| 141. |
- Nygren, Arne, 1971, et al.
(författare)
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Bertil Åkesson (1928-2013) obituary.
- 2014
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Ingår i: Memoires of Museum Victoria. - 1447-2546 .- 1447-2554. ; 71, s. 343-345
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
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| 142. |
- Nylund, Patrick, et al.
(författare)
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A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma
- 2021
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Ingår i: Cell Death and Disease. - : Springer Nature. - 2041-4889. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a heterogeneous haematological disease that remains clinically challenging. Increased activity of the epigenetic silencer EZH2 is a common feature in patients with poor prognosis. Previous findings have demonstrated that metabolic profiles can be sensitive markers for response to treatment in cancer. While EZH2 inhibition (EZH2i) has proven efficient in inducing cell death in a number of human MM cell lines, we hereby identified a subset of cell lines that despite a global loss of H3K27me3, remains viable after EZH2i. By coupling liquid chromatography-mass spectrometry with gene and miRNA expression profiling, we found that sensitivity to EZH2i correlated with distinct metabolic signatures resulting from a dysregulation of genes involved in methionine cycling. Specifically, EZH2i resulted in a miRNA-mediated downregulation of methionine cycling-associated genes in responsive cells. This induced metabolite accumulation and DNA damage, leading to G2 arrest and apoptosis. Altogether, we unveiled that sensitivity to EZH2i in human MM cell lines is associated with a specific metabolic and gene expression profile post-treatment.
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| 143. |
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| 144. |
- Nylund, Patrick, et al.
(författare)
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PVT1 interacts with the polycomb repressive complex 2 to suppress genomic regions with pro-apoptotic and tumour suppressor functions in multiple myeloma
- 2024
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Ingår i: Haematologica. - : Ferrata Storti Foundation. - 0390-6078 .- 1592-8721. ; 109:2, s. 567-577
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma is a heterogeneous hematological disease that originates from the bone marrow and is characterized by the monoclonal expansion of malignant plasma cells. Despite novel therapies, multiple myeloma remains clinically challenging. A common feature among patients with poor prognosis is the increased activity of the epigenetic silencer EZH2, which is the catalytic subunit of the PRC2. Interestingly, the recruitment of PRC2 lacks sequence specificity and, to date, the molecular mechanisms that define which genomic locations are destined for PRC2-mediated silencing remain unknown. The presence of a long non-coding RNA (lncRNA)-binding pocket on EZH2 suggests that lncRNA could potentially mediate PRC2 recruitment to specific genomic regions. Here, we coupled RNA immunoprecipitation sequencing, RNA-sequencing and chromatin immunoprecipitation-sequencing analysis of human multiple myeloma primary cells and cell lines to identify potential lncRNA partners to EZH2. We found that the lncRNA plasmacytoma variant translocation 1 (PVT1) directly interacts with EZH2 and is overexpressed in patients with a poor prognosis. Moreover, genes predicted to be targets of PVT1 exhibited H3K27me3 enrichment and were associated with pro-apoptotic and tumor suppressor functions. In fact, PVT1 inhibition independently promotes the expression of the PRC2 target genes ZBTB7C, RNF144A and CCDC136. Altogether, our work suggests that PVT1 is an interacting partner in PRC2-mediated silencing of tumor suppressor and pro-apoptotic genes in multiple myeloma, making it a highly interesting potential therapeutic target.
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| 145. |
- Nylund, Patrick
(författare)
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Targeting molecular mechanisms for epigenetic silencing in multiple myeloma : Implications for biology and precision medicine
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple myeloma (MM) is a heterogeneous haematological cancer where malignant plasma cells clonally expand within the bone marrow. The transcriptional repressor PRC2 and its catalytic subunit EZH2 play a major role in MM, as PRC2 re-targeting results in a MM-specific gene silencing profile. In paper I, we explored the metabolic response to EZH2 inhibition (EZH2i). A global loss of H3K27me3 was found in all EZH2i-treated MM cell lines. EZH2i-sensitive cell lines acquired a unique metabolic signature, following the upregulation of a cluster of miRNAs which target methionine cycling-associated genes and are silenced by H3K27me3. These miRNAs were not upregulated in resistant cell lines, due to additional DNA methylation-mediated silencing.Therefore, in paper II we sought to evaluate the combinatorial effect of DNA demethylation agents and EZH2 inhibitors. Here, we provided a comprehensive map of the reconfiguration of the epigenome in primary MM samples. Furthermore, we demonstrated a direct protein-protein interaction between DNMT1 and EZH2 and showed that co-inhibition of these enzymes has an enhanced effect in synergistically activating genes regulating apoptosis and cell cycling. PRC2 lacks sequence specificity but contains a lncRNA binding pocket. In paper III, we hypothesized that PRC2 targeting to specific genomic regions could be mediated by lncRNAs in the context of MM. Coupling RIP- and RNA-seq, we identified a physical interaction between the lncRNA PVT1 and EZH2, as well as 270 genes potentially targeted by the EZH2-PVT1 axis. In addition, we found that independent inhibition of EZH2 and PVT1 resulted in the upregulation of the tumour suppressor genes ZBTB7C, RNF144A and CCDC136, suggesting a functional interdependency between these two epigenetic regulators. In paper IV we investigated the effects of dual G9a/DNMT inhibition in MM cells, resulting in suppressed expression of MM-associated oncogenes and increased tumour cell death. By coupling ChIP-seq, DNA methylation arrays and RNA-seq, we identified a group of genes silenced by G9a and/or DNMTs that when activated, blocked MM proliferative potential by activating genes with tumour suppressor function. In summary, this thesis highlights the strong interconnection between the dysregulation of epigenetic/metabolic regulatory mechanisms and MM pathogenesis, providing insights into how these mechanisms can be targeted to promote anti-MM effects.
