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1.	Gullbo, Joachim, et al. (författare) Development and characterization of two human tumor sublines expressing high-grade resistance to the cyanoguadine CHS 828 2004 Ingår i: Anti-Cancer Drugs. ; 15:1, s. 45-54 Tidskriftsartikel (refereegranskat)
2.	Gullbo, Joachim, et al. (författare) Development and characterization of two human tumor sublines expressing high-grade resistance to the cyanoguanidine CHS 828 2004 Ingår i: Anti-Cancer Drugs. ; 15:1, s. 45-54 Tidskriftsartikel (refereegranskat)
3.	Westman, Fredrik, et al. (författare) A Robust CMOS Bluetooth Radio/Modem System-on-Chip 2002 Ingår i: IEEE Circuit and Systems Magazine. ; , s. 7-9 Tidskriftsartikel (refereegranskat)
4.	Öberg, Fredrik, et al. (författare) Herbal melanin activates TLR4/NF-kappaB signaling pathway 2009 Ingår i: Phytomedicine. - : Elsevier BV. - 0944-7113 .- 1618-095X. ; 16:5, s. 477-84 Tidskriftsartikel (refereegranskat)abstract Expression of many pro-inflammatory cytokines is controlled by the NF-kappaB signaling pathway. NF-kappaB is induced by LPS through activation of TLR4. Melanins extracted from fungal, plant and human sources modulate cytokine production and activate NF-kappaB pathway. We showed that a herbal melanin (HM) from Nigella sativa L. modulates cytokine production and suggested it as a ligand for TLR4. In this study we investigated the possibility that the HM-induced cytokine production is via an NF-kappaB signaling pathway. We found that HM induced the degradation of IkappaBalpha, a key step in the activation of NF-kappaB. Moreover, addition of IkappaB kinase (IKK) specific inhibitors effectively inhibited the observed HM-induced production of IL-8 and IL-6 by TLR4-transfected HEK293 cells and THP-1 cells. Our results have also shown that HM induced cleavage of caspase 8, and that this cleavage was partially abrogated by IKK inhibitors. We suggest that HM can modulate the inflammatory response by inducing IL-8 and IL-6 production via TLR4-dependent activation of the NF-kappaB signaling pathway.
5.	Agarwal, Prasoon, et al. (författare) An Epigenomic Map of Multiple Myeloma Reveals the Importance of Polycomb Gene Silencing for the Malignancy 2014 Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 124:21 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
6.	Agarwal, Prasoon, et al. (författare) Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target. 2016 Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:6, s. 6809-6923 Tidskriftsartikel (refereegranskat)abstract Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.
7.	Agarwal, Prasoon, et al. (författare) The epigenomic map of multiple myeloma reveals the importance of Polycomb gene silencing for the malignancy Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Multiple myeloma (MM) is characterized by accumulation of post-germinal center, isotype switched, long-living plasma cells with retained proliferation capacity within the bone marrow. MM is highly heterogeneous and remains fatal. This heterogeneity has hampered identification of a common underlying mechanism for disease establishment and the development of targeted therapy. We recently provided proof-of-principle that gene silencing associated with H3K27me3 contributes to the malignancy of MM. Here we present the first epigenomic map of MM for H3K27me3 and H3K4me3 derived by ChIP- and RNA sequencing from freshly-isolated bone marrow plasma cells from four patients. We compile lists of targets common among the patients as well as unique to MM when compared with PBMCs. Indicating the clinical relevance of our findings, we find increased silencing of H3K27me3 targets with disease progression and in patients presenting with a poor prognosis. Bivalent genes further significantly correlated to under-expressed genes in MM and were unique to MM when compared to PBMCs. Furthermore, bivalent genes, unlike H3K27me3 targets, significantly associated with transcriptional activation upon Polycomb inhibition indicating a potential for drug targeting. Thus, we suggest that gene silencing by Polycomb plays an important role in the development of the malignant phenotype of the MM cell during tumor progression.
8.	Alzrigat, Mohammad, et al. (författare) EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions. 2017 Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:6, s. 10213-10224 Tidskriftsartikel (refereegranskat)abstract Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.
9.	Alzrigat, Mohammad (författare) Targeted Inhibition of Polycomb Repressive Complexes in Multiple Myeloma : Implications for Biology and Therapy 2017 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Multiple myeloma (MM) is a hematological malignancy of antibody producing plasmablasts/plasma cells. MM is characterized by extensive genetic and clonal heterogeneity, which have hampered the attempts to identify a common underlying mechanism for disease establishment and development of appropriate treatment regimes. This thesis is focused on understanding the role of epigenetic regulation of gene expression mediated by the polycomb repressive complexes 1 and 2 (PRC1 and 2) in MM and their impact on disease biology and therapy.In paper I the genome-wide distribution of two histone methylation marks; H3K27me3 and H3K4me3 were studied in plasma cells isolated from newly diagnosed MM patients or age-matched normal donors. We were able to define targets of H3K27me3, H3K4me3 and bivalent (carry both marks) which are, when compared to normal individuals, unique to MM patients. The presence of H3K27me3 correlated with silencing of MM unique H3K27me3 targets in MM patients at advanced stages of the disease. Notably, the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also showed that inhibition of the PRC2 enzymatic subunit EZH2 using highly selective inhibitors (GSK343 and UNC1999) demonstrated anti-myeloma activity using relevant in vitro models of MM. These data suggest an important role for gene repression mediated by PRC2 in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.In paper II we further explored the therapeutic potential of UNC1999, a highly selective inhibitor of EZH2 in MM. We showed that EZH2 inhibition by UNC1999 downregulated important MM oncogenes; IRF-4, XBP-1, BLIMP-1and c-MYC. These oncogenes have been previously shown to be crucial for disease establishment, growth and progression. We found that EZH2 inhibition reactivated the expression of microRNAs genes previously found to be underexpressed in MM and which possess potential tumor suppressor functions. Among the reactivated microRNAs we identified miR-125a-3p and miR-320c as predicted negative regulators of the MM-associated oncogenes. Notably, we defined miR-125a-3p and miR-320c as targets of EZH2 and H3K27me3 in MM cell lines and patients samples. These findings described for the first time PRC2/EZH2/H3K27me3 as regulators of microRNA with tumor suppressor functions in MM. This further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.In paper III we evaluated the therapeutic potential of targeting PRC1 in MM using the recently developed chemical PTC-209; an inhibitor targeting the BMI-1 subunit of PRC1. Using MM cell lines and primary cells isolated from newly diagnosed or relapsed MM patients, we found that PTC-209 has a potent anti-MM activity. We showed, for the first time in MM, that PTC-209 anti-MM effects were mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, but that other subunits of the PRC1 complex were not affected. We showed that PTC-209 reduced MM cell viability via significant induction of apoptosis. More importantly, we demonstrated that PTC-209 shows synergistic anti-MM activity with other epigenetic inhibitors targeting EZH2 (UNC1999) and BET-bromodomains (JQ1). This work highlights the potential use of BMI-1 and PRC1 as potential therapeutic targets in MM alone or in combination with other anti-MM agents including epigenetic inhibitors.
10.	Alzrigat, Mohammad, et al. (författare) The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain 2017 Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:61, s. 103731-103743 Tidskriftsartikel (refereegranskat)abstract Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.
