| 1. |
- Zarb, Yvette, et al.
(författare)
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Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response
- 2019
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Ingår i: Brain. - : OXFORD UNIV PRESS. - 0006-8950 .- 1460-2156. ; 142:4, s. 885-902
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Tidskriftsartikel (refereegranskat)abstract
- Brain calcifications are commonly detected in aged individuals and accompany numerous brain diseases, but their functional importance is not understood. In cases of primary familial brain calcification, an autosomally inherited neuropsychiatric disorder, the presence of bilateral brain calcifications in the absence of secondary causes of brain calcification is a diagnostic criterion. To date, mutations in five genes including solute carrier 20 member 2 (SLC20A2), xenotropic and polytropic retrovirus receptor 1 (XPR1), myogenesis regulating glycosidase (MYORG), platelet-derived growth factor B (PDGFB) and platelet-derived growth factor receptor beta (PDGFRB), are considered causal. Previously, we have reported that mutations in PDGFB in humans are associated with primary familial brain calcification, and mice hypomorphic for PDGFB (Pdgfb(ret/ret)) present with brain vessel calcifications in the deep regions of the brain that increase with age, mimicking the pathology observed in human mutation carriers. In this study, we characterize the cellular environment surrounding calcifications in Pdgfb(ret/ret) animals and show that cells around vessel-associated calcifications express markers for osteoblasts, osteoclasts and osteocytes, and that bone matrix proteins are present in vessel-associated calcifications. Additionally, we also demonstrate the osteogenic environment around brain calcifications in genetically confirmed primary familial brain calcification cases. We show that calcifications cause oxidative stress in astrocytes and evoke expression of neurotoxic astrocyte markers. Similar to previously reported human primary familial brain calcification cases, we describe high interindividual variation in calcification load in Pdgfb(ret/ret) animals, as assessed by ex vivo and in vivo quantification of calcifications. We also report that serum of Pdgfb(ret/ret) animals does not differ in calcification propensity from control animals and that vessel calcification occurs only in the brains of Pdgfb(ret/ret) animals. Notably, ossification of vessels and astrocytic neurotoxic response is associated with specific behavioural and cognitive alterations, some of which are associated with primary familial brain calcification in a subset of patients.
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| 2. |
- Arboleda, Carolina, et al.
(författare)
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Towards clinical grating-interferometry mammography
- 2019
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Ingår i: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; , s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Grating-interferometry-based mammography (GIM) might facilitate breast cancer detection, as several research works have demonstrated in a pre-clinical setting, since it is able to provide attenuation, differential phase contrast, and scattering images simultaneously. In order to translate this technique to the clinics, it has to be adapted to cover a large field-of-view within a clinically acceptable exposure time and radiation dose. Methods: We set up a grating interferometer that fits into a standard mammography system and fulfilled the aforementioned conditions. Here, we present the first mastectomy images acquired with this experimental device. Results and conclusion: Our system performs at a mean glandular dose of 1.6 mGy for a 5-cm-thick, 18%-dense breast, and a field-of-view of 26 × 21 cm2. It seems to be well-suited as basis for a clinical-environment device. Further, dark-field signals seem to support an improved lesion visualization. Evidently, the effective impact of such indications must be evaluated and quantified within the context of a proper reader study. Key Points: • Grating-interferometry-based mammography (GIM) might facilitate breast cancer detection, since it is sensitive to refraction and scattering and thus provides additional tissue information. • The most straightforward way to do grating-interferometry in the clinics is to modify a standard mammography device. • In a first approximation, the doses given with this technique seem to be similar to those of conventional mammography.
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| 3. |
- Bertani, Valeria, et al.
