1,064-nm diode laser therapy of onychomycosis: results of a prospective open treatment of 82 toenails - Renner, Regina; Gruesser, Kathrin; Sticherling, Michael (Dermatology, 2015)
Onychomycosis is one of the most prevalent nail disorders in adults, where conventional topical therapy is often protracted and in most cases ineffective. On the other hand, systemic/oral therapy is not suitable for all patients and might be associated with relevant side effects. Therefore, laser therapy can be used as an alternative to or extension of existing treatment protocols.We used diode laser treatment for onychomycosis to evaluate the efficacy of this treatment as single therapy as well as in combination with an ongoing antimycotic treatment.We used a 1,064-nm diode laser (FOX Laser, ARC Laser GmbH, Germany) in pulse mode with a spot size of 4 mm. The laser's settings were: 8 W, with a pulse duration of 80 ms and a repetition rate of 5.6 Hz; the energy fluence/pulse was 5.1 J/cm(2), and a total energy of 250-500 J for large and/or thickened nails (digit I), 120-200 J for medium nails (digits II-IV) and 60-120 J for small and/or very thin nail plates (digit V) was counted in the laser display. Two to three passes where applied continuously over the entire area of the nail (nail plate, nail folds and eponychium) in a grid pattern. Eighty-two affected toenails were treated at least twice every 8 weeks; all nails treated were clinically diagnosed as onychomycosis. The evaluation of the treated nails was conducted by two dermatologists, initially by semiquantitative visual examination, followed by evaluation with the Onychomycosis Severity Index (OSI). In addition, the patients were asked to state their satisfaction with the treatment and its results in a written questionnaire.All nails showed an improvement ranging between 14 and 56% including the analytical evaluation scale (OSI). Two dermatologists evaluated 34 nails. Both reported significant improvement and/or good clinical improvement, which corresponds to about 41% for both evaluations. The mean OSI of all patients was 18.9/19.9 before treatment which changed to 14.3/14.8 after treatment. This corresponds to an improvement of about 25% (-4.6/-5.1) compared to the initial value. Specifically the subgroup with positive antimycotic culture and no additional antimycotic treatment showed an improvement of about 25%. This improvement can be attributed to the effect of the diode laser treatment. When evaluating the OSI of all nails, it appears that about 15-20% of the severe OSIs improved and changed to a moderate level, while a similar portion of patients with moderate onychomycosis improved to mild onychomycosis. Patient satisfaction was measured to an average value of 4.6 out of a maximum of 10 points. About 60% of the treated patients would recommend the treatment to their family members or friends.This investigation demonstrated that diode laser treatment of onychomycosis provides acceptable results with minimal to no side effects. Further clinical evaluations could help to establish better therapy protocols, especially for those patients who had no benefit from the laser treatment, or could also be used as an add-on to an existing therap
EVALuna2:19549

12/15-Lipoxygenase-mediated enzymatic lipid oxidation regulates DC maturation and function - Rothe, Tobias; Gruber, Florian; Uderhardt, Stefan; Ipseiz, Natacha; Rössner, Susanne; Oskolkova, Olga; Blueml, Stephan; Leitinger, Norbert; Bicker, Wolfgang; Bochkov, Valery N.; Yamamoto, Masayuki; Steinkasserer, Alexander; et al. (Journal of Clinical Investigation, 2015)
DCs are able to undergo rapid maturation, which subsequently allows them to initiate and orchestrate T cell-driven immune responses. DC maturation must be tightly controlled in order to avoid random T cell activation and development of autoimmunity. Here, we determined that 12/15-lipoxygenase-meditated (12/15-LO-mediated) enzymatic lipid oxidation regulates DC activation and fine-tunes consecutive T cell responses. Specifically, 12/15-LO activity determined the DC activation threshold via generation of phospholipid oxidation products that induced an antioxidative response dependent on the transcription factor NRF2. Deletion of the 12/15-LO-encoding gene or pharmacologic inhibition of 12/15-LO in murine or human DCs accelerated maturation and shifted the cytokine profile, thereby favoring the differentiation of Th17 cells. Exposure of 12/15-LO-deficient DCs to 12/15-LO-derived oxidized phospholipids attenuated both DC activation and the development of Th17 cells. Analysis of lymphatic tissues from 12/15-LO-deficient mice confirmed enhanced maturation of DCs as well as an increased differentiation of Th17 cells. Moreover, experimental autoimmune encephalomyelitis in mice lacking 12/15-LO resulted in an exacerbated Th17-driven autoimmune disease. Together, our data reveal that 12/15-LO controls maturation of DCs and implicate enzymatic lipid oxidation in shaping the adaptive immune response.
EVALuna2:13111

50-year-old woman with cold-associated attacks of white discoloration of individual fingers: Preparation for the specialist examination: part 51 50/w mit kälteabhängiger, anfallsweiser Weißverfärbung einzelner Finger: Vorbereitung auf die Facharztprüfung: Folge 51 - Sticherling, Michael (Hautarzt, 2019)
CRIS-Team Scopus Importer:2019-05-02

50-year-old Woman with cold-associated attacks of White Discoloration of individual Fingers Preparation for the Specialist Examination: Part 51 - Sticherling, Michael (Hautarzt, 2019)
CRIS-Team WoS Importer:2019-05-03

67. Arbeitssitzung (Frühjahrssymposium) der Deutschen Kontaktallergie-Gruppe (DKG) - Brans, Richard; Wagner, Nicola (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
EVALuna2:547056

A benchmark for neural network robustness in skin cancer classification - Maron, Roman C.; Schlager, Justin G.; Haggenmüller, Sarah; von Kalle, Christof; Utikal, Jochen S.; Meier, Friedegund; Gellrich, Frank F.; Hobelsberger, Sarah; Hauschild, Axel; French, Lars; Heinzerling, Lucie; Schlaak, Max; et al. (European Journal of Cancer, 2021)
Background: One prominent application for deep learning–based classifiers is skin cancer classification on dermoscopic images. However, classifier evaluation is often limited to holdout data which can mask common shortcomings such as susceptibility to confounding factors. To increase clinical applicability, it is necessary to thoroughly evaluate such classifiers on out-of-distribution (OOD) data. Objective: The objective of the study was to establish a dermoscopic skin cancer benchmark in which classifier robustness to OOD data can be measured. Methods: Using a proprietary dermoscopic image database and a set of image transformations, we create an OOD robustness benchmark and evaluate the robustness of four different convolutional neural network (CNN) architectures on it. Results: The benchmark contains three data sets—Skin Archive Munich (SAM), SAM-corrupted (SAM-C) and SAM-perturbed (SAM-P)—and is publicly available for download. To maintain the benchmark's OOD status, ground truth labels are not provided and test results should be sent to us for assessment. The SAM data set contains 319 unmodified and biopsy-verified dermoscopic melanoma (n = 194) and nevus (n = 125) images. SAM-C and SAM-P contain images from SAM which were artificially modified to test a classifier against low-quality inputs and to measure its prediction stability over small image changes, respectively. All four CNNs showed susceptibility to corruptions and perturbations. Conclusions: This benchmark provides three data sets which allow for OOD testing of binary skin cancer classifiers. Our classifier performance confirms the shortcomings of CNNs and provides a frame of reference. Altogether, this benchmark should facilitate a more thorough evaluation process and thereby enable the development of more robust skin cancer classifiers.
CRIS-Team Scopus Importer:2021-08-20
Keywords: Artificial intelligence; Benchmarking; Deep learning; Dermatology; Melanoma; Nevus; Skin neoplasms

Aberrant splicing as potential modifier of the phenotype of junctional epidermolysis bullosa - Mittwollen, R.; Wohlfart, S.; Park, J.; Grosch, Ella; Has, C.; Hohenester, E.; Schneider, Holm; Hammersen, Johanna (Journal of the European Academy of Dermatology and Venereology, 2020)
Background: A lack or dysfunction of the anchoring protein laminin-332 in the basement membrane leads to the skin blistering disorder junctional epidermolysis bullosa (JEB). The mutation c.628G>A in the gene LAMB3 encoding the laminin β3-chain is associated with generalized intermediate JEB; it may introduce an amino acid substitution (p.Glu210Lys) or disrupt splicing. Objective: This retrospective study aimed at determining the effects of aberrant splicing on the JEB phenotype. Methods: LAMB3 transcription was analysed in two siblings compound heterozygous for the LAMB3 mutations p.Glu210Lys and p.Arg635* with a diverging JEB phenotype from late childhood on. Laminin-332 levels in skin sections and in cultured keratinocytes were investigated by immunofluorescence staining. Real-time PCR was used to quantify LAMB3 expression in keratinocytes. RNA splice variants were identified by subcloning of a LAMB3 cDNA fraction and subsequent DNA sequencing. Structural models of laminin-332 helped to assess the impact of certain mutations on laminin-332 folding. Results: Both siblings showed diminished LAMB3 expression. Laminin-332 was equally reduced in skin sections obtained during infancy but differed in keratinocytes isolated during adolescence. Although aberrant LAMB3 splicing with 26 variants was detected in both patients, splicing differed significantly: the full-length LAMB3 transcript harbouring the p.Glu210Lys mutation was found more often in the patient affected less severely (14/108 vs. 5/106 clones; P = 0.03). Structural modelling predicted that several deletions in LAMB3, but not the point mutation p.Glu210Lys, have an effect on laminin-332 folding and secretion. Conclusions: Differential LAMB3 mRNA splicing in the patients may explain the disparate JEB phenotype. By elucidating the regulation of laminin-332 gene expression, these findings may contribute to the development of therapeutic strategies for JEB and might help to understand phenotype modification by splice-site mutations in other hereditary diseases.
CRIS-Team Scopus Importer:2020-06-02

A chimeric il-15/il-15rα molecule expressed on nfκb-activated dendritic cells supports their capability to activate natural killer cells† - Bosch, Naomi C.; Martin, Lena Marie; Voskens, Caroline; Berking, Carola; Seliger, Barbara; Schuler, Gerold; Schaft, Niels; Dörrie, Jan (International Journal of Molecular Sciences, 2021)
Natural killer (NK) cells, members of the innate immune system, play an important role in the rejection of HLA class I negative tumor cells. Hence, a therapeutic vaccine, which can activate NK cells in addition to cells of the adaptive immune system might induce a more comprehensive cellular response, which could lead to increased tumor elimination. Dendritic cells (DCs) are capable of activating and expanding NK cells, especially when the NFκB pathway is activated in the DCs thereby leading to the secretion of the cytokine IL-12. Another prominent NK cell activator is IL-15, which can be bound by the IL-15 receptor alpha-chain (IL-15Rα) to be transpresented to the NK cells. However, monocyte-derived DCs do neither secrete IL-15, nor express the IL-15Rα. Hence, we designed a chimeric protein consisting of IL-15 and the IL-15Rα. Upon mRNA electroporation, the fusion protein was detectable on the surface of the DCs, and increased the potential of NFκB-activated, IL-12-producing DC to activate NK cells in an autologous cell culture system with ex vivo-generated cells from healthy donors. These data show that a chimeric IL-15/IL-15Rα molecule can be expressed by monocyte-derived DCs, is trafficked to the cell surface, and is functional regarding the activation of NK cells. These data represent an initial proof-of-concept for an additional possibility of further improving cellular DC-based immunotherapies of cancer.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Adoptive cellular immunotherapy; Dendritic cell; IL-15; Natural killer cell; NF-κB

A comparative analysis of articular bone in large cohort of patients with chronic inflammatory diseases of the joints, the gut and the skin - Simon, David; Kleyer, Arnd; Englbrecht, Matthias; Stemmler, Fabian; Simon, Christoph; Berlin, Andreas; Kocijan, Roland; Haschka, Judith; Hirschmann, Simon; Atreya, Raja; Neurath, Markus; Sticherling, Michael; et al. (Bone, 2018)
Chronic inflammatory diseases are associated with bone loss. While the occurrence of systemic bone loss is well described in chronic inflammatory diseases, the impact of these conditions on articular bone has not been systematically investigated. Recent refinements in high-resolution CT assessment of the joints now allow the accurate measure of articular bone composition. In this study 476 subjects comprising healthy individuals and patients with anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA), ACPA-negative RA, Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO) and psoriatic arthritis (PsA) were subjected to high-resolution quantitative computed tomography (HR-pQCT) of the hand. Metacarpal heads were assessed for total, trabecular and cortical volumetric bone mineral density (vBMD). Only ACPA+RA, but not the remaining inflammatory diseases (ACPA-RA, CD, UC, PsO, PsA) showed significant (p < 0.001) loss of articular bone affecting both the trabecular and the cortical compartments. Age and body mass index were also associated with articular bone changes, the former with lower, the latter with higher articular bone mass. In multivariate models, presence of ACPA+RA was an independent factor for articular bone loss. Among chronic inflammatory diseases ACPA+RA is the most potent precipitator for articular bone loss pointing out the role of autoimmunity in the development of articular bone disease in the context of chronic inflammatory disease.
EVALuna2:34480

Acral lentiginous melanoma: a skin cancer with unfavourable prognostic features. A study of the German central malignant melanoma registry (CMMR) in 2050 patients - Teramoto, Y.; Keim, U.; Gesierich, A.; Schuler, Gerold; Fiedler, E.; Tueting, T.; Ulrich, C.; Wollina, Uwe; Hassel, J. C.; Gutzmer, R.; Goerdt, S.; Zouboulis, C.; et al. (British Journal of Dermatology, 2018)
BACKGROUND: Acral lentiginous melanoma (ALM) is one of the four major subtypes in cutaneous melanoma (CM). Although ALM has a poorer prognosis than other CM subtypes, the prognostic factors associated with ALM have only been verified in small-sized cohorts because of the low incidence of ALM worldwide. OBJECTIVES: To investigate the clinical characteristics of ALM and to evaluate their prognostic values based on a large dataset from the Central Malignant Melanoma Registry (CMMR) of the German Dermatologic Society. METHODS: The Kaplan-Meier method was used to estimate the potential influence of clinical and histological parameters on ALM disease-specific survival (DSS) curves, which were compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors for DSS. RESULTS: In total, 2050 patients with ALM were identified from 58 949 patients with CM recorded by the CMMR with follow-up data. In multivariate analyses, age (P = 0·006), ulceration (P = 0·013), tumour thickness (P < 0·001) and tumour spread (P < 0·001) turned out to be significant prognostic factors for DSS in ALM whereas sex, nevus association and level of invasion were not independent factors. CONCLUSIONS: ALM has the same prognostic factors as other subtypes of melanoma. Unfavourable prognosis probably derives from the delay in diagnosis in comparison with other melanoma subtypes.
EVALuna2:34403

A critical appraisal of evidence-and consensus-based guidelines for actinic keratosis - Wessely, Anja; Steeb, Theresa; Heppt, Franz; Hornung, Annkathrin; Kaufmann, Matthias; Koch, Elias; Toussaint, Frédéric; Erdmann, Michael; Berking, Carola; Heppt, Markus (Current Oncology, 2021)
Actinic keratoses (AK) are common lesions of the skin that can be effectively treated with several lesion-and field-directed treatments. Clinical practice guidelines assist physicians in choosing the appropriate treatment options for their patients. Here, we aimed to systematically identify and evaluate the methodological quality of currently available guidelines for AK. Guidelines published within the last 5 years were identified in a systematic search of guideline databases, Medline and Embase. Then, six independent reviewers evaluated the methodological quality using the tools “Appraisal of Guidelines for Research and Evaluation” (AGREE II) and “Recommendation EXcellence” (AGREE-REX). The Kruskal–Wallis (H) test was used to explore differences among subgroups and Spearman’s correlation to examine the relationship between individual domains. Three guidelines developed by consortia from Canada, Germany and the United Kingdom were eligible for the evaluation. The German guideline achieved the highest scores, fulfilling 65 to 92% of the criteria in AGREE II and 67 to 84% in AGREE-REX, whereas the Canadian guideline scored 31 to 71% of the criteria in AGREE II and 33 to 46% in AGREE-REX. The domains “stakeholder involvement“ and “values and preferences“ were identified as methodological weaknesses requiring particular attention and improvement in future guideline efforts.
CRIS-Team Scopus Importer:2021-04-02
Keywords: actinic keratosis; AGREE; Level of evidence; Practice guideline; Solar keratosis

A cross-tissue protein profiling atlas reveals distinct cDC2 subpopulations within the murine conventional dendritic cell network - Amon, Lukas; Lehmann, Christian; Seichter, A.; Heger, Lukas; Dudziak, Diana (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Actinic keratoses: Current guideline and practical recommendations Aktinische Keratosen: Aktuelle Leitlinie und praxisbezogene Empfehlungen - Nashan, D.; Hüning, S.; Heppt, Markus; Brehmer, A.; Berking, Carola (Hautarzt, 2020)
The S3 guideline “Actinic keratosis and squamous cell carcinoma of the skin” was published on 30 June 2019. Subsequently, publications, reviews and meta-analyses appeared with new questions regarding the comparability of study data and heterogeneity of the evaluations, which are caused, among other things, by divergent measurement parameters as well as insufficient consideration of pretreatments and combined treatments. This concise overview was written in the context of criticism and in view of necessary developments and research. Topics include epidemiology, pathogenesis, prevention, clinical presentation, therapy and BK5103. Therapy is divided into local destructive procedures and topical applications. Recommendations with quotation marks are based on the actual guideline. Corresponding evidence levels are given. For the implementation in daily routine basic data, side effects and features of therapeutic options are mentioned. The current developments and questions concerning actinic keratoses become clear.
CRIS-Team Scopus Importer:2020-06-09
Keywords: BK5103; Diagnosis; Precision medicine; S3 guideline; Therapy

Activated glycoprotein A repetitions predominant (GARP)-expressing regulatory T cells inhibit allergen-induced intestinal inflammation in humanized mice - Eschborn, Melanie; Weigmann, Benno; Reissig, Sonja; Waisman, Ari; Saloga, Joachim; Bellinghausen, Iris (Journal of Allergy and Clinical Immunology, 2015)
Recently, we developed a humanized mouse model of allergen-induced IgE-dependent gut inflammation in PBMC-engrafted immunodeficient mice.In the present study, we wanted to investigate the role of regulatory T (Treg) cells and their activation status in this model.Nonobese diabetic-severe combined immunodeficiency-?c(-/-) mice were injected intraperitoneally with human PBMCs from allergic donors together with the respective allergen or NaCl as control in the presence or absence of different concentrations of CD4(+)CD25(+) Treg cells of the same donor. After an additional allergen boost 1 week later, mice were challenged with the allergen rectally on day 21 and gut inflammation was monitored by a high-resolution video mini-endoscopic system evaluating translucency, granularity, fibrin production, vascularity, and stool.Allergen-specific human IgE in mouse sera, which was detectable only in PBMC plus allergen-treated mice, was strongly inhibited by coinjection of Treg cells at a ratio of at least 1:10. Consequently, the presence of Treg cells significantly decreased IgE-dependent allergen-induced gut inflammation after rectal allergen challenge. In addition, Treg cells reduced allergen-specific proliferation and cytokine production of recovered human CD4(+) T cells in vitro. Activation of Treg cells before injection further increased all inhibitory effects. Prevention of gut inflammation also occurred by the administration of glycoprotein A repetitions predominant, a molecule expressed by activated Treg cells, whereas its blockade completely abrogated inhibition by Treg cells.These results demonstrate that allergen-specific gut inflammation in human PBMC-engrafted mice can be avoided by enhancing the numbers or activity of autologous Treg cells, which is of great interest for therapeutic intervention of allergic diseases of the intestine.
EVALuna2:2022

Active vitamin D supplementation and COVID-19 infections: review - Farid, Nakhoul; Rola, Nakhoul; Koch, Elias; Nakhoul, Nakhoul (Irish Journal of Medical Science, 2021)
SARS-CoV-2, causing the lethal disease COVid-19, is a public health emergency in the 2020 global pandemic. The outbreak and fast spreading of SARS-CoV-2 have a high morbidity and mortality specifically in elder patients with chronic diseases such as diabetes mellitus, arterial hypertension, chronic kidney disease, and organ transplanted patients with immunosuppressive therapy. Preliminary results support different treatments such as chloroquine and convalescent plasma infusion in severe cases, with good outcome. On the other hand, the efficacy of supplementation with active vitamin D, an immunomodulator hormone with antiinflammatory and antimicrobial effects, is unproven. A recent study reported that vitamin D attains antiviral effects, via blocking viral replication directly. SARS-CoV-2 primarily uses the immune evasion process during infection via the envelope spike glycoprotein, which is followed by a cytokine storm, causing severe acute respiratory disease syndrome and death. SARS-CoV-2, by using the well-known angiotensin-converting enzyme 2 by the protein spike, as the host receptor to enter into alveolar, myocardial, and renal epithelial cells, can be disrupted by vitamin D. However, the correlation between vitamin D levels and COVID-19 deaths in previous studies was insignificant. Retrospective studies demonstrated a correlation between vitamin D status and COVID-19 severity and mortality, while other studies did not find this correlation. Studies have shown that, vitamin D reduces the risk of acute viral respiratory tract infections and pneumonia via direct inhibition of viral replication, antiinflammatory and immunomodulatory effects. The data available today regarding the beneficial protective effect of vitamin D is unclear and with conflicting results. Large randomized control trials are necessary to test this hypothesis. In this review, we will explain the cross talk between the active vitamin D and the angiotensin-converting enzyme 2, and summarize the data from the literature.
CRIS-Team Scopus Importer:2021-01-15
Keywords: Angiotensin converting enzyme 2; COVID-19; Renin; SARS-CoV-2; Vitamin D

Acute urticaria—what to do? - Treudler, Regina; Zarnowski, Julia; Wagner, Nicola (Allergo Journal, 2023)
Acute urticaria (AU) is the most common cause of wheal formation. By definition, it does not persist for more than 6 weeks. It can occur at any age and is more commonly seen in atopic diathesis. Acute spontaneous urticaria is distinguished from inducible forms. This review highlights the clinical presentation, differential diagnosis, possible triggers, and therapeutic strategies. In childhood as in adulthood, viral infections are very frequently associated with acute urticaria, whereas drugs and food are less frequently described as triggers. However, it is not uncommon for multiple triggers to be present simultaneously. Therapeutically, oral nonsedating H1 antihistamines are mainly used. In some patients, concomitant short-term administration of glucocorticosteroids is also necessary.
CRIS-Team Scopus Importer:2023-11-24
Keywords: Antihistamines; Diagnosis; Differential diagnoses; Pathogenesis; Therapy

Adaptive Immune Response to and Survival Effect of Temozolomide- and Valproic Acid-induced Autophagy in Glioblastoma - Proske, Judith; Walter, Lisa; Bumes, Elisabeth; Hutterer, Markus; Vollmann-Zwerenz, Arabel; Eyüpoglu, Ilker Yasin; Savaskan, Nicolai E.; Seliger, Corinna; Hau, Peter; Uhl, Martin; Walter, Lisa (Anticancer Research, 2016)
The combination of radiotherapy, temozolomide and valproic acid (VPA) has shown some promise in retrospective analyses of patients with glioblastoma, although their mechanisms of action remain unknown.We investigated the in vitro and in vivo effects of pretreating glioma cells with temozolomide and VPA as an immunization strategy to boost an adaptive immune response in a syngeneic mouse model.Temozolomide and VPA induced autophagy in GL261 glioma cells, and caused tumor antigen-specific T-cells to become activated effector T-cells. Mice with a pre-existing glioma showed no improvement in clinical outcome when immunized with temozolomide- and VPA-treated glioma cells.Although temozolomide and VPA treatment of glioma cells can boost the adaptive immune response, in the context of a vaccine therapy, additional factors are necessary to eradicate the tumor and improve survival.
EVALuna2:22525

Adding a second skin prick test reading and modifying the cut-off for beta-lactam–specific IgE enhances the sensitivity in the routine diagnostic workup for immediate beta-lactam hypersensitivity - Rosti, Bernadette; Mahler, Vera (Contact Dermatitis, 2020)
Background: Beta-lactam (BL)–antibiotics are the most frequent reason for drug-induced hypersensitivity reactions. Because they are more efficient, less toxic, and less costly than other antibiotics, confirmation or exclusion of BL allergy is worthwhile. However, allergy tests for drug allergies are often false-negative. Objectives: To evaluate the components of a stepwise diagnostic algorithm for immediate BL hypersensitivity with regard to sensitivity (SENS). Methods: Consecutive patients with suspected allergy to BL antibiotics were retrospectively analyzed with regard to increasing sensitivity (plausible history of immediate BL hypersensitivity serving as external criterion) of (i) skin prick test (SPT) by adding a second reading (n = 746), (ii) BL-specific IgE-determination in vitro at two cut-offs (n = 539), and (iii) adding in vivo testing of minor and major BL determinants (n = 288). Results: In the history-based population indicative of immediate BL hypersensitivity (n = 457), SPT with a sole 20-minute reading identified 99 (SENS: 0.21) and SPT with 20- and 40-minute-reading identified 133 cases (SENS: 0.29). in vitro specific IgE-examination identified 31 positives at a cut-off ≥0.35 kUA/L (5.8% of tested) and 99 at cut-off ≥0.11 kUA/L (18.4% of tested). In 203 SPT-negative individuals, immediate BL hypersensitivity was identified by additional tests: in 79 by specific IgE (cut-off ≥0.11 kUA/L) (thereof 53 identified solely by this test) and in 150 by in vivo testing of BL determinants in combination with Penicillin and Ampicillin intradermally (thereof 124 solely by this test); in 26 individuals both additional tests were positive. The combination of the three outpatient-based test modalities—(i) optimized SPT, (ii) specific IgE at optimized cut-off, and (iii) in vivo testing of BL determinants/Penicillin/Ampicillin—identified altogether 336/457 individuals with immediate BL-hypersensitivity (SENS: 0.73), whereas the combination of the two (i) + (ii) identified 212/457 (SENS: 0.46); (i) + (iii) 283/457 (SENS: 0.61). Conclusions: To overcome the low sensitivity of allergological tests, optimized reading times of the SPT of BL, a lower cut-off for in vitro detection of BL-specific IgE, and intradermal testing of Penicillin, Ampicillin, and BL-determinants contribute to overall sensitivity under real life conditions to diagnose immediate BL-hypersensitivity.
CRIS-Team Scopus Importer:2020-08-07
Keywords: allergy; beta-lactam antibiotics; cut-off; reading times; sensitivity; skin prick test; specific IgE

ADF Winter School-An exciting concept of the Arbeitsgemeinschaft Dermatologische Forschung to connect young scientists and clinician scientists in Dermatology at the top of Germany - Yazdi, Amir S.; Barlin, Meltem; Boehm, Katharina; Gendrisch, Fabian; Ghorbanalipoor, Saeedeh; Haeberle, Stefanie; Hamel, Annamarie; Huening, Svea; Huettner, Clemens; Iwanova, Irina; Kanaki, Theodora; Kimeswenger, Susanne; et al. (Experimental Dermatology, 2017)
EVALuna2:35411

A disease network-based deep learning approach for characterizing melanoma - Lai, Xin; Zhou, Jinfei; Wessely, Anja; Heppt, Markus; Maier, Andreas; Berking, Carola; Vera, Julio; Zhang, Le (International Journal of Cancer, 2021)
Multiple types of genomic variations are present in cutaneous melanoma and some of the genomic features may have an impact on the prognosis of the disease. The access to genomics data via public repositories such as The Cancer Genome Atlas (TCGA) allows for a better understanding of melanoma at the molecular level, therefore making characterization of substantial heterogeneity in melanoma patients possible. Here, we proposed an approach that integrates genomics data, a disease network, and a deep learning model to classify melanoma patients for prognosis, assess the impact of genomic features on the classification and provide interpretation to the impactful features. We integrated genomics data into a melanoma network and applied an autoencoder model to identify subgroups in TCGA melanoma patients. The model utilizes communities identified in the network to effectively reduce the dimensionality of genomics data into a patient score profile. Based on the score profile, we identified three patient subtypes that show different survival times. Furthermore, we quantified and ranked the impact of genomic features on the patient score profile using a machine-learning technique. Follow-up analysis of the top-ranking features provided us with the biological interpretation of them at both pathway and molecular levels, such as their mutation and interactome profiles in melanoma and their involvement in pathways associated with signaling transduction, immune system and cell cycle. Taken together, we demonstrated the ability of the approach to identify disease subgroups using a deep learning model that captures the most relevant information of genomics data in the melanoma network.
CRIS-Team Scopus Importer:2021-11-26
Keywords: autoencoder; disease network; genomics; melanoma; neural network; systems medicine

Adjuvant melanoma treatment: real-world data from the DACH region - Schumann, K.; Mangana, J.; Dummer, R.; Sindrilaru, M.; Reinhardt, L.; Meier, F.; Gutzmer, R.; Schatton, K.; Amaral, T.; Eigentler, T.; Peitsch, W.; Hillen, U.; et al. (EXPERIMENTAL DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-14

