tumor microenvironment (TME), rather than eliminating it. We propose NGL-1 as a new local stroma and immunomodulatory molecule, with pro-tumor roles in pancreatic cancer., Statement of Significance: Here we uncovered the pro-tumor roles of the synaptic protein NGL-1 in the tumor microenvironment of pancreatic cancer, defining a new target that simultaneously modulates tumor cell, fibroblast, and immune cell functions. This study reports a new pathway where NGL-1 controls TGF-β, AP-1 transcription factor members and NFAT1, modulating the immunosuppressive microenvironment in pancreatic cancer. Our findings highlight NGL-1 as a new stromal immunomodulator in pancreatic cancer.- Published
- 2024
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19. Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling.
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Dudgeon C, Casabianca A, Harris C, Ogier C, Bellina M, Fiore S, Bernet A, Ducarouge B, Goldschneider D, Su X, Pitarresi J, Hezel A, De S, Narrow W, Soliman F, Shields C, Vendramini-Costa DB, Prela O, Wang L, Astsaturov I, Mehlen P, and Carpizo DR
- Subjects
- Humans, Netrin-1, Retinoids, Hepatic Stellate Cells metabolism, Cell Line, Tumor, Netrin Receptors, DNA-Binding Proteins, Transcription Factors, Proto-Oncogene Proteins c-ets, Pancreatic Neoplasms pathology, Carcinoma, Pancreatic Ductal pathology, Liver Neoplasms metabolism
- Abstract
The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor due to changes in cell plasticity governed by a distinct transcriptome. Therapeutic strategies that target this distinct biology are needed. We detect an upregulation of the neuronal axon guidance molecule Netrin-1 in PDAC liver metastases that signals through its dependence receptor (DR), uncoordinated-5b (Unc5b), to facilitate metastasis in vitro and in vivo. The mechanism of Netrin-1 induction involves a feedforward loop whereby Netrin-1 on the surface of PDAC-secreted extracellular vesicles prepares the metastatic niche by inducing hepatic stellate cell activation and retinoic acid secretion that in turn upregulates Netrin-1 in disseminated tumor cells via RAR/RXR and Elf3 signaling. While this mechanism promotes PDAC liver metastasis, it also identifies a therapeutic vulnerability, as it can be targeted using anti-Netrin-1 therapy to inhibit metastasis using the Unc5b DR cell death mechanism., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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20. Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies.
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Restifo D, McDermott JR, Cvetkovic D, Dos Santos T, Ogier C, Surumbayeva A, Handorf EA, Schimke C, Ma C, Cai KQ, Olszanski AJ, Kathad U, Bhatia K, Sharma P, Kulkarni A, and Astsaturov I
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- Humans, DNA Repair, Animals, Adenocarcinoma, DNA Damage, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Alcohol Oxidoreductases genetics, Antineoplastic Agents pharmacology
- Abstract
The greater efficacy of DNA-damaging drugs for pancreatic adenocarcinoma (PDAC) relies on targeting cancer-specific vulnerabilities while sparing normal organs and tissues due to their inherent toxicities. We tested LP-184, a novel acylfulvene analog, for its activity in preclinical models of PDAC carrying mutations in the DNA damage repair (DDR) pathways. Cytotoxicity of LP-184 is solely dependent on prostaglandin reductase 1 (PTGR1), so that PTGR1 expression robustly correlates with LP-184 cytotoxicity in vitro and in vivo. Low-passage patient-derived PDAC xenografts with DDR deficiencies treated ex vivo are more sensitive to LP-184 compared with DDR-proficient tumors. Additional in vivo testing of PDAC xenografts for their sensitivity to LP-184 demonstrates marked tumor growth inhibition in models harboring pathogenic mutations in ATR, BRCA1, and BRCA2. Depletion of PTGR1, however, completely abrogates the antitumor effect of LP-184. Testing combinatorial strategies for LP-184 aimed at deregulation of nucleotide excision repair proteins ERCC3 and ERCC4 established synergy. Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184., (©2023 American Association for Cancer Research.)
- Published
- 2023
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21. Trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer growth and immune suppression via phospholipid scramblase anoctamin 6 (ANO6).
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Ogier C, Solomon AMC, Lu Z, Recoules L, Klochkova A, Gabitova-Cornell L, Bayarmagnai B, Restifo D, Surumbayeva A, Vendramini-Costa DB, Deneka AY, Francescone R, Lilly AC, Sipman A, Gardiner JC, Luong T, Franco-Barraza J, Ibeme N, Cai KQ, Einarson MB, Nicolas E, Efimov A, Megill E, Snyder NW, Bousquet C, Cros J, Zhou Y, Golemis EA, Gligorijevic B, Soboloff J, Fuchs SY, Cukierman E, and Astsaturov I
- Abstract
In pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels. This raises an unresolved question of how PDAC cells obtain essential metabolites and water-insoluble lipids. We have found a critical role for cancer-associated fibroblasts (CAFs) in obtaining and transferring lipids from blood-borne particles to PDAC cells via trogocytosis of CAF plasma membranes. We have also determined that CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) is an essential CAF trogocytosis regulator required to promote PDAC cell survival. During trogocytosis, cancer cells and CAFs form synapse-like plasma membranes contacts that induce cytosolic calcium influx in CAFs via Orai channels. This influx activates ANO6 and results in phosphatidylserine exposure on CAF plasma membrane initiating trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. Importantly, ANO6-dependent trogocytosis also supports the immunosuppressive function of pancreatic CAFs towards cytotoxic T cells by promoting transfer of excessive amounts of cholesterol. Further, blockade of ANO6 antagonizes tumor growth via disruption of delivery of exogenous cholesterol to cancer cells and reverses immune suppression suggesting a potential new strategy for PDAC therapy.
- Published
- 2023
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22. NetrinG1 + cancer-associated fibroblasts generate unique extracellular vesicles that support the survival of pancreatic cancer cells under nutritional stress.
