The Experts below are selected from a list of 65991 Experts worldwide ranked by ideXlab platform
Eugenia Dogliotti - One of the best experts on this subject based on the ideXlab platform.
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aphidicolin resistant and sensitive base excision repair in wild type and dna polymerase beta defective mouse Cells
DNA Repair, 2004Co-Authors: Eleonora Parlanti, Barbara Pascucci, Gloria Terrados, Luis Blanco, Eugenia DogliottiAbstract:Abstract Several DNA polymerases (Pols) can add complementary bases at the gap created during the base excision repair (BER). To characterize the BER resynthesis step, the repair of a single abasic site by wild-type and Pol β-defective mouse Cell extracts was analysed in the presence of aphidicolin, a specific inhibitor of replicative Pols. We show that there is a competition between distributive and processive Pols for the nucleotide addition at the primer terminus. In wild-type Cell extracts, the initial nucleotide insertion involves mainly Pol β but the elongation step is carried out by a replicative Pol. Conversely, in Pol β-Null Cell extracts the synthesis step is carried out by a replicative Pol without any switching to an auxiliary polymerase. We present evidence that short-patch repair synthesis occurs even in the absence of both Pol β and replicative Pols. Exogeneously added purified human Pol λ was unable to stimulate this back-up synthesis.
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aphidicolin resistant and sensitive base excision repair in wild type and dna polymerase beta defective mouse Cells
DNA Repair, 2004Co-Authors: Eleonora Parlanti, Barbara Pascucci, Gloria Terrados, Luis Blanco, Eugenia DogliottiAbstract:Abstract Several DNA polymerases (Pols) can add complementary bases at the gap created during the base excision repair (BER). To characterize the BER resynthesis step, the repair of a single abasic site by wild-type and Pol β-defective mouse Cell extracts was analysed in the presence of aphidicolin, a specific inhibitor of replicative Pols. We show that there is a competition between distributive and processive Pols for the nucleotide addition at the primer terminus. In wild-type Cell extracts, the initial nucleotide insertion involves mainly Pol β but the elongation step is carried out by a replicative Pol. Conversely, in Pol β-Null Cell extracts the synthesis step is carried out by a replicative Pol without any switching to an auxiliary polymerase. We present evidence that short-patch repair synthesis occurs even in the absence of both Pol β and replicative Pols. Exogeneously added purified human Pol λ was unable to stimulate this back-up synthesis.
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dna polymerase β is required for efficient dna strand break repair induced by methyl methanesulfonate but not by hydrogen peroxide
Nucleic Acids Research, 2000Co-Authors: Paola Fortini, Barbara Pascucci, Federico Belisario, Eugenia DogliottiAbstract:The most frequent DNA lesions in mammalian genomes are removed by the base excision repair (BER) via multiple pathways that involve the replacement of one or more nucleotides at the lesion site. The biological consequences of a BER defect are at present largely unknown. We report here that mouse Cells defective in the main BER DNA polymerase β (Pol β) display a decreased rate of DNA single-strand breaks (ssb) rejoining after methyl methanesulfonate damage when compared with wild-type Cells. In contrast, Pol β seems to be dispensable for hydrogen peroxide-induced DNA ssb repair, which is equally efficient in normal and defective Cells. By using an in vitro repair assay on single abasic site-containing circular duplex molecules, we show that the long-patch BER is the predominant repair route in Pol β-Null Cell extract. Our results strongly suggest that the Pol β-mediated single nucleotide BER is the favorite pathway for repair of N-methylpurines while oxidation-induced ssb, likely arising from oxidized abasic sites, are the substrate for long-patch BER.
Tomasz Skorski - One of the best experts on this subject based on the ideXlab platform.
