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Tsokos, Maria

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Tsokos

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Maria

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Tsokos, Maria
Author's Publications: search.filters.isAuthorOfPublication.f481c2d0-a2c9-48eb-a12c-10dd3aa86e01

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    C3a Enhances the Formation of Intestinal Organoids through C3aR1
    (Frontiers Media S.A., 2017) Matsumoto, Naoya; Satyam, Abhigyan; Geha, Mayya; Lapchak, Peter; Dalle Lucca, Jurandir J.; Tsokos, Maria; Tsokos, George
    C3a is important in the regulation of the immune response as well as in the development of organ inflammation and injury. Furthermore, C3a contributes to liver regeneration but its role in intestinal stem cell function has not been studied. We hypothesized that C3a is important for intestinal repair and regeneration. Intestinal organoid formation, a measure of stem cell capacity, was significantly limited in C3-deficient and C3a receptor (C3aR) 1-deficient mice while C3a promoted the growth of organoids from normal mice by supporting Wnt-signaling but not from C3aR1-deficient mice. Similarly, the presence of C3a in media enhanced the expression of the intestinal stem cell marker leucine-rich repeat G-protein-coupled receptor 5 (Lgr5) and of the cell proliferation marker Ki67 in organoids formed from C3-deficient but not from C3aR1-deficient mice. Using Lgr5.egfp mice we showed significant expression of C3 in Lgr5+ intestinal stem cells whereas C3aR1 was expressed on the surface of various intestinal cells. C3 and C3aR1 expression was induced in intestinal crypts in response to ischemia/reperfusion injury. Finally, C3aR1-deficient mice displayed ischemia/reperfusion injury comparable to control mice. These data suggest that C3a through interaction with C3aR1 enhances stem cell expansion and organoid formation and as such may have a role in intestinal regeneration.
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    Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma
    (BioMed Central, 2015) Kalra, Neetu; Zhang, Jingli; Thomas, Anish; Xi, Liqiang; Cheung, Mitchell; Talarchek, Jacqueline; Burkett, Sandra; Tsokos, Maria; Chen, Yuanbin; Raffeld, Mark; Miettinen, Markku; Pastan, Ira; Testa, Joseph R; Hassan, Raffit
    Background: The development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models. Methods: We established primary mesothelioma cultures from pleural and ascitic fluids of five patients with advanced mesothelioma. Electron microscopy and immunohistochemistry (IHC) confirmed their mesothelial origin. Patient derived xenografts were generated by injecting the cells in nude or SCID mice, and malignant potential of the cells was analyzed by soft agar colony assay. Molecular profiles of the primary patient tumors, early passage cell cultures, and patient derived xenografts were assessed using mutational analysis, fluorescence in situ hybridization (FISH) analysis and IHC. Results: Primary cultures from all five tumors exhibited morphologic and IHC features consistent to those of mesothelioma cells. Mutations of BAP1 and CDKN2A were each detected in four tumors. BAP1 mutation was associated with the lack of expression of BAP1 protein. Three cell cultures, all of which were derived from BAP1 mutant primary tumors, exhibited anchorage independent growth and also formed tumors in mice, suggesting that BAP1 loss may enhance tumor growth in vivo. Both early passage cell cultures and mouse xenograft tumors harbored BAP1 mutations and CDKN2A deletions identical to those found in the corresponding primary patient tumors. Conclusions: The mesothelioma patient derived tumor xenografts with mutational alterations that mimic those observed in patient tumors which we established can be used for preclinical development of novel drug regimens and for studying the functional aspects of BAP1 biology in mesothelioma. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1362-2) contains supplementary material, which is available to authorized users.
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    Protein phosphatase 2A is requisite for the function of regulatory T cells
    (2015) Apostolidis, Sokratis A.; Rodríguez-Rodríguez, Noé; Suárez-Fueyo, Abel; Dioufa, Nikolina; Ozcan, Esra; Crispín, José C.; Tsokos, Maria; Tsokos, George
    Immune homeostasis depends on the proper function of regulatory T (Treg) cells. Compromised Treg cell suppressive activity leads to autoimmune disease, graft rejection and promotes anti-tumor immunity. Here we report the previously unrecognized requirement of the serine/threonine phosphatase Protein Phosphatase 2A (PP2A) for the function of Treg cells. Treg cells exhibited high PP2A activity and Treg cell-specific ablation of the PP2A complex resulted in a severe, multi-organ, lymphoproliferative autoimmune disorder. Mass spectrometric analysis revealed that PP2A associates with components of the mTOR pathway and suppresses mTORC1 activity. In the absence of PP2A, Treg cells altered their metabolic and cytokine profile and were unable to suppress effector immune responses. Therefore, PP2A is requisite for the function of Treg cells and the prevention of autoimmunity.