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  • 1
    Language: English
    In: The Journal of Urology, August 2016, Vol.196(2), pp.570-578
    Description: Penile squamous cell carcinoma is a rare but aggressive cancer. Little is known about pivotal events in tumor pathogenesis and metastasis. Lymph node metastasis is the prevailing prognostic factor while clinical detection in patients remains difficult. Our aim was to identify distinct miRNAs that are differentially expressed in metastatic vs nonmetastatic penile carcinoma, which may serve as diagnostic biomarkers for disease progression. TaqMan® arrays and quantitative polymerase chain reaction were applied to analyze miRNA profiles in penile squamous cell carcinoma specimens and glans tissue from 24 patients. The prognostic value of deregulated miRNAs was analyzed using the Kaplan-Meier method. The Spearman test was applied to determine a potential linkage between distinctive miRNAs in individual patients. Loss of miR-1 (p = 0.0048), miR-101 (p = 0.0001) and miR-204 (p = 0.0004) in metastasizing tumors and associated metastases (p = 0.0151, 0.0019 and 0.0003, respectively) distinguished patients with metastatic and nonmetastatic penile squamous cell carcinoma. These 3 miRNAs showed a coherent expression pattern. Consistently, patients with low levels of all 3 miRNAs had worse survival (p = 0.03). We identified a coordinately regulated miRNA target hub that is over expressed in penile squamous cell carcinoma and associated with lymphovascular invasion. Our results provide evidence of a novel multiple miRNA based signature associated with lymph node metastasis and unfavorable prognosis of penile squamous cell carcinoma. The integrated loss of miR-1, miR-101 and miR-204 may predict the formation of metastases in penile cancer at an early stage.
    Keywords: Penile Neoplasms ; Carcinoma, Squamous Cell ; Neoplasm Metastasis ; Micrornas ; Mortality ; Medicine
    ISSN: 0022-5347
    E-ISSN: 1527-3792
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  • 2
    Language: English
    In: Cell Cycle, 15 October 2011, Vol.10(20), pp.3554-3565
    Description: Chronic hepatitis B virus (HBV) infection is the major risk for hepatocellular carcinomas (HCC). HBV X protein (HBx) and p53 tumor suppressor family interactions may be crucial for HCC induction. We compared p53 and p73 interactions with HBx in normal and HCC tumor cell lines differing in their...
    Keywords: Biology
    ISSN: 1538-4101
    E-ISSN: 1551-4005
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  • 3
    In: EMBO reports, December 2014, Vol.15(12), pp.1315-1329
    Description: Malignant melanoma is highly lethal due to its aggressive invasive properties and metastatic dissemination. The transcription factor E2F1 is crucial for melanoma progression through poorly understood mechanisms. Here, we show that the miR‐224/miR‐452 cluster is significantly increased in advanced melanoma and invasive/metastatic cell lines that express high levels of E2F1. miR‐224/miR‐452 expression is directly activated by E2F1 through transactivation of the gene. Ectopic expression of miR‐224/miR‐452 in less aggressive cells induces and cytoskeletal rearrangements and enhances migration/invasion. Conversely, miR‐224/miR‐452 depletion in metastatic cells induces the reversal of , inhibition of motility, loss of the invasive phenotype and an absence of lung metastases in mice. We identify the metastasis suppressor as new target of miR‐224/miR‐452 that induces feedback inhibition of E2F1 and show that miR‐224/452‐mediated downregulation of is essential for E2F1‐induced and invasion. The E2F1‐miR‐224/452‐TXNIP axis constitutes a molecular signature that predicts patient survival and may help to set novel therapies. The E2F1‐miR‐244/452‐ pathway is shown to be crucial for melanoma invasion and metastasis . By activating the expression of miR‐224/452, E2F1 leads to the downregulation of its inhibitor, , and induces . In early primary tumors, high levels of TXNIP restrict E2F1 activity through p16 activation and subsequent inhibition of RB. Increasingly high levels of E2F1 during cancer progression lead to the transcriptional upregulation of the miR‐224/452 cluster. miR‐224 and miR‐452 repress the expression of TXNIP to induce E2F1‐dependent EMT and invasion. The E2F1‐miR‐244/452‐ pathway is shown to be crucial for melanoma invasion and metastasis . By activating the expression of miR‐224/452, E2F1 leads to the downregulation of its inhibitor, , and induces .
