495 results on '"Woetmann, Anders"'
Search Results
152. Deficient SOCS3 and SHP-1 Expression in Psoriatic T Cells
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Eriksen, Karsten W., primary, Woetmann, Anders, additional, Skov, Lone, additional, Krejsgaard, Thorbjørn, additional, Bovin, Lone F., additional, Hansen, Mikkel L., additional, Grønbæk, Kirsten, additional, Billestrup, Nils, additional, Nissen, Mogens H., additional, Geisler, Carsten, additional, Wasik, Mariusz A., additional, and Ødum, Niels, additional
- Published
- 2010
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153. γc-Signaling Cytokines Induce a Regulatory T Cell Phenotype in Malignant CD4+ T Lymphocytes
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Kasprzycka, Monika, primary, Zhang, Qian, additional, Witkiewicz, Agnieszka, additional, Marzec, Michal, additional, Potoczek, Magdalena, additional, Liu, Xiaobin, additional, Wang, Hong Yi, additional, Milone, Michael, additional, Basu, Samik, additional, Mauger, Joanne, additional, Choi, John K., additional, Abrams, J. Todd, additional, Hou, J. Steven, additional, Rook, Alain H., additional, Vonderheid, Eric, additional, Woetmann, Anders, additional, Odum, Niels, additional, and Wasik, Mariusz A., additional
- Published
- 2008
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154. EGFR induces expression of IRF-1viaSTAT1 and STAT3 activation leading to growth arrest of human cancer cells
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Andersen, Peter, primary, Pedersen, Mikkel Wandahl, additional, Woetmann, Anders, additional, Villingshøj, Mette, additional, Stockhausen, Marie-Thérése, additional, Ødum, Niels, additional, and Poulsen, Hans Skovgaard, additional
- Published
- 2007
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155. Midline 1 controls polarization and migration of murine cytotoxic T cells.
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Boding, Lasse, Hansen, Ann K., Nielsen, Morten M., Meroni, Germana, Braunstein, Thomas H., Woetmann, Anders, Ødum, Niels, Bonefeld, Charlotte M., and Geisler, Carsten
- Subjects
CYTOTOXIC T cells ,MICROTUBULES ,EMBRYOLOGY ,ALLERGIES ,EXOCYTOSIS ,UROPODA - Abstract
Midline 1 (MID1) is a microtubule-associated ubiquitin ligase that regulates protein phosphatase 2 A levels. Loss-of-function mutations in MID1 lead to the human X-linked Opitz G/BBB (OS) syndrome characterized by defective midline development during embryogenesis. We have recently shown that MID1 is strongly up-regulated in murine cytotoxic T lymphocytes (CTLs), and that it has a significant impact on exocytosis of lytic granules and the killing capacity of CTLs. The aims of the present study were to determine the localization of MID1 in migrating CTLs, and to investigate whether MID1 affects CTL polarization and migration. We found that MID1 mainly localizes to the uropod of migrating CTLs and that it has a substantial impact on CTL polarization and migration in vitro. Furthermore, analysis of contact hypersensitivity responses supported that MID1 controls effector functions of CTLs in hapten-challenged skin in vivo. These results provide significant new knowledge on the role of MID1 in CTL biology. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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156. Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins
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Woetmann, Anders, primary, Lovato, Paola, additional, Eriksen, Karsten W., additional, Krejsgaard, Thorbjørn, additional, Labuda, Tord, additional, Zhang, Qian, additional, Mathiesen, Anne-Merethe, additional, Geisler, Carsten, additional, Svejgaard, Arne, additional, Wasik, Mariusz A., additional, and Ødum, Niels, additional
- Published
- 2006
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157. STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes
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Zhang, Qian, primary, Wang, Hong Y., additional, Woetmann, Anders, additional, Raghunath, Puthiyaveettil N., additional, Odum, Niels, additional, and Wasik, Mariusz A., additional
- Published
- 2006
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158. Cancer Cells Become Susceptible to Natural Killer Cell Killing after Exposure to Histone Deacetylase Inhibitors Due to Glycogen Synthase Kinase-3–Dependent Expression of MHC Class I–Related Chain A and B
- Author
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Skov, Søren, primary, Pedersen, Marianne Terndrup, additional, Andresen, Lars, additional, Thor Straten, Per, additional, Woetmann, Anders, additional, and Ødum, Niels, additional
- Published
- 2005
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159. Bi-phasic Effect of Interferon (IFN)-α
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Eriksen, Karsten Wessel, primary, Sommer, Viveca Horst, additional, Woetmann, Anders, additional, Rasmussen, Anette Bødker, additional, Brender, Christine, additional, Svejgaard, Arne, additional, Skov, Søren, additional, Geisler, Carsten, additional, and Ødum, Niels, additional
- Published
- 2004
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160. Constitutive STAT3 Activation in Intestinal T Cells from Patients with Crohn's Disease
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Lovato, Paola, primary, Brender, Christine, additional, Agnholt, Jørgen, additional, Kelsen, Jens, additional, Kaltoft, Keld, additional, Svejgaard, Arne, additional, Eriksen, Karsten Wessel, additional, Woetmann, Anders, additional, and Ødum, Niels, additional
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- 2003
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161. Protein Phosphatase 2A (PP2A) Regulates Interleukin-4-mediated STAT6 Signaling
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Woetmann, Anders, primary, Brockdorff, Johannes, additional, Lovato, Paola, additional, Nielsen, Mette, additional, Leick, Vagn, additional, Rieneck, Klaus, additional, Svejgaard, Arne, additional, Geisler, Carsten, additional, and Ødum, Niels, additional
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- 2003
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162. Vitamin D Up-Regulates the Vitamin D Receptor by Protecting It from Proteasomal Degradation in Human CD4+ T Cells.
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Kongsbak, Martin, von Essen, Marina R., Boding, Lasse, Levring, Trine B., Schjerling, Peter, Lauritsen, Jens P. H., Woetmann, Anders, Ødum, Niels, Bonefeld, Charlotte M., and Geisler, Carsten
- Subjects
VITAMIN D ,MESSENGER RNA ,CD4 antigen ,T cells ,IMMUNOREGULATION ,PROTEIN expression - Abstract
The active form of vitamin D
3 , 1,25(OH)2 D3 , has significant immunomodulatory properties and is an important determinant in the differentiation of CD4+ effector T cells. The biological actions of 1,25(OH)2 D3 are mediated by the vitamin D receptor (VDR) and are believed to correlate with the VDR protein expression level in a given cell. The aim of this study was to determine if and how 1,25(OH)2 D3 by itself regulates VDR expression in human CD4+ T cells. We found that activated CD4+ T cells have the capacity to convert the inactive 25(OH)D3 to the active 1,25(OH)2 D3 that subsequently up-regulates VDR protein expression approximately 2-fold. 1,25(OH)2 D3 does not increase VDR mRNA expression but increases the half-life of the VDR protein in activated CD4+ T cells. Furthermore, 1,25(OH)2 D3 induces a significant intracellular redistribution of the VDR. We show that 1,25(OH)2 D3 stabilizes the VDR by protecting it from proteasomal degradation. Finally, we demonstrate that proteasome inhibition leads to up-regulation of VDR protein expression and increases 1,25(OH)2 D3 -induced gene activation. In conclusion, our study shows that activated CD4+ T cells can produce 1,25(OH)2 D3 , and that 1,25(OH)2 D3 induces a 2-fold up-regulation of the VDR protein expression in activated CD4+ T cells by protecting the VDR against proteasomal degradation. [ABSTRACT FROM AUTHOR]- Published
- 2014
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163. THE ROLE OF CASPASE 3 AND BclxLIN THE ACTION OF INTERLEUKIN 7 (IL-7): A SURVIVAL FACTOR IN ACTIVATED HUMAN T CELLS
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Amos, Claire L., primary, Woetmann, Anders, additional, Nielsen, Mette, additional, Geisler, Carsten, additional, Ødum, Niels, additional, Brown, Barry L., additional, and Dobson, Pauline R.M., additional
- Published
- 1998
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164. Apoptosis following interleukin-2-withdraw from T cells: Evidence for a regulatory role of CD18 (β2-integrin) molecules
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Woetmann, Anders, primary, Gladstone, Paul, additional, Ledbetter, Jeffrey A., additional, Svejgaard, Arne, additional, Ødum, Niels, additional, and Röpke, Carsten, additional
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- 1997
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165. PKC-θ exists in an oxidized inactive form in naive human T cells.