Adjuvant treatment and outcome of stage III melanoma patients: Results of a multicenter real-world German Dermatologic Cooperative Oncology Group (DeCOG) study - Lodde, Georg C.; Hassel, Jessica; Wulfken, Lena M.; Meier, Friedegund; Mohr, Peter; Kähler, Katharina; Hauschild, Axel; Schilling, Bastian; Loquai, Carmen; Berking, Carola; Hüning, Svea; Eckardt, Julia; et al. (European Journal of Cancer, 2023)
Purpose: Clinical trials demonstrated significantly improved recurrence-free survival (RFS) of melanoma patients receiving adjuvant treatment. As data from controlled trials are based on selected populations, we investigated adjuvantly treated stage III melanoma patients under real-world conditions. Patients and methods: In a prior multicenter cohort study, stage III-IV melanoma patients were analysed for their choice of adjuvant therapy. In this follow-up study, we examined RFS, overall and melanoma-specific survival (MSS) and response to the subsequent treatment of 589 stage III patients (232 BRAF-mutated) receiving adjuvant PD-1 inhibitors (PD1; n = 479) or targeted therapy (TT; n = 110). Results: The median follow-up of the total cohort was 25.7 months. The main reason for premature discontinuation of adjuvant therapy was disease progression in PD1- (28.8%, n = 138/479) and adverse events in TT-treated patients (28.2%, n = 31/110). Among BRAF-mutated patients, RFS at 24 months was 49% (95% CI 40.6–59.0%) for PD1- and 67% (95% CI 58–77%) for TT-treated patients. The risk of recurrence was higher for BRAF-mutated PD1 than TT (hazard ratio 1.99; 95% CI 1.34–2.96; hazard ratio adjusted for age, sex and tumour stage, 2.21; 95% CI 1.48–3.30). Twenty-four months MSS was 87% (95% CI 81.0–94.1) for PD1 and 92% (95% CI 86.6–97.0) for TT. Response to subsequent systemic treatment for unresectable disease was 22% for all PD1- and 16% for TT-treated patients. Conclusions: PD1-treated patients had more and earlier recurrences than TT patients. In BRAF-mutated patients, adjuvant TT might prevent early recurrences more effectively than PD1 treatment. Management of recurrence despite adjuvant treatment is challenging, with low response to current therapeutic options. Data availability statement: The datasets generated during and/or analysed during the current study are available for qualified researchers from the corresponding authors upon request.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Adjuvant treatment; BRAF; Immunotherapy; Melanoma; PD1; Real-world; Targeted therapy

Adjuvant treatment with pegylated interferon α-2a versus low-dose interferon α-2a in patients with high-risk melanoma: a randomized phase III DeCOG trial - Eigentler, T. K.; Gutzmer, R.; Hauschild, A.; Heinzerling, Lucie; Schadendorf, D.; Nashan, D.; Hoelzle, E.; Kiecker, F.; Becker, J.; Sunderkoeter, C.; Moll, I.; Richtig, E.; et al. (Annals of Oncology, 2016)
BACKGROUND: Adjuvant treatment with interferon (IFN)-α-2a improved disease-free survival (DFS) and showed a trend for improving overall survival (OS) in melanoma. This trial was designed to examine whether PEG-IFN is superior to IFN with regard to distant metastasis-free survival (DMFS), DFS and OS. PATIENTS AND METHODS: In this multicenter, open-label, prospective randomized phase III trial, patients with resected cutaneous melanoma stage IIA(T3a)-IIIB (AJCC 2002) were randomized to receive PEG-IFN (180 μg subcutaneously 1×/week; 24 months) or IFN α-2a (3MIU subcutaneously 3×/week; 24 months). Randomization was stratified for stage, number of metastatic nodes, age and previous IFN treatment. The primary end point was DMFS; secondary end points were OS, DFS, quality of life (QoL) and tolerability. RESULTS: A total of 909 patients were enrolled (451 PEG-IFN versus 458 IFN). Neither 5-year DMFS [PEG-IFN 61.0% versus IFN 67.3%; hazard ratio (HR) 1.16, P = 0.21] nor 5-year OS (PEG-IFN 73.2% versus IFN 75.2%; HR 1.05, P = 0.70) nor 5-year DFS (PEG-IFN 57.3% versus IFN 60.9%; HR 1.09, P = 0.40) showed significant differences. Subgroup analyses in patients ± ulcerated primaries and of different tumor stages did not find differences in DMFS, OS or DFS between the treatment groups. One hundred and eighteen patients (26.2%) in the PEG-IFN and 61 patients (13.3%) in the IFN population did not receive the full dosage and length of treatment due to adverse events (P < 0.001). Leukopenia and elevation of liver enzymes were more common in the PEG-IFN arm (56% versus 23.5% LCP; 19.1% versus 9.4% AST; 33.0% versus 16.5% ALT). QoL was identical for nearly all domains. CONCLUSION: PEG-IFN did not improve the outcome over IFN. A higher percentage of patients under PEG-IFN discontinued treatment due to toxicity. CLINICAL TRIALSGOV IDENTIFIER: NCT00204529.
EVALuna2:33941

Adrenaline autoinjector is underprescribed in typical cold urticaria patients - Bizjak, Mojca; Košnik, Mitja; Dinevski, Dejan; Thomsen, Simon Francis; Fomina, Daria; Borzova, Elena; Kulthanan, Kanokvalai; Meshkova, Raisa; Aarestrup, Fernando Monteiro; Ahsan, Dalia Melina; Al-Ahmad, Mona; Altrichter, Sabine; et al. (Allergy, 2022)
CRIS-Team Scopus Importer:2022-03-25
Keywords: adrenaline autoinjector; cold urticaria; COLD-CE; cold-induced anaphylaxis

Advanced neural networks for classification of MRI in psoriatic arthritis, seronegative, and seropositive rheumatoid arthritis - Folle, Lukas; Bayat, Sara; Kleyer, Arnd; Fagni, Filippo; Kapsner, Lorenz; Schlereth, Maja; Meinderink, Timo; Breininger, Katharina; Tascilar, Koray; Krönke, Gerhard; Uder, Michael; Sticherling, Michael; et al. (Rheumatology, 2022)
Objectives: To evaluate whether neural networks can distinguish between seropositive rheumatoid arthritis (RA), seronegative RA and psoriatic arthritis (PsA) based on inflammatory patterns from hand MRI and to test how psoriasis patients with subclinical inflammation fit into such patterns. Methods: ResNet neural networks were utilized to compare (i) seropositive RA vs. PsA, (ii) seronegative RA vs. PsA and (iii) seropositive vs. seronegative RA with respect to hand MRI data. Results from T1 coronal, T2 coronal, T1 coronal and axial fat suppressed contrast-enhanced (CE) and T2 fat suppressed axial sequences were used. The performance of such trained networks was analyzed by the area-under-the-receiver-operating-characteristic curve (AUROC) with and without presentation of demographic and clinical parameters. Additionally, the trained networks were applied to psoriasis patients without clinical arthritis. Results: MRI scans from 649 patients (135 seronegative RA, 190 seropositive RA, 177 PsA, 147 psoriasis) were fed into ResNet neural networks. AUROC was 75% for seropositive RA vs. PsA, 74% for seronegative RA vs. PsA and 67% for seropositive vs. seronegative RA. All MRI sequences were relevant for classification, however, when deleting contrast agent-based sequences the loss of performance was only marginal. The addition of demographic and clinical data to the networks did not provide significant improvements for classification. Psoriasis patients were mostly assigned to PsA by the neural networks, suggesting that a PsA-like MRI pattern may be present early in the course of psoriatic disease. Conclusion: Neural networks can be successfully trained to distinguish MRI inflammation related to seropositive RA, seronegative RA, and PsA.
Keywords: Rheumatoid arthritis; Psoriatic arthritis; neural networks; deep learning

Adverse events 2.0-Let us get SERIOs New reporting for adverse event outcomes needed in the era of immunooncology - Heinzerling, Lucie; Ascierto, Paolo A.; Dummer, Reinhard; Gogas, Helen; Grob, Jean-Jacques; Lebbe, Celeste; Long, Georgina V.; Mcarthur, Grant; Moslehi, Javid J.; Neilan, Tomas G.; Ribas, Antoni; Robert, Caroline; et al. (European Journal of Cancer, 2019)
CRIS-Team WoS Importer:2019-05-17

Aetiology, comorbidities and cofactors of chronic leg ulcers: retrospective evaluation of 1 000 patients from 10 specialised dermatological wound care centers in Germany - Jockenhoefer, Finja; Gollnick, Harald; Herberger, Katharina; Isbary, Georg; Renner, Regina; Stuecker, Markus; Valesky, Eva; Wollina, Uwe; Weichenthal, Michael; Karrer, Sigrid; Kuepper, Bernhard; Roesch, Alexander; et al. (International Wound Journal, 2016)
Numerous comorbidities and cofactors have been known to influence wound healing processes. In this multicentre study, clinical data of 1 000 patients with chronic leg ulcers from ten specialised dermatological wound care centers were analysed. The patient cohort comprised 567 females and 433 males with an average age of 69·9 years. The wounds persisted on average for 40·8 months and had a mean size of 43·7 cm(2) . Venous leg ulcers represented the most common entity accounting for 51·3% of all chronic wounds, followed by mixed-type ulcers in 12·9% and arterial ulcerations in 11·0% of the patients. Vasculitis was diagnosed in 4·5%, trauma in 3·2%, pyoderma gangrenosum in 2·8%, lymphoedema in 1·7%, neoplasia in 1·0% and delayed post-surgical wound healing in 0·6% of the included patients. In total, 70·5% of patients suffered from arterial hypertension, 45·2% were obese, 27·2% had non-insulin dependent diabetes, and 24·4% dyslipidaemia. Altogether 18·4% suffered from metabolic syndrome. Cofactors and comorbidities of patients with chronic leg ulcers have previously been studied but not in detail. Here, we were able to demonstrate the existence of several potentially relevant cofactors, comorbidities of their associations and geographical distributions, which should be routinely examined in patients with chronic leg ulcers and - if possible - treated.
EVALuna2:19632

A fast and robust method to clone and functionally validate T-cell receptors - Birkholz, Katrin; Hofmann, Christian; Hoyer, Stefanie; Schulz, Bastian; Harrer, Thomas; Kämpgen, Eckhart; Schuler, Gerold; Dörrie, Jan; Schaft, Niels (Journal of Immunological Methods, 2009)
Sequencing, cloning and functional testing of T-cell-receptor (TCR) α- and β-chains from T-cell clones is often required in immunotherapy and in immunological research. However, the determination of the TCR chains by a simple PCR is not possible, since, in contrast to the 3′ constant domain and untranslated region (UTR), no conserved sequences are present in the 5′ region. Furthermore, subsequent functional testing of cloned TCRs requires laborious cell-culture experiments, often involving primary human material and time-consuming viral transduction strategies. Here we present a universal PCR-based protocol, adapted from the capswitch technology, that allows for amplification of the TCR α- and β-chain mRNAs without knowledge of the TCR variable domain subtype by attaching a designed sequence to the mRNA's 5′ end. Two different MelanA/HLA-A2-specific and one HIVgag/HLA-A2-specific TCR were cloned that way, and were functionally tested by a newly developed easy, fast, and low-cost method: we electroporated Jurkat T cells simultaneously with TCR-encoding RNA and an NFAT-reporter construct, and measured the activation status of the cells upon specific stimulation. The results of this assay correlated with the cytokine release, functional avidity, proliferative activity, and the ability to recognize MelanA/HLA-A2-presenting tumor cells of bulk T cells electroporated with RNA encoding the same TCR. Together these two protocols represent a rapid and low-cost tool for the identification and functional testing of TCRs of T-cell clones, which can then be applied in immunotherapy or immunological research. © 2009 Elsevier B.V. All rights reserved.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Cellular immunology; Immunotherapy; Signal transduction; T cells; TCR

Age as a Key Factor in the Pattern, Extent and timing Process of Distant Metastasis in Patients with malignant Melanoma. A Study by the German Central Register of Malignant Melanoma - Gassenmaier, M.; Leiter, U.; Eigentler, T.; Roecken, M.; Keim, U.; Gesierich, A.; Moritz, R.; Heinzerling, Lucie; Tueting, T.; Wollina, U.; Garbe, C. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Age as key factor for pattern, timing, and extent of distant metastasis in patients with cutaneous melanoma: A study of the German Central Malignant Melanoma Registry - Gassenmaier, Maximilian; Keim, Ulrike; Leiter, Ulrike; Eigentler, Thomas K.; Roecken, Martin; Gesierich, Anja; Moritz, Rose K. C.; Heinzerling, Lucie; Tueting, Thomas; Wollina, Uwe; Garbe, Claus (Journal of the American Academy of Dermatology, 2019)
Background: Melanoma incidence rates rise as people age, but the impact of aging on distant metastasis is unclear.
CRIS-Team WoS Importer:2019-04-23

A gene regulatory architecture that controls region-independent dynamics of oligodendrocyte differentiation - Cantone, Martina; Küspert, Melanie; Reiprich, Simone; Lai, Xin; Eberhardt, Martin; Göttle, Peter; Beyer, Felix; Azim, Kasum; Küry, Patrick; Wegner, Michael; Vera, Julio (Glia, 2019)
Oligodendrocytes (OLs) facilitate information processing in the vertebrate central nervous system via axonal ensheathment. The structure and dynamics of the regulatory network that mediates oligodendrogenesis are poorly understood. We employed bioinformatics and meta-analysis of high-throughput datasets to reconstruct a regulatory network underpinning OL differentiation. From this network, we identified families of feedforward loops comprising the transcription factors (TFs) Olig2, Sox10, and Tcf7l2 and their targets. Among the targets, we found eight other TFs related to OL differentiation, suggesting a hierarchical architecture in which some TFs (Olig2, Sox10, and Tcf7l2) regulate via feedforward loops the expression of others (Sox2, Sox6, Sox11, Nkx2-2, Nkx6-2, Hes5, Myt1, and Myrf). Model simulations with a kinetic model reproduced the mechanisms of OL differentiation only when in the model, Sox10-mediated repression of Tcf7l2 by miR-338/miR-155 was introduced, a prediction confirmed in genetic functional experiments. Additional model simulations suggested that OLs from dorsal regions emerge through BMP/Sox9 signaling.
EVALuna2:35752

A GMP-compliant protocol to expand and transfect cancer patient T cells with mRNA encoding a tumor-specific chimeric antigen receptor - Krug, Christian; Wiesinger, Manuel; Abken, Hinrich; Schuler-Thurner, Beatrice; Schuler, Gerold; Dörrie, Jan; Schaft, Niels (Cancer Immunology Immunotherapy, 2014)
Chimeric antigen receptors (CARs), which combine an antibody-derived binding domain (single chain fragment variable) with T-cell-activating signaling domains, have become a promising tool in the adoptive cellular therapy of cancer. Retro- and lenti-viral transductions are currently the standard methods to equip T cells with a CAR; permanent CAR expression, however, harbors several risks like uncontrolled auto-reactivity. Modification of T cells by electroporation with CAR-encoding RNA to achieve transient expression likely circumvents these difficulties. We here present a GMP-compliant protocol to activate and expand T cells for clinical application. The protocol is optimized in particular to produce CAR-modified T cells in clinically sufficient numbers under full GMP-compliance from late-stage cancer patients. This protocol allows the generation of 6.7 × 10(8) CAR-expressing T cells from one patient leukapheresis. The CAR-engineered T cells produced pro-inflammatory cytokines after stimulation with antigen-bearing tumor cells and lysed tumor cells in an antigen-specific manner. This functional capacity was maintained after cryopreservation. Taken together, we provide a clinically applicable protocol to transiently engineer sufficient numbers of antigen-specific patient T cells for use in adoptive cell therapy of cancer.
EVALuna2:19440

Agranulocytosis with Immune Checkpoint-Blockade - a retrospective, multicenter Evaluation - Zaremba, A.; Martaki, A.; Salzmann, M.; Baroudjian, B.; Sachse, M. M.; Gesierich, A.; Reinhardt, L.; Meier, F.; Hassel, J. C.; Ugurel, S.; Roesch, A.; Schadendorf, D.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

A humanized mouse identifies the bone marrow as a niche with low therapeutic IgG activity - Lux, Anja; Seeling, Michaela; Baerenwaldt, Anne; Lehmann, Birgit; Schwab, Inessa; Repp, Roland; Meidenbauer, Norbert; Mackensen, Andreas; Hartmann, Arndt; Heidkamp, Gordon Frederik; Dudziak, Diana; Nimmerjahn, Falk (Cell Reports, 2014)
Genetic differences between humans and in vivo model systems, including mice and nonhuman primates, make it difficult to predict the efficacy of immunoglobulin G (IgG) activity in humans and understand the molecular and cellular mechanisms underlying that activity. To bridge this gap, we established a small-animal model system that allowed us to study human IgG effector functions in the context of an intact human immune system without the interference of murine Fc? receptors expressed on mouse innate immune effector cells in vivo. Using a model of B cell depletion with different human IgG variants that recognize CD20, we show that this humanized mouse model can provide unique insights into the mechanism of human IgG activity in vivo. Importantly, these studies identify the bone marrow as a niche with low therapeutic IgG activity.
EVALuna2:6588

Aktinische Keratosen - Heppt, Markus; Steeb, T.; Szeimies, R. M.; Berking, Carola (Hautarzt, 2020)
Actinic keratoses (AK) are common precancerous cutaneous lesions in fair-skinned individuals as a result of cumulative exposure to ultraviolet radiation. Due to their high prevalence, AK account for a large disease burden, in particular in older persons. As AK may potentially progress into invasive cutaneous squamous cell carcinoma, guidelines recommend early and consequent treatment. Numerous lesion- and field-directed interventions with different efficacy and safety profiles are currently licensed in Germany. The appropriate intervention should be chosen together with the patient based on his or her motivation and expectations towards the treatment.
CRIS-Team Scopus Importer:2020-06-05
Keywords: 5‑Fluorouracil; Ingenol mebutate; Non-melanoma skin cancer; Photodynamic therapy; Squamous cell carcinoma

ALK Inhibitors Do Not Increase Sensitivity to Radiation in EML4-ALK Non-small Cell Lung Cancer - Fleschutz, Kathrin; Walter, Lisa; Leistner, Rumo; Heinzerling, Lucie (Anticancer Research, 2020)
BACKGROUND/AIM: ALK inhibitors like Crizotinib, Ceritinib and Alectinib are targeted therapies used in patients with anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC). Since in this tumor entity radiotherapy is employed sequentially or concomitantly, potential synergistic effects were investigated, which may support the hypothesis of induced radiosensitization by using ALK inhibitors. MATERIALS AND METHODS: Two cell lines expressing wild-type (WT) or echinoderm microtubule-associated protein-like 4 (EML4)-ALK were treated with ALK inhibitors, followed by irradiation. Cell survival, cell death, cell cycle and phosphorylation of H2A histone family, member X (H2AX) were examined. RESULTS: Combined treatment with ALK-inhibitors plus 10 Gy-irradiation led to effects similar to those of sole radiotherapy, but was more effective than sole drug treatment. CONCLUSION: There is no clear evidence of sensitization to radiation by treating EML4-ALK mutated cells with ALK inhibitors.
CRIS-Team Scopus Importer:2020-09-11
Keywords: Alectinib; ALK inhibitors; anaplastic lymphoma kinase; Ceritinib; Crizotinib; NSCLC; radiation

Allergenic and microbiological hazards caused by skin markings during medical procedures? - Maronna, Andreas; Psaier, Sigrid; Geier, Johannes; Mahler, Vera; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2017)
EVALuna2:35403

Allergic contact dermatitis caused by a catheter system containing sodium metabisulfite - Grosch, Ella; Mahler, Vera (Contact Dermatitis, 2017)
EVALuna2:35412

Allergologische und mikrobiologische Gefährdung durch Hautmarkierung bei medizinischen Prozeduren? - Maronna, Andreas; Psaier, Sigrid; Geier, Johannes; Mahler, Vera; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2017)
EVALuna2:35419

Allogeneic ABCB5+ mesenchymal stem cells for treatment-refractory chronic venous ulcers: a phase I/IIa clinical trial. - Kerstan, Andreas; Dieter, Kathrin; Niebergall-Roth, Elke; Dachtler, Ann-Kathrin; Kraft, Korinna; Stücker, Markus; Daeschlein, Georg; Juenger, Michael; Goerge, Tobias; Meyer-Pannwitt, Ulrich; Erfurt-Berge, Cornelia; von Engelhardt, Charlotte; et al. (JID Innovations, 2022)
A significant number of chronic venous ulcers (CVUs) fail to heal despite of guideline-conform standard of care. Skin-derived ABCB5+ mesenchymal stem cells (MSCs) can dampen the sustained IL-1β-driven inflammation present in chronic wounds. Based on their wound healing-facilitating effects in a mouse CVU model and an autologous first-in-human study, ABCB5+ MSCs have emerged as a potential candidate for cell-based advanced therapy of non-healing CVUs. In the present interventional, multicenter, single-arm, phase I/IIa clinical trial, subjects whose CVU had emerged as standard therapy-resistant received one or two topical applications of 1×106 allogeneic ABCB5+ MSCs/cm2 wound area in addition to standard treatment. Out of 83 treatment-emergent adverse events, only three were judged related to the cell product; they were mild or moderate and recovered without sequelae. Wound size markedly decreased from baseline to week 12, resulting in a median wound size reduction of 76% (full analysis set, N=31), 78% (per-protocol set, N=27) and 87% (subset of responders; n=21). In conclusion, the study treatment was well tolerated and safe. The treatment elicited a profound wound size reduction within 12 weeks, identifying ABCB5+ MSCs as a potential candidate for adjunctive therapy of otherwise incurable CVUs. These results justify the conduct of a larger, randomized, controlled trial to confirm clinical efficacy.
EVALuna2:495670

Alopecia areata- Clinical Picture and Therapy Response of Heterogeneous Disease - Busch, D.; Sticherling, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Alzheimer's disease protease-containing plasma extracellular vesicles transfer to the hippocampus via the choroid plexus - Lee, Jung Hyun; Ostalecki, Christian; Oberstein, Timo; Schierer, Stefan; Zinser, Elisabeth; Eberhardt, Martin; Blume, Katja; Plosnita, Bianca; Stich, Lena; Bruns, Heiko; Coras, Roland; Vera González, Julio; et al. (EBioMedicine, 2022)
Background: Plasma extracellular vesicles (pEV) can harbor a diverse array of factors including active proteases and the amyloid-precursor-protein (APP) cleavage product Aβ, involved in plaque formation in Alzheimer`s diseases (AD). A potential role of such vesicles in AD pathology is unexplored. Methods: In a case-control study of randomly selected patients with AD and other neurological diseases (n = 14), and healthy controls (n = 7), we systematically analyzed the content of pEV, using different assay systems. In addition, we determined their entry path into brain tissue, employing animal (mice) injection experiments with ex vivo generated EV that were similar to AD-pEV, followed by multi antigen analysis (MAA) of brain tissue (n = 4 per condition). The results were compared with an IHC staining of human brain tissue in a small cohort of AD patients (n = 3) and controls with no neurodegenerative diseases (n = 3). Findings: We show that pEV levels are considerably upregulated in AD patients. Besides numerous inflammatory effectors, AD-pEV contained α-, β- and γ-secretases, able to cleave APP in in target cells. In vitro generated EV with similar characteristics as AD-pEV accumulated in the choroid plexus (CP) of injected animals and reached primarily hippocampal neurons. Corroborating findings were made in human brain samples. An inhibitor of hyaluronic-acid-synthetase (HAS) blocked uploading of proteases and Hyaluronan onto EV in vitro and abolished CP targeting in animal injection experiments. Interpretation: We conclude that protease-containing pEV could be part of a communication axis between the periphery and the brain that could be become detrimental depending on pEV concentration and duration of target cell impact.
CRIS-Team Scopus Importer:2022-03-04
Keywords: Alzheimer's disease; APP; Aβ; BACE; Choroid plexus; Hippocampus; Hyaluronan; Hyaluronic acid synthetase; Plasma extracellular vesicles; Secretases

A matter of perspective: Imputation methods and their effects illustrated with the use of data from the PRIME study - Reich, Kristian; Bachhuber, Teresa; Melzer, Nima; Sieder, Christian; Sticherling, Michael (2018)
EVALuna2:34782

A Mixed Methods Assessment of the Management Role of Physicians - Rechtien, Laura; Gradel, Maximilian; Fischer, Martin R.; Graupe, Tanja; Dimitriadis, Konstantinos (Advances in Medical Education and Practice, 2022)
Introduction: Physicians are increasingly confronted with new requirements in their daily job, which go beyond the mere treatment of patients. The aim of this Mixed-Method-Study is to better understand management as it relates to physicians’ daily work, to clarify the physicians’ perception of their management role and to examine physician’s self-assessed competence in these functions. Methods: We used three different instruments: Semi-structured interviews, a self-assessment survey and direct observations to evaluate managerial activities performed by residents. Both latter were based on instruments established for management research. Results: Interviewed residents were familiar with the term “Management” but had difficulties in defining it. Concerning managerial functions in context of their daily work, we identified three main categories: Self-management, Patient-management and Management of the ward. In this context, physicians named numerous examples of management tasks and for which they felt ill prepared. Eighty-eight residents participated in the self-assessment survey and rated the majority of the management tasks as necessary for the residents’ work. Although physicians estimated the proportion of managerial work to comprise only 40.6%, a much higher number of mere management tasks could be identified through direct observations (n = 12). Activities related to management were more often observed than genuine physician tasks. Discussion: This study illustrates the prominent role of management activities in context of the residents’ work, while at the same time showing that residents do not feel sufficiently educated, prepared nor competent in management tasks.
CRIS-Team Scopus Importer:2022-09-30
Keywords: medical curriculum; medical education; physician’s leadership; physician’s manager role; physician’s managerial skills

A model-based strategy to investigate the role of microRNA regulation in cancer signalling networks - Nikolov, Svetoslav; Vera, Julio; Schmitz, Ulf; Wolkenhauer, Olaf (Theory in Biosciences, 2011)
In this paper we present and discuss a model-based approach to link miRNA translational control with cell signalling networks. MicroRNAs are small regulatory RNAs that are able to regulate the activity and the stability of specific messenger RNA and have been implicated in tumour progression due to their ability to translationally regulate critical oncogenes and tumour suppressors. In our approach, data on protein-protein interactions and miRNA regulation, obtained from bioinformatics databases, are integrated with quantitative experimental data using mathematical modelling. Predictive computational simulations and qualitative (bifurcation) analyses of those mathematical models are employed to further support the investigation of such multifactorial networks in the context of cancer progression. We illustrate our approach with the C-Myc/E2F signalling network, involved in the progression of several tumour subtypes, including colorectal cancer.
Keywords: Systems biology; Translational regulation; Bioinformatics; miRNA; Cancer networks

A Modified Surgical Technique for Kidney Transplantation in Mice - Yin, Decheng; Fu, Jian; Chen, Rongjun; Shushakova, Nelli; Allabauer, Ida; Wei, Xinyi; Schiffer, Mario; Dudziak, Diana; Rong, Song; Hörning, André (Journal of Visualized Experiments, 2022)
Kidney transplantation in mice is a complicated and challenging surgery procedure. There are very few publications demonstrating the key steps of this operation. Therefore, this article introduces the technique and points out the surgical caveats associated with this operation. In addition, important modifications in comparison to the conventional procedure are demonstrated. Firstly, a patch of the abdominal aorta is cut and prepared so that the proximal bifurcations of the renal artery, including the ureteral artery are transected together with the donor kidney en bloc. This reduces the risk of a ureter necrosis and avoids the development of a urinary tract occlusion. Secondly, a new method of the vascular anastomosis is demonstrated that allows the operator to flexibly increase or decrease the size of the anastomosis after renal transplant reperfusion has already been initiated. This avoids the development of vessel strictures and intraabdominal bleeding. Thirdly, a technique that enables the anastomosis of the delicate donor ureter and the recipient bladder that does not cause a trauma is shown. Adopting this protocol can shorten the operation time and reduces the damage to the recipient's bladder, thereby significantly increasing the operation success rate for the recipient mice.
CRIS-Team Scopus Importer:2022-08-19

A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival - Ugurel, S.; Loquai, C.; Kaehler, K.; Hassel, J.; Berking, C.; Zimmer, L.; Haubitz, I.; Satzger, I.; Mueller-Brenne, T.; Mikhaimer, N. C.; Becker, J. C.; Kilian, K. J.; et al. (Annals of Oncology, 2015)
Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib.This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600-mutated stage IV melanoma patients before single-agent therapy with the BRAF inhibitor vemurafenib.A total of 300 patients from 14 centers were included into this study with a median follow-up time of 13.0 months. Median progression-free survival (PFS) was 5.1 months; median overall survival (OS) was 7.6 months. Best response under vemurafenib was associated with serum lactate dehydrogenase (LDH; <= versus >upper normal limit; P = 0.0000001), Eastern Cooperative Oncology Group (ECOG) overall performance status (OPS) (0 versus >= 1; P = 0.00089), and BRAF mutation subtype (V600E versus V600K; P = 0.016). Multivariate analysis identified ECOG OPS >= 1 [hazard ratio (HR) = 1.88; P = 0.00005], immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH (HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012), ECOG OPS >= 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P = 0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014), immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95% confidence interval 0.50-0.98; P = 0.039) were found as predictors.Our data demonstrate that the type of pretreatment strongly influences the outcome of vemurafenib therapy, with a precedent immunotherapy showing a positive, and a prior chemotherapy and kinase inhibitors showing a negative impact on survival, respectively. Moreover, we show that the patient's OPS, serum LDH, age, and gender independently impact vemurafenib therapy outcome. These findings should be taken into account for the future design of therapy sequencing in BRAF V600 mutation-positive melanoma patients.
EVALuna2:19580

Analyses of association of psoriatic arthritis and psoriasis vulgaris with functional NCF1 variants - Löhr, Sabine; Ekici, Arif Bülent; Uebe, Steffen; Büttner, Christian; Köhm, Michaela; Behrens, Frank; Böhm, Beate; Sticherling, Michael; Schett, Georg; Simon, David; Mössner, Rotraut; Nimeh, Ali; et al. (Rheumatology, 2019)
CRIS-Team Scopus Importer:2019-07-02

Analysis of complex behavior of stem cell populations in colonic crypts - Vera González, Julio; et al. (International Journal Bioautomation, 2015)
Mathematical models of the stem cell populations in colonic crypts can contribute to a better understanding of basic mechanisms underlying tissue organization. We here study the complex dynamic behaviour of a time delay model that describes stem cells in the niche of colonic crypts. We analyze the conditions for the various regimes that would lead to oscillations. The work presented here the first description of a chaotic system describing stem cell population dynamics in colonic crypt
Keywords: Time delay model; Nonlinear analysis; Stem cells; Colonic crypts

