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  • 1
    Publication Date: 2018-07-17
    Description: Purpose: Primary central nervous system posttransplant lymphoproliferative disorder (PCNS-PTLD) is a complication of solid organ transplantation with a poor prognosis and typically associated with Epstein–Barr virus (EBV). We hypothesized EBV lytic-phase protein expression would allow successful treatment with antiviral therapy. Patients and Methods: Thirteen patients were treated with zidovudine (AZT), ganciclovir (GCV), dexamethasone, and rituximab in EBV + PCNS-PTLD. Twice-daily, intravenous AZT 1,500 mg, GCV 5 mg/kg, and dexamethasone 10 mg were given for 14 days. Weekly rituximab 375 mg/m 2 was delivered for the first 4 weeks. Twice-daily valganciclovir 450 mg and AZT 300 mg started day 15. Lytic and latent protein expression was assessed using in situ hybridization and immunohistochemistry. Immunoblot assay assessed lytic gene activation. Cells transfected with lytic kinase vectors were assessed for sensitivity to our therapy using MTS tetrazolium and flow cytometry. Results: The median time to response was 2 months. Median therapy duration was 26.5 months. Median follow-up was 52 months. The estimated 2-year overall survival (OS) was 76.9% (95% CI, 44.2%–91.9%). Overall response rate (ORR) was 92% (95% CI, 64%–100%). BXLF1/vTK and BGLF4 expression was found in the seven tumor biopsies evaluated. Lytic gene expression was induced in vitro using the four-drug regimen. Transfection with viral kinase cDNA increased cellular sensitivity to antiviral therapy. Conclusions: EBV + PCNS-PTLD expressed lytic kinases and therapy with AZT, GCV, rituximab and dexamethasone provided durable responses. Induction of the lytic protein expression and increased cellular sensitivity to antiviral therapy after transfection with viral kinase cDNA provides a mechanistic rationale for our approach. Clin Cancer Res; 24(14); 3273–81. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  34. Wissenschaftliche Jahrestagung der Deutschen Gesellschaft für Phoniatrie und Pädaudiologie (DGPP), Dreiländertagung D-A-CH; 20170914-20170917; Bern, Schweiz; DOCV33 /20170830/
    Publication Date: 2017-08-30
    Description: Hintergrund: Ziel dieser Arbeit war es zu prüfen, ob sich mittels artikulatorischer Sprachsynthese perzeptiv überzeugende Sequenzen in den grundlegenden Emotionen (Angst, Ekel, Freude, Trauer und Wut) durch die Modulation von klassischen prosodischen Merkmalen (z.B. Tonhöhe), kombiniert mit verschiedenen Phonationsarten, generieren lassen. Aufgrund physiologischer Zusammenhänge sowie Hinweisen aus der Literatur ist ein Einfluss von Vokaltraktlänge, Artikulationsgenauigkeit und Nasalität als sekundäre prosodische Merkmale anzunehmen. In Perzeptionsstudien wurde deshalb zusätzlich der Einfluss der sekundären prosodischen Merkmale auf die Wahrnehmung synthetisch generierter emotionaler Äußerungen untersucht.Material und Methoden: Von einem deutschen Profisprecher wurden fünf einphrasige emotional neutrale Sätze eingesprochen. Diese Äußerungen wurden mit VocalTractLab 2.1 möglichst originalgetreu re-synthetisiert. Durch Modulation der Merkmale Tonhöhe und -umfang, subglottischer Druck, Sprechgeschwindigkeit und Phonationsart wurde emotionales Sprachmaterial erzeugt. In einem weiteren Schritt wurden die Sequenzen hinsichtlich Nasalität, Vokaltraktlänge und verminderter Artikulationsgenauigkeit selektiv oder in Kombination manipuliert. In Hörexperimenten mit normakusen Probanden (N=48) erfolgte die kategoriale Zuordnung der perzipierten Emotionen sämtlicher generierter Stimuli.Ergebnisse: Die Sequenzen der Kategorien Angst, Freude, Neutral und Trauer wurden in allen Untertests signifikant über Zufallsniveau korrekt zugeordnet. Die zusätzliche systematische Manipulation der sekundären prosodischen Merkmale ergab für die Kategorien Ekel, Freude, Trauer und Wut signifikant höhere Erkennungsraten.Diskussion: Die Erkennungsraten der synthetisch erzeugten Sequenzen für die Emotionskategorien Angst, Ekel, Freude und Trauer sind vergleichbar mit denen von geschauspielerten natürlich-sprachigen Emotionsäußerungen. Die Erkennungsraten der Kategorie Wut zeigen hingegen, dass sich die Synthese unter Berücksichtigung weiterer Merkmalsmanipulationen möglicherweise noch verbessern ließe.Fazit: Neben dem Beitrag weitere Merkmale zur Beschreibung des emotionalen Sprechausdrucks zu finden (Grundlagenforschung) tragen die Ergebnisse dieser Arbeit dazu bei, die Entwicklung der emotionalen Sprachsynthese, sowie auch der emotionalen Spracherkennung voranzutreiben. Diese Gebiete sind eng mit dem Bereich der Mensch-Maschine-Kommunikation verwoben und neue Erkenntnisse weisen auch dort einen Nutzen auf (z.B. im Bereich der Dialogsysteme/bei elektronischen Kommunikationshilfen).