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Essen, Marina Rode, Kongsbak, Martin, Levring, Trine Bøegh, Hansen, Ann Kathrine, Boding, Lasse, Lauritsen, Jens Peter Holst, Woetmann, Anders, Baier, Gottfried, Ødum, Niels, Bonefeld, Charlotte Menné, and Geisler, Carsten
- Abstract
PKC-θ plays a central role in TCR-induced IL-2 production and T-cell proliferation. The aim of the present study was to analyse how PKC-θ is regulated in human T cells during T-cell activation and differentiation. We show that PKC-θ is found in a high-molecular disulfide-linked complex in naïve T cells, and that PKC-θ most likely is inactive in this form. In parallel with the accumulation of the major redox regulators, glutathione and thioredoxin, PKC-θ is gradually reduced to the 82 k Da active form during T-cell activation. We demonstrate that PKC-θ is recruited to the plasma membrane in the disulfide-linked form in naïve T cells, and that activation of PKC-θ is redox dependent and requires de novo synthesis of glutathione. This is the first study that shows that the activity of PKC-θ is regulated by the intracellular redox state, and that PKC-θ is recruited to the plasma membrane in an inactive form in naïve T cells. Our observations underscore the existence of major differences in TCR signaling in naïve versus primed T cells. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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166. Vascular endothelial growth factor receptor-3 expression in mycosis fungoides.
- Author
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Pedersen, Ida Holst, Willerslev-Olsen, Andreas, Vetter-Kauczok, Claudia, Krejsgaard, Thorbjørn, Lauenborg, Britt, Kopp, Katharina Luise, Geisler, Carsten, Bonefeld, Charlotte M., Zhang, Qian, Wasik, Mariusz A., Dabelsteen, Sally, Woetmann, Anders, Becker, Jurgen C., and Odum, Niels
- Subjects
VASCULAR endothelial growth factor receptors ,MYCOSIS fungoides ,LYMPHOMAS ,TUMORS ,STROMAL cells ,T cells - Abstract
Here, we have studied vascular endothelial growth factor receptor-3 (VEGFR-3) expression in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL). Immunohistochemistry revealed that in two-thirds of 34 patients, VEGFR-3 was expressed in situ by both tumor and stromal cells irrespective of the disease stage. The natural VEGFR-3 ligand, VEGF-C, partially protected malignant T-cell lines from growth inhibition by the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA). Whereas the malignant T cells did not produce VEGF-C in vitro, its expression was induced during tumor formation in vivo in a xenograft mouse model of MF. In conclusion, malignant and stromal cells express high levels of VEGFR-3 in all stages of MF. Moreover, malignant T cells trigger enhanced VEGF-C expression in fibroblasts, suggesting that cross-talk between tumor and stromal cells plays a role in lymphangiogenesis and possibly disease progression. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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167. Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma
- Author
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Gluud, Maria, Pallesen, Emil M.H., Buus, Terkild B., Gjerdrum, Lise Mette Rahbek, Lindahl, Lise M., Kamstrup, Maria R., Bzorek, Michael, Danielsen, Maria, Bech, Rikke, Monteiro, Madalena N., Blümel, Edda, Willerslev-Olsen, Andreas, Lykkebo-Valløe, Anders, Vadivel, Chella Krishna, Krejsgaard, Thorbjørn, Bonefeld, Charlotte Menne, Geisler, Carsten, Becker, Jürgen C., Koralov, Sergei B., Iversen, Lars, Litman, Thomas, Woetmann, Anders, and Ødum, Niels
- Abstract
Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterized by the accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms that hamper quality of life and are entry sites for bacterial infection, a major cause of morbidity and mortality in advanced diseases. The mechanism driving the pathological processes that compromise the skin barrier remains unknown. Here, we report increased transepidermal water loss and compromised expression of the skin barrier proteins filaggrin and filaggrin-2 in areas adjacent to TOX-positive T cells in CTCL skin lesions. Malignant T cells secrete mediators (including cytokines such as interleukin 13 [IL-13], IL-22, and oncostatin M) that activate STAT3 signaling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, the repression of filaggrins can be counteracted by a cocktail of antibodies targeting these cytokines/receptors, small interfering RNA–mediated knockdown of JAK1/STAT3, and JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, tofacitinib, increases filaggrin expression in lesional skin from patients with mycosis fungoides. Taken together, these findings indicate that malignant T cells secrete cytokines that induce skin barrier defects via a JAK1/STAT3-dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for patients with CTCL with advanced disease and a compromised skin barrier.
- Published
- 2022
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168. Publisher Correction: Inhibition of succinate dehydrogenase activity impairs human T cell activation and function.
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Nastasi, Claudia, Willerlev-Olsen, Andreas, Dalhoff, Kristoffer, Ford, Shayne L., Gadsbøll, Anne-Sofie Østergaard, Buus, Terkild Brink, Gluud, Maria, Danielsen, Morten, Litman, Thomas, Bonefeld, Charlotte Mennè, Geisler, Carsten, Ødum, Niels, and Woetmann, Anders
- Subjects
SUCCINATE dehydrogenase ,T cells - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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169. Inhibition of protein phosphatase 2A induces serine/threonine phosphorylation, subcellular...
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Woetmann, Anders and Nielsen, Mette
- Subjects
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PHOSPHATASES , *SERINE proteinases , *ANTIGEN-antibody reactions , *T cells , *PHYSIOLOGY , *STRUCTURE-activity relationships - Abstract
Presents a study which examined the role of serine/threonine phosphatases in signal transducers and activators of transcription 3 (STAT3) signaling in human antigen-specific CD4+ T cell lines and cutaneous T cell lymphoma lines. Materials and method used; Results; Discussion.
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- 1999
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170. Notch1 as a potential therapeutic target in cutaneous T-cell lymphoma
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Kamstrup, Maria R., Gjerdrum, Lise Mette Rahbek, Biskup, Edyta, Thyssing Lauenborg, Britt, Ralfkiaer, Elisabeth, Woetmann, Anders, Ødum, Niels, and Gniadecki, Robert
- Abstract
Deregulation of Notch signaling has been linked to the development of T-cell leukemias and several solid malignancies. Yet, it is unknown whether Notch signaling is involved in the pathogenesis of mycosis fungoides and Sézary syndrome, the most common subtypes of cutaneous T-cell lymphoma. By immunohistochemistry of 40 biopsies taken from skin lesions of mycosis fungoides and Sézary syndrome, we demonstrated prominent expression of Notch1 on tumor cells, especially in the more advanced stages. The γ-secretase inhibitor I blocked Notch signaling and potently induced apoptosis in cell lines derived from mycosis fungoides (MyLa) and Sézary syndrome (SeAx, HuT-78) and in primary leukemic Sézary cells. Specific down-regulation of Notch1 (but not Notch2 and Notch3) by siRNA induced apoptosis in SeAx. The mechanism of apoptosis involved the inhibition of nuclear factor-κB, which is the most important prosurvival pathway in cutaneous T-cell lymphoma. Our data show that Notch is present in cutaneous T-cell lymphoma and that its inhibition may provide a new way to treat cutaneous T-cell lymphoma.
