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6. Endolysin Inhibits Skin Colonization by Patient-Derived Staphylococcus Aureus and Malignant T-Cell Activation in Cutaneous T-Cell Lymphoma

Author

Pallesen, Emil M.H., Gluud, Maria, Vadivel, Chella Krishna, Buus, Terkild B., de Rooij, Bob, Zeng, Ziao, Ahmad, Sana, Willerslev-Olsen, Andreas, Röhrig, Christian, Kamstrup, Maria R., Bay, Lene, Lindahl, Lise, Krejsgaard, Thorbjørn, Geisler, Carsten, Bonefeld, Charlotte M., Iversen, Lars, Woetmann, Anders, Koralov, Sergei B., Bjarnsholt, Thomas, Frieling, Johan, Schmelcher, Mathias, and Ødum, Niels

Published
2023
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8. Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma

Author

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

Published
2023
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11. Bimekizumab Versus Secukinumab Continuous Maintenance of PASI 90 and PASI 100 Responses through One Year in Patients with Moderate to Severe Plaque Psoriasis: Post-HOC Results from the BE RADIANT Phase 3b Trial

Author

Merola, Joseph, primary, Conrad, Curdin, additional, Foley, Peter, additional, Iversen, Lars, additional, Langley, Richard, additional, Kokolakis, Georgios, additional, Davis, Leah, additional, Hoepken, Bengt, additional, Dixon, Joe, additional, and Warren, Richard, additional

Published
2024
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12. Staphylococcus aureus Induces Signal Transducer and Activator of Transcription 5‒Dependent miR-155 Expression in Cutaneous T-Cell Lymphoma

Author

Willerslev-Olsen, Andreas, Gjerdrum, Lise Mette Rahbek, 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

Published
2021
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13. Secukinumab and Dead Sea Climatotherapy Impact Resolved Psoriasis Skin Differently Potentially Affecting Disease Memory.

Author

Emmanuel, Thomas, Ignatov, Borislav, Bertelsen, Trine, Litman, Thomas, Nielsen, Morten Muhlig, Brent, Mikkel Bo, Touborg, Toke, Rønsholdt, Anders Benjamin, Petersen, Annita, Boye, Mette, Kaaber, Ida, Sortebech, Daniel, Lybæk, Dorte, Steiniche, Torben, Bregnhøj, Anne, Eidsmo, Liv, Iversen, Lars, and Johansen, Claus

Subjects
END of treatment, PSORIASIS, DISEASE duration, DISEASE relapse, IMMUNOHISTOCHEMISTRY, SKIN, IODINE isotopes
Abstract

Secukinumab and Dead Sea treatment result in clear skin for many psoriasis patients, through distinct mechanisms. However, recurrence in the same areas after treatments suggests the existence of a molecular scar. We aimed to compare the molecular and genetic differences in psoriasis patients who achieved complete response from secukinumab and Dead Sea climatotherapy treatments. We performed quantitative immunohistochemical and transcriptomic analysis, in addition to digital spatial profiling of skin punch biopsies. Histologically, both treatments resulted in a normalization of the lesional skin to a level resembling nonlesional skin. Interestingly, the transcriptome was not normalized by either treatments. We revealed 479 differentially expressed genes between secukinumab and Dead Sea climatotherapy at the end of treatment, with a psoriasis panel identifying SERPINB4, SERPINB13, IL36G, IL36RN, and AKR1B10 as upregulated in Dead Sea climatotherapy compared with secukinumab. Using digital spatial profiling, pan-RAS was observed to be differentially expressed in the microenvironment surrounding CD103+ cells, and IDO1 was differentially expressed in the dermis when comparing the two treatments. The differences observed between secukinumab and Dead Sea climatotherapy suggest the presence of a molecular scar, which may stem from mechanistically different pathways and potentially contribute to disease recurrence. This may be important for determining treatment response duration and disease memory. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma

