Eine übermäßige Phagozytose von Myelomzellen induziert Pyroptose in Myelom-assoziierten Makrophagen und beeinträchtigt die Wirksamkeit therapeutischer Antikörper - Flamann, Cindy; Biedermann, Alexander; Mougiakakos, D.; Bitterer, Katrin; Karg, K.; Bittenbring, J.; Büttner-Herold, Maike; Liebisch, G.; Leffler, M.; Lischer, Christopher; Eberhardt, Martin; Vera-Gonzales, J.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

Ein Lues-ähnliches Bild verursacht durch PVL-positive Staphylokokken - Busch, Dorothee; Schliep, Stefan; Berking, Carola; Bosch-Voskens, Caroline (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
CRIS-Team Scopus Importer:2023-05-05

Ein Lues-ähnliches Bild verursacht durch PVL-positive Staphylokokken - Busch, Dorothee; Schliep, Stefan; Berking, Carola; Bosch-Voskens, Caroline (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
EVALuna2:537510

Elective Discontinuation of Checkpoint Inhibitor Therapy in Patients with advanced Melanoma - Persa, O. D.; Schatton, K.; Ruebben, A.; Berking, Carola; Erdmann, M.; Schlaak, M.; Mauch, C.; Steeb, T. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Electrocardiographic features of immune checkpoint inhibitor associated myocarditis - Zlotoff, Daniel A.; Hassan, Malek Z.O.; Zafar, Amna; Alvi, Raza M.; Awadalla, Magid; Mahmood, Syed S.; Zhang, Lili; Chen, Carol L.; Ederhy, Stephane; Barac, Ana; Banerji, Dahlia; Jones-O'connor, Maeve; et al. (Journal for ImmunoTherapy of Cancer, 2021)
Background Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis. Methods From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested. Results Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39). Conclusions The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.
CRIS-Team Scopus Importer:2021-03-19
Keywords: autoimmunity; immune tolerance; immunotherapy; inflammation; self tolerance

Electroporated Antigen-Encoding mRNA Is Not a Danger Signal to Human Mature Monocyte-Derived Dendritic Cells - Hoyer, Stefanie; Gerer, Kerstin F.; Pfeiffer, Isabell A.; Prommersberger, Sabrina; Hoefflin, Sandra; Jaitly, Tanushree; Beltrame, Luca; Cavalieri, Duccio; Schuler, Gerold; Vera, Julio; Schaft, Niels; Dörrie, Jan (Journal of immunology research, 2015)
For therapeutic cancer vaccination, the adoptive transfer of mRNA-electroporated dendritic cells (DCs) is frequently performed, usually with monocyte-derived, cytokine-matured DCs (moDCs). However, DCs are rich in danger-sensing receptors which could recognize the exogenously delivered mRNA and induce DC activation, hence influencing the DCs' immunogenicity. Therefore, we examined whether electroporation of mRNA with a proper cap and a poly-A tail of at least 64 adenosines had any influence on cocktail-matured moDCs. We used 16 different RNAs, encoding tumor antigens (MelanA, NRAS, BRAF, GNAQ, GNA11, and WT1), and variants thereof. None of those RNAs induced changes in the expression of CD25, CD40, CD83, CD86, and CD70 or the secretion of the cytokines IL-8, IL-6, and TNFα of more than 1.5-fold compared to the control condition, while an mRNA encoding an NF-B-activation protein as positive control induced massive secretion of the cytokines. To determine whether mRNA electroporation had any effect on the whole transcriptome of the DCs, we performed microarray analyses of DCs of 6 different donors. None of 60,000 probes was significantly different between mock-electroporated DCs and MelanA-transfected DCs. Hence, we conclude that no transcriptional programs were induced within cocktail-matured DCs by electroporation of single tumor-antigen-encoding mRNAs.
CRIS-Team Scopus Importer:2021-10-01

Electroporation of mRNA as a Universal Technology Platform to Transfect a Variety of Primary Cells with Antigens and Functional Proteins - Sauerer, Tatjana; Albrecht, Leoni; Sievers, Nico M.; Gerer, Kerstin F.; Hoyer, Stefanie; Dörrie, Jan; Schaft, Niels (RNA Vaccines, 2024)
Electroporation (EP) of mRNA into human cells is a broadly applicable method to transiently express proteins of choice in a variety of different cell types. We have spent more than two decades to optimize and adapt this method, first for antigen-loading of dendritic cells (DCs) and subsequently for T cells, B cells, bulk PBMCs, and several cell lines. In this regard, antigens were introduced, processed, and presented in context of MHC class I and II. Next to that, functional proteins like adhesion receptors, T-cell receptors (TCRs), chimeric antigen receptors (CARs), constitutively active signal transducers (i.e. caIKK), and others were successfully expressed. We have also established this protocol under full GMP compliance as part of a manufacturing license to produce mRNA-electroporated DCs and mRNA-electroporated T cells for therapeutic applications in clinical trials. Therefore, we here want to share our universal mRNA electroporation protocol and the experience we have gathered with this method. The advantages of the transfection method presented here are: (1) easy adaptation to different cell types; (2) scalability from 106 to approximately 108 cells per shot; (3) high transfection efficiency (80–99%); (4) homogenous protein expression; (5) GMP compliance if the EP is performed in a class A clean room; and (6) no transgene integration into the genome. The provided protocol involves: OptiMEM® as EP medium, a square-wave pulse with 500 V, and 4 mm cuvettes. To adapt the protocol to differently sized cells, simply the pulse time has to be altered. Thus, we share an overview of proven electroporation settings (including recovery media), which we have established for various cell types. Next to the basic protocol, we also provide an extensive list of hints and tricks, which, in our opinion, are of great value for everyone who intends to use this transfection technique.
CRIS-Team Scopus Importer:2024-08-23
Keywords: Antigen expression; B cell; CAR; GMP; Immunotherapy; Monocyte; Monocyte-derived DC (moDC); mRNA electroporation; NK cell; PBMC; Protein expression; T cell; TCR

Electroporation of mRNA as universal technology platform to transfect a variety of primary cells with antigens and functional proteins - Gerer, Kerstin F.; Hoyer, Stefanie; Dörrie, Jan; Schaft, Niels (RNA Vaccines - Methods and Protocols, 2017)
Electroporation (EP) of mRNA into human cells is a broadly applicable method to transiently express proteins of choice in a variety of different cell types. We have spent more than a decade to optimize and adapt this method, first for antigen-loading of dendritic cells (DCs), and subsequently for T cells, B cells, bulk PBMCs, and several cell lines. In this regard, antigens were introduced, processed, and presented in context of MHC class I and II. Next to that, functional proteins like adhesion receptors, T-cell receptors (TCRs), chimeric antigen receptors (CARs), constitutively active signal transducers, and others were successfully expressed. We have also established this protocol under full GMP compliance as part of a manufacturing license to produce mRNA-electroporated DCs for therapeutic vaccination in clinical trials. Therefore, we here want to share our universal mRNA electroporation protocol and the experience we have gathered with this method. The advantages of the transfection method presented here are: (1) easy adaptation to different cell types, (2) scalability from 106to approximately 108cells per shot, (3) high transfection efficiency (80-99 %), (4) homogenous protein expression, (5) GMP compliance if the EP is performed in a class A clean room, and (6) no transgene integration into the genome. The provided protocol involves: Opti-MEM® as EP medium, a square-wave pulse with 500 V, and 4 mm cuvettes. To adapt the protocol to differently sized cells, simply the pulse time is altered. Next to the basic protocol, we also provide an extensive list of hints and tricks, which in our opinion are of great value for everyone who intends to use this transfection technique.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Antigen expression; B cell; CAR; GMP; Immunotherapy; Monocyte-derived DC (moDC); mRNA electroporation; Protein expression; T cell; TCR

Electroporation of siRNA into Mouse Bone Marrow-Derived Macrophages and Dendritic Cells - Siegert, Isabel; Schatz, Valentin; Prechtel, Alexander T.; Steinkasserer, Alexander; Bogdan, Christian; Jantsch, Jonathan (Methods in Molecular Biology, 2014)
Dendritic cells (DC) and macrophages (M?) play a pivotal role in antimicrobial defense, in the regulation of immune responses, and in maintaining tissue homeostasis. The analysis of DC and M? function relies on primary cells albeit these cells are known to be difficult to transfect. This makes the use of small interfering RNA (siRNA) for targeted manipulation of gene expression by RNA interference difficult. In the following chapter, we provide a detailed protocol for the successful transfer of siRNA via electroporation into a defined population of mouse bone marrow-derived M? or DC that does not cause toxicity to the myeloid cells or nonspecific alterations of their biological functions. Factors that influence the transfection and knockdown rate will be highlighted.
EVALuna2:7575

Elevated aluminum excretion in patients by long-term subcutaneous immunotherapy – A cross-sectional case-control study - Hiller, Julia; Göen, Thomas; Drexler, Hans; Berking, Carola; Wagner, Nicola (International Journal of Hygiene and Environmental Health, 2024)
Background: Aluminum (Al) adjuvants have been used in vaccines and subcutaneous immunotherapy (SCIT) for decades. Despite indisputable neurotoxic properties of Al, there is no clear evidence of a causal relationship between their use and any neurotoxic side effects. However, recent rat studies have shown an accumulation of Al from adjuvants in tissues, especially in bones. Objectives: Since the human toxicokinetics of Al-adjuvants are poorly understood, this study aimed to evaluate whether up-dosed or long-term SCIT with Al-coupled extracts leads to increased Al load in humans. Methods: This observational cross-sectional case-control study explored Al excretion in hymenoptera venom allergy patients recruited in 2020 before initiation (n = 10) and during ongoing (n = 12) SCIT with Al-based preparations. Urine samples were collected before and 24 h after the SCIT injections and analyzed for aluminum content by using atomic absorption spectrometry. The cumulative administered Al dose was extracted from patient records. Patients receiving long-term immunotherapy were treated between 2.8 and 13.6 years (mean 7.1). Other potential sources of Al exposure were surveyed. Results: Patients who had received Al-coupled immunotherapy for several years showed significantly (p < 0.001) higher Al excretion than the controls at initiation of immunotherapy (mean 18.2 μg/gC vs. 7.9 μg/gC) and predominantly (73%) were above the 95th percentile of the general populations' exposure (>15 μg/gC), however, without reaching levels of toxicological concern (>50 μg/gC). Taking both groups together excreted Al levels correlated with the cumulative administered Al dose from SCIT (linear regression: Alurine = 8.258 + 0.133*Alcum; p = 0.001). Discussion: These results suggest a relevant iatrogenic contribution of long-term SCIT to human internal Al burden and potential accumulation. Considering the medical benefits of Al-adjuvants and SCIT a differentiated risk-benefit analysis is needed. For certain scenarios of potential toxicological concern in clinical practice biomonitoring might be advisable.
CRIS-Team Scopus Importer:2024-03-15
Keywords: Adjuvant; Aluminum; Biomonitoring; Immunologic desensitization; Risk assessment; Venom hypersensitivity

Emerging functional markers for cancer stem cell-based therapies: Understanding signaling networks for targeting metastasis - Marquardt, Stephan; Solanki, Manish; Spitschak, Alf; Vera, Julio; Puetzer, Brigitte M. (Seminars in Cancer Biology, 2018)
Metastasis is one of the most challenging issues in cancer patient management, and effective therapies to specifically target disease progression are missing, emphasizing the urgent need for developing novel anti-metastatic therapeutics. Cancer stem cells (CSCs) gained fast attention as a minor population of highly malignant cells within liquid and solid tumors that are responsible for tumor onset, self-renewal, resistance to radio- and chemotherapies, and evasion of immune surveillance accelerating recurrence and metastasis. Recent progress in the identification of their phenotypic and molecular characteristics and interactions with the tumor microenvironment provides great potential for the development of CSC-based targeted therapies and radical improvement in metastasis prevention and cancer patient prognosis. Here, we report on newly uncovered signaling mechanisms controlling CSC's aggressiveness and treatment resistance, and CSC-specific agents and molecular therapeutics, some of which are currently under investigation in clinical trials, gearing towards decisive functional CSC intrinsic or surface markers. One special research focus rests upon subverted regulatory pathways such as insulin-like growth factor 1 receptor signaling and its interactors in metastasis-initiating cell populations directly related to the gain of stem cell- and EMT-associated properties, as well as key components of the E2F transcription factor network regulating metastatic progression, microenvironmental changes, and chemoresistance. In addition, the study provides insight into systems biology tools to establish complex molecular relationships behind the emergence of aggressive phenotypes from high-throughput data that rely on network-based analysis and their use to investigate immune escape mechanisms or predict clinical outcome-relevant CSC receptor signaling signatures. We further propose that customized vector technologies could drastically enhance systemic drug delivery to target sites, and summarize recent progress and remaining challenges. This review integrates available knowledge on CSC biology, computational modeling approaches, molecular targeting strategies, and delivery techniques to envision future clinical therapies designed to conquer metastasis-initiating cells.
EVALuna2:203615

Employing Graph Representations for Cell-Level Characterization of Melanoma MELC Samples - Rivera Monroy, Luis Carlos; Rist, Leonhard; Eberhardt, Martin; Ostalecki, Christian; Baur, Andreas; Vera, Julio; Breininger, Katharina; Maier, Andreas (2023 IEEE 20th International Symposium on Biomedical Imaging (ISBI), 2023)
Histopathology imaging is crucial for the diagnosis and treatment of skin diseases. For this reason, computer-assisted approaches have gained popularity and shown promising results in tasks such as segmentation and classification of skin disorders. However, collecting essential data and sufficiently high-quality annotations is a challenge. This work describes a pipeline that uses suspected melanoma samples that have been characterized using Multi-Epitope-Ligand Cartography (MELC). This cellular level characterization of the tissue is then represented as a graph and finally used to train a graph neural network. This imaging technology, combined with the methodology proposed in this work, achieves a classification accuracy of 87 %, outperforming existing approaches by 10 %.<br

EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells - Lindner, Pablo; Paul, Sushmita; Eckstein, Markus; Hampel, Chuanpit; Muenzner, Julienne K.; Erlenbach-Wuensch, Katharina; Ahmed, Husayn P.; Mahadevan, Vijayalakshmi; Brabletz, Thomas; Hartmann, Arndt; Vera, Julio; Schneider-Stock, Regine (Cell Death & Disease, 2020)
Epigenetic deregulation remarkably triggers mechanisms associated with tumor aggressiveness like epithelial–mesenchymal transition (EMT). Since EMT is a highly complex, but also reversible event, epigenetic processes such as DNA methylation or chromatin alterations must be involved in its regulation. It was recently described that loss of the cell cycle regulator p21 was associated with a gain in EMT characteristics and an upregulation of the master EMT transcription factor ZEB1. In this study, in silico analysis was performed in combination with different in vitro and in vivo techniques to identify and verify novel epigenetic targets of ZEB1, and to proof the direct transcriptional regulation of SETD1B by ZEB1. The chorioallantoic-membrane assay served as an in vivo model to analyze the ZEB1/SETD1B interaction. Bioinformatical analysis of CRC patient data was used to examine the ZEB1/SETD1B network under clinical conditions and the ZEB1/SETD1B network was modeled under physiological and pathological conditions. Thus, we identified a self-reinforcing loop for ZEB1 expression and found that the SETD1B associated active chromatin mark H3K4me3 was enriched at the ZEB1 promoter in EMT cells. Moreover, clinical evaluation of CRC patient data showed that the simultaneous high expression of ZEB1 and SETD1B was correlated with the worst prognosis. Here we report that the expression of chromatin modifiers is remarkably dysregulated in EMT cells. SETD1B was identified as a new ZEB1 target in vitro and in vivo. Our study demonstrates a novel example of an activator role of ZEB1 for the epigenetic landscape in colorectal tumor cells.
CRIS-Team Scopus Importer:2020-03-20

Endogenous Expression of the Human CD83 Attenuates EAE Symptoms in Humanized Transgenic Mice and Increases the Activity of Regulatory T Cells - Zinser, Elisabeth; Naumann, Ronald; Wild, Andreas; Michalski, Julia; Deinzer, Anja; Stich, Lena; Kuhnt, Christine; Steinkasserer, Alexander; Knippertz, Ilka (Frontiers in Immunology, 2019)
The CD83 is a type I membrane protein and part of the immunoglobulin superfamily of receptors. CD83 is involved in the regulation of antigen presentation and dendritic cell dependent allogeneic T cell proliferation. A soluble form of CD83 inhibits dendritic cell maturation and function. Furthermore, CD83 is expressed on activated B cells, T cells, and in particular on regulatory T cells. Previous studies on murine CD83 demonstrated this molecule to be involved in several immune-regulatory processes, comprising that CD83 plays a key role in the development and function of different immune cells. In order to get further insights into the function of the human CD83 and to provide preclinical tools to guide the function of CD83/sCD83 for therapeutic purposes we generated Bacterial Artificial Chromosomes (BAC) transgenic mice. BACs are excellent tools for manipulating large DNA fragments and are utilized to engineer transgenic mice by pronuclear injection. Two different founders of BAC transgenic mice expressing human CD83 (BAC-hCD83(tg) mice) were generated and were examined for the hCD83 expression on different immune cells as well as both the in vitro and in vivo role of human CD83 (hCD83) in health and disease. Here, we found the hCD83 molecule to be present on activated DCs, B cells and subtypes of CD4(+) T cells. CD8(+) T cells, on the other hand, showed almost no hCD83 expression. To address the function of hCD83, we performed in vitro mixed lymphocyte reactions (MLR) as well as suppression assays and we used the in vivo model of experimental autoimmune encephalomyelitis (EAE) comparing wild-type and hCD83-BAC mice. Results herein showed a clearly diminished capacity of hCD83-BAC-derived T cells to proliferate accompanied by an enhanced activation and suppressive activity of hCD83-BAC-derived Tregs. Furthermore, hCD83-BAC mice were found to recover faster from EAE-associated symptoms than wild-type mice, encouraging the relevance also of the hCD83 as a key molecule for the regulatory phenotype of Tregs in vitro and in vivo.
CRIS-Team WoS Importer:2019-07-12

Engineering Therapeutic Regulatory T Cells to Overexpress G Protein-Coupled Receptor 15 Improves Functional Fitness for In Vivo Gut Homing - Müller, Tanja; Liu, Lijuan; Wiesinger, Manuel; Atreya, Imke; Atreya, Raja; Bacher, Petra; Becker, Christoph; Bojarski, Christian; Britzen-Laurent, Nathalie; Bosch-Voskens, Caroline; Chang, Hyun Dong; Diefenbach, Andreas; et al. (Gastroenterology, 2025)
CRIS-Team Scopus Importer:2025-01-31

Engulfment of mast cell secretory granules on skin inflammation boosts dendritic cell migration and priming efficiency - Dudeck, Jan; Froebel, Julia; Kotrba, Johanna; Lehmann, Christian; Dudziak, Diana; Speier, Stephan; Nedospasov, Sergei A.; Schraven, Burkhart; Dudeck, Anne (Journal of Allergy and Clinical Immunology, 2019)
Background: Mast cells (MCs)are best known as key effector cells of allergic reactions, but they also play an important role in host defense against pathogens. Despite increasing evidence for a critical effect of MCs on adaptive immunity, the underlying mechanisms are poorly understood. Objective: Here we monitored MC intercellular communication with dendritic cells (DCs), MC activation, and degranulation and tracked the fate of exocytosed mast cell granules (MCGs)during skin inflammation. Methods: Using a strategy to stain intracellular MCGs in vivo, we tracked the MCG fate after skin inflammation–induced MC degranulation. Furthermore, exogenous MCGs were applied to MC-deficient mice by means of intradermal injection. MCG effects on DC functionality and adaptive immune responses in vivo were assessed by combining intravital multiphoton microscopy with flow cytometry and functional assays. Results: We demonstrate that dermal DCs engulf the intact granules exocytosed by MCs on skin inflammation. Subsequently, the engulfed MCGs are actively shuttled to skin-draining lymph nodes and finally degraded inside DCs within the lymphoid tissue. Most importantly, MCG uptake promotes DC maturation and migration to skin-draining lymph nodes, partially through MC-derived TNF, and boosts their T-cell priming efficiency. Surprisingly, exogenous MCGs alone are sufficient to induce a prominent DC activation and T-cell response. Conclusion: Our study highlights a unique feature of peripheral MCs to affect lymphoid tissue–borne adaptive immunity over distance by modifying DC functionality through delivery of granule-stored mediators.
CRIS-Team Scopus Importer:2019-05-03
Keywords: adaptive immune response; dendritic cells; Mast cells; skin inflammation; T-cell response

Enhancing lentiviral transduction to generate melanoma-specific human T cells for cancer immunotherapy - Simon, Bianca; Harrer, Dennis C.; Thirion, Christian; Schuler-Thurner, Beatrice; Schuler, Gerold; Uslu, Ugur (Journal of Immunological Methods, 2019)
Introduction of a tumor antigen-specific T cell receptor (TCR) into patient-derived lymphocytes has already exhibited promising results for the treatment of melanoma and other malignancies in clinical trials. However, insufficient or unsuccessful ex vivo manufacturing of engineered T cells due to low expansion and/or transduction rate can still be observed in some patients. Thus, we isolated human CD8+ T cells from healthy donors and equipped them with a gp100-specific TCR using a lentiviral construct in combination with a novel chemical lentiviral transduction enhancer (Lentiboost) to increase the rate of transduced cells. Following experiments to determine the ideal multiplicity of infection (MOI) and to analyze the efficacy of the transduction enhancer using a GFP-encoding lentivirus, we analyzed in the next step the transduction rate, cell count, and functionality of gp100 TCR-transduced T cells, i.e. antigen-specific cytokine secretion and lytic capacity. In order to increase the number of transduced cells, antigen-specific stimulation was performed, either once for 1 week (1st activation) or twice for another week (2nd activation). In general, each cycle of antigen-specific stimulation resulted in expansion of TCR-positive cells, while no further significant increase of transduced cells was observed after 2nd activation. Cytokine production pattern of transduced cells after antigen encounter, however, revealed significant antigen-specific secretion of TNF and IFNγ after the 1st as well as the 2nd activation. Furthermore, TCR T cells, either activated once or twice, showed significant cytotoxicity towards antigen-positive tumor cells. Taken together, these results show that it is feasible to transduce human T cells using a lentiviral construct in combination with this novel lentiviral transduction enhancer, which shows potential in the growing field of cancer immunotherapy.
CRIS-Team Scopus Importer:2019-06-25
Keywords: Adoptive T cell therapy; gp100; Lentiboost; Lentivirus; T cell receptor; Tumor antigen

Entwicklung und Evaluation eines interprofessionellen Lehrkonzepts zum modernen Wundmanagement - Bergendahl, Lukas; Werner, Felix; Schmidt, Anita; Ronicke, Moritz; Renner, Regina; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-10-09

Environment affects dendritic cells' response via Aryl Hydrocarbon Receptor ligands: a comparison between endogenous and exogenous ligands - Sadeghi Shermeh, Atefeh; Wild, Andreas; Michalski, Julia; Steinkasserer, Alexander (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Environmental signals rather than layered ontogeny imprint the function of type 2 conventional dendritic cells in young and adult mice - Papaioannou, Nikos E.; Salei, Natallia; Rambichler, Stephan; Ravi, Kaushikk; Popovic, Jelena; Küntzel, Vanessa; Lehmann, Christian; Fiancette, Remi; Salvermoser, Johanna; Gajdasik, Dominika W.; Mettler, Ramona; Messerer, Denise; et al. (Nature Communications, 2021)
Conventional dendritic cells (cDC) are key activators of naive T cells, and can be targeted in adults to induce adaptive immunity, but in early life are considered under-developed or functionally immature. Here we show that, in early life, when the immune system develops, cDC2 exhibit a dual hematopoietic origin and, like other myeloid and lymphoid cells, develop in waves. Developmentally distinct cDC2 in early life, despite being distinguishable by fate mapping, are transcriptionally and functionally similar. cDC2 in early and adult life, however, are exposed to distinct cytokine environments that shape their transcriptional profile and alter their ability to sense pathogens, secrete cytokines and polarize T cells. We further show that cDC2 in early life, despite being distinct from cDC2 in adult life, are functionally competent and can induce T cell responses. Our results thus highlight the potential of harnessing cDC2 for boosting immunity in early life.
CRIS-Team Scopus Importer:2021-01-29

Envisioning the application of systems biology in cancer immunology - Jaitly, Tanushree; Gupta, Shailendra K.; Wolkenhauer, Olaf; Schuler, Gerold; Vera, Julio (Cancer Immunology: A Translational Medicine Context, 2020)
Biomedical research is nowadays concerned with the investigation of complex biological networks, in which dozens to thousands of proteins, genes, and miRNAs interact to control cellular or tissue-level phenotypes. Investigation of these complex biological networks requires the use of various experimental methodologies that generate massive amounts of quantitative data. In this scenario, Systems Biology emerged a decade ago as a methodological approach that combines quantitative experimental data, mathematical modeling, and other tools from computational biology, aiming to understand the regulation of these complex biochemical systems. The interaction between tumors and the immune system is not an exception to this scenario. The immune system is by definition a multiscale system not only because it involves biochemical networks that regulate the fate of immune cells, but also because immune cells communicate with each other by direct contact or through secretion of local or global signals. Furthermore, tumor and immune cells communicate, and this interaction is affected by the features of the microenvironment in which the tumor is hosted. Altogether, we are envisioning a complex multiscale biological system, whose analysis requires a systemic view to succeed integrating massive amounts of quantitative experimental data coming from different temporal and spatial scales. In this book chapter, we introduce the elements of the systems biology approach. Furthermore, we discuss some published results that suggest how systems biology can be used in the context of oncology and tumor immunology, with a focus on the development and assessment of anticancer therapies. To facilitate the reading, the chapter contains a glossary of systems biology terms.
CRIS-Team Scopus Importer:2020-06-19
Keywords: Biochemical Networks; Computational Approaches; Immunolgy; Omics; Tumor

Eosinophil-cationic protein - a novel liquid prognostic biomarker in melanoma - Krueckel, Annika; Moreira, Alvaro; Froehlich, Waltraud; Schuler, Gerold; Heinzerling, Lucie (BMC Cancer, 2019)
BackgroundThe role of eosinophils in cancer is not yet completely understood, but patients with eosinophilia show a trend towards longer survival in several types of cancer, including melanoma. However, eosinophil count at initial diagnosis of metastatic melanoma does not predict survival. Since eosinophil cationic protein (ECP) mediates anticancer effects, such as tissue remodelling and cytotoxic activity, we investigated this marker as an early prognostic marker in metastatic melanoma.MethodsSerum of 56 melanoma patients was collected at the time of diagnosis of metastatic disease. ECP levels as measured by ELISA were correlated with overall survival (OS) in patients before systemic therapy with immunotherapy or chemotherapy. Statistical analyses were performed using the Log-Rank (Mantel-Cox) test.ResultsThe median OS for patients with high serum ECP above 12.2ng/ml was 12months (n=39), compared to 28months for patients with ECP below this threshold (n=17; p=0.0642). In patients with cutaneous melanoma, excluding patients with uveal and mucosal melanoma, the survival difference was even more striking (p=0.0393). ECP's effect size on OS was observed independently of the consecutive therapy. ECP levels were not correlated with LDH levels.ConclusionECP seems to be a novel prognostic serum marker for the outcome of melanoma patients, which is independent of LDH and easy to perform in clinical practice. The striking negative prognostic value of high ECP level is unanticipated and can guide patient management.
CRIS-Team WoS Importer:2019-03-22

Eosinophil-cationic protein: A novel liquid prognostic biomarker in melanoma - Moreira, Alvaro; Krueckel, Annika; Schuler, Gerold; Heinzerling, Lucie (2018)
EVALuna2:203621

Eosinophilic count as a biomarker for prognosis of melanoma patients and its importance in the response to immunotherapy - Moreira, Alvaro; Leisgang, Waltraud; Schuler, Gerold; Heinzerling, Lucie (Immunotherapy, 2017)
AIM: The prognostic role of eosinophils in cancer has been controversial. Some entities such as gastrointestinal cancers show a better survival, while others such as Hodgkin's lymphoma a worse survival in patients with eosinophilia. Patients who exhibited an increase in eosinophils upon therapy with ipilimumab or pembrolizumab were shown to survive longer. We wanted to investigate whether eosinophilia is a prognostic marker in metastatic melanoma. METHODS: In total, 173 patients with metastatic melanoma from our data base (median age 60 years; n = 86 with immunotherapy, n = 87 without immunotherapy) were analyzed for eosinophil counts and survival over the course of 12 years. Eosinophilic count was detected by peripheral blood smear. The ethical committee had approved this retrospective study. RESULTS: Melanoma patients with eosinophilia at any point in their course of disease show a trend toward longer survival independently of their therapy. There is a statistically significant difference for the patients who survive at least 12 months (p < 0.005). In patients with checkpoint inhibitor therapy, survival was significantly prolonged in every patient with eosinophilia (p < 0.05). Furthermore, 69% of the patients treated with immunotherapy experienced at least once an eosinophilia of 5% or greater compared with 46% in the immunotherapy naive-group; for an eosinophilia of 10% values were 30 and 9%, respectively. Interestingly, in patients with more than 20% eosinophils (n = 7) survival was prolonged with a median of 35 months (range 19-60 months) as compared with 16 months (range 1-117 months). CONCLUSION: Eosinophilia is a prognostic marker in patients with metastatic melanoma.
EVALuna2:34325

Eosinophilic count as a biomarker for prognosis of melanoma patients - Moreira, Alvaro; Heinzerling, Lucie (2017)
EVALuna2:34330

Eosinophilic Fasciitis by Treatment with Checkpoint Inhibitors in metastatic Melanoma - Toussaint, Frédéric; Erdmann, M.; Moreira, Alvaro; Kirchberger, M. C.; Schuler, Gerold; Heinzerling, Lucie (2018)
EVALuna2:34779

Eosinophilic polymorphic and pruritic eruption associated with radiotherapy: case report and overview of disease characteristics - Löbelenz, L.; Schliep, S.; Wörl, Petra; Uslu, Ugur (Clinical and Experimental Dermatology, 2019)
CRIS-Team Scopus Importer:2019-06-25

