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Sökning: WFRF:(Ferris Robert L.)

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1.
  • Jiang, Xia, et al. (författare)
  • Shared heritability and functional enrichment across six solid cancers
  • 2019
  • Ingår i: Nature Communications. - Nature Publishing Group. - 2041-1723 .- 2041-1723. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (<em>r</em><em>g</em> = 0.57, <em>p</em> = 4.6 × 10−8), breast and ovarian cancer (<em>r</em><em>g</em> = 0.24, <em>p</em> = 7 × 10−5), breast and lung cancer (<em>r</em><em>g</em> = 0.18, <em>p </em>=1.5 × 10−6) and breast and colorectal cancer (<em>r</em><em>g</em> = 0.15, <em>p</em> = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.</p>
2.
  • Jiang, Xia, et al. (författare)
  • Shared heritability and functional enrichment across six solid cancers
  • 2019
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.</p>
3.
  • Sims, Rebecca, et al. (författare)
  • Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
  • 2017
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 49:9, s. 1373-
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P &lt; 1 x 10(-4)) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P &lt; 5 x 10(-8)) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p. Pro522Arg, P = 5.38 x 10(-10), odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p. Ser209Phe, P = 4.56 x 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p. Arg62His, P = 1.55 x 10(-14), OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.</p>
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4.
  • Wang, Li-San, et al. (författare)
  • Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
  • 2015
  • Ingår i: JAMA neurology. - 2168-6157. ; 72:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
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5.
  • Villa, Luisa L., et al. (författare)
  • Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions
  • 2007
  • Ingår i: New England Journal of Medicine. - Massachusetts Medical Society. - 0028-4793. ; 356:19, s. 1915-1927
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Human papillomavirus types 16 (HPV-16) and 18 (HPV-18) cause approximately 70% of cervical cancers worldwide. A phase 3 trial was conducted to evaluate a quadrivalent vaccine against HPV types 6, 11, 16, and 18 (HPV-6/11/16/18) for the prevention of high-grade cervical lesions associated with HPV-16 and HPV-18. METHODS: In this randomized, double-blind trial, we assigned 12,167 women between the ages of 15 and 26 years to receive three doses of either HPV-6/11/16/18 vaccine or placebo, administered at day 1, month 2, and month 6. The primary analysis was performed for a per-protocol susceptible population that included 5305 women in the vaccine group and 5260 in the placebo group who had no virologic evidence of infection with HPV-16 or HPV-18 through 1 month after the third dose (month 7). The primary composite end point was cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18. RESULTS: Subjects were followed for an average of 3 years after receiving the first dose of vaccine or placebo. Vaccine efficacy for the prevention of the primary composite end point was 98% (95.89% confidence interval [CI], 86 to 100) in the per-protocol susceptible population and 44% (95% CI, 26 to 58) in an intention-to-treat population of all women who had undergone randomization (those with or without previous infection). The estimated vaccine efficacy against all high-grade cervical lesions, regardless of causal HPV type, in this intention-to-treat population was 17% (95% CI, 1 to 31). CONCLUSIONS: In young women who had not been previously infected with HPV-16 or HPV-18, those in the vaccine group had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to HPV-16 or HPV-18 than did those in the placebo group.
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6.
  • Muñoz, Nubia, et al. (författare)
  • Impact of Human Papillomavirus (HPV)-6/11/16/18 Vaccine on All HPV-Associated Genital Diseases in Young Women.
