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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 07 January 2014, Vol.111(1), pp.409-14
    Description: A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.
    Keywords: Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic ; Antineoplastic Agents, Alkylating -- Pharmacology ; Brain Neoplasms -- Drug Therapy ; Cell Cycle Proteins -- Metabolism ; Glioblastoma -- Drug Therapy ; Glioma -- Drug Therapy ; Intracellular Signaling Peptides and Proteins -- Metabolism ; O(6)-Methylguanine-DNA Methyltransferase -- Pharmacology ; Tor Serine-Threonine Kinases -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Molecular Imaging and Biology, 2016, Vol.18(2), pp.243-248
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s11307-015-0890-0 Byline: Paul Flechsig (1,6), Clemens Kratochwil (2), Arne Warth (3,6), Daniel Rath (2), Viktoria Eichwald (4), Peter E. Huber (5), Hans-Ulrich Kauczor (1,6), Uwe Haberkorn (2,7), Frederik L. Giesel (2,7) Keywords: Lung cancer; Orthotopic lung cancer model; [[.sup.18]F]FDG/PET-CT; Computed tomography Abstract: Purpose The demand to optimize multidisciplinary treatment strategies in patients with benign and malignant diseases of the lung and other organs has led to the increased need of mechanistic proof-of-concept studies in preclinical small animal models using new non-invasive imaging methods. Therefore, we evaluated the role of microPET and microCT for mediastinal lymph node staging in an orthotopic lung cancer model in rats. Procedures Human lung cancer cells (NCI-H460) were injected transthoracically in nude rats (NIH-RNU). After 2 weeks of tumour growth, animals underwent multiphase contrast-enhanced microCT using ExiTron nano 12000 as a contrast agent and dynamic microPET using the tracer 2-deoxy-2[-[.sup.18]F]fluoro-d-glucose [([.sup.18]F]FDG). Thereafter, animals were sacrificed for histological analysis. Results Late phase micro X-ray computed tomography (microCT) revealed the best delineation of lymph node metastases, as compared to earlier scans. In terms of an increased [[.sup.18]F]FDG uptake over time, dynamic micro positron emission tomography (microPET) delineated lymph node metastases and enabled metabolic examinations of the induced lung cancer metastases. Conclusion The combination of contrast-enhanced microCT and dynamic microPET is feasible in rats for the visualization of mediastinal lymph node metastases. Author Affiliation: (1) Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany (2) Department of Nuclear Medicine, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany (3) Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany (4) Core Facility Small Animal Imaging, German Cancer Research Center, Heidelberg, Germany (5) Molecular Radiation Oncology, German Cancer Research Center and University Hospital Center Heidelberg, Heidelberg, Germany (6) Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research DZL, Heidelberg, Germany (7) Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany Article History: Registration Date: 21/08/2015 Online Date: 02/09/2015
    Keywords: Lung cancer ; Orthotopic lung cancer model ; [F]FDG/PET-CT ; Computed tomography
    ISSN: 1536-1632
    E-ISSN: 1860-2002
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  • 3
    Language: English
    In: Diagnostic and interventional radiology (Ankara, Turkey), 2016, Vol.22(1), pp.35-9
    Description: Staging of lung cancer is typically performed with fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET/CT); however, false positive PET scans can occur due to inflammatory disease. The CT scan is used for anatomic registration and attenuation correction. Herein, we evaluated x-ray attenuation (XRA) within nodes on CT and correlated this with the presence of malignancy in an orthotopic lung cancer model in rats. 1×10⁶ NCI-H460 cells were injected transthoracically in six National Institutes of Health nude rats and six animals served as controls. After two weeks, animals were sacrificed; lymph nodes were extracted and scanned with a micro-CT to determine their XRA prior to histologic analysis. Median CT density in malignant lymph nodes (n=20) was significantly higher than benign lymph nodes (n=12; P = 0.018). Short-axis diameter of metastatic lymph nodes was significantly different than benign nodes (3.4 mm vs. 2.4 mm; P = 0.025). Area under the curve for malignancy was higher for density-based lymph node analysis compared with size measurements (0.87 vs. 0.7). XRA of metastatic mediastinal lymph nodes is significantly higher than benign nodes in this lung cancer model. This suggests that information on nodal density may be useful when used in combination with the results of FDG-PET in determining the likelihood of malignant adenopathy.