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- 2010
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171. Ectopic expression of B-lymphoid kinase in cutaneous T-cell lymphoma
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Krejsgaard, Thorbjørn, Vetter-Kauczok, Claudia S., Woetmann, Anders, Kneitz, Hermann, Eriksen, Karsten W., Lovato, Paola, Zhang, Qian, Wasik, Mariusz A., Geisler, Carsten, Ralfkiaer, Elisabeth, Becker, Juergen C., and Ødum, Niels
- Abstract
B-lymphoid kinase (Blk) is exclusively expressed in B cells and thymocytes. Interestingly, transgenic expression of a constitutively active form of Blk in the T-cell lineage of mice results in the development of T-lymphoid lymphomas. Here, we demonstrate nuclear factor–kappa B (NF-κB)–mediated ectopic expression of Blk in malignant T-cell lines established from patients with cutaneous T-cell lymphoma (CTCL). Importantly, Blk is also expressed in situ in lesional tissue specimens from 26 of 31 patients with CTCL. Already in early disease the majority of epidermotropic T cells express Blk, whereas Blk expression is not observed in patients with benign inflammatory skin disorders. In a longitudinal study of an additional 24 patients biopsied for suspected CTCL, Blk expression significantly correlated with a subsequently confirmed diagnosis of CTCL. Blk is constitutively tyrosine phosphorylated in malignant CTCL cell lines and spontaneously active in kinase assays. Furthermore, targeting Blk activity and expression by Src kinase inhibitors and small interfering RNA (siRNA) inhibit the proliferation of the malignant T cells. In conclusion, this is the first report of Blk expression in CTCL, thereby providing new clues to the pathogenesis of the disease.
- Published
- 2009
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172. Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins
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Woetmann, Anders, Lovato, Paola, Eriksen, Karsten W., Krejsgaard, Thorbjørn, Labuda, Tord, Zhang, Qian, Mathiesen, Anne-Merethe, Geisler, Carsten, Svejgaard, Arne, Wasik, Mariusz A., and Ødum, Niels
- Abstract
Bacterial toxins including staphylococcal enterotoxins (SEs) have been implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). Here, we investigate SE-mediated interactions between nonmalignant T cells and malignant T-cell lines established from skin and blood of CTCL patients. The malignant CTCL cells express MHC class II molecules that are high-affinity receptors for SE. Although treatment with SE has no direct effect on the growth of the malignant CTCL cells, the SE-treated CTCL cells induce vigorous proliferation of the SE-responsive nonmalignant T cells. In turn, the nonmalignant T cells enhance proliferation of the malignant cells in an SE- and MHC class II–dependent manner. Furthermore, SE and, in addition, alloantigen presentation by malignant CTCL cells to irradiated nonmalignant CD4+ T-cell lines also enhance proliferation of the malignant cells. The growth-promoting effect depends on direct cell-cell contact and soluble factors such as interleukin-2. In conclusion, we demonstrate that SE triggers a bidirectional cross talk between nonmalignant T cells and malignant CTCL cells that promotes growth of the malignant cells. This represents a novel mechanism by which infections with SE-producing bacteria may contribute to pathogenesis of CTCL.
- Published
- 2007
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173. STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1)in malignant T lymphocytes
- Author
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Zhang, Qian, Wang, Hong Y., Woetmann, Anders, Raghunath, Puthiyaveettil N., Odum, Niels, and Wasik, Mariusz A.
- Abstract
In this study, we demonstrated that STAT3, a well-characterized transcription factor expressed in continuously activated oncogenic form in the large spectrum of cancer types, induces in malignant T lymphocytes the expression of DNMT1, the key effector of epigenetic gene silencing. STAT3 binds in vitro to 2 STAT3 SIE/GAS-binding sites identified in promoter 1 and enhancer 1 of the DNMT1gene. STAT3 also binds to the promoter 1 region and induces its activity in vivo. Treatment of the malignant T lymphocytes with STAT3 siRNA abrogates expression of DNMT1, inhibits cell growth, and induces programmed cell death. In turn, inhibition of DNMT1 by a small molecule inhibitor, 5-aza-2-deoxy-cytidine, and 2 DNMT1 antisense DNA oligonucleotides inhibits the phosphorylation of STAT3. These data indicate that STAT3 may in part transform cells by fostering epigenetic silencing of tumor-suppressor genes. They also indicate that by inducing DNMT1, STAT3 facilitates its own persistent activation in malignant T cells. Finally, these data provide further rationale for therapeutically targeting STAT3 in T-cell lymphomas and, possibly, other malignancies.
- Published
- 2006
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174. JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL).
- Author
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Vadivel, Chella Krishna, Gluud, Maria, Torres-Rusillo, Sara, Boding, Lasse, Willerslev-Olsen, Andreas, Buus, Terkild B., Nielsen, Tea Kirkegaard, Persson, Jenny L., Bonefeld, Charlotte M., Geisler, Carsten, Krejsgaard, Thorbjorn, Fuglsang, Anja T., Odum, Niels, and Woetmann, Anders
- Subjects
CELL nuclei ,GENE expression ,PHOSPHORYLATION ,SKIN diseases ,T cells ,TRANSFERASES ,NUCLEAR proteins ,SEZARY syndrome ,T-cell lymphoma ,SIGNAL peptides ,IN vitro studies ,JANUS kinases - Abstract
Simple Summary: JAK3 plays an important role in the pathogenesis of cutaneous T cell lymphoma. JAK3 belongs to the Janus kinase family of receptor-associated tyrosine kinases located in cytoplasm adjacent to the plasma membrane. In this study, we show that JAK3 can also be ectopically expressed in the nucleus in CTCL cell lines and primary cells from CTCL patients. Importantly, JAK3 interacts with the nuclear protein RNA polymerase II and phosphorylates Histone H3. Thus, our data provide first evidence for nuclear expression of JAK3 and interactions with key nuclear proteins in malignant T cells suggesting a novel non-canonical role in CTCL. Perturbation in JAK-STAT signaling has been reported in the pathogenesis of cutaneous T cell lymphoma (CTCL). JAK3 is predominantly associated with the intra-cytoplasmic part of IL-2Rγc located in the plasma membrane of hematopoietic cells. Here we demonstrate that JAK3 is also ectopically expressed in the nucleus of malignant T cells. We detected nuclear JAK3 in various CTCL cell lines and primary malignant T cells from patients with Sézary syndrome, a leukemic variant of CTCL. Nuclear localization of JAK3 was independent of its kinase activity whereas STAT3 had a modest effect on nuclear JAK3 expression. Moreover, JAK3 nuclear localization was only weakly affected by blockage of nuclear export. An inhibitor of the nuclear export protein CRM1, Leptomycin B, induced an increased expression of SOCS3 in the nucleus, but only a weak increase in nuclear JAK3. Importantly, immunoprecipitation experiments indicated that JAK3 interacts with the nuclear protein POLR2A, the catalytic subunit of RNA Polymerase II. Kinase assays showed tyrosine phosphorylation of recombinant human Histone H3 by JAK3 in vitro—an effect which was blocked by the JAK inhibitor (Tofacitinib citrate). In conclusion, we provide the first evidence of nuclear localization of JAK3 in malignant T cells. Our findings suggest that JAK3 may have a cytokine-receptor independent function in the nucleus of malignant T cells, and thus a novel non-canonical role in CTCL. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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175. Tumor necrosis factor induces rapid down-regulation of TXNIP in human T cells.
