In vitro assessment of checkpoint-induced cytokine levels as new tool in the therapeutic decision-making process after checkpoint-induced cytokine release syndrome in metastatic melanoma - Kramer, Rafaela; Bender-Säbelkampf, Sophia; Berking, Carola; Heppt, Markus; Erdmann, Michael; Bosch-Voskens, Caroline (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner. - Albert, Heike; Collin, Mattias; Dudziak, Diana; Ravetch, J. V.; Nimmerjahn, Falk (Proceedings of the National Academy of Sciences of the United States of America, 2008)
IgG antibodies are potent inducers of proinflammatory responses. During autoimmune diseases such as arthritis and systemic lupus erythematosus, IgG autoantibodies are responsible for the chronic inflammation and destruction of healthy tissues by cross-linking Fc receptors on innate immune effector cells. The sugar moiety attached to the asparagine-297 residue in the constant domain of the antibody is critical for the overall structure and function of the molecule. Removal of this sugar domain leads to the loss of the proinflammatory activity, suggesting that in vivo modulation of antibody glycosylation might be a strategy to interfere with autoimmune processes. In this work, we investigated whether removal of the majority of the IgG-associated sugar domain by endoglycosidase S (EndoS) from Streptococcus pyogenes is able to interfere with autoimmune inflammation. We demonstrate that EndoS injection efficiently removes the IgG-associated sugar domain in vivo and interferes with autoantibody-mediated proinflammatory processes in a variety of autoimmune models. Importantly, however, we observed a differential impact of EndoS-mediated sugar side chain hydrolysis on IgG activity depending on the individual IgG subclass.

Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma - Zimmer, Lisa; Apuri, Susmitha; Eroglu, Zeynep; Kottschade, Lisa A.; Forschner, Andrea; Gutzmer, Ralf; Schlaak, Max; Heinzerling, Lucie; Krackhardt, Angela M.; Loquai, Carmen; Markovic, Svetomir N.; Joseph, Richard W.; et al. (European Journal of Cancer, 2017)
BACKGROUND: The anti-programmed cell death-1 (PD-1) inhibitors pembrolizumab and nivolumab alone or in combination with ipilimumab have shown improved objective response rates and progression-free survival compared to ipilimumab only in advanced melanoma patients. Anti-PD-1 therapy demonstrated nearly equal clinical efficacy in patients who had progressed after ipilimumab or were treatment-naïve. However, only limited evidence exists regarding the efficacy of ipilimumab alone or in combination with nivolumab after treatment failure to anti-PD-therapy. PATIENTS AND METHODS: A multicenter retrospective study in advanced melanoma patients who were treated with nivolumab (1 or 3 mg/kg) and ipilimumab (1 mg or 3 mg/kg) or ipilimumab (3 mg/kg) alone after treatment failure to anti-PD-1 therapy was performed. Patient, tumour, pre- and post-treatment characteristics were analysed. RESULTS: In total, 47 patients were treated with ipilimumab (ipi-group) and 37 patients with ipilimumab and nivolumab (combination-group) after treatment failure to anti-PD-1 therapy. Overall response rates for the ipi- and the combination-group were 16% and 21%, respectively. Disease control rate was 42% for the ipi-group and 33% for the combination-group. One-year overall survival rates for the ipi- and the combination-group were 54% and 55%, respectively. CONCLUSIONS: Ipilimumab should be considered as a viable treatment option for patients with failure to prior anti-PD-1 therapy, including those with progressive disease as best response to prior anti-PD-1. In contrast, the combination of ipilimumab and nivolumab appears significantly less effective in this setting compared to treatment-naïve patients.
EVALuna2:34335

Ipilimumab in metastatic melanoma patients with pre-existing autoimmune disorders - Kaehler, Katharina C.; Eigentler, Thomas K.; Gesierich, Anja; Heinzerling, Lucie; Loquai, Carmen; Meier, Friedegund; Meiss, Frank; Pfoehler, Claudia; Schlaak, Max; Terheyden, Patrick; Thoms, Kai M.; Ziemer, Mirjana; et al. (Cancer Immunology, Immunotherapy, 2018)
BACKGROUND: Ipilimumab and programmed death (PD) 1-antibodies are effective treatment options in metastatic melanoma. The safety and efficacy of ipilimumab in patients with pre-existing autoimmune disorders (AD) has only been evaluated in a selected number of patients. METHODS: We performed a retrospective analysis in 14 German skin cancer centers for patients with metastatic melanoma and pre-existing AD treated with ipilimumab. RESULTS: 41 patients with 44 pre-existing AD were treated with ipilimumab (thyroiditis n = 15, rheumatoid n = 11, dermatologic n = 10, Crohn's disease/ulcerative colitis n = 3, neurological n = 2, sarcoidosis n = 2, pancreatitis n = 1). 3 out of 41 patients had two AD, 11 patients required immunosuppressants at the time of induction of ipilimumab. 12 patients (29.2%) experienced a flare of their pre-existing AD, mainly patients with rheumatoid or dermatologic diseases. Additional immune-related adverse events (irAEs) occurred in 12 patients (29.2%). In 23 patients (56%) neither a change of their AD nor additional irAEs were observed. Objective responses were seen in five patients (one complete remission, four partial remissions, 12.1%). CONCLUSION: This is the largest series of patients with pre-existing AD and treatment with ipilimumab reported. Flares of pre-existing AD were observed but manageable. Response rates and occurrence of new irAEs were comparable to previous trials. Thus, in this patient subgroup, ipilimumab can be a treatment option after a thorough discussion of pros and cons and taking severity and activity of the preexisting AD into account.
EVALuna2:34383

Isolated melanoma cells in sentinel lymph node in stage IIIA melanoma correlate with a favorable prognosis similar to stage IB - Amaral, Teresa; Nanz, Lena; Stadler, Rudolf; Berking, Carola; Ulmer, Anja; Forschner, Andrea; Meiwes, Andreas; Wolfsperger, Frederik; Meraz-Torres, Francisco; Chatziioannou, Eftychia; Martus, Peter; Flatz, Lukas; et al. (European Journal of Cancer, 2024)
Background: The American Joint Committee on Cancer 8th edition (AJCC v8) defines sentinel lymph nodes (SLN) containing any tumor cells as positive SLN. Consequently, even thin melanomas with isolated tumor cells (ic) in SLN are classified as stage IIIA, making them candidates for adjuvant therapy. Objectives and endpoints: We aimed to evaluate survival outcomes of melanoma stage IIIA (ic) and compare them with stage IIIA with lymph node (LN) metastases > 0.1 mm. Primary endpoints were relapse-free survival (RFS) and distant metastases-free survival (DMFS). Secondary endpoint was melanoma specific survival (MSS). Results: The discovery cohort from the Department of Dermatology, University Hospital Tuebingen, included 237 patients; confirmation cohort included 143 patients from the DeCOG trial. The Tuebingen cohort included 95 patients with stage IIIA (ic) and 142 patients with stage IIIA. The DeCOG trial included 39 patients with stage IIIA (ic) and 104 patients with stage IIIA. In the Tuebingen cohort, 10-year RFS rates for stage IIIA (ic) and IIIA were 84% (95% CI 75–94) and 49% (95% CI 39–59), respectively (p < 0.001). 10-year DMFS rates for stage IIIA (ic) and IIIA were 89% (95% CI 81–97) and 56% (95% CI 45–67), respectively; (p < 0.001). In the DeCOG cohort, 10-year RFS for stage IIIA (ic) and stage IIIA were 88% (95% CI 78–99) and 35% (95% CI 7–62), respectively; (p = 0.009). 10-year DMFS for stage IIIA (ic) and IIIA was 88% (95% CI 77–99) and 60% (95% CI 39–80), respectively (p = 0.061). Conclusion: Stage IIIA (ic) melanoma exhibits a prognosis similar to stage IB. Recommendation of adjuvant therapy in Stage IIIA (ic) warrants thorough discussion.
CRIS-Team Scopus Importer:2024-03-01
Keywords: Adjuvant therapy; Early stage; Isolated cells; Melanoma; Sentinel lymph node biopsy

Is tebentafusp superior to combined immune checkpoint blockade and other systemic treatments in metastatic uveal melanoma? A comparative efficacy analysis with population adjustment - Petzold, Anne; Steeb, Theresa; Wessely, Anja; Koch, Elias; Vera, Julio; Berking, Carola; Heppt, Markus (Cancer Treatment Reviews, 2023)
Background: Distinct systemic treatments exist for metastatic uveal melanoma. Tebentafusp and combined immune checkpoint blockade (ICB) with ipilimumab plus anti-PD-1 antibodies are the most commonly used treatment options but their comparative efficacy is unclear. The aim of this study is to compare currently available systemic treatments regarding overall survival (OS) and progression-free survival (PFS) with a focus on the comparison of tebentafusp versus combined ICB. Methods: The protocol for this study was defined a priori and registered online in the PROSPERO international prospective register of systematic reviews (CRD42022308356, date of registration: 7.2.2022). We performed a systematic literature search in Medline, Embase, and Central to identify eligible studies reporting Kaplan-Meier curves or individual-level survival data showing OS and PFS for metastatic uveal melanoma patients treated with systemic treatments. Kaplan-Meier curves were digitized using the “WebPlotDigitizer” program. Individual-level survival data were subsequently remodelled and pooled for distinct treatment groups. To compare the OS of tebentafusp versus combined ICB, we used matching-adjusted indirect comparison (MAIC), two-stage MAIC (2SMAIC), and simulated treatment comparison (STC) together with digitized individual-level survival data as population-adjusted models. Results: Overall, 55 independent studies were included of which 2,682 patients were evaluable for OS and 2,258 for PFS. Tebentafusp showed the highest median OS (mOS) of 22.4 months (95% confidence interval (CI): 19.9–29.6) compared to combined ICB (mOS: 15.7 months (95% CI: 14.4–17.9)), anti-PD-(L)1 antibody (mOS: 10.9 months (95% CI: 9.8–13.4)), chemotherapy (mOS: 9.95 months (95% CI: 8.9–11.2)), targeted therapies (mOS: 8.86 months (95% CI: 7.5–10.8)), and anti-CTLA-4 antibody (mOS: 7.8 months (95% CI: 6.8–9.3). The median PFS (mPFS) was similar among the treatment groups ranging from 2.7 months to 3.4 months. For the comparison of tebentafusp versus combined ICB, the hazard ratio (HR) was 0.641 (95% CI: 0.449–0.915) in the unadjusted model, whereas the population-adjusted models showed a HR of 0.386 (95% CI: 0.236–0.631) using MAIC, 0.378 (95% CI: 0.234–0.612) applying 2SMAIC and 0.284 (95% CI: 0.184–0.440) using STC. Conclusions: Tebentafusp achieved the best results compared to combined ICB and other systemic treatments, although these results have to be interpreted with caution due to the approximative methodical approach and high heterogeneity of included studies.
CRIS-Team Scopus Importer:2023-03-23
Keywords: Immune checkpoint blockade; Individual patient data; Population-adjusted models; Survival; Tebentafusp; Uveal melanoma

Itching and Neurodermatitis: Results from the German Neurodermatitis Register TREATgermany - Haufe, Eva; Heinrich, Luise; Weisshaar, Elke; Abraham, Susanne; Heratizadeh, Annice; Harder, Inken; Kleinheinz, Andreas; Wollenberg, Andreas; Wiemers, Franca; Augustin, Matthias; Zink, Alexander; Von Kiedrowski, Ralph; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-02-28

Itching and treatments in atopic dermatitis (AD): results from the German AD registry TREATgermany - Weisshaar, Elke; Bentz, Philipp; Haufe, Eva; Heinrich, Luise; Apfelbacher, Christian; Heratizadeh, Annice; Abraham, Susanne; Harder, Inken; Kleinheinz, Andreas; Wollenberg, Andreas; Schäkel, Knut; Wiemers, Franca; et al. (British Journal of Dermatology, 2023)
CRIS-Team Scopus Importer:2023-05-05

Itching in Atopic Dermatitis: Patient-and Physician-reported Outcomes in the German Atopic Dermatitis Registry TREATgermany - Weisshaar, Elke; Bentz, Philipp; Apfelbacher, Christian; Haufe, Eva; Heinrich, Luise; Heratizadeh, Annice; Abraham, Susanne; Harder, Inken; Kleinheinz, Andreas; Wollenberg, Andreas; Schäkel, Knut; Wiemers, Franca; et al. (Acta Dermato-Venereologica, 2023)
TREATgermany is an investigator-initiated prospective disease registry. It investigates physician-and patient-reported disease severity (Eczema Area and Severity Index (EASI), objective Scoring Atopic Dermatitis (oSCORAD), Investigator Global Assessment, Patient-Oriented Eczema Measure (POEM), Patient Global Assessment (PGA)), patient-reported symptoms (itch, sleep loss, depressive symptoms), therapy courses and dermatological quality of life (DLQI) in moderate-to-severe atopic dermatitis with SCORAD > 20. 1,134 atopic dermatitis patients (mean age 41.0 ± 14.7 years, 42.5% females) were enrolled by 40 German recruiting sites (dermatological clinics and practices) between June 2016 and April 2021. The cur-rent analysis focuses on itch scores obtained with a numerical rating scale (NRS)) documented for the pre-vious 3 days prior to baseline visit. The results show that 97.2% (1,090 of 1,121) patients experienced itch. Itch severity correlated moderately with severity of atopic dermatitis oSCORAD (rho = 0.44 (0.39–0.48)) and EASI score (rho = 0.41 (0.36–0.46)). A strong cor-relation was found with self-reported disease severity as PGA (rho = 0.68 (0.65–0.71)), POEM sum score (rho = 0.66 (0.63–0.69)) and dermatological quality of life impairment DLQI (rho = 0.61 (0.57–0.65)). Itch as a subjective complaint is more closely correlated with patient-reported outcomes than with objective assessments by the physician.
CRIS-Team Scopus Importer:2023-02-10
Keywords: EASI; POEM; pruritus; quality of life; registry

Itching in patients with chronic hand eczema: data from the CARPE registry - Ruppert, Linda; Apfelbacher, Christian; Molin, Sonja; Bauer, Andrea; Mahler, Vera; Schmitt, Jochen; Elsner, Peter; Diepgen, Thomas L.; Weisshaar, Elke (Dermatology, 2014)
Itching is a leading symptom of chronic hand eczema (CHE) having a great impact on patients. The determinants of itching in CHE are unclear.We performed a cross-sectional analysis investigating factors associated with the presence and severity of itch in CHE patients from the CARPE registry.We present baseline data on itch in relationship with sociodemographic factors, severity of CHE, atopy, contact allergy, treatment and patient- reported outcomes including health-related quality of life (HRQoL).Of 1,051 patients with CHE, 78.1% reported itching. Significant positive associations with itching were observed for younger age groups (17-25 and 26-45 years), for moderate, severe and very severe CHE and for small/moderate impairment in HRQoL. Atopic skin diathesis, hardly being able to realize treatment recommendations and very or extremely large impairments in HRQoL were associated with itch severity.Taking the identified variables into account may help identify vulnerable groups most affected by (severe) itch.
EVALuna2:19506

Itch, sleep loss, depressive symptoms, fatigue, and productivity loss in patients with moderate-to-severe atopic dermatitis: Analyses of TREATgermany registry data - Birkner, Thomas; Siegels, Doreen; Heinrich, Luise; Haufe, Eva; Abraham, Susanne; Heratizadeh, Annice; Harder, Inken; Bell, Magnus; Fell, Isabell; Worm, Margitta; Handrick, Christiane; Effendy, Isaak; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
Background: TREATgermany is a multicenter registry including patients with moderate-to-severe atopic dermatitis (AD) from currently 74 study centers (university clinics, hospitals and practices) in Germany. As of August 31, 2021, 1,230 adult patients were enrolled. Methods: In TREATgermany, patients and physicians fill in questionnaires pertaining to symptoms, disease severity, quality of life, depressiveness, and fatigue. In particular, limitations in work performance are assessed using the Work Limitations Questionnaire (WLQ). To assess associations between occupational performance/work limitations and symptoms, correlations and regression models were calculated. Results: The examined sample of 228 employed patients reported an average of 6% at-work productivity loss within the past two weeks prior to enrolment in the registry. The WLQ productivity loss score was moderately associated with itch (r = 0.32) and sleep loss (r = 0.39) and strongly associated with depressive symptoms (r = 0.68) and fatigue (r = 0.60). Conclusions: The analyses of the registry data show that moderate-to-severe atopic dermatitis has a negative impact on the work productivity of the patients. The analyses further point out the relevant associations between work productivity, depressive symptoms, and fatigue highlighting the disease burden caused by the psychological components of AD.
CRIS-Team Scopus Importer:2023-09-29
Keywords: Atopic dermatitis; productivity loss; registry; work limitations

Juckreiz, Schlafstörungen, depressive Symptome, Fatigue und Einschränkungen der Arbeitsproduktivität bei Patienten mit moderater bis schwerer atopischer Dermatitis: Daten aus dem TREATgermany-Register - Birkner, Thomas; Siegels, Doreen; Heinrich, Luise; Haufe, Eva; Abraham, Susanne; Heratizadeh, Annice; Harder, Inken; Bell, Magnus; Fell, Isabell; Worm, Margitta; Handrick, Christiane; Effendy, Isaak; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
CRIS-Team Scopus Importer:2023-11-10
Keywords: Arbeitseinschränkungen; Atopic dermatitis; Atopische Dermatitis; productivity loss; Produktivitätsverlust; Register; registry; work limitations

Just One Position-Independent Lysine Residue Can Direct MelanA into Proteasomal Degradation following N-Terminal Fusion of Ubiquitin - Setz, Christian; Friedrich, Melanie; Hahn, Sabine; Dörrie, Jan; Schaft, Niels; Schuler, Gerold; Schubert, Ulrich (PLoS ONE, 2013)
N-terminal stable in frame fusion of ubiquitin (Ub) has been shown to target the fusion protein for proteasomal degradation. This pathway, called the Ub fusion degradation (UFD), might also elevate MHC class I (MHC-I) antigen presentation of specific antigens. The UFD, mainly studied on cytosolic proteins, has been described to be mediated by polyubiquitination of specific lysine residues within the fused Ub moiety. Using the well characterized melanoma-specific antigen MelanA as a model protein, we analyzed the requirements of the UFD for ubiquitination and proteasomal degradation of a transmembrane protein. Here we show that fusion of the non-cleavable UbG76V variant to the N-terminus of MelanA results in rapid proteasomal degradation via the endoplasmic reticulum-associated degradation (ERAD) pathway and, consequently, leads to an increased MHC-I antigen presentation. While lysine residues within Ub are dispensable for these effects, the presence of one single lysine residue, irrespectively of its location along the fusion protein, is sufficient to induce degradation of MelanA. These results show that the ubiquitination, ER to cytosol relocation and proteasomal degradation of a transmembrane protein can be increased by N-terminal fusion of Ub at the presence of at least one, position independent lysine residue. These findings are in contrast to the conventional wisdom concerning the UFD and indicate a new concept to target a protein into the ubiquitin-proteasome system (UPS) and thus for enhanced MHC-I antigen presentation, and might open up new possibilities in the development of tumor vaccines. © 2013 Setz et al.
CRIS-Team Scopus Importer:2021-10-01

Kinetic modeling-based detection of genetic signatures that provide chemoresistance via the E2F1-p73/DNp73-miR-205 network - Vera González, Julio; et al. (Cancer Research, 2013)
Drug resistance is a major cause of deaths from cancer. E2F1 is a transcription factor involved in cell proliferation, apoptosis and metastasis through an intricate regulatory network, which includes other transcription factors like p73 and cancer-related microRNAs like miR-205. To investigate the emergence of drug resistance, we developed a methodology that integrates experimental data with a network biology and kinetic modeling approach. Using a regulatory map developed to summarize knowledge on E2F1 its interplay with p73/DNp73 and miR-205 in cancer drug responses, we derived a kinetic model that represents the network response to certain genotoxic and cytostatic anti-cancer drugs. By perturbing the model parameters we mimic heterogeneous cell configurations referred to as in silico cell lines. These were used to detect genetic signatures characteristic for single or double drug resistance. We identified a signature composed of high E2F1 and low miR-205 expression that promotes resistance to genotoxic drugs. In this signature, downregulation of miR-205 can be mediated by an imbalance in the p73/DNp73 ratio or by dysregulation of other cancer-related regulators of miR-205 expression like TGFβ-1 or TWIST1. In addition, we found that a genetic signature composed of high E2F1, low miR-205 and high ERBB3 can render tumor cells insensitive to both cytostatic and genotoxic drugs. Our model simulations also suggested that conventional genotoxic drug treatment favors selection of chemoresistant cells in genetically heterogeneous tumors, in a manner requiring dysregulation of incoherent feedforward loops that involve E2F1, p73/DNp73 and miR-205. <
Keywords: Computational modelling; melanoma; network biology; cancer therapy resistance; miRNAs; Transcription factors; systems biology

Kit regulates HSC engraftment across the human-mouse species barrier - Cosgun, Kadriye Nehir; Rahmig, Susann; Mende, Nicole; Reinke, Soeren; Hauber, Ilona; Schaefer, Carola; Petzold, Anke; Weisbach, Henry; Heidkamp, Gordon Frederik; Purbojo, Ariawan; Cesnjevar, Robert; Platz, Alexander; et al. (Cell Stem Cell, 2014)
In-depth analysis of the cellular and molecular mechanisms regulating human HSC function will require a surrogate host that supports robust maintenance of transplanted human HSCs in vivo, but the currently available options are problematic. Previously we showed that mutations in the Kit receptor enhance engraftment of transplanted HSCs in the mouse. To generate an improved model for human HSC transplantation and analysis, we developed immune-deficient mouse strains containing Kit mutations. We found that mutation of the Kit receptor enables robust, uniform, sustained, and serially transplantable engraftment of human HSCs in adult mice without a requirement for irradiation conditioning. Using this model, we also showed that differential KIT expression identifies two functionally distinct subpopulations of human HSCs. Thus, we have found that the capacity of this Kit mutation to open up stem cell niches across species barriers has significant potential and broad applicability in human HSC research.
EVALuna2:19491

Kutanes Plattenepithelkarzinom - Leiter, U.; Gutzmer, R.; Alter, M.; Ulrich, C.; Meiwes, A.; Heppt, Markus; Steeb, T.; Berking, Carola; Lonsdorf, A. S.; Sachse, M. M.; Garbe, C.; Hillen, U. (Hautarzt, 2020)
Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers of the Caucasian population and accounts for 20% of all skin tumours. An S3 guideline of the German Guideline Program in Oncology has been available since 2019. The diagnosis is based on the clinical examination. Excision and histological confirmation is required for all clinically suspicious lesions to allow prognostic assessment and correct treatment. The therapy of first choice is complete excision with histological control of the surgical margin. In cSCC with risk factors such as tumor thickness >6 mm, sentinel lymph node biopsy may be discussed, but there is currently no clear evidence of its prognostic and therapeutic relevance. Adjuvant radiation therapy may be considered in cases of high risk of recurrence and should be tested in cases of inoperable tumors. The indication for electrochemotherapy should also be considered in the treatment of local or locoregional recurrence. The immune checkpoint inhibitor cemiplimab is approved for the treatment of inoperable or metastasized cSCC. In case of contraindications, chemotherapeutic agents, epidermal growth factor receptor (EGFR) inhibitors or palliative radiotherapy can be used. Since the evidence is low in these cases, a systemic therapy should be used preferentially within clinical studies. Follow-up care should be risk-adapted and includes a dermatological control, supplemented by ultrasound examinations in high-risk patients.
CRIS-Team Scopus Importer:2020-07-10
Keywords: Aftercare; Diagnosis; Management; Non melanoma skin cancer; Treatment

Label-free discrimination of extracellular vesicles from large lipoproteins. - Kashkanova, Anna D.; Blessing, Martin; Reischke, Marie; Baur, Jan-Ole; Baur, Andreas; Sandoghdar, Vahid; Van Deun, Jan (Journal of Extracellular Vesicles, 2023)
Extracellular vesicles (EVs) are increasingly gaining interest as biomarkers and therapeutics. Accurate sizing and quantification of EVs remain problematic, given their nanometre size range and small scattering cross-sections. This is compounded by the fact that common EV isolation methods result in co-isolation of particles with comparable features. Especially in blood plasma, similarly-sized lipoproteins outnumber EVs to a great extent. Recently, interferometric nanoparticle tracking analysis (iNTA) was introduced as a particle analysis method that enables determining the size and refractive index of nanoparticles with high sensitivity and precision. In this work, we apply iNTA to differentiate between EVs and lipoproteins, and compare its performance to conventional nanoparticle tracking analysis (NTA). We show that iNTA can accurately quantify EVs in artificial EV-lipoprotein mixtures and in plasma-derived EV samples of varying complexity. Conventional NTA could not report on EV numbers, as it was not able to distinguish EVs from lipoproteins. iNTA has the potential to become a new standard for label-free EV characterization in suspension.
EVALuna2:538267

Landscape of Bone Marrow Metastasis in Human Neuroblastoma Unraveled by Transcriptomics and Deep Multiplex Imaging - Lazic, Daria; Kromp, Florian; Rifatbegovic, Fikret; Repiscak, Peter; Kirr, Michael; Mivalt, Filip; Halbritter, Florian; Bernkopf, Marie; Bileck, Andrea; Ussowicz, Marek; Ambros, Inge M.; Ambros, Peter F.; et al. (Cancers, 2021)
Simple Summary Bone marrow metastasis frequently occurs in patients with solid cancers and most often leads to poor outcome. Yet, the composition of bone marrow metastases, including tumor and surrounding cells, has so far not been characterized. Herein, we aimed to investigate the diversity of tumor and surrounding cells, i.e., the microenvironment, in bone marrow metastases, using the childhood tumor neuroblastoma as a model. To this end, we screened genome-wide datasets to define a panel of cell-specific markers for multiplex microscopy of metastatic bone marrow samples, and developed DeepFLEX, a computational pipeline for subsequent image analysis. Thereby, we identified 35,000 single cells covering metastasized tumor cells, and various types of developing immune and bone marrow cells. In parallel, we analyzed the transcriptome, i.e., all genes that are expressed as mRNA, of 38 patients with and without bone marrow metastasis. We found vast tumor cell diversity and identified a marker protein, FAIM2, which can help to identify a broader range of tumor cell variants. In addition we showed that tumor cell metastasis in the bone marrow is associated with an immune response resembling inflammation, and the presence of cells that can repress an immune attack against cancer cells. Our study suggests that metastatic tumor cells are shaping the bone marrow microenvironment and builds the basis to further investigate its clinical relevance. While the bone marrow attracts tumor cells in many solid cancers leading to poor outcome in affected patients, comprehensive analyses of bone marrow metastases have not been performed on a single-cell level. We here set out to capture tumor heterogeneity and unravel microenvironmental changes in neuroblastoma, a solid cancer with bone marrow involvement. To this end, we employed a multi-omics data mining approach to define a multiplex imaging panel and developed DeepFLEX, a pipeline for subsequent multiplex image analysis, whereby we constructed a single-cell atlas of over 35,000 disseminated tumor cells (DTCs) and cells of their microenvironment in the metastatic bone marrow niche. Further, we independently profiled the transcriptome of a cohort of 38 patients with and without bone marrow metastasis. Our results revealed vast diversity among DTCs and suggest that FAIM2 can act as a complementary marker to capture DTC heterogeneity. Importantly, we demonstrate that malignant bone marrow infiltration is associated with an inflammatory response and at the same time the presence of immuno-suppressive cell types, most prominently an immature neutrophil/granulocytic myeloid-derived suppressor-like cell type. The presented findings indicate that metastatic tumor cells shape the bone marrow microenvironment, warranting deeper investigations of spatio-temporal dynamics at the single-cell level and their clinical relevance.
CRIS-Team WoS Importer:2021-09-24

Langjährig rezidivierende „akute Urtikaria-Symptomatik“als Manifestation einer anstrengungsinduzierten Anaphylaxie auf Weizenmehl (WDEIA) - Wagner, Nicola; Reese, Imke (Allergologie, 2021)
CRIS-Team Scopus Importer:2021-06-25
Keywords: Anaphylaxis; Induced anaphylaxis; Urticaria; WDEIA-recurrent urticaria; Wheat dependent exercise

Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway - Busch, Leonhard; Mougiakakos, Dimitrios; Büttner-Herold, Maike; Müller, Miriam J.; Volmer, Dietrich A.; Bach, Christian; Fabri, Mario; Bittenbring, Jörg T.; Neumann, Frank; Boxhammer, Rainer; Nolting, Jens; Bisht, Savita; et al. (Leukemia, 2018)
Macrophages are key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD38 antibody MOR202, currently introduced in multiple myeloma (MM) therapy. Therefore, it is important to understand how antibody-mediated effector functions of myeloma-associated macrophages (MAMs) are regulated. Here, we focused on the effects of vitamin D, a known regulator of macrophage effector functions. Consequently, it was the aim of this study to assess whether modulation of the vitamin D pathway alters the tumoricidal activity of MAMs. Here, we demonstrate that MAMs display a defective vitamin D pathway with reduced expression level of CYP27B1 and limited tumoricidal activity which can be restored by the IMiD lenalidomide in vitro. Furthermore, our data indicate that the vitamin D pathway of MAMs from MM patients does recover during an IMiD-containing therapy shown by an improved MOR202-mediated cytotoxic activity of these MAMs against primary MM cells ex vivo. Here, the ex vivo cytotoxic activity could be further enhanced by vitamin D supplementation. These data suggest that vitamin D holds a key role for the effector functions of MAMs and that vitamin D supplementation in IMiD combination trials could further increase the therapeutic efficacy of anti-CD38 antibodies such as MOR202, which remains to be investigated in clinical studies.
EVALuna2:34165

