95 results on '"Iversen, Lars"'
Search Results
2. Efficacy and Safety of the Heat Shock Protein 90 Inhibitor RGRN-305 in Hidradenitis Suppurativa: A Parallel-Design Double-Blind Trial
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Ben Abdallah, Hakim, Bregnhøj, Anne, Emmanuel, Thomas, Ghatnekar, Gautam, Johansen, Claus, and Iversen, Lars
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IMPORTANCE: Hidradenitis suppurativa is a painful immune-mediated disorder with limited treatment options; hence, a need exists for new treatments. OBJECTIVE: To evaluate the feasibility of heat shock protein 90 inhibition by RGRN-305 as a novel mechanism of action in treating moderate to severe hidradenitis suppurativa. DESIGN, SETTING, AND PARTICIPANTS: This was a parallel-design, double-blind, proof-of-concept, placebo-controlled randomized clinical trial conducted between September 22, 2021, and August 29, 2022, at the Department of Dermatology, Aarhus University Hospital in Denmark. The study included a 1- to 30-day screening period, a 16-week treatment period, and a 4-week follow-up period. Eligibility criteria included age 18 years or older and moderate to severe hidradenitis suppurativa with 6 or more inflammatory nodules or abscesses in at least 2 distinct anatomic regions. Of 19 patients screened, 15 patients were enrolled in the study. Intention-to-treat analysis was performed. INTERVENTIONS: Patients were randomly assigned (2:1) to receive oral RGRN-305, 250-mg tablet, or matching placebo once daily for 16 weeks. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was the percentage of patients achieving Hidradenitis Suppurativa Clinical Response 50 (HiSCR-50) at week 16. Secondary efficacy end points included HiSCR-75 or HiSCR-90, Hidradenitis Suppurativa Physician’s Global Assessment, Dermatology Life Quality Index scores, and a pain numeric rating scale. Safety was assessed by adverse events, physical examinations, clinical laboratory measurements, and electrocardiograms. RESULTS: A total of 15 patients were enrolled, completed the study, and were included in all analyses (10 [67%] female; median age, 29 [IQR, 23-41] years). The primary end point HiSCR-50 at week 16 was achieved by a higher percentage in the RGRN-305 group (60% [6 of 10]) than in the placebo group (20% [1 of 5]). Improvements were also observed across all secondary end points at week 16, including higher rates of the harder-to-reach HiSCR levels; 50% (5 of 10) achieved HiSCR-75 and 30% (3 of 10) achieved HiSCR-90, whereas none of the placebo-treated patients achieved HiSCR-75 or HiSCR-90. RGRN-305 was well tolerated, with no deaths or serious adverse events, and treatment-emergent adverse events were similarly frequent between the RGRN-305 and placebo groups. CONCLUSIONS AND RELEVANCE: The findings of this trial suggest that heat shock protein 90 inhibition by RGRN-305 offers a novel mechanism of action in treating hidradenitis suppurativa, warranting further evaluation in larger trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05286567
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- 2024
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3. Calcipotriol and Betamethasone Dipropionate Cream Based on PAD Technology for the Treatment of Plaque Psoriasis: A Narrative Review.
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Torres, Tiago, Galván, Jordi, Crutchley, Nigel, Praestegaard, Morten, Iversen, Lars, Gisondi, Paolo, Carrascosa, José Manuel, Halioua, Bruno, Bewley, Anthony, and Pinter, Andreas
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- 2023
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4. Calcipotriene and Betamethasone Dipropionate PAD-Cream Demonstrates Greater Treatment Efficacy in Patients with Moderate-to-Severe Psoriasis Compared to Topical Suspension/Gel: A Subgroup Analysis of Two Phase 3 Studies.
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Stein Gold, Linda, Pinter, Andreas, Armstrong, April, Augustin, Matthias, Arenberger, Petr, Bhatia, Neil, Praestegaard, Morten, Iversen, Lars, and Reich, Adam
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- 2023
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5. Treatment Preferences in Young Adults with Moderate to Severe Psoriasis: A Qualitative Study from the Nordic Countries.
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Balieva, Flora Nicol, Catton, Louise, Claréus, Birgitta W., Danielsen, Kjersti, Fierens, Frederik, Iversen, Lars, Koulu, Leena, Osmanecevic, Amra, Pasternack, Rafael, and Skov, Lone
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- 2023
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6. Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma
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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
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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.
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- 2023
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7. Cytotype and genotype predict mortality and recruitment in Colorado quaking aspen (Populus tremuloides).
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Blonder, Benjamin, Ray, Courtenay A., Walton, James A., Castaneda, Marco, Chadwick, K. Dana, Clyne, Michael O., Gaüzère, Pierre, Iversen, Lars L., Lusk, Madison, Strimbeck, G. Richard, Troy, Savannah, and Mock, Karen E.
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ASPEN (Trees) ,POPULUS tremuloides ,GENETIC variation ,DEMOGRAPHY ,GENOTYPES - Abstract
Species responses to climate change depend on environment, genetics, and interactions among these factors. Intraspecific cytotype (ploidy level) variation is a common type of genetic variation in many species. However, the importance of intraspecific cytotype variation in determining demography across environments is poorly known. We studied quaking aspen (Populus tremuloides), which occurs in diploid and triploid cytotypes. This widespread tree species is experiencing contractions in its western range, which could potentially be linked to cytotype‐dependent drought tolerance. We found that interactions between cytotype and environment drive mortality and recruitment across 503 plots in Colorado. Triploids were more vulnerable to mortality relative to diploids and had reduced recruitment on more drought‐prone and disturbed plots relative to diploids. Furthermore, there was substantial genotype‐dependent variation in demography. Thus, cytotype and genotype variation are associated with decline in this foundation species. Future assessment of demographic responses to climate change will benefit from knowledge of how genetic and environmental mosaics interact to determine species' ecophysiology and demography. [ABSTRACT FROM AUTHOR]
