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Berlin Brandenburg

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  • 1
    In: Journal of Neurochemistry, October 2014, Vol.131(2), pp.251-264
    Description: Human glioblastomas may be hierarchically organized. Within this hierarchy, glioblastoma‐initiating cells have been proposed to be more resistant to radiochemotherapy and responsible for recurrence. Here, established stem cell markers and stem cell attributed characteristics such as self‐renewal capacity and tumorigenicity have been profiled in primary glioblastoma cultures to predict radiosensitivity. Furthermore, the sensitivity to radiotherapy of different subpopulations within a single primary glioblastoma culture was analyzed by a flow cytometric approach using Nestin, SRY (sex‐determining region Y)‐box 2 (SOX2) and glial fibrillary acidic protein. The protein expression of Nestin and SOX2 as well as the mRNA levels of Musashi1, L1 cell adhesion molecule, CD133, Nestin, and pleiomorphic adenoma gene‐like 2 inversely correlated with radioresistance in regard to the clonogenic potential. Only CD44 protein expression correlated positively with radioresistance. In terms of proliferation, Nestin protein expression and Musashi1, pleiomorphic adenoma gene‐like 2, and CD133 mRNA levels are inversely correlated with radioresistance. Higher expression of stem cell markers does not correlate with resistance to radiochemotherapy in the cancer genome atlas glioblastoma collective. SOX2 expressing subpopulations exist within single primary glioblastoma cultures. These subpopulations predominantly form the proliferative pool of the primary cultures and are sensitive to irradiation. Thus, profiling of established stem cell markers revealed a surprising result. Except CD44, the tested stem cell markers showed an inverse correlation between expression and radioresistance. Markers used to define glioma‐initiating cells (GIC) are generally not defining a more resistant, but rather a more sensitive group of glioma cells. An exemption is CD44 expression. Also proliferation of the GIC culture itself was not systematically associated with radiosensitivity or – resistance, but a SOX‐2 positive, proliferative subgroup within a GIC culture is showing the highest radiosensitivity. Markers used to define glioma‐initiating cells (GIC) are generally not defining a more resistant, but rather a more sensitive group of glioma cells. An exemption is CD44 expression. Also proliferation of the GIC culture itself was not systematically associated with radiosensitivity or – resistance, but a SOX‐2 positive, proliferative subgroup within a GIC culture is showing the highest radiosensitivity.
    Keywords: Cd133 ; Glioma‐Initiating Cells ; Profiling ; Radiotherapy Sensitivity ; Sox2 ; Stem Cell Markers
    ISSN: 0022-3042
    E-ISSN: 1471-4159
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  • 2
    Language: English
    In: Kidney International, 02 December 2012, Vol.82(12), pp.1297-1303
    Description: Since beta-2 microglobulin (B2M) is a surrogate marker for middle molecular weight uremic toxins and the major protein component in dialysis-related amyloidosis, it has been frequently studied in dialysis patients. It is not known, however, whether B2M has an impact in patients with chronic kidney disease (CKD) not yet on dialysis. Here we studied the relationship of plasma B2M levels to clinical and cardiovascular outcomes in 142 patients (mean age of 67 years) at different stages of CKD. B2M levels increased with CKD stage and thus were highest in hemodialysis patients. Baseline B2M levels were associated with vascular calcification but not with arterial stiffness or bone density. During a mean follow-up of 969 days, 44 patients died and 49 suffered a cardiovascular event. Higher B2M levels were independently associated with overall and cardiovascular mortality and cardiovascular events in the whole cohort and with cardiovascular events in the predialysis cohort. Moreover, B2M appeared to be a better predictor than well-established factors associated with outcomes in this population, such as estimated glomerular filtration rate ((eGFR), only for predialysis patients), inflammation biomarkers, and other factors included in a propensity score. Thus, we confirm the strong relationship between B2M levels and eGFR and confirm the power of B2M to predict overall and cardiovascular mortality and cardiovascular events in patients at different stages of CKD.