11.	Andersson, Ann-Catrin, et al. (författare) ERV3 in relation to cell differentiation in normal and neoplastic monocytes Annan publikation (övrigt vetenskapligt/konstnärligt)
12.	Arvidsson, Anna K, et al. (författare) Klimatanpassning av vägkonstruktion, drift och underhåll 2012 Rapport (övrigt vetenskapligt/konstnärligt)abstract Klimatförändringarna är en realitet och påverkar vårt samhälle och därigenom även våra transporter. Genom att klimatanpassa transportsystemen blir systemen mer robusta och risken för transportstörningar blir mindre. För vägars konstruktion, drift och underhåll innebär klimatanpassningen i de flesta fall relativt stora förändringar men det saknas idag en övergripande bild av det totala klimatanpassningsbehovet nationellt sett samt vilka åtgärder som behöver tas och som är rimliga att tas. Eftersom klimatförändringarna generellt varierar mellan Sveriges klimatzoner är det förenat med stora svårigheter att förutsäga vilken påverkan klimatförändringarna får på vägarnas beteende och livslängd. Inom vinterväghållningen i Sverige kommer saltanvändandet totalt sett att minska på grund av det varmare klimatet. Plogningstillfällena kommer antagligen minska, men beredskapen bör inte minskas för mycket eftersom de mer extrema tillfällena kommer att öka. För att lyckas klimatanpassa vägtransportsystemen så att de blir robusta konstaterar vi att det finns ett stort behov för att ta fram mer kunskap om vägkonstruktionens påverkan av ett förändrat klimat, samt inom drift och underhåll hur man skall anpassa sig genom olika typer av varierande och flexibla klimatanpassningsåtgärder och till effekterna av extrema väderhändelser.
13.	Atienza Párraga, Alba, et al. (författare) Dual DNMT/EZH2 inhibition synergistically re-configures the epigenome and promotes anti-tumour effects in multiple myeloma Annan publikation (övrigt vetenskapligt/konstnärligt)
14.	Atienza-Párraga, Alba, et al. (författare) Epigenomic re-configuration of primary multiple myeloma underlies the synergistic effect of combined DNMT and EZH2 inhibition. Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Multiple myeloma (MM) is characterized by an overexpression of EZH2 and a subsequent increase in H3K27me3-mediated silencing. However, the genome-wide redistribution of this mark in context with other epigenetic tags remains largely unexplored. Here, we show that EZH2 physically interacts with DNMT1 and that combined inhibition leads to a reduced G2/M arrest and increased apoptosis in MM. In addition, we present a catalogue of the genomic regulatory regions in normal plasma cells (NPC) as defined by their individual combination of histone marks. We used ChIP-seq and ATAC-seq data to generate whole-genome NPC chromatin annotations which we further analysed using DNA methylation arrays and RNA-seq. Comparison between NPC and MM demonstrated that, despite the global hypomethylation, enhancers show a tendency towards a higher DNA methylation levels in MM, whereas Polycomb and heterochromatic sites, highly methylated in NPC, show intermediate levels of the mark. Across all examined regulatory regions, 5-azacytidine treatment strongly reduced DNA methylation in MM. Furthermore, we find an extensive re-structuration of the global histone patterns in MM. We noticed a widespread increase in H3K27me3 except at active TSSs/promoters and enhancers, where we found a selective gain of the mark, suggestive of a directed silencing. In contrast, poised TSSs lose H3K27me3 and gain the activation mark H3K27ac, reflecting potential activation. Taken together, we present a comprehensive map of the epigenomic changes in MM as compared to NPC and provide insights into the interplay between EZH2 and DNMT1 in MM.
15.	Bahram, Fuad, et al. (författare) Posttranslational regulation of Myc function in response to phorbol ester/interferon-gamma-induced differentiation of v-Myc-transformed U-937 monoblasts 1999 Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 93:11, s. 3900-3912 Tidskriftsartikel (refereegranskat)abstract The transcription factors of the Myc/Max/Mad network are important regulators of cell growth, differentiation, and apoptosis and are frequently involved in tumor development. Constitutive expression of v-Myc blocks phorbol ester (TPA)-induced differentiation of human U-937 monoblasts. However, costimulation with interferon-gamma (IFN-gamma) and TPA restores terminal differentiation and G1 cell-cycle arrest despite continuous expression of v-Myc. The mechanism by which TPA + IFN-gamma counteract v-Myc activity has not been unravelled. Our results show that TPA + IFN-gamma treatment led to an inhibition of v-Myc- and c-Myc-dependent transcription, and a specific reduction of v-Myc:Max complexes and associated DNA-binding activity, whereas the steady state level of the v-Myc protein was only marginally affected. In contrast, TPA + IFN-gamma costimulation neither increased the expression of Mad1 or other mad/mnt family genes nor altered heterodimerization or DNA-binding activity of Mad1. The reduced amount of v-Myc:Max heterodimers in response to treatment was accompanied by partial dephosphorylation of v-Myc and c-Myc. Phosphatase treatment of Myc:Max complexes lead to their dissociation, thus mimicking the effect of TPA + IFN-gamma. In addition to modulation of the expression of Myc/Max/Mad network proteins, posttranslational negative regulation of Myc by external signals may, therefore, be an alternative biologically important level of control with potential therapeutic relevance for hematopoietic and other tumors with deregulated Myc expression.
16.	Botling, Johan, et al. (författare) CD49f (alpha 6 integrin) and CD66a (BGP) are specifically induced by retinoids during human monocytic differentiation 1995 Ingår i: Leukemia. - 0887-6924 .- 1476-5551. ; 9:12, s. 2034-41 Tidskriftsartikel (refereegranskat)abstract Retinoic acid (RA) and 1,25(OH)2-cholecalciferol (VitD3) are potent regulators of normal and malignant myeloid cells. In the human monoblast cell line U-937 they induce terminal differentiation, and the resulting phenotypes display both common and distinct, inducer-specific, properties. This paper shows that in U-937 cells the two retinoids, all-trans and 9-cis RA, induced the expression of CD49f (alpha 6 integrin subunit) and CD66a (biliary glycoprotein, BGP) mRNA and protein. In contrast, expression of CD49f and CD66a was not found in untreated or VitD3-induced cells. Cytokine-induced modulation of CD49f and CD66a expression was restricted to the retinoid-induced U-937 cells. The retinoid specific induction of CD49f and CD66a was confirmed in the related monoblastic cell line THP-1. Human blood monocytes and the monocytic cell line Mono Mac 6 responded poorly to RA, with respect to the regulation of CD49f and CD66a expression, indicating that early monocytic precursors were targets for the retinoid-specific regulation. Thus, the expression of CD49f and CD66a is developmentally regulated and specifically induced by all-trans and 9-cis Ra in human monocytic cells.