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- 2021
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8. International eDelphi Study to Reach Consensus on the Methotrexate Dosing Regimen in Patients With Psoriasis
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van Huizen, Astrid M., Menting, Stef P., Gyulai, Rolland, Iversen, Lars, van der Kraaij, Gayle E., Middelkamp-Hup, Maritza A., Warren, Richard B., Spuls, Phyllis I., Schejtman, Adrián A., Egeberg, Alexander, Firooz, Alireza, Kumar, Alur S., Oakley, Amanda, Foulkes, Amy, Ramos, Andrea Machado Coelho, Fougerousse, Anne-Claire, Carija, Antoanela, Akman-Karakas, Ayse, Horváth, Barbara, Fábos, Béata, Matlock, Benjamin Hidalgo, Claréus, Birgitta Wilson, Castro, Carla, Ferrándiz, Carlos, Correa, Carolina Cortés, Marchesi, Carolina, Goujon, Catherine, Gonzalez, Cesar, Maldonado-García, César, Hong, Chih-ho, Griffiths, Christopher E.M., Vestergaard, Christian, Echeverría, Christina Mariela, de la Cruz, Claudia, Conrad, Curdin, Törocsik, Dániel, Drvar, Daniela Ledic, Balak, Deepak, Jullien, Denis, Appelen, Diebrecht, Kim, Dong Hyun, de Jong, Elke M.G.J., El Gamal, Emad, Laffitte, Emmanuel, Mahé, Emmanuel, Sonkoly, Enikö, Colombo, Erika Páez, Vilarrasa, Eva, Willaert, Fabienne, Novoa, Farah D., Handjani, Farhad, Valenzuela, Fernando, Vílchez-Márquez, Francisco, Gonzalez, Gabriela Otero, Krisztián, Gáspár, Damiani, Giovanni, Krnjevic-Pezic, Gordana, Pellerano, Graciela, Carretero, Gregorio, Hunter, Hamish J. A., Riad, Hassan, Oon, Hazel H., Boonen, Hugo P.J., Moussa, Iftin Osman, García-Doval, Ignacio, Csányi, Ildíko, Brajac, Ines, Turchin, Irina, Grozdev, Ivan, Weinberg, Jeffrey M., Nicolopoulos, Jenny, Wells, Jillian, Lambert, Jo L.W., Ingram, John R., Prinz, Jörg Christoph, de Souza Sittart, José Alexandre, Sanchez, Jose Luis, Hsiao, Josephine Pa-Fan, Castro-Ayarza, Juan Raul, Maul, Julia-Tatjana, van den Reek, Juul M.P.A., Trcko, Katarina, Barber, Kirk, Reich, Kristian, Gebauer, Kurt Aaron, Khobzei, Kuzma, Maul, Lara V., Massari, Larisa Prpic, Fardet, Laurence, le Cleach, Laurence, Misery, Laurent, Chandrashekar, Laxmisha, Muresanu, Lidia Irinel, Lecluse, Lidian, Skov, Lone, Frez, Ma. Lorna, Babic, Lucija Tomic, Puig, Lluís, Gomez, Luis Castro, Ramam, M., Dutil, Maha, El-Sayed, Mahira Hamdy, Olszewska, Malgorzata, Schram, Mandy Elvira, Franco, Manuel Dario, Llamas-Velasco, Mar, Gonçalo, Margarida, Velásquez-Lopera, Margarita M., Abad, Maria Eugenia, de Oliveira, Maria de Fátima Santos Paim, Seyger, Marieke M. B., Kaštelan, Marija, Rademaker, Marius, Sikora, Mariusz, Lebwohl, Mark, Wiseman, Marni C., Ferran, Marta, van Doorn, Martijn, Danespazhooh, Maryam, Bylaite-Bucinskiene, Matilda, Gooderham, Melinda J., Polic, Melita Vukšic, de Rie, Menno A., Zheng, Min, Gómez-Flores, Minerva, Salleras i Redonnet, Montse, Silverberg, Nanette B., Doss, Nejib, Yawalkar, Nikhil, Chosidow, Olivier, Zargari, Omid, de la Cueva, Pablo, Fernandez-Peñas, Pablo, Cárdenas Rojas, Paola J., Gisondi, Paolo, Grewal, Parbeer, Sator, Paul, Luna, Paula Carolina, Félix, Paulo Antonio Oldani, Varela, Paulo, Holló, Péter, Cetkovska, Petra, Calzavara-Pinton, Piergiacomo, Ghislain, Pierre-Dominique, Araujo, Raquel Ruiz, Romiti, Ricardo, Kui, Róbert, Ceovic, Romana, Vender, Ronald, Lafuente-Urrez, Rosario Fátima, del-Río, Rubén, Gulin, Sandra J., Handa, Sanjeev, Mahil, Satveer K., Kolalapudi, Seetharam A., Marrón, Servando E., Azimi, Seyyede Zeinab, Janmohamed, Sherief R., da Cruz Costa, Sidney Augusto, Choon, Siew Eng, Urbancek, Slavomir, Ayanlowo, Olusola, Margasin, Susana M., Wong, Tak-Wah, Mälkönen, Tarja, Hurtová, Tatiana, Reciné, Tatiana Riveros, Huldt-Nystrøm, Theis, Torres, Tiago, Liu, Tong-Yun, Leonidze, Tsira, Sharma, Vinod Kumar, Weightman, Warren, Gulliver, Wayne, and Veldkamp, Wendelien
- Abstract
IMPORTANCE: A clear dosing regimen for methotrexate in psoriasis is lacking, and this might lead to a suboptimal treatment. Because methotrexate is affordable and globally available, a uniform dosing regimen could potentially optimize the treatment of patients with psoriasis worldwide. OBJECTIVE: To reach international consensus among psoriasis experts on a uniform dosing regimen for treatment with methotrexate in adult and pediatric patients with psoriasis and identify potential future research topics. DESIGN, SETTING, AND PARTICIPANTS: Between September 2020 and March 2021, a survey study with a modified eDelphi procedure that was developed and distributed by the Amsterdam University Medical Center and completed by 180 participants worldwide (55 [30.6%] resided in non-Western countries) was conducted in 3 rounds. The proposals on which no consensus was reached were discussed in a conference meeting (June 2021). Participants voted on 21 proposals with a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree) and were recruited through the Skin Inflammation and Psoriasis International Network and European Academy of Dermatology and Venereology in June 2020. Apart from being a dermatologist/dermatology resident, there were no specific criteria for participation in the survey. The participants worked mainly at a university hospital (97 [53.9%]) and were experienced in treating patients with psoriasis with methotrexate (163 [91.6%] had more than 10 years of experience). MAIN OUTCOMES AND MEASURES: In a survey with eDelphi procedure, we tried to reach consensus on 21 proposals. Consensus was defined as less than 15% voting disagree (1-3). For the consensus meeting, consensus was defined as less than 30% voting disagree. RESULTS: Of 251 participants, 180 (71.7%) completed all 3 survey rounds, and 58 participants (23.1%) joined the conference meeting. Consensus was achieved on 11 proposals in round 1, 3 proposals in round 2, and 2 proposals in round 3. In the consensus meeting, consensus was achieved on 4 proposals. More research is needed, especially for the proposals on folic acid and the dosing of methotrexate for treating subpopulations such as children and vulnerable patients. CONCLUSIONS AND RELEVANCE: In this eDelphi consensus study, consensus was reached on 20 of 21 proposals involving methotrexate dosing in patients with psoriasis. This consensus may potentially be used to harmonize the treatment with methotrexate in patients with psoriasis.
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- 2022
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9. Single-Molecule Study of Thermomyces lanuginosus Lipase in a Detergency Application System Reveals Diffusion Pattern Remodeling by Surfactants and Calcium.
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Moses, Matias E., Lund, Philip M., Bohr, Søren S.-R., Iversen, Josephine F., Kæstel-Hansen, Jacob, Kallenbach, Amalie S., Iversen, Lars, Christensen, Sune M., and Hatzakis, Nikos S.
