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- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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- Czamara, D, et al.
(författare)
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Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2548-
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
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| 14. |
- Galluzzi, L, et al.
(författare)
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Consensus guidelines for the definition, detection and interpretation of immunogenic cell death
- 2020
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Ingår i: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
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- Garg, G, et al.
(författare)
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Patients presenting with metastases: stage IV uveal melanoma, an international study
- 2022
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Ingår i: The British journal of ophthalmology. - : BMJ. - 1468-2079 .- 0007-1161. ; 106:4, s. 510-517
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Tidskriftsartikel (refereegranskat)abstract
- To analyse ocular and systemic findings of patients presenting with systemic metastasis.Methods and analysisIt is an international, multicentre, internet-enabled, registry-based retrospective data analysis. Patients were diagnosed between 2001 and 2011. Data included: primary tumour dimensions, extrascleral extension, ciliary body involvement, American Joint Committee on Cancer (AJCC)-tumour, node, metastasis staging, characteristics of metastases.ResultsOf 3610 patients with uveal melanoma, 69 (1.9%; 95% CI 1.5 to 2.4) presented with clinical metastasis (stage IV). These melanomas originated in the iris, ciliary body and choroid in 4%, 16% and 80% of eyes, respectively. Using eighth edition AJCC, 8 (11%), 20 (29%), 24 (35%), and 17 (25%) belonged to AJCC T-categories T1–T4. Risk of synchronous metastases increased from 0.7% (T1) to 1.5% (T2), 2.6% (T3) and 7.9% (T4). Regional lymph node metastases (N1a) were detected in 9 (13%) patients of whom 6 (67%) had extrascleral extension. Stage of systemic metastases (known for 40 (59%) stage IV patients) revealed 14 (35%), 25 (63%) and 1 (2%) had small (M1a), medium-sized (M1b) and large-sized (M1c) metastases, respectively. Location of metastases in stage IV patients were liver (91%), lung (16%), bone (9%), brain (6%), subcutaneous tissue (4%) and others (5%). Multiple sites of metastases were noted in 24%. Compared with the 98.1% of patients who did not present with metastases, those with synchronous metastases had larger intraocular tumours, more frequent extrascleral extension, ciliary body involvement and thus a higher AJCC T-category.ConclusionsThough higher AJCC T-stage was associated with risk for metastases at diagnosis, even small T1 tumours were stage IV at initial presentation. The liver was the most common site of metastases; however, frequent multiorgan involvement supports initial whole-body staging.
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- Vedunova, M, et al.
(författare)
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DC vaccines loaded with glioma cells killed by photodynamic therapy induce Th17 anti-tumor immunity and provide a four-gene signature for glioma prognosis
- 2022
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 13:12, s. 1062-
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Tidskriftsartikel (refereegranskat)abstract
- Gliomas, the most frequent type of primary tumor of the central nervous system in adults, results in significant morbidity and mortality. Despite the development of novel, complex, multidisciplinary, and targeted therapies, glioma therapy has not progressed much over the last decades. Therefore, there is an urgent need to develop novel patient-adjusted immunotherapies that actively stimulate antitumor T cells, generate long-term memory, and result in significant clinical benefits. This work aimed to investigate the efficacy and molecular mechanism of dendritic cell (DC) vaccines loaded with glioma cells undergoing immunogenic cell death (ICD) induced by photosens-based photodynamic therapy (PS-PDT) and to identify reliable prognostic gene signatures for predicting the overall survival of patients. Analysis of the transcriptional program of the ICD-based DC vaccine led to the identification of robust induction of Th17 signature when used as a vaccine. These DCs demonstrate retinoic acid receptor-related orphan receptor-γt dependent efficacy in an orthotopic mouse model. Moreover, comparative analysis of the transcriptome program of the ICD-based DC vaccine with transcriptome data from the TCGA-LGG dataset identified a four-gene signature (CFH, GALNT3, SMC4, VAV3) associated with overall survival of glioma patients. This model was validated on overall survival of CGGA-LGG, TCGA-GBM, and CGGA-GBM datasets to determine whether it has a similar prognostic value. To that end, the sensitivity and specificity of the prognostic model for predicting overall survival were evaluated by calculating the area under the curve of the time-dependent receiver operating characteristic curve. The values of area under the curve for TCGA-LGG, CGGA-LGG, TCGA-GBM, and CGGA-GBM for predicting five-year survival rates were, respectively, 0.75, 0.73, 0.9, and 0.69. These data open attractive prospects for improving glioma therapy by employing ICD and PS-PDT-based DC vaccines to induce Th17 immunity and to use this prognostic model to predict the overall survival of glioma patients.
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| 28. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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