Impact of off-label use regulations on patient care in dermatology – a prospective study of cost-coverage applications filed by tertiary dermatology clinics throughout Germany - Werner, R. N.; Pennitz, A.; Eisert, L.; Schmidle, P.; Zink, Alexander; Abraham, S.; Schaekel, K.; Wolff,; Goebeler, M.; Plange, J.; Sollfrank, Lukas; Zielbauer, S.; et al. (Journal of the European Academy of Dermatology and Venereology, 2022)
Background: In dermatology, a medical speciality with a relatively high number of rare diseases, physicians often have to resort to off-label treatment options. To avoid claims, physicians in Germany can file a cost-coverage request (off-label application, OL-A). Objectives: Our aim was to investigate the extent to which the current regulations affect patient care. Material and methods: Prospective cohort study among tertiary dermatology clinics throughout Germany, consecutively including OL-As (05/2019–09/2020) and assessing the follow-up correspondence. We modelled regressions to assess factors associated with cost-coverage decisions and the time needed by health insurers to process the OL-As. Results: Thirteen clinics provided data on 121 OL-As, two of which applied for on-label treatments. Of the remaining 119 OL-As, 70 (58.8%) were immediately approved and 44 (37.0%) rejected. Including cases with one or more appeals, 87 of 119 OL-As (73.1%) were finally approved and 26 (21.9%) rejected. There was an association of the final approval rate with (1) the class of medication/treatment, with approval rates being significantly lower for JAK inhibitors than for biologics (OR 0.16, 95%-CI: 0.03–0.82); (2) German state, with approval rates being lower in eastern than in western states (OR 0.30, 95%-CI 0.12–0.76); and (3) cost of the intervention (no linear trend). However, none of these predictors was significant in our multiple logistic regression models. The median health insurer's processing time (first response) was 29 days (IQR 22–38). Our analyses showed no evidence of an association with the predictors we assessed. In cases approved, the median time from the decision to file an OL-A to the actual initiation of the treatment was 65.5 days (IQR 51–92). Conclusions: Our study points to substantial delays and inequalities in the provision of timely health care for dermatological patients with rare diseases, often involving treatments for which there is no adequate approved therapy.
CRIS-Team Scopus Importer:2022-07-15

Impact of Plasma Membrane Domains on IgG Fc Receptor Function - Kara, Sibel; Amon, Lukas; Lühr, Jennifer; Nimmerjahn, Falk; Dudziak, Diana; Lux, Anja (Frontiers in Immunology, 2020)
Lipid cell membranes not only represent the physical boundaries of cells. They also actively participate in many cellular processes. This contribution is facilitated by highly complex mixtures of different lipids and incorporation of various membrane proteins. One group of membrane-associated receptors are Fc receptors (FcRs). These cell-surface receptors are crucial for the activity of most immune cells as they bind immunoglobulins such as immunoglobulin G (IgG). Based on distinct mechanisms of IgG binding, two classes of Fc receptors are now recognized: the canonical type I FcγRs and select C-type lectin receptors newly referred to as type II FcRs. Upon IgG immune complex induced cross-linking, these receptors are known to induce a multitude of cellular effector responses in a cell-type dependent manner, including internalization, antigen processing, and presentation as well as production of cytokines. The response is also determined by specific intracellular signaling domains, allowing FcRs to either positively or negatively modulate immune cell activity. Expression of cell-type specific combinations and numbers of receptors therefore ultimately sets a threshold for induction of effector responses. Mechanistically, receptor cross-linking and localization to lipid rafts, i.e., organized membrane microdomains enriched in intracellular signaling proteins, were proposed as major determinants of initial FcR activation. Given that immune cell membranes might also vary in their lipid compositions, it is reasonable to speculate, that the cell membrane and especially lipid rafts serve as an additional regulator of FcR activity. In this article, we aim to summarize the current knowledge on the interplay of lipid rafts and IgG binding FcRs with a focus on the plasma membrane composition and receptor localization in immune cells, the proposed mechanisms underlying this localization and consequences for FcR function with respect to their immunoregulatory capacity.
CRIS-Team Scopus Importer:2020-07-24
Keywords: cell membrane; CLR; FcγR; lipid rafts; membrane; membrane localization; type I FcR; type II FcR

Impact of radiotherapy and sequencing of systemic therapy on survival outcomes in melanoma patients with previously untreated brain metastasis: a multicenter DeCOG study on 450 patients from the prospective skin cancer registry ADOREG - Franklin, C.; Mohr, P.; Bluhm, L.; Grimmelmann, I.; Gutzmer, R.; Meier, F.; Garzarolli, M.; Weichenthal, M.; Herbst, R.; Pfohler, C.; Terheyden, P.; Utikal, J. S.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Impact of the digital health application ViViRA on spinal mobility, physical function, quality of life and pain perception in spondyloarthritides patients: a randomized controlled trial - Palm von Alten Blaskowitz, Paloma Alexandra; Liphardt, Anna-Maria; Bouzas, Claudia; Coppers, Birte; Petit, Pascal; Vuillerme, Nicolas; Bundle, Vanessa; Rudolf, Sebastian; Knitza, Johannes; Raimondo, Maria Gabriella; Labinsky, Hannah; Hatscher, Lukas; et al. (Arthritis Research & Therapy, 2024)
Background: Spondyloarthritides (SpAs) are a group of common rheumatic diseases that often cause limited mobility and lower back pain. Physiotherapy is an integral part of treatment, but access to physiotherapy limits treatment success. Digital health applications (DHAs) enable home-based physiotherapy and could significantly improve access for SpAs patients. The aim is to investigate the clinical effects of the DHA ViViRA compared with those of standard physiotherapy. Methods: SpAs patients with chronic back pain were enrolled in a randomized controlled trial. The intervention group received ViViRA DHA, whereas the control group received standard physiotherapy. Pain (verbal rating scale, PAIN-Detect), quality of life (SF-36) and mobility (BASMI) were assessed at baseline and after 12 weeks as the primary outcomes. Results: Data from 59 participants (71.2% female, mean age 45.2 years) were analyzed. The intervention group showed a significant improvement in mobility (average BASMI score: baseline: 1.1 [range 0.7–1.5]; follow-up: 1.0 [range 0.5–1.4]; p = 0.05), whereas the control group showed a significant decrease in mobility (baseline: 1.5 [range 1.1–1.9]; follow-up: 1.8 [range 1.4–2.2]; p = 0.00). The intervention group demonstrated lower pain intensity (VRS pain level at week 3.5 ± 2.8) than did the control group (VRS pain level at week 4.5 ± 2) after 12 weeks. Conclusion: Our results highlight the efficacy of DHAs such as ViViRA in the treatment of lower back pain in SpAs patients. Compared with the current gold standard, physiotherapy, DHA use results in superior outcomes. However, further larger studies are needed to confirm these promising results. Trial registration: The study is registered in the German clinical trial registry (DRKS) under the following ID: DRKS00031254.
CRIS-Team Scopus Importer:2025-02-04
Keywords: DHA; Digital health application; E-Health; Mobility; Physical function; Psoriatic spondylitis; Spondyloarthritides; Spondyloarthropathy; ViViRA

IMPACT OF TOLL-LIKE RECEPTOR 9 IN INFLAMMATORY ARTHRITIS AND OSTEOCLASTOGENESIS - Fischer, Anita; Boehm, Christina; Koenders, Marije; Van Den Berg, Wim; Rothe, Tobias; Krönke, Gerhard; Dudziak, Diana; Steiner, Guenter (2017)
EVALuna2:34374

Impaired Wound Healing with Imatinib Mesylate Therapy - Ronicke, Moritz; Erfurt-Berge, Cornelia (Advances in Skin & Wound Care, 2021)
ABSTRACT: Medication-induced ulcers are generally rare. Although the tyrosine kinase inhibitor imatinib mesylate is frequently prescribed, the occurrence of ulcers related to the medication has not been previously described. Herein, the authors report a case of a patient with impaired wound healing that was attributed to imatinib mesylate treatment. Providers should maintain suspicion for medication-induced ulcers, particularly if treatment for the presumed underlying cause of an ulcer fails.
CRIS-Team Scopus Importer:2021-02-05

Impairment of gustatory and olfactory senses in plaque psoriasis - Rueter, P.; Gruenthaler, V.; Zopf, Yurdagül; Sticherling, Michael (2017)
EVALuna2:34082

Impairment of Taste and Smell in Psoriasis- another Cause of Impaired Calorie Intake? - Gruenthaler, V.; Rueter, P.; Zopf, Yurdagül; Sticherling, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Impfungen in aller Munde – Relevanz auch für die Dermatologie? - Sticherling, Michael (Hautarzt, 2021)
CRIS-Team Scopus Importer:2021-02-05

Impfungen in der Dermatologie - Sticherling, Michael (Hautarzt, 2021)
Vaccinations are among the most successful prophylactic measures in medicine. As they are applied to healthy subjects, regulatory steps before licensing of any vaccination are strictly based on clinically controlled studies as well as on registry data in the further course. The probability and relevance of adverse reactions to vaccinations have to be weighed against any harm through the respective natural infection as well as the vaccination-induced protection against infections. Intolerance reactions to vaccinations are far more suspected than proven and altogether rare. Among these, specific dermatoses like psoriasis, atopic dermatitis and lichen planus are found as well as allergic reactions and a number of more nonspecific skin symptoms. Apart from provocation or exacerbation of an underlying dermatological disease, various intolerance reactions may be encountered which are classically allergologic or anaphylactoid. People with chronic dermatoses, especially those on immunosuppressive and immunomodulatory therapy, should have all recommended standard vaccinations. Vaccinations should not be administered during acute skin manifestations and relevant comedication—especially if immunomodulatory or immunosuppressive—has be taken into account in the decision to vaccinate and to define the time point of any vaccination. Inactivated vaccines may be administered even during ongoing immunosuppressive therapy, but may result in decreased immunological reactions and protection to infection. Live vaccines should be avoided.
CRIS-Team Scopus Importer:2021-02-05
Keywords: Adverse reactions; Atopic dermatitis; Intolerance reactions; Lichen planus; Psoriasis

Implementation of dupilumab in routine care of atopic eczema. Results from the German national registry TREATgermany - Abraham, Susanne; Haufe, Eva; Harder, Inken; Heratizadeh, Annice; Kleinheinz, Andreas; Wollenberg, Andreas; Weisshaar, Elke; Augustin, Matthias; Wiemers, Franca; Zink, Alexander; Biedermann, Tilo; Von Kiedrowski, Ralph; et al. (British Journal of Dermatology, 2020)
The German atopic eczema (AE)-registry TREATgermany is a non-interventional multicenter patient cohort study for adult patients with currently moderate-to-severe disease activity or current/previous anti-inflammatory systemic treatment.1,2 Dupilumab has demonstrated to be an effective treatment for patients with moderate-to-severe AE in clinical trials.3-5 Real world evidence is now needed to evaluate its effectiveness and safety in routine care.
EVALuna2:212857

Implications of the COVID-19 Pandemic for the Development and Update of Clinical Practice Guidelines: Viewpoint - Steeb, Theresa; Follmann, Markus; Hagen, Ralf Matthias; Berking, Carola; Heppt, Markus (Journal of Medical Internet Research, 2020)
Following the rapid spread of a new type of coronavirus (SARS-CoV-2), nearly all countries have introduced temporary restrictions affecting daily life, with "social distancing" as a key intervention for slowing the spread of the virus. Despite the pandemic, the development or actualization of medical guidelines, especially in the rapidly changing field of oncology, needs to be continued to provide up-to-date evidence- and consensus-based recommendations for shared decision making and maintaining the treatment quality for patients. In this viewpoint, we describe the potential strengths and limitations of online conferences for medical guideline development. This viewpoint will assist guideline developers in evaluating whether online conferences are an appropriate tool for their guideline conference and audience.
CRIS-Team WoS Importer:2021-01-15