Analysis of IFN gamma-mediated Transcriptome Changes in Merkel Cell Carcinoma Cell Lines via Nanopore Sequencing - Sauerer, Tatjana; Lischer, Christopher; Berking, Carola; Vera-Gonzalez, J.; Dörrie, Jan (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Analysis of periarticular bone changes in patients with cutaneous psoriasis without associated psoriatic arthritis - Simon, Dominic; Faustini, F.; Englbrecht, Matthias; Kleyer, Arnd; Kocijan, R.; Haschka, Judith; Finzel, Stephanie; Kraus, Sebastian; Hueber, Axel; Sticherling, Michael; Schett, Georg; Rech, J. (Annals of the Rheumatic Diseases, 2016)
To search for structural bone changes in the joints of psoriasis patients without psoriatic arthritis (PsA).55 psoriasis patients without any current or past symptoms of arthritis or enthesitis and 47 healthy controls were examined by high-resolution peripheral quantitative CT scans of the metacarpophalangeal joints. Number, size and exact localisation of erosions and enthesiophytes were recorded by analysing axial scans of the metacarpal heads and phalangeal bases and were confirmed in additional coronal and/or sagittal sections. In addition, we collected demographic and clinical data including subtype, duration and severity of psoriasis.Psoriasis patients showed a larger and significantly increased number of enthesiophytes (total number 306; mean±SD/patient 5.62±3.30) compared with healthy controls (total number 138; mean±SD/patient 3.04±1.81, p<0.001). Enthesiophytes were typically found at the dorsal and palmar sides of the metacarpal heads where functional entheses related to extensor and flexor tendons are localised. Bone erosions were rare and not significantly different between psoriasis patients and healthy controls. If present, erosions were almost exclusively found at the radial side of the second metacarpal head in both psoriasis patients and healthy controls.Psoriasis patients without PsA show substantial signs of enthesiophyte formation compared with healthy controls. These changes represent new bone formation at mechanically exposed sites of the joint and substantiate the concept of the existence of a 'Deep Koebner Phenomenon' at enthesial sites in psoriasis patients.
EVALuna2:13130

Analysis of the German DRG data for livedoid vasculopathy and calciphylaxis - Renner, R.; Dissemond, J.; Goerge, T.; Hoff, N.; Kroeger, K.; Erfurt-Berge, Cornelia (Journal of the European Academy of Dermatology and Venereology, 2017)
BACKGROUND: Livedoid vasculopathy and calciphylaxis are rare skin disorders. Large cohorts of patients have been missing so far for detailed analysis. PATIENTS AND METHODS: Data from diagnosis-related groups (DRGs) of hospitalized cases of livedoid vasculopathy (ntotal = 1357) and calciphylaxis (ntotal = 699) were analysed for the years 2008-2013 concerning sex, age and frequency of diagnosis. To avoid deviations to non-relevant secondary diagnosis and due to changes in ICD-10 indices, we selected the two most recent available years 2013 and 2014 for evaluation of the accompanying diagnoses for both, livedoid vasculopathy (n = 519) and calciphylaxis (n = 324). Those were additionally evaluated as possible comorbidity. RESULTS: The male-female ratio for livedoid vasculopathy was 2.1:1. Patients older than 45 years comprehended 74.7% of all patients with peaks between the ages of 45-50 and 70-75. Livedoid vasculopathy patients suffered from cardiovascular and renal diseases. Coding of coagulation disorders was found rarely in our analysis. For calciphylaxis, we calculated a male-female ratio of 1.7:1. Most of the patients were at an age between 65 and 80 years. Diagnosis at an age under 35 years was rare. In general, most calciphylaxis patients showed end-stage renal disease with need of dialysis and presented with the resulting complications. CONCLUSIONS: Our data analysis shows relevant comorbidity and cofactors of these rare diseases like livedoid vasculopathy and calciphylaxis in Germany by a large number of cases.
EVALuna2:35399

Anaphylaxie im mittleren Lebensalter - Francuzik, W.; Kraft, M.; Scherer Hofmeier, K.; Ruëff, F.; Pföhler, C.; Treudler, R.; Lang, R.; Hawranek, T.; Wagner, Nicola; Worm, M. (Allergologie, 2021)
Age is one of the most important factors influencing the course of anaphylaxis: moreover, the frequency of elicitors of anaphylaxis is age-associated. We analyzed 8,465 anaphylactic episodes in adult patients in three age groups with a focus on patients in the middle-age group (35 – 65 years old). Insect venom was the most frequent trigger in this age group (51.2%) followed by drugs (22.8%) and food (17.3%). Severe reactions were observed in 40.1% of middle-aged patients and occurred more frequently in this age group than in patients below 35 years (27.6%) and less frequently than in patients over 65 years (55.6%). The symptoms and comorbidity profile also changed with age, most significantly regarding the increase in rates of concomitant cardiologic diseases and (severe) cardiovascular symptoms.
CRIS-Team Scopus Importer:2021-05-07
Keywords: Anaphylactic reaction; Anaphylaxis; Drug allergy; Food allergy; Middle age; Severe allergic reaction; Venom allergy

Anaphylaxis in middle-aged patients. - Francuzik, Wojciech; Kraft, Magdalena; Scherer Hofmeier, Kathrin; Ruëff, Franziska; Pfoehler, Claudia; Treudler, Regina; Lang, Roland; Hawranek, Thomas; Wagner, Nicola; Worm, Margitta (Allergologie Select, 2021)
Age is one of the most important factors influencing the course of anaphylaxis: moreover, the frequency of elicitors of anaphylaxis is age-associated. We analyzed 8,465 anaphylactic episodes in adult patients in three age groups with a focus on patients in the middle-age group (35 - 65 years old). Insect venom was the most frequent trigger in this age group (51.2%) followed by drugs (22.8%) and food (17.3%). Severe reactions were observed in 40.1% of middle-aged patients and occurred more frequently in this age group than in patients below 35 years (27.6%) and less frequently than in patients over 65 years (55.6%). The symptoms and comorbidity profile also changed with age, most significantly regarding the increase in rates of concomitant cardiologic diseases and (severe) cardiovascular symptoms.
EVALuna2:471577
Keywords: anaphylaxis; anaphylactic reaction; severe allergic reaction; middle age; venom allergy; food allergy; drug allergy

A network medicine approach for identifying diagnostic and prognostic biomarkers and exploring drug repurposing in human cancer - Zhang, Le; Fan, Shiwei; Vera, Julio; Lai, Xin (Computational and Structural Biotechnology Journal, 2023)
Cancer is a heterogeneous disease mainly driven by abnormal gene perturbations in regulatory networks. Therefore, it is appealing to identify the common and specific perturbed genes from multiple cancer networks. We developed an integrative network medicine approach to identify novel biomarkers and investigate drug repurposing across cancer types. We used a network-based method to prioritize genes in cancer-specific networks reconstructed using human transcriptome and interactome data. The prioritized genes show extensive perturbation and strong regulatory interaction with other highly perturbed genes, suggesting their vital contribution to tumorigenesis and tumor progression, and are therefore regarded as cancer genes. The cancer genes detected show remarkable performances in discriminating tumors from normal tissues and predicting survival times of cancer patients. Finally, we developed a network proximity approach to systematically screen drugs and identified dozens of candidates with repurposable potential in several cancer types. Taken together, we demonstrated the power of the network medicine approach to identify novel biomarkers and repurposable drugs in multiple cancer types. We have also made the data and code freely accessible to ensure reproducibility and reusability of the developed computational workflow.
CRIS-Team Scopus Importer:2023-01-06
Keywords: Drug repositioning; Gene prioritization; Machine learning; Network oncology; Pan-cancer diagnosis and prognosis; Systems medicine

A new method to monitor antigen-specific CD8+ T cells, avoiding additional target cells and the restriction to human leukocyte antigen haplotype. - Prommersberger, S.; Hoefflin, S.; Schuler-Thurner, Beatrice; Schuler, Gerold; Schaft, Niels; Dörrie, Jan (Gene Therapy, 2015)
Therapeutic vaccination of cancer patients with dendritic cells aims at inducing a strong tumor-specific T-cell response. Testing new target antigens for their immunogenicity is crucial to evaluate their suitability for this approach. Here we demonstrate a comfortable and reliable method to detect antigen-specific CD8(+) T-cell responses without the knowledge of the precise T-cell epitope and without the usage of additional target cells. We used the CD8(+) T cells themselves and electroporated them with RNA encoding the respective tumor antigen. The cells expressed, processed and presented the antigen and were capable of stimulating each other in functional readouts. For the model antigen MelanA, the number of interferon-?-secreting cells obtained with this method highly correlated with the numbers obtained by exogenous peptide loading (R(2)=0.8). The method was also applicable for the tumor-associated antigen Wilms' tumor protein 1. This system is quick and easy to perform, independent of the donors human leukocyte antigen type and circumvents the need for additional cells as targets. It can be used in preclinical research to test new antigens for their immunogenic potential and for immunomonitoring in cancer patients.
EVALuna2:19552

A new promising candidate to overcome drug resistant herpes simplex virus infections - Zinser, Elisabeth; Krawczyk, Adalbert; Mühl-Zürbes, Petra; Aufderhorst, Ulrich; Drassner, Christina; Stich, Lena; Zaja, Mirko; Strobl, Stefan; Steinkasserer, Alexander; Heilingloh, Christiane (Antiviral Research, 2018)
Infections with Herpes simplex viruses (HSV) belong to the most common human diseases worldwide, resulting in symptoms ranging from painful, but commonly self-limiting lesions of the orofacial or genital tract to severe infections of the eye or life-threatening generalized infections. Frequent HSV-reactivations at the eye may lead to the development of herpetic stromal keratitis, which is one of the major causes of infectious blindness in developed countries. The vast majority of life-threatening generalized infections occur in immunocompromised individuals, such as transplant recipients or patients suffering from advanced human immunodeficiency virus (HIV) infection with concurrent HSV-reactivation. Over the past decades, Acyclovir (ACV) became the golden standard for the treatment of HSV infections. However, long-term antiviral treatment, as it is required mainly in immunocompromised patients, led to the emergence of resistances towards ACV and other antivirals. Therefore, there is a clear need for the development of new potent antivirals which combine good oral bioavailability and tolerability with low side effects. In the current study we present SC93305 as a novel potent antiviral substance that proved to be highly effective not only against different HSV-1 and HSV-2 strains but also towards ACV- and multi-resistant HSV-1 and HSV-2 isolates. SC93305 shows comparable antiviral activity as reported for ACV and very importantly it does not interfere with the activation of specific immune cells. Here we report that SC93305 does not affect the biological function of dendritic cells (DC), the most potent antigen presenting cells of the immune system to induce antiviral immune responses, nor T cell stimulation or the release of inflammatory cytokines. Thus, SC93305 is a new and promising candidate for the treatment of HSV-1 and HSV-2 infections and in particular also for the inhibition of drug-resistant HSV-1/2 strains.
EVALuna2:34804

A new semisynthetic cardenolide analog 3β-[2-(1-amantadine)-1-on-ethylamine]-digitoxigenin (AMANTADIG) affects G2/M cell cycle arrest and miRNA expression profiles and enhances proapoptotic survivin-2B expression in renal cell carcinoma cell lines - Nolte, Elke; Wach, Sven; Silva, Izabella Thais; Lukat, Sabine; Ekici, Arif Bülent; Munkert, Jennifer; Müller-Uri, Frieder; Kreis, Wolfgang; Simões, Cláudia M. O.; Vera González, Julio; Wullich, Bernd; Taubert, Helge; et al. (Oncotarget, 2017)
EVALuna2:9377
Keywords: Cardiac glycoside analog; Cell cycle; 3β-[2-(1-amantadine)-1-on-ethylamine]-digitoxigenin; Human renal cell carcinoma cells; MiRNA

An Image Based Object Recognition System for Wound Detection and Classification of Diabetic Foot and Venous Leg Ulcers. - Hüsers, Jens; Moelleken, Maurice; Richter, Mats L.; Przysucha, Mareike; Malihi, Leila; Busch, Dorothee; Götz, Nina Alexandra; Heggemann, Jan; Hafer, Guido; Wiemeyer, Stefan; Babitsch, Birgit; Heidemann, Gunther; et al. (Studies in health technology and informatics, 2022)
Venous leg ulcers and diabetic foot ulcers are the most common chronic wounds. Their prevalence has been increasing significantly over the last years, consuming scarce care resources. This study aimed to explore the performance of detection and classification algorithms for these types of wounds in images. To this end, algorithms of the YoloV5 family of pre-trained models were applied to 885 images containing at least one of the two wound types. The YoloV5m6 model provided the highest precision (0.942) and a high recall value (0.837). Its mAP_0.5:0.95 was 0.642. While the latter value is comparable to the ones reported in the literature, precision and recall were considerably higher. In conclusion, our results on good wound detection and classification may reveal a path towards (semi-) automated entry of wound information in patient records. To strengthen the trust of clinicians, we are currently incorporating a dashboard where clinicians can check the validity of the predictions against their expertise.
EVALuna2:504966

An integrative network-driven pipeline for systematic identification of lncRNA-associated regulatory network motifs in metastatic melanoma - Singh, Nivedita; Eberhardt, Martin; Wolkenhauer, Olaf; Vera, Julio; Gupta, Shailendra K. (BMC Bioinformatics, 2020)
BACKGROUND: Melanoma phenotype and the dynamics underlying its progression are determined by a complex interplay between different types of regulatory molecules. In particular, transcription factors (TFs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) interact in layers that coalesce into large molecular interaction networks. Our goal here is to study molecules associated with the cross-talk between various network layers, and their impact on tumor progression. RESULTS: To elucidate their contribution to disease, we developed an integrative computational pipeline to construct and analyze a melanoma network focusing on lncRNAs, their miRNA and protein targets, miRNA target genes, and TFs regulating miRNAs. In the network, we identified three-node regulatory loops each composed of lncRNA, miRNA, and TF. To prioritize these motifs for their role in melanoma progression, we integrated patient-derived RNAseq dataset from TCGA (SKCM) melanoma cohort, using a weighted multi-objective function. We investigated the expression profile of the top-ranked motifs and used them to classify patients into metastatic and non-metastatic phenotypes. CONCLUSIONS: The results of this study showed that network motif UCA1/AKT1/hsa-miR-125b-1 has the highest prediction accuracy (ACC = 0.88) for discriminating metastatic and non-metastatic melanoma phenotypes. The observation is also confirmed by the progression-free survival analysis where the patient group characterized by the metastatic-type expression profile of the motif suffers a significant reduction in survival. The finding suggests a prognostic value of network motifs for the classification and treatment of melanoma.
CRIS-Team Scopus Importer:2020-08-07
Keywords: Data integration; LncRNA; Melanoma; MiRNA; Network approach; RNA motif; Systems biology; Transcription factor

An Interactive Macrophage Signal Transduction Map Facilitates Comparative Analyses of High-Throughput Data - Wentker, Pia; Eberhardt, Martin; Dreyer, Florian; Bertrams, Wilhelm; Cantone, Martina; Griss, Kathrin; Schmeck, Bernd; Vera, Julio (Journal of Immunology, 2017)
Macrophages (Mϕs) are key players in the coordination of the lifesaving or detrimental immune response against infections. The mechanistic understanding of the functional modulation of Mϕs by pathogens and pharmaceutical interventions at the signal transduction level is still far from complete. The complexity of pathways and their cross-talk benefits from holistic computational approaches. In the present study, we reconstructed a comprehensive, validated, and annotated map of signal transduction pathways in inflammatory Mϕs based on the current literature. In a second step, we selectively expanded this curated map with database knowledge. We provide both versions to the scientific community via a Web platform that is designed to facilitate exploration and analysis of high-throughput data. The platform comes preloaded with logarithmic fold changes from 44 data sets on Mϕ stimulation. We exploited three of these data sets-human primary Mϕs infected with the common lung pathogens Streptococcus pneumoniae, Legionella pneumophila, or Mycobacterium tuberculosis-in a case study to show how our map can be customized with expression data to pinpoint regulated subnetworks and druggable molecules. From the three infection scenarios, we extracted a regulatory core of 41 factors, including TNF, CCL5, CXCL10, IL-18, and IL-12 p40, and identified 140 drugs targeting 16 of them. Our approach promotes a comprehensive systems biology strategy for the exploitation of high-throughput data in the context of Mϕ signal transduction. In conclusion, we provide a set of tools to help scientists unravel details of Mϕ signaling. The interactive version of our Mϕ signal transduction map is accessible online at https://vcells.net/macrophage.
EVALuna2:35413

Annual Health Care Utilization and Costs for Treatment of Cutaneous and Anogenital Warts Among a Commercially Insured Population in the US, 2017-2019 Reply - Heppt, Markus; Steeb, Theresa; Berking, Carola (JAMA Dermatology, 2022)
CRIS-Team WoS Importer:2022-05-13

An open, multicentre, randomized clinical study in patients with bullous pemphigoid comparing methylprednisolone and azathioprine with methylprednisolone and dapsone - Sticherling, Michael; Franke, A.; Aberer, E.; Glaeser, R.; Hertl, Michael; Pfeiffer, C.; Rzany, B.; Schneider, S.; Shimanovich, I.; Werfel, T.; Wilczek, A.; Zillikens, Detlef; et al. (British Journal of Dermatology, 2017)
BACKGROUND: Current treatment of bullous pemphigoid (BP) is based on the long-term use of topical and/or systemic corticosteroids, which are associated with a high rate of adverse events and increased mortality. OBJECTIVES: To study the corticosteroid-sparing potential of azathioprine and dapsone. METHODS: This was a prospective, multicentre, randomized, nonblinded clinical trial that compared the efficacy and safety of two parallel groups of patients with BP treated with oral methylprednisolone 0·5 mg kg-1 per day in combination with either azathioprine 1·5-2·5 mg kg-1 per day or dapsone 1·5 mg kg-1 per day. Nine German and Austrian departments of dermatology included 54 patients based on clinical lesions, positive direct immunofluorescence (IF) microscopy and detection of serum autoantibodies by indirect IF microscopy, immunoblotting or enzyme-linked immunosorbent assay. The primary end point was the time until complete tapering of methylprednisolone, and the most important secondary end point was the cumulative corticosteroid dose. RESULTS: In eight patients (five azathioprine, three dapsone), methylprednisolone could be discontinued after a median time of 251 days in the azathioprine group and 81 days in the dapsone group. The median cumulative corticosteroid dose was 2·65 g for azathioprine compared with 1·92 g for dapsone (P = 0·06). The median numbers of days when corticosteroids were applied were 148 and 51, respectively (P = 0·24). No significant difference in the number of adverse events was seen between the treatment arms. Four patients (8%) died within the observation period of 12 months. CONCLUSIONS: Due to the lower than intended number of patients, the results of the primary and secondary end points were not or only barely significant. Dapsone appeared to have a moderately higher corticosteroid-sparing potential than azathioprine. The combination regimen of either drug with oral methylprednisolone is associated with a relatively low 1-year mortality in this vulnerable patient population.
EVALuna2:34338

Another step on the road towards standardized outcome reporting for congenital melanocytic naevi: one more to go! - Heppt, Markus; Steeb, Theresa; Berking, Carola (British Journal of Dermatology, 2021)
CRIS-Team Scopus Importer:2021-09-10

A novel antiproliferative, pro-apoptotic Approach for the Treatment of actinic Keratoses: Tirbanibulin (KX2-391) - Heppt, Markus; Ocker, W. G.; Melzer, A. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Antibody-based immunotherapy of aciclovir resistant ocular herpes simplex virus infections - Bauer, Dirk; Keller, Jessica; Alt, Mira; Schubert, Axel; Aufderhorst, Ulrich Wilhelm; Palapys, Vivien; Kasper, Maren; Heilingloh, Christiane; Dittmer, Ulf; Laffer, Bjoern; Eis-Huebinger, Anna Maria; Verjans, Georges M.; et al. (Virology, 2017)
The increasing incidence of aciclovir- (ACV) resistant strains in patients with ocular herpes simplex virus (HSV) infections is a major health problem in industrialized countries. In the present study, the humanized monoclonal antibody (mAb) hu2c targeting the HSV-1/2 glycoprotein B was examined for its efficacy towards ACV-resistant infections of the eye in the mouse model of acute retinal necrosis (ARN). BALB/c mice were infected by microinjection of an ACV-resistant clinical isolate into the anterior eye chamber to induce ARN and systemically treated with mAb hu2c at 24h prior (pre-exposure prophylaxis) or at 24, 40, and 56h after infection (post-exposure immunotherapy). Mock treated controls and ACV-treated mice showed pronounced retinal damage. Mice treated with mAb hu2c were almost completely protected from developing ARN. In conclusion, mAb hu2c may become a reliable therapeutic option for drug/ACV-resistant ocular HSV infections in humans in order to prevent blindness.
EVALuna2:36335

Antigen delivery to CD11c+CD8- dendritic cells induces protective immune responses against experimental melanoma in mice in vivo - Neubert, Kirsten; Lehmann, Christian; Heger, Lukas; Baranska, Anna; Staedtler, Anna Maria; Buchholz, Veit R.; Yamazaki, Sayuri; Heidkamp, Gordon Frederik; Eissing, Nathalie; Zebroski, Henry; Nussenzweig, Michel C.; Nimmerjahn, Falk; et al. (Journal of Immunology, 2014)
Dendritic cells (DCs) are central modulators of immune responses and, therefore, interesting target cells for the induction of antitumor immune responses. Ag delivery to select DC subpopulations via targeting Abs to DC inhibitory receptor 2 (DCIR2, clone 33D1) or to DEC205 was shown to direct Ags specifically to CD11c(+)CD8(-) or CD11c(+)CD8(+) DCs, respectively, in vivo. In contrast to the increasing knowledge about the induction of immune responses by efficiently cross-presenting CD11c(+)CD8(+) DCs, little is known about the functional role of Ag-presenting CD11c(+)CD8(-) DCs with regard to the initiation of protective immune responses. In this study, we demonstrate that Ag targeting to the CD11c(+)CD8(-) DC subpopulation in the presence of stimulating anti-CD40 Ab and TLR3 ligand polyinosinic-polycytidylic acid induces protective responses against rapidly growing tumor cells in naive animals under preventive and therapeutic treatment regimens in vivo. Of note, this immunization protocol induced a mixed Th1/Th2-driven immune response, irrespective of which DC subpopulation initially presented the Ag. Our results provide important information about the role of CD11c(+)CD8(-) DCs, which have been considered to be less efficient at cross-presenting Ags, in the induction of protective antitumor immune responses.
EVALuna2:19490

Antigen targeting of Fc receptors induces strong and functional relevant T cell responses in vivo independent of ITAM signaling but dependent on dendritic cell subsets - Lehmann, Christian; Baranska, A.; Heidkamp, Gordon Frederik; Amon, Lukas; Seeling, Michaela; Soulat, D.; Krug, A. B.; Ravetch, J. V.; Leusen, J. H. W.; Nimmerjahn, Falk; Dudziak, Diana (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Antigen targeting of Fc receptors induces strong T cell responses in vivo independent of ITAM signaling but dependent on dendritic cell subset - Lehmann, Christian; Baranska, A.; Heidkamp, Gordon Frederik; Seeling, Michaela; Soulat, D.; Krug, A.; Ravetch, J.; Leusen, J.; Nimmerjahn, Falk; Dudziak, Diana (2018)
EVALuna2:34795

Antigen targeting of Fc-receptors induces strong T cell responses in vivo independent of ITAM signaling but dependent on dendritic cell subset - Lehmann, C. H. K.; Baranska, A.; Heidkamp, G. F.; Heger, L.; Neubert, K.; Lühr, Jennifer; Hoffmann, Alana; Reimer, Katharina; Brückner, Christin; Beck, S.; Seeling, M.; Kießling, Melissa; et al. (2017)
EVALuna2:33396

Antigen targeting of Fc-receptors induces strong T cell responses in vivo independent of ITAM signaling but dependent on dendritic cell subsets - Lehmann, Christian; Baranska, A.; Heidkamp, Gordon Frederik; Heger, Lukas; Neubert, K.; Lühr, Jennifer; Hoffmann, Alana; Reimer, Katharina; Brückner, Christin; Beck, S.; Seeling, Michaela; Kießling, Melissa; et al. (2017)
EVALuna2:33397

Antigen targeting of Fc-receptors induces strong T cell responses in vivo independent of ITAM signalling - Lehmann, Christian; Baranska, Anna; Heidkamp, Gordon Frederik; Kiessling, M.; Soulat, Didier; Krug, A.; Ravetch, J. V.; Leusen, J. H.; Nimmerjahn, Falk; Dudziak, Diana (JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2016)
Created from Fastlane, WoS look-up

Antigen targeting of Fc-receptors induces strong T cell responses in vivo independent of ITAM signalling - Lehmann, Christian; Baranska, Anna; Heidkamp, Gordon Frederik; Kiessling, M.; Soulat, D.; Krug, A.; Ravetch, J. V.; Leusen, J. H.; Nimmerjahn, Falk; Dudziak, Diana (Journal of Investigative Dermatology, 2016)

Anti-PD-1 Therapy in SUFU mutant Patients with Gorlin-Goltz Syndrome - Moreira, Alvaro; Kirchberger, M. C.; Toussaint, Frédéric; Erdmann, M.; Schuler, Gerold; Heinzerling, Lucie (2018)
EVALuna2:34776

Anti-TNF-refractory colitis after checkpoint inhibitor therapy: Possible role of CMV-mediated immunopathogenesis - Lankes, Katharina; Hundorfean, Gheorghe; Harrer, Thomas; Pommer, Ansgar J.; Agaimy, Abbas; Angelovska, Irena; Tajmir-Riahi, Azadeh; Göhl, Jonas; Schuler, Gerold; Neurath, Markus; Hohenberger, Werner; Heinzerling, Lucie (OncoImmunology, 2016)
Immune-related adverse events (irAEs) induced by checkpoint inhibitors are well known. Since fatal outcomes have been reported early detection and adequate management are crucial. In particular, colitis is frequently observed and can result in intestinal perforation. This is the first report of an autoimmune colitis that was treated according to algorithms but became resistant due to a CMV reactivation. The 32-y-old male patient with metastatic melanoma treated within an anti-PD-1/ipilimumab combination study developed severe immune-mediated colitis (CTCAE grade 3) with up to 18 watery stools per day starting 2 weeks after treatment initiation. After improving upon therapy with immunosuppressive treatment (high dose steroids and infliximab) combined with parenteral nutrition diarrhea again exacerbated. Additionally, the patient had asymptomatic grade 3 CTCAE amylase and lipase elevation. Colitis was monitored by weekly endoscopies and colon biopsies were analyzed histologically with CMV staining, multi-epitope ligand cartography (MELC) and qRT-PCR for inflammatory genes. In the course, CMV reactivation was detected in the colon and treated with antiviral medication in parallel to a reduction of corticosteroids. Subsequently, symptoms improved. The patient showed a complete response for 2 y now including regression of bone metastases. CMV reactivation under checkpoint inhibitor therapy in combination with immunosuppressive treatment for autoimmune side effects has to be considered in these patients and if present treated. Potentially, CMV reactivation is underdiagnosed. Treatment algorithms should include CMV diagnostics.
EVALuna2:2063

A One-Armed Phase I Dose Escalation Trial Design: Personalized Vaccination with IKKβ-Matured, RNA-Loaded Dendritic Cells for Metastatic Uveal Melanoma - Koch, Elias; Schaft, Niels; Kummer, Mirko; Berking, Carola; Schuler, Gerold; Hasumi, Kenichiro; Dörrie, Jan; Schuler-Thurner, Beatrice (Frontiers in Immunology, 2022)
Uveal melanoma (UM) is an orphan disease with a mortality of 80% within one year upon the development of metastatic disease. UM does hardly respond to chemotherapy and kinase inhibitors and is largely resistant to checkpoint inhibition. Hence, further therapy approaches are urgently needed. To improve clinical outcome, we designed a trial employing the 3rd generation personalized IKKβ-matured RNA-transfected dendritic cell (DC) vaccine which primes T cells and in addition activates NK cells. This ongoing phase I trial [NCT04335890 (www.clinicaltrials.gov), Eudract: 2018-004390-28 (www.clinicaltrialsregister.eu)] investigates patients with treatment-naive metastatic UM. Monocytes are isolated by leukapheresis, differentiated to immature DCs, matured with a cytokine cocktail, and activated via the NF-κB pathway by electroporation with RNA encoding a constitutively active mutant of IKKβ. Three types of antigen-RNA are co-electroporated: i) amplified mRNA of the tumor representing the whole transcriptome, ii) RNA encoding driver mutations identified by exome sequencing, and iii) overexpressed non-mutated tumor antigens detected by transcriptome sequencing. This highly personalized DC vaccine is applied by 9 intravenous infusions in a staggered schedule over one year. Parallel to the vaccination, standard therapy, usually an immune checkpoint blockade (ICB) as mono (anti-PD-1) or combined (anti-CTLA4 and anti-PD-1) regimen is initiated. The coordinated vaccine-induced immune response encompassing tumor-specific T cells and innate NK cells should synergize with ICB, perhaps resulting in measurable clinical responses in this resistant tumor entity. Primary outcome measures of this trial are safety, tolerability and toxicity; secondary outcome measures comprise overall survival and induction of antigen-specific T cells.
CRIS-Team Scopus Importer:2022-03-04
Keywords: IKKβ-matured dendritic cells; Immune checkpoint blockade; metastatic uveal melanoma; personalized vaccine; tumor antigen vaccine; tumor antigens

A phase I dose escalation and expansion study of intratumorally administered CV8102 as a single-agent or in combination with anti-PD-1 antibodies in patients with advanced solid tumors - Eigentler, Thomas; Krauss, Juergen; Schreiber, Jutta; Weishaupt, Carsten; Terheyden, Patrick; Heinzerling, Lucie; Mohr, Peter; Weide, Benjamin; Ochsenreither, Sebastian; Becker, Juergen; Bauernfeind, Franz-Georg; Brossart, Peter; et al. (JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2019)
CRIS-Team WoS Importer:2019-11-29