Author

Lindahl, Lise M., Willerslev-Olsen, Andreas, Gjerdrum, Lise M.R., Nielsen, Pia R., Blümel, Edda, Rittig, Anne H., Celis, Pamela, Herpers, Bjorn, Becker, Jürgen C., Stausbøl-Grøn, Birgitte, Wasik, Mariusz A., Gluud, Maria, Fredholm, Simon, Buus, Terkild B., Johansen, Claus, Nastasi, Claudia, Peiffer, Lukas, Kubat, Linda, Bzorek, Michael, Eriksen, Jens O., Krejsgaard, Thorbjørn, Bonefeld, Charlotte M., Geisler, Carsten, Mustelin, Tomas, Langhoff, Erik, Givskov, Michael, Woetmann, Anders, Kilian, Mogens, Litman, Thomas, Iversen, Lars, and Odum, Niels

Published
2019
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18. Ras activation by SOS: Allosteric regulation by altered fluctuation dynamics

Author

Iversen, Lars, Tu, Hsiung-Lin, Lin, Wan-Chen, Christensen, Sune M, Abel, Steven M, Iwig, Jeff, Wu, Hung-Jen, Gureasko, Jodi, Rhodes, Christopher, Petit, Rebecca S, Hansen, Scott D, Thill, Peter, Yu, Cheng-Han, Stamou, Dimitrios, Chakraborty, Arup K, Kuriyan, John, and Groves, Jay T

Subjects
Underpinning research, 1.1 Normal biological development and functioning, Allosteric Regulation, Catalytic Domain, Crystallography, X-Ray, Enzyme Activation, Humans, Kinetics, Nucleotides, Protein Interaction Domains and Motifs, Proto-Oncogene Proteins p21(ras), Son of Sevenless Protein, Drosophila, General Science & Technology
Abstract

Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS by Ras-guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average.

Published
2014

19. Heat shock protein 90 inhibition attenuates inflammation in models of atopic dermatitis: a novel mechanism of action.

Author

Ben Abdallah, Hakim, Bregnhøj, Anne, Ghatnekar, Gautam, Iversen, Lars, and Johansen, Claus

Subjects
HEAT shock proteins, ATOPIC dermatitis, T cells, INFLAMMATION, MAST cells
Abstract

Background: Heat shock protein 90 (HSP90) is an important chaperone supporting the function of many proinflammatory client proteins. Recent studies indicate HSP90 inhibition may be a novel mechanism of action for inflammatory skin diseases; however, this has not been explored in atopic dermatitis (AD). Objectives: Our study aimed to investigate HSP90 as a novel target to treat AD. Methods: Experimental models of AD were used including primary human keratinocytes stimulated with cytokines (TNF/IFNg or TNF/IL-4) and a mouse model established by MC903 applications. Results: In primary human keratinocytes using RT-qPCR, the HSP90 inhibitor RGRN-305 strongly suppressed the gene expression of Th1-(TNF, IL1B, IL6) and Th2-associated (CCL17, CCL22, TSLP) cytokines and chemokines related to AD. We next demonstrated that topical and oral RGRN-305 robustly suppressed MC903-induced AD-like inflammation in mice by reducing clinical signs of dermatitis (oedema and erythema) and immune cell infiltration into the skin (T cells, neutrophils, mast cells). Interestingly, topical RGRN-305 exhibited similar or slightly inferior efficacy but less weight loss compared with topical dexamethasone. Furthermore, RNA sequencing of skin biopsies revealed that RGRN-305 attenuated MC903-induced transcriptome alterations, suppressing genes implicated in inflammation including AD-associated cytokines (Il1b, Il4, Il6, Il13), which was confirmed by RT-qPCR. Lastly, we discovered using Western blot that RGRN-305 disrupted JAK-STAT signaling by suppressing the activity of STAT3 and STAT6 in primary human keratinocytes, which was consistent with enrichment analyses from the mouse model. Conclusion: HSP90 inhibition by RGRN-305 robustly suppressed inflammation in experimental models mimicking AD, proving that HSP90 inhibition may be a novel mechanism of action in treating AD. [ABSTRACT FROM AUTHOR]

Published
2024
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22. Sensory properties analysis of a calcipotriol and betamethasone dipropionate cream vehicle formulated with an innovative PAD Technology for the treatment of plaque psoriasis on the skin and scalp