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 3
    Keywords: CANCER ; EXPRESSION ; COMBINATION ; DISEASE ; RISK ; GENE ; GENE-EXPRESSION ; IMPACT ; BIOLOGY ; MOLECULAR-BIOLOGY ; ASSOCIATION ; polymorphism ; single nucleotide polymorphism ; VARIANTS ; gene expression ; NUMBER ; MUTATION ; genetics ; SNP ; colorectal cancer ; COLORECTAL-CANCER ; REGION ; MUTATIONS ; INDIVIDUALS ; SERIES ; HEALTHY ; heredity ; molecular biology ; molecular ; RE ; VARIANT ; INCREASE ; METAANALYSIS ; ALLELES ; LOCUS ; single-nucleotide polymorphism ; ENGLAND ; 8Q24 ; INCREASES ; GENOME-WIDE ASSOCIATION ; association study ; SCAN ; GENOME-WIDE
    Abstract: The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (ORper allele = 1.19; 95% CI: 1.15-1.23; P-trend = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression
    Type of Publication: Journal article published
    PubMed ID: 18753146
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  • 4
    Keywords: MUTATIONS ; SURVEILLANCE ; CARRIERS ; PREDICTION ; FAMILY-HISTORY ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; DISEASE RISK ; ADENOMATOUS POLYPS ; TYPE-2 DIABETES RISK
    Abstract: Objective Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data. Design Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39 266) and in combination with gender, age and FH (n=11 324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks. Results The median number of risk alleles was greater in cases than controls (10 vs 9, p〈2.2x10(-16)), confirmed in external validation sets (Sweden p=1.2x10(-6), Finland p-2x10(-5)). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with 〉5% predicted 10-year absolute risk. Conclusion Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.
    Type of Publication: Journal article published
    PubMed ID: 22490517
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  • 5
    Keywords: carcinoma ; POPULATION ; GENE-EXPRESSION ; MARKER ; OVARIAN-CANCER ; PROSTATE-CANCER ; METAANALYSIS ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; PLATFORM
    Abstract: Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 x 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
    Type of Publication: Journal article published
    PubMed ID: 25378557
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  • 6
    Keywords: EXPRESSION ; GENE ; BREAST-CANCER ; OVARIAN-CANCER ; PROSTATE-CANCER ; telomere length ; COMMON VARIANT ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; FUNCTIONAL VARIATION
    Abstract: Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 x 10(-6) to P = 7.7 x 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 x 10(-18), CLPTM1L P = 1.5 x 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.
    Type of Publication: Journal article published
    PubMed ID: 25487306
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  • 7
    Abstract: The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 x 10-7). The association was stronger in those with 〉/=10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.European Journal of Human Genetics advance online publication, 7 May 2014; doi:10.1038/ejhg.2014.74.
    Type of Publication: Journal article published
    PubMed ID: 24801760
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  • 8
    Keywords: POLYMORPHISMS ; SUSCEPTIBILITY LOCUS ; VARIANTS ; BREAST ; METAANALYSIS ; GENOME-WIDE ASSOCIATION ; ESTROGEN-RECEPTOR-ALPHA ; GENOTYPE IMPUTATION ; SUPER-ENHANCERS ; CELL IDENTITY
    Abstract: Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86x10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76x10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.
    Type of Publication: Journal article published
    PubMed ID: 26330482
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  • 9
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  21. Jahrestagung der Deutschen Gesellschaft für Pädiatrische Infektiologie (DGPI); 20130425-20130427; Würzburg; DOC13dgpi67 /20130328/
    Publication Date: 2013-03-29
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 10
    Keywords: CANCER ; FOLLOW-UP ; NEW-YORK ; RISK ; SAMPLE ; ASSOCIATION ; SUSCEPTIBILITY ; VARIANTS ; DISCOVERY ; BREAST-CANCER ; genetics ; meta-analysis ; SNP ; colorectal cancer ; etiology ; COLORECTAL-CANCER ; PROSTATE-CANCER ; REPLICATION ; INDIVIDUALS ; beta-catenin ; SERIES ; germline mutations ; heredity ; RE ; VARIANT ; SNPs ; METAANALYSIS ; POWER ; USA ; ENGLAND ; COMMON VARIANT ; SAMPLE-SIZE ; 8Q24 ; GENOME-WIDE ASSOCIATION ; genetic variants ; CADHERIN GENE CDH1 ; CDH1 ; FAMILIAL GASTRIC-CANCER ; GENOME-WIDE ; JUVENILE POLYPOSIS
    Abstract: Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 x 10(-10)), 16q22.1 (rs9929218, CDH1; P = 1.2 x 10(-8)), 19q13.1 (rs10411210, RHPN2; P = 4.6 x 10(-9)) and 20p12.3 (rs961253; P = 2.0 x 10(-10)). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC
    Type of Publication: Journal article published
    PubMed ID: 19011631
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