| 41. |
- Sandén, Emma, et al.
(author)
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Aberrant immunostaining pattern of the CD24 glycoprotein in clinical samples and experimental models of pediatric medulloblastomas
- 2015
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In: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 0167-594X .- 1573-7373. ; 123:1, s. 1-13
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Journal article (peer-reviewed)abstract
- The CD24 glycoprotein is a mediator of neuronal proliferation, differentiation and immune suppression in the normal CNS, and a proposed cancer biomarker in multiple peripheral tumor types. We performed a comparative analysis of CD24 gene expression in a large cohort of pediatric and adult brain tumors (n = 813), and further characterized protein expression in tissue sections (n = 39), primary brain tumor cultures (n = 12) and a novel orthotopic group 3 medulloblastoma xenograft model. Increased CD24 gene expression was demonstrated in ependymomas, medulloblastomas, anaplastic astrocytomas and glioblastomas, although medulloblastomas displayed higher expression than all other tumor entities. Preferential expression of CD24 in medulloblastomas was confirmed at protein level by immunostaining and computerized image analysis of cryosections. Morphologies and immunophenotyping of CD24(+) cells in tissue sections tentatively suggested disparate functions in different tumor subsets. Notably, protein staining of medulloblastoma cells was associated with prominent cytoplasmic and membranous granules, enabling rapid and robust identification of medulloblastoma cells in clinical tissue samples, as well as in experimental model systems. In conclusion, our results implicate CD24 as a clinically and experimentally useful medulloblastoma immunomarker. Although our results encourage further functional studies of CD24 as a potential molecular target in subsets of brain tumors, the promiscuous expression of CD24 in vivo highlights the importance of specificity in the future design of such targeted treatment.
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| 42. |
- Schill, Fredrika, et al.
(author)
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Pituitary Metastases : A Nationwide Study on Current Characteristics With Special Reference to Breast Cancer
- 2019
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In: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 104:8, s. 3379-3388
-
Journal article (peer-reviewed)abstract
- Objective: To investigate the contemporary presentation of pituitary metastases. Patients: Thirty-eight patients diagnosed with pituitary metastases from 1996 to 2018 in Sweden.Methods: Pituitary metastases were confirmed by histopathology (n = 27) or considered highly likely according to radiological findings, including rapid tumor progression (n = 11). Medical records were reviewed and cellar images reexamined centrally.Results: Breast and lung cancers were the most common primary tumors, in 45% and 21% of patients, respectively. Sixty-seven percent of breast cancers overexpressed human epidermal growth factor receptor 2 (HER2); 53% of pituitary metastases from breast cancers appeared >= 10 years after diagnosis of the primary tumor. At presentation, 71% appeared to have ACTH deficiency, 65% had TSH deficiency, and 26% had diabetes insipidus. Fatigue, nausea/vomiting, loss of appetite, weight loss, myalgia, and/or arthralgia were reported in 47% of patients with morning cortisol <100 nmol/L vs 23% with cortisol >= 200 nmol/L. Sixteen patients had visual field defects, and eight had diplopia. Intrasellar and suprasellar tumor growth was the most frequent finding. Initially, a pituitary adenoma was considered the etiology in 18% of patients. Radiotherapy, pituitary surgery, and chemotherapy were used in 68%, 68%, and 11% of patients, respectively. One and 2 years after diagnosis of pituitary metastases, 50% and 26% of patients were alive.Conclusion: Pituitary metastases may be mistaken for pituitary adenomas and can appear late, especially in breast cancer. Breast cancers overexpressing HER2 seem prone to metastasize to the pituitary. Hypocortisolism may be misdiagnosed as cancer-related malaise. An increased awareness of pituitary metastases and undiagnosed pituitary failure can improve management in these patients.
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| 43. |
- Smith, Ruben, et al.
(author)
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18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers
- 2016
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 139:9, s. 2372-2379
-
Journal article (peer-reviewed)abstract
- Tau positron emission tomography ligands provide the novel possibility to image tau pathologyin vivo. However, little is known about howin vivo brain uptake of tau positron emission tomography ligands relates to tau aggregates observed post-mortem. We performed tau positron emission tomography imaging with F-18-AV-1451 in three patients harbouring a p.R406W mutation in theMAPT gene, encoding tau. This mutation results in 3- and 4-repeat tau aggregates similar to those in Alzheimer's disease, and many of the mutation carriers initially suffer from memory impairment and temporal lobe atrophy. Two patients with short disease duration and isolated memory impairment exhibited F-18-AV-1451 uptake mainly in the hippocampus and adjacent temporal lobe regions, correlating with glucose hypometabolism in corresponding regions. One patient died after 26 years of disease duration with dementia and behavioural deficits. Pre-mortem, there was F-18-AV-1451 uptake in the temporal and frontal lobes, as well as in the basal ganglia, which strongly correlated with the regional extent and amount of tau pathology in post-mortem brain sections. Amyloid-beta (F-18-flutemetamol) positron emission tomography scans were negative in all cases, as were stainings of brain sections for amyloid. This provides strong evidence that F-18-AV-1451 positron emission tomography can be used to accurately quantifyin vivo the regional distribution of hyperphosphorylated tau protein.