17.	Botling, Johan, et al. (författare) Retinoic acid receptor/retinoid X receptor heterodimers can be activated through both subunits providing a basis for synergistic transactivation and cellular differentiation 1997 Ingår i: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258 .- 1083-351X. ; 272:14, s. 9443-9 Tidskriftsartikel (refereegranskat)abstract The receptor for 9-cis-retinoic acid, retinoid X receptor (RXR), forms heterodimers with several nuclear receptors, including the receptor for all-trans-retinoic acid, RAR. Previous studies have shown that retinoic acid receptor can be activated in RAR/RXR heterodimers, whereas RXR is believed to be a silent co-factor. In this report we show that efficient growth arrest and differentiation of the human monocytic cell line U-937 require activation of both RAR and RXR. Also, we demonstrate that the allosteric inhibition of RXR is not obligatory and that RXR can be activated in the RAR/RXR heterodimer in the presence of RAR ligands. Remarkably, RXR inhibition by RAR can also be relieved by an RAR antagonist. Moreover, the dose response of RXR agonists differ between RXR homodimers and RAR/RXR heterodimers, indicating that these complexes are pharmacologically distinct. Finally, the AF2 activation domain of both subunits contribute to activation even if only one of the receptors is associated with ligand. Our data emphasize the importance of signaling through both subunits of a heterodimer in the physiological response to retinoids and show that the activity of RXR is dependent on both the identity and the ligand binding state of its partner.
18.	Botling, Johan, et al. (författare) Vitamin D3 and retinoic acid induced monocytic differentiation : Interactions between the endogenous vitamin D3, retinoic acid and retinoid X receptors in U-937 cells 1996 Ingår i: Cell growth & differentiation. - 1044-9523. ; 7:9, s. 1239-49 Tidskriftsartikel (refereegranskat)abstract Retinoic acid (RA) and 1,25 alpha-dihydroxycholecalciferol (VitD3) are potent regulators of hematopoletic differentiation. Yet, little is known as to how the RA and VitD3 receptor network operates in hematopoietic cells, and whether receptor interactions can explain the interplay between the RA- and VitD3-signaling pathways during differentiation. Therefore, we analyzed the expression, DNA binding, and transcriptional activity of the endogenous RA and VitD3 receptors [retinoic acid receptors (RARs), retinoid X receptors (RXRs), and VitD3 receptor (VDR)] in the U-937 cell line, in which RA and VitD3 induce distinct monocytic differentiation pathways. VitD3 induction resulted in the formation of VDR/RXR DNA-binding complexes on both VitD3 response elements and RA response elements (RAREs). However, transcriptional activation was only observed from a VitD3 response element-driven reporter construct. Several DNA-binding complexes were detected on RAREs in undifferentiated cells. Stimulation by RA resulted in increased RAR beta/RXR DNA binding, activated RARE-dependent transcription, and increased expression of RAR-beta. Concomitant stimulation by VitD3 inhibited the RA-stimulated formation of RAR beta/RXR heterodimers, favoring VDR/RXR binding to the RARE. Also, VitD3 inhibited the expression of CD23 and CD49f, characteristic markers of retinoid-induced U-937 cell differentiation. In contrast, neither the RA-stimulated, RARE-mediated transcription nor the induced RAR-beta expression was suppressed by VitD3, suggesting that VitD3 selectively inhibited the retinoid-induced differentiation program but not the RARE-mediated signal. These results demonstrate a complex role for VitD3 in modifying the retinoid differentiation pathway and may have implications for differentiation-inducing therapy of hematopoietic tumors.
19.	Carlborg, Carl Fredrik, 1981-, et al. (författare) BEYOND PDMS: : OFF-STOCHIOMETRY THIOL-ENE BASED SOFT LITHOGRAPHY FOR RAPID PROTOTYPING OF MICROFLUIDIC DEVICES 2010 Ingår i: 14th International Conference on Miniaturized Systems for Chemistry and Life Sciences (micro TAS 2010). - 9781618390622 ; , s. 70-72 Konferensbidrag (refereegranskat)abstract We present an easy to use, rapid fabrication platform for microfluidic systems, based on micro-molding of novel thiolene based polymer formulations. The novel fabrication platform addresses major drawbacks of PDMS by allowing large freedom in material and surface properties, including: (photo)patterning of stable surface modifications, bonding without plasma treatment, rapid UV or thermal curing, variable E-modulus, minimized leaching of uncured components [1] and suppressed non-specific binding of biomolecules [2]. This process is potentially suited for both rapid prototyping in the laboratory and medium-scale commercial production, bridging the “development gap”.
20.	Carlborg, Carl Fredrik, et al. (författare) Beyond PDMS: off-stoichiometry thiol–ene (OSTE) based soft lithography for rapid prototyping of microfluidic devices 2011 Ingår i: Lab on a Chip. - : RSC Publishing. - 1473-0197 .- 1473-0189. ; 11:18, s. 3136-3147 Tidskriftsartikel (refereegranskat)abstract In this article we introduce a novel polymer platform based on off-stoichiometry thiol–enes (OSTEs), aiming to bridge the gap between research prototyping and commercial production of microfluidic devices. The polymers are based on the versatile UV-curable thiol–ene chemistry but takes advantage of off-stoichiometry ratios to enable important features for a prototyping system, such as one-step surface modifications, tuneable mechanical properties and leakage free sealing through direct UV-bonding. The platform exhibits many similarities with PDMS, such as rapid prototyping and uncomplicated processing but can at the same time mirror the mechanical and chemical properties of both PDMS as well as commercial grade thermoplastics. The OSTE-prepolymer can be cast using standard SU-8 on silicon masters and a table-top UV-lamp, the surface modifications are precisely grafted using a stencil mask and the bonding requires only a single UV-exposure. To illustrate the potential of the material we demonstrate key concepts important in microfluidic chip fabrication such as patterned surface modifications for hydrophobic stops, pneumatic valves using UV-lamination of stiff and rubbery materials as well as micromachining of chip-to-world connectors in the OSTE-materials.
21.	Chivasso, Clara, et al. (författare) Unraveling human aqp5-pip molecular interaction and effect on aqp5 salivary glands localization in ss patients 2021 Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:8 Tidskriftsartikel (refereegranskat)abstract Saliva secretion requires effective translocation of aquaporin 5 (AQP5) water channel to the salivary glands (SGs) acinar apical membrane. Patients with Sjögren’s syndrome (SS) display abnormal AQP5 localization within acinar cells from SGs that correlate with sicca manifestation and glands hypofunction. Several proteins such as Prolactin-inducible protein (PIP) may regulate AQP5 trafficking as observed in lacrimal glands from mice. However, the role of the AQP5-PIP complex remains poorly understood. In the present study, we show that PIP interacts with AQP5 in vitro and in mice as well as in human SGs and that PIP misexpression correlates with an altered AQP5 distribution at the acinar apical membrane in PIP knockout mice and SS hMSG. Furthermore, our data show that the protein-protein interaction involves the AQP5 C-terminus and the N-terminal of PIP (one molecule of PIP per AQP5 tetramer). In conclusion, our findings highlight for the first time the role of PIP as a protein controlling AQP5 localization in human salivary glands but extend beyond due to the PIP-AQP5 interaction described in lung and breast cancers.