  • 2010
  • Ingår i: Journal of the National Cancer Institute. - Oxford University Press. - 1460-2105. ; 102, s. 325-339
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The impact of the prophylactic vaccine against human papillomavirus (HPV) types 6, 11, 16, and 18 (HPV6/11/16/18) on all HPV-associated genital disease was investigated in a population that approximates sexually naive women in that they were "negative to 14 HPV types" and in a mixed population of HPV-exposed and -unexposed women (intention-to-treat group). Methods This analysis studied 17 622 women aged 15-26 years who were enrolled in one of two randomized, placebo-controlled, efficacy trials for the HPV6/11/16/18 vaccine (first patient on December 28, 2001, and studies completed July 31, 2007). Vaccine or placebo was given at day 1, month 2, and month 6. All women underwent cervicovaginal sampling and Papanicolaou (Pap) testing at day 1 and every 6-12 months thereafter. Outcomes were any cervical intraepithelial neoplasia; any external anogenital and vaginal lesions; Pap test abnormalities; and procedures such as colposcopy and definitive therapy. Absolute rates are expressed as women with endpoint per 100 person-years at risk. Results The average follow-up was 3.6 years (maximum of 4.9 years). In the population that was negative to 14 HPV types, vaccination was up to 100% effective in reducing the risk of HPV16/18-related high-grade cervical, vulvar, and vaginal lesions and of HPV6/11-related genital warts. In the intention-to-treat group, vaccination also statistically significantly reduced the risk of any high-grade cervical lesions (19.0% reduction; rate vaccine = 1.43, rate placebo = 1.76, difference = 0.33, 95% confidence interval [CI] = 0.13 to 0.54), vulvar and vaginal lesions (50.7% reduction; rate vaccine = 0.10, rate placebo = 0.20, difference = 0.10, 95% CI = 0.04 to 0.16), genital warts (62.0% reduction; rate vaccine = 0.44, rate placebo = 1.17, difference = 0.72, 95% CI = 0.58 to 0.87), Pap abnormalities (11.3% reduction; rate vaccine = 10.36, rate placebo = 11.68, difference = 1.32, 95% CI = 0.74 to 1.90), and cervical definitive therapy (23.0% reduction; rate vaccine = 1.97, rate placebo = 2.56, difference = 0.59, 95% CI = 0.35 to 0.83), irrespective of causal HPV type. Conclusions High-coverage HPV vaccination programs among adolescents and young women may result in a rapid reduction of genital warts, cervical cytological abnormalities, and diagnostic and therapeutic procedures. In the longer term, substantial reductions in the rates of cervical, vulvar, and vaginal cancers may follow.
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7.
  • Brown, Darron R., et al. (författare)
  • The Impact of Quadrivalent Human Papillomavirus (HPV; Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine on Infection and Disease Due to Oncogenic Nonvaccine HPV Types in Generally HPV-Naive Women Aged 16-26 Years
  • 2009
  • Ingår i: 24th International Papillomavirus Conference and Clinical Workshop,2007-11-03 - 2007-11-09. - University of Chicago Press.
  • Konferensbidrag (refereegranskat)abstract
    • Background. Human papillomavirus (HPV)-6/11/16/18 vaccine reduces the risk of HPV-6/11/16/18-related cervical intraepithelial neoplasia (CIN) 1-3 or adenocarcinoma in situ (AIS). Here, its impact on CIN1-3/AIS associated with nonvaccine oncogenic HPV types was evaluated. Methods. We enrolled 17,622 women aged 16-26 years. All underwent cervicovaginal sampling and Pap testing at regular intervals for up to 4 years. HPV genotying was performed for biopsy samples, and histological diagnoses were determined by a pathology panel. Analyses were conducted among subjects who were negative for 14 HPV types on day 1. Prespecified analyses included infection of >= 6 months' duration and CIN1-3/AIS due to the 2 and 5 most common HPV types in cervical cancer after HPV types 16 and 18, as well as all tested nonvaccine types. Results. Vaccination reduced the incidence of HPV-31/45 infection by 40.3% (95% confidence interval [CI], 13.9% to 59.0%) and of CIN1-3/AIS by 43.6% (95% CI, 12.9% to 64.1%), respectively. The reduction in HPV-31/33/45/52/58 infection and CIN1-3/AIS was 25.0% (95% CI, 5.0% to 40.9%) and 29.2% (95% CI, 8.3% to 45.5%), respectively. Efficacy for CIN2-3/AIS associated with the 10 nonvaccine HPV types was 32.5% (95% CI, 6.0% to 51.9%). Reductions were most notable for HPV-31. Conclusions. HPV-6/11/16/18 vaccine reduced the risk of CIN2-3/AIS associated with nonvaccine types responsible for similar to 20% of cervical cancers. The clinical benefit of cross-protection is not expected to be fully additive to the efficacy already observed against HPV-6/11/16/18-related disease, because women may have >1 CIN lesion, each associated with a different HPV type.
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8.