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Raghavan KS, Francescone R, Franco-Barraza J, Gardiner JC, Vendramini-Costa DB, Luong T, Pourmandi N, Andren A, Kurimchak A, Ogier C, Campbell PM, Duncan JS, Lyssiotis CA, Languino LR, and Cukierman E
- Subjects
- Humans, Integrin alpha5beta1 metabolism, Tumor Microenvironment, Pancreatic Neoplasms, Cancer-Associated Fibroblasts metabolism, Pancreatic Neoplasms metabolism, Carcinoma, Pancreatic Ductal metabolism, Extracellular Vesicles metabolism
- Abstract
It is projected that in 5 years, pancreatic cancer will become the second deadliest cancer in the United States. A unique aspect of pancreatic ductal adenocarcinoma (PDAC) is its stroma; rich in cancer-associated fibroblasts (CAFs) and a dense CAF-generated extracellular matrix (ECM). These pathogenic stroma CAF/ECM units cause the collapse of local blood vessels rendering the tumor microenvironment nutrient-poor. PDAC cells are able to survive this state of nutrient stress via support from CAF-secreted material, which includes small extracellular vesicles (sEVs). The tumor-supportive CAFs possess a distinct phenotypic profile, compared to normal-like fibroblasts, expressing NetrinG1 (NetG1) at the plasma membrane, and active Integrin α
5 β1 localized to the multivesicular bodies; traits indicative of poor patient survival. We herein report that NetG1+ CAFs secrete sEVs that stimulate Akt-mediated survival in nutrient-deprived PDAC cells, protecting them from undergoing apoptosis. Further, we show that NetG1 expression in CAFs is required for the pro-survival properties of sEVs. Additionally, we report that the above-mentioned CAF markers are secreted in distinct subpopulations of EVs; with NetG1 being enriched in exomeres, and Integrin α5 β1 being enriched in exosomes. Finally, we found that NetG1 and Integrin α5 β1 were detected in sEVs collected from plasma of PDAC patients, while their levels were significantly lower in plasma-derived sEVs of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF-EVs elucidates novel avenues in tumor-stroma interactions and pathogenic stroma detection., Competing Interests: Conflicts: C.A. Lyssiotis has received consulting fees from Astellas Pharmaceuticals, Odyssey Therapeutics, and T-Knife Therapeutics, and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015). E. Cukierman has two patents pending that relate to this study and wishes to disclose she is currently a consultant and SAB member for Phenomic AI.- Published
- 2022
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23. Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer.
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Gabitova-Cornell L, Surumbayeva A, Peri S, Franco-Barraza J, Restifo D, Weitz N, Ogier C, Goldman AR, Hartman TR, Francescone R, Tan Y, Nicolas E, Shah N, Handorf EA, Cai KQ, O'Reilly AM, Sloma I, Chiaverelli R, Moffitt RA, Khazak V, Fang CY, Golemis EA, Cukierman E, and Astsaturov I
- Subjects
- 3-Hydroxysteroid Dehydrogenases genetics, 3-Hydroxysteroid Dehydrogenases metabolism, Animals, Atorvastatin pharmacology, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal metabolism, Cell Differentiation drug effects, Cell Differentiation genetics, Cell Line, Tumor, Epithelial-Mesenchymal Transition drug effects, Epithelial-Mesenchymal Transition genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Kaplan-Meier Estimate, Mice, Inbred C57BL, Mice, Knockout, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms metabolism, Signal Transduction genetics, Transforming Growth Factor beta metabolism, Xenograft Model Antitumor Assays methods, Biosynthetic Pathways genetics, Carcinoma, Pancreatic Ductal genetics, Cholesterol, LDL biosynthesis, Pancreatic Neoplasms genetics, Transforming Growth Factor beta genetics
- Abstract
Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate-limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by Kras
G12D expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1, enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests that activation of transforming growth factor β signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote the basal type of PDAC, conferring poor outcomes in patients., Competing Interests: Declaration of Interests I.A. served as a consultant for Caris Life Sciences, Inc., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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24. An auristatin-based antibody-drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer.
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Bourillon L, Bourgier C, Gaborit N, Garambois V, Llès E, Zampieri A, Ogier C, Jarlier M, Radosevic-Robin N, Orsetti B, Delpech H, Theillet C, Colombo PE, Azria D, Pèlegrin A, Larbouret C, and Chardès T
- Subjects
- Animals, Antibodies, Monoclonal, Murine-Derived administration & dosage, Antibodies, Monoclonal, Murine-Derived pharmacology, Carcinoma, Pancreatic Ductal metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation radiation effects, Cell Survival drug effects, Cell Survival radiation effects, Chemoradiotherapy, Humans, Immunoconjugates chemistry, Immunoconjugates pharmacology, Immunologic Factors pharmacology, Mice, Oligopeptides administration & dosage, Oligopeptides pharmacology, Pancreatic Neoplasms metabolism, Phosphorylation drug effects, Phosphorylation radiation effects, STAT3 Transcription Factor metabolism, Treatment Outcome, Xenograft Model Antitumor Assays, Carcinoma, Pancreatic Ductal therapy, Immunoconjugates administration & dosage, Immunologic Factors administration & dosage, Pancreatic Neoplasms therapy
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemotherapy and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic markers. We previously generated the nonligand competing anti-HER3 antibody 9F7-F11 that binds to pancreatic tumor cells and induces tumor regression in vivo in experimental models. Here, we asked whether coupling 9F7-F11 with a radiosensitizer, such as monomethylauristatin E (MMAE), by using the antibody-drug conjugate (ADC) technology could improve radiation therapy efficacy in PDAC. We found that the MMAE-based HER3 antibody-drug conjugate (HER3-ADC) was efficiently internalized in tumor cells, increased the fraction of cells arrested in G2/M, which is the most radiosensitive phase of the cell cycle, and promoted programmed cell death of irradiated HER3-positive pancreatic cancer cells (BxPC3 and HPAC cell lines). HER3-ADC decreased the clonogenic survival of irradiated cells by increasing DNA double-strand break formation (based on γH2AX level), and by modulating DNA damage repair. Tumor radiosensitization with HER3-ADC favored the inhibition of the AKT-induced survival pathway, together with more efficient caspase 3/PARP-mediated apoptosis. Incubation with HER3-ADC before irradiation synergistically reduced the phosphorylation of STAT3, which is involved in chemoradiation resistance. In vivo, the combination of HER3-ADC with radiation therapy increased the overall survival of mice harboring BxPC3, HPAC cell xenografts or patient-derived xenografts, and reduced proliferation (KI67-positive cells). Combining auristatin radiosensitizer delivery via an HER3-ADC with radiotherapy is a new promising therapeutic strategy in PDAC., (© 2019 UICC.)