Leukoreduction system chambers are an efficient, valid, and economic source of functional monocyte-derived dendritic cells and lymphocytes - Pfeiffer, Isabell A.; Zinser, Elisabeth; Strasser, Erwin; Stein, Marcello F.; Dörrie, Jan; Schaft, Niels; Steinkasserer, Alexander; Knippertz, Ilka (Immunobiology, 2013)
The demand for human monocyte-derived dendritic cells (moDCs), as well as for primary human B and T lymphocytes for immunological research purposes has been increased in recent years. Classically, these monocytes are isolated from blood, leukapheresis products or buffy coats of healthy donors by plastic adherence of peripheral blood mononuclear cells (PBMCs), followed by stimulation with granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, while lymphocytes are usually isolated from the non-adherent fraction (NAF) by magnetic cell sorting. However, donor-blood is a limited resource and not every blood bank offers leukapheresis products or buffy coats for laboratory use. Additionally, a leukapheresis is very expensive and also the generation/isolation of cells is time- and cost-intensive. To overcome some of these obstacles, we evaluated if low-cost leukoreduction system chambers (LRSCs), which arise after routine donor plateletpheresis procedures, and are usually discarded, would be an alternative and appropriate source of PBMCs to generate moDCs and to isolate lymphocytes. By analyzing the number and phenotype of immature and mature dendritic cells (DCs), as well as of B and T lymphocytes derived from LRSCs, we found all cells to be of high quantity and quality. Further investigations on DCs comprising transwell migration assays, allogeneic mixed lymphocyte reactions (MLR), cytokine secretion assays, and cytotoxic T cell induction assays revealed high migratory, as well as stimulatory capacity of these cells. In addition, DCs and T cells were efficiently electroporated with mRNA and showed characteristic cytokine production after co-culture, demonstrating LRSCs as an efficient, valid, and economic source for generation of moDCs and lymphocytes for research purposes. © 2013 Elsevier GmbH.
CRIS-Team Scopus Importer:2021-10-01
Keywords: B cell; Leukoreduction system chamber; Monocyte-derived dendritic cell; Peripheral blood mononuclear cell; T cell

Life-threatening Autoimmune Cardiomyopathy Reproducibly Induced in a Patient by Checkpoint Inhibitor Therapy - Tajmir-Riahi, Azadeh; Bergmann, Tanja; Schmid, Michael; Agaimy, Abbas; Schuler, Gerold; Heinzerling, Lucie (Journal of Immunotherapy, 2018)
Checkpoint inhibitors induce a plethora of immune-related adverse events (irAEs) including autoimmune colitis, hepatitis, endocrinopathies, and rarer side effects like neuritis. Here, a case of autoimmune cardiomyopathy (grade 3 CTCAE) and myocarditis under combination therapy with nivolumab plus ipilimumab in a 72-year-old melanoma patient is reported. Treatment induced a partial response for 14 months. However, after 10 infusions the patient developed dyspnea, edema of the legs, ascites and a weight gain of 10 kg because of a decompensated heart insufficiency with a reduced ejection fraction from formerly 48%-50% to 15%. Ischemia and viral infections were ruled out. Histopathology showed hypertrophic myocarditis with interstitial lymphocytes. Prednisolone improved the patient's condition within 3 days, leading to a 25% and 30% ejection fraction after 2 and 8 weeks, respectively, and clinical symptoms subsided completely. Importantly, reinduction of anti-PD1 therapy resulted in a flare of myocarditis. Awareness for potentially life-threatening irAE of checkpoint inhibitors like autoimmune cardiomyopathy and myocarditis is crucial to rapidly initiate adequate treatment.
EVALuna2:34413

Limited Dose-Dependent Effects of Vedolizumab on Various Leukocyte Subsets - Becker, Emily; Schweda, Anna; Ullrich, Karen; Voskens, Caroline; Atreya, Raja; Müller, Tanja; Atreya, Imke; Neurath, Markus; Zundler, Sebastian (Clinical and Translational Gastroenterology, 2022)
OBJECTIVES: The anti-α4β7 integrin antibody vedolizumab (VDZ) is successfully used for the treatment of inflammatory bowel diseases. However, only a subgroup of patients respond to therapy. VDZ is administered at a fixed dose, leading to a wide range of serum concentrations in patients. Previous work from our group showed a dose-dependent preferential binding of VDZ to effector compared with regulatory CD4 + T cells. Therefore, we aimed to determine the dose-dependent binding profile of VDZ to other leukocyte subsets. METHODS: We characterized α4β7 integrin expression on CD8 + T cells, CD19 + B cells, CD14 + monocytes, natural killer cells, and eosinophils from patients with inflammatory bowel disease and healthy controls. We studied the binding of VDZ to these cells at different concentrations and investigated the functional consequences for dynamic adhesion and transmigration in vitro . RESULTS: The expression of α4β7 differed between the analyzed leukocyte subsets and was significantly higher on eosinophils from inflammatory bowel disease patients compared with controls. Almost all α4β7-expressing cells from these subsets were bound by VDZ at a concentration of 10 μg/mL. Dynamic cell adhesion was significantly impaired in all subsets, but there were no dose-dependent differences in the inhibition of adhesion. DISCUSSION: Our data suggest that α4β7-expressing CD8 + T cells, CD19 + B cells, CD14 + monocytes, natural killer cells, and eosinophils are a target of VDZ. However, there do not seem to be concentration-dependent differences, regarding the effects on these cells in the clinically relevant range. Thus, the reported exposure-efficacy characteristic of VDZ can probably mainly be attributed to CD4 + T-cell subsets.
CRIS-Team Scopus Importer:2022-07-08

Limited Effect of Anti-PD-1 in advanced Skin Tumors of Patients with hemato-oncological Primary Disease: A retrospective multi-center Study of ADO - Leiter-Stoeppke, U.; Loquai, C.; Meier, F.; Rafei-Shamsabadi, D.; Hassel, J.; Glutsch, V.; Sirokay, J.; Schlecht, N.; Ruebben, A.; Gutzmer, R.; Kaehler, K.; Gambichler, T.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Lipase elevation and type 1 diabetes mellitus related to immune checkpoint inhibitor therapy – A multicentre study of 90 patients from the German Dermatooncology Group - Grimmelmann, Imke; Momma, Michael; Zimmer, Lisa; Hassel, Jessica C.; Heinzerling, Lucie; Pföhler, Claudia; Loquai, Carmen; Ruini, Cristel; Utikal, Jochen; Thoms, Kai Martin; Kähler, Katharina C.; Eigentler, Thomas; et al. (European Journal of Cancer, 2021)
Aim: Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear. Patients and methods: Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres. Results: We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1–181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of ICI resulted in decrease of lipase after reinduction of ICI lipase levels increased again in 12 of 24 patients. In 18 patients (27%), ICI was continued unchanged, and in 12 (67%) of them, lipase levels normalised. Twenty-two patients were identified with newly diagnosed type I diabetes mellitus related to ICI, and 12 (55%) thereof had also lipase elevation mainly shortly before or after the diagnosis of diabetes. Fourteen (64%) patients had other irAE, mainly thyroiditis. Irrespective of lipase elevation, patients frequently showed a rapid onset with ketoacidosis, decreased c-peptide, and strongly increased blood glucose levels. Conclusion: Increased serum lipase during ICI is often not associated with pancreatitis but with other irAE as possible cause. Therefore, it might be sufficient to regularly monitor blood glucose levels and perform further workup only in case of signs or symptoms of pancreatitis and/or exocrine pancreas insufficiency.
CRIS-Team Scopus Importer:2021-05-21
Keywords: Diabetes; Diabetes mellitus; Immune checkpoint inhibitors; Immune-related adverse events; Ipilimumab; Lipase; Nivolumab; Pancreatitis; PD-1 inhibitor; Pembrolizumab

Lipase Elevations and Diabetes under Checkpoint Inhibition - Experience in 80 Patients - Weihkopf, D.; Satzger, I.; Zimmer, L.; Eigentler, T.; Haessel, J.; Heinzerling, Lucie; Herbst, R.; Kahler, K.; Loquai, C.; Meier, F.; Pfoehler, C.; Ruini, C.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Liver-directed treatment is associated with improved survival and increased response to immune checkpoint blockade in metastatic uveal melanoma: results from a retrospective multicenter trial - Koch, Elias; Petzold, Anne; Wessely, Anja; Dippel, Edgar; Eckstein, Markus; Gesierich, Anja; Gutzmer, Ralf; Hassel, Jessica C.; Knorr, Harald; Kreuzberg, Nicole; Leiter, Ulrike; Loquai, Carmen; et al. (Frontiers of Medicine, 2023)
Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.
CRIS-Team Scopus Importer:2023-07-21
Keywords: anti-CTLA-4; anti-PD-1; immune checkpoint blockade; liver-directed therapy; SIRT; uveal melanoma

Loading of Primary Human T Lymphocytes with Citrate-Coated Superparamagnetic Iron Oxide Nanoparticles Does Not Impair Their Activation after Polyclonal Stimulation - Mühlberger, Marina; Unterweger, Harald; Band, Julia; Lehmann, Christian; Heger, Lukas; Dudziak, Diana; Alexiou, Christoph; Lee, Geoffrey; Janko, Christina (Cells, 2020)
For the conversion of immunologically cold tumors, characterized by a low T cell infiltration, into hot tumors, it is necessary to enrich T cells in the tumor area. One possibility is the use of magnetic fields to direct T cells into the tumor. For this purpose, primary T cells that were freshly isolated from human whole blood were loaded with citrate-coated superparamagnetic iron oxide nanoparticles (SPIONCitrate). Cell toxicity and particle uptake were investigated by flow cytometry and atomic emission spectroscopy. The optimum loading of the T cells without any major effect on their viability was achieved with a particle concentration of 75 mu g Fe/mL and a loading period of 24 h. The cellular content of SPIONCitrate was sufficient to attract these T cells with a magnet which was monitored by live-cell imaging. The functionality of the T cells was only slightly influenced by SPIONCitrate, as demonstrated by in vitro stimulation assays. The proliferation rate as well as the expression of co-stimulatory and inhibitory surface molecules (programmed cell death 1 (PD-1), lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin and mucin domain containing 3 (Tim-3), C-C motif chemokine receptor 7 (CCR7), CD25, CD45RO, CD69) was investigated and found to be unchanged. Our results presented here demonstrate the feasibility of loading primary human T lymphocytes with superparamagnetic iron oxide nanoparticles without influencing their viability and functionality while achieving sufficient magnetizability for magnetically controlled targeting. Thus, the results provide a strong fundament for the transfer to tumor models and ultimately for new immunotherapeutic approaches for cancer treatment.
CRIS-Team WoS Importer:2020-04-21

Localized Scleroderma of the Head and Face Area: A Retrospective Cross-sectional Study of 96 Patients from 5 German Tertiary Referral Centres - Kreuter, Alexander; Mitrakos, Georg; Hofmann, Silke C.; Lehmann, Percy; Sticherling, Michael; Krieg, Thomas; Lahner, Nina; Tigges, Christian; Hunzelmann, Nicolas; Moinzadeh, Pia (Acta Dermato-Venereologica, 2018)
EVALuna2:34377

Locally renewing resident synovial macrophages provide a protective barrier for the joint - Culemann, Stephan; Grüneboom, Anika; Nicolás-Ávila, José Ángel; Weidner, Daniela; Lämmle, Katrin Franziska; Rothe, Tobias; Quintana, Juan A.; Kirchner, Philipp; Krljanac, Branislav; Eberhardt, Martin; Ferrazzi, Fulvia; Kretzschmar, Elke; et al. (Nature, 2019)
Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis1. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX3CR1+ tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX3CR1− mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX3CR1+ lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.
CRIS-Team Scopus Importer:2019-08-16

Lokaltherapeutisches Vorgehen bei Blasen der Haut: Ein Positionspapier der Initiative Chronische Wunden (ICW) e. V. - Dissemond, Joachim; Bueltemann, Anke; Gerber, Veronika; Motzkus, Martin; Münter, Christian; Erfurt-Berge, Cornelia (Die Dermatologie, 2022)
Blisters of the skin can be caused by very different diseases. Therefore, it is an interdisciplinary and interprofessionally relevant challenge. In the clinical routine different local therapeutic procedures are currently practiced. Either the blister is left in place or the blister is punctured and the blister roof is left in place; alternatively, the complete blister roof is ablated. Each of these approaches has potential advantages and disadvantages. A review of the current literature and consensus by the experts of the Initiative Chronische Wunde (ICW) e.V. was performed. The following approaches are recommended: uncomplicated blisters without pressure pain: leave blisters in place; pressure painful and palmar and plantar localized blisters: puncture blister and leave roof; ruptured blisters without clinical signs of infection: leave remnants of bladder roof; ruptured bladders with clinical signs of infection: remove remnants of the blister roof; blisters in burns of grade 2a or higher or in cases of unclear burn depth or chemical burn: remove blister roof. This is followed in each case by the application of a sterile wound dressing. There is no single correct local therapeutic procedure for blisters on the skin. When planning a therapeutic concept, the genesis of the blisters should be clarified and, if necessary, causal treatment should be given. Local therapy is then based on various individual factors. Thus, the approach chosen together with the patient can vary between individuals.
EVALuna2:506744

Long-term Effectiveness of Interventions for actinic Keratoses: Results of a systematic Review and Network Meta-Analysis - Steeb, Theresa; Wessely, Anja; Petzold, Anne; Brinker, T.; Schmitz, L.; Lei-Ter-Stoppke, U.; Garbe, C.; Schöffski, Oliver; Berking, Carola; Heppt, Markus (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Long-term efficacy of canakinumab in the treatment of Schnitzler syndrome - Krause, Karoline; Bonnekoh, Hanna; Ellrich, André; Tsianakas, Athanasios; Wagner, Nicola; Fischer, Jörg; Maurer, Marcus (Journal of Allergy and Clinical Immunology, 2020)
CRIS-Team Scopus Importer:2020-02-18

Long-term efficacy of interventions for actinic keratosis: protocol for a systematic review and network meta-analysis - Steeb, Theresa; Heppt, Markus; Becker, Lars; Kohl, Christoph; French, Lars E.; Berking, Carola (Systematic Reviews, 2019)
BACKGROUND: Actinic keratoses (AK) are common precancerous lesions of the skin due to cumulative sun exposure. A variety of interventions are available for the treatment; however, the majority of randomised controlled trials (RCTs) and meta-analyses focus on short-term efficacy outcomes. This network meta-analysis aims to investigate the long-term (> 12 months) efficacy of interventions for AK. METHODS: To identify relevant studies, we will perform a systematic literature research in MEDLINE, Embase, and CENTRAL and hand-search pertinent trial registers. Two authors will independently screen titles and abstracts for eligibility. We will include RCTs with an inter-individual (parallel arm) design. The study population includes patients with a clinical or histopathologic diagnosis of AK. Eligibility will be restricted to the following interventions: surgical approaches, cryosurgery, ablative laser treatment, topical drug treatment with 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac, or photodynamic therapy. As outcomes, we will consider the following endpoints: (1) the participant complete clearance rate, (2) the participant partial clearance rate, (3) the lesion-specific clearance, (4) the mean lesion reduction per patient, and (5) the number of withdrawals due to adverse events after at least 12 months after the end of treatment. Monotherapy or placebo will serve as a comparison. Estimates of effects from individual studies will be pooled using a random-effects model. Heterogeneity will be evaluated based on I2 and chi-square test. The risk of bias will be estimated with the Cochrane Risk of Bias Tool by two review authors independently. The quality of evidence of the outcomes will be assessed with the GRADE approach. A network meta-analysis will be performed to combine direct and indirect evidence from the included RCTs. DISCUSSION: The potential of interventions to achieve a sustained clearance of AK has not been assessed to date. To investigate the long-term efficacy of interventions is important as the natural disease course is highly variable and relapses occur frequently even after initial lesion clearance. This review will help to set a framework for clinical decision making in patients with AK. SYSTEMATIC REVIEW REGISTRATION: CRD42018095903 (PROSPERO).
EVALuna2:211408

LONG-TERM HUMORAL RESPONSE TO SARS-COV-2 VACCINATION IN PATIENTS WITH IMMUNE-MEDIATED INFLAMMATORY DISEASE - Tascilar, Koray; Simon, David; Kleyer, Arnd; Fagni, Filippo; Krönke, Gerhard; Meder, Christine; Dietrich, Peter; Orlemann, Till; Kliem, Thorsten; Moessner, J.; Liphardt, Anna-Maria; Schönau, Verena; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Long-Term Management of Advanced Basal Cell Carcinoma: Current Challenges and Future Perspectives - Heppt, Markus; Gebhardt, Christoffer; Hassel, Jessica C.; Alter, Mareike; Gutzmer, Ralf; Leiter, Ulrike; Berking, Carola (Cancers, 2022)
Simple Summary Local therapies are no longer an option for locally advanced basal cell carcinoma. Abnormal activation of the hedgehog signaling pathway leads to uncontrolled tumor growth. Hedgehog pathway inhibitors are an effective treatment option for this kind of tumor. However, treatment-related toxicity under long-term treatment may lead to limitations in quality of life, and thus to therapy interruption or even discontinuation. This review summarizes pertinent treatment adjustments and novel therapeutic strategies for effective treatment of locally advanced basal cell carcinoma. The first-line therapy for locally advanced basal cell carcinoma (laBCC) is Hedgehog pathway inhibitors (HHIs), as they achieve good efficacy and duration of response. However, toxicity in the course of long-term treatment may lead to a decrease in the quality of life, and consequently to interruption or even discontinuation of therapy. As HHI therapy is a balancing act between effectiveness, adverse events, quality of life, and adherence, numerous successful treatment strategies have evolved, such as dose reduction and dose interruptions with on-off treatment schedules or interruptions with re-challenge after progression. As a small percentage of patients show primary or acquired resistance to HHIs, the inhibition of programmed cell death protein 1 (PD-1) has been approved as a second-line therapy, which may also be accompanied by immune-related toxicities and non-response. Thus, optimization of current treatment schedules, novel agents, and combination strategies are urgently needed for laBCC. Here, we narratively model the treatment sequence for patients with laBCC and summarize the current state of approved treatment regimens and therapeutic strategies to optimize the long-term management of laBCC.
CRIS-Team WoS Importer:2022-10-28

Long-term, open-label extension study of the efficacy and safety of epicutaneous immunotherapy for peanut allergy in children: PEOPLE 3-year results - Fleischer, David M.; Shreffler, Wayne G.; Campbell, Dianne E.; Green, Todd D.; Anvari, Sara; Assa'ad, Amal; Bégin, Philippe; Beyer, Kirsten; Bird, J. Andrew; Brown-Whitehorn, Terri; Byrne, Aideen; Chan, Edmond S.; et al. (Journal of Allergy and Clinical Immunology, 2020)
Background: The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 μg, daily epicutaneous peanut protein; DBV712 250 μg). Objective: We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study. Methods: Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 μg, subjects who had received DBV712 250 μg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment. Results: Of 213 eligible subjects who had received DBV712 250 μg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%). Conclusions: These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen.
CRIS-Team Scopus Importer:2020-08-21
Keywords: desensitization; eliciting dose; epicutaneous immunotherapy; EPIT; food allergy; immunotherapy; Peanut allergy; sustained unresponsiveness

Long-term recurrence rates of actinic keratosis: A systematic review and pooled analysis of randomized controlled trials - Steeb, Theresa; Wessely, Anja; Petzold, Anne; Brinker, Titus J.; Schmitz, Lutz; Schöffski, Oliver; Berking, Carola; Heppt, Markus (Journal of the American Academy of Dermatology, 2021)
CRIS-Team Scopus Importer:2021-06-18

Look-alikes with opposite consequences: Cutaneous Botryomycosis presenting as cutaneous metastases in a patient with a history of metastatic lung cancer - Bosch-Voskens, C.; Woerl, P.; Kiesewetter, Franklin; Schliep, S. (2017)
EVALuna2:34368

Loss of Phosphatase and Tensin Homolog in APCs Impedes Th17-Mediated Autoimmune Encephalomyelitis - Sahin, Emine; Brunner, Julia S.; Kral, Julia B.; Kuttke, Mario; Hanzl, Leslie; Datler, Hannes; Paar, Hannah; Neuwinger, Nick; Saferding, Victoria; Zinser, Elisabeth; Halfmann, Angela; Soukup, Klara; et al. (Journal of Immunology, 2015)
The PI3K signaling cascade in APCs has been recognized as an essential pathway to initiate, maintain, and resolve immune responses. In this study, we demonstrate that a cell type-specific loss of the PI3K antagonist phosphatase and tensin homolog (PTEN) in myeloid cells renders APCs toward a regulatory phenotype. APCs deficient for PTEN exhibit reduced activation of p38 MAPK and reduced expression of T cell-polarizing cytokines. Furthermore, PTEN deficiency leads to upregulation of markers for alternative activation, such as Arginase 1, with concomitant downregulation of inducible NO synthase in APCs in vitro and in vivo. As a result, T cell polarization was dysfunctional in PTEN(-/-) APCs, in particular affecting the Th17 cell subset. Intriguingly, mice with cell type-specific deletions of PTEN-targeting APCs were protected from experimental autoimmune encephalomyelitis, which was accompanied by a pronounced reduction of IL-17- and IL-22-producing autoreactive T cells and reduced CNS influx of classically activated monocytes/macrophages. These observations support the notion that activation of the PI3K signaling cascade promotes regulatory APC properties and suppresses pathogenic T cell polarization, thereby reducing the clinical symptoms and pathology of experimental autoimmune encephalomyelitis.
EVALuna2:13151

L Particles Transmit Viral Proteins from Herpes Simplex Virus 1-Infected Mature Dendritic Cells to Uninfected Bystander Cells, Inducing CD83 Downmodulation - Heilingloh, Christiane; Kummer, Mirko; Muehl-Zuerbes, Petra; Drassner, Christina; Daniel, Christoph; Klewer, Monika; Steinkasserer, Alexander (Journal of Virology, 2015)
Mature dendritic cells (mDCs) are known as the most potent antigen-presenting cells (APCs) since they are also able to prime/induce naive T cells. Thus, mDCs play a pivotal role during the induction of antiviral immune responses. Remarkably, the cell surface molecule CD83, which was shown to have costimulatory properties, is targeted by herpes simplex virus 1 (HSV-1) for viral immune escape. Infection of mDCs with HSV-1 results in downmodulation of CD83, resulting in reduced T cell stimulation. In this study, we report that not only infected mDCs but also uninfected bystander cells in an infected culture show a significant CD83 reduction. We demonstrate that this effect is independent of phagocytosis and transmissible from infected to uninfected mDCs. The presence of specific viral proteins found in these uninfected bystander cells led to the hypothesis that viral proteins are transferred from infected to uninfected cells via L particles. These L particles are generated during lytic replication in parallel with full virions, called H particles. L particles contain viral proteins but lack the viral capsid and DNA. Therefore, these particles are not infectious but are able to transfer several viral proteins. Incubation of mDCs with L particles indeed reduced CD83 expression on uninfected bystander DCs, providing for the first time evidence that functional viral proteins are transmitted via L particles from infected mDCs to uninfected bystander cells, thereby inducing CD83 downmodulation.HSV-1 has evolved a number of strategies to evade the host's immune system. Among others, HSV-1 infection of mDCs results in an inhibited T cell activation caused by degradation of CD83. Interestingly, CD83 is lost not only from HSV-1-infected mDCs but also from uninfected bystander cells. The release of so-called L particles, which contain several viral proteins but lack capsid and DNA, during infection is a common phenomenon observed among several viruses, such as human cytomegalovirus (HCMV), Epstein-Barr virus, and HSV-1. However, the detailed function of these particles is poorly understood. Here, we provide for the first time evidence that functional viral proteins can be transferred to uninfected bystander mDCs via L particles, revealing important biological functions of these particles during lytic replication. Therefore, the transfer of viral proteins by L particles to modulate uninfected bystander cells may represent an additional strategy for viral immune escape.
EVALuna2:19522

Lungs Ailment - other Comorbidity of the Psoriasis? - Moreira, Alvaro; Sticherling, Michael (2017)
EVALuna2:34355

Macrophage immunity and metabolism in cancer: Novel diagnostic and therapeutic strategies - Leavenworth, Jianmei W.; Lai, Xin; Miao, Hongming; Wang, Di; Zhao, Huakan; Li, Yongsheng (Frontiers in Immunology, 2022)
CRIS-Team WoS Importer:2023-02-10

MAGNETIC RESONANCE IMAGING (MRI) OF HANDS OF PSORIASIS PATIENTS: HIGH INCIDENCE OF INFLAMMATION - Simon, David; Faustini, F.; Englbrechtl, M.; Kleyer, Arnd; Kocijan, R.; Haschka, J.; Kraus, S.; Hueber, Axel; Sticherling, Michael; Schell, G.; Rech, Jürgen (2014)
EVALuna2:12862

Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor-Associated Myocarditis - Zhang, Lili; Zlotoff, Daniel A.; Awadalla, Magid; Mahmood, Syed S.; Nohria, Anju; Hassan, Malek Z.O.; Thuny, Franck; Zubiri, Leyre; Chen, Carol L.; Sullivan, Ryan J.; Alvi, Raza M.; Rokicki, Adam; et al. (Circulation, 2020)
CRIS-Team Scopus Importer:2020-06-26
Keywords: corticosteroid; immunotherapy; myocarditis

Malignant Tumors as important Differential Diagnosis of chronic Ulcers - Toussaint, Frédéric; Erdmann, M.; Berking, Carola; Erfurt-Berge, Cornelia (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

Malignant Tumours Presenting as Chronic Leg or Foot Ulcers - Toussaint, Frédéric; Erdmann, Michael; Berking, Carola; Erfurt-Berge, Cornelia (Journal of Clinical Medicine, 2021)
Our purpose was to collect data on the incidence of malignant skin tumours presenting as chronic leg or foot ulcers in a tertiary centre, and to analyse the frequency and type of initial clinical misdiagnoses in these cases. A retrospective chart review of cases with melanoma or other malignant neoplasms of the skin of the lower extremity treated in a tertiary centre during January 2010 until February 2020 was conducted to identify cases that presented as chronic ulcers. Out of 673 cases, 26 (3.9%) were identified with a total of 27 malignant tumours presenting as chronic ulcers of the lower leg or foot. Therefrom, seven were diagnosed as melanoma, eight as squamous cell carcinoma, and twelve as basal cell carcinoma. The mean interval until diagnosis for all tumour types was 44.4 months (median 24 months). A delay in correct treatment occurred in 12 out of 26 cases (46%) as a result of misdiagnosis with subsequent treatment as chronic leg or foot ulcers of a different etiology. Misdiagnoses were venous ulcer, traumatic wound, mixed arterial and venous ulcer, arterial ulcer, and ulcer of an unknown origin. Malignant ulcers presenting as chronic ulcers are rare, but often lead to misdiagnosis.
CRIS-Team WoS Importer:2021-06-25

Malignome als Ursache von chronischen Wunden - Siegling, Michael; Erfurt-Berge, Cornelia (Chirurgische Praxis, 2023)
The differentiation between primary and secondary malignant wounds is often complicated. Primary tumours of the skin such as basal cell carcinoma, squamous cell carcinoma, malignant melanoma, cutaneous lymphoma and sarcoma alike cutaneous metastasis can ulcerate and ultimately manifest as malignant wounds. Similarly, initially tumour-free chronic wounds can transform into secondary malignancies via malignant transformation. A correct and timely diagnosis is essential and forms the basis of the subsequent curative or palliative therapy. In the context of wound management of chronic and palliative wounds, disease-oriented treatment and the patients‘wishes should go hand in hand. In order to fulfil the holistic empathic approach of wound care, high importance should be attached to psychological aspects, prevention of off odours, exudate management, wound rinse and wound cleansing as well as to an individual pain therapy.
CRIS-Team Scopus Importer:2023-10-20
Keywords: chronic wounds; malignant transformation; malignant wounds; tumours; wound management

Management maligner Wunden - Kirchberger, Michael; Erfurt-Berge, Cornelia (Zeitschrift für Gerontologie und Geriatrie, 2019)
Malignant wounds arise either primary or secondary in the context of a malignant transformation of already existing wounds. A plethora of skin tumors, such as basal cell carcinoma, squamous cell carcinoma, melanoma, lymphoma as well as cutaneous metastases of other malignancies can ulcerate and be the cause of malignant wounds. Ulcerating tumors or metastases of the skin can however mimic chronic wounds from other causes and remain unrecognized over a longer period. In patients with chronic ulcerations, the correct and timely diagnosis is paramount. Based on this, the stage and disease-oriented treatment should be chosen in harmony with the wishes of the patient. In addition, general measures, such as atraumatic dressing changes to reduce pain and bleeding and the use of antiseptic dressing materials to prevent bacterial colonization and associated odors should be considered.
CRIS-Team Scopus Importer:2019-11-12
Keywords: Malignancy; Malignant wounds; Tumor; Ulcers; Wound therapy

