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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  126. Kongress der Deutschen Gesellschaft für Chirurgie; 20090428-20090501; München; DOC09dgch11419 /20090423/
    Publication Date: 2009-05-06
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
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    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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  • 4
    Abstract: Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015. Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420081 cases (median cases, 2526 per disease) and 1093105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
    Type of Publication: Journal article published
    PubMed ID: 28241208
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  • 5
    Keywords: EXPRESSION ; COLORECTAL-CANCER ; MYOCARDIAL-INFARCTION ; COLONY-STIMULATING FACTOR ; CORONARY-HEART-DISEASE ; ATHEROSCLEROSIS RISK ; GENOME-WIDE ASSOCIATION ; LYMPHOCYTE ; CHARGE CONSORTIUM ; DIFFERENTIAL LEUKOCYTE COUNT ; GENETIC-VARIANTS ; PROSTATE-CANCER SUSCEPTIBILITY
    Abstract: White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.
    Type of Publication: Journal article published
    PubMed ID: 21738480
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  • 6
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    German Medical Science; Düsseldorf, Köln
    In:  123. Kongress der Deutschen Gesellschaft für Chirurgie; 20060502-20060505; Berlin; DOC06dgch5340 /20060502/
    Publication Date: 2006-05-09
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 7
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Medizinische Informatik, Biometrie und Epidemiologie; VOL: 3; DOC11 /20070717/
    Publication Date: 2007-07-18
    Description: Purpose: Application of multinomial logistic regression for diagnostic support of acute abdominal pain, a diagnostic problem with many differential diagnoses. Methods: The analysis is based on a prospective data base with 2280 patients with acute abdominal pain, characterized by 87 variables from history and clinical examination and 12 differential diagnoses. Associations between single variables from history and clinical examination and the final diagnoses were investigated with multinomial logistic regression. Results: Exemplarily, the results are presented for the variable rigidity. A statistical significant association was observed for generalized rigidity and the diagnoses appendicitis, bowel obstruction, pancreatitis, perforated ulcer, multiple and other diagnoses and for localized rigidity and appendicitis, diverticulitis, biliary disease and perforated ulcer. Diagnostic profiles were generated by summarizing the statistical significant associations. As an example the diagnostic profile of acute appendicitis is presented. Conclusions: Compared to alternative approaches (e.g. independent Bayes, loglinear model) there are advantages for multinomial logistic regression to support complex differential diagnostic problems, provided potential traps are avoided (e.g. alpha-error, interpretation of odds ratio).
    Description: Ziel: Exemplarische Anwendung der multinominalen logistischen Regression zur Unterstützung der Diagnosestellung bei akuten Bauchschmerzen, einem diagnostischen Problem mit vielen Differentialdiagnosen. Methodik: Grundlage der Untersuchung bildete eine prospektive Datenbank von 2280 Patienten mit akuten Bauschmerzen, charakterisiert durch 87 Variablen der Anamnese und klinischen Untersuchung und 12 Differentialdiagnosen. Assoziationen zwischen Einzelparametern der Anamnese und klinischen Untersuchung und der Diagnose der akuten Bauchschmerzen wurden mit Hilfe der multinominalen logistischen Regression untersucht und bewertet. Ergebnisse: Beispielhaft werden die Ergebnisse für die Variable "Abwehrspannung" (Ausprägung: nein, lokalisiert, generalisiert) dargestellt. Ein statistisch signifikanter Zusammenhang (p〈0.001) wurde zwischen der Ausprägung "generalisierte Abwehrspannung" und den Diagnosen Appendizitis, Ileus, Pankreatitis, Ulkusperforation, multiple und andere Diagnosen und der Ausprägung "lokalisierte Abwehrspannung" und den Diagnosen Appendizitis, Divertikulitis, Gallenwegserkrankung und Ulkusperforation ermittelt. Durch Zusammenfassung statistisch signifikanter Variablenausprägungen wird beispielhaft für die Diagnose "akute Appendizitis" ein diagnostisches Profil erstellt. Schlussfolgerungen: Im Vergleich zu alternativen Modellen (z.B. Unabhängigkeits-Bayes Theorem, loglineares Modell) besitzt die multinominale logistische Regression für die Diagnoseunterstützung bei mehr als zwei Diagnosen Vorteile, vorausgesetzt potentielle Fallstricke werden bei der Anwendung beachtet (z.B. alpha-Fehler, Interpretation des Odds ratios).
    Keywords: multinomial logistic regression ; acute abdominal pain ; diagnosis ; multinominale logistische Regression ; akute Bauchschmerzen ; Diagnose ; ddc: 610
    Language: German
    Type: article
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  • 8
    Abstract: The high prevalence and great diversity of p53 tumor suppressor gene mutations in human tumors call for development of therapeutic molecules that rescue function of aberrant p53 protein. P53 mutations also offer new approaches to the study of the origins of mutations in human cancer. An experimental mouse model with a genetically modified but normal functioning p53 gene harboring the human rather than the murine core domain, would be of considerable benefit to research on both cancer therapeutics and etiology; however, it is uncertain whether such mice would permit biological functions of p53 to be retained. Using a Cre/lox P gene-targeting approach, we have constructed a human p53 knock-in (hupki) mouse strain in which exons 4-9 of the endogenous mouse p53 allele were replaced with the homologous, normal human p53 gene sequence. The chimeric p53 allele (p53(KI)) is properly spliced, transcribed in various tissues at levels equivalent to wild-type mice, and yields cDNA with the anticipated sequence, that is, with a core domain matching that of humans. The hupki p53 protein binds to p53 consensus sequences in gel mobility shift assays and accumulates in the nucleus of hupki fibroblasts in response to UV irradiation, as is characteristic of wild-type p53. Induction of various p53-regulated genes in spleen of gamma-irradiated homozygous hupki mice (p53(KI/KI)), and the kinetics of p53-dependent apoptosis in thymocytes are similar to results with wild-type (p53(+/+)) mice, further indicating normal p53 pathway function in the hupki strain. The mice are phenotypically normal and do not develop spontaneous tumors at an early age, in contrast to knock-out (p53(-/-)) strains with a defective p53 gene. The chimeric (p53(KI)) allele thus appears to provide a biological equivalent to the endogenous murine (p53(+)) gene. This strain is a unique tool for examining in vivo spontaneous and induced mutations in human p53 gene sequences for comparison with published human tumor p53 mutation spectra. In addition, the hupki strain paves the way for mouse models in pre-clinical testing of pharmaceuticals designed to modulate DNA-binding activity of human p53.
    Type of Publication: Journal article published
    PubMed ID: 11313961
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  • 9
    ISSN: 0168-583X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    ISSN: 0168-583X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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