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    German Medical Science GMS Publishing House; Düsseldorf
    In:  46. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 32. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), Wissenschaftliche Herbsttagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR); 20180919-20180922; Mannheim; DOCER.18 /20190205/
    Publication Date: 2019-02-06
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 3
    Keywords: ACID, BINDING, BIOLOGICAL EVALUATION, CELLS, DIAGNOSIS, FOCI, hormone, imaging, INJECTION, IN-VITRO,
    Abstract: Although F-18-FDG PET is widely used for metastatic melanoma diagnosis, it is less accurate than desirable, particularly for small foci. Since both melanotic and amelanotic melanomas overexpress receptors for a-melanocyte-stimulating hormone (alpha-MSH; receptor name, melanocortin type 1 receptor [MC1 R]), radiolabeled alpha-MSH analogs are potential candidates for melanoma diagnosis. The aim of this study was to develop a positron emitter-labeled a-MSH analog suitable for PET imaging of melanoma metastases. Methods: A short linear alpha-MSH analog, [NIe(4),Asp(5),D-Phe(7)]-alpha-MSH4-11 (NAPamide), was newly designed and conjugated to the metal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to enable radiometal incorporation. Compared with our previously reported DOTA-alpha-MSH analog, DOTA-MSHoct ([DOTA-betaAla(3),NIe(4),Asp(5),DPhe(7),Lys(10)]-alpha-MSH3-10), the major modification lies in the conjugation of DOTA to the C-terminal end of the peptide via the E-amino group of Lys(11), as opposed to the N-terminal alpha-amino group. After labeling with In-111, Ga-67, and the short-lived positron emitter Ga-68, DOTA-NAPamide was characterized in vitro and in vivo using the mouse melanoma B16F1cell line. Results: DOTA-NAPamide exhibited an almost 7-fold higher MC1R binding potency as compared with DOTA-MSHoct. In B16F1 melanoma-bearing mice, both (111)in-DOTA-NAPamide and Ga-67-DOTA-NAPamide behaved more favorably than (111)InDOTA-MSHoct. Both radiopeptides exhibited higher tumor and lower kidney uptake leading to tumor-to-kidney ratios of the 4-to 48-h area under the curve that were 4.6 times (In-111) and 7.5 times (Ga-67) greater than that obtained with In-111-DOTA-MSHoct. In addition, the 4-h kidney uptake of Ga-67-DOTA-NAPamide could be reduced by 64% by coinjection of 15 Mg L-lysine, without affecting tumor uptake. Skin primary melanoma as well as lung and liver melanoma metastases could be easily visualized on tissue section autoradiographs after systemic injection of 67Ga-DOTA-NAPamide. The melanoma selectivity of DOTA-NAPamide was confirmed by PET imaging studies using (68)GaDOTA-NAPamide. Tumor uptake was found to be highest when the smallest amount of peptide was administered. Conclusion: DOTA-NAPamide labeled with either In-111 or Ga-67/Ga-68 is in every way superior to In-111-DOTA-MSHoct in murine models of
    Type of Publication: Journal article published
    PubMed ID: 14734683
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  • 4
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; IONIZING-RADIATION ; proliferation ; radiotherapy ; SURVIVAL ; tumor ; TUMOR-CELLS ; BLOOD ; CELL-PROLIFERATION ; COMBINATION ; ENDOTHELIAL GROWTH-FACTOR ; FACTOR RECEPTOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; THERAPY ; TOXICITY ; TYROSINE KINASE ; VITRO ; imaging ; MICE ; radiation ; PHOSPHORYLATION ; TYROSINE KINASE INHIBITOR ; MAGNETIC-RESONANCE ; MOLECULE ; magnetic resonance imaging ; CELL-SURVIVAL ; ASSAY ; COLORECTAL-CANCER ; chemotherapy ; MIGRATION ; STRATEGIES ; RANDOMIZED-TRIAL ; AKT ; REGIMENS ; signaling ; FACTOR RECEPTORS ; SINGLE ; molecular ; RE ; MULTITARGETED ANTIFOLATE ; TUMOR-GROWTH ; cancer therapy ; endothelial cells ; BLOOD-VESSELS ; normalization ; cell proliferation ; TYROSINE KINASES ; ionizing radiation ; TUMOR VASCULATURE ; ASSAYS ; KINASES ; COMBINED THERAPY ; PEMETREXED DISODIUM
    Abstract: It has been suggested that chemotherapy and radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple therapy combination consisting of SU11657 (a multitargeted small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases), Pemetrexed (a multitargeted folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G, and caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and chemotherapy induced endothelial cell Akt phosphorylation, but SU11657 could attenuate this process in vitro and in vivo in A431 human tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple therapy further decreased tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater tumor growth delay versus all other therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431 tumor, we found that the regimen with radiotherapy (7.5 Gy single dose), given after the institution of SU11657 treatment, was more effective than radiotherapy preceding SU11657 treatment. Accordingly, we found that SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 +/- 2.6 to 4.2 +/- 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with SU11657 may result in: (a) normalization of tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/chemotherapy, and (b) direct resensitization of endothelial cells to radio/ chemotherapy. We conclude that trimodal cancer therapy combining antiangiogenesis, chemotherapy, and radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy
