| 1. |
- Fresard, Laure, et al.
(author)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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In: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Journal article (peer-reviewed)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 2. |
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| 3. |
- Tiegs, Scott D., et al.
(author)
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Global patterns and drivers of ecosystem functioning in rivers and riparian zones
- 2019
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In: Science Advances. - Washington : American Association of Advancement in Science. - 2375-2548. ; 5:1
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Journal article (peer-reviewed)abstract
- River ecosystems receive and process vast quantities of terrestrial organic carbon, the fate of which depends strongly on microbial activity. Variation in and controls of processing rates, however, are poorly characterized at the global scale. In response, we used a peer-sourced research network and a highly standardized carbon processing assay to conduct a global-scale field experiment in greater than 1000 river and riparian sites. We found that Earth's biomes have distinct carbon processing signatures. Slow processing is evident across latitudes, whereas rapid rates are restricted to lower latitudes. Both the mean rate and variability decline with latitude, suggesting temperature constraints toward the poles and greater roles for other environmental drivers (e.g., nutrient loading) toward the equator. These results and data set the stage for unprecedented "next-generation biomonitoring" by establishing baselines to help quantify environmental impacts to the functioning of ecosystems at a global scale.
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| 4. |
- Villa, Luisa L., et al.
(author)
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Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions
- 2007
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 356:19, s. 1915-1927
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Journal article (peer-reviewed)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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| 5. |
- Klug, Stefanie J, et al.
(author)
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TP53 codon 72 polymorphism and cervical cancer : a pooled analysis of individual data from 49 studies
- 2009
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In: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 10:8, s. 772-784
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Journal article (peer-reviewed)abstract
- BACKGROUND: Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer. METHODS: Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy-Weinberg equilibrium, study quality, and the material used to determine TP53 genotype. FINDINGS: The pooled estimates (OR) for invasive cervical cancer were 1.22 (95% CI 1.08-1.39) for arginine homozygotes compared with heterozygotes, and 1.13 (0.94-1.35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy-Weinberg equilibrium (1.71 [1.21-2.42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1.35 [1.15-1.58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1.39 [1.13-1.73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes). INTERPRETATION: Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies.
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| 6. |
- Villa, Luisa L., et al.
(author)
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Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18
- 2006
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In: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 24:27-28, s. 5571-5583
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Journal article (peer-reviewed)abstract
- Human papillomavirus (HPV) infection causes cervical cancer and genital warts. Young women (1106) were randomized to receive one of three formulations of a quadrivalent HPV (Types 6/11/16/18) L1 virus-like particle (VLP) vaccine or one of two placebo formulations. The goal was to assess vaccine safety and immunogenicity in baseline HPV 6/11/16 or 18-naive and previously infected subjects. All three formulations were highly immunogenic. At Month 2 (postdose 1), among women with vaccine-type antibodies at baseline, vaccine-induced anti-HPV responses were similar to 12- to 26-fold higher than those observed in baseline-naive women, suggesting an anamnestic response. Following an initial, similar sized decline, anti-HPV responses plateaued and remained stable through end-of-study (3.0 years). No vaccine-related serious adverse experiences were reported. (c) 2006 Elsevier Ltd. All rights reserved.
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| 7. |
- Scott, David R, et al.
(author)
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Use of human papillomavirus DNA testing to compare equivocal cervical cytologic interpretations in the United States, Scandinavia, and the United Kingdom
- 2002
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In: Cancer. - : John Wiley and Sons Inc.. - 1097-0142 .- 0008-543X. ; 96:1, s. 14-20
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Journal article (peer-reviewed)abstract
- BACKGROUND: Human papillomavirus (HPV) DNA testing may be useful in clarifying equivocal cervical cytologic interpretations. One application might be to standardize the meaning of equivocal interpretations from laboratories in various regions. Because international differences may be particularly marked, international comparisons of emerging data will require clear translations of "equivocal" and similar terms. METHODS: To perform a three-country comparison, the authors selected a morphologically diverse set of 188 conventional Papanicolaou tests initially classified as "squamous atypia" from a study of more than 20,000 women in Portland, Oregon (1989-1990). Previously, five U.S. expert cytopathologists independently interpreted the slides with screening cytotechnologists' marks in place. For this comparison, one British and two Scandinavian reviewers involved in HPV research reviewed the slides after original marks had been removed. The authors compared all eight reviewers' classifications of negative, equivocal, or abnormal in a series of pairwise comparisons using the kappa statistic. They then compared cytologic interpretations with HPV DNA testing. RESULTS: Oncogenic HPV DNA detection was significantly associated with increasingly abnormal interpretations for each reader. The British reader tended to rate tests as more abnormal than the American pathologists did, whereas the Scandinavians tended to rate tests as more normal. Reference to the HPV DNA standard clarified the tendency of readers to render systematically more or less severe interpretations. For example, the Scandinavian cytologists discounted subtle (often HPV-associated) changes in favor of cytologic certainty, making HPV triage of equivocal tests less applicable there. CONCLUSIONS: International research on cytopathology, particularly on the possible uses of HPV DNA testing, will require calibration of local cytologic definitions.