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- 2021
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10. Sand, gravel, and UN Sustainable Development Goals: Conflicts, synergies, and pathways forward
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Bendixen, Mette, Iversen, Lars L., Best, Jim, Franks, Daniel M., Hackney, Christopher R., Latrubesse, Edgardo M., and Tusting, Lucy S.
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Sand, gravel, and crushed stone are the most mined materials on Earth. Aggregates constitute the foundation for modern civilization and are essential for providing shelter, infrastructure, and communication, but are an increasingly scarce resource. Here, we review the interconnections between the impacts of aggregate mining and the services they provide. We show that the conflicting impacts on the environment and humankind disrupt the net positive effects of aggregate mining on sustainable development. Focusing on low- and middle-income countries, we link these interconnections to the United Nations Sustainable Development Goals and identify critical obstacles to a sustainable future for global aggregate resources. Our assessment identifies an urgent need to improve knowledge on: (1) direct and indirect impacts of extraction on human health, (2) system-level impacts on ecosystems and the services they provide, and (3) how to meet the projected trajectories of global aggregate demand.
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- 2021
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11. Single-Molecule Study of Thermomyces lanuginosusLipase in a Detergency Application System Reveals Diffusion Pattern Remodeling by Surfactants and Calcium
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Moses, Matias E., Lund, Philip M., Bohr, Søren S.-R., Iversen, Josephine F., Kæstel-Hansen, Jacob, Kallenbach, Amalie S., Iversen, Lars, Christensen, Sune M., and Hatzakis, Nikos S.
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Lipases comprise one of the major enzyme classes in biotechnology with applications within, e.g., baking, brewing, biocatalysis, and the detergent industry. Understanding the mechanisms of lipase function and regulation is therefore important to facilitate the optimization of their function by protein engineering. Advances in single-molecule studies in model systems have provided deep mechanistic insights on lipase function, such as the existence of functional states, their dependence on regulatory cues, and their correlation to activity. However, it is unclear how these observations translate to enzyme behavior in applied settings. Here, single-molecule tracking of individual Thermomyces lanuginosuslipase (TLL) enzymes in a detergency application system allowed real-time direct observation of spatiotemporal localization, and thus diffusional behavior, of TLL enzymes on a lard substrate. Parallelized imaging of thousands of individual enzymes allowed us to observe directly the existence and quantify the abundance and interconversion kinetics between three diffusional states that we recently provided evidence to correlate with function. We observe redistribution of the enzyme’s diffusional pattern at the lipid–water interface as well as variations in binding efficiency in response to surfactants and calcium, demonstrating that detergency effectors can drive the sampling of lipase functional states. Our single-molecule results combined with ensemble activity assays and enzyme surface binding efficiency readouts allowed us to deconvolute how application conditions can significantly alter protein functional dynamics and/or surface binding, both of which underpin enzyme performance. We anticipate that our results will inspire further efforts to decipher and integrate the dynamic nature of lipases, and other enzymes, in the design of new biotechnological solutions.
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- 2021
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12. Calcipotriol/Betamethasone Dipropionate Cutaneous Foam Treatment for Psoriasis in Patients With BSA 5–15% and PGA ≥ 3: Post-Hoc Analysis From Three Randomized Controlled Trials.
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Iversen, Lars, Kurvits, Merle, Snel-Prentø, Anja Marieke, and Menter, Alan
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- 2020
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13. Towards a holistic understanding of artisanal aggregate mining in Rwanda
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Bendixen, Mette, Huang, Ke, Dos Santos, Nicolas, Mubagowindekwe, Maurice, Twizere, Moussa, Habinema, Placide, and Iversen, Lars L.
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Sand, gravel and crushed stones are the most mined solid materials on Earth and key ingredients in infrastructure development and modern societies. However, the pressure from the growing population for constructing new buildings and expanding living spaces has resulted in an increased demand for these resources, especially in the Global South. For instance, Africa's population is expected to grow from 1 to 2.4 billion in 2050 which would increase the pressure on these limited resources. Present knowledge of aggregate mining is largely limited to the negative effects of the extraction and lacks a nuanced understanding of the benefits to humans and society that the resources also provide. This article examines the variation in present-day aggregate extraction activities in the context of Rwanda, a country in East Africa that has experienced a significant infrastructure development in the last decades. Here we provide an overview of present-day aggregate mining activities across Rwanda to offer more nuances and details on the processes of mining operations to the present discussion. Going forward, the research community must, in a more holistic view, consider the intricate character of these practices and their impacts on economic development and how these resources offer a potential to alleviate poverty and develop countries.
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- 2024
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14. Staphylococcus aureusinduces drug resistance in cancer T cells in Sézary syndrome
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Vadivel, Chella Krishna, Willerslev-Olsen, Andreas, Namini, Martin R. J., Zeng, Ziao, Yan, Lang, Danielsen, Maria, Gluud, Maria, Pallesen, Emil M. H., Wojewoda, Karolina, Osmancevic, Amra, Hedebo, Signe, Chang, Yun-Tsan, Lindahl, Lise M., Koralov, Sergei B., Geskin, Larisa J., Bates, Susan E., Iversen, Lars, Litman, Thomas, Bech, Rikke, Wobser, Marion, Guenova, Emmanuella, Kamstrup, Maria R., Ødum, Niels, and Buus, Terkild B.
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•Enterotoxins from S aureusbacteria induce drug resistance in primary malignant T cells in SS.•Targeting bacteria, their toxins, and downstream signaling pathways in malignant T cells abrogate the induction of drug resistance.
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- 2024
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15. IκBζ is a key player in the antipsoriatic effects of secukinumab.
