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  • 1
    Language: English
    In: The International Journal of Behavioral Consultation and Therapy, Spring, 2007, Vol.3(1), p.123(22)
    Keywords: Mental Disorders -- Care And Treatment ; Mental Disorders -- Research ; Psychotherapy -- Health Aspects ; Sexually Abused Children -- Health Aspects
    ISSN: 1555-7855
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  • 2
    In: International Journal of Cancer, 15 November 2015, Vol.137(10), pp.2296-2309
    Description: Cellular transformation is initiated by the activation of oncogenes and a closely associated developmental reprogramming of the epigenetic landscape. Transcription factors, regulators of chromatin states and microRNAs influence cell fates in development and stabilize the phenotypes of normal, differentiated cells and of cancer cells. The miR‐302/367 cluster, predominantly expressed in human embryonic stem cells (hESs), can promote the cellular reprogramming of human and mouse cells and contribute to the generation of iPSC. We have used the epigenetic reprogramming potential of the miR‐302/367 cluster to “de‐program” tumor cells, that is, hift their gene expression pattern towards an alternative program associated with more benign cellular phenotypes. Induction of the miR‐302/367 cluster in extensively mutated U87MG glioblastoma cells drastically suppressed the expression of transformation related proteins, for example, the reprogramming factors OCT3/4, SOX2, KLF4 and c‐MYC, and the transcription factors POU3F2, SALL2 and OLIG2, required for the maintenance of glioblastoma stem‐like tumor propagating cells. It also diminished PI3K/AKT and STAT3 signaling, impeded colony formation in soft agar and cell migration and suppressed pro‐inflammatory cytokine secretion. At the same time, the miR‐302/367 cluster restored the expression of neuronal markers of differentiation. Most notably, miR‐302/367 cluster expressing cells lose their ability to form tumors and to establish liver metastasis in nude mice. The induction of the miR‐302/367 cluster in U87MG glioblastoma cells suppresses the expression of multiple transformation related genes, abolishes the tumor and metastasis formation potential of these cells and can potentially become a new approach for cancer therapy. What's new? The transformation of normal cells into malignant cells shares many similarities with the reprogramming of somatic cells into pluripotent cells, raising the possibility that reprogramming factors may be used to counteract cellular transformation. This study demonstrates that reversion of transformation and normalization of cellular properties can be achieved in highly‐aberrant glioblastoma cells through the expression of the miR‐302/367 cluster. miR‐302/367 drastically changes the gene expression pattern and abolishes transformation‐related phenotypes in a coordinated fashion. miR‐302/367 prevents tumor and metastasis formation and restores features of neuronal differentiation. Such “deprogramming” of tumor cells could potentially become a new concept for cancer therapy.
    Keywords: Tumor Suppression ; Mir‐302/367 Regulated Gene Expression ; Epigenetic Regulation Of The Tumor Cell State
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    Language: English
    In: PLoS ONE, 01 January 2012, Vol.7(12), p.e52640
    Description: BACKGROUND: Mutations in the chromodomain helicase DNA binding protein 7 gene (CHD7) lead to CHARGE syndrome, an autosomal dominant multiple malformation disorder. Proteins involved in chromatin remodeling typically act in multiprotein complexes. We previously demonstrated that a part of human CHD7 interacts with a part of human CHD8, another chromodomain helicase DNA binding protein presumably being involved in the pathogenesis of neurodevelopmental (NDD) and autism spectrum disorders (ASD). Because identification of novel CHD7 and CHD8 interacting partners will provide further insights into the pathogenesis of CHARGE syndrome and ASD/NDD, we searched for additional associated polypeptides using the method of stable isotope labeling by amino acids in cell culture (SILAC) in combination with mass spectrometry. PRINCIPLE FINDINGS: The hitherto uncharacterized FAM124B (Family with sequence similarity 124B) was identified as a potential interaction partner of both CHD7 and CHD8. We confirmed the result by co-immunoprecipitation studies and showed a direct binding to the CHD8 part by direct yeast two hybrid experiments. Furthermore, we characterized FAM124B as a mainly nuclear localized protein with a widespread expression in embryonic and adult mouse tissues. CONCLUSION: Our results demonstrate that FAM124B is a potential interacting partner of a CHD7 and CHD8 containing complex. From the overlapping expression pattern between Chd7 and Fam124B at murine embryonic day E12.5 and the high expression of Fam124B in the developing mouse brain, we conclude that Fam124B is a novel protein possibly involved in the pathogenesis of CHARGE syndrome and neurodevelopmental disorders.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 17 May 2016, Vol.113(20), pp.5688-93
    Description: Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and activated BCR signaling in BL by quantitative phosphoproteomics to identify novel BCR effectors and potential drug targets. We identified and quantified ∼16,000 phospho-sites in BL cells. Among these sites, 909 were related to tonic BCR signaling, whereas 984 phospho-sites were regulated upon BCR engagement. The majority of the identified BCR signaling effectors have not been described in the context of B cells or lymphomas yet. Most of these newly identified BCR effectors are predicted to be involved in the regulation of kinases, transcription, and cytoskeleton dynamics. Although tonic and activated BCR signaling shared a considerable number of effector proteins, we identified distinct phosphorylation events in tonic BCR signaling. We investigated the functional relevance of some newly identified BCR effectors and show that ACTN4 and ARFGEF2, which have been described as regulators of membrane-trafficking and cytoskeleton-related processes, respectively, are crucial for BL cell survival. Thus, this study provides a comprehensive dataset for tonic and activated BCR signaling and identifies effector proteins that may be relevant for BL cell survival and thus may help to develop new BL treatments.