A phase I dose-escalation and expansion trial of intratumorally administered CV8102, alone and in combination with anti-PD-1 in patients with advanced solid tumours - Krauss, J.; Eigentler, T.; Schreiber, J.; Weishaupt, C.; Terheyden, P.; Heinzerling, Lucie; Mohr, P.; Weide, B.; Ochsenreither, S.; Gutzmer, R.; Becker, J. C.; Kiecker, F.; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

A review of serious adverse effects under treatment with checkpoint inhibitors - Heinzerling, Lucie; Goldinger, Simone M. (Current Opinion in Oncology, 2017)
PURPOSE OF REVIEW: The aim of this article is to raise awareness of physicians for the serious side-effects of immune-checkpoint blocking antibodies. As checkpoint inhibitors can induce severe side-effects and are increasingly being used also in subspecialties besides dermatology and oncology, with less experience with these drugs available, knowledge has to be spread. Early recognition and adequate management is essential. RECENT FINDINGS: Recent reports on side-effects document cases of serious side-effects involving all organ systems. These include formerly little referenced and life-threatening side-effects such as cardiotoxicity and neurotoxicity. Furthermore, important additional findings are the inclusion of CMV reactivation in the differential diagnosis or the side-effect profile in special patient populations, that is, in transplant patients, patients with autoimmune disease or previous toxicity to ipilimumab. SUMMARY: Checkpoint inhibitor treatment induces a wide range of serious side-effects. However, with prompt diagnosis and adequate treatment these can mostly be safely managed. Documentation and reporting of serious side-effects remains important to share knowledge and thus ensure optimal patient care.
EVALuna2:34336

Are YouTube videos on cutaneous squamous cell carcinoma a useful and reliable source for patients? - Reinhardt, Lydia; Steeb, Theresa; Harlaß, Matthias; Brütting, Julia; Meier, Friedegund; Berking, Carola (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
EVALuna2:510787

Arming T cells with a gp100-specific TCR and a CSPG4-specific CAR using combined DNA-and RNA-based receptor transfer - Simon, Bianca; Harrer, Dennis C.; Schuler-Thurner, Beatrice; Schuler, Gerold; Uslu, Ugur (Cancers, 2019)
Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two receptors into the same T cell to generate T cells expressing two additional receptors (TETARs). We generated these TETARs by lentiviral transduction of a gp100-specific T cell receptor (TCR) and subsequent electroporation of mRNA encoding a second-generation CSPG4-specific chimeric antigen receptor (CAR). Following pilot experiments to optimize the combined DNA-and RNA-based receptor transfer, the functionality of TETARs was compared to T cells either transfected with the TCR only or the CAR only. After transfection, TETARs clearly expressed both introduced receptors on their cell surface. When stimulated with tumor cells expressing either one of the antigens or both, TETARs were able to secrete cytokines and showed cytotoxicity. The confirmation that two antigen-specific receptors can be functionally combined using two different methods to introduce each receptor into the same T cell opens new possibilities and opportunities in cancer immunotherapy. For further evaluation, the use of these TETARs in appropriate animal models will be the next step towards a potential clinical use in cancer patients.
CRIS-Team Scopus Importer:2019-06-21
Keywords: Antigen loss; Cancer; Chimeric antigen receptor; Electroporation; Immune escape; Immunotherapy; Lentiviral transduction; Lentivirus; Melanoma

Artificial Intelligence and Its Effect on Dermatologists' Accuracy in Dermoscopic Melanoma Image Classification: Web-Based Survey Study - Maron, Roman C.; Utikal, Jochen S.; Hekler, Achim; Hauschild, Axel; Sattler, Elke; Sondermann, Wiebke; Haferkamp, Sebastian; Schilling, Bastian; Heppt, Markus; Jansen, Philipp; Reinholz, Markus; Franklin, Cindy; et al. (Journal of Medical Internet Research, 2020)
BACKGROUND: Early detection of melanoma can be lifesaving but this remains a challenge. Recent diagnostic studies have revealed the superiority of artificial intelligence (AI) in classifying dermoscopic images of melanoma and nevi, concluding that these algorithms should assist a dermatologist's diagnoses. OBJECTIVE: The aim of this study was to investigate whether AI support improves the accuracy and overall diagnostic performance of dermatologists in the dichotomous image-based discrimination between melanoma and nevus. METHODS: Twelve board-certified dermatologists were presented disjoint sets of 100 unique dermoscopic images of melanomas and nevi (total of 1200 unique images), and they had to classify the images based on personal experience alone (part I) and with the support of a trained convolutional neural network (CNN, part II). Additionally, dermatologists were asked to rate their confidence in their final decision for each image. RESULTS: While the mean specificity of the dermatologists based on personal experience alone remained almost unchanged (70.6% vs 72.4%; P=.54) with AI support, the mean sensitivity and mean accuracy increased significantly (59.4% vs 74.6%; P=.003 and 65.0% vs 73.6%; P=.002, respectively) with AI support. Out of the 10% (10/94; 95% CI 8.4%-11.8%) of cases where dermatologists were correct and AI was incorrect, dermatologists on average changed to the incorrect answer for 39% (4/10; 95% CI 23.2%-55.6%) of cases. When dermatologists were incorrect and AI was correct (25/94, 27%; 95% CI 24.0%-30.1%), dermatologists changed their answers to the correct answer for 46% (11/25; 95% CI 33.1%-58.4%) of cases. Additionally, the dermatologists' average confidence in their decisions increased when the CNN confirmed their decision and decreased when the CNN disagreed, even when the dermatologists were correct. Reported values are based on the mean of all participants. Whenever absolute values are shown, the denominator and numerator are approximations as every dermatologist ended up rating a varying number of images due to a quality control step. CONCLUSIONS: The findings of our study show that AI support can improve the overall accuracy of the dermatologists in the dichotomous image-based discrimination between melanoma and nevus. This supports the argument for AI-based tools to aid clinicians in skin lesion classification and provides a rationale for studies of such classifiers in real-life settings, wherein clinicians can integrate additional information such as patient age and medical history into their decisions.
CRIS-Team Scopus Importer:2020-09-25
Keywords: artificial intelligence; deep learning; dermatology; diagnosis; machine learning; melanoma; neural network; nevi; skin neoplasm

Artificial intelligence in cancer target identification and drug discovery - You, Yujie; Lai, Xin; Pan, Yi; Zheng, Huiru; Vera, Julio; Liu, Suran; Deng, Senyi; Zhang, Le (Signal Transduction and Targeted Therapy, 2022)
Artificial intelligence is an advanced method to identify novel anticancer targets and discover novel drugs from biology networks because the networks can effectively preserve and quantify the interaction between components of cell systems underlying human diseases such as cancer. Here, we review and discuss how to employ artificial intelligence approaches to identify novel anticancer targets and discover drugs. First, we describe the scope of artificial intelligence biology analysis for novel anticancer target investigations. Second, we review and discuss the basic principles and theory of commonly used network-based and machine learning-based artificial intelligence algorithms. Finally, we showcase the applications of artificial intelligence approaches in cancer target identification and drug discovery. Taken together, the artificial intelligence models have provided us with a quantitative framework to study the relationship between network characteristics and cancer, thereby leading to the identification of potential anticancer targets and the discovery of novel drug candidates.
CRIS-Team WoS Importer:2022-05-20

A single-center, retrospective Analysis for the Detection of Distant Metastases in Patients with regionally metastatic Melanoma in the Era of effective adjuvant Therapies - Toussaint, Frédéric; Kramer, Robert; Bender-Säbelkampf, Sophia; Hornung-Eichler, Annkathrin; Karimi, Bita; Heppt, Markus; Bosch-Voskens, Caroline; Berking, Carola; Erdmann, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

ASSESSING SIMILARITY OF STUDIES FOR NETWORK META-ANALYSIS: THE USE OF FEASIBILITY ASSESSMENT AND SENSITIVITY ANALYSES TO ESTIMATE THE EFFICACY OF TIRBANIBULIN, A NEW DRUG FOR ACTINIC KERATOSIS - Heppt, Markus; Dykukha,; Chapman-Rounds, M.; Graziadio, S.; Edwards, M. (VALUE IN HEALTH, 2022)
CRIS-Team WoS Importer:2023-03-10

Assessment of sorafenib induced changes in tumor perfusion of uveal melanoma metastases with dynamic contrast-enhanced ultrasound (DCE-US) - Wildner, Dane; Heinzerling, Lucie; Scheulen, Max E.; Kämpgen, Eckhart; Schuler, Gerold; Strobel, Deike; Janka, Rolf Matthias; Neurath, Markus; Sturm, Jörg; Knieling, Ferdinand (Journal of Cancer Research and Clinical Oncology, 2021)
Purpose Dynamic contrast-enhanced ultrasound (DCE-US) was used to monitor early response to sorafenib therapy in patients with liver metastases from uveal melanoma. Methods In total, 21 patients with liver metastases were recruited within a prospective trial and underwent daily sorafenib therapy. DCE-US of a target lesion was performed before initiation of treatment, on day 15 and 56. Two independent blinded investigators performed software analysis for DCE-US parameters and inter-observer-correlation was calculated. Response to treatment was evaluated on day 56. DCE-US parameters were correlated with clinical response and RECIST1.1 criteria. Results Inter-observer-correlation (r) of DCE-US parameters [time-to-peak (TTP), mean-transit-time (MTT), peak intensity (PI), regional blood volume (RBV), regional blood flow (RBF)] at baseline, day 15, and day 56 was highly significant (r-range 0.73-0.97, all p < 0.001). Out of 17 evaluable patients, 12 patients survived day 56 (clinical responders, cRE), whereas, five patients died before day 56 and were classified as non-responders (cNR). TTP values significantly increased in the cRE group 15 days after initiation of treatment for investigator 1 (p = 0.034) and at day 56 for both investigators (p = 0.028/0.028). MTT had increased significantly in the cRE group on day 56 (p = 0.037/0.022). In the cNR group changes for TTP and MTT remained insignificant. Thus, increase of the DCE-US parameters TTP and MTT are associated with response to treatment and prognosis. Conclusion An increase of TTP and MTT at frequent intervals could serve as a surrogate marker for early response evaluation to anti-angiogenic treatment of metastatic uveal melanoma.
CRIS-Team WoS Importer:2021-06-04

Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals - Basmanav, F. Buket; Cesarato, Nicole; Kumar, Sheetal; Borisov, Oleg; Kokordelis, Pavlos; Ralser, Damian J.; Wehner, Maria; Axt, Daisy; Xiong, Xing; Thiele, Holger; Dolgin, Vadim; Gossmann, Yasmina; et al. (JAMA Dermatology, 2022)
Importance Uncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed flat. Only about 100 known cases have been reported so far.
CRIS-Team WoS Importer:2022-09-16

Assessment of the Quality, Understandability, and Reliability of YouTube Videos as a Source of Information on Basal Cell Carcinoma:Web-Based Analysis - Steeb, Theresa; Reinhardt, Lydia; Harlaß, Matthias; Heppt, Markus; Meier, Friedegund; Berking, Carola (JMIR Cancer, 2022)
Background: Patients with skin cancer increasingly watch online videos to acquire disease-related information. Until now, no scientific evaluation of the quality of videos available for German-speaking patients with basal cell carcinoma (BCC) has been performed. Objective: In this study, we aimed to identify and evaluate videos about BCC provided on YouTube. Methods: A video search on YouTube was conducted in July 2020, using German BCC-related keywords (eg, "Basalzellkarzinom," "Basaliom," "weißer hautkrebs," and "heller hautkrebs"). The first three pages (ie, 60 videos) were searched by two independent researchers for each keyword. Two authors evaluated videos that met the predefined eligibility criteria. The quality of the information of the videos was evaluated using the DISCERN tool and the Global Quality Scale (GQS). The understandability and actionability were assessed with the Patient Education Materials Assessment Tool for Audiovisual Materials (PEMAT-A/V). The reliability was assessed with the JAMA (Journal of the American Medical Association) criteria score. Subgroup differences were identified using the Kruskal-Wallis test. Results: A total of 41 videos were included in the evaluation. The mean assessment scores were as follows: DISCERN, 3.3 (SD 0.80); GQS, 3.8 (SD 1.1); JAMA, 27.74% (SD 22.1%); understandability, 70.8% (SD 13.3%); and actionability, 45.9% (SD 43.7%). These values indicated that the videos were of medium to good quality and had good understandability, low actionability, and poor reliability. The quality of videos provided by health professionals was significantly higher than that of videos provided by laypersons. Conclusions: Optimization of health-related videos about BCC is desirable. In particular, adaptation to reliability criteria is necessary to support patient education and increase transparency.
CRIS-Team Scopus Importer:2022-03-25
Keywords: basal cell carcinoma; information; internet; patient education; quality; reliability; shared decision-making; videos; YouTube

Assessment of the Severity of Atopic Dermatitis by Physicians and Patients depending on Gender: Results from the German Atopic Dermatitis Registry TREATgermany - Heinrich, L.; Haufe, E.; Abraham, S.; Heratizadeh, A.; Harder,; Kleinheinz, A.; Wollenberg, A.; Weisshaar, E.; Wiemers, F.; Ertner, K.; Schaekel, K.; Augustin, M.; et al. (GESUNDHEITSWESEN, 2021)
CRIS-Team WoS Importer:2022-05-20

Assessment of Two Commonly used Dermal Regeneration Templates in a Swine Model without Skin Grafting - Eisler, Wiebke; Baur, Jan-Ole; Held, Manuel; Rahmanian-Schwarz, Afshin; Daigeler, Adrien; Denzinger, Markus (Applied Sciences, 2022)
In the medical care of partial and full-thickness wounds, autologous skin grafting is still the gold standard of dermal replacement. In contrast to spontaneous reepithelializing of superficial wounds, deep dermal wounds often lead to disturbing scarring, with cosmetically or functionally unsatisfactory results. However, modern wound dressings offer promising approaches to surface reconstruction. Against the background of our future aim to develop an innovative skin substitute, we investigated the behavior of two established dermal substitutes, a crosslinked and a non-crosslinked collagen biomatrix. The products were applied topically on a total of 18 full-thickness skin defects paravertebrally on the back of female Göttingen Minipigs—six control wounds remained untreated. The evaluation was carried out planimetrically (wound closure time) and histologically (neoepidermal cell number and epidermis thickness). Both treatment groups demonstrated significantly faster reepithelialization than the controls. The histologic examination verified the highest epidermal thickness in the crosslinked biomatrix-treated wounds, whereas the non-crosslinked biomatrix-treated wounds showed a higher cell density. Our data presented a positive influence on epidermal regeneration with the chosen dermis substitutes even without additional skin transplantation and, thus, without additional donor site morbidity. Therefore, it can be stated that the single biomatrix application might be used in a clinical routine with small wounds, which needs to be investigated further in a clinical setting to determine the size and depths of a suitable wound bed. Nevertheless, currently available products cannot solely achieve wound healing that is equal to or superior to autologous tissue. Thus, the overarching aim still is the development of an innovative skin substitute to manage surface reconstruction without additional skin grafting.
CRIS-Team Scopus Importer:2022-04-15
Keywords: animal model; dermal regeneration; Integra; Matriderm; skin substitute; wound healing

Association analyses of functional NCF1 variants in psoriatic arthritis and psoriasis vulgaris - Hüffmeier, Ulrike; Löhr, Sabine; Ekici, Arif Bülent; Uebe, S.; Koehm, M.; Behrens, F.; Boehm, B.; Sticherling, Michael; Schett, Georg; Moessner, R.; Nimeh, A.; Assmann, G.; et al. (EUROPEAN JOURNAL OF HUMAN GENETICS, 2019)
CRIS-Team WoS Importer:2019-10-25

Association of an initial Exanthem with Vemurafenib and Cobimetinib for a better Therapeutic Success in metastatic Melanoma Patients - Kaehler, K.; Bohne, A. S.; Gutzmer, R.; Satzger, I.; Meier, F.; Reinhardt, L.; Zimmer, L.; Schadendorf, D.; Heppt, M.; Gesierich, A.; Thoms, K. M.; Utikal, J.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Association of Fabry Disease and Psoriasis - therapeutically significant? - Sollfrank, Lukas; Sticherling, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-04-16

Association of Structural Entheseal Lesions With an Increased Risk of Progression From Psoriasis to Psoriatic Arthritis - Simon, David; Tascilar, Koray; Kleyer, Arnd; Bayat, Sara; Kampylafka, Eleni; Sokolova, Maria; Zekovic, Ana; Hueber, Axel; Rech, Jürgen; Schuster, Louis; Engel, Klaus; Sticherling, Michael; et al. (Arthritis and Rheumatology, 2021)
Objective. To test whether the presence of structural entheseal lesions in psoriasis patients influences the risk of progression to psoriatic arthritis (PsA).
CRIS-Team WoS Importer:2022-01-07

A Systematic Review and Meta-Analysis of Interventions for Actinic Keratosis from Post-Marketing Surveillance Trials - Steeb, Theresa; Wessely, Anja; Harla, Matthias; Heppt, Franz; Koch, Elias; Leiter, Ulrike; Garbe, Claus; Schöffski, Oliver; Berking, Carola; Heppt, Markus (Journal of Clinical Medicine, 2020)
Multiple interventions are available for the treatment of actinic keratosis (AK) showing high efficacy in pivotal trials. However, data from post-marketing surveillance studies have received little attention until now. Here, we systematically investigate interventions for AK from post-marketing surveillance trials as a proxy for real-world efficacy and tolerability. A systematic literature search was conducted in Medline, Embase, and CENTRAL. Pertinent trial registers were hand-searched until 25 March 2020. Results were pooled using a random-effects model to calculate pooled proportions and relative risks (RR) or were described qualitatively. Eleven records with a total sample size ofn= 4109 were included. Three of the studies had an active-controlled design, while seven were single-armed. Participant complete clearance ranged from 23.1% for diclofenac sodium 3% gel to 88.9% for ingenol mebutate 0.05% gel. The lesion-specific clearance rate for photodynamic therapy (PDT) was 74% (95% confidence interval (CI) 56-87%). The recurrence rate was significantly higher for diclofenac sodium 3% in comparison to imiquimod 5% cream (RR 1.10, 95% CI 1.02-1.1.8) and ranged from 10.6% for ingenol mebutate 0.015% gel to 23.5% for PDT. Few patients discontinued the trials due to adverse events. The results from the majority of the post-marketing surveillance studies deviated from those of pivotal trials.
CRIS-Team WoS Importer:2020-08-21

A systems biology approach to characterize the function of miRNAs in dendritic cell-mediated immunogenicity and therapeutic cancer vaccination - Lai, X.; Dreyer, F.; Jaitly, T.; Gerer, K. F.; Schuler, Gerold; Dörrie, Jan; Schaft, Niels; Vera, Julio (2017)
EVALuna2:34309

A systems' biology approach to study microRNA-mediated gene regulatory networks - Lai, Xin; Bhattacharya, Animesh; Schmitz, Ulf; Kunz, Manfred; Wolkenhauer, Olaf; Vera González, Julio (BioMed Research International, 2013)
MicroRNAs (miRNAs) are potent effectors in gene regulatory networks where aberrant miRNA expression can contribute to human diseases such as cancer. For a better understanding of the regulatory role of miRNAs in coordinating gene expression, we here present a systems biology approach combining data-driven modeling and model-driven experiments. Such an approach is characterized by an iterative process, including biological data acquisition and integration, network construction, mathematical modeling and experimental validation. To demonstrate the application of this approach, we adopt it to investigate mechanisms of collective repression on p21 by multiple miRNAs. We first construct a p21 regulatory network based on data from the literature and further expand it using algorithms that predict molecular interactions. Based on the network structure, a detailed mechanistic model is established and its parameter values are determined using data. Finally, the calibrated model is used to study the effect of different miRNA expression profiles and cooperative target regulation on p21 expression levels in different biological context
Keywords: miRNAs; bioiformatics; network biology; systems biology

A Therapeutic Antiviral Antibody Inhibits the Anterograde Directed Neuron-to-Cell Spread of Herpes Simplex Virus and Protects against Ocular Disease - Bauer, Dirk; Alt, Mira; Dirks, Miriam; Buch, Anna; Heilingloh, Christiane; Dittmer, Ulf; Giebel, Bernd; Goergens, Andre; Palapys, Vivien; Kasper, Maren; Eis-Huebinger, Anna M.; Sodeik, Beate; et al. (Frontiers in Microbiology, 2017)
Herpes simplex virus (HSV) is a leading cause of blindness and viral encephalitis in the developed world. Upon reactivation from sensory neurons, HSV returns via axonal transport to peripheral tissues where it causes, e.g., severe, potentially blinding ocular diseases. In the present study we investigated whether the HSV-1/2 glycoprotein B-specific antibody mAb 2c or its humanized counterpart mAb hu2c can protect from ocular disease in a mouse model of HSV-1-induced acute retinal necrosis (ARN). In this model the viral spread from the initially infected to the contralateral eye resembles the routes taken in humans upon HSV reactivation. Systemic antibody treatment prior or early after infection effectively protected the mice from the development of ARN. These observations suggest that the antibody potently neutralized the infection and inhibited the viral transmission, since there was almost no virus detectable in the contralateral eyes and trigeminal ganglia of antibody treated mice. Besides of neutralizing free virus or limiting the infection via activating the complement or cellular effector functions, blocking of the anterograde directed neuron-to-cell spread of HSV represents a viable mode of action how mAb 2c protected the mice from ARN. We proved this hypothesis using a microfluidic chamber system. Neurons and epithelial cells were cultured in two separate compartments where the neurons sent axons via connecting microgrooves to the epithelial cells. Neurons were infected with a reporter HSV-1 strain expressing mCherry, and the co-culture was treated with neutralizing antibodies. In contrast to commercial polyclonal human HSV-neutralizing immunoglobulins, mAb 2c effectively blocked the anterograde directed neuron-to-cell transmission of the virus. Our data suggest that the humanized HSV-1/2-gB antibody protects mice from ocular disease by blocking the neuronal spread of HSV. Therefore, mAb hu2c may become a potent novel therapeutic option for severe ocular HSV infections.
EVALuna2:36336

A Tribute to Robert (Bob) Sim-Personal Memories of Working in Bob's Lab - Williams, Samantha; Steinkasserer, Alexander (Viruses, 2021)
This article is intended as a tribute to Robert B. Sim through the sharing of personal memories and anecdotes from two of Bob's lab members who worked in his lab between 1989 to 1994.
CRIS-Team Scopus Importer:2021-10-29
Keywords: complement; obituary; Robert B. Sim

Atypische Mykobakteriose unter TNF-Blocker - Kaufmann, Matthias; Erfurt-Berge, Cornelia; Wörl, Petra (Deutsches Ärzteblatt international, 2022)
CRIS-Team Scopus Importer:2022-07-22

Author Correction: DeepNAPSI multi-reader nail psoriasis prediction using deep learning. - Folle, Lukas; Fenzl, Pauline; Fagni, Filippo; Thies, Mareike; Christlein, Vincent; Meder, Christine; Simon, David; Minopoulou, Ioanna; Sticherling, Michael; Schett, Georg; Maier, Andreas; Kleyer, Arnd (Scientific Reports, 2023)
EVALuna2:538275

Authors’ reply to Dr. Bailong’s commentary: Assessing the sedation effect of dexmedetomidine during hysteroscopic surgery - Bingol Tanriverdi, Tugba; Koceroglu, Ikbal; Devrim, Sibel; Gura Celik, Melek (Journal of Clinical Pharmacy and Therapeutics, 2019)
CRIS-Team Scopus Importer:2019-07-23

Autocrine TNF is critical for the survival of human dendritic cells by regulating BAK, BCL-2, and FLIP L - Lehner, Manfred; Kellert, Beate; Proff, Julia; Schmid, Martina A.; Diessenbacher, Philip; Enßer, Armin; Dörrie, Jan; Schaft, Niels; Leverkus, Martin; Kämpgen, Eckhart; Holter, Wolfgang (Journal of Immunology, 2012)
The life span of dendritic cells (DCs) is determined by the balance of pro- and antiapoptotic proteins. In this study, we report that serum-free cultured human monocyte-derived DCs after TLR stimulation with polyinosinic acid-polycytidylic acid or LPS underwent apoptosis, which was correlated with low TNF production. Apoptosis was prevented by the addition of exogenous TNF or by concomitant stimulation with R-848, which strongly amplified endogenous TNF production. Neutralization of TNF confirmed that DC survival was mediated by autocrine TNF induced either by stimulation with R-848 or by ligation of CD40. DCs stimulated by polyinosinic acid-polycytidylic acid or IFN-β, another known inducer of DC apoptosis, were characterized by high levels and activation of the proapoptotic protein BAK. The ratio of antiapoptotic BCL-2 to BAK correlated best with the survival of activated DCs. Addition of TNF increased this ratio but had little effect on BAX and XIAP. Knockdown experiments using small interfering RNAs confirmed that the survival of activated and also of immature DCs was regulated by BAK and showed that TNF was protective only in the presence of FLIP L. Together, our data demonstrate that the survival of DCs during differentiation and activation depends on autocrine TNF and that the inhibition of BAK plays an important role in this process. Copyright © 2012 by The American Association of Immunologists, Inc.
CRIS-Team Scopus Importer:2021-10-01

Autoimmune Colitis and Subsequent CMV-induced Hepatitis After Treatment With Ipilimumab - Uslu, Ugur; Agaimy, Abbas; Hundorfean, Gheorghe; Harrer, Thomas; Schuler, Gerold; Heinzerling, Lucie (Journal of Immunotherapy, 2015)
Ipilimumab, a humanized CTLA-4 antibody, improves overall survival in patients with metastatic melanoma. However, immune-related adverse effects occur in about 65% of ipilimumab-treated patients and have to be adequately managed. A 55-year-old patient developed grade 3 autoimmune colitis 7 weeks after initiation of ipilimumab treatment and subsequently hepatitis with grade 3 elevation of transaminases and ?-glutamyl transferase. Colitis manifested with up to 18 watery and bloody stools per day and severe attacks of abdominal pain. After exclusion of infectious causes, immunosuppression with corticosteroids was initiated. Because of recurrent abdominal pain, spontaneous perforation of the colon had to be excluded. Elevated liver function tests (grade 3 CTCAE) occurred and differential diagnosis included immune-mediated, toxic, and viral hepatitis. It is interesting to note that, not an immune-mediated but a cytomegalovirus-induced hepatitis was diagnosed by serum blood tests and liver biopsy and was subsequently successfully treated. Careful elaboration of the patient under immunotherapy was essential as further immunosuppression mandatory for autoimmune hepatitis would have worsened the viral hepatitis. In conclusion, cytomegalovirus reactivation should be included in the differential in patients under immunotherapy with checkpoint inhibitors and has to be considered as a cause for morbidity.
EVALuna2:1966

Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis - Voskens, Caroline; Stoica, Diane; Rosenberg, Marita; Vitali, Francesco; Zundler, Sebastian; Ganslmayer, Marion; Knott, Heike; Wiesinger, Manuel; Wunder, Jutta; Kummer, Mirko; Siegmund, Britta; Schnoy, Elisabeth; et al. (Gut, 2022)
Objective Ulcerative colitis (UC) is a chronic, debilitating immune-mediated disease driven by disturbed mucosal homeostasis, with an excess of intestinal effector T cells and an insufficient expansion of mucosal regulatory T cells (Tregs). We here report on the successful adoptive transfer of autologous, ex vivo expanded Tregs in a patient with refractory UC and associated primary sclerosing cholangitis (PSC), for which effective therapy is currently not available.
CRIS-Team WoS Importer:2022-04-29

Autologous whole tumor cell-based vaccines generated with high hydrostatic pressure bear immunogenic potential and act synergistically with radiotherapy to retard tumor growth - Frey, Benjamin; Seitz, C.; Weiss, E. M.; Rueckert, M.; Schlücker, Eberhard; Schaft, Niels; Fietkau, Rainer; Gaipl, Udo (2017)
EVALuna2:32864

Automated closed-system manufacturing of human monocyte-derived dendritic cells for cancer immunotherapy - Erdmann, Michael; Uslu, Ugur; Wiesinger, Manuel; Bruening, Mareke; Altmann, Tobias; Strasser, Erwin; Schuler, Gerold; Schuler-Thurner, Beatrice (Journal of Immunological Methods, 2018)
Dendritic cell (DC)-based vaccines have been successfully used for immunotherapy of cancer and infections. A major obstacle is the need for high-level class A cleanroom cGMP facilities for DC generation. The CliniMACS Prodigy® (Prodigy) represents a new platform integrating all GMP-compliant manufacturing steps in a closed system for automated production of various cellular products, notably T cells, NK cells and CD34+ cells. We now systematically tested its suitability for producing human mature monocyte-derived DCs (Mo-DCs), and optimized it by directly comparing the Prodigy approach to our established standard production of Mo-DCs from elutriated monocytes in dishes or bags. Upon step-by-step identification of an optimal cell concentration for the Prodigy's CentriCult culture chamber, the total yield (% of input CD14+ monocytes), phenotype, and functionality of mature Mo-DCs were equivalent to those generated by the standard protocol. Technician's labor time was comparable for both methods, but the Prodigy approach significantly reduced hands-on time and high-level clean room resources. In summary, using our optimized conditions for the CliniMACS Prodigy, human Mo-DCs for clinical application can be generated almost automatically in a fully closed system. A significant drawback of the Prodigy approach was, however, that due to the limited size of the CentriCult culture chamber, in contrast to our standard semi-closed elutriation approach, only one fourth of an apheresis could be processed at once.
EVALuna2:203616