Management of cutaneous squamous cell carcinoma Vorgehen bei kutanem Plattenepithelkarzinom - Leiter, U.; Gutzmer, R.; Alter, M.; Ulrich, C.; Meiwes, A.; Heppt, Markus; Steeb, Theresa; Berking, Carola; Lonsdorf, A. S.; Sachse, M.; Hillen, U. (Onkologe, 2021)
Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers of the Caucasian population and accounts for 20% of all skin tumors. An S3 guideline of the German Oncology Guidelines Program has been available since 2019. The diagnosis is based on the clinical examination. Excision and histological confirmation is required for all clinically suspicious lesions to allow prognostic assessment and correct treatment. The therapy of first choice is complete excision with histological control of the surgical margin. In cutaneous SCC with risk factors such as tumor thickness > 6 mm, sentinel lymph node biopsy (SLNB) may be discussed, but there is currently no clear evidence regarding its prognostic and therapeutic relevance. Adjuvant radiotherapy may be considered if there is a high risk of recurrence, radiotherapy should be considered in case of inoperable tumors. For inoperable local or locoregional recurrence, electrochemotherapy can also be indicated. In case of inoperable/or metastasized SCC, the immune checkpoint inhibitor cemiplimab is approved and recommended as the therapy of first choice. In case of contraindications, chemotherapeutics, epidermal growth factor receptor (EGFR) inhibitors or palliative radiotherapy can be used. Since evidence is limited, systemic therapy should preferably be performed in clinical studies. Follow-up should be risk-adapted and includes dermatological examinations supplemented by ultrasound examinations in high-risk patients.
CRIS-Team Scopus Importer:2021-04-30
Keywords: Diagnostic techniques and procedures; Margins of excision; Sentinel lymph node biopsy; Skin and connective tissue diseases; Treatment

Management of patients with calciphylaxis: current perspectives - Erfurt-Berge, Cornelia; Renner, Regina (Chronic Wound Care Management and Research, 2019)
Calciphylaxis (CP) is a rare disorder presenting with painful ischemic skin ulcerations. Its association with end-stage renal disease, but also non-uremic cases have been described. Several risk factors, like metabolic syndrome, calcium-phosphate imbalance, anticoagulative medication and female gender have been discussed. Multidisciplinary therapeutic approaches are necessary since evidence-based guidelines are missing due to lack of pathophysiological understanding of the disease and the absence of studies with large patient cohorts. However, strategies for local wound therapy, reduction of risk factors and systemic therapies are being developed. Changes in duration, frequency and method of hemodialysis and specific medication to lower the calcium upload can be effective in uremic CP cases. Systemic treatments with cinacalcet, sodium thiosulfate or bisphosphonates have been applied successfully in CP patients, but large placebo-controlled randomized trials are still needed to gather better insight into this fatal disease.
CRIS-Team WoS Importer:2019-10-25

Management of side effects of immune checkpoint blockade by anti-CTLA-4 and anti-PD-1 antibodies in metastatic melanoma - Kaehler, Katharina C.; Hassel, Jessica C.; Heinzerling, Lucie; Loquai, Carmen; Moessner, Rotraut; Ugurel, Selma; Zimmer, Lisa; Gutzmer, Ralf (Journal der Deutschen Dermatologischen Gesellschaft, 2016)
CTLA-4 and PD-1 are potential targets for tumor-induced downregulation of lymphocytic immune responses. Immune checkpoint-modifying monoclonal antibodies oppose these effects, inducing T cell-mediated immune responses to various tumors including melanoma. Both anti-CTLA-4 and anti-PD-1 antibodies modify the interaction between tumor, antigen-presenting cells, and T lymphocytes. With respect to overall survival, clinical studies have shown a major benefit for the anti-CTLA-4 antibody ipilimumab as well as the two anti-PD-1 antibodies nivolumab and pembrolizumab. Following approval of ipilimumab in 2011, the latter two achieved market authorization in the summer of 2015. Immune responses thus induced and enhanced inevitably entail autoimmune phenomena, affecting various organs to varying degrees. Knowledge of these side effects is crucial with regard to prevention and management by treating physicians. Typically occurring early on and presenting with pronounced and persistent diarrhea, colitis represents a major and severe side effect. Other immune-mediated disorders include dermatitis, hypophysitis, thyroiditis, hepatitis, iridocyclitis as well as other less common autoimmune phenomena. Early recognition and initiation of treatment can reduce risks and sequelae for patients. This review describes the mechanisms of action of immune checkpoint blockade as well as its clinical effects in metastatic melanoma, with a detailed focus on the spectrum of adverse events and their therapeutic management.
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Managing toxicities of immunotherapies - a side effect register for rare and severe side effects of checkpoint Inhibitor therapy - Heinzerling, Lucie; Schuler, Gerold (2018)
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MAPK blockade, toxicities, pathogenesis and management - Moreira, Alvaro; Lebbe, Celeste; Heinzerling, Lucie (Current Opinion in Oncology, 2021)
Purpose of review BRAF/MEK inhibitor has changed the treatment landscape in patients with advanced and metastatic melanoma with prolonged overall survival and progression-free survival. Since three treatment combinations exist with similar efficacy therapy decisions are often made based on the side effect profile. Additionally, on-target side effects or class effects have to be properly managed to ensure treatment adherence. Recent findings Sequential treatment with BRAF/MEK inhibition and immunotherapy might increase toxicity with a sepsis-like syndrome and triple therapy with concomitant BRAF/MEK inhibition and anti-PD1/PD-L1 antibody therapy induces severe side effects in the vast majority of patients. Toxicity of combination therapy with BRAF/MEK inhibitors is generally manageable, reversible and infrequently associated with treatment discontinuation. In case of persisting off-target effects the change to another combination therapy can resolve side effects.
CRIS-Team WoS Importer:2021-02-26

Mass Spectrometric Characterization of HSV-1 L-Particles From Human Dendritic Cells and BHK21 Cells and Analysis of Their Functional Role - Birzer, Alexandra; Kraner, Max; Heilingloh, Christiane Silke; Mühl-Zürbes, Petra; Hofmann, Jörg; Steinkasserer, Alexander; Popella, Linda (Frontiers in Microbiology, 2020)
Herpes simplex virus type 1 (HSV-1) is a very common human pathogenic virus among the world’s population. The lytic replication cycle of HSV-1 is, amongst others, characterized by a tripartite viral gene expression cascade, the assembly of nucleocapsids involving their subsequent nuclear egress, tegumentation, re-envelopment and the final release of progeny viral particles. During productive infection of a multitude of different cell types, HSV-1 generates not only infectious heavy (H-) particles, but also non-infectious light (L-) particles, lacking the capsid. In monocyte-derived mature dendritic cells (mDCs), HSV-1 causes a non-productive infection with the predominant release of L-particles. Until now, the generation and function of L-particles is not well understood, however, they are described as factors transferring viral components to the cellular microenvironment. To obtain deeper insights into the L-particle composition, we performed a mass-spectrometry-based analysis of L-particles derived from HSV-1-infected mDCs or BHK21 cells and H-particles from the latter one. In total, we detected 63 viral proteins in both H- and L-particle preparations derived from HSV-1-infected BHK21 cells. In L-particles from HSV-1-infected mDCs we identified 41 viral proteins which are differentially distributed compared to L-particles from BHK21 cells. In this study, we present data suggesting that L-particles modify mDCs and suppress their T cell stimulatory capacity. Due to the plethora of specific viral proteins incorporated into and transmitted by L-particles, it is tempting to speculate that L-particles manipulate non-infected bystander cells for the benefit of the virus.
CRIS-Team Scopus Importer:2020-10-23
Keywords: BHK21 cells; dendritic cells; heavy particles; HSV-1; immunomodulatory effect; light particles; mass spectrometry; T cell stimulation

Mast-Cell-Derived TNF Amplifies CD8(+) Dendritic Cell Functionality and CD8(+) T Cell Priming - Dudeck, Jan; Ghouse, Shanawaz Mohammed; Lehmann, Christian; Hoppe, Anja; Schubert, Nadja; Nedospasov, Sergei A.; Dudziak, Diana; Dudeck, Anne (Cell Reports, 2015)
Mast cells are critical promoters of adaptive immunity in the contact hypersensitivity model, but the mechanism of allergen sensitization is poorly understood. Using Mcpt5-CreTNF(FL/FL) mice, we show here that the absence of TNF exclusively in mast cells impaired the expansion of CD8(+) T cells upon sensitization and the T-cell-driven adaptive immune response to elicitation. T cells primed in the absence of mast cell TNF exhibited a diminished efficiency to transfer sensitization to naive recipients. Specifically, mast cell TNF promotes CD8(+) dendritic cell (DC) maturation and migration to draining lymph nodes. The peripherally released mast cell TNF further critically boosts the CD8(+) T-cell-priming efficiency of CD8(+) DCs, thereby linking mast cell effects on T cells to DC modulation. Collectively, our findings identify the distinct potential of mast cell TNF to amplify CD8(+) DC functionality and CD8(+) T-cell-dominated adaptive immunity, which may be of great importance for immunotherapy and vaccination approaches.
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Mathematical modelling in biomedicine: A primer for the curious and the skeptic - Vera, Julio; Lischer, Christopher; Nenov, Momchil; Nikolov, Svetoslav; Lai, Xin; Eberhardt, Martin (International Journal of Molecular Sciences, 2021)
In most disciplines of natural sciences and engineering, mathematical and computational modelling are mainstay methods which are usefulness beyond doubt. These disciplines would not have reached today’s level of sophistication without an intensive use of mathematical and computational models together with quantitative data. This approach has not been followed in much of molecular biology and biomedicine, however, where qualitative descriptions are accepted as a satisfactory replacement for mathematical rigor and the use of computational models is seen by many as a fringe practice rather than as a powerful scientific method. This position disregards mathematical thinking as having contributed key discoveries in biology for more than a century, e.g., in the connection between genes, inheritance, and evolution or in the mechanisms of enzymatic catalysis. Here, we discuss the role of computational modelling in the arsenal of modern scientific methods in biomedicine. We list frequent misconceptions about mathematical modelling found among biomedical experimentalists and suggest some good practices that can help bridge the cognitive gap between modelers and experimental researchers in biomedicine. This manuscript was written with two readers in mind. Firstly, it is intended for mathematical modelers with a background in physics, mathematics, or engineering who want to jump into biomedicine. We provide them with ideas to motivate the use of mathematical modelling when discussing with experimental partners. Secondly, this is a text for biomedical researchers intrigued with utilizing mathematical modelling to investigate the pathophysiology of human diseases to improve their diagnostics and treatment.
CRIS-Team Scopus Importer:2021-01-22
Keywords: Biomathematics; Computational drug discovery; Computational modelling; Data-driven mathematical modelling; Mathematical oncology; Scientific method; Systems biology

Maturation of monocyte-derived DCs leads to increased cellular stiffness, higher membrane fluidity, and changed lipid composition - Lühr, Jennifer; Alex, Nils; Amon, Lukas; Kraeter, Martin; Kubankova, Marketa; Sezgin, Erdinc; Lehmann, Christian; Heger, Lukas; Heidkamp, Gordon Frederik; Smith, Ana-Suncana; Zaburdaev, Vasily; Böckmann, Rainer; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Maturation of Monocyte-Derived DCs Leads to Increased Cellular Stiffness, Higher Membrane Fluidity, and Changed Lipid Composition - Luhr, Jennifer J.; Alex, Nils; Amon, Lukas; Krater, Martin; Kubankova, Marketa; Sezgin, Erdinc; Lehmann, Christian; Heger, Lukas; Heidkamp, Gordon Frederik; Smith, Ana-Suncana; Zaburdaev, Vasily; Böckmann, Rainer; et al. (Frontiers in Immunology, 2020)
Dendritic cells (DCs) are professional antigen-presenting cells of the immune system. Upon sensing pathogenic material in their environment, DCs start to mature, which includes cellular processes, such as antigen uptake, processing and presentation, as well as upregulation of costimulatory molecules and cytokine secretion. During maturation, DCs detach from peripheral tissues, migrate to the nearest lymph node, and find their way into the correct position in the net of the lymph node microenvironment to meet and interact with the respective T cells. We hypothesize that the maturation of DCs is well prepared and optimized leading to processes that alter various cellular characteristics from mechanics and metabolism to membrane properties. Here, we investigated the mechanical properties of monocyte-derived dendritic cells (moDCs) using real-time deformability cytometry to measure cytoskeletal changes and found that mature moDCs were stiffer compared to immature moDCs. These cellular changes likely play an important role in the processes of cell migration and T cell activation. As lipids constitute the building blocks of the plasma membrane, which, during maturation, need to adapt to the environment for migration and DC-T cell interaction, we performed an unbiased high-throughput lipidomics screening to identify the lipidome of moDCs. These analyses revealed that the overall lipid composition was significantly changed during moDC maturation, even implying an increase of storage lipids and differences of the relative abundance of membrane lipids upon maturation. Further, metadata analyses demonstrated that lipid changes were associated with the serum low-density lipoprotein (LDL) and cholesterol levels in the blood of the donors. Finally, using lipid packing imaging we found that the membrane of mature moDCs revealed a higher fluidity compared to immature moDCs. This comprehensive and quantitative characterization of maturation associated changes in moDCs sets the stage for improving their use in clinical application.
CRIS-Team Scopus Importer:2020-12-25
Keywords: cell mechanics; cellular stiffness; cholesterol; lipidomics; lipids; low-density lipoprotein; maturation; monocyte-derived dendritic cells

MCS-18, a natural product isolated from Helleborus purpurascens, inhibits maturation of dendritic cells in ApoE-deficient mice and prevents early atherosclerosis progression - Dietel, Barbara; Muench, Rabea; Kühn, Constanze; Kerek, Franz; Steinkasserer, Alexander; Achenbach, Stephan; Garlichs, Christoph; Zinser, Elisabeth (Atherosclerosis, 2014)
Inflammation accelerates both plaque progression and instability in the pathogenesis of atherosclerosis. The inhibition of dendritic cell (DC) maturation is a promising approach to suppress excessive inflammatory immune responses and has been shown to be protective in several autoimmune models. The aim of this study was to investigate the immune modulatory effects of the natural substance MCS-18, an inhibitor of DC maturation, regarding the progression of atherosclerosis in ApoE-deficient mice.ApoE-deficient mice were fed for twelve weeks with a Western-type diet (n = 32) or normal chow (control group; n = 16). Animals receiving high-fat diet were treated with MCS-18 (500 ?g/kg body weight, n = 16) or saline (n = 16) twice a week. After 12 weeks, animals were transcardially perfused and sacrificed. The percentage of mature DCs (CD3(-)/CD19(-)/CD14(-)/NK1.1(-)/CD11c(+)/MHCII(+)/CD83(+)/CD86(+)) and T cell subpopulations (CD4(+)/CD25(+)/Foxp3(+), CD3/CD4/CD8) was analyzed in peripheral blood and in the spleen using flow cytometry. Plaque size was determined in the aortic root and the thoracoabdominal aorta using en-face staining. Immunohistochemical stainings served to detect inflammatory cells in the aortic root. Several cytokines and chemokines were determined in serum using multiplex assays.In splenic cells derived from saline-treated atherosclerotic mice an increased DC maturation, reflected by the upregulation of CD83 and CD86 expression, was observed. The enhanced expression of both maturation markers was absent in MCS-18 treated atherosclerotic mice. While the percentage of splenic Foxp3 expressing Treg was increased in animals receiving MCS-18 compared to saline-treated atherosclerotic mice, cytotoxic T cells were reduced in the spleen and in atherosclerotic lesions of the aortic root. Furthermore, proatherogenic cytokines (e.g. IL-6 and IFN-?) and chemokines (e.g. MIP-1?) were decreased in serum of MCS-18-treated animals when compared to saline-treated atherosclerotic mice. Also plaque size in the aortic root and the thoracoabdominal aorta was significantly lower following administration of MCS-18.This study provides for the first time evidence that MCS-18 is able to prevent the onset of atherosclerosis in ApoE-deficient mice. The observed anti-atherogenic effect is associated with the suppression of DC maturation and an inhibited migration and proliferation of cytotoxic T cells.
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Mechanical Regulation of Epithelial Tissue Homeostasis - Kaliman, Sara; Hubert, Maxime; Wollnik, Carina; Nuic, Lovro; Vurnek, Damir; Gehrer, Simone; Lovrić, Jakov; Dudziak, Diana; Rehfeldt, Florian; Smith, Ana-Suncana (Physical Review X, 2021)
Despite recent efforts to understand homeostasis in epithelial tissues, there are many unknowns surrounding this steady state. It is considered to be regulated by mechanoresponse, but unlike for single cells, this idea remains heavily debated for tissues. Here, we show that changes in matrix stiffness induce a nonequilibrium transition from tubular to squamous Madin-Darby Canine Kidney II tissues. Nonetheless, despite different cell morphologies and densities, all homeostatic tissues display equivalent topologies, which, hence, must be actively targeted and regulated. On the contrary, the mechanoresponse induces dramatic changes in the large-scale organization of the colonies. On stiff gels, this yields an unreported cooperative state of motile cells displaying higher densities than in the arrested homeostatic state, which suggests a more complex relation between cell density and motility than previously anticipated. Our results unequivocally relate the mechanosensitive properties of individual cells to the evolving macroscopic structures, an effect that could be important for understanding the emergent pathologies of living tissues.
CRIS-Team WoS Importer:2021-08-20

Meeting Report: 47th Annual Meeting of the “Arbeitsgemeinschaft Dermatologische Forschung” - Stary, Georg; Fabri, Mario; Gebhardt, Christoffer; Eming, Rüdiger; Matthias, Julia; Vorobyev, Artem; Effern, Maike; Strobl, Johanna; Günther, Claudia; Zielinski, Christina; Dudziak, Diana; Géraud, Cyril; et al. (Experimental Dermatology, 2022)
CRIS-Team Scopus Importer:2022-03-18

Meeting Report of the Pathogenesis of Pemphigus and Pemphigoid Meeting in Munich, September 2016 - Schmidt, Enno; Spindler, Volker; Eming, Ruediger; Amagai, Masayuki; Antonicelli, Frank; Baines, John F.; Belheouane, Meriem; Bernard, Philippe; Borradori, Luca; Caproni, Marzia; Di Zenzo, Giovanni; Grando, Sergei; et al. (Journal of Investigative Dermatology, 2017)
Autoimmune blistering diseases are a heterogeneous group of about a dozen complex disorders that are characterized by intraepidermal (pemphigus) and subepidermal blistering (pemphigoid diseases and dermatitis herpetiformis). The Pathogenesis of Pemphigus and Pemphigoid Meeting, organized by the Departments of Dermatology in Lübeck and Marburg and the Institute of Anatomy and Cell Biology, Munich, was held in September 2016 in Munich. The meeting brought together basic scientists and clinicians from all continents dedicating their work to autoimmune blistering diseases. Considerable advances have been made in describing incidences and prevalences of these diseases and linking comorbidities with autoantibody reactivities and clinical variants, for example, dipeptidyl peptidase-IV inhibitor-associated noninflammatory bullous pemphigoid. Although new entities are still being described, diagnosis of most autoimmune blistering diseases can now be achieved using standardized and widely available serological test systems. Various experimental mouse models of pemphigus and pemphigoid disease are increasingly being used to understand mechanisms of central and peripheral tolerance and to evaluate more specific treatment approaches for these disorders, such as molecules that target autoreactive T and B cells and anti-inflammatory mediators, that is, dimethyl fumarate, phosphodiesterase 4, and leukotriene B4 inhibitors in pemphigoid disorders, and chimeric antigen receptor T cells in pemphigus. Very recent experimental data about the immunopathology and the determinants of autoantibody formation and keratinocyte susceptibility in pemphigus were discussed. With regard to cellular mechanisms leading to the loss of cell-cell adhesion, new ideas were shared in the field of signal transduction. Major steps were taken to put the various partly contradictory and controversial findings about the effects of pemphigus autoantibodies and other inflammatory mediators into perspective and broaden our view of the complex pathophysiology of this disease. Finally, two investigator-initiated multicenter trials highlighted doxycycline and dapsone as valuable medications in the treatment of bullous pemphigoid.
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MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients - Kirchberger, Michael Constantin; Ugurel, Selma; Mangana, Johanna; Heppt, Markus Valentin; Eigentler, Thomas Kurt; Berking, Carola; Schadendorf, Dirk; Schuler, Gerold; Dummer, Reinhard; Heinzerling, Lucie (European Journal of Cancer, 2018)
BACKGROUND: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though BRAF mutations can be effectively targeted with specific inhibitors, this approach has proven more challenging in cases of NRAS mutations. Previous reports suggested that immunotherapy might be more successful in NRAS-mutated compared to BRAF-mutated or BRAF/NRAS wildtype melanoma. PATIENTS AND METHODS: In this study, overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients. Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which Q61 mutations were predominant (95%). RESULTS: Patients with NRAS mutant melanoma showed similar response rates to checkpoint inhibitor therapy compared to NRAS wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13% for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median overall survival of patients with NRAS mutant melanoma was significantly lower with 21 months compared to 33 months in NRAS wildtype melanoma patients (P = 0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma. CONCLUSIONS: Immune checkpoint inhibition shows comparable response rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less favourable in case of NRAS mutation. Additional MEK inhibition might improve clinical benefit.
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Melanocytes as an emerging key player in niche regulation of limbal stem cells - Schlötzer-Schrehardt, Ursula; Polisetti, Naresh; Zenkel, Matthias; Naschberger, Elisabeth; Heger, Lukas; Dudziak, Diana; Stürzl, Michael; Kruse, Friedrich (2018)
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Melanocytes as emerging key players in niche regulation of limbal epithelial stem cells - Polisetti, Naresh; Gießl, Andreas; Zenkel, Matthias; Heger, Lukas; Dudziak, Diana; Naschberger, Elisabeth; Stich, Lena; Steinkasserer, Alexander; Kruse, Friedrich; Schlötzer-Schrehardt, Ursula (Ocular Surface, 2021)
Purpose: Limbal melanocytes (LMel) represent essential components of the corneal epithelial stem cell niche and are known to protect limbal epithelial stem/progenitor cells (LEPCs) from UV damage by transfer of melanosomes. Here, we explored additional functional roles for LMel in niche homeostasis, immune regulation and angiostasis. Methods: Human corneoscleral tissues were morphologically analyzed in normal, inflammatory and wound healing conditions. The effects of LMel on LEPCs were analyzed in direct and indirect co-culture models using electron microscopy, immunocytochemistry, qRT-PCR, Western blotting and functional assays; limbal mesenchymal stromal cells and murine embryonic 3T3 fibroblasts served as controls. The immunophenotype of LMel was assessed by flow cytometry before and after interferon-γ stimulation, and their immunomodulatory properties were analyzed by mixed lymphocytes reaction, monocyte adhesion assays and cytometric bead arrays. Their angiostatic effects on human umbilical cord endothelial cells (HUVECs) were evaluated by proliferation, migration, and tube formation assays. Results: LMel and LEPCs formed structural units in the human limbal stem cell niche in situ, which could be functionally replicated, including melanosome transfer, by co-cultivation in vitro. LMel supported LEPCs during clonal expansion and during epithelial wound healing by stimulating proliferation and migration, and suppressed their differentiation through direct contact and paracrine effects. Under inflammatory conditions, LMel were increased in numbers and upregulated expression of ICAM-1 and MHC II molecules (HLA-DR), but lacked expression of HLA-G, -DP, -DQ and costimulatory molecules CD80 and CD86. They were also found to be potent suppressors of alloreactive T- cell proliferation and cytokine secretion, which largely depended on direct cell-cell interaction. Moreover, the LMel secretome exerted angiostatic activity by inhibiting vascular endothelial cell proliferation and capillary network formation. Conclusion: These findings suggest that LMel are not only professional melanin-producing cells, but exert various non-canonical functions in limbal niche homeostasis by regulating LEPC maintenance, immune responses, and angiostasis. Their potent regulatory, immunomodulatory and anti-angiogenic properties may have important implications for future regenerative cell therapies.
CRIS-Team Scopus Importer:2021-09-03
Keywords: Angiostasis; Immune regulation; Inflammation; Limbal niche; Limbal stem cells; Melanocytes; Wound healing

Melanoma 2.0. Skin cancer as a paradigm for emerging diagnostic technologies, computational modelling and artificial intelligence - Vera, Julio; Lai, Xin; Baur, Andreas; Erdmann, Michael; Gupta, Shailendra; Gutta, Cristiano; Heinzerling, Lucie; Heppt, Markus; Kazmierczak, Philipp Maximilian; Kunz, Manfred; Lischer, Christopher; Putzer, Brigitte M.; et al. (Briefings in Bioinformatics, 2022)
We live in an unprecedented time in oncology. We have accumulated samples and cases in cohorts larger and more complex than ever before. New technologies are available for quantifying solid or liquid samples at the molecular level. At the same time, we are now equipped with the computational power necessary to handle this enormous amount of quantitative data. Computational models are widely used helping us to substantiate and interpret data. Under the label of systems and precision medicine, we are putting all these developments together to improve and personalize the therapy of cancer. In this review, we use melanoma as a paradigm to present the successful application of these technologies but also to discuss possible future developments in patient care linked to them. Melanoma is a paradigmatic case for disruptive improvements in therapies, with a considerable number of metastatic melanoma patients benefiting from novel therapies. Nevertheless, a large proportion of patients does not respond to therapy or suffers from adverse events. Melanoma is an ideal case study to deploy advanced technologies not only due to the medical need but also to some intrinsic features of melanoma as a disease and the skin as an organ. From the perspective of data acquisition, the skin is the ideal organ due to its accessibility and suitability for many kinds of advanced imaging techniques. We put special emphasis on the necessity of computational strategies to integrate multiple sources of quantitative data describing the tumour at different scales and levels.
CRIS-Team WoS Importer:2022-11-04

Melanoma in Pregnancy: CLAUDIUS - a retrospective, multicenter Study to evaluate the Risk of transplacental Transmission to the unborn Child - Gaiser, M. R.; Mueller, V.; Erdmann, Michael; Buehler, B.; Dugas-Breit, S.; Schatton, K.; Reinhardt, L.; Mengoni, M.; Mickler, M.; Pfoehler, C.; Weishaupt, C.; Herbst, R.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Melanoma Segmentation and Classification Employing Imaging and Graph Encodings - Rivera Monroy, Luis; Eberhardt, Martin; Ostalecki, Christian; Baur, Andreas; Vera, Julio; Maier, Andreas (Proceedings - 2022 IEEE/ACM International Conference on Connected Health: Applications, Systems and Engineering Technologies, CHASE 2022, 2022)
Histopathology imaging is crucial for the diagnosis and the decision on treating associated tissue diseases. For this reason, Computer-assisted approaches have gained popularity and shown promise in tasks such as segmentation and classification. However, collecting a significant amount of data and high-quality annotations remains a challenge. This work describes a pipeline for toponomy profiling on the population of cells that combines melanoma multidimensional fluorescent imaging, a supervised segmentation of the region of interest, and graph unsupervised embedded representation.The Multi-Epitope-Ligand Cartography (MELC) provides a range of data shown to be optimal for solving supervised and unsuper-vised tasks. This imaging technique and the methodology, such as the one presented here, are promising for further improvement in the study of diagnostic techniques and therapies for skin diseases, such as melanoma.
CRIS-Team Scopus Importer:2023-03-07
Keywords: melanoma; microscopy; neural networks; segmentation

Merkel Cell Carcinoma of the Head and Neck Compared to Other Anatomical Sites in a Real-World Setting: Importance of Surgical Therapy for Facial Tumors - Kirchberger, Michael; Heppt, Markus V.; Schuler, Gerold; Berking, Carola; Heinzerling, Lucie (Facial Plastic Surgery, 2019)
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin tumor with a high propensity for nodal involvement, local recurrence, and distant metastases. Up to 50% of MCC arises on head and neck (HN), which may impede oncological treatment due to insufficiently wide excisions and a lower rate of sentinel lymph node detection due to more complicated lymph drainage. Several studies have compared the clinical outcome of HN-MCC with those of non-head and neck (NHN) MCC yielding inconsistent results. This single-center, retrospective analysis compared the clinical outcome of 26 HN-MCC patients with 30 NHN-MCC patients. Overall survival (OS) and disease-free survival (DFS) were calculated with the Kaplan-Meier method assuming proportional hazards. The mean resection margins were 1.6 and 2.0 cm for the HN and NHN cohort, respectively. Local relapses were more frequently observed in patients with HN-MCC (19 vs. 10%). Patients with HN-MCC had a median OS of 4.3 years compared with 7.5 years in patients with NHN-MCC (p = 0.277). The median OS by tumor stage was 11, 3, 2, and 3 years in stage I, II, III, and IV disease, respectively (p = 0.009). The median DFS in HN-MCC was 10 years and not reached in the cohort with NHN-MCC patients (p = 0.939). Our data suggest a trend toward poorer outcomes of HN-MCC compared with NHN-MCC. Patients with MCC on the head and neck carry a higher risk for local relapse, requiring resolute surgical treatment also in facial localizations at early stages.
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Mesenchymal-Like Migration Strategies of Immune Cells in a 3D Environment - Czerwinski, Tina; Mark, Christoph; Roessner, Susanne; Bosch-Voskens, Caroline; Bhattacharjee, Tapomoy; Angelini, Thomas E.; Fabry, Ben (BIOPHYSICAL JOURNAL, 2020)
CRIS-Team WoS Importer:2020-03-13

Microglial expression of CD83 governs cellular activation and restrains neuroinflammation in experimental autoimmune encephalomyelitis - Sinner, Pia; Peckert-Maier, Katrin; Mohammadian, Hashem; Kuhnt, Christine; Draßner, Christina; Panagiotakopoulou, Vasiliki; Rauber, Simon; Linnerbauer, Mathias; Haimon, Zhana; Royzman, Dmytro; Kronenberg-Versteeg, Deborah; Ramming, Andreas; et al. (Nature Communications, 2023)
Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue, and the initial response of microglia determines the severity of neuro-inflammatory diseases. The CD83 molecule has been recently shown to modulate the activation status of dendritic cells and macrophages. Although the expression of CD83 is associated with early microglia activation in various disease settings, its functional relevance for microglial biology has been elusive. Here, we describe a thorough assessment of CD83 regulation in microglia and show that CD83 expression in murine microglia is not only associated with cellular activation but also with pro-resolving functions. Using single-cell RNA-sequencing, we reveal that conditional deletion of CD83 results in an over-activated state during neuroinflammation in the experimental autoimmune encephalomyelitis model. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system, deteriorating resolving mechanisms and exacerbating the disease. Thus, CD83 in murine microglia orchestrates cellular activation and, consequently, also the resolution of neuroinflammation.
CRIS-Team Scopus Importer:2023-08-11

