54 results on '"Schneider, Stefan W."'
Search Results
2. Imitation eines Hodgkin-Lymphoms durch Frühmanifestation einer Methotrexat-assoziierten lymphoproliferativen Erkrankung
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Burg, Maria Rosa and Schneider, Stefan W.
- Abstract
Eine Langzeittherapie mit Methotrexat (MTX) ist als Auslöser einer MTX-assoziierten lymphoproliferativen Erkrankung (MTX-LPD) bekannt. Unter einer Kombinationstherapie mit MTX und Ustekinumab kam es bei einer 58-jährigen Patientin mit Psoriasis vulgaris und Pityriasis rubra pilaris innerhalb von 4 Monaten zu einer generalisierten Lymphadenopathie. Die Histologie deutete zunächst auf ein Hodgkin-Lymphom hin. Nur die Zusammenschau mit dem klinischen Hintergrund konnte die Diagnose einer MTX-LPD aufzeigen. Unseres Wissens ist dies der erste Fall einer MTX-LPD nach nur 4 Monaten Therapie.
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- 2024
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3. Pikosekundenlaser in der Dermatologie
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Nguyen, Lynhda, Schneider, Stefan W., and Herberger, Katharina
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Hintergrund: Der Pikosekundenlaser gehört zu den jüngsten in der Dermatologie genutzten Lasersystemen. Ursprünglich wurde er zur Optimierung von Tätowierungsentfernungen entwickelt, Fortschritte in dieser Technologie erweiterten das Indikationsspektrum des Pikosekundenlasers jedoch erheblich. Ziel der Arbeit: Dieser Artikel gibt eine Übersicht über den technischen Hintergrund sowie die Indikationen des Pikosekundenlasers in der dermatologischen Lasermedizin und erläutert die Möglichkeiten und Grenzen dieses Lasersystems. Material und Methoden: Grundlage dieses Beitrages sind systematische Literaturanalyse sowie Erfahrungen aus der klinischen Praxis in der universitären Laserambulanz. Ergebnisse: Der Pikosekundenlaser ermöglicht durch Impulse im Pikosekundenbereich und den Wirkmechanismus des „laser-induced optical breakdown“ eine besonders schonende und effektive Behandlung. Im Vergleich zu den gütegeschalteten Lasern weist der Pikosekundenlaser weniger hitzeinduzierte Nebenwirkungen auf und geht mit einer geringeren Schmerzintensität sowie einer kürzeren Ausfallzeit einher. Insbesondere durch die fraktionierte nichtablative Anwendung haben sich zusätzliche Anwendungsgebiete ergeben, darunter die Hautverjüngung und Narbentherapie. Schlussfolgerung: Der Pikosekundenlaser findet ein breites Anwendungsspektrum in der dermatologischen Lasermedizin. Die aktuelle Datenlage deutet darauf hin, dass der Laser eine effektive Methode mit einem geringen Nebenwirkungsprofil ist. Um die Wirksamkeit, Verträglichkeit und Patientenzufriedenheit evidenzbasiert beurteilen zu können, sind weitere prospektive Studien notwendig.
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- 2023
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4. Immunoglobulin M pemphigoid.
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Boch, Katharina, Hammers, Christoph M., Goletz, Stephanie, Kamaguchi, Mayumi, Ludwig, Ralf J., Schneider, Stefan W., Zillikens, Detlef, Hadaschik, Eva, and Schmidt, Enno
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Background: Pemphigoid diseases are a heterogeneous group of autoimmune blistering disorders characterized by predominant deposition of immunoglobulin G or immunoglobulin A autoantibodies against structural proteins of the dermoepidermal junction (DEJ). Sole linear immunoglobulin M (IgM) deposits at the DEJ in pemphigoid diseases have been observed; however, IgM-specific target antigens have not been identified.Objective: Characterization of patients with IgM pemphigoid.Methods: Skin biopsy specimens and sera from IgM-positive patients were assessed using histopathology, direct and indirect immunofluorescence microscopy, enzyme-linked immunosorbent assays, immunoblotting, cryosection assay, complement fixation test, and internalization assays.Results: Tissue-bound linear IgM deposits along the DEJ and circulating IgM autoantibodies against type XVII collagen (Col17) were detected. These circulating IgM autoantibodies showed no complement activating or blister inducing capacity, but the ability of Col17 internalization ex vivo.Limitations: Limited number of patients.Conclusion: This study provides further evidence for the role of IgM autoantibodies in pemphigoid disease and highlights Col17 as a target antigen in IgM pemphigoid. [ABSTRACT FROM AUTHOR]- Published
- 2021
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5. Differentialdiagnose Ulcus cruris, Ursachen und Therapie
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Klingelhöller, Carmen and Schneider, Stefan W.
