| 1. |
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| 2. |
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| 3. |
- Ferreira, MA, et al.
(författare)
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Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1741-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
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| 4. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 9. |
- Hakkaart, C, et al.
(författare)
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Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 1061-
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Tidskriftsartikel (refereegranskat)abstract
- The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
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| 11. |
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| 12. |
- Boxall, A. B. A., et al.
(författare)
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Pharmaceuticals and Personal Care Products in the Environment: What Are the Big Questions?
- 2012
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Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 120:9, s. 1221-1229
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Over the past 10-15 years, a substantial amount of work has been done by the scientific, regulatory, and business communities to elucidate the effects and risks of pharmaceuticals and personal care products (PPCPs) in the environment. OBJECTIVE: This review was undertaken to identify key outstanding issues regarding the effects of PPCPs on human and ecological health in order to ensure that future resources will be focused on the most important areas. DATA SOURCES: To better understand and manage the risks of PPCPs in the environment, we used the "key question" approach to identify the principle issues that need to be addressed. Initially, questions were solicited from academic, government, and business communities around the world. A list of 101 questions was then discussed at an international expert workshop, and a top-20 list was developed. Following the workshop, workshop attendees ranked the 20 questions by importance. DATA SYNTHESIS: The top 20 priority questions fell into seven categories: a) prioritization of substances for assessment, b) pathways of exposure, c) bioavailability and uptake, a effects characterization, e) risk and relative risk, f) antibiotic resistance, and g) risk management. CONCLUSIONS: A large body of information is now available on PPCPs in the environment. This exercise prioritized the most critical questions to aid in development of future research programs on the topic.
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| 13. |
- Hamdi, Yosr, et al.
(författare)
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Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression : identification of a modifier of breast cancer risk at locus 11q22.3
- 2017
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 161:1, s. 117-134
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
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| 15. |
- Ashbolt, N. J., et al.
(författare)
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Human Health Risk Assessment (HHRA) for Environmental Development and Transfer of Antibiotic Resistance
- 2013
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Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 121:9, s. 993-1001
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: Only recently has the environment been clearly implicated in the risk of antibiotic resistance to clinical outcome, but to date there have been few documented approaches to formally assess these risks. OBJECTIVE: We examined possible approaches and sought to identify research needs to enable human health risk assessments (HHRA) that focus on the role of the environment in the failure of anti-biotic treatment caused by antibiotic-resistant pathogens. METHODS: The authors participated in a workshop held 4-8 March 2012 in Quebec, Canada, to define the scope and objectives of an environmental assessment of antibiotic-resistance risks to human health. We focused on key elements of environmental-resistance-development "hot spots," exposure assessment (unrelated to food), and dose response to characterize risks that may improve antibiotic-resistance management options. DISCUSSION: Various novel aspects to traditional risk assessments were identified to enable an assessment of environmental antibiotic resistance. These include a) accounting for an added selective pressure on the environmental resistome that, over time, allows for development of antibiotic-resistant bacteria (ARB); b) identifying and describing rates of horizontal gene transfer (HGT) in the relevant environmental " hot spot" compartments; and c) modifying traditional dose-response approaches to address doses of ARB for various health outcomes and pathways. CONCLUSIONS: We propose that environmental aspects of antibiotic-resistance development be included in the processes of any HHRA addressing ARB. Because of limited available data, a multi-criteria decision analysis approach would be a useful way to undertake an HHRA of environmental antibiotic resistance that informs risk managers.
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| 16. |
- Brandt, K. K., et al.