    Keywords: Beta-2 Microglobulin ; Cardiovascular Disease ; Chronic Kidney Disease ; Mortality ; Uremic Toxins ; Medicine
    ISSN: 0085-2538
    E-ISSN: 1523-1755
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  • 3
    In: PLoS ONE, 2014, Vol.9(2)
    Description: Glioblastoma (GB) is associated with poor patient survival owing to uncontrolled tumor proliferation and resistance to apoptosis. Human ether-a-go-go-related gene K + channels (hERG; Kv11.1, KCNH 2) are expressed in multiple cancer cells including GB and control cell proliferation and death. We hypothesized that pharmacological targeting of hERG protein would inhibit tumor growth by inducing apoptosis of GB cells. The small molecule hERG ligand doxazosin induced concentration-dependent apoptosis of human LNT-229 (EC 50  = 35 µM) and U87MG (EC 50  = 29 µM) GB cells, accompanied by cell cycle arrest in the G0/G1 phase. Apoptosis was associated with 64% reduction of hERG protein. HERG suppression via siRNA-mediated knock down mimicked pro-apoptotic effects of doxazosin. Antagonism of doxazosin binding by the non-apoptotic hERG ligand terazosin resulted in rescue of protein expression and in increased survival of GB cells. At the molecular level doxazosin-dependent apoptosis was characterized by activation of pro-apoptotic factors (phospho-erythropoietin-producing human hepatocellular carcinoma receptor tyrosine kinase A2, phospho-p38 mitogen-activated protein kinase, growth arrest and DNA damage inducible gene 153, cleaved caspases 9, 7, and 3), and by inactivation of anti-apoptotic poly-ADP-ribose-polymerase, respectively. In summary, this work identifies doxazosin as small molecule compound that promotes apoptosis and exerts anti-proliferative effects in human GB cells. Suppression of hERG protein is a crucial molecular event in GB cell apoptosis. Doxazosin and future derivatives are proposed as novel options for more effective GB treatment.
    Keywords: Research Article ; Biology ; Medicine
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: PloS one, 2013, Vol.8(3), pp.e57227
    Description: Metabolic stimuli, pressure, and fluid shear stress (FSS) are major mediators of vascular plasticity. The exposure of the vessel wall to increased laminar FSS is the main trigger of arteriogenesis, the remodelling of pre-existent arterio-arteriolar anastomoses to functional conductance arteries. In this study, we have used an in vitro bioreactor to investigate cell-specific interactions, molecular mechanisms as well as time-dependent effects under laminar FSS conditions. This bioreactor termed "artificial artery" can be used for screening potential arterio-protective substances, pro-arteriogenic factors, and for investigating biomarkers of cardiovascular diseases such as cardiac diseases. The bioreactor is built up out of 14 hollow fiber membranes colonized with endothelial cells (HUVECs) on the inside and smooth muscle cells (HUASMCs) on the outside. By means of Hoechst 33342 staining as well as immunocytochemistry of ß-catenin and α-smooth-muscle-actin, a microporous polypropylene membrane was characterized as being the appropriate polymer for co-colonization. Defined arterial flow conditions (0.1 N/m2 and 3 N/m2), metabolic exchange, and cross-talk of HUVECs and HUASMCs through hollow fibers mimic physiological in vivo conditions of the vasculature. Analysing mono- and co-culture secretomes by MALDI-TOF-TOF mass spectrometry, we could show that HUVECs secreted Up4A upon 3 N/m2. A constant cellular secretion of randomly chosen peptides verified viability of the "artificial artery" for a cultivation period up to five days. qRT-PCR analyses revealed an up-regulation of KLF2 and TIMP1 as mechano-regulated genes and demonstrated arterio-protective, homeostatic FSS conditions by a down-regulation of EDN1. Expression analyses of VWF and EDN1 furthermore confirmed that RNA of both cell types could separately be isolated without cross-contamination. CCND1 mRNA expression in HUVECs did not change upon FSS indicating a quiescent endothelial phenotype. Taken together, the "artificial artery" provides a solid in vitro model to test pharmacological active compounds for their impact on arterio-damaging or arterio-protective properties on vascular response.
