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  1. Article ; Online: The oncogenic fusion landscape in pediatric CNS neoplasms.

    Roosen, Mieke / Odé, Zelda / Bunt, Jens / Kool, Marcel

    Acta neuropathologica

    2022  Volume 143, Issue 4, Page(s) 427–451

    Abstract: Pediatric neoplasms in the central nervous system (CNS) are the leading cause of cancer-related deaths in children. Recent developments in molecular analyses have greatly contributed to a more accurate diagnosis and risk stratification of CNS tumors. ... ...

    Abstract Pediatric neoplasms in the central nervous system (CNS) are the leading cause of cancer-related deaths in children. Recent developments in molecular analyses have greatly contributed to a more accurate diagnosis and risk stratification of CNS tumors. Additionally, sequencing studies have identified various, often entity specific, tumor-driving events. In contrast to adult tumors, which often harbor multiple mutated oncogenic drivers, the number of mutated genes in pediatric cancers is much lower and many tumors can have a single oncogenic driver. Moreover, in children, much more than in adults, fusion proteins play an important role in driving tumorigenesis, and many different fusions have been identified as potential driver events in pediatric CNS neoplasms. However, a comprehensive overview of all the different reported oncogenic fusion proteins in pediatric CNS neoplasms is still lacking. A better understanding of the fusion proteins detected in these tumors and of the molecular mechanisms how these proteins drive tumorigenesis, could improve diagnosis and further benefit translational research into targeted therapies necessary to treat these distinct entities. In this review, we discuss the different oncogenic fusions reported in pediatric CNS neoplasms and their structure to create an overview of the variety of oncogenic fusion proteins to date, the tumor entities they occur in and their proposed mode of action.
    MeSH term(s) Adult ; Carcinogenesis ; Central Nervous System Neoplasms/genetics ; Child ; Humans ; Oncogene Fusion/genetics ; Oncogene Proteins, Fusion/genetics
    Chemical Substances Oncogene Proteins, Fusion
    Language English
    Publishing date 2022-02-15
    Publishing country Germany
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 1079-0
    ISSN 1432-0533 ; 0001-6322
    ISSN (online) 1432-0533
    ISSN 0001-6322
    DOI 10.1007/s00401-022-02405-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: CRISPR-Mediated Non-Viral Site-Specific Gene Integration and Expression in T Cells: Protocol and Application for T-Cell Therapy.

    Odé, Zelda / Condori, Jose / Peterson, Nicolas / Zhou, Sheng / Krenciute, Giedre

    Cancers

    2020  Volume 12, Issue 6

    Abstract: T cells engineered with chimeric antigen receptors (CARs) show great promise in the treatment of some cancers. Modifying T cells to express CARs generally relies on T-cell transduction using viral vectors carrying a transgene, resulting in semi-random ... ...

    Abstract T cells engineered with chimeric antigen receptors (CARs) show great promise in the treatment of some cancers. Modifying T cells to express CARs generally relies on T-cell transduction using viral vectors carrying a transgene, resulting in semi-random DNA integration within the T-cell genome. While this approach has proven successful and is used in generating the Food and Drug Administration (FDA, USA) approved B-lymphocyte antigen CD19-specific CAR T cells, it is possible the transgene could integrate into a locus that would lead to malignant transformation of the engineered T cells. In addition, manufacturing viral vectors is time-consuming and expensive. One way to overcome these challenges is site-specific gene integration, which can be achieved through clustered regularly interspaced short palindromic repeat (CRISPR) mediated editing and non-viral DNA, which serves as a template for homology-directed repair (HDR). This non-viral gene editing approach provides a rapid, highly specific, and inexpensive way to engineer T cells. Here, we describe an optimized protocol for the site-specific knock-in of a large transgene in primary human T cells using non-viral double stranded DNA as a repair template. As proof-of-principle, we targeted the T-cell receptor alpha constant (
    Language English
    Publishing date 2020-06-26
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers12061704
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Blood-brain barrier permeability following conventional photon radiotherapy - A systematic review and meta-analysis of clinical and preclinical studies.

    Hart, Elvin't / Odé, Zelda / Derieppe, Marc P P / Groenink, Lucianne / Heymans, Martijn W / Otten, René / Lequin, Maarten H / Janssens, Geert O R / Hoving, Eelco W / van Vuurden, Dannis G

    Clinical and translational radiation oncology

    2022  Volume 35, Page(s) 44–55

    Abstract: Radiotherapy (RT) is a cornerstone treatment strategy for brain tumours. Besides cytotoxicity, RT can cause disruption of the blood-brain barrier (BBB), resulting in an increased permeability into the surrounding brain parenchyma. Although this effect is ...

