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  • 1
    Keywords: CANCER ; IN-VITRO ; human ; VITRO ; CLASSIFICATION ; screening ; DIFFERENTIATION ; DNA ; papillomavirus ; antibodies ; antibody ; prevention ; ASSAY ; CERVICAL-CANCER ; human papillomavirus ; VIRUS-LIKE PARTICLES ; HPV ; HUMAN-PAPILLOMAVIRUS ; VACCINE ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; ESTABLISHMENT ; FEASIBILITY ; YOUNG-WOMEN ; IMPLEMENTATION ; WORLDWIDE ; PRODUCTS ; SWITZERLAND ; ASSAYS ; CANDIDATE ; serological ; serology ; CONTROLLED-TRIAL ; DNA evaluation ; HUMAN-PAPILLOMAVIRUS-16
    Abstract: International reference materials such as International Standard reagents facilitate quality assurance of essential biopharmaceutical products and related in vitro diagnostic tests. Standardization of antibody and DNA measurements and harmonization of laboratory procedures are key to the success of cancer prevention strategies through screening methods as well as for development and implementation of vaccination against the human papillomavirus (HPV). The WHO supported the preparation and initial analysis of a panel of candidate serological and DNA reference reagents aimed at facilitating inter-laboratory comparisons and detection of HPV worldwide. Two international collaborative studies assessed the performance of various HPV antibody and HPV-DNA detection assays and examined the feasibility of generating HPV antibody and DNA standard reagents. These studies showed that improvement in performance and comparability of assays is urgently needed and that the use of the same International Standard reference reagent could significantly improve performance and comparability. It is hoped that the establishment of International Units and International Standards for HPV antibody and DNA analysis will be pursued with high priority. (c) 2006 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16950007
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  • 2
    Keywords: CELLS ; CELL ; human ; MODEL ; GENOME ; PROTEIN ; PROTEINS ; SAMPLE ; SAMPLES ; TUMORS ; PATIENT ; DNA ; INFECTION ; CARCINOGENESIS ; tumour ; SKIN ; BINDING ; E7 ; OPEN READING FRAME ; SEQUENCES ; skin carcinogenesis ; PCR ; SWEDEN ; HPV ; INFECTIONS ; NONMELANOMA SKIN CANCERS ; real-time PCR ; BIOPSY ; RETINOBLASTOMA PROTEIN ; EPIDERMODYSPLASIA-VERRUCIFORMIS ; REAL-TIME ; E6 PROTEINS ; microbiology ; ENGLAND ; HUMAN PAPILLOMAVIRUSES ; retinoblastoma ; BIOPSIES ; E7 PROTEIN ; viral ; virology ; biotechnology ; GENOMES ; HPV types ; HPV DNA ; HEALTHY SKIN ; MALIGNANT-TRANSFORMATION
    Abstract: Two novel human papillomaviruses (HPVs), HPV93 and HPV96, with genomes of 7450 and 7438 bp, respectively, are described. The Ll open reading frame of HPV93 showed highest identity to HPV24 (79%) and that of HPV96 had highest identity to HPV92 (71 %). Real-time PCR for HPV92, 93 and 96 on stripped biopsies from tumours and healthy skin from 269 immunocompetent patients found HPV DNA in 2.6 % of tumours and in 0.4 % of healthy skin samples. Double infections were observed in two tumours. HPV92 was detected in four, HPV93 in two and HPV96 in three tumours. The range of viral loads spanned from one copy per 45 cells to one copy per 10 000 cells. The E7 proteins of HPV92, 93 and 96 were found to bind the retinoblastoma protein (pRb). These results suggest a possible role for these HPV types in skin carcinogenesis that deserves further study,
    Type of Publication: Journal article published
    PubMed ID: 17412976
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  • 3
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    Abstract: BACKGROUND: In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). METHODS AND FINDINGS: We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for 〉/=15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7). CONCLUSIONS: Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.
