Standardized Computer-Assisted Analysis of PRAME Immunoreactivity in Dysplastic Nevi and Superficial Spreading Melanomas - Koch, Elias; Erdmann, Michael; Berking, Carola; Kiesewetter, Franklin; Kramer, Rafaela; Schliep, Stefan; Heppt, Markus (International Journal of Molecular Sciences, 2023)
PRAME (PReferentially expressed Antigen in MElanoma) is a cancer testis antigen that is frequently expressed in melanoma compared to benign melanocytic proliferations and nevi. However, the interpretation of the intensity and distribution of PRAME immunostaining is not standardized a lot, which makes interpretation difficult. PRAME-stained histological slides of superficial spreading melanomas (SSM) and dysplastic nevi (DN) were digitized and analyzed using the digital pathology and image platform QuPath. t-tests and ROC AUCs were performed with SPSS. A p-value of <0.05 was used for statistical significance, and a ROC AUC score of >0.8 was considered a good result. A cut-off score was defined in an evaluation cohort and subsequently analyzed in an independent validation cohort. In total, 81 PRAME-stained specimens were included. The evaluation cohort included 32 (50%) SSM and 32 (50%) DN, and the mean of PRAME-positive cells/mm2 for the entire lesion was 455.3 (SD 428.2) in SSM and 60.5 (SD 130.1; p < 0.001) in DN. The ROC AUC of PRAME-positive cells of the entire lesion was 0.866, and in the epidermis it was 0.901. The defined cut-off score to distinguish between DN and SSM was 97.67 cells/mm2. In the validation cohort, 16 out of 17 cases (94.1%) were correctly classified by the cut-off score. The computer-aided assessment of PRAME immunostaining is a useful tool in dermatopathology to distinguish between DN and SSM. Lesions with a moderate expression and indifferent morphologic features will remain a challenge for dermatopathologists.
CRIS-Team Scopus Importer:2023-04-21
Keywords: computer-assisted analysis; dysplastic nevus; immunohistochemistry; melanoma; PRAME

Status report on the atopic dermatitis registry TREATgermany Statusbericht zum Neurodermitisregister TREATgermany - Siegels, D.; Haufe, E.; Heinrich, L.; Werfel, T.; Weidinger, S.; Schmitt, Jochen; Abraham, S.; Asefi, M.; Asmussen, Andrea; Augustin, M.; Bell, Magnus; Bieber, T.; et al. (Allergologie, 2021)
CRIS-Team Scopus Importer:2021-10-22
Keywords: Atopic dermatitis; Atopic eczema; Clinical registry; Clinical symptom severity; Systemic treatment

Stellenwert der Biopsie in der Diagnostik chronischer Wunden – ein Positionspapier der Initiative Chronische Wunden (ICW) e. V. - Erfurt-Berge, Cornelia; Bültemann, A.; Gerber, V.; Motzkus, M.; Rembe, J. D.; Dissemond, J. (Die Dermatologie, 2023)
Diagnostic assessment of chronic wounds is essential for the initiation of causal therapeutic treatment. For diagnostic classification of the wound genesis, it may be necessary to take a tissue sample for histological and/or microbiological processing. If there is clinical suspicion of a specific cause of the wound such as a neoplasm, an inflammatory dermatosis or a pathogen-induced wound, a tissue sample for further diagnosis is required immediately. If the ulceration does not respond sufficiently to adequate causal therapy, a tissue sample for further evaluation is recommended after 12 weeks. The choice of the correct sampling technique, further storage, transport and processing are just as decisive for a reliable result as the specific question for the diagnostic laboratory.
CRIS-Team Scopus Importer:2023-12-15
Keywords: Differential diagnosis; Histology; Leg ulcer; Microbiology; Tissue sample

Step-by-step Improvement of mRNA-electroporated dendritic Cells in a Phase I / II Clinical Study in cutaneous Melanoma Patients: better Survival correlates with a higher Immunoscore and increased Expression of PEBP1 in the Blood - Dörrie, Jan; Schaft, Niels; Gross, S.; Ostalecki, Christian; Eberhardt, Martin; Vera-Gonzales, J.; Uslu, Ugur; Moreira, Alvaro; Koch, Elias; Kummer, Mirko; Erdmann, M.; Schliep, S.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

Stereotactic radiation therapy for liver metastases: factors affecting local control and survival. - Andratschke, Nicolaus H. J.; Nieder, Carsten; Heppt, Franz; Molls, Michael; Zimmermann, Frank (Radiation Oncology, 2015)
To report on outcome and toxicity of stereotactic body radiotherapy (SBRT) for liver metastases in patients not eligible for surgery.From 2000 to 2009, 74 patients with 91 liver metastases from different primaries have been treated with SBRT at our institution. Median planning target volume was 123 ccm (range: 10.6-1074 ccm). Treatment consisted of 3-5 fractions with 5-12.5 Gy/ fraction prescribed to the surrounding 60-95% isodose with daily image guidance. Regular follow-up included CT or MRI imaging until tumor progression.Median local recurrence-free interval was 23 months with a local control rate of 74.7%, 48.3% and 48.3% after 1, 2 and 3 years. Only minimum biologically effective dose (BED) to gross tumor volume (GTV) remained as independent significant factor for local control in multivariate analysis. No local recurrences were observed in lesions (n = 12) which received a minimal BED to the GTV of 120 Gy. Including 26 local recurrences, 67 patients (91%) showed disease progression after SBRT with a median time of 5 months. Median overall survival was 27 months with survival rates of 77%, 30% and 27% at 1, 3 and 5 years. On multivariate analysis only GTV volume remained as independent significant prognostic factor for overall survival (p = 0.002). No grade 3 to 5 acute toxicity and no grade 4 or 5 late toxicity occurred.SBRT for liver metastases was well tolerated in this non-selected patient cohort and yielded good local control despite the considerable size of most lesions treated. Long-term survival is possible after SBRT.
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Stereotactic radiosurgery and combined immune checkpoint therapy with ipilimumab and nivolumab in patients with melanoma brain metastases: A retrospective monocentric toxicity analysis - Bodensohn, Raphael; Werner, Simone; Reis, Jonas; Pazos Escudero, Montserrat; Kaempfel, Anna Lena; Hadi, Indrawati; Forbrig, Robert; Manapov, Farkhad; Corradini, Stefanie; Belka, Claus; Theurich, Sebastian; Heinzerling, Lucie; et al. (Clinical and Translational Radiation Oncology, 2023)
Purpose and objective: Adding stereotactic radiosurgery (SRS) to combined immune checkpoint therapy with ipilimumab and nivolumab (IPI + NIVO) has led to promising results for patients with melanoma brain metastases (MBM). This study retrospectively analyzes the toxicity profile depending on the timing of SRS with regard to IPI + NIVO. Materials and methods: For this study, the clinical database was searched for all patients with MBM who were treated with SRS and IPI + NIVO. The patients were separated into three groups: group A completed IPI + NIVO (usually up to four cycles) >14 days before SRS, in group B IPI + NIVO was initiated>14 days after SRS, and group C received SRS concurrently to IPI + NIVO. Treatment related toxicity was obtained from clinical and neuroradiological records. Analyses were performed using the Fisher-Yates-test. Results: 31 patients were assessed including six (19.4 %), seven (22.6 %) and 18 (58.1 %) patients, in groups A, B and C, respectively. Baseline prognostic markers between groups were balanced. In total, five (16.1 %) patients experienced neurological grade 3 toxicities related to SRS. All of these five patients were in group C, which was near-significantly correlated with a risk for grade 3 toxicities (p = 0.058). Post-hoc analyses showed that a maximum time period of seven days between SRS and IPI + NIVO was significantly correlated with grade 3 toxicity (p = 0.048). Conclusion: Application of SRS to IPI + NIVO within a seven-day span was related to higher toxicity rates in this retrospective analysis. After previous studies focused on immune checkpoint monotherapies with SRS and declared it as safe, this study indicates that concomitant application of IPI + NIVO and SRS might increase side effects. Prospective validation is warranted to corroborate these findings.
CRIS-Team Scopus Importer:2023-01-27
Keywords: Checkpoint inhibition; Intracranial hemorrhage; Ipilimumab; Nivolumab; Radiation necrosis; Side effects; Stereotactic radiosurgery

Still Alive and Kicking: In-Vitro-Generated GM-CSF Dendritic Cells! - Lutz, Manfred B.; Inaba, Kayo; Schuler, Gerold; Romani, Nikolaus (Immunity, 2016)
EVALuna2:19572

Stoma care in pyoderma gangrenosum - Summa, Scarlett; Hofmann, Gabriele; Erfurt-Berge, Cornelia (Coloproctology, 2021)
Pyoderma gangrenosum is a rare inflammatory skin disorder presenting with ulcerations. Peristomal pyoderma gangrenosum confronts the treating physician with diagnostic and therapeutic challenges. Pyoderma gangrenosum is often not recognized early enough but an interdisciplinary treatment approach should be initiated as soon as possible as wound care alone will not lead to healing of these skin alterations. Wound care in combination with stoma care is often difficult in these cases and with unreliable obturation of stoma and infiltration of the skin protection materials it is associated with impairments in the quality of life of the person affected. The aim of wound care is to protect the wound from stoma leakage and to ensure sufficient stoma care by changing the materials for stoma care at regular intervals.
CRIS-Team WoS Importer:2021-12-31

Strong and sustained effector function of memory- versus naïve-derived T cells upon T-cell receptor RNA transfer: Implications for cellular therapy - Thomas, Simone; Klobuch, Sebastian; Besold, Katrin; Plachter, Bodo; Dörrie, Jan; Schaft, Niels; Theobald, Matthias; Herr, Wolfgang (European Journal of Immunology, 2012)
Current protocols used to select CMV-specific T cells for adoptive immunotherapy focus on virus-specific memory T cells from seropositive donors. However, this strategy is not feasible in patients undergoing allogeneic haematopoietic stem-cell transplantation (HSCT) from CMV-seronegative donors. Here, we redirected T cells of CMV-seronegative donors with a human genetically engineered TCR recognizing an HLA-A*0201-binding peptide epitope of CMVpp65. To facilitate clinical translation of this approach, we used a non-viral expression system based on in vitro transcribed RNA and electroporation. Although memory and naïve-derived T-cell subsets were both efficiently transfected by TCR-RNA, memory-derived T cells showed much stronger levels of HLA-A*0201-restricted cytolytic activity to CMV-infected fibroblasts and maintained acquired function for 5-10 days. In addition to redirection of CD8+ cytotoxic T cells, TCR-RNA transfection was capable of redirecting CD4+ T cells into potent Ag-specific Th cells that efficiently triggered maturation of DCs. Our data suggest that memory rather than naïve-derived T cells are the preferred subset for transient TCR expression by RNA electroporation, providing more efficient and sustained virus-specific CD4+ and CD8+ T-cell function. CMV TCR-RNA may represent a suitable therapeutic 'off-the-shelf' reagent to be used in severe CMV infections of HSCT patients when endogenous CMV-specific T-cell immunity is insufficient. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Cytomegalovirus; Memory T cells; Naive T cells; RNA; T-cell receptor

STRUCTURAL ENTHESEAL LESIONS IN PSORIASIS PATIENTS ARE ASSOCIATED WITH AN INCREASED RISK OF PROGRESSION TO PSORIATIC ARTHRITIS - A PROSPECTIVE COHORT STUDY - Simon, David; Tascilar, K.; Kleyer, Arnd; Bayat, Sara; Kampylafka, E.; Hueber, Axel; Rech, Jürgen; Schuster, Louis; Engel, K.; Sticherling, Michael; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Subclinical joint inflammation in patients with psoriasis without concomitant psoriatic arthritis: a cross-sectional and longitudinal analysis - Faustini, Francesca; Simon, Dominic; Oliveira, Isabelle; Kleyer, Arnd; Haschka, Judith; Englbrecht, Matthias; Cavalcante, Alan Rodrigues; Kraus, Sebastian; Tabosa, Taiane Ponte; Figueiredo, Camille; Hueber, Axel; Kocijan, Roland; et al. (Annals of the Rheumatic Diseases, 2016)
To search for subclinical inflammatory joint disease in patients with psoriasis without psoriatic arthritis (PsA), and to determine whether such changes are associated with the later development of PsA.Eighty-five subjects without arthritis (55 with psoriasis and 30 healthy controls) received high field MRI of the hand. MRI scans were scored for synovitis, osteitis, tenosynovitis and periarticular inflammation according to the PsAMRIS method. Patients with psoriasis additionally received complete clinical investigation, high-resolution peripheral quantitative CT for detecting erosions and enthesiophytes and were followed up for at least 1 year for the development of PsA.47% of patients with psoriasis showed at least one inflammatory lesion on MRI. Synovitis was the most prevalent inflammatory lesion (38%), while osteitis (11%), tenosynovitis (4%) and periarticular inflammation (4%) were less frequent. The mean (±SD) PsAMRIS synovitis score was 3.0±2.5 units. Enthesiophytes and bone erosions were not different between patients with psoriasis with or without inflammatory MRI changes. The risk for developing PsA was as high as 60% if patients had subclinical synovitis and symptoms related to arthralgia, but only 13% if patients had normal MRIs and did not report arthralgia.Prevalence of subclinical inflammatory lesions is high in patients with cutaneous psoriasis. Arthralgia in conjunction with MRI synovitis constitutes a high-risk constellation for the development of PsA.
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SUBJECTIVE ASSESSMENT OF PHYSICAL FUNCTION DOES NOT SUFFICIENTLY EXPLAIN VARIANCE OF MEASURED HAND FUNCTION AND GRIP STRENGTH IN ARTHRITIS PATIENTS AND NON-ARTHRITIS CONTROLS - Liphardt, Anna-Maria; Tascilar, Koray; Coppers, Birte; Manger, Eva; Liehr, Sonja; Bieniek, Lisa Maria; Bayat, Sara; Simon, David; Sticherling, Michael; Rech, Jürgen; Hueber, A.; Schett, Georg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Subsets of CD1c+ DCs: Dendritic Cell Versus Monocyte Lineage - Heger, Lukas; Hofer, Thomas P.; Bigley, Venetia; de Vries, I. Jolanda M.; Dalod, Marc; Dudziak, Diana; Ziegler-Heitbrock, Loems (Frontiers in Immunology, 2020)
Currently three bona fide dendritic cell (DC) types are distinguished in human blood. Herein we focus on type 2 DCs (DC2s) and compare the three defining markers CD1c, CD172, and CD301. When using CD1c to define DC2s, a CD14+ and a CD14− subset can be detected. The CD14+ subset shares features with monocytes, and this includes substantially higher expression levels for CD64, CD115, CD163, and S100A8/9. We review the current knowledge of these CD1c+CD14+ cells as compared to the CD1c+CD14− cells with respect to phenotype, function, transcriptomics, and ontogeny. Here, we discuss informative mutations, which suggest that two populations have different developmental requirements. In addition, we cover subsets of CD11c+CD8− DC2s in the mouse, where CLEC12A+ESAMlow cells, as compared to the CLEC12A−ESAMhigh subset, also express higher levels of monocyte-associated markers CD14, CD3, and CD115. Finally, we summarize, for both man and mouse, the data on lower antigen presentation and higher cytokine production in the monocyte-marker expressing DC2 subset, which demonstrate that the DC2 subsets are also functionally distinct.
CRIS-Team Scopus Importer:2020-10-30
Keywords: CD14; CD172; CD1c; CD301; DC subsets; DC2; dendritic cells

Successful Treatment of a primary cutaneous aggressive epidermotropic CD8+T-cell Lymphoma with Nivolumab - Toussaint, Frédéric; Erdmann, M.; Grosch, Ella; Schuler, Gerold; Schliep, S.; Heinzerling, Lucie (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Successful treatment of refractory palmoplantar psoriasis in a psoriatic arthritis patient with the JAK inhibitor tofacitinib - Valor-Mendez, Larissa; Sticherling, Michael; Kleyer, Arnd; Schett, Georg (Clinical and Experimental Rheumatology, 2021)
CRIS-Team WoS Importer:2021-03-26

Successful treatment of ulcerative necrobiosis lipoidica with JAK inhibitor - Erfurt-Berge, Cornelia; Sticherling, Michael (Journal of the European Academy of Dermatology and Venereology, 2020)
Necrobiosis lipoidica (NL) is a rare granulomatous disease that predominantly affects middle aged women and is often associated with diabetes mellitus and other metabolic disorders 1 . About 30 % of the patients develop ulcerations within NL lesions on the lower leg, which complicate the course of disease and are often recalcitrant to standard wound care procedures 2 . Systemic therapies for NL are reported only for single cases or in small case series with varying outcome 3 . Randomized controlled trials are missing due to the character of NL as an orphan disease.
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Sudden Otovestibular Dysfunction in 3 Metastatic Melanoma Patients Treated With Immune Checkpoint Inhibitors - Stuermer, Suzan H.; Lechner, Axel; Berking, Carola (Journal of Immunotherapy, 2021)
Immune-related adverse events have been described in 86%-96% of high-risk melanoma patients treated with immune checkpoint inhibitors (ICI), while in 17%-59% of cases these are classified as severe or even life-threatening. The most common immune-related adverse events include diarrhea, fatigue, hypothyroidism, and hepatitis. Bilateral uveitis and unspecific vertigo have been described in 1% of cases, respectively, in the pivotal studies of ICIs, but the affection of the vestibule-cochlear system has not been reported before. In this case series, we present 3-stage IV melanoma patients with sudden onset of otovestibular dysfunction (hearing loss and vestibulopathy), partly combined with uveitis because of ICIs. We describe detailed diagnostic work-up and therapeutic interventions and discuss possible pathogenic mechanisms of this rare and disabling event.
CRIS-Team WoS Importer:2021-06-11

Suppression of proatherogenic leukocyte interactions by MCS-18 - Impact on advanced atherosclerosis in ApoE-deficient mice - Kühn, Constanze; Tauchi, Miyuki; Stumpf, Christian; Daniel, Christoph; Bäuerle, Tobias; Schwarz, Marc; Kerek, Franz; Steinkasserer, Alexander; Zinser, Elisabeth; Achenbach, Stephan; Dietel, Barbara (Atherosclerosis, 2016)
Atherosclerosis is associated with chronic inflammatory responses of the arterial blood vessels. The previously observed protective effect of the MCS-18 substance against the initiation of atherosclerosis in a murine model was explained by its pronounced anti-inflammatory activity. Here, we investigated its impact on murine plaque progression in advanced atherosclerosis and on proatherogenic processes.ApoE-deficient mice were fed a high-fat diet for 12 weeks to induce atherosclerosis, followed by normal chow and intraperitoneal injections of either MCS-18 (500 ?g, n = 10) or saline (n = 10) twice a week for another 12 weeks. Plaque size was reduced in MCS-18 treated mice compared to controls (p = 0.001), which was associated with a reduced size of the lipid core (p = 0.01). There was a decrease in apoptotic cells (p = 0.02), endothelial ICAM-1 expression (p < 0.001), and macrophage density (p = 0.01) in the MCS-18 group. In addition, human and murine dendritic cells (DCs) and human umbilical vein endothelial cells (HUVECs) were treated with MCS-18 (50-200 ?g/ml) to analyze cell migration and adhesion under flow conditions. MCS-18 reduced human (p = 0.01) and murine (p = 0.006) DC migration. Furthermore, adhesion of MCS-18-treated DCs to a HUVEC monolayer was decreased (p < 0.001). Compared to controls, CD209 (p < 0.001) and CCR7 (p = 0.003) expression was decreased in MCS-18-treated DCs, while in HUVECs lower levels of ICAM-1 (p < 0.001) and of phosphorylated NF-?B-p65 (p = 0.002) were observed. Blocking of ICAM-1 reduced DC adhesion (p < 0.001).MCS-18 exhibits interesting therapeutic effects when applied in advanced murine atherosclerosis. Its antiatherogenic impact might be associated with a suppressed adhesion to the endothelium due to down-regulation of endothelial ICAM-1 expression.
EVALuna2:12031

Surveillance of patients with conjunctival melanoma in German-speaking countries: A multinational survey of the German dermatologic cooperative oncology group - Wessely, Anja; Steeb, Theresa; Berking, Carola; Schlaak, Max; Heppt, Markus; Alter, Mareike; Bayerl, Christiane; Bender, Armin; Bruning, Guido; Dabrowski, Evelyn; Debus, Dirk; Devereux, Nina; et al. (European Journal of Cancer, 2021)
CRIS-Team Scopus Importer:2020-12-11

Survival of metastatic melanoma patients after dendritic cell vaccination correlates with expression of leukocyte phosphatidylethanolamine-binding protein 1/Raf kinase inhibitory protein - Buschow, Sonja I.; Ramazzotti, Matteo; Reinieren-Beeren, Inge M. J.; Heinzerling, Lucie; Westdorp, Harm; Stefanini, Irene; Beltrame, Luca; Hato, Stanleyson V.; Ellebaek, Eva; Gross, Stefanie; Van Anh Nguyen,; Weinlich, Georg; et al. (Oncotarget, 2017)
Immunotherapy for metastatic melanoma offers great promise but, to date, only a subset of patients have responded. There is an urgent need to identify ways of allocating patients to the most beneficial therapy, to increase survival and decrease therapy-associated morbidity and costs. Blood-based biomarkers are of particular interest because of their straightforward implementation in routine clinical care. We sought to identify markers for dendritic cell (DC) vaccine-based immunotherapy against metastatic melanoma through gene expression analysis of peripheral blood mononuclear cells. A large-scale microarray analysis of 74 samples from two treatment centers, taken directly after the first round of DC vaccination, was performed. We found that phosphatidylethanolamine binding protein 1 (PEBP1)/Raf Kinase inhibitory protein (RKIP) expression can be used to identify a significant proportion of patients who performed poorly after DC vaccination. This result was validated by q-PCR analysis on blood samples from a second cohort of 95 patients treated with DC vaccination in four different centers. We conclude that low PEBP1 expression correlates with poor overall survival after DC vaccination. Intriguingly, this was only the case for expression of PEBP1 after, but not prior to, DC vaccination. Moreover, the change in PEBP1 expression upon vaccination correlated well with survival. Further analyses revealed that PEBP1 expression positively correlated with genes involved in T cell responses but inversely correlated with genes associated with myeloid cells and aberrant inflammation including STAT3, NOTCH1, and MAPK1. Concordantly, PEBP1 inversely correlated with the myeloid/lymphoid-ratio and was suppressed in patients suffering from chronic inflammatory disease.
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Survivin-specific T-cell reactivity correlates with tumor response and patient survival: A phase-II peptide vaccination trial in metastatic melanoma - Becker, Juergen C.; Andersen, Mads H.; Hofmeister-Mueller, Valeska; Wobser, Marion; Frey, Lidia; Sandig, Christiane; Walter, Steffen; Singh-Jasuja, Harpreet; Kämpgen, Eckhart; Opitz, Andreas; Zapatka, Marc; Broecker, Eva-B.; et al. (Cancer Immunology, Immunotherapy, 2012)
Keywords: Melanoma; Peptide vaccination; Survivin; T-cell reactivity; Therapy

Sustainable responses in metastatic melanoma patients with and without brain metastases after elective discontinuation of anti-PD1-based immunotherapy due to complete response - Dimitriou, Florentia; Zaremba, Anne; Allayous, Clara; Kähler, Katharina C.; Gerard, Camille L.; Festino, Lucia; Schäfer, Sarah; Toussaint, Frédéric; Heinzerling, Lucie; Hassel, Jessica C.; Ascierto, Paolo A.; Michielin, Olivier; et al. (European Journal of Cancer, 2021)
Background: Anti-PD1–based immunotherapy is currently used in most patients with advanced melanoma. Despite the remarkable data regarding overall survival, the optimal treatment duration is still unknown. Methods: We evaluated the outcome of 125 patients with advanced melanoma with and without brain metastases (MBM), treated either with anti-PD1 monotherapy (N = 97) or combined with anti-CTLA4 (N = 28) after elective treatment discontinuation due to complete response (CR) (group A, N = 86), or treatment-limiting toxicity (N = 33) and investigator's decision (ID, N = 6) (group B) with subsequent CR. Results: For group A, median duration of treatment (mDoT) was 22 months (range 5–49) and median time to CR 9 months (range 2–47). Accordingly, mDoT for group B was 3 months (range 0–36) and median time to CR 7 months (range 1–32). Seven patients from group A and three from group B experienced disease recurrence. Off-treatment survival was not reached. Median off-treatment response time (mOTRt) was 19 months (range 0–42) and 25 months (range 0–66), respectively. For MBM, mOTRt was 17 months (range 7–41) and 28 months (range 9–39), respectively. After a median follow-up of 38 months (range 9–70), seven (5.6%) patients had deceased, one (0.8%) due to melanoma. Conclusions: Treatment discontinuation is feasible also in patients with MBM. Efficacy outcomes seemed to be similar in both groups of patients who achieved CR, regardless of reason for discontinuation. In patients who experienced disease relapse, treatment re-challenge with anti-PD1 resulted in subsequent renewed response.
CRIS-Team Scopus Importer:2021-04-16
Keywords: Anti-PD1 treatment; Brain metastases; Discontinuation; Immunotherapy; Melanoma

Sweet SIGNs: IgG glycosylation leads the way in IVIG-mediated resolution of inflammation - Brückner, Christin; Lehmann, Christian; Dudziak, Diana; Nimmerjahn, Falk (International Immunology, 2017)
A hallmark of many chronic inflammatory and autoimmune diseases is that there is an impaired resolution of inflammation and return to the steady state. The infusion of high doses of pooled serum IgG preparations from thousands of donors [intravenous immunoglobulin (IVIG) therapy] has been shown to induce resolution of inflammation in a variety of chronic inflammatory and autoimmune diseases, suggesting that IgG molecules can instruct the immune system to stop inflammatory processes and initiate the return to the steady state. The aim of this review is to discuss how insights into the mechanism of IVIG activity may help to understand the molecular and cellular pathways underlying resolution of inflammation. We will put a special emphasis on pathways dependent on the IgG FC domain and IgG sialylation, as several recent studies have provided new insights into how this glycosylation-dependent pathway modulates innate and adaptive immune responses through different sets of C-type or I-type lectins.
EVALuna2:34371

Systematic symptom screening in patients with advanced cancer treated in certified oncology centers: results of the prospective multicenter German KeSBa project - Braulke, Friederike; Para, Servet; Alt-Epping, Bernd; Tewes, Mitra; Bäumer, Markus; Haberland, Birgit; Mayer-Steinacker, Regine; Hopprich, Anne; de Wit, Maike; Grabe, Michaela; Bender-Säbelkampf, Sophia; Weßling, Caroline; et al. (Journal of Cancer Research and Clinical Oncology, 2023)
Purpose: Guidelines recommend a structured symptom screening (SC) for especially advanced cancer patients (CPs). The aim of this multicenter German prospective quality assurance project KeSBa (Kennzahl Symptom- und Belastungserfassung) was to gain knowledge on SC procedures in Oncology Centers (OCs) for advanced cancer patients and a first impression on the consequences of SC. Methods: The KeSBa project consisted of three phases: pilot, 3 months screening and feedback phase. Participating OCs decided to use either the Minimal Documentation System (MIDOS) or the Integrated Palliative care Outcome Scale (IPOS) and defined the cutoff values for positive screening results. Results: Out of 172 certified German OCs, 40 (23%) participated in the KeSBa pilot phase, 29 (16.8%) in the 3 months screening phase using MIDOS (n = 18, 58.6%) or IPOS (n = 11, 41.3%) and in the feedback round. 25/29 performed paper-based screening (86.2%). 2.963 CPs were screened. Results were documented for 1255 (42.2%, SC +) positive and 874 (29.5%, SC–) negative screenings depending on the center´s schedules: 452 SC + CPs (28.4%) and 42 SC– CPs (2.6%) had contact to specialized palliative care or other supportive specialist teams afterwards, 458 SC + CPs (28.8%) and 605 SC– CPs (38.1%) remained in standard oncology care. In the feedback round missing resources (personal and IT) and improved communication were mentioned most often. Conclusion: Routine SC is feasible in advanced CPs treated in OCs but associated with considerable workload. In 42.2% of CPs SC was classified as positive, indicating the need of further diagnostics or professional judgment. SC requires staff and IT resources.
CRIS-Team Scopus Importer:2023-05-19
Keywords: Cancer; IPOS; MIDOS; Palliative; Screening; Supportive

Systemic sclerosis - the dermatological perspective - Sticherling, Michael (Journal der Deutschen Dermatologischen Gesellschaft, 2019)
Systemic scleroderma/systemic sclerosis (SSc) is an inflammatory connective tissue disease clinically characterized by two major subtypes: limited and diffuse SSc. While both conditions present with Raynaud's phenomenon (paroxysmal digital ischemia), diffuse SSc is associated with rapid disease progression and early - prognostically relevant - involvement of internal organs. Treatment is challenging. In addition to general lifestyle modifications, measures include treatments aimed at improving circulation as well as immunosuppressive and immunomodulatory drugs. However, these agents are effective only in terms of slowing disease progression.
CRIS-Team WoS Importer:2019-08-13