- Published
- 2019
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25. Targeting the NRG1/HER3 pathway in tumor cells and cancer-associated fibroblasts with an anti-neuregulin 1 antibody inhibits tumor growth in pre-clinical models of pancreatic cancer.
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Ogier C, Colombo PE, Bousquet C, Canterel-Thouennon L, Sicard P, Garambois V, Thomas G, Gaborit N, Jarlier M, Pirot N, Pugnière M, Vie N, Gongora C, Martineau P, Robert B, Pèlegrin A, Chardès T, and Larbouret C
- Subjects
- Animals, Apoptosis, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Cell Proliferation, Coculture Techniques, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Neuregulin-1 immunology, Neuregulin-1 metabolism, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Receptor, ErbB-3 immunology, Receptor, ErbB-3 metabolism, Signal Transduction, Tumor Cells, Cultured, Tumor Microenvironment, Xenograft Model Antitumor Assays, Antibodies, Monoclonal pharmacology, Cancer-Associated Fibroblasts drug effects, Carcinoma, Pancreatic Ductal prevention & control, Gene Expression Regulation, Neoplastic drug effects, Neuregulin-1 antagonists & inhibitors, Pancreatic Neoplasms prevention & control, Receptor, ErbB-3 antagonists & inhibitors
- Abstract
Neuregulin 1 (NRG1), a ligand for HER3 and HER4 receptors, is secreted by both pancreatic tumor cells (PC) and cancer-associated fibroblasts (CAFs), the latter representing the most abundant compound of pancreatic stroma. This desmoplastic stroma contributes to Pancreatic Ductal Adenocarcinoma (PDAC) aggressiveness and therapeutic failure by promoting tumor progression, invasion and resistance to chemotherapies. In the present work, we aimed at disrupting the complex crosstalk between PC and CAF in order to prevent tumor cell proliferation. To do so, we demonstrated the promising tumor growth inhibitory effect of the 7E3, an original antibody directed to NRG1. This antibody promotes antibody dependent cellular cytotoxicity in NRG1-positive PC and CAFs and inhibits NRG1-associated signaling pathway induction, by blocking NRG1-mediated HER3 activation. Moreover, 7E3 inhibits migration and growth of pancreatic cancer cells co-cultured with CAFs, both in vitro and in vivo using orthotopic pancreatic tumor xenografts. Our preclinical results demonstrate that the anti-NRG1 antibody 7E3 could represent a promising approach to target pancreatic stroma and cancer cells, thereby providing novel therapeutic options for PDAC., (Copyright © 2018. Published by Elsevier B.V.)
- Published
- 2018
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26. Neuregulin 1 Allosterically Enhances the Antitumor Effects of the Noncompeting Anti-HER3 Antibody 9F7-F11 by Increasing Its Binding to HER3.
- Author
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Le Clorennec C, Bazin H, Dubreuil O, Larbouret C, Ogier C, Lazrek Y, Garambois V, Poul MA, Mondon P, Barret JM, Mathis G, Prost JF, Pèlegrin A, and Chardès T
- Subjects
- A549 Cells, Animals, Antibodies, Anti-Idiotypic administration & dosage, Antibodies, Anti-Idiotypic immunology, Antibodies, Monoclonal, Murine-Derived immunology, Biomarkers, Tumor genetics, Cell Proliferation drug effects, Female, Fluorescence Resonance Energy Transfer, Gene Expression Regulation, Neoplastic, Humans, Mice, Neoplasms genetics, Neoplasms immunology, Neoplasms pathology, Neuregulin-1 immunology, Phosphorylation, Protein Binding, Receptor, ErbB-3 antagonists & inhibitors, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Antibodies, Monoclonal, Murine-Derived administration & dosage, Biomarkers, Tumor immunology, Neoplasms drug therapy, Neuregulin-1 genetics, Receptor, ErbB-3 immunology
- Abstract
Exploratory clinical trials using therapeutic anti-HER3 antibodies strongly suggest that neuregulin (NRG1; HER3 ligand) expression at tumor sites is a predictive biomarker of anti-HER3 antibody efficacy in cancer. We hypothesized that in NRG1-expressing tumors, where the ligand is present before antibody treatment, anti-HER3 antibodies that do not compete with NRG1 for receptor binding have a higher receptor-neutralizing action than antibodies competing with the ligand for binding to HER3. Using time-resolved-fluorescence energy transfer (TR-FRET), we demonstrated that in the presence of recombinant NRG1, binding of 9F7-F11 (a nonligand-competing anti-HER3 antibody) to HER3 is increased, whereas that of ligand-competing anti-HER3 antibodies (H4B-121, U3-1287, Ab#6, Mab205.10.2, and MOR09825) is decreased. Moreover, 9F7-F11 showed higher efficacy than antibodies that compete with the ligand for binding to HER3. Specifically, 9F7-F11 inhibition of cell proliferation and of HER3/AKT/ERK1/2 phosphorylation as well as 9F7-F11-dependent cell-mediated cytotoxicity were higher in cancer cells preincubated with recombinant NRG1 compared with cells directly exposed to the anti-HER3 antibody. This translated in vivo into enhanced growth inhibition of NRG1-expressing BxPC3 pancreatic, A549 lung, and HCC-1806 breast cell tumor xenografts in mice treated with 9F7-F11 compared with H4B-121. Conversely, both antibodies had similar antitumor effect in NRG1-negative HPAC pancreatic carcinoma cells. In conclusion, the allosteric modulator 9F7-F11 shows increased anticancer effectiveness in the presence of NRG1 and thus represents a novel treatment strategy for NRG1-addicted tumors. Mol Cancer Ther; 16(7); 1312-23. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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27. Deregulation of hypothalamic-pituitary-adrenal axis functions in an Alzheimer's disease rat model.