(författare)
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Ecotoxicological assessment of antibiotics: A call for improved consideration of microorganisms
- 2015
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Ingår i: Environment International. - : Elsevier Ltd. - 0160-4120 .- 1873-6750. ; 85, s. 189-205
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Forskningsöversikt (refereegranskat)abstract
- Antibiotics play a pivotal role in the management of infectious disease in humans, companion animals, livestock, and aquaculture operations at a global scale. Antibiotics are produced, consumed, and released into the environment at an unprecedented scale causing concern that the presence of antibiotic residues may adversely impact aquatic and terrestrial ecosystems. Herewe critically review the ecotoxicological assessment of antibiotics as related to environmental risk assessment (ERA). We initially discuss the need for more specific protection goals based on the ecosystem service concept, and suggest that the ERA of antibiotics, through the application of a mode of toxic action approach, should make more use of ecotoxicological endpoints targeting microorganisms (especially bacteria) and microbial communities. Key ecosystem services provided by microorganisms and associated ecosystem service-providing units (e.g. taxa or functional groups) are identified. Approaches currently available for elucidating ecotoxicological effects on microorganisms are reviewed in detail and we conclude that microbial community-based tests should be used to complement single-species tests to offer more targeted protection of key ecosystem services. Specifically, we propose that ecotoxicological tests should not only assess microbial community function, but also microbial diversity ('species' richness) and antibiotic susceptibility. Promising areas for future basic and applied research of relevance to ERA are highlighted throughout the text. In this regard, the most fundamental knowledge gaps probably relate to our rudimentary understanding of the ecological roles of antibiotics in nature and possible adverse effects of environmental pollution with subinhibitory levels of antibiotics. © 2015 Elsevier Ltd.
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| 17. |
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| 18. |
- Larsson, D. G. Joakim, 1969, et al.
(författare)
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Critical knowledge gaps and research needs related to the environmental dimensions of antibiotic resistance
- 2018
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 117, s. 132-138
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Forskningsöversikt (refereegranskat)abstract
- There is growing understanding that the environment plays an important role both in the transmission of antibiotic resistant pathogens and in their evolution. Accordingly, researchers and stakeholders world-wide seek to further explore the mechanisms and drivers involved, quantify risks and identify suitable interventions. There is a clear value in establishing research needs and coordinating efforts within and across nations in order to best tackle this global challenge. At an international workshop in late September 2017, scientists from 14 countries with expertise on the environmental dimensions of antibiotic resistance gathered to define critical knowledge gaps. Four key areas were identified where research is urgently needed: 1) the relative contributions of different sources of antibiotics and antibiotic resistant bacteria into the environment; 2) the role of the environment, and particularly anthropogenic inputs, in the evolution of resistance; 3) the overall human and animal health impacts caused by exposure to environmental resistant bacteria; and 4) the efficacy and feasibility of different technological, social, economic and behavioral interventions to mitigate environmental antibiotic resistance.(1)
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| 19. |
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| 20. |
- Pruden, A., et al.
(författare)
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Management Options for Reducing the Release of Antibiotics and Antibiotic Resistance Genes to the Environment
- 2013
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Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 121:8, s. 878-885
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: There is growing concern worldwide about the role of polluted soil and water environments in the development and dissemination of antibiotic resistance. OBJECTIVE: Our aim in this study was to identify management options for reducing the spread of antibiotics and antibiotic-resistance determinants via environmental pathways, with the ultimate goal of extending the useful life span of antibiotics. We also examined incentives and disincentives for action. METHODS: We focused on management options with respect to limiting agricultural sources; treatment of domestic, hospital, and industrial wastewater; and aquaculture. DISCUSSION: We identified several options, such as nutrient management, runoff control, and infrastructure upgrades. Where appropriate, a cross-section of examples from various regions of the world is provided. The importance of monitoring and validating effectiveness of management strategies is also highlighted. Finally, we describe a case study in Sweden that illustrates the critical role of communication to engage stake-holders and promote action. CONCLUSIONS: Environmental releases of antibiotics and antibiotic-resistant bacteria can in many cases be reduced at little or no cost. Some management options are synergistic with existing policies and goals. The anticipated benefit is an extended useful life span for current and future antibiotics. Although risk reductions are often difficult to quantify, the severity of accelerating worldwide morbidity and mortality rates associated with antibiotic resistance strongly indicate the need for action.
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| 21. |
- Bellucci, J. J., et al.