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Bertelsen, Trine, Ljungberg, Christine, Litman, Thomas, Huppertz, Christine, Hennze, Robert, Rønholt, Kirsten, Iversen, Lars, and Johansen, Claus
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IκBζ plays a key role in psoriasis by mediating IL-17A–driven effects, but the molecular mechanism by which IL-17A regulates IκBζ expression is not clarified. We sought to explore the molecular transformation in patients with psoriasis during anti-IL-17A (secukinumab) treatment with a focus on IκBζ. The study was an open-label, single-arm, single-center secukinumab treatment study that included 14 patients with plaque psoriasis. Skin biopsy specimens and blood samples were collected on days 0, 4, 14, 42, and 84 and processed for microarray gene expression analysis. Furthermore, in vitro experiments with human keratinocytes and synovial fibroblasts were conducted. Secukinumab improved clinical scores and histologic psoriasis features. Moreover, secukinumab altered the skin transcriptome. The major transcriptional shift appeared between day 14 and day 42 after treatment initiation, although 80 genes were differentially expressed already at day 4. Expression of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor (IκB) ζ (NFKBIZ , the gene encoding IκBζ) was reduced already after 4 days of treatment in the skin. NFKBIZ expression correlated to Psoriasis Area and Severity Index score, and NFKBIZ mRNA levels in the skin decreased during anti–IL-17A treatment. Moreover, specific NFKBIZ signature genes were significantly altered during anti–IL-17A treatment. Finally, we identified NF-κB activator 1 (Act1), p38 mitogen-activated protein kinase (MAPK), Jun NH2-terminal kinase (JNK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) as key signaling pathways in NFKBIZ/ IκBζ regulation. Our results define a crucial role for IκBζ in the antipsoriatic effect of secukinumab. Because IκBζ signature genes were regulated already after 4 days of treatment, this strongly indicates that IκBζ plays a crucial role in the antipsoriatic effects mediated by anti–IL-17A treatment. [ABSTRACT FROM AUTHOR]
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- 2020
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16. Anti-tumor necrosis factor agents in psoriasis: addressing key challenges using biosimilars
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Prignano, Francesca, Choi, Jaeyun, Pieper, Burkhard, and Iversen, Lars
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ABSTRACTIntroductionAnti-tumor necrosis factor agents are key treatment options in moderate–severe psoriasis. The advent of multiple biosimilars of these drugs provides a major opportunity to address this particular factor by helping to reduce costs. Reduced cost can help improve undertreatment, which is one of the challenges in treating moderate-severe psoriasis. There is now a wealth of real-world evidence demonstrating that patients with psoriasis can be initiated on – or transitioned to – an anti-TNF biosimilar without detrimental effects on overall safety and efficacy. Furthermore, recent results suggest that patients can be switched between different biosimilar versions of the same anti-TNF agent without any compromise in outcomes.Areas coveredIn this review, we summarized the role of anti-TNFs in psoriasis, health economic aspects of anti-TNF biosimilars, and their real-world data in clinical practice and registries.Expert opinionThe introduction and competition of anti-TNF biosimilars reduced the cost of biologics and accumulated real-world data support efficacy and safety of anti-TNF biosimilars for psoriasis treatment. Although IL-17 and IL-23 inhibitors show better efficacy in psoriasis patients, long-term efficacy and safety data of anti-TNF and cost-effectiveness of anti-TNF biosimilars may play an important role to increase patient access to biologics through greater adoption of biosimilars.
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- 2021
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17. Clinical Goals and Barriers to Effective Psoriasis Care.
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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, and Vender, Ronald
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- 2019
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18. Drivers and effects of construction-sand mining in Sub-Saharan Africa
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Bendixen, Mette, Noorbhai, Nakiya, Zhou, Joy, Iversen, Lars Lønsmann, and Huang, Ke
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•We reviewed 93 journal articles on sand mining in Sub-Saharan Africa.•91 % of literature being published within the most recent 5 years.•People mine sand due to low education, unemployment and livelihood disruption.•Extraction destructs infrastructure and causes pollution (water, air, noise).•Positive effects stem from job creation, critical buildings, income and taxes.
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- 2023
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19. Efficacy and safety of ixekizumab for the treatment of moderate-to-severe plaque psoriasis: Results through 108 weeks of a randomized, controlled phase 3 clinical trial (UNCOVER-3).
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Blauvelt, Andrew, Gooderham, Melinda, Iversen, Lars, Ball, Susan, Zhang, Lu, Agada, Noah O., and Reich, Kristian
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Background: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A, is efficacious in treating moderate-to-severe plaque psoriasis through 60 weeks.Objective: To evaluate the efficacy and safety of ixekizumab through 108 weeks of treatment in UNCOVER-3.Methods: Patients (N = 1346) were randomized 2:2:2:1 to 80 mg ixekizumab every 2 or 4 weeks, 50 mg etanercept twice weekly, or placebo. At week 12, patients switched to ixekizumab every 4 weeks during a long-term extension (LTE) period. Efficacy data were summarized using as-observed, multiple imputation (MI), and modified MI (mMI) methods.Results: For patients (N = 385) receiving the recommended dose (ixekizumab every 2 weeks on weeks 0-12 and every 4 weeks during LTE), the 108-week as-observed, MI, and mMI response rates were 93.4%, 88.3%, and 83.6%, respectively, for patients achieving ≥75% improvement from baseline in the Psoriasis Area and Severity Index, and the 108-week as-observed, MI, and mMI response rates were 82.6%, 78.3%, and 74.1%, respectively, for patients with a static Physician's Global Assessment score of 0 or 1. During LTE, 1077 (84.5%) patients reported ≥1 treatment-emergent adverse event, and 85% were mild or moderate in severity. Discontinuation because of adverse events occurred in 6.4% of patients.Limitations: There was no comparison treatment group after week 12.Conclusion: Ixekizumab is well tolerated and demonstrates persistent efficacy through 108 weeks. [ABSTRACT FROM AUTHOR]- Published
- 2017
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20. Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma
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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
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It has been proposed that CD4 T-cell responses to Staphylococcus aureus (SA) can inadvertently enhance neoplastic progression in models of skin cancer and cutaneous T-cell lymphoma (CTCL). In this prospective study, we explored the effect of transient antibiotic treatment on tumor cells and disease activity in 8 patients with advanced-stage CTCL. All patients experienced significant decrease in clinical symptoms in response to aggressive, transient antibiotic treatment. In some patients, clinical improvements lasted for more than 8 months. In 6 of 8 patients, a malignant T-cell clone could be identified in lesional skin, and a significant decrease in the fraction of malignant T cells was observed following antibiotics but an otherwise unchanged treatment regimen. Immunohistochemistry, global messenger RNA expression, and cell-signaling pathway analysis indicated that transient aggressive antibiotic therapy was associated with decreased expression of interleukin-2 high-affinity receptors (CD25), STAT3 signaling, and cell proliferation in lesional skin. In conclusion, this study provides novel evidence suggesting that aggressive antibiotic treatment inhibits malignant T cells in lesional skin. Thus, we provide a novel rationale for treatment of SA in advanced CTCL.
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- 2019
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21. Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma
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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
- Abstract
It has been proposed that CD4 T-cell responses to Staphylococcus aureus(SA) can inadvertently enhance neoplastic progression in models of skin cancer and cutaneous T-cell lymphoma (CTCL). In this prospective study, we explored the effect of transient antibiotic treatment on tumor cells and disease activity in 8 patients with advanced-stage CTCL. All patients experienced significant decrease in clinical symptoms in response to aggressive, transient antibiotic treatment. In some patients, clinical improvements lasted for more than 8 months. In 6 of 8 patients, a malignant T-cell clone could be identified in lesional skin, and a significant decrease in the fraction of malignant T cells was observed following antibiotics but an otherwise unchanged treatment regimen. Immunohistochemistry, global messenger RNA expression, and cell-signaling pathway analysis indicated that transient aggressive antibiotic therapy was associated with decreased expression of interleukin-2 high-affinity receptors (CD25), STAT3 signaling, and cell proliferation in lesional skin. In conclusion, this study provides novel evidence suggesting that aggressive antibiotic treatment inhibits malignant T cells in lesional skin. Thus, we provide a novel rationale for treatment of SA in advanced CTCL.