- Author
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Brureau A, Zussy C, Delair B, Ogier C, Ixart G, Maurice T, and Givalois L
- Subjects
- Alzheimer Disease, Animals, Humans, Male, Rats, Rats, Sprague-Dawley, Disease Models, Animal, Glucocorticoids metabolism, Hypothalamo-Hypophyseal System metabolism, Pituitary-Adrenal System metabolism, Receptors, Glucocorticoid metabolism, Receptors, Mineralocorticoid metabolism
- Abstract
Elevated cortisol evidence in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids are involved in the development and/or maintenance of AD. We investigated the hypothalamic-pituitary-adrenal (HPA) axis activity, functionality, and reactivity for up to 6 weeks after an intracerebroventricular injection of amyloid-β(25-35) peptide (Aβ(25-35)) in rat, a validated acute model of AD. Aβ(25-35) induces memory impairment, alteration of anxiety responses, HPA axis hyperactivity, and glucocorticoid (GR) and mineralocorticoid (MR) receptor increases in brain regions related to HPA axis functions. GR are progressively translocated in neurons nucleus, while membrane version of MR is evidenced in all structures considered. The MR/GR ratio was modified in all structures considered. Aβ(25-35) induces a subtle disturbance in the feedback of the HPA axis, without modifying its functionality. The reactivity alteration is long-lasting, suggesting that amyloid toxicity affects the HPA axis adaptive response to stress. These findings are evidence of progressive HPA axis deregulation after Aβ(25-35), which is associated with an imbalance of MR/GR ratio and a disruption of the glucocorticoid receptors nucleocytoplasmic shuttling, and suggest that elevated glucocorticoids observed in AD could be first a consequence of amyloid toxicity., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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28. Matrix metalloproteinase-2 (MMP-2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins.
- Author
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Ogier C, Bernard A, Chollet AM, LE Diguardher T, Hanessian S, Charton G, Khrestchatisky M, and Rivera S
- Subjects
- Animals, Astrocytes enzymology, Astrocytes ultrastructure, Cell Adhesion, Cell Movement physiology, Cell Proliferation, Female, Fluorescent Antibody Technique, Gelatinases metabolism, Immunohistochemistry, Integrin beta1 physiology, Male, Matrix Metalloproteinase 2 biosynthesis, Matrix Metalloproteinase 9 biosynthesis, Mice, Protease Inhibitors pharmacology, Reverse Transcriptase Polymerase Chain Reaction, Sepharose metabolism, Thymidine metabolism, Actins physiology, Astrocytes physiology, Cytoskeleton physiology, Integrins physiology, Matrix Metalloproteinase 2 physiology
- Abstract
Matrix Metalloproteinases (MMPs) play a role in migration of many cell types outside the central nervous system (CNS). Among neural cells, astrocytes are one of the main sources of MMPs in physiological and postlesional conditions. However, no data are available on the possible role of MMPs in astrocyte motility. Using an in vitro model of 2D migration and broad spectrum and selective MMP inhibitors, the authors demonstrated that MMP-2, but not MMP-9, is a key enzyme for astrocyte migration. In support of these data, the authors found constitutive expression of MMP-2 in astrocytes, while MMP-9 was nearly undetectable by gel zymography and immunocytochemical methods. The inhibition of migration by MMP inhibitors correlated with changes in cell morphology and in the organization of the actin cytoskeleton. In parallel, the characteristic focalized distribution of MMP-2 at the migration front observed in control cells became more diffuse and internalized by treatments that inhibited migration. The disruption of actin by cytochalasin D caused the partial recruitment of MMP-2 and gelatinolytic activity into actin aggregates, indicating a connection between the proteinase and the actin cytoskeleton. Finally, the authors found a co-localization of beta1-integrin with MMP-2 at the leading edge of migrating astrocytes. Altogether, these data provide the first evidence for the implication of MMP-2 in astrocyte motility, probably through the interaction of the proteinase with beta1-integrin that could act as a linker between pericellular proteolysis and the actin cytoskeleton.
- Published
- 2006
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29. Astrocyte reactivity to Fas activation is attenuated in TIMP-1 deficient mice, an in vitro study.
