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  • 1
    Online Resource
    Online Resource
    Higher cMET dependence of sacral compared to clival chordoma cells: contributing to a better understanding of cMET in chordoma
    Springer Science and Business Media LLC ; 2021
    In:  Scientific Reports Vol. 11, No. 1 ( 2021-06-14)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2021-06-14)
    Abstract: Chordomas are rare slow growing, malignant bone tumors of the axial skeleton with no approved medical treatment. As the majority of chordomas express cMET and its ligand, HGF, and crosstalks between EGFR and MET-signaling exist, we aimed to explore cMET activity in chordoma cell lines and clinical samples. We investigated nine chordoma patients and four chordoma cell lines for cMET expression. Two clival and two sacral chordoma cell lines were tested for chromosomal abnormalities of the MET gene locus; we studied the influence of HGF on the autocrine secretion and migration behavior, as well as protein expression and phosphorylation. Two MET/ALK inhibitors were investigated for their effects on cell viability, cell cycle, cyclin alterations, apoptosis, and downstream signaling pathways. Moderate and strong expression of membrane and cytoplasmic cMET in chordoma patients and cell lines used, as well as concentration-dependent increase in phospho cMET expression after HGF stimulation in all four chordoma cell lines was shown. U-CH2, MUG-Chor1, and UM-Chor1 are polysomic for MET. Chordoma cell lines secreted EGF, VEGF, IL-6, and MMP9 upon HGF-stimulation. Sacral cell lines showed a distinct HGF-induced migration. Both inhibitors dose-dependently inhibited cell growth, induce apoptosis and cell-cycle arrest, and suppress downstream pathways. Heterogeneous responses obtained in our in vitro setting indicate that cMET inhibitors alone or in combination with other drugs might particularly benefit patients with sacral chordomas.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-021-92018-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2615211-3
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  • 2
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    Drug combination screening as a translational approach toward an improved drug therapy for chordoma
    Springer Science and Business Media LLC ; 2021
    In:  Cellular Oncology Vol. 44, No. 6 ( 2021-12), p. 1231-1242
    Details
    In: Cellular Oncology, Springer Science and Business Media LLC, Vol. 44, No. 6 ( 2021-12), p. 1231-1242
    Abstract: Drug screening programmes have revealed epidermal growth factor receptor inhibitors (EGFR i s) as promising therapeutics for chordoma, an orphan malignant bone tumour, in the absence of a known genetic driver. Concurrently, the irreversible EGFR i afatinib (Giotrif®) is being evaluated in a multicentric Phase II trial. As tyrosine kinase inhibitor (TKI) monotherapies are invariably followed by resistance, we aimed to evaluate potential therapeutic combinations with EGFR i s. Methods We screened 133 clinically approved anticancer drugs as single agents and in combination with two EGFR i s (afatinib and erlotinib) in the clival chordoma cell line UM-Chor1. Synergistic combinations were analysed in a 7 × 7 matrix format. The most promising combination was further explored in clival (UM-Chor1, MUG-CC1) and sacral (MUG-Chor1, U-CH1) chordoma cell lines. Secretomes were analysed for receptor tyrosine kinase ligands (EGF, TGF-α, FGF-2 and VEGF-A) upon drug treatment. Results Drugs that were active as single agents ( n  = 45) included TKIs, HDAC and proteasome inhibitors, and cytostatic drugs. Six combinations were analysed in a matrix format: n  = 4 resulted in a significantly increased cell killing (crizotinib, dabrafenib, panobinostat and doxorubicin), and n  = 2 exhibited no or negligible effects (regorafenib, venetoclax). Clival chordoma cell lines were more responsive to combined EGFR-MET inhibition. EGFR-MET cross-talk (e.g. via TGF-α secretion) likely accounts for the synergistic effects of EGFR-MET inhibition. Conclusion Our screen revealed promising combinations with EGFR i s, such as the ALK/MET-inhibitor crizotinib, the HDAC-inhibitor panobinostat or the topoisomerase-II-inhibitor doxorubicin, which are part of standard chemotherapy regimens for various bone and soft-tissue sarcomas.
