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Berlin Brandenburg

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  • Immunohistochemistry
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  • 1
    Language: English
    In: Cancer research, 15 September 2016, Vol.76(18), pp.5573-83
    Description: The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here, we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation, resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies. Cancer Res; 76(18); 5573-83. ©2016 AACR.
    Keywords: Cerebellar Neoplasms -- Pathology ; Hedgehog Proteins -- Metabolism ; Kruppel-Like Transcription Factors -- Metabolism ; Medulloblastoma -- Pathology ; Nerve Tissue Proteins -- Metabolism ; Nestin -- Metabolism
    ISSN: 00085472
    E-ISSN: 1538-7445
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  • 2
    Language: English
    In: Acta Neuropathologica, 2013, Vol.126(3), pp.443-451
    Description: Mutation/loss of alpha-thalassemia/mental retardation syndrome X-linked ( ATRX ) expression has been described in anaplastic gliomas. The present study explored the role of ATRX status in the molecular classification of anaplastic gliomas and its impact on survival in the biomarker cohort of the NOA-04 anaplastic glioma trial. Patients ( n  = 133) of the NOA-04 trial were analyzed for ATRX expression using immunohistochemistry. ATRX status was correlated with age, histology, isocitrate dehydrogenase (IDH), 1p/19q, alternative lengthening of telomeres (ALT) and O6-methylguanine-DNA methyltransferase (MGMT) status, and the trial efficacy endpoints. Loss of ATRX expression was detected in 45 % of anaplastic astrocytomas (AA), 27 % of anaplastic oligoastrocytomas (AOA) and 10 % of anaplastic oligodendrogliomas (AO). It was mostly restricted to IDH mutant tumors and almost mutually exclusive with 1p/19q co-deletion. The ALT phenotype was significantly correlated with ATRX loss. ATRX and 1p/19q status were used to re-classify AOA: AOA harboring ATRX loss shared a similar clinical course with AA, whereas AOA carrying 1p/19q co-deletion shared a similar course with AO. Accordingly, in a Cox regression model including ATRX and 1p/19q status, histology was no longer significantly associated with time to treatment failure. Survival analysis showed a marked separation of IDH mutant astrocytic tumors into two groups based on ATRX status: tumors with ATRX loss had a significantly better prognosis (median time to treatment failure 55.6 vs. 31.8 months, p  = 0.0168, log rank test). ATRX status helps better define the clinically and morphologically mixed group of AOA, since ATRX loss is a hallmark of astrocytic tumors. Furthermore, ATRX loss defines a subgroup of astrocytic tumors with a favorable prognosis.
    Keywords: ATRX ; IDH ; 1p/19q ; Anaplastic glioma ; MGMT
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 3
    Language: English
    In: Nature medicine, November 2018, Vol.24(11), pp.1752-1761
    Description: Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children's Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and seven cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.
    Keywords: Biological Specimen Banks ; Immunohistochemistry ; Brain Neoplasms -- Pathology ; Xenograft Model Antitumor Assays -- Methods
    ISSN: 10788956
    E-ISSN: 1546-170X
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  • 4
    Language: English
    In: International Journal of Cancer, 10 May 2003, Vol.104(6), pp.728-734
    Description: Routine pathological examination cannot distinctively predict the clinical course of meningiomas because even histologically benign tumors may recur after gross total resection. Numerous efforts have been made for the evaluation of different immunohistochemical assays in meningioma prognosis. We investigated the prognostic significance of p16INK4a, p14ARF, p18INK4c, p21CIP1, p27KIP1 and p73 expression by immunohistochemical analysis of 271 meningiomas. All tumors were additionally stained for the proliferation markers Ki‐67 and DNA topoisomerase II alpha (TopoIIα). Significant differences between the number of p16INK4a‐, p18INK4c‐ and p21CIP1‐positive cases were noted among the 3 grades of meningiomas. p16INK4a‐ and p21CIP‐positive tumors were found to prevail among benign meningiomas, whereas p18INK4c immunostaining was closely associated to anaplastic meningiomas. The number of p16INK4a‐ and p21CIP‐positive cases was significantly lower in the cohort of recurrent meningiomas. In contrast, p18INK4c‐positive cases were clustered among recurrent meningiomas regardless of tumor grade. Immunoreactivity of p14ARF, p27KIP1 and p73 did not show any differences between meningiomas of various histology and clinical outcomes. Multivariate analysis revealed that only tumor grade and TopoIIα index are independent criteria for predicting meningioma recurrence. Thus, the immunohistochemical assessment of p16INK4a, p14ARF, p18INK4c, p21CIP1, p27KIP1 and p73 expression in meningiomas does not appear to provide prognostically useful information. Further studies are needed to identify more reliable prognostic markers and to address in more detail the role of cell cycle aberrations in these tumors. © 2003 Wiley‐Liss, Inc.