- Author
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Levring, Trine B., Kongsbak-Wismann, Martin, Rode, Anna K. O., Al-Jaberi, Fatima A. H., Lopez, Daniel V., Met, Özcan, Woetmann, Anders, Bonefeld, Charlotte M., Ødum, Niels, and Geisler, Carsten
- Subjects
TUMOR necrosis factors ,T cells ,THIOREDOXIN-interacting protein ,CELLULAR signal transduction ,TOLL-like receptors - Abstract
In addition to antigen-driven signals, T cells need co-stimulatory signals for robust activation. Several receptors, including members of the tumor necrosis factor receptor superfamily (TNFRSF), can deliver co-stimulatory signals to T cells. Thioredoxin interacting protein (TXNIP) is an important inhibitor of glucose uptake and cell proliferation, but it is unknown how TXNIP is regulated in T cells. The aim of this study was to determine expression levels and regulation of TXNIP in human T cells. We found that naïve T cells express high levels of TXNIP and that treatment of blood samples with TNF results in rapid down-regulation of TXNIP in the T cells. TNF-induced TXNIP down-regulation correlated with increased glucose uptake. Furthermore, we found that density gradient centrifugation (DGC) induced down-regulation of TXNIP. We demonstrate that DGC induced TNF production that paralleled the TXNIP down-regulation. Treatment of blood with toll-like receptor (TLR) ligands induced TNF production and TXNIP down-regulation, suggesting that damage-associated molecular patterns (DAMPs), such as endogenous TLR ligands, released during DGC play a role in DGC-induced TXNIP down-regulation. Finally, we demonstrate that TNF-induced TXNIP down-regulation is dependent on caspase activity and is caused by caspase-mediated cleavage of TXNIP. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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176. Circulating basophils in patients with type IIb autoimmune chronic spontaneous urticaria have a lower histamine content.
- Author
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Baumann, Katrine, Sørensen, Jennifer Astrup, Zhang, Ditte G., Ghazanfar, Misbah N., Skov, Per Stahl, Woetmann, Anders, and Thomsen, Simon Francis
- Published
- 2024
- Full Text
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177. Diagnostic Two-Gene Classifier in Early-Stage Mycosis Fungoides: A Retrospective Multicenter Study
- Author
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Nielsen, Pia Rude, Eriksen, Jens Ole, Lindahl, Lise Maria, Wehkamp, Ulrike, Bzorek, Michael, Andersen, Gitte, Woetmann, Anders, Iversen, Lars, Ødum, Niels, Litman, Thomas, and Gjerdrum, Lise Mette Rahbek
- Published
- 2021
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178. Staphylococcus Aureus Induces Stat5 Dependent Mir-155 Expression In Cutaneous T-Cell Lymphoma (Ctcl)
- Author
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Willerslev-Olsen, Andreas, Rahbek Gjerdrum, Lise Mette, Lindahl, Lise M., Buus, Terkild B., Pallesen, Emil M.H., Gluud, Maria, Bzorek, Michael, Nielsen, Boye S., Kamstrup, Maria R., Rittig, Anne Hald, Bonefeld, Charlotte M., Krejsgaard, Thorbjørn, Geisler, Carsten, Koralov, Sergei B., Litman, Thomas, Becker, Jurgen C., Woetmann, Anders, Iversen, Lars, and Odum, Niels
- Abstract
Staphylococcus aureusenterotoxins (SE) are believed to fuel disease activity in cutaneous T-cell lymphoma (CTCL). Recent data support this by showing that antibiotics inhibit malignant T cells in skin lesions in mycosis fungoides and Sezary syndrome, the most common forms of CTCL. Yet, it remains incompletely characterized how SE fuel disease activity. Here, we show that SE induce expression of the oncogenic microRNA mir-155 in primary malignant T cells. Thus, SE and S. aureus-isolates from lesional patient skin induce mir-155 expression, at least partly, through the IL-2Rg/JAK/STAT5 pathway, and the effect is augmented by the presence of non-malignant T cells. Importantly, mycosis fungoides lesions harbor S. aureus,express pY-STAT5, and display enhanced mir-155 expression, when compared with non-lesional and healthy skin. Preliminary data show that aggressive antibiotic therapy is associated with decreased pY-STAT5 and mir-155 expression in lesional skin in two patients with Sezary syndrome. In conclusion, we demonstrate that S. aureusand its enterotoxins induce enhanced expression of oncogenic mir-155 providing mechanistic insight into the role of S. aureusin CTCL. Our findings support that environmental stimuli such as bacteria can fuel disease progression in CTCL.
- Published
- 2021
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179. Pathogenic CD8+Epidermis-Resident Memory T Cells Displace Dendritic Epidermal T Cells in Allergic Dermatitis
- Author
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Gadsbøll, Anne-Sofie Ø., Jee, Mia H., Funch, Anders B., Alhede, Maria, Mraz, Veronika, Weber, Julie F., Callender, Lauren A., Carroll, Elizabeth C., Bjarnsholt, Thomas, Woetmann, Anders, Ødum, Niels, Thomsen, Allan R., Johansen, Jeanne D., Henson, Sian M., Geisler, Carsten, and Bonefeld, Charlotte M.
- Abstract
The skin is our interface with the outside world, and consequently it is exposed to a wide range of microbes and allergens. Recent studies have indicated that allergen-specific skin-resident memory T (TRM) cells play a role in allergic contact dermatitis (ACD). However, the composition and dynamics of the epidermal T-cell subsets during ACD are not known. Here we show that exposure of the skin to the experimental contact allergen DNFB results in a displacement of the normally occurring dendritic epidermal T cells (DETC) concomitant with an accumulation of epidermal CD8+CD69+CD103+TRMcells in mice. By studying knockout mice, we provide evidence that CD8+T cells are required for the displacement of the DETC and that DETC are not required for recruitment of CD8+TRMcells to the epidermis following allergen exposure. We demonstrate that the magnitude of the allergic reaction correlates with the number of CD8+epidermal TRMcells, which again correlates with allergen dose and number of allergen exposures. Finally, in an attempt to elucidate why CD8+epidermal TRMcells persist in the epidermis, we show that CD8+epidermal TRMcells have a higher proliferative capability and are bioenergetically more stable, displaying a higher spare respiratory capacity than DETC.
- Published
- 2020
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180. Staphylococcus aureusalpha-toxin inhibits CD8+T cell-mediated killing of cancer cells in cutaneous T-cell lymphoma
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Blümel, Edda, Munir Ahmad, Shamaila, Nastasi, Claudia, Willerslev-Olsen, Andreas, Gluud, Maria, Fredholm, Simon, Hu, Tengpeng, Surewaard, Bas G. J., Lindahl, Lise M., Fogh, Hanne, Koralov, Sergei B., Rahbek Gjerdrum, Lise Mette, Clark, Rachael A., Iversen, Lars, Krejsgaard, Thorbjørn, Bonefeld, Charlotte Menné, Geisler, Carsten, Becker, Jürgen C., Woetmann, Anders, Andersen, Mads Hald, Buus, Terkild Brink, and Ødum, Niels
- Abstract
ABSTRACTStaphylococcus aureusand its toxins have been linked to disease progression and mortality in advanced stages of cutaneous T-cell lymphoma (CTCL). CD8+T cells play a crucial role in anti-cancer responses and high CD8+T cell numbers in tumor lesions are associated with a favorable prognosis in CTCL. Here, we show that CD8+T cells from both healthy donors and Sézary syndrome patients are highly susceptible to cell death induced by Staphylococcal alpha-toxin, whereas malignant T cells are not. Importantly, alpha-toxin almost completely blocks cytotoxic killing of CTCL tumor cells by peptide-specific CD8+T cells, leading to their escape from induced cell death and continued proliferation. These findings suggest that alpha-toxin may favor the persistence of malignant CTCL cells in vivoby inhibiting CD8+T cell cytotoxicity. Thus, we propose a novel mechanism by which colonization with Staphylococcus aureusmay contribute to cancer immune evasion and disease progression in CTCL.
