| 1. |
- Brabec, Jan, et al.
(författare)
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Histogram analysis of tensor-valued diffusion MRI in meningiomas : Relation to consistency, histological grade and type
- 2022
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Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 33
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Preoperative radiological assessment of meningioma characteristics is of value for pre- and post-operative patient management, counselling, and surgical approach.PURPOSE: To investigate whether tensor-valued diffusion MRI can add to the preoperative prediction of meningioma consistency, grade and type.MATERIALS AND METHODS: 30 patients with intracranial meningiomas (22 WHO grade I, 8 WHO grade II) underwent MRI prior to surgery. Diffusion MRI was performed with linear and spherical b-tensors with b-values up to 2000 s/mm2. The data were used to estimate mean diffusivity (MD), fractional anisotropy (FA), mean kurtosis (MK) and its components-the anisotropic and isotropic kurtoses (MKA and MKI). Meningioma consistency was estimated for 16 patients during resection based on ultrasonic aspiration intensity, ease of resection with instrumentation or suction. Grade and type were determined by histopathological analysis. The relation between consistency, grade and type and dMRI parameters was analyzed inside the tumor ("whole-tumor") and within brain tissue in the immediate periphery outside the tumor ("rim") by histogram analysis.RESULTS: Lower 10th percentiles of MK and MKA in the whole-tumor were associated with firm consistency compared with pooled soft and variable consistency (n = 7 vs 9; U test, p = 0.02 for MKA 10 and p = 0.04 for MK10) and lower 10th percentile of MD with variable against soft and firm (n = 5 vs 11; U test, p = 0.02). Higher standard deviation of MKI in the rim was associated with lower grade (n = 22 vs 8; U test, p = 0.04) and in the MKI maps we observed elevated rim-like structure that could be associated with grade. Higher median MKA and lower median MKI distinguished psammomatous type from other pooled meningioma types (n = 5 vs 25; U test; p = 0.03 for MKA 50 and p = 0.03 and p = 0.04 for MKI 50).CONCLUSION: Parameters from tensor-valued dMRI can facilitate prediction of consistency, grade and type.
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| 2. |
- Brabec, Jan, et al.
(författare)
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Meningioma microstructure assessed by diffusion MRI : An investigation of the source of mean diffusivity and fractional anisotropy by quantitative histology
- 2023
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Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 37
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mean diffusivity (MD) and fractional anisotropy (FA) from diffusion MRI (dMRI) have been associated with cell density and tissue anisotropy across tumors, but it is unknown whether these associations persist at the microscopic level.PURPOSE: To quantify the degree to which cell density and anisotropy, as determined from histology, account for the intra-tumor variability of MD and FA in meningioma tumors. Furthermore, to clarify whether other histological features account for additional intra-tumor variability of dMRI parameters.MATERIALS AND METHODS: We performed ex-vivo dMRI at 200 μm isotropic resolution and histological imaging of 16 excised meningioma tumor samples. Diffusion tensor imaging (DTI) was used to map MD and FA, as well as the in-plane FA (FA IP). Histology images were analyzed in terms of cell nuclei density (CD) and structure anisotropy (SA; obtained from structure tensor analysis) and were used separately in a regression analysis to predict MD and FA IP, respectively. A convolutional neural network (CNN) was also trained to predict the dMRI parameters from histology patches. The association between MRI and histology was analyzed in terms of out-of-sample (R 2 OS) on the intra-tumor level and within-sample R 2 across tumors. Regions where the dMRI parameters were poorly predicted from histology were analyzed to identify features apart from CD and SA that could influence MD and FA IP, respectively. RESULTS: Cell density assessed by histology poorly explained intra-tumor variability of MD at the mesoscopic level (200 μm), as median R 2 OS = 0.04 (interquartile range 0.01-0.26). Structure anisotropy explained more of the variation in FA IP (median R 2 OS = 0.31, 0.20-0.42). Samples with low R 2 OS for FA IP exhibited low variations throughout the samples and thus low explainable variability, however, this was not the case for MD. Across tumors, CD and SA were clearly associated with MD (R 2 = 0.60) and FA IP (R 2 = 0.81), respectively. In 37% of the samples (6 out of 16), cell density did not explain intra-tumor variability of MD when compared to the degree explained by the CNN. Tumor vascularization, psammoma bodies, microcysts, and tissue cohesivity were associated with bias in MD prediction based solely on CD. Our results support that FA IP is high in the presence of elongated and aligned cell structures, but low otherwise. CONCLUSION: Cell density and structure anisotropy account for variability in MD and FA IP across tumors but cell density does not explain MD variations within the tumor, which means that low or high values of MD locally may not always reflect high or low tumor cell density. Features beyond cell density need to be considered when interpreting MD.
