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  • 1
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; tumor ; carcinoma ; Germany ; GENE ; GENES ; HYBRIDIZATION ; microarray ; DNA ; ASSOCIATION ; BREAST-CANCER ; IDENTIFICATION ; IN-SITU ; COPY NUMBER ; microarrays ; DESIGN ; NUMBER ; ABERRATIONS ; REGIONS ; OVEREXPRESSION ; CLUSTER ; E-cadherin ; RE ; CANDIDATE GENES ; REVERSE TRANSCRIPTION-PCR ; EXPRESSION PATTERNS ; ARRAY-CGH ; LOBULAR CARCINOMA
    Abstract: Purpose: Invasive ductal carcinoma and invasive lobular carcinoma (ILC) represent the major histologic subtypes of invasive breast cancer. They differ with regard to presentation, metastatic spread, and epidemiologic features. To elucidate the genetic basis of these differences, we analyzed copy number imbalances that differentiate the histologic subtypes. Experimental Design: High-resolution genomic profiling of 40 invasive breast cancers using matrix-comparative genomic hybridization with an average resolution of 0.5 Mb was conducted on bacterial artificial chromosome microarrays. The data were subjected to classification and unsupervised hierarchical cluster analyses. Expression of candidate genes was analyzed in tumor samples. Results: The highest discriminating power was achieved when combining the aberration patterns of chromosome arms 1q and 16p, which were significantly more often gained in ILC. These regions were further narrowed down to subregions 1q24.2-25.1, 1q25.3-q31.3, and 16p11.2. Located within the candidate gains on 1q are two genes, FMO2 and PTGS2, known to be overexpressed in ILC relative to invasive ductal carcinoma. Assessment of four candidate genes on 16p11.2 by real-time quantitative PCR revealed significant overexpression of FUS and ITGAX in ILC with 16p copy number gain. Unsupervised hierarchical cluster analysis identified three molecular subgroups that are characterized by different aberration patterns, in particular concerning gain of MYC (8q24) and the identified candidate regions on 1q24.2-25.1, 1q25.3-q31.3, and 16p11.2. These genetic subgroups differed with regard to histology, tumor grading, frequency of alterations, and estrogen receptor expression. Conclusions: Molecular profiling using bacterial artificial chromosome arrays identified DNA copy number imbalances on 1q and 16p as significant classifiers of histologic and molecular subgroups
    Type of Publication: Journal article published
    PubMed ID: 16428471
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  • 2
    Keywords: EXPRESSION ; tumor ; carcinoma ; CELL ; Germany ; human ; INFORMATION ; HEPATOCELLULAR-CARCINOMA ; HISTORY ; GENE ; GENES ; HYBRIDIZATION ; DIFFERENTIATION ; TUMORS ; RESOLUTION ; DNA ; MECHANISM ; mechanisms ; ADENOMAS ; hepatocellular carcinoma ; PROGRESSION ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; NUMBER ; CHROMOSOMAL-ABERRATIONS ; ABERRATIONS ; IN-SITU HYBRIDIZATION ; TUMOR-SUPPRESSOR GENE ; REGION ; INSTABILITY ; REGIONS ; ONCOGENE ; TRANSFORMATION ; ORAL-CONTRACEPTIVES ; CARCINOMAS ; IMBALANCES ; CLUSTER ; MOLECULAR-MECHANISM ; TUMOR-SUPPRESSOR ; INCREASE ; CLUSTER-ANALYSIS ; CHROMOSOMAL INSTABILITY ; CHIP ; tumor suppressor gene ; cluster analysis ; LOSSES ; GLYCOGEN-STORAGE-DISEASE ; genomic ; HUMAN HEPATOCELLULAR-CARCINOMA ; ARRAY CGH ; CHROMOSOMAL-ABNORMALITIES ; TUMOR-SUPPRESSOR GENES ; ARRAY-CGH ; LIVER-CELL ADENOMAS
    Abstract: Background & Alms: To gain more information about the molecular mechanisms leading to dedifferentiation of hepatocellular adenoma (HCA) and hepatocellular carcinoma (HCC), high-resolution array-based comparative genomic hybridization (array-CGH) was performed on 24 cases of HCC and 10 cases of HCA. Methods: DNA chips containing 6251 individual bacterial artificial chromosome/plasmid artificial chromosome clones were used. They allowed for a genome-wide resolution of 1 Mb and an even higher resolution of up to 100 kb for chromosome regions recurrently involved in human tumors and for regions containing known tumor-suppressor genes and oncogenes. Results: Copy number changes on the genomic scale were found by array-based comparative genomic hybridization in all cases. In HCC, gains of chromosomal regions 1q (91.6%), and 8q (58.3%), and losses of 8p (54%) were found most frequently. Hierarchic cluster analysis branched all HCA from HCC. However, in 2 adenomas with a known history of glycogenosis type I and adenomatosis hepatis gains of 1q were found, too. The critically gained region was narrowed down to bands 1q22-23. Although no significant differences in the mean number of chromosomal aberrations were seen between adenomas and well-differentiated carcinomas (2.7 vs 4.6), a significant increase accompanied the dedifferentiation of HCC (14.1 in HCC-G2 and 16.3 in HCC-G2/3; P 〈 .02). Dedifferentiation of HCC also was correlated closely to losses of 4q and 13q (P 〈 .001 and 〈 .005, respectively). Conclusions: The increased chromosomal instability during dedifferentiation of HCC leads to an accumulation of structural chromosomal aberrations and losses and gains of defined chromosome regions
    Type of Publication: Journal article published
    PubMed ID: 16979954
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  • 3