Systemic therapy with calcitonin has positive clinical effects on systemic sclerosis in patients with cutaneous manifestations - Uslu, Ugur; Streiff, Laura; Sticherling, Michael (European Journal of Dermatology, 2018)
BACKGROUND: Calcitonin gene-related peptide (CGRP) is a vasodilatory neuropeptide that plays an important role in the blood vessels of heart and peripheral circulation, a lack of which may cause vasculopathies. OBJECTIVE: In this study, the clinical course of disease, as well as the efficacy, side effects, and patient satisfaction of systemic calcitonin therapy in patients with systemic sclerosis (SSc), was evaluated. METHODS: Forty-nine patients received repetitive intravenous calcitonin infusions as first-line treatment. The average number of cycles was 12.2 ± 10.3 over a period of 30 months (each cycle: 100 U/day over 10 days). Clinical examinations, laboratory tests, and organ imaging were performed before the start of, and at regular intervals during therapy in order to evaluate organ manifestations and the clinical course of the disease. In addition, patients' own experiences of the therapy, side effects, and therapy success were evaluated with standardized questionnaires. RESULTS: Over the course of the treatment, seven patients experienced improvements in their condition with a considerable reduction in digital ulceration and improved movement (14.3%). Pulmonary function in seven patients improved during the therapy (14.3%). With regards to side effects, nausea (41.7%), headaches (33.3%), fluctuations in blood pressure (29.2%), and flushing (29.2%) were observed. Overall, 45.8% of patients evaluated the therapy as good and 58.3% would undergo further courses of therapy with calcitonin. CONCLUSIONS: Systemic calcitonin treatment seems to have positive clinical effects on SSc and contributes to relieving symptoms, especially in patients with cutaneous manifestations. No severe side effects were reported during this study.
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Systemische Sklerodermie - die dermatologische Sicht - Sticherling, Michael (Journal der Deutschen Dermatologischen Gesellschaft, 2019)
EVALuna2:212837

Systemische Therapien des Ulcus cruris - Dissemond, Joachim; Goerge, Tobias; Kroeger, Knut; Funke-Lorenz, Carolin; Reich-Schupke, Stefanie; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2018)
Successful management of patients with leg ulcers requires identification of the underlying etiology, with subsequent initiation of causal treatment, if feasible. Supplementary measures of first choice include stage-adjusted wound treatment, usually combined with compression therapy. The significance of systemic drugs has been the subject of controversial debate, depending on the underlying cause of the condition. The present review article is therefore meant to highlight current aspects of systemic drug therapies for the treatment of leg ulcers associated with chronic venous insufficiency, peripheral arterial disease, livedoid vasculopathy, vasculitis, necrobiosis lipoidica, calciphylaxis and pyoderma gangrenosum. In summary, the majority of therapeutic options presented herein are used off-label. While systemic drugs are promising options for the more common types of wounds such as venous, mixed or arterial leg ulcers, they do not represent the current standard of treatment. By contrast, systemic agents play a key role in the management of many of the other disorders presented herein. These agents primarily include immunomodulatory and rheological drugs used to expedite wound healing.
EVALuna2:34788

Systems biology-based investigation of cooperating microRNAs as monotherapy or adjuvant therapy in cancer - Lai, Xin; Eberhardt, Martin; Schmitz, Ulf; Vera, Julio (Nucleic Acids Research, 2019)
MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression by suppressing mRNA translation and reducing mRNA stability. A miRNA can potentially bind many mRNAs, thereby affecting the expression of oncogenes and tumor suppressor genes as well as the activity of whole pathways. The promise of miRNA therapeutics in cancer is to harness this evolutionarily conserved mechanism for the coordinated regulation of gene expression, and thus restoring a normal cell phenotype. However, the promiscuous binding of miRNAs can provoke unwanted off-target effects, which are usually caused by high-dose single-miRNA treatments. Thus, it is desirable to develop miRNA therapeutics with increased specificity and efficacy. To achieve that, we propose the concept of miRNA cooperativity in order to exert synergistic repression on target genes, thus lowering the required total amount of miRNAs. We first review miRNA therapies in clinical application. Next, we summarize the knowledge on the molecular mechanism and biological function of miRNA cooperativity and discuss its application in cancer therapies. We then propose and discuss a systems biology approach to investigate miRNA cooperativity for the clinical setting. Altogether, we point out the potential of miRNA cooperativity to reduce off-target effects and to complement conventional, targeted, or immune-based therapies for cancer.
CRIS-Team Scopus Importer:2019-09-17

Targeted label-free quantification of interleukin-8 in PMA-activated U937 cell secretome by nanoLC-ESI-MS/MS-sSRM. - Emirbayer, Pelin Esma; Gerer, Kerstin; Hoyer, Stefanie; Pischetsrieder, Monika (Proteomics, 2017)
Monocytes are a part of the innate immune system. Their differentiation into macrophages changes their cellular proteome and secretome. Particularly secretome components such as cytokines are crucial for immune response and inflammation in many diseases. Differentiation of human lymphoma cell line U937 can be triggered by phorbol 12-myristate 13-acetate (PMA). Screening of the cytokine release in U937 upon PMA stimulation by cytometric bead array almost exclusively showed interleukin-8. Next, a label-free nanoLC-ESI-MS/MS-sSRM method for quantification of interleukin-8 in the cell secretome was established and applied to monitor the time kinetics of PMA treatment in different concentrations. Targeted secretome analysis was achieved by scheduled SRM-MS using one proteotypic peptide as precursor ion and four mass transitions. Label-free quantification was performed by external calibration using interleukin-8 standard. Validation results indicated that the method was suited for the quantification of interleukin-8 in the secretome. The maximal interleukin-8 release of 62.4 ng/mL was observed after incubating cells treated by 50 ng/mL PMA for 48 h. The method can now be used for quantification of interleukin-8 release from different cells under various conditions. Furthermore, it can be easily expanded to other secreted proteins detected by untargeted screening methods. This article is protected by copyright. All rights reserve

Targeting Immune Cell Trafficking – Insights From Research Models and Implications for Future IBD Therapy - Wiendl, Maximilian; Becker, Elisabeth; Müller, Tanja; Voskens, Caroline; Neurath, Markus; Zundler, Sebastian (Frontiers in Immunology, 2021)
Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC) are multifactorial diseases with still unknown aetiology and an increasing prevalence and incidence worldwide. Despite plentiful therapeutic options for IBDs, the lack or loss of response in certain patients demands the development of further treatments to tackle this unmet medical need. In recent years, the success of the anti-α4β7 antibody vedolizumab highlighted the potential of targeting the homing of immune cells, which is now an important pillar of IBD therapy. Due to its complexity, leukocyte trafficking and the involved molecules offer a largely untapped resource for a plethora of potential therapeutic interventions. In this review, we aim to summarise current and future directions of specifically interfering with immune cell trafficking. We will comment on concepts of homing, retention and recirculation and particularly focus on the role of tissue-derived chemokines. Moreover, we will give an overview of the mode of action of drugs currently in use or still in the pipeline, highlighting their mechanisms and potential to reduce disease burden.
CRIS-Team Scopus Importer:2021-06-04
Keywords: homing; IBD; retention; T cell; therapy; trafficking

Targeting of DEC-205 on human dendritic cells results in efficient MHC class II-restricted antigen presentation - Birkholz, Katrin; Schwenkert, Michael; Kellner, Christian; Gross, Stefanie; Fey, Georg; Schuler-Thurner, Beatrice; Schuler, Gerold; Schaft, Niels; Dörrie, Jan (Blood, 2010)
The use of dendritic cells (DCs) in therapeutic cancer vaccination requires their loading with tumor-specific antigen(s). DEC-205, a phagocytosis receptor mediating antigen uptake, is associated with CD8+ T-cell responses in mice. Here we fused an anti-DEC-205scFv to an HLA-DP4-restricted epitope from the tumor antigen MAGE-A3, and examined the suitability and efficacy of DEC-205 to deliver a helper epitope to human monocytederived DCs (moDCs). The construct specifically bound DEC-205 on human moDCs without negative impact on DC phenotype and function. We measured antigen presentation with specific autologous CD4+ T cells, generated by TCR-RNA transfection. DEC-205 targeting resulted in significant major histocompatibility complex class II-restricted antigen presentation, and was superior to loading DCs by electroporation of mRNA encoding endosome-targeted MAGE-A3-DCLAMP or by direct peptide pulsing. Anti-DEC-205scFv-MAGE-A3 was presented 100 times more efficiently than the control constructs. DC maturation before or during incubation with anti-DEC-205scFv-MAGE-A3 reduced the interleukin-10/interleukin- 2 ratio. Moreover, we successfully applied the DEC-205 targeting strategy to moDCs from malignant melanoma patients. Again, DEC-205-targeted mature DCs (mDCs) presented the antigen more efficiently than peptide-pulsed DCs and maintained their stimulatory capacity after cryoconservation. Thus, DEC-205 targeting represents a feasible and effective method to deliver helper epitopes to DCs in anticancer vaccine strategies, which may also be suitable for DC targeting in vivo. © 2010 by The American Society of Hematology.
CRIS-Team Scopus Importer:2021-10-01

T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway - Bozec, Aline; Zaiss, Mario; Kagwiria, Rosebeth; Voll, Reinhard; Rauh, Manfred; Chen, Zhu; Müller-Schmucker, Sandra; Kroczek, Richard A.; Heinzerling, Lucie; Moser, Muriel; Mellor, Andrew L.; David, Jean-Pierre; et al. (Science Translational Medicine, 2014)
Bone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans.
EVALuna2:12912

T-cell receptor transfer for boosting HIV-1-specific T-cell immunity in HIV-1-infected patients - Mummert, Christiane; Hofmann, Christian; Hueckelhoven, Angela G.; Bergmann, Silke; Mueller-Schmucker, Sandra M.; Harrer, Ellen G.; Dörrie, Jan; Schaft, Niels; Harrer, Thomas (Aids, 2016)
Strategies to cure HIV-1 infection require the eradication of viral reservoirs. An innovative approach for boosting the cytotoxic T-lymphocyte response is the transfer of T-cell receptors (TCRs). Previously, we have shown that electroporation of TCR-encoding mRNA is able to reprogram CD8 T cells derived from healthy donors. So far, it is unknown whether the transfer of HIV-1-specific TCRs is capable to reprogram CD8 T cells of HIV-1-infected patients. To assess the efficiency of TCR-transfer by mRNA electroporation and the functionality of reprogramed T cells in HIV-1-infected patients, we performed an in-vitro analysis of TCR-transfer into T cells from HIV-1-infected patients in various stages of disease and from healthy controls.Peripheral blood mononuclear cells from 16 HIV-1-infected patients (nine HLA-A02-positive, seven HLA-A02-negative) and from five healthy controls were electroporated with mRNA-constructs encoding TCRs specific for the HLA-A02/HIV-1-gag p17 epitope SLYNTVATL (SL9). Functionality of the TCRs was measured by ?IFN-ELISpot assays.SL9/TCR transfection into peripheral blood mononuclear cells from both HLA-A02-positive and HLA-A02-negative HIV-1-infected patients and from healthy blood donors reprogramed T cells for recognition of SL9-presenting HLA-A02-positive cells in ?IFN-ELISpot assays. SL9/TCR-transfer into T cells from an immunodeficient AIDS patient could induce recognition of SL9-expressing target cells only after reversion of T-cell dysfunction by antiretroviral therapy.The transfer of HIV-1-p17-specific TCRs into T cells is functional both in HIV-1-infected patients as well as in healthy blood donors. TCR-transfer is a promising method to boost the immune system against HIV-1.
EVALuna2:13288

T-cell responses in merkel cell carcinoma: Implications for improved immune checkpoint blockade and other therapeutic options - Gehrcken, Laura; Sauerer, Tatjana; Schaft, Niels; Dörrie, Jan (International Journal of Molecular Sciences, 2021)
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with rising incidence and high mortality. Approximately 80% of the cases are caused by the human Merkel cell polyomavirus, while the remaining 20% are induced by UV light leading to mutations. The standard treatment of metastatic MCC is the use of anti-PD-1/-PD-L1-immune checkpoint inhibitors (ICI) such as Pembrolizumab or Avelumab, which in comparison with conventional chemotherapy show better overall response rates and longer duration of responses in patients. Nevertheless, 50% of the patients do not respond or develop ICI-induced, immune-related adverse events (irAEs), due to diverse mechanisms, such as down-regulation of MHC complexes or the induction of anti-inflammatory cytokines. Other immunotherapeutic options such as cytokines and pro-inflammatory agents or the use of therapeutic vaccination offer great ameliorations to ICI. Cytotoxic T-cells play a major role in the effectiveness of ICI, and tumour-infiltrating CD8+ T-cells and their phenotype contribute to the clinical outcome. This literature review presents a summary of current and future checkpoint inhibitor therapies in MCC and demonstrates alternative therapeutic options. Moreover, the importance of T-cell responses and their beneficial role in MCC treatment is discussed.
CRIS-Team Scopus Importer:2021-08-20
Keywords: Immune checkpoint blockade; Immunotherapy; Large T antigen; Merkel cell carcinoma; Merkel cell polyomavirus; T-cell response; Tumour microenvironment; Tumour mutational burden

Tebentafusp als neuartige Immuntherapie zeigt einen Überlebensvorteil beim metastasierten Uveamelanom und wird bereits in Deutschland eingesetzt. - Hassel, Jessica C.; Berking, Carola (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
EVALuna2:502114

Tebentafusp in Patients with Metastatic Uveal Melanoma: A Real-Life Retrospective Multicenter Study. - Tomsitz, Dirk; Ruf, Theresa; Heppt, Markus; Staeger, Ramon; Ramelyte, Egle; Dummer, Reinhard; Garzarolli, Marlene; Meier, Friedegund; Meier, Eileen; Richly, Heike; Gromke, Tanja; Siveke, Jens T.; et al. (Cancers, 2023)
BACKGROUND: Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting. PATIENTS AND METHODS: This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM. RESULTS: Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient. CONCLUSIONS: Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence.
EVALuna2:538270

TEMPORAL MIGRATION OF IMMUNE CELLS FROM PSORIATIC SKIN TO JOINTS INITIATING SYNOVIAL INFLAMMATION IN PSORIATIC ARTHRITIS - Raimondo, Maria Gabriella; Rauber, Simon; Xu, Cong; Mohammadian, Hashem; Vogg, Mario; Anchang, Charles Gwellem; Rigau, Aleix; Luber, M.; Labinsky, Hannah; Soare, A.; Distler, Jörg; Fearon, U.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Th17 Cell-Mediated Colitis Is Positively Regulated by Interferon Regulatory Factor 4 in a T Cell-Extrinsic Manner - Buchele, Vera; Konein, Patrick; Vogler, Tina; Kunert, Timo; Enderle, Karin; Khan, Hanif; Büttner-Herold, Maike; Lehmann, Christian; Amon, Lukas; Wirtz, Stefan; Dudziak, Diana; Neurath, Markus; et al. (Frontiers in Immunology, 2021)
Inflammatory bowel diseases (IBDs) are characterized by chronic, inflammatory gastrointestinal lesions and often require life-long treatment with immunosuppressants and repetitive surgical interventions. Despite progress in respect to the characterization of molecular mechanisms e.g. exerted by TNF-alpha, currently clinically approved therapeutics fail to provide long-term disease control for most patients. The transcription factor interferon regulatory factor 4 (IRF4) has been shown to play important developmental as well as functional roles within multiple immune cells. In the context of colitis, a T cell-intrinsic role of IRF4 in driving immune-mediated gut pathology is established. Here, we conversely addressed the impact of IRF4 inactivation in non-T cells on T cell driven colitis in vivo. Employing the CD4+CD25− naïve T cell transfer model, we found that T cells fail to elicit colitis in IRF4-deficient compared to IRF4-proficient Rag1−/− mice. Reduced colitis activity in the absence of IRF4 was accompanied by hampered T cell expansion both within the mesenteric lymph node (MLN) and colonic lamina propria (cLP). Furthermore, the influx of various myeloids, presumably inflammation-promoting cells was abrogated overall leading to a less disrupted intestinal barrier. Mechanistically, gene profiling experiments revealed a Th17 response dominated molecular expression signature in colon tissues of IRF4-proficient, colitic Rag1−/− but not in colitis-protected Rag1−/−Irf4−/− mice. Colitis mitigation in Rag1−/−Irf4−/− T cell recipients resulted in reduced frequencies and absolute numbers of IL-17a-producing T cell subsets in MLN and cLP possibly due to a regulation of conventional dendritic cell subset 2 (cDC2) known to impact Th17 differentiation. Together, extending the T cell-intrinsic role for IRF4 in the context of Th17 cell driven colitis, the provided data demonstrate a Th17-inducing and thereby colitis-promoting role of IRF4 through a T cell-extrinsic mechanism highlighting IRF4 as a putative molecular master switch among transcriptional regulators driving immune-mediated intestinal inflammation through both T cell-intrinsic and T cell-extrinsic mechanisms. Future studies need to further dissect IRF4 controlled pathways within distinct IRF4-expressing myeloid cell types, especially cDC2s, to elucidate the precise mechanisms accounting for hampered Th17 formation and, according to our data, the predominant mechanism of colitis protection in Rag1−/−Irf4−/− T cell receiving mice.
CRIS-Team Scopus Importer:2021-02-26
Keywords: inflammatory bowel disease (IBD); interferon regulatory factor 4 (IRF4); intestinal inflammation; myeloid cells; Th17

The acidic protein rich in leucines Anp32b is an immunomodulator of inflammation in mice - Chemnitz, Jan; Pieper, Dorothea; Stich, Lena; Schumacher, Udo; Balabanov, Stefan; Spohn, Michael; Grundhoff, Adam; Steinkasserer, Alexander; Hauber, Joachim; Zinser, Elisabeth (Scientific Reports, 2019)
ANP32B belongs to a family of evolutionary conserved acidic nuclear phosphoproteins (ANP32A-H). Family members have been described as multifunctional regulatory proteins and proto-oncogenic factors affecting embryonic development, cell proliferation, apoptosis, and gene expression at various levels. Involvement of ANP32B in multiple processes of cellular life is reflected by the previous finding that systemic gene knockout (KO) of Anp32b leads to embryonic lethality in mice. Here, we demonstrate that a conditional KO of Anp32b is well tolerated in adult animals. However, after immune activation splenocytes isolated from Anp32b KO mice showed a strong commitment towards Th17 immune responses. Therefore, we further analyzed the respective animals in vivo using an experimental autoimmune encephalomyelitis (EAE) model. Interestingly, an exacerbated clinical score was observed in the Anp32b KO mice. This was accompanied by the finding that animal-derived T lymphocytes were in a more activated state, and RNA sequencing analyses revealed hyperactivation of several T lymphocyte-associated immune modulatory pathways, attended by significant upregulation of Tfh cell numbers that altogether might explain the observed strong autoreactive processes. Therefore, Anp32b appears to fulfill a role in regulating adequate adaptive immune responses and, hence, may be involved in dysregulation of pathways leading to autoimmune disorders and/or immune deficiencies.
CRIS-Team WoS Importer:2019-04-02

The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages - Hannemann, Nicole; Jordan, Jutta; Paul, Sushmita; Reid, Stephen; Baenkler, Hanns-Wolf; Sonnewald, Sophia; Bäuerle, Tobias; Vera, Julio; Schett, Georg; Bozec, Aline (Journal of Immunology, 2017)
Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis. Their polarization and activation are controlled by transcription factors such as NF-?B and the AP-1 transcription factor member c-Fos. Surprisingly, little is known about the role of the AP-1 transcription factor c-Jun in macrophage activation. In this study, we show that mRNA and protein levels of c-Jun are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment cluster analyses of microarray data using wild-type and c-Jun-deleted macrophages highlight the central function of c-Jun in macrophages, in particular for immune responses, IL production, and hypoxia pathways. Mice deficient for c-Jun in macrophages show an amelioration of inflammation and bone destruction in the serum-induced arthritis model. In vivo and in vitro gene profiling, together with chromatin immunoprecipitation analysis of macrophages, revealed direct activation of the proinflammatory factor cyclooxygenase-2 and indirect inhibition of the anti-inflammatory factor arginase-1 by c-Jun. Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating cyclooxygenase-2 and arginase-1 levels.
EVALuna2:13412

The Art of Making Moulages - a hidden Art? - Sticherling, Michael; Groenhardt, K.; Saake, Marc (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

The CD83 Molecule – An Important Immune Checkpoint - Grosche, Linda; Knippertz, Ilka; König, Christina; Royzman, Dmytro; Wild, Andreas; Zinser, Elisabeth; Sticht, Heinrich; Muller, Yves; Steinkasserer, Alexander; Lechmann, Matthias (Frontiers in Immunology, 2020)
The CD83 molecule has been identified to be expressed on numerous activated immune cells, including B and T lymphocytes, monocytes, dendritic cells, microglia, and neutrophils. Both isoforms of CD83, the membrane-bound as well as its soluble form are topic of intensive research investigations. Several studies revealed that CD83 is not a typical co-stimulatory molecule, but rather plays a critical role in controlling and resolving immune responses. Moreover, CD83 is an essential factor during the differentiation of T and B lymphocytes, and the development and maintenance of tolerance. The identification of its interaction partners as well as signaling pathways have been an enigma for the last decades. Here, we report the latest data on the expression, structure, and the signaling partners of CD83. In addition, we review the regulatory functions of CD83, including its striking modulatory potential to maintain the balance between tolerance versus inflammation during homeostasis or pathologies. These immunomodulatory properties of CD83 emphasize its exceptional therapeutic potential, which has been documented in specific preclinical disease models.
CRIS-Team Scopus Importer:2020-05-08
Keywords: autoimmunity; CD83; immune tolerance; Treg cells; viral escape mechanism

The CD83 molecule expressed by dendritic cells is a checkpoint to regulate resolution of inflammation as well as homeostasis within periphery and CNS - Wild, Andreas; Krzyzak, Lena; Mattner, Jochen; Winkler, Thomas; Nitschke, Lars; Steinkasserer, Alexander (2018)
EVALuna2:36214

The COVID-19 pandemic: implications for patients undergoing immunomodulating or immunosuppressive treatments in dermatology - Reinholz, Markus; French, Lars E.; Berking, Carola; Heppt, Markus (European Journal of Dermatology, 2020)
CRIS-Team WoS Importer:2021-02-26

The current spectrum of contact sensitization in patients with chronic leg ulcers or stasis dermatitis - new data from the Information Network of Departments of Dermatology (IVDK) - Geier, Johannes; Mahler, Vera; Erfurt-Berge, Cornelia (Contact Dermatitis, 2017)
BACKGROUND: Patients with lower leg dermatitis, chronic venous insufficiency or chronic leg ulcers have a high prevalence of contact sensitization. OBJECTIVES: To identify the current spectrum of contact allergens in these patients. PATIENTS AND METHODS: Data of the Information Network of Departments of Dermatology on 5264 patients with the above diagnoses from the years 2003 to 2014 (study group) were compared with data on 4881 corresponding patients from 1994 to 2003 (historical control group) and with a current control group without these diagnoses (n = 55 510). RESULTS: Allergic contact dermatitis was diagnosed less frequently in the study group than in the historical control group (25.9% versus 16.9%; p < 0.001), and contact sensitization to most allergens had declined. The allergen spectrum, however, was largely unchanged. Important allergens are Myroxylon pereirae (balsam of Peru) (14.8% positive reactions), fragrance mix I (11.4%), lanolin alcohol (7.8%), colophonium (6.6%), neomycin sulfate (5.0%), cetearyl alcohol (4.4%), oil of turpentine (3.1%), and paraben mix (2.6%). Patch testing with additional series showed sensitization to Amerchol L-101 (9.7%), tert-butyl hydroquinone (8.7%), framycetin sulfate (5.0%), and gentamicin sulfate (3.1%). CONCLUSIONS: Topical preparations for treating the above-mentioned conditions should not contain fragrances, Myroxylon pereirae, and colophonium. The special allergen spectrum has to be considered in patch testing.
EVALuna2:35405

The delivery of antigens to dendritic cells is a potent futureoption for anti-tumor therapies - Lehmann, Christian; Heger, Lukas; Neubert, K.; Harzer, Christina; Amon, Lukas; Yamazaki, S.; Heidkamp, Gordon Frederik; Eissing, N.; Krug, A.; Leusen, J.; Ravetch, J.; Nimmerjahn, Falk; et al. (2017)
EVALuna2:34372

The distribution of C-type lectin receptors in the Dendritic cell membrane - Lühr, Jennifer; Eissing, N.; Heidkamp, Gordon Frederik; Lehmann, C. H. K.; Heger, Lukas; Dudziak, Diana (2017)
EVALuna2:34370

The Effect of Hyperthermia and Radiotherapy Sequence on Cancer Cell Death and the Immune Phenotype of Breast Cancer Cells - Sengedorj, Azzaya; Hader, Michael; Heger, Lukas; Frey, Benjamin; Dudziak, Diana; Fietkau, Rainer; Ott, Oliver; Scheidegger, Stephan; Barba, Sergio Mingo; Gaipl, Udo; Rückert, Michael (Cancers, 2022)
Hyperthermia (HT) is an accepted treatment for recurrent breast cancer which locally heats the tumor to 39–44◦C, and it is a very potent sensitizer for radiotherapy (RT) and chemotherapy. However, currently little is known about how HT with a distinct temperature, and particularly, how the sequence of HT and RT changes the immune phenotype of breast cancer cells. Therefore, human MDA-MB-231 and MCF-7 breast cancer cells were treated with HT of different temperatures (39, 41 and 44◦C), alone and in combination with RT (2 × 5 Gy) in different sequences, with either RT or HT first, followed by the other. Tumor cell death forms and the expression of immune checkpoint molecules (ICMs) were analyzed by multicolor flow cytometry. Human monocyte-derived dendritic cells (moDCs) were differentiated and co-cultured with the treated cancer cells. In both cell lines, RT was the main stressor for cell death induction, with apoptosis being the prominent cell death form in MCF-7 cells and both apoptosis and necrosis in MDA-MB-231 cells. Here, the sequence of the combined treatments, either RT or HT, did not have a significant impact on the final outcome. The expression of all of the three examined immune suppressive ICMs, namely PD-L1, PD-L2 and HVEM, was significantly increased on MCF-7 cells 120 h after the treatment of RT with HT of any temperature. Of special interest for MDA-MB-231 cells is that only combinations of RT with HT of both 41 and 44◦C induced a significantly increased expression of PD-L2 at all examined time points (24, 48, 72, and 120 h). Generally, high dynamics of ICM expression can be observed after combined RT and HT treatments. There was no significant difference between the different sequences of treatments (either HT + RT or RT + HT) in case of the upregulation of ICMs. Furthermore, the co-culture of moDCs with tumor cells of any treatment had no impact on the expression of activation markers. We conclude that the sequence of HT and RT does not strongly affect the immune phenotype of breast cancer cells. However, when HT is combined with RT, it results in an increased expression of distinct immune suppressive ICMs that should be considered by including immune checkpoint inhibitors in multimodal tumor treatments with RT and HT. Further, combined RT and HT affects the immune system in the effector phase rather than in the priming phase.
CRIS-Team Scopus Importer:2022-04-29
Keywords: breast cancer; dendritic cell activation; hyperthermia; hyperthermia treatment sequence; immune checkpoint molecules; immune phenotype; radiotherapy

The effects of dexmedetomidine and tramadol on post-operative pain and agitation, and extubation quality in paediatric patients undergoing adenotonsillectomy surgery: A randomized trial - Koceroglu, Ikbal; Devrim, Sibel; Bingol Tanriverdi, Tugba; Gura Celik, Melek (Journal of Clinical Pharmacy and Therapeutics, 2019)
What is known and objective Adenotonsillectomies are common surgical procedures performed under general anaesthesia in childhood. Post-operative pain and agitation are complications associated with this procedure. We compared the effects of dexmedetomidine and tramadol on post-operative pain, agitation, haemodynamic parameters, and extubation quality in patients undergoing an adenotonsillectomy using sevoflurane as an anaesthetic agent. Methods Sixty paediatric patients who had undergone an adenotonsillectomy were included in this study. The patients were randomized into two groups that received either dexmedetomidine (n = 30) or tramadol (n = 30). Haemodynamic variables, extubation time, post-operative pain, agitation and adverse events were recorded for all patients. Post-operative pain was assessed with the pain point system scale (PPSS), and agitation was assessed using the Riker Sedation-Agitation Scale (SAS). Results Patients in the dexmedetomidine group had significantly lower heart rates than the tramadol group. In addition, patients in the dexmedetomidine group had significantly lower post-operative PPSS and Riker SAS scores than patients in the tramadol group. Not breathing, cough-bucking and desaturation after extubation occurred less frequently in patients who received dexmedetomidine than in patients who received tramadol. However, the time to extubation was significantly longer for patients who received dexmedetomidine. What is new and conclusion Our study demonstrated that dexmedetomidine was more effective than tramadol for mitigating post-operative pain and agitation in paediatric patients following an adenotonsillectomy with sevoflurane. Although dexmedetomidine was associated with a longer time to extubation, it was also associated with fewer complications following extubation compared with tramadol.
CRIS-Team WoS Importer:2019-12-13

The future of affordable cancer immunotherapy - Schaft, Niels; Dörrie, Jan; Schuler, Gerold; Schuler-Thurner, Beatrice; Sallam, Husam; Klein, Shiri; Eisenberg, Galit; Frankenburg, Shoshana; Lotem, Michal; Khatib, Areej (Frontiers in Immunology, 2023)
The treatment of cancer was revolutionized within the last two decades by utilizing the mechanism of the immune system against malignant tissue in so-called cancer immunotherapy. Two main developments boosted cancer immunotherapy: 1) the use of checkpoint inhibitors, which are characterized by a relatively high response rate mainly in solid tumors; however, at the cost of serious side effects, and 2) the use of chimeric antigen receptor (CAR)-T cells, which were shown to be very efficient in the treatment of hematologic malignancies, but failed to show high clinical effectiveness in solid tumors until now. In addition, active immunization against individual tumors is emerging, and the first products have reached clinical approval. These new treatment options are very cost-intensive and are not financially compensated by health insurance in many countries. Hence, strategies must be developed to make cancer immunotherapy affordable and to improve the cost-benefit ratio. In this review, we discuss the following strategies: 1) to leverage the antigenicity of “cold tumors” with affordable reagents, 2) to use microbiome-based products as markers or therapeutics, 3) to apply measures that make adoptive cell therapy (ACT) cheaper, e.g., the use of off-the-shelf products, 4) to use immunotherapies that offer cheaper platforms, such as RNA- or peptide-based vaccines and vaccines that use shared or common antigens instead of highly personal antigens, 5) to use a small set of predictive biomarkers instead of the “sequence everything” approach, and 6) to explore affordable immunohistochemistry markers that may direct individual therapies.
CRIS-Team Scopus Importer:2023-09-29
Keywords: adoptive cell therapy; affordable; biomarkers; immunohistochemistry; immunotherapy; microbiome; RNA-based vaccines