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| 8. |
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| 9. |
- Stoler, Aaron B., et al.
(author)
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Combined Effects Of Road Salt And An Insecticide On Wetland Communities
- 2017
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In: Environmental Toxicology and Chemistry. - : John Wiley & Sons. - 0730-7268 .- 1552-8618. ; 36:3, s. 771-779
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Journal article (peer-reviewed)abstract
- As the numbers of chemical contaminants in freshwater ecosystems increase, it is important to understand whether contaminants interact in ecologically important ways. The present study investigated the independent and interactive effects of 2 contaminants that frequently co-occur in freshwater environments among higher latitudes, including a commonly applied insecticide (carbaryl) and road salt (NaCl). The hypothesis was that the addition of either contaminant would result in a decline in zooplankton, an algal bloom, and the subsequent decline of both periphyton and periphyton consumers. Another hypothesis was that combining the contaminants would result in synergistic effects on community responses. Outdoor mesocosms were used with communities that included phytoplankton, periphyton, zooplankton, amphipods, clams, snails, and tadpoles. Communities were exposed to 4 environmentally relevant concentrations of salt (27 mg Cl- L-1, 77 mg Cl- L-1, 277 mg Cl- L-1, and 727 mg Cl- L-1) fully crossed with 4 carbaryl treatments (ethanol, 0 mu gL(-1), 5 mu g L-1, and 50 mu g L-1) over 57 d. Contaminants induced declines in rotifer and cladoceran zooplankton, but only carbaryl induced an algal bloom. Consumers exhibited both positive and negative responses to contaminants, which were likely the result of both indirect community interactions and direct toxicity. In contrast to the hypothesis, no synergistic effects were found, although copepod densities declined when high concentrations of both chemicals were combined. The results suggest that low concentrations of salt and carbaryl are likely to have mostly independent effects on aquatic communities. (C) 2016 SETAC
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| 10. |
- Stoler, A. B., et al.
(author)
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Effects of a common insecticide on wetland communities with varying quality of leaf litter inputs
- 2017
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In: Environmental Pollution. - : Elsevier. - 0269-7491 .- 1873-6424. ; 226, s. 452-462
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Journal article (peer-reviewed)abstract
- Chemical contamination of aquatic systems often co-occurs with dramatic changes in surrounding terrestrial vegetation. Plant leaf litter serves as a crucial resource input to many freshwater systems, and changes in litter species composition can alter the attributes of freshwater communities. However, little is known how variation in litter inputs interacts with chemical contaminants. We investigated the ecological effects resulting from changes in tree leaf litter inputs to freshwater communities, and how those changes might interact with the timing of insecticide contamination. Using the common insecticide malathion, we hypothesized that inputs of nutrient-rich and labile leaf litter (e.g., elm [Ulmus spp.] or maple [Acer spp.]) would reduce the negative effects of insecticides on wetland communities relative to inputs of recalcitrant litter (e.g., oak [Quercus spp.]). We exposed artificial wetland communities to a factorial combination of three litter species treatments (elm, maple, and oak) and four insecticide treatments (no insecticide, small weekly doses of 10 mu g L-1, and either early or late large doses of 50 mu g L-1). Communities consisted of microbes, algae, snails, amphipods, zooplankton, and two species of tadpoles. After two months, we found that maple and elm litter generally induced greater primary and secondary production. Insecticides induced a reduction in the abundance of amphipods and some zooplankton species, and increased phytoplanlcton. In addition, we found interactive effects of litter species and insecticide treatments on amphibian responses, although specific effects depended on application regime. Specifically, with the addition of insecticide, elm and maple litter induced a reduction in gray tree frog survival, oak and elm litter delayed tree frog metamorphosis, and oak and maple litter reduced green frog tadpole mass. Our results suggest that attention to local forest composition, as well as the timing of pesticide application might help ameliorate the harmful effects of pesticides observed in freshwater systems. (C) 2017 Elsevier Ltd. All rights reserved.
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