Automated Good Manufacturing Practice–compliant generation of human monocyte-derived dendritic cells from a complete apheresis product using a hollow-fiber bioreactor system overcomes a major hurdle in the manufacture of dendritic cells for cancer vaccines - Uslu, Ugur; Erdmann, Michael; Wiesinger, Manuel; Schuler, Gerold; Schuler-Thurner, Beatrice (Cytotherapy, 2019)
Background: Although dendritic cell (DC)–based cancer vaccines represent a promising treatment strategy, its exploration in the clinic is hampered due to the need for Good Manufacturing Practice (GMP) facilities and associated trained staff for the generation of large numbers of DCs. The Quantum bioreactor system offered by Terumo BCT represents a hollow-fiber platform integrating GMP-compliant manufacturing steps in a closed system for automated cultivation of cellular products. In the respective established protocols, the hollow fibers are coated with fibronectin and trypsin is used to harvest the final cell product, which in the case of DCs allows processing of only one tenth of an apheresis product. Materials and Results: We successfully developed a new protocol that circumvents the need for fibronectin coating and trypsin digestion, and makes the Quantum bioreactor system now suitable for generating large numbers of mature human monocyte-derived DCs (Mo-DCs) by processing a complete apheresis product at once. To achieve that, it needed a step-by-step optimization of DC-differentiation, e.g., the varying of media exchange rates and cytokine concentration until the total yield (% of input CD14+ monocytes), as well as the phenotype and functionality of mature Mo-DCs, became equivalent to those generated by our established standard production of Mo-DCs in cell culture bags. Conclusions: By using this new protocol for the Food and Drug Administration–approved Quantum system, it is now possible for the first time to process one complete apheresis to automatically generate large numbers of human Mo-DCs, making it much more feasible to exploit the potential of individualized DC-based immunotherapy.
CRIS-Team Scopus Importer:2019-11-12
Keywords: adoptive cell transfer; cell therapy; cellular therapy; dendritic cell vaccine; dendritic cells; immunotherapy; monocyte-derived dendritic cells; vaccines

Automatic Classification of Diabetic Foot Ulcer Images - A Transfer-Learning Approach to Detect Wound Maceration - Hüsers, Jens; Hafer, Guido; Heggemann, Jan; Wiemeyer, Stefan; Przysucha, Mareike; Dissemond, Joachim; Moelleken, Maurice; Erfurt-Berge, Cornelia; Hübner, Ursula (Studies in Health Technology and Informatics, 2022)
Diabetic foot ulcer (DFU) is a chronic wound and a common diabetic complication as 2% - 6% of diabetic patients witness the onset thereof. The DFU can lead to severe health threats such as infection and lower leg amputations, Coordination of interdisciplinary wound care requires well-written but time-consuming wound documentation. Artificial intelligence (AI) systems lend themselves to be tested to extract information from wound images, e.g. maceration, to fill the wound documentation. A convolutional neural network was therefore trained on 326 augmented DFU images to distinguish macerated from unmacerated wounds. The system was validated on 108 unaugmented images. The classification system achieved a recall of 0.69 and a precision of 0.67. The overall accuracy was 0.69. The results show that AI systems can classify DFU images for macerations and that those systems could support clinicians with data entry. However, the validation statistics should be further improved for use in real clinical settings. In summary, this paper can contribute to the development of methods to automatic wound documentation.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Clinical Decision Support System; Convolutional Neural Networks; Diabetic Foot Ulcer; Health Information Technology; Image Classification; Transfer Learning; Wound Care

Automatic Wound Type Classification with Convolutional Neural Networks - Malihi, Leila; Hüsers, Jens; Richter, Mats L.; Moelleken, Maurice; Przysucha, Mareike; Busch, Dorothee; Heggemann, Jan; Hafer, Guido; Wiemeyer, Stefan; Heidemann, Gunther; Dissemond, Joachim; Erfurt-Berge, Cornelia; et al. (Advances in Informatics, Management and Technology in Healthcare, 2022)
Chronic wounds are ulcerations of the skin that fail to heal because of an underlying condition such as diabetes mellitus or venous insufficiency. The timely identification of this condition is crucial for healing. However, this identification requires expert knowledge unavailable in some care situations. Here, artificial intelligence technology may support clinicians. In this study, we explore the performance of a deep convolutional neural network to classify diabetic foot and venous leg ulcers using wound images. We trained a convolutional neural network on 863 cropped wound images. Using a hold-out test set with 80 images, the model yielded an F1-score of 0.85 on the cropped and 0.70 on the full images. This study shows promising results. However, the model must be extended in terms of wound images and wound types for application in clinical practice.
CRIS-Team Scopus Importer:2022-07-15
Keywords: Clinical Decision Support System; Convolutional Neural Networks; Diabetic Foot Ulcer; Health Information Technology; Image Classification; Transfer Learning; Wound Care

Autophagic degradation of lamins facilitates the nuclear egress of herpes simplex virus type 1 - Turan, Aykut; Grosche, Linda; Krawczyk, Adalbert; Mühl-Zürbes, Petra; Drassner, Christina; Düthorn, Alexandra; Kummer, Mirko; Hasenberg, Mike; Voortmann, Sylvia; Jastrow, Holger; Dörrie, Jan; Schaft, Niels; et al. (The Journal of Cell Biology, 2019)
Dendritic cells (DCs) are crucial for the induction of potent antiviral immune responses. In contrast to immature DCs (iDCs), mature DCs (mDCs) are not permissive for infection with herpes simplex virus type 1 (HSV-1). Here, we demonstrate that HSV-1 infection of iDCs and mDCs induces autophagy, which promotes the degradation of lamin A/C, B1, and B2 in iDCs only. This in turn facilitates the nuclear egress of progeny viral capsids and thus the formation of new infectious particles. In contrast, lamin protein levels remain stable in HSV-1-infected mDCs due to an inefficient autophagic flux. Elevated protein levels of KIF1B and KIF2A in mDCs inhibited lamin degradation, likely by hampering autophagosome-lysosome fusion. Therefore, in mDCs, fewer progeny capsids were released from the nuclei into the cytosol, and fewer infectious virions were assembled. We hypothesize that inhibition of autophagic lamin degradation in mDCs represents a very powerful cellular counterstrike to inhibit the production of progeny virus and thus viral spread.
CRIS-Team WoS Importer:2019-02-21

Autophagy in diabetic nephropathy: a review - Koch, Elias; Nakhoul, Rola; Nakhoul, Farid; Nakhoul, Nakhoul (International Urology and Nephrology, 2020)
Diabetes mellitus (DM) is the leading cause of end stage renal disease. 40% of the patients worldwide will require replacement therapy after 20 years of DM worldwide. Early-stage diabetic nephropathy is characterized by hyperfiltration related to hypeglycemia-induced afferent artery vasodilatation with micro-and macroalbuminuria. Later on, proteinuria with arterial hypertension may appear, culminating in glomerular filtration rate (GFR) decline and end stage renal disease. Forty percent of diabetic patients develop microvascular and macrovascular complications, with increased risk among patients with genetic predisposition, such as Haptoglobin 2–2 phenotype. The most frequent complications in the daily clinical practice are diabetic kidney disease, diabetic retinopathy and vascular disease, such as coronary artery disease and stroke. Various pathways are involved in the pathogenesis of diabetic kidney disease. Chronic systemic inflammation and the inflammatory response, such as increased circulating cytokines (Interleukins), have been recognized as main players in the development and progression of diabetic kidney disease. DM is also associated with increased oxidative stress, and alterations in carbohydrate, lipid and protein metabolism. Overexpression of the renin-angiotensin-aldosterone system (RAAS) in the kidney, the vitamin D-Vitamin D receptor-klotho axis, and autophagy. Differences in the ATG5 protein levels or ATG5 gene expression involved in the autophagy process have been associated with diabetic complications such as diabetic kidney disease. Under normal blood glucose level, autophagy is an important protective mechanism in renal epithelial cells, including podocytes, proximal tubular, mesangial and endothelial cells. Down regulation of the autophagic mechanism, as in hyperglycemic condition, can contribute to the development and progression of diabetic kidney disease.
CRIS-Team Scopus Importer:2020-07-24
Keywords: Atg5; Autophagy; Diabetic nephropathy; Rapamune; Retinopathy; Sodium-glucose cotransporter inhibitors; Vitamin D

Autophagy-Mediated Breakdown of the nuclear lamina facilitates nuclear egress of HSV-1 capsids and thus generation of progeny virus in dendritic cells - Turan, A.; Krawczyk, A.; Grosche, Linda; Mühl-Zürbes, Petra; Drassner, C.; Hasenberg, M.; Voortmann, S.; Jastrow, H.; Kraner, Max; Doehner, K.; Sodeik, B.; Heilingloh, Christiane; et al. (2018)
EVALuna2:36213

A web-based comprehensive map including regulatory pathways subverted in melanoma that can be visualized, browsed and used for analysing cell line and patient high through put data - Dreyer, Florian; Cantone, Martina; Eberhardt, Martin; Schuler, Gerold; Vera, Julio (2016)
EVALuna2:19614

A web platform for the network analysis of high-throughput data in melanoma and its use to investigate mechanisms of resistance to anti-PD1 immunotherapy - Dreyer, Florian; Cantone, Martina; Eberhardt, Martin; Jaitly, Tanushree; Walter, Lisa; Wittmann, Jürgen; Gupta, Shailendra; Khan, Faiz M.; Wolkenhauer, Olaf; Puetzer, Brigitte M.; Jäck, Hans-Martin; Heinzerling, Lucie; et al. (Biochimica et Biophysica Acta - Molecular Basis of Disease, 2018)
Cellular phenotypes are established and controlled by complex and precisely orchestrated molecular networks. In cancer, mutations and dysregulations of multiple molecular factors perturb the regulation of these networks and lead to malignant transformation. High-throughput technologies are a valuable source of information to establish the complex molecular relationships behind the emergence of malignancy, but full exploitation of this massive amount of data requires bioinformatics tools that rely on network-based analyses. In this report we present the Virtual Melanoma Cell, an online tool developed to facilitate the mining and interpretation of high-throughput data on melanoma by biomedical researches. The platform is based on a comprehensive, manually generated and expert-validated regulatory map composed of signaling pathways important in malignant melanoma. The Virtual Melanoma Cell is a tool designed to accept, visualize and analyze user-generated datasets. It is available at: https://www.vcells.net/melanoma. To illustrate the utilization of the web platform and the regulatory map, we have analyzed a large publicly available dataset accounting for anti-PD1 immunotherapy treatment of malignant melanoma patients.
EVALuna2:34379
Keywords: Therapy resistance; Databases; Network genomics; Systems biology; Immunotherapy; Melanoma

A web tool for the oligodendrocyte differentiation data and network analysis - Cantone, Martina; Eberhardt, Martin; Küspert, Melanie; Reiprich, Simone; Wegner, Michael; Vera, Julio (2017)
EVALuna2:33481

Bacterial Adherence and Dwelling Probability: Two Drivers of Early Alveolar Infection by Streptococcus pneumoniae Identified in Multi-Level Mathematical Modeling - Santos, Guido; Lai, Xin; Eberhardt, Martin; Vera, Julio (Frontiers in Cellular and Infection Microbiology, 2018)
Pneumococcal infection is the most frequent cause of pneumonia, and one of the most prevalent diseases worldwide. The population groups at high risk of death from bacterial pneumonia are infants, elderly and immunosuppressed people. These groups are more vulnerable because they have immature or impaired immune systems, the efficacy of their response to vaccines is lower, and antibiotic treatment often does not take place until the inflammatory response triggered is already overwhelming. The immune response to bacterial lung infections involves dynamic interactions between several types of cells whose activation is driven by intracellular molecular networks. A feasible approach to the integration of knowledge and data linking tissue, cellular and intracellular events and the construction of hypotheses in this area is the use of mathematical modeling. For this paper, we used a multi-level computational model to analyse the role of cellular and molecular interactions during the first 10 h after alveolar invasion of Streptococcus pneumoniae bacteria. By "multi-level" we mean that we simulated the interplay between different temporal and spatial scales in a single computational model. In this instance, we included the intracellular scale of processes driving lung epithelial cell activation together with the scale of cell-to-cell interactions at the alveolar tissue. In our analysis, we combined systematic model simulations with logistic regression analysis and decision trees to find genotypic-phenotypic signatures that explain differences in bacteria strain infectivity. According to our simulations, pneumococci benefit from a high dwelling probability and a high proliferation rate during the first stages of infection. In addition to this, the model predicts that during the very early phases of infection the bacterial capsule could be an impediment to the establishment of the alveolar infection because it impairs bacterial colonization.
EVALuna2:34792

Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab - Weide, Benjamin; Martens, Alexander; Hassel, Jessica C.; Berking, Carola; Postow, Michael A.; Bisschop, Kees; Simeone, Ester; Mangana, Johanna; Schilling, Bastian; Di Giacomo, Anna Maria; Brenner, Nicole; Kaehler, Katharina; et al. (Clinical Cancer Research, 2016)
PURPOSE: Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) after pembrolizumab treatment in melanoma patients. EXPERIMENTAL DESIGN: Serum lactate dehydrogenase (LDH), routine blood count parameters, and clinical characteristics were investigated in 616 patients. Endpoints were OS and best overall response following pembrolizumab treatment. Kaplan-Meier analysis and Cox regression were applied for survival analysis. RESULTS: Relative eosinophil count (REC) ≥1.5%, relative lymphocyte count (RLC) ≥17.5%, ≤2.5-fold elevation of LDH, and the absence of metastasis other than soft-tissue/lung were associated with favorable OS in the discovery (n = 177) and the confirmation (n = 182) cohort and had independent positive impact (all P < 0.001). Their independent role was subsequently confirmed in the validation cohort (n = 257; all P < 0.01). The number of favorable factors was strongly associated with prognosis. One-year OS probabilities of 83.9% versus 14.7% and response rates of 58.3% versus 3.3% were observed in patients with four of four compared to those with none of four favorable baseline factors present, respectively. CONCLUSIONS: High REC and RLC, low LDH, and absence of metastasis other than soft-tissue/lung are independent baseline characteristics associated with favorable OS of patients with melanoma treated with pembrolizumab. Presence of four favorable factors in combination identifies a subgroup with excellent prognosis. In contrast, patients with no favorable factors present have a poor prognosis, despite pembrolizumab, and additional treatment advances are still needed. A potential predictive impact needs to be further investigated. Clin Cancer Res; 22(22); 5487-96. ©2016 AACR.
EVALuna2:19606

Baseline characteristics, disease severity and treatment history of patients with atopic dermatitis included in the German AD Registry TREATgermany - Heratizadeh, A.; Haufe, E.; Stoelzl, D.; Abraham, S.; Heinrich, L.; Kleinheinz, A.; Wollenberg, A.; Weisshaar, E.; Augustin, M.; Wiemers, F.; Zink, A.; Von Kiedrowski, R.; et al. (Journal of the European Academy of Dermatology and Venereology, 2020)
Background The Atopic Dermatitis (AD) TREATgermany registry was initiated by the German Society for Dermatology (DDG) in 2011 to evaluate the 'real-life' situation of health care for patients with AD.
CRIS-Team WoS Importer:2020-02-28

B cells are critical for autoimmune pathology in Scurfy mice. - Aschermann, Susanne; Lehmann, Christian; Mihai, Sidonia; Schett, Georg; Dudziak, Diana; Nimmerjahn, Falk (Proceedings of the National Academy of Sciences of the United States of America, 2013)
Impaired regulatory T-cell function results in a severe chronic autoimmune disease affecting multiple organs in Scurfy mice and humans with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Previous studies have shown that T helper cells but not cytotoxic T cells are critical for the disease pathology. Whether this T-cell subset is responsible directly for tissue inflammation or rather indirectly via the interaction with B cells or myeloid cells is largely unknown. To study this and to identify potential therapeutic targets for this lethal disease we investigated the contribution of B cells to this complex autoimmune phenotype. We show that B cells and the production of autoantibodies plays a major role for skin, liver, lung, and kidney inflammation and therapeutic depletion of B cells resulted in reduced tissue pathology and in prolonged survival. In contrast, the absence of B cells did not impact systemic T-cell activation and hyperreactivity, indicating that autoantibody production by B cells may be a major factor for the autoimmune pathology in mice deficient for regulatory T cells.

B-cells in psoriasis? - Banki, Simon; Heusinger, Juliane; Herter-Kermann, T.; Sticherling, Michael (EXPERIMENTAL DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-14

BCL2 Inhibition Reveals a Dendritic Cell-Specific Immune Checkpoint That Controls Tumor Immunosurveillance - Zhao, Liwei; Liu, Peng; Mao, Misha; Zhang, Shuai; Bigenwald, Camille; Dutertre, Charles Antoine; Lehmann, Christian; Pan, Hui; Paulhan, Nicolas; Amon, Lukas; Buqué, Aitziber; Yamazaki, Takahiro; et al. (Cancer Discovery, 2023)
We developed a phenotypic screening platform for the functional exploration of dendritic cells (DC). Here, we report a genome-wide CRISPR screen that revealed BCL2 as an endogenous inhibitor of DC function. Knockout of BCL2 enhanced DC antigen presentation and activation as well as the capacity of DCs to control tumors and to synergize with PD-1 blockade. The pharmacologic BCL2 inhibitors venetoclax and navitoclax phenocopied these effects and caused a cDC1-dependent regression of orthotopic lung cancers and fibrosarcomas. Thus, solid tumors failed to respond to BCL2 inhibition in mice constitutively devoid of cDC1, and this was reversed by the infusion of DCs. Moreover, cDC1 depletion reduced the therapeutic efficacy of BCL2 inhibitors alone or in combination with PD-1 blockade and treatment with venetoclax caused cDC1 activation, both in mice and in patients. In conclusion, genetic and pharmacologic BCL2 inhibition unveils a DC-specific immune checkpoint that restrains tumor immunosurveillance. SIGNIFICANCE: BCL2 inhibition improves the capacity of DCs to stimulate anticancer immunity and restrain cancer growth in an immunocompetent context but not in mice lacking cDC1 or mature T cells. This study indicates that BCL2 blockade can be used to sensitize solid cancers to PD-1/PD-L1-targeting immunotherapy. This article is featured in Selected Articles from This Issue, p. 2293.
CRIS-Team Scopus Importer:2023-11-17

Behandlung der Psoriasis mit Secukinumab: Praxisrelevante Hinweise - Körber, Andreas; Augustin, Matthias; Behrens, Frank; Gerdes, Sascha; von Kiedrowski, Ralph; Schäkel, Knut; Sticherling, Michael; Wilsmann-Theis, Dagmar; Wohlrab, Johannes; Simon, Jan Christoph (Hautarzt, 2021)
Background: Moderate to severe plaque psoriasis can be treated effectively with immunomodulating biologicals such as the interleukin-17A inhibitor secukinumab. In practice, however, questions often arise as to how to proceed in special situations, such as infections, comorbidity, pregnancy, or surgery. Objectives: To address frequent questions about the treatment of plaque psoriasis with secukinumab in a consensus document of German psoriasis experts that supplements current guidelines. Methods: In a virtual expert meeting in May 2020, practical aspects of the treatment of psoriasis were discussed based on the experience of the participants and on current literature. The results of this discussion were summarized in the present consensus document. Results: This article provides practical guidance on case history, documentation of previous therapies, severity of psoriasis, and comorbidities before starting therapy with secukinumab. For patients treated with secukinumab, the course of action in case of vaccinations, chronic or acute infections, surgical interventions, special manifestations of psoriasis, and comorbidities including history of cancer and autoimmune disorders is discussed. Questions regarding family planning and health policy regulations are also addressed. Discussion: The recommendations for the treatment of psoriasis with secukinumab summarized in this consensus document may contribute to achieve optimal therapy for patients and to improve their quality of life.
CRIS-Team Scopus Importer:2021-08-27
Keywords: Biological products; Comorbidity; Infections; Perioperative management; Special situations

Beruflich erworbene MRSA-Besiedelung in der berufsdermatologischen Begutachtung (BK-Nr. 3101) - Erfurt-Berge, Cornelia; Schmidt, Anne; Angelovska, Irena; Mahler, Vera (Hautarzt, 2020)
Background: Person-to-person transmitted infectious diseases can cause occupational diseases (OD). These are subsumed as BK-No. 3101 in the German list of OD which applies for individuals with a considerably higher risk for infection as a consequence of their professional activity compared to the general population. Objectives: The special medical and insurance law aspects of a work-related MRSA colonization are presented using the example of an expert opinion case and an evaluation of the BK reports of suspected occupational disease (BK No. 3101) of the German Social Accident Insurance (DGUV). Patients and methods: The BK documentation of the DGUV from 2007–2012 and the patient cohort from the Department of Dermatology, University Hospital Erlangen, presenting for expert assessment from 2007–2012 were retrospectively analysed for human-to-human transmitted infectious diseases of the skin (BK-No. 3101). Results: Person-to-person transmission of infectious diseases of the skin is rare in the field of occupational dermatology. In the DGUV cohort, suspected BK-No. 3101cases amounted to 2.6% of all notified cases; recognized BK-No. 3101 cases accounted for 4.2% of all recognized cases, amongst which 9 were caused by MRSA. In contrast to a symptomatic infection, an asymptomatic MRSA colonization is not being recognized as BK-No. 3101. Bacterial superantigens can trigger atopic dermatitis (AD). In particular cases, occupationally acquired MRSA can elicit AD and may justify classification as an OD (BK-No. 3101). Conclusions: Early detection of MRSA colonization and eradication are necessary for rehabilitation. Management of skin diseases due to infectious diseases within the framework of OD is presented.
CRIS-Team Scopus Importer:2020-06-16
Keywords: Abnormal health condition; Asymptomatic MRSA colonization; Communicable disease; Occupation diseases; Occupational disease evaluation proceedings

Beyond Cancer: Regulation and Function of PD-L1 in Health and Immune-Related Diseases - Beenen, Amke C.; Sauerer, Tatjana; Schaft, Niels; Dörrie, Jan (International Journal of Molecular Sciences, 2022)
Programmed Cell Death 1 Ligand 1 (PD-L1, CD274, B7-H1) is a transmembrane protein which is strongly involved in immune modulation, serving as checkpoint regulator. Interaction with its receptor, Programmed Cell Death Protein 1 (PD-1), induces an immune-suppressive signal, which modulates the activity of T cells and other effector cells. This mediates peripheral tolerance and contributes to tumor immune escape. PD-L1 became famous due to its deployment in cancer therapy, where blockage of PD-L1 with the help of therapeutic antagonistic antibodies achieved impressive clinical responses by reactivating effector cell functions against tumor cells. Therefore, in the past, the focus has been placed on PD-L1 expression and its function in various malignant cells, whereas its role in healthy tissue and diseases apart from cancer remained largely neglected. In this review, we summarize the function of PD-L1 in non-cancerous cells, outlining its discovery and origin, as well as its involvement in different cellular and immune-related processes. We provide an overview of transcriptional and translational regulation, and expression patterns of PD-L1 in different cells and organs, and illuminate the involvement of PD-L1 in different autoimmune diseases as well as in the context of transplantation and pregnancy.
CRIS-Team WoS Importer:2022-08-26

Beyond-Mild Psoriasis: A Consensus Statement on Calcipotriol and Betamethasone Dipropionate Foam for the Topical Treatment of Adult Patients - Aschoff, Roland; Bewley, Anthony; Dattola, Annunziata; De Simone, Clara; Lahfa, Mourad; Llamas-Velasco, Mar; Martorell, Antonio; Pavlovic, Mira; Sticherling, Michael (Dermatology and Therapy, 2021)
Introduction There are clear treatment options for mild psoriasis where topical therapies are the mainstay, and for severe psoriasis where systemic therapy (biologic or non-biologic) is necessary. However, there is less clarity in the 'grey zone' of patients in the moderate or so-called 'beyond-mild' segment. There are frequent delays to the initiation, discontinuation, switching and dose change in treatment, and many patients fail to continue treatment because of concerns about safety or lack of efficacy. Treatment with topical therapies, such as calcipotriol and betamethasone dipropionate (Cal/BD) combinations, may be suitable for these patients. Method These consensus recommendations on the use of topical therapies including Cal/BD foam for beyond-mild psoriasis originated from a modified Delphi process of European clinical experts. In the process, the experts iteratively refined a series of draft statements, which had to receive >= 80% approval to be incorporated into the consensus. Results The experts identified three main themes: Cal/BD foam as monotherapy, as an add-on to non-biologic systemic therapies and as an add-on to systemic biologics. The consensus emphasises disease factors and patient preference in treatment choice, summarises the evidence base for Cal/BD foam monotherapy for flare treatment as well as long-term management, and identifies the potential for improved treatment outcomes, such as reduced time to onset of action and reduced systemic dose to minimise side effects for add-on Cal/BD therapy to non-biologic systemics. The recommendations regarding add-on Cal/BD foam to biologics are similar to those for non-biologic systemic therapies, but also include suggestions for patients on biologics who are late responders. As clinical choices of Cal/BD combination vary, we have here often used 'Cal/BD' without reference to any particular formulation. Conclusions These recommendations aim to give practical guidance to those treating patients with beyond-mild psoriasis, to support patients' use of topical preparations and to optimise treatment outcomes.
CRIS-Team WoS Importer:2021-09-24

Bin-based visualization of cytokine-co-expression patterns of IL-10-producing CD4 T cell subsets - Mohr, Elodie; Hinnenthal, Timo; Gryzik, Stefanie; Hoang, Yen; Lischke, Timo; Retzlaff, Jimmy; Mekonnen, Ariana; Paul, Friedemann; Valleriani, Angelo; Radbruch, Andreas; Vera, Julio; Baumgrass, Ria (European Journal of Immunology, 2022)
CRIS-Team Scopus Importer:2022-10-07
Keywords: cytokine; cytometry; IL-10; pattern perception; T cells

BIOACTIVE GLASSES AND THE IMMUNE SYSTEM: RECENT FINDINGS AND FUTURE PERSPECTIVES - Boccaccini, Aldo R.; Schuhladen, Katharina; Steinkasserer, Alexander; Zinser, Elisabeth (TISSUE ENGINEERING PART A, 2022)
CRIS-Team WoS Importer:2022-08-12

BISPECIFIC ANTIBODIES ENABLE SYNTHETIC AGONISTIC RECEPTOR T CELL THERAPY IN MELANOMA - Benmebarek, M.; Maerkl, F.; Keyl, J.; Cadilha, B.; Geiger, M.; Karches, C.; Obeck, H.; Schwerdtfeger, M.; Briukhovetska, D.; Jobst, J.; Mueller, Pj; Seifert, M.; et al. (JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2022)
Background Immunotherapies, like immune checkpoint inhibition and tumor infiltrating lymphocytes, have had remarkable success in treating melanoma. However, many patients do still not respond or relapse with therapy-resistant disease. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with EGFRvIII synthetic agonistic receptors (E3 SAR) that are selectively activated by a cross-linking bispecific antibody (BiAb) specific for both SAR T cell and melanoma-associated antigens. Materials and Methods Murine as well as human SAR constructs were generated and T cells were retrovirally transduced to stably express the SAR constructs. We validated our approach in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens TYRP1 and MCSP. SAR T cells were functionally characterised by proving specific activation and proliferation of SAR T cells, as well as their tumor-directed cytotoxicity, in vitro and in vivo. Results Both on a mRNA and protein level, MCSP and TYRP1 were shown to be differentially expressed in treatment-naive as well as treatment-resistant melanoma patients compared to samples from healthy donors. Crosslinking anti-TYRP1 x anti-E3 and anti-MCSP x anti-E3 BiAb mediated conditional antigen-dependent activation, proliferation of SAR-T cells and lead to tumor cell lysis in all models tested. In vivo, anti-tumoral activity and tumor-free survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further confirmed in several xenograft models. Conclusions Here, we apply the SAR x BiAb approach in an effortto deliver specific and conditional activation of SAR transduced T cells, and targeted tumor cell lysis in melanoma models. The modularity of our approach is key for targeting melanoma and is essential towards personalised immunotherapies addressing cancer heterogeneity. Due to variations of antigen expression in primary melanoma tissues, we propose that a dual-targeting approach, either simultaneous or sequential, could mitigate issues of heterogeneity and deliver therapeutic benefit to patient
CRIS-Team WoS Importer:2022-12-23

Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma - Maerkl, Florian; Benmebarek, Mohamed-Reda; Keyl, Julius; Cadilha, Bruno L.; Geiger, Martina; Karches, Clara; Obeck, Hannah; Schwerdtfeger, Melanie; Michaelides, Stefanos; Briukhovetska, Daria; Stock, Sophia; Jobst, Jakob; et al. (Journal for ImmunoTherapy of Cancer, 2023)
BACKGROUND: Melanoma is an immune sensitive disease, as demonstrated by the activity of immune check point blockade (ICB), but many patients will either not respond or relapse. More recently, tumor infiltrating lymphocyte (TIL) therapy has shown promising efficacy in melanoma treatment after ICB failure, indicating the potential of cellular therapies. However, TIL treatment comes with manufacturing limitations, product heterogeneity, as well as toxicity problems, due to the transfer of a large number of phenotypically diverse T cells. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with synthetic agonistic receptors (SAR) that are selectively activated by bispecific antibodies (BiAb) targeting SAR and melanoma-associated antigens. METHODS: Human as well as murine SAR constructs were generated and transduced into primary T cells. The approach was validated in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens tyrosinase-related protein 1 (TYRP1) and melanoma-associated chondroitin sulfate proteoglycan (MCSP) (CSPG4). SAR T cells were functionally characterized by assessing their specific stimulation and proliferation, as well as their tumor-directed cytotoxicity, in vitro and in vivo. RESULTS: MCSP and TYRP1 expression was conserved in samples of patients with treated as well as untreated melanoma, supporting their use as melanoma-target antigens. The presence of target cells and anti-TYRP1 × anti-SAR or anti-MCSP × anti-SAR BiAb induced conditional antigen-dependent activation, proliferation of SAR T cells and targeted tumor cell lysis in all tested models. In vivo, antitumoral activity and long-term survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further validated in several xenograft models, including a patient-derived xenograft model. CONCLUSION: The SAR T cell-BiAb approach delivers specific and conditional T cell activation as well as targeted tumor cell lysis in melanoma models. Modularity is a key feature for targeting melanoma and is fundamental towards personalized immunotherapies encompassing cancer heterogeneity. Because antigen expression may vary in primary melanoma tissues, we propose that a dual approach targeting two tumor-associated antigens, either simultaneously or sequentially, could avoid issues of antigen heterogeneity and deliver therapeutic benefit to patients.
CRIS-Team Scopus Importer:2023-06-02
Keywords: immunotherapy; adoptive; melanoma

