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  • 1
    Language: English
    In: Clinical Neuroradiology, 2007, Vol.17(3), pp.180-186
    Description: Byline: Leonie Jestaedt (1,3), Mirko Pham (1), Andreas J. Bartsch (1), Ekkehard Kunze (2), Klaus Roosen (2), Laszlo Solymosi (1), Martin Bendszus (1) Keywords: Cerebral vasospasm; Balloon angioplasty; Infarction; Aneurysm; Subarachnoid hemorrhage; Zerebraler Vasospasmus; Ballonangioplastie; Infarkt; Aneurysma; Subarachnoidale Blutung Abstract: Abstract Background and Purpose: Vasospasm of the cerebral vessels remains a major source for morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH). The purpose of this study was to evaluate the frequency of infarction after transluminal balloon angioplasty (TBA) in patients with severe SAH-related vasospasm. Patients and Methods: 20 consecutive patients with angiographically confirmed vasospasm (median Hunt & Hess grade II, median Fisher grade IV) were included in this study. Treatment consisted of TBA in severe vasospasm of the middle cerebral artery (MCA), whereas vasospasm of the anterior cerebral artery (ACA) was not considered for TBA and served as a control group. A total of 30 MCA segments revealing extensive vasospasm were treated with TBA. In 33 ACA segments severe vasospasm was present. For both vessel territories cerebral infarction on follow-up CT was assessed as a marker of adverse outcome. Results: In the MCA territory, infarction occurred after TBA in two of 30 vessels (7%). In the ACA territory 14 of 33 ACA territories with confirmed severe vasospasm developed infarction (42%). This was a significantly lower rate of infarction in the TBA group (p 〈 0.001, Fisher's exact test). Conclusion: In a population of patients with a high risk for vasospasm-related infarction after SAH the frequency of infarction in vessel territories after TBA amounts to 7% and is considerably lower than in vessels with vasospasm not undergoing TBA. Abstract (German): Zusammenfassung Hintergrund und Ziel: Zerebrale Vasospasmen sind eine der Hauptursachen fur Morbiditat und Mortalitat nach aneurysmatischen Subarachnoidalblutungen (SAB). Ziel dieser Studie war, die relative Haufigkeit von Infarkten nach perkutaner transluminaler Ballonangioplastie (PTA) bei Patienten mit schweren Vasospasmen zu ermitteln und mit einer Kontrollgruppe ohne PTA zu vergleichen. Patienten und Methodik: 20 konsekutive Patienten mit angiographisch gesicherten Vasospasmen (Median Hunt & Hess II, Median Fisher IV) wurden eingeschlossen. Schwere Spasmen der A. cerebri media (MCA) wurden zusatzlich zur konservativen Therapie mittels PTA behandelt, wahrend Spasmen der A. cerebri anterior (ACA) rein konservativ behandelt wurden. Insgesamt 30 MCA-Segmente mit Vasospasmen wurden dilatiert. In 33 ACA-Segmenten konnten schwere Vasospasmen nachgewiesen werden. Beide Gefassterritorien wurden im Verlauf im nativen CT auf Infarkte als Marker fur unerwunschtes Outcome untersucht. Ergebnisse: Nach PTA traten in zwei von 30 behandelten MCA-Territorien Infarkte auf (7%). Nach konservativer Behandlung traten in 14 von 33 ACA-Territorien Infarkte auf (42%). Somit kam es nach PTA zu signifikant weniger Infarkten als bei konservativer Behandlung (p 〈 0,001, Fisher-Exakttest). Schlussfolgerung: In einer Patientengruppe mit hohem Risiko fur spasmusassoziierte Infarkte nach SAB betragt die Haufigkeit zerebraler Infarkte in mit PTA behandelten Gefassterritorien 7%. Sie ist damit signifikant niedriger als in Gefassen mit Spasmen, die konservativ behandelt werden. Author Affiliation: (1) Department of Neuroradiology, University of Wuerzburg, Germany (2) Department of Neurosurgery, University of Wuerzburg, Germany (3) Department of Neuroradiology, University of Wuerzburg, Josef-Schneider-Strasse 11, 97080, Wurzburg, Germany Article History: Registration Date: 01/01/2007 Received Date: 28/05/2007 Accepted Date: 25/06/2007
    Keywords: Cerebral vasospasm ; Balloon angioplasty ; Infarction ; Aneurysm ; Subarachnoid hemorrhage
    ISSN: 0939-7116
    E-ISSN: 1615-6706
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  • 2
    In: Nature, 2011, Vol.478(7368), p.197
    Description: Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    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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  • 4