- Author
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Ogier C, Creidy R, Boucraut J, Soloway PD, Khrestchatisky M, and Rivera S
- Subjects
- Animals, Animals, Newborn, Antibodies adverse effects, Astrocytes enzymology, Blotting, Western methods, Brain cytology, Cell Count methods, Cell Death drug effects, Cell Proliferation, Cells, Cultured, Chemokine CCL2 metabolism, Electrophoretic Mobility Shift Assay methods, Enzyme Activation physiology, Enzyme-Linked Immunosorbent Assay methods, Flow Cytometry methods, Glial Fibrillary Acidic Protein metabolism, Immunohistochemistry methods, Intercellular Adhesion Molecule-1 metabolism, Lymphocytes physiology, Matrix Metalloproteinase 9 metabolism, Mice, Mice, Knockout, Receptors, Tumor Necrosis Factor immunology, Tetrazolium Salts, Thiazoles, Thymidine metabolism, Tritium metabolism, Tumor Necrosis Factor-alpha adverse effects, fas Receptor, Astrocytes physiology, Gene Expression Regulation, Developmental genetics, Receptors, Tumor Necrosis Factor metabolism, Tissue Inhibitor of Metalloproteinase-1 deficiency
- Abstract
Background: Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional secreted protein with pleiotropic actions, including the inhibition of matrix metalloproteinases (MMPs), cell death/survival and growth promoting activities. After inflammatory challenge, the levels of TIMP-1 are highly and selectively upregulated in astrocytes among glial cells, but little is know about its role in these neural cells. We investigated the influence of TIMP-1 null mutation in the reactivity of cultured astrocytes to pro-inflammatory stimuli with TNF-alpha and anti-Fas antibody., Results: When compared to WT, mutant astrocytes displayed an overall increased constitutive gelatinase expression and were less responsive to Fas-mediated upregulation of MMP-9, of monocyte chemoattractant protein-1 (MCP-1) and of intercellular cell adhesion molecule-1 (ICAM-1), all markers of astrocyte inflammatory response. In contrast, TNF-alpha treatment induced all these factors similarly regardless of the astrocyte genotype. The incorporation of 3H-thymidin, a marker of cell proliferation, increased in wild-type (WT) astrocytes after treatment with anti-Fas antibody or recombinant TIMP-1 but not in mutant astrocytes. Finally, lymphocyte chemotaxis was differentially regulated by TNF-alpha in WT and TIMP-1 deficient astrocytes., Conclusion: We provide evidence that the alteration of the MMP/TIMP balance in astrocytes influences their reactivity to pro-inflammatory stimuli and that Fas activation modulates the expression of members of the MMP/TIMP axis. We hypothesise that the Fas/FasL transduction pathway and the MMP/TIMP system interact in astrocytes to modulate their inflammatory response to environmental stimuli.
- Published
- 2005
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30. [The MMP/TIMP system in the nervous system].
- Author
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Rivera S, Jourquin J, Ogier C, Bernard A, Charton G, Tremblay E, and Khrestchatisky M
- Subjects
- Blood-Brain Barrier, Humans, Leukocytes physiology, Nervous System embryology, Neuronal Plasticity, Permeability, Matrix Metalloproteinases physiology, Nervous System physiopathology, Tissue Inhibitor of Metalloproteinases physiology
- Abstract
The matrix metalloproteinases (MMP) belong to a growing family of secreted or membrane-bound (MT-MMP) enzymes that cleave protein components of the extracellular matrix and bioactive factors involved in intercellular signaling. MMP activity is counterbalanced by their four physiological inhibitors, the tissue inhibitors of MMP (TIMPs). Together, MMP and TIMP control cell-cell and cell-matrix interactions associated with physiological processes. However, the breakdown of the protease-inhibitor balance may lead to the loss of tissue homeostasis and the development of degenerative and tumorigenic processes in various tissues. The emerging idea is that the MMP/TIMP system also plays a major role in the pathology and physiology of the nervous system and that mastering MMP activity will set the basis for new and more efficient therapeutic strategies against nervous system disorders.
- Published
- 2004
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31. [Matrix metalloproteinases and their inhibitors, modulators of neuro-immune interactions and of pathophysiological processes in the nervous system].
- Author
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Khrestchatisky M, Jourquin J, Ogier C, Charton G, Bernard A, Tremblay E, and Rivera S
- Subjects
- Animals, Blood-Brain Barrier physiology, Disease Models, Animal, Humans, Nervous System Diseases enzymology, Metalloendopeptidases metabolism, Nervous System Diseases immunology, Nervous System Diseases physiopathology, Tissue Inhibitor of Metalloproteinases metabolism
- Abstract
The matrix metalloproteinases (MMPs) belong to a growing family of Zn2+-dependent endopeptidases, secreted or membrane-bound (MT-MMP), that regulate or degrade by proteolytic cleavage protein components of the extracellular matrix, cytokines, chemokines, cell adhesion molecules and a variety of membrane receptors. MMP activity is counterbalanced by their physiological inhibitors, the tissue inhibitors of MMPs (TIMPs), a family of 4 secreted multifunctional proteins that have growth promoting activities. In physiological conditions MMP activity is tightly regulated and altered MMP regulation is associated with pathological processes including inflammation, cell proliferation, cell death and tissue remodeling. The MMP/TIMP system is involved in the development and function of cells of the immune system by promoting their differentiation, activation, migration across basement membranes and tissues. In the last years, data has accumulated indicating that the MMP/TIMP system is expressed in the nervous system where it regulates neuro-immune interactions and plays a major role in pathophysiological processes. In this review, we present recent in vivo and in vitro studies that highlight the contribution of the MMP/TIMP system to various diseases of the nervous system, involving blood brain barrier breakdown, neuroinflammation, glial reactivity, neuronal death, reactive plasticity, and to developmental and physiological processes including cell migration, axonal sprouting and neuronal plasticity. This review also alludes to the beneficial effects of synthetic MMP inhibitors in different animal models of neuropathology. In all, a further understanding of the role of MMPs and TIMPs in the nervous system should contribute to unravel mechanisms of neuronal plasticity and pathology and set the basis of new therapeutic strategies in nervous system disorders based on the development of synthetic MMP inhibitors.
- Published
- 2003
32. Gelatinase B and TIMP-1 are regulated in a cell- and time-dependent manner in association with neuronal death and glial reactivity after global forebrain ischemia.