Epidemiology, comorbidities, and healthcare utilization of patients with chronic urticaria in Germany - Weller, K.; Maurer, M.; Bauer, A.; Wedi, B.; Wagner, Nicola; Schliemann, S.; Kramps, T.; Baeumer, D.; Multmeier, J.; Hillmann, E.; Staubach, P. (Journal of the European Academy of Dermatology and Venereology, 2021)
Background: Comprehensive data on the epidemiology and comorbidities of chronic urticaria (CU) in Germany are either limited, or not contemporary. Objectives: To investigate the epidemiology of CU, overall comorbidities and healthcare resource utilized by patients with CU in Germany, using an anonymized statutory health insurance (SHI) database. Methods: Anonymized SHI claims research database of the Institute for Applied Health Research, Berlin [InGef] (01 January 2015–30 September 2018) was used to analyse insured individuals with a confirmed diagnosis of CU (ICD-10-GM codes). Twelve-month diagnosed prevalence and incidence, comorbidities (vs. atopic dermatitis and psoriasis), and healthcare utilization by patients with CU were investigated. Results: Of 4 693 772 individuals of all ages listed in the database, 3 538 540 were observable during 2017. Overall, 17 524 patients (˜0.5%) were diagnosed with CU; chronic spontaneous urticaria (CSU: 71.2%), chronic inducible urticaria (CIndU: 19.7%), CSU+CIndU (9.1%). Females, vs. males, had higher diagnosed prevalence (0.62% vs. 0.37%) and diagnosed incidence (0.18% vs. 0.11%) of CU among all patients. Patients most frequently visited general practitioners (41.3% of total visits). Hypertensive diseases (43.5%), lipoprotein metabolism disorders (32.1%) and affective disorders (26.0%) were the most frequently reported comorbidities of special interest. Rates of most comorbidities of special interests were similar to atopic dermatitis and psoriasis patients, and all higher vs. overall population. More than half (54.1%) of all CU patients were not prescribed any treatment. Second-generation H1-antihistamines were the most commonly prescribed medication for adult (17.9%) and paediatric (27.9%) patients. Patients with CIndU (paediatric, 15.5%; adult, 7.8%) were more often hospitalized versus patients with CSU (paediatric, 9.9%; adult, 4.6%). Conclusions: In Germany, prevalence of CU along with multiple comorbidities may pose increased burden on the healthcare system. Awareness of adhering to treatment guidelines, and aiming for complete control of urticaria, needs to be driven and may improve outcomes.
CRIS-Team Scopus Importer:2021-11-19

Epidemiology of patch tested patients with permanent tattoos—A comparative analysis of 9693 IVDK patients (2020–2022) - Schubert, S.; Oppel, E.; Bauer, A.; Schröder-Kraft, C.; Löffler, H.; Strom, K.; Worm, M.; Brans, R.; Wagner, Nicola; Angela, Y.; Geier, J.; Beiteke, Ulrike; et al. (Contact Dermatitis, 2024)
Background: Permanent tattooing is the invasive introduction of tattoo ink (pigments) into the dermis. The ink and aftercare cosmetics applied on pre-damaged skin may contain skin sensitisers. Objectives: To identify patient characteristics and the pattern of sensitisation in tattooed patients patch tested within the Information Network of Departments of Dermatology (IVDK). Patients and Methods: Comparative analysis of patient characteristics and reaction frequencies to baseline series allergens in 1648 consecutive patients with and 8045 consecutive patients without permanent tattoos. Non-overlapping 95%-confidence intervals were considered as significant. Results: Having permanent tattoos was related with female sex, age <40 years, tobacco smoking, atopic dermatitis, (occupational) hand dermatitis and being employed in particular occupational groups (e.g., healthcare workers, mechanics, hairdressers). Sensitisation to nickel was increased in tattooed patients and associated with female sex (OR 4.23 [95%-CI, 3.48–5.18]), age ≥40 years (OR 1.26 [95%-CI, 1.08–1.49]), tobacco smoking (OR 1.19 [95%-CI, 1.01–1.40]) and having permanent tattoos (OR 1.27 [95%-CI, 1.05–1.53]). Conclusions: The association between nickel sensitisation and permanent tattoos is probably confounded by past reactions to pierced costume jewellery. Socio-economic factors most probably contribute to the connection between tattoos, tobacco smoking, occupational or hand dermatitis, and being employed in particular occupational groups.
CRIS-Team Scopus Importer:2024-07-26
Keywords: allergic contact dermatitis; nickel; patch test; permanent make-up; tattoo; tattoo aftercare cosmetics

Epidermotropie von Immunzellen unterscheidet Pyoderma gangraenosum vom Ulcus cruris venosum - Ronicke, Moritz; Baur, Andreas; Kirr, Michael; Erdmann, Michael; Erfurt-Berge, Cornelia; Ostalecki, Christian (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
HINTERGRUND UND ZIELE: Pyoderma gangraenosum ist eine ulzerierende, autoinflammatorische Erkrankung. Es gibt keine eindeutigen histopathologischen Merkmale zur Differenzierung von anderen Ursachen chronischer Wunden wie dem Ulcus cruris venosum. Ziel dieser Studie war es, histopathologische Merkmale von Pyoderma gangraenosum und Unterschiede zu venösen Ulzerationen zu detektieren. PATIENTEN UND METHODIK: Acht Gewebeproben von Pyoderma gangraenosum, zwölf Proben von Ulcus cruris venosum und sechs Proben von gesunder Haut wurden einer immunhistologischen Multi-Antigen-Analyse unterzogen. Das Immuninfiltrat und seine räumliche Verteilung wurden anhand von Fluoreszenzbildern mit einer Gewebezytometriesoftware analysiert. ERGEBNISSE: Die dichte epidermale Präsenz von CD45RO+ -T-Gedächtnis-Zellen und die Rarefizierung von CD1a+ -Langerhans-Zellen in der Epidermis waren Marker für Pyoderma gangraenosum, welche auch auf eine epidermale Immunreaktion schließen lassen. Darüber hinaus konnte dermal eine hohe Anzahl CD11c+ CD68+ pro-inflammatorischer M1-Makrophagen nachgewiesen werden. Diese überstieg die Anzahl der in venösen Ulzerationen beobachteten Makrophagen deutlich. SCHLUSSFOLGERUNGEN: Die histopathologischen Unterschiede zwischen Pyoderma gangraenosum und Ulcus cruris venosum können zur Unterscheidung der beiden Erkrankungen herangezogen werden und somit eine wichtige Hilfe zur schnellen Einleitung einer adäquaten Therapie sein. Darüber hinaus deuten unsere Daten auf einen antigengesteuerten Prozess in der Epidermis hin, möglicherweise unter Beteiligung von CD1a+ Langerhans-Zellen.
CRIS-Team Scopus Importer:2022-06-03

Epidermotropism of inflammatory cells differentiates pyoderma gangrenosum from venous leg ulcers - Ronicke, Moritz; Baur, Andreas; Kirr, Michael; Erdmann, Michael; Erfurt-Berge, Cornelia; Ostalecki, Christian (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
Background and objectives Pyoderma gangrenosum is an ulcerative autoinflammatory disease, lacking distinct histopathological characteristics to differentiate from other ulcerating conditions, like venous leg ulcers. The objective of this study was therefore to find histopathological characteristics of pyoderma gangrenosum in a head-to-head comparison to venous leg ulcers. Patients and methods Eight tissue samples of pyoderma gangrenosum, twelve samples of venous leg ulcers and six samples of healthy skin were stained using an immunohistological multi antigen staining technology. The immune infiltrate and its spatial distribution were analyzed with contextual tissue cytometry software using fluorescence images. Results The dense epidermal presence of CD45RO(+) memory T cells and the rarefication of CD1a(+) Langerhans cells in the epidermis were defining markers for pyoderma gangrenosum, implicating an epidermal immune reaction. In addition, high numbers of CD11c(+)CD68(+) pro-inflammatory M1 macrophages were detected in the dermis, significantly extending the numbers seen in venous leg ulcers. Conclusions The histopathological differences found between pyoderma gangrenosum and venous leg ulcer can be used to distinguish between the two diseases and thus provide an important aid for the rapid initiation of adequate therapy. In addition, our data hint at an antigen-driven process in the epidermis, possibly involving CD1a(+) Langerhans cells.
CRIS-Team WoS Importer:2022-05-13

Erkennen und Management relevanter Komorbiditäten bei chronischer spontaner Urtikaria - Wagner, Nicola; Berking, Carola (Die Dermatologie, 2024)
Various mechanisms contributing to the activity of chronic spontaneous urticaria (CU) have been postulated. Associated comorbidities are increasingly leading to the discovery of further signaling pathways which may support the activity of chronic urticaria or contribute to low-grade systemic inflammation. Moreover psychoimmunological factors may also be involved. The aim of this work is to improve the clinical care of patients with CU by increasing knowledge regarding optional influencing factors due to comorbidities and to possibly influence disease activity. Chronic urticaria due to autoimmune mechanisms may dispose to other autoimmune diseases, especially autoimmune thyroiditis, which can trigger chronic disease. Association of CU with metabolic syndrome has received little attention to date. Obesity may contribute to low-grade systemic inflammation by cytokine-secreting adipose tissue and hence to mediator-release of mast cells. Furthermore, neuroimmunological pathways, especially increased release of substance P, an activating ligand of Mas-related G protein-coupled receptor X2 (MRGPX2) on mast cells, should be addressed when optimizing therapy.
CRIS-Team Scopus Importer:2024-03-08
Keywords: Chronic disease; Co-factors; Disease progression; Risk factors; Treatment optimization

European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes) - Kandolf, Lidija; Peris, Ketty; Malvehy, Josep; Mosterd, Klara; Heppt, Markus; Fargnoli, Maria Concetta; Berking, Carola; Arenberger, Petr; Bylaite-Bučinskiene, Matilda; del Marmol, Veronique; Dirschka, Thomas; Dreno, Brigitte; et al. (Journal of the European Academy of Dermatology and Venereology, 2024)
A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology, the European Dermatology Forum, the European Academy of Dermatology and Venereology, and the European Union of Medical Specialists was formed to develop European recommendations on AK diagnosis and treatment, based on current literature and expert consensus. This guideline addresses the epidemiology, diagnostics, risk stratification and treatments in immunocompetent as well as immunosuppressed patients. Actinic keratoses (AK) are potential precursors of cutaneous squamous cell carcinoma (cSCC) and display typical histopathologic and immunohistochemical features of this malignancy in an early stage. They can develop into cSSC in situ and become invasive in a low percentage of cases. AK is the most frequent neoplasia in white populations, frequently occurring within a cancerous field induced by ultraviolet radiation. Since it cannot be predicted, which lesion will progress to cSCC and when treatment is usually recommended. The diagnosis of AK and field cancerization is made by clinical examination. Dermatoscopy, confocal microscopy, optical coherence tomography or line-field confocal-OCT can help in the differential diagnosis of AK and other skin neoplasms. A biopsy is indicated in clinically and/or dermatoscopically suspicious and/or treatment-refractory lesions. The choice of treatment depends on patients' and lesion characteristics. For single non-hyperkeratotic lesions, the treatment can be started upon patient's request with destructive treatments or topical treatments. For multiple lesions, field cancerization treatment is advised with topical treatments and photodynamic therapy. Preventive measures such as sun protection, self-examination and repeated field cancerization treatments of previously affected skin areas in high-risk patients are advised.
CRIS-Team Scopus Importer:2024-05-17

European Dermatology Forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: localized scleroderma, systemic sclerosis and overlap syndromes - Knobler, R.; Moinzadeh, P.; Hunzelmann, N.; Kreuter, A.; Cozzio, A.; Mouthon, L.; Cutolo, M.; Rongioletti, F.; Denton, C. P.; Rudnicka, L.; Frasin, L. A.; Smith, V.; et al. (Journal of the European Academy of Dermatology and Venereology, 2017)
The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this guideline provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes of systemic sclerosis with diseases of the rheumatological spectrum.
EVALuna2:34344

European dermatology forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxedema, scleredema and nephrogenic systemic fibrosis - Knobler, R.; Moinzadeh, P.; Hunzelmann, N.; Kreuter, A.; Cozzio, A.; Mouthon, L.; Cutolo, M.; Rongioletti, F.; Denton, C. P.; Rudnicka, L.; Frasin, L. A.; Smith, V.; et al. (Journal of the European Academy of Dermatology and Venereology, 2017)
The term 'sclerosing diseases of the skin' comprises specific dermatological entities which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this guideline provides clinicians with an overview of the diagnosis and treatment of scleromyxedema, scleredema (of Buschke) and nephrogenic systemic sclerosis (nephrogenic fibrosing dermopathy).
EVALuna2:34341

European patch test results with audit allergens as candidates for inclusion in the European Baseline Series, 2019/20: Joint results of the ESSCAA and the EBSB working groups of the ESCD, and the GEIDACC - Uter, Wolfgang; Wilkinson, S. Mark; Aerts, Olivier; Bauer, Andrea; Borrego, Leopoldo; Buhl, Timo; Cooper, Susan M.; Dickel, Heinrich; Gallo, Rosella; Gimenez-Arnau, Ana M.; John, Swen M.; Navarini, Alexander A.; et al. (Contact Dermatitis, 2022)
Background: In 2019, a number of allergens (haptens), henceforth, “the audit allergens,” were considered as potential additions to the European Baseline Series (EBS), namely, sodium metabisulfite, 2-bromo-2-nitropropane-1,3-diol, diazolidinyl urea, imidazolidinyl urea, Compositae mix II (2.5% or 5% pet), linalool hydroperoxides (lin-OOH), limonene hydroperoxides (lim-OOH), benzisothiazolinone (BIT), octylisothiazolinone (OIT), decyl glucoside, and lauryl glucoside; Evernia furfuracea (tree moss), was additionally tested by some departments as well. Objectives: To collect further data on patch test reactivity and clinical relevance of the audit allergens in consecutive patients across Europe. Methods: Patch test data covering the audit allergens in 2019 and 2020 were collected by those departments of the European Surveillance System on Contact Allergies testing these, as well as further collaborators from the EBS working group of the European Society of Contact Dermatitis (ESCD), and the Spanish Grupo Español de Investigación en Dermatitis de Contacto y Alergia Cutánea. As patch test outcome, reactions between day (D) 3 and D5 were considered. Results: Altogether n = 12 403 patients were tested with any of the audit allergen. Positive reactions were most common to lin-OOH 1% pet. (8.74% [95%CI: 8.14–9.37%]), followed by lin-OOH 0.5% pet., and lim-OOH 0.3% pet (5.41% [95% CI: 4.95–5.89%]). Beyond these terpene hydroperoxides, BIT 0.1% pet. was the second most common allergen with 4.72% (95% CI: 4.2–5.28%), followed by sodium metabisulfite 1% pet. (3.75% [95%CI: 3.32–4.23%]) and Compositae mix 5% pet. (2.31% [95% CI: 1.84–2.87%]). For some allergens, clinical relevance was frequently difficult to ascertain. Conclusions: Despite many positive patch test reactions, it remains controversial whether lin- and lim-OOH should be tested routinely, while at least the two preservatives BIT and sodium metabisulfite appear suitable. The present results are a basis for further discussion and ultimately decision on their implementation into routine testing among the ESCD members.
CRIS-Team Scopus Importer:2022-03-04
Keywords: baseline series; benzisothiazolinone; clinical epidemiology; contact allergy; decyl glucoside; patch testing; RRID:SCR_001905; sodium metabisulfite; surveillance

European Surveillance System on Contact Allergies (ESSCA): Characteristics of patients patch tested and diagnosed with irritant contact dermatitis - Loman, Laura; Uter, Wolfgang; Armario-Hita, Jose C.; Ayala, Fabio; Balato, Anna; Ballmer-Weber, Barbara K.; Bauer, Andrea; Bircher, Andreas J.; Buhl, Timo; Czarnecka-Operacz, Magdalena; Dickel, Heinrich; Fuchs, Thomas; et al. (Contact Dermatitis, 2021)
Background Irritant contact dermatitis (ICD) is caused by the acute locally toxic effect of a strong irritant, or the cumulative exposure to various weaker physical and/or chemical irritants.
CRIS-Team WoS Importer:2021-05-28

European Surveillance System on Contact Allergies (ESSCA): Contact allergies in relation to body sites in patients with allergic contact dermatitis - Oosterhaven, Jart A. F.; Uter, Wolfgang; Aberer, Werner; Armario-Hita, Jose C.; Ballmer-Weber, Barbara K.; Bauer, Andrea; Czarnecka-Operacz, Magdalena; Elsner, Peter; Garcia-Gavin, Juan; Gimenez-Arnau, Ana M.; John, Swen M.; Krecisz, Beata; et al. (Contact Dermatitis, 2019)
Background: Analyses of the European Surveillance System on Contact Allergies (ESSCA) database have focused primarily on the prevalence of contact allergies to the European baseline series, both overall and in subgroups of patients. However, affected body sites have hitherto not been addressed.
CRIS-Team WoS Importer:2019-04-16

Evaluating deep learning-based melanoma classification using immunohistochemistry and routine histology: A three center study - Wies, Christoph; Schneider, Lucas; Haggenmüller, Sarah; Bucher, Tabea Clara; Hobelsberger, Sarah; Heppt, Markus; Ferrara, Gerardo; Krieghoff-Henning, Eva I.; Brinker, Titus J. (PLoS ONE, 2024)
Pathologists routinely use immunohistochemical (IHC)-stained tissue slides against MelanA in addition to hematoxylin and eosin (H&E)-stained slides to improve their accuracy in diagnosing melanomas. The use of diagnostic Deep Learning (DL)-based support systems for automated examination of tissue morphology and cellular composition has been well studied in standard H&E-stained tissue slides. In contrast, there are few studies that analyze IHC slides using DL. Therefore, we investigated the separate and joint performance of ResNets trained on MelanA and corresponding H&E-stained slides. The MelanA classifier achieved an area under receiver operating characteristics curve (AUROC) of 0.82 and 0.74 on out of distribution (OOD)-datasets, similar to the H&E-based benchmark classification of 0.81 and 0.75, respectively. A combined classifier using MelanA and H&E achieved AUROCs of 0.85 and 0.81 on the OOD datasets. DL MelanA-based assistance systems show the same performance as the benchmark H&E classification and may be improved by multi stain classification to assist pathologists in their clinical routine.
CRIS-Team Scopus Importer:2024-02-02

Evaluating HIV Prevention Programs: Herpes Simplex Virus Type 2 Antibodies as Biomarker for Sexual Risk Behavior in Young Adults in Resource-Poor Countries - Behling, Juliane; Chan, Adrienne K.; Zeh, Clement; Nekesa, Carolyne; Heinzerling, Lucie (PLoS ONE, 2015)
Measuring effectiveness of HIV prevention interventions is challenged by bias when using self-reported knowledge, attitude or behavior change. HIV incidence is an objective marker to measure effectiveness of HIV prevention interventions, however, because new infection rates are relatively low, prevention studies require large sample sizes. Herpes simplex virus type 2 (HSV-2) is similarly transmitted and more prevalent and could thus serve as a proxy marker for sexual risk behavior and therefore HIV infection.HSV-2 antibodies were assessed in a sub-study of 70,000 students participating in an education intervention in Western Province, Kenya. Feasibility of testing for HSV-2 antibodies was assessed comparing two methods using Fisher's exact test. Three hundred and ninety four students (aged 18 to 22 years) were randomly chosen from the cohort and tested for HIV, Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis. Out of these, 139 students were tested for HSV-2 with ELISA and surveyed for sexual risk behavior and 89 students were additionally tested for HSV-2 with a point-of-contact (POC) test.Prevalence rates were 0.5%, 1.8%, 0.3% and 2.3% for HIV, Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis, respectively. Prevalence of HSV-2 antibodies was 3.4 % as measured by POC test (n=89) and 14.4 % by ELISA (n=139). Specificity of the POC test compared with ELISA was 100%, and the sensitivity only 23.1%. Associations between self-reported sexual behavior and HSV-2 serostatus could not be shown.Associations between self-reported sexual risk behavior and HSV-2 serostatus could not be shown, probably due to social bias in interviews since its transmission is clearly linked. HSV-2 antibody testing is feasible in resource-poor settings and shows higher prevalence rates than other sexually transmitted diseases thus representing a potential biomarker for evaluation of HIV prevention interventions.
EVALuna2:19581

Evaluating the Efficacy and Safety of 4% 5-Fluorouracil Cream in Patients with Actinic Keratosis: An Expert Opinion - Stockfleth, Eggert; Heppt, Markus; Bégeault, Nathalie; Delarue, Alain (Acta Dermato-Venereologica, 2023)
Actinic keratosis is a lesion that develops in sun-exposed areas of the skin and is considered to be a precancerous condition or an early in situ squamous cell carcinoma. Treatment of actinic keratosis is important for reducing skin cancer risk, with treatment choice based on patient-, lesion- and treatment-related considerations. Of the topical treatments used for field-directed therapy, those containing 5-fluorouracil are among the most effective and widely prescribed. The most recently developed topical 5-fluorouracil preparation (Tolak®; Pierre Fabre, France) contains 4% 5-fluorouracil in an aqueous cream. This narrative review discusses data on 4% 5-fluorouracil cream to treat actinic keratosis, and provides the authors' expert opinion on issues associated with it use. The effect of the cream has been evaluated in phase 2 and 3 trials of adult patients with actinic keratosis on the face, ears or scalp. These trials included patients with severe baseline disease, defined by high lesion counts and large-size treatment fields, which possibly affected the proportion of patients who were able to achieve complete clearance. Other efficacy parameters (e.g. percentage change in lesion count, ≥ 75% clearance of lesions or clinically significant changes in validated severity scales) should also be assessed to fully evaluate 4% 5-fluorouracil treatment efficacy in these patients. Nevertheless, 4% 5-fluorouracil is associated with high efficacy, a low level of recurrence and a satisfactory safety profile.
CRIS-Team Scopus Importer:2023-12-01

Evaluation of Long-term Clearance Rates of Interventions for Actinic Keratosis. A Systematic Review - Steeb, Theresa; Wessely, Anja; Petzold, Anne; Brinker, Titus Josef; Schmitz, Lutz; Leiter, Ulrike; Garbe, Claus; Schöffski, Oliver; Berking, Carola; Heppt, M. V. (JAMA Dermatology, 2021)
Importance Multiple interventions are available for the treatment of actinic keratosis (AK). However, most randomized clinical trials and meta-analyses focus on short-term efficacy outcomes. Objective To investigate and synthesize the long-term efficacy (≥12 months) of interventions for AK from parallel-arm randomized clinical trials. Data Sources Searches in MEDLINE, Embase, and Central were conducted from inception until April 6, 2020. The reference lists of the included studies and pertinent trial registers were hand searched. The study was completed February 27, 2021. Study Selection Two reviewers screened the titles and abstracts of 2741 records. Finally, 17 published reports (original studies and follow-up reports) referring to 15 independent randomized clinical trials with an overall sample size of 4252 patients were included. Data Extraction and Synthesis Two reviewers independently extracted data on study, patient, and intervention characteristics. Network meta-analysis (NMA) of each outcome was conducted with a frequentist approach. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidance for NMA was used to assess the certainty of evidence. The revised Cochrane risk-of-bias tool for randomized clinical trials was used to evaluate the methodologic quality. Main Outcomes and Measures Participant complete clearance, participant partial clearance, and lesion-specific clearance were the outcomes, with each assessed at least 12 months after the end of treatment. Results Data from 15 independent randomized clinical trials including 4252 patients were extracted and synthesized. Ten studies were included in an NMA for the outcome of participant complete clearance, with photodynamic therapy with aminolevulinate (ALA-PDT) showing the most favorable risk ratio (RR) compared with placebo (RR, 8.06; 95% CI, 2.07-31.37; GRADE, moderate), followed by imiquimod, 5% (RR, 5.98; 95% CI, 2.26-15.84; GRADE, very low), photodynamic therapy with methyl aminolevulinate (MAL-PDT) (RR, 5.95; 95% CI, 1.21-29.41; GRADE, low), and cryosurgery (RR, 4.67; 95% CI, 1.36-16.66; GRADE, very low). Similarly, ALA-PDT had the highest RR in the NMA for lesion-specific clearance (RR, 5.08; 95% CI, 2.49-10.33; GRADE, moderate). No NMA was possible for participant partial clearance owing to poor reporting of this outcome. Conclusions and Relevance This systematic review and network meta-analysis found that therapy including ALA-PDT, imiquimod, 5%, MAL-PDT, and cryosurgery was associated with significant long-term efficacy in the NMA. This study provides data for a possible use in an evidence-based framework for selecting interventions with sustained lesion clearanc
CRIS-Team WoS Importer:2021-08-13

Evaluation of Melanoma Prediction Studies Using the Prediction Model Risk of Bias Assessment Tool (PROBAST) - Kaiser, Isabelle; Mathes, Sonja; Pfahlberg, Annette; Uter, Wolfgang; Heppt, Markus; Steeb, Theresa; Diehl, Katharina; Gefeller, Olaf (Jahrestagung der DGEpi, 2022)

Evaluation of PD-L1 Expression and HPV Genotyping in Anal Squamous Cell Carcinoma - Wessely, Anja; Heppt, Markus; Kammerbauer, Claudia; Steeb, Theresa; Kirchner, Thomas; Flaig, Michael J.; French, Lars E.; Berking, Carola; Schmoeckel, Elisa; Reinholz, Markus (Cancers, 2020)
Simple Summary
CRIS-Team WoS Importer:2020-11-06

Evidence for liver and peripheral immune cells secreting tumor-suppressive extracellular vesicles in melanoma patients - Lee, Jung Hyun; Eberhardt, Martin; Blume, Katja; Vera, Julio; Baur, Andreas (EBioMedicine, 2020)
Background: Before and after surgery melanoma patients harbor elevated levels of extracellular vesicles in plasma (pEV), suppressing tumor cell activity. However, due to technical reasons and lack of cell-specific biomarkers, their cellular origin remains obscure. Methods: We mimicked the interaction of tumor cells with liver cells and PBMC in vitro, and compared newly secreted EV-associated miRNAs and protein factors with those detected in melanoma patient`s pEV. Findings: Our results suggest that pEV from melanoma patients are secreted in part by residual or relapsing tumor cells, but also by liver and peripheral blood mononuclear cells (PBMC). Our approach identified factors that were seemingly associated either with tumor cell activity, or the counteracting immune system, including liver cells. Notably, the presence/absence of these factors correlated with the clinical stage and tumor relapse. Interpretation: Our study may provide new insights into the innate immune defense against tumor cells and implies that residual tumor cells could be more active than previously thought. In addition we provide some preliminary evidence that pEV marker patterns could be used to predict cancer relapse.
CRIS-Team Scopus Importer:2020-12-04
Keywords: Circulating tumor cells; Liver cells; Melanoma.; miRNA; Pev origin; Plasma extracellular vesicles (pev); Pro-inflammatory cytokines

Exosomal lncRNAs and cancer: connecting the missing links - Naderi-Meshkin, Hojjat; Lai, Xin; Amirkhah, Raheleh; Vera, Julio; Rasko, John E. J.; Schmitz, Ulf (Bioinformatics, 2019)
Motivation: Extracellular vesicles (EVs), including exosomes and microvesicles, are potent and clinically valuable tools for early diagnosis, prognosis and potentially the targeted treatment of cancer. The content of EVs is closely related to the type and status of the EV-secreting cell. Circulating exosomes are a source of stable RNAs including mRNAs, microRNAs and long noncoding RNAs (lncRNAs).
CRIS-Team WoS Importer:2019-03-06

Exosomal ROR1 in peritoneal fluid identifies peritoneal disseminated PDAC and is associated with poor survival - Mittelstädt, Anke; Anthuber, Anna; David, Paul; Podolska, Malgorzata; Benard, Alan; Brunner, Maximilian; Krautz, Christian; Jacobsen, Anne; Denz, Axel; Weber, Klaus; Merkel, Susanne; Hackner, Danilo; et al. (Frontiers in Immunology, 2024)
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and peritoneal dissemination is one major cause for this poor prognosis. Exosomes have emerged as promising biomarkers for gastrointestinal cancers and can be found in all kinds of bodily fluids, also in peritoneal fluid (PF). This is a unique sample due to its closeness to gastrointestinal malignancies. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been identified as a potential biomarker in human cancers and represents a promising target for an immunotherapy approach, which could be considered for future treatment strategies. Here we prospectively analyzed the exosomal surface protein ROR1 (exo-ROR1) in PF in localized PDAC patients (PER-) on the one hand and peritoneal disseminated tumor stages (PER+) on the other hand followed by the correlation of exo-ROR1 with clinical-pathological parameters. Methods: Exosomes were isolated from PF and plasma samples of non-cancerous (NC) (n = 15), chronic pancreatitis (CP) (n = 4), localized PDAC (PER-) (n = 18) and peritoneal disseminated PDAC (PER+) (n = 9) patients and the surface protein ROR1 was detected via FACS analysis. Additionally, soluble ROR1 in PF was analyzed. ROR1 expression in tissue was investigated using western blots (WB), qPCR, and immunohistochemistry (IHC). Exosome isolation was proven by Nano Tracking Analysis (NTA), WB, Transmission electron microscopy (TEM), and BCA protein assay. The results were correlated with clinical data and survival analysis was performed. Results: PDAC (PER+) patients have the highest exo-ROR1 values in PF and can be discriminated from NC (p <0.0001), PDAC (PER-) (p <0.0001), and CP (p = 0.0112). PDAC (PER-) can be discriminated from NC (p = 0.0003). In plasma, exo-ROR1 is not able to distinguish between the groups. While there is no expression of ROR1 in the exocrine pancreatic tissue, PDAC and peritoneal metastasis show expression of ROR1. High exo-ROR1 expression in PF is associated with lower overall survival (p = 0.0482). Conclusion: With exo-ROR1 in PF we found a promising diagnostic and prognostic biomarker possibly discriminating between NC, PDAC (PER-) and PDAC (PER+) and might shed light on future diagnostic and therapeutic concepts in PDAC.
CRIS-Team Scopus Importer:2024-06-14
Keywords: biomarker; exosomes; PDAC; peritoneal carcinomatosis; peritoneal fluid; peritoneal lavage; ROR1; targeted therapy

Experiences of In-Patients with Skin Cancer in a German University Hospital Setting: A Cross-Sectional Survey - Steeb, Theresa; Wessely, Anja; Merkl, Heike; Voskens, Caroline; Erdmann, Michael; Heinzerling, Lucie; Berking, Carola; Heppt, Markus (Patient Preference and Adherence, 2021)
Purpose: An important measure of hospital quality is the satisfaction of the patients receiving in-patient care. This cross-sectional study aimed to assess skin cancer patients' experiences in a university hospital setting as a measure of quality of cancer care.
CRIS-Team WoS Importer:2021-01-29

Expert consensus on practical aspects in the treatment of chronic urticaria - Bauer, Andrea; Dickel, Heinrich; Jakob, Thilo; Kleinheinz, Andreas; Lippert, Undine; Metz, Martin; Schliemann, Sibylle; Schwichtenberg, Uwe; Staubach, Petra; Valesky, Eva; Wagner, Nicola; Wedi, Bettina; et al. (Allergo Journal, 2021)
Background: Chronic urticaria (CU) is a common disease which represents a considerable burden for many patients. The current urticaria guideline describes the evidence-based diagnosis and treatment of CU. In addition, however, questions often arise in everyday practice that are not addressed by the guideline. Methods: In May 2020, a digital meeting with German urticaria experts was held, in which practical aspects of CU treatment were discussed and supporting aids for everyday clinical treatment formulated. The resulting advice in this document focus on practical questions and the available literature and experiences of the participants. Results: The diagnosis of CU can be made in a short time by means of a thorough anamnesis, a physical examination, and a basic laboratory chemical diagnosis. For this purpose, practical recommendations for everyday practice are given in this paper. An extended diagnosis is only indicated in a few cases and should always be carried out in parallel with an effective therapy. In general, CU should always be treated in the same way, regardless of whether wheals, angioedema or both occur. Symptomatic therapy should be carried out according to the treatment steps recommended by the guidelines. This publication provides practical advice on issues in everyday practice, such as the procedure in the current coronavirus disease 2019 (COVID-19) pandemic, the cardiac risk under higher dosed H1 antihistamines, the self-administration of omalizumab as well as vaccination under omalizumab therapy. In addition to treatment recommendations, topics such as documentation in the practice and family planning with urticaria will be discussed. Discussion: These supporting treatment recommendations serve as an addendum to the current CU guideline and provide support in dealing with CU patients in everyday practice. The aim is to ensure that patients suffering from CU achieve complete freedom of symptoms with the help of an optimal therapy.
CRIS-Team Scopus Importer:2021-04-09
Keywords: Diagnostics; H1 antihistamines; Omalizumab; Therapy; Treatment recommendations