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- 2019
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22. Endolysin Inhibits Skin Colonization by Patient-Derived Staphylococcus Aureusand Malignant T-Cell Activation in Cutaneous T-Cell Lymphoma
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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
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Staphylococcus aureusis suspected to fuel disease activity in cutaneous T-cell lymphomas. In this study, we investigate the effect of a recombinant, antibacterial protein, endolysin (XZ.700), on S. aureusskin colonization and malignant T-cell activation. We show that endolysin strongly inhibits the proliferation of S. aureusisolated from cutaneous T-cell lymphoma skin and significantly decreases S. aureusbacterial cell counts in a dose-dependent manner. Likewise, ex vivo colonization of both healthy and lesional skin by S. aureusis profoundly inhibited by endolysin. Moreover, endolysin inhibits the patient-derived S. aureusinduction of IFNγand the IFNγ-inducible chemokine CXCL10in healthy skin. Whereas patient-derived S. aureusstimulates activation and proliferation of malignant T cells in vitro through an indirect mechanism involving nonmalignant T cells, endolysin strongly inhibits the effects of S. aureuson activation (reduced CD25 and signal transducer and activator of transcription 5 phosphorylation) and proliferation (reduced Ki-67) of malignant T cells and cell lines in the presence of nonmalignant T cells. Taken together, we provide evidence that endolysin XZ.700 inhibits skin colonization, chemokine expression, and proliferation of pathogenic S. aureusand blocks their potential tumor-promoting effects on malignant T cells.
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- 2023
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23. Single-cell heterogeneity in Sézary syndrome
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Buus, Terkild Brink, Willerslev-Olsen, Andreas, Fredholm, Simon, Blümel, Edda, Nastasi, Claudia, Gluud, Maria, Hu, Tengpeng, Lindahl, Lise M., Iversen, Lars, Fogh, Hanne, Gniadecki, Robert, Litvinov, Ivan V., Persson, Jenny L., Bonefeld, Charlotte Menné, Geisler, Carsten, Christensen, Jan Pravsgaard, Krejsgaard, Thorbjørn, Litman, Thomas, Woetmann, Anders, and Ødum, Niels
- Abstract
Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial treatment responses are often good, the vast majority of patients with SS fail to respond to ongoing therapy. We hypothesize that malignant T cells are highly heterogeneous and harbor subpopulations of SS cells that are both sensitive and resistant to treatment. Here, we investigate the presence of single-cell heterogeneity and resistance to histone deacetylase inhibitors (HDACi) within primary malignant T cells from patients with SS. Using single-cell RNA sequencing and flow cytometry, we find that malignant T cells from all investigated patients with SS display a high degree of single-cell heterogeneity at both the mRNA and protein levels. We show that this heterogeneity divides the malignant cells into distinct subpopulations that can be isolated by their expression of different surface antigens. Finally, we show that treatment with HDACi (suberanilohydroxamic acid and romidepsin) selectively eliminates some subpopulations while leaving other subpopulations largely unaffected. In conclusion, we show that patients with SS display a high degree of single-cell heterogeneity within the malignant T-cell population, and that distinct subpopulations of malignant T cells carry HDACi resistance. Our data point to the importance of understanding the heterogeneous nature of malignant SS cells in each individual patient to design combinational and new therapies to counter drug resistance and treatment failure.
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- 2018
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24. SATB1 in Malignant T Cells
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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
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Deficient expression of SATB1 hampers thymocyte development and results in inept T-cell lineages. Recent data implicate dysregulated SATB1 expression in the pathogenesis of mycosis fungoides, the most frequent variant of cutaneous T-cell lymphoma. Here, we report on a disease stage-associated decrease of SATB1 expression and an inverse expression of STAT5 and SATB1 in situ. STAT5 inhibited SATB1 expression through induction of microRNA-155. Decreased SATB1 expression triggered enhanced expression of IL-5 and IL-9 (but not IL-6 and IL-32), whereas increased SATB1 expression had the opposite effect, indicating that the microRNA-155 target SATB1 is a repressor of IL-5 and IL-9 in malignant T cells. In accordance, inhibition of STAT5 and its upstream activator JAK3 triggered increased SATB1 expression and a concomitant suppression of IL-5 and IL-9 expression in malignant T cells. In conclusion, we provide a mechanistic link between the proto-oncogenic JAK3/STAT5/microRNA-155 pathway, SATB1, and cytokines linked to CTCL severity and progression, indicating that SATB1 dysregulation is involved in cutaneous T-cell lymphoma pathogenesis.
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- 2018
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25. 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, Thorbjørn, Johansen, Claus, Litman, Thomas, Woetmann, Anders, Odum, Niels, and Iversen, Lars
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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.
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- 2018
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26. 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, Thorbjørn, Johansen, Claus, Litman, Thomas, Woetmann, Anders, Odum, Niels, and Iversen, Lars
- 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.
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- 2018
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27. Delta progradation in Greenland driven by increasing glacial mass loss
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Bendixen, Mette, Lønsmann Iversen, Lars, Anker Bjørk, Anders, Elberling, Bo, Westergaard-Nielsen, Andreas, Overeem, Irina, Barnhart, Katy R., Abbas Khan, Shfaqat, Box, Jason E., Abermann, Jakob, Langley, Kirsty, and Kroon, Aart
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Climate changes are pronounced in Arctic regions and increase the vulnerability of the Arctic coastal zone. For example, increases in melting of the Greenland Ice Sheet and reductions in sea ice and permafrost distribution are likely to alter coastal morphodynamics. The deltas of Greenland are largely unaffected by human activity, but increased freshwater runoff and sediment fluxes may increase the size of the deltas, whereas increased wave activity in ice-free periods could reduce their size, with the net impact being unclear until now. Here we show that southwestern Greenland deltas were largely stable from the 1940s to 1980s, but prograded (that is, sediment deposition extended the delta into the sea) in a warming Arctic from the 1980s to 2010s. Our results are based on the areal changes of 121 deltas since the 1940s, assessed using newly discovered aerial photographs and remotely sensed imagery. We find that delta progradation was driven by high freshwater runoff from the Greenland Ice Sheet coinciding with periods of open water. Progradation was controlled by the local initial environmental conditions (that is, accumulated air temperatures above 0 °C per year, freshwater runoff and sea ice in the 1980s) rather than by local changes in these conditions from the 1980s to 2010s at each delta. This is in contrast to a dominantly eroding trend of Arctic sedimentary coasts along the coastal plains of Alaska, Siberia and western Canada, and to the spatially variable patterns of erosion and accretion along the large deltas of the main rivers in the Arctic. Our results improve the understanding of Arctic coastal evolution in a changing climate, and reveal the impacts on coastal areas of increasing ice mass loss and the associated freshwater runoff and lengthening of open-water periods.
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- 2017
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28. Patient Preferences for Topical Psoriasis Treatments are Diverse and Difficult to Predict.