    Type of Publication: Journal article published
    PubMed ID: 15867359
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  • 5
    Abstract: Mesenchymal stem cells (MSC) comprise a promising tool for cellular therapy. These cells are usually culture expanded prior to their application. However, a precise molecular definition of MSC and the sequel of long-term in vitro culture are yet unknown. In this study, we have addressed the impact of replicative senescence on human MSC preparations. Within 43 to 77 days of cultivation (7 to 12 passages), MSC demonstrated morphological abnormalities, enlargement, attenuated expression of specific surface markers, and ultimately proliferation arrest. Adipogenic differentiation potential decreased whereas the propensity for osteogenic differentiation increased. mRNA expression profiling revealed a consistent pattern of alterations in the global gene expression signature of MSC at different passages. These changes are not restricted to later passages, but are continuously acquired with increasing passages. Genes involved in cell cycle, DNA replication and DNA repair are significantly down-regulated in late passages. Genes from chromosome 4q21 were over-represented among differentially regulated transcripts. Differential expression of 10 genes has been verified in independent donor samples as well as in MSC that were isolated under different culture conditions. Furthermore, miRNA expression profiling revealed an up-regulation of hsa-mir-371, hsa-mir-369-5P, hsa-mir-29c, hsa-mir-499 and hsa-let-7f upon in vitro propagation. Our studies indicate that replicative senescence of MSC preparations is a continuous process starting from the first passage onwards. This process includes far reaching alterations in phenotype, differentiation potential, global gene expression patterns, and miRNA profiles that need to be considered for therapeutic application of MSC preparations.
    Type of Publication: Journal article published
    PubMed ID: 18493317
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  • 6
    Abstract: Mesenchymal stem cells (MSCs) have been shown to attenuate pulmonary damage induced by bleomycin-based anticancer treatments, but the influence of bleomycin on the stem cells themselves remains largely unknown. Here, we demonstrate that human bone marrow-derived MSCs are relatively sensitive to bleomycin exposure compared to adult fibroblasts. MSCs revealed increased levels of apoptosis after bleomycin treatment, while cellular morphology, stem cell surface marker expression and the ability for adhesion and migration remained unchanged. Bleomycin treatment also resulted in a reduced adipogenic differentiation potential of these stem cells. MSCs were found to efficiently repair DNA double strand breaks induced by bleomycin, mostly through non-homologous end joining repair. Low mRNA and protein expression levels of the inactivating enzyme bleomycin hydrolase were detected in MSCs that may contribute to the observed bleomycin-sensitive phenotype of these cells. The sensitivity of MSCs against bleomycin needs to be taken into consideration for ongoing and future treatment protocols investigating these stem cells as a potential treatment option for bleomycin-induced pulmonary damage in the clinic.
    Type of Publication: Journal article published
    PubMed ID: 27215195
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  • 7
    Keywords: GROWTH ; IRRADIATION ; DIFFERENTIATION ; TISSUE ; fibroblasts ; REPAIR ; sensitivity ; STROMAL CELLS ; HUMAN BONE-MARROW ; RADIORESISTANCE
    Abstract: Purpose: Mesenchymal stem cells (MSCs) have the ability to migrate to lesion sites and undergo differentiation into functional tissues. Although this function may be important for tissue regeneration after radiation therapy, the influence of ionizing radiation (IR) on cellular survival and the functional aspects of differentiation and stem cell characteristics of MSCs have remained largely unknown. Methods and Materials: Radiation sensitivity of human primary MSCs from healthy volunteers and primary human fibroblast cells was examined, and cellular morphology, cell cycle effects, apoptosis, and differentiation potential after exposure to IR were assessed. Stem cell gene expression patterns after exposure to IR were studied using gene arrays. Results: MSCs were not more radiosensitive than human primary fibroblasts, whereas there were considerable differences regarding radiation sensitivity within individual MSCs. Cellular morphology, cytoskeletal architecture, and cell motility were not markedly altered by IR. Even after high radiation doses up to 10 Gy, MSCs maintained their differentiation potential. Compared to primary fibroblast cells, MSCs did not show an increase in irradiation-induced apoptosis. Gene expression analyses revealed an upregulation of various genes involved in DNA damage response and DNA repair, but expression of established MSC surface markers appeared only marginally influenced by IR. Conclusions: These data suggest that human MSCs are not more radiosensitive than differentiated primary fibroblasts. In addition, upon photon irradiation, MSCs were able to retain their defining stem cell characteristics both on a functional level and regarding stem cell marker expression.