Improved survival of advanced melanoma patients receiving immunotherapy with concomitant antithrombotic therapy - A multicenter study on 2419 patients from the prospective skin cancer registry ADOReg. - Kött, Julian; Zell, Tim; Zimmermann, Noah; Rünger, Alessandra; Smit, Daniel J.; Abeck, Finn; Geidel, Glenn; Hansen-Abeck, Inga; Heidrich, Isabel; Weichenthal, Michael; Ugurel, Selma; Leiter, Ulrike; et al. (European Journal of Cancer, 2025)
BACKGROUND: Cancer immunotherapy has revolutionized melanoma treatment, but the high number of non-responders still emphasizes the need for improvement of therapy. One potential avenue for enhancing anti-tumor treatment is through the modulation of coagulation and platelet activity. Both have been found to play an important role in the tumor microenvironment, tumor growth and metastasis. Preclinical studies indicate a beneficial effect, clinical data has been inconsistent. METHODS: We examined a cohort of advanced, non-resectable melanoma patients (n = 2419) derived from the German prospective multicenter skin cancer registry ADOReg, who were treated with immune checkpoint inhibitors (ICI). The patients were classified based on whether it was documented that they received platelet aggregation inhibition (PAI) (n = 137) (acetylsalicylic acid (ASA) or clopidogrel), anticoagulation (AC) (n = 185) (direct oral anticoagulation (DOAC), phenprocoumon, heparins) at the start of ICI or no antithrombotic medication (n = 2097) at any point during ICI treatment. The study endpoints were best overall response (BOR), progression-free survival (PFS) and overall survival (OS). RESULTS: A significantly improved PFS was observed in patients documented to receive ASA (15.1 vs 6.4 months, HR 0.67, 95 % CI: 0.5 to 0.88, p = 0.0047) as well as in patients to receive AC (15.1 vs. 6.4 months, HR 0.7, 95 % CI: 0.53 to 0.91, p = 0.01) compared to patients for whom no antithrombotic medication was documented. Multivariate analysis of OS showed significant risk reduction in patients who received DOAC (HR 0.68, 95 % CI: 0.49 to 0.92, p = 0.0170) or phenprocoumon (HR: 0.44, 95 % CI: 0.19 to 0.85, p = 0.0301). CONCLUSION: Our study indicates a positive prognostic effect of anticoagulant and antiplatelet concomitant medication in melanoma patients receiving ICI. Further studies are needed to confrim the cancer-related benefit of adding anticoagulation or platelet inhibition to ICI treatment.
EVALuna2:576539

Increased CD47 expression inhibits phagocytosis of alloreactive donor T cells after allo-HSCT - Flamann, Cindy; Matos, C.; Kreutz, M.; Shaikh, H.; Beilhack, A.; Büttner-Herold, Maike; Lischer, Christopher; Völkl, Simon; Kellner, C.; Zeun, J.; Kremer, Andreas; Bitterer, Katrin; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

Increased Motility and Suppression of Ex Vivo–Expanded Regulatory T Cells Designed for Adoptive Transfer Therapy in Ulcerative Colitis - Müller, Tanja; Liu, Lijuan; Czerwinski, Tina; Wiesinger, Manuel; Dedden, Mark; Paap, Eva-Maria; Ullrich, Karen; Atreya, Imke; Siegmund, Britta; Atreya, Raja; Fabry, Ben; Berking, Carola; et al. (Cellular and Molecular Gastroenterology and Hepatology, 2023)
CRIS-Team Scopus Importer:2023-06-02

Increased prevalence of irritant hand eczema in health care workers in a dermatological clinic due to increased hygiene measures during the SARS-CoV-2 pandemic - Reinholz, Markus; Kendziora, Benjamin; Frey, Surina; Oppel, Eva Maria; Rueff, Franziska; Clanner-Engelshofen, Benjamin Maximilian; Heppt, Markus; French, Lars Einar; Wollenberg, Andreas (European Journal of Dermatology, 2021)
Background: Hand hygiene measures in the general population and in health care workers have increased considerably since the outbreak of the COVID-19 pandemic. Objectives: To investigate the prevalence and symptoms of hand eczema, as well as hygiene measures and concepts of care, in German health care workers. Materials & Methods: This was an observational questionnaire study to investigate hygiene and skin care habits, as well as the prevalence and symptoms of hand eczema in 66 nurses and doctors of our dermatology department before and during the SARS-CoV-2 pandemic. Results: Hand washing and hand disinfection procedures increased significantly during the COVID-19 pandemic. Self-diagnosed hand eczema was reported by 33% of the participants, with a median duration of 14 days. The majority of staff currently affected by hand eczema were free of eczema a month previously (82%) and would treat their skin condition with emollients (77%). Erythema, scaling, burning and fissures were reported by 66.1% of the participants and were classified as predominant signs of toxic-irritant hand dermatitis rather than contact allergy. Conclusion: Overall, the SARS-CoV-2 pandemic has led to a significant increase in the incidence of signs of irritant hand eczema despite intensified emollient use as a preventive measure. Awareness of the prevalence of hand eczema in health care workers in Germany during the COVID-19 pandemic should be raised, and preventive measures should be intensified.
CRIS-Team Scopus Importer:2021-08-20
Keywords: corona virus; COVID-19; dermatology; hand eczema; health care workers; SARS-CoV-2

Increased serum NfL and GFAP levels indicate different subtypes of neurologic immune-related adverse events during treatment with immune checkpoint inhibitors - Schmitt, Christina; Müller, Katharina J.; Tiedt, Steffen; Kramer, Nora; Manger, Isabel; Knauss, Samuel; Müller-Jensen, Leonie; Huehnchen, Petra; Boehmerle, Wolfgang; Schöberl, Florian; Heinzerling, Lucie; von Baumgarten, Louisa (International Journal of Cancer, 2025)
Neurologic immune-related adverse events (nirAEs) represent rare, yet severe side effects associated with immune checkpoint inhibitor (ICI) therapy. Given the absence of established diagnostic biomarkers for nirAEs, we aimed to evaluate the diagnostic utility of serum Neurofilament Light Chain (NfL) and Glial Fibrillary Acidic Protein (GFAP). Fifty-three patients were included at three comprehensive cancer centers, of these 20 patients with manifest nirAEs and 11 patients with irHypophysitis. Controls included patients without any irAE (n = 8) and other irAEs (n = 14). Using a single-molecule enzyme-linked immunosorbent assay (Simoa), serum levels were measured prior to, during and after the manifestation of (n)irAEs in 80 samples. Symptom severity of the (n)irAEs was graded according to the Common Criteria for Adverse Events (CTCAE) version 5.0. Serum NfL levels were significantly higher in the nirAE group (n = 20) compared to irHypophysitis (n = 11; p =.0025) and controls (n = 22; p =.0384). Subgroup analysis demonstrated a significant elevation of NfL in nirAEs of the peripheral nerves (PNirAE) in contrast to neuromuscular syndromes (NMirAE) (p =.0260). GFAP levels were highest in patients with nirAE affecting the central nervous system (CNSirAE) compared to PNirAE and NMirAE (p =.0064). Symptom severity of nirAEs was associated with increased levels of NfL and GFAP (p =.0069,.0092). Individuals with elevated NfL levels exhibited less favorable outcomes of the (n)irAEs (p =.0199). Measurement of NfL and GFAP may be helpful for the differentiation of the broad spectrum of nirAEs and may serve as an indicator of symptom severity. Further investigation is needed to evaluate their potential as diagnostic and prognostic biomarkers.
CRIS-Team Scopus Importer:2025-01-31
Keywords: biomarker; immune checkpoint inhibitors; melanoma; neurological immune-related adverse events; neurotoxicity

Increased skin and mucosal toxicity in the combination of vemurafenib with radiation therapy - Merten, Ricarda; Hecht, Markus; Haderlein, Marlen; Distel, Luitpold; Fietkau, Rainer; Heinzerling, Lucie; Semrau, Sabine (Strahlentherapie und Onkologie, 2014)
Palliative radiotherapy is often required for patients with metastatic malignant melanoma in the case of bone or brain metastases. Since BRAF inhibitor therapy is highly efficient in V600-mutated melanomas, there is hesitation to stop it during radiotherapy. Consequently, radiotherapy under simultaneous vemurafenib treatment is frequently needed.We report the case of a patient receiving palliative radiotherapy of spinal bone metastases before and during vemurafenib therapy. The skin reactions were quantitatively scored using computer-assisted digital image evaluation.Radiotherapy without vemurafenib was tolerated very well, whereas radiotherapy under simultaneous vemurafenib treatment resulted in accentuated skin reactions. Furthermore, the patient developed dysphagia and had to be hospitalized for parenteral nutrition. In the quantitative analysis, there was a twofold increase in pigmentation and erythema of the irradiated skin area of the thoracic spine when vemurafenib was combined with radiotherapy compared with radiotherapy treatment alone. This is the first reported case of a patient showing no complications during radiotherapy without vemurafenib but remarkable skin and mucosal toxicity under concurrent vemurafenib therapy. Thus, a genetically conditioned individually elevated radiosensitivity can definitely be excluded. Compared with other reported cases, radiosensitization was not limited to the skin, but also affected the esophageal mucosa.Vemurafenib is a strong radiosensitizer. Patients receiving radiotherapy under simultaneous vemurafenib treatment should be monitored very closely.
EVALuna2:18209

Increasing Participation Rates in Germany's Skin Cancer Screening Program (HELIOS): Protocol for a Mixed Methods Study - Steeb, Theresa; Heppt, Markus; Erdmann, Michael; Wessely, Anja; Klug, Stefanie J.; Berking, Carola (JMIR Research Protocols, 2021)
Background: In 2008, a nationwide skin cancer screening (SCS) program was implemented in Germany. However, participation rates remain low.
CRIS-Team WoS Importer:2022-02-04

Indications and Use of Isotretinoin in Facial Plastic Surgery - Heppt, Markus V.; Kirchberger, Michael C.; Ruzicka, Thomas; Berking, Carola; Heppt, Werner J. (Facial Plastic Surgery, 2018)
Isotretinoin is a first generation retinoid with pleiotropic effects on keratinocyte differentiation, proliferation, and activity of sebaceous glands. For years, there has been intense debate on whether the use of isotretinoin combined with cosmetic or surgical procedures is safe and potentially more efficient than either therapy alone. Due to delays in wound healing and keloid formation, conservative recommendations were not to combine isotretinoin with any plastic surgery or local treatment at 6 to 12 months after discontinuation of the drug. However, there is increasing evidence that a combination approach is not only safe, but may also provide excellent cosmetic outcomes in acne scars, sebaceous gland hyperplasia, and thick-skinned patients undergoing facial plastic surgery. In particular, low-dose regimens of isotretinoin may offer advantages over standard dosage treatments because of better tolerability and safety in long-term use adjunct with surgical interventions. In this article, the authors aim to summarize the current evidence on the use of isotretinoin in facial plastic surgery and to share their experience from selected patients.
EVALuna2:156320

Individualisierte Präzisionsmedizin - Wullich, Bernd; Taubert, Helge; Goebell, Peter; Kuwert, Torsten; Beck, Michael; Schott, Christian; Baur, Andreas; Eckstein, Markus; Wach, Sven (Die Urologie, 2023)
Spectacular advances have been made in personalized medicine , which has rapidly revolutionized our traditional understanding of disease diagnosis and treatment. Molecular testing of tissue and liquid samples using next generation sequencing has developed into a key technology in this scenario. It can be used for both the determination of biomarkers for diagnostic, prognostic and predictive purposes, as well as the possible improvement of treatment outcome through the use of targeted therapies and the avoidance of therapies in the event of special resistance situations. In addition to drugs that have already been approved, which among other things intervene in cellular DNA repair, many new drugs have been developed and are in clinical testing. Furthermore, new possibilities in molecular imaging have dramatically expanded our understanding of tumor spread and created new approaches for targeted therapies.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Biomarkers; Cancer; Liquid biopsy; Next generation sequencing; PSMA