    Keywords: B-Cell Receptor ; Cancer Biology ; Lymphoma ; Phosphoproteome ; Signal Transduction ; Receptors, Antigen, B-Cell -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 5
    Language: English
    In: Cellular Signalling, May 2011, Vol.23(5), pp.893-900
    Description: B cells require signals transduced by the B cell antigen receptor (BCR) to provide humoral adaptive immunity. These signals are modulated by co-receptors like the Fcγ receptor IIb (FcγRIIb) that prevents activation of B cells after co-ligation with the BCR. Positive and negative effectors need to be precisely organized into signaling complexes, which requires adapter proteins like the growth factor receptor-bound protein 2 (Grb2). Here, we address the question how Grb2-mediated signal integration is affected by FcγRIIb. Our data reveal that concomitant engagement of BCR and FcγRIIb leads to markedly increased Grb2-mediated formation of ternary protein complexes comprising downstream of kinase-3 (Dok-3), Grb2, and the SH2 domain-containing inositol phosphatase (SHIP). Consistently, we found Grb2 to be required for full FcγRIIb-mediated negative regulation. To investigate how FcγRIIb influences the entire Grb2 interactions, we utilized quantitative mass spectrometry to make a differential interactome analysis. This approach revealed a shift of Grb2 interactions towards negative regulators like Dok-3, SHIP and SHP-2 and reduced binding to other proteins like CD19. Hence, we provide evidence that Grb2-mediated signal integration is a dynamic process that is important for the crosstalk between the BCR and its co-receptor FcγRIIb.
    Keywords: B Cell Activation ; Fc Gamma Riib ; Ca2+ Mobilization ; Grb2 ; Dok-3 ; Ship ; Silac ; Biology
    ISSN: 0898-6568
    E-ISSN: 1873-3913
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  • 6
  • 7
    Language: English
    In: Sexuality and Culture, 2002, Vol.6(2), pp.3-24
    Description: Whether symptomatic or asymptomatic, children labeled sexually abused are routinely offered treatment at considerable financial cost. One result of this is that mental health professionals are being charged with exploiting the problem of child sexual abuse (CSA). Is the routine provision of psychotherapy for children and adolescents labeled sexually abused warranted? In this paper, it is argued that the evidence indicates it is not warranted. Further, its provision is not in the best interests of either the children or mental health professionals. A number of recommendations are given which follow from the evidence.
    Keywords: Child Sexual Abuse ; Mental Health Services ; Psychotherapy ; Mental & Emotional Health Problems ; Article;
    ISSN: 1095-5143
    E-ISSN: 1936-4822
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  • 8
  • 9
    Language: English
    In: Cancer Research, 10/01/2014, Vol.74(19 Supplement), pp.LB-325-LB-325
    Description: Acute Myeloid Leukemia (AML) results from a combination of oncogenic events that can involve multiple signal transduction pathways including mutation-induced activation of tyrosine kinases. Kinase inhibitors are increasingly studied as promising targeted approaches either alone or in combination with other agents. However, only subsets of patients respond to respective targeted therapies. Internal tandem duplication (ITD) of FLT3 is one of the most common mutations in AML. It causes constitutive activation of FLT3. Quizartinib (AC220) is an example of a potent FLT3 inhibitor that was studied in a recent phase II open-label study in patients with relapsed/refractory AML. However, the presence of activating mutations within FLT3 can predict response to a certain extent only.Here, we investigated whether large-scale analyses of phosphorylation-based signalling events allows identification of more accurate markers based on the hypothesis that the read-out is closer to the mode of action of FLT3 inhibitors. Therefore, we applied quantitative mass-spectrometry to globally profile the phosphoproteome of 12 pre-treatment bone marrow aspirates obtained from AML patients treated with the quizartinib. A signature derived from this analysis consists of five phospho-sites within the proteins EEPD1, BCL11A, RANBP3, RP3, and LMN1 and it accurately predicted response to treatment with AC220 as revealed by validation in additional independent nine AML patients.Although the combined signature of five phospho-sites showed the highest prediction accuracy, we could demonstrate that in particular phosphorylation of S640 on BCL11A and S333 on RANBP3 lead to almost equally good predictions if used as individual markers. Furthermore, we could show that in case of BCL11A, EEPD1, and LMN1 the expression of the total protein correlates with its phosphorylation and thus with response. The phosphorylation markers were identified and validated in bone marrow aspirates. Although, it is clinical standard procedure to use bone marrow aspirates for diagnosis of AML patients, a predictive test that can be applied to peripheral blood samples would have many advantages. Indeed, we could show that the phosphorylation of the marker proteins strongly correlate between bone marrow and peripheral blood samples from the same patients, suggesting that the phosphorylation or protein markers can be measured and are predictive in both, bone marrow and peripheral blood samples.Citation Format: Christoph Schaab, Felix Oppermann, Martin Klammer, Heike Pfeifer, Andreas Tebbe, Thomas Oellerich, Juergen Krauter, Mark Levis, Alexander Perl, Henrik Daub, Bjoern Steffen, Klaus Godl, Hubert Serve. Global analysis of the phosphoproteome of human blasts reveals predictive phosphorylation markers for the treatment of acute myeloid leukemia with quizartinib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-325. doi:10.1158/1538-7445.AM2014-LB-325
    Keywords: Medicine;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 10
    Language: English
    In: Cancer Research, 07/01/2018, Vol.78(13 Supplement), pp.1500-1500
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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