Expert Consensus on practice-relevant Aspects during the Treatment of chronic Urticaria - Bauer, Andrea; Dickel, Heinrich; Jakob, Thilo; Kleinheinz, Andreas; Lippert, Undine; Metz, Martin; Schliemann, Sibylle; Schwichtenberg, Uwe; Staubach, Petra; Valesky, Eva; Wagner, Nicola; Wedi, Bettina; et al. (Allergo Journal, 2021)
CRIS-Team WoS Importer:2021-04-23

Explainable artificial intelligence in skin cancer recognition: A systematic review - Hauser, Katja; Kurz, Alexander; Haggenmüller, Sarah; Maron, Roman C.; von Kalle, Christof; Utikal, Jochen S.; Meier, Friedegund; Hobelsberger, Sarah; Gellrich, Frank F.; Sergon, Mildred; Hauschild, Axel; French, Lars E.; et al. (European Journal of Cancer, 2022)
Background: Due to their ability to solve complex problems, deep neural networks (DNNs) are becoming increasingly popular in medical applications. However, decision-making by such algorithms is essentially a black-box process that renders it difficult for physicians to judge whether the decisions are reliable. The use of explainable artificial intelligence (XAI) is often suggested as a solution to this problem. We investigate how XAI is used for skin cancer detection: how is it used during the development of new DNNs? What kinds of visualisations are commonly used? Are there systematic evaluations of XAI with dermatologists or dermatopathologists? Methods: Google Scholar, PubMed, IEEE Explore, Science Direct and Scopus were searched for peer-reviewed studies published between January 2017 and October 2021 applying XAI to dermatological images: the search terms histopathological image, whole-slide image, clinical image, dermoscopic image, skin, dermatology, explainable, interpretable and XAI were used in various combinations. Only studies concerned with skin cancer were included. Results: 37 publications fulfilled our inclusion criteria. Most studies (19/37) simply applied existing XAI methods to their classifier to interpret its decision-making. Some studies (4/37) proposed new XAI methods or improved upon existing techniques. 14/37 studies addressed specific questions such as bias detection and impact of XAI on man-machine-interactions. However, only three of them evaluated the performance and confidence of humans using CAD systems with XAI. Conclusion: XAI is commonly applied during the development of DNNs for skin cancer detection. However, a systematic and rigorous evaluation of its usefulness in this scenario is lacking.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Artificial intelligence; Dermatology; Man-machine systems; Skin neoplasms; Systematic review

Expression of Senescence Markers - Is Predictive for Immune Therapy with Checkpoint Inhibitors? - Moreira, Alvaro; Gross, S.; Kirchberger, M. C.; Erdmann, M.; Schuler, Gerold; Heinzerling, Lucie (2018)
EVALuna2:34778

Extensive furuncular myiasis in a travel returnee from Africa - Rechtien, Laura; Kaufmann, Matthias; Sticherling, Michael (Journal of the European Academy of Dermatology and Venereology, 2023)
CRIS-Team Scopus Importer:2023-02-17

Extracellular vesicles from mature dendritic cells (DC) differentiate monocytes into immature DC - Schierer, Stefan; Ostalecki, Christian; Zinser, Elisabeth; Lamprecht, Ricarda; Plosnita, Bianca; Stich, Lena; Dörrie, Jan; Lutz, Manfred B.; Schuler, Gerold; Baur, Andreas (Life Science Alliance, 2018)
During inflammation, murine and human monocytes can develop into dendritic cells (DC), but this process is not entirely understood. Here, we demonstrate that extracellular vesicles (EV) secreted by mature human DC (maDC) differentiate peripheral monocytes into immature DC, expressing a unique marker pattern, including 6-sulfo LacNAc (slan), Zbtb46, CD64, and CD14. While EV from both maDC and immature DC differentiated monocytes similar to GM-CSF/IL-4 stimulation, only maDC-EV produced precursors, which upon maturation stimulus developed into T-cell-activating and IL-12p70-secreting maDC. Mechanistically, maDC-EV induced cell signaling through GM-CSF, which was abundant in EV as were IL-4 and other cytokines and chemokines. When injected into the mouse skin, murine maDC-EV attracted immune cells including monocytes that developed activation markers typical for inflammatory cells. Skin-injected EV also reached lymph nodes, causing a similar immune cell infiltration. We conclude that DC-derived EV likely serve to perpetuate an immune reaction and may contribute to chronic inflammation.
EVALuna2:36337

Extracellular Vesicles in the Plasma of Melanoma Patients under-press beta Catenin in Tumor Cells by using miRNA-34a - Baur, A.; Lee, J. H.; Dindorf, J.; Eberhardt, Martin; Lai, Xin; Ostalecki, Christian; Koliha, N.; Wild, Stefanie; Gross, S.; Schuler, Gerold; Vera González, Julio (2018)
EVALuna2:34772

Ex vivo expanded NK Cells from Melanoma Patients receive their Migration in a 3D Model and lyse autologous Melanoma Cells - Rossner, S.; Czerwinski, Tina; Mark, Christoph; Gross, S.; Karg, Margarete; Bosch, Jacobus J.; Schuler-Thurner, Beatrice; Fabry, Ben; Schuler, Gerold; Bosch-Voskens, C. (2018)
EVALuna2:34775

Ex vivo expanded NK cells up-regulate natural cytotoxicity receptors able to mediate autologous melanoma cell killing - Roessner, S.; Gross, S.; Karg, M.; Hamann, A.; Campana, D.; Schuler-Thurner, Beatrice; Bosch, Jacobus J.; Schuler, Gerold; Voskens, C. J. (2017)
EVALuna2:34314

Factors Influencing Disease Progression in Patients with Head and Neck Melanoma - Uslu, Ugur; Schuler, Gerold; Breuninger, Helmut (Anticancer Research, 2017)
BACKGROUND: Histological parameters as well as the status of sentinel lymph node are known to be strong prognostic factors in patients with melanoma. PATIENTS AND METHODS: In this study, we retrospectively analyzed 1,384 patients who were diagnosed with head and neck melanoma between 1976 and 2010 regarding prognostic factors [tumor thickness, level of invasion, sentinel lymph node (SLN) status, ulceration, histological subtype, localization, and gender], overall survival, and disease-free survival. RESULTS: Patients who developed metastases had a significantly thicker tumor than patients without metastases. Additionally, a thicker tumor was often associated with a higher level of invasion (Clark level). There was no overall survival benefit in patients who underwent SLN dissection when compared to patients who did not (p=0.07). Compared to SLN-negative patients, patients with SLN involvement had a significantly shorter disease-free period (p<0.001) and shorter overall survival time (p<0.001). CONCLUSION: In summary, tumor thickness is the most important prognostic factor. SLN dissection does not affect the overall survival of patients with melanoma. However, a positive SLN is a marker for a worse outcome in these patients.
EVALuna2:34319

Factors influencing the adjuvant therapy decision: Results of a real-world multicenter data analysis of 904 melanoma patients - Lodde, Georg; Forschner, Andrea; Hassel, Jessica; Wulfken, Lena M.; Meier, Friedegund; Mohr, Peter; Kähler, Katharina; Schilling, Bastian; Loquai, Carmen; Berking, Carola; Hüning, Svea; Schatton, Kerstin; et al. (Cancers, 2021)
Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74–80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68–80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24–38), and fear of adverse events (21.1%, 95% CI 16–28) and impaired quality of life (11.9%, 95% CI 7–16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47–59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.
CRIS-Team Scopus Importer:2021-05-21
Keywords: Adjuvant treatment; BRAF; Checkpoint blocker; Melanoma; PD-1; Targeted therapy

FAM13A is associated with non-small cell lung cancer (NSCLC) progression and controls tumor cell proliferation and survival - Eisenhut, Felix; Heim, Lisanne; Trump, Sonja; Mittler, Susanne; Sopel, Nina; Andreev, Katerina; Ferrazzi, Fulvia; Ekici, Arif Bülent; Rieker, Ralf; Springel, Rebekka; Assmann, Vera Elisabeth; Lechmann, Matthias; et al. (OncoImmunology, 2017)
Genome-wide association studies (GWAS) associated Family with sequence similarity 13, member A (FAM13A) with non-small cell lung cancer (NSCLC) occurrence. Here, we found increased numbers of FAM13A protein expressing cells in the tumoral region of lung tissues from a cohort of patients with NSCLC. Moreover, FAM13A inversely correlated with CTLA4 but directly correlated with HIF1? levels in the control region of these patients. Consistently, FAM13A RhoGAP was found to be associated with T cell effector molecules like HIF1? and Tbet and was downregulated in immunosuppressive CD4(+)CD25(+)Foxp3(+)CTLA4(+) T cells. TGF?, a tumor suppressor factor, as well as siRNA to FAM13A, suppressed both isoforms of FAM13A and inhibited tumor cell proliferation. RNA-Seq analysis confirmed this finding. Moreover, siRNA to FAM13A induced TGF? levels. Finally, in experimental tumor cell migration, FAM13A was induced and TGF? accelerated this process by inducing cell migration, HIF1?, and the FAM13A RhoGAP isoform. Furthermore, siRNA to FAM13A inhibited tumor cell proliferation and induced cell migration without affecting HIF1?. In conclusion, FAM13A is involved in tumor cell proliferation and downstream of TGF? and HIF1?, FAM13A RhoGAP is associated with Th1 gene expression and lung tumor cell migration. These findings identify FAM13A as key regulator of NSCLC growth and progression.
EVALuna2:6835

Fasten the seat belt: Increasing safety of CAR T-cell therapy - Simon, Bianca; Uslu, Ugur (Experimental Dermatology, 2020)
After the recent success and approvals of chimeric antigen receptor (CAR) T cells in haematological malignancies, its efficacy is currently evaluated in a broad spectrum of tumor entities including melanoma. However, severe and potentially life-threatening side effects like cytokine release syndrome, neurologic toxicities, and the competing risk of morbidity and mortality from the treatment itself are still a major limiting factor in the current CAR T-cell landscape. In addition, especially in solid tumors, the lack of ideal target antigens to avoid on-target/off-tumor toxicities also restricts its use. While various groups are working on strategies to boost CAR T-cell efficacy, mechanisms to increase engineered T-cell safety should not move out of focus. Thus, the aim of this article is to summarize and to discuss current and potential future strategies and mechanisms to increase CAR T-cell safety in order to enable the wide use of this promising approach in melanoma and other tumor entities.
CRIS-Team Scopus Importer:2020-07-17
Keywords: adoptive T-cell therapy; cancer; chimeric antigen receptor; cytokine release syndrome; neurotoxicity

Fatal and Near-Fatal Anaphylaxis: Data From the European Anaphylaxis Registry and National Health Statistics - Höfer, Veronika; Dölle-Bierke, Sabine; Francuzik, Wojciech; Ruëff, Franziska; Sabouraud-Leclerc, Dominique; Treudler, Regina; Moeser, Anne; Hartmann, Karin; Pföhler, Claudia; Wagner, Nicola; Ensina, Luis Felipe; Wedi, Bettina; et al. (The Journal of Allergy and Clinical Immunology: In Practice, 2024)
Background: Anaphylaxis is a serious systemic reaction—data on fatal and near-fatal reactions are limited. Objective: To better understand clinical patterns and risks factors of severe anaphylaxis by a deep analysis of data from fatal and near-fatal anaphylaxis. Methods: Data from the European Anaphylaxis Registry on fatal/near-fatal anaphylactic reactions and national data on anaphylaxis fatalities were investigated. Results: A total of 305 fatal/near-fatal reactions among children and adults including 35 fatalities from the European Anaphylaxis Registry were identified. The most frequent elicitors were drugs, insects, and food. Male patients (66%/60%) were more frequently affected. Male sex, higher age, concomitant mastocytosis, and cardiovascular disease were associated with a more severe outcome. With increasing reaction severity, skin symptoms were less frequently observed (45% of fatal reactions). In parallel, anaphylaxis mortality rates were studied. The data show that anaphylaxis mortality rates increased in Germany from 0.48 (2009) to 0.59 per 1,000,000 population per year (2020). This increase was apparent only in the female population. In this data set, drugs were the most frequent elicitor of anaphylaxis fatalities, and the rate for this increased over time. Conclusions: We identified not only elicitors but also individual factors to be associated with an increased risk of fatal anaphylaxis. Such patients should be recognized and managed with great caution. The increase in drug-induced fatalities points to the need for a better allergological care of patients suffering from drug hypersensitivity.
CRIS-Team Scopus Importer:2024-01-12
Keywords: Allergy; Anaphylaxis; Fatality; Mortality; Risk factors; Severity

Fatigue and Atopic Dermatitis: Results from the German Atopic Dermatitis Registery TREATgermany - Helmert, C.; Haufe, E.; Abraham, S.; Heratizadeh, A.; Harder,; Kleinheinz, A.; Wollenberg, A.; Wiemers, F.; Weisshaar, E.; Augustin, M.; Von Kiedrowski, R.; Wildberg, J.; et al. (GESUNDHEITSWESEN, 2021)
CRIS-Team WoS Importer:2022-05-20

Fcγ receptor IIB (FcγRIIB) maintains humoral tolerance in the human immune system in vivo. - Bärenwaldt, Anne; Lux, Anja; Danzer, Heike; Spriewald, Bernd M.; Ullrich, Evelyn; Heidkamp, Gordon Frederik; Dudziak, Diana; Nimmerjahn, Falk (Proceedings of the National Academy of Sciences of the United States of America, 2011)
Maintenance of immunological tolerance is crucial to prevent development of autoimmune disease. The production of autoantibodies is a hallmark of many autoimmune diseases and studies in mouse model systems suggest that inhibitory signaling molecules may be important checkpoints of humoral tolerance. By generating humanized mice with normal and functionally impaired Fcγ receptor IIB (FcγRIIB) variants, we show that the inhibitory Fcγ-receptor is a checkpoint of humoral tolerance in the human immune system in vivo. Impaired human FcγRIIB function resulted in the generation of higher levels of serum immunoglobulins, the production of different autoantibody specificities, and a higher proportion of human plasmablasts and plasma cells in vivo. Our results suggest that the inhibitory FcγRIIB may be an important checkpoint of humoral tolerance in the human immune system.

FcγRIV deletion reveals its central role for IgG2a and IgG2b activity in vivo. - Nimmerjahn, Falk; Lux, Anja; Albert, Heike; Woigk, Melissa; Lehmann, Christian; Dudziak, Diana; Smith, Patrick; Ravetch, J. V. (Proceedings of the National Academy of Sciences of the United States of America, 2010)
Cellular Fcγ receptors are essential for IgG-dependent effector functions in vivo. There is convincing evidence that selective activating Fcγ receptors are responsible for the activity of individual IgG subclasses. Thus, IgG1 activity is absent in FcγRIII-deficient mice, and several studies suggest that the activity of the most potent IgG subclasses, IgG2a and IgG2b, might be dependent on either individual or a combination of activating FcγRs. To study the role of individual activating FcγRs for IgG subclass activity, we generated an FcγRIV-deficient mouse and showed that a variety of IgG2a- and IgG2b-dependent effector functions are impaired in the absence of this activating Fc receptor in models of autoimmunity and antibody-dependent cellular cytotoxicity.

Fear of cancer progression in patients with stage IA malignant melanoma - Wagner, Tobias; Augustin, Matthias; Blome, Christine; Forschner, Andrea; Garbe, Claus; Gutzmer, Ralf; Hauschild, Axel; Heinzerling, Lucie; Livingstone, Elisabeth; Loquai, Carmen; Schadendorf, Dirk; Terheyden, Patrick; et al. (European Journal of Cancer Care, 2018)
We aimed to determine the prevalence and importance of fear of cancer progression (FoP) in melanoma patients with stage IA tumours to assess psychosocial and demographic factors associated with severity of FoP and to determine the relationship of FoP and quality of life (QoL). One hundred and thirty-six patients with stage IA melanoma completed the short version of the Fear of Progression Questionnaire (FoP-Q-SF), the Hospital Anxiety and Depression Scale (HADS) and the EORTC-QLQ-C30. We found a mean FoP-Q-SF sum score of 30.2 points (±8.4 points SD). In this study, 33% of patients reported high FoP at or above the cutoff-value of 34 points. Higher FoP was found in women (p < 0.01), young (p = 0.03) and employed (p = 0.02) patients. Being confronted with a cancer diagnosis in closely related persons predicted higher FoP (p < 0.01). FoP correlated positively with the HADS anxiety (r = 0.50, p < 0.01) and depression scales (r = 0.26, p < 0.01) and negatively with the EORTC-QLQ-C30 global health state (r = -0.32, p < 0.01). FoP is considerably prevalent in low-risk melanoma patients and associated with reduced QoL, cancer in related persons, women sex and participation in working life. Considerably high levels of FoP, even in patients with low-risk malignancies, underline the need for psychosocial support and psychotherapeutic interventions for melanoma patients.
EVALuna2:34765

Fear of progression in patients with low-risk malignant melanoma - Wagner, T.; Augustin, M.; Blome, C.; Forschner, A.; Garbe, C.; Gutzmer, R.; Hauschild, A.; Heinzerling, Lucie; Livingstone, E.; Mueller-Brenne, T.; Loquai, C.; Schadendorf, D.; et al. (2017)
EVALuna2:34364

Federated Learning for Decentralized Artificial Intelligence in Melanoma Diagnostics - Haggenmüller, Sarah; Schmitt, Max; Krieghoff-Henning, Eva; Hekler, Achim; Maron, Roman C.; Wies, Christoph; Utikal, Jochen S.; Meier, Friedegund; Hobelsberger, Sarah; Gellrich, Frank F.; Sergon, Mildred; Hauschild, Axel; et al. (JAMA Dermatology, 2024)
Importance: The development of artificial intelligence (AI)-based melanoma classifiers typically calls for large, centralized datasets, requiring hospitals to give away their patient data, which raises serious privacy concerns. To address this concern, decentralized federated learning has been proposed, where classifier development is distributed across hospitals. Objective: To investigate whether a more privacy-preserving federated learning approach can achieve comparable diagnostic performance to a classical centralized (ie, single-model) and ensemble learning approach for AI-based melanoma diagnostics. Design, Setting, and Participants: This multicentric, single-arm diagnostic study developed a federated model for melanoma-nevus classification using histopathological whole-slide images prospectively acquired at 6 German university hospitals between April 2021 and February 2023 and benchmarked it using both a holdout and an external test dataset. Data analysis was performed from February to April 2023. Exposures: All whole-slide images were retrospectively analyzed by an AI-based classifier without influencing routine clinical care. Main Outcomes and Measures: The area under the receiver operating characteristic curve (AUROC) served as the primary end point for evaluating the diagnostic performance. Secondary end points included balanced accuracy, sensitivity, and specificity. Results: The study included 1025 whole-slide images of clinically melanoma-suspicious skin lesions from 923 patients, consisting of 388 histopathologically confirmed invasive melanomas and 637 nevi. The median (range) age at diagnosis was 58 (18-95) years for the training set, 57 (18-93) years for the holdout test dataset, and 61 (18-95) years for the external test dataset; the median (range) Breslow thickness was 0.70 (0.10-34.00) mm, 0.70 (0.20-14.40) mm, and 0.80 (0.30-20.00) mm, respectively. The federated approach (0.8579; 95% CI, 0.7693-0.9299) performed significantly worse than the classical centralized approach (0.9024; 95% CI, 0.8379-0.9565) in terms of AUROC on a holdout test dataset (pairwise Wilcoxon signed-rank, P <.001) but performed significantly better (0.9126; 95% CI, 0.8810-0.9412) than the classical centralized approach (0.9045; 95% CI, 0.8701-0.9331) on an external test dataset (pairwise Wilcoxon signed-rank, P <.001). Notably, the federated approach performed significantly worse than the ensemble approach on both the holdout (0.8867; 95% CI, 0.8103-0.9481) and external test dataset (0.9227; 95% CI, 0.8941-0.9479). Conclusions and Relevance: The findings of this diagnostic study suggest that federated learning is a viable approach for the binary classification of invasive melanomas and nevi on a clinically representative distributed dataset. Federated learning can improve privacy protection in AI-based melanoma diagnostics while simultaneously promoting collaboration across institutions and countries. Moreover, it may have the potential to be extended to other image classification tasks in digital cancer histopathology and beyond..
CRIS-Team Scopus Importer:2024-02-23

Fertilität, Kontrazeption und Teratogenität bei Immuncheckpointblockade - Hassel, Jessica C.; Berking, Carola (Die Dermatologie, 2023)
Background: Immune checkpoint inhibitors (ICI) are now being used in a number of dermato-oncological indications. In particular, the approval for adjuvant therapy of high-risk stage IIB/C and III melanoma means that more patients of fertile age receive ICI. Objectives: This raises the question of how ICIs affect male and female fertility and whether they are teratogenic. Materials and methods: Compilation of current data from the summary of product characteristics (SmPCs) and by literature search (PubMed). Results: Immune-related adverse events of ICI can impair fertility in the acute stage, and especially in the case of endocrine side effects, also in the long term. These include hypothyroidism, as well as adrenal and pituitary insufficiency. However, fertility can usually be restored with hormone replacement. Direct autoimmune effects on the reproductive organs are probably very rare, although immune-related orchitis has been described. Reliable contraception should be used in women of childbearing age. Pregnant women should only receive ICI in urgent exceptional cases, because the miscarriage rate is probably significantly increased. Conclusions: Unfortunately, the current data on patient counselling is still very sparse. Scientific studies on the influence of ICI on fertility and teratogenicity are urgently needed.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Autoimmune-associated side effects; Endocrine side effects; High-risk melanoma; Immunotherapy; Miscarriage risk

Fertilität, Teratogenität und Kontrazeption bei BRAF-/MEK-Inhibition - Livingstone, Elisabeth; Berking, Carola (Die Dermatologie, 2023)
Background: Targeted mutation-based therapy with BRAF and MEK inhibitors has become an integral part of systemic therapy for metastatic melanoma in the advanced setting and for the adjuvant therapy of melanoma in stage III after complete resection. Due to the increased chances of survival and early use in the adjuvant situation, fertility preservation as well as aspects of teratogenicity and pregnancy are increasingly relevant in patients who are often still young. Objectives: To communicate the published and study-based information on fertility preservation, teratogenicity and pregnancy under therapy with BRAF and MEK inhibitors. Materials and methods: Summaries of product characteristics as well as studies and case reports on BRAF and MEK inhibitors published in PubMed were used as sources of information. Results: There are no specific preclinical studies or experience in humans on fertility, teratogenicity, and contraception with targeted therapy. Recommendations can only be derived from toxicity studies and individual case reports. Conclusions: Patients should be offered counseling on the options for fertility-protective measures before starting targeted therapy. Due to unclear teratogenicity, adjuvant melanoma therapy with dabrafenib and trametinib should not be initiated in pregnant patients. In the advanced metastatic situation, BRAF and MEK inhibitors should only be given after extensive interdisciplinary education and counselling of the pregnant patient and her partner. Patients should be informed about the need for adequate contraception during targeted therapy.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Fertility preservation; Melanoma; Pharmaceutic adjuvants; Systemic chemotherapy treatment; Targeted therapy

Fertility preservation and management of pregnancy in melanoma patients requiring systemic therapy - Hassel, J. C.; Livingstone, E.; Allam, J. P.; Behre, H. M.; Bojunga, J.; Klein, H. H.; Landsberg, J.; Nawroth, F.; Schuering, A.; Susok, L.; Thoms, K. M.; Kiesel, L.; et al. (ESMO Open, 2021)
Melanoma is one of the most common cancers in adolescents and adults at fertile age, especially in women. With novel and more effective systemic therapies that began to profoundly change the dismal outcome of melanoma by prolonging overall survival, the wish for fertility preservation or even parenthood has to be considered for a growing portion of melanoma patients-from the patients' as well as from the physicians' perspective. The dual blockade of the mitogen-activated protein kinase pathway by B-Raf proto-oncogene serine/threonine kinase and mitogen-activated protein kinase inhibitors and the immune checkpoint inhibition by anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte-associated protein-4 monoclonal antibodies constitute the current standard systemic approaches to combat locally advanced or metastatic melanoma. Here, the preclinical data and clinical evidence of these systemic therapies are reviewed in terms of their potential gonadotoxicity, teratogenicity, embryotoxicity and fetotoxicity. Recommendations for routine fertility and contraception counseling of melanoma patients at fertile age are provided in line with interdisciplinary recommendations for the diagnostic work-up of these patients and for fertility-protective measures. Differentiated recommendations for the systemic therapy in both the adjuvant and the advanced, metastatic treatment situation are given. In addition, the challenges of pregnancy during systemic melanoma therapy are discussed.
CRIS-Team WoS Importer:2021-10-29

Fertility preservation in patients with melanoma—a huge relief for those affected Fertilitätserhalt beim Melanom – eine große Entlastung der Betroffenen - Berking, Carola; Hassel, Jessica C.; Livingstone, Elisabeth (Die Dermatologie, 2023)
CRIS-Team Scopus Importer:2023-07-07

First-line checkpoint inhibitor therapy in metastatic acral lentiginous melanoma compared to other types of cutaneous melanoma: A multicenter study from the prospective skin cancer registry ADOREG - Reinhard, Sören; Utikal, Jochen Sven; Zaremba, Anne; Lodde, Georg; von Wasielewski, Imke; Klespe, Kai Christian; Meier, Friedegund; Haferkamp, Sebastian; Kähler, Katharina C.; Herbst, Rudolf; Gebhardt, Christoffer; Sindrilaru, Anca; et al. (European Journal of Cancer, 2025)
Background: Melanoma is the main cause of skin cancer-related death. Treatment with immune checkpoint inhibitors (CPI) has improved the prognosis in recent years. However, subtypes of melanoma differ in their response. Acral lentiginous melanoma (ALM) has a worse prognosis compared to cutaneous melanoma other than ALM (CM) and is therefore of particular relevance. Aims: To evaluate the efficacy of CPI in first-line treatment of patients with advanced ALM compared CM. Methods: Retrospective analysis of patients with metastatic ALM (n = 45) or CM (n = 328) who received first-line CPI therapy from the multicenter prospective skin cancer registry ADOREG. Study endpoints were best overall response (BOR), progression-free survival (PFS) and overall survival (OS). Results: ALM patients had significantly higher rates of ulcerated tumors, loco regional metastases and fewer BRAF-mutated tumors compared to CM patients. Combined CPI was administered in 48.9 % ALM patients and 39.3 % of CM patients, while the remaining patients received PD-1 monotherapy. OS trended to be shorter in patients with ALM (18.1 vs. 43.8 months, p = 0.10) with no significant differences in PFS (7.0 vs. 11.5 months, p = 0.21). In patients with CM, median OS with combined CPI was not reached, whereas the median OS after PD-1 monotherapy was 37.8 months (p = 0.22). Conversely, in patients with ALM, OS with combined CPI was 17.8 months, compared to 26 months with PD-1 monotherapy (p = 0.15). There were no significant differences in BOR between patients with ALM or CM. Conclusion: Analysis of this real-world cohort of patients with metastatic melanoma showed a trend towards poorer survival outcomes upon first-line treatment with CPI in ALM compared to cutaneous melanoma of other subtypes.
CRIS-Team Scopus Importer:2025-04-01
Keywords: Checkpoint inhibition; Melanoma; Response

First real-world insights on benefit of apremilast treatment in patients with moderate to severe psoriasis after switching from fumaric acid esters from the APART Study - an interim analysis - Mrowietz, U.; Ertner, K.; Sticherling, Michael; Grosse, V.; Popp, G.; Roemmler-Zehrer, J.; Lampl, M.; Helget, U.; Gomez, Nunez N. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Food-Induced Anaphylaxis: Data From the European Anaphylaxis Registry - Dölle-Bierke, Sabine; Höfer, Veronika; Francuzik, Wojciech; Näher, Anatol Fiete; Bilo, Maria Beatrice; Cichocka-Jarosz, Ewa; Lopes de Oliveira, Lucila C.; Fernandez-Rivas, Montserrat; García, Blanca E.; Hartmann, Karin; Jappe, Uta; Köhli, Alice; et al. (The Journal of Allergy and Clinical Immunology: In Practice, 2023)
Background: Food is one of the most common elicitors of anaphylaxis, with an increasing incidence over recent years. Objectives: To characterize elicitor-specific phenotypes and identify factors enhancing the risk or severity of food-induced anaphylaxis (FIA). Methods: We analyzed data from the European Anaphylaxis Registry applying an age- and sex-matched analysis of associations (Cramer's V) for single food triggers and calculated odds ratios (ORs) for severe FIA. Results: We identified 3,427 cases of confirmed FIA showing an age-dependent elicitor ranking (for children: peanut, cow's milk, cashew, and hen's egg; and for adults: wheat flour, shellfish, hazelnut, and soy). The age- and sex-matched analysis revealed defined symptom patterns for wheat and cashew. Wheat-induced anaphylaxis was more frequently associated with cardiovascular symptoms (75.7%; Cramer's V = 0.28) and cashew-induced anaphylaxis with gastrointestinal symptoms (73.9%; Cramer's V = 0.20). Furthermore, concomitant atopic dermatitis was slightly associated with anaphylaxis to hen's egg (Cramer's V = 0.19) and exercise was strongly associated with anaphylaxis to wheat (Cramer's V = 0.56). Additional factors influencing the severity were alcohol intake in wheat anaphylaxis (OR = 3.23; CI, 1.31-8.83) and exercise in peanut anaphylaxis (OR = 1.78; CI, 1.09-2.95). Conclusions: Our data show that FIA is age-dependent. In adults, the range of elicitors inducing FIA is broader. For some elicitors, the severity of FIA seems to be related to the elicitor. These data require confirmation in future studies considering a clear differentiation between augmentation and risk factors in FIA.
CRIS-Team Scopus Importer:2023-04-28
Keywords: Cashew; Food anaphylaxis; Hazelnut; Peanut; Phenotype; Risk factors; Shellfish; Wheat