Blockade of CCR7 leads to decreased dendritic cell migration to draining lymph nodes and promotes graft survival in low-risk corneal transplantation - Hos, D.; Dörrie, Jan; Schaft, Niels; Bock, F.; Notara, M.; Kruse, Friedrich; Krautwald, S.; Cursiefen, C.; Bachmann, B. O. (Experimental Eye Research, 2016)
The chemokine receptor CCR7 is essential for migration of mature dendritic cells (DCs) to the regional lymph nodes, and it has been shown that blocking of CCR7 improves graft survival after high-risk corneal transplantation in vascularized recipient corneas. However, it is so far unknown whether blocking of CCR7 reduces migration of DCs from the avascular cornea to the draining lymph nodes and whether this leads to improved graft survival also in the low-risk setting of corneal transplantation, which accounts for the majority of perforating transplantations performed. Therefore, in this study, pellets containing Freund's adjuvant and bovine serum albumin (BSA) conjugated to Alexa488 fluorescent dye were implanted into the corneal stroma of BALB/c mice to analyze antigen uptake by corneal DCs and their migration to the regional lymph nodes. After pellet implantation, mice were either treated by local administration of a CCR7 blocking fusion protein that consisted of CCL19 fused to the Fc part of human IgG1 or a control-IgG. In vivo fluorescence microscopy showed uptake of Alexa488-conjugated BSA by corneal DCs within 8 h. Furthermore, analysis of single cell suspensions of draining lymph nodes prepared after 48 h revealed that 2.1 ± 0.3% of CD11c(+) cells were also Alexa488(+). Importantly, DC migration was significantly reduced after topical administration of CCL19-IgG (1.2 ± 0.2%; p < 0.05). To test the effect of CCR7 blockade on graft rejection after allogeneic low-risk keratoplasty, corneal transplantations were performed using C57BL/6-mice as donors and BALB/c-mice as recipients. Treatment mice received two intraperitoneal loading doses of CCL19-IgG prior to transplantation, followed by local treatment with CCL19-IgG containing eye drops for the first two weeks after transplantation. Control mice received same amounts of control-IgG. Kaplan-Meier survival analysis showed that in the CCL19-IgG treated group, 76% of the grafts survived through the end of the 8 week observation period, whereas 38% of the grafts survived in the control group (p < 0.05). Taken together, our study shows that blockade of CCR7 reduces the migration of mature corneal DCs to the draining lymph nodes and leads to improved graft survival in low-risk corneal transplantation.
EVALuna2:19600

Block Excision of Iridociliary Tumors Enables Molecular Profiling and Immune Vaccination - Heindl, Ludwig M.; Koch, Konrad R.; Hermann, Manuel M.; Merkelbach-Bruse, Sabine; Schultheis, Anne M.; Wagener, Svenja; Buettner, Reinhard; Mauch, Cornelia; Schuler-Thurner, Beatrice; Schuler, Gerold; Cursiefen, Claus (Ophthalmology, 2017)
EVALuna2:34326

Blood-Based Biomarkers of Inflammation and Tissue Remodeling Can Discriminate Between Rheumatoid Arthritis, Psoriasis, and Psoriatic Arthritis and Are Associated with Hand Function - Port Linares, Helena; Coppers, Birte; Bayat, Sara; Elie-Tino, Godonou; Fagni, Filippo; Corte, Giulia; Bay-Jensen, Anne-Christine; Tascilar, Koray; Hueber, Axel; Schönau, Verena; Sticherling, Michael; Heinrich, Simon; et al. (poster, American College of Rheumatology Convergence, 2023)

Blood eosinophilia is an on-treatment biomarker in patients undergoing vaccination with dendritic cells that correlates with long-term patient outcome - Moreira, Alvaro; Vass, V.; Erdmann, M.; Sponagl, F.; Schuler, Gerold; Schuler-Thurner, Beatrice (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Blood eosinophilia is an on-treatment biomarker in patients with solid tumors undergoing dendritic cell vaccination with autologous tumor-RNA - Moreira, Alvaro; Erdmann, Michael; Uslu, Ugur; Vass, Verona; Schuler, Gerold; Schuler-Thurner, Beatrice (Pharmaceutics, 2020)
Background: The approvals of immune checkpoint inhibitors for several cancer types and the rapidly growing recognition that T cell-based immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of cancer vaccines, including dendritic cell (DC)-based immunotherapy. Blood and tissue biomarkers to identify responders and long-term survivors and to optimize cost and cost-effectiveness of treatment are greatly needed. We wanted to investigate whether blood eosinophilia is a predictive biomarker for patients with solid tumors receiving vaccinations with DCs loaded with autologous tumor-RNA. Methods: In total, 67 patients with metastatic solid tumors, who we treated with autologous monocyte-derived DCs transfected with total tumor mRNA, were serially analyzed for eosinophil counts and survival over the course of up to 14 years. Eosinophilic counts were performed on peripheral blood smears. Results: Up to 87% of the patients treated with DC-based immunotherapy experienced at least once an eosinophilia of ≥ 5% after initiation of therapy; 61 % reached levels of ≥ 10% eosinophils, and 13% of patients showed eosinophil counts of 20% or above. While prevaccination eosinophil levels were not associated with survival, patients with blood eosinophilia at any point after initiation of DC-based immunotherapy showed a trend towards longer survival. There was a statistically significant difference for the patients with eosinophil counts of 20% or more (p = 0.03). In those patients, survival was prolonged to a median of 58 months (range 2-111 months), compared to a median of 20 months (range 0-119 months) in patients with lower eosinophil counts. In 12% of the patients, an immediate increase in eosinophil count of at least 10 percentage points could be detected after the first vaccine, which also appeared to correlate with survival (65 vs. 24 months; p = 0.06). Conclusion: Blood eosinophilia appears to be an early, on-therapy biomarker in patients with solid tumors undergoing vaccination with RNA-transfected DC, specifically autologous tumor mRNA-transfected DC vaccines, and it correlates with long-term patient outcome. Eosinophilia should be systematically investigated in future trials.
CRIS-Team Scopus Importer:2020-03-17
Keywords: Biomarkers; Dendritic cell vaccines; Eosinophils

Blood Eosinophils Are Associated with Efficacy of Targeted Therapy in Patients with Advanced Melanoma - Wendlinger, Simone; Wohlfarth, Jonas; Kreft, Sophia; Siedel, Claudia; Kilian, Teresa; Dischinger, Ulrich; Heppt, Markus; Wistuba-Hamprecht, Kilian; Meier, Friedegund; Goebeler, Matthias; Schadendorf, Dirk; Gesierich, Anja; et al. (Cancers, 2022)
Background: Eosinophils appear to contribute to the efficacy of immunotherapy and their frequency was suggested as a predictive biomarker. Whether this observation could be transferred to patients treated with targeted therapy remains unknown. Methods: Blood and serum samples of healthy controls and 216 patients with advanced melanoma were prospectively and retrospectively collected. Freshly isolated eosinophils were phenotypically characterized by flow cytometry and co-cultured in vitro with melanoma cells to assess cytotoxicity. Soluble serum markers and peripheral blood counts were used for correlative studies. Results: Eosinophil-mediated cytotoxicity towards melanoma cells, as well as phenotypic characteristics, were similar when comparing healthy donors and patients. However, high relative pre-treatment eosinophil counts were significantly associated with response to MAPKi (p = 0.013). Eosinophil-mediated cytotoxicity towards melanoma cells is dose-dependent and requires proximity of eosinophils and their target in vitro. Treatment with targeted therapy in the presence of eosinophils results in an additive tumoricidal effect. Additionally, melanoma cells affected eosinophil phenotype upon co-culture. Conclusion: High pre-treatment eosinophil counts in advanced melanoma patients were associated with a significantly improved response to MAPKi. Functionally, eosinophils show potent cytotoxicity towards melanoma cells, which can be reinforced by MAPKi. Further studies are needed to unravel the molecular mechanisms of our observations.
CRIS-Team Scopus Importer:2022-05-20
Keywords: biomarker; eosinophils; melanoma

Bone microstructure and volumetric bone mineral density in patients with hyperuricemia with and without psoriasis - Simon, David; Haschka, J.; Muschitz, C.; Kocijan, A.; Baierl, A.; Kleyer, Arnd; Schett, Georg; Kapiotis, S.; Resch, H.; Sticherling, Michael; Rech, Jürgen; Kocijan, R. (Osteoporosis international, 2020)
Summary: We analyzed volumetric bone mineral density (vBMD) and bone microstructure using HR-pQCT in subjects with normouricemia (NU) and subjects with hyperuricemia (HU) with and without psoriasis (PSO). HU was associated with higher cortical vBMD and thickness. Differences in average and trabecular vBMD were found between patients with PSO + HU and NU. Introduction: Hyperuricemia (HU) and gout are co-conditions of psoriasis and psoriatic arthritis. Current data suggest a positive association between HU and areal bone mineral density (BMD) and a negative influence of psoriasis on local bone, even in the absence of arthritis. However, the influence of the combination of HU and psoriasis on bone is still unclear. The aim of this study was to assess the impact of HU with and without psoriasis on bone microstructure and volumetric BMD (vBMD). Methods: Healthy individuals with uric acid levels within the normal range (NU), with hyperuricemia (HU), patients with hyperuricemia and psoriasis (PSO + HU), and patients with uric acid within the normal range and psoriasis (PSO + NU) were included in our study. Psoriasis patients had no current or past symptoms of arthritis. Average, trabecular, and cortical vBMD (mgHA/cm3); trabecular number (Tb.N, 1/mm) and thickness (Tb.Th, mm); inhomogeneity of the network (1/N.SD, mm); and cortical thickness (Ct.Th., mm) were carried out at the ultradistal radius using high-resolution peripheral quantitative computed tomography. In addition, bone turnover markers such as DKK-1, sclerostin, and P1NP were analyzed. Results: In total, 130 individuals were included (44 NU participants (34% female), 50 HU (24%), 16 PSO + HU (6%), 20 PSO + NU (60%)). Subjects were aged: NU 54.5 (42.8, 62.1), HU 57.5 (18.6, 65.1), PSO + HU 52.0 (42.3, 57.8), and PSO + NU 42.5 (34.8, 56.8), respectively. After adjusting for age, sex, BMI, and diabetes, patients in the HU group revealed significantly higher values of cortical vBMD (p < 0.001) as well as cortical thickness (p = 0.04) compared to the NU group. PSO + NU showed no differences to NU, but PSO + HU demonstrated both lower average (p = 0.03) and trabecular vBMD (p = 0.02). P1NP was associated with average, cortical, and trabecular vBMD as well as cortical thickness while sclerostin levels were related to trabecular vBMD. Conclusion: Hyperuricemia in otherwise healthy subjects was associated with a better cortical vBMD and higher cortical thickness. However, patients with both psoriasis and hyperuricemia revealed a lower vBMD.
CRIS-Team Scopus Importer:2020-01-21
Keywords: Bone Mineral Density; HR-pQCT; Hyperuricemia; Psoriasis

Bone Microstructure in Patients with Cutaneous Psoriasis and No History of Psoriatic Arthritis Shows Bone Anabolic Changes at a Greater Extent Than in Healthy Controls - Simon, David; Faustini, Francesca; Englbrecht, Matthias; Kleyer, Arnd; Kocijan, Roland; Haschka, Judith; Finzel, Stephanie; Kraus, Sebastian; Hueber, Axel; Sticherling, Michael; Schett, Georg; Rech, Jürgen (2014)
EVALuna2:13229

BRAF and MEK inhibitors affect dendritic cell maturation and T cell stimulation - Hoyer, Stefanie; Eberlein, V.; Schuler, Gerold; Berking, Carola; Heinzerling, Lucie; Schaft, Niels; Dörrie, Jan (EXPERIMENTAL DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-14

BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation - Hoyer, Stefanie; Eberlein, Valentina; Schuler, Gerold; Berking, Carola; Heinzerling, Lucie; Schaft, Niels; Dörrie, Jan (International Journal of Molecular Sciences, 2021)
BRAF and MEK inhibitor (BRAFi/MEKi) combinations are currently the standard treatment for patients with BRAFV600 mutant metastatic melanoma. Since the RAS/RAF/MEK/ERK-pathway is crucial for the function of different immune cells, we postulated an effect on their function and thus interference with anti-tumor immunity. Therefore, we examined the influence of BRAFi/MEKi, either as single agent or in combination, on the maturation of monocyte-derived dendritic cells (moDCs) and their interaction with T cells. DCs matured in the presence of vemurafenib or vemurafenib/cobimetinib altered their cytokine secretion and surface marker expression profile. Upon the antigen-specific stimulation of CD8+ and CD4+ T cells with these DCs or with T2.A1 cells in the presence of BRAFi/MEKi, we detected a lower expression of activation markers on and a lower cytokine secretion by these T cells. However, treatment with any of the inhibitors alone or in combination did not change the avidity of CD8+ T cells in peptide titration assays with T2.A1 cells. T-helper cell/DC interaction is a bi-directional process that normally results in DC activation. Vemurafenib and vemurafenib/cobimetinib completely abolished the helper T-cell-mediated upregulation of CD70, CD80, and CD86 but not CD25 on the DCs. The combination of dabrafenib/trametinib affected DC maturation and activation as well as T-cell activation less than combined vemurafenib/cobimetinib did. Hence, for a potential combination with immunotherapy, our data indicate the superiority of dabrafenib/trametinib treatment.
Keywords: vemurafenib; dabrafenib; cobimetinib; trametinib; BRAF inhibitor; MEK inhibitor; DCs; T cells; immunotherapy; melanoma

BRAF and MEK inhibitors change human immune cell phenotype and function; possible consequences for combination therapy - Hoyer, S.; Eberlein, V.; Babalija, L.; Gerer, K.; Walter, L.; Schuler, Gerold; Schaft, Niels; Heinzerling, Lucie; Dörrie, Jan (2018)
EVALuna2:34394

BRAF and MEK inhibitors influence human immune cell phenotype and function - Hoyer, S.; Eberlein, V.; Babalija, L.; Gerer, K. F.; Walter, L.; Schuler, Gerold; Schaft, Niels; Heinzerling, Lucie; Dörrie, Jan (2017)
EVALuna2:34310

BRAF and MEK Inhibitors Influence the Function of Reprogrammed T Cells: Consequences for Adoptive T-Cell Therapy - Dörrie, Jan; Babalija, Lek; Hoyer, Stefanie; Gerer, Kerstin F.; Schuler, Gerold; Heinzerling, Lucie; Schaft, Niels (International Journal of Molecular Sciences, 2018)
BRAF and MEK inhibitors (BRAFi/MEKi), the standard treatment for patients with BRAFV600 mutated melanoma, are currently explored in combination with various immunotherapies, notably checkpoint inhibitors and adoptive transfer of receptor-transfected T cells. Since two BRAFi/MEKi combinations with similar efficacy are approved, potential differences in their effects on immune cells would enable a rational choice for triple therapies. Therefore, we characterized the influence of the clinically approved BRAFi/MEKi combinations dabrafenib (Dabra) and trametinib (Tram) vs. vemurafenib (Vem) and cobimetinib (Cobi) on the activation and functionality of chimeric antigen receptor (CAR)-transfected T cells. We co-cultured CAR-transfected CD8⁺ T cells and target cells with clinically relevant concentrations of the inhibitors and determined the antigen-induced cytokine secretion. All BRAFi/MEKi reduced this release as single agents, with Dabra having the mildest inhibitory effect, and Dabra + Tram having a clearly milder inhibitory effect than Vem + Cobi. A similar picture was observed for the upregulation of the activation markers CD25 and CD69 on CAR-transfected T cells after antigen-specific stimulation. Most importantly, the cytolytic capacity of the CAR-T cells was significantly inhibited by Cobi and Vem + Cobi, whereas the other kinase inhibitors showed no effect. Therefore, the combination Dabra + Tram would be more suitable for combining with T-cell-based immunotherapy than Vem + Cobi.
EVALuna2:34407

Braf inhibitors and radiation do not act synergistically to inhibit WT and V600E BRAF human melanoma - Walter, Lisa; Heinzerling, Lucie (Anticancer Research, 2018)
Keywords: Radiotherapy; V600E mutant BRAF; Dabrafenib; Melanoma; Vemurafenib; BRAF inhibitor; BRAF

BRAF Inhibitors and Radiation Do Not Act Synergistically to Inhibit WT and V600E BRAF Human Melanoma - Walter, Lisa; Heinzerling, Lucie (Anticancer Research, 2018)
BACKGROUND/AIM: Recent evidence suggests that melanoma patients treated with BRAF inhibitors experience radiosensitization with an increased frequency of side-effects. This could also imply increased effectiveness when treating melanoma. MATERIALS AND METHODS: To test whether the BRAF inhibitors dabrafenib and vemurafenib together with ionizing radiation more effectively inhibit melanoma cells, primary human melanoma tumor cell lines expressing wild-type (WT) or mutant V600E BRAF were analyzed by cell survival, cell death, and cell-cycle testing. RESULTS: All melanoma cell lines examined were radioresistant in these assays. BRAF inhibitor treatment alone suppressed cell survival more effectively than radiation in all the mutant V600E BRAF cell lines, and vemurafenib, but not dabrafenib, also inhibited cell survival in the WT BRAF cell lines at clinically relevant concentrations. However, when cells were treated with BRAF inhibitor followed by radiation, there was no increased effect on the suppression of cell survival. Vemurafenib induced more necrosis than radiation in most melanoma cell lines, irrespective of BRAF status, but this effect was not additive with the combination treatment. BRAF inhibitors and radiation had variable, but independent effects on the induction of cell-cycle arrest. CONCLUSION: These results suggest that BRAF inhibitors and ionizing radiation do not act synergistically to inhibit the growth of primary human melanoma cells.
EVALuna2:34396
Keywords: Radiotherapy; V600E mutant BRAF; Dabrafenib; Melanoma; Vemurafenib; BRAF inhibitor; BRAF

Breaking barriers: NEK2 inhibition shines in multiple myeloma treatment - Lischer, Christopher; Bruns, Heiko (Cell Reports Medicine, 2023)
In their article, Cheng et al.1 reveal that NEK2 loss reshapes the tumor microenvironment, reducing tumor-associated macrophages and decreasing T cell exhaustion. They show that this ultimately favors the immune system's anti-cancer response in multiple myeloma.
CRIS-Team Scopus Importer:2023-10-20

Breaking Entry-and Species Barriers: LentiBOOST® Plus Polybrene Enhances Transduction Efficacy of Dendritic Cells and Monocytes by Adenovirus 5 - Strack, Astrid; Deinzer, Anja; Thirion, Christian; Schrödel, Silke; Dörrie, Jan; Sauerer, Tatjana; Steinkasserer, Alexander; Knippertz, Ilka (Viruses, 2022)
Due to their ability to trigger strong immune responses, adenoviruses (HAdVs) in general and the serotype5 (HAdV-5) in particular are amongst the most popular viral vectors in research and clinical application. However, efficient transduction using HAdV-5 is predominantly achieved in coxsackie and adenovirus receptor (CAR)-positive cells. In the present study, we used the transduc-tion enhancer LentiBOOST® comprising the polycationic Polybrene to overcome these limitations. Using LentiBOOST® /Polybrene, we yielded transduction rates higher than 50% in murine bone marrow-derived dendritic cells (BMDCs), while maintaining their cytokine expression profile and their capability to induce T-cell proliferation. In human dendritic cells (DCs), we increased the transduction rate from 22% in immature (i)DCs or 43% in mature (m)DCs to more than 80%, without inducing cytotoxicity. While expression of specific maturation markers was slightly upregulated using LentiBOOST® /Polybrene on iDCs, no effect on mDC phenotype or function was observed. Moreover, we achieved efficient HAdV5 transduction also in human monocytes and were able to subsequently differentiate them into proper iDCs and functional mDCs. In summary, we introduce LentiBOOST® comprising Polybrene as a highly potent adenoviral transduction agent for new in-vitro applications in a set of different immune cells in both mice and humans.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Adenoviral transduction; Adenovirus; Dendritic cells; LentiBOOST®; Monocytes; T cells

Brn3a expression is epigenetically controlled by HDAC2 in melanocytes and melanoma - Heppt, Markus; Wessely, A.; Hornig, E.; Kammerbauer, C.; Graf, S.; Besch, R.; French, L. E.; Kuphal, Silke; Kappelmann-Fenzl, Melanie; Boßerhoff, Anja Katrin; Berking, Carola (EXPERIMENTAL DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-14

Buffy coat volume reduction for optimization of leucapheresis harvests produced by the autoMNC program - Burk, Samaya; Erdmann, M.; Weiss, D.; Eckstein, Reinhold; Strasser, Erwin (Vox Sanguinis, 2015)
Buffy coat (BC) volume reduction was evaluated in leucapheresis (LA) harvests due to the target monocyte yield and the red blood cell (RBC) content. A packed erythrocyte volume (PEV) of 7.5 ml should not be exceeded to avoid RBC debulking with loss of leucocytes (WBCs) and the monocyte fraction during monocyte counterflow elutriation, a next step of monocyte enrichment prior to cell culture.Two hundred and fifty-three 5-l leucaphereses (autoMNC program) performed in 102 healthy blood donors (24 female and 78 male donors) were retrospectively analysed. Different categories of BC volumes were compared due to the quality of the LA products measured by blood counts and flow cytometry.Collection of maximum BC volume of 10 ml and more each collection cycle (product volume: 169 ± 21 ml) resulted in 1.58 ± 0·41 × 10e9 CD14(+) monocytes and high volume of packed erythrocyte (18.4 ± 8.8 ml). Low BC volume collection below 6 ml each collection cycle produced only 1.07 ± 0.40 × 10e9 CD14(+) monocytes but reduced PEV significantly by 64% (6.7 ± 4.1 ml).By reduction of the BC volume, the PEV in LA products could be reduced, which is a precondition for counterflow elutriation of monocytes. A BC volume between 7 and 8 ml per collection cycle should be adjusted to reduce PEV to 7.5 ml without relevant monocyte loss.
EVALuna2:15992

Can checkpoint inhibitor therapy improve response to chemotherapy? - Boßerhoff, Anja Katrin; Schuler, Gerold; Heinzerling, Lucie; Schilling, Bastian; Haferrkamp, Sebastian; Kirchberger, MC (2017)
EVALuna2:4767

Can checkpoint inhibitor therapy improve response to chemotherapy? - Kirchberger, Michael Constantin; Schilling, Bastian; Haferkamp, Sebastian; Boßerhoff, Anja Katrin; Schuler, Gerold; Heinzerling, Lucie (Journal of Cancer Research and Clinical Oncology, 2018)
EVALuna2:34410

Can Gamification Contribute to Computer Modeling-Driven Biomedical Research? - Vera, Julio; Santos Rosales, Guido (Frontiers in Physiology, 2018)
EVALuna2:34787

Can Synthetic Images Improve CNN Performance in Wound Image Classification? - Malihi, Leila; Hübner, Ursula; Richter, Mats L.; Moelleken, Maurice; Przysucha, Mareike; Busch, Dorothee; Heggemann, Jan; Hafer, Guido; Wiemeyer, Stefan; Heidemann, Gunther; Dissemond, Joachim; Erfurt-Berge, Cornelia; et al. (Caring is Sharing – Exploiting the Value in Data for Health and Innovation, 2023)
For artificial intelligence (AI) based systems to become clinically relevant, they must perform well. Machine Learning (ML) based AI systems require a large amount of labelled training data to achieve this level. In cases of a shortage of such large amounts, Generative Adversarial Networks (GAN) are a standard tool for synthesising artificial training images that can be used to augment the data set. We investigated the quality of synthetic wound images regarding two aspects: (i) improvement of wound-type classification by a Convolutional Neural Network (CNN) and (ii) how realistic such images look to clinical experts (n = 217). Concerning (i), results show a slight classification improvement. However, the connection between classification performance and the size of the artificial data set is still unclear. Regarding (ii), although the GAN could produce highly realistic images, the clinical experts took them for real in only 31% of the cases. It can be concluded that image quality may play a more significant role than data size in improving the CNN-based classification result.
CRIS-Team Scopus Importer:2023-06-02
Keywords: artificial intelligence; classification; convolutional neural network; data augmentation; generative adversarial networks; synthetic images; wound imaging

Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy - Heinzerling, Lucie; Ott, Patrick A.; Hodi, F. Stephen; Husain, Aliya N.; Tajmir-Riahi, Azadeh; Tawbi, Hussein; Pauschinger, Matthias; Gajewski, Thomas F.; Lipson, Evan J.; Luke, Jason J. (Journal for ImmunoTherapy of Cancer, 2016)
Immune-checkpoint blocking antibodies have demonstrated objective antitumor responses in multiple tumor types including melanoma, non-small cell lung cancer (NSCLC), and renal cell cancer (RCC). In melanoma, an increase in overall survival has been demonstrated with anti-CTLA-4 and PD-1 inhibition. However, a plethora of immune-mediated adverse events has been reported with these agents. Immune-mediated cardiotoxicity induced by checkpoint inhibitors has been reported in single cases with variable presentation, including myocarditis and pericarditis. Among six clinical cancer centers with substantial experience in the administration of immune-checkpoint blocking antibodies, eight cases of immune-related cardiotoxicity after ipilimumab and/or nivolumab/pembrolizumab were identified. Diagnostic findings, treatment and follow-up are reported. A large variety of cardiotoxic events with manifestations such as heart failure, cardiomyopathy, heart block, myocardial fibrosis and myocarditis was documented. This is the largest case series to date describing cardiotoxicity of immune-checkpoint blocking antibodies. Awareness, monitoring of patients with pre-existing cardiac disorders and prompt evaluation by the treatment team is essential. Treatment including application of steroids is critical for patient safety.
EVALuna2:33930

Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis - Zhang, Lili; Awadalla, Magid; Mahmood, Syed S.; Nohria, Anju; Hassan, Malek Z.O.; Thuny, Franck; Zlotoff, Daniel A.; Murphy, Sean P.; Stone, James R.; Golden, Doll Lauren Alexandra; Alvi, Raza M.; Rokicki, Adam; et al. (European Heart Journal, 2020)
AIMS: Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented. METHODS AND RESULTS: From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE. CONCLUSION: These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.
CRIS-Team Scopus Importer:2020-05-19
Keywords: Cardiovascular magnetic resonance; Immune checkpoint inhibitor; Myocarditis

CARs and Drugs: Pharmacological Ways of Boosting CAR-T-Cell Therapy - Harrer, Dennis Christoph; Dörrie, Jan; Schaft, Niels (International Journal of Molecular Sciences, 2023)
The development of chimeric antigen receptor T cells (CAR-T cells) has marked a new era in cancer immunotherapy. Based on a multitude of durable complete remissions in patients with hematological malignancies, FDA and EMA approval was issued to several CAR products targeting lymphoid leukemias and lymphomas. Nevertheless, about 50% of patients treated with these approved CAR products experience relapse or refractory disease necessitating salvage strategies. Moreover, in the vast majority of patients suffering from solid tumors, CAR-T-cell infusions could not induce durable complete remissions so far. Crucial obstacles to CAR-T-cell therapy resulting in a priori CAR-T-cell refractory disease or relapse after initially successful CAR-T-cell therapy encompass antigen shutdown and CAR-T-cell dysfunctionality. Antigen shutdown predominately rationalizes disease relapse in hematological malignancies, and CAR-T-cell dysfunctionality is characterized by insufficient CAR-T-cell proliferation and cytotoxicity frequently observed in patients with solid tumors. Thus, strategies to surmount those obstacles are being developed with high urgency. In this review, we want to highlight different approaches to combine CAR-T cells with drugs, such as small molecules and antibodies, to pharmacologically boost CAR-T-cell therapy. In particular, we discuss how certain drugs may help to counteract antigen shutdown and CAR-T-cell dysfunctionality in both hematological malignancies and solid tumors.
CRIS-Team Scopus Importer:2023-02-24
Keywords: combination; drugs; immunotherapy; microenvironment; pharmaceuticals

CARs: Beyond T Cells and T Cell-Derived Signaling Domains. - Sievers, Nico M.; Dörrie, Jan; Schaft, Niels (International Journal of Molecular Sciences, 2020)
When optimizing chimeric antigen receptor (CAR) therapy in terms of efficacy, safety, and broadening its application to new malignancies, there are two main clusters of topics to be addressed: the CAR design and the choice of transfected cells. The former focuses on the CAR construct itself. The utilized transmembrane and intracellular domains determine the signaling pathways induced by antigen binding and thereby the cell-specific effector functions triggered. The main part of this review summarizes our understanding of common signaling domains employed in CARs, their interactions among another, and their effects on different cell types. It will, moreover, highlight several less common extracellular and intracellular domains that might permit unique new opportunities. Different antibody-based extracellular antigen-binding domains have been pursued and optimized to strike a balance between specificity, affinity, and toxicity, but these have been reviewed elsewhere. The second cluster of topics is about the cellular vessels expressing the CAR. It is essential to understand the specific attributes of each cell type influencing anti-tumor efficacy, persistence, and safety, and how CAR cells crosstalk with each other and bystander cells. The first part of this review focuses on the progress achieved in adopting different leukocytes for CAR therapy.
CRIS-Team Scopus Importer:2020-05-29
Keywords: 2B4; Chimeric antigen receptor (CAR); DAP10; Intracellular signaling domain; Myeloid cells; NK cell; NKG2D; NKT cell; T cell; γ/δ T cells