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- 2022
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6. Pre‐analytical factors affecting the establishment of a single tube assay for multiparameter liquid biopsy detection in melanoma patients.
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Schneegans, Svenja, Lück, Lelia, Besler, Katharina, Bluhm, Leonie, Stadler, Julia‐Christina, Staub, Janina, Greinert, Rüdiger, Volkmer, Beate, Kubista, Mikael, Gebhardt, Christoffer, Sartori, Alexander, Irwin, Darryl, Serkkola, Elina, Hällström, Taija, Lianidou, Evi, Sprenger‐Haussels, Markus, Hussong, Melanie, Mohr, Peter, Schneider, Stefan W., and Shaffer, Jonathan
- Abstract
The combination of liquid biomarkers from a single blood tube can provide more comprehensive information on tumor development and progression in cancer patients compared to single analysis. Here, we evaluated whether a combined analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and circulating cell‐free microRNA (miRNA) in total plasma and extracellular vesicles (EV) from the same blood sample is feasible and how the results are influenced by the choice of different blood tubes. Peripheral blood from 20 stage IV melanoma patients and five healthy donors (HD) was collected in EDTA, Streck, and Transfix tubes. Peripheral blood mononuclear cell fraction was used for CTC analysis, whereas plasma and EV fractions were used for ctDNA mutation and miRNA analysis. Mutations in cell‐free circulating DNA were detected in 67% of patients, with no significant difference between the tubes. CTC was detected in only EDTA blood and only in 15% of patients. miRNA NGS (next‐generation sequencing) results were highly influenced by the collection tubes and could only be performed from EDTA and Streck tubes due to hemolysis in Transfix tubes. No overlap of significantly differentially expressed miRNA (patients versus HD) could be found between the tubes in total plasma, whereas eight miRNA were commonly differentially regulated in the EV fraction. In summary, high‐quality CTCs, ctDNA, and miRNA data from a single blood tube can be obtained. However, the choice of blood collection tubes is a critical pre‐analytical variable. [ABSTRACT FROM AUTHOR]
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- 2020
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7. Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model
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Feinauer, Manuel J., Schneider, Stefan W., Berghoff, Anna S., Robador, Jose Ramon, Tehranian, Cedric, Karreman, Matthia A., Venkataramani, Varun, Solecki, Gergely, Grosch, Julia Katharina, Gunkel, Katharina, Kovalchuk, Bogdana, Mayer, Frank Thomas, Fischer, Manuel, Breckwoldt, Michael O., Brune, Maik, Schwab, Yannick, Wick, Wolfgang, Bauer, Alexander T., and Winkler, Frank
- Abstract
Clinically relevant brain metastases (BMs) frequently form in cancer patients, with limited options for effective treatment. Circulating cancer cells must first permanently arrest in brain microvessels to colonize the brain, but the critical factors in this process are not well understood. Here, in vivo multiphoton laser-scanning microscopy of the entire brain metastatic cascade allowed unprecedented insights into how blood clot formation and von Willebrand factor (VWF) deposition determine the arrest of circulating cancer cells and subsequent brain colonization in mice. Clot formation in brain microvessels occurred frequently (>95%) and specifically at intravascularly arrested cancer cells, allowing their long-term arrest. An extensive clot embedded ∼20% of brain-arrested cancer cells, and those were more likely to successfully extravasate and form a macrometastasis. Mechanistically, the generation of tissue factor-mediated thrombin by cancer cells accounted for local activation of plasmatic coagulation in the brain. Thrombin inhibition by treatment with low molecular weight heparin or dabigatran and an anti-VWF antibody prevented clot formation, cancer cell arrest, extravasation, and the formation of brain macrometastases. In contrast, tumor cells were not able to directly activate platelets, and antiplatelet treatments did reduce platelet dispositions at intravascular cancer cells but did not reduce overall formation of BMs. In conclusion, our data show that plasmatic coagulation is activated early by intravascular tumor cells in the brain with subsequent clot formation, which led us to discover a novel and specific mechanism that is crucial for brain colonization. Direct or indirect thrombin and VWF inhibitors emerge as promising drug candidates for trials on prevention of BMs.