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| 146. |
- Olson, Fredrik J., 1975, et al.
(författare)
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Circulating matrix metalloproteinase 9 levels in relation to sampling methods, femoral and carotid atherosclerosis.
- 2008
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Ingår i: Journal of internal medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 263:6, s. 626-35
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To examine whether circulating levels of matrix metalloproteinase 9 (MMP-9) were associated with ultrasound-assessed intima-media thickness (IMT) and echolucent plaques in the carotid and femoral arteries. To examine preanalytical sources of variability in MMP-9 concentrations related to sampling procedures. SUBJECTS AND DESIGN: Plasma and serum MMP-9 levels were compared with ultrasound assessed measures of femoral and carotid atherosclerosis, in a cross-sectional study of 61-year-old men (n = 473). Preanalytical sources of variability in MMP-9 levels were examined in 10 healthy subjects. Main outcome measures were circulating levels of MMP-9 in serum and plasma, IMT of the carotid and femoral arteries, and plaque status based on size and echolucency. SETTING: Research unit at university hospital. RESULTS: Plasma concentrations of total and active MMP-9 were associated with femoral artery IMT independently of traditional cardiovascular risk factors, and were higher in subjects with moderate to large femoral plaques. Plasma MMP-9 concentration was higher in men with echolucent femoral plaques (P = 0.006) compared with subjects without femoral plaques. No similar associations were found for carotid plaques. MMP-9 concentrations were higher in serum than in plasma, and higher when sampling was performed with Vacutainer than with syringe. MMP-9 levels in serum were more strongly associated with peripheral neutrophil count compared with MMP-9 levels in plasma. CONCLUSIONS: Plasma MMP-9 levels were associated with atherosclerosis in the femoral artery, and total MMP-9 concentration was higher in men with echolucent femoral plaques. The choice of sample material and sampling method affect the measurements of circulating MMP-9 levels.
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| 147. |
- Olson, Fredrik J., 1975, et al.
(författare)
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Up- and downstream structural differences in carotid plaque composition - implications for studies of human symptomatic carotid plaques
- 2008
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Ingår i: Atherosclerosis Supplements. - 1567-5688. ; 9:1
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Konferensbidrag (refereegranskat)abstract
- Background and aims: Blood passing a protruding plaque causes high laminar shear stress at the upstream shoulder with increased risk of rupture, whereas blood flow is turbulent causing low shear stress at the downstream shoulder, where plaque growth generally occurs. Low shear stress induces cell adhesion, inflammation and apoptosis. Cap shoulders are of key interest in the mechanisms leading to development of rupture-prone plaques. Our aim was to explore morphology and composition of human carotid endarterectomies in up- and downstream parts, and to relate the occurrence of macrophages in shoulder regions to that in the entire plaque. Methods: Endarterectomies from 87 patients with symptomatic carotid atherosclerosis were divided transversely into 3mm pieces (4-18 paraffin-embedded pieces/plaque). Sections were prepared and histologically classified for plaque vulnerability features: AHA classification, thin cap, plaque rupture, and surface thrombosis; and were also immunohistochemically stained for macrophages and other components. Clinical information was collected, to correlate results with clinical history and risk factors. Results: On average, the most stenotic part of the plaque was 3mm into the internal carotid artery, from the bifurcation. Plaque vulnerability features were most prevalent at this level, and were less frequent in distal sections upstream. Macrophage content was higher downstream of the stenosis than in upstream parts. The shoulder regions contained less than 10% of all macrophages. Conclusions: Upstream and downstream parts of human symptomatic carotid atherosclerotic plaques differed significantly in morphology and composition. Only a small fraction of macrophages in the plaques were located in the cap shoulder regions.