    Keywords: Lung Neoplasms -- Diagnostic Imaging ; Lymph Nodes -- Diagnostic Imaging ; Tomography, X-Ray Computed -- Methods
    ISSN: 13053825
    E-ISSN: 1305-3612
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  • 4
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, 2017, Vol.37(3), pp.495-505
    Description: OBJECTIVE—: Vascular smooth muscle cells (VSMC) play a key role in the pathogenesis of atherosclerosis, the globally leading cause of death. The transmembrane orphan receptor endosialin (CD248) has been characterized as an activation marker of cells of the mesenchymal lineage including tumor-associated pericytes, stromal myofibroblasts, and activated VSMC. We, therefore, hypothesized that VSMC-expressed endosialin may display functional involvement in the pathogenesis of atherosclerosis. APPROACH AND RESULTS—: Expression of endosialin was upregulated during atherosclerosis in apolipoprotein E (ApoE)–null mice and human atherosclerotic samples analyzed by quantitative real-time polymerase chain reaction and immunohistochemistry. Atherosclerosis, assessed by Oil Red O staining of the descending aorta, was significantly reduced in ApoE/endosialin-deficient mice on Western-type diet. Marker analysis of VSMC in lesions induced by shear stress–modifying cast implantation around the right carotid artery identified a more pronounced contractile VSMC phenotype in the absence of endosialin. Moreover, in addition to contributing to neointima formation, endosialin also potentially regulated the proinflammatory phenotype of VSMC as evidenced in surrogate cornea pocket assay experiments in vivo and corresponding flow cytometry and ELISA analyses in vitro. CONCLUSIONS—: The experiments identify endosialin as a potential regulator of phenotypic remodeling of VSMC contributing to atherosclerosis. The association of endosialin with atherosclerosis and its absent expression in nonatherosclerotic samples warrant further consideration of endosialin as a therapeutic target and biomarker.
    Keywords: Medicine;
    ISSN: 1079-5642
    E-ISSN: 15244636
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  • 5
    Language: English
    In: Journal of translational medicine, 30 April 2015, Vol.13, pp.136
    Description: Osteosarcoma (OS) is the most common pediatric primary malignant bone tumor. As the prognosis for patients following standard treatment did not improve for almost three decades, functional preclinical models that closely reflect important clinical cancer characteristics are urgently needed to develop and evaluate new treatment strategies. The objective of this study was to establish an orthotopic xenotransplanted mouse model using patient-derived tumor tissue. Fresh tumor tissue from an adolescent female patient with osteosarcoma after relapse was surgically xenografted into the right tibia of 6 immunodeficient BALB/c Nu/Nu mice as well as cultured into medium. Tumor growth was serially assessed by palpation and with magnetic resonance imaging (MRI). In parallel, a primary cell line of the same tumor was established. Histology and high-resolution array-based comparative genomic hybridization (aCGH) were used to investigate both phenotypic and genotypic characteristics of different passages of human xenografts and the cell line compared to the tissue of origin. A primary OS cell line and a primary patient-derived orthotopic xenotranplanted mouse model were established. MRI analyses and histopathology demonstrated an identical architecture in the primary tumor and in the xenografts. Array-CGH analyses of the cell line and all xenografts showed highly comparable patterns of genomic progression. So far, three further primary patient-derived orthotopic xenotranplanted mouse models could be established. We report the first orthotopic OS mouse model generated by transplantation of tumor fragments directly harvested from the patient. This model represents the morphologic and genomic identity of the primary tumor and provides a preclinical platform to evaluate new treatment strategies in OS.
    Keywords: Cell Culture Techniques ; Cell Line, Tumor ; Disease Models, Animal ; Bone Neoplasms -- Pathology ; Osteosarcoma -- Pathology
    E-ISSN: 1479-5876
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  • 6
    Language: English
    In: Acta neuropathologica, April 2017, Vol.133(4), pp.629-644
    Description: Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular D-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations. BAY 1436032 strongly reduces 2-HG levels in cells carrying IDH1-R132H, -R132C, -R132G, -R132S and -R132L mutations. Cells not carrying IDH mutations were unaffected. BAY 1436032 did not exhibit toxicity in vitro or in vivo. The pharmacokinetic properties of BAY 1436032 allow for oral administration. In two independent experiments, BAY 1436032 has been shown to significantly prolong survival of mice intracerebrally transplanted with human astrocytoma carrying the IDH1R132H mutation. In conclusion, we developed a pan-inhibitor targeting tumors with different IDH1R132 mutations.