Microneedling-assisted photodynamic therapy for the treatment of actinic keratosis: Results from a systematic review and meta-analysis - Steeb, Theresa; Niesert, Anne Charlotte; French, Lars E.; Berking, Carola; Heppt, Markus (Journal of the American Academy of Dermatology, 2020)
CRIS-Team Scopus Importer:2020-01-21

Microscopic polyangiitis after alemtuzumab treatment in relapsing-remitting MS - Sauer, Eva-Maria; Schliep, Stefan; Manger, Bernhard; Lee, De-Hyung; Linker, Ralf (Neurology, Neuroimmunology and Neuroinflammation, 2018)
EVALuna2:35512

Mild hyperthermia enhances human monocyte-derived dendritic cell functions and offers potential for applications in vaccination strategies - Knippertz, Ilka; Stein, Marcello F.; Dörrie, Jan; Schaft, Niels; Mueller, Ina; Deinzer, Anja; Steinkasserer, Alexander; Nettelbeck, Dirk. M. (International Journal of Hyperthermia, 2011)
Dendritic cell (DC)-based immunotherapy has been shown to be a promising strategy for anti-cancer therapy. Nevertheless, only a low overall clinical response rate has been observed in vaccinated patients with advanced cancer and therefore methods to improve DC immuno-stimulatory functions are currently under intense investigation. In this respect, we exposed human monocyte-derived DCs to a physiological temperature stress of 40°C for up to 24 h followed by analysis for (i) expression of different heat shock proteins, (ii) survival, (iii) cell surface maturation markers, (iv) cytokine secretion, and (v) migratory capacity. Furthermore, we examined the ability of heat-shocked DCs to prime nave CD8 + T cells after loading with MelanA peptide, by transfection with MelanA RNA, or by transduction with MelanA by an adenovirus vector. The results clearly indicate that in comparison to control DCs, which remained at 37°C, heat-treated cells revealed no differences concerning the survival rate or their migratory capacity. However, DCs exposed to thermal stress showed a time-dependent enhanced expression of the immune-chaperone heat shock protein 70A and both an up-regulation of co-stimulatory molecules such as CD80, CD83, and CD86 and of the inflammatory cytokine TNF-α. Moreover, these cells had a markedly improved capacity to prime autologous nave CD8 + T cells in vitro in an antigen-specific manner, independent of the method of antigen-loading. Thus, our strategy of heat treatment of DCs offers a promising means to improve DC functions during immune activation which, as a physical method, facilitates straight-forward applications in clinical DC vaccination protocols. © 2011 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Cytotoxic T lymphocytes; Dendritic cells; Hsp70; Hyperthermia; Immunotherapy

MiR-205-5p and miR-342-3p cooperate in the repression of the E2F1 transcription factor in the context of anticancer chemotherapy resistance - Lai, Xin; Gupta, Shailendra K.; Schmitz, Ulf; Marquardt, Stephan; Knoll, Susanne; Spitschak, Alf; Wolkenhauer, Olaf; Puetzer, Brigitte M.; Vera, Julio (Theranostics, 2018)
High rates of lethal outcome in tumour metastasis are associated with the acquisition of invasiveness and chemoresistance. Several clinical studies indicate that E2F1 overexpression across high-grade tumours culminates in unfavourable prognosis and chemoresistance in patients. Thus, fine-tuning the expression of E2F1 could be a promising approach for treating patients showing chemoresistance. Methods: We integrated bioinformatics, structural and kinetic modelling, and experiments to study cooperative regulation of E2F1 by microRNA (miRNA) pairs in the context of anticancer chemotherapy resistance. Results: We showed that an enhanced E2F1 repression efficiency can be achieved in chemoresistant tumour cells through two cooperating miRNAs. Sequence and structural information were used to identify potential miRNA pairs that can form tertiary structures with E2F1 mRNA. We then employed molecular dynamics simulations to show that among the identified triplexes, miR-205-5p and miR-342-3p can form the most stable triplex with E2F1 mRNA. A mathematical model simulating the E2F1 regulation by the cooperative miRNAs predicted enhanced E2F1 repression, a feature that was verified by in vitro experiments. Finally, we integrated this cooperative miRNA regulation into a more comprehensive network to account for E2F1-related chemoresistance in tumour cells. The network model simulations and experimental data indicate the ability of enhanced expression of both miR-205-5p and miR-342-3p to decrease tumour chemoresistance by cooperatively repressing E2F1. Conclusions: Our results suggest that pairs of cooperating miRNAs could be used as potential RNA therapeutics to reduce E2F1-related chemoresistance.
EVALuna2:34806
Keywords: Molecular dynamics simulation; Kinetic modelling; MicroRNA; Chemotherapy resistance; E2F1

miR-638 promotes melanoma metastasis and protects melanoma cells from apoptosis and autophagy - Bhattacharya, Animesh; Schmitz, Ulf; Raatz, Yvonne; Schoenherr, Madeleine; Kottek, Tina; Schauer, Marianne; Franz, Sandra; Saalbach, Anja; Anderegg, Ulf; Wolkenhauer, Olaf; Schadendorf, Dirk; Simon, Jan C.; et al. (Oncotarget, 2015)
The present study identified miR-638 as one of the most significantly overexpressed miRNAs in metastatic lesions of melanomas compared with primary melanomas. miR-638 enhanced the tumorigenic properties of melanoma cells in vitro and lung colonization in vivo. mRNA expression profiling identified new candidate genes including TP53INP2 as miR-638 targets, the majority of which are involved in p53 signalling. Overexpression of TP53INP2 severely attenuated proliferative and invasive capacity of melanoma cells which was reversed by miR-638. Depletion of miR-638 stimulated expression of p53 and p53 downstream target genes and induced apoptosis and autophagy. miR-638 promoter analysis identified the miR-638 target transcription factor associated protein 2? (TFAP2A/AP-2?) as a direct negative regulator of miR-638, suggestive for a double-negative regulatory feedback loop. Taken together, miR-638 supports melanoma progression and suppresses p53-mediated apoptosis pathways, autophagy and expression of the transcriptional repressor TFAP2A/AP-2?.
EVALuna2:19520

Mobility range, level of pain and sleep quality of patients with venous leg ulcers - Siegling, Michael; Renner, Regina; Erfurt-Berge, Cornelia (International Wound Journal, 2023)
This study aimed to compare mobility range, level of pain and sleep quality in patients with venous leg ulcers to age- and gender-matched controls without ulcers. Twenty patients with venous leg ulceration and 20 matched controls each answered a questionnaire, completed the short-physical performance battery, filled in a subject diary and wore a smartwatch for 1 week. The median daily step counts of the ulcer group (3622 steps/day) and the control group (5133 steps/day) were significantly different (P =.017). Significant correlations between total step count and age, duration of physical outdoor activities and scores in the short-physical performance battery were observed in the ulcer group. The scores in the short-physical performance battery were significantly different in both groups (P =.005), indicating weaker physical performance in the ulcer group. The greatest difference in the self-reported level of pain between the two groups was stated during movement. On average, the ulcer group slept shorter by 1 h 38 min (P =.002) and had 0.7 wake phases per night (P =.019) more than the control group. Assessing mobility in patients with venous leg ulcers can be used to develop preventive and interventional concepts to improve and individualise physical therapies.
CRIS-Team Scopus Importer:2023-05-05
Keywords: mobility; pain; sleep quality; smartwatch; venous leg ulcers

Model-based genotype-phenotype mapping used to investigate gene signatures of immune sensitivity and resistance in melanoma micrometastasis - Santos Rosales, Guido; Nikolov, Svetoslav; Lai, Xin; Eberhardt, Martin; Dreyer, Florian; Paul, Sushmita; Schuler, Gerold; Vera, Julio (Scientific Reports, 2016)
In this paper, we combine kinetic modelling and patient gene expression data analysis to elucidate biological mechanisms by which melanoma becomes resistant to the immune system and to immunotherapy. To this end, we systematically perturbed the parameters in a kinetic model and performed a mathematical analysis of their impact, thereby obtaining signatures associated with the emergence of phenotypes of melanoma immune sensitivity and resistance. Our phenotypic signatures were compared with published clinical data on pretreatment tumor gene expression in patients subjected to immunotherapy against metastatic melanoma. To this end, the differentially expressed genes were annotated with standard gene ontology terms and aggregated into metagenes. Our method sheds light on putative mechanisms by which melanoma may develop immunoresistance. Precisely, our results and the clinical data point to the existence of a signature of intermediate expression levels for genes related to antigen presentation that constitutes an intriguing resistance mechanism, whereby micrometastases are able to minimize the combined anti-tumor activity of complementary responses mediated by cytotoxic T cells and natural killer cells, respectively. Finally, we computationally explored the efficacy of cytokines used as low-dose co-adjuvants for the therapeutic anticancer vaccine to overcome tumor immunoresistance.
EVALuna2:19575

Model-Based Phenotypic Signatures Governing the Dynamics of the Stem and Semi-differentiated Cell Populations in Dysplastic Colonic Crypts - Nikolov, Svetoslav; Santos Rosales, Guido; Wolkenhauer, Olaf; Vera, Julio (Bulletin of Mathematical Biology, 2018)
Mathematical modeling of cell differentiated in colonic crypts can contribute to a better understanding of basic mechanisms underlying colonic tissue organization, but also its deregulation during carcinogenesis and tumor progression. Here, we combined bifurcation analysis to assess the effect that time delay has in the complex interplay of stem cells and semi-differentiated cells at the niche of colonic crypts, and systematic model perturbation and simulation to find model-based phenotypes linked to cancer progression. The models suggest that stem cell and semi-differentiated cell population dynamics in colonic crypts can display chaotic behavior. In addition, we found that clinical profiling of colorectal cancer correlates with the in silico phenotypes proposed by the mathematical model. Further, potential therapeutic targets for chemotherapy resistant phenotypes are proposed, which in any case will require experimental validation.
EVALuna2:34801

Modelling of protein kinase signaling pathways in melanoma and other cancers - Kunz, Manfred; Vera, Julio (Cancers, 2019)
Melanoma is a highly aggressive tumor with a strong dependence on intracellular signaling pathways. Almost half of all melanomas are driven by mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) with BRAFV600E being the most prevalent mutation. Recently developed targeted treatment directed against mutant BRAF and downstream mitogen-activated protein kinase (MAPK) MAP2K1 (also termed MEK1) have improved overall survival of melanoma patients. However, the MAPK signaling pathway is far more complex than a single chain of consecutively activated MAPK enzymes and it contains nested-, inherent feedback mechanisms, crosstalk with other signaling pathways, epigenetic regulatory mechanisms, and interacting small non-coding RNAs. A more complete understanding of this pathway is needed to better understand melanoma development and mechanisms of treatment resistance. Network reconstruction, analysis, and modelling under the systems biology paradigm have been used recently in different malignant tumors including melanoma to analyze and integrate ‘omics’ data, formulate mechanistic hypotheses on tumorigenesis, assess and personalize anticancer therapy, and propose new drug targets. Here we review the current knowledge of network modelling approaches in cancer with a special emphasis on melanoma.
CRIS-Team Scopus Importer:2019-05-03
Keywords: BRAF oncogene; Checkpoint inhibitors; Feedback regulation; Mitogen-activated protein kinase signaling; Systems biology; Targeted cancer therapy

Model soups improve performance of dermoscopic skin cancer classifiers - Maron, Roman C.; Hekler, Achim; Haggenmüller, Sarah; von Kalle, Christof; Utikal, Jochen S.; Müller, Verena; Gaiser, Maria; Meier, Friedegund; Hobelsberger, Sarah; Gellrich, Frank F.; Sergon, Mildred; Hauschild, Axel; et al. (European Journal of Cancer, 2022)
Background: Image-based cancer classifiers suffer from a variety of problems which negatively affect their performance. For example, variation in image brightness or different cameras can already suffice to diminish performance. Ensemble solutions, where multiple model predictions are combined into one, can improve these problems. However, ensembles are computationally intensive and less transparent to practitioners than single model solutions. Constructing model soups, by averaging the weights of multiple models into a single model, could circumvent these limitations while still improving performance. Objective: To investigate the performance of model soups for a dermoscopic melanoma-nevus skin cancer classification task with respect to (1) generalisation to images from other clinics, (2) robustness against small image changes and (3) calibration such that the confidences correspond closely to the actual predictive uncertainties. Methods: We construct model soups by fine-tuning pre-trained models on seven different image resolutions and subsequently averaging their weights. Performance is evaluated on a multi-source dataset including holdout and external components. Results: We find that model soups improve generalisation and calibration on the external component while maintaining performance on the holdout component. For robustness, we observe performance improvements for pertubated test images, while the performance on corrupted test images remains on par. Conclusions: Overall, souping for skin cancer classifiers has a positive effect on generalisation, robustness and calibration. It is easy for practitioners to implement and by combining multiple models into a single model, complexity is reduced. This could be an important factor in achieving clinical applicability, as less complexity generally means more transparency.
CRIS-Team Scopus Importer:2022-09-09
Keywords: Artificial intelligence; Calibration; Deep learning; Dermatology; Ensembles; Generalisation; Melanoma; Model soups; Nevus; Robustness

Modern diabetes devices for continuous blood sugar measuring: Limitations due to contact allergies - Kamann, Stefanie; Wagner, Nicola; Oppel, Eva (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
During the past years, diabetes diseases have increased significantly worldwide. However, new technologies such as continuous glucose measurement using a subcutaneous sensor are developing just as rapidly. A continuous improvement in insulin pump therapy is also contributing to an improved quality of life. A common feature of these modern devices for diabetes therapy is that they remain fixed in place on the skin for several days. In recent years, skin reactions, in particular pronounced contact dermatitis due to the devices and their adhesives have been increasingly reported. In particular, isobornyl acrylate, which used to be included in a glucose measurement sensor set, was identified as a main allergen. Development of contact allergy can result both in a necessity to quit the measuring system and in allergic cross-reactions to other systems.
CRIS-Team WoS Importer:2021-11-19

Moderne Sensortechnik zur kontinuierlichen Glukosemessung: Anwendungseinschränkungen durch Kontaktallergien - Kamann, Stefanie; Wagner, Nicola; Oppel, Eva (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
Diabetes-Erkrankungen haben in den letzten Jahren weltweit stark zugenommen. Genauso rasant entwickeln sich jedoch auch neue Technologien wie die kontinuierliche Glukosemessung mittels subkutaner Sensoren. Auch die stetig optimierte Insulinpumpentherapie trägt zur verbesserten Lebensqualität bei. Diesen modernen Geräten zur Diabetestherapie ist gemein, dass sie über mehrere Tage an einer Stelle auf der Haut fixiert werden. In den letzten Jahren wurde zunehmend über Hautreaktionen, insbesondere ausgeprägte Kontaktallergien, im Haftareal berichtet. Als Hauptallergen wurde Isobornylacrylat identifiziert, das initial in einem Sensorset zur Glukosemessung enthalten war. Die Entwicklung einer Kontaktallergie kann sowohl den notwendigen kompletten Verzicht auf das Messsystem als auch Kreuzreaktionen zu anderen Systemen bedeute
CRIS-Team Scopus Importer:2021-12-17

Modulation of urelumab glycosylation separates immune stimulatory activity from organ toxicity - Reitinger, Carmen; Ipsen Escobedo, Andrea; Hornung, Chiara; Heger, Lukas; Dudziak, Diana; Lux, Anja; Nimmerjahn, Falk (Frontiers in Immunology, 2022)
Checkpoint control and immunomodulatory antibodies have become important tools for modulating tumor or self-reactive immune responses. A major issue preventing to make full use of the potential of these immunomodulatory antibodies are the severe side-effects, ranging from systemic cytokine release syndrome to organ-specific toxicities. The IgG Fc-portion has been demonstrated to contribute to both, the desired as well as the undesired antibody activities of checkpoint control and immunomodulatory antibodies via binding to cellular Fcγ-receptors (FcγR). Thus, choosing IgG subclasses, such as human IgG4, with a low ability to interact with FcγRs has been identified as a potential strategy to limit FcγR or complement pathway dependent side-effects. However, even immunomodulatory antibodies on the human IgG4 background may interact with cellular FcγRs and show dose limiting toxicities. By using a humanized mouse model allowing to study the immunomodulatory activity of human checkpoint control antibodies in vivo, we demonstrate that deglycosylation of the CD137-specific IgG4 antibody urelumab results in an amelioration of liver toxicity, while maintaining T cell stimulatory activity. In addition, our results emphasize that antibody dosing impacts the separation of side-effects of urelumab from its therapeutic activity via IgG deglycosylation. Thus, glycoengineering of human IgG4 antibodies may be a possible approach to limit collateral damage by immunomodulatory antibodies and allow for a greater therapeutic window of opportunity.
CRIS-Team Scopus Importer:2022-10-28
Keywords: CD137; Fc-receptors; glycosylation; therapeutic antibody; urelumab

Molecular dynamics simulations of the delta and omicron SARS-CoV-2 spike – ACE2 complexes reveal distinct changes between both variants - Socher, Eileen; Heger, Lukas; Paulsen, Friedrich; Zunke, Friederike; Arnold, Philipp (Computational and Structural Biotechnology Journal, 2022)
SARS-CoV-2, the virus causing the COVID-19 pandemic, changes frequently through the appearance of mutations constantly leading to new variants. However, only few variants evolve as dominating and will be considered as “Variants of Concern” (VOCs) by the world health organization (WHO). At the end of 2020 the alpha (B.1.1.7) variant appeared in the United Kingdom and dominated the pandemic situation until mid of 2021 when it was substituted by the delta variant (B.1.617.2) that first appeared in India as predominant. At the end of 2021, SARS-CoV-2 omicron (B.1.1.529) evolved as the dominating variant. Here, we use in silico modeling and molecular dynamics (MD) simulations of the receptor-binding domain of the viral spike protein and the host cell surface receptor ACE2 to analyze and compare the interaction pattern between the wild type, delta and omicron variants. We identified residue 493 in delta (glutamine) and omicron (arginine) with altered binding properties towards ACE2.<br
Keywords: COVID-19; SARS-CoV-2; B.1.427/B.1.429; B.1.617.2; B.1.617.1; B.1.1.529; Epsilon variant; Delta variant; Kappa variant; Omicron variant; VOC; Spike protein; Receptor-binding domain; ACE2; Receptor interface; Molecular dynamics simulations

Monitoring skin metastases during immuno- and targeted therapy using total-body 3D photography - Erdmann, M.; Heinzerling, Lucie; Schuler, Gerold; Berking, Carola; Schliep, S. (Journal of the European Academy of Dermatology and Venereology, 2020)
CRIS-Team Scopus Importer:2020-08-14

Monocyte-Derived signals activate human natural Killer cells in response to Leishmania Parasites - Messlinger, Helena; Sebald, Heidi; Heger, Lukas; Dudziak, Diana; Bogdan, Christian; Schleicher, Ulrike (Frontiers in Immunology, 2018)
Activated natural killer (NK) cells release interferon (IFN)-gamma, which is crucial for the control of intracellular pathogens such as Leishmania. In contrast to experimental murine leishmaniasis, the human NK cell response to Leishmania is still poorly characterized. Here, we investigated the interaction of human blood NK cells with promastigotes of different Leishmania species (Leishmania major, Leishmania mexicana, Leishmania infantum, and Leishmania donovani). When peripheral blood mononuclear cells or purified NK cells and monocytes (all derived from healthy blood donors from Germany without a history of leishmaniasis) were exposed to promastigotes, NK cells showed increased surface expression of the activation marker CD69. The extent of this effect varied depending on the Leishmania species; differences between dermotropic and viscerotropic L. infantum strains were not observed. Upregulation of CD69 required direct contact between monocytes and Leishmania and was partly inhibitable by anti-interleukin (IL)-18. Unexpectedly, IL-18 was undetectable in most of the supernatants (SNs) of monocyte/parasite cocultures. Confocal fluorescence microscopy of non-permeabilized cells revealed that Leishmania-infected monocytes trans-presented IL-18 to NK cells. Native, but not heat-treated SNs of monocyte/Leishmania cocultures also induced CD69 on NK cells, indicating the involvement of a soluble heat-labile factor other than IL-18. A role for the NK cell-activating cytokines IL-1 beta, IL-2, IL-12, IL-15, IL-21, and IFN-alpha/beta was excluded. The increase of CD69 was not paralleled by NK cell IFN-gamma production or enhanced cytotoxicity. However, prior exposure of NK cells to Leishmania parasites synergistically increased their IFN-gamma release in response to IL-12, which was dependent on endogenous IL-18. CD1c(+) dendritic cells were identified as possible source of Leishmania-induced IL-12. Finally, we observed that direct contact between Leishmania and NK cells reduced the expression of CD56 mRNA and protein on NK cells. We conclude that Leishmania activate NK cells via trans-presentation of IL-18 by monocytes and by a monocyte-derived soluble factor. IL-12 is needed to elicit the IFN-gamma-response of NK cells, which is likely to be an important component of the innate control of the parasite.
EVALuna2:33305

Monocytes Elicit a Neutrophil-Independent Th1/Th17 Response Upon Immunization With a Mincle-Dependent Glycolipid Adjuvant - Desel, Christiane; Murray, Peter J.; Lehmann, Christian; Heger, Lukas; Christensen, Dennis; Andersen, Peter; Mack, Matthias; Dudziak, Diana; Lang, Roland (Frontiers in Immunology, 2022)
Successful subunit vaccination with recombinant proteins requires adjuvants. The glycolipid trehalose-dibehenate (TDB), a synthetic analog of the mycobacterial cord factor, potently induces Th1 and Th17 immune responses and is a candidate adjuvant for human immunization. TDB binds to the C-type lectin receptor Mincle and triggers Syk-Card9-dependent APC activation. In addition, interleukin (IL)-1 receptor/MyD88-dependent signaling is required for TDB adjuvanticity. The role of different innate immune cell types in adjuvant-stimulated Th1/Th17 responses is not well characterized. We investigated cell recruitment to the site of injection (SOI) and to the draining lymph nodes (dLNs) after immunization with the TDB containing adjuvant CAF01 in a protein-based vaccine. Recruitment of monocytes and neutrophils to the SOI and the dramatic increase in lymph node cellularity was partially dependent on both Mincle and MyD88. Despite their large numbers at the SOI, neutrophils were dispensable for the induction of Th1/Th17 responses. In contrast, CCR2-dependent monocyte recruitment was essential for the induction of Th1/Th17 cells. Transport of adjuvant to the dLN did not require Mincle, MyD88, or CCR2. Together, adjuvanticity conferred by monocytes can be separated at the cellular level from potential tissue damage by neutrophils.
CRIS-Team WoS Importer:2022-06-03

Monocyte Subsets Responsible for Immunoglobulin G-Dependent Effector Functions In Vivo - Biburger, Markus; Aschermann, Susanne; Schwab, Inessa; Lux, Anja; Albert, Heike; Danzer, Heike; Woigk, Melissa; Dudziak, Diana; Nimmerjahn, Falk (Immunity, 2011)
Immunoglobulin G (IgG) antibodies confer protection against pathogenic microorganisms, serve as therapeutics in tumor therapy, and are involved in destruction of healthy tissues during autoimmune diseases. Understanding the molecular pathways and effector cell types involved in antibody-mediated effector functions is a prerequisite to modulate these activities. In this study we used two independent model systems to identify innate immune effector cells required for IgG activity in vivo. We first defined the precise repertoire of receptors for the IgG Fc fragment (FcγR) on innate immune effector cells in the blood and on tissue-resident macrophage populations. Despite expression of relevant activating FcγRs on various phagocyte populations, our data indicate that the majority of these cell types are dispensable for IgG activity in vivo. In contrast, IgG-dependent effector functions were selectively impaired in animals lacking the CX CR1 Ly6C CD11c monocyte subset, which expressed the full set of FcγRs required for IgG activity. © 2011 Elsevier Inc.

Morphologische Kriterien vesikulobullöser Hauterkrankungen in der konfokalen In-vivo-Laserscanmikroskopie - Samhaber, Kinga T.; Buhl, Timo; Brauns, Birka; Hofmann, Lars; Mitteldorf, Christina; Seitz, Cornelia S.; Schoen, Michael P.; Rosenbergers, Albert; Haenssle, Holger A. (Journal der Deutschen Dermatologischen Gesellschaft, 2016)
Konfokale Laserscanmikroskopie (Reflectance confocal microscopy; RCM) kann eine nützliche Methode für die genaue, schnelle und nicht-invasive Diagnose für vesikullobullöse Hauterkrankungen (VSD) am Krankenbett sein. Das primäre Ergebnis dieser Studie war eine deskriptive statistische Analyse von RCM-Merkmalen, die mit einer ausgewählten Gruppe an VSD einhergehen.Monozentrische Beobachtungsstudie an einer Universitätsklinik für Dermatologie. Vierzig Hautläsionen bei 24 Patienten mit bullösem Pemphigoid (BP), Infektion mit Varizella Zoster (VZI) oder allergischer Kontaktdermatitis (ACD) wurden ausgewertet.Patienten mit BP, VZI und ACD wurden auf die Anwesenheit eines großen Spektrums an RCM-Merkmalen hin untersucht, darunter die histopathologische Korrelation von Spongiose, Vesikel/Hautblasen, epidermaler Nekrose, pleomorphen, ballonierte Keratinozyten und entzündlichen Infiltraten. Die drei Erkrankungen zeigten spezifische Muster für Auftreten dieser RCM-Merkmale. Wir identifizierten mit Hilfe einer multivariaten Regressionsanalyse einen Satz morphologischer Merkmale bei BP (Vesikel/Hautblasen an der dermoepidermalen Junktionszone, entzündliche Infiltrate in Hautblasen und basalen Epidermisschichten, Spongiose in basalen Epidermisschichten), VZI (Akantholyse im Stratum spinosum, epidermale Nekrose, pleomorphe, ballonierte Keratinozyten, multinukleäre Riesenzellen) und ACD (Mikrovesikel, Spongiose und auffällige entzündliche Infiltrate im Stratum granulosum/spinosum).RCM scheint ein nützliches Werkzeug bei der Analyse und der Unterscheidung einer ausgewählten Gruppe von VSDs zu sein und bietet eine gute Korrelation mit histopathologischen Untersuchungsergebnissen.
EVALuna2:19620

Morphology as indicator of adaptive changes of model tissues in osmotically and chemically changing environments - Höllring, Kevin; Vurnek, Damir; Gehrer, Simone; Dudziak, Diana; Hubert, Maxime; Smith, Ana-Suncana (Biomaterials Advances, 2023)
We investigate the formation and maintenance of the homeostatic state in the case of 2D epithelial tissues following an induction of hyperosmotic conditions, using media enriched with 80 to 320 mOsm of mannitol, NaCl, and urea. We characterise the changes in the tissue immediately after the osmotic shock, and follow it until the new homeostatic state is formed. We characterise changes in cooperative motility and proliferation pressure in the tissue upon treatment with the help of a theoretical model based on the delayed Fisher-Kolmogorov formalism, where the delay in density evolution is induced by the the finite time of the cell division. Finally we explore the adaptation of the homeostatic tissue to highly elevated osmotic conditions by evaluating the morphology and topology of cells after 20 days in incubation. We find that hyperosmotic environments together with changes in the extracellular matrix induce different mechanical states in viable tissues, where only some remain functional. The perspective is a relation between tissue topology and function, which could be explored beyond the scope of this manuscript. Experimental investigation of morphological effect of change of osmotic conditions on long-term tissue morphology and topology Effect of osmotic changes on transient tissue growth behaviour Analysis of recovery process of tissues post-osmotic-shock Toxicity limits of osmolytes in mid- to long-term tissue evolution Tissue adaptation to physiological changes in environment Long-term tissue stabilisation under altered osmotic conditions.
CRIS-Team Scopus Importer:2023-11-03
Keywords: Epithelium topology and morphology; Fisher-Kolmogorov theory; Hyperosmotic conditions; Model tissue development; Tissue adaptation

Multi-antigen imaging reveals inflammatory dc, adam17 and neprilysin as effectors in keloid formation - Rath, Mathias; Pitiot, Alain; Kirr, Michael; Fröhlich, Waltraud; Plosnita, Bianca; Schliep, Stefan; Bauerschmitz, Jürgen; Baur, Andreas; Ostalecki, Christian (International Journal of Molecular Sciences, 2021)
Keloid is an aberrant scarring process of the skin, characterized by excessive extracellular matrix synthesis and deposition. The pathogenesis of this prevalent cutaneous disorder is not fully understood; however, a persistent inflammatory process is observed. To obtain more insight into this process, we analyzed lesional, perilesional and healthy tissue using multi-antigen-analysis (MAA) in conjunction with a data mining approach. Here, we demonstrate that monocyte-derived inflammatory dendritic cells (CD1a+, CD11c+, CD14+) and activated CD4+ T lymphocytes (CD45 RO+) dominated the immune infiltration in keloids while associating with fibroblasts. In perilesional tissue, precursor immune cells were dominant in the perivascular area, suggesting that they were attracted by an immune process, potentially in the lesional area. Supporting this hypothesis, only in keloid lesions, high levels of ADAM10/17 and Neprilysin (CD10) were observed in both fibroblasts and leukocytes. The spatial proximity of these two cell types, which could be confirmed by image analysis only in lesional tissue, could be a potential factor leading to the activation of fibroblasts. Our findings provide new insight into the pathogenesis of keloid formation and reveal metalloproteinases as a target for therapeutical intervention.
CRIS-Team Scopus Importer:2021-09-10
Keywords: Dendritic cells; Multiplex imaging; Proteases; Scar; Single-cell analysis; Tumor biology; Tumor microenvironment