The Generation of CAR-Transfected Natural Killer T Cells for the Immunotherapy of Melanoma - Simon, Bianca; Wiesinger, Manuel; Maerz, Johannes; Wistuba-Hamprecht, Kilian; Weide, Benjamin; Schuler-Thurner, Beatrice; Schuler, Gerold; Dörrie, Jan; Uslu, Ugur (International Journal of Molecular Sciences, 2018)
Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR. The CAR expression on NKT cells and their in vitro functionality were analyzed. A transfection efficiency of more than 80% was achieved. Upon stimulation with melanoma cells, CAR-NKT cells produced cytokines antigen-specifically. Compared with conventional CAR-T cells, cytokine secretion of CAR-NKT cells was generally lower. Specific cytotoxicity, however, was similar with CAR-NKT cells showing a trend towards improved cytotoxicity. Additionally, CAR-NKT cells could kill target cells through their endogenous TCRs. In summary, it is feasible to generate CAR-NKT cells by using mRNA electroporation. Their CAR-mediated cytotoxicity is at least equal to that of conventional CAR-T cells, while their intrinsic cytotoxic activity is maintained. Thus, CAR-NKT cells may represent a valuable alternative to conventional CAR-T cells for cancer immunotherapy.
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The Generation of CAR-transfected NKT Cells for the Immunotherapy of Melanoma - Simon, B.; Wiesinger, M.; Marz, J.; Wistuba-Hamprecht, K.; Weide, B.; Schuler-Thurner, Beatrice; Schuler, Gerold; Dörrie, Jan; Uslu, Ugur (2018)
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The genetic basis for most patients with pustular skin disease remains elusive - Mössner, R.; Wilsmann-Theis, D.; Oji, V.; Gkogkolou, P.; Löhr, S.; Schulz, P.; Körber, A.; Prinz, J. C.; Renner, R.; Schäkel, K.; Vogelsang, L.; Peters, K. P.; et al. (British Journal of Dermatology, 2017)
Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause/ contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP).To better understand the disease-relevance of these genes, we screened our cohorts of patients with pustular skin diseases (primarily GPP and palmoplantar pustular psoriasis [PPP]) for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN.Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, 2 with acute generalized exanthematous pustulosis and 4 with acrodermatitis continua suppurativa Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number-variants, 258 PPP patients for coding changes in AP1S3. 11 heterozygous IL36RN mutations carriers were analyzed for a 2(nd) non-coding IL36RN mutation. Genotype-phenotype-correlations in carriers/ non-carriers of IL36RN mutations were assessed within the GPP cohort.The majority of patients (GPP:64%) did not carry rare variants in any of the three genes. Bi-allelic and mono-allelic IL36RN mutations were identified in 15 and 5 GPP patients, respectively. Non-coding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype-correlation observed for IL36RN mutation carriers was early age of disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutations carriers.The identification of IL36RN mutation carriers harboring additional rare variants in CARD14 or AP1S3, indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest additional disease-causing genetic factors in heterozygous IL36RN mutation carriers outside IL36RN. This article is protected by copyright. All rights reserved.
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THE GERMAN AD REGISTRY TREATGERMANY: RESULTS FROM AN INTERIM DATA ANALYSIS ON BASELINE CHARACTERISTICS, COMORBIDITIES AND TREATMENT HISTORY - Heratizadeh, Annice; Haufe, Eva; Stoelzl, Dora; Abraham, Susanne; Heinrich, Luise; Kleinheinz, Andreas; Wollenberg, Andreas; Weisshaar, Elke; Augustin, Matthias; Wiemers, Franca; Zink, Alexander; Von Kiedrowski, Ralph; et al. (ACTA DERMATO-VENEREOLOGICA, 2021)
CRIS-Team WoS Importer:2021-05-07

The global impact of the COVID-19 pandemic on the management and course of chronic urticaria - Kocaturk, Emek; Salman, Andac; Cherrez-Ojeda, Ivan; Criado, Paulo Ricardo; Peter, Jonny; Comert-Ozer, Elif; Abuzakouk, Mohamed; Agondi, Rosana Camara; Al-Ahmad, Mona; Altrichter, Sabine; Arnaout, Rand; Arruda, Luisa Karla; et al. (Allergy, 2020)
Introduction The COVID-19 pandemic dramatically disrupts health care around the globe. The impact of the pandemic on chronic urticaria (CU) and its management are largely unknown.
CRIS-Team WoS Importer:2021-01-22

The IKZF1–IRF4/IRF5 axis controls polarization of myeloma-associated macrophages - Mougiakakos, Dimitrios; Bach, Christian; Böttcher, Martin; Beier, Fabian; Röhner, Linda; Stoll, Andrej; Rehli, Michael; Gebhard, Claudia; Lischer, Christopher; Eberhardt, Martin; Vera, Julio; Büttner-Herold, Maike; et al. (Cancer Immunology Research, 2021)
The bone marrow niche has a pivotal role in progression, survival, and drug resistance of multiple myeloma cells. Therefore, it is important to develop means for targeting the multiple myeloma bone marrow microenvironment. Myeloma-associated macrophages (MAM) in the bone marrow niche are M2 like. They provide nurturing signals to multiple myeloma cells and promote immune escape. Reprogramming M2-like macrophages toward a tumoricidal M1 phenotype represents an intriguing therapeutic strategy. This is especially interesting in view of the successful use of mAbs against multiple myeloma cells, as these therapies hold the potential to trigger macrophage-mediated phagocytosis and cytotoxicity. In this study, we observed that MAMs derived from patients treated with the immunomodulatory drug (IMiD) lenalidomide skewed phenotypically and functionally toward an M1 phenotype. Lenalidomide is known to exert its beneficial effects by modulating the CRBN-CRL4 E3 ligase to ubiquitinate and degrade the transcription factor IKAROS family zinc finger 1 (IKZF1). In M2-like MAMs, we observed enhanced IKZF1 levels that vanished through treatment with lenalidomide, yielding MAMs with a bioenergetic profile, T-cell stimulatory properties, and loss of tumor-promoting capabilities that resemble M1 cells. We also provide evidence that IMiDs interfere epigenetically, via degradation of IKZF1, with IFN regulatory factors 4 and 5, which in turn alters the balance of M1/M2 polarization. We validated our observations in vivo using the CrbnI391V mouse model that recapitulates the IMiD-triggered IKZF1 degradation. These data show a role for IKZF1 in macrophage polarization and can provide explanations for the clinical benefits observed when combining IMiDs with therapeutic antibodies. See related Spotlight on p. 254
CRIS-Team Scopus Importer:2021-03-19

The Influence of MHC Class II on B Cell Defects Induced by Invariant Chain/CD74 N-Terminal Fragments - Schneppenheim, Janna; Loock, Ann-Christine; Huettl, Susann; Schweizer, Michaela; Luellmann-Rauch, Renate; Oberg, Hans-Heinrich; Arnold, Philipp; Lehmann, Christian; Dudziak, Diana; Kabelitz, Dieter; Lucius, Ralph; Lennon-Dumenil, Ana-Maria; et al. (Journal of Immunology, 2017)
The invariant chain (CD74) mediates assembly and targeting of MHC class II (MHCII) complexes. In endosomes, CD74 undergoes sequential degradation by different proteases, including cathepsin S (CatS) and the intramembrane protease signal peptide peptidase-like 2a (SPPL2a). In their absence, CD74 N-terminal fragments (NTFs) accumulate. In SPPL2a-/- B cells, such an NTF impairs endosomal trafficking and BCR signal transduction. In mice, this leads to a loss of splenic B cells beyond the transitional stage 1. To gain insight into CD74 determinants and the role of MHCII, we compared B cells from CatS-/- , SPPL2a-/- , and SPPL2a-MHCII double-deficient mice. We assessed differentiation of B cells in bone marrow and spleen and analyzed their endosomal morphology, BCR expression, and signal transduction. We demonstrate that MHCII is dispensable for the B cell phenotype of SPPL2a-/- mice, further supporting a CD74-intrinsic effect. Despite significant vacuolization of endosomal compartments similar to SPPL2a-/- B cells, CatS-/- traditional stage 1 B cells show unimpaired degradation of endocytic cargo, have intact BCR signaling, and do not exhibit any relevant defects in maturation. This could indicate that CD74 NTF-induced structural changes of endosomes are not directly involved in these processes. We further found that the block of CD74 degradation in CatS-/- B cells is incomplete, so that NTF levels are significantly lower than in SPPL2a-/- B cells. This suggests a dose dependency and threshold for the CD74 NTF-associated impairment of B cell signaling and maturation. In addition, different functional properties of the longer, MHCII-bound CD74 NTF could contribute to the milder phenotype of CatS-/- B cells.
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The involvement of Toll-like receptor 9 in the pathogenesis of erosive autoimmune arthritis - Fischer, Anita; Abdollahi-Roodsaz, Shahla; Boehm, Christina; Niederreiter, Birgit; Meyer, Brigitte; Yau, Anthony C. Y.; Lonnblom, Erik; Joosten, Leo A. B.; Koenders, Marije; Lehmann, Christian; Dudziak, Diana; Krönke, Gerhard; et al. (Journal of Cellular and Molecular Medicine, 2018)
Endogenous nucleic acids and their receptors may be involved in the initiation of systemic autoimmune diseases including rheumatoid arthritis (RA). As the role of the DNA sensing Toll-like receptor (TLR) 9 in RA is unclear, we aimed to investigate its involvement in the pathogenesis of autoimmune arthritis using three different experimental models of RA. The data obtained revealed involvement of TLR9 in the T cell-dependent phase of inflammatory arthritis. In rats with pristane-induced arthritis (PIA), TLR9 inhibition before disease onset reduced arthritis significantly and almost completely abolished bone erosion. Accordingly, serum levels of IL-6, α-1-acid-glycoprotein and rheumatoid factor were reduced. Moreover, in TLR9-/- mice, streptococcal cell wall (SCW)-induced arthritis was reduced in the T cell-dependent phase, whereas T cell-independent serum-transfer arthritis was not affected. Remarkably, while TLR7 expression did not change during in vitro osteoclastogenesis, TLR9 expression was higher in precursor cells than in mature osteoclasts and partial inhibition of osteoclastogenesis was achieved only by the TLR9 antagonist. These results demonstrate a pivotal role for TLR9 in the T cell-dependent phases of inflammatory arthritis and additionally suggest some role during osteoclastogenesis. Hence, endogenous DNA seems to be crucially involved in the pathophysiology of inflammatory autoimmune arthritis.
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The Major Immediate-Early Protein IE2 of Human Cytomegalovirus Is Sufficient to Induce Proteasomal Degradation of CD83 on Mature Dendritic Cells - Heilingloh, Christiane; Grosche, Linda; Kummer, Mirko; Mühl-Zürbes, Petra; Kamm, Lisa; Scherer, Myriam; Latzko, Melanie; Stamminger, Thomas; Steinkasserer, Alexander (Frontiers in Microbiology, 2017)
Human cytomegalovirus (HCMV) is the prototypic beta-herpesvirus and widespread throughout the human population. While infection is asymptomatic in healthy individuals, it can lead to high morbidity and mortality in immunocompromised persons. Importantly, HCMV evolved multiple strategies to interfere with immune cell function in order to establish latency in infected individuals. As mature DCs (mDCs) are antigen-presenting cells able to activate naïve T cells they play a crucial role during induction of effective antiviral immune responses. Interestingly, earlier studies demonstrated that the functionally important mDC surface molecule CD83 is down-regulated upon HCMV infection resulting in a reduced T cell stimulatory capacity of the infected cells. However, the viral effector protein and the precise mechanism of HCMV-mediated CD83 reduction remain to be discovered. Using flow cytometric analyses, we observed significant down-modulation of CD83 surface expression becoming significant already 12 h after HCMV infection. Moreover, Western bot analyses revealed that, in sharp contrast to previous studies, loss of CD83 is not restricted to the membrane-bound molecule, but also occurs intracellularly. Furthermore, inhibition of the proteasome almost completely restored CD83 surface expression during HCMV infection. Results of infection kinetics and cycloheximide-actinomycin D-chase experiments, strongly suggested that an HCMV immediate early gene product is responsible for the induction of CD83 down-modulation. Consequently, we were able to identify the major immediate early protein IE2 as the viral effector protein that induces proteasomal CD83 degradation.
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The Nectin-1 Expression correlates with the Susceptibility of malignant Melanoma to oncolytic Herpes Simplex Viruses in vitro and in vivo - Schwertner, B.; Linder, G.; Stauner, C. Toledo; Klapproth, E.; Magnus, C.; Rohrhofer, A.; Gross, S.; Schuler-Thurner, Beatrice; Oettl, V.; Feichtgruber, N.; Drexler, K.; Evert, K.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

The need for regular training in skin cancer screening: a cross-sectional study among general practitioners in Germany - Steeb, Theresa; Reinhardt, Lydia; Strasser, C.; Wessely, Anja; Schelling, J.; Petzold, Anne; Heppt, Markus; Meier, Friedegund; Berking, Carola (Journal of the European Academy of Dermatology and Venereology, 2022)
CRIS-Team Scopus Importer:2022-07-15

The Neural Crest Transcription Factor SOX10 is essential for the Survival of Uveal Melanoma Cells - Wessely, A.; Kammerbauer, C.; Berking, Carola; Heppt, Markus (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

The novel role of lymphatic vessels in the pathogenesis of ocular diseases - Clahsen, Thomas; Hadrian, Karina; Notara, Maria; Schlereth, Simona L.; Howaldt, Antonia; Prokosch, Verena; Volatier, Thomas; Hos, Deniz; Schroedl, Falk; Kaser-Eichberger, Alexandra; Heindl, Ludwig M.; Steven, Philipp; et al. (Progress in Retinal and Eye Research, 2023)
Historically, the eye has been considered as an organ free of lymphatic vessels. In recent years, however, it became evident, that lymphatic vessels or lymphatic-like vessels contribute to several ocular pathologies at various peri- and intraocular locations. The aim of this review is to outline the pathogenetic role of ocular lymphatics, the respective molecular mechanisms and to discuss current and future therapeutic options based thereon. We will give an overview on the vascular anatomy of the healthy ocular surface and the molecular mechanisms contributing to corneal (lymph)angiogenic privilege. In addition, we present (i) current insights into the cellular and molecular mechanisms occurring during pathological neovascularization of the cornea triggered e.g. by inflammation or trauma, (ii) the role of lymphatic vessels in different ocular surface pathologies such as dry eye disease, corneal graft rejection, ocular graft versus host disease, allergy, and pterygium, (iii) the involvement of lymphatic vessels in ocular tumors and metastasis, and (iv) the novel role of the lymphatic-like structure of Schlemm's canal in glaucoma. Identification of the underlying molecular mechanisms and of novel modulators of lymphangiogenesis will contribute to the development of new therapeutic targets for the treatment of ocular diseases associated with pathological lymphangiogenesis in the future. The preclinical data presented here outline novel therapeutic concepts for promoting transplant survival, inhibiting metastasis of ocular tumors, reducing inflammation of the ocular surface, and treating glaucoma. Initial data from clinical trials suggest first success of novel treatment strategies to promote transplant survival based on pretransplant corneal lymphangioregression.
CRIS-Team Scopus Importer:2023-06-30
Keywords: Corneal (lymph)angiogenic privilege; Corneal immune reaction; Glaucoma; Limbal stem cells; Lymphangiogenesis; Transplantation

The ontogenetic path of human dendritic cells - Amon, Lukas; Lehmann, Christian; Heger, Lukas; Heidkamp, Gordon Frederik; Dudziak, Diana (Molecular Immunology, 2020)
Dendritic cells (DCs) orchestrate adaptive immune responses. In healthy individuals, DCs are drivers and fine-tuners of T cell responses directed against invading pathogens or cancer cells. In parallel, DCs control autoreactive T cells, thereby maintaining T cell tolerance. Under various disease conditions, a disruption of this delicate balance can lead to chronic infections, tumor evasion, or autoimmunity. While great efforts have been made to unravel the origin and development of this powerful cell type in mice, only little is known about the ontogeny of human DCs. Here, we summarize the current understanding of the developmental path of DCs from hematopoietic stem cells to fully functional DCs in their local tissue environment and provide a template for the identification of DCs across various tissues.
CRIS-Team Scopus Importer:2020-03-06
Keywords: Conventional; DC; Human; Ontogeny; Progeny; Transcription factor

The outweigh of toxicity versus risk of recurrence for adjuvant interferon therapy: a survey in German melanoma patients and their treating physicians - Kähler, Katharina C.; Blome, Christine; Forschner, Andrea; Gutzmer, Ralf; Hauschild, Axel; Heinzerling, Lucie; Livingstone, Elisabeth; Loquai, Carmen; Müller-Brenne, Tina; Schadendorf, Dirk; Utikal, Jochen; Wagner, Tobias; et al. (Oncotarget, 2018)
After more than two decades with interferon alfa-2a and 2b (IFN) as the only approved drugs in the adjuvant setting for melanoma, new treatment approaches like immune checkpoint inhibitors and BRAF-MEK inhibitors improve the progression free survival (PFS) and also the overall survival (OS). We compared physicians' preferences ("utilities") for health states associated with IFN therapy to their patients' preferences. Utilities describe a preference for a specific health state on a scale of 0 (as bad as death) to 1.0 (perfect health). Setting: We assessed utilities for health states associated with adjuvant IFN using the standard gamble technique in 108 physicians and 130 melanoma patients. Four IFN toxicity scenarios and three outcome scenarios were given to the participants. Both groups were asked for the 5-year disease free survival (DFS) they would need to accept the described IFN-related side effects. Results: In both groups, utilities for melanoma relapse were significantly lower than for IFN side effects, showing that toxicity was more acceptable than relapse. Physicians indicated higher utilities for each scenario and needed lower 5-year DFS both in case of mild-to-moderate and severe side effects. Patients were willing to tolerate mild-to-moderate and severe toxicity for a 50% and 75% chance of 5-year DFS, while physicians only required a chance of 40% and 50%, respectively. Conclusion: Both physicians and patients rated melanoma recurrence much lower than even severe IFN side effects. In direct comparison, physicians rated cancer-related scenarios more positively and accepted IFN toxicity for an even lower treatment benefit.
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The p.Arg435His Variation of IgG3 With High Affinity to FcRn Is Associated With Susceptibility for Pemphigus Vulgaris-Analysis of Four Different Ethnic Cohorts - Recke, Andreas; Konitzer, Sarah; Lemcke, Susanne; Freitag, Miriam; Sommer, Nele Maxi; Abdelhady, Mohammad; Amoli, Mahsa M.; Benoit, Sandrine; El-Chennawy, Farha; Eldarouti, Mohammad; Eming, Ruediger; Glaeser, Regine; et al. (Frontiers in Immunology, 2018)
IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and the highest degree of allelic variability among all constant immunoglobulin genes. Due to its genetic position, IgG3 is often the first isotype an antibody switches to before IgG1 or IgG4. Compared with the other IgG subclasses, it has a reduced half-life which is probably connected to a decreased affinity to the neonatal Fc receptor (FcRn). However, a few allelic variants harbor an amino acid replacement of His435 to Arg that reverts the half-life of the resulting IgG3 to the same level as the other IgG subclasses. Because of its functional impact, we hypothesized that the p.Arg435His variation could be associated with susceptibility to autoantibody-mediated diseases like pemphigus vulgaris (PV) and bullous pemphigoid (BP). Using a set of samples from German, Turkish, Egyptian, and Iranian patients and controls, we were able to demonstrate a genetic association of the p.Arg435His variation with PV risk, but not with BP risk. Our results suggest a hitherto unknown role for the function of IgG3 in the pathogenesis of PV.
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The Quality of Guidelines for the Treatment of Cutaneous Melanoma: A methodological Assessment - Steeb, T.; Wessely, A.; Drexler, K.; Salzmann, M.; Toussaint, Frédéric; Heinzerling, Lucie; Reinholz, M.; Berking, Carola; Heppt, Markus (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

The quality of national skin cancer screening from the perspective of general practitioners: A questionnaire-based comparison between Saxony and Bavaria (SaBaScreen) - Strasser, C.; Reinhardt, L.; Steeb, Theresa; Wessely, Anja; Schelling, Jörg; Petzold, Anne; Heppt, Markus; Meier, F.; Berking, Carola (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

The quality of practice guidelines for melanoma: A methodologic appraisal with the agree ii and agree-rex instruments - Steeb, Theresa; Wessely, Anja; Drexler, Konstantin; Salzmann, Martin; Toussaint, Frédéric; Heinzerling, Lucie; Reinholz, Markus; Berking, Carola; Heppt, Markus (Cancers, 2020)
Multiple guidelines on cutaneous melanoma (CM) are available from several consortia and countries. To provide up-to-date guidance in the rapidly changing field of melanoma treatment, guideline developers have to provide regular updates without compromises of quality. We performed a systematic search in guideline databases, Medline and Embase to identify guidelines on CM. The methodological quality of the identified guidelines was independently assessed by five reviewers using the instruments “Appraisal of Guidelines for Research and Evaluation” (AGREE II) and “Recommendation EXcellence” (AGREE-REX). We performed descriptive analysis, explored subgroup differences using the Kruskal–Wallis (H) test and examined the relationship between distinct domains and items of the instruments with Spearman’s correlation. Six guidelines by consortia from Australia, France, Germany, Scotland, Spain and the United States of America were included. The German guideline fulfilled 71%–98% of criteria in AGREE II and 78%–96% for AGREE-REX, obtaining the highest scores. Deficiencies in the domains of “applicability” and “values and preferences” were observed in all guidelines. The German and Spanish guidelines significantly differed from each other in most of the domains. The domains “applicability” and “values and preferences” were identified as methodological weaknesses requiring careful revision and improvement in the future.
CRIS-Team Scopus Importer:2020-06-26
Keywords: AGREE; Cutaneous melanoma; Level of evidence; Melanoma treatment; Practice guideline

Therapeutic cancer vaccination with ex vivo rna-transfected dendritic cells—an update - Dörrie, Jan; Schaft, Niels; Schuler, Gerold; Schuler-Thurner, Beatrice (Pharmaceutics, 2020)
Over the last two decades, dendritic cell (DC) vaccination has been studied extensively as active immunotherapy in cancer treatment and has been proven safe in all clinical trials both with respect to short and long-term side effects. For antigen-loading of dendritic cells (DCs) one method is to introduce mRNA coding for the desired antigens. To target the whole antigenic repertoire of a tumor, even the total tumor mRNA of a macrodissected biopsy sample can be used. To date, reports have been published on a total of 781 patients suffering from different tumor entities and HIV-infection, who have been treated with DCs loaded with mRNA. The majority of those were melanoma patients, followed by HIV-infected patients, but leukemias, brain tumors, prostate cancer, renal cell carcinomas, pancreatic cancers and several others have also been treated. Next to antigen-loading, mRNA-electroporation allows a purposeful manipulation of the DCs’ phenotype and function to enhance their immunogenicity. In this review, we intend to give a comprehensive summary of what has been published regarding clinical testing of ex vivo generated mRNA-transfected DCs, with respect to safety and risk/benefit evaluations, choice of tumor antigens and RNA-source, and the design of better DCs for vaccination by transfection of mRNA-encoded functional proteins.
CRIS-Team Scopus Importer:2020-02-04
Keywords: Clinical trial; Dendritic cells; Electroporation; Immunotherapy; RNA; Therapeutic vaccination

Therapeutische Optionen der Necrobiosis lipoidica - Erfurt-Berge, Cornelia; Arnet, Lisa (Internistische Praxis, 2023)
Necrobiosis lipoidica (NL) is a granulomatous inflammatory skin disease with characteristic yellow-brown, central atrophic plaques, which usually occur pretibially on both lower legs. The diagnosis is often made based on the typical clinical presentation. In case of equivocal findings, a biopsy can rule out differential diagnoses. Because it is a rare disease and the pathogenesis is still poorly understood, there are currently no guidelines for the targeted, standard treatment of NL patients. Typically, NL usually develops in middle age and affects women more frequently. In addition, NL is often observed in combination with endocrine disorders such as diabetes mellitus or thyroid dysfunction. Also discussed is an association with metabolic syndrome, which may additionally favor the development of ulcerations and thus complicate the course of the disease. Various topical and systemic therapeutic options are available, occasionally in combination. The use of topical corticosteroids is recommended by experts generally. Some patients may benefit from topical calcineurin inhibitors, compression therapy, or phototherapy. In case of recalcitrant or ulcerated lesions, systemic therapy is often initiated. In this regard, systemic corticosteroids are used as the primary option. However, off-label therapies such as fumaric acid esters, dapsone, biologics, or JAK inhibitors have also shown promising effects in some case reports. However, due to the lack of randomized trials with large patient collectives, the efficacy of individual therapeutic options cannot be conclusively evaluated.
CRIS-Team Scopus Importer:2023-10-20
Keywords: chronic wounds; granulomatous dermatosis; necrobiosis lipoidica; systemic therapy

Therapy Management of the first Recurrence after adjuvant Therapy in Stage III: multicenter real-world Data - Lodde, G.; Forschner, A.; Hassel, J. C.; Wulfken, L. M.; Meier, F.; Mohr, P.; Kaehler, K.; Schilling, B.; Loquai, C.; Berking, Carola; Huening, S.; Eckardt, J.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Therapy Options for Patients with Advanced Basal Cell Carcinoma - Kirchberger, M. C. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Therapy preferences in melanoma treatment - willingness to pay and preference of quality versus length of life of patients, physicians and healthy controls - Krammer, Ramona; Heinzerling, Lucie (PLoS ONE, 2014)
New melanoma therapies, like e.g. ipilimumab, improve survival. However, only a small subset of patients benefits while 60% encounter side effects. Furthermore, these marginal benefits come at a very high price of EUR110'000 per treatment. This study examines attitudes towards melanoma therapy options of physicians, healthy individuals and patients, their willingness to pay and preference of quality versus length of life.Based on findings from a focus group questionnaires were developed and pretested. After obtaining ethical approval and informed consent surveys were conducted in a total of 90 participants (n = 30 for each group). Statistical analyses were conducted using R.Attitudes vastly differed between healthy participants, physicians and melanoma patients. Whereas melanoma patients show a high willingness to endure side effects despite very small survival gains (down to 1 extra week) or even only hope with no survival benefit, healthy controls are more critical, while physicians are the most therapy adverse. Consequently, if given EUR100'000 and the free decision what to spend the money on the willingness to pay for therapy was much higher in the patient group (68%) compared to 28% of healthy controls and only 43% of the physicians, respectively. When lowering the amount of cash that could be received instead of ipilimumab to EUR50'000 or EUR10'000 to test price sensitivity 69% (+1%) and 76% (+8%) of melanoma patients, respectively, preferred ipilimumab over cash. When judging on societal spending even melanoma patients opted for spending on ipilimumab in only 21%.The judgment about the benefits of new treatment options largely differs between groups, physicians being the most critical against therapy. Price elasticity was low.
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Therapy preferences in melanoma treatment—Willingness to pay and preference of quality versus length of life of patients, physicians, healthy individuals and physicians with oncological disease - Weiß, Julia; Kirchberger, Michael; Heinzerling, Lucie (Cancer Medicine, 2020)
Background: In recent years, monoclonal antibodies such as ipilimumab, nivolumab, and pembrolizumab have made a significant impact on the treatment of advanced melanoma. Combination of immune checkpoint inhibitors leads to improved survival and response rates of 58%-61% as compared to monotherapy (36%-44%). However, the price for the better response rates is also a higher frequency of severe adverse events (59%) as compared to monotherapy (17%-21%). This study examines attitudes towards melanoma therapy options of physicians, healthy individuals, melanoma patients, and physicians with oncological disease, their willingness to pay, and preference of quality versus length of life. Methods: After obtaining ethical approval and informed consent surveys were conducted in 111 participants divided into four groups: melanoma patients (n = 30), healthy individuals as controls (n = 30), physicians (n = 27), and physicians with oncological disease (n = 24). Statistical analyses were conducted using SPSS statistics (version 25, IBM), applying the Pearson´s chi-squared test, Spearman correlation coefficient, Wilcoxon-Mann-Whitney test, and Kruskal-Wallis test. Results: Life prolongation is more valued by melanoma patients and physicians with oncological disease compared to healthy controls and healthy physicians. In total, 30% of melanoma patients opt for a life prolonging therapy in all cases, even if this life prolongation is only marginal. Physicians are the strongest proponents of combination immunotherapy. Conclusion: The valuation of the different treatment options differs in the four study groups with affected people valuing life prolongation much more. The individual value of cancer therapies is high, but differs from the societal standpoint.
CRIS-Team Scopus Importer:2020-07-24
Keywords: cancer management; clinical guidelines; immunology; quality of life