Four-and-a-Half LIM-Domain Protein 2 (FHL2) Induces Neuropeptide Y (NPY) in Macrophages in Visceral Adipose Tissue and Promotes Diet-Induced Obesity - Sommer, Judith; Ehnis, Hanna; Seitz, Tatjana; Schneider, Julia; Wild, Andreas; Moceri, Sandra; Buechler, Christa; Bozec, Aline; Weber, Georg; Merkel, Susanne; Beckervordersandforth, Ruth; Steinkasserer, Alexander; et al. (International Journal of Molecular Sciences, 2023)
Obesity is characterized by the expansion of the adipose tissue, usually accompanied by inflammation, with a prominent role of macrophages infiltrating the visceral adipose tissue (VAT). This chronic inflammation is a major driver of obesity-associated comorbidities. Four-and-a-half LIM-domain protein 2 (FHL2) is a multifunctional adaptor protein that is involved in the regulation of various biological functions and the maintenance of the homeostasis of different tissues. In this study, we aimed to gain new insights into the expression and functional role of FHL2 in VAT in diet-induced obesity. We found enhanced FHL2 expression in the VAT of mice with Western-type diet (WTD)-induced obesity and obese humans and identified macrophages as the cellular source of enhanced FHL2 expression in VAT. In mice with FHL2 deficiency (FHL2KO), WTD feeding resulted in reduced body weight gain paralleled by enhanced energy expenditure and uncoupling protein 1 (UCP1) expression, indicative of activated thermogenesis. In human VAT, FHL2 was inversely correlated with UCP1 expression. Furthermore, macrophage infiltration and the expression of the chemokine MCP-1, a known promotor of macrophage accumulation, was significantly reduced in WTD-fed FHL2KO mice compared with wild-type (wt) littermates. While FHL2 depletion did not affect the differentiation or lipid metabolism of adipocytes in vitro, FHL2 depletion in macrophages resulted in reduced expressions of MCP-1 and the neuropeptide Y (NPY). Furthermore, WTD-fed FHL2KO mice showed reduced NPY expression in VAT compared with wt littermates, and NPY expression was enhanced in VAT resident macrophages of obese individuals. Stimulation with recombinant NPY induced not only UCP1 expression and lipid accumulation but also MCP-1 expression in adipocytes. Collectively, these findings indicate that FHL2 is a positive regulator of NPY and MCP-1 expression in macrophages and herewith closely linked to the mechanism of obesity-associated lipid accumulation and inflammation in VAT. Thus, FHL2 appears as a potential novel target to interfere with the macrophage–adipocyte crosstalk in VAT for treating obesity and related metabolic disorders.
CRIS-Team Scopus Importer:2023-11-03
Keywords: adipocytes; FHL2; macrophages; MCP-1; NPY; obesity; thermogenesis

Four cases of erysipelas-like inflammation in patients with metastatic melanoma treated with checkpoint inhibitors - Pföhler, Claudia; Hassel, Jessica C.; Heinzerling, Lucie; Müller, Cornelia S.L. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-10-16

FRA-1 TRANSCRIPTION FACTOR EXPRESSION IN MACROPHAGES FOSTER INFLAMMATION DURING RHEUMATOID ARTHRITIS DEVELOPMENT - Hannemann, Nicole; Schnelzer, Anne; Jordan, Jutta; Eberhardt, Martin; Schleicher, Ulrike; Hueber, Axel; Reid, Stephen; Sonnewald, Sophia; Bäuerle, Tobias; Vera, Julio; Bogdan, Christian; Schett, Georg; et al. (2017)
EVALuna2:13497

From relative to absolute Treatment Goals - Correlation of PASI 90 and PASI <=2 in three clinical Studies with Secukinumab - Reich, Kristian; Bachhuber, Teresa; Melzer, Nima; Sieder, Christian; Sticherling, Michael (2018)
EVALuna2:34398

From relative to absolute treatment outcomes-Correlation of PASI 90 and PASI <= 2 in three clinical trials with secukinumab - Reich, Kristian; Bachhuber, Teresa; Melzer, Nima; Sieder, Christian; Sticherling, Michael (2018)
EVALuna2:34781

Fumaric Acid Esters and TNF alpha Inhibitors - Do they affect the Fertility of male Patients with Psoriasis? - Heppt, Franz; Colsmann, A.; Maronna, A.; Uslu, Ugur; Heppt, M.; Kiesewetter, Franklin; Sticherling, Michael (2017)
EVALuna2:34352

Fumaric Acid Esters: Patient Characteristics and Duration of Therapy from the PsoBest German Psoriasis Registry - Augustin, M.; Reich, K.; Spehr, C.; Rustenbach, S. J.; Mrowietz, U.; Radtke, M. A.; Wilsman-Theis, D.; Sticherling, Michael; Thaci, D. (2017)
EVALuna2:34356

Functionalization of T lymphocytes for magnetically controlled immune therapy: Selection of suitable superparamagnetic iron oxide nanoparticles - Mühlberger, Marina; Janko, Christina; Unterweger, Harald; Schreiber, Eveline; Band, Julia; Lehmann, Christian; Dudziak, Diana; Lee, Geoffrey; Alexiou, Christoph; Tietze, Rainer (Journal of Magnetism and Magnetic Materials, 2019)
According to the World Health Organization, cancer is the second most important cause of death in Europe. Due to its manifold manifestations, it is not possible to treat all patients according to a uniform scheme. However, all solid tumors have one thing in common: independent of the tumor's molecular subgroup and the treatment protocol, the immune status of the tumor, especially the amount of tumor infiltrating lymphocytes (TILs), is important for the patient's clinical outcome - the higher the number of TILs, the better the outcome. For this reason it seems desirable to increase the number of TILs. One way to accumulate T cells in the tumor area is to make them magnetizable and attract them with an external magnetic field. Magnetization can be achieved by superparamagnetic iron oxide nanoparticles (SPIONs) which can be bound to the cells' surface or internalized into the cells. For this study, SPIONs with different coatings were synthesized and incubated with immortalized mouse T lymphocytes. SPIONs only stabilized with lauric acid (LA) coated in situ or afterwards showed high toxicity. Addition of an albumin layer increased the biocompatibility but reduced cellular uptake. To increase the cellular uptake the albumin coated particles were aminated, leading to both higher uptake and toxicity, dependent on the degree of amination. In the presence of an externally applied magnetic field, T cells loaded with selected types and amounts of SPIONs were guidable. With this promising pilot study we already can demonstrate that it is possible to attract SPION bearing T cells by an external magnet. To sum up, biocompatibility and uptake of SPIONs by T cells are opposing events. Thus, for the functionalization of T cells with SPIONs the balance between uptake and toxicity must be evaluated carefully.
EVALuna2:35445

Functionalization Of T Lymphocytes With Citrate-Coated Superparamagnetic Iron Oxide Nanoparticles For Magnetically Controlled Immune Therapy - Mühlberger, Marina; Janko, Christina; Unterweger, Harald; Friedrich, Ralf P.; Friedrich, Bernhard; Band, Julia; Cebulla, Nadine; Alexiou, Christoph; Dudziak, Diana; Lee, Geoffrey; Tietze, Rainer (International Journal of Nanomedicine, 2019)
Purpose: Immune activation with T cell tumor infiltration is beneficial for the prognosis of patients suffering from solid cancer. Depending on their immune status, solid tumors can be immunologically classified into three groups: "hot" tumors are infiltrated with T lymphocytes, "cold" tumors are not infiltrated and "immune excluded" tumors are only infiltrated in the peripheral tumor tissue. Checkpoint inhibitors provide new therapeutic options for "hot" tumors by triggering the immune response of T cells. In order to enable this for cold tumors as well, T cells must be enriched in the tumor. Therefore, we use the principle of magnetic targeting to guide T cells loaded with citrate-coated superparamagnetic iron oxide nanoparticles (SPIONCitrate) to the tumor by an externally applied magnetic field. Methods: SPIONCitrate were produced by alkaline coprecipitation of iron(II) and iron(III) chloride and in situ coating with sodium citrate. The concentration-dependent cytocompatibility of the particles was determined by flow cytometry and blood stability assays. Atomic emission spectroscopy was used for the quantification of the particle uptake into T lymphocytes. The attractability of the loaded cells was observed by live-cell imaging in the presence of an externally applied magnetic field. Results: SPIONCitrate displayed good cytocompatibility to T cells and did not show any sign of aggregation in blood. Finally, SPIONCitrate-loaded T cells were strongly attracted by a small external magnet. Conclusion: T cells can be "magnetized" by incorporation of SPIONCitrate for magnetic targeting. The production of the particle-cell hybrid system is straightforward, as the loading process only requires basic laboratory devices and the loading efficiency is sufficient for cells being magnetically controllable. For these reasons, SPIONCitrate are potential suitable candidates for magnetic T cell targeting.
EVALuna2:209938

Functional modulation of regulatory T cells (Tregs) and analyses of the underlying mechanisms - Marosán, Anita; Steinkasserer, Alexander; Wild, Andreas (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-02-17

Functional Specialization of Dendritic Cell Subsets - Heger, Lukas; Amon, Lukas; Lehmann, Christian; Baranska, Anna; Heidkamp, Gordon; Dudziak, Diana (Elsevier, 2022)
Dendritic cells (DCs) are sentinels of the immune system. Under inflammatory conditions, DCs undergo various phenotypical changes, including DC migration, upregulation of co-stimulatory and activating molecules, secretion of cytokines, but also the processing of the engulfed antigens. The DC presents short antigenic peptides on the DC surface as peptide MHC class I or MHC class II complexes to CD8+ or CD4+ T cells, respectively. This article will provide a detailed overview on the antigen processing machineries and specialized functions of the increasing variety of DC subsets in mice and men.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Antigen presentation; Antigen processing; Antigen targeting; Autophagy; CLR; Cross-presentation; DC; Dendritic cell subsets; FcR; Immune responses; MHC-I; MHC-II; PDC; TLR

Functional Specialization of Dendritic Cell Subsets - Heidkamp, Gordon Frederik; Lehmann, Christian; Heger, Lukas; Baransk, A.; Hoffmann, A.; Lühr, Jennifer; Dudziak, Diana (Functional Cell Biology, 2016)
Dendritic cells (DCs) are sentinels of the immune system. Under inflammatory conditions DCs undergo various phenotypical changes, including DC migration, upregulation of co-stimulatory and activating molecules, secretion of cytokines, but also the processing of the engulfed antigens. The DC presents short antigenic peptides on the DC surface as peptide MHC class I or MHC class II complexes to CD8+ or CD4+ T cells, respectively. This article will provide a detailed overview on the antigen processing machineries and specialized functions of the increasing variety of DC subsets in mice and men.
Created from Fastlane, Scopus look-up
Keywords: Antigen presentation; Antigen processing; Antigen targeting; Autophagy; CLR; Cross-presentation; DC; Dendritic cell subsets; FcR; Immune responses; MHC-I; MHC-II; PDC; TLR

FV03 MEK Inhibitors improved the Survival of NRAS-mutated Melanoma Patients by using Checkpoint Inhibitors: Results of a retrospective, multicenter Analysis of 364 Patients - Kirchberger, M. C.; Ugurel, S.; Mangana, J.; Heppt, M.; Eigentler, T.; Berking, C.; Schadendorf, D.; Schuler, Gerold; Dummer, R.; Heinzerling, Lucie (2018)
EVALuna2:34766

gamma/delta T cells RNA-transfected with a T-cell receptor and a chimeric antigen receptor specific for melanoma - Harrer, D.; Simon, B.; Schuler, Gerold; Uslu, Ugur; Hoyer, S.; Dörrie, Jan; Schaft, Niels (2016)
EVALuna2:19612

Gastrointestinal: Eruptive seborrheic keratoses: sign of Leser-Trélat in gastric adenocarcinoma - Kirchberger, M. C. (Journal of Gastroenterology and Hepatology, 2019)
CRIS-Team Scopus Importer:2019-07-12

Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma - Monteiro, Ana Carolina; Muenzner, Julienne K.; Andrade, Fernando; Rius, Flávia Eichemberger; Ostalecki, Christian; Geppert, Carol-Immanuel; Agaimy, Abbas; Hartmann, Arndt; Fujita, André; Schneider-Stock, Regine; Jasiulionis, Miriam Galvonas (Molecular Oncology, 2019)
The high mortality rate of melanoma is broadly associated with its metastatic potential. Tumor cell dissemination is strictly dependent on vascularization; therefore, angiogenesis and lymphangiogenesis play an essential role in metastasis. Hence, a better understanding of the players of tumor vascularization and establishing them as new molecular biomarkers might help to overcome the poor prognosis of melanoma patients. Here, we further characterized a linear murine model of melanoma progression and showed that the aggressiveness of melanoma cells is closely associated with high expression of angiogenic factors, such as Vegfc, Angpt2, and Six1, and that blockade of the vascular endothelial growth factor pathway by the inhibitor axitinib abrogates their tumorigenic potential in vitro and in the in vivo chicken chorioallantoic membrane assay. Furthermore, analysis of The Cancer Genome Atlas data revealed that the expression of the angiogenic factor ANGPT2 (P-value = 0.044) and the lymphangiogenic receptor VEGFR-3 (P-value = 0.002) were independent prognostic factors of overall survival in melanoma patients. Enhanced reduced representation bisulfite sequencing-based methylome profiling revealed for the first time a link between abnormal VEGFC, ANGPT2, and SIX1 gene expression and promoter hypomethylation in melanoma cells. In patients, VEGFC (P-value = 0.031), ANGPT2 (P-value < 0.001), and SIX1 (P-value = 0.009) promoter hypomethylation were independent prognostic factors of shorter overall survival. Hence, our data suggest that these angio- and lymphangiogenesis factors are potential biomarkers of melanoma prognosis. Moreover, these findings strongly support the applicability of our melanoma progression model to unravel new biomarkers for this aggressive human disease.
CRIS-Team Scopus Importer:2019-06-18
Keywords: angiogenesis; biomarkers; DNA methylation; melanoma; prognosis

Gene network-based and ensemble modeling-based selection of tumor-associated antigens with a predicted low risk of tissue damage for targeted immunotherapy - Lischer, Christopher; Eberhardt, Martin; Flamann, Cindy; Berges, Johannes; Güse, Esther; Wessely, Anja; Weich, Adrian; Retzlaff, Jimmy; Dörrie, Jan; Schaft, Niels; Wiesinger, Manuel; März, Johannes; et al. (Journal for ImmunoTherapy of Cancer, 2024)
Background Tumor-associated antigens and their derived peptides constitute an opportunity to design off-the-shelf mainline or adjuvant anti-cancer immunotherapies for a broad array of patients. A performant and rational antigen selection pipeline would lay the foundation for immunotherapy trials with the potential to enhance treatment, tremendously benefiting patients suffering from rare, understudied cancers. Methods We present an experimentally validated, data-driven computational pipeline that selects and ranks antigens in a multipronged approach. In addition to minimizing the risk of immune-related adverse events by selecting antigens based on their expression profile in tumor biopsies and healthy tissues, we incorporated a network analysis-derived antigen indispensability index based on computational modeling results, and candidate immunogenicity predictions from a machine learning ensemble model relying on peptide physicochemical characteristics. Results In a model study of uveal melanoma, Human Leukocyte Antigen (HLA) docking simulations and experimental quantification of the peptide–major histocompatibility complex binding affinities confirmed that our approach discriminates between high-binding and low-binding affinity peptides with a performance similar to that of established methodologies. Blinded validation experiments with autologous T-cells yielded peptide stimulation-induced interferon-γ secretion and cytotoxic activity despite high interdonor variability. Dissecting the score contribution of the tested antigens revealed that peptides with the potential to induce cytotoxicity but unsuitable due to potential tissue damage or instability of expression were properly discarded by the computational pipeline. Conclusions In this study, we demonstrate the feasibility of the de novo computational selection of antigens with the capacity to induce an anti-tumor immune response and a predicted low risk of tissue damage. On translation to the clinic, our pipeline supports fast turn-around validation, for example, for adoptive T-cell transfer preparations, in both generalized and personalized antigen-directed immunotherapy settings.
CRIS-Team Scopus Importer:2024-05-24

Generalisierte pustulöse Psoriasis: Überblick zum Status quo und Ergebnisse einer Diskussionsrunde - Reich, Kristian; Augustin, Matthias; Gerdes, Sascha; Ghoreschi, Kamran; Kokolakis, Georgios; Mößner, Rotraut; Mrowietz, Ulrich; Navarini, Alexander A.; Pinter, Andreas; Schäkel, Knut; Staubach, Petra; Sticherling, Michael; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
CRIS-Team Scopus Importer:2022-06-24

Generalized pustular psoriasis: overview of the status quo and results of a panel discussion - Reich, Kristian; Augustin, Matthias; Gerdes, Sascha; Ghoreschi, Kamran; Kokolakis, Georgios; Mößner, Rotraut; Mrowietz, Ulrich; Navarini, Alexander A.; Pinter, Andreas; Schäkel, Knut; Staubach, Petra; Sticherling, Michael; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
Generalized pustular psoriasis (GPP) is a rare, severe, potentially life-threatening, autoinflammatory, neutrophilic skin disease that may be accompanied by fever and leukocytosis. This paper describes the current state of knowledge on GPP in terms of classification, (differential) diagnosis and prevalence. We present a comparison of the genetics and pathoimmunology of GPP and psoriasis vulgaris with the central mechanisms of autoimmunology and autoinflammation. The currently available therapeutic options, expert recommendations for therapy, and data from early clinical trials investigating targeted therapies will be summarized. We present the results of our discussion with 13 experts for psoriasis vulgaris and GPP and give an integrated overview of indication and therapy based on our personal experience and present an outlook on further research questions. Collectively, this article highlights the high unmet need in GPP, as there exists no satisfactory method of diagnosis or treatment to date and new treatment options will be of great therapeutic benefit to those affected.
CRIS-Team Scopus Importer:2022-06-17

General practitioners’ perspectives on statutory skin cancer screening–A questionnaire-based cross-sectional survey in Germany - Reinhardt, Lydia; Strasser, Cristin; Steeb, Theresa; Petzold, Anne; Heppt, Markus; Wessely, Anja; Berking, Carola; Meier, Friedegund (PLoS ONE, 2024)
Background In Germany, skin cancer screening (SCS) is available free of charge every two years to all those with statutory health insurance over the age of 35. General Practitioners (GP) can carry out the screening if they have completed an 8-hour training course. GPs play a crucial role in the implementation of SCS and act as gatekeepers between initial patient contact and referral to dermatologists. Objective To record how comprehensively GPs carry out SCS in terms of patient information and body examination, as well as to explore GPs opinions on the feasibility of SCS. Methods A cross-sectional survey was conducted. A questionnaire was sent to GPs with permission to perform SCS in two regions of Germany (Bavaria and Saxony) between August and September 2021. Data were analyzed using descriptive analysis. Subgroup analysis was performed according to regions (federal state, location of physician´s office), professional experience (experience in years, number of monthly screenings, age) and gender. Open questions were evaluated using qualitative content analysis. Results In the survey, 204 GPs responded. Genitalia (40.7%, 83/203), anal fold (62.3%, 127/204) and oral mucosa (66.7%, 136/204) were the least examined body regions during screening. Information on risks (false-positive findings: 18.6%, 38/203; false-negative findings: 13.2%, 27/203; overdiagnosis: 7.8%, 16/203) and benefits (48.0%, 98/202) were not always provided. GPs who performed screenings more frequently were more likely to provide information about the benefits of SCS (p<0.001; >10 vs. <5 screenings per month). Opinions were provided on uncertainties, knowledge requirements, structural and organizational requirements of SCS, SCS training and evaluation. The organization and remuneration of the SCS programme was seen as a barrier to implementation. GPs expressed uncertainties especially in unclear findings and in dermatoscopy. Conclusion Uncertainties in the implementation of the SCS should be addressed by offering refresher courses. Good networking between GPs and dermatologists is essential to improve SCS quality.
CRIS-Team Scopus Importer:2024-08-16

Generation of an oncolytic herpes simplex virus 1 expressing human MelanA - Boscheinen, Jan; Thomann, Sabrina; Knipe, David M.; Deluca, Neal; Schuler-Thurner, Beatrice; Gross, Stefanie; Dörrie, Jan; Schaft, Niels; Bach, Christian; Rohrhofer, Anette; Werner-Klein, Melanie; Schmidt, Barbara; et al. (Frontiers in Immunology, 2019)
Robust anti-tumor immunity requires innate as well as adaptive immune responses. We have shown that plasmacytoid dendritic cells develop killer cell-like activity in melanoma cell cocultures after exposure to the infectious but replication-deficient herpes simplex virus 1 (HSV-1) d106S. To combine this innate effect with an enhanced adaptive immune response, the gene encoding human MelanA/MART-1 was inserted into HSV-1 d106S via homologous recombination to increase direct expression of this tumor antigen. Infection of Vero cells using this recombinant virus confirmed MelanA expression by Western blotting, flow cytometry, and immunofluorescence. HSV-1 d106S-MelanA induced expression of the transgene in fibroblast and melanoma cell lines not naturally expressing MelanA. Infection of a melanoma cell line with CRISPR-Cas9-mediated knockout of MelanA confirmed de novo expression of the transgene in the viral context. Dependent on MelanA expression, infected fibroblast and melanoma cell lines induced degranulation of HLA-matched MelanA-specific CD8+ T cells, followed by killing of infected cells. To study infection of immune cells, we exposed peripheral blood mononuclear cells and in vitro-differentiated macrophages to the parental HSV-1 d106S, resulting in expression of the transgene GFP in CD11c+ cells and macrophages. These data provide evidence that the application of MelanA-encoding HSV-1 d106S could enhance adaptive immune responses and re-direct MelanA-specific CD8+ T cells to tumor lesions, which have escaped adaptive immune responses via downregulation of their tumor antigen. Hence, HSV-1 d106S-MelanA harbors the potential to induce innate immune responses in conjunction with adaptive antitumor responses by CD8+ T cells, which should be evaluated in further studies.
CRIS-Team Scopus Importer:2019-05-14
Keywords: Cytotoxic T cell response; Herpes virus; Malignant melanoma; Oncolytic viruses; Vaccine

Generation of CD8(+) T cells expressing two additional T-cell receptors (TETARs) for personalised melanoma therapy. - Hoefflin, Sandra; Prommersberger, Sabrina; Uslu, Ugur; Schuler, Gerold; Schmidt, Christopher W.; Lennerz, Volker; Dörrie, Jan; Schaft, Niels (Cancer Biology & Therapy, 2015)
Adoptive T-cell therapy of cancer often fails due to the tumor cells' immune escape mechanisms, like antigen loss or down-regulation. To anticipate immune escape by loss of a single antigen, it would be advantageous to equip T cells with multiple specificities. To study the possible interference of 2 T-cell receptors (TCRs) in one cell, and to examine how to counteract competing effects, we generated TETARs, CD8(+) T cells expressing two additional T-cell receptors by simultaneous transient transfection with 2 TCRs using RNA electroporation. The TETARs were equipped with one TCR specific for the common melanoma antigen gp100 and one TCR recognizing a patient-specific, individual mutation of CCT6A (chaperonin containing TCP1, subunit 6A) termed "CCT6A(m) TCR." These CD8(+) T cells proved functional in cytokine secretion and lytic activity upon stimulation with each of their cognate antigens, although some reciprocal inhibition was observed. Murinisation of the CCT6A(m) TCR increased and prolonged its expression and increased the lytic capacity of the dual-specific T cells. Taken together, we generated functional, dual-specific CD8(+) T cells directed against a common melanoma-antigen and an individually mutated antigen for the use in personalised adoptive T-cell therapy of melanoma. The intended therapy would involve repetitive injections of the RNA-transfected cells to overcome the transiency of TCR expression. In case of autoimmunity-related side effects, a cessation of treatment would result in a disappearance of the introduced receptors, which increases the safety of this approach.
EVALuna2:19563

Genetic Analysis of MPO Variants in Four Psoriasis Subtypes in Patients from Germany - Haskamp, Stefan; Horowitz, Joseph; Oji, Vinzenz; Philipp, Sandra; Sticherling, Michael; Schäkel, Knut; Schuhmann, Sarah; Prinz, Jörg C.; Burkhardt, Harald; Behrens, Frank; Böhm, Beate; Köhm, Michaela; et al. (Journal of Investigative Dermatology, 2021)
CRIS-Team Scopus Importer:2021-03-26

Genetic characterization of advanced conjunctival melanoma and response to systemic treatment - Lodde, Georg C.; Jansen, Philipp; Möller, Inga; Sucker, Antje; Hassel, Jessica C.; Forschner, Andrea; Eckardt, Julia; Meier, Friedegund; Reinhardt, Lydia; Kähler, Katharina C.; Ziemer, Mirjana; Schlaak, Max; et al. (European Journal of Cancer, 2022)
Background: Conjunctival melanoma is a rare type of ocular melanoma, which is prone to local recurrence and metastasis and can lead to patient death. Novel therapeutic strategies have revolutionized cutaneous melanoma management. The efficacy of these therapies in conjunctival melanoma, however, has not been evaluated in larger patient cohorts. Methods: In this multi-center retrospective cohort study with additional screening of the ADOREG database, data were collected from 34 patients with metastatic conjunctival melanoma who received targeted therapy (TT) (BRAF ± MEK inhibitors) or immune checkpoint inhibitors (ICI) (anti-PD-1 ± anti-CTLA4). In 15 cases, tissue was available for targeted next-generation-sequencing (611 genes) and RNA sequencing. Driver mutations, tumor mutational burden, copy number variations and inflammatory/IFNγ gene expression signatures were determined. Results: Genetic characterization identified frequent BRAF (46.7%, 7/15), NRAS (26.7%, 4/15), NF1 (20%, 3/15), and TERT promoter (46.7%, 7/15) mutations. UV associated C>T and CC>TT mutations were common. Median follow-up time after start of first TT or ICI therapy was 13.2 months. In 26 patients receiving first-line ICI, estimated one-year progression-free survival (PFS) rate was 42.0%, PFS and overall survival (OS) 6.2 and 18.0 months, respectively. First-line TT was given to 8 patients, estimated one-year PFS rate was 54.7%, median PFS and OS 12.6 and 29.1 months, respectively. Conclusions: Our findings support the role of UV irradiation in conjunctival melanoma and the genetic similarity with cutaneous melanoma. Conjunctival melanoma patients with advanced disease benefit from both targeted therapies (BRAF ± MEK inhibitors) and immune checkpoint inhibitors.
CRIS-Team Scopus Importer:2022-03-18
Keywords: BRAF; Conjunctival melanoma; Immune checkpoint inhibition; Mutational analysis; PD-1; Systemic treatment; Targeted therapy

Genital ulcers as diagnostic clue for acute myeloid leukaemia - Schröder, Sina; Krause, Stefan; Erfurt-Berge, Cornelia (International Wound Journal, 2018)
Acute myeloid leukaemia is a myeloid neoplasm with an extremely varying clinical appearance. Skin lesions are common for specific subtypes of acute myeloid leukaemia but are often misinterpreted. Here, we present a case of acute myeloid leukaemia in a young woman exhibiting genital ulcerations and gingival erosions.
EVALuna2:34278

Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants - Jin, Ying; Andersen, Genevieve; Yorgov, Daniel; Ferrara, Tracey M.; Ben, Songtao; Brownson, Kelly M.; Holland, Paulene J.; Birlea, Stanca A.; Siebert, Janet; Hartmann, Arndt; Lienert, Anne-Marie; Van Geel, Nanja; et al. (Nature Genetics, 2016)
Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes, with epidemiological association with other autoimmune diseases. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment.
EVALuna2:19619

German S1 guideline: diagnosis and treatment of livedovasculopathy - Schiffmann, Marie-Luise; Dissemond, Joachim; Erfurt-Berge, Cornelia; Hafner, Juerg; Itzlinger-Monshi, Babak Alexander; Jungkunz, Hans Wilfried; Kahle, Birgit; Kreuter, Alexander; Scharffetter-Kochanek, Karin; Lutze, Stine; Rappersberger, Klemens; Schneider, Stefan Werner; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team WoS Importer:2021-11-12

German YouTube™ videos as a source of information on cutaneous melanoma: a critical appraisal - Steeb, Theresa; Reinhardt, L.; Görgmayr, C.; Weingarten, H.; Doppler, A.; Brütting, J.; Meier, F.; Berking, Carola (Journal of the European Academy of Dermatology and Venereology, 2020)
CRIS-Team Scopus Importer:2020-06-02

Glaucoma-TrEl: A web-based interactive database to build evidence-based hypotheses on the role of trace elements in glaucoma - Choudhari, Jyoti Kant; Eberhardt, Martin; Chatterjee, Tanushree; Hohberger, Bettina; Vera, Julio (BMC Research Notes, 2022)
Objective: Glaucoma is a chronic neurological disease that is associated with high intraocular pressure (IOP), causes gradual damage to retinal ganglion cells, and often culminates in vision loss. Recent research suggests that glaucoma is a complex multifactorial disease in which multiple interlinked genes and pathways play a role during onset and development. Also, differential availability of trace elements seems to play a role in glaucoma pathophysiology, although their mechanism of action is unknown. The aim of this work is to disseminate a web-based repository on interactions between trace elements and protein-coding genes linked to glaucoma pathophysiology. Results: In this study, we present Glaucoma-TrEl, a web database containing information about interactions between trace elements and protein-coding genes that are linked to glaucoma. In the database, we include interactions between 437 unique genes and eight trace elements. Our analysis found a large number of interactions between trace elements and protein-coding genes mutated or linked to the pathophysiology of glaucoma. We associated genes interacting with multiple trace elements to pathways known to play a role in glaucoma. The web-based platform provides an easy-to-use and interactive tool, which serves as an information hub facilitating future research work on trace elements in glaucoma.
CRIS-Team Scopus Importer:2022-12-02
Keywords: glaucoma; Intraocular pressure; Optic nerve; Oxidative stress; Protein-trace element interactions

Gleichzeitiges Auftreten zweier malignomverdächtiger Hautveränderungen - Kaufmann, Matthias; Erdmann, Michael; Schliep, Stefan; Voskens, Caroline; Berking, Carola; Bauerschmitz, Jürgen (Die Dermatologie, 2024)
CRIS-Team Scopus Importer:2024-06-14