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Iversen, Lars and Jakobsen, Henny
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- 2016
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29. Association Between Changes in Coronary Artery Disease Progression and Treatment With Biologic Agents for Severe Psoriasis
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Hjuler, Kasper Fjellhaugen, Bøttcher, Morten, Vestergaard, Christian, Bøtker, Hans Erik, Iversen, Lars, and Kragballe, Knud
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IMPORTANCE: Inflammatory pathways of psoriasis share similarities with the mechanisms identified in atherosclerosis, and the association between psoriasis and cardiovascular disease due to accelerated coronary artery disease is well established. The effect of anti-inflammatory drugs on the development of coronary atherosclerosis remains essentially unknown. OBJECTIVE: To investigate the association of biological therapy with changes in coronary artery disease progression, measured by repeated coronary computed tomography (CT). DESIGN, SETTING, AND PARTICIPANTS: This single-center prospective, controlled, observer-blinded clinical study at a tertiary dermatology university hospital clinic enrolled patients with severe psoriasis initiating biological therapy and matched controls not receiving systemic therapy from April 11, 2011, through June 30, 2014. INTERVENTIONS: Biological therapy approved for psoriasis (adalimumab, etanercept, infliximab, ustekinumab) with the possibility to switch between treatments to ensure tight control of inflammation. MAIN OUTCOMES AND MEASURES: Patients underwent noncontrast coronary artery calcium (CAC) CT and contrast-enhanced coronary CT angiography at baseline and after 13 months of follow-up. Changes in CAC score, number of coronary plaques, severity of narrowing, composition, and vessel wall volume were measured. RESULTS: There were 28 treated patients (mean [SD] age, 49.2 [10.2] years; 71% men; mean [SD] Psoriasis Area Severity Index [PASI], 15.4 [4.3]) and 28 controls (mean [SD] age, 52.8 [10.6] years; 71% men; mean [SD] PASI, 12.4 [3.9]). The CAC scores remained stable in the intervention group (mean [SD] yearly CAC change, −16 [56]; P = .15) and progressed in the control group (14 [29]; P = .02) (intervention vs controls: P = .02). The number of segments with luminal abnormalities remained unchanged in both groups. The severity of luminal narrowing in the diseased segments was unchanged in the intervention group (Wilcoxon W = 76, n = 483, P = .39) but increased at follow-up in the control group (Wilcoxon W = 281, n = 414, P = .02). Automated vessel wall volume index remained unchanged from baseline to follow-up in the intervention group (mean [SD] baseline, 7.1 [1.5], follow-up, 7.1 [1.7]; P = .91), while controls demonstrated statistically nonsignificant progression (baseline, 8.3 [1.6], follow-up, 8.9 [2.2]; P = .06). CONCLUSIONS AND RELEVANCE: Clinically effective treatment with biologic agents was associated with reduced coronary artery disease progression in patients with severe psoriasis. These findings support a beneficial effect of biologic anti-inflammatory agents in preventing cardiovascular disease progression in addition to disease control in inflammatory diseases.
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- 2016
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30. Time is running out for sand
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Bendixen, Mette, Best, Jim, Hackney, Chris, and Iversen, Lars Lønsmann
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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.
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- 2019
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31. Psoriasis and Risk of Mental Disorders in Denmark
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Leisner, Michelle Z., Riis, Jette L., Schwartz, Sara, Iversen, Lars, Østergaard, Søren D., and Olsen, Morten S.
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- 2019
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32. Characterization of TNF-α– and IL-17A–Mediated Synergistic Induction of DEFB4Gene Expression in Human Keratinocytes through IκBζ
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Johansen, Claus, Bertelsen, Trine, Ljungberg, Christine, Mose, Maike, and Iversen, Lars
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Human β-defensin 2 (hBD2), encoded by the DEFB4gene, is an antimicrobial peptide playing an essential role in inflammatory processes in the skin. hBD2 expression is regulated synergistically by tumor necrosis factor-α (TNF-α) and IL-17A; however, the underlying regulatory mechanisms are unknown. The purpose of this study was to characterize the molecular mechanism by which TNF-α and IL-17A synergistically induce hBD2 expression. In cultured human keratinocytes we show that a constitutive noninducible binding of the transcription factor organic cation transporter 1 (OCT1) to the DEFB4promoter is crucial for IL-17A/TNF-α–mediated synergistic induction of hBD2 but not the synergistic induction of CCL20, IL8, IL17Cand LCN2. Interestingly, stimulation with IL-17A results in a p38 mitogen-activated protein kinase–dependent accumulation of inhibitor of nuclear factor κB ζ (IκBζ), which is a necessity for synergistic induction of hBD2. Finally, co-stimulation with TNF-α induces DNA binding of NF-κB and activator protein 1 (AP-1) to two specific sites in the DEFB4promoter region. Hence, our study shows how two inflammatory stimuli are integrated by three different signaling pathways into the regulation of one specific target gene involving the three specific transcription factors OCT1, NF-κB, and AP-1 as well as the transcriptional cofactor IκBζ. These findings may be important in psoriasis, where TNF-α and IL-17A have been identified as key pathogenic cytokines.
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- 2016
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33. Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma
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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
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Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient–derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region β chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk–dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis.
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- 2016
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34. Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma
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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
- Abstract
Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient–derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region β chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk–dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis.
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- 2016
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35. Subsequent cancers, mortality, and causes of death in patients with mycosis fungoides and parapsoriasis: A Danish nationwide, population-based cohort study.
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Lindahl, Lise M., Fenger-Grøn, Morten, and Iversen, Lars
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Background Data on subsequent cancers, prognostic factors for mortality, and causes of death are limited in mycosis fungoides (MF) and parapsoriasis. Objectives To assess subsequent cancers, mortality, and causes of death in MF and parapsoriasis. Methods Using the Danish nationwide population-based registries, we identified 368 MF patients and 582 parapsoriasis patients and compared them with the general Danish population for subsequent cancers, mortality, and causes of death. Results Subsequent cancers were significantly increased in parapsoriasis patients (standardized incidence ratio [SIR], 2.0 [95% confidence interval {CI}, 1.6-2.5]), and a trend was observed in MF (SIR, 1.2 [95% CI, 0.9-1.5]). Mortality was significantly increased in MF (SIR, 2.0 [95% CI, 1.8-2.3]) and parapsoriasis (SIR, 1.3 [95% CI, 1.1-1.5]). Excess mortality from MF was highest during the first 5 years of follow-up, and causes of increased death included both malignant and nonmalignant diseases. Limitations We have no information regarding clinical stage, treatments, and patient lifestyles. Conclusion Patients with parapsoriasis had a significantly increased risk of subsequent cancers and increased mortality. In addition, the highest excess mortality in the MF group was observed during the first 5 years of follow-up, which suggests that MF exists in both an aggressive and a more indolent form. [ABSTRACT FROM AUTHOR]
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- 2014
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36. Religiøse ledere. Makt og avmakt i norske trossamfunn.