    Type of Publication: Journal article published
    PubMed ID: 26808155
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  • 5
    Abstract: Ninety-one HIV-infected individuals (61 men and 30 women) were randomized to vaccination either with quadrivalent (Gardasil) or bivalent (Cervarix) HPV vaccine. Neutralizing and specific HPV-binding serum antibodies were measured at baseline and 12 months after the first vaccine dose. Presence of neutralizing and binding antibodies had good agreement (average Kappa for HPV types 6, 11, 16, 18, 31, 33 and 45 was 0.65). At baseline, 88% of subjects had antibodies against at least one genital HPV. Following vaccination with Cervarix, all subjects became seropositive for HPV16 and 18. After Gardasil vaccination, 96% of subjects seroconverted for HPV16 and 73% for HPV18. Levels of HPV16-specific antibodies were 〈1 international unit (IU) in 87% of study subjects before vaccination but 〉10IU in 85% of study subjects after vaccination. Antibodies against non-vaccine HPV types appeared after Gardasil vaccination for 〉50% of vaccinated females for HPV 31, 35 and 73 and for 〉50% of Cervarix-vaccinated females for HPV 31, 33, 35, 45, 56 and 58. Cross-reactivity with non-genital HPV types was also detected. In conclusion, HIV-infected subjects responded to HPV vaccination with induction of neutralizing antibodies against both vaccine and non-vaccine types.
    Type of Publication: Journal article published
    PubMed ID: 26896686
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  • 6
    Keywords: SPECTRA ; CANCER ; carcinoma ; CELL ; human ; MODEL ; MODELS ; DISEASE ; DISEASES ; RISK ; SITE ; SITES ; SAMPLE ; SAMPLES ; PATIENT ; DNA ; INFECTION ; RISK-FACTORS ; SKIN ; LESIONS ; risk factors ; skin cancer ; PATHOGENESIS ; PCR ; SWEDEN ; HPV ; BENIGN ; MULTIVARIATE ; CARCINOMAS ; squamous cell carcinoma ; PREVALENCE ; RENAL-TRANSPLANT RECIPIENTS ; BIOPSY ; SKIN-CANCER ; basal cell carcinoma ; CELL CARCINOMA ; INTERVAL ; methods ; ACTINIC KERATOSES ; USA ; odds ratio ; RISK-FACTOR ; CANCERS ; E ; SPECTRUM ; SQUAMOUS-CELL ; HERPES-SIMPLEX ; HUMAN PAPILLOMAVIRUSES ; BIOPSIES ; HPV types ; ULTRAVIOLET-IRRADIATION
    Abstract: Background. A spectrum of cutaneous human papillomaviruses (HPVs) is detectable in nonmelanoma skin cancers, as well as in healthy skin, but the significance that the presence of these types of HPV DNA has for the pathogenesis of skin cancer remains unclear. Methods. We studied 349 nonimmunosuppressed patients with skin lesions (82 with squamous cell carcinomas, 126 with basal cell carcinomas, 49 with actinic keratoses, and 92 with benign lesions). After superficial skin had been removed by tape, paired biopsy samples-from the lesion and from healthy skin from the same patient-were tested for HPV DNA. Risk factors for HPV DNA were analyzed in multivariate models. Results. Overall, 12% of healthy skin samples were positive for HPV DNA, compared with 26% of benign lesions, 22% of actinic keratoses, 18% of basal cell carcinomas, and 26% of squamous cell carcinomas. HPV DNA was associated with sites extensively exposed to the sun, both for the lesions (odds ratio [OR], 4.45 [95% confidence interval {CI}, 2.44-8.111) and for the healthy skin samples (OR, 3.65 [95% CI 1.79-7.44]). HPV types of Beta-papillomavirus species 2 predominate in squamous cell carcinomas (OR, 4.40 [95% CI, 1.92-10.06]), whereas HPV types of Beta-papillomavirus species 1 are primarily found in benign lesions (OR, 3.47 [95% CI, 1.72-6.99]). Conclusions. Cutaneous HPV types are primarily detected at sites extensively exposed to the sun. HPV types of Beta-papillomavirus species 2, but not of species 1, are associated with squamous cell carcinoma
    Type of Publication: Journal article published
    PubMed ID: 17703418
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  • 7