    Type of Publication: Journal article published
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  • 8
    Keywords: CANCER ; IN-VITRO ; BONE-MARROW ; CARCINOMA-CELLS ; FACTOR-BETA ; TGF-BETA ; IMATINIB MESYLATE ; GROWTH-FACTOR-RECEPTOR ; PULMONARY-FIBROSIS ; FRACTIONATED-IRRADIATION
    Abstract: INTRODUCTION: Mesenchymal stem cells (MSCs) can regenerate damaged tissues and may therefore be of importance for normal tissue repair after cancer treatment. Small molecule receptor kinase inhibitors (RKIs) have recently been introduced into cancer treatment. However, the influence of these drugs-particularly in combination with radiotherapy-on the survival of MSCs is largely unknown. METHODS: The sensitivity of human primary MSCs from healthy volunteers and primary human fibroblast cells to small molecule kinase inhibitors of the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and transforming growth factor beta (TGFbeta) receptors, as well to inhibitors of c-Kit, was examined in combination with ionizing radiation (IR); cell survival and proliferation were assessed. Expression patterns of different kinase receptors and ligands were investigated using gene arrays. RESULTS: MSCs were highly sensitive to the tyrosine kinase inhibitors SU14816 (imatinib) and SU11657 (sunitinib), but showed only moderate sensitivity to the selective TGFbeta receptor 1 inhibitor LY2109761. Primary adult human fibroblasts were comparably resistant to all three inhibitors. The addition of IR had an additive or supra-additive effect in the MSCs, but this was not the case for differentiated fibroblasts. Proliferation was markedly reduced in MSCs following kinase inhibition, both with and without IR. Gene expression analysis revealed high levels of the PDGF alpha and beta receptors, and lower levels of the TGFbeta receptor 2 and Abl kinase. IR did not alter the expression of kinase receptors or their respective ligands in either MSCs or adult fibroblasts. CONCLUSION: These data show that MSCs are highly sensitive to RKIs and combination treatments incorporating IR. Expression analyses suggest that high levels of PDGF receptors may contribute to this effect.
    Type of Publication: Journal article published
    PubMed ID: 24863573
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  • 9
    Keywords: IONIZING-RADIATION ; IRRADIATION ; SURVIVAL ; DIFFERENTIATION ; TISSUE ; fibroblasts ; LINE ; sensitivity ; STROMAL CELLS ; HUMAN BONE-MARROW
    Abstract: Mesenchymal stem cells (MSCs) participate in regeneration of tissues damaged by ionizing radiation. However, radiation can damage MSCs themselves. Here we show that cellular morphology, adhesion and migration abilities were not measurably altered by photon or carbon ion irradiation. The potential for differentiation was unaffected by either form of radiation, and established MSC surface markers were found to be stably expressed irrespective of radiation treatment. MSCs were able to efficiently repair DNA double strand breaks induced by both high-dose photon and carbon ion radiation. We have shown for the first time that MSCs are relatively resistant to therapeutic carbon ion radiotherapy. Additionally, this form of radiation did not markedly alter the defining stem cell properties or the expression of established surface markers in MSCs.
    Type of Publication: Journal article published
    PubMed ID: 25504442
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  • 10
    Keywords: GROWTH-FACTOR ; DNA-REPAIR ; HOMOLOGOUS RECOMBINATION ; STRAND-BREAK REPAIR ; DEPENDENT PROTEIN-KINASE ; HUMAN BONE-MARROW ; MARROW STROMAL CELLS ; INDUCED INTESTINAL INJURY ; DOSE IONIZING-RADIATION ; HEMATOPOIETIC PROGENITOR
    Abstract: Mesenchymal stem cells (MSCs) comprise a heterogeneous population of multipotent stromal cells and can be isolated from various tissues and organs. Due to their regenerative potential, they have been subject to intense research efforts, and they may provide an efficient means for treating radiation-induced tissue damage. MSCs are relatively resistant to ionizing radiation and retain their stem cell characteristics even after high radiation doses. The underlying mechanisms for the observed MSC radioresistance have been extensively studied and may involve efficient DNA damage recognition, double strand break repair and evasion of apoptosis. Here, we present a concise review of the published scientific data on the radiobiological features of MSCs. The involvement of different DNA damage recognition and repair pathways in the creation of a radioresistant MSC phenotype is outlined, and the roles of apoptosis, senescence and autophagy regarding the reported radioresistance are summarized. Finally, potential influences of the radioresistant MSCs for the clinic are discussed with respect to the repair and radioprotection of irradiated tissues.
    Type of Publication: Journal article published
    PubMed ID: 26203772
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