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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; CELL ; Germany ; neoplasms ; GENE ; GENE-EXPRESSION ; GENES ; transcription ; cell line ; MESSENGER-RNA ; primary ; recombination ; SEQUENCE ; SEQUENCES ; TARGET ; LYMPHOMA ; MALIGNANCIES ; UP-REGULATION ; CELL-LINE ; LINE ; LYMPHOCYTES ; INSTABILITY ; SOMATIC HYPERMUTATION ; B-CELL LYMPHOMA ; GENOMIC INSTABILITY ; HIGH-LEVEL ; MALIGNANCY ; ONCOLOGY ; RE ; COSTIMULATION ; LEVEL ; AID ; USA ; GERMINAL-CENTER ; B-LYMPHOCYTES ; cancer research ; HODGKIN LYMPHOMA ; genomic ; B-CELL ; LIMIT ; ACCESSIBILITY ; DIVERSIFICATION ; CLASS SWITCH RECOMBINATION ; SWITCHES ; ANTIBODY DIVERSIFICATION ENZYME ; CLASS-SWITCH RECOMBINATION ; DNA DEAMINATION ; HIGH-LOAD ; mediastinal B-cell lymphoma
    Abstract: Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in activated B lymphocytes and is potentially implicated in genomic instability of B-cell malignancies. For unknown reasons, B-cell neoplasms often lack SHM and CSR in spite of high MD expression. Here, we show that primary mediastinal B-cell hTnphoma (PMBL), an immunoglobulin (Ig)-negative lymphoma that possesses hypermutated, class-switched Ig aenes. expresses high levels of AID with an intact primary structure but does not do CSR in 14 of 16 cases analyzed. Absence of CSR coincided with low Ig germ-line transcription, whereas high level germ-line transcription was observed only in those two cases with active CSR. Interleukin-4/CD40L costimulation induced CSR and a marked up-regulation of,germ-line transcription in the PMBL-derived cell line MedB-1. In the PMBL cell line Karpas 1106P, CSR was not inducible and germ-line transcription remained low on stimulation. However, Karpas 1106P, but not MedB-1, had ongoing SHM of the Ig gene and BCL6. These genes were transcribed in Karpas 1106P, whereas transcription was undetectable or low in MedB-1 cells. Thus, accessibility of the target sequences seems to be a major limiting factor for AID-dependent somatic gene diversification in PMBL
    Type of Publication: Journal article published
    PubMed ID: 17638864
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  • 2
    Keywords: EXPRESSION ; SURVIVAL ; BLOOD ; CELL ; Germany ; GENE ; GENES ; PATIENT ; recombination ; ANTIGEN ; ASSOCIATION ; LYMPHOMA ; DIFFERENCE ; MUTATION ; ABERRATIONS ; DELETIONS ; B-CELLS ; AGGRESSIVE VARIANTS ; ATM GENE ; CD38 EXPRESSION ; CENTROCYTIC LYMPHOMA ; CHROMOSOMAL IMBALANCES ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; COMPLETE REMISSION ; IMMUNOGLOBULIN GENES ; MAJOR TRANSLOCATION CLUSTER ; SOMATIC HYPERMUTATION
    Abstract: Immunoglobulin variable heavy chain gene (V-H) mutation status and VDJ rearrangement structure were analyzed in 141 patients with mantle cell lymphoma (MCL) and correlated with biologic and clinical characteristics; 29% of the MCLs displayed mutated V-H using a 98% germline homology cutoff. Striking differences occurred in the VH mutation subgroups with respect to the use of specific V genes. Rearrangements involving V4-34 and V3-21 were almost exclusively unmutated, whereas rearrangements using V4-59 and V3-23 were typically mutated. Significant association occurred between mutated V-H with shorter CDR3 lengths and the use of J(H)4b. V3-21 and V4-59 were involved in highly characteristic rearrangements, implying that antigen specificity might have been involved in MCL development. There was no evidence for isotype switch recombination or Bcl-6 expression in any MCL. ZAP70 expression was not different in V-H-mutated or unmutated MCL. Although the deletions 11q- and 17p- showed a balanced distribution, an overrepresentation was observed for trisomies +3q, +8q, and tetraploidy in the V-H-unmutated subgroup and +12q in the V-H-mutated subgroup. Clinically, mutated V-H was associated with a higher rate of complete remission, but there was no correlation between VH mutation status and other clinical characteristics or overall survival. (Blood. 