Individualized neoantigen peptide immunization of a metastatic pancreatic cancer patient: a case report of combined tumor and liquid biopsy - Roehnisch, Tim; Martos-Contreras, Mari Carmen; Manoochehri, Mehdi; Nogueira, Mauro; Bremm, Franziska; Dörrie, Jan; Christoph, Jan; Kunz, Meik; Schönharting, Wolfgang (Frontiers in Immunology, 2024)
This report details a case of pancreatic cancer with liver metastasis that exhibited a positive immune response to personalized immunization therapy. Our study involved the identification of neoantigens and their corresponding immunogenic peptides using an in-house bioinformatic pipeline. This process included the identification of somatic mutations through DNA/RNA sequencing of solid tumor tissue and blood liquid biopsy. Computational prediction techniques were then employed to identify novel epitopes, followed by the design and manufacture of patient-specific immunization peptides. In combination with standard-of-care chemotherapy, the patient received a sequence of 5 biweekly prime injections followed by 2 boost injections 2 and 5 months later. The peptides were emulsified in Montanide and the injection-site was conditioned with nivolumab and imiquimod. The combined regimen of peptide immunization and chemotherapy resulted in a notable decline in CA19-9 tumor marker levels following both prime and boost applications. Subsequent MRI assessments revealed a reduction in the size of liver metastases several months post-immunization initiation. Importantly, the patient showed and improved overall survival and reported an improved quality of life without experiencing significant treatment-related adverse effects. This case underscores the potential benefits of personalized peptide-based immunization as an adjunctive therapy in the treatment of advanced pancreatic cancer, showcasing promising outcomes in tumor marker reduction, tumor shrinkage, and enhanced patient well-being.
CRIS-Team Scopus Importer:2024-07-12
Keywords: case report; immunotherapy; neoantigen; pancreatic ductal adenocarcinoma; peptide immunization

Induction of anti-tumor responses via antigen targeting of dendritic cells in vivo - Amon, Lukas; Lehmann, Christian; Baranska, A.; Heidkamp, Gordon Frederik; Heger, Lukas; Lühr, Jennifer; Hofmann, Andrea; Nimmerjahn, Falk; Dudziak, Diana (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Infektiöse Reisedermatosen - Rongisch, Robert; Schmidt, Enno; Deresz, Nicolai; Deresz, Katharina; Schöfer, Helmut; Schäkel, Knut; Jakob, Thilo; Maurer, Marcus; Sticherling, Michael; Sunderkötter, Cord; Babilas, Philipp; Spornraft-Ragaller, Petra; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-07-31

Inflammasomes in dendritic cells: Friend or foe? - Hatscher, Lukas; Amon, Lukas; Heger, Lukas; Dudziak, Diana (Immunology Letters, 2021)
Inflammasomes are cytosolic multiprotein complexes that crucially contribute to host defense against pathogens but are also involved in the pathogenesis of autoinflammatory diseases. Inflammasome formation leads to activation of effector caspases (caspase-1, 4, 5, or 11), the proteolytic maturation of IL-1β and IL-18 as well as cleavage of the pore-forming protein Gasdermin D. Dendritic cells are major regulators of immune responses as they bridge innate and adaptive immunity. We here summarize the current knowledge on inflammasome expression and formation in murine bone marrow-, human monocyte-derived as well as murine and human primary dendritic cells. Further, we discuss both, the beneficial and detrimental, involvement of inflammasome activation in dendritic cells in cancer, infections, and autoimmune diseases. As inflammasome activation is typically accompanied by Gasdermin D-mediated pyroptosis, which is an inflammatory form of programmed cell death, inflammasome formation in dendritic cells seems ill-advised. Therefore, we propose that hyperactivation, which is inflammasome activation without the induction of pyroptosis, may be a general model of inflammasome activation in dendritic cells to enhance Th1, Th17 as well as cytotoxic T cell responses.
CRIS-Team Scopus Importer:2021-05-21
Keywords: Dendritic cell; Hyperactivation; Inflammasome; NLRP3; T cell response; Vaccination

Inflammatory markers in autoimmunity induced by checkpoint inhibitors - Husain, Beate; Kirchberger, Michael; Erdmann, Michael; Schüpferling, Sabine; Abolhassani, Amir Reza; Fröhlich, Waltraud; Berking, Carola; Heinzerling, Lucie (Journal of Cancer Research and Clinical Oncology, 2021)
Purpose: Immune checkpoint inhibitors (ICI) are highly effective in several cancer entities, but also invoke a variety of immune-related adverse events (irAE). These are mostly reversible, but can be life-threatening or even fatal. Currently, the pathogenesis is not fully understood, but crucial for effective treatment. Prediction and early detection of irAE could be facilitated and treatment optimized if relevant biomarkers and effector mechanisms were better characterized. Methods: This study included a total of 45 irAE in patients with metastatic melanoma who were treated with ICI. All patients underwent a complete work-up with exclusion of other causes. Longitudinal blood samples were analyzed for a panel of soluble markers and compared to baseline and to patients who did not experience any irAE. Measurements included LDH, interleukin (IL)-6, IL-1β, IL-17, C-reactive protein (CRP) and tumor necrosis factor (TNF)-alpha as well as tumor markers S100 and melanoma inhibitory activity (MIA). Results: During the early onset of irAE increases in serum IL-6 (from mean 24.4 pg/ml at baseline to 51.0 pg/ml; p = 0.003) and CRP (from mean 7.0 mg/l at baseline to 17.7 mg/l; p = 0.001) and a decrease in MIA (from mean 5.4 pg/ml at baseline to 4.8 pg/ml; p = 0.035) were detected. No changes in IL-17 were noted. These effects were observed for irAE of different organ systems. Conclusion: Increases of a combination of IL-6 and CRP serum levels can be used for the early detection of irAE and tailored management. Interestingly, changes in MIA serum levels also correlate with irAE onset.
CRIS-Team Scopus Importer:2021-04-23
Keywords: Cytokines; Immune checkpoint inhibitors; Immune-related adverse events; Melanoma

Influence of adjuvant therapies on organ-specific recurrence of cutaneous melanoma: A multicenter study on 1383 patients of the prospective DeCOG registry ADOReg - Wohlfeil, Sebastian A.; Kranzmann, Leonie; Weiß, Christel; von Wasielewski, Imke; Klespe, Kai C.; Kähler, Katharina C.; Weichenthal, Michael; Schadendorf, Dirk; Zimmer, Lisa; Mohr, Peter; Meier, Friedegund; Pfoehler, Claudia; et al. (International Journal of Cancer, 2024)
This study investigated whether adjuvant treatments in stage III cutaneous melanoma (CM) influenced patterns of recurrence. Patients with primary (n = 1033) or relapsed CM (n = 350) who received adjuvant therapies with Nivolumab (N), Pembrolizumab (P), or Dabrafenib and Trametinib (D + T) were extracted from the prospective multicenter real-world skin cancer registry ADOReg. Endpoints were progression-free survival (PFS), distant metastasis-free survival (DMFS), organ-specific DMFS, and overall survival (OS). For primary cases, D + T indicated an improved PFS (1- and 2-year PFS: 90.9%; 82.7%) as compared to P (81.0%, 73.9%; p =.0208), or N (83.8%, 75.2%; p =.0539). BRAF-mutated(mut) CM demonstrated significantly lower PFS (p =.0022) and decreased DMFS (p =.0580) when treated with immune checkpoint inhibitor (ICI) instead of D + T. Besides, NRAS-mut CM tended to perform worse than wt CM upon ICI (PFS: p =.1349; DMFS: p =.0540). OS was similar between the groups. Relapsed cases showed decreased PFS, DMFS, and OS in comparison to primary (all: p <.001), without significant differences between the subgroups. Organ-specific DMFS was significantly altered for primary cases with bone (p =.0367) or brain metastases (p =.0202). In relapsed CM, the frequency of liver (D + T: 1.5%; P: 12%; N: 9%) and LN metastases (D + T: 1.5%; P: 12%; N: 10.2%) was significantly lower with adjuvant D + T than ICI. NRAS-mut CM showed increased recurrence in primary and relapsed cases. These data show that adjuvant D + T is superior to ICI in primary BRAF-mut CM.
CRIS-Team Scopus Importer:2024-07-19
Keywords: adjuvant treatment; immune checkpoint inhibition; melanoma; targeted therapy; therapy resistance

Influence of previous Radiotherapy on the Success of an immune-oncologic Therapy in metastatic Melanoma - a retrospective multicenter Study of ADO - Knispel, S.; Zimmer, L.; Gutzmer, R.; Heinzerling, Lucie; Weishaupt, C.; Pfoehler, C.; Gesierich, A.; Herbst, R.; Kaehler, K.; Weide, B.; Schlaak, M.; Loquai, C.; et al. (2018)
EVALuna2:34774

Influence of Swiprosin2/EFhd1 on the metabolic control of B cell differentiation and humoral immunity - Urbanczyk, Sophia; Stein, Marcello F.; Duetting, S.; Mougiakakos, Dimitrios; Boesl, M.; Reimer, Dorothea; Steinmetz, Tobit; Schuh, Wolfgang; Bozec, Aline; Winkler, Thomas; Jäck, Hans-Martin; Mielenz, Dirk (2017)
EVALuna2:13653

Influence of the Immune Checkpoint Inhibitors on the Hemostatic Potential of Blood Plasma - Patalakh, Iryna; Wandersee, Alexandra; Schlüter, Julian; Erdmann, Michael; Hackstein, Holger; Cunningham, Sarah (Transfusion Medicine and Hemotherapy, 2024)
Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized classical treatment approaches of various cancer entities, but are also associated with a number of side effects. One of these may be life-threatening clotting disorders with the risk of thrombotic or hemorrhagic complications, the mechanisms of which are still poorly understood. In the present study, we analyzed the direct effects of pembrolizumab, nivolumab, and ipilimumab on platelet aggregation as well as plasma coagulation followed by fibrinolysis in an ex vivo model. Methods: Microplate spectrometry was used to analyze aggregation, coagulation, and fibrinolysis in platelet-free (PFP) and platelet-rich (PRP) healthy donor plasma samples treated with pembrolizumab, nivolumab, ipilimumab, and appropriate isotype controls. Aggregation was induced by TRAP-6. Clotting of PFP and PRP followed by lysis was initiated with a tissue factor in a mixture of phosphatidylserine:phosphatidylcholine and the addition of t-PA. Among other parameters, the area under the curve (AUC) was used to compare the effect of ICIs on aggregation, coagulation, and fibrinolysis. Results: Upon direct contact with platelets, pembrolizumab stimulated platelet aggregation in PRP, while nivolumab and ipilimumab promoted disaggregation with corresponding changes in the AUC. Pembrolizumab and nivolumab, both PD-1 receptor inhibitors, had no effect on the plasma coagulation cascade. Ipilimumab, a CTLA-4 receptor inhibitor, significantly increased the rate of PRP clotting. When clotting was followed by lysis, all ICIs were found to prolong the growth of the PRP-derived fibrin clot and delay its elimination. This was manifested by an increase in AUC relative to control PRP. Conclusion: This study characterizes the potential impact of pembrolizumab, nivolumab, and ipilimumab on hemostasis. Nivolumab and ipilimumab are able to reduce aggregation and increase the procoagulant properties of platelets, which can cause side effects associated with hemostatic imbalance leading to thrombosis or bleeding. The observed ICI-specific effects may contribute to our understanding of the mechanisms by which ICI affects platelets and suggest how, in a clinical setting, to reduce coagulation disorders during ICI treatment in the future
Keywords: Immune checkpoint inhibitors; Aggregation; Coagulation; Fibrinolysis; Platelet-rich plasma; Platelets; Thrombocytes

