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  • DKFZ Publication Database  (23)
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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; proliferation ; tumor ; BLOOD ; CELL ; Germany ; human ; VITRO ; NEW-YORK ; POPULATION ; PROTEIN ; cell line ; LINES ; PATIENT ; RESPONSES ; IFN-GAMMA ; DONOR ; ANTIGENS ; DENDRITIC CELLS ; T cell ; T cells ; T-CELL ; T-CELLS ; CELL-LINES ; E7 ; papillomavirus ; LIMITATION ; STIMULATION ; TARGET ; ASSAY ; cervical cancer ; CERVICAL-CANCER ; human papillomavirus ; TYPE-16 ; GENOTYPES ; HPV ; E6 ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; POPULATIONS ; ONCOPROTEIN ; VACCINE ; CANCER-PATIENTS ; CD8(+) ; ELISPOT ; EPITOPE ; EPITOPES ; IMMUNOTHERAPY ; intraepithelial neoplasia ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; E7 ONCOPROTEIN ; IMMUNOGENICITY ; TARGETS ; INTERFERON-GAMMA ; 14 HIGH-RISK ; ENZYME-IMMUNOASSAY ; HUMAN BLOOD ; immunotherapy,T cell response,cytotoxic T cell,uterine cancer,tumor infiltrating lymphocytes ; INFILTRATING LYMPHOCYTES
    Abstract: Purpose. Human papillomavirus (HPV) type 16 and 18 are the most prevalent genotypes in cervical cancers. The viral oncoproteins E6 and E7 are considered to be tumor-specific targets for immunotherapy. HPV E7 antigen-loaded dendritic cells (DC) were evaluated as cellular tumor vaccine. Methods. Autologous monocyte-derived DCs loaded with recombinant HPV16 or HPV18 E7 oncoprotein were used to induce in vitro a specific T cell response. Specificities of activated T cells were determined. Results. E7-specific T cells could be identified in 18/20 T cell lines from healthy blood donors. CD4(+) T cell responses (13/16) were found by proliferation assay. CD8(+) CTLs (12/18) were detectable by interferon-gamma (IFN-gamma) ELISpot analysis. Seven donors reacted in both assays and only 2/20 T cell lines did not react in any assay. Thus, specific T cells could be activated in 〉80% of healthy individuals. T cell lines from suitable donors were specific for HLA-A*0201-restricted epitopes. Furthermore, HPV E7 antigen-loaded DC stimulated specific responses in freshly isolated tumor infiltrating lymphocyte (TIL) populations of cervical cancer patients. Conclusion. Autologous dendritic cells loaded with HPV E7 protein can induce T cell responses in healthy individuals by in vitro stimulation and evoke responses in TIL from cervical cancer biopsies. Since there are no limitations with respect to specific HLA-haplotypes, these findings may be a basis for the development of a therapeutic protein-based DC tumor vaccine against cervical cancer for HPV16- and HPV18-positive patients
    Type of Publication: Journal article published
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  • 2
    Keywords: CELLS ; EXPRESSION ; proliferation ; tumor ; carcinoma ; KINASE ; DISEASE ; PROTEIN ; DIFFERENTIATION ; TUMORS ; CONTRAST ; ACTIVATED PROTEIN-KINASE ; PHOSPHORYLATION ; BREAST ; IN-SITU ; LESIONS ; immunohistochemistry ; MALIGNANCIES ; PATTERNS ; EPITHELIAL-CELLS ; CARCINOMAS ; INTERCELLULAR COMMUNICATION ; MALIGNANCY ; MOLECULAR-BASIS ; BASAL LAMINA ; breast carcinoma ; connexin43 ; GAP JUNCTIONAL COMMUNICATION ; gap junctions
    Abstract: We applied an antiserum (SA226P) specifically recognizing the phosphorylated form of connexin43 (P-Cx43) to human breast samples including normal breast samples, with fibrocystic disease (FCD), fibroadenomas (FA), in situ and infiltrating carcinomas of all major types, and miscellaneous extramarnmary tumors. The findings were compared with those obtained with commercial antisera recognizing all Cx43 forms (pan-Cx43). A subset of samples was stained for Her2-neu and p44/42 to mitogen-activated protein kinase. Paraffin step sections were used. Immunoblots were performed on frozen samples of a representative subset of cases. In the normal breast, FCD, and FA, SA226P stained strongly