The RNA world in the 21st century-a systems approach to finding non-coding keys to clinical questions - Schmitz, Ulf; Naderi-Meshkin, Hojjat; Gupta, Shailendra K.; Wolkenhauer, Olaf; Vera, Julio (Briefings in Bioinformatics, 2016)
There was evidence that RNAs are a functionally rich class of molecules not only since the arrival of the next-generation sequencing technology. Non-coding RNAs (ncRNA) could be the key to accelerated diagnosis and enhanced prediction of disease and therapy outcomes as well as the design of advanced therapeutic strategies to overcome yet unsatisfactory approaches.In this review, we discuss the state of the art in RNA systems biology with focus on the application in the systems biomedicine field. We propose guidelines for analysing the role of microRNAs and long non-coding RNAs in human pathologies. We introduce RNA expression profiling and network approaches for the identification of stable and effective RNomics-based biomarkers, providing insights into the role of ncRNAs in disease regulation. Towards this, we discuss ways to model the dynamics of gene regulatory networks and signalling pathways that involve ncRNAs. We also describe data resources and computational methods for finding putative mechanisms of action of ncRNAs. Finally, we discuss avenues for the computer-aided design of novel RNA-based therapeutics.
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The Road to Effective Cancer Immunotherapy—A Computational Perspective on Tumor Epitopes in Anti-Cancer Immunotherapy - Lischer, Christopher; Vera González, Julio (Systems Medicine, 2021)
A current option for anti-cancer immunotherapy is to make use of epitopes which can guide cytotoxic T cells to destroy the tumor. It is however difficult to find immunogenic epitopes which engage the T cells sufficiently to fight cancer effectively. Additionally, cancer heterogeneity makes the development of such epitopes even more difficult since there is little general overlap between two cancers. Hence an epitope-based approach requires the use of many modern aspects of biological science like bioinformatics, next-generation sequencing and biostatistics. In this article, we provide a broad introduction to the topic from a computational perspective and offer insights into current paradigms of data-driven epitope selection, explain some fundamental workflows and outline avenues for future research in vitro and in silico.<br
Keywords: Antigen presentation; Bioinformatics; Cancer; Decision support systems; Epitopes; Immunoinformatics; Immunology; Immunotherapy; Introduction; Systems biology; Workflows

The role of age, neutrophil infiltration and antibiotics timing in the severity of streptococcus pneumoniae pneumonia. Insights from a multi-level mathematical model approach - Santos, Guido; Vera, Julio (International Journal of Molecular Sciences, 2020)
Bacterial pneumonia is one of the most prevalent infectious diseases and has high mortality in sensitive patients (children, elderly and immunocompromised). Although an infection, the disease alters the alveolar epithelium homeostasis and hinders normal breathing, often with fatal consequences. A special case is hospitalized aged patients, which present a high risk of infection and death because of the community acquired version of the Streptococcus pneumoniae pneumonia. There is evidence that early antibiotics treatment decreases the inflammatory response during pneumonia. Here, we investigate mechanistically this strategy using a multi-level mathematical model, which describes the 24 first hours after infection of a single alveolus from the key signaling networks behind activation of the epithelium to the dynamics of the local immune response. With the model, we simulated pneumonia in aged and young patients subjected to different antibiotics timing. The results show that providing antibiotics to elderly patients 8 h in advance compared to young patients restores in aged individuals the effective response seen in young ones. This result suggests the use of early, probably prophylactic, antibiotics treatment in aged hospitalized people with high risk of pneumonia.
CRIS-Team Scopus Importer:2020-11-20
Keywords: Inflammation; Macrophages; Mathematical model; Monocytes; Multi-level; Neutrophils; Pneumonia; Streptococcus pneumoniae

The role of cooperativity in a p53-miR34 dynamical mathematical model - Nikolov, Svetoslav; Wolkenhauer, Olaf; Vera, Julio; Nenov, Momchil (Journal of Theoretical Biology, 2020)
The objective of this study is to evaluate the role of cooperativity, captured by the Hill coefficient, in a minimal mathematical model describing the interactions between p53 and miR-34a. The model equations are analyzed for negative, none and normal cooperativity using a specific version of bifurcation theory and they are solved numerically. Special attention is paid to the sign of so-called first Lyapunov value. Interpretations of the results are given, both according to dynamic theory and in biological terms. In terms of cell signaling, we propose the hypothesis that when the outgoing signal of a system spends a physiologically significant amount of time outside of its equilibrium state, then the value of that signal can be sampled at any point along the trajectory towards that equilibrium and indeed, at multiple points. Coupled with non-linear behavior, such as that caused by cooperativity, this feature can account for a complex and varied response, which p53 is known for. From dynamical point of view, we found that when cooperativity is negative, the system has only one stable equilibrium point. In the absence of cooperativity, there is a single unstable equilibrium point with a critical boundary of stability. In the case with normal cooperativity, the system can have one, two, or three steady states with both, bi-stability and bi-instability occurring.
CRIS-Team Scopus Importer:2020-04-14
Keywords: Cooperativity; Numerical analysis; p53-miR34 dynamics; Qualitative analysis

The role of immune checkpoint blockade in uveal melanoma - Wessely, Anja; Steeb, Theresa; Erdmann, Michael; Heinzerling, Lucie; Vera, Julio; Schlaak, Max; Berking, Carola; Heppt, Markus (International Journal of Molecular Sciences, 2020)
Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies.
CRIS-Team Scopus Importer:2020-02-14
Keywords: CTLA-4; Cytotoxic T lymphocyte-associated antigen; Immune checkpoint blockade; Ipilimumab; Nivolumab; Ocular melanoma; PD-1; Pembrolizumab; Programmed death 1; Uveal melanoma

The Role of MicroRNAs in Cancer Biology and Therapy from a Systems Biology Perspective - Lai, Xin; Schmitz, Ulf; Vera, Julio (Springer, 2022)
Since the discovery of microRNAs (miRNAs) in Caenorhabditis elegans, our understanding of their cellular function has progressed continuously. Today, we have a good understanding of miRNA-mediated gene regulation, miRNA-mediated cross talk between genes including competing endogenous RNAs, and miRNA-mediated signaling transduction both in normal human physiology and in diseases. Besides, these noncoding RNAs have shown their value for clinical applications, especially in an oncological context. They can be used as reliable biomarkers for cancer diagnosis and prognosis and attract increasing attention as potential therapeutic targets. Many achievements made in the miRNA field are based on joint efforts from computational and molecular biologists. Systems biology approaches, which integrate computational and experimental methods, have played a fundamental role in uncovering the cellular functions of miRNAs. In this chapter, we review and discuss the role of miRNAs in oncology from a system biology perspective. We first describe biological facts about miRNA genetics and function. Next, we discuss the role of miRNAs in cancer progression and review the application of miRNAs in cancer diagnostics and therapy. Finally, we elaborate on the role that miRNAs play in cancer gene regulatory networks. Taken together, we emphasize the importance of systems biology approaches in our continued efforts to study miRNA cancer regulation.
CRIS-Team Scopus Importer:2022-12-02
Keywords: Bioinformatics; Circulating miRNA; Mathematical modelling; Metastamir; mRNA destabilization; Network biology; Oncomir; Posttranscriptional gene regulation; Translation repression; Tumor suppressor miRNA

The simultaneous siRNA-mediated downregulation of inhibitory receptors to improve CAR-T cell immunotherapy of melanoma - Simon, B.; Harrer, D.; Weide, B.; Schuler, Gerold; Schuler-Thurner, Beatrice; Dörrie, Jan; Schaft, Niels; Uslu, Ugur (2017)
EVALuna2:34317

The simultaneous siRNA-mediated downregulation of PD-1 and CTLA-4 to improve CAR-T cell immunotherapy of melanoma - Simon, B.; Harrer, D.; Schuler-Thurner, Beatrice; Dörrie, Jan; Schaft, Niels; Schuler, Gerold; Uslu, Ugur (2018)
EVALuna2:34395

The siRNA-mediated downregulation of PD-1 alone or simultaneously with CTLA-4 shows enhanced in vitro CAR-T-cell functionality for further clinical development towards the potential use in immunotherapy of melanoma - Simon, Bianca; Harrer, Dennis C.; Schuler-Thurner, Beatrice; Schaft, Niels; Schuler, Gerold; Dörrie, Jan; Uslu, Ugur (Experimental Dermatology, 2018)
Chimeric antigen receptor (CAR)-T cells have been used successfully for cancer immunotherapy. While substantial tumor regression was observed in leukaemia and lymphoma, CAR therapy of solid tumors needs further improvement. A major obstacle to the efficiency of engineered T cells is posed by triggering of inhibitory receptors, for example programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), leading to an impaired antitumor activity. To boost CAR-T-cell function, we co-electroporated T cells with both, mRNA encoding a CAR specific for chondroitin sulphate proteoglycan 4 (CSPG4) and small-interfering RNAs (siRNAs) to downregulate PD-1 (siPD-1) and CTLA-4 (siCTLA-4). Flow cytometry revealed that activation-induced upregulation of both PD-1 and CTLA-4 was suppressed when compared to CAR-T cells electroporated with negative control siRNA. The siRNA transfection showed no influence on CAR expression of engineered T cells. Functionality assays were performed using PD-L1- and CD80-transfected melanoma cells endogenously expressing CSPG4. CAR-T cells transfected with siPD-1 alone showed improvement in cytokine secretion. Additionally, CAR-T cells transfected with either siPD-1 alone or together with siCTLA-4 exhibited a significantly increased cytotoxicity. No or only little effects were observed when CAR-T cells were co-transfected with siCTLA-4 only. Taken together, it is feasible to optimize CAR-T cells by co-transfection of CAR-encoding mRNA and siRNAs to downregulate inhibitory receptors. Our in vitro data indicate an improvement of the functionality of these CAR-T cells, suggesting that this strategy could represent a novel method to enhance CAR-T-cell immunotherapy of cancer.
EVALuna2:34375

The soluble CD83 molecule accelerates wound closure and improves wound healing quality - Royzman, Dmytro; Peckert-Maier, Katrin; Stich, Lena; Wild, Andreas; Ostalecki, Christian; Seyferth, Stefan; Eming, Sabine A.; Fuchs, Maximilian; Kunz, Meik; Sturmer, Ewa K.; Peters, Eva M. J.; Berking, Carola; et al. (WOUND REPAIR AND REGENERATION, 2022)
CRIS-Team WoS Importer:2022-09-16

The soluble CD83 protein prevents bone destruction by inhibiting the formation of osteoclasts and inducing resolution of inflammation in arthritis - Royzman, Dmytro; Andreev, Darja; Stich, Lena; Peckert, Katrin; Wild, Andreas; Zinser, Elisabeth; Mühl-Zürbes, Petra; Jones, Evan; Adam, Susanne; Frey, Silke; Fuchs, Maximilian; Kunz, Meik; et al. (Frontiers in Immunology, 2022)
Here we show that soluble CD83 induces the resolution of inflammation in an antigen-induced arthritis (AIA) model. Joint swelling and the arthritis-related expression levels of IL-1 beta, IL-6, RANKL, MMP9, and OC-Stamp were strongly reduced, while Foxp3 was induced. In addition, we observed a significant inhibition of TRAP(+) osteoclast formation, correlating with the reduced arthritic disease score. In contrast, cell-specific deletion of CD83 in human and murine precursor cells resulted in an enhanced formation of mature osteoclasts. RNA sequencing analyses, comparing sCD83- with mock treated cells, revealed a strong downregulation of osteoclastogenic factors, such as Oc-Stamp, Mmp9 and Nfatc1, Ctsk, and Trap. Concomitantly, transcripts typical for pro-resolving macrophages, e.g., Mrc1/2, Marco, Klf4, and Mertk, were upregulated. Interestingly, members of the metallothionein (MT) family, which have been associated with a reduced arthritic disease severity, were also highly induced by sCD83 in samples derived from RA patients. Finally, we elucidated the sCD83-induced signaling cascade downstream to its binding to the Toll-like receptor 4/(TLR4/MD2) receptor complex using CRISPR/Cas9-induced knockdowns of TLR4/MyD88/TRIF and MTs, revealing that sCD83 acts via the TRIF-signaling cascade. In conclusion, sCD83 represents a promising therapeutic approach to induce the resolution of inflammation and to prevent bone erosion in autoimmune arthritis.
CRIS-Team WoS Importer:2022-09-09

The tanning habits and interest in sunscreen of Google users: what happened in 12 years? - Kirchberger, Michael C.; Heppt, Markus V.; Eigentler, Thomas K.; Kirchberger, Markus A.; Schuler, Gerold; Heinzerling, Lucie (Photodermatology Photoimmunology & Photomedicine, 2017)
BACKGROUND: The incidence of melanoma has been rising worldwide. One possible reason for this is natural and artificial UV exposure. Only little data on actual consumer statistics from tanning studios and the usage of sunscreen are available. Therefore, it is difficult to describe trends for both and identify the impact of preventive measures. METHODS: To gain knowledge about the popularity of 'tanning bed' and 'sunscreen', normalized search volumes for both search queries were obtained from Google Trends for 11 countries between January 2004 and June 2016. RESULTS: With few exceptions, worldwide interest in 'tanning bed' has been declining, whereas interest in 'sunscreen' has been increasing. The assessed countries from the Southern Hemisphere showed minor interest in tanning compared to the Northern Hemisphere. Both search queries were observed to fluctuate in a seasonal pattern. Skin cancer prevention measures influence the interest in tanning beds and sunscreen. CONCLUSION: Google Trends data can act as a first surrogate marker to evaluate the influence of skin cancer campaigns on the popularity of tanning beds and sunscreen. Fine-tuning of skin cancer campaigns according to seasonal and geographic trends and behaviors may help to maximize their success.
EVALuna2:34324

The Topical Effect of rhGDF-5 Embedded in a Collagen–Gelatin Scaffold for Accelerated Wound Healing - Eisler, Wiebke; Held, Manuel; Rahmanian-Schwarz, Afshin; Schiefer, Jennifer; Rahmanian, Shahab; Daigeler, Adrien; Baur, Jan-Ole (Applied Sciences, 2022)
The application of exogenous growth factors such as the recombinant human growth and differentiation factor 5 (rhGDF-5) represents a major research topic with great potential for the treatment of complex wounds. In a randomized, controlled minipig study, the topical effect of rhGDF-5 on full-thickness skin defects was evaluated. A total of 60 deep dermal wounds were either treated with rhGDF-5 embedded in an innovative collagen scaffold or another commonly used collagen matrix or left untreated. Wound healing was analyzed by planimetric analysis to determine wound closure over time. After 21 days, the areas of the initial wounds were excised, and the newly formed tissue was examined histologically. In comparison to untreated wounds, all examined matrices accelerated dermal wound healing. The largest acceleration of wound healing was seen with the high-dose rhGDF-5-treated wounds, which, compared to the untreated wounds, accelerated wound healing by 2.58 days, improved the neoepidermal thickness by 32.40 µm, and increased the epidermal cell density by 44.88 cells. The innovative collagen scaffold delivered rhGDF-5 adequately, served as a template to guide proliferating and restructuring cells, and accelerated wound healing. Thus, this composite product offers a novel tool for developing effective wound dressings in regenerative medicine.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Collagen scaffold; Composite biomaterial; Growth factor; RhGDF-5; Wound healing

The transfection of natural killer T cells with a tumor-antigen specific chimeric antigen receptor (CAR) for melanoma immunotherapy - Simon, B.; Wiesinger, M.; Maerz, J.; Wistuba-Hamprecht, K.; Weide, B.; Schuler-Thurner, Beatrice; Schuler, Gerold; Dörrie, Jan; Uslu, Ugur (EXPERIMENTAL DERMATOLOGY, 2019)
CRIS-Team WoS Importer:2019-03-26

The value of convolutional neural networks in the diagnosis of melanoma simulators - Heppt, Markus; Berking, Carola (Journal of the European Academy of Dermatology and Venereology, 2020)
CRIS-Team Scopus Importer:2020-06-26

The value of total body photography for the early detection of melanoma: A systematic review - Hornung, Annkathrin; Steeb, Theresa; Wessely, Anja; Brinker, Titus J.; Breakell, Thomas; Erdmann, Michael; Berking, Carola; Heppt, Markus (International Journal of Environmental Research and Public Health, 2021)
Early detection of melanoma is critical to reduce the mortality and morbidity rates of this tumor. Total body photography (TBP) may aid in the early detection of melanoma. To summarize the current evidence on TBP for the early detection of melanoma, we performed a systematic literature search in Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) for eligible records up to 6th August 2020. Outcomes of interest included melanoma incidence, incisional and excisional biopsy rates, as well as the Breslow’s index of detected tumors. Results from individual studies were described qualitatively. The risks of bias and applicability of the included studies was assessed using the QUADAS-2 checklist. In total, 14 studies published between 1997 and 2020 with an overall sample size of n = 12082 (range 100–4692) were included in the qualitative analysis. Individuals undergoing TBP showed a trend towards a lower Breslow’s thickness and a higher proportion of in situ melanomas compared to those without TBP. The number needed to excise one melanoma varied from 3:1 to 14.3:1 and was better for lesions that arose de novo than for tracked ones. The included studies were judged to be of unclear methodological concern with specific deficiencies in the domains “flow and timing” and “reference standard”. The use of TBP can improve the early detection of melanoma in high-risk populations. Future studies are warranted to reduce the heterogeneity of phenotypic risk factor definition and the technical implementation of TBP. Artificial intelligence-assisted analysis of images derived from 3-D TBP systems and digital dermoscopy may further improve the early detection of melanoma.
CRIS-Team Scopus Importer:2021-03-05
Keywords: Artificial intelligence; Early detection; Melanoma; Photography; Prevention; Skin cancer; Total body photographic cutaneous surveillance

The α4β1 Homing Pathway Is Essential for Ileal Homing of Crohn's Disease Effector T Cells In Vivo - Zundler, Sebastian; Fischer, Anika; Schillinger, Daniela; Binder, Marie-Theres; Atreya, Raja; Rath, Timo; Lopez Posadas, Rocío; Voskens, Caroline J.; Watson, Alastair; Atreya, Imke; Neufert, Clemens; Neurath, Markus (Inflammatory Bowel Diseases, 2017)
BACKGROUND: The precise mechanisms controlling homing of T effector (Teff) cells to the inflamed gut in Crohn's disease (CD) are still unclear, and clinical outcome data from patients with inflammatory bowel disease treated with the anti-α4β7 integrin antibody vedolizumab suggest differences between ulcerative colitis and CD. METHODS: Expression of homing molecules was studied with flow cytometry and immunohistochemistry. Their functional role was investigated in in vitro adhesion assays and in a humanized mouse model of T cell homing to the inflamed gut in vivo. RESULTS: Despite in vitro blockade of CD Teff adhesion to mucosal vascular addressin cell adhesion molecule-1 (MadCAM-1) and in contrast to previous observations in ulcerative colitis, anti-α4β7 treatment did not result in reduced Teff cell homing to the colon in vivo. However, the integrin α4β1 was expressed in higher levels on Teffs from patients with CD compared with controls, while its expression in the peripheral blood declined, and its expression in the intestine increased during the course of clinical vedolizumab treatment. Consistently, adhesion of CD Teffs to vascular cell adhesion molecule-1 (VCAM-1) was blocked by inhibition of α4 and α4β1 in vitro. Moreover, in vivo homing of CD Teffs to the ileum was reduced by inhibition of α4 and α4β1 integrins, but not α4β7 integrins. CONCLUSIONS: Our findings suggest that Teff cell homing to the ileum through the axis α4β1-VCAM-1 is an essential and nonredundant pathway in CD in vivo, possibly affecting efficacy of clinical treatment with antiadhesion compounds.
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Third-Kind Encounters in Biomedicine: Immunology Meets Mathematics and Informatics to Become Quantitative and Predictive - Eberhardt, Martin; Lai, Xin; Tomar, Namrata; Gupta, Shailendra; Schmeck, Bernd; Steinkasserer, Alexander; Schuler, Gerold; Vera, Julio (Methods in Molecular Biology, 2016)
The understanding of the immune response is right now at the center of biomedical research. There are growing expectations that immune-based interventions will in the midterm provide new, personalized, and targeted therapeutic options for many severe and highly prevalent diseases, from aggressive cancers to infectious and autoimmune diseases. To this end, immunology should surpass its current descriptive and phenomenological nature, and become quantitative, and thereby predictive.Immunology is an ideal field for deploying the tools, methodologies, and philosophy of systems biology, an approach that combines quantitative experimental data, computational biology, and mathematical modeling. This is because, from an organism-wide perspective, the immunity is a biological system of systems, a paradigmatic instance of a multi-scale system. At the molecular scale, the critical phenotypic responses of immune cells are governed by large biochemical networks, enriched in nested regulatory motifs such as feedback and feedforward loops. This network complexity confers them the ability of highly nonlinear behavior, including remarkable examples of homeostasis, ultra-sensitivity, hysteresis, and bistability. Moving from the cellular level, different immune cell populations communicate with each other by direct physical contact or receiving and secreting signaling molecules such as cytokines. Moreover, the interaction of the immune system with its potential targets (e.g., pathogens or tumor cells) is far from simple, as it involves a number of attack and counterattack mechanisms that ultimately constitute a tightly regulated multi-feedback loop system. From a more practical perspective, this leads to the consequence that today's immunologists are facing an ever-increasing challenge of integrating massive quantities from multi-platforms.In this chapter, we support the idea that the analysis of the immune system demands the use of systems-level approaches to ensure the success in the search for more effective and personalized immune-based therapies.
EVALuna2:19605

THP-1-derived macrophages render lung epithelial cells hypo-responsive to Legionella pneumophila - a systems biology study - Schulz, Christine; Lai, Xin; Bertrams, Wilhelm; Jung, Anna Lena; Sittka-Stark, Alexandra; Herkt, Christina Elena; Janga, Harshavadhan; Zscheppang, Katja; Stielow, Christina; Schulte, Leon; Hippenstiel, Stefan; Vera, Julio; et al. (Scientific Reports, 2017)
Immune response in the lung has to protect the huge alveolar surface against pathogens while securing the delicate lung structure. Macrophages and alveolar epithelial cells constitute the first line of defense and together orchestrate the initial steps of host defense. In this study, we analysed the influence of macrophages on type II alveolar epithelial cells during Legionella pneumophila-infection by a systems biology approach combining experimental work and mathematical modelling. We found that L. pneumophila-infected THP-1-derived macrophages provoke a pro-inflammatory activation of neighboring lung epithelial cells, but in addition render them hypo-responsive to direct infection with the same pathogen. We generated a kinetic mathematical model of macrophage activation and identified a paracrine mechanism of macrophage-secreted IL-1β inducing a prolonged IRAK-1 degradation in lung epithelial cells. This intercellular crosstalk may help to avoid an overwhelming inflammatory response by preventing excessive local secretion of pro-inflammatory cytokines and thereby negatively regulating the recruitment of immune cells to the site of infection. This suggests an important but ambivalent immunomodulatory role of macrophages in lung infection.
EVALuna2:35404

Three generations of suffering: cryopyrin-associated periodic syndrome with NLRP3 mutation in a family - Wagner, Nicola; Manger, Bernhard; Kittler, Julia; Rech, Jürgen; Sticherling, Michael; Berking, Carola; Kirchberger, Michael Constantin (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-12-24

Threshold Optimization for Tumor Markers S100b and MIA in Uveal Melanoma - A Single Center Analysis - Glaser, Naemi; Petzold, Anne; Wessely, Anja; Kaufmann, Matthias; Koch, Elias; Knorr, Harald; Voskens, Caroline; Heppt, Markus; Berking, Carola; Erdmann, Michael (Anticancer Research, 2023)
Background/Aim: Uveal melanoma (UM) is the most common malignant tumor of the eye in adults. Metastases develop in 50% of the patients, predominantly in the liver. In UM, the cut-off concentrations of the bloodbased tumor markers S100b and MIA are inconclusive. Patients and Methods: In this retrospective monocenter study, we statistically evaluated 1,878 S100b and 1,768 MIA measurements in 244 patients with UM from 2011-2020. Threshold optimization was performed using receiver operating characteristic (ROC) curves. Results: A total of 171 patients with non-metastatic UM (nmUM) and 73 patients with metastatic UM (mUM) showed no differences in sex, age at diagnosis or the affected eye. In mUM, 80% of the patients developed metastases to the liver at a median of 46 months after initial diagnosis. The sensitivity and specificity of S100b was 16.10% and 94.52%, and that of MIA was 31.86% and 81.42%, respectively. ROC curves revealed poor values for the area under the curve of 0.57 for S100b and 0.55 for MIA. The optimal cut-off concentration to detect metastases was 0.14 μg/l for S100b and 17.4 ng/ml for MIA. With at least one tumor marker elevated, optimized sensitivity was 20.40% and specificity 96.76%. Conclusion: Current thresholds for S100b and MIA in UM are not able to detect early metastatic disease and require additional diagnostics to clarify false positive results. Threshold optimization considering both S100b and MIA results in a better diagnostic validity with an acceptable specificity and a poor sensitivity. Highly sensitive blood-based and imaging methods to detect metastases early in UM are urgently needed.
CRIS-Team Scopus Importer:2023-11-03
Keywords: MIA; S100b; threshold optimization; tumor marker; Uveal melanoma

Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83 - Von Rohrscheidt, Julia; Petrozziello, Elisabetta; Nedjic, Jelena; Federle, Christine; Krzyzak, Lena; Ploegh, Hidde L.; Ishido, Satoshi; Steinkasserer, Alexander; Klein, Ludger (Journal of Experimental Medicine, 2016)
Deficiency of CD83 in thymic epithelial cells (TECs) dramatically impairs thymic CD4 T cell selection. CD83 can exert cell-intrinsic and -extrinsic functions through discrete protein domains, but it remains unclear how CD83's capacity to operate through these alternative functional modules relates to its crucial role in TECs. In this study, using viral reconstitution of gene function in TECs, we found that CD83's transmembrane domain is necessary and sufficient for thymic CD4 T cell selection. Moreover, a ubiquitination-resistant MHCII variant restored CD4 T cell selection in Cd83(-/-) mice. Although during dendritic cell maturation CD83 is known to stabilize MHCII through opposing the ubiquitin ligase March1, regulation of March1 did not account for CD83's TEC-intrinsic role. Instead, we provide evidence that MHCII in cortical TECs (cTECs) is targeted by March8, an E3 ligase of as yet unknown physiological substrate specificity. Ablating March8 in Cd83(-/-) mice restored CD4 T cell development. Our results identify CD83-mediated MHCII stabilization through antagonism of March8 as a novel functional adaptation of cTECs for T cell selection. Furthermore, these findings suggest an intriguing division of labor between March1 and March8 in controlling inducible versus constitutive MHCII expression in hematopoietic antigen-presenting cells versus TECs.
EVALuna2:26036

Thymic stromal lymphopoietin deficiency attenuates experimental autoimmune encephalomyelitis - Eckhardt, J.; Döbbeler, Marina; Koenig, C.; Kuczera, K.; Kuhnt, C.; Ostalecki, C.; Zinser, E.; Mak, T. W.; Steinkasserer, Alexander; Lechmann, Matthias (Clinical and Experimental Immunology, 2015)
In the present study we examined the role of thymic stromal lymphopoietin (TSLP) in experimental autoimmune encephalomyelitis (EAE). Here, we report that TSLP knock-out (KO) mice display a delayed onset of disease and an attenuated form of EAE. This delayed onset was accompanied by a reduced number of encephalitogenic T helper type 1 (Th1) cells in the central nervous system (CNS) of TSLP KO mice. In addition, CD4(+) and CD8(+) T cells from CNS of TSLP KO mice show a reduced activation status in comparison to wild-type mice. It is noteworthy that we could also show that lymph node cells from TSLP KO mice expanded less efficiently and that interleukin (IL)-6-, interferon (IFN)-? and tumour necrosis factor (TNF)-? levels were reduced. Furthermore, CD3(+) T cells isolated in the preclinical phase from myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55))-immunized TSLP KO mice showed a reduced response after secondary exposure to MOG(35-55), indicating that differentiation of naive T cells into MOG(35-55)-specific effector and memory T cells was impaired in KO mice. The addition of recombinant TSLP enhanced T cell proliferation during MOG(35-55) restimulation, showing that T cells also respond directly to TSLP. In summary, these data demonstrate that expression of, and immune activation by, TSLP contributes significantly to the immunopathology of EAE.
EVALuna2:19524

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes - Würfel, Franziska; Erber, Ramona; Hübner, Hanna; Hein, Alexander; Lux, Michael P.; Jud, Sebastian; Kremer, Anita; Kranich, Hannah; Mackensen, Andreas; Häberle, Lothar; Hack, Carolin; Rauh, Claudia; et al. (Breast Care, 2018)
Background: Despite advancements in the treatment of primary and metastatic breast cancer, many patients lack a durable response to these treatments. Patients with triplenegative breast cancer (TNBC) and human epidermal growth factor receptor 2(HER2)-positive breast cancer who do not have a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a very poor prognosis. Tumor-infiltrating lymphocytes (TILs) have been identified as a predictive marker for pCR after NACT in TNBC and HER2-positive breast cancer. These patient populations could also be suitable for novel treatment strategies including neoepitope-based therapies. This work analyses the effect of TILs on the pCR in neoadjuvantly treated patients in the TILGen study and presents the procedures aimed at establishing neoepitope-based therapies in this study. Methods: Neoadjuvantly treated HER2positive and TNBC patients were eligible for the presented analysis concerning the association between TILs and pCR. A total of 146 patients could be identified within the TILGen study. TILs were evaluated as percentage of stromal tumor tissue in core biopsies at primary diagnosis. The phenotype 'lymphocyte-predominant breast cancer' (LPBC) was associated with pCR by logistic regression adjusted for estrogen receptor status, progesterone receptor status, HER2 status, age at diagnosis, and grading. Results: LPBC was seen in 24 (16.4%) patients. In this patient group, 66.7% achieved a pCR, while the pCR rate was 32.8% in patients with a low TIL count. The adjusted odds ratio was 6.60 (95% confidence interval 2.02-21.56; p < 0.01). Conclusion: TILs are a strong predictor of pCR in TNBC and HER2-positive breast cancer patients. Implications for the use of this information including the effect on prognosis might help to identify patients most likely to benefit from a neoepitope-based therapy approach. (C) 2018 S. Karger GmbH, Freiburg
EVALuna2:34061