Influence of TNF-alpha inhibitors and fumaric acid esters on male fertility in psoriasis patients - Heppt, Franz; Colsman, A.; Maronna, A.; Uslu, Ugur; Heppt, M. V.; Kiesewetter, Franklin; Sticherling, Michael (Journal of the European Academy of Dermatology and Venereology, 2017)
OBJECTIVE: Is there any influence of a therapy with TNF-alpha inhibitors or fumaric acid esters and of disease activity status on male fertility and sperm quality in patients with psoriasis? METHODS: In this monocentric, open-label, prospective study, semen samples were collected from patients receiving either TNF-alpha inhibitors or fumaric acid esters for moderate-to-severe plaque psoriasis. Semen was analysed at baseline before onset of the systemic therapy and monitored every 3 months under therapy. Sperm parameters were assessed according to the current WHO definitions. RESULTS: In total, 101 semen specimens from 27 patients were obtained. Mean Psoriasis Area and Severity Index (PASI) score at baseline was 11.05. Only 14.8% of patients showed a normozoospermia without any other abnormal seminal values. 85.2% of patients had at least one sperm/seminal abnormality, including two patients showing an azoospermia. Interestingly, 48.1% showed sperm parameters indicative of genital tract inflammation. Therapy with TNF-alpha inhibitors or fumaric acid esters did not have any negative effects on relevant sperm parameters such as mean total sperm number, sperm concentration, total and progressive motility. No major gonadal dysfunction was observed in any patient. CONCLUSION: At baseline, many patients with psoriasis showed abnormal semen/sperm parameters and remarkably elevated leukocytes and values of seminal polymorphonuclear elastase, indicating a genital tract inflammation. Thus, genital tract inflammation may represent an important comorbidity of psoriasis, little attention paid to so far. Regarding treatment with TNF-alpha inhibitors or fumaric acid esters, no major negative (side-) effects on sperm quality were observed.
EVALuna2:34337

Influence on contact allergy of immune-mediated skin diseases such as psoriasis - Erfurt-Berge, Cornelia (British Journal of Dermatology, 2019)
CRIS-Team Scopus Importer:2019-08-02

Influenza vaccination and myocarditis among patients receiving immune checkpoint inhibitors - Awadalla, Magid; Golden, Doll Lauren Alexandra; Mahmood, Syed S.; Alvi, Raza M.; Mercaldo, Nathaniel D.; Hassan, Malek Z. O.; Banerji, Dahlia; Rokicki, Adam; Mulligan, Connor; Murphy, Sean P. T.; Jones-O'Connor, Maeve; Cohen, Justine V.; et al. (Journal for ImmunoTherapy of Cancer, 2019)
BackgroundInfluenza vaccination (FV) is recommended for patients with cancer. Recent data suggested that the administration of the FV was associated with an increase in immune-related adverse events (irAEs) among patients on immune checkpoint inhibitors (ICIs). Myocarditis is an uncommon but serious complication of ICIs and may also result from infection with influenza. There are no data testing the relationship between FV and the development of myocarditis on ICIs.MethodsPatients on ICIs who developed myocarditis (n=101) (cases) were compared to ICI-treated patients (n=201) without myocarditis (controls). A patient was defined as having the FV if they were administered the FV from 6months prior to start of ICI to anytime during ICI therapy. Alternate thresholds for FV status were also tested. The primary comparison of interest was the rate of FV between cases and controls. Patients with myocarditis were followed for major adverse cardiac events (MACE), defined as the composite of cardiogenic shock, cardiac arrest, hemodynamically significant complete heart block and cardiovascular death.ResultsThe FV was administered to 25% of the myocarditis cases compared to 40% of the non-myocarditis ICI-treated controls (p=0.01). Similar findings of lower rates of FV administration were noted among myocarditis cases when alternate thresholds were tested. Among the myocarditis cases, those who were vaccinated had 3-fold lower troponin levels when compared to unvaccinated cases (FV vs. No FV: 0.12 [0.02, 0.47] vs. 0.40 [0.11, 1.26] ng/ml, p=0.02). Within myocarditis cases, those administered the FV also had a lower rate of other irAEs when compared to unvaccinated cases (36 vs. 55% p=0.10) including lower rates of pneumonitis (12 vs. 36%, p=0.03). During follow-up (175 [IQR 89, 363] days), 47% of myocarditis cases experienced a MACE. Myocarditis cases who received the FV were at a lower risk of cumulative MACE when compared to unvaccinated cases (24 vs. 59%, p=0.002).ConclusionThe rate of FV among ICI-related myocarditis cases was lower than controls on ICIs who did not develop myocarditis. In those who developed myocarditis related to an ICI, there was less myocardial injury and a lower risk of MACE among those who were administered the FV.
CRIS-Team WoS Importer:2019-03-06

Inhibited Arginase-1 Expression by Fra-1 in Myeloid Cells Enhance Rheumatoid Arthritis Inflammation - Hannemann, Nicole; Schnelzer, A.; Jordan, J.; Eberhardt, Martin; Schleicher, Ulrike; Uebe, Steffen; Ekici, Arif Bülent; Reid, Stephen; Sonnewald, Sophia; Bäuerle, Tobias; Bogdan, Christian; Vera, Julio; et al. (2017)
EVALuna2:33310

Inhibiting the neural crest transcription factor SOX10 leads to cell cycle arrest and apoptosis in uveal melanoma cells - Wessely, A.; Kammerbauer, C.; Lischer, Christopher; Vera González, Julio; Berking, Carola; Heppt, Markus (EXPERIMENTAL DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-14

INHIBITION OF ARGINASE-1 EXPRESSION BY THE TRANSCRIPTION FACTOR FRA-1 IN MACROPHAGES EXACERBATES RHEUMATOID ARTHRITIS INFLAMMATION - Hannemann, Nicole; Cao, Shan; Schnelzer, A.; Jordan, J.; Eberhardt, Martin; Schleicher, Ulrike; Uebe, Steffen; Ekici, Arif Bülent; Rech, Jürgen; Bäuerle, Tobias; Bogdan, Christian; Vera, Julio; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-05-17

Inhibition of Melanoma Cell-Intrinsic Tim-3 Stimulates MAPK-Dependent Tumorigenesis. - Schatton, Tobias; Itoh, Yuta; Martins, Christina; Rasbach, Erik; Singh, Praveen; Silva, Mariana; Mucciarone, Kyla; Heppt, Markus; Geddes-Sweeney, Jenna; Stewart, Kate; Brandenburg, Anne; Liang, Jennifer; et al. (Cancer Research, 2022)
T-cell immunoglobulin mucin family member 3 (Tim-3) is an immune checkpoint receptor that dampens effector functions and causes terminal exhaustion of cytotoxic T cells. Tim-3 inhibitors are under investigation in immuno-oncology (IO) trials, because blockade of T-cell-Tim-3 enhances antitumor immunity. Here, we identify an additional role for Tim-3 as a growth-suppressive receptor intrinsic to melanoma cells. Inhibition of melanoma cell-Tim-3 promoted tumor growth in both immunocompetent and immunocompromised mice, while melanoma-specific Tim-3 overexpression attenuated tumorigenesis. Ab-mediated Tim-3 blockade inhibited growth of immunogenic murine melanomas in T-cell-competent hosts, consistent with established antitumor effects of T-cell-Tim-3 inhibition. In contrast, Tim-3 Ab administration stimulated tumorigenesis of both highly and lesser immunogenic murine and human melanomas in T-cell-deficient mice, confirming growth-promoting effects of melanoma-Tim-3 antagonism. Melanoma-Tim-3 activation suppressed, while its blockade enhanced, phosphorylation of pro-proliferative downstream MAPK signaling mediators. Finally, pharmacologic MAPK inhibition reversed unwanted Tim-3 Ab-mediated tumorigenesis in T-cell-deficient mice and enhanced desired antitumor activity of Tim-3 interference in T-cell-competent hosts. These results identify melanoma-Tim-3 blockade as a mechanism that antagonizes T-cell-Tim-3-directed IO therapeutic efficacy. They further reveal MAPK targeting as a combination strategy for circumventing adverse consequences of unintended melanoma-Tim-3 inhibition. SIGNIFICANCE: Tim-3 is a growth-suppressive receptor intrinsic to melanoma cells, the blockade of which promotes MAPK-dependent tumorigenesis and thus counteracts antitumor activity of T-cell-directed Tim-3 inhibition.
EVALuna2:506741

Initial and repeat reactions in the European Anaphylaxis Registry a comparative analysis - Hoefer, V.; Doelle-Bierke, S.; Rueff, F.; Hartmann, K.; Pfoehler, C.; Treudler, R.; Wagner, Nicola; Worm, M. (ALLERGOLOGIE, 2022)
CRIS-Team WoS Importer:2023-03-24

Innate extracellular vesicles from melanoma patients suppress beta-catenin in tumor cells by miRNA-34a - Lee, Jung-Hyun; Dindorf, Jochen; Eberhardt, Martin; Lai, Xin; Ostalecki, Christian; Koliha, Nina; Gross, Stefani; Blume, Katja; Bruns, Heiko; Wild, Stefan; Schuler, Gerold; Vera, Julio; et al. (Life Science Alliance, 2019)
Upon tumor development, new extracellular vesicles appear in circulation. Our knowledge of their relative abundance, function, and overall impact on cancer development is still preliminary. Here, we demonstrate that plasma extracellular vesicles (pEVs) of non-tumor origin are persistently increased in untreated and post-excision melanoma patients, exhibiting strong suppressive effects on the proliferation of tumor cells. Plasma vesicle numbers, miRNAs, and protein levels were elevated two-to tenfold and detected many years after tumor resection. The vesicles revealed individual and clinical stage-specific miRNA profiles as well as active ADAM10. However, whereas pEV from patients preventing tumor relapse down-regulated beta-catenin and blocked tumor cell proliferation in an miR-34a-dependent manner, pEV from metastatic patients lost this ability and stimulated beta-catenin-mediated transcription. Cancer-induced pEV may constitute an innate immune mechanismsuppressing tumor cell activity including that of residual cancer cells present after primary surgery.
CRIS-Team WoS Importer:2019-05-17

Insights From the Apremilast After Switching From Fumaric Acid Ester Treatment (APART) Study: An Interim Real-World Safety Analysis - Mrowietz, Ulrich; Ertner, Konstantin; Sticherling, Michael; Grosse, Virginia; Popp, Georg; Schwichtenberg, Uwe; Karl, Lars; Schenck, Florian; Ramaker-Brunke, Jutta; Roemmler-Zehrer, Josefine; Helget, Ursula; Gomez, Natalie Nunez (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-02-28

