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      OncoTargets and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the pathological basis of cancers, potential targets for therapy and treatment protocols to improve the management of cancer patients. Publishing high-quality, original research on molecular aspects of cancer, including the molecular diagnosis, since 2008. Sign up for email alerts here. 50,877 Monthly downloads/views I 4.345 Impact Factor I 7.0 CiteScore I 0.81 Source Normalized Impact per Paper (SNIP) I 0.811 Scimago Journal & Country Rank (SJR)

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      The correlation of BER protein, IRF3 with CD8+ T cell and their prognostic significance in upper tract urothelial carcinoma

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          Abstract

          Objectives

          Tumor-infiltrating lymphocytes (TILs) play a crucial role in anti-tumor immunity. Basic studies have found that stimulator of interferon genes (STING), activated by sensing DNA damage, plays a role in recruiting and activating TILs in tumors. However, the correlation between base excision repair (BER) pathway, STING pathway and TILS and their effect on prognosis in upper urinary tract urothelial carcinoma (UTUC) are still unclear. The aim of this study was to investigate the prognostic effect of those proteins expression for disease-free survival (DFS) and overall survival (OS) and explore the correlation between these makers.

          Methods

          We evaluated immunohistochemical expression of BER pathway (APE1, NTH1, OGG1, XRCC1, polβ), STING pathway (STING, IRF3), TILs (CD4, CD8, CD20) and PD-L1, PD-L2 in 88 UTUC patients to determine the predictive significance in DFS, OS and the correlation between them.

          Results

          We found that interferon regulatory factor3 (IRF3) (HR: 0.451, 95% CI 0.243–0.837, p=0.024) and CD8 (HR: 0.522, 95% CI 0.295–0.926, p=0.014) are independent prognostic factors for DFS, APE1 (HR: 1.932, 95% CI 1.005–3.714, P=0.048), polβ (HR: 2.620, 95% CI 1.373–5.000, P=0.003), CD8 (HR: 0.323, 95% CI 0.151–0.693, P=0.004) were independent prognostic factors for OS. A model consisting of stage, grade, lymphovascular invasion and expression of APE1, polβ, IRF3, CD4, CD8 that predicts 3-year OS. Furthermore, DNA damage repair protein polβ is associated with CD8+ T cells in TME.

          Conclusion

          We found that DNA damage, IRF3 and TILs are independent predictors for prognosis. We also provided clinical evidence that DNA damage repair-activated STING pathway can induce the recruitment and activation of TILs, which is consistent with preclinical models.

          Most cited references30

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          The Role of Tumor-Infiltrating Lymphocytes in Development, Progression, and Prognosis of Non-Small Cell Lung Cancer.

          A malignant tumor is not merely an accumulation of neoplastic cells, but constitutes a microenvironment containing endothelial cells, fibroblasts, structural components, and infiltrating immune cells that impact tumor development, invasion, metastasis, and outcome. Hence, the evolution of cancers reflects intricate cellular and molecular interactions between tumor cells and constituents of the tumor microenvironment. Recent studies have shed new light on this complex interaction between tumor and host immune cells and the resulting immune response. The composition of the immune microenvironment differs across patients as well as in cancers of the same type, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, and macrophages. The type, density, location, and organization of immune cells within solid tumors define the immune contexture, which has proved to be a major determinant of tumor characteristics and patient outcome. Lung cancer consists mostly of non-small cell lung cancer (85%); it is our most deadly malignant disease, with the 5-year survival rate being merely 15%. This review focuses on the immune contexture; the tumor-suppressing roles of tumor-infiltrating lymphocytes; and the relevance of this immune contexture for cancer diagnostics, prognostication, and treatment allocation, with an emphasis on non-small cell lung cancer.
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            DNA repair in mammalian cells: Base excision repair: the long and short of it.

            Base excision repair (BER) is the primary DNA repair pathway that corrects base lesions that arise due to oxidative, alkylation, deamination, and depurinatiation/depyrimidination damage. BER facilitates the repair of damaged DNA via two general pathways - short-patch and long-patch. The shortpatch BER pathway leads to a repair tract of a single nucleotide. Alternatively, the long-patch BER pathway produces a repair tract of at least two nucleotides. The BER pathway is initiated by one of many DNA glycosylases, which recognize and catalyze the removal of damaged bases. The completion of the BER pathway is accomplished by the coordinated action of at least three additional enzymes. These downstream enzymes carry out strand incision, gap-filling and ligation. The high degree of BER conservation between E. coli and mammals has lead to advances in our understanding of mammalian BER. This review will provide a general overview of the mammalian BER pathway. (Part of a Multi-author Review).
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              Prognostic and predictive impact of intra- and peritumoral immune infiltrates.

              Leukocyte infiltrates into or around tumor cell nests are found in the context of protumorigenic inflammation and anticancer immunosurveillance. Hence, the detailed composition, density, architecture, and function of leukocyte infiltrates must be analyzed to understand their prognostic impact. The ectopic presence within tumors of high endothelial venule cells, which are normally characteristic for secondary lymphoid organs, correlates with a more pronounced infiltration by T lymphocytes and has a positive predictive impact on local advanced breast cancer treated with neoadjuvant chemotherapy. Recent progress in the field indicates that immune infiltrates of the primary tumors, as well as of metastases, are not only independent prognostic biomarkers but can also constitute predictive factors, suggesting that the pretherapeutic immune response can determine the efficacy of conventional chemotherapies. Moreover, accumulating evidence indicates that chemotherapy can stimulate anticancer immune responses coupled with an increased intratumoral lymphoid infiltration, which correlates with tumor mass reduction and patient survival. Improved methods for the automation of immunohistochemistry and digitalized image analyses will pave the way to an improved understanding of the complex interplay between cancer parenchyma, stroma, and immune effectors, as well as to the routine evaluation of immune-related parameters to the clinical management of cancer patients. ©2011 AACR.
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                Author and article information

                Journal
                Onco Targets Ther
                Onco Targets Ther
                OTT
                ott
                OncoTargets and therapy
                Dove
                1178-6930
                24 September 2019
                2019
                : 12
                : 7725-7735
                Affiliations
                [1 ]Department of Urology, Daping Hospital & Army Medical Center of PLA, Third Military Medical University (Army Medical University) , Chongqing 400042, People’s Republic of China
                [2 ]Cancer Center, Daping Hospital & Army Medical Center of PLA, Third Military Medical University (Army Medical University) , Chongqing 400042, People’s Republic of China
                [3 ]Department of Pathology, Daping Hospital & Army Medical Center of PLA, Third Military Medical University (Army Medical University) , Chongqing 400042, People’s Republic of China
                Author notes
                Correspondence: Jun Jiang Department of Urology, Daping Hospital & Army Medical Center of PLA, Third Military Medical University (Army Medical University) , Chongqing400042, People’s Republic of ChinaTel +86 236 875 7151Fax +86 236 889 4062 Email jiangjun_64@163.com
                [*]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0002-8725-0373
                Article
                222422
                10.2147/OTT.S222422
                6768150
                31576137
                b4921fa0-3a21-4793-a041-5b630481879d
                © 2019 Wang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 10 July 2019
                : 30 August 2019
                Page count
                Figures: 4, Tables: 4, References: 49, Pages: 11
                Categories
                Original Research

                Oncology & Radiotherapy
                ber,irf3,tumor-infiltrating lymphocytes,prognosis
                Oncology & Radiotherapy
                ber, irf3, tumor-infiltrating lymphocytes, prognosis

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