    Keywords: Models, Biological ; Tissue Engineering ; Arteries -- Physiology ; Blood Circulation -- Physiology
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Current Neurology and Neuroscience Reports, 2014, Vol.14(4), pp.1-10
    Description: Gliomas have been viewed for decades as inaccessible for a meaningful antitumor immune response as they grow in a sanctuary site protected from infiltrating immune cells. Moreover, the glioma microenvironment constitutes a hostile environment for an efficient antitumor immune response as glioma-derived factors such as transforming growth factor β and catabolites of the essential amino acid tryptophan paralyze T-cell function. There is growing evidence from preclinical and clinical studies that a meaningful antitumor immunity exists in glioma patients and that it can be activated by vaccination strategies. As a consequence, the concept of glioma immunotherapy appears to be experiencing a renaissance with the first phase 3 randomized immunotherapy trials entering the clinical arena. On the basis of encouraging results from other tumor entities using immunostimulatory approaches by blocking endogenous T-cell suppressive pathways mediated by cytotoxic T-lymphocyte antigen 4 or programmed cell death protein 1/programmed cell death protein 1 ligand 1 with humanized antibodies, there is now a realistic and promising option to combine active immunotherapy with agents blocking the immunosuppressive microenvironment in patients with gliomas to allow a peripheral antitumor immune response induced by vaccination to become effective. Here we review the current clinical and preclinical evidence of antimicroenvironment immunotherapeutic strategies in gliomas.
    Keywords: Tryptophan ; Kynurenine ; Tryptophan 2,3-dioxygenase ; Indoleamine 2,3-dioxygenase ; Aryl hydrocarbon receptor ; Cytotoxic T-lymphocyte antigen 4 ; Programmed cell death protein 1
    ISSN: 1528-4042
    E-ISSN: 1534-6293
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  • 6
    Language: English
    In: Nature, 03 December 2015, Vol.528(7580), pp.93-8
    Description: Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
    Keywords: Astrocytoma -- Pathology ; Brain Neoplasms -- Pathology ; Gap Junctions -- Metabolism
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 7
    In: PLoS ONE, 2013, Vol.8(3)
    Description: Metabolic stimuli, pressure, and fluid shear stress (FSS) are major mediators of vascular plasticity. The exposure of the vessel wall to increased laminar FSS is the main trigger of arteriogenesis, the remodelling of pre-existent arterio-arteriolar anastomoses to functional conductance arteries. In this study, we have used an in vitro bioreactor to investigate cell-specific interactions, molecular mechanisms as well as time-dependent effects under laminar FSS conditions. This bioreactor termed “artificial artery” can be used for screening potential arterio-protective substances, pro-arteriogenic factors, and for investigating biomarkers of cardiovascular diseases such as cardiac diseases. The bioreactor is built up out of 14 hollow fiber membranes colonized with endothelial cells (HUVECs) on the inside and smooth muscle cells (HUASMCs) on the outside. By means of Hoechst 33342 staining as well as immunocytochemistry of ß-catenin and α-smooth-muscle-actin, a microporous polypropylene membrane was characterized as being the appropriate polymer for co-colonization. Defined arterial flow conditions (0.1 N/m2 and 3 N/m2), metabolic exchange, and cross-talk of HUVECs and HUASMCs through hollow fibers mimic physiological in vivo conditions of the vasculature. Analysing mono- and co-culture secretomes by MALDI-TOF-TOF mass spectrometry, we could show that HUVECs secreted Up4A upon 3 N/m2. A constant cellular secretion of randomly chosen peptides verified viability of the “artificial artery” for a cultivation period up to five days. qRT-PCR analyses revealed an up-regulation of KLF2 and TIMP1 as mechano-regulated genes and demonstrated arterio-protective, homeostatic FSS conditions by a down-regulation of EDN1. Expression analyses of VWF and EDN1 furthermore confirmed that RNA of both cell types could separately be isolated without cross-contamination. CCND1 mRNA expression in HUVECs did not change upon FSS indicating a quiescent endothelial phenotype. Taken together, the “artificial artery” provides a solid in vitro model to test pharmacological active compounds for their impact on arterio-damaging or arterio-protective properties on vascular response.