  • Joura, Elmar A., et al. (författare)
  • HPV antibody levels and clinical efficacy following administration of a prophylactic quadrivalent HPV vaccine
  • 2008
  • Ingår i: Vaccine. - Elsevier. - 1873-2518. ; 26:52, s. 6844-6851
  • Tidskriftsartikel (refereegranskat)abstract
    • The efficacy of the quadrivalent Human Papillomavirus (HPV) vaccine is thought to be mediated by humoral immunity. We evaluated the correlation between quadrivalent HPV vaccine-induced serum anti-HPV responses and efficacy. 17,622 women were vaccinated at day 1, and months 2 and 6. At day I and at 6-12 months intervals for up to 48 months, subjects underwent Papanicolaou and genital HPV testing. No immune correlate of protection could be found due to low number of cases. Although 40% of vaccine subjects were anti-HPV 18 seronegative at end-of-study, efficacy against HPV 18-related disease remained high (98.4%; 95% CI: 90.5-100.0) despite high attack rates in the placebo group. These results suggest vaccine-induced protection via immune memory, or lower than detectable HPV 18 antibody titers. (C) 2008 Elsevier Ltd. All rights reserved.
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9.
  • Villa, Luisa L., et al. (författare)
  • Prophylactic efficacy of a quadrivalent human papillomavirus (HPV) vaccine in women with virological evidence of HPV infection
  • 2007
  • Ingår i: Journal of Infectious Diseases. - Oxford University Press. - 1537-6613. ; 196:10, s. 1438-1446
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. A quadrivalent (types 6, 11, 16, and 18) human papillomavirus (HPV) L1 virus-like-particle (VLP) vaccine has been shown to be 95%-100% effective in preventing cervical and genital disease related to HPV-6,-11,-16, and-18 in 16-26-year-old women naive for HPV vaccine types. Because most women in the general population are sexually active, some will have already been infected with >= 1 HPV vaccine types at the time vaccination is offered. Here, we assessed whether such infected women are protected against disease caused by the remaining HPV vaccine types. Methods. Two randomized, placebo-controlled trials of the quadrivalent (types 6, 11, 16, and 18) HPV vaccine enrolled 17,622 women without consideration of baseline HPV status. Among women infected with 1-3 HPV vaccine types at enrollment, efficacy against genital disease related to the HPV vaccine type or types for which subjects were naive was assessed. Results. Vaccination was 100% effective (95% confidence interval [CI], 79%-100%) in preventing incident cervical intraepithelial neoplasia 2 or 3 or cervical adenocarcinoma in situ caused by the HPV type or types for which the women were negative at enrollment. Efficacy for preventing vulvar or vaginal HPV-related lesions was 94% (95% CI, 81%-99%). Conclusions. Among women positive for 1-3 HPV vaccine types before vaccination, the quadrivalent HPV vaccine protected against neoplasia caused by the remaining types. These results support vaccination of the general population without prescreening.
10.
  • Wheeler, Cosette M., et al. (författare)
  • The Impact of Quadrivalent Human Papillomavirus (HPV; Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine on Infection and Disease Due to Oncogenic Nonvaccine HPV Types in Sexually Active Women Aged 16-26 Years
  • 2009
  • Ingår i: 24th International Papillomavirus Conference and Clinical Workshop,2007-11-03 - 2007-11-09. - University of Chicago Press.
  • Konferensbidrag (refereegranskat)abstract
    • Background. We evaluated the impact of a quadrivalent human papillomavirus (HPV) vaccine on infection and cervical disease related to 10 nonvaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) associated with >20% of cervical cancers. The population evaluated included HPV-naive women and women with preexisting HPV infection and/or HPV-related disease at enrollment. Methods. Phase 3 efficacy studies enrolled 17,622 women aged 16-26 years. Subjects underwent cervicovaginal sampling and Pap testing on day 1 and then at 6-12-month intervals for up to 4 years. HPV typing was performed on samples from enrollment and follow-up visits, including samples obtained for diagnosis or treatment of HPV-related disease. All subjects who received >= 1 dose and returned for follow-up were included. Results. Vaccination reduced the rate of HPV-31/33/45/52/58 infection by 17.7% (95% confidence interval [CI], 5.1% to 28.7%) and of cervical intraepithelial neoplasia (CIN) 1-3 or adenocarcinoma in situ (AIS) by 18.8% (95% CI, 7.4% to 28.9%). Vaccination also reduced the rate of HPV-31/58/59-related CIN1-3/AIS by 26.0% (95% CI, 6.7% to 41.4%), 28.1% (95% CI, 5.3% to 45.6%), and 37.6% (95% CI, 6.0% to 59.1%), respectively. Although a modest reduction in HPV-31/33/45/52/58-related CIN2 or worse was observed, the estimated reduction was not statistically significant. Conclusions. These cross-protection results complement the vaccine's prophylactic efficacy against disease associated with HPV-6, -11, -16, and - 18. Long-term monitoring of vaccinated populations are needed to fully ascertain the population-based impact and public health significance of these findings.
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