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- 2020
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181. Staphylococcal alpha-toxin tilts the balance between malignant and non-malignant CD4+T cells in cutaneous T-cell lymphoma
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Blümel, Edda, Willerslev-Olsen, Andreas, Gluud, Maria, Lindahl, Lise M., Fredholm, Simon, Nastasi, Claudia, Krejsgaard, Thorbjørn, Surewaard, Bas G. J., Koralov, Sergei B., Hu, Tengpeng, Persson, Jenny L., Bonefeld, Charlotte Menné, Geisler, Carsten, Iversen, Lars, Becker, Jürgen C., Andersen, Mads Hald, Woetmann, Anders, Buus, Terkild Brink, and Ødum, Niels
- Abstract
ABSTRACTStaphylococcus aureusis implicated in disease progression in cutaneous T-cell lymphoma (CTCL). Here, we demonstrate that malignant T cell lines derived from CTCL patients as well as primary malignant CD4+T cells from Sézary syndrome patients are considerably more resistant to alpha-toxin-induced cell death than their non-malignant counterparts. Thus, in a subset of Sézary syndrome patients the ratio between malignant and non-malignant CD4+T cells increases significantly following exposure to alpha-toxin. Whereas toxin-induced cell death is ADAM10 dependent in healthy CD4+T cells, resistance to alpha-toxin in malignant T cells involves both downregulation of ADAM10 as well as other resistance mechanisms. In conclusion, we provide first evidence that Staphylococcus aureusderived alpha-toxin can tilt the balance between malignant and non-malignant CD4+T cells in CTCL patients. Consequently, alpha-toxin may promote disease progression through positive selection of malignant CD4+T cells, identifying alpha-toxin as a putative drug target in CTCL.
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- 2019
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182. Malignant inflammation in cutaneous T-cell lymphoma: a hostile takeover
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Lindahl, Lise M, Mongan, Nigel P., Wasik, Mariusz A., Litvinov, Ivan V., Iversen, Lars, Langhoff, Erik, Woetmann, Anders, and Odum, Niels
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Cutaneous T-cell lymphoma, Malignant T cells, Inflammation, Pathogenesis, Cancer, Infection - Abstract
Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of chronically inflamed skin lesions containing malignant T cells. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients, the disease never progresses beyond this stage, but in approximately one third of patients, the disease becomes progressive, and the skin lesions start to expand and evolve. Eventually, overt tumors develop and the malignant T cells may disseminate to the blood, lymph nodes, bone marrow, and visceral organs, often with a fatal outcome. The transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation. This shift does not appear to be an epiphenomenon but rather a critical step in disease progression. Emerging evidence supports that the malignant T cells take control of the inflammatory environment, suppressing cellular immunity and anti-tumor responses while promoting a chronic inflammatory milieu that fuels their own expansion. Here, we review the inflammatory changes associated with disease progression in CTCL and point to their wider relevance in other cancer contexts. We further define the term "malignant inflammation" as a pro-tumorigenic inflammatory environment orchestrated by the tumor cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL.
183. The inhibitory checkpoint, PD-L2, is a target for effector T cells: Novel possibilities for immune therapy.
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Ahmad, Shamaila Munir, Martinenaite, Evelina, Holmström, Morten, Jørgensen, Mia Aaboe, Met, Özcan, Nastasi, Claudia, Klausen, Uffe, Donia, Marco, Pedersen, Lars Møller, Munksgaard, Lars, Ødum, Niels, Woetmann, Anders, Svane, Inge Marie, and Andersen, Mads Hald
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PROGRAMMED cell death 1 receptors ,CANCER immunotherapy ,T cell receptors - Abstract
Cell surface molecules of the B7/CD28 family play an important role in T-cell activation and tolerance. The relevance of the PD-1/PD-L1 pathway in cancer has been extensively studied whereas PD-L2 has received less attention. However, recently the expression of PD-L2 was described to be independently associated with clinical response in anti-PD1-treated cancer patients. Here, we investigated whether PD-L2 might represent a natural target that induces specific T cells. We identified spontaneous specific T-cell reactivity against two epitopes located in the signal peptide of PD-L2 from samples from patients with cancer as well as healthy individuals ex vivo. We characterized both CD8+and CD4+PD-L2-specific T cells. Interestingly, the epitope in PD-L2 that elicited the strongest response was equivalent to a potent HLA-A2-restricted epitope in PD-L1. Importantly, PD-L1-specific and PD-L2-specific T cells did not cross-react; therefore, they represent different T-cell antigens. Moreover, PD-L2-specific T cells reacted to autologous target cells depending on PD-L2 expression. These results suggested that activating PD-L2 specific T cells (e.g., by vaccination) might be an attractive strategy for anti-cancer immunotherapy. Accordingly, PD-L2 specific T cells can directly support anti-cancer immunity by killing of target cells, as well as, indirectly, by releasing pro-inflammatory cytokines at the microenvironment in response to PD-L2-expressing immune supressive cells. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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184. CD100 boosts the inflammatory response in the challenge phase of allergic contact dermatitis in mice.
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Mraz, Veronika, Funch, Anders B., Jee, Mia H., Gadsbøll, Anne‐Sofie Ø., Weber, Julie F., Yeung, Kelvin, Lohmann, Rebecca K. D., Hawkes, Alana, Ødum, Niels, Woetmann, Anders, McKay, Dianne, Witherden, Deborah, Geisler, Carsten, and Bonefeld, Charlotte M.
- Abstract
Background: Allergic contact dermatitis (ACD) is an inflammatory disease with a complex pathophysiology in which epidermal‐resident memory CD8+ T (TRM) cells play a key role. The mechanisms involved in the activation of CD8+ TRM cells during allergic flare‐up responses are not understood. Methods: The expression of CD100 and its ligand Plexin B2 on CD8+ TRM cells and keratinocytes before and after allergen exposure was determined by flow cytometry and RT‐qPCR. The role of CD100 in the inflammatory response during the challenge phase of ACD was determined in a model of ACD in CD100 knockout and wild‐type mice. Results: We show that CD8+ TRM cells express CD100 during homeostatic conditions and up‐regulate it following re‐exposure of allergen‐experienced skin to the experimental contact allergen 1‐fluoro‐2,4‐dinitrobenzene (DNFB). Furthermore, Plexin B2 is up‐regulated on keratinocytes following exposure to some contact allergens. We show that loss of CD100 results in a reduced inflammatory response to DNFB with impaired production of IFNγ, IL‐17A, CXCL1, CXCL2, CXCL5, and IL‐1β and decreased recruitment of neutrophils to the epidermis. Conclusion: Our study demonstrates that CD100 is expressed on CD8+ TRM cells and is required for full activation of CD8+ TRM cells and the flare‐up response of ACD. [ABSTRACT FROM AUTHOR]
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- 2023
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185. Positive basophil histamine release assay predicts insufficient response to standard‐dosed omalizumab in patients with chronic spontaneous urticaria.
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Baumann, Katrine, Jørgensen, Astrid‐Helene Ravn, Sørensen, Jennifer Astrup, Zhang, Ditte Georgina, Ghazanfar, Misbah Noshela, Skov, Per Stahl, Woetmann, Anders, Vestergaard, Christian, Maurer, Marcus, and Thomsen, Simon Francis
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OMALIZUMAB , *HISTAMINE , *BASOPHILS , *URTICARIA , *OFF-label use (Drugs) - Abstract
A study published in the journal Clinical & Experimental Allergy found that a positive basophil histamine release assay (BHRA) can help identify patients with type IIb chronic spontaneous urticaria (CSU) who are less likely to respond to standard-dosed omalizumab treatment. CSU patients with type IIb autoimmunity have a higher disease severity and are more refractory to antihistamines and omalizumab. The study also found that BHRA positivity occurs in approximately one out of seven CSU patients and may be used as a predictor of a poorer response to omalizumab, indicating the need for off-label use in these patients. [Extracted from the article]
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- 2023
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186. The junctional adhesion molecule‐like protein (JAML) is important for the inflammatory response during contact hypersensitivity.
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Mraz, Veronika, Lohmann, Rebecca K. D., Menzel, Mandy, Hawkes, Alana, Vaher, Helen, Funch, Anders B., Jee, Mia H., Gadsbøll, Anne‐Sofie Ø., Weber, Julie F., Yeung, Kelvin, Ødum, Niels, Woetmann, Anders, McKay, Dianne, Witherden, Deborah, Geisler, Carsten, and Bonefeld, Charlotte M.
