| 1. |
- Choi, WJ, et al.
(författare)
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Expression of the Hutchinson-Gilford Progeria Mutation Leads to Aberrant Dentin Formation
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 15368-
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Tidskriftsartikel (refereegranskat)abstract
- Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated senescence disease, manifesting dental abnormalities and several symptoms suggestive of premature aging. Although irregular secondary dentin formation in HGPS patients has been reported, pathological mechanisms underlying aberrant dentin formation remain undefined. In this study, we analyzed the mandibular molars of a tissue-specific mouse model that overexpresses the most common HGPS mutation (LMNA, c.1824C > T, p.G608G) in odontoblasts. In the molars of HGPS mutant mice at postnatal week 13, targeted expression of the HGPS mutation in odontoblasts results in excessive dentin formation and pulp obliteration. Circumpulpal dentin of HGPS mutants was clearly distinguished from secondary dentin of wild-type (WT) littermates and its mantle dentin by considering the irregular porous structure and loss of dentinal tubules. However, the dentin was significantly thinner in the molars of HGPS mutants at postnatal weeks 3 and 5 than in those of WT mice. In vitro analyses using MDPC-23, a mouse odontoblastic cell line, showed cellular senescence, defects of signaling pathways and consequential downregulation of matrix protein expression in progerin-expressing odontoblasts. These results indicate that expression of the HGPS mutation in odontoblasts disturbs physiological secondary dentin formation. In addition, progerin-expressing odontoblasts secrete paracrine factors that can stimulate odontogenic differentiation of dental pulp cells. Taken together, our results suggest that the aberrant circumpulpal dentin of HGPS mutants results from defects in physiological secondary dentin formation and consequential pathologic response stimulated by paracrine factors from neighboring progerin-expressing odontoblasts.
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| 2. |
- Dahl, F, et al.
(författare)
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Imaging single DNA molecules for high precision NIPT
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 4549-
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Tidskriftsartikel (refereegranskat)abstract
- Cell-free DNA analysis is becoming adopted for first line aneuploidy screening, however for most healthcare programs, cost and workflow complexity is limiting adoption of the test. We report a novel cost effective method, the Vanadis NIPT assay, designed for high precision digitally-enabled measurement of chromosomal aneuploidies in maternal plasma. Reducing NIPT assay complexity is achieved by using novel molecular probe technology that specifically label target chromosomes combined with a new readout format using a nanofilter to enrich single molecules for imaging and counting without DNA amplification, microarrays or sequencing. The primary objective of this study was to assess the Vanadis NIPT assay with respect to analytical precision and clinical feasibility. Analysis of reference DNA samples indicate that samples which are challenging to analyze with low fetal-fraction can be readily detected with a limit of detection determined at <2% fetal-fraction. In total of 286 clinical samples were analysed and 30 out of 30 pregnancies affected by trisomy 21 were classified correctly. This method has the potential to make cost effective NIPT more widely available with more women benefiting from superior detection and false positive rates.
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| 3. |
- Dork, T, et al.
(författare)
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Two truncating variants in FANCC and breast cancer risk
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 12524-
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Tidskriftsartikel (refereegranskat)abstract
- Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
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| 4. |
- Li, JM, et al.
(författare)
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Associations between childhood body size and seventeen adverse outcomes: analysis of 65,057 European women
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 16917-
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Tidskriftsartikel (refereegranskat)abstract
- Large childhood body size has been consistently shown to be associated with decreased breast cancer risk. However, it is important to consider the effects of a large childhood body size on other adult diseases. It is not clear if the associations between childhood body size and adult diseases will persist if they later attain healthy weight. The associations between body size at age 7 and 17 adverse outcomes in adulthood were examined using Cox models in a Swedish study of 65,057 women. Large body size at age 7, when compared to small body size, was associated with decreased risk for breast cancer (HR [95% CI]: 0.81 [0.70–0.93]) and increased risks for anorexia (2.13 [1.63–2.77]) and bulimia (1.91 [1.35–2.70]). Neither adjusting for adult BMI nor restricting the dataset to lean adults (BMI < 25 kg/m2) attenuated the associations. While large body size at age 7 by itself was positively associated with increased risks of diabetes (1.34 [1.16–1.55]), PCOS (1.69 [1.13–2.51]) and hypertension (before age 60), the associations were no longer significant after controlling for adult BMI. No clear associations were found with the remaining adverse outcomes (cervical, uterine, melanoma, colon cancer, depression, ovarian cyst, stroke, hyperlipidemia, heart failure, myocardial infarction, and angina pectoris).
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| 5. |
- Revechon, G, et al.
(författare)
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Rare progerin-expressing preadipocytes and adipocytes contribute to tissue depletion over time
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 4405-
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Tidskriftsartikel (refereegranskat)abstract
- Accumulation of progerin is believed to underlie the pathophysiology of Hutchinson-Gilford progeria syndrome, a disease characterized by clinical features suggestive of premature aging, including loss of subcutaneous white adipose tissue (sWAT). Although progerin has been found in cells and tissues from apparently healthy individuals, its significance has been debated given its low expression levels and rare occurrence. Here we demonstrate that sustained progerin expression in a small fraction of preadipocytes and adipocytes of mouse sWAT (between 4.4% and 6.7% of the sWAT cells) results in significant tissue pathology over time, including fibrosis and lipoatrophy. Analysis of sWAT from mice of various ages showed senescence, persistent DNA damage and cell death that preceded macrophage infiltration, and systemic inflammation. Our findings suggest that continuous progerin expression in a small cell fraction of a tissue contributes to aging-associated diseases, the adipose tissue being particularly sensitive.
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| 6. |
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| 7. |
- Siafarikas, N., et al.
(författare)
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Cerebrospinal fluid markers for synaptic function and Alzheimer type changes in late life depression
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-beta 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (p(ADJ) < 0.05) and predementia AD (p(ADJ) < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (p(ADJ) < 0.001), BACE1 (p(ADJ) < 0.05) and Ng/BACE1 ratio (p(ADJ) < 0.01). All groups had significantly lower A beta 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as "predementia AD with depression".
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| 8. |
- von Oelreich, E, et al.
(författare)
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Predicting prolonged sick leave among trauma survivors
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 58-
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Tidskriftsartikel (refereegranskat)abstract
- Many survivors after trauma suffer from long-term morbidity. The aim of this observational cohort study was to develop a prognostic prediction tool for early assessment of full-time sick leave one year after trauma. Potential predictors were assessed combining individuals from a trauma register with national health registers. Two models were developed using logistic regression and stepwise backward elimination. 4458 individuals were included out of which 488 were on sick leave full-time 12 months after the trauma. One comprehensive and one simplified model were developed including nine and seven predictors respectively. Both models showed excellent discrimination (AUC 0.81). The comprehensive model had very good calibration, and the simplified model good calibration. Prediction models can be used to assess post-trauma sick leave using injury-related variables as well as factors not related to the trauma per se. Among included variables, pre-injury sick leave was the single most important predictor for full-time sick leave one year after trauma. These models could facilitate a more efficient use of resources, targeting groups for follow-up interventions to improve outcome. External validation is necessary in order to evaluate generalizability.
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