2003; 102:3003-3009) (C) 2003 by The American Society of Hematology
    Type of Publication: Journal article published
    PubMed ID: 12842981
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  • 3
    Keywords: CANCER ; EXPRESSION ; CELL ; Germany ; GENE ; HYBRIDIZATION ; DNA ; INDEX ; tumour ; CONTRAST ; chromosome ; virus ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; cytogenetics ; LYMPHOMA ; MALIGNANCIES ; NUMBER ; leukemia ; ABERRATIONS ; IN-SITU HYBRIDIZATION ; MORPHOLOGY ; ABNORMALITIES ; FLUORESCENCE ; IMBALANCES ; C-MYC ; INTERPHASE ; EPSTEIN-BARR-VIRUS ; B-CELL LYMPHOMA ; Bcl-2 ; chemoresistance ; F ; CHROMOSOMAL BREAKPOINTS ; Epstein-Barr virus ; FEATURES ; immunohistology ; molecular cytogenetics ; sporadic and endemic Burkitt's lymphoma ; TRANSLOCATIONS
    Abstract: The present study has compared immunohistological marker expression profiles and genomic imbalances in seven African endemic Burkitt's lymphomas (eBLs) with those in ten European B-cell lymphomas with MYC rearrangement as shown by fluorescence in situ hybridization (FISH) analysis. eBLs showed a typical histomorphology and a homogeneous immuno-profile: CD10+, CD38+, CD77+, bcl-2-, and IgM+. Epstein-Barr virus (EBV) DNA was present in all cases. On comparative genomic hybridization (CGH), only three out of six eBLs showed imbalances (median number of imbalances = 2), with gains on chromosome 17 in two eBLs. The European lymphomas were all highly proliferating, with a Ki-67 index of at least 90%, and included seven with morphology typical of sporadic Burkitt's lymphoma (sBL) and three immunoblastic diffuse large B-cell lymphomas with MYC rearrangement (MYC re+DLBCL). In contrast to eBL, the immuno-profiles of the European lymphomas were less homogeneous and inconsistent for CD10, CD38, CD77, IgM and bcl-2 expression. EBV DNA was not detected. In five of seven sBLs, CGH showed a higher number of imbalances (median = 6), with recurrent gains on chromosome 1q (3/7) and losses on 12q and 17p (2/7), whereas all three MYC re+DLBCLs had fewer imbalances (median = 4), with gains on 17q in two of three lymphomas. It is concluded that eBL has a homogeneous immunohistology and few secondary genomic aberrations, whereas MYC-rearranged and highly proliferating European B-cell lymphomas are a heterogeneous group that includes sBL and a subgroup of diffuse large B-cell lymphomas. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd
    Type of Publication: Journal article published
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  • 4
    Keywords: CANCER ; EXPRESSION ; tumor ; carcinoma ; Germany ; human ; LUNG ; GENE ; GENE-EXPRESSION ; HYBRIDIZATION ; PROTEIN ; MONOCLONAL-ANTIBODY ; TISSUE ; TUMORS ; kidney ; TISSUES ; BREAST-CANCER ; antibodies ; antibody ; STAGE ; IN-SITU ; PROGRESSION ; ARRAYS ; metastases ; HETEROZYGOSITY ; REGION ; MONOCLONAL-ANTIBODIES ; CARCINOMAS ; NORMAL TISSUE ; HISTONE ACETYLTRANSFERASE ; ovarian carcinoma ; METHYLATION ; MITOSIS ; DEFICIENCY ; ONCOLOGY ; pancreas ; RE ; PATTERN ; ARRAY ; mRNA ; MALIGNANT PROGRESSION ; biomarker ; monoclonal antibodies ; EPITHELIAL TUMORS ; USA ; LOSSES ; MAMMARY-CARCINOMA ; SET ; NOV ; cDNA array ; NUCLEAR-MEMBRANE ; epigenetic regulation ; hMOF ; RECESSIVE CEREBELLAR-ATAXIA ; SYNE-1