Global Circumferential and Radial Strain Among Patients With Immune Checkpoint Inhibitor Myocarditis - Quinaglia, Thiago; Gongora, Carlos; Awadalla, Magid; Hassan, Malek Z.O.; Zafar, Amna; Drobni, Zsofia D.; Mahmood, Syed S.; Zhang, Lili; Coelho-Filho, Otavio R.; Suero-Abreu, Giselle A.; Rizvi, Muhammad A.; Sahni, Gagan; et al. (Journal of the American College of Cardiology : Cardiovascular imaging, 2022)
Background: Global circumferential strain (GCS) and global radial strain (GRS) are reduced with cytotoxic chemotherapy. There are limited data on the effect of immune checkpoint inhibitor (ICI) myocarditis on GCS and GRS. Objectives: This study aimed to detail the role of GCS and GRS in ICI myocarditis. Methods: In this retrospective study, GCS and GRS from 75 cases of patients with ICI myocarditis and 50 ICI-treated patients without myocarditis (controls) were compared. Pre-ICI GCS and GRS were available for 12 cases and 50 controls. Measurements were performed in a core laboratory blinded to group and time. Major adverse cardiovascular events (MACEs) were defined as a composite of cardiogenic shock, cardiac arrest, complete heart block, and cardiac death. Results: Cases and controls were similar in age (66 ± 15 years vs 63 ± 12 years; P = 0.20), sex (male: 73% vs 61%; P = 0.20) and cancer type (P = 0.08). Pre-ICI GCS and GRS were also similar (GCS: 22.6% ± 3.4% vs 23.5% ± 3.8%; P = 0.14; GRS: 45.5% ± 6.2% vs 43.6% ± 8.8%; P = 0.24). Overall, 56% (n = 42) of patients with myocarditis presented with preserved left ventricular ejection fraction (LVEF). GCS and GRS were lower in myocarditis compared with on-ICI controls (GCS: 17.5% ± 4.2% vs 23.6% ± 3.0%; P < 0.001; GRS: 28.6% ± 6.7% vs 47.0% ± 7.4%; P < 0.001). Over a median follow-up of 30 days, 28 cardiovascular events occurred. A GCS (HR: 4.9 [95% CI: 1.6-15.0]; P = 0.005) and GRS (HR: 3.9 [95% CI: 1.4-10.8]; P = 0.008) below the median was associated with an increased event rate. In receiver-operating characteristic (ROC) curves, GCS (AUC: 0.80 [95% CI: 0.70-0.91]) and GRS (AUC: 0.76 [95% CI: 0.64-0.88]) showed better performance than cardiac troponin T (cTnT) (AUC: 0.70 [95% CI: 0.58-0.82]), LVEF (AUC: 0.69 [95% CI: 0.56-0.81]), and age (AUC: 0.54 [95% CI: 0.40-0.68]). Net reclassification index and integrated discrimination improvement demonstrated incremental prognostic utility of GRS over LVEF (P = 0.04) and GCS over cTnT (P = 0.002). Conclusions: GCS and GRS are lower in ICI myocarditis, and the magnitude of reduction has prognostic significance.
CRIS-Team Scopus Importer:2022-11-04
Keywords: cardiovascular risk stratification; immune checkpoint inhibitors; myocarditis; strain modalities survival analysis

Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis - Awadalla, Magid; Mahmood, Syed S.; Groarke, John D.; Hassan, Malek Z.O.; Nohria, Anju; Rokicki, Adam; Murphy, Sean P.; Mercaldo, Nathaniel D.; Zhang, Lili; Zlotoff, Daniel A.; Reynolds, Kerry L.; Alvi, Raza M.; et al. (Journal of the American College of Cardiology, 2020)
Background: There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis. Objectives: This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis. Methods: This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death. Results: Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8). Conclusions: GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.
CRIS-Team Scopus Importer:2020-02-04
Keywords: global longitudinal strain; immune checkpoint inhibitors; major adverse cardiac events; myocarditis

GM-CSF Monocyte-Derived Cells and Langerhans Cells As Part of the Dendritic Cell Family - Lutz, Manfred B.; Strobl, Herbert; Schuler, Gerold; Romani, Nikolaus (Frontiers in Immunology, 2017)
Dendritic cells (DCs) and macrophages (Mph) share many characteristics as components of the innate immune system. The criteria to classify the multitude of subsets within the mononuclear phagocyte system are currently phenotype, ontogeny, transcription patterns, epigenetic adaptations, and function. More recently, ontogenetic, transcriptional, and proteomic research approaches uncovered major developmental differences between Flt3L-dependent conventional DCs as compared with Mphs and monocyte-derived DCs (MoDCs), the latter mainly generated in vitro from murine bone marrow-derived DCs (BM-DCs) or human CD14+ peripheral blood monocytes. Conversely, in vitro GM-CSF-dependent monocyte-derived Mphs largely resemble MoDCs whereas tissue-resident Mphs show a common embryonic origin from yolk sac and fetal liver with Langerhans cells (LCs). The novel ontogenetic findings opened discussions on the terminology of DCs versus Mphs. Here, we bring forward arguments to facilitate definitions of BM-DCs, MoDCs, and LCs. We propose a group model of terminology for all DC subsets that attempts to encompass both ontogeny and function.
EVALuna2:34313

GMP-compliant human monocyte-derived dendritic cells for cancer vaccination generated by using the Quantum (R) hollow fiber bioreactor system - Uslu, Ugur; Uslu, U.; Erdmann, M.; Wiesinger, M.; Schuler, Gerold; Schuler-Thurner, Beatrice (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2020-01-28

Good Manufacturing Practice-Compliant Production and Lot-Release ofEx VivoExpanded Regulatory T Cells As Basis for Treatment of Patients with Autoimmune and Inflammatory Disorders - Wiesinger, Manuel; Stoica, Diane; Roessner, Susanne; Lorenz, Carmen; Fischer, Anika; Atreya, Raja; Neufert, Clemens; Atreya, Imke; Scheffold, Alexander; Schuler-Thurner, Beatrice; Neurath, Markus; Schuler, Gerold; et al. (Frontiers in Immunology, 2017)
In recent years, the exploration of regulatory T cell (Treg)-based cellular therapy has become an attractive strategy to ameliorate inflammation and autoimmunity in various clinical settings. The main obstacle to the clinical application of Treg in human is their low number circulating in peripheral blood. Therefore,ex vivoexpansion is inevitable. Moreover, isolation of Treg bears the risk of concurrent isolation of unwanted effector cells, which may trigger or deteriorate inflammation upon adoptive Treg transfer. Here, we present a protocol for the GMP-compliant production, lot-release and validation ofex vivoexpanded Tregs for treatment of patients with autoimmune and inflammatory disorders. In the presented production protocol, large numbers of Treg, previously enriched from a leukapheresis product by using the CliniMACS®system, areex vivoexpanded in the presence of anti-CD3/anti-CD28 expander beads, exogenous IL-2 and rapamycin during 21 days. The expanded Treg drug product passed predefined lot-release criteria. These criteria include (i) sterility testing, (ii) assessment of Treg phenotype, (iii) assessment of non-Treg cellular impurities, (iv) confirmation of successful anti-CD3/anti-CD28 expander bead removal after expansion, and (v) confirmation of the biological function of the Treg product. Furthermore, the Treg drug product was shown to retain its stability and suppressive function for at least 1 year after freezing and thawing. Also, dilution of the Treg drug product in 0.9% physiological saline did not affect Treg phenotype and Treg function for up to 90 min. These data indicate that these cells are ready to use in a clinical setting in which a cell infusion time of up to 90 min can be expected. The presented production process has recently undergone on site GMP-conform evaluation and received GMP certification from the Bavarian authorities in Germany. This protocol can now be used for Treg-based therapy of various inflammatory and autoimmune disorders.
EVALuna2:33800

Grade 4 Neutropenia Secondary to Immune Checkpoint Inhibition — A Descriptive Observational Retrospective Multicenter Analysis - Zaremba, Anne; Kramer, Rafaela; De Temple, Viola; Bertram, Stefanie; Salzmann, Martin; Gesierich, Anja; Reinhardt, Lydia; Baroudjian, Barouyr; Sachse, Michael M.; Mechtersheimer, Gunhild; Johnson, Douglas B.; Weppler, Alison M.; et al. (Frontiers in Oncology, 2021)
Introduction: Immune checkpoint inhibitors (ICI) are increasingly being used to treat numerous cancer types. Together with improved recognition of toxicities, this has led to more frequent identification of rare immune-related adverse events (irAE), for which specific treatment strategies are needed. Neutropenia is a rare hematological irAE that has a potential for a high mortality rate because of its associated risk of sepsis. Prompt recognition and timely treatment of this life-threatening irAE are therefore critical to the outcome of patients with immune-related neutropenia. Methods: This multicenter international retrospective study was conducted at 17 melanoma centers to evaluate the clinical characteristics, diagnostics, treatment, and outcomes of melanoma patients with grade 4 neutropenia (<500 neutrophils/µl blood) treated with ICI between 2014 and 2020. Some of these patients received metamizole in addition to ICI (ICI+/met+). Bone marrow biopsies (BMB) of these patients were compared to BMB from non-ICI treated patients with metamizole-induced grade 4 neutropenia (ICI-/met+). Results: In total, 10 patients (median age at neutropenia onset: 66 years; seven men) with neutropenia were identified, equating to an incidence of 0.14%. Median onset of neutropenia was 6.4 weeks after starting ICI (range 1.4–49.1 weeks). Six patients showed inflammatory symptoms, including fever (n=3), erysipelas (n=1), pharyngeal abscess (n=1), and mucositis (n=1). Neutropenia was diagnosed in all patients by a differential blood count and additionally performed procedures including BMB (n=5). Nine of 10 patients received granulocyte colony-stimulating factors (G-CSF) to treat their grade 4 neutropenia. Four patients received systemic steroids (including two in combination with G-CSF, and one in combination with G-CSF and additional ciclosporin A). Four patients were treated with one or more antibiotic treatment lines, two with antimycotic treatment, and one with additional antiviral therapy. Five patients received metamizole concomitantly with ICI. One fatal outcome was reported. BMB indicated a numerically lower CD4+ to CD8+ T cells ratio in patients with irNeutropenia than in those with metamizole-induced neutropenia. Conclusion: Grade 4 neutropenia is a rare but potentially life-threatening side effect of ICI treatment. Most cases were sufficiently managed using G-CSF; however, adequate empiric antibiotic, antiviral, and antimycotic treatments should be administered if neutropenic infections are suspected. Immunosuppression using corticosteroids may be considered after other causes of neutropenia have been excluded.
CRIS-Team Scopus Importer:2021-12-10
Keywords: adverse events; hematotoxicity; immune checkpoint inhibition; malignant melanoma; neutropenia

Graph neural networks in multi-stained pathological imaging: extended comparative analysis of Radiomic features - Rivera Monroy, Luis Carlos; Rist, Leonhard; Ostalecki, Christian; Bauer, Andreas; Vera, Julio; Breininger, Katharina; Maier, Andreas (International Journal of Computer Assisted Radiology and Surgery, 2024)
Purpose This study investigates the application of Radiomic features within graph neural networks (GNNs) for the classification of multiple-epitope-ligand cartography (MELC) pathology samples. It aims to enhance the diagnosis of often misdiagnosed skin diseases such as eczema, lymphoma, and melanoma. The novel contribution lies in integrating Radiomic features with GNNs and comparing their efficacy against traditional multi-stain profiles. Methods We utilized GNNs to process multiple pathological slides as cell-level graphs, comparing their performance with XGBoost and Random Forest classifiers. The analysis included two feature types: multi-stain profiles and Radiomic features. Dimensionality reduction techniques such as UMAP and t-SNE were applied to optimize the feature space, and graph connectivity was based on spatial and feature closeness. Results Integrating Radiomic features into spatially connected graphs significantly improved classification accuracy over traditional models. The application of UMAP further enhanced the performance of GNNs, particularly in classifying diseases with similar pathological features. The GNN model outperformed baseline methods, demonstrating its robustness in handling complex histopathological data. Conclusion Radiomic features processed through GNNs show significant promise for multi-disease classification, improving diagnostic accuracy. This study’s findings suggest that integrating advanced imaging analysis with graph-based modeling can lead to better diagnostic tools. Future research should expand these methods to a wider range of diseases to validate their generalizability and effectivenes
Keywords: Radiomics; Multi-array imaging; Graph neural network; MELC; Histopathological analysis

Grb2 Is Important for T Cell Development, Th Cell Differentiation, and Induction of Experimental Autoimmune Encephalomyelitis - Radtke, Daniel; Lacher, Sonja M.; Szumilas, Nadine; Sandrock, Lena; Ackermann, Jochen; Nitschke, Lars; Zinser, Elisabeth (Journal of Immunology, 2016)
The small adaptor protein growth factor receptor-bound protein 2 (Grb2) modulates and integrates signals from receptors on cellular surfaces in inner signaling pathways. In murine T cells, Grb2 is crucial for amplification of TCR signaling. T cell-specific Grb2(fl/fl) Lckcre(tg) Grb2-deficient mice show reduced T cell numbers due to impaired negative and positive selection. In this study, we found that T cell numbers in Grb2(fl/fl) CD4cre(tg) mice were normal in the thymus and were only slightly affected in the periphery. Ex vivo analysis of CD4(+) Th cell populations revealed an increased amount of Th1 cells within the CD4(+) population of Grb2(fl/fl) CD4cre(tg) mice. Additionally, Grb2-deficient T cells showed a greater potential to differentiate into Th17 cells in vitro. To test whether these changes in Th cell differentiation potential rendered Grb2(fl/fl) CD4cre(tg) mice more prone to inflammatory diseases, we used the murine Th1 cell-and Th17 cell-driven model of experimental autoimmune encephalomyelitis (EAE). In contrast to our expectations, Grb2(fl/fl) CD4cre(tg) mice developed a milder form of EAE. The impaired EAE disease can be explained by the reduced proliferation rate of Grb2-deficient CD4(+) T cells upon stimulation with IL-2 or upon activation by allogeneic dendritic cells, because the activation of T cells by dendritic cells and the subsequent T cell proliferation are known to be crucial factors for the induction of EAE. In summary, Grb2-deficient T cells show defects in T cell development, increased Th1 and Th17 cell differentiation capacities, and impaired proliferation after activation by dendritic cells, which likely reduce the clinical symptoms of EAE.

Growing interest in hair loss - Moreira, Alvaro (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Guidelines for DC preparation and flow cytometric analysis of human lymphohematopoietic tissues - Heger, Lukas; Dudziak, Diana; Amon, Lukas; Hatscher, Lukas; Kaszubowski, Tomasz; Lehmann, Christian (European Journal of Immunology, 2022)
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. Within this article, detailed protocols are presented that allow for the generation of single cell suspensions from human lymphohematopoietic tissues including blood, spleen, thymus, and tonsils with a focus on the subsequent analysis of DC via flow cytometry, as well as flow cytometric cell sorting of primary human DC. Further, prepared single cell suspensions as well as cell sorter-purified DC can be subjected to other applications including cellular enrichment procedures, RNA sequencing, functional assays, and many more. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
CRIS-Team WoS Importer:2023-01-13

Guidelines for DC preparation and flow cytometry analysis of mouse lymphohematopoietic tissues - Amon, Lukas; Dudziak, Diana; Backer, Ronald A. A.; Clausen, Bjoern E.; Gmeiner, Christina; Heger, Lukas; Jacobi, Lukas; Lehmann, Christian; Probst, Hans-Christian; Seichter, Anna; Tchitashvili, Giorgi; Tochoedo, Nounagnon Romaric; et al. (European Journal of Immunology, 2022)
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human DC from lymphoid organs, and various non-lymphoid tissues. Within this chapter, detailed protocols are presented that allow for the generation of single-cell suspensions from mouse lymphohematopoietic tissues including spleen, peripheral lymph nodes, and thymus, with a focus on the subsequent analysis of DC by flow cytometry. However, prepared single-cell suspensions can be subjected to other applications including sorting and cellular enrichment procedures, RNA sequencing, Western blotting, and many more. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
Created from Fastlane, Scopus look-up
Keywords: dendritic cells; high-parameter flow cytometry; mouse lymphoid tissues; myeloid cells; single-cell suspension preparation

Guidelines for DC preparation and flow cytometry analysis of mouse nonlymphoid tissues - Probst, Hans Christian; Stoitzner, Patrizia; Amon, Lukas; Backer, Ronald A.; Brand, Anna; Chen, Jianzhou; Clausen, Björn E.; Dieckmann, Sophie; Dudziak, Diana; Heger, Lukas; Hodapp, Katrin; Hornsteiner, Florian; et al. (European Journal of Immunology, 2022)
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various nonlymphoid tissues. DC are sentinels of the immune system present in almost every mammalian organ. Since they represent a rare cell population, DC need to be extracted from organs with protocols that are specifically developed for each tissue. This article provides detailed protocols for the preparation of single-cell suspensions from various mouse nonlymphoid tissues, including skin, intestine, lung, kidney, mammary glands, oral mucosa and transplantable tumors. Furthermore, our guidelines include comprehensive protocols for multiplex flow cytometry analysis of DC subsets and feature top tricks for their proper discrimination from other myeloid cells. With this collection, we provide guidelines for in-depth analysis of DC subsets that will advance our understanding of their respective roles in healthy and diseased tissues. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all coauthors, making it an essential resource for basic and clinical DC immunologists.
Created from Fastlane, Scopus look-up
Keywords: Dendritic cells; Discrimination of dendritic cell subsets; Mouse nonlymphoid tissue; Multiplex flow cytometry analysis; Tissue digestion protocols

Guidelines for mouse and human DC functional assays - Clausen, Bjoern E.; Amon, Lukas; Backer, Ronald A.; Berod, Luciana; Bopp, Tobias; Brand, Anna; Burgdorf, Sven; Chen, Luxia; Da, Meihong; Distler, Ute; Dress, Regine J.; Dudziak, Diana; et al. (European Journal of Immunology, 2022)
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. Recent studies have provided evidence for an increasing number of phenotypically distinct conventional DC (cDC) subsets that on one hand exhibit a certain functional plasticity, but on the other hand are characterized by their tissue- and context-dependent functional specialization. Here, we describe a selection of assays for the functional characterization of mouse and human cDC. The first two protocols illustrate analysis of cDC endocytosis and metabolism, followed by guidelines for transcriptomic and proteomic characterization of cDC populations. Then, a larger group of assays describes the characterization of cDC migration in vitro, ex vivo, and in vivo. The final guidelines measure cDC inflammasome and antigen (cross)-presentation activity. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.<br

Guidelines for mouse and human DC generation - Lutz, Manfred B.; Ali, Shafaqat; Audiger, Cindy; Autenrieth, Stella E.; Berod, Luciana; Bigley, Venetia; Cyran, Laura; Dalod, Marc; Dörrie, Jan; Dudziak, Diana; Florez-Grau, Georgina; Giusiano, Lucila; et al. (European Journal of Immunology, 2022)
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. This article provides protocols with top ticks and pitfalls for preparation and successful generation of mouse and human DC from different cellular sources, such as murine BM and HoxB8 cells, as well as human CD34(+) cells from cord blood, BM, and peripheral blood or peripheral blood monocytes. We describe murine cDC1, cDC2, and pDC generation with Flt3L and the generation of BM-derived DC with GM-CSF. Protocols for human DC generation focus on CD34(+) cell culture on OP9 cell layers for cDC1, cDC2, cDC3, and pDC subset generation and DC generation from peripheral blood monocytes (MoDC). Additional protocols include enrichment of murine DC subsets, CRISPR/Cas9 editing, and clinical grade human DC generation. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
CRIS-Team WoS Importer:2022-11-11

Guidelines for preparation and flow cytometry analysis of human nonlymphoid tissue DC - Dudziak, Diana; Heger, Lukas; Agace, William W.; Bakker, Joyce; de Gruijl, Tanja D.; Dress, Regine J.; Dutertre, Charles Antoine; Fenton, Thomas M.; Fransen, Marieke F.; Ginhoux, Florent; Heyman, Oded; Horev, Yael; et al. (European Journal of Immunology, 2025)
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs, and various nonlymphoid tissues. Within this article, detailed protocols are presented that allow for the generation of single-cell suspensions from human nonlymphoid tissues including lung, skin, gingiva, intestine as well as from tumors and tumor-draining lymph nodes with a subsequent analysis of dendritic cells by flow cytometry. Further, prepared single-cell suspensions can be subjected to other applications including cellular enrichment procedures, RNA sequencing, functional assays, etc. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
CRIS-Team Scopus Importer:2025-02-17
Keywords: dendritic cells; flow cytometry; nonlymphoid tissues; tumor; tumor-draining lymph node

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition) - Cossarizza, Andrea; Acs, Andreas; Adam, Dieter; Adam-Klages, Sabine; Agace, William W.; Aghaeepour, Nima; Akdis, Mübeccel; Allez, Matthieu; Almeida, Larissa Nogueira; Alvisi, Giorgia; Anderson, Graham; Andrä, Immanuel; et al. (European Journal of Immunology, 2019)
These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
CRIS-Team Scopus Importer:2019-10-29

Guidelines for uveal melanoma: a critical appraisal of systematically identified guidelines using the AGREE II and AGREE-REX instrument - Steeb, Theresa; Hayani, Kinan M.; Förster, Paul; Liegl, Raffael; Toussaint, Frédéric; Schlaak, Max; Berking, Carola; Heppt, Markus (Journal of Cancer Research and Clinical Oncology, 2020)
Purpose: Clinical practice guidelines provide recommendations for the management of diseases. In orphan conditions such as uveal melanoma (UM), guideline developers are challenged to provide practical and useful guidance even in the absence of high-quality evidence. Here, we assessed the methodological quality and identified deficiencies of international guidelines on UM as a base for future guideline development. Methods: A systematic search was carried out in guideline databases, Medline and Embase until 27th May 2019 for guidelines on UM published between 2004 and 2019. Five independent reviewers assessed the methodological quality of the identified guidelines using the instruments “Appraisal of Guidelines for Research and Evaluation II” (AGREE II) and AGREE-REX (Recommendation EXcellence). Descriptive analysis was performed and subgroup differences were explored with the Kruskal–Wallis (H) test. The relationship between the individual domains and items of the instruments were examined using Spearman’s correlation. Results: Five guidelines published from 2014 to 2018 by consortia of the United States of America, Canada and the United Kingdom (UK) were included. The highest scores were obtained by the UK guideline fulfilling 48–86% of criteria in AGREE II and 30–60% for AGREE-REX. All guidelines showed deficiencies in the domains “editorial independence”, “applicability”, and “recommendation”. Subgroup differences were identified only for the domain “editorial independence”. Conclusion: The UK guideline achieved the highest scores with both instruments and may serve as a basis for future guideline development in UM. The domains “editorial independence”, “recommendation”, and “applicability” were identified as methodological weaknesses and require particular attention and improvement in future guidelines.
CRIS-Team Scopus Importer:2020-02-25
Keywords: AGREE; Guideline; Ocular melanoma; Orphan disease; Practice guideline; Uveal melanoma

Guselkumab demonstrates long-term efficacy and maintenance of treatment response postwithdrawal in systemic treatment-naïve patients and nonresponders to fumaric acid esters: results from parts II and III of a randomized active-comparator-controlled phase IIIb trial (POLARIS). - Thaçi, Diamant; Pinter, Andreas; Sebastian, Michael; Termeer, Christian; Sticherling, Michael; Gerdes, Sascha; Schäkel, Knut; Wegner, Sven; Krampe, Stefanie; Bartz, Holger; Rausch, Christian; Taut, Friedemann; et al. (British Journal of Dermatology, 2024)
BACKGROUND: The anti-interleukin-23 antibody guselkumab (GUS) demonstrated favourable week 24 efficacy and safety over fumaric acid esters (FAE) in systemic treatment-naïve patients with moderate-to-severe plaque psoriasis (study part I). OBJECTIVES: To compare, in study part II, the sustainability of treatment responses (weeks 24-32) in GUS- and FAE-treated patients and treatment responses (weeks 32-56) in patients treated with GUS and FAE and in FAE nonresponders switching to GUS; and, in part III, to investigate the maintenance of response through week 100 in patients withdrawn from GUS at week 56. METHODS: At week 0, systemic treatment-naïve patients were randomized 1 : 1 to GUS or FAE as per label. At week 32, patients with a Psoriasis Area and Severity Index (PASI) 75 (≥ 75% improvement in PASI score) response (r) continued assigned treatment (GUSr-GUS; FAEr-FAE), whereas nonresponders (nr) received GUS (FAEnr-GUS; GUSnr-GUS). GUS-treated patients with a week 56 PASI 90 response (≥ 90% improvement in PASI score) were withdrawn (w) and followed until loss of response or week 100. RESULTS: At week 32, 98% (n = 54/55) of GUS- and 41% (n = 14/34) of FAE-treated patients were PASI 75 responders. At week 56, 91%, 50% and 80% of GUSr-GUS, FAEr-FAE and FAEnr-GUS patients, respectively, achieved a PASI 90 response; 72%, 29% and 45%, respectively, achieved a Dermatology Life Quality Index score of 0/1. At week 100, 44 weeks postwithdrawal, 47% (n = 17/36) and 25% (n = 3/12) of GUS-GUSw and FAE-GUSw patients, respectively, maintained a PASI score ≤ 5. Overall, the adverse event and discontinuation rates were lower for GUS than FAE. CONCLUSIONS: In these exploratory analyses, GUS, as a first-line systemic treatment or second-line systemic treatment in FAE nonresponders, was associated with long-term clinical efficacy up to week 100, including a withdrawal period.
EVALuna2:547035

Guselkumab is superior to fumaric acid esters in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment: results from a randomized, active-comparator-controlled phase IIIb trial (POLARIS) - Thaci, D.; Pinter, A.; Sebastian, M.; Termeer, C.; Sticherling, Michael; Gerdes, S.; Wegner, S.; Krampe, S.; Bartz, H.; Rausch, C.; Mensch, A.; Eyerich, K. (British Journal of Dermatology, 2020)
Background Guselkumab, a fully human interleukin-23 antibody, is approved for systemic treatment of patients with moderate-to-severe plaque psoriasis. Objectives To compare the efficacy and safety of guselkumab with those of fumaric acid esters (FAE) in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment. Methods Eligible patients were randomized to this multicentre, randomized, open-label, assessor-blinded, active-comparator-controlled phase IIIb study to receive guselkumab 100 mg by subcutaneous injection or oral FAE according to local label guidelines. Results Through week 24, 56 of 60 patients completed guselkumab treatment and 36 of 59 completed FAE treatment. The primary endpoint (proportion of patients with >= 90% improvement from their baseline Psoriasis Area and Severity Index; PASI 90 response) was achieved by significantly more patients receiving guselkumab than FAE at week 24 (82% vs. 14%, P < 0 center dot 001). Analysis of the major secondary endpoints confirmed a statistically significant difference between the treatments with regards to PASI 75 response (90% vs. 27%, P < 0 center dot 001) and Dermatology Life Quality Index score of 0 or 1 (no effect at all on the patient's quality of life; 62% vs. 17%, P < 0 center dot 001). More patients in the guselkumab group achieved completely clear skin (PASI 100 response) than in the FAE group (32% vs. 3%, P < 0 center dot 001). The incidence of adverse events was lower with guselkumab than with FAE (73% vs. 98%). Overall, 28% of patients on FAE discontinued due to an adverse event, compared with none receiving guselkumab. No new safety findings were observed for guselkumab. Conclusions Guselkumab demonstrated superiority over FAE in systemic-treatment-naive patients with moderate-to-severe plaque psoriasis through 24 weeks. What's already known about this topic?
CRIS-Team WoS Importer:2020-01-28

HAND FUNCTION IS IMPAIRED IN PATIENTS WITH RHEUMATOID ARTHRITIS, PSORIATIC ARTHRITIS, AND PSORIASIS COMPARED TO HEALTHY CONTROLS - Liphardt, Anna-Maria; Liehr, Sonja; Manger, Eva; Bieniek, Lisa; Kleyer, Arnd; Simon, David; Tascilar, Koray; Sticherling, Michael; Rech, Jürgen; Schett, Georg; Hueber, Axel (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Harmonisation of Outcome Parameters and Evaluation (HOPE) for actinic keratosis: protocol for the development of a core outcome set - Heppt, Markus V.; Steeb, Theresa; Schmitz, Lutz; Garbe, Claus; French, Lars E.; Leiter, Ulrike; Berking, Carola (Trials, 2019)
BACKGROUND: Actinic keratoses (AK) are common skin lesions that can progress to invasive squamous cell carcinoma of the skin. A variety of lesion- or field-targeted treatment options exist and their efficacy has been demonstrated in numerous randomised controlled trials (RCTs). However, the reported endpoints are highly heterogeneous, making it difficult to assess and compare distinct treatment options and to reach an evidence-based choice of therapy. METHODS: A systematic literature search will be conducted to analyse which endpoints are reported in RCTs. The focus will be on effectiveness, tolerability, cosmesis, and patient satisfaction. The reported endpoints of these studies, as well as their frequency and data collection times, will be documented in a standardised way to generate a comprehensive list of reported endpoints. In order to complete the identified outcomes in the literature search, focus groups on affected patients and structured interviews with board-certified dermatologists will be conducted to identify both patient- and practice-relevant endpoints. After the identification phase, the evaluation of the endpoints follows. In a two-stage Delphi procedure, experts including patient representatives will evaluate the endpoints in a standardised and transparent manner. A final face-to-face consensus meeting will be conducted after the last Delphi round in which a final list of core outcomes will be consented. DISCUSSION: The development of a standardised endpoint set for the treatment of AK will contribute to improving the comparability of therapeutic options. Our catalogue will enhance the synthesis of evidence for the future by reducing heterogeneity in outcomes between RCTs and hence contribute to improving the quality of research, evidence-based and patient-centred treatment. TRIAL REGISTRATION: Core Outcome Measures for Effectiveness ( COMET ) database. Registered in December 2018.
EVALuna2:209212

Harnessing the complete repertoire of conventional dendritic cell functions for cancer immunotherapy - Amon, Lukas; Hatscher, Lukas; Heger, Lukas; Dudziak, Diana; Lehmann, Christian (Pharmaceutics, 2020)
The onset of checkpoint inhibition revolutionized the treatment of cancer. However, studies from the last decade suggested that the sole enhancement of T cell functionality might not suffice to fight malignancies in all individuals. Dendritic cells (DCs) are not only part of the innate immune system, but also generals of adaptive immunity and they orchestrate the de novo induction of tolerogenic and immunogenic T cell responses. Thus, combinatorial approaches addressing DCs and T cells in parallel represent an attractive strategy to achieve higher response rates across patients. However, this requires profound knowledge about the dynamic interplay of DCs, T cells, other immune and tumor cells. Here, we summarize the DC subsets present in mice and men and highlight conserved and divergent characteristics between different subsets and species. Thereby, we supply a resource of the molecular players involved in key functional features of DCs ranging from their sentinel function, the translation of the sensed environment at the DC:T cell interface to the resulting specialized T cell effector modules, as well as the influence of the tumor microenvironment on the DC function. As of today, mostly monocyte derived dendritic cells (moDCs) are used in autologous cell therapies after tumor antigen loading. While showing encouraging results in a fraction of patients, the overall clinical response rate is still not optimal. By disentangling the general aspects of DC biology, we provide rationales for the design of next generation DC vaccines enabling to exploit and manipulate the described pathways for the purpose of cancer immunotherapy in vivo. Finally, we discuss how DC-based vaccines might synergize with checkpoint inhibition in the treatment of malignant diseases.
CRIS-Team Scopus Importer:2020-07-24
Keywords: Antigen targeting; Cancer therapy; Checkpoint inhibition; Dendritic cells; Pattern recognition receptors; T cells; Tumor microenvironment; Vaccination

Harnessing the Participation of Dendritic Cells in Immunity and Tolerance - Boscardin, Silvia Beatriz; Dudziak, Diana; Muenz, Christian; Rosa, Daniela Santoro (Frontiers in Immunology, 2020)
CRIS-Team Scopus Importer:2020-11-13
Keywords: antigen presentation; DC subtypes; dendritic cell; dendritic cell activation; dendritic cell vaccine therapy