    Abstract: BACKGROUND: The reliable identification of non-small cell lung cancers (NSCLC) with chromosomal breaks in the gene of the anaplastic lymphoma kinase (ALK) is crucial for the induction of therapy with ALK-inhibitors. In order to ensure a reliable detection of ALK-breaks by means of fluorescence in situ hybridization (FISH) testing, round robin tests are essential. In preparation of a nation (German)-wide round robin test we initiated a pre-testing phase involving 8 experts in FISH-diagnostics to identify NSCLC cases (n = 10) with a pre-tested ALK-status. In addition, ALK immunohistochemistry (IHC) was performed to assess ALK protein expression. MATERIAL AND METHODS: Sections derived from a tissue microarray, each consisting of 3 cores from 10 NSCLC cases, were independently tested for ALK protein expression by IHC and genomic ALK-breaks by FISH involving 8 institutes of pathology. Based on a pre-screening, 5 cases were identified to be clearly ALK-break negative, whereas the remaining 5 cases were ALK-break positive including one case with low percentage (20%) of positive cells. The latter had been additionally tested by RT-PCR. RESULTS: The 5 unequivocal ALK-break negative NSCLC were almost consistently scored negative by means of FISH and IHC by all 8 experts. Interestingly, 4 of the 5 cases with pre-defined ALK-breaks revealed homogenous FISH results whereas IHC for the detection of ALK protein expression showed heterogeneous results. The remaining case (low number of ALK-break positive cells) was scored negative by 3 experts and positive by the other 5. RT-PCR revealed the expression of an EML4-ALK fusion gene variant 1. CONCLUSION: ALK-break negative NSCLC cases revealed concordant homogeneous results by means of FISH and IHC (score 0-1) by all 8 experts. Discordant FISH results were raised in one ALK-break positive case with a low number of affected tumor cells. The remaining 4 ALK-break positive cases revealed concordant FISH data whereas the ALK-IHC revealed very diverse results. The cases with concordant FISH results provide an excellent basis for round robin ALK-FISH testing. As long as standardized ALK-IHC protocols are missing, ALK protein expression cannot by regarded as the method of choice for identification of patients eligible for treatment with ALK inhibitors.
    Type of Publication: Journal article published
    PubMed ID: 23669200
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  • 4
    Abstract: Since acute myeloid leukemia (AML) is characterized by the blockade of hematopoietic differentiation and cell death, we interrogated RIPK3 signaling in AML development. Genetic loss of Ripk3 converted murine FLT3-ITD-driven myeloproliferation into an overt AML by enhancing the accumulation of leukemia-initiating cells (LIC). Failed inflammasome activation and cell death mediated by tumor necrosis factor receptor caused this accumulation of LIC exemplified by accelerated leukemia onset in Il1r1(-/-), Pycard(-/-), and Tnfr1/2(-/-) mice. RIPK3 signaling was partly mediated by mixed lineage kinase domain-like. This link between suppression of RIPK3, failed interleukin-1beta release, and blocked cell death was supported by significantly reduced RIPK3 in primary AML patient cohorts. Our data identify RIPK3 and the inflammasome as key tumor suppressors in AML.
    Type of Publication: Journal article published
    PubMed ID: 27411587
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  • 5
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    German Medical Science; Düsseldorf, Köln
    In:  77. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie e.V.; 20060524-20060528; Mannheim; DOC06hnod573 /20060424/
    Publication Date: 2006-04-25
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 6
    Keywords: TRIAL ; PREOPERATIVE CHEMOTHERAPY ; ESTROGEN ; SUBTYPES ; GENE-EXPRESSION SIGNATURE ; PATHOLOGISTS GUIDELINE RECOMMENDATIONS ; AMERICAN-SOCIETY ; CLINICAL-ONCOLOGY/COLLEGE ; PHARMACOGENOMIC PREDICTOR ; RECURRENCE SCORE
    Abstract: Breast cancer is a heterogeneous disease of different subtypes on the molecular, histopathological, and clinical level. Genomic profiling techniques have led to several prognostic and predictive gene signatures of breast cancer that may further refine outcome prediction, especially in clinically equivocal situations. In particular, the predictive value of today's most important therapeutic targets, ER and HER2, are strongly influenced by the proliferative status of the tumor. Genomic assays are generally performed in a centralized manner, whereas routine pathological evaluation is mostly done on a decentralized basis, making the comparison of these methods difficult. Thus, there remains considerable uncertainty about the use of the new molecular markers in routine clinical decision making and their role in patient selection or stratification for future clinical trials. To address this concern, a group of representatives from breast cancer research groups in the areas of breast pathology, genomic profiling, and clinical trials critically reviewed all available data. Consensus recommendations are made on the practical use of molecular markers in breast cancer management and their incorporation into future clinical trials.