22.	Dimberg, Anna, et al. (författare) Inhibition of monocytic differentiation by phosphorylation-deficient Stat1 is associated with impaired expression of Stat2, ICSBP/IRF8 and C/EBP epsilon 2006 Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 64:3, s. 271-279 Tidskriftsartikel (refereegranskat)abstract Monocytic differentiation is coordinated through the ordered activation of multiple signalling pathways, controlling transcription of specific subsets of genes that regulate the development of the mature phenotype. To identify key transcription factors involved in this process, we used the human monoblastic U-937 cell line as a model of monocytic differentiation. U-937 cells can be differentiated by treatment with all-trans retinoic acid (ATRA) and 1,25 alpha-dihydroxycholecalciferol (VitD3), resulting in G(0)/G(1)-arrested cells expressing monocytic surface markers. We have previously shown that ATRA-induced differentiation and cell cycle arrest specifically requires Stat1 activation, through phosphorylation of tyrosine 701 and serine 727. In this report, we used U-937 cells expressing phosphorylation-deficient mutants of Stat1 (Stat1Y701F and Stat1S727A) to determine myeloid-specific transcription factors that are activated downstream of Stat1 during induced monocytic differentiation. We demonstrate that ATRA-induced upregulation of Stat2, ICSBP/IRF8 and C/EBP epsilon, key transcription factors linked to myelomonocytic differentiation, is selectively impaired in cells expressing mutant Stat1. In contrast, ATRA-induced expression of PU.1, C/EBP alpha, C/EBP beta and IRF-1 was unaffected. Taken together, our data suggest that ATRA-induced regulation of Stat2, ICSBP and C/EBP epsilon is dependent on active Stat1, and that a failure to correctly regulate these transcription factors is associated with the inhibition of monocytic differentiation.
23.	Dimberg, Anna, et al. (författare) Inhibition of retinoic acid-induced differentiation of human monoblastic U-937 cells by phosphorylation deficient Stat1 is associated with impaired expression of Stat2, ICSBP and C/EBP-ε Annan publikation (övrigt vetenskapligt/konstnärligt)
24.	Dimberg, Anna, et al. (författare) Retinoic acid-induced cell cycle arrest of human myeloid cell lines is associated with sequential down-regulation of c-Myc and cyclin E and post-transcriptional upregulation of p27Kip1 2002 Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 99:6, s. 2199-2206 Tidskriftsartikel (refereegranskat)abstract All-trans retinoic acid (ATRA) is a potential therapeutic agent for the treatment of hematopoietic malignancies, because of its function as an inducer of terminal differentiation of leukemic blasts. Although the efficacy of ATRA as an anticancer drug has been demonstrated by the successful treatment of acute promyelocytic leukemia (APL), the molecular mechanisms of ATRA-induced cell cycle arrest of myeloid cells have not been fully investigated. In this study, we show that the onset of ATRA-induced G0/G1 arrest of human monoblastic U-937 cells is linked to a sharp down-regulation of c-Myc and cyclin E levels and an increase in p21WAF1/CIP1 expression. This is followed by an increase in p27Kip1 protein expression due to enhanced protein stability. The importance of an early decrease in Myc expression for these events was demonstrated by the failure of a U-937 subline with constitutive exogenous expression of v-Myc to cell cycle arrest and regulate cyclin E and p27Kip1 in response to ATRA. Preceding the initiation of G1 arrest, a transient rise in retinoblastoma protein (pRb), p107, and cyclin A levels was detected. Later, a rapid fall in the levels of cyclins A and B and a coordinate dephosphorylation of pRb at Ser780, Ser795, and Ser807/811 coincided with the accumulation of cells in G1. These results thus identify a decrease in c-Myc and cyclin E levels and a posttranscriptional up-regulation of p27Kip1 as important early changes, and position them in the complex chain of events regulating ATRA-induced cell cycle arrest of myeloid cells.
25.	Dimberg, Anna, et al. (författare) Serine-727 phosphorylated Stat1 is required for ATRA-induced G0/G1 arrest and the associated regulation of cyclins and p27Kip1 Tidskriftsartikel (refereegranskat)
26.	Dimberg, Lina, et al. (författare) Ectopic and IFN-induced expression of Fas overcomes resistance to Fas-mediated apoptosis in multiple myeloma cells. 2005 Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. Tidskriftsartikel (refereegranskat)abstract Multiple myeloma (MM) is an as yet incurable B cell malignancy. Increased survival in vitro is a hallmark of MM cells, implying that a therapeutic potential may lie in circumventing anti-apoptotic signals. We have previously reported that interferons (IFNs) sensitize MM cells to Fas/CD95-mediated apoptosis (1). In the present study, we explore the mechanism underlying this effect. In a wide screening of apoptosis-related genes, Apo2L/TRAIL and Fas were identified as IFN-targets. Sensitization to Fas-mediated apoptosis by IFNs was not affected by blocking Apo2L/TRAIL, suggesting that Apo2L/TRAIL is not a key mediator in this process. In contrast, we found that an elevated Fas expression was functionally linked to increased susceptibility to Fas-mediated apoptosis. This was further supported by the finding that IFN-treatment enhanced Fas-mediated caspase-8 activation, one of the earliest signaling events down-stream receptor activation. In addition, IFN treatment attenuated the IL-6 dependent activation of Stat3, interfering with a known survival-pathway in MM that has previously been linked with resistance to Fas-mediated apoptosis. Taken together, our results show that IFN-induced up-regulation of Fas sensitizes MM cells to Fas-mediated apoptosis and suggest that attenuation of Stat3 activation may be a potentially important event in this process.
27.	Dimberg, Lina Y, et al. (författare) Ectopic and IFN-induced expression of Fas overcomes resistance to Fas-mediated apoptosis in multiple myeloma cells 2005 Ingår i: Blood. - 1528-0020. ; 106:4, s. 1346-1354 Tidskriftsartikel (refereegranskat)
28.	Dimberg, Lina Y., et al. (författare) Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma 2012 Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 12, s. 318- Tidskriftsartikel (refereegranskat)abstract Background: Multiple myeloma (MM) is at present an incurable malignancy, characterized by apoptosis-resistant tumor cells. Interferon (IFN) treatment sensitizes MM cells to Fas-induced apoptosis and is associated with an increased activation of Signal transducer and activator of transcription (Stat)1. The role of Stat1 in MM has not been elucidated, but Stat1 has in several studies been ascribed a pro-apoptotic role. Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM. Methods: To delineate the role of Stat1 in IFN mediated sensitization to apoptosis, sub-lines of the U-266-1970 MM cell line with a stable expression of the active mutant Stat1C were utilized. The influence of Stat1C constitutive transcriptional activation on endogenous Stat3 expression and activation, and the expression of apoptosis-related genes were analyzed. To determine whether Stat1 alone would be an important determinant in sensitizing MM cells to apoptosis, the U-266-1970-Stat1C cell line and control cells were exposed to high throughput compound screening (HTS). Results: To explore the role of Stat1 in IFN mediated apoptosis sensitization of MM, we established sublines of the MM cell line U-266-1970 constitutively expressing the active mutant Stat1C. We found that constitutive nuclear localization and transcriptional activity of Stat1 was associated with an attenuation of IL-6-induced Stat3 activation and up-regulation of mRNA for the pro-apoptotic Bcl-2 protein family genes Harakiri, the short form of Mcl-1 and Noxa. However, Stat1 activation alone was not sufficient to sensitize cells to Fas-induced apoptosis. In a screening of > 3000 compounds including bortezomib, dexamethasone, etoposide, suberoylanilide hydroxamic acid (SAHA), geldanamycin (17-AAG), doxorubicin and thalidomide, we found that the drug response and IC50 in cells constitutively expressing active Stat1 was mainly unaltered. Conclusion: We conclude that Stat1 alters IL-6 induced Stat3 activity and the expression of pro-apoptotic genes. However, this shift alone is not sufficient to alter apoptosis sensitivity in MM cells, suggesting that Stat1 independent pathways are operative in IFN mediated apoptosis sensitization.