- Author
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Rivera S, Ogier C, Jourquin J, Timsit S, Szklarczyk AW, Miller K, Gearing AJ, Kaczmarek L, and Khrestchatisky M
- Subjects
- Animals, Apoptosis physiology, Astrocytes metabolism, Astrocytes pathology, Brain Ischemia pathology, Gene Expression Regulation, Enzymologic physiology, Immunohistochemistry, In Situ Hybridization, Male, Microglia metabolism, Microglia pathology, Neuroglia pathology, Neurons pathology, Prosencephalon pathology, Rats, Rats, Wistar, Time Factors, Brain Ischemia metabolism, Matrix Metalloproteinase 9 metabolism, Neuroglia metabolism, Neurons metabolism, Prosencephalon metabolism, Tissue Inhibitor of Metalloproteinase-1 metabolism
- Abstract
Matrix metalloproteinases (MMPs) belong to a large family of endopeptidases that regulate the pericellular environment through the cleavage of protein components of the extracellular matrix, membrane receptors and cytokines. MMP activity is controlled by the multifunctional tissue inhibitors of metalloproteinases (TIMPs). Proteases and their inhibitors are critically involved in developmental and pathological processes in numerous organs, including the brain. Global transient cerebral ischemia induces selective delayed neuronal death and neuroinflammation. We compared, in discrete vulnerable and resistant areas of the ischemic rat hippocampus, the kinetics and cellular distribution of gelatinase B and its principal inhibitor TIMP-1 and we assessed by in situ zymography, the net gelatinolytic activity at the cellular level. We show that gelatinases are expressed and active in neurons, suggesting that MMPs play a role in maintaining neural homeostasis. In the ischemic rat brain, expression and activity of gelatinase B, and expression of TIMP-1 are altered in a time-, region- and cell-dependent manner. Gelatinase B is induced first in reactive microglia and subsequently in reactive astrocytes. In situ, increases in gelatinase activity accompanied the progression of neuronal death and glial reactivity. Our results suggest that MMPs and TIMPs are involved in cell viability and tissue remodelling in the ischemic brain, and reinforces the idea that the MMP/TIMP system contributes both to neuronal demise and tissue repair in the context of glial reactivity.
- Published
- 2002
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33. [Characterization of activated rosette-forming lymphocytes by monoclonal antibodies].
- Author
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Ogier C and Sighinolfi L
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Rosette Formation, T-Lymphocytes, Helper-Inducer analysis, T-Lymphocytes, Regulatory analysis, Antibodies, Monoclonal, Lymphocytes immunology
- Published
- 1985
34. Busulfan, antimetabolites, radiotherapy, and cost of treatment in chronic myelocytic leukemia. A non-controlled, non-randomized monocenter study with historical controls.
- Author
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Ogier C and Reizenstein P
- Subjects
- Costs and Cost Analysis, Drug Therapy, Combination, Humans, Leukemia, Myeloid economics, Leukemia, Myeloid radiotherapy, Radiography, Spleen diagnostic imaging, Busulfan therapeutic use, Cytarabine therapeutic use, Leukemia, Myeloid drug therapy, Thioguanine therapeutic use
- Abstract
The possibilities were studied of achieving remission more quickly, of preventing conceivably alkylator-induced blastic transformation, and of prolonging survival in chronic myelocytic leukemia (CML) by replacing busulfan induction of remission by antimetabolite induction. The promise of the project was not considered to merit a prospective, controlled, randomized multicenter study, and therefore a retrospective, non-controlled, non-randomized pilot study was elected. One antimetabolite-treated group (cytosine arabinoside and thioguanine) and two busulfan-treated patient groups were studied. One of the latter two groups received splenic irradiation in addition to busulfan. No statistically significant differences between the busulfan groups were found in the time to achieve remission, the length of the first, unmaintained remission, the frequency of blastic metamorphosis or the cost of treatment. The actuarial survival curves of all three groups were similar. The antimetabolite induction was well tolerated and led to a statistically significantly more rapid remission than busulfan. However, the remission was significantly shorter, and no significant difference in the frequency of blastic metamorphosis was found between the groups. The median cost (from diagnosis to death) of hospitalization, visits, treatment, and part of the loss of production was approximately 106 000 Sw. cr. in the busulfan + radiotherapy group, 116 000 in the busulfan group, and 178 000 in the antimetabolite group. It is suggested that a prospective, randomized, controlled study could confirm that the present antimetabolite induction may lead to a more rapid remission induction in CML without more side-effects. However, to prevent early relapse, antimetabolite induction should be combined with busulfan maintenance treatment.
- Published
- 1981
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- View/download PDF
35. [Effect of 3 different thymus extracts on T lymphocytes from patients with lymphoma and solid tumors in the advanced phase].
- Author
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Ogier C, Moratelli S, and Ballerini G
- Subjects
- Aged, Humans, Lymphocyte Activation drug effects, Lymphoma immunology, Middle Aged, Rosette Formation, Neoplasms immunology, T-Lymphocytes drug effects, Thymus Extracts pharmacology
- Published
- 1983
36. Cells responsible for tumor surveillance in man: effects of radiotherapy, chemotherapy, and biologic response modifiers.
- Author
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Reizenstein P, Ogier C, Blomgren H, Petrini B, and Wasserman J
- Subjects
- Humans, Killer Cells, Natural immunology, Macrophages immunology, T-Lymphocytes immunology, Adjuvants, Immunologic pharmacology, Antigens, Neoplasm immunology, Antineoplastic Agents pharmacology, Immunity, Cellular drug effects, Immunity, Cellular radiation effects, Immunologic Surveillance drug effects, Immunologic Surveillance radiation effects, Neoplasms immunology
- Abstract
Currently, the most probable theory of tumor surveillance is neither the existence of any tumor-specific, antigen-dependent, T-cell-mediated cytotoxic effect that could eliminate spontaneous tumors in man and that could be used for some kind of vaccination against tumors, nor the complete absence of any surveillance or defense systems against tumors. What is probable is the cooperation of a number of antigen-independent, relatively weakly cytotoxic or possibly only cytostatic humoral and cellular effects, including nutritional immunity, tumor necrosis factor, certain cytokines, and the cytotoxic effects mediated by macrophages, NK cells, NK-like cells, and certain stimulated T-cells. One question remaining to be solved is why these antigen-independent effects do not attack normal cells. A number of plausible hypotheses are discussed. The hypothetical surveillance system is modulated both by traditional cancer treatment and by attempts at immunomodulation. Radiotherapy reduced the T-helper cell function for almost a decade, but not those of macrophages or NK cells. T-cell changes have no prognostic implication, supporting, perhaps, the suggestion of a major role for macrophages and NK cells. Cyclic adjuvant chemotherapy reduces the peripheral lymphocyte population and several lymphocyte functions but not NK activity. Most of the parameters were normalized some years following treatment, but NK activity remained elevated and Th/Ts cell ratio was still decreased. This might possibly be taken to support the surveillance role of NK cells. Bestatin increases the frequency of lymphocytes forming rosettes with sheep red blood cells (but not their mitogenic responses), enhances NK activity, and augments the phagocytic capacity of granulocytes and monocytes (but not their cytotoxic activity). Improved survival with Bestatin treatment following chemotherapy has been observed in patients with melanoma Stages 1b and II and in patients with acute nonlymphatic leukemia, where BCG also seems active, although possibly only in patient groups with less than 49% complete remissions.