    Type of Publication: Journal article published
    PubMed ID: 21472705
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  • 7
  • 8
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    German Medical Science; Düsseldorf, Köln
    In:  GMS Current Posters in Otorhinolaryngology - Head and Neck Surgery; VOL: 2; DOC139 /20060424/
    Publication Date: 2006-04-24
    Description: Das Akustikusneurinom (AN) ist ein gutartiger Tumor, der aus den Schwann-Zellen des VIII. Hirnnervs hervorgeht. Es werden verschiedene genetische Auslöser für die Entstehung des AN diskutiert. Bislang existieren jedoch kaum Kenntnisse hinsichtlich der wachstumsbeeinflussenden Faktoren.Ziel dieser immunhistochemischen Studie war es, die Expression des neurotrophen Faktors Erythropoietin (EPO) und seines Rezeptors EPO-R an einer Serie von 38 AN der sporadischen Variante und an 16 AN, die sich im Rahmen einer Neurofibromatose Typ II manifestierten, zu untersuchen. Zusätzlich erfolgte der Nachweis des Hypoxia Inducible Factor-1a (HIF-1a), der den wichtigsten Regulator der EPO-Expression darstellt, sowie des anti-apoptotischen Proteins bcl-2. Um die Bedeutung von EPO für das Wachstumsverhalten des AN zu untersuchen, wurde der Ki-67-Proliferationsindex (PI) sowie die Vaskularisation der Tumoren ermittelt.36 der 54 (66%) untersuchten AN zeigten eine positive Immunreaktion für EPO und in 46 Fällen (85%) ließ sich EPO-R nachweisen. In 41 Fällen (76%) konnte HIF-1a, in 48 Fällen (89%) bcl-2 nachgewiesen werden. Die Expression von EPO und EPO-R korrelierte dabei mit der Expression von bcl-2. AN mit hoher Expression von HIF-1a, EPO und bcl-2 zeigten einen signifikant höheren PI.Die in beiden Varianten des AN demonstrierte Expression von EPO und EPO-R legt eine funktionelle Bedeutung für das biologische und klinische Verhalten dieses Tumors nahe. Die Korrelation der Expression von EPO und EPO-R mit bcl-2 kann als Hinweis gewertet werden, dass EPO seine anti-apoptotische Wirkung auch im AN über bcl-2 entfaltet. Die Korrelation der Expression von HIF-1a, EPO und bcl-2 mit dem PI spricht für eine Bedeutung dieser Faktoren für das Wachstumsverhalten des AN.
    Keywords: ddc: 610
    Language: German
    Type: article
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  • 9
    ISSN: 1432-119X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary In the present study unstimulated and stimulated human blood monocytes, untreated and phorbol ester treated U-937 cells, as well as human peritoneal and alveolar macrophages were studied with respect to their surface membrane properties. Binding of different lectins and electrophoretic patterns of tritium labeled surface glycoproteins were compared. The analysis of surface glycoproteins could be interpreted as evidence for a common origin of the analysed cell populations. Furthermore, banding patterns of glycoproteins might be useful to define certain activation states within monocyte/macrophage differentiation. In contrast, lectin binding pattern did not clearly discriminate macrophage subpopulations.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-0584
    Keywords: EBV ; Hodgkin's disease ; Proliferation Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The role of Epstein-Barr virus (EBV) in the pathogenesis of Hodgkin's disease (HD) has not yet been clarified. Using RNA in situ hybridization (ISH) and immunohistochemistry (IHC), the occurrence of small Epstein-Barr virus encoded RNA (EBER) and latent membrane protein-1 (LMP-1) was studied in 22 tissue samples from 21 patients between 4 and 17 years of age with Hodgkin's disease. EBER was detected in eight of 21 patients (38%) in Hodgkin and Reed-Sternberg cells and reactive lymphocytes irrespective of initial clinical stage and histological subtype, whereas LMP-1, positive in ten of 21 patients (48%), was restricted to neoplastic cells. All cases positive for EBER expressed LMP-1 as well. Additionally, oncoprotein Bcl-2 was identified in nine of 21 patients (43%), indicating, besides immortalization of HD cells by EBV, a further growth advantage due to apoptosis prevention by overexpression of this protein. Proliferation-associated antigens Ki-S1 and Ki-S5 were highly expressed in Hodgkin and Reed-Sternberg cells. CD 30 antigen was found in most cases, using two different antibodies (90% and 80%). The presence of this protein, which belongs to the family of nerve growth factor receptor (NGFR), is related to high expression of Ki-67 protein, detected by Ki-S5. CD 20 antigen was detectable in only three of 21 patients (14%). If we compare results of ISH and IHC with clinical data, the occurrence of EBV genome in children with HD seems to have no adverse effect on the final outcome of these patients.
    Type of Medium: Electronic Resource
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