29.	Dimberg, Lina Y, et al. (författare) The effect of Stat1 over-expression on the apoptosis-related gene profile and drug sensitivity of multiple myeloma cells Annan publikation (övrigt vetenskapligt/konstnärligt)
30.	Enlund, Fredrik, 1968, et al. (författare) Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors. 2004 Ingår i: Experimental cell research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 292:1, s. 21-8 Tidskriftsartikel (refereegranskat)abstract Chromosome translocations in neoplasia commonly result in fusion genes that may encode either novel fusion proteins or normal, but ectopically expressed proteins. Here we report the cloning of a novel fusion gene in a common type of salivary and bronchial gland tumor, mucoepidermoid carcinomas (MEC), as well as in benign Warthin's tumors (WATs). The fusion, which results from a t(11;19)(q21-22;p13) translocation, creates a chimeric gene in which exon 1 of a novel gene of unknown function, designated WAMTP1, is linked to exons 2-5 of the recently identified Mastermind-like Notch coactivator MAML2. In the fusion protein, the N-terminal basic domain of MAML2, which is required for binding to intracellular Notch (Notch ICD), is replaced by an unrelated N-terminal sequence from WAMTP1. Mutation analysis of the N-terminus of WAMTP1-MAML2 identified two regions of importance for nuclear localization (amino acids 11-20) and for colocalization with MAML2 and Notch1 ICD in nuclear granules (amino acids 21-42). Analyses of the Notch target genes HES5 and MASH1 in MEC tumors with and without the WAMTP1-MAML2 fusion revealed upregulation of HES5 and downregulation of MASH1 in fusion positive MECs compared to normal salivary gland tissue and MECs lacking the fusion. These findings suggest that altered Notch signaling plays an important role in the genesis of benign and malignant neoplasms of salivary and bronchial gland origin.
31.	Enthoven, Paul, 1955-, et al. (författare) Patients experiences of the BetterBack model of care for low back pain in primary care : a qualitative interview study 2021 Ingår i: International Journal of Qualitative Studies on Health and Well-being. - : Taylor & Francis. - 1748-2623 .- 1748-2631. ; 16:1 Tidskriftsartikel (refereegranskat)abstract Purpose: The aim of this study was to describe patient experiences of received primary care for low back pain (LBP) according to the BetterBack Model of Care (MoC) with a focus on illness beliefs and self-management enablement. Methods: Individual interviews were conducted with 15 adults 4-14 months after receiving treatment according to the BetterBack MoC for LBP in primary care in Sweden. Data were analysed using content analysis. Results: When analysing the data, the following theme emerged; "Participant understanding of their treatment for low back pain and self-management strategies-a matter of support systems", comprising the following categories: "Knowledge translation", "Interaction and dialogue", "The health care professional support" and "Form organization". Participants experienced that they had better knowledge about their LBP and received tools to better manage their health condition. The participants expressed good communication with the treating physiotherapist and provided suggestions to further improve the treatment of LBP. Conclusions: Participants experienced that they had gained new knowledge about their health problems and after the treatment they had the tools to handle their back problems. This suggests that the BetterBack MoC may be used as a basis for a support system to provide valuable tools for self-management for patients with low back pain.
32.	Ericsson, Per, et al. (författare) Toward 17µm pitch heterogeneously integrated Si/SiGe quantum well bolometer focal plane arrays 2011 Ingår i: Infrared Technology and Applications XXXVII. - : SPIE - International Society for Optical Engineering. ; , s. 801216-1-801216-9 Konferensbidrag (refereegranskat)abstract Most of today's commercial solutions for un-cooled IR imaging sensors are based on resistive bolometers using either Vanadium oxide (VOx) or amorphous Silicon (a-Si) as the thermistor material. Despite the long history for both concepts, market penetration outside high-end applications is still limited. By allowing actors in adjacent fields, such as those from the MEMS industry, to enter the market, this situation could change. This requires, however, that technologies fitting their tools and processes are developed. Heterogeneous integration of Si/SiGe quantum well bolometers on standard CMOS read out circuits is one approach that could easily be adopted by the MEMS industry. Due to its mono crystalline nature, the Si/SiGe thermistor material has excellent noise properties that result in a state-ofthe- art signal-to-noise ratio. The material is also stable at temperatures well above 450°C which offers great flexibility for both sensor integration and novel vacuum packaging concepts. We have previously reported on heterogeneous integration of Si/SiGe quantum well bolometers with pitches of 40μm x 40μm and 25μm x 25μm. The technology scales well to smaller pixel pitches and in this paper, we will report on our work on developing heterogeneous integration for Si/SiGe QW bolometers with a pixel pitch of 17μm x 17μm.
33.	Eriksson, Anna, 1977-, et al. (författare) AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and a dose dependent reduction of kinase activity in acute myeloid leukemia 2014 Ingår i: Biochemical Pharmacology. - : Elsevier. - 0006-2952 .- 1356-1839. ; 87:2, s. 284-291 Tidskriftsartikel (refereegranskat)abstract AKN-028 is a novel tyrosine kinase inhibitor with preclinical activity in acute myeloid leukemia (AML), presently undergoing investigation in a phase I/II study. It is a potent inhibitor of the FMS-like kinase 3 (FLT3) but shows in vitro activity in a wide range of AML samples. In the present study, we have characterized the effects of AKN-028 on AML cells in more detail. AKN-028 induced a dose-dependent G(0)/arrest in AML cell line MV4-11. Treatment with AKN-028 caused significantly altered gene expression in all AML cell types tested (430 downregulated, 280 upregulated transcripts). Subsequent gene set enrichment analysis revealed enrichment of genes associated with the proto-oncogene and cell cycle regulator c-Myc among the downregulated genes in both AKN-028 and midostaurin treated cells. Kinase activity profiling in AML cell lines and primary AML samples showed that tyrosine kinase activity, but not serine/threonine kinase activity, was inhibited by AKN-028 in a dose dependent manner in all samples tested, reaching approximately the same level of kinase activity. Cells sensitive to AKN-028 showed a higher overall tyrosine kinase activity than more resistant ones, whereas serine/threonine kinase activity was similar for all primary AML samples. In summary, AKN-028 induces cell cycle arrest in AML cells, downregulates Myc-associated genes and affect several signaling pathways. AML cells with high global tyrosine kinase activity seem to be more sensitive to the cytotoxic effect of AKN-028 in vitro.
34.	Frick, Anna, 1982, et al. (författare) X-ray structure of human aquaporin 2 and its implications for nephrogenic diabetes insipidus and trafficking. 2014 Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 111:17, s. 6305-10 Tidskriftsartikel (refereegranskat)abstract Human aquaporin 2 (AQP2) is a water channel found in the kidney collecting duct, where it plays a key role in concentrating urine. Water reabsorption is regulated by AQP2 trafficking between intracellular storage vesicles and the apical membrane. This process is tightly controlled by the pituitary hormone arginine vasopressin and defective trafficking results in nephrogenic diabetes insipidus (NDI). Here we present the X-ray structure of human AQP2 at 2.75 Å resolution. The C terminus of AQP2 displays multiple conformations with the C-terminal α-helix of one protomer interacting with the cytoplasmic surface of a symmetry-related AQP2 molecule, suggesting potential protein-protein interactions involved in cellular sorting of AQP2. Two Cd(2+)-ion binding sites are observed within the AQP2 tetramer, inducing a rearrangement of loop D, which facilitates this interaction. The locations of several NDI-causing mutations can be observed in the AQP2 structure, primarily situated within transmembrane domains and the majority of which cause misfolding and ER retention. These observations provide a framework for understanding why mutations in AQP2 cause NDI as well as structural insights into AQP2 interactions that may govern its trafficking.
