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- Roswall, N., et al.
(författare)
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Long-Term Exposure to Transportation Noise and Risk of Incident Stroke: A Pooled Study of Nine Scandinavian Cohorts
- 2021
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Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 129:10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Transportation noise is increasingly acknowledged as a cardiovascular risk factor, but the evidence base for an association with stroke is sparse. OBJECTIVE: We aimed to investigate the association between transportation noise and stroke incidence in a large Scandinavian population. METHODS: We harmonized and pooled data from nine Scandinavian cohorts (seven Swedish, two Danish), totaling 135,951 participants. We identified residential address history and estimated road, railway, and aircraft noise for all addresses. Information on stroke incidence was acquired through linkage to national patient and mortality registries. We analyzed data using Cox proportional hazards models, including socioeconomic and lifestyle confounders, and air pollution. RESULTS: During follow-up (median = 19.5 y), 11,056 stroke cases were identified. Road traffic noise (Lden) was associated with risk of stroke, with a hazard ratio (HR) of 1.06 [95% confidence interval (CI): 1.03, 1.08] per 10-dB higher 5-y mean time-weighted exposure in analyses adjusted for individual- and area-level socioeconomic covariates. The association was approximately linear and persisted after adjustment for air pollution [particulate matter (PM) with an aerodynamic diameter of <= 2.5 mu m (PM2.5) and NO2]. Stroke was associated with moderate levels of 5-y aircraft noise exposure (40-50 vs. <= 40 dB) (HR = 1.12; 95% CI: 0.99, 1.27), but not with higher exposure (>= 50 dB, HR = 0.94; 95% CI: 0.79, 1.11). Railway noise was not associated with stroke. DISCUSSION: In this pooled study, road traffic noise was associated with a higher risk of stroke. This finding supports road traffic noise as an important cardiovascular risk factor that should be included when estimating the burden of disease due to traffic noise.
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- Klionsky, DJ, et al.
(författare)
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Autophagy in major human diseases
- 2021
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Ingår i: The EMBO journal. - : EMBO. - 1460-2075 .- 0261-4189. ; 40:19, s. e108863-
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Polymeri, Erini, et al.
(författare)
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Artificial intelligence-based measurements of PET/CT imaging biomarkers are associated with disease-specific survival of high-risk prostate cancer patients
- 2021
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 55:6, s. 427-433
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Tidskriftsartikel (refereegranskat)abstract
- Objective Artificial intelligence (AI) offers new opportunities for objective quantitative measurements of imaging biomarkers from positron-emission tomography/computed tomography (PET/CT). Clinical image reporting relies predominantly on observer-dependent visual assessment and easily accessible measures like SUVmax, representing lesion uptake in a relatively small amount of tissue. Our hypothesis is that measurements of total volume and lesion uptake of the entire tumour would better reflect the disease`s activity with prognostic significance, compared with conventional measurements. Methods An AI-based algorithm was trained to automatically measure the prostate and its tumour content in PET/CT of 145 patients. The algorithm was then tested retrospectively on 285 high-risk patients, who were examined using F-18-choline PET/CT for primary staging between April 2008 and July 2015. Prostate tumour volume, tumour fraction of the prostate gland, lesion uptake of the entire tumour, and SUVmax were obtained automatically. Associations between these measurements, age, PSA, Gleason score and prostate cancer-specific survival were studied, using a Cox proportional-hazards regression model. Results Twenty-three patients died of prostate cancer during follow-up (median survival 3.8 years). Total tumour volume of the prostate (p = 0.008), tumour fraction of the gland (p = 0.005), total lesion uptake of the prostate (p = 0.02), and age (p = 0.01) were significantly associated with disease-specific survival, whereas SUVmax (p = 0.2), PSA (p = 0.2), and Gleason score (p = 0.8) were not. Conclusion AI-based assessments of total tumour volume and lesion uptake were significantly associated with disease-specific survival in this patient cohort, whereas SUVmax and Gleason scores were not. The AI-based approach appears well-suited for clinically relevant patient stratification and monitoring of individual therapy.
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| 6. |
- Polymeri, Erini, et al.
(författare)
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Deep learning-based quantification of PET/CT prostate gland uptake : association with overall survival
- 2020
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Ingår i: Clinical Physiology and Functional Imaging. - Chichester : Blackwell Publishing. - 1475-0961 .- 1475-097X. ; 40:2, s. 106-113
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To validate a deep-learning (DL) algorithm for automated quantification of prostate cancer on positron emission tomography/computed tomography (PET/CT) and explore the potential of PET/CT measurements as prognostic biomarkers. Material and methods: Training of the DL-algorithm regarding prostate volume was performed on manually segmented CT images in 100 patients. Validation of the DL-algorithm was carried out in 45 patients with biopsy-proven hormone-naïve prostate cancer. The automated measurements of prostate volume were compared with manual measurements made independently by two observers. PET/CT measurements of tumour burden based on volume and SUV of abnormal voxels were calculated automatically. Voxels in the co-registered 18F-choline PET images above a standardized uptake value (SUV) of 2·65, and corresponding to the prostate as defined by the automated segmentation in the CT images, were defined as abnormal. Validation of abnormal voxels was performed by manual segmentation of radiotracer uptake. Agreement between algorithm and observers regarding prostate volume was analysed by Sørensen-Dice index (SDI). Associations between automatically based PET/CT biomarkers and age, prostate-specific antigen (PSA), Gleason score as well as overall survival were evaluated by a univariate Cox regression model. Results: The SDI between the automated and the manual volume segmentations was 0·78 and 0·79, respectively. Automated PET/CT measures reflecting total lesion uptake and the relation between volume of abnormal voxels and total prostate volume were significantly associated with overall survival (P = 0·02), whereas age, PSA, and Gleason score were not. Conclusion: Automated PET/CT biomarkers showed good agreement to manual measurements and were significantly associated with overall survival. © 2019 The Authors. Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine
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| 7. |
- Toft, A., et al.