    Abstract Radiotherapy (RT) is a cornerstone treatment strategy for brain tumours. Besides cytotoxicity, RT can cause disruption of the blood-brain barrier (BBB), resulting in an increased permeability into the surrounding brain parenchyma. Although this effect is generally acknowledged, it remains unclear how and to what extent different radiation schemes affect BBB integrity. The aim of this systematic review and meta-analysis is to investigate the effect of photon RT regimens on BBB permeability, including its reversibility, in clinical and preclinical studies. We systematically reviewed relevant clinical and preclinical literature in PubMed, Embase, and Cochrane search engines. A total of 69 included studies (20 clinical, 49 preclinical) were qualitatively and quantitatively analysed by meta-analysis and evaluated on key determinants of RT-induced BBB permeability in different disease types and RT protocols. Qualitative data synthesis showed that 35% of the included clinical studies reported BBB disruption following RT, whereas 30% were inconclusive. Interestingly, no compelling differences were observed between studies with different calculated biological effective doses based on the fractionation schemes and cumulative doses; however, increased BBB disruption was noted during patient follow-up after treatment. Qualitative analysis of preclinical studies showed RT BBB disruption in 78% of the included studies, which was significantly confirmed by meta-analysis (p < 0.01). Of note, a high risk of bias, publication bias and a high heterogeneity across the studies was observed. This systematic review and meta-analysis sheds light on the impact of RT protocols on BBB integrity and opens the discussion for integrating this factor in the decision-making process of future RT, with better study of its occurrence and influence on concomitant or adjuvant therapies.
    Language English
    Publishing date 2022-05-04
    Publishing country Ireland
    Document type Journal Article ; Review
    ISSN 2405-6308
    ISSN (online) 2405-6308
    DOI 10.1016/j.ctro.2022.04.013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Cell-surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery.

    Haydar, Dalia / Houke, Haley / Chiang, Jason / Yi, Zhongzhen / Odé, Zelda / Caldwell, Kenneth / Zhu, Xiaoyan / Mercer, Kimberly S / Stripay, Jennifer L / Shaw, Timothy I / Vogel, Peter / DeRenzo, Christopher / Baker, Suzanne J / Roussel, Martine F / Gottschalk, Stephen / Krenciute, Giedre

    Neuro-oncology

    2020  Volume 23, Issue 6, Page(s) 999–1011

    Abstract: Background: Immunotherapy with chimeric antigen receptor (CAR) T cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present, it is unclear which CAR target antigens are consistently ... ...

    Abstract Background: Immunotherapy with chimeric antigen receptor (CAR) T cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present, it is unclear which CAR target antigens are consistently expressed across different pediatric brain tumor types. In addition, the extent of HLA class I expression is unknown, which is critical for tumor recognition by conventional αβTCR T cells.
    Methods: We profiled 49 low- and high-grade pediatric brain tumor patient-derived orthotopic xenografts (PDOX) by flow analysis for the expression of 5 CAR targets (B7-H3, GD2, IL-13Rα2, EphA2, and HER2), and HLA class I. In addition, we generated B7-H3-CAR T cells and evaluated their antitumor activity in vitro and in vivo.
    Results: We established an expression hierarchy for the analyzed antigens (B7-H3 = GD2 >> IL-13Rα2 > HER2 = EphA2) and demonstrated that antigen expression is heterogenous. All high-grade gliomas expressed HLA class I, but only 57.1% of other tumor subtypes had detectable expression. We then selected B7-H3 as a target for CAR T-cell therapy. B7-H3-CAR T cells recognized tumor cells in an antigen-dependent fashion. Local or systemic administration of B7-H3-CAR T cells induced tumor regression in PDOX and immunocompetent murine glioma models resulting in a significant survival advantage.
    Conclusions: Our study highlights the importance of studying target antigen and HLA class I expression in PDOX samples for the future design of immunotherapies. In addition, our results support active preclinical and clinical exploration of B7-H3-targeted CAR T-cell therapies for a broad spectrum of pediatric brain tumors.
    MeSH term(s) Animals ; Antigens, Surface ; B7 Antigens ; Brain Neoplasms/therapy ; Child ; Humans ; Mice ; Receptors, Chimeric Antigen ; T-Lymphocytes ; Xenograft Model Antitumor Assays
    Chemical Substances Antigens, Surface ; B7 Antigens ; Receptors, Chimeric Antigen
    Language English
    Publishing date 2020-11-20
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2028601-6
    ISSN 1523-5866 ; 1522-8517
    ISSN (online) 1523-5866
    ISSN 1522-8517
    DOI 10.1093/neuonc/noaa278
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5307: Show issues Location:
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