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| 44. |
- Smith, Ruben, et al.
(author)
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18F-AV1451 pet detects tau pathology in mapt mutation carriers and correlates strongly with immunohistochemistry of tau aggregates
- 2016
-
In: Alzheimer's and Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 12:7 Suppl, s. 723-724
-
Conference paper (peer-reviewed)abstract
- Background: The Tau PET ligand 18F-AV1451 has been shown to reliably detect paired helical filaments of tau in Alzheimer's disease, but it is not yet known whether it binds to the tau aggregates present in patients with mutations in the gene (MAPT) coding for the tau protein. Further, no study has yet compared the cerebral retention of 18F -AV1451 with the tau aggregates revealed using neuropathology. Methods: Three patients from a Swedish family carrying the R406W mutation of MAPT were assessed with cognitive tests and subjects underwent 18F-AV1451 and 18F-Flutemetamol PET scans. Further one of younger subjects also underwent an 18F-FDG PET scan. The oldest subject died two weeks after the scan and the brain was processed for neuropathology. Tau immunohistochemistry was performed on brain sections from affected and unaffected brain regions. Results: Two mutation carriers, aged 56 and 60 years, had disease durations of 5-10 years and still only exhibited mild-moderate episodic memory impairment and no clear behavioural deficits. The MRI revealed only slight cortical atrophy and 18F-AV1451 PET imaging showed uptake in the hippocampus and the temporal lobes, especially in the inferior and anterior parts (Fig 1A, B). The uptake of 18F - AV1451 correlated well with hypometabolism revealed with FGD PET in one of the subjects. The third case, 76 years, had a disease duration of ≥20 years and exhibited clear cognitive impairment, behavioural disturbances, mutism and dysphagia. The CT scan showed generalised cortical atrophy with a pronounced temporal lobe atrophy and 18F -AV1451 PET imaging revealed uptake in the temporal and frontal lobes, as well as in the basal ganglia (Fig 1 C). The regional uptake of 18F -AV1451 correlated strongly with the tau aggregates revealed using immunohistochemistry (R2 = 0.80, P <0.01; Fig 2). All cases exhibited negative amyloid (18F -flutemetamol) PET scans. Conclusions: The in vivo uptake of 18F-AV1451 reflects the regional amount of tau aggregates revealed by neuropathological examination. Further, tau pathology in MAPT mutation carriers is accurately detected with 18F -AV1451 PET, which consequently can be used to track the effects of anti-tau therapies in this patient group. (Figure Presented) .
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| 45. |
- Smith, Ruben, et al.
(author)
-
Correlation of in Vivo [18F]Flortaucipir with Postmortem Alzheimer Disease Tau Pathology
- 2019
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In: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 76:3, s. 310-310
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Journal article (peer-reviewed)abstract
- Importance: In Alzheimer disease (AD), tau filaments form neuronal inclusions in neurites (neuropil threads) and in somata (neurofibrillary tangles), and neurite tau pathology constitutes the most common pathology. Positron emission tomography (PET) ligands have been developed to detect in vivo tau pathology in AD. However, the association of AD tau pathology post mortem with in vivo tau PET retention has not been established. Therefore, there is a need to investigate the associations of tau PET with postmortem tau pathology in AD. Objective: To study the association of regional in vivo retention of the tau PET ligand [18F]flortaucipir (previously known as AV1451) with the density of tau neuropathology in the corresponding brain regions in a patient with AD. Design, Setting, and Participants: The patient was a man in his 40s with AD caused by a PSEN1 mutation. Between May 2015 and December 2016, he underwent 2 [18F]flortaucipir PET scans at Lund University Hospital, Lund, Sweden. Postmortem analysis was performed 12 months after the last PET scan. Tau pathology was assessed using phosphorylated tau (AT8) immunohistochemistry and Gallyas silver staining. In addition to the regional total tau pathology burden, the density of tau-positive neurites and intrasomal tau tangles were quantified using a stereology-based method. Further, β-amyloid-containing plaques were detected using 4G8 immunohistochemistry. Data were analyzed between January 2018 and August 2018. Main Outcomes and Measures: Regional standardized uptake value ratios of [18F]flortaucipir were compared with the amount of tau pathology in the corresponding brain areas. Results: In this patient, the clinical disease symptoms progressed rapidly in life, paralleled with an annual increase of tau PET retention of 20% to 40% in many cortical regions. Compared with postmortem immunohistochemistry, regional in vivo uptake of [18F]flortaucipir was correlated with the density of tau-positive neurites (AT8: rs = 0.87; P <.001; Gallyas: rs = 0.92; P <.001), intrasomal tau tangles (AT8: rs = 0.65; P =.01; Gallyas: rs = 0.84; P <.001), and total tau burden (AT8: rs = 0.84; P <.001; Gallyas: rs = 0.82; P <.001). No correlations between [18F]flortaucipir and β-amyloid pathology were found. Conclusions and Relevance: These results indicate that [18F]flortaucipir PET retention is a robust in vivo measure of the total AD tau burden.