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes - Würfel, Franziska; Erber, Ramona; Hübner, Hanna; Hein, Alexander; Lux, Michael P.; Jud, Sebastian; Kremer, Anita; Kranich, Hannah; Mackensen, Andreas; Häberle, Lothar; Hack, Carolin; Rauh, Claudia; et al. (Breast Care, 2018)
Background: Despite advancements in the treatment of primary and metastatic breast cancer, many patients lack a durable response to these treatments. Patients with triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2(HER2)-positive breast cancer who do not have a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a very poor prognosis. Tumor-infiltrating lymphocytes (TILs) have been identified as a predictive marker for pCR after NACT in TNBC and HER2-positive breast cancer. These patient populations could also be suitable for novel treatment strategies including neoepitope-based therapies. This work analyses the effect of TILs on the pCR in neoadjuvantly treated patients in the TILGen study and presents the procedures aimed at establishing neoepitope-based therapies in this study. Methods: Neoadjuvantly treated HER2-positive and TNBC patients were eligible for the presented analysis concerning the association between TILs and pCR. A total of 146 patients could be identified within the TILGen study. TILs were evaluated as percentage of stromal tumor tissue in core biopsies at primary diagnosis. The phenotype ‘lymphocyte-predominant breast cancer' (LPBC) was associated with pCR by logistic regression adjusted for estrogen receptor status, progesterone receptor status, HER2 status, age at diagnosis, and grading. Results: LPBC was seen in 24 (16.4%) patients. In this patient group, 66.7% achieved a pCR, while the pCR rate was 32.8% in patients with a low TIL count. The adjusted odds ratio was 6.60 (95% confidence interval 2.02-21.56; p < 0.01). Conclusion: TILs are a strong predictor of pCR in TNBC and HER2-positive breast cancer patients. Implications for the use of this information including the effect on prognosis might help to identify patients most likely to benefit from a neoepitope-based therapy approach.<br

Tilting the Balance: Therapeutic Prospects of CD83 as a Checkpoint Molecule Controlling Resolution of Inflammation - Peckert-Maier, Katrin; Royzman, Dmytro; Langguth, Pia; Marosán, Anita; Strack, Astrid; Sadeghi Shermeh, Atefeh; Steinkasserer, Alexander; Zinser, Elisabeth; Wild, Andreas (International Journal of Molecular Sciences, 2022)
Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) protein has emerged as an interesting potential candidate for such a “pro-resolution” therapy. This molecule occurs in a membrane-bound and a soluble isoform (mCD83 and sCD83, respectively), both of which are involved in resolution of inflammation. Originally described as a maturation marker on dendritic cells (DCs), mCD83 is also expressed by activated B and T cells as well as regulatory T cells (Tregs) and controls turnover of MHC II molecules in the thymus, and thereby positive selection of CD4+ T cells. Additionally, it serves to confine overshooting (auto-)immune responses. Consequently, animals with a conditional deletion of CD83 in DCs or regulatory T cells suffer from impaired resolution of inflammation. Pro-resolving effects of sCD83 became evident in pre-clinical autoimmune and transplantation models, where application of sCD83 reduced disease symptoms and enhanced allograft survival, respectively. Here, we summarize recent advances regarding CD83-mediated resolution of inflammatory responses, its binding partners as well as induced signaling pathways, and emphasize its therapeutic potential for future clinical trials.
CRIS-Team Scopus Importer:2022-01-14
Keywords: Adoptive transfer; CD83; IDO/TGF-β-axis; Pro-resolving macrophages; Resolution of inflammation; Transplantation

Tirbanibulin 1% Ointment Significantly Reduces the Actinic Keratosis Area and Severity Index in Patients with Actinic Keratosis: Results from a Real-World Study - Kirchberger, Michael; Gfesser, Michael; Erdmann, Michael; Schliep, Stefan; Berking, Carola; Heppt, Markus (Journal of Clinical Medicine, 2023)
Background: Actinic keratosis (AK) is a cutaneous lesion resulting from the proliferation of atypical epidermal keratinocytes caused by long-term exposure to ultraviolet radiation. AK may progress to cutaneous squamous cell carcinoma (cSCC) and therefore is often treated with topical agents such as 5-fluorouracil, diclofenac, imiquimod, and photodynamic therapy. Tirbanibulin has been approved based on two phase III trials in the USA. However, real-world evidence for tirbanibulin is absent. Methods: This was a single-centre study of adult patients with clinically typical, visible AK on the face or scalp treated with tirbanibulin 1% ointment. Treatment was administered as per label once daily for 5 consecutive days on the same lesions or field. Treatment outcomes were assessed 4 weeks after treatment, with additional optional assessments conducted at later time points. Efficacy was measured using the actinic keratosis area and severity index (AKASI) and digital dermoscopy. Results: A total of 33 patients were treated of whom 30 were analysed. The median AKASI score was 5.6 (1.4–11) pre-treatment and 1.2 (0–7.4) post-treatment (p < 0.0001). Complete clearance as defined by AKASI scores less than 1 was achieved in 47% (n = 14) and 57% (n = 13) at the first and second follow-up, respectively. All local reactions resolved spontaneously and without sequelae. The most common local reactions were erythema (80%, n = 26) and flaking or scaling (43%, n = 13). Conclusions: Tirbanibulin 1% ointment significantly and rapidly reduced the AKASI score in a real-world setting. The complete clearance rates were in line with those observed in the two pivotal trials.
CRIS-Team Scopus Importer:2023-08-11
Keywords: actinic keratosis; AKASI score; Klisyri

TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection - Schleicher, Ulrike; Paduch, Katrin; Debus, Andrea; Obermeyer, Stephanie; Koenig, Till; Kling, Jessica C.; Ribechini, Eliana; Dudziak, Diana; Mougiakakos, Dimitrios; Murray, Peter J.; Ostuni, Renato; Koerner, Heinrich; et al. (Cell Reports, 2016)
Neutralization or deletion of tumor necrosis factor (TNF) causes loss of control of intracellular pathogens in mice and humans, but the underlying mechanisms are incompletely understood. Here, we found that TNF antagonized alternative activation of macrophages and dendritic cells by IL-4. TNF inhibited IL-4-induced arginase 1 (Arg1) expression by decreasing histone acetylation, without affecting STAT6 phosphorylation and nuclear translocation. In Leishmania major-infected C57BL/6 wild-type mice, type 2 nitric oxide (NO) synthase (NOS2) was detected in inflammatory dendritic cells or macrophages, some of which co-expressed Arg1. In TNF-deficient mice, Arg1 was hyperexpressed, causing an impaired production of NO in situ. A similar phenotype was seen in L. major-infected BALB/c mice. Arg1 deletion in hematopoietic cells protected these mice from an otherwise lethal disease, although their disease-mediating T cell response (Th2, Treg) was maintained. Thus, deletion or TNF-mediated restriction of Arg1 unleashes the production of NO by NOS2, which is critical for pathogen control.
EVALuna2:7700

Tolerability and efficacy of BRAF and MEK inhibitors for metastasized melanoma after intra-class switch: a multicenter, retrospective study - Salzmann, M.; Wald, A.; Stege, H.; Loquai, C.; Zimmer, L.; Hayani, K.; Heinzerling, Lucie; Gutzmer, R.; Enk, A.; Hassel, J. C. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Tolerability of BRAF/MEK inhibitor combinations: Adverse event evaluation and management - Heinzerling, Lucie; Eigentler, Thomas K.; Fluck, Michael; Hassel, Jessica C.; Heller-Schenck, Daniela; Leipe, Jan; Pauschinger, Mathias; Vogel, Arndt; Zimmer, Lisa; Gutzmer, Ralf (ESMO Open, 2019)
The inhibition of the mitogen-activated protein kinases signalling pathway through combined use of BRAF and MEK inhibitors (BRAFi+MEKi) represents an established therapeutic option in patients with BRAF-mutated, advanced melanoma. These efficient therapies are well tolerated with mostly moderate and reversible side effects and a discontinuation rate due to adverse events of 11.5%-15.7%. Median duration of therapy ranges between 8.8 and 11.7 months. Based on data from confirmatory trials, safety profiles of three BRAFi+MEKi combinations were reviewed, that is, dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib. Many adverse events are class effects, such as cutaneous, gastrointestinal, ocular, cardiac and musculoskeletal events; some adverse events are substance associated. Fever (dabrafenib) and photosensitivity (vemurafenib) are the most common and clinically prominent examples. Other adverse events are less frequent and the association to one substance is less strong such as anaemia, facial paresis (encorafenib), neutropenia (dabrafenib), skin rash, QTc prolongation and increased liver function tests (vemurafenib). This narrative review provides recommendations for monitoring, adverse event evaluation and management focusing on the clinically relevant side effects of the three regimens.
CRIS-Team Scopus Importer:2019-06-04
Keywords: adverse events; BRAF; MEK; melanoma; safety

"Toolkit Dermatology for minor surgical Procedures" - Options of Use at various University Locations during the Corona Pandemic - Wittbecker, Linda; Pham, Christina; Bandholz, Thyra Caroline; Schuh, Sandra; Welzel, Julia; Busse, Laura; Hornung, Thorsten; Gihl, Julia; Erfurt-Berge, Cornelia; Glaeser, Regine (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-02-04

Topical application of soluble CD83 induces IDO-mediated immune modulation, increases Foxp3+ T cells, and prolongs allogeneic corneal graft survival - Bock, Felix; Roessner, Susanne; Onderka, Jasmine; Lechmann, Matthias; Pallotta, Maria Teresa; Fallarino, Francesca; Boon, Louis; Nicolette, Charles; Debenedette, Mark A.; Tcherepanova, Irina Y.; Grohmann, Ursula; Steinkasserer, Alexander; et al. (Journal of Immunology, 2013)
Modulation of immune responses is one of the main research aims in transplant immunology. In this study, we investigate the local immunomodulatory properties of soluble CD83 (sCD83) at the graft-host interface using the high-risk corneal transplantation model. In this model, which mimics the inflammatory status and the preexisting vascularization of high-risk patients undergoing corneal transplantation, allogeneic donor corneas are transplanted onto sCD83-treated recipient animals. This model allows the direct and precise application of the immune modulator at the transplantation side. Interestingly, sCD83 was able to prolong graft survival after systemic application as well as after topical application, which is therapeutically more relevant. The therapeutic effect was accompanied by an increase in the frequency of regulatory T cells and was mediated by the immune-regulatory enzyme IDO and TGF-?. In vitro, sCD83 induced long-term IDO expression in both conventional and plasmacytoid dendritic cells via autocrine or paracrine production of TGF-?, a cytokine previously shown to be an essential mediator of IDO-dependent, long-term tolerance. These findings open new treatment avenues for local immune modulation after organ and tissue transplantation.
EVALuna2:21223

Topical therapy of psoriasis vulgaris - a treatment pathway - Koerber, Andreas; Wilsmann-Theis, Dagmar; Augustin, Matthias; Von Kiedrowski, Ralph; Mrowietz, Ulrich; Rosenbach, Thomas; Meller, Stephan; Pinter, Andreas; Sticherling, Michael; Gerdes, Sascha (Journal der Deutschen Dermatologischen Gesellschaft, 2019)
In daily practice topical treatment of psoriasis and its subtypes is of high importance. It is standard for the treatment of mild psoriasis and is used to support treatment of moderate-to-severe psoriasis. When optimizing psoriasis treatment not only the choice of suitable compounds, but also the formulation aspect matters. Developments in the latter field were not considered in the 2017 published update of the current S3-guideline on psoriasis. The presented pathway was prepared during a PsoNet speaker conference and confirmed by the national psoriasis care conference. It aims to illustrate current treatment options.
CRIS-Team WoS Importer:2019-05-09

Towards a pro-resolving concept in systemic lupus erythematosus - Böltz, Sebastian; Hagen, Melanie; Knopf, Jasmin; Mahajan, Aparna; Schick, Maximilian; Zhao, Yi; Erfurt-Berge, Cornelia; Rech, Jürgen; Munoz Becerra, Luis; Herrmann, Martin (Seminars in Immunopathology, 2019)
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with prominent chronic inflammatory aspects. SLE most often affects women (9:1) in childbearing age. The multifactorial nature of the etiopathogenesis of SLE involves a deficient clearance of dead and dying cells. This is supported by the occurrence of autoantibodies directed against autoantigens modified in dying and dead cells (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12) that are deposited in various tissues, including skin, kidneys, joints, muscles, and brain. The subsequent hyperinflammatory response often leads to irreparable tissue damage and organ destruction. In healthy individuals, dead and dying cells are rapidly removed by macrophages in an anti-inflammatory manner, referred to as efferocytosis. In SLE, extensive and prolonged cell death (apoptosis, necrosis, neutrophil extracellular trap (NET) formation) leads to autoantigens leaking out of the not cleared cell debris. These neo-epitopes are subsequently presented to B cells by follicular dendritic cells in the germinal centers of secondary lymphoid tissues conditioning the break of self-tolerance. Activation of autoreactive B cells and subsequent production of autoantibodies facilitate the formation of immune complexes (ICs) fueling the inflammatory response and leading to further tissue damage. ICs may also be ingested by phagocytes, which then produce further pro-inflammatory cytokines. These processes establish a vicious circle that leads to sustained inflammation. This review highlights the cell death–related events in SLE, the protagonists involved in SLE pathogenesis, the resolution of inflammation in various tissues affected in SLE, and explores strategies for intervention to restore hemostasis in a hyperinflammatory state.
CRIS-Team Scopus Importer:2019-11-19
Keywords: Apoptosis; Clearance; Inflammation; Neutrophil extracellular traps (NETs); Resolution; Secondary necrosis; Systemic lupus erythematosus (SLE)

Transcriptional Analysis identifies long non-coding RNAs as potential biomarkers in pneumonia and COPD exacerbation - Bertrams, W.; Griss, K.; Han, M.; Seidel, K.; Klemmer, A.; Sittka-Stark, A.; Hippenstiel, S.; Suttorp, N.; Finkernagel, F.; Wilhelm, J.; Greulich, T.; Vogelmeier, C.; et al. (PNEUMOLOGIE, 2020)
CRIS-Team WoS Importer:2020-11-27

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation - Bertrams, W.; Griss, K.; Han, M.; Eberhardt, M.; Seidel, K.; Klemmer, A.; Sittka-Stark, A.; Hippenstiel, S.; Suttorp, N.; Finkernagel, F.; Wilhelm, J.; Greulich, T.; et al. (PNEUMOLOGIE, 2020)
CRIS-Team WoS Importer:2020-11-27

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation - Bertrams, Wilhelm; Griss, Kathrin; Han, Maria; Seidel, Kerstin; Klemmer, Andreas; Sittka-Stark, Alexandra; Hippenstiel, Stefan; Suttorp, Norbert; Finkernagel, Florian; Wilhelm, Jochen; Greulich, Timm; Vogelmeier, Claus F.; et al. (Scientific Reports, 2020)
Lower respiratory infections, such as community-acquired pneumonia (CAP), and chronic obstructive pulmonary disease (COPD) rank among the most frequent causes of death worldwide. Improved diagnostics and profound pathophysiological insights are urgent clinical needs. In our cohort, we analysed transcriptional networks of peripheral blood mononuclear cells (PBMCs) to identify central regulators and potential biomarkers. We investigated the mRNA- and miRNA-transcriptome of PBMCs of healthy subjects and patients suffering from CAP or AECOPD by microarray and Taqman Low Density Array. Genes that correlated with PBMC composition were eliminated, and remaining differentially expressed genes were grouped into modules. One selected module (120 genes) was particularly suitable to discriminate AECOPD and CAP and most notably contained a subset of five biologically relevant mRNAs that differentiated between CAP and AECOPD with an AUC of 86.1%. Likewise, we identified several microRNAs, e.g. miR-545-3p and miR-519c-3p, which separated AECOPD and CAP. We furthermore retrieved an integrated network of differentially regulated mRNAs and microRNAs and identified HNF4A, MCC and MUC1 as central network regulators or most important discriminatory markers. In summary, transcriptional analysis retrieved potential biomarkers and central molecular features of CAP and AECOPD.
CRIS-Team Scopus Importer:2020-02-07

Transcriptional control of dendritic cell development and functions - Amon, Lukas; Lehmann, Christian; Baranska, Anna; Schoen, Janina; Heger, Lukas; Dudziak, Diana (Immunobiology of Dendritic Cells Part B, 2019)
Dendritic cells (DCs) are major regulators of adaptive immunity, as they are not only capable to induce efficient immune responses, but are also crucial to maintain peripheral tolerance and thereby inhibit autoimmune reactions. DCs bridge the innate and the adaptive immune system by presenting peptides of self and foreign antigens as peptide MHC complexes to T cells. These properties render DCs as interesting target cells for immunomodulatory therapies in cancer, but also autoimmune diseases. Several subsets of DCs with special properties and functions have been described. Recent achievements in understanding transcriptional programs on single cell level, together with the generation of new murine models targeting specific DC subsets, advanced our current understanding of DC development and function. Thus, DCs arise from precursor cells in the bone marrow with distinct progenitor cell populations splitting the monocyte populations and macrophage populations from the DC lineage, which upon lineage commitment can be separated into conventional cDC1, cDC2, and plasmacytoid DCs (pDCs). The DC populations harbor intrinsic programs enabling them to react for specific pathogens in dependency on the DC subset, and thereby orchestrate T cell immune responses. Similarities, but also varieties, between human and murine DC subpopulations are challenging, and will require further investigation of human specimens under consideration of the influence of the tissue micromilieu and DC subset localization in the future.
CRIS-Team Scopus Importer:2019-11-29
Keywords: Antigen presentation; BatF3; CDP; Cross-presentation; DC; Dendritic cell; IRF; Lineage commitment; Ontogeny; Progenitor; Transcription factor; Zbtb46

Transcriptional Profiling of Ligand Expression in Cell Specific Populations of the Adult Mouse Forebrain That Regulates Neurogenesis - Azim, Kasum; Akkermann, Rainer; Cantone, Martina; Vera, Julio; Jadasz, Janusz J.; Kuery, Patrick (Frontiers in Neuroscience, 2018)
In the adult central nervous system (CNS), the subventricular zone (SVZ) of the forebrain is the largest and most active source of neural stem cells (NSCs) that generates mainly neurons and few glial cells lifelong. A large body of evidence has shed light on the distinct families of signaling ligands (i.e., morphogens, growth factors, secreted molecules that alter signaling pathways) in regulating NSC biology. However, most of the research has focused on the mRNA expression of individual or few signaling ligands and their pathway components in specific cell types of the CNS in the context of neurogenesis. A single unifying study that underlines the expression of such molecules comprehensively in different cell types in spatial contexts has not yet been reported. By using whole genome transcriptome datasets of individual purified cell specific populations of the adult CNS, the SVZ niche, NSCs, glial cells, choroid plexus, and performing a bioinformatic meta-analysis of signaling ligands, their expression in the forebrain was uncovered. Therein, we report that a large plethora of ligands are abundantly expressed in the SVZ niche, largely from the vasculature than from other sources that may regulate neurogenesis. Intriguingly, this sort of analysis revealed a number of ligands with unknown functions in neurogenesis contexts that warrants further investigations. This study therefore serves as a framework for investigators in the field for understanding the expression patterns of signaling ligands and pathways regulating neurogenesis.
EVALuna2:34797

Transcriptional Targeting of Mature Dendritic Cells with Adenoviral Vectors via a Modular Promoter System for Antigen Expression and Functional Manipulation - Knippertz, Ilka; Deinzer, Anja; Dörrie, Jan; Schaft, Niels; Nettelbeck, Dirk M.; Steinkasserer, Alexander (International Journal of Microbiology and Immunology Research, 2016)
To specifically target dendritic cells (DCs) to simultaneously express different therapeutic transgenes for inducing immune responses against tumors, we used a combined promoter system of adenoviral vectors. We selected a 216 bp short Hsp70B'. core promoter induced by a mutated, constitutively active heat shock factor (mHSF) 1 to drive strong gene expression of therapeutic transgenes Melan A, BclxL, and IL-12p70 in HeLa cells, as well as in mature DCs ( mDCs). As this involves overexpressing mHSF1, we first evaluated the resulting effects on DCs regarding upregulation of heat shock proteins and maturation markers, toxicity, cytokine profile, and capacity to induce antigen-specific CD8+ T cells. Second, we generated the two-vector-based "modular promoter" system, where one vector contains the mHSF1 under the control of the human CD83 promoter, which is specifically active only in DCs and after maturation. mHSF1, in turn, activates the Hsp70B.. core promotor-driven expression of transgenes MelanA and IL-12p70 in the DC-like cell line XS52 and in human mature and hence immunogenic DCs, but not in tolerogenic immature DCs. These in vitro experiments provide the basis for an in vivo targeting of mature DCs for the expression of multiple transgenes. Therefore, this modular promoter system represents a promising tool for future DC-based immunotherapies in vivo.
EVALuna2:19603

Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis - Hannemann, Nicole; Cao, Shan; Eriksson, Daniel; Schnelzer, Anne; Jordan, Jutta; Eberhardt, Martin; Schleicher, Ulrike; Rech, Jürgen; Uebe, Steffen; Ekici, Arif Bülent; Canete, Juan D.; Chen, Xiaoxiang; et al. (Journal of Clinical Investigation, 2019)
The polarization of macrophages is regulated by transcription factors, such as NF-κB and activator protein 1 (AP-1). In this manuscript, we delineated the role of the transcription factor Fos-related antigen 1 (Fra-1) during macrophage activation and development of arthritis. Network level interaction analysis of microarray data derived from Fra-1- or Fra-2-deficient macrophages revealed a central role of Fra-1, but not of Fra-2, in orchestrating the expression of genes related to wound response, Toll-like receptor activation, and interleukin signaling. ChIP sequencing and standard ChIP analyses of macrophages identified arginase 1 (Arg1) as a target of Fra-1. Luciferase reporter assays revealed that Fra-1 downregulated Arg1 expression by direct binding to the promoter region. Using macrophage-specific Fra-1- or Fra-2-deficient mice, we observed enhanced expression and activity of Arg1 and a reduction of arthritis in the absence of Fra-1, but not of Fra-2. This phenotype was reversed by treatment with the arginase inhibitor Nω-hydroxy-nor-arginine, while -arginine supplementation increased arginase activity and alleviated arthritis, supporting the notion that reduced arthritis in macrophage-specific Fra-1-deficient mice resulted from enhanced Arg1 expression and activity. Moreover, patients with active rheumatoid arthritis (RA) showed increased Fra-1 expression in the peripheral blood and elevated Fra-1 protein in synovial macrophages compared with RA patients in remission. In addition, the Fra-1/ARG1 ratio in synovial macrophages was related to RA disease activity. In conclusion, these data suggest that Fra-1 orchestrates the inflammatory state of macrophages by inhibition of Arg1 expression and thereby impedes the resolution of inflammation.
CRIS-Team Scopus Importer:2019-07-16

Transcription factor Sox10 induces the microRNAs miR-335, miR-338 and miR-155 to ensure correct timing of oligodendrocyte development - Küspert, Melanie; Reiprich, Simone; Cantone, Martina; Weider, Matthias; Baroti, Tina; Wittstatt, Jan; Vera, Julio; Wegner, Michael (GLIA, 2019)
CRIS-Team WoS Importer:2020-01-10

Transcription factor Sox10 regulates oligodendroglial Sox9 levels via microRNAs. - Reiprich, Simone; Cantone, Martina; Weider, Matthias; Baroti, Tina; Wittstatt, Jan; Schmitt, Christian; Küspert, Melanie; Vera, Julio; Wegner, Michael (Glia, 2017)
During development of myelin-forming oligodendrocytes in the central nervous system the two closely related transcription factors Sox9 and Sox10 play essential roles that are partly shared and partly unique. Whereas Sox9 primarily functions during oligodendroglial specification, Sox10 is uniquely required to induce terminal differentiation and myelination. During this process, Sox10 protein levels rise substantially. As this coincides with a reciprocal decrease in Sox9, we postulated that Sox10 influences Sox9 amounts in differentiating oligodendrocytes. Here we show that Sox9 levels are indeed inversely coupled to Sox10 levels such that Sox10 deletion in oligodendroglial cells evokes a reciprocal increase in Sox9. We furthermore provide evidence that this coupling involves upregulation of microRNAs miR335 and miR338 as direct transcriptional targets of Sox10. The two microRNAs in turn recognize the 3′-UTR of Sox9 mRNA and may thereby reduce Sox9 protein levels posttranscriptionally in oligodendroglial cells. Such a mechanism may enable oligodendroglial cells to adapt the ratio of both related Sox proteins in a manner required for successful lineage progression and differentiation. Mathematical modeling furthermore shows that the identified regulatory circuit has the potential to convert a transient stimulus into an irreversible switch of cellular properties and may thus contribute to terminal differentiation of oligodendrocytes.
EVALuna2:33479
Keywords: glia; HMG; miR338; oligodendrocyte; Sox

Transcriptomes of MPO-deficient patients with generalized pustular psoriasis reveals expansion of CD4+cytotoxic T cells and an involvement of complement system and interferon pathways - Hüffmeier, Ulrike; Frey, Benjamin; Becker, Ina; Atreya, Imke; Berking, Carola; Moessner, R.; Wilsmann-Theis, D.; Uebe, Steffen; Kirchner, P.; Haskamp, Stefan (JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-11-05

Transcriptomes of MPO-Deficient Patients with Generalized Pustular Psoriasis Reveals Expansion of CD4+ Cytotoxic T Cells and an Involvement of the Complement System - Haskamp, Stefan; Frey, Benjamin; Becker, Ina; Schulz-Kuhnt, Anja; Atreya, Imke; Berking, Carola; Pauli, David; Ekici, Arif Bülent; Berges, Johannes; Mößner, Rotraut; Wilsmann-Theis, Dagmar; Sticherling, Michael; et al. (Journal of Investigative Dermatology, 2022)
Generalized pustular psoriasis is a severe psoriatic subtype characterized by epidermal neutrophil infiltration. Although variants in IL36RN and MPO have been shown to affect immune cells, a systematic analysis of neutrophils and PBMC subsets and their differential gene expression dependent on MPO genotypes was not performed yet. We assessed the transcriptomes of MPO-deficient patients using single-cell RNA sequencing of PBMCs and RNA sequencing of neutrophils in a stable disease state. Cell-type annotation by multimodal reference mapping of single-cell RNA-sequencing data was verified by flow cytometry of surface and intracellular markers; the proportions of CD4+ cytotoxic T lymphocytes and other CD4+ effector cells were increased in generalized pustular psoriasis, whereas the frequencies of naïve CD4+ T cells were significantly lower. The expression of FGFBP2 marking CD4+ cytotoxic T lymphocytes and CD8+ effector memory T cells was elevated in patients with generalized pustular psoriasis with disease-contributing variants compared with that in noncarriers (P = 0.0015). In neutrophils, differentially expressed genes were significantly enriched in genes of the classical complement activation pathway. Future studies assessing affected cell types and pathways will show their contribution to generalized pustular psoriasis's pathogenesis and indicate whether findings can be transferred to the acute epidermal situation and whether depletion or inactivation of CD4+ cytotoxic T lymphocytes may be a reasonable therapeutic approach.
CRIS-Team Scopus Importer:2022-07-08

Transfer of mRNA Encoding Invariant NKT Cell Receptors Imparts Glycolipid Specific Responses to T Cells and γδT Cells. - Shimizu, Kanako; Shinga, Jun; Yamasaki, Satoru; Kawamura, Masami; Dörrie, Jan; Schaft, Niels; Sato, Yusuke; Iyoda, Tomonori; Fujii, Shin-Ichiro (PLoS ONE, 2015)
Cell-based therapies using genetically engineered lymphocytes expressing antigen-specific T cell receptors (TCRs) hold promise for the treatment of several types of cancers. Almost all studies using this modality have focused on transfer of TCR from CD8 cytotoxic T lymphocytes (CTLs). The transfer of TCR from innate lymphocytes to other lymphocytes has not been studied. In the current study, innate and adaptive lymphocytes were transfected with the human NKT cell-derived TCRα and β chain mRNA (the Vα24 and Vβ11 TCR chains). When primary T cells transfected with NKT cell-derived TCR were subsequently stimulated with the NKT ligand, α-galactosylceramide (α-GalCer), they secreted IFN-γ in a ligand-specific manner. Furthermore when γδT cells were transfected with NKT cell-derived TCR mRNA, they demonstrated enhanced proliferation, IFN-γ production and antitumor effects after α-GalCer stimulation as compared to parental γδT cells. Importantly, NKT cell TCR-transfected γδT cells responded to both NKT cell and γδT cell ligands, rendering them bi-potential innate lymphocytes. Because NKT cell receptors are unique and universal invariant receptors in humans, the TCR chains do not yield mispaired receptors with endogenous TCR α and β chains after the transfection. The transfection of NKT cell TCR has the potential to be a new approach to tumor immunotherapy in patients with various types of cancer.
EVALuna2:19544

Transfer of mRNA encoding recombinant immunoreceptors reprograms CD4+ and CD8+ T cells for use in the adoptive immunotherapy of cancer - Birkholz, K.; Hombach, A.; Krug, C.; Reuter, S.; Kershaw, Michael; Kämpgen, Eckhart; Schuler, Gerold; Abken, H.; Schaft, Niels; Dörrie, Jan (Gene Therapy, 2009)
Human T lymphocytes can be redirected with a new defined specificity by expression of a chimeric T-cell receptor (immunoreceptor) for the use in adoptive immunotherapy of cancer. Whereas standard procedures use retroviral gene transduction to constitutively express immunoreceptors in T cells, we here explored for the first time mRNA electroporation to achieve transient immunoreceptor expression, and thereby minimizing the risk of persistence of potential autoaggression. CD4+ and CD8+ T cells were efficiently transfected with immunoreceptors specific for ErbB2 and CEA. The immunoreceptor expression was transient with half-maximal expression at day 2 and no detectable immunoreceptor expression at day 9 after electroporation. Immunoreceptor-transfected T cells were specifically activated upon coincubation with ErbB2+ and CEA+ tumor cells, respectively, resulting in secretion of interferon-γ (IFNγ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNFα). Furthermore, immunoreceptor-transfected CD8+ T cells specifically lysed ErbB2+ and CEA+ tumor cells, respectively. The RNA-transfected T cells retained their cytotoxic function after 2 days of activation and exhibited cytolytic activities like retrovirally transduced T cells. RNA electroporation of T cells thereby provides a versatile tool for transient immunoreceptor expression, which may be of advantage in avoiding the persistence of unintended autoaggression.
CRIS-Team Scopus Importer:2021-10-01