Multicentric Sentinel Healthcare Research Project of Skin Cancer Centers in Nuremberg, Erlangen, Regensburg and Wuerzburg - Enzelsberger, K.; Debus, D.; Schultz, E.; Haferkamp, S.; Hegemann, M. V.; Stolze, I.; Erdmann, M.; Schellerer, Vera (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Multicomponent compression system use in patients with chronic venous insufficiency: A real-life prospective study - Stücker, Markus; Münter, Karl Christian; Erfurt-Berge, Cornelia; Lützkendorf, Steffen; Eder, Stephan; Möller, Udo; Dissemond, Joachim (Journal of Wound Care, 2021)
Objective: Compression therapy is the cornerstone of therapeutic management of patients with chronic venous insufficiency (CVI). This study aimed to evaluate the efficacy and safety of a multicomponent compression system in an unselected population of patients with CVI problems under real-life conditions. Method: A prospective, multicentre, observational study with a multicomponent two-bandage compression system (UrgoK2, Laboratoires Urgo, France) was conducted in 103 centres in Germany. Main outcomes included wound healing rate, wound healing progression, assessment of oedema and ankle mobility, local tolerability and acceptance of the compression therapy. Results: A total of 702 patients with venous leg ulcers (VLU) and/or with lower limb oedema due to CVI were treated with the evaluated system for a mean (±standard deviation) duration of 27±17 days. By the last visit, 30.9% of wounds had healed and 61.8% had improved. Limb oedema was resolved in 66.7% of patients and an improvement of ankle mobility was reported in 44.2% of patients. The skin condition under the compression therapy was also considered as improved in 73.9% of patients and a substantial reduction of pain was achieved, both in number of patients reporting pain and in pain intensity. Compression therapy with the evaluated system was 'very well' or 'well' tolerated and 'very well' or 'well' accepted by >95% of patients. These positive outcomes were in line with the general opinion of physicians on the evaluated compression bandages, which were judged 'very useful' or 'useful' for >96.6% of patients. Similar results were reported regardless of the treated condition, VLU and/or limb oedema. Conclusion: Real-life data documented in this large observational study of non-selected patients receiving compression therapy in daily practice confirm the benefits and safety profile of the evaluated compression system. This study also confirms the high-level of performance and acceptability of the system, regardless of the characteristics of the wounds or patients at initiation of the treatment. The data support the use of this multicomponent compression system as one first-line intervention in patients with symptoms caused by CVI.
CRIS-Team Scopus Importer:2021-05-28
Keywords: Chronic venous insufficiency; Compression therapy; Leg ulcers; Lower limb oedema; Observational study; Oedema; Wound; Wound healing

Multiepitope tissue analysis reveals SPPL3-mediated ADAM10 activation as a key step in the transformation of melanocytes - Ostalecki, Christian; Lee, Jung-Hyun; Dindorf, Jochen; Collenburg, Lena; Schierer, Stephan; Simon, Beate; Schliep, Stefan; Kremmer, Elisabeth; Schuler, Gerold; Baur, Andreas (Science Signaling, 2017)
The evolution of cancer is characterized by the appearance of specific mutations, but these mutations are translated into proteins that must cooperate to induce malignant transformation. Using a systemic approach with the multiepitope ligand cartography (MELC) technology, we analyzed protein expression profiles (PEPs) in nevi and BRAFV600E-positive superficial spreading melanomas (SSMs) from patient tissues to identify key transformation events. The PEPs in nevi and SSMs differed predominantly in the abundance of specific antigens, but the PEPs of nevi- and melanoma-associated keratinocytes gradually changed during the transformation process. A stepwise change in PEP with similar properties occurred in keratinocytes cocultured with melanoma cells. Analysis of the individual steps indicated that activation of the metalloproteinase ADAM10 by signal peptide peptidase-like 3 (SPPL3) triggered by mutant BRAFV600E was a critical transformation event. SPPL3-mediated ADAM10 activation involved the translocation of SPPL3 and ADAM10 into Rab4- or Rab27-positive endosomal compartments. This endosomal translocation, and hence ADAM10 activation, was inhibited by the presence of the tumor suppressor PTEN. Our findings suggest that systematic tissue antigen analysis could complement whole-genome approaches to provide more insight into cancer development.
EVALuna2:34322

Multi-level cancer profiling through joint cell-graph representations - Rivera Monroy, Luis; Rist, Leonhard; Wilm, Frauke; Ostalecki, Christian; Baur, Andreas; Vera González, Julio; Breininger, Katharina; Maier, Andreas (Smart Health, 2024)
Computer-aided analysis of digitized pathology samples has significantly advanced with the rapid progression of machine and Deep Learning (DL) methods. However, most existing approaches primarily focus on features extracted from patches due to the large image sizes. This focus limits the ability of Convolutional Neural Networks (CNNs) to capture global information from the samples, resulting in an incomplete phenotypical and topological representation and thereby restricting the diagnostic capabilities of these methods. The recent emergence of Graph Neural Networks (GNNs) offers new opportunities to overcome these limitations through graph-driven representations of pathological samples. This work introduces a graph-based framework that encompasses diverse cancer types and integrates different imaging modalities. In this framework, histopathology samples are represented as graphs, and a pipeline facilitating cell-wise and disease classification is developed. The results support this motivation: for cell-wise classification, we achieved an average accuracy of , and for disease-wise classification, an average accuracy of 83%, outperforming reference models such as XGBoost and standard CNNs. This approach not only provides flexibility in combining various diseases but also extends to integrating different staining technique
Keywords: Fluorescence microscopy imageGraph deep learningMultiplex imagingDigital pathology

Multi-Level Computational Modeling of Anti-Cancer Dendritic Cell Vaccination Utilized to Select Molecular Targets for Therapy Optimization - Lai, Xin; Keller, Christine; Santos Rosales, Guido; Schaft, Niels; Dörrie, Jan; Vera, Julio (Frontiers in Cell and Developmental Biology, 2022)
Dendritic cells (DCs) can be used for therapeutic vaccination against cancer. The success of this therapy depends on efficient tumor-antigen presentation to cytotoxic T lymphocytes (CTLs) and the induction of durable CTL responses by the DCs. Therefore, simulation of such a biological system by computational modeling is appealing because it can improve our understanding of the molecular mechanisms underlying CTL induction by DCs and help identify new strategies to improve therapeutic DC vaccination for cancer. Here, we developed a multi-level model accounting for the life cycle of DCs during anti-cancer immunotherapy. Specifically, the model is composed of three parts representing different stages of DC immunotherapy – the spreading and bio-distribution of intravenously injected DCs in human organs, the biochemical reactions regulating the DCs’ maturation and activation, and DC-mediated activation of CTLs. We calibrated the model using quantitative experimental data that account for the activation of key molecular circuits within DCs, the bio-distribution of DCs in the body, and the interaction between DCs and T cells. We showed how such a data-driven model can be exploited in combination with sensitivity analysis and model simulations to identify targets for enhancing anti-cancer DC vaccination. Since other previous works show how modeling improves therapy schedules and DC dosage, we here focused on the molecular optimization of the therapy. In line with this, we simulated the effect in DC vaccination of the concerted modulation of combined intracellular regulatory processes and proposed several possibilities that can enhance DC-mediated immunogenicity. Taken together, we present a comprehensive time-resolved multi-level model for studying DC vaccination in melanoma. Although the model is not intended for personalized patient therapy, it could be used as a tool for identifying molecular targets for optimizing DC-based therapy for cancer, which ultimately should be tested in in vitro and in vivo experiments.
CRIS-Team Scopus Importer:2022-03-04
Keywords: bio-distribution; cellular therapy; dendritic cell vaccine; gene networks; immunotherapy; kinetic modeling; melanoma; systems medicine

Multiple Dermal Abscesses by Trichophyton rubrum in an Immunocompromised Patient - Toussaint, Frédéric; Sticherling, Michael (Frontiers in Medicine, 2019)
We report the case of a 52-year-old man who presented with a 10 year history of multiple nodules with purulent drainage on the upper extremities. Several attempts of treatment with oral antibiotics had been unsuccessful. A skin biopsy specimen showed a dermal abscess with branched septate hyphae. A mycological culture of pus and of the biopsy specimen revealed Trichophyton rubrum. Deeper dermatophytosis presenting as dermal abscesses is a rare disease which occurs normally in immunocompromised conditions. Our patient was on immunosuppressive therapy with methylprednisolone and azathioprine because of inflammatory demyelinating polyneuropathy and presented with extensive abscesses. In cases of dermal abscesses it is important to not only consider bacterial but also fungal infections as underlying cause.
CRIS-Team WoS Importer:2019-05-24

Multiple dermal Abscesses by Trichophyton rubrum in an immunosuppressed Patients - Toussaint, Frédéric; Sticherling, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Multiple interferon regulatory factor and NF-κB sites cooperate in mediating cell-type-and maturation-specific activation of the human CD83 promoter in dendritic cells - Stein, Marcello F.; Lang, Stefan; Winkler, Thomas; Deinzer, Anja; Erber, Sebastian; Nettelbeck, Dirk M.; Naschberger, Elisabeth; Jochmann, Ramona; Stürzl, Michael; Slany, Robert; Werner, Thomas; Steinkasserer, Alexander; et al. (Molecular and Cellular Biology, 2013)
CD83 is one of the best-known surface markers for fully mature dendritic cells (mature DCs), and its cell-type-and maturationspecific regulation makes the CD83 promoter an interesting tool for the genetic modulation of DCs. To determine the mechanisms regulating this DC-and maturation-specific CD83 expression, chromatin immunoprecipitation (ChIP)-on-chip microarray, biocomputational, reporter, electrophoretic mobility shift assay (EMSA), and ChIP analyses were performed. These studies led to the identification of a ternary transcriptional activation complex composed of an upstream regulatory element, a minimal promoter, and an enhancer, which have not been reported in this arrangement for any other gene so far. Notably, these DNA regions contain a complex framework of interferon regulatory factor (IRF)-and NF-κB transcription factor-binding sites mediating their arrangement. Mutation of any of the IRF-binding sites resulted in a significant loss of promoter activity, whereas overexpression of NF-κB transcription factors clearly enhanced transcription. We identified IRF-1, IRF-2, IRF-5, p50, p65, and cRel to be involved in regulating maturation-specific CD83 expression in DCs. Therefore, the characterization of this promoter complex not only contributes to the knowledge of DC-specific gene regulation but also suggests the involvement of a transcriptional module with binding sites separated into distinct regions in transcriptional activation as well as cell-type-and maturation-specific transcriptional targeting of DCs. © 2013, American Society for Microbiology.

Multiple thoracic Erosions after Vacation in Tunisia - Meder, Christine; Sticherling, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-04-16

Multiplex Tissue Analysis of the Tumor Microenvironment and Crucial Factors in Melanoma Pathogenesis - Ostalecki, Christian; Lee, Jung-Hyun; Schierer, Stephan; Collenburg, Lena; Schuler, Gerold; Baur, Andreas (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection - Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio (Frontiers in Physiology, 2017)
Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung.
EVALuna2:35406

Murine CD83-positive T cells mediate suppressor functions in vitro and in vivo - Kreiser, Simon; Eckhardt, Jenny; Kuhnt, Christine; Stein, Marcello F.; Krzyzak, Lena; Seitz, Christine; Tucher, Christine; Knippertz, Ilka; Becker, Christoph; Günther, Claudia; Steinkasserer, Alexander; Lechmann, Matthias (Immunobiology, 2015)
The CD83 molecule (CD83) is a well-known surface marker present on mature dendritic cells (mDC). In this study, we show that CD83 is also expressed on a subset of T cells which mediate regulatory T cell (Treg)-like suppressor functions in vitro and in vivo. Treg-associated molecules including CD25, cytotoxic T lymphocyte antigen-4 (CTLA-4), glucocorticoid-induced TNFR family-related gene (GITR), Helios and neuropilin-1 (NRP-1) as well as forkhead box protein 3 (FOXP3) were specifically expressed by these CD83(+) T cells. In contrast, CD83(-) T cells showed a naive T cell phenotype with effector T cell properties upon activation. Noteworthy, CD83(-) T cells were not able to upregulate CD83 despite activation. Furthermore, CD83(+) T cells suppressed the proliferation and inflammatory cytokine release of CD83(-) T cells in vitro. Strikingly, stimulated CD83(+) T cells released soluble CD83 (sCD83), which has been reported to possess immunosuppressive properties. In vivo, using the murine transfer colitis model we could show that CD83(+) T cells were able to suppress colitis symptoms while CD83(-) T cells possessed effector functions. In addition, this CD83 expression is also conserved on expanded human Treg. Thus, from these studies we conclude that CD83(+) T cells share important features with regulatory T cells, identifying CD83 as a novel lineage marker to discriminate between different T cell populations.
EVALuna2:1841

Mutations in IL36RN in patients with generalized pustular psoriasis - Koerber, Andreas; Moessner, Rotraut; Renner, Regina; Sticht, Heinrich; Wilsmann-Theis, Dagmar; Schulz, Peter; Sticherling, Michael; Traupe, Heiko; Hüffmeier, Ulrike (Journal of Investigative Dermatology, 2013)
EVALuna2:9180

Mutations in the B.1.1.7 SARS-CoV-2 Spike Protein Reduce Receptor-Binding Affinity and Induce a Flexible Link to the Fusion Peptide - Socher, Eileen; Conrad, Marcus; Heger, Lukas; Paulsen, Friedrich; Sticht, Heinrich; Zunke, Friederike; Arnold, Philipp (Biomedicines, 2021)
The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. Amino acid exchanges within the SARS-CoV-2 spike protein variant of B.1.1.7 affect inter-monomeric contact sites within the trimer (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the spike protein. However, the molecular consequences of mutations within B.1.1.7 on spike protein dynamics and stability or ACE2 binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein trimer. Furthermore, we found increased flexibility in direct spatial proximity of the fusion peptide due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7. This study also implies a reduced binding affinity for B.1.1.7 with ACE2, as the N501Y mutation restructures the RBD-ACE2 interface, significantly decreasing the linear interaction energy between the RBD and ACE2. Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD-ACE2 interface. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7.
CRIS-Team WoS Importer:2021-06-04
Keywords: COVID-19; SARS-CoV-2; B.1.1.7; molecular dynamics simulation; ACE2; receptor binding

Mycobacterial Cord Factor Reprograms the Macrophage Response to IFN-γ towards Enhanced Inflammation yet Impaired Antigen Presentation and Expression of GBP1 - Huber, Alexandra; Killy, Barbara; Grummel, Nadine; Bodendorfer, Barbara; Paul, Sushmita; Wiesmann, Veit; Naschberger, Elisabeth; Zimmer, Jana; Wirtz, Stefan; Schleicher, Ulrike; Vera, Julio; Ekici, Arif Bülent; et al. (Journal of Immunology, 2020)
Mycobacteria survive in macrophages despite triggering pattern recognition receptors and T cell-derived IFN-γ production. Mycobacterial cord factor trehalose-6,6-dimycolate (TDM) binds the C-type lectin receptor MINCLE and induces inflammatory gene expression. However, the impact of TDM on IFN-γ-induced macrophage activation is not known. In this study, we have investigated the cross-regulation of the mouse macrophage transcriptome by IFN-γ and by TDM or its synthetic analogue trehalose-6,6-dibehenate (TDB). As expected, IFN-γ induced genes involved in Ag presentation and antimicrobial defense. Transcriptional programs induced by TDM and TDB were highly similar but clearly distinct from the response to IFN-γ. The glycolipids enhanced expression of a subset of IFN-γ-induced genes associated with inflammation. In contrast, TDM/TDB exerted delayed inhibition of IFN-γ-induced genes, including pattern recognition receptors, MHC class II genes, and IFN-γ-induced GTPases, with antimicrobial function. TDM downregulated MHC class II cell surface expression and impaired T cell activation by peptide-pulsed macrophages. Inhibition of the IFN-γ-induced GTPase GBP1 occurred at the level of transcription by a partially MINCLE-dependent mechanism that may target IRF1 activity. Although activation of STAT1 was unaltered, deletion of Socs1 relieved inhibition of GBP1 expression by TDM. Nonnuclear Socs1 was sufficient for inhibition, suggesting a noncanonical, cytoplasmic mechanism. Taken together, unbiased analysis of transcriptional reprogramming revealed a significant degree of negative regulation of IFN-γ-induced Ag presentation and antimicrobial gene expression by the mycobacterial cord factor that may contribute to mycobacterial persistence.
CRIS-Team Scopus Importer:2020-09-18

Mycophenolate Mofetil for the Treatment of Ipilimumab-induced Autoimmune Colitis in Patients with metastatic Melanoma - Naoum, C.; Majenka, P.; Loquai, C.; Kaehler, K.; Heinzerling, Lucie; Dudda, M.; Hassel, J. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Myeloid cells and the microenvironment, microorganisms and metabolism - Bogdan, Christian; Steinkasserer, Alexander (Immunobiology, 2015)
EVALuna2:7673

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases - Haskamp, Stefan; Bruns, Heiko; Hahn, Madelaine; Hoffmann, Markus; Gregor, Anne; Löhr, Sabine; Hahn, Jonas; Ringer, Mark; Flamann, Cindy; Frey, Benjamin; Lesner, Adam; Thiel, Christian; et al. (American Journal of Human Genetics, 2020)
Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%–41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E−08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E−09); this effect was stronger when including IL36RN mutations (1.48E−13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.
CRIS-Team Scopus Importer:2020-09-11
Keywords: ACH; acrodermatitis continua suppurativa Hallopeau; activation of IL-36 precursors; acute generalized 4 exanthematous pustulosis; AGEP; efferocytosis; generalized pustular psoriasis; GPP; impaired NETosis; MPO deficiency; myeloperoxidase; oligogenic inheritance

Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor–Associated Myocarditis - Thavendiranathan, Paaladinesh; Zhang, Lili; Zafar, Amna; Drobni, Zsofia D.; Mahmood, Syed S.; Cabral, Marcella; Awadalla, Magid; Nohria, Anju; Zlotoff, Daniel A.; Thuny, Franck; Heinzerling, Lucie; Barac, Ana; et al. (Journal of the American College of Cardiology, 2021)
Background: Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited. Objectives: This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis. Methods: In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. Results: Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 ± 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction <55%. Across all patients, mean z-scores for T1 and T2 values were 2.9 ± 1.9 (p < 0.001) and 2.2 ± 2.1 (p < 0.001), respectively. On Siemens 1.5-T scanner (n = 67), native T1 (1,079.0 ± 55.5 ms vs. 1,000.3 ± 22.1 ms; p < 0.001) and T2 (56.2 ± 4.9 ms vs. 49.8 ± 2.2 ms; p < 0.001) values were elevated compared with reference values. Abnormal T1 and T2 values were seen in 78% and 43% of the patients, respectively. Applying the modified Lake Louise Criteria, 95% met the nonischemic myocardial injury criteria and 53% met the myocardial edema criteria. Native T1 values had excellent discriminatory value for subsequent MACE, with an area under the curve of 0.91 (95% confidence interval: 0.84 to 0.98). Native T1 values (for every 1-unit increase in z-score, hazard ratio: 1.44; 95% confidence interval: 1.12 to 1.84; p = 0.004) but not T2 values were independently associated with subsequent MACE. Conclusions: The use of T1 mapping and application of the modified Lake Louise Criteria provides important diagnostic value, and T1 mapping provides prognostic value in patients with ICI myocarditis.
CRIS-Team Scopus Importer:2021-03-26
Keywords: cardiovascular magnetic resonance; immune checkpoint inhibitor; Lake Louise Criteria; major adverse cardiovascular event; myocarditis; T1 mapping; T2 mapping

Myocarditis in Patients Treated With Immune Checkpoint Inhibitors - Mahmood, Syed S.; Fradley, Michael G.; Cohen, Justine V.; Nohria, Anju; Reynolds, Kerry L.; Heinzerling, Lucie; Sullivan, Ryan J.; Damrongwatanasuk, Rongras; Chen, Carol L.; Gupta, Dipti; Kirchberger, Michael C.; Awadalla, Magid; et al. (Journal of the American College of Cardiology, 2018)
BACKGROUND: Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized. OBJECTIVES: The authors sought to understand the presentation and clinical course of ICI-associated myocarditis. METHODS: After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block. RESULTS: The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates. CONCLUSIONS: Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.
EVALuna2:34388

Myocarditis in the Setting of Cancer Therapeutics Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology - Bonaca, Marc P.; Olenchock, Benjamin A.; Salem, Joe-Elie; Wiviott, Stephen D.; Ederhy, Stephane; Cohen, Ariel; Stewart, Garrick C.; Choueiri, Toni K.; Di Carli, Marcelo; Allenbach, Yves; Kumbhani, Dharam J.; Heinzerling, Lucie; et al. (Circulation, 2019)
Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor-associated myocarditis. Although the full spectrum of immune checkpoint inhibitor-associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor-associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.
CRIS-Team WoS Importer:2019-07-26

Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors - Moreira, Alvaro; Loquai, Carmen; Pfoefer, Claudia; Kaehler, Katharina C.; Knauss, Samuel; Heppt, Markus V.; Gutzmer, Ralf; Dimitriou, Florentia; Meier, Friedegund; Mitzel-Rink, Heidrun; Schuler, Gerold; Terheyden, Patrick; et al. (European Journal of Cancer, 2019)
AIM: To characterise clinical presentation, laboratory and histopathologic characteristics and assess the treatment and outcome of neuromuscular side-effects of checkpoint therapy. METHODS: The side-effect registry and the institutional database from ten skin cancer centres were queried for reports on myositis and neuromuscular side-effects induced by checkpoint inhibitors. In total, 38 patients treated with ipilimumab, tremelimumab, nivolumab and pembrolizumab for metastatic skin cancer were evaluated and characterised. RESULTS: Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases. CONCLUSION: Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.
EVALuna2:36556

Nachwuchs für die Dermatologie begeistern: Die DDG auf dem Bundeskongress der Bundesvertretung der Medizinstudierenden in Deutschland e. V - Huening, Svea; Rode, Susen; Nashan, Dorothee; Emmert, Steffen; Uslu, Ugur (Journal der Deutschen Dermatologischen Gesellschaft, 2019)
EVALuna2:212829

NanoString technology distinguishes anti-TIF-1γ+ from anti-Mi-2+ dermatomyositis patients - Preusse, Corinna; Eede, Pascale; Heinzerling, Lucie; Freitag, Kiara; Koll, Randi; Froehlich, Waltraud; Schneider, Udo; Allenbach, Yves; Benveniste, Olivier; Schaenzer, Anne; Goebel, Hans-Hilmar; Stenzel, Werner; et al. (Brain Pathology, 2021)
Dermatomyositis (DM) is a systemic idiopathic inflammatory disease affecting skeletal muscle and skin, clinically characterized by symmetrical proximal muscle weakness and typical skin lesions. Recently, myositis-specific autoantibodies (MSA) became of utmost importance because they strongly correlate with distinct clinical manifestations and prognosis. Antibodies against transcription intermediary factor 1γ (TIF-1γ) are frequently associated with increased risk of malignancy, a specific cutaneous phenotype and limited response to therapy in adult DM patients. Anti-Mi-2 autoantibodies, in contrast, are typically associated with classic DM rashes, prominent skeletal muscle weakness, better therapeutic response and prognosis, and less frequently with cancer. Nevertheless, the sensitivity of autoantibody testing is only moderate, and alternative reliable methods for DM patient stratification and prediction of cancer risk are needed. To further investigate these clinically distinct DM subgroups, we herein analyzed 30 DM patients (n = 15 Mi-2+ and n = 15 TIF-1 γ+) and n = 8 non-disease controls (NDC). We demonstrate that the NanoString technology can be used as a very sensitive method to clearly differentiate these two clinically distinct DM subgroups. Using the nCounter PanCancer Immune Profiling Panel™, we identified a set of significantly dysregulated genes in anti-TIF-1γ+ patient muscle biopsies including VEGFA, DDX58, IFNB1, CCL5, IL12RB2, and CD84. Investigation of type I IFN-regulated transcripts revealed a striking type I interferon signature in anti-Mi-2+ patient biopsies. Our results help to stratify both subgroups and predict, which DM patients require an intensified diagnostic procedure and might have a poorer outcome. Potentially, this could also have implications for the therapeutic approach.
CRIS-Team Scopus Importer:2021-06-11
Keywords: dermatomyositis; Mi-2; myositis-specific antibody; NanoString; skeletal muscle; TIF-1γ

Nebenwirkungsmanagement bei Immun-Checkpoint-Blockade durch CTLA-4- und PD-1-Antikörper beim metastasierten Melanom – ein Update - Kähler, Katharina C.; Hassel, Jessica C.; Heinzerling, Lucie; Loquai, Carmen; Thoms, Kai Martin; Ugurel, Selma; Zimmer, Lisa; Gutzmer, Ralf (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-06-16

Necrobiosis lipoidica - Clinical Findings and Therapeutic Approaches [Necrobiosis lipoidica - Klinische Charakteristika und therapeutische Ansätze] - Schliep, S.; Erfurt-Berge, Cornelia (Aktuelle Dermatologie, 2019)
Necrobiosis lipoidica is a rare granulomatous skin disorder presenting with yellowish-brown plaques preferentially on the lower extremities. The appearance of ulcerative lesions can complicate the course of the disease. Clear therapeutic recommendations are still missing since large randomized controlled trials are lacking due to small number of patients. Next to corticosteroids the use of fumaric acid esters and biologicals represent encouraging therapeutic approaches.
CRIS-Team Scopus Importer:2019-05-02

Nectin-1 determines the susceptibility of malignant melanoma to oncolytic herpes simplex virus in vitro and in vivo - Schwertner, B.; Lindner, 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. (EXPERIMENTAL DERMATOLOGY, 2022)
CRIS-Team WoS Importer:2022-03-04

Nectin-1 expression correlates with the susceptibility of malignant melanoma to oncolytic herpes simplex virus in vitro and in vivo - Schwertner, Barbara; Lindner, Georg; Toledo Stauner, Camila; Klapproth, Elisa; Magnus, Clara; Rohrhofer, Anette; Gross, Stefanie; Schuler-Thurner, Beatrice; Öttl, Veronika; Feichtgruber, Nicole; Drexler, Konstantin; Evert, Katja; et al. (Cancers, 2021)
Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus, is approved for intralesional injection of unresectable stage IIIB/IVM1a melanoma. However, it is still unclear which parameter(s) predict treatment response or failure. Our study aimed at characterizing surface receptors Nectin-1 and the herpes virus entry mediator (HVEM) in addition to intracellular molecules cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) as potential bio-markers for oncolytic virus treatment. In 20 melanoma cell lines, oncolytic activity of T-VEC was correlated with the expression of Nectin-1 but not HVEM, as evaluated via flow cytometry and immunohistochemistry. Knockout using CRISPR/Cas9 technology confirmed the superior role of Nectin-1 over HVEM for entry and oncolytic activity of T-VEC. Neither cGAS nor STING as evaluated by Western Blot and immunohistochemistry correlated with T-VEC induced oncolysis. The role of these biomarkers was retrospectively analyzed for the response of 35 cutaneous melanoma metastases of 21 patients to intralesional T-VEC injection, with 21 (60.0%) of these lesions respond-ing with complete (n = 16) or partial regression (n = 5). Nectin-1 expression in pretreatment biopsies significantly predicted treatment outcome, while the expression of HVEM, cGAS, and STING was not prognostic. Altogether, Nectin-1 served as biomarker for T-VEC-induced melanoma regression in vitro and in vivo.
CRIS-Team Scopus Importer:2021-06-25
Keywords: Herpes simplex virus; Malignant melanoma; Nectin-1; Oncolytic; T-VEC

Neoadjuvant imatinib in advanced primary or locally recurrent dermatofibrosarcoma protuberans: a multicenter phase II DeCOG trial with long-term follow-up - Ugurel, Selma; Mentzel, Thomas; Utikal, Jochen; Helmbold, Peter; Mohr, Peter; Pföhler, Claudia; Schiller, Meinhard; Hauschild, Axel; Hein, Rüdiger; Kämpgen, Eckhart; Kellner, Ivonne; Leverkus, Martin; et al. (Clinical Cancer Research, 2014)
Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor. COL1A1-PDGFB gene fusion is frequent in DFSP, rendering tumor cell proliferation and survival dependent on PDGFR? (platelet-derived growth factor receptor ?) signaling. This trial investigated imatinib as neoadjuvant treatment of DFSP, including long-term follow-up.The primary endpoint of this multicenter phase II trial was response; secondary endpoints were safety, tumor relapse, and response biomarkers. Patients with advanced primary or locally recurrent DFSP and measurable disease by RECIST (response evaluation criteria in solid tumors) were eligible and received imatinib 600 mg/d until definitive surgery with histopathologic proof of tumor-free margins.Sixteen patients received imatinib, and 14 patients were evaluable for all endpoints. Median treatment duration was 3.1 months; median tumor shrinkage was 31.5%. Best overall response was 7.1% complete response (CR), 50.0% partial response (PR), 35.7% stable disease, and 7.1% progressive disease (PD). Toxicity was moderate with 25.0% grade 3 and 4 events. During a median follow-up of 6.4 years, one patient developed secondary resistance to imatinib but responded to second-line sunitinib. This patient also presented local recurrence, distant metastasis, and death from DFSP. Exploratory analysis showed that response to imatinib was associated with decreased tumor cellularity and formation of strong hyalinic fibrosis. Weak PDGFRB phosphorylation and pigmented-type DFSP were associated with nonresponse. Additional to PDGFRB, the kinases EGFR and insulin receptor were found activated in a high percentage of DFSPs.The neoadjuvant use of imatinib 600 mg/d in DFSP is efficacious and well tolerated. Long-term follow-up results do not definitely support smaller surgical margins after successful imatinib pretreatment, and presume that secondary resistance to imatinib might promote accelerated disease progression.
EVALuna2:19472

