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  • 1
    Language: German
    Description: 99 p.
    Keywords: Hanse ; Geschichte
    ISBN: 9783864030963
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  • 2
    Language: English
    In: PLoS ONE, 2012, Vol.7(3), p.e34128
    Description: Prostate cancer susceptibility has previously been associated with truncating germline variants in the gene TP53AIP1 (tumor protein p53 regulated apoptosis inducing protein 1). For two apparently recurrent mutations (p.Q22fs and p.S32X) a remarkable OR of 5.1 was reported for prostate cancer risk. Since these findings have not been validated so far, we genotyped p.Q22fs and p.S32X in two German series with a total of 1,207 prostate cancer cases and 1,495 controls. The truncating variants were not significantly associated with prostate cancer in none of the two cohorts, nor in the combined analysis [odds ratio (OR) = 1.16; 95% confidence interval (CI 95%) = 0.62–2.15; p = 0.66]. Carriers showed no significant differences in family history of prostate cancer, age at diagnosis, Gleason score or PSA at diagnosis when compared to non-carrier prostate cancer cases. The large sample size of the combined cohort rejects a high-risk effect greater than 2.2 and indicates a limited role of TP53AIP1 in prostate cancer predisposition.
    Keywords: Research Article ; Biology ; Medicine ; Genetics And Genomics ; Public Health And Epidemiology ; Urology ; Oncology
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(4), p.e0120174
    Description: Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). Previously, it has been shown that infiltrating CD4-positive T cells and M2 macrophages are associated with several fibrotic conditions. Therefore, the characteristics of the peritoneal cell infiltrate in EPS may be of interest to understand EPS pathogenesis. In this study, we aim to elucidate the composition of the peritoneal cell infiltrate in EPS patients and relate the findings to clinical outcome.We studied peritoneal membrane biopsies of 23 EPS patients and compared them to biopsies of 15 PD patients without EPS. The cellular infiltrate was characterized by immunohistochemistry to detect T cells (CD3-positive), CD4-positive (CD4+) and CD8-positive T cell subsets, B cells (CD20-positive), granulocytes (CD15-positive), macrophages (CD68-positive), M1 (CD80-positive), and M2 (CD163-positive) macrophages. Tissues were analysed using digital image analysis. Kaplan-Meier survival analysis was performed to investigate the survival in the different staining groups.The cellular infiltrate in EPS biopsies was dominated by mononuclear cells. For both CD3 and CD68, the median percentage of area stained was higher in biopsies of EPS as opposed to non-EPS patients (p〈0.001). EPS biopsies showed a higher percentage of area stained for CD4 (1.29% (0.61-3.20)) compared to CD8 (0.71% (0.46-1.01), p = 0.04), while in the non-EPS group these cells were almost equally represented (respectively 0.28% (0.05-0.83) versus 0.22% (0.17-0.43), p = 0.97). The percentage of area stained for both CD80 and CD163 was higher in EPS than in non-EPS biopsies (p〈0.001), with CD163+ cells being the most abundant phenotype. Virtually no CD20-positive and CD15-positive cells were present in biopsies of a subgroup of EPS patients. No relation was found between the composition of the mononuclear cell infiltrate and clinical outcome.A characteristic mononuclear cell infiltrate consisting of CD4+ and CD163+ cells dominates the peritoneum of EPS patients. These findings suggest a role for both CD4+ T cells and M2 macrophages in the pathogenesis of EPS.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 4
    In: Proceedings of the National Academy of Sciences of the United States, Oct 15, 2002, Vol.99(21), p.13783(6)
    Description: In human diseases related to tumor-suppressor genes, it is suggested that only the complete loss of the protein results in specific symptoms such as tumor formation, whereas simple reduction of protein quantity to 50%, called haploinsufficiency, essentially does not affect cellular behavior. Using a model of gene expression, it was presumed that haploinsufficiency is related to an increased noise in gene expression also in vivo [Cook, D. L., Gerber, A. N. & Tapscott, S. J. (1998) Proc. Natl. Acad. Sci. USA 95, 15641-15646]. Here, we demonstrate that haploinsufficiency of the tumor-suppressor gene neurofibromatosis type 1 (NF1) results in an increased variation of dendrite formation in cultured NF1 melanocytes. These morphological differences between NF1 and control melanocytes can be described by a mathematical model in which the cell is considered to be a self-organized automaton. The model describes the adjustment of the cells to a set point and includes a noise term that allows for stochastic processes. It describes the experimental data of control and NF1 melanocytes. In the cells haploinsufficient for NF1 we found an altered signal-to-noise ratio detectable as increased variation in dendrite formation in two of three investigated morphological parameters. We also suggest that in vivo NF1 haploinsufficiency results in an increased noise in cellular regulation and that this effect of haploinsufficiency may be found also in other tumor suppressors.