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multilevel dysregulation of stat3 activation in anaplastic lymphoma kinase positive t Null Cell lymphoma
Journal of Immunology, 2002Co-Authors: Qian Zhang, Puthryaveett N Raghunath, Liquan Xue, Miroslaw Majewski, David F Carpentieri, Niels Odum, Stephan W Morris, Tomasz SkorskiAbstract:Accumulating evidence indicates that expression of anaplastic lymphoma kinase (ALK), typically due to t(2;5) translocation, defines a distinct type of T/Null-Cell lymphoma (TCL). The resulting nucleophosmin (NPM) /ALK chimeric kinase is constitutively active and oncogenic. Downstream effector molecules triggered by NPM/ALK remain, however, largely unidentified. Here we report that NPM/ALK induces continuous activation of STAT3. STAT3 displayed tyrosine phosphorylation and DNA binding in all (four of four) ALK+ TCL Cell lines tested. The activation of STAT3 was selective because none of the other known STATs was consistently tyrosine phosphorylated in these Cell lines. In addition, malignant Cells in tissue sections from all (10 of 10) ALK+ TCL patients expressed tyrosine-phosphorylated STAT3. Transfection of BaF3 Cells with NPM/ALK resulted in tyrosine phosphorylation of STAT3. Furthermore, STAT3 was constitutively associated with NPM/ALK in the ALK+ TCL Cell lines. Additional studies into the mechanisms of STAT3 activation revealed that the ALK+ TCL Cells expressed a positive regulator of STAT3 activation, protein phosphatase 2A (PP2A), which was constitutively associated with STAT3. Treatment with the PP2A inhibitor calyculin A abrogated tyrosine phosphorylation of STAT3. Finally, ALK+ T Cells failed to express a negative regulator of activated STAT3, protein inhibitor of activated STAT3. These data indicate that NPM/ALK activates STAT3 and that PP2A and lack of protein inhibitor of activated STAT3 may be important in maintaining STAT3 in the activated state in the ALK+ TCL Cells. These results also suggest that activated STAT3, which is known to display oncogenic properties, as well as its regulatory molecules may represent attractive targets for novel therapies in ALK+ TCL.
Simon Ball - One of the best experts on this subject based on the ideXlab platform.
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cytomegalovirus associated cd4 cd28 Null Cells in nkg2d dependent glomerular endothelial injury and kidney allograft dysfunction
American Journal of Transplantation, 2016Co-Authors: Shazia Shabir, Helen Smith, Baksho Kaul, Annette Pachnio, S Jham, S Kuravi, Simon BallAbstract:Emerging data suggest that expansion of a circulating population of atypical, cytotoxic CD4(+) T Cells lacking costimulatory CD28 (CD4(+) CD28(Null) Cells) is associated with latent cytomegalovirus (CMV) infection. The purpose of the current study was to increase the understanding of the relevance of these Cells in 100 unselected kidney transplant recipients followed prospectively for a median of 54 months. Multicolor flow cytometry of peripheral blood mononuclear Cells before transplantation and serially posttransplantation was undertaken. CD4(+) CD28(Null) Cells were found predominantly in CMV-seropositive patients and expanded in the posttransplantation period. These Cells were predominantly effector-memory phenotype and expressed markers of endothelial homing (CX3CR1) and cytotoxicity (NKG2D and perforin). Isolated CD4(+) CD27(-) CD28(Null) Cells proliferated in response to peripheral blood mononuclear Cells previously exposed to CMV-derived (but not HLA-derived) antigens and following such priming incubation with glomerular endothelium resulted in signs of endothelial damage and apoptosis (release of fractalkine and von Willebrand factor; increased caspase 3 expression). This effect was mitigated by NKG2D-blocking antibody. Increased CD4(+) CD28(Null) Cell frequencies were associated with delayed graft function and lower estimated glomerular filtration rate at end follow-up. This study suggests an important role for this atypical cytotoxic CD4(+) CD28(Null) Cell subset in kidney transplantation and points to strategies that may minimize the impact on clinical outcomes.
Jon C Aster - One of the best experts on this subject based on the ideXlab platform.
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molecular biology of anaplastic lymphoma kinase positive anaplastic large Cell lymphoma
Journal of Clinical Oncology, 2002Co-Authors: Jeffery L Kutok, Jon C AsterAbstract:ABSTRACT: Anaplastic large-Cell lymphoma (ALCL) provides an exCellent example of how molecular insights into tumor pathogenesis are influencing and improving tumor classification. ALCL was described initially as a subtype of T-Cell/Null-Cell lymphoma characterized by unusual tumor Cell morphology and the expression of CD30. However, it was soon recognized that a subset of ALCLs contained chromosomal translocations involving anaplastic lymphoma kinase (ALK), a novel receptor tyrosine kinase gene. These rearrangements create chimeric genes encoding self-associating, constitutively active ALK fusion proteins that activate a number of downstream effectors, including phospholipase C-gamma, phosphoinositol 3'-kinase, RAS, and signal transducer and activator of transcription proteins, all of which seem potentially important in Cellular transformation. Not all tumors classified as ALCLs have ALK rearrangements and, conversely, ALK rearrangements occur in lymphomas of widely varying morphology. Hence, only molecul...