Network- and systems-based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy - Lai, Xin; Dreyer, Florian; Cantone, Martina; Eberhardt, Martin; Gerer, Kerstin F.; Jaitly, Tanushree; Uebe, Steffen; Lischer, Christopher; Ekici, Arif Bülent; Wittmann, Jürgen; Jäck, Hans-Martin; Schaft, Niels; et al. (Theranostics, 2021)
Dendritic cells (DCs) are professional antigen-presenting cells that induce and regulate adaptive immunity by presenting antigens to T cells. Due to their coordinative role in adaptive immune responses, DCs have been used as cell-based therapeutic vaccination against cancer. The capacity of DCs to induce a therapeutic immune response can be enhanced by re-wiring of cellular signalling pathways with microRNAs (miRNAs). Methods: Since the activation and maturation of DCs is controlled by an interconnected signalling network, we deploy an approach that combines RNA sequencing data and systems biology methods to delineate miRNA-based strategies that enhance DC-elicited immune responses. Results: Through RNA sequencing of IKKβ-matured DCs that are currently being tested in a clinical trial on therapeutic anti-cancer vaccination, we identified 44 differentially expressed miRNAs. According to a network analysis, most of these miRNAs regulate targets that are linked to immune pathways, such as cytokine and interleukin signalling. We employed a network topology-oriented scoring model to rank the miRNAs, analysed their impact on immunogenic potency of DCs, and identified dozens of promising miRNA candidates, with miR-15a and miR-16 as the top ones. The results of our analysis are presented in a database that constitutes a tool to identify DC-relevant miRNA-gene interactions with therapeutic potential (www.synmirapy.net/dc-optimization). Conclusions: Our approach enables the systematic analysis and identification of functional miRNA-gene interactions that can be experimentally tested for improving DC immunogenic potenc
CRIS-Team WoS Importer:2020-12-11
Keywords: dendritic cell; therapeutic vaccination in cancer; systems biology; network biology; microRNAs: bioinformatics

Neural Networks for Distinguishing Rheumatoid Arthritis from Psoriatic Arthritis by Using Magnetic Resonance Imaging - Folle, Lukas; Bayat, Sara; Kleyer, Arnd; Fagni, Filippo; Kapsner, Lorenz; Schlereth, Maja; Meinderink, Timo; Breininger, Katharina; Tascilar, Koray; Krönke, Gerhard; Uder, Michael; Sticherling, Michael; et al. (Arthritis Rheumatol., 2022)

Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy - Zimmer, Lisa; Goldinger, Simone M.; Hofmann, Lars; Loquai, Carmen; Ugurel, Selma; Thomas, Ioannis; Schmidgen, Maria I.; Gutzmer, Ralf; Utikal, Jochen S.; Goeppner, Daniela; Hassel, Jessica C.; Meier, Friedegund; et al. (European Journal of Cancer, 2016)
Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail.Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
EVALuna2:19571

Neurological side effects of checkpoint inhibitors - Knauss, S.; Roque, L. Ginesta; Huehnchen, P.; Heinzerling, Lucie; Boehmerle, W.; Endres, M. (Der Nervenarzt, 2019)
Background. In recent years the treatment of many tumor entities has been revolutionized by the use of modern immunotherapies with checkpoint inhibitors; however, good response rates are contrasted by many immune-mediated side effects. Neurological immune-mediated side effects are rare but often severe complications of checkpoint inhibitor treatment.
CRIS-Team WoS Importer:2019-02-27

Neuromuscular Side Effects of Immune Checkpoint Inhibitors - Moreira, Alvaro; Loquai, C.; Knauss, S.; Gutzmer, R.; Dimitriou, F.; Meier, F.; Heppt, M.; Mitzel-Rink, H.; Schuler, Gerold; Terheyden, P.; Thoms, K. M.; Zimmer, L.; et al. (2018)
EVALuna2:34768

NFATc1 deficiency in T cells protects mice from experimental autoimmune encephalomyelitis - Reppert, Sarah; Zinser, Elisabeth; Holzinger, Corinna; Sandrock, Lena; Koch, Sonja; Finotto, Susetta (European Journal of Immunology, 2015)
NFATc1 is a member of the nuclear factor of activated T cells (NFAT) family of transcription factors. NFAT is activated upon T-cell receptor activation followed by intracytoplasmatic calcium influx where calmodulin, a calcium sensor protein, activates the phosphatase calcineurin that dephosphorylates NFAT proteins and results in NFAT nuclear import. Here, we show the analysis of conditional NFATc1-deficient mice bearing a deletion of NFATc1 in CD4(+) and CD8(+) T cells. NFATc1-deficient CD4(+) T cells polarized under Th17 conditions express reduced levels of the Th17-associated transcription factor ROR?T (where ROR is RAR-related orphan receptor) as well as the Th17-associated cytokines IL-17A, IL-17F, IL-21, and IL-10. In the murine model of experimental EAE, we found a strong reduction of the disease outcome in conditional NFATc1-deficient mice, as compared with control littermates. This was accompanied by a diminished inflammation in the brain and spinal cord and reduced IL-17A and IFN-? expression by antigen-specific spleen, spinal cord, and brain cells. Altogether, these results reveal an important role of NFATc1 in inducing Th17-cell responses and IFN-?, both being relevant for the EAE development.
EVALuna2:25967

NF-κB activation triggers NK-cell stimulation by monocyte-derived dendritic cells. - Bosch, Naomi C.; Voll, Reinhard E.; Voskens, Caroline J.; Gross, Stefanie; Seliger, Barbara; Schuler, Gerold; Schaft, Niels; Dörrie, Jan (Therapeutic Advances in Medical Oncology, 2019)
Background: In therapeutic cancer vaccination, monocyte-derived dendritic cells (moDCs) efficiently activate specific T-cell responses; however, optimizing the activation of innate immune cells could support and improve the antitumor effects. A major disadvantage of moDCs matured with the standard cytokine cocktail (consisting of IL-1 beta, IL-6, TNF alpha, and PGE(2)) is their inability to secrete IL-12p70. IL-12 prominently activates natural killer (NK) cells, which are crucial in innate antitumor immunity, as they act as helper cells for the induction of a cytotoxic T lymphocyte (CTL) response and are also able to directly kill the tumor. Methods: Previously we have shown that triggering the NF-kappa B pathway in moDCs by transfection of mRNA encoding constitutively active IKK beta (caIKK beta) led to IL-12p70 secretion and improved the dendritic cells' capability to activate and expand CTLs with a memory-like phenotype. In this study, we examined whether such dendritic cells could activate autologous NK cells. Results: moDCs matured with the standard cytokine cocktail followed by transfection with the caIKK beta-RNA were able to activate autologous NK cells, detected by the upregulation of CD54, CD69, and CD25 on the NK cells, their ability to secrete IFN gamma, and their high lytic activity. Moreover, the ability of NK-cell activation was not diminished by simultaneous T-cell activation. Conclusion: The capacity of caIKK beta-DCs to activate both the adaptive and innate immune response indicates an enhanced potential for clinical efficacy.
CRIS-Team WoS Importer:2019-12-27

Non-magnetic chromatographic separation of colloidally metastable superparamagnetic iron oxide nanoparticles and suspension cells - Mühlberger, Marina; Janko, Christina; Unterweger, Harald; Band, Julia; Schreiber, Eveline; Lehmann, Christian; Dudziak, Diana; Lee, Geoffrey; Alexiou, Christoph; Tietze, Rainer (Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences, 2019)
For magnetic control of cells for biomedical applications such as targeting of immune cells to tumors, cells must be magnetizable. For that, cells are incubated with superparamagnetic iron oxide nanoparticles (SPIONs)to take them up and thus become magnetizable. When using adherent cells, non-ingested SPIONs can be easily removed by rinsing of the particles regardless of their colloidal stability in cell culture medium. However, if suspension cells such as T cells are to be loaded with SPIONs, established methods to separate excess nanoparticles from cells are based on physicochemical parameters such as density, size or magnetizability. Thus, colloidal stability of the particles is of great importance, since only colloidally stable SPIONs can be completely separated from the cells due to their physicochemical differences. Aggregates of colloidally meta- or unstable particles cannot, however, be separated from cells due to their overlapping sizes and densities. Thus, development of an alternative method for the separation of nanoparticle aggregates from suspension cells is urgently needed. Here, we present an affinity chromatographic separation method based on immunohistochemical properties of the respective cells. A desthiobiotinylated antibody against a cellular surface antigen (here CD90.2 receptor on EL4 T cells)is immobilized on a streptavidin agarose column optimized for cell purification. Subsequently the column is loaded with the particle/cell suspension so that the cells bind to the column. After removing the particles by washing, the cells can be gently eluted with biotin solution under physiological conditions. This allows >95% of the excess iron concentration to be removed while maintaining cell viability.
CRIS-Team Scopus Importer:2019-07-09
Keywords: Affinity chromatography; Antibody; Biotin; Cell viability; Desthiobiotin; Streptavidin

Non-professional phagocytosis: a general feature of normal tissue cells - Seeberg, Jacob; Loibl, Monika; Moser, Fabian; Schwegler, Manuela; Büttner-Herold, Maike; Daniel, Christoph; Engel, Felix; Hartmann, Arndt; Schlötzer-Schrehardt, Ursula; Goppelt-Strübe, Margarete; Schellerer, Vera; Naschberger, Elisabeth; et al. (Scientific Reports, 2019)
Non-professional phagocytosis by cancer cells has been described for decades. Recently, non-professional phagocytosis by normal tissue cells has been reported, which prompted us to take a closer look at this phenomenon. Non-professional phagocytosis was studied by staining cultured cells with live-cell staining dyes or by staining paraffin-embedded tissues by immunohistochemistry. Here, we report that each of 21 normal tissue cell lines from seven different organs was capable of phagocytosis, including ex vivo cell cultures examined before the 3rd passage as well as the primary and virus-transformed cell lines. We extended our analysis to an in vivo setting, and we found the occurrence of non-professional phagocytosis in healthy skin biopsies immediately after resection. Using dystrophin immunohistochemistry for membrane staining, human post-infarction myocardial tissue was assessed. We found prominent signs of non-professional phagocytosis at the transition zone of healthy and infarcted myocardia. Taken together, our findings suggest that non-professional phagocytosis is a general feature of normal tissue cells.
CRIS-Team Scopus Importer:2019-08-27

Nonviral RNA transfection to transiently modify T cells with chimeric antigen receptors for adoptive therapy - Riet, Tobias; Holzinger, Astrid; Dörrie, Jan; Schaft, Niels; Schuler, Gerold; Abken, Hinrich (Synthetic Messenger RNA and Cell Metabolism Modulation, 2013)
Redirecting T cells with a chimeric antigen receptor (CAR) of prede fined specificity showed remarkable ef ficacy in the adoptive therapy trials of malignant diseases. The CAR consists of a single chain fragment of variable region (scFv) antibody targeting domain covalently linked to the CD3 z signalling domain of the T cell receptor complex to mediate T cell activation upon antigen engagement. By using an antibodyderived targeting domain a CAR can potentially redirect T cells towards any target expressed on the cell surface as long as a binding domain is available. Antibody-mediated targeting moreover circumvents MHC restriction of the targeted antigen, thereby broadening the potential of applicability of adoptive T cell therapy. While T cells were so far genetically modi fied by viral transduction, transient modification with a CAR by RNA transfection gained increasing interest during the last years. This chapter focuses on methods to modify human T cells from peripheral blood with a CAR by electroporation of in vitro transcribed RNA and to test modi fied T cells for function for use in adoptive immunotherapy. © Springer Science+Business Media New York 2013.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Adoptive cell therapy; Chimeric antigen receptor; Electroporation; In vitro transcription; RNA; T cell

Noonan Syndrome with multiple Lentigines (Leopard Syndrome) - Case Description of a 45-year-old Patient - Sponagl, F.; Sticherling, Michael; Seybold, H.; Erdmann, M.; Wagner, N. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Norm- and hypo-fractionated radiotherapy is capable of activating human dendritic cells - Kulzer, Lorenz; Rubner, Yvonne; Deloch, Lisa; Allgäuer, Andrea; Frey, Benjamin; Fietkau, Rainer; Dörrie, Jan; Schaft, Niels; Gaipl, Udo (Journal of Immunotoxicology, 2014)
Abstract Despite the transient immunosuppressive properties of local radiotherapy (RT), this classical treatment modality of solid tumors is capable of inducing immunostimulatory forms of tumor-cell death. The resulting 'immunotoxicity' in the tumor, but not in healthy tissues, may finally lead to immune-mediated destruction of the tumor. However, little is known about the best irradiation scheme in this setting. This study examines the immunological effects of differently irradiated human colorectal tumor cells on human monocyte-derived dendritic cells (DC). Human SW480 tumor cells were irradiated with a norm-fractionation scheme (5 × 2 Gy), a hypo-fractionated protocol (3 × 5 Gy), and with a high single irradiation dose (radiosurgery; 1 × 15 Gy). Subsequently, human immature DC (iDC) were co-incubated with supernatants (SN) of these differently treated tumor cells. Afterwards, DC were analyzed regarding the expression of maturation markers, the release of cytokines, and the potential to stimulate CD4(+) T-cells. The co-incubation of iDC with SN of tumor cells exposed to norm- or hypo-fractionated RT resulted in a significantly increased secretion of the immune activating cytokines IL-12p70, IL-8, IL-6, and TNF?, compared to iDC co-incubated with SN of tumor cells that received a high single irradiation dose or were not irradiated. In addition, DC-maturation markers CD80, CD83, and CD25 were also exclusively elevated after co-incubation with the SN of fractionated irradiated tumor cells. Furthermore, the SN of tumor cells that were irradiated with norm- or hypo-fractionated RT triggered iDC to stimulate CD4(+) T-cells not only in an allogenic, but also in an antigen-specific manner like mature DC. Collectively, these results demonstrate that norm- and hypo-fractionated RT induces a fast human colorectal tumor-cell death with immunogenic potential that can trigger DC maturation and activation in vitro. Such findings may contribute to the improvement of irradiation protocols for the most beneficial induction of anti-tumor immunity.
EVALuna2:18178

Nutritional and functional status in geriatric day hospital patients-MNA short form versus full MNA - Schrader, Eva; Grosch, Ella; Bertsch, T.; Sieber, Cornel; Volkert, Dorothee (Journal of Nutrition, Health & Aging, 2016)
The aims of this study were to determine the prevalence of malnutrition in patients of a geriatric day hospital using the Mini Nutritional Assessment short form (MNA-SF) and the full MNA, to compare both tools, and to examine the relationship between nutritional and functional status.Cross-sectional study.Geriatric day hospital.190 patients (72.1% female, median 80 years) aged 65 years or older.In consecutively admitted geriatric day hospital patients nutritional status was assessed by MNA-SF and full MNA, and agreement between both tools calculated by Cohen's kappa. Basic activities of daily living (ADL), instrumental activities of daily living (IADL) and short physical performance battery (SPPB) were determined and related to MNA categories (Chi(2)-test, Mann-Whitney-U-test).36.3 % and 44.7% of the patients were at risk of malnutrition, 8.9 % and 5.8 % were malnourished according to MNA-SF and full MNA, respectively. Agreement between both MNA forms was moderate (?=0.531). No significant associations between MNA-SF and ADL, IADL and SPPB, and between full MNA and SPPB were observed. According to full MNA, the proportion of patients with limitations in ADL and IADL significantly increased with declining nutritional status (ADL: 2.1 vs. 8.2 vs. 18.2 %, p=0.044; IADL: 25.5 vs. 47.1 vs. 54.5 %, p=0.005) with a simultaneous decrease of the proportion of patients without limitations. Well-nourished patients reached significantly higher ADL scores than patients at risk of malnutrition (95 (-100) vs. 95 (85- 100), p=0.005) and significantly higher IADL scores than patients at risk or malnourished (8 (6-8) vs. 7 (5-8) vs. 6 (4-8), p=0.004).The high prevalence of risk of malnutrition and the observed association between functional status and nutritional status according to full MNA call for routine nutritional screening using this tool in geriatric day hospital patients.
Keywords: Nutritional status; mini nutritional assessment; functional status; geriatric day hospital patients

Nutrition status in patients with wounds: a cross-sectional analysis of 50 patients with chronic leg ulcers or acute wounds - Renner, Regina; Garibaldi, Melina Da Silva; Benson, Sven; Ronicke, Moritz; Erfurt-Berge, Cornelia (European Journal of Dermatology, 2019)
Background: The possible impact of nutritional status on healing and course of disease in patients with chronic wounds is widely suggested, however, most data are based on small groups of patients with no control group and minor afflictions. Clear diagnostic strategies are missing. Objectives: To analyse in detail the nutritional status of chronic wound patients relative to healthy controls based on a large patient population. Material and Methods: We screened a group of 50 patients for their nutritional status based on body mass index (BMI), the Mini-Nutritional Assessment (MNA), and Nutritional Risk Screening (NRS), as well as additional laboratory investigations. Twenty-five patients suffered from chronic venous leg ulcers and were compared with a matching control group of 25 patients with acute surgical wounds. Results: Patients with chronic venous leg ulcers showed significantly higher BMI, hyperhomo-cysteinaemia, and higher levels of serum copper but significantly lower levels of vitamin B6, B9 and C, as well as a significantly lower level of zinc. Vitamin D deficiency was present in both groups, however, severe vitamin D deficiency was present only in the leg ulcer group. Mobility was significantly reduced in patients with leg ulcers. Conclusion: Ulcer patients are often obese but suffer from qualitative malnutrition, including a lack of vitamin D, which might be explained by reduced mobility and being housebound. Hypoalbuminaemia, as a sign of protein deficiency, was observed significantly more often in patients with chronic leg ulcers, irrespective of wound area or wound duration.
CRIS-Team WoS Importer:2020-02-14

Objective and subjective hand function reflect grade of tenosynovitis in patients with psoriasis and psoriatic arthritis - Coppers, Birte; Bayat, Sara; Elie-Tino, Godonou; Valor-Mendez, Larissa; Simon, David; Corte, Giulia; Tascilar, Koray; Hueber, Axel; Bohr, Daniela; Schönau, Verena; Sticherling, Michael; Schett, Georg; et al. (poster, Deutsche Gesellschaft für Rheumatologie Kongress, 2023)

Occlusive cutaneous vasculopathies as cause of chronic ulcers - Ronicke, Moritz; Berking, Carola; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2024)
The term occluding vasculopathies covers a large number of different conditions. These often manifest as skin ulcers. Occluding vasculopathies should be considered in the differential diagnosis of leg ulcers. The term “occlusive vasculopathies” encompasses pathophysiologically related entities that share structural or thrombotic obliteration of small cutaneous vessels. In this article, we will focus on livedoid vasculopathy with and without antiphospholipid syndrome and calciphylaxis with differentiation from hypertonic leg ulcer as the most relevant differential diagnoses of leg ulcer. The term also includes vascular occlusion, for example due to oxalate or cholesterol embolism, and septic vasculopathy. This often leads to acral ulceration and is therefore not a differential diagnosis with classic leg ulcers. It will not be discussed in this article. Occlusive vasculopathy may be suspected in the presence of the typical livedo racemosa or (non-inflammatory) retiform purpura as a sign of reduced cutaneous perfusion in the wound area. Inflammatory dermatoses, especially vasculitides, must be differentiated. This is achieved by histopathological evaluation of a tissue sample of sufficient size and depth taken at the appropriate time. In addition, specific laboratory parameters, particularly coagulation parameters, can support the diagnosis.
CRIS-Team Scopus Importer:2024-03-15
Keywords: calciphylaxis; chronic wounds; livedoid vasculopathy; Martorell's ulcer; vasculopathy

Occupational palmoplantar psoriasis: a clinical case series with consideration of the S1 guidelines on expert medical assessments of occupational psoriasis - Angelovska, Irena; Mahler, Vera (Journal der Deutschen Dermatologischen Gesellschaft, 2014)
Constitutional diseases represent a challenge in the expert assessment of occupational diseases. It is necessary to distinguish professional causes from the spontaneous course of the disease. Recently, a guideline for the assessment of work-related psoriasis has been consented in Germany. We present a case series in which it was applied.129 expert assessments from the Department of dermatology University hospital Erlangen and court cases in established juridical databases were researched for cases with psoriasis and the applicability of the guideline.The guideline was applicable in the n = 6 (3.6 %) identified medical expert opinions. They were fully recognized by the workers compensation boards. The search for law sentences on work-related psoriasis in German court cases yielded a total of four sentences, in one of which the psoriasis was recognized as an occupational disease (BK 5101).In comparison with hand eczema psoriasis of the hands is rare. As has been demonstrated in our case series psoriasis as a constitutional disease may be recognized as an occupational disease (BK 5101) according to the legal system in Germany, if the influence of occupational exposure can be made sufficiently probable and other legal conditions of an occupational disease are met.
EVALuna2:19456

Occupational skin diseases: actual state analysis of patient management pathways in 28 European countries - Mahler, Vera; Aalto-Korte, K.; Alfonso, J. H.; Bakker, J. G.; Bauer, A.; Bensefa-Colas, L.; Boman, A.; Bourke, J.; Bubas, M.; Bulat, Petar; Chaloupka, Jiri; Constandt, L.; et al. (Journal of the European Academy of Dermatology and Venereology, 2017)
BACKGROUND: Work-related skin diseases (WSD) are caused or worsened by a professional activity. Occupational skin diseases (OSD) need to fulfil additional legal criteria which differ from country to country. OSD range amongst the five most frequently notified occupational diseases (musculoskeletal diseases, neurologic diseases, lung diseases, diseases of the sensory organs, skin diseases) in Europe. OBJECTIVE: To retrieve information and compare the current state of national frameworks and pathways to manage patients with occupational skin disease with regard to prevention, diagnosis, treatment and rehabilitation in different European countries. METHODS: A questionnaire-based survey of the current situation regarding OSD patient management pathways was carried out with experts on occupational dermatology and/or occupational medicine from 28 European countries contributing to the European Cooperation in Science and Technology (COST) Action TD 1206 (StanDerm) (www.standerm.eu). RESULTS: Besides a national health service or a statutory health insurance, most European member states implemented a second insurance scheme specifically geared at occupational diseases [insurance against occupational risks (synonyms: insurance against work accidents and occupational injuries; statutory social accident insurance)]. Legal standards for the assessment of occupationally triggered diseases with a genetic background differ between different countries, however, in most European member states recognition as OSD is possible. In one-third of the countries UV light-induced tumours can be recognized as OSD under specific conditions. CONCLUSION: OSD definitions vary between European countries and are not directly comparable, which hampers comparisons between statistics collected in different countries. Awareness of this fact and further efforts for standardization are necessary.
EVALuna2:34186

Ocular diseases in metastatic cutaneous melanoma: review of 108 consecutive patients in two German tertiary centers - Grajewski, Rafael S.; Schuler-Thurner, Beatrice; Mauch, Cornelia; Kreuzberg, Nicole; Koch, Konrad R.; Bergua, Antonio; Cursiefen, Claus; Heindl, Ludwig M. (Graefes Archive For Clinical and Experimental Ophthalmology, 2014)
To analyze the incidence and spectrum of ocular disease in patients with metastatic cutaneous melanoma.One hundred and eight consecutive patients with metastatic cutaneous melanoma were screened for ocular diseases using standardized eye examination, including measurement of visual acuity and intraocular pressure, slit-lamp examination, funduscopy in mydriasis, and spectral-domain optical coherence tomography (SDOCT) of the retina. Selected cases with atypical findings underwent electrophysiological studies. One patient was examined for hypercortisolism by a dexamethasone suppression test.Ocular diseases were found in 65 out of 108 patients (60 %) with metastatic cutaneous melanoma, significantly more often in older patients (p = 0.004). Cataract was present in 27 patients (25 %), pseudophakia in 22 patients (20 %), macular disease in 29 patients (28 %), diabetic retinopathy in ten patients (9 %), hypertensive retinal disease in 14 patients (13 %), retinal venous and arterial occlusive disease in three patients (3 %), optic neuropathy in four patients (4 %), and uveitis in one patient (1 %). Eight patients (8 %) had choroidal or iridal nevi, one patient (1 %) choroidal hemangioma, and one patient (1 %) choroidal metastasis. No patient had periocular neoplastic lesions. Paraneoplastic retinopathy manifesting as acute exudative polymorphous vitelliform maculopathy (AEPVM)-like disease was diagnosed in two patients (2 %) with multifocal central serous chorioretinopathy and development of vitelliform or fibrin-like subretinal deposits in one patient.Patients with metastatic cutaneous melanoma reveal ocular diseases with a spectrum similar to the normal population of this age range. Very rarely, uveal metastasis as well as paraneoplastic retinopathy can occur.
EVALuna2:19483

Okkludierende kutane Vaskulopathien als Ursachen chronischer Unterschenkelulzerationen - Ronicke, Moritz; Berking, Carola; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2024)
CRIS-Team Scopus Importer:2024-04-12
Keywords: Calciphylaxie; chronische Wunden; Livedovaskulopathie; Ulcus cruris hypertonicum Martorell; Vaskulopathie

Old Age, nodular Melanoma, Tumor Thickness and Ulceration are Risk Factors for regional and systemic Metastases in Melanoma Patients after negative Sentinel Node Biopsy - Erdmann, M.; Dominik, S.; Göhl, Jonas; Grützmann, Robert; Schuler, Gerold; Schellerer, Vera (2017)
EVALuna2:15294

O-linked N-acetylglucosaminylation of Sp1 inhibits the human immunodeficiency virus type 1 promoter - Jochmann, Ramona; Thurau, Mathias; Jung, Susan; Hofmann, Christian; Naschberger, Elisabeth; Kremmer, Elisabeth; Harrer, Thomas; Miller, Matthew; Schaft, Niels; Stürzl, Michael (Journal of Virology, 2009)
Human immunodeficiency virus type 1 (HIV-1) gene expression and replication are regulated by the promoter/enhancer located in the U3 region of the proviral 5′ long terminal repeat (LTR). The binding of cellular transcription factors to specific regulatory sites in the 5′ LTR is a key event in the replication cycle of HIV-1. Since transcriptional activity is regulated by the posttranslational modification of transcription factors with the monosaccharide O-linked N-acetyl-D-glucosamine (O-GlcNAc), we evaluated whether increased O-GlcNAcylation affects HIV-1 transcription. In the present study we demonstrate that treatment of HIV-1-infected lymphocytes with the O-GlcNAcylation-enhancing agent glucosamine (GlcN) repressed viral transcription in a dose-dependent manner. Overexpression of O-GlcNAc transferase (OGT), the sole known enzyme catalyzing the addition of O-GlcNAc to proteins, specifically inhibited the activity of the HIV-1 LTR promoter in different T-cell lines and in primary CD4+ T lymphocytes. Inhibition of HIV-1 LTR activity in infected T cells was most efficient (>95%) when OGT was recombinantly overexpressed prior to infection. O-GlcNAcylation of the transcription factor Sp1 and the presence of Sp1-binding sites in the LTR were found to be crucial for this inhibitory effect. From this study, we conclude that O-GlcNAcylation of Sp1 inhibits the activity of the HIV-1 LTR promoter. Modulation of Sp1 O-GlcNAcylation may play a role in the regulation of HIV-1 latency and activation and links viral replication to the glucose metabolism of the host cell. Hence, the establishment of a metabolic treatment might supplement the repertoire of antiretroviral therapies against AIDS. Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Created from Fastlane, Scopus look-up

Oncological System Therapy to the bitter End? - Berking, Carola (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team WoS Importer:2021-10-08

One allergen is not enough - RNAi-based down regulation of multiple allergens in tomato plants - Paulus, Kathrin; Mahler,; Sonnewald, Uwe (Allergy, 2015)

One set to collect them all? The development of a core domain set for medium-to-giant congenital melanocytic naevi - Heppt, Markus; Steeb, T.; Berking, Carola (British Journal of Dermatology, 2021)
CRIS-Team Scopus Importer:2021-04-02

One Website to Gather them All: Usability Testing of the New German SKin Cancer INFOrmation (SKINFO) Website-A Mixed-methods Approach - Steeb, Theresa; Bruetting, Julia; Reinhardt, Lydia; Hoffmann, Julia; Weiler, Nina; Heppt, Markus; Erdmann, Michael; Doppler, Astrid; Weber, Christiane; Schadendorf, Dirk; Meier, Friedegund; Berking, Carola (Journal of Cancer Education, 2022)
Skin cancer patients increasingly search the internet to acquire disease-related information. However, information on the internet may be misleading. Recently, SKINFO has been launched, a website exclusively created for German-speaking skin cancer patients providing information as well as additional resources of verified quality. Here, we describe the results of the first usability test of SKINFO using a mixed-methods approach. Ten adult patients with skin cancer were recruited for usability testing in the skin cancer units of the University Hospitals of Erlangen and Dresden, Germany. Testing consisted of three different scenarios where patients were asked to find specific information on the SKINFO website guided by the think-aloud method. Descriptive analysis and content analyses were performed. All patients would recommend SKINFO and appreciated its content, design, and structure. Think-aloud analysis identified the topics layout, navigation, and content and structure which would benefit from refinement. Major criticism included the navigation through the website, and the desire for more specific information addressing patients' relatives and the latest, up-to-date information. Overall, usability testing showed that the unique web-based information platform has the potential to support patients coping with skin cancer and thus strengthen informed decision-making.
CRIS-Team WoS Importer:2023-01-27