    Keywords: P16ink4a ; P18ink4c ; P21cip1 ; Immunohistochemistry ; Meningioma ; Recurrence
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 5
    Language: English
    In: Neuropathology and Applied Neurobiology, 06/2011, Vol.37(4), pp.423-427
    Keywords: Engineering;
    ISSN: Neuropathology and Applied Neurobiology
    ISSN: 03639061
    E-ISSN: 03051846
    E-ISSN: 10969853
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  • 6
    Language: English
    In: Cancer research, 15 October 2010, Vol.70(20), pp.8003-14
    Description: Medulloblastoma is the most common malignant pediatric brain tumor and is one of the leading causes of cancer-related mortality in children. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk medulloblastoma. Through mRNA expression profiling, we identified LIM and SH3 protein 1 (LASP1) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. In an independent validation cohort of 101 medulloblastoma samples, the abundance of LASP1 mRNA was significantly associated with 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n = 207), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival. In vitro experiments in medulloblastoma cell lines showed a strong reduction of cell migration, increased adhesion, and decreased proliferation upon LASP1 knockdown by small interfering RNA-mediated silencing, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medulloblastoma.
    Keywords: Adaptor Proteins, Signal Transducing -- Genetics ; Cerebellar Neoplasms -- Genetics ; Cytoskeletal Proteins -- Genetics ; Homeodomain Proteins -- Genetics ; Medulloblastoma -- Genetics
    ISSN: 00085472
    E-ISSN: 1538-7445
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  • 7
    In: Journal of Pediatric Hematology/Oncology, 2010, Vol.32(6), pp.511-514
    Description: Spinal glioblastoma multiforme (GBM) is rare in children. New therapeutic options should be explored given the poor outcomes reported. We describe the case of an infant with spinal GBM whose condition worsened despite radiotherapy and chemotherapy. Immunohistochemical analysis of the tumor sample showed activation of the Raf-MEK-ERK pathway. Targeted pharmacologic therapy with sorafenib plus valproic acid led to decrease in the size of the tumor and improvement of symptoms. We conclude that regulation of the mitogen-activated protein kinase pathway using sorafenib plus valproic acid warrants further investigation for the management of childhood GBM.
    Keywords: Antineoplastic Combined Chemotherapy Protocols -- Therapeutic Use ; Glioblastoma -- Drug Therapy ; Neoplasm Recurrence, Local -- Drug Therapy ; Spinal Cord Neoplasms -- Drug Therapy;
    ISSN: 1077-4114
    E-ISSN: 15363678
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  • 8
    In: Hypertension, 2010, Vol.56(1), pp.105-111
    Description: In vascular smooth muscle cells, Axl is a key receptor tyrosine kinase, because it is upregulated in injury, increases migration and neointima formation, and is activated by reactive oxygen species. Reaction of glutathione with cysteine residues (termed “glutathiolation”) is an important posttranslational redox modification that may alter protein activity and protein-protein interactions. To investigate the mechanisms by which reactive oxygen species increase Axl-dependent vascular smooth muscle cell function we assayed for glutathiolated proteins that associated with Axl in a redox-dependent manner. We identified glutathiolated nonmuscle myosin heavy chain (MHC)-IIB as a novel Axl interacting protein. This interaction was specific in that other myosins did not interact with Axl. The endogenous ligand for Axl, Gas6, increased production of reactive oxygen species in vascular smooth muscle cells and also increased the association of Axl with MHC-IIB. Antioxidants ebselen and N-acetylcysteine decreased the association of Axl with MHC-IIB in response to both Gas6 and reactive oxygen species. Blocking the Axl–MHC-IIB interaction with the specific myosin II inhibitor blebbistatin decreased phosphorylation of Axl and activation of extracellular signal–regulated kinase 1/2 and Akt. Association of MHC-IIB with Axl was increased in balloon-injured rat carotid vessels. Finally, expression of MHC-IIB was upregulated in the neointima of the carotid artery after balloon injury similar to upregulation of Axl protein expression, as shown in our previous studies. These results demonstrate a novel interaction between Axl and MHC-IIB in response to reactive oxygen species. This interaction provides a direct link between Axl and molecular motors crucial for directed cell migration, which may mediate increased migration in vascular dysfunction.
    Keywords: Carotid Artery Diseases -- Metabolism ; Intercellular Signaling Peptides and Proteins -- Metabolism ; Muscle, Smooth, Vascular -- Metabolism ; Nonmuscle Myosin Type IIB -- Metabolism ; Proto-Oncogene Proteins -- Metabolism ; Receptor Protein-Tyrosine Kinases -- Metabolism;
    ISSN: 0194-911X
    E-ISSN: 15244563
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  • 9
    Language: English
    In: Acta Neuropathologica, 2012, Vol.124(6), p.875(7)
    Keywords: Immunohistochemistry – Analysis ; Criminal Investigation – Analysis ; Protein Binding – Analysis ; Brain Tumors – Prognosis ; Brain Tumors – Analysis ; Microrna – Analysis
    ISSN: 0001-6322
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  • 10
    Language: English
    In: Acta neuropathologica, 2014, Vol.128(2), pp.279-289
    Description: Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies
    Keywords: Brain Neoplasms -- Metabolism ; Neoplasms, Germ Cell and Embryonal -- Metabolism ; Neuroectodermal Tumors, Primitive -- Metabolism;
    ISSN: 0001-6322
    ISSN: 1432-0533
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