    Abstract: In a study on gene deregulation in ovarian carcinoma we found a mRNA ceding for a 350 kDa protein, Drop1, to be downregulated 20- to 180-fold in the majority of ovarian and mammary carcinomas. The mRNA is encoded by a set of exons in the 5' region of the SYNE1 gene. Immunohistochemical staining for Drop1 protein by a specific monoclonal antibody corresponds to the pattern seen for the mRNA. cDNA arrays of matched pairs of tumor and normal tissue and in situ hybridizations confirmed the drastic loss of Drop1 mRNA as a common feature in uterus, cervix, kidney, lung, thyroid and pancreas carcinomas, already at early tumor stages and in all metastases. Two-hybrid studies suggest a role of this deficiency in the malignant progression of epithelial tumors. (c) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18709643
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  • 5
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; SURVIVAL ; tumor ; carcinoma ; CELL ; COMBINATION ; Germany ; IN-VIVO ; MODEL ; MODELS ; THERAPY ; VITRO ; VIVO ; PROTEINS ; SAMPLE ; SAMPLES ; TIME ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; INDEX ; TISSUES ; CONTRAST ; ANTITUMOR-ACTIVITY ; TARGET ; MOUSE ; resistance ; CARCINOMA CELLS ; CELL-DEATH ; MEMBRANE ; CARCINOMA-CELLS ; adenocarcinoma ; NORMAL TISSUE ; REVEALS ; CHILDREN ; pancreatic cancer ; pancreatic carcinoma ; TRAIL ; HUMAN PROSTATE-CANCER ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; DRUG-INDUCED APOPTOSIS ; INHIBITORS ; PANCREATIC-CANCER ; THERAPIES ; DECOY RECEPTORS ; development ; X-LINKED INHIBITOR ; pancreatic adenocarcinoma ; USA ; ANTAGONISTS ; pancreatic tumor ; IRRADIATION-INDUCED APOPTOSIS ; XIAP ; therapeutic ; ALPHA-DEPENDENT APOPTOSIS
    Abstract: Evasion of apoptosis is a characteristic feature of pancreatic cancer, a prototypic cancer that is refractory to current treatment approaches. Hence, there is an urgent need to design rational strategies that counter apoptosis resistance. To explore X-linked inhibitor of apoptosis (XIAP) as a therapeutic target in pancreatic cancer, we analyzed the expression of XIAP in pancreatic tumor samples and evaluated the effect of small molecule XIAP inhibitors alone and in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against pancreatic carcinoma in vitro and in vivo. Here, we report that XIAP is highly expressed in pancreatic adenocarcinoma samples compared with normal pancreatic ducts. Small molecule XIAP inhibitors synergize with TRAIL to induce apoptosis and to inhibit long-term clonogenic survival of pancreatic carcinoma cells. In contrast, they do not reverse the lack of toxicity of TRAIL on nonmalignant cells in vitro or normal tissues in vivo, pointing to a therapeutic index. Most importantly, XIAP inhibitors cooperate with TRAIL to trigger apoptosis and suppress pancreatic carcinoma growth in vivo in two preclinical models, i.e., the chorioallantoic membrane model and a mouse xenograft model. Parallel immunohistochemical analysis of tumor tissue under therapy reveals that the XIAP inhibitor acts in concert with TRAIL to cause caspase-3 activation and apoptosis. In conclusion, our findings provide, for the first time, evidence in vivo that XIAP inhibitors prime pancreatic carcinoma cells for TRAM-induced apoptosis and potentiate the antitumor activity of TRAIL against established pancreatic carcinoma. These findings build the rationale for further (pre)clinical development of XIAP inhibitors and TRAIL against pancreatic cancer. [Cancer Res 2009;69(6):2425-34]
