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  • 1
    Keywords: Germany ; MECHANISM ; mechanisms ; MELANOMA ; MOLECULAR-MECHANISM ; RE ; LINEAGE SURVIVAL ; MITF
    Type of Publication: Journal article published
    PubMed ID: 17014045
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  • 2
    Keywords: CANCER ; ACTIVATION ; SKIN ; INDUCED APOPTOSIS ; chemotherapy ; MUTATIONS ; MUTANT P53 ; SIMIAN-VIRUS-40 ; DNA-DAMAGE RESPONSE ; nutlin-3
    Abstract: Merkel cell carcinoma (MCC) is a rare and very aggressive skin cancer with viral etiology. The tumor-associated Merkel cell polyoma virus (MCV) belongs to a group of viruses encoding T antigens (TAs) that can induce tumorigenesis by interfering with cellular tumor-suppressor proteins like p53. To explore possible modes of p53 inactivation in MCC p53 sequencing, expression analysis and reporter gene assays for functional analyses were performed in a set of MCC lines. In one MCV-negative and one MCV-positive cell line, p53 inactivating mutations were found. In the majority of MCC lines, however, wild-type p53 is expressed and displays some transcriptional activity, which is yet not sufficient to effectively restrict cellular survival or growth in these cell cultures. Interestingly, the MCV TAs are not responsible for this critical lack in p53 activity, as TA knockdown in MCV-positive MCC cells does not induce p53 activity. In contrast, inhibition of the ubiquitin ligase HDM-2 (human double minute 2) by Nutlin-3a leads to p53 activation and p53-dependent apoptosis or cell cycle arrest in five out of seven p53 wild-type MCC lines, highlighting p53 as a potential target for future therapies of this aggressive tumor.
    Type of Publication: Journal article published
    PubMed ID: 23563200
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  • 3
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; SURVIVAL ; tumor ; CELL ; Germany ; IN-VIVO ; VITRO ; VIVO ; GENE ; transcription ; cell line ; TISSUE ; TUMORS ; LINES ; PATIENT ; ACTIVATION ; TRANSCRIPTION FACTOR ; MARKER ; REDUCTION ; TISSUES ; CELL-LINES ; NO ; AMPLIFICATION ; COPY NUMBER ; ASSAY ; NUMBER ; RATES ; CELL-LINE ; chemotherapy ; LINE ; MELANOMA ; METASTATIC MELANOMA ; PCR ; ONCOGENE ; MALIGNANT-MELANOMA ; MELANOMA PATIENTS ; real-time PCR ; cell lines ; ONCOLOGY ; RE ; PATIENT SURVIVAL ; chemosensitivity ; LINEAGE ; REAL-TIME ; TUMOR TISSUE ; biomarker ; analysis ; methods ; USA ; correlation ; cancer research ; in vivo ; LINEAGE SURVIVAL ; MITF ; quantitative ; MELANOMAS ; LUMINESCENCE ; chemotherapeutics ; MASTER REGULATOR
    Abstract: Purpose: The microphthalmia-associated transcription factor (MITF) is regarded as a key oncogene of the melanocytic lineage since it was detected by a genome-wide analysis to be strongly amplified in 15% to 20% of metastatic melanomas. MITF gene amplification was shown to be associated with a reduced survival in metastatic melanoma patients, and reduction of MITF activity was shown to sensitize melanoma cell lines to chemotherapeutics, suggesting the intratumoral MITF gene copy number as a predictive biomarker of response and survival after chemotherapy. Patients and Methods: To validate this hypothesis, we investigated MITF gene amplification in tumor tissues obtained from 116 metastatic melanoma patients before an individualized sensitivity-directed chemotherapy using quantitative real-time PCR. MITF amplification rates were correlated with tumor chemosensitivity quantified by an ATP-based luminescence assay and with chemotherapy outcome in terms of response and survival. Results: Of 116 tumor tissues, 104 were evaluable for MITF gene amplification. Strong amplification (〉= 4 copies per cell) was detected in 24 of 104 tissues (23%), whereas 62 of 104 tissues (60%) harbored 〉3 copies per cell. Strong MITF gene amplification was associated with a reduced disease-specific survival (P = 0.031). However, no correlation was found between MITF copy number and in vitro chemosensitivity or in vivo chemotherapy response. Conclusion: Our findings suggest that strong amplifications of the melanoma oncogene MITF affects patient survival but does not influence tumor chemosensitivity and chemotherapy response. Thus, the MITF gene copy number seems a useful prognostic marker in metastatic melanoma but could not be confirmed as a predictive marker of chemosensitivity and chemotherapy response