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Iversen, Lars Laird
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- 2014
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37. Hospital-based comprehensive cardiac rehabilitation versus usual care among patients with congestive heart failure, ischemic heart disease, or high risk of ischemic heart disease: 12-Month results of a randomized clinical trial.
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Zwisler, Ann-Dorthe Olsen, Soja, Anne Merete Boas, Rasmussen, Søren, Frederiksen, Marianne, Abadini, Sadollah, Appel, Jon, Rasmussen, Hanne, Gluud, Christian, Iversen, Lars, Sigurd, Bjarne, Madsen, Mette, and Fischer-Hansen, Jørgen
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HOSPITAL care ,CARDIAC rehabilitation ,CORONARY disease ,MYOCARDIAL infarction - Abstract
Background: Current guidelines broadly recommend comprehensive cardiac rehabilitation (CCR), although evidence for this is still limited. We investigated the 12-month effect of hospital-based CCR versus usual care (UC) for a broadly defined group of cardiac patients within the modern therapeutic era of cardiology. Methods: We conducted a centrally randomized single-center clinical trial with blinded assessment of the primary outcome: registry-based composite of total mortality, myocardial infarction, or acute first-time readmission due to heart disease. Other outcomes were hospitalization, risk profile, and quality of life. The trial included 770 participants (20-94 years) with congestive heart failure (12%), ischemic heart disease (58%), or high risk of ischemic heart disease (30%). Comprehensive cardiac rehabilitation is composed of 6 weeks of intensive intervention and systematic follow-up for 10.5 months. Results: We randomized 380 patients to CCR versus 390 to UC. Randomization was well balanced. The primary outcome occurred in 31% of both groups (relative risk 0.96, 95% confidence interval 0.78-1.26). Compared with the UC group, CCR significantly reduced length of stay by 15% (95% confidence interval 1.1%-27.1%, P = .04), mean number of cardiac risk factors above target (4.5 vs 4.1, P = .01), patients with systolic blood pressure below target (P = .003), physically inactivity (P = .01), and unhealthy dietary habits (P = .0003). Short-Form-36 and Hospital Anxiety and Depression Scale did not differ significantly. Conclusion: At 12 months, the CCR and UC groups did not differ regarding the primary composite outcome. Comprehensive cardiac rehabilitation significantly reduced length of hospital stay and improved cardiac risk factors. [Copyright &y& Elsevier]
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- 2008
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38. Residue 259 in Protein-Tyrosine Phosphatase PTP1B and PTPα Determines the Flexibility of Glutamine 262.
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Peters, Günther H., Iversen, Lars F., Andersen, Henrik S., Møller, Niels Peter H., and Olsen, Ole H.
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- 2004
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39. Steric Hindrance as a Basis for Structure-Based Design of Selective Inhibitors of Protein ...
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Iversen, Lars Fogh, Andersen, Henrik Sune, Moller, Karin Bach, Olsen, Ole Hvilsted, Peters, Gunther H., Branner, Sven, Mortensen, Steen B., Hansen, Thomas Kruse, Lau, Jesper, Yu Ge, Holsworth, Daniel D., Newman, Michael J., and Moller, Niels Peter Hundahl
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- 2001
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40. Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation
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Krejsgaard, Thorbjørn, Willerslev-Olsen, Andreas, Lindahl, Lise M., Bonefeld, Charlotte M., Koralov, Sergei B., Geisler, Carsten, Wasik, Mariusz A., Gniadecki, Robert, Kilian, Mogens, Iversen, Lars, Woetmann, Anders, and Odum, Niels
- Abstract
Patients with cutaneous T-cell lymphoma (CTCL) are frequently colonized with Staphylococcus aureus (SA). Eradication of SA is, importantly, associated with significant clinical improvement, suggesting that SA promotes the disease activity, but the underlying mechanisms remain poorly characterized. Here, we show that SA isolates from involved skin express staphylococcal enterotoxins (SEs) that induce crosstalk between malignant and benign T cells leading to Stat3-mediated interleukin-10 (IL-10) production by the malignant T cells. The SEs did not stimulate the malignant T cells directly. Instead, SEs triggered a cascade of events involving cell-cell and asymmetric cytokine interactions between malignant and benign T cells, which stimulated the malignant T cells to express high levels of IL-10. Much evidence supports that malignant activation of the Stat3/IL-10 axis plays a key role in driving the immune dysregulation and severe immunodeficiency that characteristically develops in CTCL patients. The present findings thereby establish a novel link between SEs and immune dysregulation in CTCL, strengthening the rationale for antibiotic treatment of colonized patients with severe or progressive disease.
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- 2014
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41. Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation
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Krejsgaard, Thorbjørn, Willerslev-Olsen, Andreas, Lindahl, Lise M., Bonefeld, Charlotte M., Koralov, Sergei B., Geisler, Carsten, Wasik, Mariusz A., Gniadecki, Robert, Kilian, Mogens, Iversen, Lars, Woetmann, Anders, and Odum, Niels
- Abstract
Patients with cutaneous T-cell lymphoma (CTCL) are frequently colonized with Staphylococcus aureus(SA). Eradication of SA is, importantly, associated with significant clinical improvement, suggesting that SA promotes the disease activity, but the underlying mechanisms remain poorly characterized. Here, we show that SA isolates from involved skin express staphylococcal enterotoxins (SEs) that induce crosstalk between malignant and benign T cells leading to Stat3-mediated interleukin-10 (IL-10) production by the malignant T cells. The SEs did not stimulate the malignant T cells directly. Instead, SEs triggered a cascade of events involving cell-cell and asymmetric cytokine interactions between malignant and benign T cells, which stimulated the malignant T cells to express high levels of IL-10. Much evidence supports that malignant activation of the Stat3/IL-10 axis plays a key role in driving the immune dysregulation and severe immunodeficiency that characteristically develops in CTCL patients. The present findings thereby establish a novel link between SEs and immune dysregulation in CTCL, strengthening the rationale for antibiotic treatment of colonized patients with severe or progressive disease.
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- 2014
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42. 27383 Bimekizumab response maintenance up to 1 year in patients with moderate to severe plaque psoriasis: Pooled results from three phase 3 trials.
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Blauvelt, Andrew, Tada, Yayoi, Iversen, Lars, Mrowietz, Ulrich, Lebwohl, Mark, Wang, Maggie, Vanvoorden, Veerle, Cullen, Eva, Staelens, Fabienne, and Papp, Kim A.
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- 2021
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43. 26874 Long-term efficacy and safety of tildrakizumab in patients with moderate-to-severe psoriasis who were partial responders or nonresponders to etanercept: Post hoc analysis through 5 years from the reSURFACE 2 phase 3 trial.