Author

García, Nuria, Guiró, Pere, Galván, Jordi, Crutchley, Nigel, Praestegaard, Morten, Iversen, Lars, and Torres, Tiago

Subjects
Pharmacology, pharmaceutical technology, skin cream, Molecular Medicine, calcipotriol, rheology, psoriasis, General Medicine, perception, betamethasone dipropionate
Abstract

Background: In psoriasis, poor treatment adherence is frequently related to low efficacy and limited cosmetic acceptability from the patients' perspective. This study aimed to characterize the sensorial attributes of a calcipotriol (CAL) and betamethasone dipropionate (BDP)-cream vehicle based on polyaphron dispersion (PAD) Technology and to compare them with the conventional ointment and oleogel formulations for psoriasis. Methods: A panel of 16 experts assessed sensory properties at four different stages: appearance, pick up, rub out and afterfeel. Descriptive sensory analysis was used to evaluate relevant attributes. Each attribute was rated on a line scale (range 0-100%). Active ingredients were not used because panellists were healthy volunteers, and vehicle formulations needed to be used instead. Results: CAL/BDP PAD-cream vehicle was evaluated as having a low stickiness, low grease behaviour, good wetness, and good spreadability. Ointment showed the least desirable behaviour regarding these properties. Moreover, once CAL/BDP PAD-cream vehicle was absorbed, the gloss disappeared quickly, leaving low stickiness and a low amount of residue. This afterfeel behaviour was not observed with ointment. The oleogel formulation had good sensory properties, similar to CAL/BDP PAD-cream vehicle, but with lower integrity of shape, lower wetness and higher greasiness. Conclusion: Overall, CAL/BDP PAD-cream vehicle has the desirable requirements for a topical product for the treatment of psoriasis, with better sensory properties than ointment and easier manipulation than oleogel, which may lead to greater acceptance and adherence.

Published
2023

23. SATB1 in Malignant T Cells

Author

Fredholm, Simon, Willerslev-Olsen, Andreas, Met, Özcan, Kubat, Linda, Gluud, Maria, Mathiasen, Sarah L., Friese, Christina, Blümel, Edda, Petersen, David L., Hu, Tengpeng, Nastasi, Claudia, Lindahl, Lise M., Buus, Terkild B., Krejsgaard, Thorbjørn, Wasik, Mariusz A., Kopp, Katharina L., Koralov, Sergei B., Persson, Jenny L., Bonefeld, Charlotte M., Geisler, Carsten, Woetmann, Anders, Iversen, Lars, Becker, Jürgen C., and Ødum, Niels

Published
2018
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25. Clinical Goals and Barriers to Effective Psoriasis Care

Author

Strober, Bruce E., van der Walt, Joelle M., Armstrong, April W., Bourcier, Marc, Carvalho, Andre V. E., Chouela, Edgardo, Cohen, Arnon D., de la Cruz, Claudia, Ellis, Charles N., Finlay, Andrew Y., Gottlieb, Alice B., Gudjonsson, Johann E., Iversen, Lars, Kleyn, C. Elise, Leonardi, Craig L., Lynde, Charles W., Ryan, Caitriona, Theng, Colin T., Valenzuela, Fernando, Vender, Ronald, Wu, Jashin J., Young, Helen S., and Kimball, Alexa B.

Published
2019
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27. Efficacy and safety of oral roflumilast for moderate-to-severe psoriasis—a randomized controlled trial (PSORRO)

Author

Gyldenløve, Mette, primary, Meteran, Howraman, additional, Sørensen, Jennifer A., additional, Fage, Simon, additional, Yao, Yiqiu, additional, Lindhardsen, Jesper, additional, Nissen, Christoffer V., additional, Todberg, Tanja, additional, Thomsen, Simon F., additional, Skov, Lone, additional, Zachariae, Claus, additional, Iversen, Lars, additional, Nielsen, Mia-Louise, additional, and Egeberg, Alexander, additional

Published
2023
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28. Staphylococcus aureus enterotoxins induce FOXP3 in neoplastic T cells in Sézary syndrome