    Type of Publication: Journal article published
    PubMed ID: 17975146
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  • 4
    Keywords: RECEPTOR ; CANCER ; CELLS ; SURVIVAL ; tumor ; carcinoma ; Germany ; CLASSIFICATION ; DIAGNOSIS ; FOLLOW-UP ; COHORT ; DISEASE ; HISTORY ; LONG-TERM ; NEW-YORK ; POPULATION ; GENE ; PROTEIN ; SAMPLE ; SAMPLES ; PATIENT ; RANTES ; DNA ; IMPACT ; primary ; polymorphism ; NO ; PROGRESSION ; MELANOMA ; METASTATIC MELANOMA ; PCR ; MULTIVARIATE ; IMMUNE-RESPONSE ; IMMUNOTHERAPY ; vaccination ; chemokine ; SERUM ; ONCOLOGY ; TUMOR-GROWTH ; PATIENT SURVIVAL ; CCR5 ; analysis ; methods ; USA ; immunology
    Abstract: Purpose Chemokines influence both tumor progression and anti-tumor immune response. A 32-bp-deletion polymorphism in the chemokine receptor 5 gene (CCR5 Delta 32) has been shown to result in a non-functional protein. This study was aimed at evaluating the potential impact of this gene polymorphism on disease progression and treatment outcome in patients with melanoma. patients and methods CCR5 genotyping was performed by PCR on DNA extracted from serum samples of 782 cutaneous melanoma patients with known disease history and long-term clinical follow-up. Genotypes were correlated with patient survival and types of treatment. Results Of 782 melanoma patients, 90 (11.5%) were heterozygous and 12 (1.5%) were homozygous for CCR5 Delta 32. Analyzing the complete cohort, the disease-specific survival from date of primary diagnosis was not influenced by CCR5 status. Similarly, no significant impact could be detected on the treatment outcome of stage III patients. In 139 stage IV patients receiving immunotherapy, CCR5 Delta 32 was associated with a decreased survival compared to patients not carrying the deletion (median 12.5 vs. 20.3 months, P = 0.029). Multivariate analysis revealed the CCR5 genotype as an independent factor impacting disease-specific survival in this patient population (P = 0.002), followed by gender (P = 0.019) and pathological classification of the primary (pT; P = 0.022). Conclusion The presence of the CCR5 Delta 32 polymorphism in patients with stage IV melanoma results in a decreased survival following immunotherapy and may help to select patients less likely to benefit from this type of treatment
    Type of Publication: Journal article published
    PubMed ID: 17909797
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  • 5
  • 6
    Keywords: CANCER ; CELL ; Germany ; KINASE ; GENE ; PATIENT ; RESPONSES ; primary ; DOMAIN ; ANTIGEN ; T cell ; T-CELL ; MR ; IDENTIFICATION ; PROGRESSION ; MUTATION ; MELANOMA ; METASTATIC MELANOMA ; LYMPHOCYTES ; MUTATIONS ; IMMUNITY ; CANCER-RESEARCH ; SELECTION ; MELANOMA PATIENTS ; CTL ; BRAF ; CANCER VACCINES ; T-CELL EPITOPES
    Abstract: Activating BRAF somatic missense mutations within the kinase domain are present in 60-66% of melanomas. The vast majority of these represent a single substitution of glutamate for valine (V599E). Here, we demonstrate spontaneous HLA-B*2705-restrieted cytotoxic T-cell responses against an epitope derived from (V599E)BRaf. These T-cell responses were mutation specific as the corresponding epitope derived from wildtype BRaf was not recognized. The loss of the (V599E)BRAF genotype during progression from primary to metastatic melanoma in patients with (V599E)BRaf specific T-cell responses suggests an active immune selection of nonmutated melanoma clones by the tumor-bearing host
    Type of Publication: Journal article published
    PubMed ID: 15289355
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  • 7
    Keywords: CELLS ; EXPRESSION ; proliferation ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; KINASE ; PATHWAY ; LUNG-CANCER ; PROTEIN ; LINES ; ACTIVATION ; SKIN ; ACTIVATED PROTEIN-KINASE ; CELL-LINES ; PHOSPHORYLATION ; signal transduction ; SIGNAL ; MAP KINASE ; IN-SITU ; MUTATION ; PROSTATE-CANCER ; SIGNAL-TRANSDUCTION ; CELL-LINE ; LINE ; MELANOMA ; MUTATIONS ; cell lines ; TUMOR CELLS ; BRAF ; Ras ; CELL CARCINOMA ; TUMOR-CELL ; ERK ; MAP ; IMMUNOHISTOCHEMICAL ANALYSIS ; RELEVANCE ; KINASE INHIBITOR ; BRAF GENE ; INHIBITOR PROTEIN ; RAF ; RAF KINASE