and extensively most myoepithelial cells (MECs); luminal cells remained unstained. In proliferative FCD and some cellular FA, SA226P stained MEC and the capillary endothelium (CE). In ductal and lobular in situ carcinomas, SA226P reacted strongly and diffusely with the remaining MEC, the CE, and the transformed luminal cells. SA226P stained all infiltrating carcinomas except the tubular variant. In all breast carcinomas, the CE within and adjacent to tumors and some myofibroblasts stained with SA226P. By contrast, pan-Cx43 stained weakly and sporadically the MEC and rare samples of invasive carcinomas. Notably, Mab p44/42 reacted in parallel with the samples stained with SA226P, whereas reactions with Her2 were negative. Immunoblot findings paralleled those obtained immunohistochemically. We conclude that P-Cx43, restricted to MEC in the normal breast, is up-regulated in the same cells in hyperplasias and dysplasias and FA and is strongly up-regulated in invasive carcinomas. Notably, in some proliferative FCD and in most in situ and infiltrating carcinomas, P-Cx43 is strongly expressed in CE within and adjacent to the lesions but not away from them. These findings were paralleled by the strong nuclear reactions noted with Mab p44/42. These phenomena, although not exclusive to malignancy, are particularly conspicuous in breast carcinomas and seemingly reflect active proliferation associated with abnormal gap junctional intercellular communication. (c) 2005 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15948121
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  • 3
    Keywords: CANCER ; EXPRESSION ; carcinoma ; PATHWAY ; PATHWAYS ; TUMORS ; mechanisms ; WOMEN ; p53 ; human papillomavirus ; HPV ; intraepithelial neoplasia ; TRENDS ; YOUNG-WOMEN ; p16(INK4A) ; VULVAR CANCER
    Abstract: OBJECTIVE: The incidence of vulvar squamous cell carcinomas located between the clitoris and urethra in young women is rising in distinct geographic regions, but characteristics of the tumors indicating certain carcinogenic mechanisms are unknown. The present study aimed at characterizing these vulvar cancers for their human papillomavirus (HPV), p16, and p53 status, revealing potential pathways of carcinogenesis. MATERIALS AND METHODS: Squamous cell vulvar cancers of the anterior fourchette were retrospectively collected from 8 German hospitals, with additional squamous cell cancers located at other sites of the vulva from 2 of the hospitals. All tumors were analyzed for HPV DNA by polymerase chain reaction and for p16 and p53 expression by immunohistochemistry. RESULTS: Potentially HPV-associated tumors (HPV and p16 positive, 21.4% [27/126] of the anterior fourchette and 27.7% [13/47] from other locations), p53-overexpressing tumors (35.7% [45/126] and 29.8% [14/47]), and a third group (HPV/p16 negative/p53 not overexpressed, 42.9% [54/126] and 42.6% [20/47]) were observed among tumors from the anterior fourchette as well as among vulvar cancers from other locations. Women with vulvar cancers of the anterior fourchette were of young age irrespective of the HPV/p16/p53 status. CONCLUSIONS: Different types of vulvar cancers can be found in squamous cell tumors of the anterior fourchette, similar to the finding in vulvar cancers from other locations and to what has previously been reported for vulvar squamous cell carcinomas in general.
    Type of Publication: Journal article published
    PubMed ID: 23645067
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  • 4
    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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  • 5
    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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  • 6
    Abstract: Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 x 10(-30)), OSECs (P = 2.4 x 10(-23)) and HMECs (P = 6.7 x 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.
