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  • 1
    Keywords: CANCER ; PROTECTION ; BLOOD ; carcinoma ; evaluation ; human ; ALGORITHM ; RISK ; GENE ; INFECTION ; CARCINOGENESIS ; ANTIGEN ; BINDING ; ASSOCIATION ; LESIONS ; WOMEN ; cervical cancer ; HPV ; HPV16 ; VACCINE ; HLA class I ; EPITOPES ; intraepithelial neoplasia ; cervical carcinoma ; HLA ; PERIPHERAL-BLOOD ; E6 prototype ; E6 variant
    Abstract: Persistent infection with human papillomavirus (HPV), particularly HPV16, represents the prime risk factor in cervical carcinogenesis. HPV variants (e.g., within the E6 gene) together with immunogenetic factors of the host may be responsible either for effective viral clearance, or alternatively, for viral persistence. Peripheral blood from 27 HPV16 positive Swedish women with cervical carcinoma, who had previously been tested for HPV16 E6 variants, was used for human leukocyte antigen (HLA) class 1 typing. Women with HLA- B*44, HLA-B*51, or HLA-B*57 who were infected with the HPV16 E6 variant L83V had an approximately four- to fivefold increased risk for cancer compared with controls (odds ratio [OR] = 3.5, 95 % CI = 1.1-11.1, OR = 4.2, 95% CI = 1.19-14.69, or OR = 4.67, 95176 CI = 1.2-18.6, respectively). Epitope predictive algorithm with SYFPEITHI revealed that the variant at amino acid 83 affects the binding affinity in association with HLA- B*44. Interestingly, the HLA-B*15 allele seems protective because it was absent in HPV16 positive cancer. It is concluded that specific HLA class I alleles, combined with certain HPV16 E6 variants, may be crucial for immune surveillance in cervical carcinogenesis. The evaluation of associations of HLA alleles with HPV variants may be helpful in defining prognostic markers and in designing vaccines capable of mediating immune protection against HPV infection
    Type of Publication: Journal article published
    PubMed ID: 12691704
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  • 2
    Keywords: CANCER ; EXPRESSION ; tumor ; carcinoma ; CELL ; human ; KINASE ; PATHWAY ; GENE ; GENE-EXPRESSION ; GENES ; EPITHELIA ; DNA ; INFECTION ; CONTRAST ; papillomavirus ; LESIONS ; PROGRESSION ; gene expression ; ASSAY ; smoking ; inactivation ; PCR ; human papillomavirus ; HPV ; HUMAN-PAPILLOMAVIRUS ; SQUAMOUS-CELL CARCINOMA ; HEAD ; NECK ; squamous cell carcinoma ; TOBACCO ; ALCOHOL ; PREVALENCE ; GREECE ; head and neck ; ORAL-CANCER ; NECK-CANCER ; CELL CARCINOMA ; PRIMARY TUMORS ; head and neck cancers,tumor suppressor gene expression,human papillomavirus ; P16
    Abstract: To further characterize the biological and clinical role of molecular alterations involved in oral squamous carcinogenesis, the immunohistochemical expression level of two tumor suppressor genes, fragile histidine triad and p16(INK4a), in non-carcinomatous squamous epithelia and head and neck squamous cell carcinoma was determined. In addition, human papillomavirus infection determined by PCR assay and the use of alcohol and cigarettes were evaluated. In this study 28 non-carcinomatous squamous epithelia and 57 head and neck squamous cell carcinoma were considered. The expression levels of fragile histidine triad were lower in head and neck squamous cell carcinoma than in non-carcinomatous squamous epithelia. In contrast, p16(INK4a) is expressed in malignant lesions (51% of the cases analyzed), but not in non-carcinomatous squamous epithelia. No correlation between gene expression alterations of the two tumor suppressors was observed. PCR analysis showed that HPV DNA was present in 5 of the 57 malignant lesions analyzed (8.8%). None of the factors described above, despite changes in gene expression and HPV infection, appears to be associated with alcohol use and/or tobacco smoking and clinical outcome. Our data showed that fragile histidine triad and p16(INK4a) expression are altered in malignant lesions. Most likely, the decreasing levels of fragile histidine triad is directly involved in cancer development, while the accumulation of p16(INK4a) in head and neck squamous cell carcinoma may be the consequence of loss of functional tumor suppressor retinoblastoma pathway
    Type of Publication: Journal article published
    PubMed ID: 14719099
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  • 3
    Keywords: CANCER ; CANCER CELLS ; CELLS ; tumor ; human ; NEW-YORK ; RISK ; GENE ; PROTEIN ; PROTEINS ; TUMORS ; COMPLEX ; COMPLEXES ; INFECTION ; RISK-FACTORS ; CARCINOGENESIS ; MUTATION ; cervical cancer ; CERVICAL-CANCER ; p53 ; CANCER-CELLS ; HPV ; DEGRADATION ; ONCOPROTEIN ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; human papilloma virus ; TP53 ; CARCINOMA CELL-LINES ; E6 ONCOPROTEIN ; E6-mediated p53 inactivation ; E6AP ; HPV INFECTION ; MULTICENTRIC CASE-CONTROL ; P53 CODON- 72 POLYMORPHISM ; UBE3A