Author

Willerslev-Olsen, Andreas, Buus, Terkild B., Nastasi, Claudia, Blümel, Edda, Gluud, Maria, Bonefeld, Charlotte M., Geisler, Carsten, Lindahl, Lise M., Vermeer, Maarten, Wasik, Mariusz A., Iversen, Lars, Becker, Jürgen C., Andersen, Mads Hald, Gjerdrum, Lise M. R., Litvinov, Ivan V., Litman, Thomas, Krejsgaard, Thorbjørn, Woetmann, Anders, and Ødum, Niels

Published
2020
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31. Transcriptomic Analysis of Hidradenitis Suppurativa: A Unique Molecular Signature with Broad Immune Activation.

Author

Ben Abdallah, Hakim, Bregnhøj, Anne, Iversen, Lars, and Johansen, Claus

Subjects
HIDRADENITIS suppurativa, TRANSCRIPTOMES, ATOPIC dermatitis, RNA sequencing, MYELOID cells, B cells
Abstract

Hidradenitis suppurativa is a chronic inflammatory skin disease with limited treatment options. The poorly understood pathogenesis hinders the development of effective treatments; therefore, a pressing need exists to further elucidate the molecular mechanisms in hidradenitis suppurativa. This study investigated the underlying inflammatory pathways and cell types in hidradenitis suppurativa using transcriptomic approaches with RNA sequencing of lesional and non-lesional skin biopsies from hidradenitis suppurativa, which was jointly analyzed with previously published transcriptomic data from atopic dermatitis and psoriasis patients. The differential expression and pathway enrichment analyses demonstrated the activation of multiple inflammatory processes, including the innate and adaptive immune systems, implicated in the hidradenitis suppurativa pathogenesis. In agreement, hidradenitis suppurativa exhibited a unique and heterogeneous cell type signature involving lymphoid and myeloid cells such as B cells and macrophages. Furthermore, hidradenitis suppurativa displayed increased expression of TH1/2/17 signatures with no predominant TH signatures unlike psoriasis (TH1/17) and atopic dermatitis (TH2). In summary, our study provides molecular insights into the pathomechanisms in hidradenitis suppurativa, revealing a strong and widespread immune activation, which may benefit from treatment strategies offering a broad immunomodulation of various key inflammatory pathways. Our data not only corroborate previously reported findings but also enhance our understanding of the immune dysregulation in hidradenitis suppurativa, uncovering novel and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Published
2023
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33. ImmUniverse Consortium: Multi-omics integrative approach in personalized medicine for immune-mediated inflammatory diseases

Author

Vetrano, Stefania, Bouma, Gerben, Benschop, Robert J, Birngruber, Thomas, Costanzo, Antonio, D'Haens, GRAM, Frasca, Loredana, Hillenbrand, Rainer, Iversen, Lars, Johansen, Claus, Kaser, Arthur, Koenen, Hans JPM, Noehammer, Christa, Peyrin-Biroulet, Laurent, Raes, Jeroen, Ricotti, Leonardo, Rosenstiel, Philip, Satagopam, Venkata P, Schreiber, Stefan, Vermeire, Severine, Wollenberg, Andreas, Weidinger, Stephan, Ziemek, Daniel, Danese, Silvio, ImmUniverse Consortium, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Apollo - University of Cambridge Repository, Iversen, Lars [0000-0003-1816-4508], and Department of Bio-engineering Sciences

Subjects
Science & Technology, atopic dermatitis, liquid biopsy, FOS: Clinical medicine, Immunology, NK T-CELLS, Dermatitis, Atopic, All institutes and research themes of the Radboud University Medical Center, MICROBIOME, IL-13, immunomediated diseases, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], LIPUS, Quality of Life, Disease Progression, Immunology and Allergy, Humans, dOFM, Precision Medicine, omic analyses, Life Sciences & Biomedicine, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], POPULATION, Biomarkers, ulcerative colitis
Abstract