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- 2021
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8. Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model
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Feinauer, Manuel J., Schneider, Stefan W., Berghoff, Anna S., Robador, Jose Ramon, Tehranian, Cedric, Karreman, Matthia A., Venkataramani, Varun, Solecki, Gergely, Grosch, Julia Katharina, Gunkel, Katharina, Kovalchuk, Bogdana, Mayer, Frank Thomas, Fischer, Manuel, Breckwoldt, Michael O., Brune, Maik, Schwab, Yannick, Wick, Wolfgang, Bauer, Alexander T., and Winkler, Frank
- Abstract
Clinically relevant brain metastases (BMs) frequently form in cancer patients, with limited options for effective treatment. Circulating cancer cells must first permanently arrest in brain microvessels to colonize the brain, but the critical factors in this process are not well understood. Here, in vivo multiphoton laser-scanning microscopy of the entire brain metastatic cascade allowed unprecedented insights into how blood clot formation and von Willebrand factor (VWF) deposition determine the arrest of circulating cancer cells and subsequent brain colonization in mice. Clot formation in brain microvessels occurred frequently (>95%) and specifically at intravascularly arrested cancer cells, allowing their long-term arrest. An extensive clot embedded ∼20% of brain-arrested cancer cells, and those were more likely to successfully extravasate and form a macrometastasis. Mechanistically, the generation of tissue factor-mediated thrombin by cancer cells accounted for local activation of plasmatic coagulation in the brain. Thrombin inhibition by treatment with low molecular weight heparin or dabigatran and an anti-VWF antibody prevented clot formation, cancer cell arrest, extravasation, and the formation of brain macrometastases. In contrast, tumor cells were not able to directly activate platelets, and antiplatelet treatments did reduce platelet dispositions at intravascular cancer cells but did not reduce overall formation of BMs. In conclusion, our data show that plasmatic coagulation is activated early by intravascular tumor cells in the brain with subsequent clot formation, which led us to discover a novel and specific mechanism that is crucial for brain colonization. Direct or indirect thrombin and VWF inhibitors emerge as promising drug candidates for trials on prevention of BMs.
- Published
- 2021
- Full Text
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9. The von Willebrand factor Tyr2561 allele is a gain-of-function variant and a risk factor for early myocardial infarction
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Schneppenheim, Reinhard, Hellermann, Natalie, Brehm, Maria A., Klemm, Ulrike, Obser, Tobias, Huck, Volker, Schneider, Stefan W., Denis, Cécile V., Tischer, Alexander, Auton, Matthew, März, Winfried, Xu, Emma-Ruoqi, Wilmanns, Matthias, and Zotz, Rainer B.