    Keywords: Tumor Suppressor Genes -- Physiological Aspects ; Neurofibromatosis -- Physiological Aspects
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 5
    In: International Journal of Cancer, 15 February 2018, Vol.142(4), pp.757-768
    Description: Only a fraction of breast cancer (BC) cases can be yet explained by mutations in genes or genomic variants discovered in linkage, genome‐wide association and sequencing studies. The known genes entailing medium or high risk for BC are strongly enriched for a function in DNA double strand repair. Thus, aiming at identifying low frequency variants conferring an intermediate risk, we here investigated 17 variants (MAF: 0.01–0.1) in 10 candidate genes involved in DNA repair or cell cycle control. In an exploration cohort of 437 cases and 1189 controls, we show the variant rs3810813 in the gene to be significantly associated with both BC (≤60 years; OR = 2.6(1.6–3.9),  = 1.6E‐05) and decreased DNA repair capacity (≤60 years; beta = 37.8(17.9–57.8),  = 5.3E‐4). BC association was confirmed in a verification cohort ( = 2441). Both associations were absent from cases diagnosed 〉60 years and stronger the earlier the diagnosis. By imputation we show that rs3810813 tags a haplotype with 5 additional variants with the same allele frequency ( 〉 0.9), and a pattern of association very similar for both phenotypes (cases  0.9). Our findings propose a risk variant with high penetrance on the haplotype spanning to be functionally associated to BC predisposition via decreased repair capacity and suggest this variant is carried by a fraction of these haplotypes that is enriched in early onset BC cases. What's new? While genome‐wide associations studies (GWASs) have successfully identified susceptibility genes in breast cancer, they have largely missed rare and low‐frequency alleles. Here, using a candidate gene approach focused on low‐frequency alleles, a new susceptibility locus was discovered for early‐onset breast cancer. The haplotype carrying the causal variant spanned the / gene and was associated with reduced DNA repair capacity. Because the variant was absent in patients over age 60, the association could not be detected by GWAS without age stratification. The findings suggest that the low‐frequency variant is highly penetrant and may carry significant risk for early‐onset breast cancer.
