| 1. |
- 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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| 2. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Fazey, Ioan, et al.
(författare)
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Transforming knowledge systems for life on Earth : Visions of future systems and how to get there
- 2020
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Ingår i: Energy Research & Social Science. - : Elsevier. - 2214-6296 .- 2214-6326. ; 70
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Tidskriftsartikel (refereegranskat)abstract
- Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent.
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| 4. |
- Moayyeri, Alireza, et al.
(författare)
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Genetic determinants of heel bone properties : genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:11, s. 3054-3068
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
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