CAR-T cell therapy in melanoma: A future success story? - Simon, Bianca; Uslu, Ugur (Experimental Dermatology, 2018)
Chimeric antigen receptor (CAR)-T cells are one of the impressive recent success stories of anti-cancer immunotherapy. Especially in haematological malignancies, this treatment strategy has shown promising results leading to the recent approval of two CAR-T cell constructs targeting CD19 in the United States and the European Union. After the huge success in haematological cancers, the next step will be the evaluation of its efficacy in different solid tumors, which is currently investigated in preclinical as well as clinical settings. A commonly examined tumor model in the context of immunotherapy is melanoma, since it is known for its immunogenic features. However, the first results of CAR-T cell therapy in solid tumors did not reveal the same impressive outcomes that were observed in haematological malignancies, as engineered cells need to cope with several challenges. Obstacles include the lack of migration of CAR-T cells from blood vessels to the tumor site as well as the immunosuppressive tumor microenvironment within solid tumors. Another hurdle is posed by the identification of an ideal target antigen to avoid on-target/off-tumor toxicities. Regarding immune escape mechanisms, which can be developed by tumor cells to bypass immune recognition, the observation of antigen loss should also be considered. This article gives an overview of the challenges displayed in CAR-T cell therapy for the use in solid tumors and discusses different new strategies and approaches that deal with these problems in order to improve CAR-T cell therapy, particularly for its use in melanoma.
EVALuna2:203618

CAR/TCR-transfected gamma/delta T cells for immunotherapy of melanoma - Harrer, D. C.; Simon, B.; Fujii, S.; Shimizu, K.; Uslu, U.; Schoch, L.; Schuler, Gerold; Gerer, K. F.; Hoyer, S.; Dörrie, Jan; Schaft, Niels (2017)
EVALuna2:34323

CAR-T-Zellen auf dem Weg zur praktischen Anwendung in der dermatologischen Onkologie - Uslu, Ugur (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-03-19

Case report: Bullous pemphigoid in HIV-1-positive patients: interplay or coincidence? A case series and review of the literature - Foerster, Yannick; Sollfrank, Lukas; Rechtien, Laura; Harrer, Thomas; Berking, Carola; Sticherling, Michael (Frontiers in Immunology, 2023)
Bullous pemphigoid (BP) is an autoimmune inflammatory skin disease, mostly affecting the elderly population. Therefore, patients often have multiple comorbidities, but there is inconsistent data regarding the relationship between HIV-1 infection and BP, which has been rarely reported in combination. Herein, we describe three patients who presented with BP and concomitant HIV-1 infection that was well controlled with modern combined antiretroviral therapy. All patients received topical and oral corticosteroids. Depending on the individual severity, further add-on therapeutics, such as azathioprine, dapsone, doxycycline and the interleukin 4/13 antibody dupilumab, were added to the therapy regimen. All patients recovered from pruritic skin lesions and blistering. The cases are further discussed in the context of the current study landscape. In conclusion, HIV-1 infection shifts the cytokine profile from T-helper type 1 (TH1) towards T-helper type 2 (TH2), resulting in the excessive secretion of distinct cytokines, such as interleukin 4 (IL-4) and interleukin 10 (IL-10). With IL-4 being a main driver in the pathogenesis of BP, HIV-1-positive patients may benefit greatly from targeting IL-4 with monoclonal antibodies.
CRIS-Team Scopus Importer:2023-07-07
Keywords: aids; bullous pemphigoid; COVID-19; dupilumab; HIV-1; immune reconstitution inflammatory syndrome; iris

Case report: Patient specific combination of surgery and immunotherapy in advanced squamous cell carcinoma of the head and neck – a case series and review of literature - Olmos, Manuel; Lutz, Rainer; Büntemeyer, Tjark-Ole; Glajzer, Jacek; Nobis, Christopher-Philipp; Ries, Jutta; Möst, Tobias; Eckstein, Markus; Hecht, Markus; Gostian, Antoniu-Oreste; Erdmann, Michael; Foerster, Yannick; et al. (Frontiers in Immunology, 2022)
Background: Prognosis of patients with recurrent or metastatic head and neck cancer is generally poor. Adjuvant immunotherapy (IT) featuring immune checkpoint inhibition (ICI) is standard of care in advanced stage head and neck squamous cell carcinoma (HNSCC) and cutaneous squamous cell carcinoma (CSCC). ICI response rates in CSCC are described as higher than in HNSCC. IT is constantly shifting into earlier disease stages which confronts the surgeon with immunotherapeutically pre-treated patients. It is therefore becoming increasingly difficult to assess which patients with symptomatic tumor disease and a lack of curative surgical option might benefit from salvage surgery. Case presentations: The following 6 cases describe therapeutic decision-making regarding ICI and (salvage) surgery in patients with advanced stage HNSCC or CSCC. Cases A and B focus on neoadjuvant ICI followed by salvage surgery. In Cases C and D salvage surgery was performed after short-term stabilization with partial response to ICI. The last two cases (Cases E and F) address the surgical approach after failure of ICI. All cases are discussed in the context of the current study landscape and with focus on individual decision-making. For better understanding, a timetable of the clinical course is given for each case. Conclusions: ICI is rapidly expanding its frontiers into the neoadjuvant setting, frequently confronting the surgeon with heavily pretreated patients. Salvage surgery is a viable therapeutic concept despite the rise of systemic treatment options. Decision-making on surgical intervention in case of a salvage surgery remains an individual choice. For neoadjuvant ICI monitoring regarding pathological tumor response or tumor necrosis rate, we suggest correlation between the initial biopsy and the definite tumor resectate in order to increase its significance as a surrogate marker. Scheduling of neoadjuvant ICI should be further investigated, as recent studies indicate better outcomes with shorter time frames.
CRIS-Team Scopus Importer:2022-11-25
Keywords: anti-PD 1; checkpoint inhibition; CSCC; HNSCC; immunotherapy; neoadjuvant; OSCC; salvage surgery

Case Report: The many faces of bullous pemphigoid - Rechtien, Laura; Sollfrank, Lukas; Foerster, Yannick; Berking, Carola; Sticherling, Michael (Frontiers in Immunology, 2023)
The pemphigoid group comprises a number of bullous skin diseases with autoantibodies against different constituents of the basement membrane zone that result in subepidermal detachment and clinically characteristic tense blisters, erosions, urticarial erythema, and itching. Apart from the most frequent type of bullous pemphigoid with antibodies against BP180, which is found predominantly in elderly patients, the disease may present at other ages and different pathogenic conditions. Here, four cases are presented of young age (3 months and 25, 34, and 46 years) and in association with vaccination, pregnancy, or metastatic cancer. Though anti-BP180 was found in all cases, a different pathogenic background may be found in any of them, resulting in characteristic clinical manifestation, yet demanding specifically adapted therapeutic approaches.
CRIS-Team Scopus Importer:2023-11-03
Keywords: bullous autoimmune disease; bullous pemphigoid; COVID-19 vaccination; juvenile pemphigoid; pemphigoid gestationis

Cash is king: the balance of costs and effectiveness of treatments for actinic keratosis - Steeb, T.; Heppt, Franz; Berking, Carola (British Journal of Dermatology, 2020)
CRIS-Team Scopus Importer:2020-04-17

Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro - Flynn, Charlotte M.; Garbers, Yvonne; Düsterhöft, Stefan; Wichert, Rielana; Lokau, Juliane; Lehmann, Christian; Dudziak, Diana; Schröder, Bernd; Becker-Pauly, Christoph; Rose-John, Stefan; Aparicio-Siegmund, Samadhi; Garbers, Christoph (Scientific Reports, 2020)
The cytokine interleukin-6 (IL-6) fulfills its pleiotropic functions via different modes of signaling. Regenerative and anti-inflammatory activities are mediated via classic signaling, in which IL-6 binds to the membrane-bound IL-6 receptor (IL-6R). For IL-6 trans-signaling, which accounts for the pro-inflammatory properties of the cytokine, IL-6 activates its target cells via soluble forms of the IL-6R (sIL-6R). We have previously shown that the majority of sIL-6R in human serum originates from proteolytic cleavage and mapped the cleavage site of the IL-6R. The cleavage occurs between Pro-355 and Val-356, which is the same cleavage site that the metalloprotease ADAM17 uses in vitro. However, sIL-6R serum levels are unchanged in hypomorphic ADAM17ex/ex mice, making the involvement of ADAM17 questionable. In order to identify other proteases that could be relevant for sIL-6R generation in vivo, we perform a screening approach based on the known cleavage site. We identify several candidate proteases and characterize the cysteine protease cathepsin S (CTSS) in detail. We show that CTSS is able to cleave the IL-6R in vitro and that the released sIL-6R is biologically active and can induce IL-6 trans-signaling. However, CTSS does not use the Pro-355/Val-356 cleavage site, and sIL-6R serum levels are not altered in Ctss−/− mice. In conclusion, we identify a novel protease of the IL-6R that can induce IL-6 trans-signaling, but does not contribute to steady-state sIL-6R serum levels.
CRIS-Team Scopus Importer:2020-12-25

CD83 acts as immediate early response gene in activated macrophages and exhibits specific intracellular trafficking properties - Langguth, Pia; Peckert, Katrin; Beck, Philipp; Kuhnt, Christine; Draßner, Christina; Deinzer, Andrea; Steinkasserer, Alexander; Wild, Andreas (Biochemical and Biophysical Research Communications, 2023)
Macrophages (MΦ) are remarkably plastic cells, which assume phenotypes in every shade between a pro-inflammatory classical activation, and anti-inflammatory or resolving activation. Therefore, elucidation of mechanisms involved in shaping MΦ plasticity and function is key to understand their role during immunological balance. The immune-modulating CD83 molecule is expressed on activated immune cells and various tissue resident MΦ, rendering it an interesting candidate for affecting MΦ biology. However, in-depth analyses of the precise kinetics and trafficking of CD83 within pro-inflammatory, LPS activated bone-marrow-derived MΦ have not been performed. In this study, we show that activation with LPS leads to a very fast and strong, but transient increase of CD83 expression on these cells. Its expression peaks within 2 h of stimulation and is thereby faster than the early activation antigen CD69. To trace the CD83 trafficking through MΦs, we employed multiple inhibitors, thereby revealing a de novo synthesis and transport of the protein to the cell surface followed by lysosomal degradation, all within 6 h. Moreover, we found a similar expression kinetic and trafficking in human monocyte derived MΦ. This places CD83 at a very early point of MΦ activation suggesting an important role in decisions regarding the subsequent cellular fate.
CRIS-Team Scopus Importer:2023-02-10
Keywords: CD83; expression; intracellular trafficking; lipopolysaccharide; macrophages

CD83 and GRASP55 interact in human dendritic cells - Stein, Marcello F.; Blume, Katja; Heilingloh, Christiane; Kummer, Mirko; Biesinger, Brigitte; Sticht, Heinrich; Steinkasserer, Alexander (Biochemical and Biophysical Research Communications, 2015)
CD83 is one of the best known surface markers for mature human dendritic cells (DCs). The full-length 45 kDa type-I membrane-bound form (mbCD83) is strongly glycosylated upon DCs maturation. As co-stimulatory properties of CD83 are attributed to mbCD83 surface expression is required for efficient T-cell stimulation by mature DCs. By yeast two-hybrid screening, we were able to identify GRASP55 as interaction partner of CD83. DCs maturation induces endogenous CD83 protein expression with simultaneous regulation of CD83 glycosylation, interaction and co-localization with GRASP55 and CD83 surface exposure. GRASP55 is especially known for its role in maintaining Golgi architecture, but also plays a role in Golgi transport of specific cargo proteins bearing a C-terminal valine residue. Here we additionally demonstrate that binding of CD83 and GRASP55 rely on the C-terminal TELV-motif of CD83. Mutation of this TELV-motif not only disrupted binding to GRASP55, but also altered the glycosylation pattern of CD83 and reduced its membrane expression. Here we show for the first time that GRASP55 interacts with CD83 shortly after induction of DC maturation and that this interaction plays a role in CD83 glycosylation as well as in surface expression of CD83 on DCs.
EVALuna2:8259

CD83 expressed by macrophages is an important immune checkpoint molecule for the resolution of inflammation - Peckert-Maier, Katrin; Langguth, Pia; Strack, Astrid; Stich, Lena; Mühl-Zürbes, Petra; Kuhnt, Christine; Drassner, Christina; Zinser, Elisabeth; Wrage, Marius; Mattner, Jochen; Steinkasserer, Alexander; Royzman, Dmytro; et al. (Frontiers in Immunology, 2023)
Excessive macrophage (M phi) activation results in chronic inflammatory responses or autoimmune diseases. Therefore, identification of novel immune checkpoints on M phi, which contribute to resolution of inflammation, is crucial for the development of new therapeutic agents. Herein, we identify CD83 as a marker for IL-4 stimulated pro-resolving alternatively activated M phi (AAM). Using a conditional KO mouse (cKO), we show that CD83 is important for the phenotype and function of pro-resolving M phi. CD83-deletion in IL-4 stimulated M phi results in decreased levels of inhibitory receptors, such as CD200R and MSR-1, which correlates with a reduced phagocytic capacity. In addition, CD83-deficient M phi upon IL-4 stimulation, show an altered STAT-6 phosphorylation pattern, which is characterized by reduced pSTAT-6 levels and expression of the target gene Gata3. Concomitantly, functional studies in IL-4 stimulated CD83 KO M phi reveal an increased production of pro-inflammatory mediators, such as TNF-alpha, IL-6, CXCL1 and G-CSF. Furthermore, we show that CD83-deficient M phi have enhanced capacities to stimulate the proliferation of allo-reactive T cells, which was accompanied by reduced frequencies of Tregs. In addition, we show that CD83 expressed by M phi is important to limit the inflammatory phase using a full-thickness excision wound healing model, since inflammatory transcripts (e.g. Cxcl1, Il6) were increased, whilst resolving transcripts (e.g. Ym1, Cd200r, Msr-1) were decreased in wounds at day 3 after wound infliction, which reflects the CD83 resolving function on M phi also in vivo. Consequently, this enhanced inflammatory milieu led to an altered tissue reconstitution after wound infliction. Thus, our data provide evidence that CD83 acts as a gatekeeper for the phenotype and function of pro-resolving M phi.
CRIS-Team WoS Importer:2023-03-17

CD83 expression is essential for Treg cell differentiation and stability - Döbbeler, Marina; Koenig, Christina; Krzyzak, Lena; Seitz, Christine; Wild, Andreas; Ulas, Thomas; Bassler, Kevin; Kopelyanskiy, Dmitry; Butterhof, Alina; Kuhnt, Christine; Kreiser, Simon; Stich, Lena; et al. (JCI Insight, 2018)
Foxp3-positive regulatory T cells (Tregs) are crucial for the maintenance of immune homeostasis and keep immune responses in check. Upon activation, Tregs are transferred into an effector state expressing transcripts essential for their suppressive activity, migration, and survival. However, it is not completely understood how different intrinsic and environmental factors control differentiation. Here, we present for the first time to our knowledge data suggesting that Treg-intrinsic expression of CD83 is essential for Treg differentiation upon activation. Interestingly, mice with Treg-intrinsic CD83 deficiency are characterized by a proinflammatory phenotype. Furthermore, the loss of CD83 expression by Tregs leads to the downregulation of Treg-specific differentiation markers and the induction of an inflammatory profile. In addition, Treg-specific conditional knockout mice showed aggravated autoimmunity and an impaired resolution of inflammation. Altogether, our results show that CD83 expression in Tregs is an essential factor for the development and function of effector Tregs upon activation. Since Tregs play a crucial role in the maintenance of immune tolerance and thus prevention of autoimmune disorders, our findings are also clinically relevant.
EVALuna2:36212

CD83 Modulates B Cell Activation and Germinal Center Responses - Krzyzak, Lena; Seitz, Christine; Urbat, Anne; Hutzler, Stefan; Ostalecki, Christian; Glaesner, Joachim; Hiergeist, Andreas; Gessner, Andre; Winkler, Thomas; Steinkasserer, Alexander; Nitschke, Lars (Journal of Immunology, 2016)
CD83 is a maturation marker for dendritic cells. In the B cell lineage, CD83 is expressed especially on activated B cells and on light zone B cells during the germinal center (GC) reaction. The function of CD83 during GC responses is unclear. CD83(-/-) mice have a strong reduction of CD4(+) T cells, which makes it difficult to analyze a functional role of CD83 on B cells during GC responses. Therefore, in the present study we generated a B cell-specific CD83 conditional knockout (CD83 B-cKO) model. CD83 B-cKO B cells show defective upregulation of MHC class II and CD86 expression and impaired proliferation after different stimuli. Analyses of GC responses after immunization with various Ags revealed a characteristic shift in dark zone and light zone B cell numbers, with an increase of B cells in the dark zone of CD83 B-cKO mice. This effect was not accompanied by alterations in the level of IgG immune responses or by major differences in affinity maturation. However, an enhanced IgE response was observed in CD83 B-cKO mice. Additionally, we observed a strong competitive disadvantage of CD83-cKO B cells in GC responses in mixed bone marrow chimeras. Furthermore, infection of mice with Borrelia burgdorferi revealed a defect in bacterial clearance of CD83 B-cKO mice with a shift toward a Th2 response, indicated by a strong increase in IgE titers. Taken together, our results show that CD83 is important for B cell activation and modulates GC composition and IgE Ab responses in vivo.

CD83 orchestrates immunity toward self and non-self in dendritic cells - Wild, Andreas; Krzyzak, Lena; Peckert, Katrin; Stich, Lena; Kuhnt, Christine; Butterhof, Alina; Seitz, Christine; Mattner, Jochen; Grner, Niklas; Gänsbauer, Maximilian; Purtak, Martin; Soulat, Didier; et al. (JCI Insight, 2019)
Dendritic cells (DCs) are crucial to balance protective immunity and autoimmune inflammatory processes. Expression of CD83 is a well-established marker for mature DCs, although its physiological role is still not completely understood. Using a DC-specific CD83-conditional KO (CD83(Delta DC)) mouse, we provide new insights into the function of CD83 within this cell type. Interestingly, CD83-deficient DCs produced drastically increased IL-2 levels and displayed higher expression of the costimulatory molecules CD25 and OX40L, which causes superior induction of antigen-specific T cell responses and compromises Treg suppressive functions. This also directly translates into accelerated immune responses in vivo. Upon Salmonella typhimurium and Listeria monocytogenes infection, CD83(Delta DC) mice cleared both pathogens more efficiently, and CD83-deficient DCs expressed increased IL-12 levels after bacterial encounter. Using the experimental autoimmune encephalomyelitis model, autoimmune inflammation was dramatically aggravated in CD83(Delta DC) mice while resolution of inflammation was strongly reduced. This phenotype was associated with increased cell influx into the CNS accompanied by elevated Th17 cell numbers. Concomitantly, CD83(Delta DC) mice had reduced Treg numbers in peripheral lymphoid organs. In summary, we show that CD83 ablation on DCs results in enhanced immune responses by dysregulating tolerance mechanisms and thereby impairing resolution of inflammation, which also demonstrates high clinical relevance.
CRIS-Team WoS Importer:2019-11-01

CD8+ T-cell priming and boosting: More antigen-presenting DC, or more antigen per DC? - Schaft, Niels; Wellner, Verena; Wohn, Christian; Schuler, Gerold; Dörrie, Jan (Cancer Immunology, Immunotherapy, 2013)
RNA transfection is a standard method to load dendritic cells (DC) with antigen for therapeutic cancer vaccination. While electroporation yields high transfection efficiency and satisfying expression levels, lipofection results in only few cells expressing high amounts of antigen. We compared antigen loading of human monocyte-derived DC by MelanA RNA electroporation and lipofection. No differences in phenotype or migrational capacity were detected, but lipofected DC induced stronger cytokine secretion by antigen-specific T cells and were superior in priming and boosting of MelanA-specific CD8+ T cells. Interestingly, T cells stimulated with the differently transfected DC did not differ in their functional avidity. To determine whether the amount of antigen per cell is indeed responsible for the superiority of the lipofected DC, we increased the amount of MelanA RNA fivefold and mixed those DC with mock-electroporated ones to mimic the antigen distribution of lipofected cells. This significantly improved the stimulatory capacity, indicating that indeed the amount of antigen per cell seems to be the responsible feature for the observed superiority of lipofected DCs. These data suggest that a few DC that express high amounts of antigen are more immunogenic than many DC expressing lower amounts, although this needs to be tested in a two-armed immunogenicity trial. © 2013 Springer-Verlag Berlin Heidelberg.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Antigen presentation; Dendritic cells; Electroporation; Lipofection; T cells

Cdc42-dependent actin dynamics controls maturation and secretory activity of dendritic cells - Schulz, Anna M.; Stutte, Susanne; Hogl, Sebastian; Luckashenak, Nancy; Dudziak, Diana; Leroy, Celine; Forne, Ignasi; Imhof, Axel; Mueller, Stephan A.; Brakebusch, Cord H.; Lichtenthaler, Stefan F.; Brocker, Thomas (The Journal of Cell Biology, 2015)
Cell division cycle 42 (Cdc42) is a member of the Rho guanosine triphosphatase family and has pivotal functions in actin organization, cell migration, and proliferation. To further study the molecular mechanisms of dendritic cell (DC) regulation by Cdc42, we used Cdc42-deficient DCs. Cdc42 deficiency renders DCs phenotypically mature as they up-regulate the co-stimulatory molecule CD86 from intracellular storages to the cell surface. Cdc42 knockout DCs also accumulate high amounts of invariant chain-major histocompatibility complex (MHC) class II complexes at the cell surface, which cannot efficiently present peptide antigens (Ag's) for priming of Ag-specific CD4 T cells. Proteome analyses showed a significant reduction in lysosomal MHC class II-processing proteins, such as cathepsins, which are lost from DCs by enhanced secretion. As these effects on DCs can be mimicked by chemical actin disruption, our results propose that Cdc42 control of actin dynamics keeps DCs in an immature state, and cessation of Cdc42 activity during DC maturation facilitates secretion as well as rapid up-regulation of intracellular molecules to the cell surface.
EVALuna2:19559

Cellular and humoral immune responses to SARS-CoV-2 vaccination in patients after CD19.CAR T-cell therapy - Reimann, Hannah; Kremer, Anita; Blumenberg, Viktoria; Schmidt, Katja; Aigner, Michael; Jacobs, Benedikt; Eisenhauer, Nina; Kämpf, Alina; Rösler, Wolf; Kharboutli, Soraya; Mougiakakos, Dimitrios; Lang, Vanessa; et al. (Blood Advances, 2023)
EVALuna2:512817

Centrosomal protein TRIM43 restricts herpesvirus infection by regulating nuclear lamina integrity - Full, Florian; Van Gent, Michiel; Sparrer, Konstantin M. J.; Chiang, Cindy; Zurenski, Matthew A.; Scherer, Myriam; Brockmeyer, Norbert H.; Heinzerling, Lucie; Stürzl, Michael; Korn, Klaus; Stamminger, Thomas; Enßer, Armin; et al. (Nature Microbiology, 2019)
Tripartite motif (TRIM) proteins mediate antiviral host defences by either directly targeting viral components or modulating innate immune responses. Here we identify a mechanism of antiviral restriction in which a TRIM E3 ligase controls viral replication by regulating the structure of host cell centrosomes and thereby nuclear lamina integrity. Through RNAi screening we identified several TRIM proteins, including TRIM43, that control the reactivation of Kaposi's sarcoma-associated herpesvirus. TRIM43 was distinguished by its ability to restrict a broad range of herpesviruses and its profound upregulation during herpesvirus infection as part of a germline-specific transcriptional program mediated by the transcription factor DUX4. TRIM43 ubiquitinates the centrosomal protein pericentrin, thereby targeting it for proteasomal degradation, which subsequently leads to alterations of the nuclear lamina that repress active viral chromatin states. Our study identifies a role of the TRIM43-pericentrin-lamin axis in intrinsic immunity, which may be targeted for therapeutic intervention against herpesviral infections.
EVALuna2:35255

CHALLENGES OF NETWORK META-ANALYSIS FOR SAFETY OUTCOMES: THE ANALYSIS OF TIRBANIBULIN AGAINST COMMON TREATMENTS IN EUROPE FOR ACTINIC KERATOSIS - Heppt, Markus; Dykukha, I.; Chapman-Rounds, M.; Graziadio, S.; Edwards, M. (VALUE IN HEALTH, 2022)
CRIS-Team WoS Importer:2023-03-10

Characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis: A retrospective multicentre cohort study - Müller-Jensen, Leonie; Zierold, Sarah; Versluis, Judith M.; Boehmerle, Wolfgang; Huehnchen, Petra; Endres, Matthias; Mohr, Raphael; Compter, Annette; Blank, Christian U.; Hagenacker, Tim; Meier, Friedegund; Reinhardt, Lydia; et al. (European Journal of Cancer, 2022)
Aim: Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis. Methods: In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre. Results: Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43). Conclusions: ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.
CRIS-Team Scopus Importer:2022-10-07
Keywords: Anti-LGI1 encephalitis; Encephalitis; Herpetic encephalitis; Immune checkpoint inhibitor; Immune-related adverse events; Immunotherapy; Neurotoxicity

Characterization and Expansion of Autologous GMP-ready Regulatory T Cells for TREG-based Cell Therapy in Patients with Ulcerative Colitis - Voskens, Caroline J.; Fischer, Anika; Roessner, Susanne; Lorenz, Carmen; Hirschmann, Simon; Atreya, Raja; Neufert, Clemens; Atreya, Imke; Neurath, Markus; Schuler, Gerold (Inflammatory Bowel Diseases, 2017)
BACKGROUND: A local imbalance between regulatory (Treg) and effector T cells is believed to play a major role in gut-specific inflammation, including ulcerative colitis (UC). Restoration of this balance through an adoptive Treg transfer is an attractive new treatment approach in patients who are refractory to current standard therapies. It was our goal to develop a Good Manufacturing Practices (GMP)-conform protocol for expansion of UC Treg cells as a rational backbone for future studies on Treg therapy in UC. METHODS: CD25 blood T cells derived from patients with UC were ex vivo expanded in the presence of IL-2, rapamycin, and anti-CD3/anti-CD28 expander beads using a GMP-conform protocol. Cells were subsequently assessed for stability and function. RESULTS: Patient-derived ex vivo rapamycin-expanded GMP-ready CD25 cells were polyclonal, hypomethylated at intron 1 of the FoxP3 locus, and suppressive in carboxyfluorescein succinimidyl ester-dilution assays against autologous peripheral blood-derived and allogeneic colon-derived responder cells. Function was mediated by soluble factors, including toxic granules. In addition to CD4 T cells, suppressive hypermethylated CD8 T-cell subsets were also induced during the expansion process. CONCLUSIONS: Patient-derived rapamycin-expanded CD25 cells are stable and functional, and as such, ready to serve in a phase I dose-escalation safety study in UC.
EVALuna2:33805

Characterization and Manipulation of the Crosstalk Between Dendritic and Natural Killer Cells Within the Tumor Microenvironment - Jacobs, Benedikt; Gebel, Veronika; Heger, Lukas; Greze, Victoria; Schild, Hansjorg; Dudziak, Diana; Ullrich, Evelyn (Frontiers in Immunology, 2021)
Cellular therapy has entered the daily clinical life with the approval of CAR T cell therapeutics and dendritic cell (DCs) vaccines in the US and the EU. In addition, numerous other adoptive cellular products, including natural killer (NK) cells, are currently evaluated in early phase I/ II clinical trials for the treatment of cancer patients. Despite these promising accomplishments, various challenges remain to be mastered in order to ensure sustained therapeutic success. These include the identification of strategies by which tumor cells escape the immune system or establish an immunosuppressive tumor microenvironment (TME). As part of the innate immune system, DCs and NK cells are both present within the TME of various tumor entities. While NK cells are well known for their intrinsic anti-tumor activity by their cytotoxicity capacities and the secretion of pro-inflammatory cytokines, the role of DCs within the TME is a double-edged sword as different DC subsets have been described with either tumor-promoting or -inhibiting characteristics. In this review, we will discuss recent findings on the interaction of DCs and NK cells under physiological conditions and within the TME. One focus is the crosstalk of various DC subsets with NK cells and their impact on the progression or inhibition of tumor growth. In addition, we will provide suggestions to overcome the immunosuppressive outcome of the interaction of DCs and NK cells within the TME.
CRIS-Team Scopus Importer:2021-06-11
Keywords: cellular therapies; DC-NK cell interaction; dendritic cells; NK cells; tumor microenvironment

Characterization of Checkpoint Inhibitor-associated Diabetes mellitus - Experience in 12 Patients - Satzger, I.; Momma, M.; Thoms, K. M.; Eigentler, T.; Schultz, E.; Loquai, C.; Zimmer, L.; Heinzerling, Lucie; Kaehler, K.; Herbst, R.; Utikal, J.; Hassel, J.; et al. (2018)
EVALuna2:34771