- Abstract
Background: The junctional adhesion molecule‐like protein (JAML) plays important roles in wound healing and activation of epidermal γδ T cells in mice. Whether JAML plays a role in contact hypersensitivity (CHS), the animal model of allergic contact dermatitis (ACD), is not known. Methods: To examine the role of JAML in CHS, we used various mouse models of CHS in JAML knockout (KO) and wild‐type (WT) mice. Furthermore, the expression of the JAML ligand coxsackievirus and adenovirus receptor (CXADR) on keratinocytes was accessed in vitro and in vivo. Results: JAML KO mice had a diminished inflammatory response during both the sensitization and elicitation phase of CHS and had reduced numbers of CD8+ and CD4+ T cells in the epidermis. Furthermore, interferon γ (IFNγ), interleukin 1β (IL‐1β) and CXCL10 production were significantly reduced in JAML KO mice during the elicitation phase. We found that CD8+ T cells express JAML and that JAML is essential for rapid flare‐up responses to contact allergens. Finally, we show that keratinocytes up‐regulate the JAML ligand CXADR following exposure to contact allergens. Conclusion: Our study is the first to show a central role of JAML in CHS and reveals a potential new target for the treatment of ACD in humans. [ABSTRACT FROM AUTHOR]
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- 2023
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187. Validation of a diagnostic microRNA classifier in cutaneous T-cell lymphomas.
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Marstrand, Troels, Ahler, Charlotte B., Ralfkiaer, Ulrik, Clemmensen, Anders, Kopp, Katharina L., Sibbesen, Nina A., Krejsgaard, Thorbjørn, Litman, Thomas, Wasik, Mariusz A., Bonefeld, Charlotte M., Grønbæk, Kirsten, Gjerdum, Lise Mette Rahbek, Gniadecki, Robert, Ralfkiaer, Elisabeth, Geisler, Carsten, Woetmann, Anders, Røpke, Mads A., Glue, Christian, Skov, Lone, and Odum, Niels
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LYMPHOMAS ,DIAGNOSIS ,LYMPHOPROLIFERATIVE disorders ,POLYMERASE chain reaction ,T cells ,MICRORNA ,CANCER - Abstract
The article reports on research which was conducted to investigate the validity of a diagnostic microRNA classifier in cutaneous T-cell lymphomas (CTCL). Researchers evaluated the classifier with 78 patients using a standard TaqMan real-time quantitative polymerase chain reaction (qRT-PCR) assay. They found that while the classifier is diagnostically informative in a wide variety of malignancies, it alone is not sufficient to identify cases of CTCL.
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- 2014
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188. CD4+ T cells inhibit the generation of CD8+ epidermal‐resident memory T cells directed against clinically relevant contact allergens.
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Funch, Anders Boutrup, Weber, Julie Friis, Lohmann, Rebecca Kitt Davidson, Mraz, Veronika, Yeung, Kelvin, Jee, Mia Hamilton, Ødum, Niels, Woetmann, Anders, Johansen, Jeanne Duus, Geisler, Carsten, and Menné Bonefeld, Charlotte
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IMMUNOLOGIC memory , *ALLERGENS , *T cells , *CELL analysis , *CONTACT dermatitis - Abstract
Background: CD8+ epidermal‐resident memory T (TRM) cells play central roles in local flare‐up responses to experimental contact allergens by inducing massive influx of neutrophils to the epidermis upon allergen challenge. Whether similar immunopathogenic mechanisms are involved in the responses to clinically relevant contact allergens is unknown. Methods: The immune response to cinnamal, ρ‐phenylenediamine (PPD) and methylisothiazolinone (MI) was studied in a well‐established mouse model for allergic contact dermatitis that includes formation of TRM cells by ELISA, flow cytometry, fluorescence microscopy analyses and cell depletion protocols. Results: We show that the formation of CD4+ and CD8+ epidermal TRM cells and the inflammatory response are highly allergen‐dependent. However, the magnitude of the flare‐up responses correlated with the number of epidermal CD8+ TRM cells, CXCL1/CXCL2 release and recruitment of neutrophils to the epidermis. Finally, depletion of CD4+ T cells strongly enhanced the number of epidermal CD8+ TRM cells, the flare‐up response and the epidermal infiltration of neutrophils for all allergens. Conclusion: As the first, this study demonstrates that clinically relevant contact allergens have the ability to generate pathogenic, epidermal CD8+ TRM cells that recruit neutrophils following re‐exposure to the allergen, but that this normally is counteracted by the simultaneous induction of anti‐inflammatory CD4+ T cells. [ABSTRACT FROM AUTHOR]
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- 2023
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189. Cluster analysis identifies six clinical subtypes of hidradenitis suppurativa characterised by distinct comorbidities, inflammatory and metabolic profiles, patient-reported outcomes and treatment patterns.
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Jørgensen, Astrid-Helene R., Arildsen, Nicolai S., Yiqiu Yao, Holm, Jesper G., Nielsen, Valdemar W., Ring, Hans C., Woetmann, Anders, and Thomsen, Simon F.
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- 2023
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190. Imbalanced IL-1B and IL-18 Expression in Sézary Syndrome.
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Manfrere, Kelly Cristina Gomes, Torrealba, Marina Passos, Ferreira, Frederico Moraes, de Sousa, Emanuella Sarmento Alho, Miyashiro, Denis, Teixeira, Franciane Mouradian Emidio, Custódio, Ricardo Wesley Alberca, Nakaya, Helder I., Ramos, Yasmin Alefe Leuzzi, Sotto, Mirian Nacagami, Woetmann, Anders, Ødum, Niels, Duarte, Alberto José da Silva, Sanches, José Antonio, and Sato, Maria Notomi
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MONONUCLEAR leukocytes , *SEZARY syndrome , *INTERLEUKIN-1 , *CUTANEOUS T-cell lymphoma , *MESSENGER RNA - Abstract
Sézary syndrome (SS) is a rare and aggressive type of cutaneous T-cell lymphoma, with an abnormal inflammatory response in affected skin. The cytokines IL-1B and IL-18, as key signaling molecules in the immune system, are produced in an inactive form and cleave to the active form by inflammasomes. In this study, we assessed the skin, serum, peripheral mononuclear blood cell (PBMC) and lymph-node samples of SS patients and control groups (healthy donors (HDs) and idiopathic erythroderma (IE) nodes) to investigate the inflammatory markers IL-1B and IL-18 at the protein and transcript expression levels, as potential markers of inflammasome activation. Our findings showed increased IL-1B and decreased IL-18 protein expression in the epidermis of SS patients; however, in the dermis layer, we detected increased IL-18 protein expression. In the lymph nodes of SS patients at advanced stages of the disease (N2/N3), we also detected an enhancement of IL-18 and a downregulation of IL-1B at the protein level. Moreover, the transcriptomic analysis of the SS and IE nodes confirmed the decreased expression of IL1B and NLRP3, whereas the pathway analysis indicated a further downregulation of IL1B-associated genes. Overall, the present findings showed compartmentalized expressions of IL-1B and IL-18 and provided the first evidence of their imbalance in patients with Sézary syndrome. [ABSTRACT FROM AUTHOR]
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- 2023
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191. Concomitant Inhibition of FASN and SREBP Provides a Promising Therapy for CTCL.
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Chi, Cheng, Harth, Lisa, Galera, Marina Ramírez, Torrealba, Marina Passos, Vadivel, Chella Krishna, Geisler, Carsten, Bonefeld, Charlotte Menné, Nielsen, Pia Rude, Bzorek, Michael, Becker, Jürgen C., Gjerdrum, Lise Mette Rahbek, Ødum, Niels, and Woetmann, Anders
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CELL cycle proteins , *GENE expression , *CELL survival , *ENZYMES , *CELL proliferation , *CELL lines , *TRANSCRIPTION factors , *CUTANEOUS T-cell lymphoma - Published
- 2022
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192. Induced Human Regulatory T Cells Express the Glucagon-like Peptide-1 Receptor.