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| 3. |
- Burguillos Garcia, Miguel, et al.
(författare)
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Microglia-Secreted Galectin-3 Acts as a Toll-like Receptor 4 Ligand and Contributes to Microglial Activation.
- 2015
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 10:9, s. 1626-1638
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Tidskriftsartikel (refereegranskat)abstract
- Inflammatory response induced by microglia plays a critical role in the demise of neuronal populations in neuroinflammatory diseases. Although the role of toll-like receptor 4 (TLR4) in microglia's inflammatory response is fully acknowledged, little is known about endogenous ligands that trigger TLR4 activation. Here, we report that galectin-3 (Gal3) released by microglia acts as an endogenous paracrine TLR4 ligand. Gal3-TLR4 interaction was further confirmed in a murine neuroinflammatory model (intranigral lipopolysaccharide [LPS] injection) and in human stroke subjects. Depletion of Gal3 exerted neuroprotective and anti-inflammatory effects following global brain ischemia and in the neuroinflammatory LPS model. These results suggest that Gal3-dependent-TLR4 activation could contribute to sustained microglia activation, prolonging the inflammatory response in the brain.
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| 4. |
- Durmo, Faris, et al.
(författare)
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Assessment of Amide proton transfer weighted (APTw) MRI for pre-surgical prediction of final diagnosis in gliomas
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:12
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Radiological assessment of primary brain neoplasms, both high (HGG) and low grade tumors (LGG), based on contrast-enhancement alone can be inaccurate. We evaluated the radiological value of amide proton transfer weighted (APTw) MRI as an imaging complement for pre-surgical radiological diagnosis of brain tumors.METHODS: Twenty-six patients were evaluated prospectively; (22 males, 4 females, mean age 55 years, range 26-76 years) underwent MRI at 3T using T1-MPRAGE pre- and post-contrast administration, conventional T2w, FLAIR, and APTw imaging pre-surgically for suspected primary/secondary brain tumor. Assessment of the additional value of APTw imaging compared to conventional MRI for correct pre-surgical brain tumor diagnosis. The initial radiological pre-operative diagnosis was based on the conventional contrast-enhanced MR images. The range, minimum, maximum, and mean APTw signals were evaluated. Conventional normality testing was performed; with boxplots/outliers/skewness/kurtosis and a Shapiro-Wilk's test. Mann-Whitney U for analysis of significance for mean/max/min and range APTw signal. A logistic regression model was constructed for mean, max, range and Receiver Operating Characteristic (ROC) curves calculated for individual and combined APTw signals.RESULTS: Conventional radiological diagnosis prior to surgery/biopsy was HGG (8 patients), LGG (12 patients), and metastasis (6 patients). Using the mean and maximum: APTw signal would have changed the pre-operative evaluation the diagnosis in 8 of 22 patients (two LGGs excluded, two METs excluded). Using a cut off value of >2.0% for mean APTw signal integral, 4 of the 12 radiologically suspected LGG would have been diagnosed as high grade glioma, which was confirmed by histopathological diagnosis. APTw mean of >2.0% and max >2.48% outperformed four separate clinical radiological assessments of tumor type, P-values = .004 and = .002, respectively.CONCLUSIONS: Using APTw-images as part of the daily clinical pre-operative radiological evaluation may improve diagnostic precision in differentiating LGGs from HGGs, with potential improvement of patient management and treatment.
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| 5. |
- Durmo, Faris, et al.