Hautveränderungen um Wunden: Ein Positionspapier der Fachgesellschaft Initiative Chronische Wunden (ICW) e.V. - Dissemond, Joachim; Bültemann, Anke; Gerber, Veronika; Motzkus, Martin; Rembe, Julian Dario; Erfurt-Berge, Cornelia (Deutsche Medizinische Wochenschrift, 2024)
Many patients with chronic wounds have skin changes that can provide important clues as to the etiology of the wound and/or inappropriate treatment. As the largest human organ, the skin is easily accessible for clinical inspection. However, healthcare professional teams currently do not always assess and document these skin changes correctly and consistently. The board of the professional society Initiative Chronische Wunden (ICW) e. V. has therefore decided to draw up a position paper to clarify the most important technical terms for skin changes around wounds. One focus here is on the definition and differentiated description of the wound edge and wound surrounding skin. Atrophies, blisters, eczema, erythema, hemorrhages, hyperpigmentation, hypopigmentation, hyperkeratosis, maceration, necrosis, oedema, pustules, sclerosis and scales are then described in more detail and placed in a clinical context.
CRIS-Team Scopus Importer:2024-09-13

Have We Ignored Vector-Associated Microbiota While Characterizing the Function of Langerhans Cells in Experimental Cutaneous Leishmaniasis? - Nerb, Benedikt; Dudziak, Diana; Gessner, André; Feuerer, Markus; Ritter, Uwe (Frontiers in Tropical Diseases, 2022)
CRIS-Team Scopus Importer:2024-12-16
Keywords: dendritic cells; experimental cutaneous leishmaniasis; Langerhans cells; lymph node; microbiome; skin; T cell-mediated immunity

HDAC2 Is Involved in the Regulation of BRN3A in Melanocytes and Melanoma - Heppt, Markus; Wessely, Anja; Hornig, Eva; Kammerbauer, Claudia; Graf, Saskia A.; Besch, Robert; French, Lars E.; Matthies, Alexander Oliver; Kuphal, Silke; Kappelmann-Fenzl, Melanie; Boßerhoff, Anja Katrin; Berking, Carola (International Journal of Molecular Sciences, 2022)
The neural crest transcription factor BRN3A is essential for the proliferation and survival of melanoma cells. It is frequently expressed in melanoma but not in normal melanocytes or benign nevi. The mechanisms underlying the aberrant expression of BRN3A are unknown. Here, we investigated the epigenetic regulation of BRN3A in melanocytes and melanoma cell lines treated with DNA methyltransferase (DNMT), histone acetyltransferase (HAT), and histone deacetylase (HDAC) inhibitors. DNMT and HAT inhibition did not significantly alter BRN3A expression levels, whereas panHDAC inhibition by trichostatin A led to increased expression. Treatment with the isoform-specific HDAC inhibitor mocetinostat, but not with PCI-34051, also increased BRN3A expression levels, suggesting that class I HDACs HDAC1, HDAC2, and HDAC3, and class IV HDAC11, were involved in the regulation of BRN3A expression. Transient silencing of HDACs 1, 2, 3, and 11 by siRNAs revealed that, specifically, HDAC2 inhibition was able to increase BRN3A expression. ChIP-Seq analysis uncovered that HDAC2 inhibition specifically increased H3K27ac levels at a distal enhancer region of the BRN3A gene. Altogether, our data suggest that HDAC2 is a key epigenetic regulator of BRN3A in melanocytes and melanoma cells. These results highlight the importance of epigenetic mechanisms in regulating melanoma oncogenes.
CRIS-Team Scopus Importer:2022-02-04
Keywords: BRN3A; ChIP-Seq; DNA methylation; Epigenetic regulation; HAT; HDAC; Melanoma

HDAC2 is involved in the regulation of Brn3a in melanocytes and melanoma - Heppt, Markus; Wessely, Anja; Hornig, E.; Kammerbauer, C.; Graf, S.; Besch, R.; French, L. E.; Kuphal, Silke; Kappelmann-Fenzl, Melanie; Boßerhoff, Anja Katrin; Berking, Carola (EXPERIMENTAL DERMATOLOGY, 2023)
CRIS-Team WoS Importer:2023-06-02

Health literacy and information needs among German skin cancer patients in comparison to people without skin cancer: A survey - Hoffmann, Julia; Steeb, Theresa; Weber, Christiane; Doppler, Astrid; Schmitt, Jochen; Schadendorf, Dirk; Berking, Carola; Meier, Friedegund (JEADV Clinical Practice, 2023)
Background: An increasing number of patients are seeking health information on the internet. Health literacy and the quality of information are crucial to enable patients to find relevant high-quality information. Objectives: To investigate the relevance of quality criteria for health information and to determine the health literacy of skin cancer patients (SC) in comparison to those without skin cancer (NSC). Methods: Between December 2021 until February 2022 we undertook an online survey on the importance of multiple criteria to investigate the relevance of quality criteria of online health information. SC and NSC were eligible for participation. The questionnaire assessed participants´ health information-seeking behavior and the evaluation of relevance of quality criteria for health information on a 5-point-LIKERT-Scale. The participants´ health literacy was measured according to the health literacy measurement scale ranging from 0-100. Comparisons between SC and NSC were investigated with t-tests. Results: We retrieved data from 268 participants, of whom 98 (38%) were SC. Participants assigned the highest relevance to the health information topics treatment (4.7 ± 0.64) and effects of a disease (4.49 ± 0.76). Participants ranked the content of information with a mean of 4.72 (±0.57) to be the most relevant criterion, followed by objectivity (4.61 ± 0.67) and completeness of the information (4.59 ± 0.61). Participants showed the highest competence in understanding of information (62.4 ± 22.5) and in disease prevention (58.32 ± 22.9). They reached low values in accessing health related information (46.78 ± 25.62) and appraising it (33.16 ± 20.11). Subgroup analysis indicated that SC had a greater need for practical information that is helpful in dealing with a disease compared to NSC. They showed significantly lower health literacy than NSC. Conclusions: Our study documents that SC and NSC have a high need for different dimensions of quality of health information. These differences in the importance of criteria should be considered in the development of future targeted health information.
CRIS-Team Scopus Importer:2024-12-16
Keywords: health communication; health information; health literacy; quality criteria; skin cancer; survey

Health-related quality of life (EuroQol 5D-5L) in patients with autoimmunity in the context of immunotherapy: A large dataset comprising cancer patients after cessation of checkpoint inhibitor therapy and patients with autoimmune diseases - Schulz, Thomas U.; Zierold, Sarah; Sachse, Michael M.; Pesch, Giulia; Tomsitz, Dirk; Schilbach, Katharina; Kähler, Katharina C.; French, Lars E.; Heinzerling, Lucie (Data in Brief, 2022)
This dataset contains demographic, clinical, and health-related quality of life (HRQoL) data from 2905 patients including 200 cancer patients after immune checkpoint inhibitor (ICI) cessation and 2705 patients with a wide variety of autoimmune diseases. Within this multicenter, cross-sectional survey study data were collected questionnaire-based in cancer patients (ICI-patients) ≥ 18 years of age who had received at least one dose of ICI with ≥ 12 weeks since ICI discontinuation. Patients with autoimmune diseases (AI-patients) were ≥ 18 years, had at least one autoimmune disease and had never received ICI. ICI-patients were recruited in three skin cancer centers and via support groups. AI-patients were recruited in an outpatient clinic for internal medicine and via support groups. Specific questionnaires for ICI-patients/AI-patients were provided paper-based for patients from outpatient clinics and online for patients from support groups. Both questionnaires contained sections with demographic information, clinical data, and the standardized patient-reported outcome measure EuroQol 5D-5L (EQ-5D-5L) to assess HRQoL. Clinical data focused on autoimmunity and therapy of autoimmunity in (1) ICI-patients referring to particularly persistent immune-related adverse events (persistent irAEs) and in (2) AI-patients referring to respective autoimmune diseases. Additionally, specific items on cancer and cancer therapy were included in ICI-patients, and AI-patients were asked about the presence of acute exacerbations of autoimmune diseases. This dataset contains the raw data for ICI-patients and AI-patients, analyzed data on patient demographics, clinical characteristics and HRQoL scores among ICI-patients with/without persistent irAEs and among AI-patients. The data provide a basis for further investigations within the cohort of ICI-patients after ICI cessation and/or for AI-patients with different autoimmune diseases with regard to HRQoL, autoimmunity and therapy of autoimmunity.
CRIS-Team Scopus Importer:2022-11-11
Keywords: Chronic toxicities; hypothyroidism; Long-term sequelae; Melanoma; Persistent immune-related adverse events (persistent irAEs); Sarcoidosis; Sjogren's syndrome; Vitiligo

H. E. Becher - his Importance as a Sculptor and Medalist for Moulage Art in Germany - Sticherling, Michael; Emmerling, Johanna (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-04-16

Hematological immune related adverse events after treatment with immune checkpoint inhibitors - Kramer, Rafaela; Zaremba, Anne; Moreira, Alvaro; Ugurel, Selma; Johnson, Douglas B.; Hassel, Jessica C.; Salzmann, Martin; Gesierich, Anja; Weppler, Alison; Spain, Lavinia; Loquai, Carmen; Dudda, Milena; et al. (European Journal of Cancer, 2021)
Introduction: With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes. Patients and methods: Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres. Results: In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1–128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis). Conclusion: Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Anaemia; Anti-CTLA-4-Antibody; Anti-PD1-Antibody; Autoimmunity; Haematotoxicity; Hemophagocytic lymphohistiocytosis; Leucopaenia; Neutropenia; Side-effects; Thrombocytopenia

Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial - Leyvraz, S.; Piperno-Neumann, S.; Suciu, S.; Baurain, J. F.; Zdzienicki, M.; Testori, A.; Marshall, E.; Scheulen, M.; Jouary, T.; Negrier, S.; Vermorken, J. B.; Kämpgen, Eckhart; et al. (Annals of Oncology, 2014)
In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM.Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points.Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade >=3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade >=3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths.HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental.2004-002245-12 and NCT00110123.
EVALuna2:19469

Herpes simplex infection in a patient with rheumatoid arthritis treated with baricitinib: a case report - Valor-Méndez, Larissa; Voskens, Caroline; Rech, Jürgen; Kleyer, Arnd; Schett, Georg (Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-04-19

Herpes simplex virus type 1 ICP0 induces CD83 degradation in mature dendritic cells independent of its E3 ubiquitin ligase function - Heilingloh, Christiane; Muehl-Zuerbes, Petra; Steinkasserer, Alexander; Kummer, Mirko (Journal of General Virology, 2014)
Mature dendritic cells (mDCs) are the most potent antigen-presenting cells known today, as they are the only antigen-presenting cells able to induce naïve T-cells. Therefore, they play a crucial role during the induction of effective antiviral immune responses. Interestingly, the surface molecule CD83 expressed on mDCs is targeted by several viruses. As CD83 has been shown to exert co-stimulatory functions on mDCs, its downmodulation represents a viral immune escape mechanism. Mechanistically, it has been shown that herpes simplex virus type 1 infection leads to proteasomal degradation of CD83, resulting in a strongly diminished T-cell stimulatory capacity of the infected mDC. Previous data suggest that the viral immediate-early protein ICP0 (infected-cell protein 0) plays an important role in this process. In the present study, we showed that ICP0 is sufficient to induce CD83 degradation in the absence of any other viral factor. However, the mechanism of ICP0-mediated CD83 degradation is not yet understood. Here, we provide evidence that ubiquitination of lysine residues is, despite the published E3 ubiquitin ligase activity of ICP0, not necessary for CD83 degradation. This finding was underlined by the observation that expression of an ICP0 mutant lacking the E3 ubiquitin ligase domain in mDCs still induced CD83 degradation. Finally, inhibition of E1 activating enzyme using the specific inhibitor 4[4-(5-nitro-furan-2-ylmethylene)-3.5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester did not prevent CD83 degradation. Taken together, our data provide strong evidence that ICP0 alone induces CD83 degradation independent of its E3 ubiquitin ligase function and of the ubiquitin machinery.
EVALuna2:26033

Herpes Simplex Virus Type 1 Propagation, Titration and Single-step Growth Curves - Grosche, Linda; Döhner, Katinka; Düthorn, Alexandra; Hickford-Martinez, Ana; Steinkasserer, Alexander; Sodeik, Beate (Bio-protocol, 2019)
Given the endemic seroprevalence of herpes simplex viruses (HSV), its associated human diseases, and the emergence of acyclovir-resistant strains, there is a continuous need for better antiviral therapies. Towards this aim, identifying mechanistic details of how HSV-1 manipulates infected cells, how it modulates the immune responses, and how it causes diseases are essential. Measuring titers and growth kinetics of clinical isolates and viral mutants are important for a thorough characterization of viral phenotypes in vitro and in vivo. We provide protocols for the preparation as well as titration of HSV-1 stocks, and explain how to perform single-step growth curves to characterize the functions of viral proteins or host factors during infection. In particular, we describe methods to prepare and characterize high-titer HSV-1 stocks with low genome to titer ratios that are required for infection studies in cell culture and animal experiments.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Herpes simplex virus type 1; Plaque assay; Single-step growth curve; Virus propagation

Herpes simplex virus type-2 paralyzes the function of monocyte-derived dendritic cells - Grosche, Linda; Mühl-Zürbes, Petra; Ciblis, Barbara; Krawczyk, Adalbert; Kuhnt, Christine; Kamm, Lisa; Steinkasserer, Alexander; Heilingloh, Christiane (Viruses, 2020)
Herpes simplex viruses not only infect a variety of different cell types, including dendritic cells (DCs), but also modulate important cellular functions in benefit of the virus. Given the relevance of directed immune cell migration during the initiation of potent antiviral immune responses, interference with DC migration constitutes a sophisticated strategy to hamper antiviral immunity. Notably, recent reports revealed that HSV-1 significantly inhibits DC migration in vitro. Thus, we aimed to investigate whether HSV-2 also modulates distinct hallmarks of DC biology. Here, we demonstrate that HSV-2 negatively interferes with chemokine-dependent in vitro migration capacity of mature DCs (mDCs). Interestingly, rather than mediating the reduction of the cognate chemokine receptor expression early during infection, HSV-2 rapidly induces β2 integrin (LFA-1)-mediated mDC adhesion and thereby blocks mDC migration. Mechanistically, HSV-2 triggers the proteasomal degradation of the negative regulator of β2 integrin activity, CYTIP, which causes the constitutive activation of LFA-1 and thus mDC adhesion. In conclusion, our data extend and strengthen recent findings reporting the reduction of mDC migration in the context of a herpesviral infection. We thus hypothesize that hampering antigen delivery to secondary lymphoid organs by inhibition of mDC migration is an evolutionary conserved strategy among distinct members of Herpesviridae.
CRIS-Team Scopus Importer:2020-02-04
Keywords: Adhesion; CYTIP; Cytohesin-1; Dendritic cells; HSV-1; HSV-2; LFA-1; Migration

Heterogeneity and function of conventional dendritic cells from early to adult life - Schraml, B.; Papaioannou, N.; Shakiba, R.; Ravi, K.; Kuentzel, V.; Salei, N.; Lehman, C. H.; Fiancette, R.; Messerer, D.; Ohnmacht, C.; Haller, D.; Staub, T.; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system - Beyer, Felix; Jadasz, Janusz; Samper Agrelo, Iria; Schira-Heinen, Jessica; Groh, Janos; Manousi, Anastasia; Buetermann, Christine; Estrada, Veronica; Reiche, Laura; Cantone, Martina; Vera, Julio; Vigano, Francesca; et al. (Glia, 2019)
Apart from dedicated oligodendroglial progenitor cells, adult neural stem cells (aNSCs) can also give rise to new oligodendrocytes in the adult central nervous system (CNS). This process mainly confers myelinating glial cell replacement in pathological situations and can hence contribute to glial heterogeneity. Our previous studies demonstrated that the p57kip2 gene encodes an intrinsic regulator of glial fate acquisition and we here investigated to what degree its modulation can affect stem cell-dependent oligodendrogenesis in different CNS environments. We therefore transplanted p57kip2 knockdown aNSCs into white and gray matter (WM and GM) regions of the mouse brain, into uninjured spinal cords as well as in the vicinity of spinal cord injuries and evaluated integration and differentiation in vivo. Our experiments revealed that under healthy conditions intrinsic suppression of p57kip2 as well as WM localization promote differentiation toward myelinating oligodendrocytes at the expense of astrocyte generation. Moreover, p57kip2 knockdown conferred a strong benefit on cell survival augmenting net oligodendrocyte generation. In the vicinity of hemisectioned spinal cords, the gene knockdown led to a similar induction of oligodendroglial features; however, newly generated oligodendrocytes appeared to suffer more from the hostile environment. This study contributes to our understanding of mechanisms of adult oligodendrogenesis and glial heterogeneity and further reveals critical factors when considering aNSC mediated cell replacement in injury and disease.
CRIS-Team WoS Importer:2019-10-29

Hierarchical Levels of Biological Systems and their Integration as a Principal Cause for Tumour Occurrence - Nikolov, Svetoslav; Dimitrov, Assen; Vera, Julio (Nonlinear Dynamis, Psychology, and Life Sciences, 2019)
The development of new theories, mathematical methods and models for effective control of complex systems is one of the main problems for modern science. Biological systems are complex and hierarchically organized, with the behaviour of higher levels influencing the dynamics of the lower ones and vice versa. Hierarchical organization can be observed from subcellular to supercellular levels. When biological systems are far from their steady states, then nonlinear dependences take place, and a slight external impact can cause unexpected and unpredictable (chaotic, irregular) behaviour in these systems, resulting in fractal hierarchical structures. By examining tumours as strange (chaotic) attractors, we define in this article the hypothesis that the cause of their occurrence, development and spread (metastasis) is due to disorders in the hierarchical structure and integration of cell signalling pathways in tumour cells. An essential point in this article is the thesis (contrary to the view that the only causality in hierarchical systems is physical causality, i.e. there is no "top-down,' "holistic causality,' "intelligent causality,' etc.) that hierarchical systems are built on the principle of communication. Intelligent systems (in particular biological) that do not interact as mechanical objects, but on the basis of different meanings of biochemical signals obtained after their interpretation, participate in this communication.
CRIS-Team Scopus Importer:2019-07-16

High volume of polysorbate-containing (Tween® 80) solutions induces false-positive results in intradermal test - Wagner, N.; Podda, M. (Journal of the European Academy of Dermatology and Venereology, 2018)
BACKGROUND: Intradermal test is used to detect causative allergens in IgE-mediated hypersensitivity. The surfactant polysorbate 80 can be added to intradermal test solutions to more reliably dissolve the allergen and ensure a constant bioavailability of the injected allergen. Polysorbate 80 has, however, some histamine-releasing properties which could blur the difference to the histamine-induced wheal. Routinely serving as a control. OBJECTIVE: Allergen-free polysorbate 80 containing (0.005%) test solutions were therefore systematically tested at different injection volumes to see whether polysorbate can falsify skin reactions and if yes whether conditions can be identified to avoid this. METHODS: In a partly blinded study, 30 patients were tested intracutaneously at the back: each received at three separate sites 0.05 mL of polysorbate-containing solvent, 0.02 mL polysorbate-containing solvent as well as 0.02 mL polysorbate-free solvent. After 15 min, wheal and erythema were documented and planimetrically quantified. RESULTS: Unexpectedly 23 of 30 (77%) patients showed false-positive test reactions to the volume of 0.05 mL of the polysorbate-containing solvent whereas the polysorbate-containing solvent with 0.02 mL and the polysorbate-free solvent with 0.02 mL injection volume had no reinforcing effect on skin test reaction. CONCLUSIONS: Different volumes of polysorbate-containing solutions, all recommended by manufacturers for intradermal tests, may significantly influence test results. The study shows that a polysorbate 80 used at 0.005% in solvents for intradermal test to provide a better bioavailability of allergens produces false-positive reactivity in a surprising and a hitherto unknown 77% if the 0.05 mL volume is injected. It is, therefore, mandatory to strictly adhere to an intradermal test volume of 0.02 mL as only then falsifying effects of the polysorbate additive are avoided, and comparable test results are ensured.
EVALuna2:34761

HIV-1 mRNA electroporation of PBMC: A simple and efficient method to monitor T-cell responses against autologous HIV-1 in HIV-1-infected patients - Etschel, Jennifer K.; Hueckelhoven, Angela G.; Hofmann, Christian; Zitzelsberger, Kathrin; Maurer, Katja; Bergmann, Silke; Müller-Schmucker, Sandra; Wittmann, Jürgen; Spriewald, Bernd; Dörrie, Jan; Schaft, Niels; Harrer, Thomas (Journal of Immunological Methods, 2012)
Efficient monitoring of HIV-1-specific T-cells is crucial for the development of HIV-1 vaccines and immunotherapies. Currently, mainly peptides and vaccinia vectors are used for detection of HIV-1-specific cytotoxic T-lymphocytes (CTL), however, as HIV-1 is a variable virus, it is unknown to what extent the T-cell response against the autologous virus is under- or overestimated by using antigens from heterologous viral strains. Therefore, we established a new method for immunomonitoring of CTL using electroporation of peripheral blood mononuclear cells (PBMC) with mRNA derived from autologous viral strains. From six HIV-1-infected patients virus derived mRNA was produced after PCR-based cloning of autologous gag (n = 5) and/or nef genes (n = 3) from plasma and electroporated into PBMC from patients and healthy donors. Electroporation of PBMC with mRNA resulted in efficient protein expression with good induction of γ-interferon (γ-IFN) release by specific T-cells comparable to peptide pools and better than recombinant vaccinia viruses. Three mRNA encoded autologous Gag proteins and one autologous mRNA encoded Nef protein were better recognized by autologous PBMC in comparison to heterologous mRNA encoded Gag or Nef proteins (SF2 or HXB2). However, in one case each, mRNA encoded autologous Gag or Nef, respectively, was recognized less efficiently due to the presence of CTL escape mutations. In summary, electroporation of PBMC with mRNA is a very efficient, easy and rapid method for immunomonitoring of HIV-1-specific T-cell responses against autologous viral strains. Our data demonstrate that patients' CTL responses against autologous viral strains may be under- or overestimated by using antigens from heterologous viral strains. © 2012 Elsevier B.V.
CRIS-Team Scopus Importer:2021-10-01
Keywords: CTL; HIV-1; Immunomonitoring; MRNA electroporation

HIV-1 Nef-Induced Secretion of the Proinflammatory Protease TACE into Extracellular Vesicles Is Mediated by Raf-1 and Can Be Suppressed by Clinical Protein Kinase Inhibitors - Zhao, Zhe; Fagerlund, Riku; Baur, Andreas; Saksela, Kalle (Journal of Virology, 2021)
Chronic immune activation is an important driver of human immunodeficiency virus type 1 (HIV-1) pathogenesis and has been associated with the presence of tumor necrosis factor-a converting enzyme (TACE) in extracellular vesicles (EVs) circulating in infected individuals. We have recently shown that activation of the Src-family tyrosine kinase hematopoietic cell kinase (Hck) by HIV-1 Nef can trigger the packaging of TACE into EVs via an unconventional protein secretion pathway. Using a panel of HIV-1 Nef mutants and natural HIV-2 and simian immunodeficiency virus (SIV) Nef alleles, we now show that the capacity to promote TACE secretion depends on the superior ability of HIV-1-like Nef alleles to induce Hck kinase activity, whereas other Nef effector functions are dispensable. Strikingly, among the numerous Src-family downstream effectors, serine/threonine kinase Raf-1 was found to be necessary and alone sufficient to trigger the secretion of TACE into EVs. These data reveal the involvement of Raf-1 in regulation of unconventional protein secretion and highlight the importance of Raf-1 as a cellular effector of Nef, thereby suggesting a novel rationale for testing pharmacological inhibitors of the Raf-MAPK pathway to treat HIV-associated immune activation. IMPORTANCE Chronic immune activation contributes to the immunopathogenesis of human immunodeficiency virus type 1 (HIV-1) infection and is associated with poor recovery of the immune system despite potent antiretroviral therapy, which is observed in 10% to 40% drug-treated patients depending on the definition of immune reconstitution. We have previously shown that the HIV pathogenicity factor Nef can promote loading of the proinflammatory protease TACE into extracellular vesicles (EVs), and the levels of such TACE-containing EVs circulating in the blood correlate with low CD4 lymphocyte counts in HIV patients receiving antiretroviral therapy. Here, we show that Nef promotes uploading of TACE into EVs by triggering unconventional secretion via activation of the Hck/Raf/mitogen-activated protein kinase (MAPK) cascade. We find that several pharmaceutical inhibitors of these kinases that are currently in clinical use for other diseases can potently suppress this pathogenic deregulation and could thus provide a novel strategy for treating HIV-associated immune activation.
CRIS-Team Scopus Importer:2021-05-14
Keywords: ADAM17; Extracellular vesicles; Hck; HIV-1; Kinase inhibitor; Nef; Raf; TACE

HIV Activates the Tyrosine Kinase Hck to Secrete ADAM Protease-Containing Extracellular Vesicles - Lee, J. H.; Zhao, Z.; Ostalecki, Christian; Kesti, T.; Bruns, Heiko; Simon, B.; Harrer, Thomas; Saksela, K.; Baur, A. S. (EBioMedicine, 2018)
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HIV-Nef and ADAM17-Containing Plasma Extracellular Vesicles Induce and Correlate with Immune Pathogenesis in Chronic HIV Infection - Lee, Jung-Hyun; Schierer, Stephan; Blume, Katja; Dindorf, Jochen; Wittki, Sebastian; Xiang, Wei; Ostalecki, Christian; Koliha, Nina; Wild, Stefan; Schuler, Gerold; Fackler, Oliver T.; Saksela, Kalle; et al. (EBioMedicine, 2016)
Antiretroviral therapy (ART) efficiently suppresses HIV replication but immune activation and low CD4 T cell counts often persist. The underlying mechanism of this ART-resistant pathogenesis is not clear. We observed that levels of plasma extracellular vesicles (pEV) are strongly elevated in HIV infection and do not decline during ART. Surprisingly, these vesicles contained the viral accessory proteins Nef and Vpu, which are assumed to be not expressed under efficient ART, as well as pro-inflammatory effectors, including activated ADAM17. HIV pEV were characterized by the presence of activated ?v?3 and absence of CD81 and Tsg101. Correlating with immune activation, peripheral monocytes ingested large amounts of pEV, giving rise to an increased population of CD1c(+) CD14(+) cells that secreted inflammatory cytokines. Importantly, the pro-inflammatory content, particularly ADAM17 activity, correlated with low T cell counts. Preliminary evidence suggested that HIV pEV derived from peripheral mononuclear cells and from an unknown myeloid cell population. In summary we propose an important role of pro-inflammatory pEV in chronic HIV infection due to ongoing viral Nef activity.
EVALuna2:4716

HIV Nef- and Notch1-dependent Endocytosis of ADAM17 Induces Vesicular TNF Secretion in Chronic HIV Infection - Ostalecki, Christian; Wittki, Sebastian; Lee, Jung-Hyun; Geist, Miriam M.; Tibroni, Nadine; Harrer, Thomas; Schuler, Gerold; Fackler, Oliver T.; Baur, Andreas (EBioMedicine, 2016)
Tumor necrosis factor (TNF) is a key cytokine in HIV replication and pathogenesis. For reasons that are not entirely clear, the cytokine remains upregulated despite anti-retroviral therapy (ART). Here we demonstrate that HIV Nef induces an alternative TNF secretion mechanism that remains active in chronic infection. Ingestion of Nef-containing plasma extracellular vesicles (pEV) from ART patients by primary immune cells, but also Nef expression, induced intracellular proTNF cleavage and secretion of vesicular TNF endosomes. Key event was the Nef-mediated routing of the TNF-converting enzyme ADAM17 into Rab4+ early endosomes and the Rab27+ secretory pathway. Analysis of lymph-node tissue by multi-epitope-ligand-cartography (MELC) confirmed a vesicular TNF secretion phenotype that co-localized with persistent Nef expression, and implicated Notch1 as an essential co-factor. Surprisingly Notch1 had no transcriptional effect but was required for the endosomal trafficking of ADAM17. We conclude that Nef expression and Nef-containing pEV mobilize TNF from endosomal compartments in acute and chronic infection.
EVALuna2:13372

HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases - Lee, Jung-Hyun; Wittki, Sebastian; Braeu, Tanja; Dreyer, Florian; Kraetzel, Kirsten; Dindorf, Jochen; Johnston, Ian C. D.; Gross, Stefanie; Kremmer, Elisabeth; Zeidler, Reinhard; Schlötzer-Schrehardt, Ursula; Lichtenheld, Mathias; et al. (Molecular Cell, 2013)
The HIV Nef protein recruits the polycomb protein Eed and mimics an integrin receptor signal for reasons that are not entirely clear. Here we demonstrate that Nef and Eed complex with the integrin effector paxillin to recruit and activate TNF? converting enzyme (TACE alias ADAM 17) and its close relative ADAM10. The activated proteases cleaved proTNF? and were shuttled into extracellular vesicles (EVs). Peripheral blood mononuclear cells that ingested these EVs released TNF?. Analyzing the mechanism, we found that Pak2, an established host cell effector of Nef, phosphorylated paxillin on Ser272/274 to induce TACE-paxillin association and shuttling into EVs via lipid rafts. Conversely, Pak1 phosphorylated paxillin on Ser258, which inhibited TACE association and lipid raft transfer. Interestingly, melanoma cells used an identical mechanism to shuttle predominantly ADAM10 into EVs. We conclude that HIV-1 and cancer cells exploit a paxillin/integrin-controlled mechanism to release TACE/ADAM10-containing vesicles, ensuring better proliferation/growth conditions in their microenvironment.
EVALuna2:12854

How does Nutrition Affect Wound Healing? - Renner, Regina; Erfurt-Berge, Cornelia (Phlebologie, 2022)
Interference during the complex wound healing process might lead to a delayed or absence of wound closure. One possible disruptive factor can be wrong nutrition. It is necessary to differentiate between quantitative and qualitative malnutrition. Preferential obese patients suffer from a qualitative malnutrition and sarkopenia.
CRIS-Team WoS Importer:2022-07-29

How neural crest transcription factors contribute to melanoma heterogeneity, cellular plasticity, and treatment resistance - Wessely, Anja; Steeb, Theresa; Berking, Carola; Heppt, Markus (International Journal of Molecular Sciences, 2021)
Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.
CRIS-Team Scopus Importer:2021-06-18
Keywords: Cellular plasticity; FOXD3; Melanoma; MITF; MSX1; Neural crest; PAX3; Phenotype switch; SOX10