    Keywords: Genes ; Cancer ; Breast Cancer ; Genomes ; DNA Repair ; Susceptibility ; Alleles ; Age ; Breast Cancer ; Genomes ; Haplotypes ; Genes ; Risk ; Breast Cancer ; Cell Cycle ; Exploration ; Cases (Containers) ; Haplotypes ; Gene Sequencing ; DNA Repair ; Repair ; Gene Frequency ; Cancer ; Deoxyribonucleic Acid–DNA ; Breast ; Haplotypes ; Loci ; Health Risks ; Cell Cycle ; Mutation ; Deoxyribonucleic Acid–DNA;
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 6
    In: Prostate, October 2014, Vol.74(14), pp.1444-1451
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/pros.22860/abstract Byline: Christiane Maier, Kathleen Herkommer, Manuel Luedeke, Antje Rinckleb, Mark Schrader, Walther Vogel ABSTRACT BACKGROUND One of the known risk factors for prostate cancer (PrCa) is germline mutations in the BRCA2 gene. Previous searches for clinical characteristics which could identify a subgroup of patients enriched for mutation carriers revealed early onset and aggressive PrCa as useful parameters, but they are rather unspecific. METHODS Identification of BRCA2 mutation carriers by sequencing all exons of BRCA2 in a German cohort of 382 familial PrCa cases and of 92 sporadic PrCa cases with early onset ([less than or equal to]60 years). To define a subgroup of PrCa patients enriched for BRCA2 mutation carriers, we used clinical parameters including a detailed family history (FH) for PrCa and breast cancer. RESULTS Five BRCA2 mutations and ten variants of unknown significance (VUS) were identified. While the VUS were evenly distributed among the groups, mutation carriers were lacking from the sporadic cases and over represented among familial cases with aggressive disease. High prostate specific antigen (PSA) at diagnosis (〉20ng/ml) was the only criterion with significant enrichment of mutation carriers (6.4%, P=0.0005). In men with aggressive disease, death from PrCa (6.3% including FH of lethal PrCa; P=0.05) and FH of both prostate and breast cancer (4.8%; P=0.3) increased the frequency of mutation carriers. Larger studies and/or meta-analyses are needed to validate these parameters. CONCLUSIONS We have identified three potentially useful criteria, high PSA, death from PrCa (patient or FH), and aggressive PrCa in combination with FH of breast and prostate cancer. If confirmed, they may become useful for the decision which patients may benefit from BRCA2 testing. Prostate 74:1444-1451, 2014. [c] 2014 Wiley Periodicals, Inc. Article Note: Conflict of interest: All authors declare that no conflicts of interest exist. Supporting information: Additional Supporting Information may be found in the online version of this article Additional supporting information may be found in the online version of this article at the publisher's web-site. CAPTION(S): Table SI. Rare coding variants in BRCA2 in which clinical relevance was excluded Table SII. Frequency of BRCA2 variants of unknown significance (VUS) in patients with adverse parameters of PrCa (aggressive disease)
    Keywords: Prostate Cancer ; Mutation ; Sequencing ; Family History
    ISSN: 0270-4137
    E-ISSN: 1097-0045
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  • 7
    Language: English
    In: PLoS ONE, 01 October 2010, Vol.5(10), p.e13707
    Description: Hypersensitivity reactions against nonsteroidal antiinflammatory drugs (NSAIDs) like diclofenac (DF) can manifest as Type I-like allergic reactions including systemic anaphylaxis. However, except for isolated case studies experimental evidence for an IgE-mediated pathomechanism of DF hypersensitivity is lacking. In this study we aimed to investigate the possible involvement of drug- and/or metabolite-specific antibodies in selective DF hypersensitivity.DF, an organochemically synthesized linkage variant, and five major Phase I metabolites were covalently coupled to carrier proteins. Drug conjugates were analyzed for coupling degree and capacity to crosslink receptor-bound IgE antibodies from drug-sensitized mice. With these conjugates, the presence of hapten-specific IgE antibodies was investigated in patients' samples by ELISA, mediator release assay, and basophil activation test. Production of sulfidoleukotrienes by drug conjugates was determined in PBMCs from DF-hypersensitive patients. All conjugates were shown to carry more than two haptens per carrier molecule. Immunization of mice with drug conjugates induced drug-specific IgE antibodies capable of triggering mediator release. Therefore, the conjugates are suitable tools for detection of drug-specific antibodies and for determination of their anaphylactic activity. Fifty-nine patients were enrolled and categorized as hypersensitive either selectively to DF or to multiple NSAIDs. In none of the patients' samples evidence for drug/metabolite-specific IgE in serum or bound to allergic effector cells was found. In contrast, a small group of patients (8/59, 14%) displayed drug/metabolite-specific IgG.We found no evidence for an IgE-mediated effector mechanism based on haptenation of protein carriers in DF-hypersensitive patients. Furthermore, a potential involvement of the most relevant metabolites in DF hypersensitivity reactions could be excluded.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: Genetics, January 2007, Vol.175(1), pp.421-8
    Description: The human genome is composed of long stretches of DNA with distinct GC contents, called isochores or GC-content domains. A boundary between two GC-content domains in the human NF1 gene region is also a boundary between domains of early- and late-replicating sequences and of regions with high and low recombination frequencies. The perfect conservation of the GC-content distribution in this region between human and mouse demonstrates that GC-content stabilizing forces must act regionally on a fine scale at this locus. To further elucidate the nature of these forces, we report here on the spectrum of human SNPs and base pair substitutions between human and chimpanzee. The results show that the mutation rate changes exactly at the GC-content transition zone from low values in the GC-poor sequences to high values in GC-rich ones. The GC content of the GC-poor sequences can be explained by a bias in favor of GC 〉 AT mutations, whereas the GC content of the GC-rich segment may result from a fixation bias in favor of AT 〉 GC substitutions. This fixation bias may be explained by direct selection by the GC content or by biased gene conversion.