    Keywords: Research Article ; Biology ; Medicine
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 01 January 2012, Vol.18(1), pp.105-17
    Description: Recent work points out a role of B7H3, a member of the B7-family of costimulatory proteins, in conveying immunosuppression and enforced invasiveness in a variety of tumor entities. Glioblastoma is armed with effective immunosuppressive properties resulting in an impaired recognition and ineffective attack of tumor cells by the immune system. In addition, extensive and diffuse invasion of tumor cells into the surrounding brain tissue limits the efficacy of local therapies. Here, 4IgB7H3 is assessed as diagnostic and therapeutic target for glioblastoma. To characterize B7H3 in glioblastoma, we conduct analyses not only in glioma cell lines and glioma-initiating cells but also in human glioma tissue specimens. B7H3 expression by tumor and endothelial cells correlates with the grade of malignancy in gliomas and with poor survival. Both soluble 4IgB7H3 in the supernatant of glioma cells and cell-bound 4IgB7H3 are functional and suppress natural killer cell-mediated tumor cell lysis. Gene silencing showed that membrane and soluble 4IgB7H3 convey a proinvasive phenotype in glioma cells and glioma-initiating cells in vitro. These proinvasive and immunosuppressive properties were confirmed in vivo by xenografted 4IgB7H3 gene silenced glioma-initiating cells, which invaded significantly less into the surrounding brain tissue in an orthotopic model and by subcutaneously injected LN-229 cells, which were more susceptible to natural killer cell-mediated cytotoxicity than unsilenced control cells. Because of its immunosuppressive and proinvasive function, 4IgB7H3 may serve as a therapeutic target in the treatment of glioblastoma.
    Keywords: B7 Antigens -- Metabolism ; Cell Movement -- Immunology ; Cytotoxicity, Immunologic -- Immunology ; Glioblastoma -- Immunology ; Killer Cells, Natural -- Immunology
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 9
    Language: English
    In: Journal of Magnetic Resonance Imaging, March 2012, Vol.35(3), pp.551-560
    Description: PURPOSE: To compare conventional magnetic resonance imaging (MRI) techniques (T2-w and Gadolinium-DTPA-enhanced T1-w images) and Gadofluorine-M (GfM), a novel contrast agent in MRI, in murine gliomas.MATERIALS AND METHODS: Growth monitoring of murine gliomas (induced in mice) was performed on a 2.3 Tesla Bruker Biospec MRI unit. First all animals were investigated with conventional MRI techniques. In group I GfM was applied at an early stage of disease, in group II at a later stage. After injection of GfM follow-up MRI was performed without further injection of contrast agent. On MR images tumor size and signal intensities were assessed. Animals were killed for histological evaluation.RESULTS: In both groups GfM delineated tumor extents larger and more precisely than conventional MRI techniques. The difference between GfM and conventional MRI techniques reached level of significance at both tumor stages. Follow-up MRI after singular injection of GfM showed persistence of GfM in tumor tissue. On tissue sections GfM-enhancing areas corresponded closely to vital tumor tissue. GfM showed a mainly intracellular accumulation.CONCLUSION: Application of GfM resulted in superior delineation of experimental glioma compared with conventional MRI techniques. Thus, GfM bears a high potential in clinical application.
    Keywords: Gadofluorine M ; Contrast Agent ; Mri ; Glioma
    ISSN: 1053-1807
    E-ISSN: 1522-2586
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  • 10
    Language: English
    In: Toxins, 24 January 2014, Vol.6(2), pp.416-29
    Description: Protein binding prevents uremic toxins from removal by conventional extracorporeal therapies leading to accumulation in maintenance dialysis patients. Weakening of the protein binding may enhance the dialytic elimination of these toxins. In ultrafiltration and equilibrium dialysis experiments, different measures to modify the plasma binding affinity and capacity were tested: (i), increasing the sodium chloride (NaCl) concentration to achieve a higher ionic strength; (ii), increasing the temperature; and (iii), dilution. The effects on the dissociation constant K(D) and the protein bound fraction of the prototypical uremic toxin indoxyl sulfate (IS) in plasma of healthy and uremic individuals were studied. Binding of IS corresponded to one site binding in normal plasma. K(D) increased linearly with the NaCl concentration between 0.15 (K(D) = 13.2 ± 3.7 µM) and 0.75 M (K(D) = 56.2 ± 2.0 µM). Plasma dilution further reduced the protein bound toxin fraction by lowering the protein binding capacity of the plasma. Higher temperatures also decreased the protein bound fraction of IS in human plasma. Increasing the NaCl concentration was effective to weaken the binding of IS also in uremic plasma: the protein bound fraction decreased from 89% ± 3% to 81% ± 3% at 0.15 and 0.75 M NaCl, respectively. Dilution and increasing the ionic strength and temperature enhance the free fraction of IS allowing better removal of the substance during dialysis. Applied during clinical dialysis, this may have beneficial effects on the long-term outcome of maintenance dialysis patients.
    Keywords: Blood Proteins -- Metabolism ; Indican -- Metabolism ; Toxins, Biological -- Metabolism
    E-ISSN: 2072-6651
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