    Keywords: Drug Development ; Idh-Mutated Glioma ; Idh1r132 Inhibitor ; Mouse Xenograft ; Pharmacology ; Therapy ; Aniline Compounds -- Pharmacology ; Antineoplastic Agents -- Pharmacology ; Astrocytoma -- Drug Therapy ; Benzimidazoles -- Pharmacology ; Brain Neoplasms -- Drug Therapy ; Isocitrate Dehydrogenase -- Antagonists & Inhibitors
    ISSN: 00016322
    E-ISSN: 1432-0533
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  • 7
    Language: English
    In: CardioVascular and Interventional Radiology, 2019, Vol.42(6), pp.905-914
    Description: Byline: Dominik F. Vollherbst (1,2), Thuy D. Do (2), Manfred Jugold (3), Viktoria Eichwald (3), Stephan Macher-Goppinger (4), Philippe L. Pereira (6), Martin Bendszus (1), Markus A. Mohlenbruch (1), Gotz M. Richter (5), Hans U. Kauczor (2), Christof M. Sommer (2,5) Keywords: Embolization; Liquid embolic; Ethibloc; Onyx; Histoacryl Abstract: Purpose To investigate the novel zein-based non-adhesive precipitating liquid embolic HEI.sub.E1_2017. Materials and Methods Zein-based liquid embolics are an own class of embolization material. In this study, HEI.sub.E1_2017, a novel zein-based liquid embolic, was investigated. Visibility was assessed in vitro in CT and MRI phantoms, embolization characteristics were assessed in vivo in the kidneys of 12 pigs. Components of HEI.sub.E1_2017 were zein as occlusion material, ethanol as solvent, and iodized oil as radiopaque material. HEI.sub.E1_2017 was used in pure (HEI-PURE) and manually modified (HEI-MOD) form and compared with 6% ethylene vinyl alcohol copolymer (EVOH). Different radiological methods (CT, MRI, DSA, cone-beam CT, and micro-CT) and histopathologic analyses were applied to compare visibility and vascular occlusion patterns. Results In CT phantoms, all embolics were definitely visible as hyperdense materials. In MRI phantoms, signal-to-noise ratio was highest for HEI-PURE, followed by HEI-MOD and EVOH. In all kidneys, embolization procedures were technically successful and without complications. In DSA, all embolics were definitely visible during and after embolization. Only EVOH caused substantial artifacts in cone-beam CT and CT. In micro-CT and histopathology, HEI-PURE showed a homogeneous occlusion from segmental arteries to glomerular capillaries. HEI-MOD demonstrated the deepest vascular penetration (up to the level of peritubular capillaries), but with an inhomogeneous distribution. For EVOH, there was inhomogeneous vascular occlusion from segmental arteries to glomerular capillaries. Conclusion HEI.sub.E1_2017 is a promising novel zein-based liquid embolic. Further preclinical and clinical studies with higher case numbers and long-term follow-up are needed to further assess the value of this embolic material. Author Affiliation: (1) 0000 0001 0328 4908, grid.5253.1, Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany (2) 0000 0001 0328 4908, grid.5253.1, Clinic of Diagnostic and Interventional Radiology, Heidelberg University Hospital, INF 110, 69120, Heidelberg, Germany (3) 0000 0004 0492 0584, grid.7497.d, German Cancer Research Center, Heidelberg, Germany (4) grid.410607.4, Institute of Pathology, Mainz University Hospital, Mainz, Germany (5) 0000 0001 0341 9964, grid.419842.2, Clinic of Diagnostic and Interventional Radiology, Klinikum Stuttgart, Stuttgart, Germany (6) 0000 0001 0142 7696, grid.492899.7, Clinic for Radiology, Minimally-invasive Therapies and Nuclear Medicine, SLK Kliniken Heilbronn GmbH, Heilbronn, Germany Article History: Registration Date: 02/02/2019 Received Date: 01/11/2018 Accepted Date: 02/02/2019 Online Date: 13/02/2019 Article note: Electronic supplementary material The online version of this article ( https://doi.org/10.1007/s00270-019-02179-9) contains supplementary material, which is available to authorized users.
    Keywords: Embolization ; Liquid embolic ; Ethibloc ; Onyx ; Histoacryl
    ISSN: 0174-1551
    E-ISSN: 1432-086X
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