- Published
- 1985
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- View/download PDF
37. [Leukocyte adherence inhibition in acute leukemia and in refractory anemia with myeloblastic excess].
- Author
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Borsetti G, Ogier C, Spanedda R, and Ballerini G
- Subjects
- Adolescent, Adult, Aged, Humans, Immunity, Cellular, Leukocyte Adherence Inhibition Test, Middle Aged, Anemia, Aplastic immunology, Leukemia, Lymphoid immunology, Leukemia, Myeloid, Acute immunology
- Published
- 1983
38. Efficacy of and errors in randomized multicenter trials. A review of 230 clinical trials.
- Author
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Reizenstein P, Delgado M, Gastiaburu J, Lomme L, Ogier C, Pals H, Schellekens J, Whittaker J, and Mathé G
- Subjects
- Antineoplastic Agents therapeutic use, Clinical Trials as Topic methods, Humans, Research Design, Clinical Trials as Topic standards
- Abstract
An attempt was made to study the efficacy in and one of the errors of randomized multicenter clinical trials. Efficacy was defined for the present purpose as a statistically significant clinical difference between at least 2 of the treatment arms studied. The error studied was defined here as non-excluded protocol deviations found during a systematic record review. The nature (multicenter randomized trial or un-controlled pilot study) of 8 so-called "breakthrough" studies which seemed particularly important for future cancer treatment was also established. The number of yearly randomized trials seems to have increased by a factor of 10 between 1969 and 1981, as judged by the abstracts published by the American Society of Clinical Oncology. 23% yielded statistically significant results, which is 18% over the 5% expected chance significances. Of 174 papers and abstracts published by one group, only 18 were reviewable original studies. The corresponding figures for another group was 6 of 22. This explains why only 8 scientifically new statistical significances were found in one series of 76 original articles. The mean dose of cytostatics actually given to 192 breast cancer patients varied, as judged by a record review, between 71 and 93% of the protocol doses. These figures agree with the 15-30% of nonexcluded protocol deviations found previously. Of the 8 "breakthrough" studies, 7 were single center pilot studies without randomized controls, and only 1 was a randomized multicenter study. It is suggested that more relevant questions can be asked in multicenter randomized clinical trials if they are based on promising single center pilot results, and that record reviews should be performed so that protocol deviations can regularly be reported.
- Published
- 1983
39. [Decreased percentage of circulating T-lymphocytes in patients with thalassemic trait].
- Author
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Ogier C, Sighinolfi L, Salsini G, Ballerini G, and Vullo C
- Subjects
- Adolescent, Adult, Female, Humans, Immunity, Cellular, Male, Lymphopenia immunology, T-Lymphocytes immunology, Thalassemia immunology
- Published
- 1984
40. The use of serum ferritin to identify good and bad prognosis groups in acute myeloid leukemia.
- Author
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Ogier C, Giannoulis N, Jacobs A, and Reizenstein PG
- Subjects
- Humans, Leukemia, Myeloid, Acute blood, Prognosis, Ferritins blood, Leukemia, Myeloid, Acute diagnosis
- Published
- 1984
41. Modifying the biological response in acute myeloid leukemia. II. Effect of BCG and leukemic cells on lymphocyte response to mitogens, and on helper and suppressor activity.
- Author
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Arends-Merino A, Giscombe R, Ogier C, Reizenstein P, Sjörgen AM, and Wasserman J
- Subjects
- Concanavalin A pharmacology, Humans, Lymphocyte Activation, Macrophages immunology, Phytohemagglutinins pharmacology, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Regulatory immunology, Leukemia, Myeloid, Acute immunology, Lymphocytes immunology, Mitogens pharmacology, Monocytes immunology
- Abstract
Lymphocyte response to mitogens and to lymphocyte suppressor and monocyte helper activity was studied in 18 patients with acute myeloid leukemia in complete remission, and in 17 healthy controls. Ten patients were maintained with chemotherapy alone (CT), and eight received chemoimmunotherapy with BCG + leukemic cells (CIT). In late remission the mitogen responsiveness was increased in CT patients and decreased in CIT patients. No significant difference in lymphocyte suppressor activity could be demonstrated between patients and controls, or between CT and CIT. When autologous CIT monocytes were added to mitogen-stimulated lymphocytes they acted as helper cells. CT monocytes, in contrast, seemed to act as suppressor cells. Control monocytes also acted as helper cells, but to a significantly lesser degree than CIT monocytes.
- Published
- 1982
- Full Text
- View/download PDF
42. [Splenectomy in idiopathic thrombopenic purpura and in myelofibrosis. A retrospective study of platelet increase, hemorrhagic complications and mortality].