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Rode, Anna K. O., Buus, Terkild Brink, Mraz, Veronika, Al-Jaberi, Fatima Abdul Hassan, Lopez, Daniel Villalba, Ford, Shayne L., Hennen, Stephanie, Eliasen, Ina Primon, Klewe, Ib Vestergaard, Gharehdaghi, Leila, Dragan, Adrian, Rosenkilde, Mette M., Woetmann, Anders, Skov, Lone, Ødum, Niels, Bonefeld, Charlotte M., Kongsbak-Wismann, Martin, and Geisler, Carsten
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REGULATORY T cells , *T helper cells , *GLUCAGON-like peptide-1 receptor , *T cells , *CONTACT dermatitis , *CELL differentiation - Abstract
The glucagon-like peptide-1 receptor (GLP-1R) plays a key role in metabolism and is an important therapeutic target in diabetes and obesity. Recent studies in experimental animals have shown that certain subsets of T cells express functional GLP-1R, indicating an immune regulatory role of GLP-1. In contrast, less is known about the expression and function of the GLP-1R in human T cells. Here, we provide evidence that activated human T cells express GLP-1R. The expressed GLP-1R was functional, as stimulation with a GLP-1R agonist triggered an increase in intracellular cAMP, which was abrogated by a GLP-1R antagonist. Analysis of CD4+ T cells activated under T helper (Th) 1, Th2, Th17 and regulatory T (Treg) cell differentiation conditions indicated that GLP-1R expression was most pronounced in induced Treg (iTreg) cells. Through multimodal single-cell CITE- and TCR-sequencing, we detected GLP-1R expression in 29–34% of the FoxP3+CD25+CD127- iTreg cells. GLP-1R+ cells showed no difference in their TCR-gene usage nor CDR3 lengths. Finally, we demonstrated the presence of GLP-1R+CD4+ T cells in skin from patients with allergic contact dermatitis. Taken together, the present data demonstrate that T cell activation triggers the expression of functional GLP-1R in human CD4+ T cells. Given the high induction of GLP-1R in human iTreg cells, we hypothesize that GLP-1R+ iTreg cells play a key role in the anti-inflammatory effects ascribed to GLP-1R agonists in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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193. Omalizumab serum levels predict treatment outcomes in patients with chronic spontaneous urticaria: A three‐month prospective study.
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Ghazanfar, Misbah Noshela, Bartko, Ewa Anna, Arildsen, Nicolai Skovbjerg, Poulsen, Lars K., Jensen, Bettina Margrethe, Enevold, Christian, Holm, Jesper Grønlund, Woetmann, Anders, Ødum, Niels, and Thomsen, Simon Francis
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URTICARIA , *OMALIZUMAB , *TREATMENT effectiveness , *LONGITUDINAL method - Abstract
During the 12-week treatment period, a total of five patients (21.7%) reported at least one suspected side effect of omalizumab; headache (2 patients), fatigue (2 patients), weight gain (2 patients) and dry mouth (2 patients). Keywords: body mass index; chronic urticaria; IgE; omalizumab; pharmacokinetics EN body mass index chronic urticaria IgE omalizumab pharmacokinetics 715 718 4 04/29/22 20220501 NES 220501 Key Messages Omalizumab (anti-IgE) is effective and safe for treating antihistaminerefractory chronic spontaneous urticaria. Omalizumab serum levels predict treatment outcomes in patients with chronic spontaneous urticaria: A three-month prospective study. [Extracted from the article]
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- 2022
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194. The combination of IL-21 and IFN-α boosts STAT3 activation, cytotoxicity and experimental tumor therapy
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Eriksen, Karsten W., Søndergaard, Henrik, Woetmann, Anders, Krejsgaard, Thorbjørn, Skak, Kresten, Geisler, Carsten, Wasik, Mariusz A., and Ødum, Niels
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IMMUNOTHERAPY , *CANCER immunotherapy , *INTERLEUKINS , *INTERFERONS , *CYTOKINES , *CELLULAR therapy , *TUMOR necrosis factors , *CELLULAR signal transduction - Abstract
Abstract: For decades cytokines such as type I interferons and IL-2 have been used in immunotherapy against cancer, viral hepatitis, and autoimmune diseases such as multiple sclerosis. However, the therapeutic use of cytokines has been hampered by their pleiotropic effects on target-cells. Thus, cytokines such as IFN-α and IL-2 have multiple and severe side effects. Accordingly, they are generally used at sub-optimal doses, which limit their clinical efficacy. Here we hypothesized that a combination of IFN-α and IL-21, a novel cytokine of the IL-2 family with anti-cancer effects, will increase the anti-cancer efficacy at sub-optimal cytokine doses. We show that the combined stimulation of target-cells with IFN-α and IL-21 triggers an increased STAT3 activation whereas the activation of other STATs including STAT1/2 is unaffected. In parallel, the combined stimulation with IFN-α and IL-21 triggers a selective increase in MHC class I expression and NK- and CD8+ T-cell-mediated cytotoxicity. In an experimental in vivo model of renal carcinoma, the combined treatment of IFN-α and IL-21 also produces a significant anti-cancer effect as judged by an inhibition of tumor growth and an increased survival. Taken together our data show that the combined use of IFN-α and IL-21 boosts STAT3 signaling, cytotoxicity, and anti-tumor efficacy, suggesting that a combinatorial therapeutic use of these cytokines may benefit cancer patients. [Copyright &y& Elsevier]
- Published
- 2009
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195. Distinct contribution of hyperbaric oxygen therapy to human neutrophil function and antibiotic efficacy against Staphylococcus aureus.
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Schwartz, Franziska A., Lerche, Christian J., Christophersen, Lars, Jensen, Peter Østrup, Laulund, Anne Sofie, Woetmann, Anders, Høiby, Niels, and Moser, Claus
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HYPERBARIC oxygenation , *STAPHYLOCOCCUS aureus , *ANTIBIOTICS , *REACTIVE oxygen species , *TOBRAMYCIN - Abstract
Staphylococcus aureus (SA) causes superficial and severe endovascular infections. The present in vitro study investigates the anti‐SA mechanisms of hyperbaric oxygen therapy (HBOT) on direct bacterial killing, antibiotic potentiation, and polymorphonuclear leukocyte (PMN) enhancement. SA was exposed to isolated human PMNs, tobramycin, ciprofloxacin, or benzylpenicillin. HBOT was used as one 90‐min session. Bacterial survival was evaluated after 4 h by quantitative bacteriology. PMN functionality as reactive oxygen species (ROS) production was measured by means of dihydrorhodamine 123 analysis. We showed that HBOT exhibits significant direct anti‐SA effects. HBOT increased the anti‐SA effects of PMNs by 18% after PMA stimulation (p = 0.0004) and by 15% in response to SA (p = 0.36). HBOT showed an additive effect as growth reductions of 26% to sub‐MICs of tobramycin (p = 0.0057), 44% to sub‐MICs of ciprofloxacin (p = 0.0001), and 26% to sub‐MICs of penicillin (p = 0.038). The present in vitro study provides evidence that HBOT has differential mechanisms mediating its anti‐SA effects. Our observation supports the clinical possibility for adjunctive HBOT to augment the host immune response and optimize the efficacy of antibiotic treatments. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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196. Epidermal T cell subsets—Effect of age and antigen exposure in humans and mice.
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Gadsbøll, Anne‐Sofie Østergaard, Jee, Mia Hamilton, Ahlström, Malin Glindvad, Dyring‐Andersen, Beatrice, Woetmann, Anders, Ødum, Niels, Johansen, Jeanne Duus, Geisler, Carsten, and Bonefeld, Charlotte Menné
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T cells , *LABORATORY mice , *ANTIGENS , *ENVIRONMENTAL exposure , *MICE - Abstract
Background: Epidermal T cells play a central role in immune surveillance and in inflammatory skin diseases. Major differences in the epidermal T cell composition are found between adult humans and antigen‐inexperienced laboratory mice. Whether this is due to inborn species differences, to different environmental exposures, or a combination of the two is a matter of debate. Objectives: To investigate the role of age and exposure to antigens on epidermal T cell subsets in human and mouse skin. Methods: We isolated T cells from the epidermis from 19 infants and 26 adults, and determined the frequency of CD4+ and CD8+ αβ T cells and γδ T cells by flow cytometry. In addition, we determined the epidermal T cell composition in antigen‐inexperienced and antigen‐experienced mice. Results: We found that humans are born with very few epidermal T cells. The number increases and the composition changes with age. In antigen‐inexperienced mice, the epidermal T cell composition is unaffected by age, but it is dramatically affected by antigen exposure. Conclusion: Taken together, we show that antigen exposure, as opposed to age, is the major factor determining the composition of epidermal T cells, suggesting that the skin of antigen‐experienced mice better reflects the immunological conditions in human skin. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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197. Inhibition of succinate dehydrogenase activity impairs human T cell activation and function.