Integrating patient data into skin cancer classification using convolutional neural networks: Systematic review - Höhn, Julia; Hekler, Achim; Krieghoff-Henning, Eva; Kather, Jakob Nikolas; Utikal, Jochen Sven; Meier, Friedegund; Gellrich, Frank Friedrich; Hauschild, Axel; French, Lars; Schlager, Justin Gabriel; Ghoreschi, Kamran; Wilhelm, Tabea; et al. (Journal of Medical Internet Research, 2021)
Background: Recent years have been witnessing a substantial improvement in the accuracy of skin cancer classification using convolutional neural networks (CNNs). CNNs perform on par with or better than dermatologists with respect to the classification tasks of single images. However, in clinical practice, dermatologists also use other patient data beyond the visual aspects present in a digitized image, further increasing their diagnostic accuracy. Several pilot studies have recently investigated the effects of integrating different subtypes of patient data into CNN-based skin cancer classifiers. Objective: This systematic review focuses on the current research investigating the impact of merging information from image features and patient data on the performance of CNN-based skin cancer image classification. This study aims to explore the potential in this field of research by evaluating the types of patient data used, the ways in which the nonimage data are encoded and merged with the image features, and the impact of the integration on the classifier performance. Methods: Google Scholar, PubMed, MEDLINE, and ScienceDirect were screened for peer-reviewed studies published in English that dealt with the integration of patient data within a CNN-based skin cancer classification. The search terms skin cancer classification, convolutional neural network(s), deep learning, lesions, melanoma, metadata, clinical information, and patient data were combined. Results: A total of 11 publications fulfilled the inclusion criteria. All of them reported an overall improvement in different skin lesion classification tasks with patient data integration. The most commonly used patient data were age, sex, and lesion location. The patient data were mostly one-hot encoded. There were differences in the complexity that the encoded patient data were processed with regarding deep learning methods before and after fusing them with the image features for a combined classifier. Conclusions: This study indicates the potential benefits of integrating patient data into CNN-based diagnostic algorithms. However, how exactly the individual patient data enhance classification performance, especially in the case of multiclass classification problems, is still unclear. Moreover, a substantial fraction of patient data used by dermatologists remains to be analyzed in the context of CNN-based skin cancer classification. Further exploratory analyses in this promising field may optimize patient data integration into CNN-based skin cancer diagnostics for patients' benefits.
CRIS-Team Scopus Importer:2021-07-16
Keywords: Convolutional neural networks; Patient data; Skin cancer classification

Integration of transcriptomics data into agent-based models of solid tumor metastasis - Retzlaff, Jimmy; Lai, Xin; Berking, Carola; Vera, Julio (Computational and Structural Biotechnology Journal, 2023)
Recent progress in our understanding of cancer mostly relies on the systematic profiling of patient samples with high-throughput techniques like transcriptomics. With this approach, one can find gene signatures and networks underlying cancer aggressiveness and therapy resistance. However, omics data alone cannot generate insights into the spatiotemporal aspects of tumor progression. Here, multi-level computational modeling is a promising approach that would benefit from protocols to integrate the data generated by the high-throughput profiling of patient samples. We present a computational workflow to integrate transcriptomics data from tumor patients into hybrid, multi-scale cancer models. In the method, we conduct transcriptomics analysis to select key differentially regulated pathways in therapy responders and non-responders and link them to agent-based model parameters. We then determine global and local sensitivity through systematic model simulations that assess the relevance of parameter variations in triggering therapy resistance. We illustrate the methodology with a de novo generated agent-based model accounting for the interplay between tumor and immune cells in a melanoma micrometastasis. The application of the workflow identifies three distinct scenarios of therapy resistance.
CRIS-Team Scopus Importer:2023-03-23
Keywords: Immunotherapy; Melanoma; Multi-scale modelling; Systems biology

Intensity and longevity of SARS-CoV-2 vaccination response in patients with immune-mediated inflammatory disease: a prospective cohort study. - Simon, David; Tascilar, Koray; Fagni, Filippo; Kleyer, Arnd; Krönke, Gerhard; Meder, Christine; Dietrich, Peter; Orlemann, Till; Mößner, Johanna; Taubmann, Jule; Mutlu, Melek Yalcin; Knitza, Johannes; et al. (The Lancet Rheumatology, 2022)
Background: Concerns have been raised about the reduced immunogenicity of vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory diseases and the higher risk of breakthrough infections. The objective of our study was to investigate the intensity and longevity of SARS-CoV-2 vaccination responses in patients with immune-mediated inflammatory diseases, and to assess the effects of diagnosis, treatment, and adapted vaccination schedules. Methods: SARS-CoV-2 IgG antibody response after SARS-CoV-2 vaccination was measured over time in a large prospective cohort of healthy controls and participants with immune-mediated inflammatory diseases (attending or admitted to affiliated centres) between Dec 15, 2020, and Dec 1, 2021. Cohort participants with immune-mediated inflammatory diseases and control participants with no diagnosis of immune-mediated inflammatory diseases, were eligible for this analysis. Demographic data and disease-specific data were collected using a questionnaire. Humoral response was compared across treatment and disease groups, and with respect to the receipt of additional vaccinations. SARS-CoV-2 antibody response was measured by ELISA using optical density ratio units and modelled over time with age and sex adjustment using mixed-effects models. Using these models, marginal mean antibody titres and marginal risks of a poor response (optical density ratio <1·1) were calculated for each week starting from week 8 after the first vaccination to week 40. Findings: Among 5076 individuals registered, 2535 participants with immune-mediated inflammatory diseases (mean age 55·0 [15·2] years; 1494 [58·9%] women and 1041 [41·1%] men) and 1198 healthy controls (mean age 40·7 [13·5] years; 554 [46·2%] women and 644 [53·8%] men) were included in this analysis. Mean antibody titres were higher in healthy controls compared with people with immune-mediated inflammatory diseases at all timepoints, with a peak antibody response in healthy controls (mean optical density ratio 12·48; 95% CI 11·50-13·53) of more than twice that in participants with immune-mediated inflammatory diseases (5·50; 5·23-5·77; mean difference 6·98; 5·92-8·04). A poor response to vaccination was observed in participants with immune-mediated inflammatory diseases who were taking B-cell inhibitors (peak mean difference from healthy controls 11·68; 10·07-13·29) and T-cell inhibitors (peakmean difference from healthy controls 10·43; 8·33-12·53). Mean differences in antibody responses between different immune-mediated inflammatory diseases were small. Participants with immune-mediated inflammatory diseases who were given a third vaccine dose had higher mean antibody titres than did healthy controls vaccinated with two vaccine doses at 40 weeks after the initial vaccination (mean difference 1·34; 0·01-2·69). Interpretation: People with immune-mediated inflammatory diseases show a lower and less durable SARS-CoV-2 vaccination response and are at risk of losing humoral immune protection. Adjusted vaccination schedules with earlier booster doses or more frequent re-doses, or both, could better protect people with immune-mediated inflammatory diseases. Funding: Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Research Council, Innovative Medicine Initiative, Friedrich-Alexander-Universität Erlangen-Nürnberg, Else Kröner-Memorial Foundation.
EVALuna2:506737

Interdependence of coagulation with immunotherapy and BRAF/MEK inhibitor therapy: results from a prospective study - Beckmann, Malte; Schlüter, Julian; Erdmann, Michael; Kramer, Rafaela; Cunningham, Sarah; Hackstein, Holger; Zimmermann, Robert; Heinzerling, Lucie (Cancer Immunology, Immunotherapy, 2024)
Immune checkpoint inhibitor (ICI) therapies effectively treat a broadening spectrum of cancer entities but induce various immune-related side effects (irAEs). Recent reports suggest a correlation between ICI-induced systemic inflammation and thromboembolic events as well as an increased effectiveness by coadministration of anticoagulants. With cancer patients having a higher risk of thrombotic events per se, it is crucial to dissect and characterize the mechanisms that cause pro-coagulative effects induced by systemic tumor therapies and their potential interplay with anti-tumor response. A total of 31 patients with advanced skin cancer treated with either ICIs (n = 24) or BRAF/MEK inhibitors (n = 7) were longitudinally assessed for blood and coagulation parameters before as well as 7, 20 and 40 days after initiation of systemic tumor therapy. Changes were analyzed and compared between both groups. In addition, the influence of coagulation parameters on progression-free, recurrence-free and overall survival was investigated. The ICI cohort presented significantly increased factor VIII activity after one week of therapy (p 0.0225); while, protein S activity was reduced during the whole observation period. Additionally, von Willebrand factor activity and tissue factor concentrations increased under immunotherapy. Similar changes occurred under BRAF/MEK inhibitor therapy (BRAF/MEKi). Increased baseline levels of von Willebrand factor antigen and factor VIII:C before the start of ICI therapy correlated with a significantly higher risk of recurrence for patients receiving adjuvant immunotherapy. The findings suggest the induction of a pro-coagulant state under ICI and BRAF/MEKi and a role of coagulation parameters in the efficacy of ICI therapie
Keywords: Immune checkpoint inhibitors; BRAF/MEK inhibitors; Melanoma; Coagulation–fibrinolysis disorders; ICI-associated thrombosis; Predictive marker

Interdisciplinary Approach to Diagnostic and Therapy of Ulcus cruris - Erfurt-Berge, Cornelia; Renner, Regina (Aktuelle Dermatologie, 2021)
Eine chronische Wunde am Unterschenkel ist in der dermatologischen Ambulanz ein haufig gesehenes Krankheitsbild. Dennoch stellen Diagnostik und Therapie eine Herausforderung dar, denn es sind nicht nur die vaskularen, sondern auch die selteneren Differenzialdiagnosen, die es fruhzeitig zu erkennen und kausal zu therapieren gilt, wobei der Dermatologe oft erster konsiliarischer Ansprechpartner anderer Fachdisziplinen ist.
CRIS-Team WoS Importer:2021-03-12

Interdisciplinary Approach to the Diagnosis and Treatment of Leg Ulcers - Erfurt-Berge, Cornelia; Renner, Regina (Phlebologie, 2022)
CRIS-Team WoS Importer:2022-12-30

Interest in tanning beds and sunscreen in German-speaking countries - Kirchberger, Michael C.; Kirchberger, Laura F.; Eigentler, Thomas K.; Reinhard, Raphael; Berking, Carola; Schuler, Gerold; Heinzerling, Lucie; Heppt, Markus V. (Journal der Deutschen Dermatologischen Gesellschaft, 2017)
BACKGROUND: The growing incidence of nearly all types of skin cancer can be attributed to increased exposure to natural or artificial ultraviolet (UV) radiation. However, there is a scarcity of statistical data on risk behavior or sunscreen use, which would be important for any prevention efforts. METHODS: Using the search engine Google® , we analyzed search patterns for the terms Solarium (tanning bed), Sonnencreme (sunscreen), and Sonnenschutz (sun protection) in Germany, Austria, and Switzerland between 2004 and 2016, and compared it to search patterns worldwide. For this purpose, "normalized search volumes" (NSVs) were calculated for the various search queries. The corresponding polynomial functions were then compared with each other over the course of time. RESULTS: Since 2001, there has been a marked worldwide decrease in the search queries for tanning bed, whereas those for sunscreen have steadily increased. In German-speaking countries, on the other hand, there have - for years - consistently been more search queries for tanning bed than for sunscreen. There is an annual periodicity of the queries, with the highest NSVs for tanning bed between March and May and those for sunscreen in the summer months around June. In Germany, the city-states of Hamburg and Berlin have particularly high NSVs for tanning bed. CONCLUSIONS: Compared to the rest of the world, German-speaking countries show a strikingly unfavorable search pattern. There is still great need for education and prevention with respect to sunscreen use and avoidance of artificial UV exposure.
EVALuna2:34311

Interleukin 17 Blockade in Psoriasis Patients with Subclinical Joint Inflammation- Prospective Open Study to Influence the Course of the Disease by means of Secukinumab - Kampylafka, E.; Oliveira, I.; Linz, C.; Lerchen, V.; Englbrecht, Matthias; Simon, David; Rech, Jürgen; Kleyer, Arnd; Schett, Georg; Sticherling, Michael; Hueber, Axel (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Interleukin-17 Blockade Leads to Shifts from Stage-based Towards Response-based Disease Clusters- Comparative Data from Very Early and Established Psoriatic Arthritis - Kampylafka, Eleni; Tascilar, Koray; Lerchen, Veronika; Linz, Christina; Sokolova, Maria; Zekovic, Ana; Kleyer, Arnd; Simon, David; Rech, Jürgen; Sticherling, Michael; Schett, Georg; Hueber, Axel (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Interleukin-2 and Checkpoint Inhibition as a successful Therapy Sequence for metastatic Melanoma: Case Report and retrospective Analysis in 52 Patients - Cosgarea,; Zimmer, L.; Weide, B.; Gutzmer, R.; Heinzerling, Lucie; Weishaupt, C.; Pfoehler, C.; Gesierich, A.; Herbst, R.; Kaehler, K.; Schlaak, M.; Loquai, C.; et al. (2017)
EVALuna2:34331

Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections - Bénard, Alan; Jacobsen, Anne; Brunner, Maximilian; Krautz, Christian; Klösch, Bettina; Swierzy, Izabela; Naschberger, Elisabeth; Podolska, Malgorzata; Kouhestani, Dina; David, Paul; Birkholz, Torsten; Castellanos, Ixchel; et al. (Nature Communications, 2021)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.
CRIS-Team Scopus Importer:2021-03-05

Interleukin-3 protects against viral pneumonia in sepsis by enhancing plasmacytoid dendritic cell recruitment into the lungs and T cell priming - Benard, Alan; Hansen, Frederik; Uhle, Florian; Klösch, Bettina; Czubayko, Franziska; Mittelstädt, Anke; Jacobsen, Anne; David, Paul; Podolska, Malgorzata; Anthuber, Anna; Swierzy, Izabela; Schaack, Dominik; et al. (Frontiers in Immunology, 2023)
Rationale: Sepsis, a global health burden, is often complicated by viral infections leading to increased long-term morbidity and mortality. Interleukin-3 (IL-3) has been identified as an important mediator amplifying acute inflammation in sepsis; however, its function in the host response to viral infections during sepsis remains elusive. Objectives: To investigate the role of IL-3 during viral pneumonia in sepsis. Methods: We included septic patients from two different cohorts and used in vitro and in vivo assays. The obtained data were substantiated using a second model (SARS-CoV-2 infections). Measurements and main results: Low plasma IL-3 levels were associated with increased herpes simplex virus (HSV) airway infections in septic patients, resulting in reduced overall survival. Likewise, Il-3-deficient septic mice were more susceptible to pulmonary HSV-1 infection and exhibited higher pulmonary inflammation than control mice. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating plasmacytoid dendritic cells (pDCs) into the airways and by enhancing pDC-mediated T cell activation upon viral stimulation. Interestingly, the ability of IL-3 to improve adaptive immunity was confirmed in patients with SARS-CoV-2 infections. Conclusion: Our study identifies IL-3 as a predictive disease marker for viral reactivation in sepsis and reveals that IL-3 improves antiviral immunity by enhancing the recruitment and the function of pDCs.
CRIS-Team Scopus Importer:2023-03-24
Keywords: interleukin-3; plasmacytoid dendritic cells; sepsis; T cell priming; viral pneumonia

Inter-Rater Agreement in Assessing Risk of Bias in Melanoma Prediction Studies Using the Prediction Model Risk of Bias Assessment Tool (PROBAST): Results from a Controlled Experiment on the Effect of Specific Rater Training - Kaiser, Isabelle; Pfahlberg, Annette Bettina; Mathes, Sonja; Uter, Wolfgang; Diehl, Katharina; Steeb, Theresa; Heppt, Markus; Gefeller, Olaf (Journal of Clinical Medicine, 2023)
Assessing the risk of bias (ROB) of studies is an important part of the conduct of systematic reviews and meta-analyses in clinical medicine. Among the many existing ROB tools, the Prediction Model Risk of Bias Assessment Tool (PROBAST) is a rather new instrument specifically designed to assess the ROB of prediction studies. In our study we analyzed the inter-rater reliability (IRR) of PROBAST and the effect of specialized training on the IRR. Six raters independently assessed the risk of bias (ROB) of all melanoma risk prediction studies published until 2021 (n = 42) using the PROBAST instrument. The raters evaluated the ROB of the first 20 studies without any guidance other than the published PROBAST literature. The remaining 22 studies were assessed after receiving customized training and guidance. Gwet’s AC1 was used as the primary measure to quantify the pairwise and multi-rater IRR. Depending on the PROBAST domain, results before training showed a slight to moderate IRR (multi-rater AC1 ranging from 0.071 to 0.535). After training, the multi-rater AC1 ranged from 0.294 to 0.780 with a significant improvement for the overall ROB rating and two of the four domains. The largest net gain was achieved in the overall ROB rating (difference in multi-rater AC1: 0.405, 95%-CI 0.149–0.630). In conclusion, without targeted guidance, the IRR of PROBAST is low, questioning its use as an appropriate ROB instrument for prediction studies. Intensive training and guidance manuals with context-specific decision rules are needed to correctly apply and interpret the PROBAST instrument and to ensure consistency of ROB ratings.
CRIS-Team Scopus Importer:2023-03-24
Keywords: inter-rater agreement; inter-rater reliability; melanoma; prediction; PROBAST; risk of bias

Interventions for Actinic Keratosis in Nonscalp and Nonface Localizations: Results from a Systematic Review with Network Meta-Analysis - Steeb, Theresa; Wessely, Anja; Schmitz, Lutz; Heppt, Franz; Kirchberger, Michael; Berking, Carola; Heppt, Markus (Journal of Investigative Dermatology, 2020)
Myriad interventions are available for the treatment of actinic keratosis located on the face or scalp. However, lesions located outside the head and neck have received little attention until now. We aimed to synthesize the current knowledge of interventions for actinic keratosis in nonscalp and nonface localizations. Randomized controlled trials reporting data for these localizations were searched in MEDLINE, Embase, and The Cochrane Library CENTRAL, as well as in pertinent trial registers until 25 March 2020. A total of 13 randomized controlled trials with 1,380 patients were included in a systematic review. Five treatment modalities were evaluated and compared with placebo in a frequentist network meta-analysis, including cryosurgery, ingenol mebutate, photodynamic therapy, colchicine, and 5-fluorouracil. In the network meta-analysis, cryosurgery showed the highest participant complete clearance rates (risk ratio, 7.73; 95% confidence interval = 3.21–18.61; 10 studies; I2 = 20.3%; Grading of Recommendations Assessment, Development, and Evaluation, ++–) and lesion clearance rates (risk ratio, 2.97; 95% confidence interval = 2.45–3.59; 4 studies; I2 = 0%; Grading of Recommendations Assessment, Development, and Evaluation, ++–) compared with placebo. Ingenol mebutate demonstrated the highest participant partial clearance rates compared with placebo (risk ratio, 7.12; 95% confidence interval = 4.36–11.64; 5 studies; I2 = 0%; Grading of Recommendations Assessment, Development, and Evaluation, +++-). The mean reduction of lesions and occurrence of adverse events was poorly reported. The certainty of the evidence varied from very low to high and was limited by imprecision and study limitations.
CRIS-Team Scopus Importer:2020-08-07

Intestinal Mucosal Wound Healing and Barrier Integrity in IBD–Crosstalk and Trafficking of Cellular Players - Sommer, Katrin; Wiendl, Maximilian; Müller, Tanja; Heidbreder, Karin; Voskens, Caroline; Neurath, Markus; Zundler, Sebastian (Frontiers in Medicine, 2021)
The intestinal epithelial barrier is carrying out two major functions: restricting the entry of potentially harmful substances while on the other hand allowing the selective passage of nutrients. Thus, an intact epithelial barrier is vital to preserve the integrity of the host and to prevent development of disease. Vice versa, an impaired intestinal epithelial barrier function is a hallmark in the development and perpetuation of inflammatory bowel disease (IBD). Besides a multitude of genetic, molecular and cellular alterations predisposing for or driving barrier dysintegrity in IBD, the appearance of intestinal mucosal wounds is a characteristic event of intestinal inflammation apparently inducing breakdown of the intestinal epithelial barrier. Upon injury, the intestinal mucosa undergoes a wound healing process counteracting this breakdown, which is controlled by complex mechanisms such as epithelial restitution, proliferation and differentiation, but also immune cells like macrophages, granulocytes and lymphocytes. Consequently, the repair of mucosal wounds is dependent on a series of events including coordinated trafficking of immune cells to dedicated sites and complex interactions among the cellular players and other mediators involved. Therefore, a better understanding of the crosstalk between epithelial and immune cells as well as cell trafficking during intestinal wound repair is necessary for the development of improved future therapies. In this review, we summarize current concepts on intestinal mucosal wound healing introducing the main cellular mediators and their interplay as well as their trafficking characteristics, before finally discussing the clinical relevance and translational approaches to therapeutically target this process in a clinical setting.
CRIS-Team Scopus Importer:2021-04-16
Keywords: IBD; intestinal epithelial barrier function; intestinal epithelial cells; mucosal healing; wound healing

Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients - Bol, Kalijn F.; Figdor, Carl G.; Aarntzen, Erik H. J. G.; Welzen, Marieke E. B.; Van Rossum, Michelle M.; Blokx, Willeke A. M.; Van De Rakt, Mandy W. M. M.; Scharenborg, Nicole M.; De Boer, Annemiek J.; Pots, Jeanette M.; Nordkamp, Michel A. M. Olde; Van Oorschot, Tom G. M.; et al. (OncoImmunology, 2015)
Autologous dendritic cell (DC) therapy is an experimental cellular immunotherapy that is safe and immunogenic in patients with advanced melanoma. In an attempt to further improve the therapeutic responses, we treated 15 patients with melanoma, with autologous monocyte-derived immature DC electroporated with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively active TLR4 (caTLR4) together with mRNA encoding a tumor-associated antigen (TAA; respectively gp100 or tyrosinase). In addition, DC were pulsed with keyhole limpet hemocyanin (KLH) that served as a control antigen. Production of this DC vaccine with high cellular viability, high expression of co-stimulatory molecules and MHC class I and II and production of IL-12p70, was feasible in all patients. A vaccination cycle consisting of three vaccinations with up to 15×10(6) DC per vaccination at a biweekly interval, was repeated after 6 and 12 months in the absence of disease progression. mRNA-optimized DC were injected intranodally, because of low CCR7 expression on the DC, and induced de novo immune responses against control antigen. T cell responses against tyrosinase were detected in the skin-test infiltrating lymphocytes (SKIL) of two patients. One mixed tumor response and two durable tumor stabilizations were observed among 8 patients with evaluable disease at baseline. In conclusion, autologous mRNA-optimized DC can be safely administered intranodally to patients with metastatic melanoma but showed limited immunological responses against tyrosinase and gp100.
EVALuna2:19574

Intratumorally administered CV8102 in patients with advanced solid tumors: Preliminary results from completed dose escalation in study 008 - Eigentler, T.; Heinzerling, Lucie; Krauss, J.; Weishaupt, C.; Ochsenreither, S.; Lebbe, C.; Mohr, P.; Oliva, M.; Oberoi, H. K.; Terheyden, P.; Perez, J. M. Trigo; Robert, C.; et al. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-10-15

Intratumoral RNA-based TLR-7/-8 and RIG-I agonist CV8102 alone and in combination with anti-PD-1 in a Phase I dose-escalation and expansion trial in patients with advanced solid tumors - Eigentler, Thomas; Krauss, Juergen; Schreiber, Jutta; Weishaupt, Carsten; Terheyden, Patrick; Heinzerling, Lucie; Mohr, Peter; Weide, Benjamin; Gutzmer, Ralf; Becker, Juergen C.; Kiecker, Felix; Daehling, Angelika; et al. (CANCER RESEARCH, 2019)
CRIS-Team WoS Importer:2019-10-15

