Publications by authors named "Carl Philipp Simon-Gabriel"

4 Publications

  • Page 1 of 1

Microenvironmental stromal cells abrogate NF-κB inhibitor-induced apoptosis in chronic lymphocytic leukemia.

Haematologica 2018 01 9;103(1):136-147. Epub 2017 Nov 9.

Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Germany

Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) is known to play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). Several NF-κB inhibitors were shown to successfully induce apoptosis of CLL cells Since the microenvironment is known to be crucial for the survival of CLL cells, herein, we tested whether NF-κB inhibition may still induce apoptosis in these leukemic cells in the presence of protective stromal interaction. We used the specific NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ). Microenvironmental support was mimicked by co-culturing CLL cells with bone marrow-derived stromal cell lines (HS-5 and M2-10B4). NF-κB inhibition by DHMEQ in CLL cells could be confirmed in both the monoculture and co-culture setting. In line with previous reports, NF-κB inhibition induced apoptosis in the monoculture setting by activating the intrinsic apoptotic pathway resulting in poly (ADP-ribose) polymerase (PARP)-cleavage; however, it was unable to induce apoptosis in leukemic cells co-cultured with stromal cells. Similarly, small interfering ribonucleic acid (siRNA)-mediated downregulation induced apoptosis of CLL cells cultured alone, but not in the presence of supportive stromal cells. B-cell activating factor (BAFF) was identified as a microenvironmental messenger potentially protecting the leukemic cells from NF-κB inhibition-induced apoptosis. Finally, we show improved sensitivity of stroma-supported CLL cells to NF-κB inhibition when combining the NF-κB inhibitor with the SYK inhibitor R406 or the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, agents known to inhibit the stroma-leukemia crosstalk. We conclude that NF-κB inhibitors are not promising as monotherapies in CLL, but may represent attractive therapeutic partners for ibrutinib and R406.
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http://dx.doi.org/10.3324/haematol.2017.165381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777201PMC
January 2018

Novel mutation in two brothers with Hermansky Pudlak syndrome type 3.

Blood Cells Mol Dis 2017 09 6;67:75-80. Epub 2017 Mar 6.

Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder causing oculocutaneous albinism, bleeding disorder and ceroid lipofuscinosis. Platelets from HPS patients are characterized by impaired secretion of dense (δ)-bodies (CD63). Meanwhile, there are ten known human HPS genes, each leading to a particular clinical HPS subtype (HPS1-HPS10). We report on two Turkish brothers showing typical HPS phenotype comprising oculocutaneous albinism and bleeding symptoms. Pathological bleeding time as well as platelet aggregometry analyses revealed impaired platelet function. The brothers demonstrated absence of platelet δ-granule secretion as measured by flow cytometry. Using molecular genetic analyses, a novel homozygous 1bp-deletion in the HPS3 gene was identified in both brothers. In addition, the younger brother with HPS3 demonstrated psychomotoric retardation and cranial gliosis (magnetic resonance imaging, MRI). Array-CGH analysis revealed a de novo 0.482Mb deletion on chromosome 17 which is not present in his brother and parents. In this study, we identified a novel 1bp-deletion in the HPS3 gene causing HPS3 phenotype in two brothers. In patients with oculocutaneous albinism and increased bleeding symptoms platelet function should be analyzed. The identification of the molecular genetic defect allows the classification to a particular HPS subtype and is important for therapy and prognosis.
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http://dx.doi.org/10.1016/j.bcmd.2017.03.001DOI Listing
September 2017

Integrative Diffusion-Weighted Imaging and Radiogenomic Network Analysis of Glioblastoma multiforme.

Sci Rep 2017 03 7;7:43523. Epub 2017 Mar 7.

Department of Neuroradiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.

In the past, changes of the Apparent Diffusion Coefficient in glioblastoma multiforme have been shown to be related to specific genes and described as being associated with survival. The purpose of this study was to investigate diffusion imaging parameters in combination with genome-wide expression data in order to obtain a comprehensive characterisation of the transcriptomic changes indicated by diffusion imaging parameters. Diffusion-weighted imaging, molecular and clinical data were collected prospectively in 21 patients. Before surgery, MRI diffusion metrics such as axial (AD), radial (RD), mean diffusivity (MD) and fractional anisotropy (FA) were assessed from the contrast enhancing tumour regions. Intraoperatively, tissue was sampled from the same areas using neuronavigation. Transcriptional data of the tissue samples was analysed by Weighted Gene Co-Expression Network Analysis (WGCNA) thus classifying genes into modules based on their network-based affiliations. Subsequent Gene Set Enrichment Analysis (GSEA) identified biological functions or pathways of the expression modules. Network analysis showed a strong association between FA and epithelial-to-mesenchymal-transition (EMT) pathway activation. Also, patients with high FA had a worse clinical outcome. MD correlated with neural function related genes and patients with high MD values had longer overall survival. In conclusion, FA and MD are associated with distinct molecular patterns and opposed clinical outcomes.
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http://dx.doi.org/10.1038/srep43523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339871PMC
March 2017

Mesoscopic imaging of glioblastomas: Are diffusion, perfusion and spectroscopic measures influenced by the radiogenetic phenotype?

Neuroradiol J 2017 Feb 19;30(1):36-47. Epub 2016 Nov 19.

1 Department of Neuroradiology, Medical Centre-University of Freiburg, Germany.

The purpose of this study was to identify markers from perfusion, diffusion, and chemical shift imaging in glioblastomas (GBMs) and to correlate them with genetically determined and previously published patterns of structural magnetic resonance (MR) imaging. Twenty-six patients (mean age 60 years, 13 female) with GBM were investigated. Imaging consisted of native and contrast-enhanced 3D data, perfusion, diffusion, and spectroscopic imaging. In the presence of minor necrosis, cerebral blood volume (CBV) was higher (median ± SD, 2.23% ± 0.93) than in pronounced necrosis (1.02% ± 0.71), p = 0.0003. CBV adjacent to peritumoral fluid-attenuated inversion recovery (FLAIR) hyperintensity was lower in edema (1.72% ± 0.31) than in infiltration (1.91% ± 0.35), p = 0.039. Axial diffusivity adjacent to peritumoral FLAIR hyperintensity was lower in severe mass effect (1.08*10 mm/s ± 0.08) than in mild mass effect (1.14*10 mm/s ± 0.06), p = 0.048. Myo-inositol was positively correlated with a marker for mitosis (Ki-67) in contrast-enhancing tumor, r = 0.5, p = 0.0002. Changed CBV and axial diffusivity, even outside FLAIR hyperintensity, in adjacent normal-appearing matter can be discussed as to be related to angiogenesis pathways and to activated proliferation genes. The correlation between myo-inositol and Ki-67 might be attributed to its binding to cell surface receptors regulating tumorous proliferation of astrocytic cells.
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http://dx.doi.org/10.1177/1971400916678225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564334PMC
February 2017