| 1. |
- He, Yibo, et al.
(författare)
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A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis.
- 2023
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Although elevated levels of anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA), the in vivo functions of these antibodies remain unclear. Here, we have expressed monoclonal ACPAs derived from patients with RA, and analyzed their functions in mice, as well as their specificities. None of the ACPAs showed arthritogenicity nor induced pain-associated behavior in mice. However, one of the antibodies, clone E4, protected mice from antibody-induced arthritis. E4 showed a binding pattern restricted to skin, macrophages and dendritic cells in lymphoid tissue, and cartilage derived from mouse and human arthritic joints. Proteomic analysis confirmed that E4 strongly binds to macrophages and certainRA synovial fluid proteins such as α-enolase. The protective effect of E4 was epitope-specific and dependent on the interaction between E4-citrullinated α-enolase immune complexes with FCGR2B on macrophages, resulting in increased IL-10 secretion and reduced osteoclastogenesis. These findings suggest that a subset of ACPAs have therapeutic potential in RA.
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| 2. |
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| 3. |
- Ritchie, C., et al.
(författare)
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A systematic review shows minimal evidence for measurement properties of psychological functioning outcomes in whiplash
- 2022
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Ingår i: Journal of Clinical Epidemiology. - : Elsevier Inc.. - 0895-4356 .- 1878-5921. ; 151, s. 29-44
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The aim of this study was to systematically identify, synthesize, and appraise studies on the measurement properties of patient-reported outcome measures (PROMs) for anxiety, depression, fear of movement, pain catastrophizing, post-traumatic stress, self-efficacy, and stress in people with whiplash-associated disorders (WAD). Study Design and Setting: PsycINFO, MEDLINE, EMBASE, CINAHL, PILOTS, Web of Science, and Scopus were searched (November 9, 2021). Studies evaluating any measurement property of relevant PROMs in WAD were included. Two reviewers independently screened the studies and assessed the measurement properties in accordance with the COSMIN guidelines. Results: Measurement properties of 10 PROMs were evaluated in WAD: Pictorial Fear of Activity Scale-Cervical (PFActS-C), Tampa Scale of Kinesiophobia-11, Pain Catastrophizing Scale (PCS), Pain Self-Efficacy Questionnaire (PSEQ), PSEQ-4 item, PSEQ-2a, PSEQ-2b, Self-Efficacy Scale, Harvard Trauma Questionnaire, and Post-Traumatic Stress Diagnostic Scale. Content validity was not examined in any of these PROMs in whiplash. Moderate- or high-quality evidence showed adequate internal structure for the PSEQ, PCS, and PFActS-C, whereas the original structures of the remaining seven PROMs were not confirmed in whiplash. Conclusion: Until further research on the measurement properties of these PROMs is available, researchers may opt to use the PSEQ, PCS, or PFActS-C if the construct is aligned with research aims. © 2022 Elsevier Inc.
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| 4. |
- Scott, Aaron M., et al.
(författare)
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Population scale proteomics enables adaptive digital twin modelling in sepsis
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Sepsis is one of the leading causes of mortality in the world. Currently, the heterogeneity of sepsis makes it challenging to determine the molecular mechanisms that define the syndrome. Here, we leverage population scale proteomics to analyze a well-defined cohort of 1364 blood samples taken at time-of-admission to the emergency department from patients suspected of sepsis. We identified panels of proteins using explainable artificial intelligence that predict clinical outcomes and applied these panels to reduce high-dimensional proteomics data to a low-dimensional interpretable latent space (ILS). Using the ILS, we constructed an adaptive digital twin model that accurately predicted organ dysfunction, mortality, and early-mortality-risk patients using only data available at time-of-admission. In addition to being highly effective for investigating sepsis, this approach supports the flexible incorporation of new data and can generalize to other diseases to aid in translational research and the development of precision medicine.Competing Interest StatementThe authors have declared no competing interest.Funding StatementL.M. is funded by the Swedish Research Council (grant number VR-2020-02419), the Wallenberg foundation (grant number 2016.0023) and Alfred Österlunds Foundation. J.M. is a Wallenberg academy fellow (KAW 2017.0271) and is also funded by the Swedish Research Council (Vetenskapsrådet, VR) (2019-01646 and 2018-05795), the Wallenberg foundation (KAW2016.0023, KAW2019.0353 and KAW2020.0299), and Alfred Österlunds Foundation. E.M. is funded by Wenner-Gren Foundation (FT2020-0003), the Crafoord Foundation, and the Swedish Society of Medicine (SLS-985287). F.K. is funded by Region Skåne ALF project and the Crafoord Foundation. A.L. is funded by the Swedish Research Council VR 2023-02707 and Region Skåne ALF project 2022-0146.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval for the study was obtained from the Swedish National Ethics Committee (file numbers 2022-01454-01, 2014/741 and 2016/271).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesData produced in the present study are available upon reasonable request to the authors
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| 5. |
- Sterling, M., et al.