Intravascular Large B-Cell Lymphoma: A Review with a Focus on the Prognostic Value of Skin Involvement - Breakell, Thomas; Waibel, Heidi; Schliep, Stefan; Ferstl, Barbara; Erdmann, Michael; Berking, Carola; Heppt, Markus (Current Oncology, 2022)
Intravascular large B-cell lymphoma (IVLBCL) is an aggressive Non-Hodgkin lymphoma (NHL) characterised by the presence of neoplastic lymphoid cells within small-and medium-sized blood vessels. According to the clinical presentation, the current WHO classification distinguishes the ‘classic’ (formerly ‘Western’) from a hemophagocytic syndrome-associated (formerly ‘Asian’) variant. A third ‘cutaneous’ variant has been proposed, characterised by a good prognosis and unique clinical features. While laboratory findings can hint at diagnosis, symptoms are rather nonspecific, and deep skin biopsy supported by further measures such as bone marrow aspiration and positron emission tomography-computed tomography scanning is needed to make a definite diagnosis. Treatment is comprised of anthracycline-based chemotherapy supplemented with rituximab and central nervous system prophylaxis. While there are various prognostic models for NHL, only one is specific to IVLBCL, which does not sufficiently represent some patient groups, especially regarding the lack of differentiation within the patient collective with skin involvement. This underlines the necessity for the establishment of further prognostic models in particular for IVLBCL patients with cutaneous manifestations.
CRIS-Team Scopus Importer:2022-05-13
Keywords: dermato-oncology; intravascular large B-cell lymphoma; IVLBCL; prognostic model; R-CHOP; skin cancer

Intravenous Immunoglobulin Therapy for Pyoderma Gangrenosum: A Multicenter Retrospective Analysis in 81 Patients - Ronicke, Moritz; Sollfrank, Lukas; Vitus, Martin V.; Walter, Lukas J.; Krieter, Manuel; Moelleken, Maurice; Dissemond, Joachim; Schultz, Erwin; Lauffer, Felix; von den Driesch, Peter; Erfurt-Berge, Cornelia (American Journal of Clinical Dermatology, 2024)
Background: Pyoderma gangrenosum (PG) is rare neutrophil skin disease causing painful, progressively enlarging ulcers. Among the treatment options, intravenous immunoglobulin (IVIG) is a therapy of first choice for paraneoplastic PG. Otherwise, it is used in therapy-refractory courses. Objective: To assess the efficacy and safety of IVIG therapy in patients with PG. Methods: A retrospective chart review for patients in five dermatologic wound centres in Germany was performed. Results: Overall, 81 patients were included. IVIG was used as adjunct therapy with (methyl-) prednisolone and/or a steroid sparing therapy in 77 (95.1%) cases. Response to treatment (combined complete and partial, defined as tendency to heal and cessation of lesion progression, respectively) was 49.3% 1 month after initiation of IVIG. In total 18.8% had a complete response after 6 months. Statistically significantly higher response rates were observed in patients with diabetes mellitus and thyroid disease [odds ratio (OR) 3.49, confidence interval (CI) 1.13–10.80 and OR 6.64, CI 1.01–43.57, respectively]. Patients with solid malignancy tended to have better response (OR 4.36, CI 0.79–23.91). A higher IVIG dose was also associated with a tendency towards better response rates (OR 2.70, CI 0.84–8.63). In total, 1 (1.2%) severe adverse event (myocardial infarction with consequent death) was observed as well as three moderate adverse events, with two thromboembolic events (2.5%) and one acute kidney injury (1.2%). Other adverse events were mild or unlikely to be associated with IVIG therapy, with 14 events in 10 patients overall (12.3%). Conclusions: This multicentre retrospective study shows the important role of adjunctive IVIG therapy in patients with PG with recalcitrant courses. Identifying subgroups with a higher probability of response could improve future response rates and save patients from ineffective treatment and potential adverse events. Graphical Abstract: (Figure presented.)
CRIS-Team Scopus Importer:2024-11-22

Introducing SKINFO - the new and unique web-based information platform for German-speaking skin cancer patients - Steeb, Theresa; Hoffmann, Julia; Meier, Friedegund; Weber, Christiane; Bergmann, Maike; Mueller-Schuchardt, Anne; Weiler, Nina; Doppler, Astrid; Berking, Carola; Schadendorf, Dirk (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Investigating dynamics of inhibitory and feedback loops in ERK signalling using power-law models - Vera, Julio; et al. (Molecular Biosystems, 2010)

Investigation of a kinetic model reproducing the mechanisms of oligodendrocytes differentiation - Nikolov, S. G.; Nenov, M.; Vera, Julio (Series on Biomechanics, 2021)
Studying of the gene regulatory architecture that controls region-independent dynamics of oligodendrocyte differentiation, Cantone and co-authors derived a kinetic model in 14 ordinary differential equations (ODEs) [Cantone, M. Kuspert, M., Reiprich, S., et al., Glia 67(5), 825-843, 2019]. In this paper, we investigate a reduced version of this model. The reduced model consists four ODEs of mSox9, mSox10, mOlig2 and miR cluster. The cluster is composed of four microRNAs, namely miR17, miR335, miR338, and miR155. The model predicts that the morphogen gradients (signals) and the transcription rate of Olig2 mRNA play a key role in the dynamic behaviour of the model, such as stability, bistability and instability (including self-oscillations (stable limit cycle)).
CRIS-Team Scopus Importer:2021-07-30
Keywords: Analysis; Dynamical behaviour; Kinetic model; Oligodendrocytes

Investigation of the expression of inflammatory markers in oral biofilm samples in patients with systemic scleroderma and the association with clinical periodontal parameters— a preliminary study - Buchbender, Mayte; Lugenbühl, Amelie; Fehlhofer, Jakob Paul; Kirschneck, Christian; Ries, Jutta; Lutz, Rainer; Sticherling, Michael; Kesting, Marco Rainer; Ries, Jutta (Life, 2021)
Background: Systemic scleroderma (SSc) has multiple orofacial effects. The aim of this study was to analyze the expression of inflammatory mediators in biofilm samples. It was hypothesized that different expression levels and clinical associations might be drawn. Methods: A total of 39 biofilm samples from group 1 = SSc and group 2 = healthy control were examined for the expression levels of interleukin (IL)-2,-6, and-10; matrix metalloprotease (MMP)-9; and surface antigens CD90 and CD34 by quantitative real-time PCR and clinical parameters. Relative quantitative (RQ) gene expression was determined using the ∆∆CT method. Results: The mean bleeding on probing values (p = 0.006), clinical attachment loss (CAL) (p = 0.009), gingival recession (p = 0.020), limited mouth opening (p = 0.001) and cervical tooth defects (p = 0.011) were significantly higher in group 1. RQ expressions of IL-2 and CD34 were significantly lower, IL-6, MMP-9, and CD90 were significantly higher. There was a significant positive correlation of IL-6/MMP-9 and negative correlation of mouth opening/CAL and IL-6/CAL. Conclusion: Different expression levels of IL-2, IL-6, MMP-9, CD34 and CD90 were detected in biofilm samples from patients with SSc compared to control. An immunological correlation to the clinical parameters of mouth opening and CAL was shown; thus, we conclude that SSc might have an impact on periodontal tissues.
CRIS-Team Scopus Importer:2021-11-05
Keywords: Biofilm samples; Expression levels of cytokines; Periodontal parameters; Systemic sclero-derma (SSc)

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, Theresa; 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 CAR‐T cells with magnetic nanoparticles for controlled targeting suppresses inflammatory cytokine release and switches tumor cell death mechanism - Pfister, Felix; Carnell, Lucas; Löffler, Lisa; Boosz, Philipp; Schaft, Niels; Dörrie, Jan; Stein, René; Lenz, Malte; Spiecker, Erdmann; Huber, Christian; Haddadin, Sami; Berking, Carola; et al. (MedComm, 2025)
Therapies against hematological malignancies using chimeric antigen receptors (CAR)-T cells have shown great potential; however, therapeutic success in solid tumors has been constrained due to limited tumor trafficking and infiltration, as well as the scarcity of cancer-specific solid tumor antigens. Therefore, the enrichment of tumor-antigen specific CAR-T cells in the desired region is critical for improving therapy efficacy and reducing systemic on-target/off-tumor side effects. Here, we functionalized human CAR-T cells with superparamagnetic iron oxide nanoparticles (SPIONs), making them magnetically controllable for site-directed targeting. SPION-loaded CAR-T cells maintained their specific cytolytic capacity against melanoma cells expressing the CAR-specific antigen chondroitin sulfate proteoglycan (CSPG4). Importantly, SPIONs suppressed cytokine release in the loaded CAR-T cells, shifting the cell death phenotype in the tumor cells from pyroptosis to apoptosis. Furthermore, SPION-loaded CAR-T cells could be enriched in a dynamic flow model through an external magnetic field and be detected in MRI. These results demonstrate that lytic cytotoxicity is retained after SPION-functionalization and provides a basis for future site-specific immunotherapies against solid tumors with reduced systemic adverse side effect

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

Logic-based modeling and drug repurposing for the prediction of novel therapeutic targets and combination regimens against E2F1-driven melanoma progression. - Singh, Nivedita; Khan, Faiz M.; Bala, Lakshmi; Vera, Julio; Wolkenhauer, Olaf; Pützer, Brigitte; Logotheti, Stella; Gupta, Shailendra K. (BMC Chemistry, 2023)
Melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds the potential to prevent metastasis however, these networks entail complex feedback and feedforward regulatory motifs among various regulatory layers, which make it difficult to identify druggable components. To this end, computational approaches such as mathematical modeling and virtual screening are important tools to unveil the dynamics of these signaling networks and identify critical components that could be further explored as therapeutic targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells to reconstruct a core regulatory network underlying aggressive melanoma. Using logic-based in silico perturbation experiments of a core regulatory network, we identified that simultaneous perturbation of Protein kinase B (AKT1) and oncoprotein murine double minute 2 (MDM2) drastically reduces EMT in melanoma. Using the structures of the two protein signatures, virtual screening strategies were performed with the FDA-approved drug library. Furthermore, by combining drug repurposing and computer-aided drug design techniques, followed by molecular dynamics simulation analysis, we identified two potent drugs (Tadalafil and Finasteride) that can efficiently inhibit AKT1 and MDM2 proteins. We propose that these two drugs could be considered for the development of therapeutic strategies for the management of aggressive melanoma.
EVALuna2:569204

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

Lupus erythematosus - Sticherling, Michael; Kuhn, Annegret (Springer Berlin Heidelberg, 2022)
Lupus erythematosus (LE) is an inflammatory autoimmune disease characterized by high clinical heterogeneity and a variable course. In systemic lupus erythematosus (SLE), there is the possibility of the development of life-threatening involvement of multiple organs that can affect the skin, musculosceletal system, kidneys, and cardiovascular and central nervous systems. The disease can also be limited to the skin, and is then called cutaneous lupus erythematosus (CLE). Together with an (immune) genetic background, various environmental factors, such as smoking, medication, hormones, infections, and above all ultraviolet (UV) radiation can lead to an initial manifestation or exacerbation of the disease. New findings on the pathogenesis of CLE have also led to further therapeutic options for this autoimmune disease.
CRIS-Team Scopus Importer:2024-12-16

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

Malignancy in chronic wounds Malignome als Ursache von chronischen Wunden - Siegling, Michael; Erfurt-Berge, Cornelia (Internistische Praxis, 2022)
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:2024-12-16
Keywords: chronic wounds; malignant transformation; malignant wounds; tumours; wound management

