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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i154-i155
    Description: In the last few years, the extent of heterogeneity between tumors of a given class has become increasingly evident. Thus, tumors should optimally be treated differently according to their individual genetic alterations. Within the ICGC PedBrain Tumor Project, we have analyzed 〉150 low-grade and high-grade pediatric gliomas with whole-genome DNA and RNA sequencing, and have identified a wide variety of genetic alterations responsible for tumor growth. This includes novel point mutations, fusions and duplications in oncogenes such as NTRK2, FGFR1 and ALK. In some cases these alterations also define distinct molecular subgroups of glioma as judged by DNA methylation profiling. In order to identify new targeted therapy options for pediatric gliomas, mouse models recapitulating the human disease are required for testing of more specific inhibitors. We have therefore generated a series of novel models which are now being characterized and pre-clinically treated. Initial results with ALK or NTRK fusions show that our somatic gene transfer methods (RCAS- or in utero electroporation-based) can be used to rapidly generate new orthotopic brain tumor models, and that specific inhibitors against chosen oncogenes have a greater effect on tumor growth compared to standard therapy. The murine tumor cells can also be cultivated as neurospheres for functional testing and e.g. high-throughput screens. In addition to the basic biological understanding of tumorigenic mechanisms that can now be elucidated in more detail, we aim to rapidly translate our pre-clinical results in a manner that we hope will directly benefit patients in the clinic.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2016, Vol.11(2), p.e0149389
    Description: INTRODUCTION:Bone infections after trauma, i.e. posttraumatic osteomyelitis, pose one of the biggest problems of orthopedic surgery. Even after sufficient clinical therapy including vast debridement of infected bone and antibiotic treatment, regeneration of postinfectious bone seems to be restricted. One explanation includes the large sized defects resulting from sufficient debridement. Furthermore, it remains unclear if inflammatory processes after bone infection do affect bone regeneration. For continuing studies in this field, an animal model is needed where bone regeneration after sufficient treatment can be studied in detail. METHODS:For this purpose we created a stable infection in murine tibiae by Staphylococcus aureus inoculation. Thereafter, osteomyelitic bones were debrided thoroughly and animals were subsequently treated with antibiotics. Controls included debrided, non-infected, as well as infected animals exclusively treated with antibiotics. To verify sufficient treatment of infected bone, different assessments detecting S. aureus were utilized: agar plates, histology and RT-qPCR. RESULTS:All three detection methods revealed massive reduction or eradication of S. aureus within debrided bones 1 and 2 weeks postoperatively, whereas sole antibiotic therapy could not provide sufficient treatment of osteomyelitic bones. Debrided, previously infected bones showed significantly decreased bone formation, compared to debrided, non-infected controls. DISCUSSION:Thus, the animal model presented herein provides a reliable and fascinating tool to study posttraumatic osteomyelitis for clinical therapies.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Cancer Research, 07/01/2018, Vol.78(13 Supplement), pp.5109-5109
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 4
    In: STEM CELLS Translational Medicine, June 2016, Vol.5(6), pp.836-844
    Description: Stem cells obtained from fat pads of type 2 diabetic mice are found to be capable of reconstituting impaired bone regeneration in type 2 diabetes. These multipotent stem cells promote both angiogenesis and osteogenesis in type 2 diabetic bony defects.
    Keywords: Bone ; Stem Cells ; Diabetes Mellitus ; Fractures ; Osteogenesis
    ISSN: 2157-6564
    E-ISSN: 2157-6580
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  • 5
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 March 2019, Vol.25(6), pp.1851-1866
    Description: Pilocytic astrocytoma is the most common childhood brain tumor, characterized by constitutive MAPK activation. MAPK signaling induces oncogene-induced senescence (OIS), which may cause unpredictable growth behavior of pilocytic astrocytomas. The senescence-associated secretory phenotype (SASP) has been shown to regulate OIS, but its role in pilocytic astrocytoma remains unknown. The patient-derived pilocytic astrocytoma cell culture model, DKFZ-BT66, was used to demonstrate presence of the SASP and analyze its impact on OIS in pilocytic astrocytoma. The model allows for doxycycline-inducible switching between proliferation and OIS. Both states were studied using gene expression profiling (GEP), Western blot, ELISA, and cell viability testing. Primary pilocytic astrocytoma tumors were analyzed by GEP and multiplex assay. SASP factors were upregulated in primary human and murine pilocytic astrocytoma and during OIS in DKFZ-BT66 cells. Conditioned medium induced growth arrest of proliferating pilocytic astrocytoma cells. The SASP factors IL1B and IL6 were upregulated in primary pilocytic astrocytoma, and both pathways were regulated during OIS in DKFZ-BT66. Stimulation with rIL1B but not rIL6 reduced growth of DKFZ-BT66 cells and induced the SASP. Anti-inflammatory treatment with dexamethasone induced regrowth of senescent cells and inhibited the SASP. Senescent DKFZ-BT66 cells responded to senolytic BCL2 inhibitors. High and SASP expression in pilocytic astrocytoma tumors was associated with favorable progression-free survival. We provide evidence for the SASP regulating OIS in pediatric pilocytic astrocytoma, with IL1B as a relevant mediator. SASP expression could enable prediction of progression in patients with pilocytic astrocytoma. Further investigation of the SASP driving the unpredictable growth of pilocytic astrocytomas, and its possible therapeutic application, is warranted.
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 6
    Language: English
    In: Neuro-Oncology, 04/23/2019, Vol.21(Supplement_2), pp.ii83-ii83
    Description: Abstract Brain tumors presenting with histological and molecular features not matching any established category in the WHO classification are challenging for diagnosticians and clinicians. Albeit rare, these cases can belong to distinct, as of yet not recognized entities. Based on unsupervised...
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    Source: Oxford University Press (via CrossRef)
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  • 7
    Language: German
    Description: Hintergrund: Die posttraumatische Osteomyelitis ist eine der schwersten und häufigsten Komplikationen nach offenen Frakturverletzungen. Die klinische Therapie dieser Infektion besteht meist aus suffizientem Debridement und in der antibiotischen Nachbehandlung des Knochens. Bei der Pathogenese[zum vollständigen Text gelangen Sie über die oben angegebene URL]...
    Keywords: Osteomyelitis ; Tiermodell ; Knochenregeneration ; Medical Sciences; Medicine
    Source: DataCite
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