    Keywords: E2f1 Transcription Factor ; Epithelial‐Mesenchymal Transition ; Melanoma Metastasis ; Mi Cluster ; Thioredoxin‐Interacting Protein
    ISSN: 1469-221X
    E-ISSN: 1469-3178
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  • 4
    Language: English
    In: Journal of Neuro-Oncology, 2016, Vol.126(3), pp.585-592
    Description: There is a distinct diversity between the appearance of every glioblastoma multiforme (GBM) on pretreatment magnetic resonance imaging (MRI) with a potential impact on clinical outcome and survival of the patients. The object of this study was to determine the impact of 10 different single nucleotide polymorphisms (SNPs) on various volumetric parameters in patients harboring a GBM. We prospectively analyzed 20 steroid-naïve adult patients who had been treated for newly diagnosed GBM. The volumetry was performed using MRI with the help of a semiautomated quantitative software measuring contrast enhancing tumor volume including necrosis, central necrosis alone and peritumoral edema (PTE). We calculated ratios between the tumor volume and edema (ETR), respectively necrosis (NTR). SNP analysis was done using genomic DNA extracted from peripheral blood genotyped via PCR and sequencing. There was a strong correlation between tumor volume and PTE ( p  〈 0.001), necrosis ( p  〈 0.001) and NTR ( p  = 0.003). Age and sex had no influence on volumetric data. The Aquaporin 4-31G 〉 A SNP had a significant influence on the ETR ( p  = 0.042) by decreasing the measured edema compared with the tumor volume. The Interleukin 8-251A 〉 T SNP was significantly correlated with an increased tumor ( p  = 0.048), PTE ( p  = 0.033) and necrosis volume ( p  = 0.028). We found two SNPs with a distinct impact on pretreatment tumor characteristics, presenting a potential explanation for the individual diversity of GBM appearance on MRI and influence on survival.
    Keywords: Glioblastoma ; Volumetrics ; Edema ; Necrosis ; Polymorphism
    ISSN: 0167-594X
    E-ISSN: 1573-7373
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  • 5
    In: Journal of Molecular Cell Biology, 2013, Vol. 5(6), pp.391-403
    Description: Angiogenesis is essential for primary tumor growth and metastatic dissemination. E2F1, frequently upregulated in advanced cancers, was recently shown to drive malignant progression. In an attempt to decipher the molecular events underlying this behavior, we demonstrate that the tumor cell-associated vascular endothelial growth factor-C/receptor-3 (VEGF-C/VEGFR-3) axis is controlled by E2F1. Activation or forced expression of E2F1 in cancer cells leads to the upregulation of VEGFR-3 and its ligand VEGF-C, whereas E2F1 depletion prevents their expression. E2F1-dependent receptor induction is crucial for tumor cells to enhance formation of capillary tubes and neovascularization in mice. We further provide evidence for a positive feedback loop between E2F1 and VEGFR-3 signaling to stimulate pro-angiogenic platelet-derived growth factor B (PDGF-B). E2F1 or VEGFR-3 knockdown results in reduced PDGF-B levels, while the coexpression synergistically upregulates promoter activity and endogenous protein expression of PDGF-B. Our findings delineate an as yet unrecognized function of E2F1 as enhancer of angiogenesis via regulation of VEGF-C/VEGFR-3 signaling in tumors to cooperatively activate PDGF-B expression. Targeting this pathway might be reasonable to complement standard anti-angiogenic treatment of cancers with deregulated E2F1.