Transient response to nivolumab and relapse after infliximab in a patient with primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma - Toussaint, Frédéric; Erdmann, M.; Grosch, Ella; Schliep, S.; Schuler, Gerold; Dummer, R.; Heinzerling, Lucie (British Journal of Dermatology, 2020)
CRIS-Team WoS Importer:2020-10-02

Trauma as a Trigger Factor for the First clinical Manifestation of cutaneous Leishmaniasis - Hiernickel, J.; Bogdan, Christian; Erfurt-Berge, Cornelia (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Travel-associated infectious skin diseases - Rongisch, Robert; Schmidt, Enno; Deresz, Nicolai; Deresz, Katharina; Schoefer, Helmut; Schaekel, Knut; Jakob, Thilo; Maurer, Marcus; Sticherling, Michael; Sunderkoetter, Cord; Babilas, Philipp; Spornraft-Ragaller, Petra; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-05-12

Treatment Decision when there is an Indication for adjuvant Therapy for Melanoma - multicenter Real World Data - Lodde, G.; Forschner, A.; Wulfken, L. M.; Meier, F.; Mohr, P.; Kaehler, K. C.; Schilling, B.; Loquai, C.; Berking, Carola; Gebhardt, C.; Huening, S.; Schatton, K.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

Treatment management for BRAF-mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG - Haist, Maximilian; Stege, Henner; Rogall, Friederike; Tan, Yuqi; von Wasielewski, Imke; Klespe, Kai Christian; Meier, Friedegund; Mohr, Peter; Kähler, Katharina C.; Weichenthal, Michael; Hauschild, Axel; Schadendorf, Dirk; et al. (Journal for ImmunoTherapy of Cancer, 2023)
BACKGROUND: Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAFV600-mutant (BRAFmut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor recurrence upon upfront adjuvant therapy. METHODS: For this multicenter cohort study, we identified 515 BRAFmut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments. RESULTS: Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). Patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L ipi+nivo. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004). CONCLUSIONS: BRAFmut melanoma patients who developed DM upon upfront adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection of recurrence followed by a second adjuvant treatment with TT.
CRIS-Team Scopus Importer:2023-09-29
Keywords: Adjuvant Drug Therapy; Immune Checkpoint Inhibitors; Melanoma; Molecular Targeted Therapy; Recurrence

Treatment Motivations and Expectations in Patients with Actinic Keratosis: A German-Wide Multicenter, Cross-Sectional Trial - Steeb, Theresa; Wessely, Anja; Von Bubnoff, Dagmar; Dirschka, Thomas; Drexler, Konstantin; Falkenberg, Conrad; Hassel, Jessica C.; Hayani, Kinan; Huening, Svea; Kaehler, Katharina C.; Karrer, Sigrid; Krammer, Christian; et al. (Journal of Clinical Medicine, 2020)
Patient-centered motives and expectations of the treatment of actinic keratoses (AK) have received little attention until now. Hence, we aimed to profile and cluster treatment motivations and expectations among patients with AK in a nationwide multicenter, cross-sectional study including patients from 14 German skin cancer centers. Patients were asked to complete a self-administered questionnaire. Treatment motives and expectations towards AK management were measured on a visual analogue scale from 1-10. Specific patient profiles were investigated with subgroup and correlation analysis. Overall, 403 patients were included. The highest motivation values were obtained for the items "avoid transition to invasive squamous cell carcinoma" (mean +/- standard deviation; 8.98 +/- 1.46), "AK are considered precancerous lesions" (8.72 +/- 1.34) and "treating physician recommends treatment" (8.10 +/- 2.37; p < 0.0001). The highest expectation values were observed for the items "effective lesion clearance" (8.36 +/- 1.99), "safety" (8.20 +/- 2.03) and "treatment-related costs are covered by health insurance" (8.00 +/- 2.41; p < 0.0001). Patients aged >= 77 years and those with >= 7 lesions were identified at high risk of not undergoing any treatment due to intrinsic and extrinsic motivation deficits. Heat mapping of correlation analysis revealed four clusters with distinct motivation and expectation profiles. This study provides a patient-based heuristic tool for a personalized treatment decision in patients with AK.
CRIS-Team WoS Importer:2020-06-26

Treatment of generalised vitiligo with tacrolimus 0.1% ointment vs. UVB intense pulsed light phototherapy: a pilot study - Hartmann, Arndt; Löhberg, Lisa; Keikavoussi, Petra; Eichner, Saskia; Schuler, Gerold (Acta Dermato-Venereologica, 2014)
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Treatment of vitiligo using targeted UVB-Intense Pulsed Light (IPL)- phototherapy: evaluation of variables affecting therapeutic success - Hartmann, Arndt; Schmidt-Habel, Anne; Löhberg, Lisa; Zajitschek, Jörg; Englbrecht, Matthias; Eichner, Saskia; Schuler, Gerold (European Journal of Dermatology, 2014)
Targeted UVB intense pulsed light (IPL)-phototherapy has gained interest for repigmentation of vitiligo as it allows selective treatment, sparing the surrounding skin. However, optimal treatment frequency and duration are not known.We compared the efficacy and safety of two treatment protocols, weekly and every two weeks, for a maximum of 12 months. Variables affecting treatment response were evaluated.22 patients (16 female, 6 male; aged 15 - 67 years) with generalised vitiligo were evaluated retrospectively. UVB-IPL had been administered weekly (13 patients, group A), or every second week (9 patients, group B). In cases of no response, treatment stopped after 6 months. Regimentation was evaluated qualitatively and quantitatively.After 6 months, 12/13 patients (A), 3/9 patients (B) showed repigmentation. Due to lack of success, treatment was stopped after 6 months in 1 group A patient and 6/9 group B patients. After 12 months, lesions on the face and trunk in group A showed a mean of 70 ± 27% and 60 ± 29% repigmentation, respectively. Moderate to good repigmentation was seen in 78% of group A patients on the ulnar region on the forearms and the shins. Side effects were minimal. Treatment success depended on treatment frequency, number of treatments and the anatomical site of lesions.UVB-IPL phototherapy seems to be effective and well-tolerated in non-segmental vitiligo. A treatment frequency of weekly intervals rather than every two weeks appears preferable. Our observations will help in designing a sufficiently powered prospective clinical trial to test this hypothesis.
EVALuna2:13137

Treatment-resistant actinic keratoses are characterized by distinct clinical and histological features - Schmitz, Lutz; Brehmer, Amrei; Falkenberg, Conrad; Gambichler, Thilo; Heppt, Markus; Steeb, Theresa; Gupta, Girish; Malvehy, Josep; Dirschka, Thomas (Giornale Italiano di Dermatologia e Venereologia, 2021)
BACKGROUND: Actinic keratoses (AK) are generally treated to reduce the risk of progression into invasive cutaneous squamous cell carcinoma (cSCC). However, this risk of transformation is low, and rather than focusing on these lesions, current treatment studies report on complete clearance of AKs in an entire field. This study aimed to investigate treatment-resistant AKs (trAK) after field therapy compared to randomly chosen AKs prior to treatment. METHODS: AKs were clinically assessed according to the grade of hyperkeratosis and pain on palpation, prior to treatment. TrAKs were biop-sied and compared to AKs which were biopsied prior to any treatment. AKs were evaluated regarding histological severity (AKI-III), their basal growth grading (PROI-III), acantholysis, elastosis, follicular extension of atypical keratinocytes and accompanying infiltrate. RESULTS: Two hundred eleven AKs in 171 patients were identified. TrAKs (N.=79) were significantly more painful (64.6% vs. 22.0%; P<0.0001), showing acantholysis (57.0% vs. 33.3%; P=0.0007); and with distinct basal proliferation (PROIII) (64.4% vs. 46.2%; P=0.0099) compared to the control group (N.=132). In a multivariate analysis using logistic regression, pain and PRO III graded lesions were significant independent (P<0.0001 and P=0.0179) predictors for trAKs. Focusing on individual histological features in the trAK group, AKs with grade AKIII, PROIII or follicular extension reaching the sebaceous gland were the most common findings with 51.9%, 64.6%, and 59.5% AKs demonstrating this, respectively. CONCLUSIONS: TrAKs are often painful, showing a distinct basal proliferation (PROIII) and acantholysis. As these features are also seen in invasive cSCCs, trAKs may represent a subgroup of AKs and, for this reason, it requires further evaluations.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Acantholysis; Actinic; Disease progression; Keratosis; Pain

Trial watch : the gut microbiota as a tool to boost the clinical efficacy of anticancer immunotherapy - Daillere, Romain; Derosa, Lisa; Bonvalet, Melodie; Segata, Nicola; Routy, Bertrand; Gariboldi, Manuela; Budinska, Eva; De Vries, I. Jolanda M.; Naccarati, Alessio Gordon; Zitvogel, Valerie; Caldas, Carlos; Engstrand, Lars; et al. (OncoImmunology, 2020)
Accumulating evidence demonstrates the decisive role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade in preclinical tumor models, as well as in cancer patients. In synthesis, it appears that a normal intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. These findings have led to the design of clinical trials that evaluate the capacity of modulation of the gut microbiota to synergize with treatment and hence limit tumor progression. Along the lines of this Trial Watch, we discuss the rationale for harnessing the gut microbiome in support of cancer therapy and the progress of recent clinical trials testing this new therapeutic paradigm in cancer patients.
CRIS-Team WoS Importer:2020-06-26

Triggering of NF-κB in cytokine-matured human DCs generates superior DCs for T-cell priming in cancer immunotherapy. - Pfeiffer, Isabell; Hoyer, Stefanie; Gerer, Kerstin; Voll, Reinhard E.; Knippertz, Ilka; Gueckel, Eva; Schuler, Gerold; Schaft, Niels; Dörrie, Jan (European Journal of Immunology, 2014)
Understanding the signaling that governs the immunogenicity of human dendritic cells (DCs) is a prerequisite for improving DC-based therapeutic vaccination strategies, in which the ability of DCs to induce robust and lasting Ag-specific CTL responses is of critical importance. Cytokine-matured DCs are regularly used, but to induce memory-type CTLs, they require additional activation stimuli, such as CD4+ T-cell help or TLR activation. One common denominator of these stimuli is the activation of NF-?B. Here, we show that human monocyte-derived, cytokine cocktail-matured DCs transfected with constitutively active mutants of I?B kinases (caIKKs) by mRNA electroporation, further upregulated maturation markers, and secreted enhanced amounts of cytokines, including IL-12p70, which was produced for more than 48 h after transfection. Most importantly, cytotoxic T cells induced by caIKK-transfected DCs combined high CD27 expression, indicating a more memory-like phenotype, and a markedly enhanced secondary expandability with a high lytic capacity. In contrast, CTLs primed and expanded with unmodified cytokine cocktail-matured DCs did not maintain their proliferative capacity upon repetitive stimulations. We hypothesize that "designer" DCs expressing constitutively active I?B kinases will prove highly immunogenic also in vivo and possibly emerge as a new strategy to improve the clinical efficacy of therapeutic vaccinations against cancer and other chronic diseases.
EVALuna2:19501

Trotz einer großen Auswahl wirksame Medikamente: Psoriatiker scheinen immer noch untertherapiert zu sein - Pilz, Anna Caroline; Zink, Alexander; Schielein, Maximilian C.; Hell, Katharina; Romer, Katrin; Hillmann, Elena; Bäumer, Daniel; Reinhardt, Maximilian; Wagner, Nicola (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
Hintergrund und Ziele: Durch die Entwicklung neuer anti-psoriatischer Medikamente und verbesserte Strukturen zu deren flächendeckender Einführung hat sich die medizinische Versorgung von Psoriasis-Patienten deutlich verbessert. In dieser Studie haben wir die tatsächliche Inanspruchnahme des Gesundheitswesens untersucht und Gründe für die Unzufriedenheit der Betroffenen ermittelt. Patienten und Methodik: Diese nicht-interventionelle Querschnittsstudie wurde als anonyme Online-Befragung von 12/2018 bis 01/2019 in Deutschland durchgeführt. Teilnehmer mit einer selbstberichteten, von einem Arzt gestellten Psoriasis-Diagnose und Symptomen beantworteten Fragen zu ihrer Erkrankung, deren Einfluss auf das tägliche Leben und ihrer medizinischen Versorgung. Ergebnisse: 649 Teilnehmer mit einem mittleren Alter von 42,5 ± 13,7 Jahren und ausgewogener Geschlechterverteilung (männlich: 50,2 %) wurden ausgewertet. 54,1 % waren zum Zeitpunkt der Studie in ärztlicher Behandlung, 45,9 % nicht. Von den Teilnehmern mit medizinischer Versorgung waren 59,3 % nur mäßig oder weniger zufrieden mit ihrer Behandlung. Gründe für die Unzufriedenheit mit der Medikation waren unter anderem mangelnde Wirksamkeit und Nebenwirkungen. Von den nicht in ärztlicher Behandlung befindlichen Teilnehmern wurde “Zeitmangel des Arztes” als Hauptgrund für die Nichtinanspruchnahme ärztlicher Hilfe angegeben. Schlussfolgerungen: Trotz der Verfügbarkeit effizienter Therapieoptionen in Deutschland sind viele Betroffene mit Psoriasis unzufrieden. Diese unterbehandelte Gruppe wurde als neue Zielgruppe identifiziert.
CRIS-Team Scopus Importer:2021-08-06

Tumor location determines tissue-specific recruitment of tumor-associated macrophages and antibody-dependent immunotherapy response - Lehmann, Birgit; Biburger, Markus; Brückner, Christin; Ipsen Escobedo, Andrea; Gordan, Sina; Lehmann, Christian; Vöhringer, David; Winkler, Thomas; Schaft, Niels; Dudziak, Diana; Sirbu, Horia; Nimmerjahn, Falk; et al. (Science immunology, 2017)
Despite recent advances in activating immune cells to target tumors, the presence of some immune cells, such as tumor-associated macrophages (TAMs) or tumor-associated neutrophils (TANs), may promote rather than inhibit tumor growth. However, it remains unclear how antibody-dependent tumor immunotherapies, such as cytotoxic or checkpoint control antibodies, affect different TAM or TAN populations, which abundantly express activating Fcγ receptors. In this study, we show that the tissue environment determines which cellular effector pathways are responsible for antibody-dependent tumor immunotherapy. Although TAMs derived from Ly6Chigh monocytes recruited by the CCL2-CCR2 axis were critical for tumor immunotherapy of skin tumors, the destruction of lung tumors was CCL2-independent and required the presence of colony-stimulating factor 2–dependent tissue-resident macrophages. Our findings suggest that TAMs may have a dual role not only in promoting tumor growth in certain tissue environments on the one hand but also in contributing to tumor cell destruction during antibody-mediated immunotherapy on the other hand.
EVALuna2:15237
Keywords: Cancer; Macrophages; Tumor associated macrophages; Antibodies; Tumor therapy; Immunotherapy

Tumors as chaotic attractors - Nikolov, Svetoslav; Wolkenhauer, Olaf; Vera González, Julio (Molecular Biosystems, 2014)
Malignant tumor growth, progression and evolution share several of the features associated with strange attractors, a special type of dynamical behavior of non-linear systems. In this framework, the genetic instability of tumor cells represents a local-scale driving force for instability that lets the tumor evolve with time, while selective pressures discarding inefficient cell clones play the role of a dissipative process, providing the tumor with global stability and robustness with respect to perturbations. This setup induces global stability combined with local instability, and is in our opinion the real source of tumor robustness and plasticity, and ultimately the origin of the remarkable resistance of many tumors to anti-cancer therapies. A scientific program taking into consideration the vision of tumors as strange attractors requires the development of experimental and computational tools to link the micro- and mesoscopic perspectives of tumor biology. We here develop the idea of a tumor as a dynamical system, sharing characteristics with strange attractors and investigate several features of such systems, including: (a) local instability combined with global stability, a property inherent to the tremendous non-linearity of the biochemical regulatory circuits governing the individual fate and the interactions between tumor cells; (b) self-similarity at different levels; (c) and strong sensitivity to initial conditions in the composition and features of the tumor and its microenvironment.
EVALuna2:19516

Tumor-suppressing Plasma extracellular Vesicles (pEV) from Melanoma Patients are secreted by Liver Cells and PBMC - Baur, A.; Lee, J. H.; Eberhardt, Martin; Blume, K.; Schuler, Gerold; Vera González, Julio (2018)
EVALuna2:34773

Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011 - Schoffer, Olaf; Schuelein, Stefanie; Arand, Gerlinde; Arnholdt, Hans; Baaske, Dieter; Bargou, Ralf C.; Becker, Nikolaus; Beckmann, Matthias; Bodack, Yves; Boehme, Beatrix; Bozkurt, Tayfun; Breitsprecher, Regine; et al. (BMC Cancer, 2016)
Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients.Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival.The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97-0.97), sex (OR 1.18, 95% CI 1.11-1.25), date of diagnosis (OR 1.05, 95% CI 1.04-1.06), 'diagnosis during screening' (OR 3.24, 95% CI 2.50-4.19) and place of residence (OR 1.23, 95% CI 1.16-1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8-83.9%).No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.
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Twelve-year survival and immune correlates in dendritic cell-vaccinated melanoma patients - Gross, Stefanie; Erdmann, Michael; Haendle, Ina; Voland, Steve; Berger, Thomas; Schultz, Erwin; Strasser, Erwin; Dankerl, Peter; Janka, Rolf Matthias; Schliep, Stefan; Heinzerling, Lucie; Sotlar, Karl; et al. (JCI Insight, 2017)
BACKGROUND: Reports on long-term (≥10 years) effects of cancer vaccines are missing. Therefore, in 2002, we initiated a phase I/II trial in cutaneous melanoma patients to further explore the immunogenicity of our DC vaccine and to establish its long-term toxicity and clinical benefit after a planned 10-year followup. METHODS: Monocyte-derived DCs matured by TNFα, IL-1β, IL-6, and PGE2 and then loaded with 4 HLA class I and 6 class II-restricted tumor peptides were injected intradermally in high doses over 2 years. We performed serial immunomonitoring in all 53 evaluable patients. RESULTS: Vaccine-specific immune responses including high-affinity, IFNγ-producing CD4+ and lytic polyfunctional CD8+ T cells were de novo induced or boosted in most patients. Exposure of mature DCs to trimeric soluble CD40 ligand, unexpectedly, did not further enhance such immune responses, while keyhole limpet hemocyanin (KLH) pulsing to provide unspecific CD4+ help promoted CD8+ T cell responses - notably, their longevity. An unexpected 19% of nonresectable metastatic melanoma patients are still alive after 11 years, a survival rate similar to that observed in ipilimumab-treated patients and achieved without any major (>grade 2) toxicity. Survival correlated significantly with the development of intense vaccine injection site reactions, and with blood eosinophilia after the first series of vaccinations, suggesting that prolonged survival was a consequence of DC vaccination. CONCLUSIONS: Long-term survival in advanced melanoma patients undergoing DC vaccination is similar to ipilimumab-treated patients and occurs upon induction of tumor-specific T cells, blood eosinophilia, and strong vaccine injection site reactions occurring after the initial vaccinations. TRIAL REGISTRATION: ClinicalTrials.gov NCT00053391. FUNDING: European Community, Sixth Framework Programme (Cancerimmunotherapy LSHC-CT-2006-518234; DC-THERA LSHB-CT-2004-512074), and German Research Foundation (CRC 643, C1, Z2).
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TYPE 3 INNATE LYMPHOID CELLS ARE KEY DRIVERS OF PSORIATIC ARTHRITIS - Raimondo, M. G.; Rauber, S.; Luber, M.; Rigau, A. Rius; Weber, Stefanie; Anchang, Charles Gwellem; Agarwal, Rahul; Soare, A.; Sticherling, Michael; Rech, Jürgen; Kleyer, Arnd; Distler, Jörg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Überdiagnose von Melanomen – Ursachen, Konsequenzen und Lösungsansätze - Kutzner, Heinz; Jutzi, Tanja B.; Krahl, Dieter; Krieghoff-Henning, Eva I.; Heppt, Markus; Hekler, Achim; Schmitt, Max; Maron, Roman C.R.; Fröhling, Stefan; von Kalle, Christof; Brinker, Titus J. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-12-11

Ulcerative colitis: yet another paradoxical effect of tumour necrosis factor blockers? - Sticherling, Michael (British Journal of Dermatology, 2018)
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Unbiased high-dimensional flow cytometry identified NK and DC immune cell signature in Luminal A-type and triple negative breast cancer - Heger, Lukas; Heidkamp, Gordon Frederik; Amon, Lukas; Nimmerjahn, Falk; Bäuerle, Tobias; Maier, Andreas; Erber, Ramona; Hartmann, Arndt; Hack, Carolin; Rübner, Matthias; Hübner, Hanna; Fasching, Peter; et al. (OncoImmunology, 2024)
Breast cancer is the most common malignancy in women worldwide and a highly heterogeneous disease. Four different subtypes are described that differ in the expression of hormone receptors as well as the growth factor receptor HER2. Treatment modalities and survival rate depend on the subtype of breast cancer. However, it is still not clear which patients benefit from immunotherapeutic approaches such as checkpoint blockade. Thus, we aimed to decipher the immune cell signature of the different breast cancer subtypes based on high-dimensional flow cytometry followed by unbiased approaches. Here, we show that the frequency of NK cells is reduced in Luminal A and B as well as triple negative breast cancer and that the phenotype of residual NK cells is changed toward regulatory CD11b−CD16− NK cells. Further, we found higher frequencies of PD-1+ CD4+ and CD8+ T cells in triple negative breast cancer. Moreover, while Luminal A-type breast cancer was enriched for CD14+ cDC2 (named type 3 DC (DC3)), CD14− cDC2 (named DC2) were more frequent in triple negative breast cancer. In contrast, HER2-enriched breast cancer did not show major alterations in the composition of the immune cell compartment in the tumor microenvironment. These findings suggest that patients with Luminal A- and B-type as well as triple negative breast cancer might benefit from immunotherapeutic approaches targeting NK cells.
CRIS-Team Scopus Importer:2024-01-12
Keywords: Breast cancer; immune cell signature; NK cells; PD-1; tumor microenvironment

Uncommon Presentation of Scleromyxoedema with a Distribution Pattern Mimicking a Photodermatosis - Kirchberger, Michael Constantin; Sticherling, Michael; Erdmann, Michael (Acta Dermato-Venereologica, 2017)
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Understanding microRNA-mediated gene regulatory networks through mathematical modelling - Lai, Xin; Wolkenhauer, Olaf; Vera González, Julio (Nucleic Acids Research, 2016)
The discovery of microRNAs (miRNAs) has added a new player to the regulation of gene expression. With the increasing number of molecular species involved in gene regulatory networks, it is hard to obtain an intuitive understanding of network dynamics. Mathematical modelling can help dissecting the role of miRNAs in gene regulatory networks, and we shall here review the most recent developments that utilise different mathematical modelling approaches to provide quantitative insights into the function of miRNAs in the regulation of gene expression. Key miRNA regulation features that have been elucidated via modelling include: (i) the role of miRNA-mediated feedback and feedforward loops in fine-tuning of gene expression; (ii) the miRNA-target interaction properties determining the effectiveness of miRNA-mediated gene repression; and (iii) the competition for shared miRNAs leading to the cross-regulation of genes. However, there is still lack of mechanistic understanding of many other properties of miRNA regulation like unconventional miRNA-target interactions, miRNA regulation at different sub-cellular locations and functional miRNA variant, which will need future modelling efforts to deal with. This review provides an overview of recent developments and challenges in this field.
Keywords: miRNAs; network biology; systems biology; computational modelling

Understanding microRNA-mediated immunogenicity of dendritic cells using an integrative approach - Lai, Xin; Dreyer, Florian; Jaitly, T.; Cantone, Martina; Gerer, K. F.; Schuler, Gerold; Dörrie, Jan; Schaft, Niels; Vera, Julio (2018)
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Unilateral, intermittent, pulsating Swelling of the Forehead - Heppt, Franz; Meder, Christine; Wagner, N. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Unraveling a tumor type-specific regulatory core underlying E2F1-mediated epithelial-mesenchymal transition to predict receptor protein signatures - Khan, Faiz M.; Marquardt, Stephan; Gupta, Shailendra K.; Knoll, Susanne; Schmitz, Ulf; Spitschak, Alf; Engelmann, David; Vera, Julio; Wolkenhauer, Olaf; Puetzer, Brigitte M. (Nature Communications, 2017)
Cancer is a disease of subverted regulatory pathways. In this paper, we reconstruct the regulatory network around E2F, a family of transcription factors whose deregulation has been associated to cancer progression, chemoresistance, invasiveness, and metastasis. We integrate gene expression profiles of cancer cell lines from two E2F1-driven highly aggressive bladder and breast tumors, and use network analysis methods to identify the tumor type-specific core of the network. By combining logic-based network modeling, in vitro experimentation, and gene expression profiles from patient cohorts displaying tumor aggressiveness, we identify and experimentally validate distinctive, tumor type-specific signatures of receptor proteins associated to epithelial-mesenchymal transition in bladder and breast cancer. Our integrative network-based methodology, exemplified in the case of E2F1-induced aggressive tumors, has the potential to support the design of cohort- as well as tumor type-specific treatments and ultimately, to fight metastasis and therapy resistance.Deregulation of E2F family transcription factors is associated with cancer progression and metastasis. Here, the authors construct a map of the regulatory network around the E2F family, and using gene expression profiles, identify tumour type-specific regulatory cores and receptor expression signatures associated with epithelial-mesenchymal transition in bladder and breast cancer.
EVALuna2:35407

Unusual presentation of a cutaneous metastasis in the face arising from gastric cancer: a case report - Kirchberger, Michael (SAGE Open Medical Case Reports, 2018)
A well-known example of gastrointestinal cancers metastasizing to the skin is Sister Mary Joseph's nodule, which usually presents as a cutaneous nodule on the umbilicus. In this case, a 91-year-old man was referred to our dermatology clinic for a rapidly growing 3 cm × 2 cm ulcerative nodule at his chin. Biopsy showed skin metastasis originating from a gastric adenocarcinoma. The subcutaneous and cutaneous manifestation of gastric cancer is very rare and associated with a poor prognosis and widespread metastatic disease as presented in this case. However, skin metastasis may be the first clinically apparent sign of underlying systemic malignancy and therefore immediate clarification in case of uncertainty is recommended.
EVALuna2:212813

Updated results of 100 patients on clinical features and therapeutic options in necrobiosis lipoidica in a retrospective multicentre study - Dissemond, Joachim; Schwede, Katharina; Seitz, Anna-Theresa; Al Ghazal, Philipp; Wollina, Uwe; Renner, Regina; Erfurt-Berge, Cornelia (European Journal of Dermatology, 2015)
Necrobiosis lipoidica (NL) is a rare granulomatous disorder of unknown aetiology which can manifest in ulcerative skin lesions and is widely recognised in association with diabetes. We evaluated in total 100 patients to improve knowledge about the epidemiology and clinical course of NL. Additionally we focused on treatment options according to evidence level and expert opinion.To examine the clinical features of patients with necrobiosis lipoidica and to give recommendations for topical and systemic treatment.This multicentre retrospective study covers data from 100 patients with the diagnosis of NL of the lower leg, treated during the period between 01/2006 and 06/2014. Data from 5 German dermatological centres with 23 men and 77 women with a median age of 52 years were evaluated. We also asked 15 dermatological experts for their opinions about ulceration, associated diseases and their preferences for treatment modalities of NL.Patients' ages ranged from 15 to 95 years (median age 52 years, mean age 49.8 years). NL was significantly more common in women (77%). Ulceration of the NL was observed in 33% of cases, in particular in male patients and in patients with concomitant diabetes mellitus. Thyroidal disorders were found in 15% of all cases.Our data confirm that female sex, middle age and endocrine disorders like diabetes mellitus or thyroid dysfunction are characteristics of patients suffering from NL. Existing therapeutic options were very variable and - according to the opinion of our experts - only a few highly effective.
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Update on the management of Bowen disease with a focus on patients' needs. - Berking, Carola (British Journal of Dermatology, 2023)
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Upregulation of CCR4 in activated CD8(+) T cells indicates enhanced lung homing in patients with severe acute SARS-CoV-2 infection - Spoerl, Silvia; Kremer, Anita; Aigner, Michael; Eisenhauer, Nina; Koch, Pauline; Meretuk, Lina; Loeffler, Patrick; Tenbusch, Matthias; Maier, Clara; Überla, Klaus; Heinzerling, Lucie; Frey, Benjamin; et al. (European Journal of Immunology, 2021)
COVID-19 is a life-threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected are to date not well understood.
CRIS-Team WoS Importer:2021-05-07

Usage and effectiveness of systemic treatments in adults with severe atopic eczema: First results of the German Atopic Eczema Registry TREATgermany - Schmitt, Jochen; Abraham, Susanne; Trautmann, Freya; Stephan, Victoria; Foelster-Holst, Regina; Homey, Bernhard; Bieber, Thomas; Novak, Natalija; Sticherling, Michael; Augustin, Matthias; Kleinheinz, Andreas; Elsner, Peter; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2017)
BACKGROUND: The goal of clinical registries is to document the use and effectiveness of therapeutic interventions under real-life conditions. They are an indispensable prerequisite of evidence-based health care. METHODS: Initiated in 2011, the German Atopic Dermatitis Registry TREATgermany is the first registry of patients with severe atopic dermatitis worldwide. Adults with severe atopic dermatitis (current/prior systemic antiinflammatory treatment and/or objective SCORAD ≥ 40) are prospectively followed over the course of 24 months. Employed treatment modalities are documented, and validated measuring tools are used to assess clinical disease severity (EASI, objective SCORAD), quality of life (DLQI), symptoms (POEM), global disease severity, as well as patient satisfaction. Herein, we describe the characteristics, therapeutic selection, and effectiveness of systemic antiinflammatory treatments of patients enrolled in the registry until October 2014. RESULTS: Overall, 78 individuals (mean age 39 years, 61 % men) were enrolled at five recruitment centers. Patients frequently made use of inpatient and outpatient services. Not only was cyclosporine the most frequently administered systemic treatment, but also the most effective (EASI 50 response rate 51 %; EASI 75 response rate 34 % at 12 weeks). Azathioprine, methotrexate, oral prednisolone, mycophenolate, alitretinoin, and leflunomide were also used in some patients. CONCLUSIONS: The present analysis of the German Atopic Dermatitis Registry provides important data with respect to current medical care of adults with severe atopic dermatitis in Germany. It shows the high disease burden, the benefits of current treatment options, and the need for additional effective and safe long-term treatment options.
EVALuna2:34363