35.	Fryknäs, Mårten, et al. (författare) STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines 2007 Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 120:1, s. 189-195 Tidskriftsartikel (refereegranskat)abstract The myeloma cell line RPMI 8226/S and its doxorubicin resistant subline 8226/Dox40 were used as models to explore the potential importance of the STAT1 signaling pathway in drug and radiation resistance. The 40-fold doxorubicin resistant subline 8226/Dox40 was found to be crossresistant to single doses of 4 and 8 Gy of radiation. A genome-wide mRNA expression study comparing the 8226/Dox40 cell line to its parental line was performed to identify the underlying molecular mechanisms. Seventeen of the top 50 overexpressed genes have previously been implicated in the STAT1 signaling pathway. STAT1 was over expressed both at the mRNA and protein level. Moreover, analyses of nuclear extracts showed higher abundance of phosphorylated STAT1 (Tyr 701) in the resistant subline. Preexposure of the crossresistant cells to the STAT1 inhibiting drug fludarabine reduced expression of overexpressed genes and enhanced the effects of both doxorubicin and radiation. These results show that resistance to doxorubicin and radiation is associated with increased STAT1 signaling and can be modulated by fludarabine. The data support further development of therapies combining fludarabine and radiation.
36.	Giandomenico, Valeria, et al. (författare) Improving the Diagnosis and Management of Neuroendocrine Tumors : Utilizing New Advances in Biomarker and Molecular Imaging Science 2013 Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 98:1, s. 16-30 Tidskriftsartikel (refereegranskat)abstract Neuroendocrine tumors (NET) are malignant solid tumors that arise in hormone-secreting tissue of the diffuse neuroendocrine system or endocrine glands. Although traditionally understood to be a rare disease, the incidence and prevalence of NET have increased greatly in the past 3 decades. However, during this time, progress in diagnosis and outcome of NET has generally been modest. In order to achieve improved outcome in NET, a better understanding of NET biology combined with more reliable serum markers and better techniques to identify tumor localization and small lesions are needed. Although some NET biomarkers exist, sensitive and specific markers that predict tumor growth and behavior are generally lacking. In addition, the integration of new molecular imaging technologies in patient diagnosis and follow-up has the potential to enhance care. To discuss developments and issues required to improve diagnostics and management of NET patients, with specific focus on the latest advances in molecular imaging and biomarker science, 17 global leaders in the fields of NET, molecular imaging and biomarker technology gathered to participate in a 2-day meeting hosted by Prof. Kjell Oberg at the University of Uppsala in Sweden. During this time, findings were presented regarding methods with potential prognostic and treatment applications in NET or other types of cancers. This paper describes the symposium presentations and resulting discussions.
37.	Hassan, Osama, 1969-, et al. (författare) Cross-laminated timber flooring and concrete slab flooring : A comparativestudy of structural design, economic and environmental consequences 2019 Ingår i: Journal of Building Engineering. - : Elsevier. - 2352-7102. ; 26, s. 1-16 Forskningsöversikt (refereegranskat)abstract This paper compares cross-laminated timber (CLT) flooring and concrete slab flooring with respect to structural design, cost analysis, and greenhouse gas emissions. The effect of floor span on design values, costs, and carbondioxide emissions is analysed in terms of structural design, economy, and environmental impact. Different crosssections are chosen for this purpose. The study shows that CLT flooring has significantly lower emissions ofclimate-impact greenhouse gases, and its ability to store carbon is significantly greater than the capacity of concrete storage. From an economic point of view, the CLT material is more expensive than concrete. However, the estimated “ready-to-assemble” cost of both floor types is quite similar. The study shows that CLT flooring can compete with a concrete slab floor when it comes to a span as wide as 7m without violating the structural requirements. However, with an increase in span, it is more difficult to meet the requirements for vibration for aCLT floor than for a concrete slab. At shorter spans, the moment capacity is often a decisive factor for concrete slabs while deformation is the decisive factor for a CLT floor. For larger spans, resonance frequency and deformation are crucial for the CLT floor, while the long-term deformation of the concrete is the decisive factor in structural design.
38.	Hedfalk, Kristina, 1969, et al. (författare) Recombinant production of the human aquaporins in the yeast Pichia pastoris (Invited Review). 2013 Ingår i: Molecular membrane biology. - : Informa UK Limited. - 0968-7688 .- 1464-5203. ; 30:1, s. 15-31 Tidskriftsartikel (refereegranskat)abstract Abstract Aquaporins are water facilitating proteins embedded in the cellular membranes. Such channels have been identified in almost every living organism - including humans. These proteins are vital molecules and their malfunction can lead to several severe disorders and diseases. Hence, an increased understanding of their structure, function and regulation is of the utmost importance for developing current and future drugs. Heading towards this goal, the first problem to overcome is to acquire the proteins in sufficient amounts to enable functional and structural characterization. Using a suitable host organism, large amounts of target molecules can possibly be produced, but for membrane proteins limitations are frequently encountered. In the work described here, we have produced the 13 human aquaporins (hAQPs) in one of the most successful hosts for recombinant overproduction of eukaryotic proteins; the yeast Pichia pastoris, in order to explore the underlying bottleneck to a successful membrane protein production experiment. Here we present exceptional yield of hAQP1, whereas some other hAQPs were below the threshold needed for scaled up production. In the overproduction process, we have established methods for efficient production screening as well as for accurate determination of the initial production yield. Furthermore, we have optimized the yield of low producing targets, enabling studies of proteins previously out of reach, exemplified with hAQP4 as well as the homologue PfAQP. Taken together, our results. present insight into factors directing high production of eukaryotic membrane proteins together with suggestions on ways to optimize the recombinant production in the yeast P. pastoris.