    Type of Publication: Journal article published
    PubMed ID: 19258513
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  • 6
    Keywords: EXPRESSION ; SURVIVAL ; tumor ; Germany ; neoplasms ; GENE ; GENES ; GENOME ; HYBRIDIZATION ; microarray ; SAMPLE ; SAMPLES ; transcription ; ACTIVATION ; DNA ; mechanisms ; TARGET ; STAGE ; IN-SITU ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; LYMPHOMA ; DNA microarray ; microarrays ; ABERRATIONS ; DELETIONS ; POLYMERASE-CHAIN-REACTION ; DNA AMPLIFICATION ; FLUORESCENCE ; gene amplification ; IMBALANCES ; GAINS ; B-CELL LYMPHOMA ; CGH ; matrix-CGH ; DNA COPY-NUMBER
    Abstract: DNA amplifications are important mechanisms for protooncogene activation. Comparative genomic hybridization (CGH) to metaphase chromosome preparations has revealed amplifications in 10-20% of B-cell lymphomas (B-NHL). We analysed a series of 16 aggressive non-Hodgkin lymphomas by the new approach termed Matrix-CGH (M-CGH) using genomic DNA microarrays as hybridization target. For M-CGH, a dedicated B-cell lymphoma chip was constructed containing 496 genomic targets covering oncogenes, tumor suppressor genes as well as chromosome regions frequently altered in B-NHL. In 10 of 16 samples a total of 15 DNA amplifications were identified. The amplicons included BCL2, REL, CCND1, CCND2, JAK2, FGF4 and MDM2. Four of the 15 amplifications remained undetected by chromosomal CGH. The respective amplicons mapped to bands 2p13, 9p13-p21 and 12q24 and, were confirmed by fluorescence in situ hybridization. Furthermore, for four genomically amplified genes real-time quantitative reverse transcription polymerase chain reaction revealed elevated mRNA expression levels. These data show the superior diagnostic sensitivity of the newly developed diagnostic tool. As only a small portion of the genome (approximately 1.5%) has been analysed by the present DNA array, it is likely that gene amplifications are much more common in aggressive lymphomas than previously assumed
    Type of Publication: Journal article published
    PubMed ID: 12618769
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  • 7
    Keywords: CELLS ; EXPRESSION ; Germany ; POPULATION ; SITE ; GENE ; PROTEIN ; MONOCLONAL-ANTIBODY ; TISSUE ; recombination ; T-CELLS ; immunohistochemistry ; MALIGNANCIES ; B-CELLS ; PHENOTYPE ; RT-PCR ; ANTIBODY-RESPONSES ; MALIGNANCY ; thymus ; SUBSET ; LEVEL ; LYMPHOMAS ; lymph node ; LYMPH-NODE ; INDUCED CYTIDINE DEAMINASE ; IMMUNOGLOBULIN CLASS-SWITCH
    Abstract: Neoplastic transformation of mature B cells can be triggered by class-switch recombination of the immunoglobulin gene, which aberrantly targets a protooncogene and promotes translocation. Class-switch recombination is initiated by the B-cell-specific protein activation-induced cytidine deaminase (AID). Using immunohistochemistry with a newly generated monoclonal antibody and quantitative reverse-transcription-polymerase chain reaction (RT-PCR) on microdissected tissue from lymph node, tonsil, and thymus, we demonstrate that AID expression is found in secondary lymphoid organs outside germinal centers and in the thymic medulla at substantial levels. This is accompanied by the presence of circle transcripts, indicating class-switch recombination to be active at these sites. The dominant AID-expressing cell population outside germinal centers displays cytomorphologic properties corresponding to those that define the recently characterized interfollicular large B-cell subset. These findings indicate that interfollicular large B cells and AID-expressing B lymphocytes of the thymic medulla could give rise to mature B-cell malignancies