    Keywords: E2f1 ; Hypoxia ; Neovascularization ; Pdgf - B ; Vegfr - 3 ; Vegf - C ; Regulatory Feedback Loop
    ISSN: 1674-2788
    E-ISSN: 1759-4685
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  • 6
    Language: English
    In: Cancer Cell, 14 October 2013, Vol.24(4), pp.512-527
    Description: Dissemination of cancer cells from primary tumors is the key event in metastasis, but specific determinants are widely unknown. Here, we show that DNp73, an inhibitor of the p53 tumor suppressor family, drives migration and invasion of nonmetastatic melanoma cells. Knockdown of endogenous DNp73 reduces this behavior in highly metastatic cell lines. Tumor xenografts expressing DNp73 show a higher ability to invade and metastasize, while growth remains unaffected. DNp73 facilitates an EMT-like phenotype with loss of E-cadherin and Slug upregulation. We provide mechanistic insight toward regulation of /EPLIN by p73/DNp73 and demonstrate a direct link between the DNp73-EPLIN axis and IGF1R-AKT/STAT3 activation. These findings establish initiation of the invasion-metastasis cascade via EPLIN-dependent IGF1R regulation as major activity of DNp73.
    Keywords: Medicine
    ISSN: 1535-6108
    E-ISSN: 1878-3686
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  • 7
    Language: English
    In: Cancer Letters, 01 February 2019, Vol.442, pp.299-309
    Description: Melanoma is an aggressive cancer with poor prognosis, requiring personalized management of advanced stages and establishment of molecular markers. Melanomas derive from melanocytes, which specifically express tyrosinase, the rate-limiting enzyme of melanin-synthesis. We demonstrate that melanomas with high levels of DNp73, a cancer-specific variant of the p53 family member p73 and driver of melanoma progression show, in contrast to their less-aggressive low-DNp73 counterparts, hypopigmentation in vivo. Mechanistically, reduced melanin-synthesis is mediated by a DNp73-activated IGF1R/PI3K/AKT axis leading to tyrosinase ER-arrest and proteasomal degradation. Tyrosinase loss triggers reactivation of the EMT signaling cascade, a mesenchymal-like cell phenotype and increased invasiveness. DNp73-induced depigmentation, Slug increase and changes in cell motility are recapitulated in neural crest-derived melanophores of embryos, underscoring a previously unnoticed physiological role of tyrosinase as EMT inhibitor. This data provides a mechanism of hypopigmentation accompanying cancer progression, which can be exploited in precision diagnosis of patients with melanoma-associated hypopigmentation (MAH), currently seen as a favorable prognostic factor. The DNp73/IGF1R/Slug signature in colorless lesions might aid to clinically discriminate between patients with MAH-associated metastatic disease and those, where MAH is indeed a sign of regression.
    Keywords: Tyrosinase Degradation ; P73 ; Epithelial-Mesenchymal Transition ; Diagnostic Signature ; Melanoma Progression ; Medicine
    ISSN: 0304-3835
    E-ISSN: 1872-7980
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  • 8
    Language: English
    In: Journal of Environmental Management, September 2013, Vol.127, pp.S1-S5
    Description: Our paper introduces objectives and ideas of the special issue “Integrated land use and regional resource management – A cross-disciplinary dialogue on future perspectives for a sustainable development of regional resources” and provides an overview on the contributions of the single papers in the special issue to this topic. Furthermore, we discuss and present major challenges and demands on integrated land use and regional resource management and we come up with an analytical framework how to correspond these demands. ► The special issue presents methods and approaches for integrated land use planning. ► An analytical framework for integrated land use planning is presented. ► Contribution integrated land use planning to regional resource management is shown.