How to assess the efficacy of interventions for actinic keratosis? A review with a focus on long-term results - Steeb, Theresa; Wessely, Anja; Petzold, Anne; Schmitz, Lutz; Dirschka, Thomas; Berking, Carola; Heppt, Markus (Journal of Clinical Medicine, 2021)
Actinic keratoses (AK) are common lesions of the skin caused by cumulative sun exposure. Since AK may progress to invasive cutaneous squamous cell carcinoma (cSCC), guidelines uniformly recommend early and consequent treatment. A variety of interventions are available; however, most randomized controlled trials, meta-analyses, and guidelines focus on outcomes that are usually evaluated 8–12 weeks after the end of treatment. Importantly, these assessments can capture the short-term, transient outcomes, but do not allow any conclusions about long-term results to be drawn and do not reflect the probability of transition towards cSCC. Until now, few studies have assessed the long-term results of interventions for AK. Indeed, finding the most appropriate end-point and adjunct time point for determining the long-term results of interventions for AK remains a challenge. Here, we provide an overview of the different ways of measuring the efficacy of AK treatments, such as using recurrence rates or sustained clearance rates, and discuss methodological aspects. Furthermore, we highlight the importance of evidence from post-marketing surveillance trials for the detection of efficacy values and safety signals. Additionally, we emphasize that a follow-up period of 12 months might not be sufficient to reflect the long-term results and stress the urgent need for a longer follow-up period and regular risk-stratified surveillance.
CRIS-Team Scopus Importer:2021-10-29
Keywords: Actinic keratosis; Core outcomes; Follow-up; Long-term efficacy; Methodology; Prevention; Squamous cell carcinoma; Surveillance

HSV-1 Modulates IL-6 Receptor Expression on Human Dendritic Cells - Birzer, Alexandra; Krawczyk, Adalbert; Draßner, Christina; Kuhnt, Christine; Mühl-Zürbes, Petra; Heilingloh, Christiane; Steinkasserer, Alexander; Popella, Linda (Frontiers in Immunology, 2020)
Dendritic cells (DCs) are the guardians of the immune system since they are located in the majority of peripheral tissues. In addition, they are crucial for the induction of an effective immune response based on their unique capacity to stimulate naive T cells. During co-evolution, the human pathogen herpes simplex virus type 1 (HSV-1) has evolved several immune evasion mechanisms in order to subvert the host's immune system especially by targeting DC biology and function. Here we demonstrate that HSV-1 infection influences the IL-6 receptor (IL6R) expression both on protein and mRNA levels in/on human monocyte-derived mature DCs (mDCs). Surprisingly, reduced IL6R expression levels were also observed on uninfected bystander mDCs. Mechanistically, we clearly show that HSV-1-derived non-infectious light (L-) particles are sufficient to trigger IL6R regulation on uninfected bystander mDCs. These L-particles lack the viral DNA-loaded capsid and are predominantly produced during infection of mDCs. Our results show that the deletion of the HSV-1 tegument protein vhs partially rescued the reduced IL6R surface expression levels on/in bystander mDCs. Using a neutralizing antibody, which perturbs the transfer of L-particles to bystander mDCs, was sufficient to rescue the modulation of IL6R surface expression on uninfected bystander mDCs. This study provides evidence that L-particles transfer specific viral proteins to uninfected bystander mDCs, thereby negatively interfering with their IL6R expression levels, however, to a lesser extend compared to H-particles. Due to their immune-modulatory capacity, L-particles represent an elaborated approach of HSV-1-mediated immune evasion.
CRIS-Team Scopus Importer:2020-09-18
Keywords: bystander cells; HSV-1; IL-6 receptor; L-particles; mature dendritic cells; vhs

Human adenovirus-specific γ/δ and CD8+ T cells generated by T-cell receptor transfection to treat adenovirus infection after allogeneic stem cell transplantation. - Dörrie, Jan; Krug, Christian; Hofmann, Christian; Mueller, Ina; Wellner, Verena; Knippertz, Ilka; Schierer, Stephan; Thomas, Simone; Zipperer, Elke; Printz, Dieter; Fritsch, Gerhard; Schuler, Gerold; et al. (PLoS ONE, 2014)
Human adenovirus infection is life threatening after allogeneic haematopoietic stem cell transplantation (HSCT). Immunotherapy with donor-derived adenovirus-specific T cells is promising; however, 20% of all donors lack adenovirus-specific T cells. To overcome this, we transfected α/β T cells with mRNA encoding a T-cell receptor (TCR) specific for the HLA-A*0101-restricted peptide LTDLGQNLLY from the adenovirus hexon protein. Furthermore, since allo-reactive endogenous TCR of donor T lymphocytes would induce graft-versus-host disease (GvHD) in a mismatched patient, we transferred the TCR into γ/δ T cells, which are not allo-reactive. TCR-transfected γ/δ T cells secreted low quantities of cytokines after antigen-specific stimulation, which were increased dramatically after co-transfection of CD8α-encoding mRNA. In direct comparison with TCR-transfected α/β T cells, TCR-CD8α-co-transfected γ/δ T cells produced more tumor necrosis factor (TNF), and lysed peptide-loaded target cells as efficiently. Most importantly, TCR-transfected α/β T cells and TCR-CD8α-co-transfected γ/δ T cells efficiently lysed adenovirus-infected target cells. We show here, for the first time, that not only α/β T cells but also γ/δ T cells can be equipped with an adenovirus specificity by TCR-RNA electroporation. Thus, our strategy offers a new means for the immunotherapy of adenovirus infection after allogeneic HSCT.
EVALuna2:19437

Human Cytomegalovirus-Induced Degradation of CYTIP Modulates Dendritic Cell Adhesion and Migration - Grosche, Linda; Drassner, Christina; Mühl-Zürbes, Petra; Kamm, Lisa; Vu Thuy Khanh Le-Trilling,; Trilling, Mirko; Steinkasserer, Alexander; Heilingloh, Christiane (Frontiers in Immunology, 2017)
As potent antigen-presenting cells, dendritic cells (DCs) are essential for the initiation of effective antiviral immune responses. Viruses and especially herpesviruses, which are able to establish lifelong persistence, exploit several immune evasion mechanisms targeting DC biology. Our group has previously shown that the ?-herpesvirus herpes simplex virus type 1 inhibits mature DC (mDC) migration by inducing adhesion via degrading the cellular protein CYTIP (cytohesin-1 interacting protein), an important negative regulator of ?2-integrin activity. In the present study, we extended our analysis to the ?-herpesvirus human cytomegalovirus (HCMV), to investigate whether other herpesviridae also induce such modulations. Indeed, HCMV impairs mDC transwell migration capability following a CCL19-chemokine gradient, despite equivalent expression levels of the cognate chemokine receptor CCR7 at the corresponding time points post-infection. Remarkably, HCMV infection potently induced ?2-integrin activity on mDCs. Furthermore, directly HCMV-infected mDCs, exhibiting viral gene expression, strongly adhere to fibronectin and ICAM-1, in contrast to mDCs lacking infection or viral gene expression. Interestingly, HCMV-positive mDCs display a proteasome-dependent degradation of CYTIP. Contrasting the migration toward CCL19, elevated expression levels of the chemokine receptor CXCR4 in HCMV-infected mDCs were associated with functional CXCL12-chemotaxis under the herein used conditions. In summary, our results show that HCMV shapes mDC adhesion to compromise migration toward CCL19, but retaining CXCL12 responsiveness. Thus, we hypothesize that a preferred migration pattern toward the bone marrow, but not to secondary lymphoid organs, could ultimately cause a failure in the induction of potent antiviral immune responses.
EVALuna2:26038

Human cytomegalovirus interferes with dendritic cell adhesion and migration via the proteasomal degradation of the cytohesin-1 interacting protein - Grosche, Linda; Drassner, C.; Mühl-Zürbes, Petra; Kamm, L.; Le-Trilling, V. T. K.; Trilling, M.; Steinkasserer, Alexander; Heilingloh, Christiane (2018)
EVALuna2:36215

Human Fcγ-receptor IIb modulates pathogen-specific versus self-reactive antibody responses in lyme arthritis - Danzer, Heike; Glaesner, Joachim; Baerenwaldt, Anne; Reitinger, Carmen; Lux, Anja; Heger, Lukas; Dudziak, Diana; Harrer, Thomas; Gessner, Andre; Nimmerjahn, Falk (eLife, 2020)
Pathogen-specific antibody responses need to be tightly regulated to generate protective but limit self-reactive immune responses. While loss of humoral tolerance has been associated with microbial infections, the pathways involved in balancing protective versus autoreactive antibody responses in humans are incompletely understood. Studies in classical mouse model systems have provided evidence that balancing of immune responses through inhibitory receptors is an important quality control checkpoint. Genetic differences between inbred mouse models and the outbred human population and allelic receptor variants not present in mice; however, argue for caution when directly translating these findings to the human system. By studying Borrelia burgdorferi infection in humanized mice reconstituted with human hematopoietic stem cells from donors homozygous for a functional or a non-functional FcγRIIb allele, we show that the human inhibitory FcγRIIb is a critical checkpoint balancing protective and autoreactive immune responses, linking infection with induction of autoimmunity in the human immune system.
CRIS-Team Scopus Importer:2020-09-11
Keywords: arthritis; autoimmunity; borrelia burgdorferi; Fc-receptor; humanized mouse; immunology; inflammation; mouse

Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment - Heidkamp, Gordon Frederik; Sander, Jil; Lehmann, Christian; Heger, Lukas; Eissing, Nathalie; Baranska, Anna; Lühr, Jennifer; Hoffmann, Alana; Reimer, Katharina; Lux, Anja; Söder, Stephan; Hartmann, Arndt; et al. (Science immunology, 2016)
In mice, conventional and plasmacytoid dendritic cells (DCs) derive from separate hematopoietic precursors before they migrate to peripheral tissues. Moreover, two classes of conventional DCs (cDC1 and cDC2 DCs) and one class of plasmacytoid DCs (pDCs) have been shown to be transcriptionally and functionally distinct entities. In humans, these three DC subtypes can be identified using the cell surface markers CD1c (cDC2), CD141 (cDC1), and CD303 (pDCs), albeit it remains elusive whether DC functionality is mainly determined by ontogeny or the tissue microenvironment. By phenotypic and transcriptional profiling of these three DC subtypes in different human tissues derived from a large number of human individuals, we demonstrate that DC subpopulations in organs of the lymphohematopoietic system (spleen, thymus, and blood) are strongly defined by ontogeny rather than by signals from the microenvironment. In contrast, DC subsets derived from human lung or skin differed substantially, strongly arguing that DCs react toward modulatory signals from tissue microenvironments. Collectively, the data obtained in this study may serve as a major resource to guide further studies into human DC biology during homeostasis and inflammatio
EVALuna2:6852

Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment - Heidkamp, Gordon Frederik; Sander, J.; Lehmann, C. H. K.; Heger, Lukas; Eissing, N.; Baranska, A.; Lühr, Jennifer; Hoffmann, Alana; Reimer, Katharina; Lux, Anja; Söder, Stephan; Hartmann, Arndt; et al. (2017)
EVALuna2:33137

Human synovia contains trefoil factor family (TFF) peptides 1-3 although synovial membrane only produces TFF3: Implications in osteoarthritis and rheumatoid arthritis - Popp, Judith; Schicht, Martin; Garreis, Fabian; Klinger, Patricia; Gelse, Kolja; Sesselmann, Stefan; Tsokos, Michael; Etzold, Saskia; Stiller, Dankwart; Claassen, Horst; Paulsen, Friedrich (International Journal of Molecular Sciences, 2019)
Objective: Trefoil factor family peptide 3 (TFF3) has been shown to support catabolic functions in cases of osteoarthritis (OA). As in joint physiology and diseases such as OA, the synovial membrane (SM) of the joint capsule also plays a central role. We analyze the ability of SM to produce TFF compare healthy SM and its secretion product synovial fluid (SF) with SM and SF from patients suffering from OA or rheumatoid arthritis (RA). Methods: Real-time PCR and ELISA were used to measure the expression of TFFs in healthy SM and SM from patients suffering from OA or RA. For tissue localization, we investigated TFF1-3 in differently aged human SM of healthy donors by means of immunohistochemistry, real-time PCR and Western blot. Results: Only TFF3 but not TFF1 and -2 was expressed in SM from healthy donors as well as cases of OA or RA on protein and mRNA level. In contrast, all three TFFs were detected in all samples of SF on the protein level. No significant changes were observed for TFF1 at all. TFF2 was significantly upregulated in RA samples in comparison to OA samples. TFF3 protein was significantly downregulated in OA samples in comparison to healthy samples and cases of RA significantly upregulated compared to OA. In contrast, in SM TFF3 protein was not significantly regulated. Conclusion: The data demonstrate the production of TFF3 in SM. Unexpectedly, SF contains all three known TFF peptides. As neither articular cartilage nor SM produce TFF1 and TFF2, we speculate that these originate with high probability from blood serum.
CRIS-Team Scopus Importer:2019-12-20
Keywords: Osteoarthritis (OA); Rheumatoid arthritis (RA); Synovial fluid (SF); Synovial membrane (SM); Trefoil factor family peptides (TFF)

Human T cells expressing two additional receptors (TETARs) specific for HIV-1 recognize both epitopes - Hofmann, Christian; Hoefflin, Sandra; Hueckelhoven, Angela; Bergmann, Silke; Harrer, Ellen; Schuler, Gerold; Dörrie, Jan; Schaft, Niels; Harrer, Thomas (Blood, 2011)
Adoptive TCR transfer against rapidly mutating targets, such as HIV-1 or cancer, must counteract corresponding immune escape. Hence, we generated T cells expressing two additional receptors (TETARs) specific for HIV-1 by TCR mRNA electroporation. An HLA-A2-restricted gag-specific TCR and an HLA-B13-restricted nef-specific TCR were chosen. When both TCRs were transfected simultaneously, strong competitive effects occurred that were overcome by replacing the human constant domains of one TCR with murine counterparts and adapting the amounts of TCR-RNA used for transfection. The resulting TETAR responded to both epitopes with cytokine secretion and cytotoxic function. Cell sorting revealed that one individual cell indeed recognized both epitopes. The T cells diminished their reactivity to each epitope after stimulation but sequentially killed targets that presented the gag epitope and then targets that presented the nef epitope, or vice versa. Taken together, TETARs represent a sophisticated tool to study TCR functionality and might be a useful strategy in immunotherapy. © 2011 by The American Society of Hematology.
CRIS-Team Scopus Importer:2021-10-01

Human T cells loaded with superparamagnetic iron oxide nanoparticles retain antigen-specific TCR functionality. - Pfister, Felix; Dörrie, Jan; Schaft, Niels; Buchele, Vera; Unterweger, Harald; Carnell, Lucas R.; Schreier, Patrick; Stein, René; Kubánková, Markéta; Guck, Jochen; Hackstein, Holger; Alexiou, Christoph; et al. (Frontiers in Immunology, 2023)
BACKGROUND: Immunotherapy of cancer is an emerging field with the potential to improve long-term survival. Thus far, adoptive transfer of tumor-specific T cells represents an effective treatment option for tumors of the hematological system such as lymphoma, leukemia or myeloma. However, in solid tumors, treatment efficacy is low owing to the immunosuppressive microenvironment, on-target/off-tumor toxicity, limited extravasation out of the blood vessel, or ineffective trafficking of T cells into the tumor region. Superparamagnetic iron oxide nanoparticles (SPIONs) can make cells magnetically controllable for the site-specific enrichment. METHODS: In this study, we investigated the influence of SPION-loading on primary human T cells for the magnetically targeted adoptive T cell therapy. For this, we analyzed cellular mechanics and the T cell response after stimulation via an exogenous T cell receptor (TCR) specific for the melanoma antigen MelanA or the endogenous TCR specific for the cytomegalovirus antigen pp65 and compared them to T cells that had not received SPIONs. RESULTS: SPION-loading of human T cells showed no influence on cellular mechanics, therefore retaining their ability to deform to external pressure. Additionally, SPION-loading did not impair the T cell proliferation, expression of activation markers, cytokine secretion, and tumor cell killing after antigen-specific activation mediated by the TCR. CONCLUSION: In summary, we demonstrated that SPION-loading of T cells did not affect cellular mechanics or the functionality of the endogenous or an exogenous TCR, which allows future approaches using SPIONs for the magnetically enrichment of T cells in solid tumors.
EVALuna2:539766
Keywords: Adoptive T cell therapy; superparamagnetic iron oxide nanoparticles (SPIONs); antigen-specific T cell response; targeted immune therapy; cell deformability

Hybrid modeling of the crosstalk between signaling and transcriptional networks using ordinary differential equations and multi-valued logic - Khan, Faiz M.; Schmitz, Ulf; Nikolov, Svetoslav; Engelmann, David; Puetzer, Brigitte M.; Wolkenhauer, Olaf; Vera González, Julio (BBA - Biochimica et Biophysica Acta, 2014)
A decade of successful results indicates that systems biology is the appropriate approach to investigate the regulation of complex biochemical networks involving transcriptional and post-transcriptional regulations. It becomes mandatory when dealing with highly interconnected biochemical networks, composed of hundreds of compounds, or when networks are enriched in non-linear motifs like feedback and feedforward loops. An emerging dilemma is to conciliate models of massive networks and the adequate description of non-linear dynamics in a suitable modeling framework. Boolean networks are an ideal representation of massive networks that are humble in terms of computational complexity and data demand. However, they are inappropriate when dealing with nested feedback/feedforward loops, structural motifs common in biochemical networks. On the other hand, models of ordinary differential equations (ODEs) cope well with these loops, but they require enormous amounts of quantitative data for a full characterization of the model. Here we propose hybrid models, composed of ODE and logical sub-modules, as a strategy to handle large scale, non-linear biochemical networks that include transcriptional and post-transcriptional regulations. We illustrate the construction of this kind of models using as example a regulatory network centered on E2F1, a transcription factor involved in cancer. The hybrid modeling approach proposed is a good compromise between quantitative/qualitative accuracy and scalability when considering large biochemical networks with a small highly interconnected core, and module of transcriptionally regulated genes that are not part of critical regulatory loops. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology & Clinical Implications. Guest Editor: Yudong Cai.
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Hydradenitis suppurativa - new exploration on the famous Disease - Oetterich, Kerstin; Heppt, Franz; Sticherling, Michael (2017)
EVALuna2:34354

Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors - Sirtl, Simon; Knoll, Gertrud; Dieu Thuy Trinh,; Lang, Isabell; Siegmund, Daniela; Gross, Stefanie; Schuler-Thurner, Beatrice; Neubert, Patrick; Jantsch, Jonathan; Wajant, Harald; Ehrenschwender, Martin (Oncogene, 2018)
Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3-interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens.
EVALuna2:34786

Hypertonicity primes malignant melanoma cells for apoptosis - Calance, Diana Nicoleta; Steixner, Charlotte; Gross, Stefanie; Schuler-Thurner, Beatrice; Knoll, Gertrud; Ehrenschwender, Martin (Apoptosis, 2018)
The tumor environment critically influences responsiveness of cancer cells to chemotherapies, most of which activate the mitochondria-regulated (intrinsic) apoptotic cascade to kill malignant cells. Especially skin tumors encounter an environment with remarkable biophysical properties. Cutaneous accumulation of Na+ locally establishes osmotic pressure gradients in vivo (hypertonicity or hyperosmotic stress), but whether cutaneous hypertonicity is a factor that modulates the responsiveness of skin cancers to therapeutic apoptosis-induction has thus far not been investigated. Here, we show that hyperosmotic stress lowers the threshold for apoptosis induction in malignant melanoma, the deadliest form of skin cancer. Hypertonic conditions enforce addiction to BCL-2-like proteins to prevent initiation of the mitochondria-regulated (intrinsic) apoptotic pathway. Essentially, hyperosmotic stress primes mitochondria for death. Our work identifies osmotic pressure in the tumor microenvironment as a cell extrinsic factor that modulates responsiveness of malignant melanoma cells to therapy.
EVALuna2:34391

Hyponatremia and Nephritis - Rare Side Effects of Checkpoint Inhibitors in Patients with metastatic Melanoma - Mitzel-Rink, H.; Hassel, J.; Berking, C.; Gutzmer, R.; Heinzerling, Lucie; Majenka, P.; Meier, F.; Moreira, Alvaro; Terheyden, P.; Thoms, K. M.; Tietze, J.; Zimmer, L.; et al. (2018)
EVALuna2:34770

Identification and characterization of the specific murine NK cell subset supporting graft-versus-leukemia- and reducing graft-versus-host-effects - Meinhardt, Kathrin; Kroeger, Irena; Bauer, Ruth; Ganss, Franziska; Ovsiy, Ilja; Rothamer, Johanna; Büttner, Maike; Atreya, Imke; Waldner, Maximilian; Bittrich, Max; Lehmann, Christian; Rieger, Michael A.; et al. (OncoImmunology, 2015)
Clinical studies investigating the impact of natural killer (NK) cells in allogeneic hematopoietic stem cell transplantation settings have yielded promising results. However, NK cells are a functionally and phenotypically heterogeneous population. Therefore, we addressed the functional relevance of specific NK cell subsets distinguished by expression of CD117, CD27 and CD11b surface markers in graft-versus-leukemia (GVL)-reaction and graft-versus-host-disease (GVHD). Our results clearly demonstrate that the subset of c-Kit(-)CD27(-)CD11b(+) NK cells expressed multiple cytotoxic pathway genes and provided optimal graft-versus-leukemia-effects, while significantly reducing T cell proliferation induced by allogeneic dendritic cells. Furthermore, these NK cells migrated to inflamed intestinal tissues where graft-versus-host-colitis was efficiently mitigated. For the first time, we identified the c-Kit(-)CD27(-)CD11b(+) NK cell population as the specific effector NK cell subset capable of significantly diminishing GVHD in fully mismatched bone marrow transplantation settings. In conclusion, the subset of c-Kit(-)CD27(-)CD11b(+) NK cells not only supports GVL, but also plays a unique role in the protection against GVHD by migrating to the peripheral GVHD target organs where they exert efficient immunoregulatory activities. These new insights demonstrate the importance of selecting the optimal NK cell subset for cellular immunotherapy following allogeneic hematopoietic stem cell transplantation.
EVALuna2:1965

Identification and purification of novel low-molecular-weight lupine allergens as components for personalized diagnostics - Jappe, Uta; Karstedt, Arabella; Warneke, Daniela; Hellmig, Saskia; Böttger, Marisa; Riffelmann, Friedrich W.; Treudler, Regina; Lange, Lars; Abraham, Susanne; Dölle-Bierke, Sabine; Worm, Margitta; Wagner, Nicola; et al. (Nutrients, 2021)
Lupine flour is a valuable food due to its favorable nutritional properties. In spite of its allergenic potential, its use is increasing. Three lupine species, Lupinus angustifolius, L. luteus, and L. albus are relevant for human nutrition. The aim of this study is to clarify whether the species differ with regard to their allergen composition and whether anaphylaxis marker allergens could be identified in lupine. Patients with the following characteristics were included: lupine allergy, suspected lupine allergy, lupine sensitization only, and peanut allergy. Lupine sensitization was detected via CAP-FEIA (ImmunoCAP) and skin prick test. Protein, DNA and expressed sequence tag (EST) databases were queried for lupine proteins homologous to already known legume allergens. Different extraction methods applied on seeds from all species were examined by SDS-PAGE and screened by immunoblotting for IgE-binding proteins. The extracts underwent different and successive chromatography methods. Low-molecular-weight components were purified and investigated for IgE-reactivity. Proteomics revealed a molecular diversity of the three species, which was confirmed when investigated for IgE-reactivity. Three new allergens, L. albus profilin, L. angustifolius and L. luteus lipid transfer protein (LTP), were identified. LTP as a potential marker allergen for severity is a valuable additional candidate for molecular allergy diagnostic tests.
CRIS-Team Scopus Importer:2021-02-05
Keywords: Cross-reaction; Flour; Food allergy; Individualized diagnostics; Legumes; Lipid transfer protein; Lupine; Peanut; Profilin

Identification of circulating microRNA patterns in patients in psoriasis and psoriatic arthritis - Haschka, Judith; Simon, David; Bayat, Sara; Messner, Zora; Kampylafka, Eleni; Fagni, Filippo; Skalicky, Susanna; Hackl, Matthias; Resch, Heinrich; Zwerina, Jochen; Kleyer, Arnd; Cavallaro, Alexander Josef; et al. (Rheumatology, 2023)
Objective miRNAs are small non-coding RNAs that control gene expression. Specific intra- and extracellular miRNA signatures have been identified in various diseases. Whether certain miRNA signatures are associated with psoriasis (PsO) and PsA is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients. Methods Expression of miRNAs was analysed by reverse transcription quantitative real-time PCR (RT-qPCR) in the serum of PsA, PsO patients and healthy controls. Demographic and disease-specific characteristics and imaging data from hand MRI were recorded. In the discovery phase, 192 miRNA assays were analysed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population. Results A total of 141 patients and controls were analysed (51 PsA, 40 PsO, 50 controls). In the discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared with controls, with 33 miRNAs being changed in both (adj. P < 0.05). The 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls [area under the curve (AUC) >= 0.70, all P < 0.05]. Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly differently regulated between PsO and PsA. A combination of these miRNAs increased the AUC to 0.92 in multivariate regression model to discriminate PsO and PsA. Conclusion miRNA signatures in PsA and PsO patients differ from controls. Nine miRNAs were differentially regulated in PsA and PsO patients, five of them previously reported to be involved in bone and cartilage metabolism, indicating an intimate association of psoriatic inflammation and bone/cartilage changes.
CRIS-Team WoS Importer:2023-03-17

IDENTIFICATION OF CIRCULATING MICRORNA SIGNATURES IN PATIENTS WITH PSORIASIS WITH SUBCLINICAL JOINT DISEASE AND PATIENTS WITH PSORIATIC ARTHRITIS - Haschka, J.; Simon, David; Bayat, Sara; Messner, Z.; Kampylafka, E.; Fagni, Filippo; Skalicky, S.; Hackl, M.; Resch, H.; Zwerina, J.; Kleyer, Arnd; Sticherling, Michael; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Identification of miRNA-mRNA Modules in Colorectal Cancer Using Rough Hypercuboid Based Supervised Clustering - Paul, Sushmita; Lakatos, Petra; Hartmann, Arndt; Schneider-Stock, Regine; Vera, Julio (Scientific Reports, 2017)
Differences in the expression profiles of miRNAs and mRNAs have been reported in colorectal cancer. Nevertheless, information on important miRNA-mRNA regulatory modules in colorectal cancer is still lacking. In this regard, this study presents an application of the RH-SAC algorithm on miRNA and mRNA expression data for identification of potential miRNA-mRNA modules. First, a set of miRNA rules was generated using the RH-SAC algorithm. The mRNA targets of the selected miRNAs were identified using the miRTarBase database. Next, the expression values of target mRNAs were used to generate mRNA rules using the RH-SAC. Then all miRNA-mRNA rules have been integrated for generating networks. The RH-SAC algorithm unlike other existing methods selects a group of co-expressed miRNAs and mRNAs that are also differentially expressed. In total 17 miRNAs and 141 mRNAs were selected. The enrichment analysis of selected mRNAs revealed that our method selected mRNAs that are significantly associated with colorectal cancer. We identified novel miRNA/mRNA interactions in colorectal cancer. Through experiment, we could confirm that one of our discovered miRNAs, hsa-miR-93-5p, was significantly up-regulated in 75.8% CRC in comparison to their corresponding non-tumor samples. It could have the potential to examine colorectal cancer subtype specific unique miRNA/mRNA interactions.
EVALuna2:6844

Identification of Novel STAT6-Regulated Proteins in Mouse B Cells by Comparative Transcriptome and Proteome Analysis - Mokada Gopal, Lavanya; Boeser, Alexander; Lehmann, Christian; Drepper, Friedel; Dudziak, Diana; Warscheid, Bettina; Vöhringer, David (Journal of Immunology, 2017)
The transcription factor STAT6 plays a key role in mediating signaling downstream of the receptors for IL-4 and IL-13. In B cells, STAT6 is required for class switch recombination to IgE and for germinal center formation during type 2 immune responses directed against allergens or helminths. In this study, we compared the transcriptomes and proteomes of primary mouse B cells from wild-type and STAT6-deficient mice cultured for 4 d in the presence or absence of IL-4. Microarray analysis revealed that 214 mRNAs were upregulated and 149 were downregulated >3-fold by IL-4 in a STAT6-dependent manner. Across all samples, 5000 proteins were identified by label-free quantitative liquid chromatography/mass spectrometry. A total of 149 proteins was found to be differentially expressed >3-fold between IL-4-stimulated wild-type and STAT6(-/-) B cells (75 upregulated and 74 downregulated). Comparative analysis of the proteome and transcriptome revealed that expression of these proteins was mainly regulated at the transcriptional level, which argues against a major role for posttranscriptional mechanisms that modulate the STAT6-dependent proteome. Nine proteins were selected for confirmation by flow cytometry or Western blot. We show that CD30, CD79b, SLP-76, DEC205, IL-5R?, STAT5, and Thy1 are induced by IL-4 in a STAT6-dependent manner. In contrast, Syk and Fc receptor-like 1 were downregulated. This dataset provides a framework for further functional analysis of newly identified IL-4-regulated proteins in B cells that may contribute to germinal center formation and IgE switching in type 2 immunity.
EVALuna2:25886

Identification of two novel bullous pemphigoid- associated alleles, HLA-DQA1*05:05 and -DRB1*07:01, in Germans - Schwarm, Christian; Gola, Damian; Holtsche, Maike M.; Dieterich, Anabelle; Bhandari, Anita; Freitag, Miriam; Nürnberg, Peter; Toliat, Mohammad; Lieb, Wolfgang; Wittig, Michael; Franke, André; Worm, Margitta; et al. (Orphanet Journal of Rare Diseases, 2021)
Bullous pemphigoid (BP) is the most common autoimmune skin blistering disease characterized by autoimmunity against the hemidesmosomal proteins BP180, type XVII collagen, and BP230. To elucidate the genetic basis of susceptibility to BP, we performed the first genome-wide association study (GWAS) in Germans. This GWAS was combined with HLA locus targeted sequencing in an additional independent BP cohort. The strongest association with BP in Germans tested in this study was observed in the two HLA loci, HLA-DQA1*05:05 and HLA-DRB1*07:01. Further studies with increased sample sizes and complex studies integrating multiple pathogenic drivers will be conducted.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Autoimmune blistering skin diseases; Bullous pemphigoid; Germans; GWAS; HLA