    Type of Medium: Online Resource
    ISSN: 2211-3428 , 2211-3436
    URL: Article
    DOI: 10.1007/s13402-021-00632-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2595105-1
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  • 3
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    Cellular and Molecular Biological Alterations after Photon, Proton, and Carbon Ions Irradiation in Human Chondrosarcoma Cells Linked with High-Quality Physics Data
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 19 ( 2022-09-28), p. 11464-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 19 ( 2022-09-28), p. 11464-
    Abstract: Chondrosarcomas are particularly difficult to treat due to their resistance to chemotherapy and radiotherapy. However, particle therapy can enhance local control and patient survival rates. To improve our understanding of the basic cellular radiation response, as a function of dose and linear energy transfer (LET), we developed a novel water phantom-based setup for cell culture experiments and characterized it dosimetrically. In a direct comparison, human chondrosarcoma cell lines were analyzed with regard to their viability, cell proliferation, cell cycle, and DNA repair behavior after irradiation with X-ray, proton, and carbon ions. Our results clearly showed that cell viability and proliferation were inhibited according to the increasing ionization density, i.e., LET, of the irradiation modes. Furthermore, a prominent G2/M arrest was shown. Gene expression profiling proved the upregulation of the senescence genes CDKN1A (p21), CDKN2A (p16NK4a), BMI1, and FOXO4 after particle irradiation. Both proton or C-ion irradiation caused a positive regulation of the repair genes ATM, NBN, ATXR, and XPC, and a highly significant increase in XRCC1/2/3, ERCC1, XPC, and PCNA expression, with C-ions appearing to activate DNA repair mechanisms more effectively. The link between the physical data and the cellular responses is an important contribution to the improvement of the treatment system.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms231911464
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 4
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    Synthesis and Pharmacological In Vitro Investigations of Novel Shikonin Derivatives with a Special Focus on Cyclopropane Bearing Derivatives
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 5 ( 2021-03-09), p. 2774-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 5 ( 2021-03-09), p. 2774-
    Abstract: Melanoma is the deadliest form of skin cancer and accounts for about three quarters of all skin cancer deaths. Especially at an advanced stage, its treatment is challenging, and survival rates are very low. In previous studies, we showed that the constituents of the roots of Onosma paniculata as well as a synthetic derivative of the most active constituent showed promising results in metastatic melanoma cell lines. In the current study, we address the question whether we can generate further derivatives with optimized activity by synthesis. Therefore, we prepared 31, mainly novel shikonin derivatives and screened them in different melanoma cell lines (WM9, WM164, and MUG-Mel2 cells) using the XTT viability assay. We identified (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclopropyl-2-oxoacetate as a novel derivative with even higher activity. Furthermore, pharmacological investigations including the ApoToxGloTM Triplex assay, LDH assay, and cell cycle measurements revealed that this compound induced apoptosis and reduced cells in the G1 phase accompanied by an increase of cells in the G2/M phase. Moreover, it showed hardly any effects on the cell membrane integrity. However, it also exhibited cytotoxicity against non-tumorigenic cells. Nevertheless, in summary, we could show that shikonin derivatives might be promising drug leads in the treatment of melanoma.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22052774
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 5
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    Enhanced Osteogenic Differentiation of Human Primary Mesenchymal Stem and Progenitor Cultures on Graphene Oxide/Poly(methyl methacrylate) Composite Scaffolds
    MDPI AG ; 2020
    In:  Materials Vol. 13, No. 13 ( 2020-07-05), p. 2991-
    Details
    In: Materials, MDPI AG, Vol. 13, No. 13 ( 2020-07-05), p. 2991-
    Abstract: Due to its versatility, small size, large surface area, and ability to interact with biological cells and tissues, graphene oxide (GO) is an excellent filler for various polymeric composites and is frequently used to expand their functionality. Even though the major advantage of the incorporation of GO is the enhancement of mechanical properties of the composite material, GO is also known to improve bioactivity during biomineralization and promote osteoblast adhesion. In this study, we described the fabrication of a composite bone cement made of GO and poly(methyl methacrylate) (PMMA), and we investigated its potential to enhance osteogenic differentiation of human primary mesenchymal stem and progenitor cells. Through the analysis of three differentiation markers, namely alkaline phosphatase, secreted protein acidic and rich in cysteine, and bone morphogenetic protein-2 in the presence and in the absence of an osteogenic differentiation medium, we were able to indicate a composite produced manually with a thick GO paper as the most effective among all investigated samples. This effect was related to its developed surface, possessing a significant number of voids and pores. In this way, GO/PMMA composites were shown as promising materials for the applications in bone tissue engineering.