(författare)
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Recommendations for a core outcome measurement set for clinical trials in whiplash associated disorders
- 2023
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Ingår i: Pain. - : NLM (Medline). - 0304-3959 .- 1872-6623. ; 164:10, s. 2265-2272
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: Inconsistent reporting of outcomes in clinical trials of treatments for whiplash associated disorders (WAD) hinders effective data pooling and conclusions about treatment effectiveness. A multidisciplinary International Steering Committee recently recommended 6 core outcome domains: Physical Functioning, Perceived Recovery, Work and Social Functioning, Psychological Functioning, Quality of Life and Pain. This study aimed to reach consensus and recommend a core outcome set (COS) representing each of the 6 domains. Forty-three patient-reported outcome measures (PROMs) were identified for Physical Functioning, 2 for perceived recovery, 37 for psychological functioning, 17 for quality of life, and 2 for pain intensity. They were appraised in 5 systematic reviews following COSMIN methodology. No PROMs of Work and Social Functioning in WAD were identified. No PROMs had undergone evaluation of content validity in patients with WAD, but some had moderate-to-high-quality evidence for sufficient internal structure. Based on these results, the International Steering Committee reached 100% consensus to recommend the following COS: Neck Disability Index or Whiplash Disability Questionnaire (Physical Functioning), the Global Rating of Change Scale (Perceived Recovery), one of the Pictorial Fear of Activity Scale-Cervical, Pain Self-Efficacy Questionnaire, Pain Catastrophizing Scale, Harvard Trauma Questionnaire, or Posttraumatic Diagnostic Scale (Psychological Functioning), EQ-5D-3L or SF-6D (Quality of Life), numeric pain rating scale or visual analogue scale (Pain), and single-item questions pertaining to current work status and percent of usual work (Work and Social Functioning). These recommendations reflect the current status of research of PROMs of the 6 core outcome domains and may be modified as evidence grows.
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| 6. |
- Tanner, L., et al.
(författare)
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Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) has significant roles in the modulation of inflammation and metabolic syndromes. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study we show Ogg1-targeting siRNA mitigates bleomycin-induced pulmonary fibrosis in male mice, highlighting OGG1 as a tractable target in lung fibrosis. The small molecule OGG1 inhibitor, TH5487, decreases myofibroblast transition and associated pro-fibrotic gene expressions in fibroblast cells. In addition, TH5487 decreases levels of pro-inflammatory mediators, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis conducted in male C57BL6/J mice. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation and display roles in fibrotic murine and IPF patient lung tissue. Taken together, these data suggest that TH5487 is a potentially clinically relevant treatment for IPF but further study in human trials is required.
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| 7. |
- Bady, Pierre, et al.
(författare)
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DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome - including in elderly patients
- 2022
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Ingår i: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Elderly patients represent a growing proportion of individuals with glioblastoma, who however, are often excluded from clinical trials owing to poor expected prognosis. We aimed at identifying age-related molecular differences that would justify and guide distinct treatment decisions in elderly glioblastoma patients. The combined DNA methylome (450 k) of four IDH wild-type glioblastoma datasets, comprising two clinical trial cohorts, was interrogated for differences based on the patients age, DNA methylation (DNAm) age acceleration (DNAm age "Horvath-clock" minus patient age), DNA methylation-based tumor classification (Heidelberg), entropy, and functional methylation of DNA damage response (DDR) genes. Age dependent methylation included 19 CpGs (p-value <= 0.1, Bonferroni corrected), comprising a CpG located in the ELOVL2 gene that is part of a 13-gene forensic age predictor. Most of the age related CpGs (n = 16) were also associated with age acceleration that itself was associated with a large number of CpGs (n = 50,551). Over 70% age acceleration-associated CpGs (n = 36,348) overlapped with those associated with the DNA methylation based tumor classification (n = 170,759). Gene set enrichment analysis identified associated pathways, providing insights into the biology of DNAm age acceleration and respective commonalities with glioblastoma classification. Functional methylation of several DDR genes, defined as correlation of methylation with gene expression (r <= -0.3), was associated with age acceleration (n = 8), tumor classification (n = 12), or both (n = 4), the latter including MGMT. DNAm age acceleration was significantly associated with better outcome in both clinical trial cohorts, whereof one comprised only elderly patients. Multivariate analysis included treatment (RT, RT/TMZ -> TMZ; TMZ, RT), MGMT promoter methylation status, and interaction with treatment. In conclusion, DNA methylation features of age acceleration are an integrative part of the methylation-based tumor classification (RTK I, RTK II, MES), while patient age seems hardly reflected in the glioblastoma DNA methylome. We found no molecular evidence justifying other treatments in elderly patients, not owing to frailty or co-morbidities.