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| 46. |
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| 47. |
- Szczepankiewicz, Filip, et al.
(author)
-
Quantification of microscopic diffusion anisotropy disentangles effects of orientation dispersion from microstructure: Applications in healthy volunteers and in brain tumors
- 2015
-
In: NeuroImage. - : Elsevier BV. - 1095-9572 .- 1053-8119. ; 104, s. 241-252
-
Journal article (peer-reviewed)abstract
- The anisotropy of water diffusion in brain tissue is affected by both disease and development. This change can be detected using diffusion MRI and is often quantified by the fractional anisotropy (FA) derived from diffusion tensor imaging (DTI). Although FA is sensitive to anisotropic cell structures, such as axons, it is also sensitive to their orientation dispersion. This is a major limitation to the use of FA as a biomarker for "tissue integrity", especially in regions of complex microarchitecture. In this work, we seek to circumvent this limitation by disentangling the effects of microscopic diffusion anisotropy from the orientation dispersion. The microscopic fractional anisotropy (mu FA) and the order parameter (OP) were calculated from the contrast between signal prepared with directional and isotropic diffusion encoding, where the latter was achieved by magic angle spinning of the q-vector (qMAS). These parameters were quantified in healthy volunteers and in two patients; one patient with meningioma and one with glioblastoma. Finally, we used simulations to elucidate the relation between FA and mu FA in various micro-architectures. Generally, mu FA was high in the white matter and low in the gray matter. In the white matter, the largest differences between mu FA and FA were found in crossing white matter and in interfaces between large white matter tracts, where mu FA was high while FA was low. Both tumor types exhibited a low FA, in contrast to the mu FA which was high in the meningioma and low in the glioblastoma, indicating that the meningioma contained disordered anisotropic structures, while the glioblastoma did not. This interpretation was confirmed by histological examination. We conclude that FA from DTI reflects both the amount of diffusion anisotropy and orientation dispersion. We suggest that the mu FA and OP may complement FA by independently quantifying the microscopic anisotropy and the level of orientation coherence. (C) 2014 The Authors. Published by Elsevier Inc.
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| 48. |
- Szczepankiewicz, Filip, et al.
(author)
-
The link between diffusion MRI and tumor heterogeneity : Mapping cell eccentricity and density by diffusional variance decomposition (DIVIDE)
- 2016
-
In: NeuroImage. - : Elsevier BV. - 1053-8119. ; 142, s. 522-532
-
Journal article (peer-reviewed)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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| 49. |
- Thorén, Matilda Munksgaard, et al.
(author)
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Integrin α10, a novel therapeutic target in glioblastoma, regulates cell migration, proliferation, and survival
- 2019
-
In: Cancers. - : MDPI AG. - 2072-6694. ; 11:4
-
Journal article (peer-reviewed)abstract
- New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10Β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10Β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody-drug conjugate (ADC), an integrin a10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10Β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10Β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.
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| 50. |
- Tiselius, Elisabet, 1967-, et al.
(author)
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Asymmetrical language proficiency in dialogue interpreters : Methodological issues
- 2019
-
In: Translation, Cognition & Behavior. - : John Benjamins Publishing Company. - 2542-5277 .- 2542-5285. ; 2:2, s. 305-322
-
Journal article (peer-reviewed)abstract
- Language proficiency of dialogue interpreters, who typically work in the public service sector, is an under-researched area. Unlike as in the case of conference interpreters, there is no generally accepted definition of proficiency levels of working languages for dialogue interpreters. This article discusses language proficiency in dialogue interpreting. It presents a methodological problem, namely, how to define and determine a given interpreter’s stronger and weaker working languages. We discuss different methods for determining the individual interpreter’s stronger and weaker working languages, such as self-assessment, demographic, socio-linguistic questionnaire and test score (Dialang). We conclude that there is a need for more research in this area.
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