    Type of Publication: Journal article published
    PubMed ID: 25804953
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  • 7
  • 8
    Keywords: CANCER ; CELLS ; IN-VITRO ; tumor ; Germany ; human ; IN-VIVO ; THERAPY ; VITRO ; SYSTEM ; DISEASE ; RISK ; GENE ; GENE-TRANSFER ; DNA ; INFECTION ; INDUCTION ; ANTIGEN ; DENDRITIC CELLS ; T cells ; T-CELLS ; E7 ; OPEN READING FRAME ; papillomavirus ; HUMANS ; ASSAY ; WOMEN ; cervical cancer ; CERVICAL-CANCER ; human papillomavirus ; HIGH-RISK ; ONCOGENE ; TRANSFORMATION ; HUMAN-PAPILLOMAVIRUS ; VACCINE ; SAFETY ; EPITOPE ; IMMUNOTHERAPY ; PLASMID DNA ; IMMUNODEFICIENCY-VIRUS TYPE-1 ; IMMUNIZATION ; MUTATIONAL ANALYSIS ; ASSAYS ; cytotoxic T lymphocyte ; BACTERIAL-DNA ; RISK-FACTOR ; in vivo ; tumor regression ; tumor protection ; ENHANCED IMMUNOGENICITY ; gene shuffling ; HPV16 E7 ; in vitro immunization
    Abstract: Anew and very promising approach in vaccine development is the application of naked DNA. In comparison to conventional vaccines it offers several advantages, especially if there is a need for the development of low cost vaccines. Infection with high-risk human papillomaviruses (hr-HPVs) is the major risk factor for the development of cervical cancer (cc), the third most common cancer in women worldwide. The HPV E7 oncogene is constitutively expressed in HPV-infected cells and represents an excellent target for immune therapy of HPV-related disease. Therefore, we chose the HPV-16 E7 as model antigen in the development of a therapeutic DNA vaccine candidate. For safety reasons the use of a transforming gene like the HPV-16 E7 for DNA vaccination is not feasible in humans. In consequence we have generated an artificial ("shuffled") HPV-16 E7-gene (HPV-16 E7SH), containing all putative cytotoxic T-lymphocyte (CTLs) epitopes and exhibiting high safety features. Here, we show the induction of a strong E7-wildtype (E7WT) directed cellular and humoral immune response including tumor protection and regression after in Vivo immunization in the murine system. Moreover, the vaccine candidate demonstrated immunogenicity in humans, demonstrated by priming of antigen-specific T cells in vitro. Importantly, the artificial HPV-gene has completely lost its transforming properties as measured in soft agar transformation assays. These results may be of importance for the development of vaccines based on oncogenes or oncoproteins. (c) 2006 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16472545
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  • 9
    Keywords: EXPRESSION ; Germany ; IN-VIVO ; PATHWAY ; PATHWAYS ; VIVO ; PROTEIN ; FAMILY ; DOMAIN ; BINDING ; ASSAY ; PLASMA ; PLASMA-MEMBRANE ; DEGRADATION ; INVOLVEMENT ; KINASE-C ; DOMAINS ; INTERCELLULAR COMMUNICATION ; CARDIAC MYOCYTES ; ASSAYS ; in vivo ; PROLINE ; JUNCTION ; connexin ; EPITHELIAL NA+ CHANNEL ; GAMMA-ENAC ; gap junction ; GAP-JUNCTION PROTEIN ; PY motif ; ubiquitylation ; WW DOMAINS
    Abstract: Connexin43 is degraded by the proteasomal as well as the lysosomal pathway with ubiquitin playing a role in both degradation pathways. So far, no ubiquitin protein ligase has been identified for any of the connexins. By using pull-down assays, here we show binding of a ubiquitin protein ligase, Nedd4, to the C-terminus of connexin43. This observation was confirmed in vivo by coimmunoprecipitation and immunofluorescence, showing colocalization of Nedd4 and connexin43. Binding of Nedd4 to its interaction partners is generally carried out by its WW domains. Our results indicate that the interaction with connexin43 occurs through all three WW domains of Nedd4. Furthermore, whereas WW1 and WW2 domains mainly interact with the unphosphorylated form of connexin43, WW3 binds phosphorylated and unphosphorylated forms equally. In addition, using the surface plasmon resonance approach we show that only the WW2 domain binds to the PY motif located at the C-terminus of connexin43. Suppression of Nedd4 expression with siRNA resulted in an accumulation of gap junction plaques at the plasma membrane, suggesting an involvement of the ubiquitin protein ligase Nedd4 in gap junction internalization
    Type of Publication: Journal article published
    PubMed ID: 16931598
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  • 10
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