Onkologische Systemtherapie bis zum bitteren Ende? - Berking, Carola (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
CRIS-Team Scopus Importer:2023-03-23

Online consensus conferences for the development and update of clinical practice guidelines: A survey among participants of the German S3 guideline on actinic keratosis and cutaneous squamous cell carcinoma - Steeb, Theresa; Follmann, Markus; Langer, Thomas; Nothacker, Monika; Wessely, Anja; Garbe, Claus; Leiter, Ulrike; Berking, Carola; Heppt, Markus (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-03-05

Online-Konsensuskonferenzen für die Entwicklung und Aktualisierung von Leitlinien für die klinische Praxis: Eine Umfrage unter den Teilnehmenden der deutschen S3-Leitlinie zur aktinischen Keratose und kutanem Plattenepithelkarzinom - Steeb, Theresa; Follmann, Markus; Langer, Thomas; Nothacker, Monika; Wessely, Anja; Garbe, Claus; Leiter, Ulrike; Berking, Carola; Heppt, Markus (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-04-30

Opportunities to inform German residents about the possibility of skin cancer screening and to inform stakeholders to take appropriate actions: A qualitative approach - Steeb, Theresa; Wessely, Anja; Heppt, Markus; Erdmann, Michael; Klug, Stefanie J.; Berking, Carola (Cancer Medicine, 2023)
Background: The national skin cancer screening (SCS) was introduced in Germany in 2008. However, public awareness and participation rates remain low. There are no campaigns or target group–specific invitation strategies for SCS yet. Thus, our aim was to derive potential suggestions on how to best inform German residents about the possibility of SCS. Methods: Semi–structured, individual interviews with male and female German residents aged =35 years were conducted in Erlangen (Germany) to explore opportunities on raising awareness of SCS. Interviews were audiotaped, transcribed verbatim, and analyzed using qualitative content analysis. Results: Overall, 39 persons were interviewed. About 79.5% (31/39) had already undergone at least one SCS. Numerous opportunities to raise awareness of the possibility of SCS were suggested which were categorized into three main topics: the role of public promotion, health–related caregivers, and health insurance. Similar themes were identified for inviting entitled persons to undergo SCS after 2 years. Furthermore, age–dependent communication approaches were proposed, that is, younger persons should be approached electronically, while the older generation should be targeted with traditional media like mail. Conclusions: The results of this project will inform stakeholders to take appropriate actions. The findings may contribute to increase participation rates in SCS and thus lead to earlier detection of skin cancer.
CRIS-Team WoS Importer:2023-05-12

Opposing functions of thymic stromal lymphopoietin-responsive basophils and dendritic cells in a mouse model of atopic dermatitis - Schwartz, Christian; Eberle, Jörg; Hoyler, Thomas; Diefenbach, Andreas; Lechmann, Matthias; Vöhringer, David (Journal of Allergy and Clinical Immunology, 2016)
EVALuna2:25878

Outcome of melanoma patients with elevated LDH treated with first-line targeted therapy or PD-1-based immune checkpoint inhibition - Knispel, Sarah; Gassenmaier, Maximilian; Menzies, Alexander M.; Loquai, Carmen; Johnson, Douglas B.; Franklin, Cindy; Gutzmer, Ralf; Hassel, Jessica C.; Weishaupt, Carsten; Eigentler, Thomas; Schilling, Bastian; Schummer, Patrick; et al. (European Journal of Cancer, 2021)
Background: Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. Methods: This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. Results: Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4–1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2–2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3–1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8–2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6–1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5–1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. Conclusions: Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.
CRIS-Team Scopus Importer:2021-03-26
Keywords: CTLA-4; Immune checkpoint inhibition; LDH; Melanoma; PD-1; Progression; Response; Survival; Targeted therapy

Outcome on 560 metastatic melanoma (MM) patients treated with pembrolizumab during the German Expanded Access Program (EAP) - Hassel, J.; Forschner, A.; Bluhm, L.; Heinzerling, Lucie; Zimmer, L.; Utikal, J.; Kaehler, K.; Schlaak, M.; Loquai, C.; Gutzmer, R.; Kieker, F.; Berking, C.; et al. (2016)
EVALuna2:33940

Overdiagnosis of melanoma – causes, consequences and solutions - 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)
Malignant melanoma is the skin tumor that causes most deaths in Germany. At an early stage, melanoma is well treatable, so early detection is essential. However, the skin cancer screening program in Germany has been criticized because although melanomas have been diagnosed more frequently since introduction of the program, the mortality from malignant melanoma has not decreased. This indicates that the observed increase in melanoma diagnoses be due to overdiagnosis, i.e. to the detection of lesions that would never have created serious health problems for the patients. One of the reasons is the challenging distinction between some benign and malignant lesions. In addition, there may be lesions that are biologically equivocal, and other lesions that are classified as malignant according to current criteria, but that grow so slowly that they would never have posed a threat to patient’s life. So far, these “indolent” melanomas cannot be identified reliably due to a lack of biomarkers. Moreover, the likelihood that an in-situ melanoma will progress to an invasive tumor still cannot be determined with any certainty. When benign lesions are diagnosed as melanoma, the consequences are unnecessary psychological and physical stress for the affected patients and incurred therapy costs. Vice versa, underdiagnoses in the sense of overlooked melanomas can adversely affect patients’ prognoses and may necessitate more intense therapies. Novel diagnostic options could reduce the number of over- and underdiagnoses and contribute to more objective diagnoses in borderline cases. One strategy that has yielded promising results in pilot studies is the use of artificial intelligence-based diagnostic tools. However, these applications still await translation into clinical and pathological routine.
CRIS-Team Scopus Importer:2020-09-04

Oxidative DNA damage in reconstituting T cells is associated with relapse and inferior survival after allo-SCT - Karl, Franziska; Liang, C.; Böttcher-Loschinski, R.; Stoll, Andrej; Flamann, Cindy; Richter, Silja; Lischer, Christopher; Völkl, Simon; Jacobs, Benedikt; Böttcher, M.; Jitschin, R.; Bruns, Heiko; et al. (Blood, 2023)
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only curative treatment option for a number of hematologic malignancies. Its therapeutic potential relies on the potency of donor T cells to eliminate residual malignant cells, the so-called graft-versus-leukemia (GVL) effect. Disease relapse remains the most frequent treatment failure and is associated with poor outcome. Therefore, it is inevitable to decipher mechanisms that weaken GVL. In recent years, studies of tumor biology have revealed that metabolic remodeling of the micromilieu can critically regulate immune responses. Accumulation of reactive oxygen species leads to a metabolic condition known as oxidative stress, which can severely hamper T cells. Currently, only a few studies, mainly using preclinical models, have demonstrated the occurrence of oxidative stress after allo-SCTs. Therefore, we sought to investigate oxidative stress in a well-characterized group of patients who underwent allo-SCT and its impact on reconstituting T cells. We identified high concentrations of serum 8-hydroxydeoxyguanosine (8-OHdG) as an established biomarker for oxidative stress. 8-OHdG is one of the major products of DNA oxidation, which is normally rapidly removed. After allo-SCT, T cells accumulated oxidative DNA damage. High cellular 8-OHdG content (8-OHdGhi) was associated not only with signs of enhanced T-cell activation but also premature exhaustion. The inability of 8-OHdGhi T cells to efficiently target malignant cells or produce cytotoxic granzyme B and interferon gamma was associated with a significantly increased relapse risk and a shorter overall survival. Taken together, our novel findings could give reason to focus on bolstering DNA repair in reconstituting T cells as a means to improve GVL efficacy.
CRIS-Team Scopus Importer:2023-03-31

Palmitoylated Proteins on AML-Derived Extracellular Vesicles Promote Myeloid-Derived Suppressor Cell Differentiation via TLR2/Akt/mTOR Signaling - Tohumeken, Sehmus; Böttcher, Martin; Stoll, Andrej; Loschinski, Romy; Panagiotidis, Konstantinos; Braun, Martina; Saul, Domenica; Baur, Andreas; Bruns, Heiko; Mackensen, Andreas; Jitschin, Regina; Mougiakakos, Dimitrios; et al. (Cancer Research, 2020)
Acute myeloid leukemia (AML) represents the most common acute leukemia among adults. Despite recent progress in diagnosis and treatment, long-term outcome remains unsatisfactory. The success of allogeneic stem cell transplantation underscores the immunoresponsive nature of AML, creating the basis for further exploiting immunotherapies. However, emerging evidence suggests that AML, similar to other malignant entities, employs a variety of mechanisms to evade immunosurveillance. In light of this, T-cell inhibitory myeloid-derived suppressor cells (MDSC) are gaining interest as key facilitators of immunoescape. Accumulation of CD14(+) HLA-DRlow monocyticMDSCs has been described in newly diagnosed AML patients, and deciphering the underlying mechanisms could help to improve anti-AML immunity. Here, we report that conventional monocytes readily takeup AML-derived extracellular vesicles (EV) and subsequently undergo MDSC differentiation. They acquired an CD14(+)HLA-DRlow phenotype, expressed the immunomodulatory indoleamine-2,3-dioxygenase, and upregulated expression of genes characteristic for MDSCs, such as S100A8/9 and cEBP beta. The Akt/mTOR pathway played a critical role in the AML-EV-induced phenotypical and functional transition of monocytes. Generated MDSCs displayed a glycolytic switch, which rendered them more susceptible toward glycolytic inhibitors. Furthermore, palmitoylated proteins on the AML-EV surface activated Toll-like receptor 2 as the initiating event of Akt/mTOR-dependent induction of MDSC. Therefore, targeting protein palmitoylation in AML blasts could block MDSC accumulation to improve immune responses.
CRIS-Team WoS Importer:2020-09-25

Palmoplantar Pustular Psoriasis Is Associated with Missense Variants in CARD14, but Not with Loss-of-Function Mutations in IL36RN in European Patients - Moessner, Rotraut; Frambach, Yvonne; Wilsmann-Theis, Dagmar; Loehr, Sabine; Jacobi, Arnd; Weyergraf, Ansgar; Mueller, Michael; Philipp, Sandra; Renner, Regina; Traupe, Heiko; Burkhardt, Harald; Kingo, Kuelli; et al. (Journal of Investigative Dermatology, 2015)
EVALuna2:9269

PaM - Development and Validation of a palliative medical Integration Model for Melanoma - Bender-Säbelkampf, Sophia; Heckel, Maria; Ostgathe, Christoph; Berking, Carola; Heppt, Markus (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Panniculitis under successful targeted inhibition of the MAPK/ERK signaling pathway in a patient with BRAF V600E-mutated spindle cell oncocytoma of the pituitary gland - Sollfrank, Lukas; Lettmaier, Sebastian; Erdmann, Michael; Uslu, Ugur (Anticancer Research, 2019)
Background: Spindle cell oncocytoma (SCO) is a rare non-neuroendocrine neoplasm of the pituitary gland. In general, surgical excision and radiation therapy is performed. However, local recurrences are frequently seen, requiring repeated surgical and radio-oncological interventions. Thus, mutational analysis of the tumor and targeted therapy may represent a valuable therapy option in these patients. Case Report: A 38-year-old female patient with past medical history of 6 surgeries (two transsphenoidal and four transcranial), radiation therapy, and chemoradiation therapy due to several recurrences of a SCO, presented for follow-up imaging. MRI of the brain showed growth of a tumor in the right parasellar region consistent with a new local recurrence, which due to its size and location was considered to be not resectable. Molecular analysis of a previously surgically removed tumor showed a BRAF V600E mutation and thus, combined targeted inhibition of the MAPK/ERK signaling pathway using a BRAF inhibitor and a MEK inhibitor was started. Due to drug-induced panniculitis, MEK inhibitor had to be stopped and BRAF inhibitor only was continued, which was well tolerated by the patient. Subsequent imaging revealed tumor regression already four weeks after therapy initiation and no disease progression has been observed to date. Conclusion: A SCO patient with BRAF V600E mutation was successfully treated using targeted inhibition of the MAPK/ERK signaling pathway. Under therapy, tumor regression was observed and the patient has been free of progressive disease for more than two years now. Thus, mutational analysis and targeted inhibition may offer an effective treatment option for SCO patients, while potential side-effects to this therapy, like observed in our case, can occur and needs to be adequately treated.
CRIS-Team Scopus Importer:2019-07-12
Keywords: Adenoma; BRAF; Cobimetinib; Dabrafenib; MEK; Panniculitis; Pituicytoma; Targeted therapy; Trametinib; Vemurafenib

PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts - Weigert, Verena; Jost, Tina; Hecht, Markus; Knippertz, Ilka; Heinzerling, Lucie; Fietkau, Rainer; Distel, Luitpold (BMC Cancer, 2020)
BACKGROUND: PARP inhibitors niraparib and talazoparib are FDA approved for special cases of breast cancer. PARP is an interesting repair protein which is frequently affected in cancer cells. We studied the combined action of talazoparib or niraparib with ionizing radiation in melanoma cells and healthy fibroblasts. METHODS: Homologous recombination (HR) status in six different melanoma cell lines and healthy fibroblasts was assessed. Cell cultures were treated with PARP inhibitors talazoparib or niraparib and ionizing radiation (IR). Apoptosis, necrosis and cell cycle distribution was analyzed via flow cytometry. Cell migration was studied by scratch assays. RESULTS: Studied melanoma cell cultures are HR deficient. Studied healthy fibroblasts are HR proficient. Talazoparib and niraparib have congruent effects within the same cell cultures. In all cell cultures, combined treatment increases cell death and G2/M arrest compared to IR. Combined treatment in melanoma cells distinctly increases G2/M arrest. Healthy fibroblasts are less affected by G2/M arrest. Treatment predominantly decelerates or does not modify migration. In two cell cultures migration is enhanced under the inhibitors. CONCLUSIONS: Although the two PARP inhibitors talazoparib and niraparib appear to be suitable for a combination treatment with ionizing radiation in our in vitro studies, a combination treatment cannot generally be recommended. There are clear interindividual differences in the effect of the inhibitors on different melanoma cells. Therefore, the effect on the cancer cells should be studied prior to a combination therapy. Since melanoma cells increase more strongly than fibroblasts in G2/M arrest, the fractional application of combined treatment should be further investigated.
CRIS-Team Scopus Importer:2020-08-28
Keywords: Cell cycle; Cell death; Homologous recombination; Ionizing radiation; Kinase inhibitor; PARP1/PARP2; Radiosensitivity

PASI <= 2 corresponds to PASI 90, irrespective of baseline severity: A post-hoc analysis of the PRIME-study - Reich, K.; Sieder, C.; Bachhuber, T.; Melzer, N.; Sticherling, Michael (2017)
EVALuna2:34343

Patch test informed consent form: position statement by European Academy of Dermatology and Venereology Task Force on Contact Dermatitis - Balato, A.; Scala, E.; Ayala, F.; Bauer, A.; Crepy, M. N.; Goncalo, M.; Johansen, J. Duus; John, S. M.; Rustemeyer, T.; Wagner, Nicola; Wilkinson, M.; Gimenez-Arnau, A. (Journal of the European Academy of Dermatology and Venereology, 2021)
Background To our knowledge, an international consensus is lacking regarding the development of an adequate informed consent form for a patch test (PT) and the information that should be included in such document. Objectives The aim of the study was to reach a consensus on the specific points that need to be addressed in a PT consent form. Methods A Delphi survey, comprising 2 rounds and 1 final discussion, was used to gather and analyse data, which was conducted over the Internet. Each statement that reached a consensus with the respondents (9 expert dermatologists from Europe) was defined as a median consensus score (MED) of >= 7 and agreement among panelists as an interquartile range (IQR) of <= 3. All study participants were members of the EADV task force on contact dermatitis. Results The expert panel addressed several topics that should be included in an informed consent form for a PT: introduction, preparation for PT, testing procedure, allowed activities, adverse events and additional authorizations. Conclusions Our results assess recommendations regarding points to be contained in an informed consent form for a PR. Future actions towards standardization and harmonization of this specific consent form are needed.
CRIS-Team WoS Importer:2021-07-30

Patch testing hydroperoxides of limonene and linalool in consecutive patients—Results of the IVDK 2018–2020 - Schubert, Steffen; Geier, Johannes; Brans, Richard; Heratizadeh, Annice; Kränke, Birger; Schnuch, Axel; Bauer, Andrea; Dickel, Heinrich; Buhl, Timo; Vieluf, Dieter; Wagner, Nicola; Worm, Margitta (Contact Dermatitis, 2023)
Background: Hydroperoxides of limonene (Lim-OOHs) and linalool (Lin-OOHs) are potent contact sensitizers. Objectives: To investigate the prevalence of positive patch test (PT) reactions to Lim-OOHs and Lin-OOHs in consecutive patients, their demographic factors and concomitant reactions. Methods: Between 7/2018 and 12/2020, Lim-OOHs 0.3% pet. and Lin-OOHs 1% pet. were patch tested in 5511 consecutive patients. We assessed PT reactivity and analysed data from patients with either positive or negative PTs to Lim-OOHs and Lin-OOHs. Results: Positive PT results to Lim-OOHs (n = 170, 3.1%) and Lin-OOHs (n = 483, 8.8%) were frequent. Most of the positive reactions were weak (LimOOHs n = 134/LinOOHs n = 429), and even more frequently, doubtful (n = 252/n = 578) or irritant reactions (n = 81/n = 178) were documented. PT reactivity to Lim-OOHs and Lin-OOHs was increased in patients with irritant reactions to sodium lauryl sulphate (SLS). The proportion of leg dermatitis and concomitant positive reactions to fragrances and essential oils was increased in patients with reactivity to these hydroperoxides. Conclusion: The observed reaction pattern suggests that both test preparations display an irritant potential with an increased risk of false positive reactions. Preparations should be chemically monitored in order to reduce irritancy. Mindful interpretation of PT results and aimed patch testing of lower concentrations is recommended.
CRIS-Team Scopus Importer:2023-05-26
Keywords: allergic contact dermatitis; autoxidation; fragrance; hydroperoxide; hydroperoxides of limonene; hydroperoxides of linalool; patch testing; sodium lauryl sulphate

Patch testing shellac in consecutive patients—Data of the Information Network of Departments of Dermatology (IVDK) 2021 - Schubert, Steffen; Worm, Margitta; Dickel, Heinrich; Wagner, Nicola; Brans, Richard; Schroder-Kraft, Claudia; Bauer, Andrea; Koch, Andre; Geier, Johannes (Contact Dermatitis, 2022)
CRIS-Team Scopus Importer:2022-10-21
Keywords: allergic contact dermatitis; cosmetics; epidemiology; patch test; shellac; tattoo

Patch test results with caine mix III and its three constituents in consecutive patients of the IVDK - Uter, Wolfgang; Worm, Margitta; Brans, Richard; Wagner, Nicola; Bauer, Andrea; Geier, Johannes (Contact Dermatitis, 2021)
CRIS-Team Scopus Importer:2021-01-29
Keywords: baseline series; benzocaine; caine mix III; cinchocaine (dibucaine); clinical epidemiology; contact allergy; RRID:SCR_001905; tetracaine

Pathogenetic Implications of BRAF Mutation Distribution in Stage IV Melanoma Patients - Baiter, Mirjam; Schuler, Gerold; Hartmann, Arndt; Schneider-Stock, Regine; Heinzerling, Lucie (Dermatology, 2015)
BRAF mutation frequencies in melanoma subtypes have clinical implications and offer pathogenetic clues.To characterize BRAF mutation status in melanoma of unknown primary (MUP) patients, in histological melanoma subtypes and by localization of primary tumors.In 179 patients with stage IV metastatic melanoma, BRAF mutation status, histological subtype and localization of primary (except for 29 MUP patients) were analyzed.BRAF mutations were found in 44.3%, of which 80.5% were BRAF V600E and 19.5% showed non-V600E BRAF mutations. BRAF mutation frequency depended on histological subtype (57.4% superficial spreading melanoma, 54.7% nodular melanoma, 11.1% mucosal melanoma, 28.6% acral lentiginous melanoma) and concerning non-V600E BRAF mutations on localization of primary. In MUP the BRAF mutation pattern resembled superficial spreading and nodular melanomas.BRAF mutation frequencies depend on histological subtype and localization of primary melanoma. Non-V600E BRAF mutations mostly occur in patients with primaries on 'head and neck' as well as 'trunk' but not on 'extremities'.
EVALuna2:6729

Patient Characteristics and Treatment Patterns in European Pediatric Patients with Psoriasis: A Real-World, Cross-Sectional Study - Sticherling, Michael; Mcpherson, Tess; Laguna, Raul De Lucas; Costanzo, Antonio; Reed, Catherine; Artime, Esther; Robert, Camille; Lucas, James; Schuster, Christopher; Mahe, Emmanuel (Dermatology and Therapy, 2022)
Introduction This study evaluated patient characteristics and treatment patterns according to weight in pediatric patients with psoriasis in a real-world setting. Methods Primary care and specialist physicians treating pediatric patients with psoriasis aged 6-17 years in five European countries were surveyed in the 2019-2020 Adelphi Real World Pediatric Psoriasis Disease Specific Programme. At least two patients with current or previous biologic use were included per physician. Patient characteristics and treatment patterns were analyzed overall and for patients weighing 25-50 kg or more than 50 kg. Results Data from 772 patients weighing 25-50 kg and 1147 weighing more than 50 kg were analyzed. Median age at diagnosis was significantly less in lighter than heavier patients (10.0 vs. 14.0 years; p < 0.001), as was median disease duration (2.2 vs. 3.0 years; p < 0.001). Topical treatments were prescribed in 59.0% of patients overall (70.3% of lighter and 51.4% of heavier patients; p < 0.001), and were used to treat mild rather than moderate-to-severe psoriasis. Conventional systemic use was low (10.8% of patients overall) and predominantly for moderate-to-severe psoriasis. In this biologic-enriched sample, most biologics (78.2%) were prescribed in older (> 13 years) patients. Biologic use increased with line of therapy (6.6% of first-line, 18.0% of second-line, 33.7% of third-line, 44.7% of fourth-line treatments). Conclusion Biologics are predominantly prescribed in older (> 13 years) and heavier (> 50 kg) patients, with little first- or second-line use. The low use of biologics in European pediatric patients with psoriasis may represent an unmet treatment need, as topical or conventional systemic agents remain the main treatment option for moderate or severe psoriasis in these patients through the treatment pathway.
CRIS-Team WoS Importer:2022-07-22

Patient-oriented Comparison of Systemic Therapies for Patients with advanced Melanoma - A multicenter Cross-sectional Study - Thiem, A.; Mashhadiakbar, P.; Hassel, J. C.; Grimmelmann, I.; Gutzmer, R.; Schlaak, M.; Heppt, Markus; Duecker, P.; Huening, S.; Schulmeyer, L.; Schilling, B.; Haferkamp, S.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Patient-oriented Comparison of Systems Therapies for advanced Melanoma: a multicenter Cross-Sectional Study - Thiem, A.; Mashhadiakbar, P.; Cussigh, Ch.; Hassel, J. C.; Grimmelmann, I.; Gutzmer, R.; Schlaak, M.; Heppt, Markus; Ducker, P.; Huning, S.; Schulmeyer, L.; Schilling, B.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-03

Patient Perception of Mobile Phone Apps for the Care and Prevention of Sexually Transmitted Diseases: Cross-Sectional Study - Jakob, Lena; Steeb, Theresa; Fiocco, Zeno; Pumnea, Teodora; Jakob, Sophia Nomi; Wessely, Anja; Rothenberger, Christoph Clemens; Brinker, Titus Josef; French, Lars Einar; Berking, Carola; Heppt, Markus (JMIR mHealth and uHealth, 2020)
BACKGROUND: In the emerging era of digitalization and electronic health, various health-related apps have been launched, including apps for sexually transmitted diseases. Until now, little has been known about how patients perceive the value of such apps. OBJECTIVE: To investigate patient's attitudes and awareness toward sexually transmitted disease-related apps in an outpatient sexually transmitted disease clinic setting. METHODS: A cross-sectional study was conducted at a dermatovenereological outpatient unit between April and July 2019. Patients completed a self-administered questionnaire on their perceptions of the popularity and usefulness of sexually transmitted disease-related apps. Descriptive analysis was performed with expression of categorical variables as frequencies and percentages. For continuous variables, the median, range, and interquartile range were indicated. Contingency tables and chi-square tests were used to investigate associations between sociodemographic data and items of the questionnaire. RESULTS: A total of 226 patients were surveyed (heterosexual: 137/193, 71.0%; homosexual: 44/193, 22.8%; bisexual: 12/193, 6.2%); 11.9% (27/225) had previously used health-related apps. Nearly half of the patients (97/214, 45.3%) specifically considered sexually transmitted disease-related apps useful, 47.8% (100/209) voted that they could supplement or support the consultation of a physician. Interestingly, only 35.1% (74/211) preferred a printed patient brochure on sexually transmitted diseases over downloading and using an app, but 64.0% (134/209) would download a sexually transmitted disease-related app recommended by their physician. General information regarding sexually transmitted diseases (93/167, 55.7%), evaluation of skin diseases based on photos or videos (78/167, 53.3%), information on the prevention of sexually transmitted diseases (76/167, 45.5%), mediation of nearby contact points or test sites (74/167, 44.3%), anonymous medical advice (69/167, 41.3%), and calculation of the risk of having a sexually transmitted disease (63/167, 37.3%) were rated as the most important features. Men were more likely than women to find sexually transmitted disease-related apps useful in general (P=.04; χ2=6.28) and to pay for such apps (P=.01; χ2=9.19). Patients aged <40 years would rather download an app recommended by their physician (P=.03; χ2=7.23), whereas patients aged >40 years preferred reading a patient brochure on sexually transmitted diseases (P=.02; χ2=8.14). CONCLUSIONS: This study demonstrated high general interest in the use of sexually transmitted disease-related apps in this sample of dermatovenereological outpatients. In particular, young age and male sex were significantly associated with a positive perception, underlining the high potential of apps in the prevention and early recognition of sexually transmitted diseases in this group. Future studies are warranted to validate these findings in other populations.
CRIS-Team Scopus Importer:2020-11-27
Keywords: health apps; mobile phone apps; sexually transmitted diseases; sexually transmitted infection

Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine - Grob, J. -J.; Amonkar, M. M.; Martin-Algarra, S.; Demidov, L. V.; Goodman, V.; Grotzinger, K.; Haney, P.; Kämpgen, Eckhart; Karaszewska, B.; Mauch, C.; Miller, W. H.; Millward, Michael; et al. (Annals of Oncology, 2014)
In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18-0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial.The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits.For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks.This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient.NCT01227889.
EVALuna2:19471

Patient preferences of German and Swiss melanoma patients with regard to life-threatening side effects in the context of adjuvant immunotherapy - a qualitative GerMelaTox-A substudy - Peters, W.; Maul, L. V.; Huning, S.; Hassel, J. C.; Heinzerling, Lucie; Loquai, C.; Gutzmer, R.; Sachse, M. M.; Blome, C.; Kah-Ler, K. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Patient-reported Outcomes and Burden of Disease in Paediatric Patients with Psoriasis: Real-world Data from EU5 and US - Seyger, Marieke M.B.; Paller, Amy; Sticherling, Michael; Bachhuber, Teresa; Thomas, Nicolas; Hetherington, James; Lucas, James; Richardson, Craig; Augustin, Matthias (Acta Dermato-Venereologica, 2023)
CRIS-Team Scopus Importer:2023-04-28

Patient-reported outcomes and burden of disease in paediatric patients with psoriasis: real-world data from the EU5 and USA - Seyger, M.; Paller, A.; Sticherling, Michael; Bachhuber, T.; Fang, J.; Hetherington, J.; Lucas, J.; Meakin, S.; Richardson, C.; Augustin, M. (BRITISH JOURNAL OF DERMATOLOGY, 2022)
CRIS-Team WoS Importer:2022-01-14

Patients' and Physicians' Preferences for Systemic Psoriasis Treatments: A Nationwide Comparative Discrete Choice Experiment (PsoCompare) - Schaarschmidt, Marthe-Lisa; Herr, Raphael M.; Gutknecht, Mandy; Wroblewska, Katharina; Gerdes, Sascha; Sticherling, Michael; Augustin, Matthias; Peitsch, Wiebke K. (Acta Dermato-Venereologica, 2018)
Systemic antipsoriatic treatment options are increasing rapidly. The aim of this nationwide discrete choice experiment was to compare patients' (n = 222) and physicians' (n = 78) preferences for outcome and process attributes of systemic antipsoriatics using Relative Importance Scores (RIS). Both groups considered Psoriasis Area and Severity Index 90 (PASI 90) to be most important (RIS 21.4 and 20.8, respectively). Moreover, patients were highly concerned about mild and severe adverse events (RIS = 18.2 and 14.2), physicians about severe adverse events (RIS = 14.9) and cost (RIS = 13.8). Compared to physicians, patients worried more about mild adverse events and treatment location, but less about cost and frequency of laboratory tests. Physicians' preferences were influenced by work experience and percentage of biological prescriptions, patients' preferences by age, disease duration and severity. Older and less severely affected patients recruited via a patient organization focused more on safety, but less on efficacy and time until response than did patients from study centres. In conclusion, these differences in trade-offs should be integrated into a shared decision-making.
EVALuna2:34404