    Keywords: Integrated Land Use ; Regional Resource Management ; Regional Planning ; Analytical Framework for Integrated Planning ; Sustainable Regional Development ; Environmental Sciences ; Economics
    ISSN: 0301-4797
    E-ISSN: 1095-8630
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  • 9
    Language: English
    In: Journal of environmental management, 2013, Vol.127S, pp.S1-S5
    Description: Our paper introduces objectives and ideas of the special issue “Integrated land use and regional resource management – A cross-disciplinary dialogue on future perspectives for a sustainable development of regional resources” and provides an overview on the contributions of the single papers in the special issue to this topic. Furthermore, we discuss and present major challenges and demands on integrated land use and regional resource management and we come up with an analytical framework how to correspond these demands. ; p. S1-S5.
    Keywords: Sustainable Development ; Resource Management ; Land Use
    ISSN: 0301-4797
    Source: AGRIS (Food and Agriculture Organization of the United Nations)
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  • 10
    Language: German
    In: Österreichische Wasser- und Abfallwirtschaft, 2018, Vol.70(9), pp.474-484
    Description: Die saisonale Abflusscharakteristik im Alpenraum hat sich im Lauf der letzten Jahrzehnte gewandelt. Die vorliegende Studie widmet sich der Untersuchung räumlicher und zeitlicher Entwicklungen von Abflussregimen. Diese Entwicklungen wurden österreichweit im Bezugszeitraum 1961–2010 an 280 anthropogen unbeeinflussten Stationen analysiert. Mittels einer Clusteranalyse wurden fünf charakteristische Regimegruppen bestimmt, die durch glaziale, nivale, pluviale sowie nivo-pluviale Merkmale geprägt sind. Ihre räumliche Verteilung zeigt trotz der topografischen und hydrologischen Heterogenität Österreichs ein deutliches Muster. Der Alpenraum wird durch nivale und glaziale Abflussregime dominiert. Bei Regimen des Flach- und Hügellandes dominierten hingegen pluviale Merkmale. In der zeitlichen Entwicklung nahmen pluviale Einflüsse in weiten Teilen signifikant zu, die in Nord-Süd-Richtung unterschiedliche Reaktionen in der mittleren saisonalen Abflusscharakteristik hervorgerufen haben. Die beobachteten Veränderungen der Abflussregime sind konsistent mit den saisonalen Trends im Niederschlag, Abfluss und der Wasserbilanz des Hydrologischen Atlas Österreichs. Der ermittelte Stand mittlerer saisonaler Abflusscharakteristiken und seine bisherige Entwicklung ist eine wichtige Informationsquelle angesichts der prognostizierten Veränderungen der Steuerfaktoren abflussbildender Prozesse durch den Klimawandel. The seasonal runoff characteristics in Alpine rivers have changed during the last decades. The present study deals with the investigation of temporal changes and spatial distribution of seasonal flow characteristics by identifying and describing flow regimes. Mean monthly flows at 280 stream gauges without significant anthropogenic influences in Austria were analyzed for the period 1961–2010. A cluster analysis was used to define five representative flow regime groups with glacial, nival, pluvial and nivo-pluvial characteristics, respectively. Although both topographic and hydrological conditions in Austria are highly heterogeneous, the spatial distribution shows a clear pattern. The alpine region was dominated by nival and glacial flow regimes, while the lowland and hilly region in the northeast was dominated by pluvial flow regimes. The temporal development showed a significant increase of pluvial characteristics over time, responding differently at mean seasonal flows north and south of the Alpine divide. The observed changes in the flow regimes were consistent with seasonal trends in precipitation, discharge and the water balance as published in the Hydrologic Atlas of Austria. The study provides new information about the temporal development and the current state of mean seasonal flow characteristics, that is of particular interest considering predicted changes of factors and processes influencing flow generation.
    Keywords: Water Balance (Hydrology) – Analysis ; Runoff – Analysis ; Rivers – Analysis ; Precipitation (Meteorology) – Analysis ; Flow (Dynamics) – Analysis;
    ISSN: 0945-358X
    E-ISSN: 1613-7566
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