    Type of Publication: Journal article published
    PubMed ID: 16269615
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  • 8
    Keywords: SURVIVAL ; CELL ; evaluation ; Germany ; DISEASE ; incidence ; SAMPLE ; SAMPLES ; MOLECULAR CHARACTERIZATION ; TIME ; PATIENT ; INDEX ; prognosis ; DELETION ; NO ; TRIAL ; TRIALS ; IN-SITU ; LYMPHOMA ; DESIGN ; DELETIONS ; REGION ; REGIONS ; EVOLUTION ; INSIGHTS ; fluorescence in situ hybridization ; ATM GENE ; CHROMOSOMAL IMBALANCES ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; MANTLE CELL LYMPHOMA ; HETEROGENEITY ; P53 GENE ; overall survival ; GENOMIC ABERRATIONS ; H MUTATION STATUS ; analysis ; methods ; LOSSES ; correlation ; BLASTOID VARIANTS ; SOMATIC MUTATIONS ; FOLLICLE MANTLE
    Abstract: Background The genetic hallmark of mantle cell lymphoma is a t(11;14)(q13;q32). However, additional genomic alterations are likely involved in the pathogenesis of this lymphoma. Design and Methods To determine the incidence and clinical relevance of these aberrations, we analyzed 103 well-characterized samples of mantle cell lymphoma by fluorescence in situ hybridization for the most common recurrent additional genomic findings. Results Screening 16 different regions we detected additional genomic aberrations in 92% of the cases of mantle cell lymphoma. Common gains included 3q26, 8q24, 15q23, 7p15, and common losses 13q14, 11q22-q23, 9p21, 1p22, 17p13, 6q27, and 8p22. Deletions 8p22, 9p21, 13q14, and gain of 7p15 were associated with evidence of clonal heterogeneity. While there was no correlation of additional genomic aberrations and VH-mutation status, gain of 15q23 and deletion 6q27 were associated with lower disease stage (p=0.01 and p=0.04, respectively). Patients with deletion 13q14 had shorter overall survival times (p=0.01), and there was a strong trend towards inferior outcome in patients with deletion 9p21 (p=0.07). In multivariable analysis, loss of 13q14 and an International Prognosis Index score ! 3 turned out to be significantly associated with inferior clinical outcome (p=0.002 and p〈0.001, respectively). Conclusions The comprehensive analysis of additional genomic aberrations in mantle cell lymphoma provided further evidence for the prognostic relevance of loss of 13q14, which warrants evaluation within prospective trials. Furthermore, our analysis gave novel insights into the pathogenesis of mantle cell lymphoma with regard to the detection of clonal heterogeneity, possibly indicating clonal evolution in this type of lymphoma
    Type of Publication: Journal article published
    PubMed ID: 18367489
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  • 9
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; proliferation ; SURVIVAL ; CELL ; Germany ; DISEASE ; GENE ; GENES ; PROTEIN ; MOLECULES ; PATIENT ; prognosis ; T cells ; T-CELL ; VARIANTS ; leukemia ; PCR ; HIGH-RISK ; CD8(+) ; IMMUNOTHERAPY ; TARGETS ; DIFFERENTIAL EXPRESSION ; MULTIPLE-MYELOMA ; TUMOR-ASSOCIATED ANTIGENS ; VARIANT ; ACUTE MYELOID-LEUKEMIA ; CLL ; MUTATION STATUS ; PROGNOSTIC MARKER ; B-cell chronic lymphocytic leukemia (B-CLL) ; cytotoxic T lymphocytes (CTL) ; receptor for hyaluronic acid mediated motility (RHAMM/CD168) ; RHAMM ; SOLUBLE CD44 ; tumor-associated antigens (TAAs)