- Abstract
The frequent von Willebrand factor (VWF) variant p.Phe2561Tyr is located within the C4 domain, which also harbors the platelet GPIIb/IIIa-binding RGD sequence. To investigate its potential effect on hemostasis, we genotyped 865 patients with coronary artery disease (CAD), 915 with myocardial infarction (MI), and 417 control patients (Ludwigshafen Risk and Cardiovascular Health Study) and performed functional studies of this variant. A univariate analysis of male and female carriers of the Tyr2561 allele aged 55 years or younger revealed an elevated risk for repeated MI (odds ratio, 2.53; 95% confidence interval [CI], 1.07-5.98). The odds ratio was even higher in females aged 55 years or younger, at a value of 5.93 (95% CI, 1.12-31.24). Cone and plate aggregometry showed that compared with Phe2561, Tyr2561 was associated with increased platelet aggregate size both in probands’ blood and with the recombinant variants. Microfluidic assays revealed that the critical shear rate for inducing aggregate formation was decreased to 50% by Tyr2561 compared with Phe2561. Differences in C-domain circular dichroism spectra resulting from Tyr2561 suggest an increased shear sensitivity of VWF as a result of altered association of the C domains that disrupts the normal dimer interface. In summary, our data emphasize the functional effect of the VWF C4 domain for VWF-mediated platelet aggregation in a shear-dependent manner and provide the first evidence that a functional variant of VWF plays a role in arterial thromboembolism.
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- 2019
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10. The von Willebrand factor Tyr2561 allele is a gain-of-function variant and a risk factor for early myocardial infarction
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Schneppenheim, Reinhard, Hellermann, Natalie, Brehm, Maria A., Klemm, Ulrike, Obser, Tobias, Huck, Volker, Schneider, Stefan W., Denis, Cécile V., Tischer, Alexander, Auton, Matthew, März, Winfried, Xu, Emma-Ruoqi, Wilmanns, Matthias, and Zotz, Rainer B.
- Abstract
The frequent von Willebrand factor (VWF) variant p.Phe2561Tyr is located within the C4 domain, which also harbors the platelet GPIIb/IIIa-binding RGD sequence. To investigate its potential effect on hemostasis, we genotyped 865 patients with coronary artery disease (CAD), 915 with myocardial infarction (MI), and 417 control patients (Ludwigshafen Risk and Cardiovascular Health Study) and performed functional studies of this variant. A univariate analysis of male and female carriers of the Tyr2561 allele aged 55 years or younger revealed an elevated risk for repeated MI (odds ratio, 2.53; 95% confidence interval [CI], 1.07-5.98). The odds ratio was even higher in females aged 55 years or younger, at a value of 5.93 (95% CI, 1.12-31.24). Cone and plate aggregometry showed that compared with Phe2561, Tyr2561 was associated with increased platelet aggregate size both in probands' blood and with the recombinant variants. Microfluidic assays revealed that the critical shear rate for inducing aggregate formation was decreased to 50% by Tyr2561 compared with Phe2561. Differences in C-domain circular dichroism spectra resulting from Tyr2561 suggest an increased shear sensitivity of VWF as a result of altered association of the C domains that disrupts the normal dimer interface. In summary, our data emphasize the functional effect of the VWF C4 domain for VWF-mediated platelet aggregation in a shear-dependent manner and provide the first evidence that a functional variant of VWF plays a role in arterial thromboembolism.