    Keywords: Base Composition ; Evolution, Molecular ; Genome ; Isochores -- Genetics ; Neurofibromin 1 -- Genetics
    ISSN: 0016-6731
    E-ISSN: 19432631
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  • 9
    Language: English
    In: The American Journal of Human Genetics, 2000, Vol.67(4), pp.873-880
    Description: Whole-genome association studies will be a powerful tool to identify genes responsible for common human diseases. A crucial task for association-mapping studies is the evaluation of the relationship between linkage disequilibrium (LD) and physical distance for the genomic region under study. Since it is known that the extent of LD is nonuniformly distributed throughout the human genome, the required marker density has to be determined specifically for the region under study. These regions may be related to isochores and chromosomal bands, as indicated by earlier cytogenetic findings concerning chiasma distribution in meiosis. Therefore we analyzed the neurofibromatosis type 1 ( ) gene region on chromosome 17q11.2, which is characterized by a nonuniform LD pattern and an L1-to-H2 isochore transition. Long-range LD within the gene was found to extend over 200 kb ( ′ = 0.937) in the L1 isochore, whereas, in the neighboring H2 isochore, no LD is apparent between markers spaced by 26 kb ( ′ = 0.144). Recombination frequencies derived from the LD are at .00019 (high LD) and .01659 (low LD) per megabase, the latter identical to the average value from segregation analysis. The boundary between these regions coincides precisely with a transition in the GC content of the sequences, with low values (37.2%) in the region with long-range LD and high values (51%) in the other. Our results suggest a correlation between the LD pattern and the isochores, at least in the region. If this correlation can be generalized, the marker densities required for association studies have to be adjusted to the regional GC content and may be chosen according to the isochores.
    Keywords: Biology
    ISSN: 0002-9297
    E-ISSN: 1537-6605
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  • 10
    Language: English
    In: The American Journal of Human Genetics, 1998, Vol.62(2), pp.278-285
    Description: Using methylation-sensitive restriction enzymes, we characterized the methylation pattern on the 5′ side of the CTG repeat in the DMPK gene of normal individuals and of patients affected with myotonic dystrophy, showing expansions of the repetitive sequence. The gene segment analyzed corresponds to the genomic I- dIII fragment carrying exons 11–15. There is constitutive methylation in intron 12 at restriction sites of II and I, localized 1,159–1,232 bp upstream of the CTG repeat, whereas most, if not all, of the other sites of II, I, and II in this region are unmethylated, in normal individuals and most of the patients. In a number of young and severely affected patients, however, complete methylation of these restriction sites was found in the mutated allele. In most of these patients, the onset of the disease was congenital. Preliminary in vivo footprinting data gave evidence for protein-DNA contact in normal genes at an Sp1 consensus binding site upstream of the CTG repeat and for a significant reduction of this interaction in cells with a hypermethylated DMPK gene.
    Keywords: Myotonic Dystrophy ; Dmpk Gene ; Ctg Repeat Expansion ; DNA Methylation ; in Vivo Footprinting ; Biology
    ISSN: 0002-9297
    E-ISSN: 1537-6605
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