    Language: English
    In: Cancer Research, 04/15/2010, Vol.70(8 Supplement), pp.1308A-1308A
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 5
    In: Spine, 2009, Vol.34(2), pp.108-114
    Description: STUDY DESIGN.: A prospective randomized controlled clinical study. OBJECTIVE.: To investigate the feasibility of a calcium phosphate cement (CaP) in balloon kyphoplasty if compared to polymethylmethacrylate (PMMA). SUMMARY OF BACKGROUND DATA.: In kyphoplasty and vertebroplasty, PMMA currently represents the standard in augmentation materials. It is characterized, however, by a lack of osseointegration and limited biocompatibility. Consequently, CaP is currently being investigated as an alternative material for vertebral augmentation. METHODS.: Inclusion criteria were 1 or 2 adjacent osteoporotic fractures of vertebral bodies in the thoracolumbar spine, patient age ≥65 years, and fracture age ≤4 months. Exclusion criteria were tumor lesions and additional posterior instrumentation. RESULTS.: A total of 60 osteoporotic vertebral body fractures in 56 patients were included. CaP and PMMA were randomly applied in 30 vertebrae each with 2-fracture-patients receiving only 1 type of cement for both vertebrae. All 60 fractures were classified compression fractures (type A). Of these, 27 were classified burst fractures (type A3). 52/56 patients experienced statistically significant pain relief (7.9 ± 1.9 to 1.8 ± 2.1 on a Visual Analog Scale from 0 “best” to 10 “worst”). Bisegmental endplate angles were restored by 6.2° ± 5.9° on average. Complications that turned out to be cement-specific were: vascular embolism (n = 2) for PMMA; subtotal cement washout (n = 1); and radiographic loss of correction (n = 9) due to cement failure in burst fractures for CaP. There was no case of cement failure, when PMMA had been used. CONCLUSION.: The routine use of the CaP tested is not currently recommended for kyphoplasty. Because of its low resistance against flexural, tractive, and shear forces compared to PMMA, in certain constellations (burst fractures), there is a higher risk of cement failure and subsequent loss of correction.
    Keywords: Aged–Adverse Effects ; Aged, 80 and Over–Chemistry ; Bone Cements–Therapeutic Use ; Calcium Phosphates–Adverse Effects ; Embolism–Therapeutic Use ; Humans–Chemically Induced ; Osteoporosis–Physiopathology ; Polymethyl Methacrylate–Complications ; Postoperative Complications–Adverse Effects ; Prospective Studies–Therapeutic Use ; Radiography–Etiology ; Spinal Fractures–Physiopathology ; Spine–Pathology ; Stress, Mechanical–Physiopathology ; Treatment Outcome–Surgery ; Vertebroplasty–Diagnostic Imaging ; Vertebroplasty–Pathology ; Vertebroplasty–Surgery ; Vertebroplasty–Instrumentation ; Vertebroplasty–Methods ; Bone Cements ; Calcium Phosphates ; Polymethyl Methacrylate ; Calcium Phosphate;
    ISSN: 0362-2436
    E-ISSN: 15281159
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  • 6
    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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  • 7
    In: Brain, 2008, Vol. 131(9), pp.2341-2352
    Description: Magnetic resonance imaging plays a pivotal role in the diagnosis and treatment monitoring of multiple sclerosis. Currently available magnetic resonance-techniques only partly reflect the extent of tissue inflammation and damage. In the present study, application of the experimental magnetic resonance-contrast agent Gadofluorine M significantly increased the sensitivity of lesion detection in myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. Gadofluorine M-enhancement on T 1 -weighted (T 1 -w) images utilizing a clinical 1.5 T magnetic resonance unit showed numerous lesions in optic nerve, spinal cord and brain, the majority of which were not detectable on standard T 2 -weighted (T 2 -w) and Gd-DTPA enhanced T 1 -w sequences. Quantitative assessment by pixel counts revealed highly significant differences in sensitivity in favour of Gadofluorine M. Gadofluorine uptake closely corresponded to inflammation and demyelination on tissue sections. These unique features of Gadofluorine M in visualizing inflammatory CNS lesions hold promise for future clinical development in multiple sclerosis.
