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      Role of chromatin assembly factor-1/p60 and poly [ADP-ribose] polymerase 1 in mycosis fungoides

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          Abstract

          Mycosis fungoides (MF) represents the most common type of cutaneous lymphoma. In the majority of patients, the disease has a slow evolution and a protracted course; however, a subset of patients shows poor oncologic outcomes. Unfortunately, there are no reliable prognostic markers for MF, and the currently available treatments are only effective in a minority of patients. This study aimed to evaluate the expression and clinical significance of PARP-1 and CAF-1/p60 in MF. Sixty-four MF representatives of the different stages of disease were assessed by immunohistochemistry for PARP-1 and CAF-1/p60. The association of PARP-1 and CAF-1/p60 with the MF stage and outcome was assessed by using Fisher’s exact test and Kaplan-Meier survival analysis with the Log-rank test; a p value < 0.05 was considered significant. PARP-1 was overexpressed in 57.9% of MF and was significantly associated with a MF stage > II ( p = 0.034) but not with the risk of death ( p = 0.237). CAF-1/p60 was overexpressed in 26.8% of MF and was significantly associated with decreased overall survival ( p < 0.001) but not with the MF stage ( p = 1). A significant association was found between PARP-1 overexpression and CAF-1/p60 overexpression ( p = 0.0025). Simultaneous overexpression of PARP-1 and CAF-1/p60 was significantly associated with decreased overall survival ( p < 0.001), although less strongly than CAF-1/p60 alone ( χ 2 = 14.916 vs 21.729, respectively). In MF, PARP-1 is overexpressed in advanced stages, while CAF-1/p60 is overexpressed in the cases with shorter overall survival, appearing as a significant prognostic marker. A role for PARP-1 inhibitors and anti-CAF-1/p60 targeted therapy may be reasonably hypothesized in MF.

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          The online version of this article (10.1007/s00428-020-02952-z) contains supplementary material, which is available to authorized users.

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          Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.

          BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
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            WHO-EORTC classification for cutaneous lymphomas.

            Primary cutaneous lymphomas are currently classified by the European Organization for Research and Treatment of Cancer (EORTC) classification or the World Health Organization (WHO) classification, but both systems have shortcomings. In particular, differences in the classification of cutaneous T-cell lymphomas other than mycosis fungoides, Sezary syndrome, and the group of primary cutaneous CD30+ lymphoproliferative disorders and the classification and terminology of different types of cutaneous B-cell lymphomas have resulted in considerable debate and confusion. During recent consensus meetings representatives of both systems reached agreement on a new classification, which is now called the WHO-EORTC classification. In this paper we describe the characteristic features of the different primary cutaneous lymphomas and other hematologic neoplasms frequently presenting in the skin, and discuss differences with the previous classification schemes. In addition, the relative frequency and survival data of 1905 patients with primary cutaneous lymphomas derived from Dutch and Austrian registries for primary cutaneous lymphomas are presented to illustrate the clinical significance of this new classification.
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              The PARP superfamily.

              Poly(ADP-ribosyl)ation is an immediate DNA-damage-dependent post-translational modification of histones and other nuclear proteins that contributes to the survival of injured proliferating cells. Poly(ADP-ribose) polymerases (PARPs) now constitute a large family of 18 proteins, encoded by different genes and displaying a conserved catalytic domain in which PARP-1 (113 kDa), the founding member, and PARP-2 (62 kDa) are so far the sole enzymes whose catalytic activity has been shown to be immediately stimulated by DNA strand breaks. A large repertoire of sequences encoding novel PARPs now extends considerably the field of poly(ADP-ribosyl)ation reactions to various aspects of the cell biology including cell proliferation and cell death. Some of these new members interact with each other, share common partners and common subcellular localizations suggesting possible fine tuning in the regulation of this post-translational modification of proteins. This review summarizes our present knowledge of this emerging superfamily, which might ultimately improve pharmacological strategies to enhance both antitumor efficacy and the treatment of a number of inflammatory and neurodegenerative disorders. A provisional nomenclature is proposed.
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                Author and article information

                Contributors
                massimo.mascolo@unina.it
                Journal
                Virchows Arch
                Virchows Arch
                Virchows Archiv
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0945-6317
                1432-2307
                24 October 2020
                24 October 2020
                2021
                : 478
                : 5
                : 961-968
                Affiliations
                [1 ]GRID grid.4691.a, ISNI 0000 0001 0790 385X, Department of Advanced Biomedical Sciences, Pathology Section, School of Medicine, , University of Naples “Federico II”, ; Via Sergio Pansini, 5, 80131 Naples, Italy
                [2 ]GRID grid.6292.f, ISNI 0000 0004 1757 1758, Haematopathology Unit, Department of Experimental Diagnostic and Specialty Medicine, S. Orsola-Malpighi Hospital, , University of Bologna, ; Bologna, Italy
                [3 ]GRID grid.4691.a, ISNI 0000 0001 0790 385X, Department of Clinical Medicine and Surgery, Dermatology Section, , University of Naples “Federico II”, ; Naples, Italy
                [4 ]GRID grid.6292.f, ISNI 0000 0004 1757 1758, Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, , University of Bologna, ; Bologna, Italy
                [5 ]GRID grid.4691.a, ISNI 0000 0001 0790 385X, Department of Clinical Medicine and Surgery, Hematology Section, , University of Naples “Federico II”, ; Naples, Italy
                Article
                2952
                10.1007/s00428-020-02952-z
                8099834
                33098490
                924d6d75-4c3a-40c2-bc1d-cef77cddc242
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 July 2020
                : 16 September 2020
                : 14 October 2020
                Funding
                Funded by: Università degli Studi di Napoli Federico II
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2021

                Pathology
                mycosis fungoides,cutaneous lymphoma,poly [adp-ribose] polymerase 1,chromatin assembly factor-1,prognosis

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