(författare)
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Mammographic calcifications undergoing percutaneous biopsy : outcome in women with and without a personal history of breast cancer
- 2023
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Ingår i: Radiologia Medica. - : Springer Science and Business Media LLC. - 0033-8362 .- 1826-6983. ; 128:2, s. 149-159
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To compare the positive predictive values (PPVs) of BI-RADS categories used to assess pure mammographic calcifications in women with and without a previous history of breast cancer (PHBC). Materials and methods: In this retrospective study, all consecutive pure mammographic calcifications (n = 320) undergoing a stereotactic biopsy between 2016 and 2018 were identified. Mammograms were evaluated in consensus by two radiologists according to BI-RADS and blinded to patient history and pathology results. Final pathologic results were used as the standard of reference. PPV of BI-RADS categories were compared between the two groups. Data were evaluated using standard statistics, Mann–Whitney U tests and Chi-square tests. Results: Two hundred sixty-eight patients (274 lesions, median age 54 years, inter-quartile range, 50–65 years) with a PHBC (n = 46) and without a PHBC (n = 222) were included. Overall PPVs were the following: BI-RADS 2, 0% (0 of 56); BI-RADS 3, 9.1% (1 of 11); BI-RADS 4a, 16.2% (6 of 37); BI-RADS 4b, 37.5% (48 of 128); BI-RADS 4c, 47.3% (18 of 38) and BI-RADS 5, 100% (4 of 4). The PPV of BI-RADS categories was similar in patients with and without a PHBC (P =.715). Calcifications were more often malignant in patients with a PHBC older than 10 years (47.3%, 9 of 19) compared to 1–2 years (25%, 1 of 4), 2–5 years (20%, 2 of 10) and 5–10 years (0%, of 13) from the first breast cancer (P =.005). Conclusion: PPV of mammographic calcifications is similar in women with or without PHBC when BI-RADS classification is strictly applied. A higher risk of malignancy was observed in patients with a PHBC longer than 10 years.
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| 4. |
- Keller, Annika, et al.
(författare)
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Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:9, s. 1077-
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Tidskriftsartikel (refereegranskat)abstract
- Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait ( idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor beta (PDGF-R beta) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-R beta. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.
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| 5. |
- Vanlandewijck, Michael, et al.
(författare)
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Functional Characterization of Germline Mutations in PDGFB and PDGFRB in Primary Familial Brain Calcification
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- Primary Familial Brain Calcification (PFBC), a neurodegenerative disease characterized by progressive pericapillary calcifications, has recently been linked to heterozygous mutations in PDGFB and PDGFRB genes. Here, we functionally analyzed several of these mutations in vitro. All six analyzed PDGFB mutations led to complete loss of PDGF-B function either through abolished protein synthesis or through defective binding and/or stimulation of PDGF-R beta. The three analyzed PDGFRB mutations had more diverse consequences. Whereas PDGF-R beta autophosphorylation was almost totally abolished in the PDGFRB L658P mutation, the two sporadic PDGFRB mutations R987W and E1071V caused reductions in protein levels and specific changes in the intensity and kinetics of PLC. activation, respectively. Since at least some of the PDGFB mutations were predicted to act through haploinsufficiency, we explored the consequences of reduced Pdgfb or Pdgfrb transcript and protein levels in mice. Heterozygous Pdgfb or Pdgfrb knockouts, as well as double Pdgfb(+/-); Pdgfrb(+/-) mice did not develop brain calcification, nor did Pdgfrb(redeye/redeye) mice, which show a 90% reduction of PDGFR beta protein levels. In contrast, Pdgfb(ret/ret) mice, which have altered tissue distribution of PDGF-B protein due to loss of a proteoglycan binding motif, developed brain calcifications. We also determined pericyte coverage in calcification-prone and non-calcification-prone brain regions in Pdgfb(ret/ret) mice. Surprisingly and contrary to our hypothesis, we found that the calcification-prone brain regions in Pdgfb(ret/ret) mice model had a higher pericyte coverage and a more intact blood-brain barrier (BBB) compared to non-calcification-prone brain regions. While our findings provide clear evidence that loss-of-function mutations in PDGFB or PDGFRB cause PFBC, they also demonstrate species differences in the threshold levels of PDGF-B/PDGF-R beta signaling that protect against small-vessel calcification in the brain. They further implicate region-specific susceptibility factor(s) in PFBC pathogenesis that are distinct from pericyte and BBB deficiency.
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