    Type of Medium: Online Resource
    ISSN: 1996-1944
    URL: Article
    DOI: 10.3390/ma13132991
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2487261-1
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  • 6
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    The role of stretch, tachycardia and sodium‐calcium exchanger in induction of early cardiac remodelling
    Wiley ; 2020
    In:  Journal of Cellular and Molecular Medicine Vol. 24, No. 15 ( 2020-08), p. 8732-8743
    Details
    In: Journal of Cellular and Molecular Medicine, Wiley, Vol. 24, No. 15 ( 2020-08), p. 8732-8743
    Abstract: Stretch and tachycardia are common triggers for cardiac remodelling in various conditions, but a comparative characterization of their role in the excitation‐transcription coupling (ETC) and early regulation of gene expression and structural changes is lacking. Here, we show that stretch and tachycardia directly induced hypertrophy of neonatal rat cardiac myocytes and also of non‐myocytes. Both triggers induced similar patterns of hypertrophy but had largely distinct gene expression profiles. ACTA1 served as good hypertrophy marker upon stretch, while RCAN1 was found increased in response to tachycardia in a rate‐dependent fashion. Mechanistically, several calcium‐handling proteins, including the sodium‐calcium exchanger (NCX), contributed to ETC. Phosphorylation of the calcium/calmodulin‐dependent protein kinase II (CaMKII) was elevated and occurred downstream of NCX activation upon tachycardia, but not stretch. Microarray profiling revealed that stretch and tachycardia regulated around 33% and 20% genes in a NCX‐dependent manner, respectively. In conclusion, our data show that hypertrophy induction by stretch and tachycardia is associated with different gene expression profiles with a significant contribution of the NCX.
    Type of Medium: Online Resource
    ISSN: 1582-1838 , 1582-4934
    URL: Issue
    URL: Article
    DOI: 10.1111/jcmm.v24.15
    DOI: 10.1111/jcmm.15504
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2076114-4
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  • 7
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    Fatty Acid–Binding Protein 4 (FABP4) Is Associated with Cartilage Thickness in End-Stage Knee Osteoarthritis
    SAGE Publications ; 2021
    In:  CARTILAGE Vol. 13, No. 2_suppl ( 2021-12), p. 1165S-1173S
    Details
    In: CARTILAGE, SAGE Publications, Vol. 13, No. 2_suppl ( 2021-12), p. 1165S-1173S
    Abstract: There is no single blood biomarker for the staging of knee osteoarthritis (KOA). The purpose of this study was to assess the relationship of obesity, serum biomarkers, the hip-knee-ankle angle (HKAA) with sonographic cartilage thickness. Methods We conducted a cross-sectional study of n = 33 patients undergoing knee arthroplasty. Body mass index (BMI) was recorded, and patients were grouped based on BMI. Serum blood samples were collected, and the following biomarkers were measured using the ELISA technique (subgroup of n = 23): oxidized low-density lipoprotein (oxLDL), soluble receptor for advanced glycation end-products (sRAGE), fatty acid–binding protein 4 (FABP4), membrane-bound phospholipase A2 (PLA2G2A). The HKAA was analyzed on full-length limb standing x-ray images. Cartilage thickness was assessed on ultrasound images. Multivariable regression analysis was performed to account for confounding. Results After adjusting for age, gender, and HKAA, obese patients had thicker medial femoral cartilage (β = 0.165, P = 0.041). Furthermore, lateral cartilage thickness was negatively correlated with FABP4 level after adjusting for of age, gender, BMI, and HKAA (β = −0.006, P = 0.001). Confirming previous studies, after adjustment, FABP4 level was associated with a higher BMI group (β = 42.99, P 〈 0.001). None of the other markers (oxLDL, PLA2G2A, and sRAGE) was associated with BMI or cartilage thickness. Discussion Our results indicate that BMI has a weak, positive association with cartilage thickness in end-stage KOA patients. FABP4 levels were negatively associated with cartilage thickness. While our study is limited by a small sample size, these results further highlight the role of FABP4 as promising biomarkers of burden of disease in KOA.