(författare)
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Endo-lysosomal protein concentrations in CSF from patients with frontotemporal dementia caused by CHMP2B mutation
- 2023
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Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionIncreasing evidence implicates proteostatic dysfunction as an early event in the development of frontotemporal dementia (FTD). This study aimed to explore potential cerebrospinal fluid (CSF) biomarkers associated with the proteolytic systems in genetic FTD caused by CHMP2B mutation. MethodsCombining solid-phase extraction and parallel reaction monitoring mass spectrometry, a panel of 47 peptides derived from 20 proteins was analyzed in CSF from 31 members of the Danish CHMP2B-FTD family. ResultsCompared with family controls, mutation carriers had significantly higher levels of complement C9, lysozyme and transcobalamin II, and lower levels of ubiquitin, cathepsin B, and amyloid precursor protein. DiscussionLower CSF ubiquitin concentrations in CHMP2B mutation carriers indicate that ubiquitin levels relate to the specific disease pathology, rather than all-cause neurodegeneration. Increased lysozyme and complement proteins may indicate innate immune activation. Altered levels of amyloid precursor protein and cathepsins have previously been associated with impaired lysosomal proteolysis in FTD. HighlightsCSF markers of proteostasis were explored in CHMP2B-mediated frontotemporal dementia (FTD).31 members of the Danish CHMP2B-FTD family were included.We used solid-phase extraction and parallel reaction monitoring mass spectrometry.Six protein levels were significantly altered in CHMP2B-FTD compared with controls.Lower CSF ubiquitin levels in patients suggest association with disease mechanisms.
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- Bachmann, Till T., et al.
(författare)
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Expert guidance on target product profile development for AMR diagnostic tests
- 2023
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Ingår i: BMJ Global Health. - : BMJ Publishing Group. - 2059-7908. ; 8:12
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Tidskriftsartikel (refereegranskat)abstract
- Diagnostics are widely considered crucial in the fight against antimicrobial resistance (AMR), which is expected to kill 10 million people annually by 2030. Nevertheless, there remains a substantial gap between the need for AMR diagnostics versus their development and implementation. To help address this problem, target product profiles (TPP) have been developed to focus developers’ attention on the key aspects of AMR diagnostic tests. However, during discussion between a multisectoral working group of 51 international experts from industry, academia and healthcare, it was noted that specific AMR-related TPPs could be extended by incorporating the interdependencies between the key characteristics associated with the development of such TPPs. Subsequently, the working group identified 46 characteristics associated with six main categories (ie, Intended Use, Diagnostic Question, Test Description, Assay Protocol, Performance and Commercial). The interdependencies of these characteristics were then identified and mapped against each other to generate new insights for use by stakeholders. Specifically, it may not be possible for diagnostics developers to achieve all of the recommendations in every category of a TPP and this publication indicates how prioritising specific TPP characteristics during diagnostics development may influence (or not) a range of other TPP characteristics associated with the diagnostic. The use of such guidance, in conjunction with specific TPPs, could lead to more efficient AMR diagnostics development.
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| 10. |
- Giovannucci, Tatiana A., et al.
(författare)
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Identification of a novel compound that simultaneously impairs the ubiquitin-proteasome system and autophagy
- 2022
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Ingår i: Autophagy. - : Taylor & Francis. - 1554-8627 .- 1554-8635. ; 18:7, s. 1486-1502
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Tidskriftsartikel (refereegranskat)abstract
- The ubiquitin-proteasome system (UPS) and macroautophagy/autophagy are the main proteolytic systems in eukaryotic cells for preserving protein homeostasis, i.e., proteostasis. By facilitating the timely destruction of aberrant proteins, these complementary pathways keep the intracellular environment free of inherently toxic protein aggregates. Chemical interference with the UPS or autophagy has emerged as a viable strategy for therapeutically targeting malignant cells which, owing to their hyperactive state, heavily rely on the sanitizing activity of these proteolytic systems. Here, we report on the discovery of CBK79, a novel compound that impairs both protein degradation by the UPS and autophagy. While CBK79 was identified in a high-content screen for drug-like molecules that inhibit the UPS, subsequent analysis revealed that this compound also compromises autophagic degradation of long-lived proteins. We show that CBK79 induces non-canonical lipidation of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) that requires ATG16L1 but is independent of the ULK1 (unc-51 like autophagy activating kinase 1) and class III phosphatidylinositol 3-kinase (PtdIns3K) complexes. Thermal preconditioning of cells prevented CBK79-induced UPS impairment but failed to restore autophagy, indicating that activation of stress responses does not allow cells to bypass the inhibitory effect of CBK79 on autophagy. The identification of a small molecule that simultaneously impairs the two main proteolytic systems for protein quality control provides a starting point for the development of a novel class of proteostasis-targeting drugs.
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