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- 2019
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11. Decreased Invasion of Urothelial Carcinoma of the Bladder by Inhibition of Matrix-Metalloproteinase 7
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Bolenz, Christian, Knauf, Daniel, John, Axel, Erben, Philipp, Steidler, Annette, Schneider, Stefan W., Günes, Cagatay, and Gorzelanny, Christian
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To measure and to modulate the invasive potential of urothelial carcinoma of the bladder (UCB) cells in a standardized preclinical setting using broad-spectrum matrix-metalloproteinase (MMPs) inhibitors and specific targeting of MMP7. MMP expression levels in UCB cells were determined by quantitative real-time PCR (qRT-PCR) and gel zymographies of cell supernatants (MMP9, MMP2 and MMP1) and cell lysates (MMP7). The invasiveness of human UCB cells (HT1197 and T24/83) and human benign urothelial cells (UROtsa) was modulated by a broad-spectrum MMP inhibitor (4-Aminobenzoyl-Gly-Pro-D-Leu-D-Ala hydroxamic acid; AHA) and by MMP7 specific siRNAs. MMP7 knockdown efficiency was assessed by qRT-PCR and western blot. Invasive potential of UCB cells was measured by a standardized trans-epithelial electrical resistance (TEER) assay. Different MMP secretion profiles were measured in UCB cells. The active form of MMP7 was exclusively detected in HT1197 cells. Characteristic TEER breakdown patterns were observed in UCB cells when compared to benign cells. Invasive potentials were significantly higher in HT1197 cells than in T24/83 and in UROtsa cells [14.8±5.75 vs. 1.5±0.56 and 1.2±0.15, respectively; p < 0.01]. AHA treatment reduced the invasive potential of HT1197 cells. Also the specific downregulation of MMP7 by siRNA lowered the HT1197 cell invasiveness [20±1.0 vs. 16±2.8; p < 0.05]. Neither AHA nor MMP-7 siRNA transfection altered the invasive potential of T24/83 cells. Invasion of UCB is partially dependent on MMPs. Specific targeting of MMP7 by siRNA reduces the invasive potential in a subgroup of UCB cells. Therefore, MMP7 represents a potential therapeutic target which warrants further investigation.
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- 2018
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12. Association of ultra-sensitive ctDNA assay to identify actionable variants and response to immune checkpoint inhibitor (ICI) therapy in metastatic melanoma.
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Gebhardt, Christoffer, Keller, Laura, Heidrich, Isabel, Koett, Julian, Geidel, Glenn, Abbott, Charles, Boyle, Sean Michael, Pugh, Jason, Chen, Richard, Simon, Ronald, Schneider, Stefan W., and Pantel, Klaus
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- 2023
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13. The endothelial glycocalyx anchors von Willebrand factor fibers to the vascular endothelium
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Kalagara, Thejaswi, Moutsis, Tracy, Yang, Yi, Pappelbaum, Karin I., Farken, Anne, Cladder-Micus, Lucia, Vidal-y-Sy, Sabine, John, Axel, Bauer, Alexander T., Moerschbacher, Bruno M., Schneider, Stefan W., and Gorzelanny, Christian
- Abstract
The dynamic change from a globular conformation to an elongated fiber determines the ability of von Willebrand factor (VWF) to trap platelets. Fiber formation is favored by the anchorage of VWF to the endothelial cell surface, and VWF-platelet aggregates on the endothelium contribute to inflammation, infection, and tumor progression. Although P-selectin and a?ß3-integrins may bind VWF, their precise role is unclear, and additional binding partners have been proposed. In the present study, we evaluated whether the endothelial glycocalyx anchors VWF fibers to the endothelium. Using microfluidic experiments, we showed that stabilization of the endothelial glycocalyx by chitosan oligosaccharides or overexpression of syndecan-1 (SDC-1) significantly supports the binding of VWF fibers to endothelial cells. Heparinase-mediated degradation or impaired synthesis of heparan sulfate (HS), a major component of the endothelial glycocalyx, reduces VWF fiber–dependent platelet recruitment. Molecular interaction studies using flow cytometry and live-cell fluorescence microscopy provided further evidence that VWF binds to HS linked to SDC-1. In a murine melanoma model, we found that protection of the endothelial glycocalyx through the silencing of heparanase increases the number of VWF fibers attached to the wall of tumor blood vessels. In conclusion, we identified HS chains as a relevant binding factor for VWF fibers at the endothelial cell surface in vitro and in vivo.