Patients Receiving Cytokine Inhibitors Have Low Prevalence of SARS-CoV-2 Infection - Simon, David; Tascilar, Koray; Krönke, Gerhard; Kleyer, Arnd; Zaiss, Mario; Heppt, Franz; Meder, Christine; Atreya, Raja; Klenske, Entcho; Dietrich, Peter; Abdullah, Abdullah; Kliem, Thorsten; et al. (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Patients with Chronic Urticaria need better Treatment: Results of the DERMLINE Online Survey - Hell, Katharina; Zink, Alexander; Schielein, Maximilian C.; Hacker, Elena; Romer, Katrin; Baeumer, Daniel; Wagner, Nicola (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-02-28

Patients with Chronic Urticaria Remain Largely Undertreated: Results from the DERMLINE Online Survey - Wagner, Nicola; Zink, Alexander; Hell, Katharina; Reinhardt, Maximilian; Romer, Katrin; Hillmann, Elena; Baeumer, Daniel; Schielein, Maximilian C. (Dermatology and Therapy, 2021)
Introduction Chronic urticaria (CU) is an unpredictable disease, with high disease burden and a significant negative impact on quality of life, especially in patients of working age. Many patients are undertreated, and there is poor awareness of strategies to manage patients with CU in the real-world setting. The current study aimed to gain a better understanding of CU from the patients' perspective, including the body areas most affected by wheals and angioedema, the disease burden and current use of the healthcare system. Methods A nationwide online survey was performed in Germany involving individuals who reported a diagnosis of CU and experienced symptoms within 3 months prior to inclusion. Results This self-report survey included 1037 participants (89.2% female), with a mean +/- standard deviation (SD) age of 33.4 +/- 11.0 years and a mean +/- SD disease duration of 10.0 +/- 9.4 years. On average, participants suffered from urticaria symptoms for 3.0 +/- 4.3 years before diagnosis. In 73% of participants, symptoms worsened due to external factors, with the majority specifying stress in their personal life or work-related stress as eliciting factors. Within the previous 3 months, 87.4 and 44.1% of participants experienced wheals and angioedema, respectively, at multiple body areas, and most (79.6%) participants had uncontrolled symptoms as measured with the Urticaria Control Test. Despite the high burden of disease, 60.3% of participants stated that they were not currently receiving treatment. The most commonly used therapies to treat CU were oral (72.8%) and non-prescription (43.3%) and prescription (47.3%) topical drugs, with 18.0% of the participants receiving injectable/infused drugs. Conclusion The majority of the participants responding to the survey reported that CU is not sufficiently controlled, thereby severely influencing a highly productive time in their life. The body areas most affected by wheals and angioedema are specified, based on data provided by a large group of affected participants. A greater awareness of disease burden and available treatment options is needed.
CRIS-Team WoS Importer:2021-05-14

PATIENTS WITH IMMUNE MEDIATED INFLAMMATORY DISEASES ARE OVERREPRESENTED IN LOW-FREQUENCY VIRAL SYMPTOM CLUSTERS - Tascilar, Koray; Simon, David; Krönke, Gerhard; Kleyer, Arnd; Ramming, Andreas; Atreya, Raja; Tenbusch, Matthias; Überla, Klaus; Berking, Carola; Sticherling, Michael; Neurath, Markus; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion - Simon, David; Tascilar, Koray; Krönke, Gerhard; Kleyer, Arnd; Zaiss, Mario; Heppt, Franz; Meder, Christine; Atreya, Raja; Klenske, Entcho; Dietrich, Peter; Abdullah, Abdullah; Kliem, Thorsten; et al. (Nature Communications, 2020)
Immune-mediated inflammatory diseases (IMIDs) of the joints, gut and skin are treated with inhibitors of inflammatory cytokines. These cytokines are involved in the pathogenesis of coronavirus disease 2019 (COVID-19). Investigating anti-SARS-CoV-2 antibody responses in IMIDs we observe a reduced incidence of SARS-CoV-2 seroconversion in IMID patients treated with cytokine inhibitors compared to patients receiving no such inhibitors and two healthy control populations, despite similar social exposure. Hence, cytokine inhibitors seem to at least partially protect from SARS-CoV-2 infection.
CRIS-Team Scopus Importer:2020-08-07

Patterns of care and follow-up care of patients with uveal melanoma in German-speaking countries: a multinational survey of the German Dermatologic Cooperative Oncology Group (DeCOG) - Steeb, Theresa; Wessely, Anja; Alter, Mareike; Bayerl, Christiane; Bender, Armin; Bruning, Guido; Dabrowski, Evelyn; Debus, Dirk; Devereux, Nina; Dippel, Edgar; Drexler, Konstantin; Dücker, Pia; et al. (Journal of Cancer Research and Clinical Oncology, 2020)
Purpose: Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. Methods: A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. Results: 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. Conclusion: Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.
CRIS-Team Scopus Importer:2020-11-27
Keywords: Background; Cross-sectional study; Follow-up; Ocular melanoma; Patterns of care; Surveillance; Treatment patterns; Uveal melanoma

People-centered care for psoriasis and urticaria: Are we overlooking Internet addiction while only considering patients and physician settings? - Schielein, Maximilian Christian; Tizek, Linda; Baeumer, Daniel; Hillmann, Elena; Romer, Katrin; Wagner, Nicola; Zink, Alexander (Journal of Dermatology, 2021)
Psoriasis and chronic urticaria (CU) are chronic skin diseases with a high impact on individuals’ life and mental health. Some studies indicate a high prevalence of Internet addiction and many affected individuals seem not to utilize healthcare, but rather search for health-related information online. The aims of the study were to assess Internet addiction as a potential comorbidity in both diseases as well as identify differences in healthcare utilization between individuals with psoriasis and CU. This cross-sectional study is based on self-reported data from individuals with psoriasis and CU living throughout Germany using the framework of an online survey from 12/2018 to 01/2019. Advertisements on Google and Facebook were used to address Internet users who searched online for information on psoriasis or CU. The study questionnaire comprised questions on demographics, current contact with physicians, and disease history as well as validated screening tools for well-being and Internet addiction. Overall, 1686 participants (74.0% female, 38.5% psoriasis) with a mean age of 36.9 ± 12.9 years were analyzed. Participants with CU were more likely female (89.2% vs 49.8%, P < 0.001) and not in medical care compared to participants with psoriasis (60.3% vs 45.9%, P < 0.001). Sixteen percent of the participants overall were screened positive for Internet addiction. Furthermore, not utilizing medical care showed a significant association with being screened positive for Internet addiction in participants with CU (adjusted odds ratio [aOR] = 1.49, 95% confidence interval [CI] 1.10–2.02), but not in those with psoriasis. The study revealed a high proportion of affected individuals not being in medical care and a high prevalence of Internet addiction, with individuals with CU not utilizing medical resources having a higher chance of being screened positive for Internet addiction. This underlines the approach of people-centered care and highlights its importance for further research.
CRIS-Team Scopus Importer:2021-01-15
Keywords: chronic skin diseases; depression; dermatology; epidemiology; Internet addiction; mental health; people-centered care

Perception of the coronavirus pandemic by patients with atopic dermatitis - Results from the TREATgermany registry - Helmert, Claudia; Siegels, Doreen; Haufe, Eva; Abraham, Susanne; Heratizadeh, Annice; Kleinheinz, Andreas; Harder, Inken; Schaekel, Knut; Effendy, Isaak; Wollenberg, Andreas; Sticherling, Michael; Stahl, Maren; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
Background TREATgermany, a registry for patients with moderate to severe atopic dermatitis (AD), established an additional questionnaire in spring 2020 to investigate the effects of the coronavirus pandemic on the daily life of patients with AD. Material and Methods A questionnaire was used to analyze general information regarding a patient's experience of the coronavirus pandemic and, using the Inventory of Life-Changing Events, the resulting personal burden. To analyze possible associations between disease severity (EASI score, oSCORAD, IGA, PGA, POEM), quality of life (DLQI) and personal burden, t-tests, analyses of variance and correlations were evaluated, controlled for sex and age. Results 58 % (n = 233) of the included 400 registry patients reported high burden scores caused by the coronavirus pandemic, regardless of an actual infection. Men showed significantly higher burden scores than women, and younger than older respondents (both P = 0.03). There were no differences in burden scores related to the physician's assessment of disease severity. However, patients with higher quality of life impairments and higher disease severity perceived the burden of the coronavirus pandemic as less severe (DLQI P = 0.019, PGA P = 0.044). Conclusions Our data show that registry patients considered the coronavirus pandemic as a life-changing event and perceived the burden differently. This should be taken into account in the treatment of patients with moderate to severe AD as well as in further studies.
CRIS-Team WoS Importer:2022-01-07

Peripheral PD-1+CD56+ T-cell frequencies correlate with outcome in stage IV melanoma under PD-1 blockade - Bochem, Jonas; Zelba, Henning; Amaral, Teresa; Spreuer, Janine; Soffel, Daniel; Eigentler, Thomas; Wagner, Nikolaus Benjamin; Uslu, Ugur; Terheyden, Patrick; Meier, Friedegund; Garbe, Claus; Pawelec, Graham; et al. (PLoS ONE, 2019)
Immune checkpoint blockade with anti-PD-1 antibodies is showing great promise for patients with metastatic melanoma and other malignancies, but despite good responses by some patients who achieve partial or complete regression, many others still do not respond. Here, we sought peripheral blood T-cell biomarker candidates predicting treatment outcome in 75 stage IV melanoma patients treated with anti-PD-1 antibodies. We investigated associations with clinical response, progression-free survival (PFS) and overall survival (OS). Univariate analysis of potential biological confounders and known biomarkers, and a multivariate model, was used to determine statistical independence of associations between candidate biomarkers and clinical outcomes. We found that a lower than median frequency of peripheral PD-1+CD56+ T-cells was associated with longer OS (p = 0.004), PFS (p = 0.041) and superior clinical benefit (p = 0.009). However, neither frequencies of CD56-CD4+ nor CD56-CD8+ T-cells, nor of the PD-1+ fraction within the CD4 or CD8 subsets was associated with clinical outcome. In a multivariate model with known confounders and biomarkers only the M-category (HR, 3.11; p = 0.007) and the frequency of PD-1+CD56+ T-cells (HR, 2.39; p = 0.028) were identified as independent predictive factors for clinical outcome under PD-1 blockade. Thus, a lower than median frequency of peripheral blood PD-1+CD56+ T-cells prior to starting anti-PD-1 checkpoint blockade is associated with superior clinical response, longer PFS and OS of stage IV melanoma patients.
CRIS-Team Scopus Importer:2019-08-27

Persistence of the IgE repertoire in birch pollen allergy - Otte, Manuel; Mahler, Vera; Kerpes, Andrea; Pabst, Oliver; Vöhringer, David (Journal of Allergy and Clinical Immunology, 2016)
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Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: Prevalence and impact on patients' health-related quality of life - Schulz, Thomas U.; Zierold, Sarah; Sachse, Michael M.; Pesch, Giulia; Tomsitz, Dirk; Schilbach, Katharina; Kähler, Katharina C.; French, Lars E.; Heinzerling, Lucie (European Journal of Cancer, 2022)
Background: Immune checkpoint inhibitors (ICIs) may induce persistent immune-related adverse events (irAEs). We investigated persistent irAEs and implications on patients' lives compared to non-ICI-induced autoimmune diseases (AIs). Methods: The multicentre, cross-sectional study comprised 200 patients with cancer ≥12 weeks after ICI cessation (ICI-patients) and 2705 patients with AIs (AI-patients), recruited in German outpatient clinics and support groups. The prevalence of persistent irAEs subdivided in long-term (12 weeks to <12 months) and chronic irAEs (≥12 months) since ICI discontinuation, health-related quality of life (HRQoL) using the EuroQol 5D-5L (EQ-Index/VAS score), and burden of autoimmune symptoms and respective therapies were assessed. Results: Long-term/chronic irAEs occurred in 51.9%/35.5% of outpatient ICI-patients, including arthralgia (16.7%/16.1%), myalgia (13.0%/14.0%), hypothyroidism (11.1%/10.8%), xerostomia (7.4%/8.6%), vitiligo (13.0%/7.5%) and hypophysitis (9.3%/7.5%). ICI-patients with long-term/chronic irAEs reported clinically significantly reduced HRQoL compared to ICI-patients without long-term/chronic irAEs (EQ-Index score: 0.767/0.752 versus 0.920/0.923, p < 0.001/0.001; EQ-VAS score: 52.2/52.0 versus 63.6/74.7, p =/< 0.040/0.001). Multiple linear regression analyses confirmed clinically significant reductions in HRQoL scores by chronic irAEs (EQ-Index/VAS score: −0.163/−23.4, p < 0.001/0.001). HRQoL, burden of autoimmune symptoms and burden of respective therapies in ICI-patients with chronic irAEs were similar to AI-patients with non-exacerbated AIs. Patients with chronic irAEs felt inadequately informed about side-effects compared to patients without chronic irAEs (p < 0.001). Conclusion: Persistent irAEs impose a significant burden on patients after ICI cessation. Especially in early tumour stages, risk-benefit ratios must be carefully evaluated, and patients need to be informed about potential long-term sequelae.
CRIS-Team Scopus Importer:2022-10-14
Keywords: Autoimmunity; Cancer survivors; Chronic immune-related adverse events (chronic irAEs); Health-related quality of life (HRQoL); Immune checkpoint inhibitors (ICIs); Immunotherapy; Long-term sequelae; Melanoma; Persistent toxicities; Prevalence

Personalized cancer immunotherapy using Systems Medicine approaches - Gupta, Shailendra K.; Jaitly, Tanushree; Schmitz, Ulf; Schuler, Gerold; Wolkenhauer, Olaf; Vera, Julio (Briefings in Bioinformatics, 2016)
The immune system is by definition multi-scale because it involves biochemical networks that regulate cell fates across cell boundaries, but also because immune cells communicate with each other by direct contact or through the secretion of local or systemic signals. Furthermore, tumor and immune cells communicate, and this interaction is affected by the tumor microenvironment. Altogether, the tumor-immunity interaction is a complex multi-scale biological system whose analysis requires a systemic view to succeed in developing efficient immunotherapies for cancer and immune-related diseases. In this review we discuss the necessity and the structure of a systems medicine approach for the design of anticancer immunotherapies. We support the idea that the approach must be a combination of algorithms and methods from bioinformatics and patient-data-driven mathematical models conceived to investigate the role of clinical interventions in the tumor-immunity interaction. For each step of the integrative approach proposed, we review the advancement with respect to the computational tools and methods available, but also successful case studies. We particularized our idea for the case of identifying novel tumor-associated antigens and therapeutic targets by integration of patient's immune and tumor profiling in case of aggressive melanoma.
EVALuna2:19569

PGAM5-MAVS interaction regulates TBK1/ IRF3 dependent antiviral responses - Yu, Yidong; Zielinska, Marta; Li, Wei; Bernkopf, Dominic; Heilingloh, Christiane; Neurath, Markus; Becker, Christoph (Scientific Reports, 2020)
Viral infections trigger host innate immune responses, characterized by the production of type-I interferons (IFN) including IFNβ. IFNβ induces cellular antiviral defense mechanisms and thereby contributes to pathogen clearance. Accumulating evidence suggests that mitochondria constitute a crucial platform for the induction of antiviral immunity. Here we demonstrate that the mitochondrial protein phosphoglycerate mutase family member 5 (PGAM5) is important for the antiviral cellular response. Following challenge of HeLa cells with the dsRNA-analog poly(I:C), PGAM5 oligomers and high levels of PGAM5 were found in mitochondrial aggregates. Using immunoprecipitation, a direct interaction of PGAM5 with the mitochondrial antiviral-signaling protein (MAVS) was demonstrated. In addition, PGAM5 deficient cells showed diminished expression of IFNβ and IFNβ target genes as compared to WT cells. Moreover, PGAM5 deficient mouse embryonic fibroblasts (MEFs) exhibited decreased phosphorylation levels of IRF3 and TBK1 when challenged with poly(I:C) intracellularly. Finally, PGAM5 deficient MEFs, upon infection with vesicular stomatitis virus (VSV), revealed diminished IFNβ expression and increased VSV replication. Collectively, our study highlights PGAM5 as an important regulator for IFNβ production mediated via the TBK1/IRF3 signaling pathway in response to viral infection.
CRIS-Team Scopus Importer:2020-06-02

Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma. - Schuler, Martin; Zimmer, Lisa; Kim, Kevin B.; Sosman, Jeffrey A.; Ascierto, Paolo A.; Postow, Michael A.; De Vos, Filip Y.F.L.; van Herpen, Carla M.L.; Carlino, Matteo S.; Johnson, Douglas B.; Berking, Carola; Reddy, Micaela B.; et al. (Clinical Cancer Research, 2022)
PURPOSE: Enhanced MAPK pathway signaling and cell-cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma and, as such, the regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination. PATIENTS AND METHODS: This is a phase Ib/II, open-label study of ribociclib + binimetinib in patients with NRAS-mutant melanoma (NCT01781572). Primary objectives were to estimate the MTD/recommended phase II dose (RP2D) of the combination (phase Ib) and to characterize combination antitumor activity at the RP2D (phase II). Tumor genomic characterization and pharmacokinetics/pharmacodynamics were also evaluated. RESULTS: Ten patients (16.4%) experienced dose-limiting toxicities in cycle 1 of phase Ib. Overall response rate in the phase II cohort (n = 41) for the selected RP2D (binimetinib 45 mg twice daily + ribociclib 200 mg once daily, 21 days on/7 days off) was 19.5% [8/41; 95% confidence interval (CI), 8.8-34.9]. The response rate was 32.5% (13/40; 95% CI, 20.1-48.0) in patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1. Median progression-free survival was 3.7 months (95% CI, 3.5-5.6) and median overall survival was 11.3 months (95% CI, 9.3-14.2) for all patients. Common treatment-related toxicities included creatine phosphokinase elevation, rash, edema, anemia, nausea, diarrhea, and fatigue. Pharmacokinetics and safety were consistent with single-agent data, supporting a lack of drug-drug interaction. CONCLUSIONS: Ribociclib + binimetinib can be safely administered and is clinically active in patients with NRAS-mutant melanoma. Co-mutations of cell-cycle genes may define a population with greater likelihood of treatment benefit. See related commentary by Moschos, p. 2977.
EVALuna2:499725

Phase I dose-escalation and expansion study of intratumoral CV8102, a RNA-based TLR- nd RIG-1 agonist in patients with advanced solid tumors - Terheyden, P.; Weishaupt, C.; Heinzerling, Lucie; Klinkhardt, U.; Krauss, J.; Mohr, P.; Kiecker, F.; Becker, J. C.; Submitter, A. Daehling; Doener, F.; Heidenreich, R.; Scheel, B.; et al. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-08

Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic uveal melanoma - Zimmer, Lisa; Vaubel, Julia; Mohr, Peter; Hauschild, Axel; Utikal, Jochen; Simon, Jan; Garbe, Claus; Herbst, Rudolf; Enk, Alexander; Kämpgen, Eckhart; Livingstone, Elisabeth; Bluhm, Leonie; et al. (PLoS ONE, 2015)
Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM.We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months.Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7-8.1), median progression-free survival 2.8 months (95% CI 2.5-2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3-4 events (36%). One drug-related death due to pancytopenia was observed.Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines.ClinicalTrials.gov NCT01355120.
EVALuna2:19596

Phenotype and risk factors of venom-induced anaphylaxis: a case-control study of the European Anaphylaxis Registry - Francuzik, Wojciech; Ruëff, Franziska; Bauer, Andrea; Bilò, Maria Beatrice; Cardona, Victoria; Christoff, George; Dölle-Bierke, Sabine; Ensina, Luis; Fernandes-Rivas, Montserat; Hawranek, Thomas; O'B Hourihane, Johnathan; Jakob, Thilo; et al. (Journal of Allergy and Clinical Immunology, 2020)
BACKGROUND: Venom-induced anaphylaxis is a common, potentially life-threatening hypersensitivity reaction associated with specific: 1) symptom profile, 2) cofactors, and 3) management. Identifying the differences in phenotypes of anaphylaxis is crucial for future management guidelines and the development of a personalized medicine approach. OBJECTIVE: This study aimed to evaluate the phenotype and risk factors of venom-induced anaphylaxis. METHODS: Using data from the European Anaphylaxis Registry (12874 cases) we identified 3612 patients with venom-induced anaphylaxis and analyzed these in comparison to sex- and age- matched anaphylaxis cases triggered by other elicitors (non-VIA n = 3605). RESULTS: Venom-induced anaphylaxis more frequently involved more than three organ systems and was associated with cardiovascular symptoms. The absence of skin symptoms during anaphylaxis correlated with baseline serum tryptase and was associated with an increased risk of a severe reaction. Intramuscular or intravenous epinephrine was administered significantly less often in venom-induced anaphylaxis, in particular in patients without prior history of anaphylaxis. Baseline serum tryptase within the upper normal range (8-11.5 ng-ml) was more frequently associated with severe anaphylaxis. CONCLUSION: Using a large cohort of VIA cases, we have validated that patients with intermediate baseline serum tryptase levels (8 - 11 ng/ml) and without skin involvement have higher risk of severe VIA. Patients receiving beta-blockers or ACE-I had a higher risk of developing severe cardiovascular symptoms (including cardiac arrest) in VIA and non-VIA cases. Patients undergoing VIA received epinephrine less frequently than non-VIA cases.
CRIS-Team Scopus Importer:2020-07-10
Keywords: anaphylaxis; beta-blockers; epinephrine (adrenaline); Hymenoptera; insect venom allergy

Phosphatase PTPN22 Regulates Dendritic Cell Homeostasis and cDC2 Dependent T Cell Responses - Purvis, Harriet A.; Clarke, Fiona; Montgomery, Anna B.; Colas, Chloe; Bibby, Jack A.; Cornish, Georgina H.; Dai, Xuezhi; Dudziak, Diana; Rawlings, David J.; Zamoyska, Rose; Guermonprez, Pierre; Cope, Andrew P. (Frontiers in Immunology, 2020)
Dendritic cells (DCs) are specialized antigen presenting cells that instruct T cell responses through sensing environmental and inflammatory danger signals. Maintaining the homeostasis of the multiple functionally distinct conventional dendritic cells (cDC) subsets that exist in vivo is crucial for regulating immune responses, with changes in numbers sufficient to break immune tolerance. Using Ptpn22-/- mice we demonstrate that the phosphatase PTPN22 is a highly selective, negative regulator of cDC2 homeostasis, preventing excessive population expansion from as early as 3 weeks of age. Mechanistically, PTPN22 mediates cDC2 homeostasis in a cell intrinsic manner by restricting cDC2 proliferation. A single nucleotide polymorphism, PTPN22R620W, is one of the strongest genetic risk factors for multiple autoantibody associated human autoimmune diseases. We demonstrate that cDC2 are also expanded in mice carrying the orthologous PTPN22619W mutation. As a consequence, cDC2 dependent CD4+ T cell proliferation and T follicular helper cell responses are increased. Collectively, our data demonstrate that PTPN22 controls cDC2 homeostasis, which in turn ensures appropriate cDC2-dependent T cell responses under antigenic challenge. Our findings provide a link between perturbations in DC development and susceptibility to a broad spectrum of PTPN22R620W associated human autoimmune diseases.
CRIS-Team Scopus Importer:2020-03-31
Keywords: autoimmunity; cDC2; dendritic cell; homeostasis; polymorphism; proliferation; PTPN22; T follicular helper cell

Photodynamic therapy 'to go' - a strengths, weaknesses, opportunities and threats analysis - Heppt, M. V.; Steeb, T.; Berking, Carola (Journal of the European Academy of Dermatology and Venereology, 2019)
EVALuna2:211758

Physician-reported Clinical Unmet Needs, Burden and Treatment Patterns of Paediatric Psoriasis Patients: A US and EU Real-world Evidence Study - Seyger, Marieke M.B.; Augustin, Matthias; Sticherling, Michael; Bachhuber, Teresa; Fang, Juanzhi; Hetherington, James; Lucas, James; Meakin, Sophie; Richardson, Craig; Paller, Amy S. (Acta Dermato-Venereologica, 2022)
This study is a retrospective analysis using data col-lected from the Adelphi Paediatric Psoriasis Disease-Specific Programme cross-sectional survey. Despite being treated for their psoriasis, a substantial proportion of paediatric patients presented with moderate (18.3%) or severe (1.3%) disease at sampling; 42.9% and 92.0% had a body surface area (BSA) of >10%, and 38.8% and 100.0% had a Psoriasis Area Severity Index (PASI) score >10, respectively. Overall, 69.9% of patients had only ever been treated with a topical therapy for their psoriasis. For patients with moderate or severe disease at sampling, 16.3% and 14.4% were currently receiving conventional systemics or biologic therapy, respectively. There is a clinical unmet need in this paediatric population; a considerable percen-tage of patients still experienced moderate or severe disease and persistent psoriasis symptoms, with nu-merous body areas affected. A significant proportion of patients were undertreated, which may explain the high burden of disease observed.
CRIS-Team Scopus Importer:2022-04-15
Keywords: clinical characteristics; paediatric psoriasis; point-in-time sur-vey; psoriasis; real-world; unmet needs

Pigmented lesions of the mucosa - Heppt, Markus; Heinzerling, Lucie (Die Dermatologie, 2022)
Background Pigmented lesions of the mucosa are a common reason to consult a dermatologist. They have heterogeneous etiologies and comprise a wide range of differential diagnoses. Both practitioners and patients are often uncertain about the malignancy of the lesions. Materials and methods Review and demonstration of the most common pigmentation disorders of the mucous membranes, including discussion of clinical findings and underlying causes. Results Pigmented mucosal lesions can be classified as either focal or multifocal-diffuse. Focal hyperpigmentation encompasses melanotic macules, nevi, deposition of exogenous materials or pigments, and oral melanoacanthoma. They are mostly benign but must be discerned from mucosal melanoma with an aggressive course and poor prognosis. Multifocal or diffuse hyperpigmentation may be drug-induced or indicative of an underlying medical condition. Importantly, as part of hereditary syndromes further diagnostic work-up is required. Conclusion Specific knowledge of the distribution and causes of pigmented mucosal lesions helps in clinical assessment between benign findings and those requiring further work-up and histologic clarification.
CRIS-Team WoS Importer:2022-09-09

Pivotal advance: Heme oxygenase 1 expression by human CD4+ T cells is not sufficient for their development of immunoregulatory capacity - Biburger, Markus; Theiner, Gabi; Schädle, Mirjam; Schuler, Gerold; Tiegs, Gisa (Journal of Leukocyte Biology, 2010)
HO-1 is the only inducible one of three isoenzymes that catalyzes the oxidative degradation of heme. HO-1 is inducible by various cellular stress factors and exerts cytoprotective and immunomodulatory effects. Recent publications demonstrated that HO-1 is constitutively expressed by CD4 CD25 T and induced in CD4 CD25 T cells upon FoxP3 transfection. Here, we investigated whether HO-1 was essential and sufficient for human T to exert immunosuppression in vitro. PGJ induced pronounced expression of HO-1 in CD4CD25 T cells without accompanying FoxP3 induction. Treatment of CD4CD25 T cells with PGJ decreased their proliferation, whereas the HO-1 inhibitor SnPP enhanced the proliferation of HO-1-expressing T, suggesting that HO-1 may modulate the proliferative capacity of T lymphocytes. HO-1 modulation by SnPP treatment of T or PGJ treatment of CD4CD25 T cells neither suppressed nor induced immune-modulatory function in these cells, respectively, as measured by responder-cell proliferation and/or IL-2 production. In summary, these data suggest that HO-1 expression by T might contribute to their typical reluctance to proliferate but does not account independently for their suppressive functions. © Society for Leukocyte Biology.
Keywords: CD4+CD25 + Tregs; Immune modulation; Proliferation; Regulatory T cells; Tolerance

Plasma-derived extracellular vesicles discriminate type-1 allergy subjects from non-allergic controls - Wagner, Nicola; Eberhardt, Martin; Vera, Julio; Cuomo, Federica; Blume, Katja; Galster, Silvia; Achenbach, Susanne; Laffert, Bernd; Kahlert, Helga; Schuler, Gerold; Berking, Carola; Baur, Andreas (World Allergy Organization Journal, 2021)
Background: Allergies are on the rise globally, with an enormous impact on affected individuals’ quality of life as well as health care resources. They cause a wide range of symptoms, from slightly inconvenient to potentially fatal immune reactions. While allergies have been described and classified phenomenologically, there is an unmet need for easily accessible biomarkers to stratify the severity of clinical symptoms. Furthermore, biomarkers marking the success of specific immunotherapy are urgently needed. Objectives: Plasma extracellular vesicles (pEV) play a role in coordinating the immune response and may be useful future biomarkers. A pilot study on differences in pEV content was carried out between patients with type I allergy, suffering from rhinoconjunctivitis with or without asthma, and voluntary non-allergic donors. Methods: We examined pEV from 38 individuals (22 patients with allergies and 16 controls) for 38 chemokines, cytokines, and soluble factors using high-throughput data mining approaches. Results: Patients with allergies had a distinct biomarker pattern, with 7 upregulated (TNF-alpha, IL-4, IL-5, IL-6, IL-17F, CCL2, and CCL17) and 3 downregulated immune mediators (IL-11, IL-27, and CCL20) in pEV compared to controls. This reduced set of 10 factors was able to discriminate controls and allergic patients better than the total array. Conclusions: The content of pEV showed potential as a target for biomarker research in allergies. Plasma EV, which are readily measurable via blood test, may come to play an important role in allergy diagnosis. In this proof-of-principle study, it could be shown that pEV's discriminate patients with allergies from controls. Further studies investigating whether the content of pEVs may predict the severity of allergic symptoms or even the induction of tolerance to allergens are needed.
CRIS-Team Scopus Importer:2021-10-08
Keywords: Allergy; Biomarkers; Extracellular vesicles-exosomes; Immune mediators; bioinformatics