Identifizierung von Biomarkern und neuen therapeutischen Zielen beim Aderhautmelanom - Wessely, Anja; Koch, Elias; Vera, Julio; Berking, Carola; Heppt, Markus (Journal der Deutschen Dermatologischen Gesellschaft, 2024)
Das Uveamelanom (UM) ist eine seltene Krebserkrankung, obwohl es der häufigste Tumor des Auges bei Erwachsenen ist. Die Patienten werden meist in Hautkrebszentren zur Behandlung der metastasierten Erkrankung vorgestellt. Es gibt jedoch erhebliche genetische, biologische und klinische Unterschiede zum kutanen Melanom. Die bei metastasiertem UM am häufigsten eingesetzten Therapien sind Tebentafusp und die kombinierte Immuncheckpoint-Blockade, die beide niedrige Ansprechraten aufweisen und mit hohen Behandlungskosten und erheblichen immunbedingten Toxizitäten verbunden sein können. Daher ist es von größter Bedeutung, einerseits Biomarker und klinische Profile zu identifizieren, die das Ansprechen auf die Behandlung vorhersagen können und andererseits neue therapeutische Ziele zu finden. Der Einsatz der Immuncheckpoint-Blockade zeigte in einer Reihe retrospektiver Studien günstigere Ergebnisse bei Patienten mit extrahepatischer Metastasierung und normalen Laktatdehydrogenase-Werten im Serum, so dass ihr Einsatz in dieser Subgruppe sinnvoller scheint. Um neue Zielmoleküle für Medikamente zu identifizieren, werden wir die Expression und Relevanz von Transkriptionsfaktoren der Neuralleiste in Bioproben von Patienten mit Next-Generation-Sequenzierung der dritten Generation analysieren. Computeralgorithmen und netzwerkbasierte Analysen werden die Identifizierung von Zielstrukturen für Medikamente erleichtern, die anschließend in Kurzzeit-Zellkulturen von Patienten validiert werden. Dieser Ansatz wird dazu beitragen, neue und personalisierte Behandlungen für das UM zu finde
CRIS-Team Scopus Importer:2024-01-19

Identifying biomarkers and novel therapeutic targets in uveal melanoma - Wessely, Anja; Koch, Elias; Vera, Julio; Berking, Carola; Heppt, Markus (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
Uveal melanoma (UM) is an orphan cancer despite being the most common eye tumor in adults. Patients often present to skin cancer centers for treatment of metastatic disease although there are significant genetic, biological, and clinical differences from cutaneous melanoma. The treatments most commonly used for metastatic UM are tebentafusp and combined immune checkpoint blockade, both of which yield low response rates and may be accompanied by high treatment costs and significant immune-related toxicities. Thus, it is of paramount importance to identify biomarkers and clinical profiles predictive of treatment response and to find novel therapeutic targets. The use of immune checkpoint blockade showed more favorable outcomes in patients with extrahepatic disease and normal levels of serum lactate dehydrogenase in a panel of retrospective studies, making its use more reasonable in this subgroup. To identify novel drug targets, we will analyze the expression and relevance of neural crest transcription factors in patient bio-specimens using next-generation nanopore sequencing. Computer algorithms and network-based analysis will facilitate the identification of druggable targets which will subsequently be validated in patient-derived short-term cell cultures. This approach will help to find novel and personalized treatments for UM.
CRIS-Team Scopus Importer:2023-11-10

"I Feel I'm in Best Hands with You!": A Survey of Patient Satisfaction in a German University Skin Cancer Centre - Steeb, Theresa; Wessely, Anja; Merkl, Heike; Kirchberger, Michael; Bosch-Voskens, Caroline; Erdmann, Michael; Heinzerling, Lucie; Berking, Carola; Heppt, Markus (Acta Dermato-Venereologica, 2021)
An important measure of hospital quality is the satisfaction of patients. The aim of this cross-sectional study, performed in the dermato-oncology unit of the university hospital in Erlangen, Germany, was to assess skin cancer patients' degree of satisfaction with healthcare services. Self-administered questionnaires on patient satisfaction regarding contact with staff, need for information, and recommendation of the skin cancer centre were distributed in the day-care unit and the outpatient department to patients between April and June 2017. Results were reported descriptively and subgroup differences were explored using the Mann-Whitney U test, binary logistic regression, or χ2 test. Overall, 496 of 571 questionnaires were returned (86.9%). The median of all satisfaction items ranged between 1 (very good) and 2 (good). The majority of patients wanted more detailed information about skin cancer (46.7%, 142/304). Long waiting times were often criticized (22.8%; 80/351). Particular attention in addressing specific needs and fears may further increase patient satisfaction.
CRIS-Team Scopus Importer:2021-08-13
Keywords: cross-sectional study; melanoma; quality improvement; quality of care; skin cancer; patient satisfaction

IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation - Faas, Maria; Ipseiz, Natacha; Ackermann, Jochen; Culemann, Stephan; Grüneboom, Anika; Schröder, Fenja; Rothe, Tobias; Scholtysek, Carina; Eberhardt, Martin; Böttcher, Martin; Kirchner, Philipp; Stoll, Cornelia; et al. (Immunity, 2021)
Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.
CRIS-Team Scopus Importer:2021-11-19
Keywords: alternatively activated macrophage; GATA3; interleukin-33; itaconate; mitochondrial rewiring; resolution of inlammation; UCP2; uncoupling

IL-9 and its receptor are predominantly involved in the pathogenesis of UC - Nalleweg, Nancy; Chiriac, Mircea Teodor; Podstawa, Eva; Lehmann, Christian; Rau, Tilman; Atreya, Raja; Krauss, Ekaterina; Hundorfean, Gheorghe; Fichtner-Feigl, Stefan; Hartmann, Arndt; Becker, Christoph; Mudter, Jonas (Gut, 2015)
Several pathogenic roles attributed over the past two decades to either T helper (Th)1 or Th2 cells are increasingly becoming associated with interleukin (IL)-17 and most recently IL-9 signalling. However, the implication of IL-9 in IBD has not been addressed so far.We investigated the expression of IL-9 and IL-9R by using peripheral blood, biopsies and surgical samples. We addressed the functional role of IL-9 signalling by analysis of downstream effector proteins. Using Caco-2 cell monolayers we followed the effect of IL-9 on wound healing.IL-9 mRNA expression was significantly increased in inflamed samples from patients with UC as compared with controls. CD3(+) T cells were major IL-9-expressing cells and some polymorphonuclear leucocytes (PMN) also expressed IL-9. IL-9 was co-localised with the key Th9 transcription factors interferon regulatory factor 4 and PU.1. Systemically, IL-9 was abundantly produced by activated peripheral blood lymphocytes, whereas its receptor was overexpressed on gut resident and circulating PMN. IL-9 stimulation of the latter induced IL-8 production in a dose-dependent manner and rendered PMN resistant to apoptosis suggesting a functional role for IL-9R signalling in the propagation of gut inflammation. Furthermore, IL-9R was overexpressed on gut epithelial cells and IL-9 induced STAT5 activation in these cells. Moreover, IL-9 inhibited the growth of Caco-2 epithelial cell monolayers in wound healing experiments.Our results provide evidence that IL-9 is predominantly involved in the pathogenesis of UC suggesting that targeting IL-9 might become a therapeutic option for patients with UC.
EVALuna2:1839

Ileal immune tonus is a prognosis marker of proximal colon cancer in mice and patients - Picard, Marion; Yonekura, Satoru; Slowicka, Karolina; Petta, Ioanna; Rauber, Conrad; Routy, Bertrand; Richard, Corentin; Iebba, Valerio; Tidjani Alou, Maryam; Becharef, Sonia; Ly, Pierre; Pizzato, Eugenie; et al. (Cell Death and Differentiation, 2020)
Ileal epithelial cell apoptosis and the local microbiota modulate the effects of oxaliplatin against proximal colon cancer by modulating tumor immunosurveillance. Here, we identified an ileal immune profile associated with the prognosis of colon cancer and responses to chemotherapy. The whole immune ileal transcriptome was upregulated in poor-prognosis patients with proximal colon cancer, while the colonic immunity of healthy and neoplastic areas was downregulated (except for the Th17 fingerprint) in such patients. Similar observations were made across experimental models of implanted and spontaneous murine colon cancer, showing a relationship between carcinogenesis and ileal inflammation. Conversely, oxaliplatin-based chemotherapy could restore a favorable, attenuated ileal immune fingerprint in responders. These results suggest that chemotherapy inversely shapes the immune profile of the ileum–tumor axis, influencing clinical outcome.
CRIS-Team Scopus Importer:2020-12-11

Images in clinical tropical medicine rhinophyma-like cutaneous leishmaniasis due to leishmania aethiopica treated successfully with liposomal Amphotericin B - Kirchberger, Michael Constantin; Schliep, Stefan; Bogdan, Christian (American Journal of Tropical Medicine and Hygiene, 2019)
CRIS-Team Scopus Importer:2019-05-02

Immune checkpoint blockade can synergize with radiation therapy, even in tumors resistant to checkpoint monotherapy - Dörrie, Jan (Embo Molecular Medicine, 2017)
Immunotherapy has evolved as a new pillar of cancer treatment during the last decade. The main breakthrough was the development of immune checkpoint blocking (ICB) antibodies, which antagonize inhibitory receptors on T cells and their ligands and thus unleash the cellular immune system against the tumor. ICB showed tremendous effects in several types of cancer. However, only a proportion of the patients suffering from tumors, which are in principle sensitive, benefit from this treatment and other kinds of neoplasia are completely resistant. Great effort is currently being undertaken to distinguish responders from non-responders, and concepts to turn the latter into the former are urgently required. One approach is to combine ICB with already well-established treatment strategies, that is, the other mainstays of cancer therapy such as surgery, radiation therapy (RT), and chemotherapy. Depending on the circumstances, both chemotherapy and RT may act either immune suppressively or immune stimulatingly. In this issue of EMBO Molecular Medicine, Azad etal () show that indeed, pancreatic ductal adenocarcinoma, which is resistant to ICB monotherapy, becomes responsive to this treatment by simultaneous RT or chemotherapy.
EVALuna2:35414

Immune-Checkpoint-Blockade for Merkel Cell Carcinoma: Clinical and molecular Biomarker-Analysis - Spassova, I.; Ugurel, S.; Zimmer, L.; Schadendorf, D.; Terheyden, P.; Andtback, H. B.; Villabona, L.; Leiter-Stoeppke, U.; Eigentler, T.; Loquai, C.; Hassel, J. C.; Gambichler, T.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis - Koch, Elias; Petzold, Anne; Wessely, Anja; Dippel, Edgar; Gesierich, Anja; Gutzmer, Ralf; Hassel, Jessica C.; Haferkamp, Sebastian; Hohberger, Bettina; Kaehler, Katharina C.; Knorr, Harald; Kreuzberg, Nicole; et al. (Cancers, 2021)
Simple Summary This retrospective multicenter study examines the influence of hepatic and extrahepatic metastases on the response of immune checkpoint blockade (ICB) in patients with metastatic uveal melanoma. A better response to dual ICB was observed in the presence of extrahepatic metastases in two recently published phase II trials. Therefore, we investigated two cohorts with and without extrahepatic metastasis and have assembled a population of 178 patients treated with ICB. The survival of this large cohort of patients with advanced UM was more favorable than that reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only. Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan-Meier method. Log-rank tests, chi(2) tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4-23.7) and the median PFS, 2.8 months (95% CI 2.5-3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.
CRIS-Team WoS Importer:2021-07-23

Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Re-Induction following Resistance or Toxicity - Koch, Elias; Petzold, Anne; Wessely, Anja; Dippel, Edgar; Gesierich, Anja; Gutzmer, Ralf; Hassel, Jessica C.; Haferkamp, Sebastian; Kähler, Katharina C.; Knorr, Harald; Kreuzberg, Nicole; Leiter, Ulrike; et al. (Cancers, 2022)
Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1–23.8) versus 9.4 months (cohort B, 95% CI: 6.1–14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities.
CRIS-Team Scopus Importer:2022-01-28
Keywords: CTLA-4; Immune checkpoint blockade; PD-1; Re-induction; Toxicity; Treatment resistance; Uveal melanoma

Immune checkpoint blockade in advanced cutaneous squamous cell carcinoma: What do we currently know in 2020? - Wessely, Anja; Steeb, Theresa; Leiter, Ulrike; Garbe, Claus; Berking, Carola; Heppt, Markus (International Journal of Molecular Sciences, 2020)
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer that predominantly arises in chronically sun-damaged skin. Immunosuppression, genetic disorders such as xeroderma pigmentosum (XP), exposure to certain drugs and environmental noxae have been identified as major risk factors. Surgical removal of cSCC is the therapy of choice and mostly curative in early stages. However, a minority of patients develop locally advanced tumors or distant metastases that are still challenging to treat. Immune checkpoint blockade (ICB) targeting CTLA-4, PD-L1 and PD-1 has tremendously changed the field of oncological therapy and especially the treatment of skin cancers as tumors with a high mutational burden. In this review, we focus on the differences between cSCC and cutaneous melanoma (CM) and their implications on therapy, summarize the current evidence on ICB for the treatment of advanced cSCC and discuss the chances and pitfalls of this therapy option for this cancer entity. Furthermore, we focus on special subgroups of interest such as organ transplant recipients, patients with hematologic malignancies, XP and field cancerization.
CRIS-Team Scopus Importer:2020-12-25
Keywords: Cemiplimab; Cutaneous squamous cell carcinoma; Immune checkpoint blockade; Pembrolizumab; Skin cancer

Immune checkpoint inhibition and targeted therapy for melanoma: A patient-oriented cross-sectional comparative multicentre study - Thiem, Alexander; Mashhadiakbar, Pegah; Cussigh, Christiane; Hassel, Jessica C.; Grimmelmann, Imke; Gutzmer, Ralf; Schlaak, Max; Heppt, Markus; Duecker, Pia; Huening, Svea; Schulmeyer, Lena; Schilling, Bastian; et al. (Journal of the European Academy of Dermatology and Venereology, 2022)
BackgroundChoosing the adequate systemic treatment for melanoma is driven by clinical parameters and personal preferences. ObjectiveEvaluation of the impact of disease and treatment on the daily life of patients receiving systemic therapy for melanoma. MethodsA German-wide, cross-sectional comparative study was conducted at 13 specialized skin cancer centres from 08/2020 to 03/2021. A questionnaire was distributed to assess patients' perception of disease and symptoms, the impact of their current treatment on quality of life (QOL) and activities, adverse events (AEs), therapeutic visits, as well as believe in and satisfaction with their current systemic melanoma treatment. Patient-reported outcomes (PROs) were rated on a continuous numerical rating scale or selected from a given list. ResultsFour hundred and fourteen patients with systemic melanoma therapy were included. 359 (87%) received immune checkpoint inhibition (ICI) and 55 (13%) targeted therapy (TT). About 1/3 of patients were adjuvantly treated, the remaining because of unresectable/metastatic melanoma. In subgroup analyses, only in the adjuvant setting, TT patients reported a significant decrease in their treatment associated QOL compared to patients with ICI (p = 0.02). Patients with TT were 1.9 times more likely to report AEs than patients with ICI, a difference being significant just for the adjuvant setting (p = 0.01). ICI treatment intervals differed significantly between adjuvant and unresectable/metastatic setting (p = 0.04), though all patients, regardless of their specific ICI drug, evaluated their treatment frequency as adequate. TT patients with dabrafenib/trametinib (n = 37) or encorafenib/binimetinib (n = 15) did not differ regarding the strain of daily pill intake. Patients older than 63 years rated various PROs better than younger patients. ConclusionsPatients evaluated their treatment mainly positively. ICI might be preferred over TT regarding QOL and patient-reported AEs in the adjuvant setting. Older melanoma patients appeared to be less impacted by their disease and more satisfied with their treatment.
CRIS-Team WoS Importer:2023-01-06

Immune checkpoint inhibition therapy for advanced skin cancer in patients with concomitant hematological malignancy: a retrospective multicenter DeCOG study of 84 patients - Leiter, Ulrike; Loquai, Carmen; Reinhardt, Lydia; Rafei-Shamsabadi, David; Gutzmer, Ralf; Kaehler, Katharina; Heinzerling, Lucie; Hassel, Jessica C.; Glutsch, Valerie; Sirokay, Judith; Schlecht, Nora; Rübben, Albert; et al. (Journal for ImmunoTherapy of Cancer, 2020)
BACKGROUND: Skin cancers are known for their strong immunogenicity, which may contribute to a high treatment efficacy of immune checkpoint inhibition (ICI). However, a considerable proportion of patients with skin cancer is immuno-compromised by concomitant diseases. Due to their previous exclusion from clinical trials, the ICI treatment efficacy is poorly investigated in these patients. The present study analyzed the ICI treatment outcome in advanced patients with skin cancer with a concomitant hematological malignancy. METHODS: This retrospective multicenter study included patients who were treated with ICI for locally advanced or metastatic melanoma (MM), cutaneous squamous cell carcinoma (cSCC), or Merkel cell carcinoma (MCC), and had a previous diagnosis of a hematological malignancy irrespective of disease activity or need of therapy at ICI treatment start. Comparator patient cohorts without concomitant hematological malignancy were extracted from the prospective multicenter skin cancer registry ADOREG. Treatment outcome was measured as best overall response, progression-free (PFS), and overall survival (OS). RESULTS: 84 patients (MM, n=52; cSCC, n=15; MCC, n=17) with concomitant hematological malignancy were identified at 20 skin cancer centers. The most frequent concomitant hematological malignancies were non-Hodgkin's lymphoma (n=70), with chronic lymphocytic leukemia (n=32) being the largest entity. While 9 patients received ICI in an adjuvant setting, 75 patients were treated for advanced non-resectable disease (55 anti-PD-1; 8 anti-PD-L1; 5 anti-CTLA-4; 7 combinations). In the latter 75 patients, best objective response (complete response+partial response) was 28.0%, disease stabilization was 25.3%, and 38.6% showed progressive disease (PD). Subdivided by skin cancer entity, best objective response was 31.1% (MM), 26.7% (cSCC), and 18.8% (MCC). Median PFS was 8.4 months (MM), 4.0 months (cSCC), and 5.7 months (MCC). 1-year OS rates were 78.4% (MM), 65.8% (cSCC), and 47.4% (MCC). Comparison with respective ADOREG patient cohorts without hematological malignancy (n=392) revealed no relevant differences in ICI therapy outcome for MM and MCC, but a significantly reduced PFS for cSCC (p=0.002). CONCLUSIONS: ICI therapy showed efficacy in advanced patients with skin cancer with a concomitant hematological malignancy. Compared with patients without hematological malignancy, the observed ICI therapy outcome was impaired in cSCC, but not in MM or MCC patients.
CRIS-Team Scopus Importer:2020-11-06
Keywords: immunotherapy; melanoma

Immune checkpoint inhibitor-induced neurotoxicity is not associated with seroprevalence of neurotropic infections - Schmitt, C.; Hoefsmit, E. P.; Fangmeier, T.; Kramer, N.; Kabakci, C.; Vera González, Julio; Versluis, J. M.; Compter, A.; Harrer, Thomas; Mijočević, H.; Schubert, S.; Hundsberger, T.; et al. (Cancer Immunology, Immunotherapy, 2023)
Background: Immune checkpoint inhibitors (ICI) substantially improve outcome for patients with cancer. However, the majority of patients develops immune-related adverse events (irAEs), which can be persistent and significantly reduce quality of life. Neurological irAEs occur in 1–5% of patients and can induce severe, permanent sequelae or even be fatal. In order to improve the diagnosis and treatment of neurological irAEs and to better understand their pathogenesis, we assessed whether previous neurotropic infections are associated with neurological irAEs. Methods: Neurotropic infections that might predispose to ICI-induced neurological irAEs were analyzed in 61 melanoma patients from 3 countries, the Netherlands, Australia and Germany, including 24 patients with neurotoxicity and 37 control patients. In total, 14 viral, 6 bacterial, and 1 protozoal infections previously reported to trigger neurological pathologies were assessed using routine serology testing. The Dutch and Australian cohorts (NL) included pre-treatment plasma samples of patients treated with neoadjuvant ICI therapy (OpACIN-neo and PRADO trials; NCT02977052). In the Dutch/Australian cohort a total of 11 patients with neurological irAEs were compared to 27 control patients (patients without neurological irAEs). The German cohort (LMU) consisted of serum samples of 13 patients with neurological irAE and 10 control patients without any documented irAE under ICI therapy. Results: The association of neurological irAEs with 21 possible preceding infections was assessed by measuring specific antibodies against investigated agents. The seroprevalence of all the tested viral (cytomegalovirus, Epstein-Barr-Virus, varicella-zoster virus, measles, rubella, influenza A and B, human herpes virus 6 and 7, herpes simplex virus 1 and 2, parvovirus B19, hepatitis A and E and human T-lymphotropic virus type 1 and 2), bacterial (Borrelia burgdorferi sensu lato, Campylobacter jejuni, Mycoplasma pneumoniae, Coxiella burnetti, Helicobacter pylori, Yersinia enterocolitica and Y. pseudotuberculosis) and protozoal (Toxoplasma gondii) infections was similar for patients who developed neurological irAEs as compared to control patients. Thus, the analysis provided no evidence for an association of described agents tested for seroprevalence with ICI induced neurotoxicity. Conclusion: Previous viral, bacterial and protozoal neurotropic infections appear not to be associated with the development of neurological irAEs in melanoma patients who underwent therapy with ICI across 3 countries. Further efforts are needed to unravel the factors underlying neurological irAEs in order to identify risk factors for these toxicities, especially with the increasing use of ICI in earlier stage disease.
CRIS-Team Scopus Importer:2023-09-01
Keywords: Checkpoint-inhibitor; Melanoma; Serology; Side effect

IMMUNE PROFILING OF PATIENTS WITH ADVANCED SOLID TUMORS TREATED WITH INTRATUMORALLY ADMINISTERED CV8102 AS A SINGLE-AGENT OR IN COMBINATION WITH ANTI-PD-1 ANTIBODIES IN PHASE I CLINICAL TRIAL - Codo, Paula; Eigentler, Thomas; Heinzerling, Lucie; Krauss, Juergen; Weishaupt, Carsten; Ochsenreither, Sebastian; Lebbe, Celeste; Mohr, Peter; Oliva, Marc; Oberoi, Honey; Terheyden, Patrick; Perez, Jose Trigo; et al. (JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2021)
CV8102 is a non-coding, non-capped RNA complexed with a carrier peptide activating the innate (via TLR7/8, RIG-I) and adaptive immune system.1 2 An ongoing phase I trial is investigating the intratumoral (i.t.) administration of CV8102 in patients with advanced cutaneous melanoma (cMEL), squamous cell carcinoma of the skin (cSCC) or head and neck (hnSCC) and adenoid cystic carcinoma (ACC), either as a single agent or in combination with systemic anti-PD-1 antibodies. Preliminary immune profiling results will be reported.<br
CRIS-Team WoS Importer:2022-04-15

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors - Nuñez, Nicolas Gonzalo; Berner, Fiamma; Friebel, Ekaterina; Unger, Susanne; Wyss, Nina; Gomez, Julia Martinez; Purde, Mette Triin; Niederer, Rebekka; Porsch, Maximilian; Lichtensteiger, Christa; Kramer, Rafaela; Erdmann, Michael; et al. (Med, 2023)
Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. Methods: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. Findings: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. Conclusions: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. Funding: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen.
CRIS-Team Scopus Importer:2023-02-17
Keywords: biomarkers for immunotherapy; cancer immunotherapy; checkpoint blockade; immune-related adverse events; Translation to patients

Immunogenic and tolerogenic effects of the chimeric IL-2-diphtheria toxin cytocidal agent Ontak(®) on CD25(+) cells - Lutz, Manfred B.; Baur, Andreas; Schuler-Thurner, Beatrice; Schuler, Gerold (OncoImmunology, 2014)
Ontak(®), a conjugate between IL-2 and a diphtheria toxin fragment, was recently investigated in cancer clinical trials aiming to kill CD25(+) regulatory T cells (Tregs). We found that the activity of Ontak(®) was more complex on Tregs and conventional T cells (Tconvs) than anticipated, including a novel strong influence on dendritic cells (DCs).
EVALuna2:19435

Immunoglobulin G-dependent inhibition of inflammatory bone remodeling requires pattern recognition receptor Dectin-1 - Seeling, Michaela; Pöhnl, Matthias; Kara, Sibel; Horstmann, Nathalie; Riemer, Carolina; Wöhner, Miriam; Liang, Chunguang; Brückner, Christin; Eiring, Patrick; Werner, Anja; Biburger, Markus; Altmann, Leon; et al. (Immunity, 2023)
Immunoglobulin G (IgG) antibodies are major drivers of inflammation during infectious and autoimmune diseases. In pooled serum IgG (IVIg), however, antibodies have a potent immunomodulatory and anti-inflammatory activity, but how this is mediated is unclear. We studied IgG-dependent initiation of resolution of inflammation in cytokine- and autoantibody-driven models of rheumatoid arthritis and found IVIg sialylation inhibited joint inflammation, whereas inhibition of osteoclastogenesis was sialic acid independent. Instead, IVIg-dependent inhibition of osteoclastogenesis was abrogated in mice lacking receptors Dectin-1 or FcγRIIb. Atomistic molecular dynamics simulations and super-resolution microscopy revealed that Dectin-1 promoted FcγRIIb membrane conformations that allowed productive IgG binding and enhanced interactions with mouse and human IgG subclasses. IVIg reprogrammed monocytes via FcγRIIb-dependent signaling that required Dectin-1. Our data identify a pathogen-independent function of Dectin-1 as a co-inhibitory checkpoint for IgG-dependent inhibition of mouse and human osteoclastogenesis. These findings may have implications for therapeutic targeting of autoantibody and cytokine-driven inflammation.
CRIS-Team Scopus Importer:2023-05-12
Keywords: bone; Dectin-1; Fc-receptor; glycosylation; IgG; inflammation; osteoclast; rheumatoid arthritis

Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors - Lennerz, Volker; Gross, Stefanie; Gallerani, Elisa; Sessa, Cristiana; Mach, Nicolas; Boehm, Steffen; Hess, Dagmar; Von Boehmer, Lotta; Knuth, Alexander; Ochsenbein, Adrian F.; Gnad-Vogt, Ulrike; Zieschang, Juergen; et al. (Cancer Immunology Immunotherapy, 2014)
Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin-vaccine-induced immune responses.This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I-binding survivin peptides in Montanide(®) ISA 51 VG, promotes anti-survivin T-cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 ?g. Secondary objectives included safety, tolerability, and clinical efficacy.In total, 49 patients who received >=2 EMD640744 injections with available baseline- and >=1 post-vaccination samples [immunologic-diagnostic (ID)-intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection-site reactions constituted the most frequent adverse event.Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.
EVALuna2:19468

Immunotherapy of uveal melanoma: vaccination against cancer : Multicenter adjuvant phase 3 vaccination study using dendritic cells laden with tumor RNA for large newly diagnosed uveal melanoma - Schuler-Thurner, Beatrice; Bartz-Schmidt, K. -U.; Bornfeld, N.; Cursiefen, C.; Fuisting, B.; Grisanti, S.; Heindl, L. M.; Holbach, L.; Keserue, M.; Knorr, H.; Koch, K.; Kruse, Friedrich; et al. (Ophthalmologe, 2015)
Uveal melanomas are the most common malignant tumors of the eye. With modern molecular biological diagnostic methods, such as chromosome 3 typing and gene expression analysis, these tumors can be categorized into highly aggressive (monosomy 3, class II) and less aggressive forms. This molecular biological stratification is primarily important for determining the risk of these tumors as no therapy is currently available that is able to prevent or delay metastases. A randomized study of patients with a poor prognosis (monosomy 3) is currently being carried out in order to determine whether a cancer vaccine prepared from autologous (patient's own) dendritic cells and uveal melanoma RNA can prevent or delay progression and further metastases of this extremely aggressive form of cancer. Inclusion in the uveal melanoma study, which hopes to provide a potential therapeutic option for patients, is only possible if patients are referred to an institution that is able to manufacture and provide this vaccination before the patient is operated on or treated with radiation. Untreated tumor material is necessary for producing the vaccine on an individualized patient basis.
EVALuna2:19521

Impact of a preceding radiotherapy on the outcome of immune checkpoint inhibition in metastatic melanoma: a multicenter retrospective cohort study of the DeCOG - Knispel, Sarah; Stang, Andreas; Zimmer, Lisa; Lax, Hildegard; Gutzmer, Ralf; Heinzerling, Lucie; Weishaupt, Carsten; Pföhler, Claudia; Gesierich, Anja; Herbst, Rudolf; Kaehler, Katharina C.; Weide, Benjamin; et al. (Journal for ImmunoTherapy of Cancer, 2020)
BACKGROUND: Immune checkpoint inhibition (ICI) is an essential treatment option in melanoma. Its outcome may be improved by a preceding radiation of metastases. This study aimed to investigate the impact of a preceding radiotherapy on the clinical outcome of ICI treatment. METHODS: This multicenter retrospective cohort study included patients who received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or anti-programmed cell death protein 1 (PD-1) ICI with or without preceding radiotherapy for unresectable metastatic melanoma. ICI therapy outcome was measured as best overall response (BOR), progression-free (PFS) and overall survival (OS). Response and survival analyses were adjusted for confounders identified by directed acyclic graphs. Adjusted survival curves were calculated using inverse probability treatment weighting. RESULTS: 835 patients who received ICI (anti-CTLA-4, n=596; anti-PD-1, n=239) at 16 centers were analyzed, whereof 235 received a preceding radiotherapy of metastatic lesions in stage IV disease. The most frequent organ sites irradiated prior to ICI therapy were brain (51.1%), lymph nodes (17.9%) and bone (17.9%). After multivariable adjustment for confounders, no relevant differences in ICI therapy outcome were observed between cohorts with and without preceding radiotherapy. BOR was 8.7% vs 13.0% for anti-CTLA-4 (adjusted relative risk (RR)=1.47; 95% CI=0.81 to 2.65; p=0.20), and 16.5% vs 25.3% for anti-PD-1 (RR=0.93; 95% CI=0.49 to 1.77; p=0.82). Survival probabilities were similar for cohorts with and without preceding radiotherapy, for anti-CTLA-4 (PFS, adjusted HR=1.02, 95% CI=0.86 to 1.25, p=0.74; OS, HR=1.08, 95% CI=0.81 to 1.44, p=0.61) and for anti-PD-1 (PFS, HR=0.84, 95% CI=0.57 to 1.26, p=0.41; OS, HR=0.73, 95% CI=0.43 to 1.25, p=0.26). Patients who received radiation last before ICI (n=137) revealed no better survival than those who had one or more treatment lines between radiation and start of ICI (n=86). In 223 patients with brain metastases, we found no relevant survival differences on ICI with and without preceding radiotherapy. CONCLUSIONS: This study detected no evidence for a relevant favorable impact of a preceding radiotherapy on anti-CTLA-4 or anti-PD-1 ICI treatment outcome in metastatic melanoma.
CRIS-Team Scopus Importer:2020-05-19
Keywords: immunology; oncology; radiotherapy

Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort - Simon, David; Tascilar, Koray; Kleyer, Arnd; Fagni, Filippo; Krönke, Gerhard; Meder, Christine; Dietrich, Peter; Orlemann, Till; Kliem, Thorsten; Moessner, Johanna; Liphardt, Anna-Maria; Schönau, Verena; et al. (Arthritis and Rheumatology, 2022)
Objective To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. Results In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). Conclusion IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.
CRIS-Team WoS Importer:2022-04-08

Impact of Nrf2 expression in reconstituting T-cells of allogeneic hematopoietic stem cell transplanted patients - Karl, Franziska; Stoll, Andrej; Gamali, S.; Böttcher-Loschinski, Romy; Böttcher, Martin; Baur, Rebecca; Jacobs, Benedikt; Rösler, Wolf; Mackensen, Andreas; Mougiakakos, Dimitrios; Völkl, Simon (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-10-23