Jochen Herms - One of the best experts on this subject based on the ideXlab platform.
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double adenomas of the pituitary reveal distinct lineage markers copy number alterations and epigenetic profiles
Pituitary, 2021Co-Authors: Christian Hagel, Michael Buchfelder, Ulrich Schuller, Jorg Flitsch, Ulrich J Knappe, Udo Kellner, Markus Bergmann, Rolf Buslei, Thomas Rudiger, Jochen HermsAbstract:Purpose Pituitary adenoma (PA) constitutes the third most common intracranial neoplasm. The mostly benign endocrine lesions express no hormone (Null Cell PA) or the pituitary hormone(s) of the Cell lineage of origin. In 0.5-1.5% of surgical specimens and in up to 10% of autopsy cases, two or three seemingly separate PA may coincide. These multiple adenomas may express different hormones, but whether or not expression of lineage-restricted transcription factors and molecular features are distinct within multiple lesions remains unknown. Methods Searching the data bank of the German Pituitary Tumor Registry 12 double pituitary adenomas with diverse lineage were identified among 3654 adenomas and 6 hypophyseal carcinomas diagnosed between 2012 and 2020. The double adenomas were investigated immunohistochemically for expression of hormones and lineage markers. In addition, chromosomal gains and losses as well as global DNA methylation profiles were assessed, whenever sufficient material was available (n = 8 PA). Results In accordance with the literature, combinations of GH/prolactin/TSH-FSH/LH adenoma (4/12), GH/prolactin/TSH-ACTH adenoma (3/12), and ACTH-FSH/LH adenoma (3/12) were observed. Further, two out of 12 cases showed a combination of a GH/prolactin/TSH adenoma with a Null-Cell adenoma. Different expression pattern of hormones were confirmed by different expression of transcription factors in 11/12 patients. Finally, multiple lesions that were molecularly analysed in 4 patients displayed distinct copy number changes and global methylation pattern. Conclusion Our data confirm and extend the knowledge on multiple PA and suggest that such lesions may origin from distinct Cell types.
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double adenomas of the pituitary reveal distinct lineage markers copy number alterations and epigenetic profiles
Pituitary, 2021Co-Authors: Christian Hagel, Michael Buchfelder, Ulrich Schuller, Jorg Flitsch, Ulrich J Knappe, Udo Kellner, Markus Bergmann, Rolf Buslei, Thomas Rudiger, Jochen HermsAbstract:Pituitary adenoma (PA) constitutes the third most common intracranial neoplasm. The mostly benign endocrine lesions express no hormone (Null Cell PA) or the pituitary hormone(s) of the Cell lineage of origin. In 0.5–1.5% of surgical specimens and in up to 10% of autopsy cases, two or three seemingly separate PA may coincide. These multiple adenomas may express different hormones, but whether or not expression of lineage-restricted transcription factors and molecular features are distinct within multiple lesions remains unknown. Searching the data bank of the German Pituitary Tumor Registry 12 double pituitary adenomas with diverse lineage were identified among 3654 adenomas and 6 hypophyseal carcinomas diagnosed between 2012 and 2020. The double adenomas were investigated immunohistochemically for expression of hormones and lineage markers. In addition, chromosomal gains and losses as well as global DNA methylation profiles were assessed, whenever sufficient material was available (n = 8 PA). In accordance with the literature, combinations of GH/prolactin/TSH–FSH/LH adenoma (4/12), GH/prolactin/TSH–ACTH adenoma (3/12), and ACTH–FSH/LH adenoma (3/12) were observed. Further, two out of 12 cases showed a combination of a GH/prolactin/TSH adenoma with a Null-Cell adenoma. Different expression pattern of hormones were confirmed by different expression of transcription factors in 11/12 patients. Finally, multiple lesions that were molecularly analysed in 4 patients displayed distinct copy number changes and global methylation pattern. Our data confirm and extend the knowledge on multiple PA and suggest that such lesions may origin from distinct Cell types.
