ORCID Profile
0000-0002-7792-0433
Current Organisations
University at Buffalo
,
Fondazione Don Carlo Gnocchi
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Publisher: Wiley
Date: 07-2019
DOI: 10.1111/JON.12650
Abstract: Quantitative neuroimaging is an important part of multiple sclerosis research and clinical trials, and measures of lesion volume (LV) and brain atrophy are key clinical trial endpoints. However, translation of these endpoints to heterogeneous historical datasets and nonstandardized clinical routine imaging has been difficult. The NeuroSTREAM technique was recently introduced as a robust and broadly applicable surrogate for brain atrophy measurement, but no such surrogate currently exists for conventional T2-LV. Therefore, we sought to develop a fully automated proxy for T2-LV with similar analytic value but increased robustness to common issues arising in clinical routine imaging. We created an algorithm to identify salient central lesion volume (SCLV), comprised of the subset of lesion voxels within a specific distance to the lateral ventricles (centrality) and with intensity at least a quantitatively-derived amount brighter than normal appearing tissue (salience). We evaluated this method on four datasets (clinical, inter-scanner, scan-rescan, and real-world multi-center), including 1.5T, 3T, Philips, Siemens, and GE scanners with heterogeneous protocols, to assess agreement with conventional T2-LV, comparative relationship with disability, reliability across scanners and between scans, and applicability to real-world scans. SCLV correlated strongly with conventional T2-LV in both research-quality (r = .90, P < .001) and real-world (r = 0.87, P < 0.001) datasets. It also showed similar correlations with Expanded Disability Status Scale, as conventional T2-LV (r = 0.48 for T2-LV vs. r = 0.45 for SCLV). Inter-scanner reproducibility (ICC) was 0.86, p < 0.001 for SCLV compared to 0.84, p < 0.001 for conventional T2-LV, whereas scan-rescan ICC was 0.999 for SCLV versus 0.997 for T2-LV. SCLV is a robust, fully-automated proxy for T2-LV in situations where conventional T2-LV is not easily or reliably calculated.
Publisher: Radiological Society of North America (RSNA)
Date: 09-2013
Abstract: To investigate the association between the development of thalamic and cortical atrophy and the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome (CIS). This prospective study was approved by the institutional review board. Informed consent was given by 216 CIS patients, and patients were treated with 30 µg of intramuscular interferon β1a once a week. They were assessed with a magnetic resonance (MR) imaging examination at baseline, 6 months, 1 year, and 2 years. Patients were evaluated within 4 months of an initial demyelinating event, had two or more brain lesions on MR images, and had two or more oligoclonal bands in cerebrospinal fluid. MR imaging measures of progression included cumulative number and volume of contrast agent-enhanced (CE) new and enlarged T2 lesions, and changes in whole-brain, tissue-specific global, and regional gray matter volumes. Regression and mixed-effect model analyses were used. Over 2 years, 92 of 216 patients (42.6%) converted to CDMS 122 (56.5%) CIS patients fulfilled McDonald 2005 criteria and 153 (70.8%) fulfilled McDonald 2010 criteria for MR imaging dissemination in time and space. The mean time to first relapse was 3.1 months, and mean annual relapse rate was 0.46. In mixed-effect model analysis, the lateral ventricle volume (P = .005), accumulation of CE (P = .007), new total T2 (P = .009) and new enlarging T2 lesions (P = .01) increase, and thalamic (P = .009) and whole-brain (P = .019) volume decrease were associated with development of CDMS. In multivariate regression analysis, decrease in thalamic volumes and increase in lateral ventricle volumes (P = .009) were MR imaging variables associated with the development of CDMS. Measurement of thalamic atrophy and increase in ventricular size in CIS is associated with CDMS development and should be used in addition to the assessment of new T2 and CE lesions.
Publisher: Public Library of Science (PLoS)
Date: 08-01-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 19-01-2023
Abstract: BAP1 is a powerful tumor suppressor gene characterized by haplo insufficiency. In iduals carrying germline BAP1 mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline BAP1 mutations are less aggressive, and these patients have significantly improved survival. We investigated the apparent paradox of a tumor suppressor gene that, when mutated, causes less aggressive mesotheliomas. We discovered that mesothelioma biopsies with biallelic BAP1 mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, BAP1 binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from in iduals carrying germline BAP1 mutations and primary cells in which BAP1 was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of BAP1 residues I675, F678, I679, and L691 -encompassing the C-terminal domain-nuclear localization signal- to A, abolished the interaction with HIF-1α. We found that BAP1 binds to the N-terminal region of HIF-1α, where HIF-1α binds DNA and dimerizes with HIF-1β forming the heterodimeric transactivating complex HIF. Our data identify BAP1 as a key positive regulator of HIF-1α in hypoxia. We propose that the significant reduction of HIF-1α activity in mesothelioma cells carrying biallelic BAP1 mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline BAP1 mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline BAP1 mutations.
Publisher: American Society of Neuroradiology (ASNR)
Date: 11-04-2013
DOI: 10.3174/AJNR.A3503
Publisher: Springer Science and Business Media LLC
Date: 16-05-2021
Publisher: SAGE Publications
Date: 06-10-2021
DOI: 10.1177/13524585211047977
Abstract: The added value of neurofilament light chain levels in serum (sNfL) to the concept of no evidence of disease activity-3 (NEDA-3) has not yet been investigated in detail. To assess whether combination of sNfL with NEDA-3 status improves identification of patients at higher risk of disease activity during the following year. We analyzed 369 blood s les from 155 early relapsing-remitting MS patients on interferon beta-1a. We compared disease activity, including the rate of brain volume loss in subgroups defined by NEDA-3 status and high or low sNfL ( 90th or 90th percentile). In patients with disease activity (EDA-3), those with higher sNFL had higher odds of EDA-3 in the following year than those with low sNFL (86.5% vs 57.9% OR = 4.25, 95% CI: [2.02, 8.95] p = 0.0001) and greater whole brain volume loss during the following year (β = −0.36% 95% CI = [−0.60, −0.13] p = 0.002). Accordingly, NEDA-3 patients with high sNfL showed numerically higher disease activity (EDA-3) in the following year compared with those with low sNfL (57.1% vs 31.1%). sNfL improves the ability to identify patients at higher risk of future disease activity, beyond their NEDA-3 status. Measurement of sNfL may assist clinicians in decision-making by providing more sensitive prognostic information.
Location: United States of America
No related grants have been discovered for Niels Bergsland.