39.	Holmgren, Claes, et al. (författare) The direct bypass of the chromatin insulator function of the H19 imprinting control region in human cancer cells: A novel mechanism of loss of IGF2 imprinting. Annan publikation (övrigt vetenskapligt/konstnärligt)
40.	Itel, F., et al. (författare) CO2 permeability of cell membranes is regulated by membrane cholesterol and protein gas channels 2012 Ingår i: Faseb Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 26:12, s. 5182-5191 Tidskriftsartikel (refereegranskat)abstract Recent observations that some membrane proteins act as gas channels seem surprising in view of the classical concept that membranes generally are highly permeable to gases. Here, we study the gas permeability of membranes for the case of CO2, using a previously established mass spectrometric technique. We first show that biological membranes lacking protein gas channels but containing normal amounts of cholesterol (30-50 mol% of total lipid), e.g., MDCK and tsA201 cells, in fact possess an unexpectedly low CO2 permeability (PCO2) of similar to 0.01 cm/s, which is 2 orders of magnitude lower than the PCO2 of pure planar phospholipid bilayers (similar to 1 cm/s). Phospholipid vesicles enriched with similar amounts of cholesterol also exhibit PCO2 approximate to 0.01 cm/s, identifying cholesterol as the major determinant of membrane PCO2. This is confirmed by the demonstration that MDCK cells depleted of or enriched with membrane cholesterol show dramatic increases or decreases in PCO2, respectively. We demonstrate, furthermore, that reconstitution of human AQP-1 into cholesterol-containing vesicles, as well as expression of human AQP-1 in MDCK cells, leads to drastic increases in PCO2, indicating that gas channels are of high functional significance for gas transfer across membranes of low intrinsic gas permeability.-Itel, F., Al-Samir, S., Oberg, F., Chami, M., Kumar, M., Supuran, C. T., Deen, P. M. T., Meier, W., Hedfalk, K., Gros, G., Endeward, V. CO2 permeability of cell membranes is regulated by membrane cholesterol and protein gas channels. FASEB J. 26, 5182-5191 (2012). www.fasebj.org
41.	Johansson, Anders, et al. (författare) Spectroscopic Measurement of Cartilage Thickness in Arthroscopy: Ex Vivo Validation in Human Knee Condyles 2012 Ingår i: Arthroscopy. - : WB Saunders. - 0749-8063 .- 1526-3231. ; 28:10, s. 1513-1523 Tidskriftsartikel (refereegranskat)abstract Purpose: To evaluate the accuracy of articular cartilage thickness measurement when implementing a new technology based on spectroscopic measurement into an arthroscopic camera. Methods: Cartilage thickness was studied by ex vivo arthroscopy at a number of sites (N = 113) in human knee joint osteoarthritic femoral condyles and tibial plateaus, removed from 7 patients undergoing total knee replacement. The arthroscopic image spectral data at each site were used to estimate cartilage thickness. Arthroscopically derived thickness values were compared with reference cartilage thickness as measured by 3 different methods: needle penetration, spiral computed tomography scanning, and geometric measurement after sample slicing. Results: The lowest mean error (0.28 to 0.30 mm) in the regression between arthroscopic and reference cartilage thickness was seen for reference cartilage thickness less than 1.5 mm. Corresponding values for cartilage thickness less than 2.0 and 2.5 mm were 0.32 to 0.40 mm and 0.37 to 0.47 mm, respectively. Cartilage thickness images-created by pixel-by-pixel regression model calculations applied to the arthroscopic images-were derived to demonstrate the clinical use of a camera implementation. Conclusions: On the basis of this investigation on osteoarthritic material, when one is implementing the spectroscopic method for estimating cartilage thickness into an arthroscopic camera, errors in the range of 0.28 to 0.30 mm are expected. This implementation does not, however, influence the fact that the spectral method performs less well in the cartilage thickness region from 1.5 to 2.5 mm and cannot assess cartilage thicker than 2.5 mm. Clinical Relevance: Imaging cartilage thickness directly in the arthroscopic camera video stream could serve as an interesting image tool for in vivo cartilage quality assessment, in connection with cartilage diagnosis, repair, and follow-up.
42.	Johansson, M W, et al. (författare) Myeloperoxidase mediates cell adhesion via the alpha M beta 2 integrin (Mac-1, CD11b/CD18). 1997 Ingår i: J Cell Sci. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 110 ( Pt 9), s. 1133-9 Tidskriftsartikel (refereegranskat)
43.	Jäderling, Fredrik, et al. (författare) Accuracy in local staging of prostate cancer by adding a three-dimensional T2-weighted sequence with radial reconstructions in magnetic resonance imaging 2018 Ingår i: Acta Radiologica Open. - : Sage Publications. - 2058-4601. ; 7:2 Tidskriftsartikel (refereegranskat)abstract Background: The evidence supporting the use of magnetic resonance imaging (MRI) in prostate cancer detection has been established, but its accuracy in local staging is questioned. Purpose: To investigate the additional value of multi-planar radial reconstructions of a three-dimensional (3D) T2-weighted (T2W) MRI sequence, intercepting the prostate capsule perpendicularly, for improving local staging of prostate cancer. Material and Methods: Preoperative, bi-parametric prostate MRI examinations in 94 patients operated between June 2014 and January 2015 where retrospectively reviewed by two experienced abdominal radiologists. Each patient was presented in two separate sets including diffusion-weighted imaging, without and with the 3D T2W set that included radial reconstructions. Each set was read at least two months apart. Extraprostatic tumor extension (EPE) was assessed according to a 5-point grading scale. Sensitivity and specificity for EPE was calculated and presented as receiver operating characteristics (ROC) with area under the curve (AUC), using histology from whole-mount prostate specimen as gold standard. Inter-rater agreement was calculated for the two different reading modes using Cohen's kappa. Results: The AUC for detection of EPE for Readers 1 and 2 in the two-dimensional (2D) set was 0.70 and 0.68, respectively, and for the 2D+3D set 0.62 and 0.65, respectively. Inter-rater agreement (Reader 1 vs. Reader 2) on EPE using Cohen's kappa for the 2D and 2D+3D set, respectively, was 0.42 and 0.17 (i.e. moderate and poor agreement, respectively). Conclusion: The addition of 3D T2W MRI with radial reconstructions did not improve local staging in prostate cancer.
44.	Jäderling, Fredrik, et al. (författare) Preoperative staging using magnetic resonance imaging and risk of positive surgical margins after prostate-cancer surgery 2019 Ingår i: Prostate Cancer and Prostatic Diseases. - : Nature Publishing Group. - 1365-7852 .- 1476-5608. ; 22:3, s. 391-398 Tidskriftsartikel (refereegranskat)abstract Background: It is unclear whether preoperative staging using Magnetic Resonance Imaging (MRI) reduces the risk of positive margins in prostate cancer. We aimed to assess the effect on surgical margins and degree of nerve sparing of a pelvic MRI presented at a preoperative MRI conference. Methods: Single institution, observational cohort study including 1037 men that underwent robot assisted radical prostatectomy between October 2013 and June 2015. Of these, 557 underwent a preoperative MRI combined with a preoperative MRI conference and 410 did not. With whole-mount prostate specimen histopathology as gold standard we assessed the ability of MRI in finding the index tumor and the sensitivity and specificity for extra prostatic extension. We calculated relative risks for positive surgical margins and non-nerve sparing procedure, adjusting for preoperative risk factors using stabilized inverse-probability weighting. Results: MRI detected the index tumor in 80% of the cases. Non-organ confined disease (pT3) at histology was present in the MRI and the non-MRI group in 42% and 24%, respectively. Rate of positive surgical margins comparing the MRI and non-MRI groups was 26.7% and 33.7%, respectively, relative risk 0.79 [95% CI 0.65-0.96], weighted relative risk (wRR) 0.69 [95% CI 0.55-0.86]. The wRR of extensive positive surgical margins was 0.45 [95% CI 0.31-0.67]. Undergoing MRI was also associated with an increased risk of being operated with a non-nerve sparing technique (wRR, 1.84 [95% CI 1.11-3.03]). Conclusions: Our study suggests that preoperative prostate MRI in combination with a preoperative MRI conference affects the degree of nerve-sparing surgery and reduces positive surgical margins.