    Keywords: Multiple Sclerosis ; Cns Inflammation ; Experimental Autoimmune Encephalomyelitis ; Magnetic Resonance Imaging ; Gadofluorine
    ISSN: 0006-8950
    E-ISSN: 1460-2156
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  • 8
    Language: English
    In: Cell Stem Cell, 07 August 2014, Vol.15(2), pp.185-198
    Description: Cancer stem cells (CSCs) have been suggested as potential therapeutic targets for treating malignant tumors, but the in vivo supporting evidence is still missing. Using a GFP reporter driven by the promoter of the nuclear receptor tailless (Tlx), we demonstrate that Tlx cells in primary brain tumors are mostly quiescent. Lineage tracing demonstrates that single Tlx cells can self-renew and generate Tlx tumor cells in primary tumors, suggesting that they are brain tumor stem cells (BTSCs). After introducing a BTSC-specific knock-out of the Tlx gene in primary mouse tumors, we observed a loss of self-renewal of BTSCs and prolongation of animal survival, accompanied by induction of essential signaling pathways mediating cell-cycle arrest, cell death, and neural differentiation. Our study demonstrates the feasibility of targeting glioblastomas and indicates the suitability of BTSCs as therapeutic targets, thereby supporting the CSC hypothesis. Zhu et al. demonstrate that cells expressing the neural stem cell marker Tlx in glioblastoma are largely quiescent, but can self-renew to generate Tlx tumors. Inducibly targeting TLx in Nestin-expressing brain tumor cells results in cell death, cell-cycle arrest, and neural differentiation.
    Keywords: Biology
    ISSN: 1934-5909
    E-ISSN: 1875-9777
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  • 9
    Language: English
    In: Oncotarget, 13 October 2015, Vol.6(31), pp.31050-68
    Description: Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer' of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.
    Keywords: Angiogenesis ; Glioblastoma ; Invasion ; Phosphatase and Tensin Homolog Deleted on Chromosome 10 (Pten) ; Vascular Endothelial Growth Factor Receptor (Vegfr)-2 ; Drug Resistance, Neoplasm ; Neovascularization, Pathologic ; Angiogenesis Inhibitors -- Pharmacology ; Brain Neoplasms -- Drug Therapy ; Glioma -- Drug Therapy ; Pten Phosphohydrolase -- Deficiency ; Vascular Endothelial Growth Factor Receptor-2 -- Metabolism
    E-ISSN: 1949-2553
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  • 10
    Language: English
    Description: Human glioblastomas may be hierarchically organized. Within this hierarchy, glioblastoma-initiating cells (GIC) 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 (GFAP). The protein expression of Nestin and SOX2 as well as the mRNA levels of Musashi1, L1CAM, CD133, Nestin and PLAGL2 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, PLAGL2 and CD133 mRNA levels inversely correlated with radioresistance. Higher expression of stem cell markers does not correlate with resistance to radiochemotherapy in a TCGA (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. This article is protected by copyright. All rights reserved.
    Keywords: Clinic for Neurology ; 610 Medicine & health
    Source: University of Zurich
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