    Keywords: IN-VITRO ; tumor ; CELL ; Germany ; IN-VIVO ; VITRO ; VIVO ; DISEASE ; GENOME ; SAMPLE ; SAMPLES ; transcription ; cell line ; COMPONENTS ; MOLECULES ; LINES ; DNA ; SERA ; FAMILY ; T cell ; T-CELL ; CELL-LINES ; OPEN READING FRAME ; SEQUENCE ; MOLECULE ; virus ; LYMPHOMA ; PATTERNS ; NUMBER ; COMPONENT ; CELL-LINE ; leukemia ; LINE ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; DIVERSITY ; REPLICATION ; SELECTION ; CHILDREN ; cell lines ; HODGKINS-DISEASE ; INITIATION ; HEPATITIS-C VIRUS ; SERUM ; FEATURES ; CHILDHOOD ; FAMILIES ; PATTERN ; TRANSFECTION ; REARRANGEMENT ; NUCLEOTIDE-SEQUENCES ; BLOOD MONONUCLEAR-CELLS ; BONE-MARROW-CELLS ; SEQUENCE HETEROGENEITY ; EVENTS ; USA ; in vivo ; genomic ; microbiology ; virology ; FULL-LENGTH ; CHICKEN-ANEMIA-VIRUS ; MINI VIRUS ; SPLICED MESSENGER-RNAS
    Abstract: The in vitro replication of the Torque teno virus (IT virus) tth8 full-length genome and particle formation in a Hodgkin's lymphoma-derived cell line after transfection with cloned viral DNA were demonstrated. Analyses of the transcription patterns of tth8 and tth7 TT virus isolates in a number of lymphoma and T-cell leukemia cell lines indicated differential additional splicing events and intragenomic rearrangement generating open reading frames which could not be deducted from the genomic sequence. We also demonstrated the presence of rearranged TT virus genomes in vivo in sera taken from pregnant mothers whose children later developed childhood leukemia, as well as sera from control mothers. Control experiments using religated cloned genomic tth8 DNA mixed with cellular DNA did not result in such subviral molecules. These subviral isolates ranged from 172 bp to full-length TT virus genomes. Possible in vivo selection for specific rearranged molecules was indicated by the presence of one isolate (561 bp) in 11 serum samples. It remains to be clarified whether selected rearranged subviral components resulting from specific Tr virus types may contribute to the initiation of disease. These data demonstrate new features of Tr viruses suggesting possible similarities to plant viruses of the family Geminiviridae, as well as raise questions about the documented plurality and diversity of anelloviruses
    Type of Publication: Journal article published
    PubMed ID: 17596318
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  • 8
    Keywords: PEPTIDE ; CANCER ; CELLS ; EXPRESSION ; tumor ; carcinoma ; Germany ; DISEASE ; PROTEIN ; PATIENT ; RESPONSES ; SERA ; INDUCTION ; E7 ; IMMUNE-RESPONSES ; antibodies ; antibody ; NO ; ASSAY ; DIFFERENCE ; colorectal cancer ; COLORECTAL-CANCER ; cervical cancer ; CERVICAL-CANCER ; MARKERS ; p53 ; LYMPHOCYTES ; REGION ; REGIONS ; HPV ; E6 ; HPV16 ; HEAD ; ONCOPROTEIN ; CANCER-PATIENTS ; immune response ; IMMUNE-RESPONSE ; T-LYMPHOCYTES ; T lymphocyte ; CANCER PATIENTS ; HEALTHY ; EARLY PROTEINS ; T lymphocytes ; SERUM ; ELISA ; ONCOLOGY ; TUMOR-SUPPRESSOR ; tumor immunity ; p16(INK4A) ; humoral immune response ; P16 ; LEVEL ; SUPPRESSOR ; USA ; CANCERS ; HUMAN-PAPILLOMAVIRUS TYPES ; response ; tumor suppressor ; AUTOIMMUNE ; epitope mapping
    Abstract: The cellular tumor suppressor p16 is strongly overexpressed in cervical cancers and precancers. We have previously demonstrated that infiltrating T lymphocytes reactive against p16 can be found in cervical cancer patients. Here, we analyzed whether 16 induces humoral immune responses. Sera of patients with cervical cancer, oropharyngeal cancer, colorectal cancer and autoimmune disease were included. A total of 919 sera were analyzed. including 486 matched sera from a cervical cancer case control study. p16 antibodies were analyzed in western blot and a newly developed peptide ELISA covering the complete p16 protein. In addition, a Luminex-based multiplex assay was used for simultaneous detection of antibodies directed against p16, p53, HPV16 E6 and HPV16 E7. In all entities, only low p16 antibody reactivity was observed. Epitope mapping