(författare)
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A Pb isotopic resolution to the Martian meteorite age paradox
- 2016
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Ingår i: Earth and Planetary Science Letters. - : Elsevier BV. - 0012-821X .- 1385-013X. ; 433, s. 241-248
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Tidskriftsartikel (refereegranskat)abstract
- Determining the chronology and quantifying various geochemical reservoirs on planetary bodies is fundamental to understanding planetary accretion, differentiation, and global mass transfer. The Pb isotope compositions of individual minerals in the Martian meteorite Chassigny have been measured by Secondary Ion Mass Spectrometry (SIMS). These measurements indicate that Chassigny has mixed with a Martian reservoir that evolved with a long-term U-238/Pb-204 (mu) value similar to two times higher than those inferred from studies of all other Martian meteorites except 4.428 Ga clasts in NWA7533. Any significant mixing between this and an unradiogenic reservoir produces ambiguous trends in Pb isotope variation diagrams. The trend defined by our new Chassigny data can be used to calculate a crystallization age for Chassigny of 4.526 +/- 0.027 Ga (2 sigma) that is clearly in error as it conflicts with all other isotope systems, which yield a widely accepted age of 1.39 Ga. Similar, trends have also been observed in the Shergottites and have been used to calculate a >4 Ga age or, alternatively, attributed to terrestrial contamination. Our new Chassigny data, however, argue that the radiogenic component is Martian, mixing occurred on the surface of Mars, and is therefore likely present in virtually every Martian meteorite. The presence of this radiogenic reservoir on Mars resolves the paradox between Pb isotope data and all other radiogenic isotope systems in Martian meteorites. Importantly, Chassigny and the Shergottites are likely derived from the northern hemisphere of Mars, while NWA 7533 originated from the Southern hemisphere, implying that the U-rich reservoir, which most likely represents some form of crust, must be widespread. The significant age difference between SNC meteorites and NWA 7533 is also consistent with an absence of tectonic recycling throughout Martian history.
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| 22. |
- Bellucci, J. J., et al.
(författare)
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Tracing martian surface interactions with the triple O isotope compositions of meteoritic phosphates
- 2020
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Ingår i: Earth and Planetary Science Letters. - : Elsevier BV. - 0012-821X .- 1385-013X. ; 531
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Tidskriftsartikel (refereegranskat)abstract
- The triple oxygen isotope compositions of phosphate grains in six martian meteorites have been measured by Secondary Ion Mass Spectrometry (SIMS) and combined together with their chlorine isotope and halogen concentrations have been used to constrain hydrosphere-lithosphere interactions on Mars. These samples include three enriched shergottites (Zagami, Roberts Massif 04262 and Larkman Nunatak 12011), one depleted shergottite (Tissint), an orthopyroxenite (Allan Hills 84001), and a regolith breccia (Northwest Africa 7533). The phosphates measured here have a range in δ18O [(18O/16O)sample/(18O/16O)Standard-1] × 103] from +1.0 to +6.8‰ and could be a result of indigenous mantle values, mixing with martian water, or replacement reactions taking place on the surface of Mars. Three samples have a Δ17O [δ17O-1000(1 + δ18O /1000)0.528-1] in equilibrium with the martian mantle (ALH 84001, Tissint, and Zagami), while three samples (LAR 12011, RBT 04262, and NWA 7533) have an elevated positive Δ17O outside of analytical uncertainty of the martian fractionation line (MFL). The phosphates in the latter group also have positive and negative δ37Cl [(37Cl/35Cl)sample/(37Cl/35Cl)standard – 1] × 103] and enrichments in halogens not seen in the rest of the sample suite. Perchlorate formation on Earth fractionates Cl in both positive and negative directions and generates a correlated positive Δ17O. Further, perchlorate has been detected in wt% amounts on the martian surface. Thus, these results strongly suggest the presence of multiple Cl isotope reservoirs on the martian surface that have interacted with the samples studied here over the last ca. 2 Ga of geologic time. The weighted average of Δ17O measurements from phosphate grains (n = 13) in NWA 7533, which are the explicit result of exchange reactions on the martian surface, yields a statistically robust mean value of 1.39 ± 0.19‰ (2σ, MSWD = 1.5, p = 0.13). This value likely represents an accurate estimate for an oxidized surface reservoir on Mars.
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| 23. |
- Curran, N. M., et al.