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| 148. |
- Párraga, Alba Atienza, 1988-
(författare)
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The Epigenome of Multiple Myeloma : From genome-wide analysis to pharmacological manipulation
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Nowadays epigenetic dysregulation is known to play a crucial role in virtually all cancers. In multiple myeloma (MM), an extensively heterogeneous malignancy, the key common feature among patients is the gene silencing imposed by the PRC2 complex through the addition of H3K27me3. This thesis focuses on the exploration of the MM epigenomic landscape, with an emphasis on both the interplay between H3K27me3 and other epigenetic tags, and on the effects of a series of inhibitors altering this profile.In paper I we provide the genome-wide H3K27me3 distribution unique to MM and demonstrate that the silencing of genes in the profile correlates with an advanced and poor-outcome disease. Reduction of H3K27me3 using the EZH2 inhibitor UNC1999 reactivates genes with anti-tumor activity and induces apoptosis in vitro.EZH2 inhibition also leads to downregulation of the MM oncogenes IRF-4, BLIMP-1, XBP-1 and c-MYC. Paper II identifies miR-125a-3p and miR-320c, predicted to target these oncogenes, as part of the PRC2 targets induced upon treatment.In addition, H3K27me3 can be recognized and bound by the PRC1 complex. In paper III we show that inhibition of PRC1 using PTC-209 induces apoptosis and this is further enhanced when PTC-209 is combined with UNC1999. Moreover, PTC-209 has been previously shown to reduce the expression of c-MYC. Combined treatment using PTC-209 and JQ1, demonstrated to downregulate c-MYC, results in additive and synergistic effects in reducing MM cell viability.In paper IV we present the first catalogue of genomic regulatory regions in normal plasma cells, as predicted by their combinations of histone marks. Using this, we demonstrate that in MM a subset of TSSs and enhancers become targeted by H3K27me3 and display high DNA methylation, pointing towards a possible silencing. Conversely, poised TSSs lose H3K27me3 and seemingly become de novo activated. Furthermore, we show that EZH2 physically interacts with the DNA methyltransferase DNMT1 and that combined inhibition using UNC1999 and the DNA hypomethylating agent AZA blocks the G2/M arrest triggered by AZA and induces apoptosis.In summary, this thesis highlights the complex interconnectivity of epigenetic mechanisms in MM and provides proof-of-principle of the anti-MM effects derived from inhibiting epigenetic components in single or combinatorial regimens.
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| 149. |
- Pin, Elisa, et al.
(författare)
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Identification of a Novel Autoimmune Peptide Epitope of Prostein in Prostate Cancer
- 2017
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 16:1, s. 204-216
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Tidskriftsartikel (refereegranskat)abstract
- There is a demand for novel targets and approaches to diagnose and treat prostate cancer (PCA). In this context, serum and plasma samples from a total of 609 individuals from two independent patient cohorts were screened for IgG reactivity against a sum of 3833 human protein fragments. Starting from planar protein arrays with 3786 protein fragments to screen 80 patients with and without PCA diagnosis, 161 fragments (4%) were chosen for further analysis based on their reactivity profiles. Adding 71 antigens from literature, the selection of antigens was corroborated for their reactivity in a set of 550 samples using suspension bead arrays. The antigens prostein (SLC45A3), TATA-box binding protein (TBP), and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) showed higher reactivity in PCA patients with late disease compared with early disease. Because of its prostate tissue specificity, we focused on prostein and continued with mapping epitopes of the 66-mer protein fragment using patient samples. Using bead-based assays and 15-mer peptides, a minimal peptide epitope was identified and refined by alanine scanning to the KPxAPFP. Further sequence alignment of this motif revealed homology to transmembrane protein 79 (TMEM79) and TGF-beta-induced factor 2 (TGIF2), thus providing a reasoning for cross-reactivity found in females. A comprehensive workflow to discover and validate IgG reactivity against prostein and homologous targets in human serum and plasma was applied. This study provides useful information when searching for novel biomarkers or drug targets that are guided by the reactivity of the immune system against autoantigens.
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| 150. |
- Pleijel, Fredrik, 1955, et al.
(författare)
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Vrijenhoekia balaenophila, a new hesionid polychaete from a whale fall off CaliforniaVrijenhoekia balaenophila, a new hesionid polychaete from a whale fall off California
- 2008
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Ingår i: Zoological Journal of the Linnean Society. - : Oxford University Press (OUP). - 0024-4082 .- 1096-3642. ; 152:4, s. 625-634
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Tidskriftsartikel (refereegranskat)abstract
- Vrijenhoekia balaenophila gen. nov., sp. nov. (Polychaeta, Hesionidae) is described from a whale carcass at near 3000 m depth in Monterey Canyon off the coast of California. The phylogenetic relationships of V. balaenophila are assessed in a parsimony analysis of morphological data together with nucleotide data from 28S rDNA, 16S rDNA and cytochrome oxidase I genes. Within the hesionids V. balaenophila belongs to Psamathini, where it is the sister group to Sirsoe. Among psamathins it is morphologically distinguished by having six glandular lip pads around the mouth opening, papilla-shaped neuropodial lobes on segment 3, extreme length of the dorsal cirri, and by a characteristic growth pattern in which the maximum number of segments is already formed in subadults, and further growth takes place through size increase of the segments.
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