    Abstract: Merkel cell carcinoma (MCC) is a highly metastatic skin tumor. To assess the relevance of the Ras/Raf/MEK/MAP kinase pathway, we analyzed for activating B-Raf mutations and we elucidated the presence of the Raf Kinase Inhibitor Protein (RKIP) and extracellular signal-regulated kinase (ERK) as well as the phosphorylation status of ERK. All MCC samples were negative for the B-Raf V600E mutation. Remarkably, RKIP, which was shown to interfere with the activation of MEK by Raf, was highly expressed in primary as well as in metastatic MCC. Immunohistochemical analysis of the phosphorylation status of ERK revealed in 42 out of 44 samples a complete lack of activated ERK in the tumor cells although ERK is expressed; in the two positive cases phosphorylated ERK was restricted to a minor fraction of the tumor cells. Western blot analysis of three MCC-derived cell lines revealed in one case the pattern present in situ (i.e. high RKIP expression and complete absence of phosphorylated ERK). In summary, our data demonstrate the inactivity of the classical MAP kinase signal transduction pathway in MCC, which seems to be because of lack of activation as well as active deactivation. These findings should be accounted for in future therapeutic approaches for this tumor
    Type of Publication: Journal article published
    PubMed ID: 16498399
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  • 8
    Keywords: EXPRESSION ; SURVIVAL ; TUMORS ; DNA ; INFECTION ; SKIN ; virus ; PREVALENCE ; FEATURES ; MCV ; ABUNDANCE
    Abstract: The majority of Merkel cell carcinomas (MCCs) are associated with the recently identified Merkel cell polyomavirus (MCV). However, as it is still unclear to which extent the presence of MCV impacts tumor characteristics or clinical outcome, we correlated the MCV status of tumor lesions obtained from 174 MCC patients including 38 MCC patients from Australia and 138 MCC patients from Germany with clinical characteristics, histomorphology, immunohistochemistry, and course of the disease. MCV DNA was present in 86% of MCCs and, in contrast to previous reports, no significant difference in MCV prevalence was present between Australian and German MCC cases. When patients were stratified according to their MCV status, only tumor localization (P = 0.001), gender (P = 0.024), and co-morbidity, i.e., frequency of patients with previous skin tumors (P = 0.024), were significantly different factors. In contrast, year of birth and diagnosis, age at diagnosis, or histological type and features representing the oncogenic phenotype such as mitotic rate or expression of p16, p53, RB1, and Ki67 were not significantly different between MCV-positive and MCV-negative MCCs. MCV status also did not influence recurrence-free, overall, and MCC-specific survival significantly. In summary, although MCV-positive and MCV-negative MCCs may have different etiologies, these tumors have comparable clinical behaviors and prognosis
    Type of Publication: Journal article published
    PubMed ID: 21562568
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  • 9
    ISSN: 1573-675X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Growth factor deprivation induced cell death of the hematopoietic cell line 32Dcl3 is widely used as a model system to study apoptotic signalling pathways. Here we show that the onset of cell death after IL-3 withdrawal can be strongly delayed by either cycloheximide or actinomycin D, indicating that de novo protein synthesis is required. Subtractive cDNA library hybridization was used to identify genes upregulated in apoptotic 32Dcl3 cells. Here we present data showing metallothionein-I (MT-I) mRNA transiently upregulated by a factor of three- to 20-fold. Increased levels of total MT-I+II protein after IL-3 withdrawal were demonstrated. An induction of MT-I RNA as well as of MT-I+II total protein was also observed in serum deprived NIH3T3 fibroblasts. Testing the effect of different inducers of apoptosis on 32Dcl3 cells we found that only IL-3 withdrawal and ethanol treatment led to an upregulation of MT-I mRNA level. Since MTs are believed to play a role in the metabolism of zinc, we tested the effect of zinc on induced cell death. When 32Dcl3 cells are treated with zinc (50-300 μM) in the absence of IL-3, loss of viability as well as degradation of the cellular DNA were delayed, indicating that zinc represses apoptosis. On the other hand zinc pre-treatment induced MT expression and accelerated the onset of apoptosis. Our data, therefore, suggest that MT exerts a proapoptotic function.