    Type of Medium: Online Resource
    ISSN: 1947-6035 , 1947-6043
    URL: Article
    DOI: 10.1177/19476035211011520
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2515870-3
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  • 8
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    Online Resource
    Activation of efficient DNA repair mechanisms after photon and proton irradiation of human chondrosarcoma cells
    Springer Science and Business Media LLC ; 2021
    In:  Scientific Reports Vol. 11, No. 1 ( 2021-12-16)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2021-12-16)
    Abstract: Although particle therapy with protons has proven to be beneficial in the treatment of chondrosarcoma compared to photon-based (X-ray) radiation therapy, the cellular and molecular mechanisms have not yet been sufficiently investigated. Cell viability and colony forming ability were analyzed after X-ray and proton irradiation (IR). Cell cycle was analyzed using flow cytometry and corresponding regulator genes and key players of the DNA repair mechanisms were measured using next generation sequencing, protein expression and immunofluorescence staining. Changes in metabolic phenotypes were determined with nuclear magnetic resonance spectroscopy. Both X-ray and proton IR resulted in reduced cell survival and a G2/M phase arrest of the cell cycle. Especially 1 h after IR, a significant dose-dependent increase of phosphorylated γH2AX foci was observed. This was accompanied with a reprogramming in cellular metabolism. Interestingly, within 24 h the majority of clearly visible DNA damages were repaired and the metabolic phenotype restored. Involved DNA repair mechanisms are, besides the homology directed repair (HDR) and the non-homologous end-joining (NHEJ), especially the mismatch mediated repair (MMR) pathway with the key players EXO1, MSH3, and PCNA. Chondrosarcoma cells regenerates the majority of DNA damages within 24 h. These molecular mechanisms represent an important basis for an improved therapy.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-021-03529-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2615211-3
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  • 9
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    Periplocin mediates TRAIL-induced apoptosis and cell cycle arrest in human myxofibrosarcoma cells via the ERK/p38/JNK pathway
    Elsevier BV ; 2020
    In:  Phytomedicine Vol. 76 ( 2020-09), p. 153262-
    Details
    In: Phytomedicine, Elsevier BV, Vol. 76 ( 2020-09), p. 153262-
    Type of Medium: Online Resource
    ISSN: 0944-7113
    URL: Article
    DOI: 10.1016/j.phymed.2020.153262
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2040195-4
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  • 10
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    ELECTRICAL ACTIVATION OF MUSCLE CELLS INFLUENCES OA CHONDROCYTES UNDER MECHANICAL STIMULATION
    Elsevier BV ; 2024
    In:  Osteoarthritis and Cartilage Vol. 32 ( 2024-04), p. S452-S453
    Details
    In: Osteoarthritis and Cartilage, Elsevier BV, Vol. 32 ( 2024-04), p. S452-S453
    Type of Medium: Online Resource
    ISSN: 1063-4584
    URL: Article
    DOI: 10.1016/j.joca.2024.02.671
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2024
    detail.hit.zdb_id: 2002544-0
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