(författare)
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The early geological history of the Moon inferred from ancient lunar meteorite Miller Range 13317
- 2019
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Ingår i: Meteoritics and Planetary Science. - : John Wiley & Sons, Ltd (10.1111). - 1086-9379 .- 1945-5100. ; 54:7, s. 1401-1430
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Miller Range (MIL) 13317 is a heterogeneous basalt-bearing lunar regolith breccia that provides insights into the early magmatic history of the Moon. MIL 13317 is formed from a mixture of material with clasts having an affinity to Apollo ferroan anorthosites and basaltic volcanic rocks. Noble gas data indicate that MIL 13317 was consolidated into a breccia between 2610 ± 780 Ma and 1570 ± 470 Ma where it experienced a complex near-surface irradiation history for ~835 ± 84 Myr, at an average depth of ~30 cm. The fusion crust has an intermediate composition (Al2O3 15.9 wt%; FeO 12.3 wt%) with an added incompatible trace element (Th 5.4 ppm) chemical component. Taking the fusion crust to be indicative of the bulk sample composition, this implies that MIL 13317 originated from a regolith that is associated with a mare-highland boundary that is KREEP-rich (i.e., K, rare earth elements, and P). A comparison of bulk chemical data from MIL 13317 with remote sensing data from the Lunar Prospector orbiter suggests that MIL 13317 likely originated from the northwest region of Oceanus Procellarum, east of Mare Nubium, or at the eastern edge of Mare Frigoris. All these potential source areas are on the near side of the Moon, indicating a close association with the Procellarum KREEP Terrane. Basalt clasts in MIL 13317 are from a very low-Ti to low-Ti (between 0.14 and 0.32 wt%) source region. The similar mineral fractionation trends of the different basalt clasts in the sample suggest they are comagmatic in origin. Zircon-bearing phases and Ca-phosphate grains in basalt clasts and matrix grains yield 207Pb/206Pb ages between 4344 ± 4 and 4333 ± 5 Ma. These ancient 207Pb/206Pb ages indicate that the meteorite has sampled a range of Pre-Nectarian volcanic rocks that are poorly represented in the Apollo, Luna, and lunar meteorite collections. As such, MIL 13317 adds to the growing evidence that basaltic volcanic activity on the Moon started as early as ~4340 Ma, before the main period of lunar mare basalt volcanism at ~3850 Ma.
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| 24. |
- Engel, J A, et al.
(författare)
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Biochemical and behavioral evidence for an interaction between ethanol and calcium channel antagonists.
- 1988
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Ingår i: Journal of neural transmission. ; 74:3, s. 181-93
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Tidskriftsartikel (refereegranskat)abstract
- In the present series of experiments we have studied the effects of the dihydropyridine calcium channel antagonist nifedipine on ethanol-induced changes in behavior and dopamine (DA) release and metabolism. The locomotor-stimulatory effect of low doses of ethanol (2.5 g/kg) was antagonized by nifedipine, whereas ethanol-induced sedation observed after higher doses (4.5 g/kg) was potentiated. Biochemical studies indicated that ethanol enhanced the metabolism and release of DA in the striatum and the DA-rich limbic regions measured by post mortem analyses of DA-metabolites by HPLC with electrochemical detection and by in vivo voltammetry in anaesthetized rats, respectively. Pretreatment with nifedipine antagonized the stimulatory effects of ethanol on the DA-system. Nifedipine reduced the preference for ethanol, estimated by the relative intake of ethanol (6% v/v) and water in a free-choice situation, suggesting an influence of nifedipine not only on the stimulatory but also on the positive reinforcing effects of ethanol. The present results suggest that the locomotor-stimulatory and positive reinforcing effects of ethanol as well as its enhancing effect on dopaminergic activity may involve an enhancement of calcium mediated mechanisms.
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| 25. |
- Joy, K. H., et al.
(författare)
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Timing of geological events in the lunar highlands recorded in shocked zircon-bearing clasts from Apollo 16
- 2020
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Ingår i: Royal Society Open Science. - : Royal Society. - 2054-5703. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Apollo 16 soil-like regolith breccia 65745,7 contains two zircon-bearing clasts. One of these clasts is a thermally annealed silica-rich rock, which mineralogically has affinities with the High Alkali Suite (Clast 1), and yields zircon dates ranging from 4.08 to 3.38 Ga. The other clast is a KREEP-rich impact melt breccia (Clast 2) and yields zircon dates ranging from 3.97 to 3.91 Ga. The crystalline cores of both grains, which yield dates ofca3.9 Ga, have undergone shock pressure modification at less than 20 GPa. We interpret that the U-Pb chronometer in these zircon grains has been partially reset by the Imbrium basin-forming event when the clasts were incorporated into the Cayley Plains ejecta blanket deposit. The zircon grains in Clast 1 have been partially decomposed, resulting in a breakdown polymineralic texture, with elevated U, Pb and Th abundances compared with those in the crystalline zircon. These decomposed areas exhibit younger dates around 3.4 Ga, suggesting a secondary high-pressure, high-temperature event, probably caused by an impact in the local Apollo 16 highlands area.
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