Peer reviewed: True, Immune mediated inflammatory diseases (IMIDs) are a heterogeneous group of debilitating, multifactorial and unrelated conditions featured by a dysregulated immune response leading to destructive chronic inflammation. The immune dysregulation can affect various organ systems: gut (e.g., inflammatory bowel disease), joints (e.g., rheumatoid arthritis), skin (e.g., psoriasis, atopic dermatitis), resulting in significant morbidity, reduced quality of life, increased risk for comorbidities, and premature death. As there are no reliable disease progression and therapy response biomarkers currently available, it is very hard to predict how the disease will develop and which treatments will be effective in a given patient. In addition, a considerable proportion of patients do not respond sufficiently to the treatment. ImmUniverse is a large collaborative consortium of 27 partners funded by the Innovative Medicine Initiative (IMI), which is sponsored by the European Union (Horizon 2020) and in-kind contributions of participating pharmaceutical companies within the European Federation of Pharmaceutical Industries and Associations (EFPIA). ImmUniverse aims to advance our understanding of the molecular mechanisms underlying two immune-mediated diseases, ulcerative colitis (UC) and atopic dermatitis (AD), by pursuing an integrative multi-omics approach. As a consequence of the heterogeneity among IMIDs patients, a comprehensive, evidence-based identification of novel biomarkers is necessary to enable appropriate patient stratification that would account for the inter-individual differences in disease severity, drug efficacy, side effects or prognosis. This would guide clinicians in the management of patients and represent a major step towards personalized medicine. ImmUniverse will combine the existing and novel advanced technologies, including multi-omics, to characterize both the tissue microenvironment and blood. This comprehensive, systems biology-oriented approach will allow for identification and validation of tissue and circulating biomarker signatures as well as mechanistic principles, which will provide information about disease severity and future disease progression. This truly makes the ImmUniverse Consortium an unparalleled approach.

Published
2022
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34. Delta progradation in Greenland driven by increasing glacial mass loss

Author

Bendixen, Mette, Lnsmann Iversen, Lars, Anker Bjrk, Anders, Elberling, Bo, Westergaard-Nielsen, Andreas, Overeem, Irina, Barnhart, Katy R., Abbas Khan, Shfaqat, Box, Jason E., Abermann, Jakob, Langley, Kirsty, and Kroon, Aart

Subjects
Glaciers -- Environmental aspects, Surface-ice melting -- Environmental aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Mette Bendixen (corresponding author) [1]; Lars Lnsmann Iversen [2]; Anders Anker Bjrk [3, 4, 5]; Bo Elberling [1]; Andreas Westergaard-Nielsen [1]; Irina Overeem [6]; Katy R. Barnhart [7]; Shfaqat [...]

Published
2017
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40. Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

Author

Willerslev-Olsen, Andreas, Krejsgaard, Thorbjørn, Lindahl, Lise M., Litvinov, Ivan V., Fredholm, Simon, Petersen, David L., Nastasi, Claudia, Gniadecki, Robert, Mongan, Nigel P., Sasseville, Denis, Wasik, Mariusz A., Bonefeld, Charlotte M., Geisler, Carsten, Woetmann, Anders, Iversen, Lars, Kilian, Mogens, Koralov, Sergei B., and Odum, Niels

Published
2016
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43. Time is running out for sand

Author

Bendixen, Mette, Best, Jim, Hackney, Chris, and Iversen, Lars Lønsmann

Subjects
Sediments (Geology) -- Measurement -- Environmental aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Sand and gravel are being extracted faster than they can be replaced. Monitor and manage this resource globally, urge Mette Bendixen and colleagues. Sand and gravel are being extracted faster than they can be replaced. Monitor and manage this resource globally, urge Mette Bendixen and colleagues., Author(s): Mette Bendixen, Jim Best, Chris Hackney, Lars Lønsmann Iversen Author Affiliations: In Lagos Lagoon in Nigeria, labourers dig sand from the sea floor by hand. [see PDF for image] [...]

Published
2019
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45. miRNA Signature in Early-stage Mycosis Fungoides

Author

Sørensen, Sissel T., primary, Litman, Thomas, additional, Gluud, Maria, additional, Celis, Pamela, additional, Torres-Rusillo, Sara, additional, Willerslev-Olsen, Andreas, additional, Ødum, Niels, additional, Iversen, Lars, additional, and Lindahl, Lise M., additional

Published
2022
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