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| 8. |
- Blank, Malou, 1975, et al.
(författare)
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Mobility patterns in inland southwestern Sweden during the Neolithic and Early Bronze Age
- 2021
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Ingår i: Archaeological and Anthropological Sciences. - : Springer Science and Business Media LLC. - 1866-9557 .- 1866-9565. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, we investigate population dynamics in the Scandinavian Neolithic and Early Bronze Age in southwestern Sweden. Human mobility patterns in Falbygden were studied by applying strontium isotope analysis combined with archaeological and bioarchaeological data, including mtDNA and sex assessment on a large dataset encompassing 141 individuals from 21 megalithic graves. In combination with other archaeological and anthropological records, we investigated the temporal and spatial scale of individual movement, mobility patterns of specific categories of people and possible social drivers behind them. Our results of strontium and biomolecular analyses suggest that mobility increased in the Late Neolithic and Early Bronze Age compared to the earlier parts of the Neolithic. The data indicate individuals moving both into and away from Falbygden. Mobility patterns and contact networks also shift over time.
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| 9. |
- Hartman, Erik, et al.
(författare)
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Interpreting biologically informed neural networks for enhanced proteomic biomarker discovery and pathway analysis
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- The incorporation of machine learning methods into proteomics workflows improves the identification of disease-relevant biomarkers and biological pathways. However, machine learning models, such as deep neural networks, typically suffer from lack of interpretability. Here, we present a deep learning approach to combine biological pathway analysis and biomarker identification to increase the interpretability of proteomics experiments. Our approach integrates a priori knowledge of the relationships between proteins and biological pathways and biological processes into sparse neural networks to create biologically informed neural networks. We employ these networks to differentiate between clinical subphenotypes of septic acute kidney injury and COVID-19, as well as acute respiratory distress syndrome of different aetiologies. To gain biological insight into the complex syndromes, we utilize feature attribution-methods to introspect the networks for the identification of proteins and pathways important for distinguishing between subtypes. The algorithms are implemented in a freely available open source Python-package ( https://github.com/InfectionMedicineProteomics/BINN ).
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| 10. |
- Mattila, Tiina M., et al.
(författare)
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Genetic continuity, isolation, and gene flow in Stone Age Central and Eastern Europe
- 2023
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Ingår i: Communications Biology. - : Springer Nature. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- The genomic landscape of Stone Age Europe was shaped by multiple migratory waves and population replacements, but different regions do not all show similar patterns. To refine our understanding of the population dynamics before and after the dawn of the Neolithic, we generated and analyzed genomic sequence data from human remains of 56 individuals from the Mesolithic, Neolithic, and Eneolithic across Central and Eastern Europe. We found that Mesolithic European populations formed a geographically widespread isolation-by-distance zone ranging from Central Europe to Siberia, which was already established 10,000 years ago. We found contrasting patterns of population continuity during the Neolithic transition: people around the lower Dnipro Valley region, Ukraine, showed continuity over 4000 years, from the Mesolithic to the end of the Neolithic, in contrast to almost all other parts of Europe where population turnover drove this cultural change, including vast areas of Central Europe and around the Danube River. Genome-wide sequencing of 56 ancient hunter-gatherer and early farmer individuals from Stone Age Central and Eastern Europe reveals striking population continuity in the east in contrast to central Europe that displays extensive admixture.
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