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Nastasi, Claudia, Willerlev-Olsen, Andreas, Dalhoff, Kristoffer, Ford, Shayne L., Gadsbøll, Anne-Sofie Østergaard, Buus, Terkild Brink, Gluud, Maria, Danielsen, Morten, Litman, Thomas, Bonefeld, Charlotte Mennè, Geisler, Carsten, Ødum, Niels, and Woetmann, Anders
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SUCCINATE dehydrogenase , *T cells , *CELL metabolism , *OXIDATIVE phosphorylation , *GLYCOLYSIS - Abstract
T cell activation is intimately linked to metabolism, as distinct metabolic requirements support the functional and phenotypical differences between quiescent and activated T cells. Metabolic transition from mitochondrial oxidative phosphorylation to aerobic glycolysis is crucial for a proper T cell activation. However, the role of tricarboxylic acid cycle (TCA), and in particular succinate dehydrogenase (SDH) in activated T cells needs further elucidation. Here we show that inhibition of SDH during activation of T cells results in strong impairment of proliferation, expression of activation markers, and production of key inflammatory cytokines, despite a concomitant increase in glycolytic metabolic activity. Similar effect of SDH inhibition were demonstrated in pre-activated T cell. Interestingly, itaconic acid, an endogenous SDH inhibitor released from activated macrophages and dendritic cells, had no immunomodulator effect. Taken together, our findings demonstrate that SDH enzyme fitness is critical for mounting and maintaining appropriate activation and function of human T cells. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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198. Prognostic miRNA classifier in early-stage mycosis fungoides: development and validation in a Danish nationwide study.
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Lindahl, Lise M., Besenbacher, Søren, Rittig, Anne H., Celis, Pamela, Willerslev-Olsen, Andreas, Gjerdrum, Lise M. R., Krejsgaard, Thørbjorn, Johansen, Claus, Litman, Thomas, Woetmann, Anders, Odum, Niels, and Iversen, Lars
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MICRORNA , *MYCOSIS fungoides , *CUTANEOUS T-cell lymphoma , *DISEASE progression , *PROGNOSIS , *PROGRESSION-free survival - Abstract
Mycosis fungoides (MF) is the most frequent form of cutaneous T-cell lymphoma. The disease often takes an indolent course, but in approximately one-third of the patients, the disease progresses to an aggressive malignancy with a poor prognosis. At the time of diagnosis, it is impossible to predict which patients develop severe disease and are in need of aggressive treatment. Accordingly, we investigated the prognostic potential of microRNAs (miRNAs) at the time of diagnosis in MF. Using a quantitative reverse transcription polymerase chain reaction platform, we analyzed miRNA expression in diagnostic skin biopsies from 154 Danish patients with early-stage MF. The patients were subdivided into a discovery cohort (n = 82) and an independent validation cohort (n = 72). The miRNA classifier was built using a LASSO (least absolute shrinkage and selection operator) Cox regression to predict progression-free survival (PFS). We developed a 3-miRNA classifier, based on miR-106b-5p, miR-148a-3p, and miR-338-3p, which successfully separated patients into high-risk and low-risk groups of disease progression. PFS was significantly different between these groups in both the discovery cohort and the validation cohort. The classifier was stronger than existing clinical prognostic factors and remained a strong independent prognostic tool after stratification and adjustment for these factors. Importantly, patients in the high-risk group had a significantly reduced overall survival. The 3-miRNA classifier is an effective tool to predict disease progression of early-stage MF at the time of diagnosis. The classifier adds significant prognostic value to existing clinical prognostic factors and may facilitate more individualized treatment of these patients. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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199. Synovial cell production of IL-26 induces bone mineralization in spondyloarthritis.
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Heftdal, Line, Andersen, Thomas, Jæhger, Ditte, Woetmann, Anders, Østgård, René, Kenngott, Elisabeth, Syrbe, Uta, Sieper, Joachim, Hvid, Malene, Deleuran, Bent, and Kragstrup, Tue
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SPONDYLOARTHROPATHIES , *BONE density , *SYNOVIAL fluid , *INTERLEUKINS , *FLOW cytometry , *THERAPEUTICS - Abstract
Spondyloarthritis (SpA) is characterized by inflammation and new bone formation and can be treated by inhibition of the proinflammatory cytokines TNF-α and IL-17A. IL-26 is considered a proinflammatory cytokine, predominantly related to Th17 cells. In the present study, we investigate IL-26 expression in SpA patients, and examine the in vitro production of IL-26 by synovial cells and the effects of IL-26 on human osteoblasts. IL-26 was measured by ELISA in plasma and synovial fluid (SF) of 15 SpA patients and in plasma samples from 12 healthy controls. Facet joints from axial SpA patients were stained for IL-26 and analyzed by fluorescence microscopy. Synovial fluid mononuclear cells, C-C motif chemokine receptor 6 memory Th17 cells, and fibroblast-like synoviocytes (FLSs) were isolated, and supernatants were analyzed for IL-26 content by ELISA. FLSs were further stained for IL-26 production and the myofibroblast marker α-smooth-muscle-actin (αSMA) and analyzed by flow cytometry. Human osteoblasts were cultured in the presence of IL-26, and the degree of mineralization was quantified. We found that IL-26 levels in SF were increased compared with plasma ( P < 0.0001). Moreover, IL-26 expression was found in facet joints of axial SpA patients within the bone marrow. IL-26 secretion was primarily found in αSMA myofibroblasts. In contrast, Th17 cells did not produce detectable amounts of IL-26. Human osteoblasts treated with IL-26 showed increased mineralization compared with untreated osteoblasts ( P = 0.02). In conclusion, IL-26 seems to be produced by myofibroblasts in the inflamed synovium and could be a possible facilitator of bone mineralization in SpA. Key messages: [ABSTRACT FROM AUTHOR]
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- 2017
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200. Malignant inflammation in cutaneous T-cell lymphoma-a hostile takeover.
- Author
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Krejsgaard, Thorbjørn, Lindahl, Lise, Mongan, Nigel, Wasik, Mariusz, Litvinov, Ivan, Iversen, Lars, Langhoff, Erik, Woetmann, Anders, and Odum, Niels
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T-cell lymphoma , *SKIN inflammation , *TRANSDERMAL medication , *DISEASE progression , *CELLULAR immunity , *ANTINEOPLASTIC agents - Abstract
Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of chronically inflamed skin lesions containing malignant T cells. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients, the disease never progresses beyond this stage, but in approximately one third of patients, the disease becomes progressive, and the skin lesions start to expand and evolve. Eventually, overt tumors develop and the malignant T cells may disseminate to the blood, lymph nodes, bone marrow, and visceral organs, often with a fatal outcome. The transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation. This shift does not appear to be an epiphenomenon but rather a critical step in disease progression. Emerging evidence supports that the malignant T cells take control of the inflammatory environment, suppressing cellular immunity and anti-tumor responses while promoting a chronic inflammatory milieu that fuels their own expansion. Here, we review the inflammatory changes associated with disease progression in CTCL and point to their wider relevance in other cancer contexts. We further define the term 'malignant inflammation' as a pro-tumorigenic inflammatory environment orchestrated by the tumor cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
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