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  • 1
    Abstract: To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events 〉2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
    Type of Publication: Journal article published
    PubMed ID: 27291797
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  • 2
    Keywords: GENE ; MOLECULAR CHARACTERIZATION ; SUSCEPTIBILITY LOCUS ; VARIANTS ; IDENTIFICATION ; microsatellite instability ; MUTATIONS ; endometriosis ; CLEAR-CELL CARCINOMA ; GRADE SEROUS CARCINOMA
    Abstract: Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P 〈 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P 〈 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
    Type of Publication: Journal article published
    PubMed ID: 24190013
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  • 3
    ISSN: 1573-7284
    Keywords: Epidemiology ; Familial aggregation ; Inflammatory bowel disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To evaluate familial aggregation of inflammatory bowel disease (IBD) in the Mediterranean area and to estimate the disease risk in first degree relatives. 427 patients with IBD were consecutively interviewed in order to obtain a complete pedigree of first degree relatives. Sufficient information was obtained in 98% of 2,685 family members. The prevalence ratio of IBD in family members was estimated and compared to the prevalence ratio of IBD in general population; the ratio was then standardized by age since the prevalence of the disease is age-dependent. The lifetime risk was assessed by the Kaplan Meier method. Thirty index cases (7%) had at least one affected first degree relative. As compared with the general population, first degree relatives of the 427 patients with IBD had a 4.38-fold increase in the age corrected risk of having the same disease. The Kaplan-Meier curve showed a higher risk at 25 years of age for offsprings (3%) than for parents (1%) and siblings (1%) whereas the crude ratio showed a higher risk for siblings (1.9%) compared to parents (0.8%) and offsprings (1%). In the Mediterranean area, the familial prevalence of IBD is higher than in the general population and comparable to North European rates.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 0173-0835
    Keywords: Genome scanning ; Mutation detection ; Deletion detection ; Amplification detection ; Intracisternal A particle element ; Retroviral-histidine tRNA element ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: We have developed a simple one-dimensional electrophoretic method, genome scanning, that can be used to identify large-scale genomic differences between two or more DNA samples. Genome scanning is especially useful in the detection of genetic amplifications, deletions, and rearrangements. The assay is essentially a high-resolution Southern analysis, comparing equivalent amounts of genomic DNA samples that are variant for a given trait. The Southern blots are hybridized to a probe sequence derived from a medium copy number repetitive element (1000-2000 copies per haploid genome) naturally dispersed throughout the genome. The hybridization pattern that results is complex and consists of hundreds of bands. If the DNA samples are otherwise equivalent, a net difference in hybridization intensity between homologous bands of different samples indicates a genetic change. In this report, we discuss the origin of the method, its premise, and review its application to mouse mutational analysis and to human cancer research (a more detailed discussion of the theory is presented elsewhere in this issue; Y. Gondo and M. H. Brilliant, Electrophoresis 1995, 16, 174-178).
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1573-2568
    Keywords: CELIAC DISEASE ; LYMPHOMA ; MORTALITY ; CAUSE OF DEATH
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract No data on mortality in celiac disease arecurrently available in southern Europe. Our aim was toevaluate mortality and the cause of death in adultceliac disease in a Mediterranean area. In all, 228adults with celiac disease were histologicallydiagnosed in our department from 1980 to 1997. Fullinformation on their state of health was obtained in 216of 228 patients. A tabulation of patient-years at risk was constructed in terms of age at diagnosisand the interval from diagnosis. Standardized mortalityratio was calculated by dividing the number of observeddeaths by the number of expected deaths. Twelve deaths were observed, whereas 3.12 deaths wereexpected (SMR = 3.8; 95% CI 2-7). The increasedmortality was mainly observed within four years fromdiagnosis (8 observed; 1.4 expected) (SMR = 5.8; 95% CI 2.5-11.5). Twelve tumors were observed (sixlymphomas). In conclusion, mortality from adult celiacdisease in our geographical area is increased comparedwith the general population, and this increased risk seems due to non-Hodgkin'slymphoma.
    Type of Medium: Electronic Resource
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  • 6
    Publication Date: 2018-12-04
    Description: Resistance to androgen receptor (AR) antagonists is a significant problem in the treatment of castration-resistant prostate cancers (CRPC). Identification of the mechanisms by which CRPCs evade androgen deprivation therapies (ADT) is critical to develop novel therapeutics. We uncovered that CRPCs rely on BRD4-HOXB13 epigenetic reprogramming for androgen-independent cell proliferation. Mechanistically, BRD4, a member of the BET bromodomain family, epigenetically promotes HOXB13 expression. Consistently, genetic disruption of HOXB13 or pharmacological suppression of its mRNA and protein expression by the novel dual-activity BET bromodomain-kinase inhibitors directly correlates with rapid induction of apoptosis, potent inhibition of tumor cell proliferation and cell migration, and suppression of CRPC growth. Integrative analysis revealed that the BRD4-HOXB13 transcriptome comprises a proliferative gene network implicated in cell-cycle progression, nucleotide metabolism, and chromatin assembly. Notably, although the core HOXB13 target genes responsive to BET inhibitors (HOTBIN10) are overexpressed in metastatic cases, in ADT-treated CRPC cell lines and patient-derived circulating tumor cells (CTC) they are insensitive to AR depletion or blockade. Among the HOTBIN10 genes, AURKB and MELK expression correlates with HOXB13 expression in CTCs of mCRPC patients who did not respond to abiraterone (ABR), suggesting that AURKB inhibitors could be used additionally against high-risk HOXB13-positive metastatic prostate cancers. Combined, our study demonstrates that BRD4-HOXB13-HOTBIN10 regulatory circuit maintains the malignant state of CRPCs and identifies a core proproliferative network driving ADT resistance that is targetable with potent dual-activity bromodomain-kinase inhibitors.
    Print ISSN: 1535-7163
    Electronic ISSN: 1538-8514
    Topics: Medicine
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