Characterization of Patients with inoperable malignant Stage IIIB-D Melanoma - Zaremba, A.; Weishaupt, C.; Glutsch, V.; Schilling, B.; Loquai, C.; Rafei-Shamsabadi, D.; Meiss, F.; Gutzmer, R.; Haferkamp, S.; Kaehler, K.; Moreira, Alvaro; Heinzerling, Lucie; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Characterization of tanning behavior assessed via online survey: Attitudes, habits, and preventive measures with focus on sunscreen use - Schneiderbanger, Constanze K.; Schuler, Gerold; Heinzerling, Lucie; Kirchberger, Michael C. (Photodermatology Photoimmunology & Photomedicine, 2019)
Background/purpose: Incidence of melanoma is increasing globally. Exposure to ultraviolet radiation (UVR) as important risk factor for developing skin cancer can be influenced by tanning behavior. Only a few studies are available concerning sun tanning behavior and protective measures. Methods: An online survey was distributed via social media to assess tanning habits and examine associated demographic and behavioral factors. Results: In total, 403 questionnaires were distributed, and mean age of respondents was 32. Having a tanned skin, feeling warm and relaxed were the most common motivations for tanning. The use of sunscreen varied and seemed to depend on the occasion of UVR exposure, constantly applied during vacation and during tanning, less commonly applied in daily life and during work. Avoiding painful solar dermatitis was more important as motivation for the use of sunscreen than skin cancer prevention. Skin aging as reason for the use of sunscreen was especially important for females younger than 26 years. The most common applied sun protection factor was 16-49. The main reason opposing the use of sunscreen was a too laborious usage, which was significantly associated with male. Beauty was the only association related to tanned skin the majority (62%) agreed with. Conclusion: The motivation for tanning and reasons for avoiding sunscreen strongly varies. Knowledge about these factors could be used for improving campaigns with respect to target groups. Clarifying the appropriate application of sunscreen, developing convenient sunscreen formulations and providing information about UVR-induced skin aging could lead to an increased usage of sunscreen and therefore to an improved UVR protection.
CRIS-Team Scopus Importer:2019-07-30
Keywords: melanoma; sunscreen; tanning; ultraviolet radiation

Characterization of the impact of immune checkpoint inhibitors on platelet activation and aggregation - Schlüter, Julian; Cunningham, Sarah; Zimmermann, Robert; Achenbach, Susanne; Kramer, Rafaela; Erdmann, Michael; Beckmann, Matthias; Heinzerling, Lucie; Hackstein, Holger (Immunobiology, 2023)
Immune checkpoint inhibitors (ICIs) are effective oncological drugs which block cellular check-point receptors typically targeted by tumor immune evasion strategies. Despite their benefits, clinicians have reported treatment-associated thromboembolism during ICI therapy in recent years. Though several theories on this ICI-associated pathogenesis exist, the direct effects of ICIs on platelets remains unknown. We therefore investigated the potential direct and indirect effect of PD-1, PD-L1 and CTLA-4-targeting ICIs on platelet functionality in multifaceted in vitro experiments. Interestingly, we could not observe a clear effect of ICI on platelet aggregation and primary hemostasis in whole blood and platelet concentrate-based assays. Furthermore, the presence of ICIs in toll-like receptor stimulation had no significant impact on platelet surface marker expression. In a second approach, we investigated the indirect immunological impact of ICIs on platelet activation by exposing platelets to supernatants from ICI- and Staphylococcal enterotoxin B-exposed PBMCs. Whereas ICIs affected IL-2 levels in supernatants, we could not detect clear differences in the secretion of pro-thrombogenic factors and platelet responses. The obtained data suggest that the direct influence of ICIs on platelet activation or the influence of altered T cell function on platelet activation cannot be considered a major factor in the development of thrombotic events.
CRIS-Team Scopus Importer:2023-01-13
Keywords: Immune checkpoint inhibitors; Platelet activation; Platelet function tests; Platelets; Thrombosis

Checkpoint-Inhibition bei Tumorerkrankungen - Ben Khaled, Najib; Piseddu, Ignazio; Boehmer, Daniel F. R.; Zierold, Sarah; Heinzerling, Lucie; Mayerle, Julia; De Toni, Enrico N. (Onkologe, 2021)
Background: The introduction of immune checkpoint inhibitors (ICI) into the therapeutic landscape in oncology over the last decade represents a fundamental advancement in cancer immunotherapy. Objectives: We review the mechanism of action of ICI and their current use in the systemic therapy of various cancers. Materials and methods: Relevant articles were identified in the PubMed database. Clinical trial information was extracted from the Clinicaltrials.gov registry; information on drug approvals were obtained from the European Medicines Agency and the U.S. Food and Drug Administration databases. Conclusions: Although substantial improvements in the treatment of many types of cancer have been achieved by ICI, durable responses and long-term survival can only be observed in a small number of patients. The development of predictive biomarkers to maximize efficacy and minimize immune-related toxicity, in addition to new combination regimens, may help unleash the full potential of ICI in cancer immunotherapy.
CRIS-Team Scopus Importer:2021-09-10
Keywords: Biomarkers; Cancer treatment; CTLA-4-Inhibitor; Immunotherapy; PD-1-PD-L1 blockade

Checkpoint inhibitor-induced eosinophilic fasciitis following high eosinophilia associated with complete response - Toussaint, Frédéric; Hammon, Matthias; Erdmann, Michael; Moreira, Alvaro; Kirchberger, Michael C.; Schuler, Gerold; Schett, Georg; Heinzerling, Lucie (Rheumatology, 2019)
CRIS-Team Scopus Importer:2019-10-01

Checkpoint-inhibitor induced Polyserositis with Edema - Zierold, Sarah; Akcetin, Larissa Semra; Gresser, Eva; Maier, Anna Marie; Koenig, Alexander; Kramer, Rafaela; Theurich, Sebastian; Tomsitz, Dirk; Erdmann, Michael; French, Lars E.; Rudelius, Martina; Heinzerling, Lucie (Cancer Immunology, Immunotherapy, 2022)
Background As immune checkpoint inhibitors (ICI) are increasingly being used due to effectiveness in various tumor entities, rare side effects occur more frequently. Pericardial effusion has been reported in patients with advanced non-small cell lung cancer (NSCLC) after or under treatment with immune checkpoint inhibitors. However, knowledge about serositis and edemas induced by checkpoint inhibitors in other tumor entities is scarce. Methods and results Four cases with sudden onset of checkpoint inhibitor induced serositis (irSerositis) are presented including one patient with metastatic cervical cancer, two with metastatic melanoma and one with non-small cell lung cancer (NSCLC). In all cases treatment with steroids was successful in the beginning, but did not lead to complete recovery of the patients. All patients required multiple punctures. Three of the patients presented with additional peripheral edema; in one patient only the lower extremities were affected, whereas the entire body, even face and eyelids were involved in the other patients. In all patients serositis was accompanied by other immune-related adverse events (irAEs). Conclusion ICI-induced serositis and effusions are complex to diagnose and treat and might be underdiagnosed. For differentiation from malignant serositis pathology of the punctured fluid can be helpful (lymphocytes vs. malignant cells). Identifying irSerositis as early as possible is essential since steroids can improve symptoms.
CRIS-Team WoS Importer:2022-06-03
Keywords: Autoimmunity; Anti-PD1-antibody; Side effects; Serositis; Pericardial effusion; Pleural effusion

Checkpoint Inhibitors - Heinzerling, Lucie; De Toni, Enrico N.; Schett, Georg; Hundorfean, Gheorghe; Zimmer, Lisa (Deutsches Ärzteblatt international, 2019)
BACKGROUND: Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening. METHODS: This review is based on pertinent articles retrieved by a search in PubMed and on an evaluation of a side-effect registry. RESULTS: Checkpoint-inhibitor-induced autoimmune side effects manifest themselves in all organ systems, most commonly as skin lesions (46-62%), autoimmune colitis (22-48%), autoimmune hepatitis (7-33%), and endocrinopathies (thyroiditis, hypophysitis, adrenalitis, diabetes mellitus; 12-34%). Rarer side effects include pneumonitis (3-8%), nephritis (1-7%), cardiac side effects including cardiomyositis (5%), and neurological side effects (1-5%). Severe (sometimes lethal) side effects arise in 17-21%, 20-28%, and 59% of patients undergoing anti-PD-1 and anti- CTLA-4 antibody treatment and the approved combination therapy, respectively. With proper monitoring, however, these side effects can be recognized early and, usually, treated with success. Endocrine side effects generally require long-term hormone substitution. Patients who have stopped taking checkpoint inhibitors because of side effects do not show a poorer response of their melanoma or shorter survival in comparison to patients who continue to take checkpoint inhibitors. CONCLUSION: The complex management of checkpoint-inhibitor-induced side effects should be coordinated in experienced centers. The creation of an interdisciplinary "tox team" with designated experts for organ-specific side effects has proven useful. Prospective registry studies based on structured documentation of side effects in routine clinical practice are currently lacking and urgently needed.
EVALuna2:69389

Checkpoint Inhibitors The Diagnosis and Treatment of Side Effects - Heinzerling, Lucie; De Toni, Enrico N.; Schett, Georg; Hundorfean, Gheorghe; Zimmer, Lisa (Deutsches Ärzteblatt international, 2019)
Background: Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-Iymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening.
CRIS-Team WoS Importer:2019-04-12

Chemical peelings for the treatment of actinic keratosis: a systematic review and meta-analysis - Steeb, T.; Koch, Elias; Wessely, A.; Wiest, L. G.; Schmitz, L.; Berking, Carola; Heppt, Markus (Journal of the European Academy of Dermatology and Venereology, 2020)
Background: Actinic keratosis (AK) is a common precancerous lesion of the skin that may be treated with chemical peelings. Despite their long-standing usage and clinical experience, no evidence-based recommendation regarding the efficacy and safety of chemical peelings for AK exists. Objectives: To systematically review and synthesize the current knowledge on chemically exfoliative peelings as interventions for AK. Methods: We performed a systematic literature research in Medline, Embase and CENTRAL and hand-searched pertinent trial registers for eligible records until 5 August 2019. Results from individual studies were pooled using a random-effects model or described in a qualitative synthesis. The risk of bias was estimated with the tools provided by the Cochrane Collaboration (randomized and non-randomized trials) and the Evidence Project (single-arm trials). Results: Four randomized controlled trials, two non-randomized controlled trials and two single-arm studies with a total sample size of n = 170 patients were included. Trichloroacetic acid (TCA) plus Jessner’s solution showed significantly lower participant complete clearance (RR 0.36, 95% CI: 0.14–0.90, two studies, I2 = 0%, P = 0.03) and lower lesion clearance (RR 0.92, 95% CI: 0.85–0.99, one study, P = 0.03) compared to 5-fluorouracil (5-FU) 5% cream. TCA as monotherapy showed lower lesion complete clearance (RR 0.75, 95% CI: 0.69–0.82, two studies, I2 = 7%, P < 0.001) and lower mean lesion reduction per patient compared to conventional photodynamic therapy (cPDT) (MD −20.48, 95% CI: −31.55 to −9.41, two studies, I2 = 43%, P = 0.0003). Pain was more pronounced in patients treated with cPDT in comparison with TCA (MD −1.71 95% CI: −3.02 to −0.41, two studies, I2 = 55%, P = 0.01). In the single-arm studies, 5-FU plus glycolic acid showed 92% lesion clearance and phenol peeling 90.6% participant complete clearance. All studies showed a high risk for bias. Conclusions: Future high-quality studies and a standardization of peeling protocols are warranted to determine the value of chemical peelings in the treatment of AK.
CRIS-Team Scopus Importer:2020-08-28

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer - Roberti, Maria Paula; Yonekura, Satoru; Duong, Connie P.M.; Picard, Marion; Ferrere, Gladys; Tidjani Alou, Maryam; Rauber, Conrad; Iebba, Valerio; Lehmann, Christian; Amon, Lukas; Dudziak, Diana; Derosa, Lisa; et al. (Nature Medicine, 2020)
The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.
CRIS-Team Scopus Importer:2020-06-02

Chimeric Antigen Receptors in Different Cell Types: New Vehicles Join the Race. - Harrer, Dennis C.; Dörrie, Jan; Schaft, Niels (Human Gene Therapy, 2018)
Adoptive cellular therapy has evolved into a powerful force in the battle against cancer, holding promise for curative responses in patients with advanced and refractory tumors. Autologous T cells, reprogrammed to target malignant cells via the expression of a chimeric antigen receptor (CAR) represent the frontrunner in this approach. Tremendous clinical regressions have been achieved using CAR-T cells against a variety of cancers both in numerous preclinical studies and in several clinical trials, most notably against acute lymphoblastic leukemia, and resulted in a very recent United States Food and Drug Administration approval of the first CAR-T-cell therapy. In most studies CARs are transferred to conventional αβT cells. Nevertheless, transferring a CAR into different cell types, such as γδT cells, natural killer cells, natural killer T cells, and myeloid cells has yet received relatively little attention, although these cell types possess unique features that may aid in surmounting some of the hurdles CAR-T-cell therapy currently faces. This review focuses on CAR therapy using effectors beyond conventional αβT cells and discusses those strategies against the backdrop of developing a safe, powerful, and durable cancer therapy.
EVALuna2:34796

Chk1 and Wee1 control genotoxic-stress induced G2-M arrest in melanoma cells - Vera, Julio; Raatz, Yvonne; Wolkenhauer, Olaf; Kottek, Tina; Bhattacharya, Animesh; Simon, Jan C.; Kunz, Manfred (Cellular Signalling, 2015)
In the present report, the role of ATR-Chk1-Wee1 and ATM-Chk2-p53-p21 pathways in stress-induced cell cycle control is analysed in melanoma cells. Treatment of p53 wild-type melanoma cells with the genotoxic agent doxorubicin induces G2-M arrest, inhibitory phosphorylation of cell cycle kinase Cdc2 (CDK1) and enhanced expression of p53/p21. Wee1 inhibition under doxorubicin pulse-treatment reduces G2-M arrest and induces apoptosis. Inhibition of upstream kinase Chk1 under doxorubicin treatment almost completely abolishes stress-induced G2-M arrest and induces enhanced apoptosis. Interestingly, Chk1 inhibition alone even further increases apoptosis. While Chk1 inhibition alone almost completely abolishes G0-G1 arrest, combined treatment with doxorubicin re-establishes G0-G1 arrest. Moreover, Chk1 inhibition alone induces only a slight p53/p21 induction, while a strong induction of both proteins is observed by the combination with doxorubicin. These findings are suggestive for a particular role of p53/p21 in G0-G1, and Chk1 in G0-G1 and G2-M arrest. In line with this, the p53-mutant SK-Mel-28 melanoma cells do not mount a significant G0-G1 arrest under combined doxorubicin and Chk1 inhibitor treatment but rather show extensive apoptosis. Moreover, knockdown of p21 dramatically reduces stress-induced G0-G1 arrest under doxorubicin and Chk1 inhibitor treatment accompanied by massive DNA damage and apoptosis induction. Treatment of melanoma cells with an inhibitor of Chk2 upstream kinase ATM and doxorubicin almost completely abolishes G0-G1 arrest. Taken together, both Chk1 and Wee1 are mediators of G2-M arrest, while p53, p21 and Chk1 are mediators of G0-G1 arrest in melanoma cells. Combined treatment with chemotherapeutic agents such as doxorubicin and Chk1 inhibitors may help to overcome apoptosis resistance of p53-proficient melanoma cells. But treatment with Chk1 inhibitor alone may even be more efficient.
EVALuna2:19518

Chronic recurrent multifocal osteomyelitis in association with pyoderma gangraenosum - Wurm, Matthias; Brecht, Ines; Lell, Michael; Brunner, Kathrin; Mitsimponas, Konstantinos Theodorou; Chada, Martin; Jahn, Julia; Neukam, Friedrich Wilhelm; von Wilmowsky, Cornelius (BMC Oral Health, 2016)
Chronic recurrent multifocal osteomyelitis (CRMO) is a rare acquired inflammatory skeletal disorder of unknown origin. CRMO was first described by Gideon in 1972 and mainly affects children and young adults of female gender. The CRMO is part of the clinical picture of non-bacterial Osteomyelitis (NBO) and typically presents a relapsing recurring course with both remission and spontaneous exacerbation. CRMO is typically encountered in the limbs and the metaphysis of long bones in particular. Usually the clinical symptoms include painful swellings of the affected regions. This case report describes the rare case of a CRMO of the mandible in association with pyoderma gangraenosum.A 14-year old female caucasian patient, residing in the south of Germany, presented in the oncological outpatient clinic of our Department of Paediatrics and Adolescent Medicine in June 2014 complaining of increasing neck pain and progressive swelling at her left cheek ongoing for about 6 weeks. These symptoms had been occurring quarterly for 4 years, but had never been as pronounced. Blood biochemistry showed a moderately elevated CRP (35 mg/l) and a significantly increased blood sedimentation rate (BSR 48/120 mm). The panoramic radiograph, however, revealed a bone alteration in the left mandibular region. Further investigations confirmed the diagnosis of CRMO.The present case underlines the fact that rare diseases might occasionally present with even more rare symptoms. These occasions can obviously be considered to present a considerable diagnostic challenge.
EVALuna2:14591

Chronische Entzündungserkrankungen in Deutschland: Eine Querschnittanalyse über Begleiterkrankungen und Arzneimitteleinsatz - Leipe, Jan; Schmelz, Renate; Riemekasten, Gabriela; Thaçi, Diamant; Henes, Jörg; Schäkel, Knut; Pinter, Andreas; Sticherling, Michael; Wegner, Joanna; Fusco, Stefano; Linke, Miriam; Weber, Valeria; et al. (Zeitschrift für Rheumatologie, 2023)
Background: Immune-mediated inflammatory diseases (IMID) can lead to a substantial disease burden for those affected, in particular by the concomitant occurrence of other IMIDs or in the presence of comorbidities. The care of patients with IMIDs is complex and involves various medical disciplines. Objective: To describe the burden of disease and the current routine drug treatment of patients with IMID. Material and methods: The retrospective cross-sectional analysis was based on statutory health insurance claims data from the InGef database. Prevalent patients with psoriasis (Pso), psoriatic arthritis (PsA), spondylarthritis (SpA), rheumatoid arthritis (RA), Crohn’s disease (MC), ulcerative colitis (CU), or connective tissue disease were identified among 3,988,695 insured patients in 2018. The concomitant occurrence of different IMIDs and the extent to which patients with IMID are affected by other comorbidities compared to a reference population were investigated. The current routine drug treatment was described based on the use of predefined forms of treatment. Results: In the database 188,440 patients with IMID (4.7%) were identified. Compared to the reference population the prevalence of comorbidities, such as depressive episodes and cardiovascular risk factors was higher in patients with IMID. For MC, CU, RA, and PsA disease-modifying antirheumatic drugs (DMARD) and classical systemic forms of treatment were used most commonly. In Pso, SpA, and connective tissue disease nonsteroidal anti-inflammatory drugs (NSAID) were the most frequently used treatment often in combination with other drugs. Conclusion: A considerable number of patients with IMIDs (16.9–27.5%) suffer from different diseases of the IMID group. They are frequently affected by accompanying illnesses and require interdisciplinary medical treatment.
CRIS-Team Scopus Importer:2023-01-13
Keywords: Chronic inflammatory diseases; Epidemiology; Pharmacotherapy; Real-world evidence; Statutory health insurance data analysis

Circulating Adaptive Immune Cells Expressing the Gut Homing Marker α4β7 Integrin Are Decreased in COVID-19 - Müller, Tanja; Becker, Elisabeth; Wiendl, Maximilian; Schulze, Lisa; Voskens, Caroline; Kremer, Andreas; Neurath, Markus; Zundler, Sebastian; Völkl, Simon (Frontiers in Immunology, 2021)
Background: Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide range of symptoms including gastrointestinal manifestations, and intestinal epithelial cells are a target of the virus. However, it is unknown how the intestinal immune system contributes to systemic immune responses in coronavirus disease 2019 (COVID-19). Methods: We characterized peripheral blood lymphocytes from patients with active COVID-19 and convalescent patients as well as healthy controls by flow cytometry. Results: The frequency and absolute number of circulating memory T and B cells expressing the gut homing integrin α4β7 integrin was reduced during COVID-19, whether gastrointestinal symptoms were present or not. While total IgA-expressing B cells were increased, gut-imprinted B cells with IgA expression were stable. Conclusion: COVID-19 is associated with a decrease in circulating adaptive immune cells expressing the key gut homing marker α4β7 suggesting that these cells are preferentially recruited to extra-intestinal tissues independently of α4β7 or that the systemic immune response against SARS-CoV-2 is at least numerically dominated by extraintestinal, particularly pulmonary, immune cell priming.
CRIS-Team Scopus Importer:2021-05-21
Keywords: COVID-19; gut homing; integrins; SARS-CoV-2 infection; T cell trafficking

Circumventing pyroptosis via hyperactivation shapes superior immune responses of human type 2 dendritic cells compared to type 3 dendritic cells - Hatscher, Lukas; Kaszubowski, Tomasz; Amon, Lukas; Dudziak, Diana; Heger, Lukas (European Journal of Immunology, 2023)
Exploiting inflammasome activation in dendritic cells (DCs) is a promising approach to fight cancer and to augment adjuvant-induced immune responses. As inflammasome formation is typically accompanied by pyroptosis, hyperactivation—defined as inflammasome activation in the absence of pyroptosis—represents a mechanism of circumventing cell death of DCs while simultaneously benefitting from inflammasome signaling. We previously demonstrated a unique specialization for inflammasome responses and hyperactivation of human cDC2 among all human DC subsets. As recent investigations revealed heterogeneity among the human cDC2 population, we aimed to analyze whether the two recently identified cDC2 subpopulations DC2 and DC3 harbor similar or different inflammasome characteristics. Here, we report that both DC2 and DC3 are inflammasome competent. We show that DC3 generally induce stronger inflammasome responses, which are associated with higher levels of cell death. Although DC2 release lower levels of inflammasome-dependent IL-1β, they induce stronger CD4+ T cell responses than DC3, which are predominantly skewed toward a TH1/TH17 phenotype. Thus, mainly DC2 seem to be able to enter a state of hyperactivation, resulting in enhanced T cell stimulatory capacity.
CRIS-Team Scopus Importer:2023-03-31
Keywords: DC2; DC3; dendritic cells; inflammasome; pyroptosis

Citrate-coated superparamagnetic iron oxide nanoparticles enable a stable non-spilling loading of t cells and their magnetic accumulation - Boosz, Philipp; Pfister, Felix; Stein, René; Friedrich, Bernhard; Fester, Lars; Band, Julia; Mühlberger, Marina; Schreiber, Eveline; Lyer, Stefan; Dudziak, Diana; Alexiou, Christoph; Janko, Christina (Cancers, 2021)
T cell infiltration into a tumor is associated with a good clinical prognosis of the patient and adoptive T cell therapy can increase anti-tumor immune responses. However, immune cells are often excluded from tumor infiltration and can lack activation due to the immune-suppressive tumor microenvironment. To make T cells controllable by external forces, we loaded primary human CD3+ T cells with citrate-coated superparamagnetic iron oxide nanoparticles (SPIONs). Since the efficacy of magnetic targeting depends on the amount of SPION loading, we investigated how experimental conditions influence nanoparticle uptake and viability of cells. We found that loading in the presence of serum improved both the colloidal stability of SPIONs and viability of T cells, whereas stimulation with CD3/CD28/CD2 and IL-2 did not influence nanoparticle uptake. Further-more, SPION loading did not impair cytokine secretion after polyclonal stimulation. We finally achieved 1.4 pg iron loading per cell, which was both located intracellularly in vesicles and bound to the plasma membrane. Importantly, nanoparticles did not spill over to non-loaded cells. Since SPION-loading enabled efficient magnetic accumulation of T cells in vitro under dynamic condi-tions, we conclude that this might be a good starting point for the investigation of in vivo delivery of immune cells.
CRIS-Team Scopus Importer:2021-09-03
Keywords: Adoptive T cell transfer; Immune therapy; Magnetic targeting; Nanomedicine; Solid tumor; Superparamagnetic iron oxide nanoparticles (SPIONs); Targeted transport

c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma: a systematic review and one-arm meta-analysis - Steeb, Theresa; Wessely, Anja; Petzold, Anne; Kohl, Christoph; Erdmann, Michael; Berking, Carola; Heppt, Markus (European Journal of Cancer, 2021)
Background: Activating genomic alterations of the receptor tyrosine kinase KIT are found preferentially in certain melanoma subtypes such as acral and mucosal melanoma or melanoma arising in chronically sun-damaged skin. However, the therapeutic value of c Kit inhibitors for these subtypes currently remains unclear. Objectives: The objective of this study was to summarise the efficacy and safety of c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma. Methods: We performed a systematic literature research in MEDLINE, Embase and CENTRAL and hand searched pertinent trial registers and conference abstracts for eligible trials until 23rd June 2020. Results were pooled using a random-effects model to calculate pooled proportions of objective response rates (ORRs) and severe adverse events (sAEs) from unselected KIT mutant or amplified cohorts. Results: Nineteen single-arm studies with an overall sample size of 601 patients were included. The studies investigated imatinib (n = 8), nilotinib (n = 7), dasatinib (n = 3) and sunitinib (n = 1). The pooled ORR for all inhibitors was 15% (95% confidence interval [CI]: 12-18%). Subgroup analysis revealed the highest ORR (20%; 95% CI: 14-26%) for nilotinib. The ORR for mucosal melanoma was 14% (95% CI: 6-24%) and 22% for acral lentiginous melanoma (95% CI: 14-30%). At least one sAE was reported in 42% of patients (95% CI: 34-50%). Conclusions: c-Kit inhibitors represent a valuable treatment option for patients with KIT mutant melanoma, in particular for mutations of exons 11 and 13. Furthermore, high-quality trials are urgently needed to investigate putative combinations of specific targeted therapies with immunotherapy. (c) 2021 Elsevier Ltd. All rights reserved.
CRIS-Team WoS Importer:2021-10-15

CLASSIFICATION OF PSORIATIC ARTHRITIS, SERONEGATIVE RHEUMATOID ARTHRITIS, AND SEROPOSITIVE RHEUMATOID ARTHRITIS USING DEEP LEARNING ON MAGNETIC RESONANCE IMAGING - Folle, Lukas; Bayat, Sara; Kleyer, Arnd; Fagni, Filippo; Kapsner, Lorenz; Schlereth, Maja; Meinderink, Timo; Breininger, Katharina; Tascilar, Koray; Krönke, Gerhard; Uder, Michael; Sticherling, Michael; et al. (Supplement 1, 2022)
Background: While MRI evaluation of joints has been primarily used to quantify inflammation at a cross-sectional and longitudinal level, less is known about the potential of MRI in distinguishing different patterns of inflammation in the various forms of arthritis. Objectives: To evaluate (i) whether deep learning using neural networks can be trained to distinguish between seropositive rheumatoid arthritis (RA+), seronegative RA (RA-), and psoriatic arthritis (PsA) based on structural inflammatory patterns on hand magnetic resonance imaging and (ii) to assess if psoriasis patients with subclinical inflammation fit into such patterns. Methods: ResNet 3D [1] neural networks were trained to distinguish (i) RA+ vs. PsA, (ii) RA- vs. PsA and (iii) RA+ vs. RA- with respect to hand MRI data. Diagnosis of patients was determined using the following guidelines: ACR/EULAR 2010 [2] for RA and CASPAR [3] for PsA. Results from T1 coronal, T2 coronal, T1 coronal and axial fat suppressed contrast-enhanced (CE) and T2 fat suppressed axial sequences were used. The performance of such trained networks was analyzed by the area-under-the-receiver-operating-characteristic curve (AUROC) with and without imputation of demographic and clinical parameters ( Figure 1A ). Additionally, the trained networks were applied to psoriasis patients without clinical signs of PsA. Results: MRI scans from 649 patients (135 RA-, 190 RA+, 177 PsA, 147 psoriasis) were included ( Table 1 ). The AUROC for differentiation between disease entities was 75% (SD 3%) for RA+ vs. PsA, 74% (SD 8%) for RA- vs. PsA, and 67% (6%) for RA+ vs. RA-. All MRI sequences were relevant for classification, however, when deleting CE sequences, the loss of performance was only marginal. The addition of patient-specific data to the networks did not provide significant improvements. Increasing amounts of training data demonstrated improved performance of the networks ( Figure 1B ). Psoriasis patients were mostly assigned to PsA by the neural networks, suggesting that PsA-like MRI pattern may be present early in the course of psoriatic disease. Conclusion: Deep learning can be successfully applied to differentiate MRI inflammatory patterns related to RA+, RA-, and PsA. Early changes in psoriasis patients can be recognized by neural networks and are characterized by a pattern that allowed the networks to classify them as PsA. <
Keywords: Rheumatoid arthritis; deep learning; neural networks

CLEC10A Is a Specific Marker for Human CD1c+ Dendritic Cells and Enhances Their Toll-Like Receptor 7/8-Induced Cytokine Secretion - Heger, Lukas; Balk, Silke; Lühr, Jennifer; Heidkamp, Gordon Frederik; Lehmann, Christian; Hatscher, Lukas; Purbojo, Ariawan; Hartmann, Arndt; Garcia-Martin, Fayna; Nishimura, Shin-Ichiro; Cesnjevar, Robert; Nimmerjahn, Falk; et al. (Frontiers in Immunology, 2018)
Dendritic cells (DCs) are major players for the induction of immune responses. Apart from plasmacytoid DCs (pDCs), human DCs can be categorized into two types of conventional DCs: CD141+ DCs (cDC1) and CD1c+ DCs (cDC2). Defining uniquely expressed surface markers on human immune cells is not only important for the identification of DC subpopulations but also a prerequisite for harnessing the DC subset-specific potential in immunomodulatory approaches, such as antibody-mediated antigen targeting. Although others identified CLEC9A as a specific endocytic receptor for CD141+ DCs, such a receptor for CD1c+ DCs has not been discovered, yet. By performing transcriptomic and flow cytometric analyses on human DC subpopulations from different lymphohematopoietic tissues, we identified CLEC10A (CD301, macrophage galactose-type C-type lectin) as a specific marker for human CD1c+ DCs. We further demonstrate that CLEC10A rapidly internalizes into human CD1c+ DCs upon binding of a monoclonal antibody directed against CLEC10A. The binding of a CLEC10A-specific bivalent ligand (the MUC-1 peptide glycosylated with N-acetylgalactosamine) is limited to CD1c+ DCs and enhances the cytokine secretion (namely TNFα, IL-8, and IL-10) induced by TLR 7/8 stimulation. Thus, CLEC10A represents not only a candidate to better define CD1c+ DCs-due to its high endocytic potential-CLEC10A also exhibits an interesting candidate receptor for future antigen-targeting approaches.
EVALuna2:34257