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- 2018
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14. Role of the Coagulation System in Genitourinary Cancers: Review
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John, Axel, Gorzelanny, Christian, Bauer, Alexander T., Schneider, Stefan W., and Bolenz, Christian
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Tumor progression is associated with aberrant hemostasis, and patients with malignant diseases have an elevated risk of developing thrombosis. A crosstalk among the vascular endothelium, components of the coagulation cascade, and cancer cells transforms the intravascular milieu to a prothrombotic, proinflammatory, and cell-adhesive state. We review the existing evidence on activation of the coagulation system and its implication in genitourinary malignancies and discuss the potential therapeutic benefit of antithrombotic agents. A literature review was performed searching the Medline database and the Cochrane Library for original articles and reviews. A second search identified studies reporting on oncological benefit of anticoagulants in genitourinary cancer. An elevated expression of procoagulatory tissue factor on tumor cells and tumor-derived microparticles seems to stimulate cancer development and progression. Several components of the hemostatic system, including D-dimers, von Willebrand Factor, thrombin, fibrin-/ogen, soluble P-selectin, and prothrombin fragments 1 + 2 were either overexpressed or overactive in genitourinary cancers. Hypercoagulation was in general associated with a poorer prognosis. Experimental models and small trials in humans showed reduced cancer progression after treatment with anticoagulants. Main limitations of these studies were heterogeneous experimental methodology, small patient numbers, and a lack of prospective validation. In conclusion, experimental and clinical evidence suggests procoagulatory activity of genitourinary neoplasms, particularly in prostate, bladder and kidney cancer. This may promote the risk of vascular thrombosis but also metastatic progression. Clinical studies linked elevated biomarkers of hemostasis with poor prognosis in patients with genitourinary cancers. Thus, anticoagulation may have a therapeutic role beyond prevention of thromboembolism.
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- 2018
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15. From morphology to clinical pathophysiology: multiphoton fluorescence lifetime imaging at patients' bedside
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Periasamy, Ammasi, So, Peter T. C., König, Karsten, Xie, Xiaoliang S., Mess, Christian, Zens, Katharina, Gorzelanny, Christian, Metze, Dieter, Luger, Thomas A., König, Karsten, Schneider, Stefan W., and Huck, Volker
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- 2017
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16. Shape and Volume of Living Aldosterone-Sensitive Cells Imaged with the Atomic Force Microscope.
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Walker, John M., Braga, Pier Carlo, Ricci, Davide, Schneider, Stefan W., Matzke, Rainer, Radmacher, Manfred, and Oberleithner, Hans
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The steroid hormone aldosterone, which is synthesized in the suprarenal glands and secreted in response to a reduction in circulating blood volume, increases water and sodium reabsorption in the kidney (1,2). Although kidney is the major target organ, various other cell types, including different epithelia, smooth muscle, and endothelium, respond to the hormone (3-6). The acute aldosterone-induced responses of target cells are an intracellular calcium change and an intracellular pH increase (3,7,8) along with activation of plasma membrane Na+/H+ exchange and plasma membrane proton conductance (9,10). Therefore, it is not surprising that researchers have postulated that these acute transmembrane shifts of electrolytes are accompanied by cell swelling (2,11). Cell swelling or shrinkage plays a critical role in endothelial cell (EC) function. ECs tightly coat the luminal surface of blood vessels, playing an important role in the regulation of vascular tone, in vascular remodeling, in the pathogenesis of arteriosclerosis, and in arterial hypertension of humans (12). It has been shown that swelling of EC may disturb cell-to-cell interactions, resulting in an increase of transendothelial permeability, a precursor mechanism in the development of arteriosclerosis (13,14). Moreover, environmental stress (e.g., mechanical forces or hyperosmolarity) induces changes in cell volume and stimulates tissue plasminogen activator synthesis (15-18). Direct evidence for the importance of cell-volume regulation of endothelial cells is the existence of a volume-sensitive protein kinase (19). [ABSTRACT FROM AUTHOR]
- Published
- 2004
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17. Anticoagulation with rivaroxaban for livedoid vasculopathy (RILIVA): a multicentre, single-arm, open-label, phase 2a, proof-of-concept trial
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Weishaupt, Carsten, Strölin, Anke, Kahle, Birgit, Kreuter, Alexander, Schneider, Stefan W, Gerss, Joachim, Eveslage, Maria, Drabik, Attyla, and Goerge, Tobias
- Abstract
Livedoid vasculopathy is a thrombotic skin disease characterised by recurrent occlusion of the cutaneous microcirculation in lower extremities, which results in skin infarctions with painful ulcerations and irreversible scar formation. Rivaroxaban is a direct factor Xa inhibitor that prevents thrombus formation. We investigated whether rivaroxaban is effective for the treatment of livedoid vasculopathy.