Using multiple real-world dermoscopic photographs of one lesion improves melanoma classification via deep learning - Hekler, Achim; Maron, Roman C.; Haggenmüller, Sarah; Schmitt, Max; Wies, Christoph; Utikal, Jochen S.; Meier, Friedegund; Hobelsberger, Sarah; Gellrich, Frank F.; Sergon, Mildred; Hauschild, Axel; French, Lars E.; et al. (Journal of the American Academy of Dermatology, 2024)
CRIS-Team Scopus Importer:2024-02-16
Keywords: artificial intelligence; deep learning; dermatology; dermoscopy; diagnosis; diagnostic accuracy; melanoma; robustness; uncertainty estimation

Using the Prediction Model Risk of Bias Assessment Tool (PROBAST) to Evaluate Melanoma Prediction Studies - Kaiser, Isabelle; Mathes, Sonja; Pfahlberg, Annette Bettina; Uter, Wolfgang; Berking, Carola; Heppt, Markus; Steeb, Theresa; Diehl, Katharina; Gefeller, Olaf (Cancers, 2022)
Rising incidences of cutaneous melanoma have fueled the development of statistical models that predict individual melanoma risk. Our aim was to assess the validity of published prediction models for incident cutaneous melanoma using a standardized procedure based on PROBAST (Prediction model Risk Of Bias ASsessment Tool). We included studies that were identified by a recent systematic review and updated the literature search to ensure that our PROBAST rating included all relevant studies. Six reviewers assessed the risk of bias (ROB) for each study using the published “PROBAST Assessment Form” that consists of four domains and an overall ROB rating. We further examined a temporal effect regarding changes in overall and domain-specific ROB rating distributions. Altogether, 42 studies were assessed, of which the vast majority (n = 34; 81%) was rated as having high ROB. Only one study was judged as having low ROB. The main reasons for high ROB ratings were the use of hospital controls in case-control studies and the omission of any validation of prediction models. However, our temporal analysis results showed a significant reduction in the number of studies with high ROB for the domain “analysis”. Nevertheless, the evidence base of high-quality studies that can be used to draw conclusions on the prediction of incident cutaneous melanoma is currently much weaker than the high number of studies on this topic would suggest.
CRIS-Team Scopus Importer:2022-07-22
Keywords: melanoma; prediction models; PROBAST; risk of bias; risk prediction

Uveal melanoma Uveamelanome - Hassel, Jessica C.; Heppt, Markus (Die Onkologie, 2023)
Uveal melanoma is rare and constitutes 5% of all melanomas. They develop mainly from pigment cells of the choroidea, less commonly from the ciliary body or the iris of the eye. The treatment of primary uveal melanoma includes surgery and radiation therapy. Especially large tumors and those with extraocular extension are enucleated. Smaller tumors can be irradiated with plaque brachytherapy or protons. Follow-up, which consists of ophthalmologic examinations, liver ultrasound, and may include assessment of the transaminases in the peripheral blood, is ideally based on the risk profile of the primary tumor and performed every 3–6 months. According to the genetic risk profile, 50% of patients develop distant metastasis, mainly in the liver. Therefore, in addition to systemic therapy, local liver-directed therapies such as chemoperfusion/chemosaturation, transarterial chemoembolization (TACE), and selective internal radiotherapy (SIRT) can be administered. To date, however, there is no definitive evidence that these treatments not only inhibit progression in the liver but improve overall survival. Treatment of choice in patients with metastases is the newly approved immunotherapy with tebentafusp, a bispecific protein consisting of a gp100-TCR (T cell receptor) fused to a CD3 antibody leading to activation of T cells in the microenvironment of the uveal melanoma. It is the first drug proven to lead to a significant survival benefit for patients with metastasized uveal melanoma compared with other systemic therapies such as immune checkpoint inhibitors and chemotherapy. Interestingly, patients with progressing metastases also have a survival benefit. However, treatment can only be given to patients with the human leukocyte antigen (HLA)-A0201 phenotype to which the TCR was designed and which is present in approximately 50% of patients. Further promising new drugs are under development.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Immunotherapy; Local liver-directed therapies; Melanoma of the eye; Tebentafusp

Vaccination with dendritic Cells for metastasized Uveal Melanoma: immunological and clinical Responses - Moreira, Alvaro; Gross, S.; Uslu, Ugur; Dörrie, Jan; Kummer, Mirko; Schliep, S.; Sponagl, F.; Lischer, Christopher; Erdmann, M.; Heinzerling, Lucie; Schuler, Gerold; Schuler-Thurner, Beatrice (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Vasoactive Therapy in Systemic Sclerosis: Real-life Therapeutic Practice in More Than 3000 Patients - Moinzadeh, Pia; Riemekasten, Gabriela; Siegert, Elise; Fierlbeck, Gerhard; Henes, Joerg; Blank, Norbert; Melchers, Inga; Mueller-Ladner, Ulf; Frerix, Marc; Kreuter, Alexander; Tigges, Christian; Lahner, Nina; et al. (Journal of Rheumatology, 2016)
Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry.The data of 3248 patients with SSc were analyzed.Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005.These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.
EVALuna2:13183

Versorgungszustand von Patienten vor Zuweisung an ein universitäres Wundzentrum - Erfurt-Berge, Cornelia; Michler, Melanie; Renner, Regina (Hautarzt, 2021)
Background and objectives: Health care for patients with chronic wounds is often protracted. This can result in decreased quality of care or delayed diagnosis of the actual cause of disease. Concurrently, there are already certified facilities for these patients. The present work investigates possible reasons for delayed referral and whether a specific selection of patients is sent to these university-based centres. Patients and methods: A retrospective patient data chart review at the point of first admission to the certified wound centre was performed to identify concerning variables about the standard of care before university presentation. Results: Records of 177 patients were analysed (53% women, 47% men; patient age range 27–95 years). The mean duration of the wound was 22 months. Vascular diagnostics had already been performed in 32% (arterial diagnostics) and 36% (phlebological diagnostics), respectively. A tissue sample had been analysed in 9% of cases, especially when wound duration exceeded > 24 months. In only 45% of cases was the external diagnosis in accord with the final diagnosis in the wound centre. Discussion: The health care situation for patients with chronic wounds outside of specialised care structures is insufficient. Early and standardized diagnostics and therapy and a reasonable admission to specialised centres is desired.
CRIS-Team Scopus Importer:2021-02-05
Keywords: Basic diagnostics; Care structure; Leg ulcer; Primary care; Quality of care

Very late reactions in the patch test with fragrance mix I and oak moss absolute: Data of the Information Network of Departments of Dermatology (IVDK) - Schubert, Steffen; Schnuch, Axel; Bauer, Andrea; Wagner, Nicola; Schroeder-Kraft, Claudia; Dickel, Heinrich; Weisshaar, Elke; Effendy, Isaak; Becker, Detlef; Buhl, Timo; Simon, Dagmar; Koch, Andre; et al. (Contact Dermatitis, 2021)
CRIS-Team WoS Importer:2021-10-01

VEXAS syndrome mimicking lupus-like disease - Valor-Mendez, Larissa; Sticherling, Michael; Zeschick, Martin; Atreya, Raja; Schmidt, Daniela; Waldfahrer, Frank; Saake, Marc; Hüffmeier, Ulrike; Schett, Georg; Rech, Jürgen (Rheumatology, 2023)
CRIS-Team WoS Importer:2023-03-17

Vier Fälle einer Erysipel-ähnlichen Entzündung bei Patienten mit metastasiertem Melanom unter Therapie mit Checkpoint-Inhibitoren. - Pföhler, Claudia; Hassel, Jessica C.; Heinzerling, Lucie; Müller, Cornelia S.L. (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
EVALuna2:470343

Wahrnehmung der Corona-Pandemie durch Neurodermitispatienten – Ergebnisse aus dem Neurodermitisregister TREATgermany - Helmert, Claudia; Siegels, Doreen; Haufe, Eva; Abraham, Susanne; Heratizadeh, Annice; Kleinheinz, Andreas; Harder, Inken; Schäkel, Knut; Effendy, Isaak; Wollenberg, Andreas; Sticherling, Michael; Stahl, Maren; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
CRIS-Team Scopus Importer:2022-02-04

Was hat die Ernährung mit der Wundheilung zu tun? - Renner, R.; Erfurt-Berge, Cornelia (Aktuelle Dermatologie, 2020)
Interference during the complex wound healing process might lead to a delayed or absence of wound closure. One possible disruptive factor can be wrong nutrition. It is necessary to differentiate between quantitative and qualitative malnutrition. Preferential obese patients suffer from a qualitative malnutrition and sarkopenia. Specific diseases require a specific nutritional recommendation. For example, patients with dialysis, decubitus, or leg ulcers often have a lack of proteins. In addition, other nutrient deficiencies with Vitamin C, zinc, folate, Vitamin D or trace elements might have a negative impact on wound healing. Prospective studies should clarify if substitution of those nutrient deficiencies might improve wound healing. It seems to be reasonable to strive for an improvement in the consumption of vitamins, trace elements and proteins adopted to a balanced alimentation and adjusted to individual dietary habits.
CRIS-Team Scopus Importer:2020-07-10

What Goes Around, Comes Around - HSV-1 Replication in Monocyte-Derived Dendritic Cells - Grosche, Linda; Kummer, Mirko; Steinkasserer, Alexander (Frontiers in Microbiology, 2017)
HSV-1 is a very successful human pathogen, known for its high sero-prevalence and the ability to infect a wide range of different cell types, including dendritic cells (DCs). As very potent antigen-presenting cells DCs play an important role in the induction of antiviral immune responses and therefore represent a strategic target for viral-mediated immune escape mechanisms. It is known that HSV-1 completes its gene expression profile in immature as well as in mature DCs, while lytic infection is only found in immature DCs (iDCs). Notably, HSV-1 infected mature DCs (mDCs) fail to release infectious progeny virions into the supernatant. Apart from HSV-1 dissemination via extracellular routes cell-to-cell spread counteracts a yet unknown mechanism by which the virus is trapped in mDCs and not released into the supernatant. The dissemination in a cell-cell contact-dependent manner enables HSV-1 to infect bystander cells without the exposure toward the extracellular environment. This supports the virus to successfully infect the host and establish latency. In this review the mechanism of HSV-1 replication in iDCs and mDCs and its immunological as well as virological implications, will be discussed.
EVALuna2:36216

What is the current State of Knowledge of Skin Cancer Patients about fertility-preserving Measures? an exploratory Cross Sectional Survey - Hornung-Eichler, Annkathrin; Steeb, T.; Erdmann, M.; Berking, Carola; Heppt, Markus (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Wheat Anaphylaxis in Adults Differs from Reactions to Other Types of Food - Kraft, Magdalena; Dölle-Bierke, Sabine; Renaudin, Jean Marie; Ruëff, Franziska; Scherer Hofmeier, Kathrin; Treudler, Regina; Pföhler, Claudia; Hawranek, Thomas; Poziomkowska-Gęsicka, Iwona; Jappe, Uta; Christoff, George; Müller, Sabine; et al. (The Journal of Allergy and Clinical Immunology: In Practice, 2021)
Background: Wheat is one of the most commonly consumed foods and a known elicitor of anaphylaxis in children and adults. Reactions in adults are often cofactor dependent and characterized by a prolonged time between food intake and the onset of symptoms making the diagnosis of wheat anaphylaxis challenging. Objective: To characterize a cohort of patients with the history of wheat anaphylaxis to better understand this atypical phenotype of anaphylaxis. Methods: Data from the European Anaphylaxis Registry from 2007 to 2019 (n = 10,636) including 250 patients (213 adults and 37 children) with a history of anaphylaxis caused by wheat were analyzed. Results: Wheat was the most common food elicitor of anaphylaxis in adults in the registry in Central Europe. Reactions to wheat in adults were frequently associated with exercise as a cofactor (82.8%) and partially delayed (57.5%). Only 36.9% of patients had atopic comorbidities, which was uncommonly low for adult patients allergic to other kinds of foods (63.2%). Anaphylaxis to wheat presented frequently with cardiovascular symptoms (86.7%) including severe symptoms such as loss of consciousness (41%) and less often with respiratory symptoms (53.6%). The reactions to wheat were more severe than reactions to other foods (odds ratio [OR] = 4.33), venom (OR = 1.58), or drugs (OR = 2.11). Conclusions: Wheat is a relevant elicitor of anaphylaxis in adults in Central Europe. Wheat anaphylaxis is highly dependent on the presence of cofactors and less frequently associated with atopic diseases compared with other food allergies. More data on mechanisms of wheat-induced anaphylaxis are required to develop preventive measures for this potentially life-threatening disease.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Anaphylactic reaction; Anaphylaxis; FDEIA; Food allergy; Omega-5-gliadin; Tri a 19; WDEIA; Wheat allergy; Wheat-dependent exercise-induced anaphylaxis

Where do we stand with immune checkpoint blockade for advanced cutaneous squamous cell carcinoma? A systematic review and critical appraisal of existing evidence - Steeb, T.; Wessely, A.; Heppt, Franz; Harlaß, M.; Berking, Carola; Heppt, Markus (British Journal of Dermatology, 2020)
Immune checkpoint blockade (ICB) has tremendously changed the field of oncological therapy. Recently, the PD-1-blocking antibody cemiplimab was approved by the FDA and the EMA for the treatment of advanced cutaneous squamous cell carcinoma (cSCC).1 However, clinical practice guidelines currently do not cover specific recommendations regarding the management of advanced cSCC with ICB. Hence, we have performed a systematic review on the current use of ICB for advanced cSCC.
EVALuna2:212852

Which patients should receive adjuvant treatment - an analysis of stage IIA-IIIA patients of the CMMR - Leiter-Stoppke, U.; Keim, U.; Amaral, T.; Forschner, A.; Berking, Carola; Gesierich, A.; Gutzmer, R.; Sunderkotter, C.; Utikal, J. S.; Zimmer, L.; Flatz, L.; Garbe, C. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Whither systems medicine? - Apweiler, Rolf; Beissbarth, Tim; Berthold, Michael R.; Bluethgen, Nils; Burmeister, Yvonne; Dammann, Olaf; Deutsch, Andreas; Feuerhake, Friedrich; Franke, Andre; Hasenauer, Jan; Hoffmann, Steve; Hoefer, Thomas; et al. (Experimental and Molecular Medicine, 2018)
New technologies to generate, store and retrieve medical and research data are inducing a rapid change in clinical and translational research and health care. Systems medicine is the interdisciplinary approach wherein physicians and clinical investigators team up with experts from biology, biostatistics, informatics, mathematics and computational modeling to develop methods to use new and stored data to the benefit of the patient. We here provide a critical assessment of the opportunities and challenges arising out of systems approaches in medicine and from this provide a definition of what systems medicine entails. Based on our analysis of current developments in medicine and healthcare and associated research needs, we emphasize the role of systems medicine as a multilevel and multidisciplinary methodological framework for informed data acquisition and interdisciplinary data analysis to extract previously inaccessible knowledge for the benefit of patients.
EVALuna2:34798

Willingness to pay for a cure of low-risk melanoma patients in Germany - Augustin, Matthias; Blome, Christine; Forschner, Andrea; Gutzmer, Ralf; Hauschild, Axel; Heinzerling, Lucie; Livingstone, Elisabeth; Loquai, Carmen; Schadendorf, Dirk; Utikal, Jochen; Wagner, Tobias; Wilden, Sophia; et al. (PLoS ONE, 2018)
Malignant melanoma is potentially life-threatening but in most cases curable if detected early. Willingness to pay (WTP) is a preference-based construct that reflects burden of disease by assessment of the monetary value for a hypothetical cure from disease. Since WTP (directly as total amount of money) has not been assessed so far in patients with low risk melanoma, it was interesting to gain insights in this patient population and then, in a second step, compare it directly with the WTP of their treating dermato-oncologists. WTP was assessed in 125 patients with low-risk melanoma and additionally in 105 treating physicians, asking for the one-time and continuous payments they would be willing to make for a sustainable cure, both as absolute sums and as percentages of monthly income. The median WTP based on one-time payment was €10,000 for patients and €100,000 for physicians; relative numbers were 100% versus 300% of monthly income. For continuous monthly payments, WTP was €500 for patients and €1000 for physicians, relative numbers 25% and 50% of income, respectively. Even after controlling for income differences, there was a significantly higher WTP in physicians for all four questions. Compared to patients with chronic skin diseases such as vitiligo, rosacea, atopic eczema and psoriasis, patients with low-risk melanoma showed a significantly higher WTP. Our data suggest that there is a relevant burden of disease even in patients with low-risk tumors. Higher WTP of physicians underlines the prevalence of differences in disease perception.
EVALuna2:34380

Wound treatment without curative intention: position paper of the Initiative Chronische Wunden (ICW) e. V. Wundbehandlung ohne kurative Zielsetzung: Ein Positionspapier der Initiative Chronische Wunden (ICW) e. V. - Dissemond, Joachim; Protz, Kerstin; Erfurt-Berge, Cornelia; Kröger, Knut; Kottner, Jan (Hautarzt, 2022)
Today, patients with chronic wounds are treated in many different fields of medicine. Despite this great interdisciplinary and interprofessional importance, there is still a lack of uniformly accepted definitions and classifications. Therefore, a group of experts from the professional society Initiative Chronische Wunden (ICW) e. V. translated and adapted the classification of chronic wounds into healable, maintenance and nonhealable wounds on the basis of the internationally published literature into German. This classification results in the aim of curative, limited respectively non-curative or palliative wound care, which are very important for everyday clinical practice. It thus becomes clear that complete wound closure is not always the central intention of wound treatment. For many patients with chronic wounds, other aspects such as the best possible quality of life and the promotion of health-related self-management as well as the avoidance of complications are important for treatment concepts. These therapy intentions should be differentiated and individually discussed with patients in order to facilitate shared decision making.
CRIS-Team Scopus Importer:2022-03-25
Keywords: Chronic wounds; Curative wound care; Maintenance wounds; Nonhealable wounds; Palliative wound care

XCR1 expression distinguishes human conventional dendritic cell type 1 with full effector functions from their immediate precursors - Heger, Lukas; Hatscher, Lukas; Liang, Chunguang; Lehmann, Christian; Amon, Lukas; Lühr, Jennifer J.; Kaszubowski, Tomasz; Nzirorera, Rayk; Schaft, Niels; Dörrie, Jan; Irrgang, Pascal; Tenbusch, Matthias; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2023)
Dendritic cells (DCs) are major regulators of innate and adaptive immune responses. DCs can be classified into plasmacytoid DCs and conventional DCs (cDCs) type 1 and 2. Murine and human cDC1 share the mRNA expression of XCR1. Murine studies indicated a specific role of the XCR1-XCL1 axis in the induction of immune responses. Here, we describe that human cDC1 can be distinguished into XCR1- and XCR1+ cDC1 in lymphoid as well as nonlymphoid tissues. Steady-state XCR1+ cDC1 display a preactivated phenotype compared to XCR1- cDC1. Upon stimulation, XCR1+ cDC1, but not XCR1- cDC1, secreted high levels of inflammatory cytokines as well as chemokines. This was associated with enhanced activation of NK cells mediated by XCR1+ cDC1. Moreover, XCR1+ cDC1 excelled in inhibiting replication of Influenza A virus. Further, under DC differentiation conditions, XCR1- cDC1 developed into XCR1+ cDC1. After acquisition of XCR1 expression, XCR1- cDC1 secreted comparable level of inflammatory cytokines. Thus, XCR1 is a marker of terminally differentiated cDC1 that licenses the antiviral effector functions of human cDC1, while XCR1- cDC1 seem to represent a late immediate precursor of cDC1.
CRIS-Team Scopus Importer:2023-08-25
Keywords: antiviral immunity; cDC1; DC differentiation; IL-12; XCR1

YouTube (R)-Videos about Skin Cancer as an Information Source for Patients: Assessment of quality, Comprehensibility and Reliability - Reinhardt, L.; Steeb, Theresa; Harlass, M.; Brutting, J.; Berking, Carola; Meier, F. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Zielgerichtete Therapie bei BRAF-mutiertem metastasierten papillären Schilddrüsenkarzinom und malignen Melanom - Bender-Säbelkampf, Sophia; Tüting, Thomas; Alter, Mareike; Horbrügger, M. (Abstractband anlässlich des 29. Deutschen Hautkrebskongresses (ADO–Jahrestagung), 2019)
We like to present a case study of an 80-year old male with a metastatic papillary thyroid cancer and malignant melanoma. A left hemithyroidectomy was performed in 2017. Due to a former existing single-sided recurrent laryngeal nerve palsy a R0-resection could not been carried through. The subsequent therapy consisted of thyroid hormone substitution and radio iodine therapy. Up until now the thyroid cancer cells don’t show an uptake anymore, further radio iodine therapy is therefor contraindicated. Further PET-CTs and ultrasounds showed an increase in size with a subtotal stenosis of the oesophagus and severe dysphagia. In January 2019 we excised a nodular melanoma occipital right. The subsequent staging showed progressive cervical lymph node metastasis and pulmonary lesions. We assign the infiltration of oesophagus and neck as metastasis of the thyroid cancer whereas the pulmonal lesions we see as metastatic stage IV melanoma. Via genomic sequencing there was a BRAF-V600-E mutation found in both melanoma and the papillary thyroid cancer. A prevalence of BRAF-mutations in thyroid cancer are found in 20–50 % and for malignant melanoma in 40–60 % (1). As there is currently no officially approved targeted therapy for BRAF mutant thyroid cancer in Europe, a few clinical studies (2) using targeted therapy however showed a therapy response rate of 70 %. As this therapy is also already indicated for mutation positive metastatic malignant melanoma and non-small cell lung cancer, the FDA recently approved Dabrafenib and Trametinib as targeted therapy in BRAF-positive anaplastic thyroid cancer. Due to the BRAF-positive malignant melanoma in our case, we could initiate a targeted therapy immediately. Recent studies showed a higher standardised uptake value and FDG PET acitivity in BRAF-positive thyroid cancer cells which leads to the hope that through a targeted therapy the once iodine-resistant thyroid cells of our patient could possibly regulate their uptake level for radio iodine therapy to be successful once again.<br

β2-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression - Hofbauer, Daniel; Mougiakakos, Dimitrios; Broggini, Luca; Zaiss, Mario; Büttner-Herold, Maike; Bach, Christian; Spriewald, Bernd; Neumann, Frank; Bisht, Savita; Nolting, Jens; Zeiser, Robert; Hamarsheh, Shaima'a; et al. (Immunity, 2021)
As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (β2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed β2m promotes β2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1β (IL-1β) and IL-18. This process depends on activation of the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficient mice lack efficient β2m-induced IL-1β production. Moreover, depletion or silencing of β2m in MM cells abrogates inflammasome activation in a murine MM model. Finally, we demonstrate that disruption of NLRP3 or IL-18 diminishes tumor growth and osteolytic bone destruction normally promoted by β2m-induced inflammasome signaling. Our results provide mechanistic evidence for β2m's role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM.
CRIS-Team Scopus Importer:2021-08-13
Keywords: inflammation; macrophages; multiple myeloma; NLRP3; phagocytosis; tumor-associated macrophages

3-D-Ganzkörperhautscanner – eine neue Ära in Klinik und Forschung? - Sitaru, Sebastian; Kaczmarczyk, Robert; Erdmann, Michael; Biedermann, Tilo; Zink, Alexander (Hautarzt, 2022)
CRIS-Team Scopus Importer:2022-03-25

A European randomised controlled trial for venous leg ulcers: A mathematical model analysis - Renner, Regina (Journal of Wound Care, 2020)
CRIS-Team Scopus Importer:2020-11-27

A qualitative study on maternal attachment behaviour as a risk factor for the onset of atopic dermatitis in the infant - Schmidt, L. E. M.; Merdha, L.; Lang, V.; Preis, S.; Bleuel, R.; Schuch, A.; Da Silva, R.; Blasini, A.; Kuschel, B.; Hauenstein, E.; Sander, M.; Niedermeier, S.; et al. (BRITISH JOURNAL OF DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-09-10

ARIA-Leitlinie 2019: Behandlung der allergischen Rhinitis im deutschen Gesundheitssystem - Klimek, L.; Bachert, C.; Pfaar, O.; Becker, S.; Bieber, T.; Brehler, R.; Buhl, R.; Casper,; Chaker, A.; Czech, W.; Fischer, J.; Fuchs, T.; et al. (Allergologie, 2020)
CRIS-Team Scopus Importer:2020-02-28
Keywords: Allergen-specific immunotherapy; Allergic asthma; Allergic diseases; Health care system; Integrated care pathway

Atopic skin diathesis rather than atopic dermatitis is associated with specific contact allergies - Forkel, Susann; Cevik, Naciye; Schill, Tillmann; Worm, Margitta; Mahler, Vera; Weisshaar, Elke; Vieluf, Dieter; Pfützner, Wolfgang; Löffler, Harald; Schön, Michael P.; Geier, Johannes; Buhl, Timo (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
Background: The association of atopic dermatitis (AD) and allergic contact dermatitis has been a matter of considerable uncertainty. Study results range from lack of any association to increased sensitization for multiple allergens, but fail to identify consistent allergen associations. Objective: We studied a large patch test cohort of patients stratified by their atopic skin diathesis using the Erlangen Atopy Score (EAS), independent of active skin disease. Methods: Retrospective multi-center data analysis from five departments of dermatology in Germany with 4,509 patients. Patients were grouped as “no atopic skin diathesis” (n = 2,165) and “atopic skin diathesis” (n = 1,743), according to EAS. Results: Significantly more individuals with atopic skin diathesis showed at least one positive patch test reaction to the baseline series compared to individuals without atopic skin diathesis (49.1 % vs. 38.3 %). In logistic regression analyses, atopic skin diathesis was associated with a significantly higher risk of sensitization to methylchloroisothiazolinone/methylisothiazolinone (OR 2.383) and methylisothiazolinone (OR 1.891), thiuram mix (OR 1.614), as well as nickel (OR 1.530), cobalt (OR 1.683), and chromium (OR 2.089). Conclusions: Atopic skin diathesis proved to be the most important intrinsic risk factor for contact sensitization to few, specific allergens. Past or present AD was a less relevant variable.
CRIS-Team Scopus Importer:2021-02-26
Keywords: atopic dermatitis; atopy score; contact allergy; eczema; metal allergy

Atopische Hautdiathese ist stärker mit spezifischen Kontaktallergien assoziiert als atopische Dermatitis - Forkel, Susann; Cevik, Naciye; Schill, Tillmann; Worm, Margitta; Mahler, Vera; Weisshaar, Elke; Vieluf, Dieter; Pfützner, Wolfgang; Löffler, Harald; Schön, Michael P.; Geier, Johannes; Buhl, Timo (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-02-26

Atopy patch testing with aeroallergens in a large clinical population of dermatitis patients in Germany and Switzerland, 2000-2015: a retrospective multicentre study - Dickel, H.; Kuhlmann, L.; Bauer, A.; Bircher, A. J.; Breuer, K.; Fuchs, T.; Grabbe, J.; Mahler, Vera; Pföhler, C.; Przybilla, B.; Rieker-Schwienbacher, J.; Schröder-Kraft, C.; et al. (Journal of the European Academy of Dermatology and Venereology, 2020)
Background: The diagnostic significance of the atopy patch test for the management of dermatitis possibly triggered by aeroallergens is still controversial. However, sufficiently large studies with routinely tested standardized aeroallergen patch test preparations in dermatitis patients are lacking. Objective: To evaluate the reaction frequency and the reaction profiles of 10 until mid-2015 commercially available, standardized aeroallergen patch test preparations of the ‘Stallerpatch’ test series (Stallergenes, Antony Cedex, France) in a large multicentre patient cohort. Methods: A retrospective data analysis of patients with suspected aeroallergen-dependent eczematous skin lesions was performed, who were patch tested in 15 Information Network of Departments of Dermatology-associated clinics between 2000 and 2015. Patients were stratified according to their atopic dermatitis (AD) status. Results: The study group included 3676 patients (median age 41 years, 34.8% males, 54.5% AD). The most common aeroallergens causing positive patch test reactions were Dermatophagoides pteronyssinus (19.6%), Dermatophagoides farinae (16.9%), birch (6.2%), timothy grass (6.0%), cat dander (5.4%), mugwort (4.9%) and dog dander (4.6%). Reactions to other pollen allergen preparations, that is 5 grasses (3.2%), cocksfoot (2.1%) and plantain (1.6%), were less common. Positive patch test reactions to aeroallergens were consistently more frequent in patients with AD. These patients showed proportionally less dubious, follicular, irritant and weak positive reactions. Independent of AD status, a patient history of past or present allergic rhinitis was associated with an increased chance of a positive aeroallergen patch test reaction to pollen allergens. Conclusion: The aeroallergen patch test is a useful add-on tool in clinical routine, especially in patients with AD and/or respiratory allergy. A patch test series comprising Dermatophagoides pteronyssinus, Dermatophagoides farinae, birch, timothy grass, cat dander and mugwort seems to be suitable. Controlled studies with specific provocation and elimination procedures are required to further evaluate the diagnostic significance of the proposed screening series.
CRIS-Team Scopus Importer:2020-03-20

