| 1. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 2. |
- Dima, Danai, et al.
(författare)
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Subcortical volumes across the lifespan : Data from 18,605 healthy individuals aged 3-90 years.
- 2022
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Ingår i: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 43:1, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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| 3. |
- Fessé, Per, 1973-
(författare)
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Epidermal Melanocyte Response to Radiotherapy
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cutaneous interfollicular melanocytes protect the skin from UV-radiation (UVR), and their response to UVR is well established. To date, the response activated in melanocytes by repeated genotoxic insults from radiotherapy (RT) has not been explored. Assuming that the molecular pathways involved in the melanocyte response to UVR are similar upon ionizing radiation, the aim of this work was to examine the effects of RT concerning UVR-response proteins and resistance to DNA damage to reveal mechanisms behind hyperpigmentation and depigmentation caused by RT. The results are based on immunostained tissue sections of 530 not sun-exposed skin punch biopsies. These are collected before, during, and after the end of adjuvant RT from the thoracic wall of breast cancer patients and the hip region of prostate cancer patients receiving curative RT. Fractionated RT with daily doses between 0.05 and 2.0 Gy, as well as hypofractionation and accelerated fractionation were investigated. Based on this clinical assay sterilizing the hair follicles, excluding migration of immature melanocytes from the bulge, it was ensured that interfollicular melanocytes are an autonomous self-renewing cell population with cells presenting different degrees of differentiation of which one fourth is immature; the melanocytes divide rarely and are absolute radioresistant to any dose schedule of RT applied, keeping the number of melanocytes intact. Hyperradiosensitivity to dose fractions of 0.05 to 0.3 Gy is observed for DNA double strand breaks (DSBs), differentiation and anti-apoptotic signaling. Proliferation is not stimulated and apoptosis is negligible upon exposure to RT, and also post-treatment. Melanocyte differentiation is maintained during RT, but dedifferentiation occurs after RT ends. The expected activation of the p53/p21 signaling upon RT appears in keratinocytes but is attenuated in melanocytes. A new observation is that melanocytes constitutively express BMI1, further upregulated upon irradiation, indicating that melanocytes have stem cell properties, which suggest that BMI1 prevents apoptosis, terminal differentiation and premature senescence and likely allows dedifferentiation by suppressing the p53/p21-mediated response to genotoxic damage, in addition to the repression of p16 and ARF. Melanocytes exhibit and accumulate a higher amount of DSBs during the RT period compared to keratinocytes, indicating reduced repair capacity of DSBs in melanocytes. Thus, only efficient pro-survival mechanisms can explain the melanocyte radioresistance regarding cell death. The findings in this thesis suggest that melanocytes are protected by activation of the BMI1-NF-kappa/β-CXCL8/CXCR2 pathway, in addition to upregulation of Bcl-2 by melanocyte-specific MITF (microphthalmia-associated transcription factor).
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| 4. |
- Frangou, Sophia, et al.
(författare)
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Cortical thickness across the lifespan : Data from 17,075 healthy individuals aged 3-90 years
- 2022
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Ingår i: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 431-451
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Tidskriftsartikel (refereegranskat)abstract
- Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
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