(författare)
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Brain Tumor Characterization Using Multibiometric Evaluation of MRI
- 2018
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Ingår i: Tomography : a journal for imaging research. - : MDPI AG. - 2379-1381. ; 4:1, s. 14-25
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to evaluate volume, diffusion, and perfusion metrics for better presurgical differentiation between high-grade gliomas (HGG), low-grade gliomas (LGG), and metastases (MET). For this retrospective study, 43 patients with histologically verified intracranial HGG (n = 18), LGG (n = 10), and MET (n = 15) were chosen. Preoperative magnetic resonance data included pre- and post-gadolinium contrast-enhanced T1-weighted fluid-attenuated inversion recover, cerebral blood flow (CBF), cerebral blood volume (CBV), fractional anisotropy, and apparent diffusion coefficient maps used for quantification of magnetic resonance biometrics by manual delineation of regions of interest. A binary logistic regression model was applied for multiparametric analysis and receiver operating characteristic (ROC) analysis. Statistically significant differences were found for normalized-ADC-tumor (nADC-T), normalized-CBF-tumor (nCBF-T), normalized-CBV-tumor (nCBV-T), and normalized-CBF-edema (nCBF-E) between LGG and HGG, and when these metrics were combined, HGG could be distinguished from LGG with a sensitivity and specificity of 100%. The only metric to distinguish HGG from MET was the normalized-ADC-E with a sensitivity of 68.8% and a specificity of 80%. LGG can be distinguished from MET by combining edema volume (Vol-E), Vol-E/tumor volume (Vol-T), nADC-T, nCBF-T, nCBV-T, and nADC-E with a sensitivity of 93.3% and a specificity of 100%. The present study confirms the usability of a multibiometric approach including volume, perfusion, and diffusion metrics in differentially diagnosing brain tumors in preoperative patients and adds to the growing body of evidence in the clinical field in need of validation and standardization.
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| 6. |
- Eckermann, Marina, et al.
(författare)
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3d phase-contrast nanotomography of unstained human skin biopsies may identify morphological differences in the dermis and epidermis between subjects
- 2021
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Ingår i: Skin Research and Technology. - : Wiley. - 0909-752X .- 1600-0846. ; 27:3, s. 316-323
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Tidskriftsartikel (refereegranskat)abstract
- Background: Enteric neuropathy is described in most patients with gastrointestinal dysmotility and may be found together with reduced intraepidermal nerve fiber density (IENFD). The aim of this pilot study was to assess whether three-dimensional (3d) imaging of skin biopsies could be used to examine various tissue components in patients with gastrointestinal dysmotility. Material and methods: Four dysmotility patients of different etiology and two healthy volunteers were included. From each subject, two 3-mm punch skin biopsies were stained with antibodies against protein gene product 9.5 or evaluated as a whole with two X-ray phase-contrast computed tomography (CT) setups, a laboratory µCT setup and a dedicated synchrotron radiation nanoCT end-station. Results: Two patients had reduced IENFD, and two normal IENFD, compared with controls. µCT and X-ray phase-contrast holographic nanotomography scanned whole tissue specimens, with optional high-resolution scans revealing delicate structures, without differentiation of various fibers and cells. Irregular architecture of dermal fibers was observed in the patient with Ehlers-Danlos syndrome and the patient with idiopathic dysmotility showed an abundance of mesenchymal ground substance. Conclusions: 3d phase-contrast tomographic imaging may be useful to illustrate traits of connective tissue dysfunction in various organs and to demonstrate whether disorganized dermal fibers could explain organ dysfunction.
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| 7. |
- El-Sayed, Najib M., et al.
(författare)
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The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease.
- 2005
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5733, s. 409-15
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Tidskriftsartikel (refereegranskat)abstract
- Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.
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| 8. |
- Nilsson, Markus, et al.
(författare)
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Imaging brain tumour microstructure
- 2018
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119. ; 182, s. 232-250
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Forskningsöversikt (refereegranskat)abstract
- Imaging is an indispensable tool for brain tumour diagnosis, surgical planning, and follow-up. Definite diagnosis, however, often demands histopathological analysis of microscopic features of tissue samples, which have to be obtained by invasive means. A non-invasive alternative may be to probe corresponding microscopic tissue characteristics by MRI, or so called ‘microstructure imaging’. The promise of microstructure imaging is one of ‘virtual biopsy’ with the goal to offset the need for invasive procedures in favour of imaging that can guide pre-surgical planning and can be repeated longitudinally to monitor and predict treatment response. The exploration of such methods is motivated by the striking link between parameters from MRI and tumour histology, for example the correlation between the apparent diffusion coefficient and cellularity. Recent microstructure imaging techniques probe even more subtle and specific features, providing parameters associated to cell shape, size, permeability, and volume distributions. However, the range of scenarios in which these techniques provide reliable imaging biomarkers that can be used to test medical hypotheses or support clinical decisions is yet unknown. Accurate microstructure imaging may moreover require acquisitions that go beyond conventional data acquisition strategies. This review covers a wide range of candidate microstructure imaging methods based on diffusion MRI and relaxometry, and explores advantages, challenges, and potential pitfalls in brain tumour microstructure imaging.
