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- Huttner, A., et al.
(författare)
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A dose-dependent plasma signature of the safety and immunogenicity of the rVSV-Ebola vaccine in Europe and Africa
- 2017
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 9:385
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Tidskriftsartikel (refereegranskat)abstract
- The 2014-2015 Ebola epidemic affected several African countries, claiming more than 11,000 lives and leaving thousands with ongoing sequelae. Safe and effective vaccines could prevent or limit future outbreaks. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSV-ZEBOV) vaccine has shown marked immunogenicity and efficacy in humans but is reactogenic at higher doses. To understand its effects, we examined plasma samples from 115 healthy volunteers from Geneva who received low-dose (LD) or high-dose (HD) vaccine or placebo. Fifteen plasma chemokines/cytokines were assessed at baseline and on days 1, 2 to 3, and 7 after injection. Significant increases in monocyte-mediated MCP-1/CCL2, MIP-1 beta/CCL4, IL-6, TNF-alpha, IL-1Ra, and IL-10 occurred on day 1. A signature explaining 68% of cytokine/chemokine vaccine-response variabilitywas identified. Its score was higher in HD versus LD vaccinees and was associated positively with vaccine viremia and negatively with cytopenia. It was higher in vaccinees with injection-site pain, fever, myalgia, chills, and headache; higher scores reflected increasing severity. In contrast, HD vaccinees who subsequently developed arthritis had lower day 1 scores than other HD vaccinees. Vaccine dose did not influence the signature despite its influence on specific outcomes. The Geneva-derived signature associated strongly (rho = 0.97) with that of a cohort of 75 vaccinees from a parallel trial in Lambarene, Gabon. Its score in Geneva HD vaccinees with subsequent arthritis was significantly lower than that in Lambarene HD vaccinees, none of whom experienced arthritis. This signature, which reveals monocytes' critical role in rVSV-ZEBOV immunogenicity and safety across doses and continents, should prove useful in assessments of other vaccines.
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| 5. |
- Maxwell, Christopher A., et al.
(författare)
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Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer
- 2011
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Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885 .- 1544-9173. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
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| 6. |
- Shu, Xiang, et al.
(författare)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Tidskriftsartikel (refereegranskat)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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| 7. |
- Walker, Logan C, et al.
(författare)
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Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.
- 2010
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Ingår i: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-542X .- 1465-5411. ; 12:6
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Tidskriftsartikel (refereegranskat)abstract
- Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.
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- van der Meer, Quinten H.A., et al.
(författare)
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Low-δ18O zircon xenocrysts in alkaline basalts; a window into the complex carbonatite-metasomatic history of the Zealandia lithospheric mantle
- 2019
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Ingår i: Geochimica et Cosmochimica Acta. - 0016-7037 .- 1872-9533. ; 254, s. 21-39
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Tidskriftsartikel (refereegranskat)abstract
- Megacrystic zircon grains from alkaline basaltic fields are rare but can provide fundamental insights into mantle metasomatic processes. Here, we report in-situ U-Pb ages, trace element concentrations and hafnium and oxygen isotopes for fourteen zircon megacrysts from two intraplate alkaline basalt locations in New Zealand. U-Pb ages indicate the zircons crystallised between 12.1 and 19.8 Ma. Zircon oxygen isotopic compositions range from low to mantle-like compositions (grain average δ18O = 3.8–5.1‰). Hafnium isotopes (εHf(t) = +3.3 to +10.4) mostly overlap with intraplate mafic rocks and clinopyroxene in metasomatized peridotitic mantle xenoliths but show no correlation with most trace element parameters or oxygen isotopes. The zircons are interpreted to have formed by the reaction between low-degree melts derived from pre-existing mantle metasomes and the depleted mantle lithosphere prior to eruption and transport to the surface. The low Hf concentration, an absence of Eu anomalies, and elevated U/Yb compared to Nb/Yb in the megacrystic zircons are interpreted to show that the source metasomes comprised subduction- and carbonatite-metasomatised lithospheric mantle. As these trace element characteristics are common for megacrystic zircon in intra-plate basaltic fields globally, they suggest the prevalence of subduction- and carbonatite-metsasomatised mantle under these intraplate volcanic regions. The unusually low δ18O was likely present prior to metasomatic enrichment and may have resulted from high-temperature hydrothermal alteration during initial mantle lithosphere formation at a mid ocean ridge or, possibly, during subduction-related processes associated with continent formation. The combination of proportionally varied contributions from carbonatite- and subduction-metasomatised lithospheric melts with asthenospheric melts may explain the variety of primitive intraplate basalt compositions, including low δ18O reported for some local intraplate lavas.
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| 11. |
- Veen, Violaine C., et al.
(författare)
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Cross-ethnic generalizability of the three-factor model of psychopathy : the youth psychopathic traits inventory in an incarcerated sample of native Dutch and Moroccan immigrant boys
- 2011
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Ingår i: International Journal of Law and Psychiatry. - : Pergamon Press. - 0160-2527 .- 1873-6386. ; 34:2, s. 127-130
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Previous research provides support for the existence of the psychopathy construct in youths. However, studies regarding the psychometric properties of psychopathy measures with ethnic minority youths are lacking.METHODS: In the present study, the three-factor structure of the Youth Psychopathic Traits Inventory (YPI) was examined for both native Dutch youth (N=158) and an ethnic minority group, Moroccans (N=141), in an incarcerated adolescent population in the Netherlands.RESULTS: Our results showed that the three-factor structure of the YPI is comparable across an ethnic majority and an ethnic minority group in an incarcerated sample in the Netherlands. Moreover, associations between psychopathic traits and mental health problems were similar for both ethnic groups.CONCLUSION: The results support the cross-ethnic generalizability of the three-factor model of psychopathy as measured through the Youth Psychopathic Traits Inventory.
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