    Type of Medium: Electronic Resource
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  • 10
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Medizinische Informatik, Biometrie und Epidemiologie; VOL: 15; DOC09 /20191206/
    Publication Date: 2019-12-07
    Description: High data quality is a precondition for valid scientific conclusions. Indicators should therefore routinely be used to evaluate data quality within the life cycle of health studies. In this project, 15 representatives of seven German population-based cohort studies assessed 51 quality indicators that were proposed in a guideline for networked medical research. The applicability of the indicators to primary data collections was assessed. In addition, their importance was evaluated using a scale ranging from 1 (essential) to 4 (not important). Moreover, their implementation in data quality assessments in the participating studies was evaluated. Comments on potential improvements could be made. Forty-three indicators were rated as applicable. Of these, 29 received a mean importance score of 2 (important) or better, nine received a mean importance score of 1.5 or better. The latter represent a potential core set of data quality indicators for cohort studies. Most indicators that were rated as highly important were used in data quality assessments of the participating studies. Points of criticism regarding the guideline related to its structure and the understandability of some indicators. It was concluded that further improvement of the data quality indicator set will increase its usefulness and applicability in primary data collections. In practice, a small subset of data quality indicators may suffice to capture the most important aspects of data quality in cohort studies.
    Description: Eine hohe Datenqualität ist wesentlich für valide wissenschaftliche Schlussfolgerungen. Indikatoren sollten daher routinemäßig angewendet werden, um die Datenqualität innerhalb des Lebenszyklus von Gesundheitsstudien zu beurteilen. In dem hier beschriebenen Projekt haben 15 Vertreter von sieben bevölkerungsbezogenen Kohortenstudien in Deutschland 51 Qualitätsindikatoren bewertet, die im Rahmen einer deutschen Leitlinie für die vernetzte medizinische Forschung vorgeschlagen wurden. Die Evaluation betraf die Anwendbarkeit der Indikatoren für primäre Datenerhebungen, deren Wichtigkeit auf einer Skala von 1 (essentiell) bis 4 (nicht wichtig) sowie deren Implementation in den teilnehmenden Kohorten. Verbesserungsvorschläge konnten gemacht werden. 43 Indikatoren wurden als anwendbar angesehen. Davon erhielten 29 eine durchschnittliche Wichtigkeit von mindestens 2 (wichtig), neun eine durchschnittliche Wichtigkeit von mindestens 1,5. Die als am wichtigsten bewerteten Indikatoren geben Hinweise auf einen für Kohortenstudien relevanten Kernsatz von Indikatoren zur Erfassung der Datenqualität. Die Mehrzahl der hoch bewerteten Indikatoren wurde in den teilnehmenden Kohorten im Rahmen der Datenqualitätssicherung betrachtet. Als Schwächen der Leitlinie wurden die Verständlichkeit einzelner Indikatoren sowie die Struktur der Leitlinie identifiziert. Das Konzept von Indikatoren zur Datenqualität sollte weiter verbessert werden, um den Nutzwert und die Anwendbarkeit im Rahmen primärer Datenerhebungen zu erhöhen. In der praktischen Anwendung reicht eine Teilmenge der Indikatoren aus, um wesentliche Aspekte der Datenqualität in Kohortenstudien zu beschreiben.
    Keywords: data quality ; cohort studies ; data quality indicators ; data monitoring ; Datenqualität ; Kohortenstudien ; Indikatoren ; Datenmonitoring ; ddc: 610
    Language: English
    Type: article
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