    Abstract: Differential expression of molecules in chronic lymphocytic leukemia (CLL) may define prognostic markers and suitable targets for immunotherapy. Expression of the tumor-associated antigen (TAA) RHAMM (receptor for hyaluronic acid-mediated motility) as well as RHAMM splicing variants was assessed in series of 72 CLL patients. Quantitative reverse transcriptase PCR showed higher RHAMM expression in high-risk CLL patients, as well as in the advanced stages of the disease. CLL cases with a higher RHAMM expression showed a significantly shorter median treatment-free survival. Among patients with mutated immunoglobulin heavy chain genes, an analysis of RHAMM expression enabled to distinguish subgroup of patients with favorable prognosis. In lymph nodes, RHAMM staining correlated with a higher Ki-67 index and CD40L expression. Functionally, stimulation with CD40L enhanced RHAMM expression in CLL. We further characterized RHAMM-specific CD8(+) T cells in patients with CLL, as the expression of TAAs might influence the clinical outcome by the means of immune reactions. The cytotoxic potential of RHAMM-specific T cells was shown against target cells bearing RHAMM-derived epitope as well as against CLL cells expressing RHAMM. In conclusion, RHAMM expression appears to be of prognostic value, as well as may reflect the proliferative capacity of CLL cells, and might therefore represent interesting target for immunotherapy
    Type of Publication: Journal article published
    PubMed ID: 19092852
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  • 10
    Keywords: CANCER ; SURVIVAL ; tumor ; CELL ; Germany ; human ; GENE ; GENES ; HYBRIDIZATION ; SAMPLE ; SAMPLES ; MOLECULAR CHARACTERIZATION ; PATIENT ; DNA ; PAIRS ; chromosome ; FREQUENCY ; DELETION ; IDENTIFICATION ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; LYMPHOMA ; NUMBER ; leukemia ; ABERRATIONS ; DELETIONS ; TUMOR-SUPPRESSOR GENE ; REGION ; PROGNOSTIC-FACTORS ; REGIONS ; ONCOGENE ; FLUORESCENCE ; ATM GENE ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; MANTLE CELL LYMPHOMA ; HIGH-FREQUENCY ; NON-HODGKINS-LYMPHOMA ; F ; ONCOLOGY ; CHROMOSOME-TRANSLOCATION ; H MUTATION STATUS
    Abstract: Tumor samples of 53 patients with t(11;14)-positive mantle cell lymphomas (MCLs) were analyzed by matrix-based comparative genomic hybridization (matrix-CGH) using a dedicated DNA array. In 49 cases, genomic aberrations were identified. In comparison to chromosomal CGH, a 50%. higher number of aberrations was found and the high specificity of,matrix-CGH was demonstrated by fluorescence in situ hybridization (FISH) analyses. The 11q gains and 13q34 deletions, which have not been described as frequent genomic aberrations in MCL, were identified by matrix-CGH in 15 and 26 cases, respectively. For several genomic aberrations, novel consensus regions were defined: 8p21 (size of the consensus region, 2.4 megabase pairs [Mbp]; candidate genes: TNFRSF10B, TNFRSF10C, TNFRSF10D); 10p13 (2.7 Mbp; BM/1); 11q13 (1.4 Mbp; RELA); 11q13 (5.2 Mbp; CCND1); 13q14 (0.4 Mbp; RFP2, BCMSUN) and 13q34 (6.9 Mbp). In univariate analyses correlating genomic aberrations and clinical course, 8p- and 13q14- deletions were associated with an inferior overall survival. These data provide a basis for further studies focusing on the identification of pathogenetically or clinically relevant genes, in MCL
    Type of Publication: Journal article published
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