Challenging a paradigm: skin sensitivity to sodium lauryl sulfate is independent of atopic diathesis - Heetfeld, A. B.; Schill, T.; Schroeder, S. S.; Forkel, S.; Mahler, Vera; Pfuetzner, W.; Schoen, M. P.; Geier, J.; Buhl, T. (British Journal of Dermatology, 2019)
Background Sodium lauryl sulfate (SLS) is the best-studied detergent in irritant contact dermatitis. In atopic dermatitis, the two major pathophysiological abnormalities concern skin barrier function and regulation of cutaneous immune responses. The probability of atopic skin diathesis can be assessed by comprehensive analysis of patient history, as well as clinical and laboratory findings, resulting in the Erlangen Atopy Score (EAS). Objectives To investigate the impacts of (i) atopic skin diathesis according to the EAS and (ii) the physician-assessed diagnoses 'atopic dermatitis', 'allergic rhinitis' and 'allergic asthma' on SLS skin reactions. Methods This is a retrospective analysis of data from 2030 consecutive patients patch tested with SLS (0 center dot 25% aqueous) from two tertiary referral centres in Germany, from 2008 to 2014. Results Patients with a high probability of atopic skin diathesis showed no significant increase in positive SLS reactions compared with patients without atopic skin diathesis (14 center dot 2% vs. 16 center dot 8%). The grading of positive SLS skin reactions (1-4) revealed no differences in patients with or without atopic skin diathesis. Furthermore, diagnoses of atopic dermatitis, allergic rhinitis or allergic asthma had no impact on positive SLS skin reactions in multivariate logistic regression analysis. Conclusions We found no association of increased skin irritability to SLS with atopic skin diathesis, atopic dermatitis, allergic rhinitis or allergic asthma in a large patient cohort. It therefore seems that the test of skin irritability with SLS, which is currently common practice in many centres, does not allow prediction of susceptibility to irritant eczematous inflammation in atopic vs. nonatopic individuals. What's already known about this topic?
CRIS-Team WoS Importer:2019-12-06

Chronic hand eczema in Germany: 5-year follow-up data from the CARPE registry - Apfelbacher, Christian J.; Ofenloch, Robert F.; Weisshaar, Elke; Molin, Sonja; Bauer, Andrea; Mahler, Vera; Heinrich, Andreas; Von Kiedrowski, Ralph; Schmitt, Jochen; Elsner, Peter; Diepgen, Thomas L. (Contact Dermatitis, 2019)
Background: The CARPE registry was set up in 2009 to prospectively investigate the management of patients with chronic hand eczema (CHE). Objectives: To report comprehensive follow-up data from the CARPE registry. Patients and methods: We investigated sociodemographic and clinical characteristics, provision of medical care, physician-assessed outcomes, and patient-reported outcomes (PROs). Data were collected between 2009 and 2016, with up to 5 years of follow-up, and are reported descriptively. Results: Overall, 1281 patients were included in the registry (53.7% female). Mean age was 47.0 years. Of the patients, 793 and 231 completed the 2-year follow-up and 5-year follow-up, respectively. At baseline, 5.4% had changed or given up their job because of CHE, the average duration of CHE was 6.1 years, and, in 22.4%, the CHE was severe according to physician global assessment. Systemic treatment (alitretinoin, acitretin, and methotrexate) was prescribed at least once to 39.0% of the patients during the course of the follow-up. Disease severity, quality of life and treatment satisfaction improved over time, and the proportion of patients receiving systemic treatments decreased. Conclusions: Under continued dermatological care, substantial improvements in disease severity and PROs over time was achieved during the course of the CARPE registry, even in patients with long-standing and severe hand eczema.
CRIS-Team Scopus Importer:2019-05-24
Keywords: hand eczema; quality of life; registry; treatment

Contact allergy induced by bisphenol A diglycidyl ether leachables from aluminium tubes for pharmaceutical use - Breuer, K.; Lipperheide, C.; Lipke, U.; Zapf, T.; Dickel, H.; Treudler, R.; Molin, S.; Mahler, Vera; Pfoehler, C.; Loeffler, H.; Schwantes, H.; Schnuch, A. (Allergy, 2015)
Aluminium tubes for pharmaceutical use are internally lacquered with epoxy resins (ER) based on bisphenol A diglycidyl ether (BADGE). Recently, it was shown that remnants of ER polymerization like BADGE are extractable from epoxy-based coatings of commercially available tubes and may leach into semi-solid drug preparations. We aimed to evaluate the safety of BADGE-contaminated macrogol ointments in individuals sensitized to ER based on BADGE by use tests.Repeated open application testing (ROAT) in 11 patients sensitized to ER based on BADGE with BADGE in macrogol ointments (3 mg/kg; 30 mg/kg, equivalent to BADGE concentration determined in macrogol ointment after storage in a commercially available tube; 300 mg/kg).The 30 mg/kg BADGE ointment elicited reactions in three patients, and another three patients reacted to 300 mg/kg BADGE ointment. No reactions to the vehicle control and 3 mg/kg BADGE were observed.Elevated BADGE concentrations in ER-coated aluminium tubes pose a risk of developing contact dermatitis to patients sensitized to ER based on BADGE. Quality standards are deemed necessary for the production of ER-coated aluminium tubes intended for pharmaceutical use and should consider the results of the present ROAT study.
EVALuna2:19547

Contact allergy to preservatives: ESSCA* results with the baseline series, 2009-2012 - Gimenez-Arnau, A. M.; Deza, G.; Bauer, A.; Johnston, G. A.; Mahler, Vera; Schuttelaar, M. -L.; Sanchez-Perez, J.; Silvestre, J. F.; Wilkinson, M.; Uter, Wolfgang (Journal of the European Academy of Dermatology and Venereology, 2017)
BACKGROUND: Allergic contact dermatitis caused by biocides is common and causes significant patient morbidity. OBJECTIVE: To describe the current frequency and pattern of patch test reactivity to biocide allergens included in the baseline series of most European countries. METHODS: Data collected by the European Surveillance System on Contact Allergies (ESSCA) network between 2009 and 2012 from 12 European countries were analysed. RESULTS: Methylisothiazolinone 0.2% aq. produced the highest prevalence of sensitization during the study period, with an overall prevalence of 4.5%. The mixture methylchloroisothiazolinone /methylisothiazolinone tested at 0.02% aq. followed closely, with 4.1% of positive reactions. Other preservatives with lower rates of sensitization, but still over 1%, include methyldibromo glutaronitrile (MDBGN) 0.5% pet. and iodopropynyl butylcarbamate (IPBC) 0.2% pet. Formaldehyde releasers and parabens yielded less than 1% positive reactions during the study period. Some regional differences in the prevalence of contact allergy to biocides among European countries were observed. CONCLUSIONS: Contact allergy to biocides is common throughout Europe, and regional differences could be explained by differences in exposure or characteristics of the population tested. Timely regulatory action for isothiazolinones is required. Although MDBGN is banned from cosmetics products since 2005, sensitization prevalence has not appeared to plateau. IPBC is an emerging allergen with an increasing prevalence over the last few years, and its inclusion in the European baseline series may be appropriate.
EVALuna2:34200

Contact sensitization in metalworkers: Data from the information network of departments of dermatology (IVDK), 2010–2018 - Schubert, Steffen; Brans, Richard; Reich, Anna; Buhl, Timo; Skudlik, Christoph; Schröder-Kraft, Claudia; Gina, Michal; Weisshaar, Elke; Mahler, Vera; Dickel, Heinrich; Schön, Michael P.; John, Swen M.; et al. (Contact Dermatitis, 2020)
Background: Metalworkers are exposed to a variety of contact allergens by handling tools, metals, metalworking fluids (MWFs), oils and greases, rubber materials, and so on. Most large-scale reports on contact allergy due to MWFs are more than 10-years-old, and there are only few studies on contact allergy in mechanics and other metal workers not exposed to MWFs. Objectives: To describe a current spectrum of contact sensitization in metalworkers with occupational dermatitis (OD). Patients and Methods: Retrospective analysis of patch test data collected by the Information Network of Departments of Dermatology (IVDK; 2010–2018), stratifying for 804 cutting metalworkers, 2197 mechanics, and 355 other metalworkers. Results: Cutting metalworkers were most frequently sensitized to monoethanolamine (12.6%), colophonium/abietic acid (11.4%) and formaldehyde releasers (up to 8.5%) from the MWF series, and formaldehyde (4.6%) and iodopropynyl butylcarbamate (4.6%) from the baseline series. Sensitization among mechanics and other metalworkers indicates possible occupational exposure to MWFs, glues, and resins, although this may not be expected from their job titles. Conclusions: The spectrum of MWF contact allergens remained largely unchanged during the last years. Taking a comprehensive occupational history is indispensable in order to not miss relevant allergen exposures.
CRIS-Team Scopus Importer:2020-10-16
Keywords: colophonium; formaldehyde releaser; iodopropynyl butylcarbamate; mechanics; metalworkers; metalworking fluid; monoethanolamine; occupational dermatitis

Developing a cosmetic series: Results from theESSCAnetwork, 2009-2018 - Horton, Emma; Uter, Wolfgang; Geier, Johannes; Ballmer-Weber, Barbara; Bauer, Andrea; Bircher, Andreas; Dickel, Heinrich; Gimenez-Arnau, Ana; Goncalo, Margarida; John, Swen Malte; Mahler, Vera; Schuttelaar, Marie L. A.; et al. (Contact Dermatitis, 2020)
Background There is considerable variability across European patch test centres as to which allergens are included in local and national cosmetics series. Objectives To propose a standardized, evidence-based cosmetic series for Europe based on up-to-date analysis of relevant contact allergens. Methods We collated data from the European Surveillance System on Contact Allergies (ESSCA) from 2009 to 2018 to determine which cosmetic allergens produce a high yield of contact allergy. Contact allergens with a prevalence of >0.3% that were considered relevant were included. Rare contact allergens were excluded if deemed no longer relevant or added to a supplemental cosmetic series for further analysis. Results Sensitization prevalences of 39 cosmetic contact allergens were tabulated. Thirty of these allergens yielded >0.3% positive reactions and are therefore included in our proposed European cosmetic series. Six were considered no longer relevant and therefore excluded. Three were included in a supplementary European cosmetic series. An additional nine allergens were included in either the core or supplemental European cosmetic series following literature review. Conclusion We have derived a potential European cosmetic series based upon the above methods. This will require ongoing investigation based upon the changing exposure profiles of cosmetic allergens as well as new and evolving substances.
CRIS-Team WoS Importer:2020-10-16

DKG statement on the use of metal alloy discs for patch testing in suspected intolerance to metal implants - Thomas, Peter; Geier, Johannes; Dickel, Heinrich; Diepgen, Thomas; Hillen, Uwe; Kreft, Burkhard; Schnuch, Axel; Szliska, Christiane; Mahler, Vera (Journal der Deutschen Dermatologischen Gesellschaft, 2015)
Intolerance reactions to metal implants may be caused by metal allergy. However, prior to implantation, 'prophetic'/prophylactic patch testing should not be performed. Pre-implant patch testing should only be done to verify or exclude metal allergy in patients with a corresponding history. In case of implant-related complications - in particular following replacement arthroplasty - such as pain, effusion, skin lesions, reduced range of motion or implant loosening, orthopedic causes should be ruled out first. Workup of suspected metal implant allergy should then be done using the DKG standard series, which includes nickel, cobalt, and chromium preparations. Various studies assessing the usefulness of metal alloy discs for patch testing have shown this particular approach to be ineffective with respect to providing reliable information on metal allergy. Any positive reaction in such tests cannot be assigned to a specific metal contained within the alloy. Furthermore, there is a risk of broad and indiscriminate use of these readily available discs. Accordingly, given the lack of additional benefit compared to patch testing with standardized metal salt preparations, we do not recommend patch testing with metal alloy discs.
EVALuna2:19562

Efficacy and safety of topical delgocitinib in patients with chronic hand eczema: data from a randomized, double-blind, vehicle-controlled phase IIa study - Worm, M.; Bauer, A.; Elsner, P.; Mahler, Vera; Molin, S.; Nielsen, T. S. S. (British Journal of Dermatology, 2019)
Background Management of chronic hand eczema (CHE) remains a challenge; effective topical treatment is limited to corticosteroids. Objectives To assess the efficacy and safety of a novel, pan-Janus kinase inhibitor (delgocitinib) in patients with CHE. Methods In this randomized, double-blind, phase IIa study, patients with CHE received delgocitinib ointment 30 mg g(-1) or vehicle ointment for 8 weeks. The primary end point was the proportion of patients achieving treatment success ['clear'/'almost clear' skin with >= 2-point improvement in the Physician's Global Assessment of disease severity (PGA)] at week 8. Secondary end points included Hand Eczema Severity Index (HECSI) score changes and the proportion of patients achieving treatment success on the Patient's Global Assessment of disease severity (PaGA). Results Ninety-one patients were randomized. More patients receiving delgocitinib (46%) than vehicle (15%) [odds ratio 4 center dot 89, 95% confidence interval (CI) 1 center dot 49-16 center dot 09; P = 0 center dot 009] achieved treatment success (PGA). Adjusted mean HECSI score at week 8 was lower with delgocitinib (13 center dot 0) than with vehicle (25 center dot 8) (adjusted mean difference -12 center dot 88, 95% CI -21 center dot 47 to -4 center dot 30; P = 0 center dot 003). More patients receiving delgocitinib than vehicle achieved treatment success by PaGA, but this did not reach statistical significance. The incidence of adverse events was similar with delgocitinib and vehicle; none led to discontinuation of delgocitinib. Conclusions Delgocitinib ointment was efficacious and well tolerated. As a plateau of efficacy was not observed, a longer treatment period may lead to increased efficacy. Further clinical studies are warranted to confirm these findings in patients with CHE.
CRIS-Team WoS Importer:2019-11-19

Factors increasing the risk for a severe reaction in anaphylaxis: An analysis of data from The European Anaphylaxis Registry - Worm, M.; Francuzik, Wojciech; Renaudin, J. -M.; Bilo, M. B.; Cardona, V.; Hofmeier, K. Scherer; Kohli, A.; Bauer, A.; Christoff, G.; Cichocka-Jarosz, E.; Hawranek, T.; Hourihane, J. O. 'B.; et al. (Allergy, 2018)
BACKGROUND: Preventive measures to decrease the frequency and intensity of anaphylactic events are essential to provide optimal care for allergic patients. Aggravating factors may trigger or increase the severity of anaphylaxis and therefore need to be recognized and avoided. OBJECTIVE: To identify and prioritize factors associated with an increased risk of developing severe anaphylaxis. METHODS: Data from the Anaphylaxis Registry (122 centers in 11 European countries) were used in logistic regression models considering existing severity grading systems, elicitors, and symptoms to identify the relative risk of factors on the severity of anaphylaxis. RESULTS: We identified higher age and concomitant mastocytosis (OR: 3.1, CI: 2.6-3.7) as the most important predictors for an increased risk of severe anaphylaxis. Vigorous physical exercise (OR: 1.5, CI: 1.3-1.7), male sex (OR: 1.2, CI: 1.1-1.3), and psychological burden (OR: 1.4, CI: 1.2-1.6) were more often associated with severe reactions. Additionally, intake of beta-blockers (OR: 1.9, CI: 1.5-2.2) and ACE-I (OR: 1.28, CI: 1.05, 1.51) in temporal proximity to allergen exposition was identified as an important factor in logistic regression analysis. CONCLUSION: Our data suggest it may be possible to identify patients who require intensified preventive measures due to their relatively higher risk for severe anaphylaxis by considering endogenous and exogenous factors.
EVALuna2:34790

Formaldehyde 2% is not a useful means of detecting allergy to formaldehyde releasers— results of the ESSCA network, 2015-2018 - Whitehouse, Heather; Uter, Wolfgang; Geier, Johannes; Ballmer-Weber, Barbara; Bauer, Andrea; Cooper, Susan; Czarnecka-Operacz, Magdalena; Dagmar, Simon; Dickel, Heinrich; Fortina, Anna Belloni; Gallo, Rosella; Gimenez-Arnau, Ana Maria; et al. (Contact Dermatitis, 2020)
Background: Studies suggest that patch testing with formaldehyde releasers (FRs) gives significant additional information to formaldehyde 1% aq. and should be considered for addition to the European baseline series (EBS). It is not known if this is also true for formaldehyde 2% aq. Objectives: To determine the frequency of sensitization to formaldehyde 2% aq. and co-reactivity with FRs. To establish whether there is justification for including FRs in the EBS. Materials and Methods: A 4-year, multi-center retrospective analysis of patients with positive patch test reactions to formaldehyde 2% aq. and five FRs. Results: A maximum of 15 067 patients were tested to formaldehyde 2% aq. and at least one FR. The percentage of isolated reactions to FR, without co-reactivity to, formaldehyde 2% aq. for each FR were: 46.8% for quarternium-15 1% pet.; 67.4% imidazolidinyl urea 2% pet.; 64% diazolidinyl urea 2% pet.; 83.3% 1,3-dimethylol-5, 5-dimethyl hydantoin (DMDM) hydantoin 2% pet. and 96.3% 2-bromo-2-nitropropane-1,3-diol 0.5% pet. This demonstrates that co-reactivity varies between FRs and formaldehyde, from being virtually non-existent in 2-bromo-2-nitropropane-1,3-diol 0.5% pet. (Cohen's kappa: 0, 95% confidence interval [CI] −0.02 to 0.02)], to only weak concordance for quaternium-15 [Cohen's kappa: 0.22, 95%CI 0.16 to 0.28)], where Cohen's kappa value of 1 would indicate full concordance. Conclusions: Formaldehyde 2% aq. is an inadequate screen for contact allergy to the formaldehyde releasers, which should be considered for inclusion in any series dependant on the frequency of reactions to and relevance of each individual allergen.
CRIS-Team Scopus Importer:2020-10-23
Keywords: 2-bromo-2-nitropropane-1; 3-diol; contact allergy; cosmetics; diazolidinyl urea; DMDM hydantoin; formaldehyde formaldehyde releasers; imidazolidinyl urea; quaternium-15

Guideline on diagnostic procedures for suspected hypersensitivity to beta-lactam antibiotics: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in collaboration with the German Society of Allergology (AeDA), German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Austrian Society for Allergology and Immunology (ÖGAI), and the Paul-Ehrlich Society for Chemotherapy (PEG) - Wurpts, Gerda; Aberer, Werner; Dickel, Heinrich; Brehler, Randolf; Jakob, Thilo; Kreft, Burkhard; Mahler, Vera; Merk, Hans F.; Mülleneisen, Norbert; Ott, Hagen; Pfützner, Wolfgang; Röseler, Stefani; et al. (Allergo Journal, 2019)
This guideline on diagnostic procedures for suspected beta-lactam antibiotic (BLA) hypersensitivity was written by the German and Austrian professional associations for allergology, and the Paul-Ehrlich Society for Chemotherapy in a consensus procedure according to the criteria of the German Association of Scientific Medical Societies. BLA such as penicillins and cephalosporins represent the drug group that most frequently triggers drug allergies. However, the frequency of reports of suspected allergy in patient histories clearly exceeds the number of confirmed cases. The large number of suspected BLA allergies has a significant impact on, e.g., the quality of treatment received by the individual patient and the costs to society as a whole. Allergies to BLA are based on different immunological mechanisms and often manifest as maculopapular exanthema, as well as anaphylaxis; and there are also a number of less frequent special clinical manifestations of drug allergic reactions. All BLA have a beta-lactam ring. BLA are categorized into different classes: penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors with different chemical structures. Knowledge of possible cross-reactivity is of considerable clinical significance. Whereas allergy to the common beta-lactam ring occurs in only a small percentage of all BLA allergic patients, cross-reactivity due to side chain similarities, such as aminopenicillins and aminocephalosporins, and even methoxyimino cephalosporins, are more common. However, the overall picture is complex and its elucidation may require further research. Diagnostic procedures used in BLA allergy are usually made up of four components: patient history, laboratory diagnostics, skin testing (which is particularly important), and drug provocation testing. The diagnostic approach—even in cases where the need to administer a BLA is acute—is guided by patient history and risk–benefit ratio in the individual case. Here again, further studies are required to extend the present state of knowledge. Performing allergy testing for suspected BLA hypersensitivity is urgently recommended not only in the interests of providing the patient with good medical care, but also due to the immense impact of putative BLA allergies on society as a whole.
CRIS-Team Scopus Importer:2019-08-02
Keywords: Allergy; Beta-lactam antibiotics; Cephalosporin; Drug hypersensitivity; Penicillin

H1-antihistamine-refractory chronic spontaneous urticaria: it's worse than we thought - first results of the multicenter real-life AWARE study - Maurer, M.; Staubach, P.; Raap, U.; Richter-Huhn, G.; Bauer, A.; Rueff, F.; Jakob, T.; Yazdi, A. S.; Mahler, Vera; Wagner, N.; Lippert, U.; Hillen, U.; et al. (Clinical and Experimental Allergy, 2017)
BACKGROUND: Most data on chronic spontaneous urticaria (CSU) originate from highly selected patient populations treated at specialized centres. Little is known about CSU patient characteristics and the burden of CSU in routine clinical practice. AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is an ongoing global study designed to assess chronic urticaria in the real-life setting. OBJECTIVE: To describe the baseline characteristics of the first 1539 German AWARE patients with H1-antihistamine-refractory CSU. METHODS: This prospective non-interventional study included patients (18-75 years) with a diagnosis of H1-antihistamine-refractory CSU for > 2 months. Baseline demographic and disease characteristics, comorbidities, and pharmacological treatments were recorded. Quality of life (QoL) was assessed using the dermatology life quality index (DLQI), chronic urticaria QoL questionnaire (CU-Q2 oL), and angioedema QoL questionnaire (AE-QoL, in cases of angioedema). Previous healthcare resource utilization and sick leave data were collected retrospectively. RESULTS: Between March and December 2014, 1539 patients were assessed in 256 sites across Germany. The percentage of females, mean age, and mean body mass index were 70%, 46.3 years, and 27 kg/m2 , respectively. The mean urticaria control test score was 7.9, one in two patients had angioedema, and the most frequent comorbidities were chronic inducible urticaria (CIndU; 24%), allergic rhinitis (18.2%), hypertension (18.1%), asthma (12%), and depression (9.5%). Overall, 57.6% of patients were receiving at least one pharmacological treatment including second-generation H1-antihistamines (46.3%), first-generation H1-antihistamines (9.1%), and corticosteroids (15.8%). The mean DLQI, total CU-Q2 oL, and total AE-QoL scores were 8.3, 36.2, and 46.8, respectively. CSU patients reported frequent use of healthcare resources, including emergency services (29.7%), general practitioners (71.9%), and additional allergists or dermatologists (50.7%). CONCLUSIONS AND CLINICAL RELEVANCE: This study reveals that German H1-antihistamine-refractory CSU patients have high rates of uncontrolled disease, angioedema, and comorbid CIndU, are undertreated, have impaired QoL, and rely heavily on healthcare resources.
EVALuna2:35410

Hand dermatitis - differential diagnoses, diagnostics, and treatment options - Mahler, Vera (Journal der Deutschen Dermatologischen Gesellschaft, 2016)
The pathogenesis of hand dermatitis is multifactorial, and includes factors such as genetic predisposition and exposure. A high incidence rate is associated with female gender, contact allergy, atopic dermatitis, and wet work. The most important risk factors for the persistence of hand dermatitis include its extent, contact allergic or atopic etiology, childhood dermatitis, and early onset (before the age of 20). The cost of illness of hand dermatitis corresponds to this seen in moderate to severe psoriasis. The diagnostic workup of hand dermatitis and its differential diagnoses requires a detailed assessment of occupational and recreational exposure. In case of possible work-related triggers, early notification of the accident insurer should be sought (via the dermatologist's report). Exposure to a contact allergen is a contributing factor in one-half of all cases of hand dermatitis. It is therefore imperative that all patients with hand dermatitis persisting for more than three months undergo patch testing. Successful and sustainable treatment of hand dermatitis starts with the proper identification and elimination of individual triggers, including the substitution of identified contact allergens and irritants, as well as optimizing preventive measures. Graded therapy taking the clinical severity into account is essential. Validated instruments may be used to monitor therapeutic efficacy.
EVALuna2:19543

High frequency of contact allergy to implant and bone cement components, in particular gentamicin, in cemented arthroplasty with complications: usefulness of late patch test reading - Thomas, Benjamin; Kulichova, Daniela; Wolf, Ronald; Summer, Burkhard; Mahler, Vera; Thomas, Peter (Contact Dermatitis, 2015)
Arthroplasty patients with complications may be sensitized to implant components.To quantify patch test reactions to implant materials in aseptic cemented arthroplasty patients with complications, and to evaluate the benefit of late patch test reading at D6.Analyses of patch test reactions to baseline series and bone cement components and of the questionnaire-aided histories of 250 consecutive patients with suspected implant allergy were performed. Patch tests were read at D2, D3, and D6.There were 187 positive reactions to the 29 allergens of the baseline series, and 52 to the seven allergens of the bone cement series. Forty-nine of 250 patients reacted to the bone cement series. In contrast to 'early allergens' such as fragrance mix, late reading at D6 increased the number of positive reactions by 11/32 for nickel, 1/5 for cobalt, and 2/4 for chromium. With bone cement components, most reactions were to gentamicin (25 of 250 patients), and 17 of 25 appeared only at D6.Late reading is useful for patch tests with metals and bone cement components. With only D2/D3 readings, 32 reactions to nickel, cobalt, chromium and bone cement components would have been missed. This underlines the utility of late reading in general and in complicated cemented arthroplasty patients, given the unexpectedly high number of gentamicin reactions.
EVALuna2:19557

HLA class II peptide tetramers vs allergen-induced proliferation for identification of allergen-specific CD4 T cells - Van Hemelen, D.; Mahler, Vera; Fischer, G.; Fae, I.; Reichl-Leb, V.; Pickl, W.; Jutel, M.; Smolinska, S.; Ebner, C.; Bohle, B.; Jahn-Schmid, B. (Allergy, 2015)
Fluorescence-labeled MHC class II/peptide tetramer complexes are considered as optimal tools to characterize allergen-specific CD4(+) T cells, but this technique is restricted to frequently expressed HLA class II molecules and knowledge of immunodominant epitopes. In contrast, allergen-stimulated proliferation assessed by CFSE dilution is less sophisticated and widely applicable. The major mugwort allergen, Art v 1, contains only one single, immunodominant, HLA-DR1-restricted epitope (Art v 125-36 ). Thus, essentially all Art v 1-reactive cells should be identified by a HLA-DRB1*01:01/Art v 119-36 tetramer.We compared specificity and sensitivity of tetramer(+) and allergen-induced proliferating (CFSE(lo) ) CD4(+) T cells by flow cytometry.The frequency of tetramer(+) CD4(+) T cells determined ex vivo in PBMC of mugwort-allergic individuals ranged from 0 to 0.029%. After 2-3 weeks of in vitro expansion, sufficient tetramer(+) T cells for phenotyping were detected in 83% of Art v 125-36 -reactive T-cell lines (TCL) from mugwort-allergic individuals, but not in TCL from healthy individuals. The tetramers defined bona fide Th2 cells. Notably, Art v 125-36 -reactive TCL depleted of tetramer(+) T cells still reacted to the peptide, and only 44% of Art v 125-36 -specific T-cell clones were detected by the tetramer. CFSE(lo) CD4(+) T cells contained only 0.3-10.7% of tetramer(+) T cells and very low proportions of Th2 cells.Allergen-specific T cells can be identified by HLA class II tetramers with high specificity, but unexpected low sensitivity. In contrast, allergen-stimulated CFSE(lo) CD4(+) T cells contain extremely high fractions of bystander cells. Therefore, for T-cell monitoring, either method should be interpreted with caution.
EVALuna2:19542

House dust mite-specific immunotherapy with two licensed vaccines: Outcome under clinical routine conditions - Mahler, Vera; Klein, Christian; Sager, Angelika; Zimmermann, Juergen (Immunity, Inflammation and Disease, 2017)
INTRODUCTION: House dust mite (HDM) allergens are major causes for the development of allergic diseases. A disease modifying effect and clinical benefit of allergen immunotherapy (AIT) has been demonstrated in a number of clinical trials. Clinical trials, however, are carried out in selected populations under specific conditions based on inclusion and exclusion criteria and may not represent the entire patient population from medical practice. Objective of this study conducted in patients with HDM allergy was to systematically collect information about the benefit of AIT under clinical routine conditions. METHODS: In this prospective, multi-center non-interventional study, 220 patients (117 adults, 103 children) with HDM allergy receiving subcutaneous AIT with Depigoid® were monitored for 2 years. Organ-specific key symptoms, health-related quality of life (QoL), and the use of concomitant anti-allergic medication were assessed at baseline and after 12 and 24 months. Effectiveness and tolerability of the AIT was assessed by physicians and patients. Occurrence of adverse events (AEs) was continuously monitored. RESULTS: Two hundred and nineteen patients (116 adults, 103 children) were evaluated. A major improvement of the total symptom-score was observed after 24 (12) months in 76% (72%) and 80% (79%) of adults and children, respectively, accompanied by a reduction in concomitant anti-allergic medication and a pronounced improvement in QoL. The effectiveness and tolerability of the AIT was estimated as very good/good by 80-90% of physicians and patients. AEs were observed in 4/117 adults (3.4%) and in 7/103 children (6.8%). Serious AEs were reported in three adults and one child: A grade-II anaphylactic reaction (one adult) controlled by oral antihistamines (no hospitalization) classified as "definitely," three others as not (2) or possibly (1) drug-related. CONCLUSIONS: The data collected from 220 patients confirm the efficacy, tolerability/safety, and acceptance of AIT with Depigoid® in adults and children with HDM allergy under routine clinical conditions.
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