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| 9. |
- Pandiloski, Ninoslav, et al.
(författare)
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DNA methylation governs the sensitivity of repeats to restriction by the HUSH-MORC2 corepressor
- 2024
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Ingår i: Nature Communications. - 2041-1723. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- The human silencing hub (HUSH) complex binds to transcripts of LINE-1 retrotransposons (L1s) and other genomic repeats, recruiting MORC2 and other effectors to remodel chromatin. How HUSH and MORC2 operate alongside DNA methylation, a central epigenetic regulator of repeat transcription, remains largely unknown. Here we interrogate this relationship in human neural progenitor cells (hNPCs), a somatic model of brain development that tolerates removal of DNA methyltransferase DNMT1. Upon loss of MORC2 or HUSH subunit TASOR in hNPCs, L1s remain silenced by robust promoter methylation. However, genome demethylation and activation of evolutionarily-young L1s attracts MORC2 binding, and simultaneous depletion of DNMT1 and MORC2 causes massive accumulation of L1 transcripts. We identify the same mechanistic hierarchy at pericentromeric α-satellites and clustered protocadherin genes, repetitive elements important for chromosome structure and neurodevelopment respectively. Our data delineate the epigenetic control of repeats in somatic cells, with implications for understanding the vital functions of HUSH-MORC2 in hypomethylated contexts throughout human development.
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| 10. |
- Szczepankiewicz, Filip, et al.
(författare)
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The link between diffusion MRI and tumor heterogeneity : Mapping cell eccentricity and density by diffusional variance decomposition (DIVIDE)
- 2016
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119. ; 142, s. 522-532
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Tidskriftsartikel (refereegranskat)abstract
- The structural heterogeneity of tumor tissue can be probed by diffusion MRI (dMRI) in terms of the variance of apparent diffusivities within a voxel. However, the link between the diffusional variance and the tissue heterogeneity is not well-established. To investigate this link we test the hypothesis that diffusional variance, caused by microscopic anisotropy and isotropic heterogeneity, is associated with variable cell eccentricity and cell density in brain tumors. We performed dMRI using a novel encoding scheme for diffusional variance decomposition (DIVIDE) in 7 meningiomas and 8 gliomas prior to surgery. The diffusional variance was quantified from dMRI in terms of the total mean kurtosis (MKT), and DIVIDE was used to decompose MKT into components caused by microscopic anisotropy (MKA) and isotropic heterogeneity (MKI). Diffusion anisotropy was evaluated in terms of the fractional anisotropy (FA) and microscopic fractional anisotropy (μFA). Quantitative microscopy was performed on the excised tumor tissue, where structural anisotropy and cell density were quantified by structure tensor analysis and cell nuclei segmentation, respectively. In order to validate the DIVIDE parameters they were correlated to the corresponding parameters derived from microscopy. We found an excellent agreement between the DIVIDE parameters and corresponding microscopy parameters; MKA correlated with cell eccentricity (r = 0.95, p < 10− 7) and MKI with the cell density variance (r = 0.83, p < 10− 3). The diffusion anisotropy correlated with structure tensor anisotropy on the voxel-scale (FA, r = 0.80, p < 10− 3) and microscopic scale (μFA, r = 0.93, p < 10− 6). A multiple regression analysis showed that the conventional MKT parameter reflects both variable cell eccentricity and cell density, and therefore lacks specificity in terms of microstructure characteristics. However, specificity was obtained by decomposing the two contributions; MKA was associated only to cell eccentricity, and MKI only to cell density variance. The variance in meningiomas was caused primarily by microscopic anisotropy (mean ± s.d.) MKA = 1.11 ± 0.33 vs MKI = 0.44 ± 0.20 (p < 10− 3), whereas in the gliomas, it was mostly caused by isotropic heterogeneity MKI = 0.57 ± 0.30 vs MKA = 0.26 ± 0.11 (p < 0.05). In conclusion, DIVIDE allows non-invasive mapping of parameters that reflect variable cell eccentricity and density. These results constitute convincing evidence that a link exists between specific aspects of tissue heterogeneity and parameters from dMRI. Decomposing effects of microscopic anisotropy and isotropic heterogeneity facilitates an improved interpretation of tumor heterogeneity as well as diffusion anisotropy on both the microscopic and macroscopic scale.
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