- Author
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Hellström P, Ogier C, Askergren J, Sundblad R, and Reizenstein P
- Subjects
- Adult, Aged, Female, Follow-Up Studies, Humans, Intraoperative Complications, Male, Middle Aged, Postoperative Complications, Primary Myelofibrosis mortality, Prognosis, Purpura, Thrombocytopenic mortality, Retrospective Studies, Hemorrhage etiology, Platelet Count, Primary Myelofibrosis therapy, Purpura, Thrombocytopenic therapy, Splenectomy
- Abstract
In a retrospective study of 39 splenectomies, patients with increased blood cell breakdown (13 cases of idiopathic thrombocytopenic purpura (ITP), 5 cases of hereditary spherocytosis, 2 of Felty's syndrome and 2 of autoimmune hemolytic anemia) were compared with those patients also presenting decreased blood cell production [14 cases of myelofibrosis (MF) with splenomegaly and 3 cases of advanced chronic myelogeneous leukemia (CML)]. Platelet regeneration post-operatively was significantly (p less than 0.01) more rapid in the ITP than in the MF group. Only 1/22 patients in the ITP group had major post-operative complications as compared to 10/17 in the MF group. None of the patients in the ITP group died within 25 days of operation as compared to 5/17 in the MF group. Only 3/22 patients in the ITP group lost more than 800 ml of blood during the operation as compared to 8/17 with MF. No statistically significant higher blood loss was found in patients with less than 30 x 10(9) platelets/l preoperatively, compared to those with higher platelet counts. However, correlation between the splenic weights and amount of blood loss was statistically significant (p less than 0.01). Thus, splenectomy seems much better tolerated in patients with ITP, even if platelets are low, than in patients with myelofibrosis.
- Published
- 1981
43. [Pseudo-Gaucher cells in a case of multiple myeloma].
- Author
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Gallerani A, Ogier C, and Ballerini G
- Subjects
- Bone Marrow pathology, Female, Humans, Middle Aged, Gaucher Disease pathology, Multiple Myeloma pathology
- Published
- 1985
44. Difference between young and old patients in characteristics of leukemic cells: older patients have cells growing excessively in vitro, with low antigenicity despite high HLA-DR antigens.
- Author
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Giannoulis N, Ogier C, Hast R, Lindblom B, Sjögren AM, and Reizenstein P
- Subjects
- Adolescent, Adult, Age Factors, Aged, Colony-Forming Units Assay, Cytotoxicity, Immunologic, Female, HLA-DR Antigens, Humans, Leukemia, Myeloid, Acute blood, Lymphocyte Culture Test, Mixed, Male, Middle Aged, Antigens, Neoplasm immunology, Histocompatibility Antigens Class II immunology, Leukemia, Myeloid, Acute immunology, Neoplastic Stem Cells immunology, Stem Cells immunology
- Abstract
Fifty-six patients with acute, non-lymphatic leukemia in the initial phase were studied. The poor prognostic signs were excessive in vitro growth, many HLA-DR-positive cells, or a low ratio of leukemic cell antigenicity to HLA-DR positivity and age. The cells from older patients formed more clusters (P less than 0.05), and they had less capacity to stimulate normal allogeneic lymphocytes (P less than 0.05) than those from younger patients. Cells forming many clusters also were more often (P less than 0.01) HLA-DR-positive than those forming few clusters. It is suggested that the prognosis in old patients with acute leukemia is poor in part because their leukemic cells have characteristics different from those of young patients.
- Published
- 1984
- Full Text
- View/download PDF
45. [Infusion of high-dosage immunoglobulin G in the therapy of idiopathic thrombocytopenic purpura].
- Author
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Ogier C, Sighinolfi L, Serino ML, and Ballerini G
- Subjects
- Adult, Age Factors, Autoimmune Diseases therapy, Drug Administration Schedule, Humans, Immunoglobulin G administration & dosage, Infusions, Parenteral, Immunoglobulin G therapeutic use, Purpura, Thrombocytopenic therapy
- Published
- 1985
46. Determination of glucocorticoid receptors in leukemic myeloblasts by isoelectric focusing in polyacrylamide gel.
- Author
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Ogier C, Humla S, Nordenskjöld B, and Skoog L
- Subjects
- Acute Disease, Cell Count, Electrophoresis, Polyacrylamide Gel, Humans, Isoelectric Focusing, Leukemia mortality, Ligands, Trypsin pharmacology, Leukemia, Myeloid, Acute pathology, Receptors, Glucocorticoid analysis
- Abstract
We investigated the optimal conditions for measuring glucocorticoid receptor in blast cells from patients with acute nonlymphocytic leukemia. Cytosol receptor measured with isoelectric focusing was saturated after 60 min of incubation at 0 degrees C with 100 nM of either dexamethasone or triamcinolone. Saturation was achieved when cytosol from at least 7 X 10(6) cells was used for incubation. Trypsin treatment of the cytosol resulted in a sharpened peak of receptor focusing at pH 5.6 with no loss of receptor-bound radioactivity. The two physical forms of glucocorticoid receptor were isolated with DEAE cellulose chromatography. They were both found to focus at pH 5.6 during isoelectric focusing.
- Published
- 1985
- Full Text
- View/download PDF
47. Effect of Clostridium perfringens neuraminidase on viability and antigenicity of human leukemic myeloblasts.
- Author
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Ogier C, Sjögren AM, and Reizenstein P
- Subjects
- Cell Survival drug effects, Clostridium perfringens enzymology, DNA biosynthesis, Humans, Hydrogen-Ion Concentration, Lymphocytes drug effects, Mitomycins pharmacology, Thymidine metabolism, Leukemia, Myeloid, Acute physiopathology, Lymphocytes physiology, Neuraminidase pharmacology
- Abstract
The effect of increasing concentrations of Cl. Perfringens neuraminidase and of pH on the dye exclusion ability and lymphocyte stimulating capacity of leukemic myeloblasts was studied. The higher the neuraminidase concentration, or the lower the pH was, the more myeloblasts died and the less the myeloblasts stimulated lymphocytes. Myeloblasts treated at a neutral pH and at low enzyme concentrations retained, but did not increase their antigenicity.
- Published
- 1979
48. Heme-mediated modulation of alpha-globin chain biosynthesis in porphyria cutanea tarda associated with heterozygous beta-thalassemia.
- Author
-
Gambari R, Buzzoni D, Barbieri R, Perrotta C, Piva R, Conconi F, del Senno L, and Ogier C
- Subjects
- Female, Heterozygote, Humans, Middle Aged, Porphyrias complications, Skin Diseases complications, Thalassemia complications, Thalassemia genetics, Globins biosynthesis, Heme physiology, Porphyrias blood, Skin Diseases blood, Thalassemia blood
- Published
- 1988
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