45.	Kalushkova, Antonia (författare) Epigenetic gene regulation in multiple myeloma and mood disorders 2013 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Epigenetics continues to be redefined and new discoveries are likely to revolutionise the field still further. This thesis explores different aspects of how epigenetic regulation of gene expression contributes to human disease.Paper I explores the function of the IKKα kinase in regulating gene expression through the nuclear retinoic acid receptor (RAR). We define a set of genes requiring IKKα for their expression and found recruitment of IKKα to the RAR dependent on structural motifs in its protein sequence. This interplay between the NFκB pathway and nuclear receptor regulated transcription is important to consider when designing therapeutic strategies.Papers II and III focus on the plasma cell malignancy multiple myeloma (MM) and define a gene regulatory circuit defining an underexpressed gene profile in MM dependent on the Polycomb proteins. We provide proof-of-principle that the use of small chemical inhibitors may be operational in reactivating genes silenced by H3K27me3 and that this leads to decreased tumour load and increased survival in the 5T33 in vivo model of MM. We explored the genome-wide distribution of H3K27me3 and H3K4me3, and defined their association with gene expression in freshly-isolated malignant plasma cells from MM patients. Importantly, H3K27me3-marked genes in MM associated with more aggressive stages of the disease and less favourable survival. We present evidence that gene targeting by H3K27me3 is likely to not only involve a small population of tumour cells, but rather represent a common MM profile and further provide a rationale for evaluating epigenetic therapeutics in MM.Paper IV shows that pro-inflammatory gene expression in monocytes of psychiatric patients can be induced in vitro by sodium pump inhibitors, as the steroid hormone ouabain. We suggest that the ouabain-induced gene expression is regulated by an intricate network involving microRNAs, Polycomb and the H3K27me3 demethylase JMJD3. Our data indicates that epigenetic regulators play a role in transmitting cues between intrinsic and/extrinsic stimuli and gene expression in psychiatric illness.This thesis provides novel insights on how seemingly unrelated pathways may converge on transcriptional regulation and evidence that epigenetic modifiers contribute to the pathogenesis of human complex diseases such as multiple myeloma and mood disorders.
46.	Kalushkova, Antonia, et al. (författare) IKKα contains two conserved LXXLL co-activator motifs and is recruited to the retinoic acid receptor Annan publikation (övrigt vetenskapligt/konstnärligt)
47.	Kalushkova, Antonia, et al. (författare) Polycomb target genes are silenced in multiple myeloma 2010 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:7, s. e11483- Tidskriftsartikel (refereegranskat)abstract Multiple myeloma (MM) is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG) proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP) assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep) and the histone deacetylase inhibitor LBH589 (Panobinostat), reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies.
48.	Kerzeli, Iliana K., et al. (författare) MALT1 inhibition suppresses antigen-specific T cell responses 2024 Ingår i: Cellular Immunology. - : Elsevier. - 0008-8749 .- 1090-2163. ; 397 Tidskriftsartikel (refereegranskat)abstract The aim of this study was to assess the potential use of a selective small molecule MALT1 inhibitor in solid tumor treatment as an immunotherapy targeting regulatory T-cells (Tregs). In vitro, MALT1 inhibition suppressed the proteolytic cleavage of the MALT1-substrate HOIL1 and blocked IL-2 secretion in Jurkat cells. It selectively suppressed the proliferation of PBMC-derived Tregs, with no effect on conventional CD4+ T-cells. In vivo, however, no evident anti-tumor effect was achieved by MALT1 inhibition monotherapy or in combination with anti-CTLA4 in the MB49 cancer model. Despite decreased Treg-frequencies in lymph nodes of tumor-bearing animals, intratumoral Treg depletion was not observed. We also showed that MALT1-inhibition caused a reduction of antigen-specific CD8+ T-cells in an adoptive T-cell transfer model. Thus, selective targeting of Tregs would be required to improve the immunotherapeutic effect of MALT1-inhibition. Also, various dosing schedules and combination therapy strategies should be carefully designed and evaluated further.
49.	Kerzeli, Iliana Kyriaki, et al. (författare) MALT1 inhibition suppresses T-cell dependent immune surveillance Annan publikation (övrigt vetenskapligt/konstnärligt)abstract MALT1 supports the development of natural regulatory T cells (Tregs), while protease-dead MALT1 (MALT1-PD) mice develop autoimmunity and an intrinsic capacity to reject syngeneic tumor transplantation. Herein, a small molecule inhibitor targeting MALT1 was developed and evaluated for potential use in Treg inhibition as part of a cancer immunotherapy strategy.In vitro, MALT1 inhibitor treatment inhibited the proteolytic cleavage of the MALT1 substrate HOIL1 in Jurkat cells and blocked IL-2 secretion by immune cells. Moreover, orally administrated MV088428 inhibited anti-CD3 induced IL-2 release in vivo. In vitro MALT1 inhibition selectively suppressed the proliferation of PBMC derived CD25+ FoxP3+ CD4+ T cells, while no direct effect was noted on the proliferation and viability of CD25- CD4+ T cells. In vivo, no evident anti-tumor effect as a monotherapy in the MB49 bladder cancer model was achieved and despite selective decrease of Treg frequencies in lymph nodes of tumor bearing animals, intratumoral Treg depletion was not observed. No synergistic anti-tumor effects were noted when MALT1 inhibitor was combined with anti-PD1 therapy, and concomitant treatment with MALT1 inhibitor abrogated the efficacy of anti-CTLA4 therapy. MALT1 inhibition had no impact on the frequencies of viable NK, lymphocyte and myeloid cells or on proliferation of conventional CD4 and CD8 T cells. However, there was a significant decrease of antigen-specific T cells in vivo upon adoptive T cell transfer and peptide vaccination. Thus, while MALT1 inhibition substantially reduced Treg populations in lymph nodes, but less so in tumors, off-target effects on antigen-experienced T cells along with the lack of impact on tumor Tregs likely abolish the compound’s efficacy. The off-target effect on antigen-experienced T cells could present implications for the use of MALT1 inhibitors for cancer indications where tumor control is likely to be mediated via T cell driven immune surveillance. Thus, dosing length and combination therapy strategies should be carefully designed and evaluated further.
50.	Kitchen, Philip, et al. (författare) Plasma Membrane Abundance of Human Aquaporin 5 Is Dynamically Regulated by Multiple Pathways. 2015 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 10:11 Tidskriftsartikel (refereegranskat)abstract Aquaporin membrane protein channels mediate cellular water flow. Human aquaporin 5 (AQP5) is highly expressed in the respiratory system and secretory glands where it facilitates the osmotically-driven generation of pulmonary secretions, saliva, sweat and tears. Dysfunctional trafficking of AQP5 has been implicated in several human disease states, including Sjögren's syndrome, bronchitis and cystic fibrosis. In order to investigate how the plasma membrane expression levels of AQP5 are regulated, we studied real-time translocation of GFP-tagged AQP5 in HEK293 cells. We show that AQP5 plasma membrane abundance in transfected HEK293 cells is rapidly and reversibly regulated by at least three independent mechanisms involving phosphorylation at Ser156, protein kinase A activity and extracellular tonicity. The crystal structure of a Ser156 phosphomimetic mutant indicates that its involvement in regulating AQP5 membrane abundance is not mediated by a conformational change of the carboxy-terminus. We suggest that together these pathways regulate cellular water flow.

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