    Abstract: Functional loss of the tumor suppressor p53 by alterations in its TP53 gene is a frequent event in cancers of different anatomical regions. Cervical cancer is strongly linked to infection by high-risk human papillomavirus (HPV) types. The viral oncoprotein E6 has the ability to associate with and neutralize the function of p53. E6 interacts with a 100-kDa cellular protein, termed E6 associated protein (E6AP; also called ubiquitin-protein ligase E3A or UBE3A), which functions as an ubiquitin protein ligase. The dimeric complex then binds p53 and E6AP catalyzes multi-ubiquitination and degradation of p53. The ability to promote p53 degradation is an exclusive property of E6 from the high,risk HPV types. Indeed, the low- risk E6 proteins lack this activity, although they can bind p53. Consistent with the E6 function of the high-risk HPV types, the majority of cervical cancer cells have a wild type p53 gene, but the protein levels are strongly decreased. Several independent studies have shown that in a small percentage of cervical tumors the p53 gene is mutated. However, this event appears to be unrelated to the presence or absence of HPV infection and the nature of the tumor
    Type of Publication: Journal article published
    PubMed ID: 12619117
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; GENE ; GENE-EXPRESSION ; MESSENGER-RNA ; DOWN-REGULATION ; human papillomavirus ; HUMAN-PAPILLOMAVIRUS ; intraepithelial neoplasia ; E7 ONCOPROTEIN ; INTERFERON-ALPHA ; GAMMA ; LASER CAPTURE MICRODISSECTION ; CYTOKINE PRODUCTION ; cervical tissue ; interferon-kappa ; quantitative real-time polymerase chain reaction
    Abstract: Interferons (IFNs) are expressed by many cell types and play a pivotal role in the generation of immune responses against viral infections. IFN-kappa, a novel type I IFN, displays a tight tropism for keratinocytes and specific lymphoid populations and exhibits functional similarities with other type I IFNs. The human papillomavirus (HPV), the etiological agent for cervical cancer, infects keratinocytes of the uterine cervix and has been shown to directly inhibit the IFN pathway. We evaluated IFN-kappa, -beta, and -gamma gene expression in HPV-negative normal and HPV-positive pre-malignant and malignant ex vivo cervical tissue covering the entire spectrum of cervical disease. Quantitative real-time polymerase chain reaction and methods previously optimized for detecting low-expressing genes in cervical tissue were used. In contrast to IFN-beta and -gamma, IFN-kappa mRNA prevalence and levels were unexpectedly higher in diseased compared with normal whole cervical tissue with highest levels observed in invasive carcinoma tissue. Strikingly, laser capture microdissection revealed an absence of IFN-kappa mRNA in diseased epithelium, whereas stromal IFN-kappa was found exclusively in diseased tissue. IFN-gamma and IFN-beta were likewise found to be upregulated in diseased cervical stroma. Immunofluorescence supports the involvement of monocytes and dendritic cells in the stromal induction of IFNs in diseased tissue. Further, using three-dimensional raft cultures in which the viral life cycle can be mimicked, human keratinocytes transfected with full-length HPV16 displayed a significant decrease in IFN-kappa mRNA compared with non-transfected human keratinocytes. Altogether, these findings show that IFN-kappa is down-regulated in cervical keratinocytes harboring HPV, which may be a contributing factor in the progression of a cervical lesion.
    Type of Publication: Journal article published
    PubMed ID: 20479716
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  • 5
  • 6
    ISSN: 1432-2307
    Keywords: In situ hybridization ; Polymerase chain reaction ; Cold start ; Hot start ; Consensus primers ; Genomic probes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract One hundred and forty-eight randomly chosen neutral-buffered formaldehyde-fixed cervical biopsies in which cervical intra-epithelial neoplasia (CIN) I–III had been diagnosed were tested for HPV (human papilloma virus) DNA by in situ hybridization (ISH) and polymerase chain reaction (PCR). For ISH, we utilized a biotinylated panprobe and type-specific, genomic probe sets. For PCR, we used the general primers GP5/GP6 and their recently described, elongated version GP5+/GP6+, and included the modification of hot-start PCR. Amplified DNA was detected by gel electrophoresis and slot blot hybridization. The positivity rate of ISH was 59% for all biopsies and 69%, 62% and 46% for CIN I, II and III, respectively. The sensitivity of GP5/GP6 was 74% with cold-start PCR and 78% with hot-start PCR. When GP5+/GP6+ was used, the sensitivity increased to 89% with cold-start PCR and to 95% with hot-start PCR. Based on the most sensitive PCR technique, HPV detection was 93%, 95% and 96% in CIN I, II and III, respectively. The number of HPV types decreased with the severity of the lesion, and HPV 16 was the predominant type. Multiple HPVs were rare and almost all HPV-positive cases could be typed. ISH and slot blot hybridization correlated well regarding HPV typing specificity. Our results confirm that distinct HPV types are present in a high proportion of cases of CIN. The sensitivity of ISH is lower than that of PCR. Furthermore, the modified general primers GP5+/GP6+ give a higher yield than GP5/GP6, while hot-start PCR increases sensitivity even further.
    Type of Medium: Electronic Resource
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