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 (Tägliche Praxis, 2022)
Die Unterscheidung zwischen primär und sekundär malignen Wunden ist oft kompliziert. Kutane Primärtumoren wie Basaliome, Plattenepithelkarzinome, maligne Melanome, kutane Lymphome und Sarkome können sich ebenso wie kutane Metastasen bei Ulzeration als maligne Wunde manifestieren. Gleichzeitig können sich initial tumorfreie chronische Wunden über eine maligne Transformation zu sekundär malignen Geschehen entwickeln. Die korrekte und frühzeitige Diagnosefindung ist essenziell und die Basis einer individuellen kurativen oder palliativen Therapie. Im Rahmen des Wundmanagements von chronischen und palliativen Wunden sind neben einer stadiengerechten und krankheitsbezogenen Therapie die Vorstellungen des Patienten von zentraler Bedeutung. Um dem ganzheitlich empathischen Ansatz der Wundversorgung gerecht zu werden, sollte auf psychologische Aspekte, die Verhinderung unangenehmer Wundgerüche, Kontrolle von Wundausscheidungen, Wundspülung und -reinigung sowie eine individuelle Schmerztherapie geachtet werden.
CRIS-Team Scopus Importer:2024-12-16
Keywords: chronic wounds; malignant transformation; malignant wounds; tumours; wound management; chronische Wunden; Hautkrebs; Hauttumoren; maligne Transformation; Maligne Wunden; Malignome; Mammakarzinom; Melanom; Plattenepithelkarzinom; Ulkus; Wundmanagement

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 Local Skin Reactions Caused by 5-FU 4% Cream for the Treatment of Actinic Keratosis: A Delphi Consensus - Brancaccio, Gabriella; Briatico, Giulia; Apalla, Zoe; Dummer, Reinhard; Eklind, Jan; Seguin, Nicole Basset; Dreno, Brigitte; Fargnoli, Maria Concetta; Guitera, Pascale; Heppt, Markus; Hoeller, Christoph; Jouary, Thomas; et al. (Dermatology Practical & Conceptual, 2025)
Introduction: Treatments such as 4% 5-fluorouracil (5-FU) cream have demonstrated strong efficacy in lesion clearance of actinic keratosis; however, local skin reactions (LSR) during treatment remain a significant challenge, potentially affecting patient adherence. Objective: We sought to build consensus on management of LSR associated with 4% 5-FU using the Delphi methodology. Methods: Twenty-eight expert dermatologists participated in a 3-round Delphi process. Experts evaluated LSR management strategies, including emollients, antibiotics, steroids, and treatment discontinuation. Agreement levels were measured using a 7-point Likert scale. Consensus was categorized as high if >80% of votes were within the 5–7 rating range and low when >25% were in the 1–3 rating range, with <25% of the votes in the 6–7 rating range. Other combinations of votes were considered as having moderate agreement. Results: High agreement was achieved for the following statements: the approved daily schedule (once daily for 4 weeks) is the most appropriate (92.9%); mild LSR generally do not require intervention and do not impact treatment adherence (96.4%); severe LSR may benefit from temporary treatment interruption and emollient use, ensuring adherence without compromising efficacy (92.9%). The use of emollients (in parallel with the treatment with 5-FU) was considered not needed by most (moderate consensus, 64.3%). Experts emphasized the importance of clear communication about LSR during baseline consultation to enhance patient compliance. Conclusion: This consensus provides practical guidance for managing LSR induced by 4% 5-FU, ensuring high adherence and optimizing treatment outcomes. Further research is needed to validate these findings and explore alternative management approaches.
CRIS-Team Scopus Importer:2025-05-23
Keywords: 5-fluorouracil; Actinic keratosis; Local skin reactions

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.
EVALuna2:19628

Managing toxicities of immunotherapies - a side effect register for rare and severe side effects of checkpoint Inhibitor therapy - Heinzerling, Lucie; Schuler, Gerold (2018)
EVALuna2:34408

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.
EVALuna2:19558

Mastocytosis in the age of precision medicine: Position paper of the German Society of Allergy (AeDA) on the management of indolent systemic mastocytosis - Siebenhaar, Frank; Brehler, Randolf; Christen, Deborah; Hartmann, Karin; Altrichter, Sabine; Joest, Marcus; aufm Kampe, Kristin; Lang, Claudia C.V.; Lippert, Undine; Mülleneisen, Norbert; Ott, Hagen; Panse, Jens; et al. (Allergo Journal, 2025)
Mastocytosis encompasses a spectrum of clonal mast cell disorders characterized by the proliferation and accumulation of atypical mast cells in various organs, including the skin, bone marrow, and gastrointestinal tract. Initially described in 1869 as a cutaneous manifestation, the systemic variant (SM), involving additional organs, was documented in 1949. Clinical distinctions are made between indolent SM (ISM), where mediator-related symptoms predominate, and more aggressive forms, in which organ dysfunction is the primary concern. In recent decades, there has been continuous progress in elucidating the pathogenesis, classification, and management of mastocytosis, aided by specialized networks such as the European Competence Network Mastocytosis (ECNM) and the German Competence Network on Mastocytosis (Kompetenznetzwerk Mastozytose e. V.). A significant therapeutic advancement has been the development of targeted tyrosine kinase inhibitors, including midostaurin and avapritinib, which have been utilized for several years in treating aggressive SM. Recently, avapritinib in lower dosage was also approved for ISM patients with moderate to severe symptoms. For patients with milder forms of ISM, a symptom-oriented basic therapy is recommended. The diagnosis of SM requires interdisciplinary collaboration and strict adherence to established diagnostic criteria. Moreover, innovative patient-centered approaches, such as the MASTHAVE® app, support ongoing follow-up and have the potential to enhance quality of life. Long-term research efforts are increasingly directed toward developing personalized therapies that target the molecular mechanisms underlying the disease.
CRIS-Team Scopus Importer:2025-04-18
Keywords: Mast cell disease; Mast cells; Mastocytosis; Personalized medicine; Tyrosin kinase inhibitors

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.
EVALuna2:11981

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

Medikamentöse Therapien des Ulcus cruris - Ronicke, Moritz; Erfurt-Berge, Cornelia (Aktuelle Dermatologie, 2024)
Chronic wounds are a burden for many patients in Germany and around the world. Drug therapies still play a subordinate role for the more common causes such as venous leg ulcers or arterial leg ulcers, although good data is available for individual therapies. For rarer entities, such as calciphylaxis, necrobiosis lipoidica and pyoderma gangrenosum, there is often a lack of reliable studies. However, drug treatments are essential for healing in those cases. Overall, there is a lack of approved therapies for all the diseases mentioned. This article discusses possible drug therapy options for all the diseasesmentioned.
CRIS-Team Scopus Importer:2024-07-19

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.
EVALuna2:34348

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.
EVALuna2:34376

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)
EVALuna2:34738

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 Carlos; 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.
EVALuna2:212830

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

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches - Welsh, Joshua A.; Goberdhan, Deborah C.I.; O’Driscoll, Lorraine; Buzas, Edit I.; Blenkiron, Cherie; Bussolati, Benedetta; Cai, Houjian; Di Vizio, Dolores; Driedonks, Tom A.P.; Erdbrügger, Uta; Falcon-Perez, Juan M.; Fu, Qing Ling; et al. (Journal of Extracellular Vesicles, 2024)
Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its ‘Minimal Information for Studies of Extracellular Vesicles’, which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.
CRIS-Team Scopus Importer:2024-03-22
Keywords: ectosomes; exosomes; extracellular particles; extracellular vesicles; guidelines; microparticles; microvesicles; minimal information requirements; MISEV; reproducibility; rigor; standardisation

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

Multi-Epitope DC Vaccines with Melanoma Antigens for Immunotherapy of Melanoma - Seretis, Athanasios; Amon, Lukas; Tripp, Christoph H.; Cappellano, Giuseppe; Hornsteiner, Florian; Dieckmann, Sophie; Vierthaler, Janine; Ortner-Tobider, Daniela; Kanduth, Markus; Steindl, Rita; Boon, Louis; den Haan, Joke M.M.; et al. (Vaccines, 2025)
Background/Objectives: The revolution for the treatment of melanoma came with the approval of checkpoint blockade antibodies. However, a substantial proportion of patients show primary or secondary resistance to this type of immunotherapy, indicating the need for alternative therapeutic strategies. Dendritic cells (DCs) of the skin are prime targets for vaccination approaches due to their potential to prime naïve T cells and their accessibility. This study aimed to develop and evaluate novel vaccines targeting the C-type lectin receptor DEC-205 to deliver melanoma-associated antigenic peptides to skin DCs. Methods: We cloned MHC-I-restricted peptides from the glycoprotein (gp)10025–33 and Tyrosinase-related protein (trp)2180–188 into the DEC-205 antibody sequence with modified peptide cutting sites from the OVA257–264 SIINFEKL peptide. We tested their potential to induce CD8+ T cell responses in both in vitro and in vivo settings. Tumor growth inhibition was evaluated in the transplantable B16.OVA melanoma murine model using a multi-epitope DC-based vaccine combining both peptides. Results: The cross-presentation of both gp100 and trp2 peptides was confirmed in vivo when peptide sequences were flanked by the OVA257–264 peptide cutting sites. Moreover, the combination of both antigenic peptides into a multi-epitope DC vaccine was required to inhibit B16.OVA melanoma growth. Conclusions: Our findings suggest that a DC-targeted vaccination approach using multiple epitopes deriving from melanoma antigens could represent a promising strategy for melanoma therapy.
CRIS-Team Scopus Importer:2025-05-09
Keywords: C-type lectin receptors; DC-targeted therapy; dendritic cells; immunotherapy; melanoma antigens

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 Carlos; 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 adhærencer ved lever og milt ved laparoskopisk bilateral adrenalektomi - Frid, Nicolai Lassen; Laursen, Rose Bryde; Zeyda, Johannes; Aagaard, Mikael (Ugeskrift for Læger, 2024)
CRIS-Team Scopus Importer:2025-02-04

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

Mutations in the splicing factor SF3B1 are linked to frequent emergence of HLA-DRlow/neg monocytes in lower-risk myelodysplastic neoplasms - Winter, Susann; Schneider, Marie; Oelschlaegel, Uta; Maggioni, Giulia; Riva, Elena; Raddi, Marco Gabriele; Bencini, Sara; Peruzzi, Benedetta; Choy, Desmond; Antunes Dos Reis, Rita; Güse, Esther; Lischer, Christopher; et al. (Leukemia, 2024)
CRIS-Team Scopus Importer:2024-05-10

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

Network and Systems Biology Approaches in Glial Cells - Vera González, Julio; Cantone, Martina; Blume, Christina (Systems Medicine: Integrative, Qualitative and Computational Approaches. Volume 2: Application Areas, 2021)
The central nervous system (CNS) is composed of many populations of functionally specialized, spatially organized and highly interacting cells, including neurons, astrocytes, oligodendrocytes and microglia. The ability of these cell populations to sustain their physiological functions is regulated by complex molecular networks. Experimental techniques that are able to produce high-throughput data (HTD) accounting for changes at the transcriptomic, proteomic or epigenomic level are revolutionizing neurobiology and helping in understanding the regulation of these molecular networks. However, HTD have to be interpreted in the context of the spatiotemporal interactions among molecular factors and cell types making up the CNS, and therefore one is forced to analyze the data from a systemic perspective. In Systems Biology mathematical modeling and Bioinformatics tools are combined to analyze and integrate HTD data. These data are used to elucidate the structure and regulation of molecular networks controlling cellular function(s) and phenotype(s) during development, normal functioning and pathophysiological conditions. In this article, we introduce the basics of Systems Biology and discuss case studies in which this methodology has been utilized to understand the regulation of glial cells in development and pathogenesis.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Astrocytes; Bioinformatics; Computational modeling; Mathematical modeling; Microglia; Morphogenes; Network biology; Oligodendrocytes; RNA-Seq; Sox factors; Systems biology; Transcriptional profiling