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Thaçi, Diamant, Griffiths, Christopher E.M., Iversen, Lars, Peserico, Andrea, Pau-Charles, Ignasi, Blauvelt, Andrew, and Reich, Kristian
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- 2021
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44. 26581 Maintenance of complete skin clearance throughout 3 years of continuous guselkumab treatment in patients with moderate-to-severe psoriasis: A post hoc analysis of 5-year data from the VOYAGE 1 trial.
- Author
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Costanzo, Antonio, Conrad, Curdin, Gramiccia, Talia, Jazra, Maria, de Jong, Elke M.G. J., Iversen, Lars, Öztürk, Bülent, Wapenaar, Robert, Wegner, Sven, Torres, Tiago, and Puig, Luis
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- 2021
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45. 26580 Efficacy of treatment with brodalumab after treatment failure of previous interleukin 17A inhibitors in patients with psoriasis.
- Author
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Loft, Nikolai, Bregnhøj, Anne, Fage, Simon, Nielsen, Claus Henrik, Enevold, Christian, Zachariae, Claus, Iversen, Lars, and Skov, Lone
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- 2021
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46. Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma
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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.
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- 2022
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47. Maintien de la réponse par bimékizumab jusqu’à 1 an chez des patients présentant un psoriasis en plaques modéré à sévère : résultats groupés de trois études de phase 3
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Konstantinou, Maria Polina, Blauvelt, Andrew, Tada, Yayoi, Iversen, Lars, Mrowietz, Ulrich, Lebwohl, Mark, Wang, Maggie, Vanvoorden, Veerle, Cullen, Eva, Staelens, Fabienne, and Papp, Kim A.
- Abstract
Du fait de la nature chronique du psoriasis en plaques, il est important de maintenir l’efficacité du traitement dans le temps. Nous rapportons ici les résultats groupés de trois études de phase 3 concernant le maintien de la réponse sur 1 an chez des patients présentant un psoriasis en plaques modéré à sévère et qui ont obtenu un blanchiment complet ou quasi complet des lésions après 16 semaines de traitement par bimékizumab.
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- 2021
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48. Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma
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Kim, Youn H., Duvic, Madeleine, Obitz, Erik, Gniadecki, Robert, Iversen, Lars, Österborg, Anders, Whittaker, Sean, Illidge, Timothy M., Schwarz, Thomas, Kaufmann, Roland, Cooper, Kevin, Knudsen, Kim M., Lisby, Steen, Baadsgaard, Ole, and Knox, Susan J.
- Abstract
The efficacy and safety of zanolimumab in patients with refractory cutaneous T-cell lymphoma (CTCL) have been assessed in two phase 2, multicenter, prospective, open-label, uncontrolled clinical studies. Patients with treatment refractory CD4+CTCL (mycosis fungoides [MF], n = 38; Sézary syndrome [SS], n = 9) received 17 weekly infusions of zanolimumab (early-stage patients, 280 and 560 mg; advanced-stage patients, 280 and 980 mg). The primary end point was objective response (OR) as assessed by composite assessment of index lesion disease activity score. Secondary end points included physician's global assessment (PGA), time to response, response duration, and time to progression. ORs were recorded for patients in both CTCL types (MF, 13 ORs; SS, 2 ORs). In the high-dose groups (560 and 980 mg dose groups), a response rate of 56% was obtained with a median response of 81 weeks. Adverse events reported most frequently included low-grade infections and eczematous dermatitis. Zanolimumab showed marked clinical efficacy in the treatment of patients with refractory MF, with early onset of response, high response rate, and durable responses. The treatment was well tolerated with no dose-related toxicity other than the targeted depletion of peripheral T cells. A pivotal study has been initiated based on these findings.
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- 2007
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49. Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma
- Author
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Kim, Youn H., Duvic, Madeleine, Obitz, Erik, Gniadecki, Robert, Iversen, Lars, Österborg, Anders, Whittaker, Sean, Illidge, Timothy M., Schwarz, Thomas, Kaufmann, Roland, Cooper, Kevin, Knudsen, Kim M., Lisby, Steen, Baadsgaard, Ole, and Knox, Susan J.
- Abstract
The efficacy and safety of zanolimumab in patients with refractory cutaneous T-cell lymphoma (CTCL) have been assessed in two phase 2, multicenter, prospective, open-label, uncontrolled clinical studies. Patients with treatment refractory CD4+ CTCL (mycosis fungoides [MF], n = 38; Sézary syndrome [SS], n = 9) received 17 weekly infusions of zanolimumab (early-stage patients, 280 and 560 mg; advanced-stage patients, 280 and 980 mg). The primary end point was objective response (OR) as assessed by composite assessment of index lesion disease activity score. Secondary end points included physician's global assessment (PGA), time to response, response duration, and time to progression. ORs were recorded for patients in both CTCL types (MF, 13 ORs; SS, 2 ORs). In the high-dose groups (560 and 980 mg dose groups), a response rate of 56% was obtained with a median response of 81 weeks. Adverse events reported most frequently included low-grade infections and eczematous dermatitis. Zanolimumab showed marked clinical efficacy in the treatment of patients with refractory MF, with early onset of response, high response rate, and durable responses. The treatment was well tolerated with no dose-related toxicity other than the targeted depletion of peripheral T cells. A pivotal study has been initiated based on these findings.
- Published
- 2007
- Full Text
- View/download PDF
50. Residue 182 influences the second step of protein-tyrosine phosphatase-mediated catalysis
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PEDERSEN, Anja K., GUO, Xiao-Ling, MØLLER, Karin B., PETERS, Günther H., ANDERSEN, Henrik S., KASTRUP, Jette S., MORTENSEN, Steen B., IVERSEN, Lars F., ZHANG, Zhong-Yin, and MØLLER, Niels Peter H.
- Abstract
Previous enzyme kinetic and structural studies have revealed a critical role for Asp181 (PTP1B numbering) in PTP (protein-tyrosine phosphatase)-mediated catalysis. In the E-P (phosphoenzyme) formation step, Asp181 functions as a general acid, while in the E-P hydrolysis step it acts as a general base. Most of our understanding of the role of Asp181 is derived from studies with the Yersinia PTP and the mammalian PTP1B, and to some extent also TC (T-cell)-PTP and the related PTPα and PTP∊. The neighbouring residue 182 is a phenylalanine in these four mammalian enzymes and a glutamine in Yersinia PTP. Surprisingly, little attention has been paid to the fact that this residue is a histidine in most other mammalian PTPs. Using a reciprocal single-point mutational approach with introduction of His182 in PTP1B and Phe182 in PTPH1, we demonstrate here that His182-PTPs, in comparison with Phe182-PTPs, have significantly decreased kcat values, and to a lesser degree, decreased kcat/Km values. Combined enzyme kinetic, X-ray crystallographic and molecular dynamics studies indicate that the effect of His182 is due to interactions with Asp181 and with Gln262. We conclude that residue 182 can modulate the functionality of both Asp181 and Gln262 and therefore affect the E-P hydrolysis step of PTP-mediated catalysis.
- Published
- 2004
- Full Text
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