revealed 2 predominant epitope regions of the p16 protein. No significant difference in p16 antibody frequency (OR = 0.9; 95% Cl = 0.6-1.3) and p-53 antibody frequency (OR = 0.6; 95% Cl = 0.3-1.2) was found between patients and healthy controls in the cervical cancer case control study. Antibodies against the HPV16 oncoproteins E6 and E7 were detected more frequently in cervical cancer patients when compared with healthy controls (E6 OR = 27.8; 95 % Cl = 11. - 69.7, E7 OR = 5.7; 95% Cl = 2.9-11.1). In conclusion. despite the strong expression of p16 and the observed induction of cellular immune responses, antibody reactivity against p16 was observed only at very low levels independent of the disease background. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18785210
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  • 9
    Keywords: CANCER ; MORTALITY ; breast cancer ; PREDISPOSITION ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; FGFR2 ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS ; hereditability ; LSP1 ; MALMO PREVENTIVE PROJECT ; multiple risk-allele GWA replication ; TNRC9
    Abstract: BACKGROUND: Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women 〈50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status. METHODS: Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression. RESULTS: Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 x 10(-20) and 1.5 x 10(-25), respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59-2.14; 10 SNPs) and 2.12 (95% CI: 1.80-2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 x 10(-4)). CONCLUSION: The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 22045194
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  • 10
    Keywords: CANCER ; carcinoma ; MODEL ; RISK ; TUMORS ; INFECTION ; ASSOCIATION ; HEALTH ; WOMEN ; cervical intraepithelial neoplasia ; VALIDITY ; nutrition ; BREAST-CANCER RISK ; POSTMENOPAUSAL WOMEN ; SERUM ; ESTROGEN ; HORMONES ; COLLABORATIVE REANALYSIS ; CONTRACEPTIVES ; INDIVIDUAL DATA
    Abstract: Background: Epidemiologic data and animal models suggest that, despite the predominant role of human papillomavirus infection, sex steroid hormones are also involved in the etiology of invasive cervical carcinoma (ICC). Methods: Ninety-nine ICC cases, 121 cervical intraepithelial neoplasia grade 3 (CIN3) cases and 2 control women matched with each case for center, age, menopausal status and blood collection-related variables, were identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Circulating levels of testosterone (T) and estradiol (E(2)); dehydroepiandrosterone sulfate (DHEAS); progesterone (premenopausal women); and sex hormone-binding globulin (SHBG) were measured using immunoassays. Levels of free (f) T and E(2) were calculated from absolute concentrations of T, E(2), and SHBG. Odds ratios (ORs) and 95% confidence intervals (CI) were computed using regularized conditional logistic regression. Results: Among premenopausal women, associations with ICC were observed for fT (OR for highest vs. lowest tertile 5.16, 95% CI, 1.50-20.1). SHBG level was associated with a significant downward trend in ICC risk. T, E(2), fE(2), and DHEAS showed nonsignificant positive association with ICC. Progesterone was uninfluential. Among postmenopausal women, associations with ICC were found for T (OR 3.14; 95% CI, 1.21-9.37), whereas E(2) and fT showed nonsignificant positive association. SHBG level was unrelated to ICC risk in postmenopausal women. No associations between any hormone and CIN3 were detected in either pre- or postmenopausal women. Conclusions: Our findings suggest for the first time that T and possibly E(2) may be involved in the etiology of ICC. Impact: The responsiveness of cervical tumors to hormone modulators is worth exploring.
    Type of Publication: Journal article published
    PubMed ID: 21994406
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