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- 2016
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18. Increased Prevalence of Filaggrin Deficiency in 51 Patients with Recessive X-Linked Ichthyosis Presenting for Dermatological Examination
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Süßmuth, Kira, Gruber, Robert, Rodriguez, Elke, Traupe, Heiko, Amler, Susanne, Sánchez-Guijo, Alberto, Valentin, Frederic, Tarinski, Tatjana, Straub, Natalia, Metze, Dieter, Schneider, Stefan W., Hausser, Ingrid, Baurecht, Hansjörg, Weidinger, Stephan, and Oji, Vinzenz
- Published
- 2018
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19. Interplay between coagulation and inflammation in cancer: Limitations and therapeutic opportunities.
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Bauer, Alexander T., Gorzelanny, Christian, Gebhardt, Christoffer, Pantel, Klaus, and Schneider, Stefan W.
- Abstract
[Display omitted] • Clinical data suggest that thrombosis limits efficacy of ICIs (e.g. anti-PD-1). • Coagulation suppresses ICIs via platelets, leukocytes and the complement system. • Molecular mechanisms of CAT envision future therapeutic targets to support ICIs. • ICIs combined with anticoagulant LMWHs may improve clinical outcome. Advances in understanding the molecular mechanisms of tumor progression have achieved impressive progress in the treatment of cancer and so-called immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Indeed, antibody-based drugs blocking immune escape of tumor cells by modulation of T cell responses are increasingly utilized for a wide range of tumor entities. Nonetheless, response rates remain limited, and the development of secondary resistance is a common problem. In addition, by increasing the immune response a variety of severe side effects are provoked. Next to autoimmune responses, activation of the complement system and skin toxicity, an increased incidence for thrombotic complications has been observed associated with an increased mortality rate. Based on this, it can be postulated that the interplay of coagulation with inflammation in the tumor microenvironment is relevant for each step in the tumor life cycle. This review focuses on the coagulation as central player fostering mechanisms associated with tumor progression. Thus, a better understanding of the molecular pathways involved in the complex interaction of circulating tumor cells, the plasmatic coagulation and immune cells may help to improve therapeutic concepts reducing mortality and morbidity associated with cancer. [ABSTRACT FROM AUTHOR]
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- 2022
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20. Mechanism and functional impact of CD40 ligand-induced von Willebrand factor release from endothelial cells
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Möller, Kerstin, Adolph, Oliver, Grünow, Jennifer, Elrod, Julia, Popa, Miruna, Ghosh, Subhajit, Schwarz, Manuel, Schwale, Chrysovalandis, Grässle, Sandra, Huck, Volker, Bruehl, Claus, Wieland, Thomas, Schneider, Stefan W., Nobiling, Rainer, Wagner, Andreas H., and Hecker, Markus
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- 2015
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21. von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans
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Bauer, Alexander T., Suckau, Jan, Frank, Kathrin, Desch, Anna, Goertz, Lukas, Wagner, Andreas H., Hecker, Markus, Goerge, Tobias, Umansky, Ludmila, Beckhove, Philipp, Utikal, Jochen, Gorzelanny, Christian, Diaz-Valdes, Nancy, Umansky, Viktor, and Schneider, Stefan W.
- Abstract
Tumor-mediated procoagulatory activity leads to venous thromboembolism and supports metastasis in cancer patients. A prerequisite for metastasis formation is the interaction of cancer cells with endothelial cells (ECs) followed by their extravasation. Although it is known that activation of ECs and the release of the procoagulatory protein von Willebrand factor (VWF) is essential for malignancy, the underlying mechanisms remain poorly understood. We hypothesized that VWF fibers in tumor vessels promote tumor-associated thromboembolism and metastasis. Using in vitro settings, mouse models, and human tumor samples, we showed that melanoma cells activate ECs followed by the luminal release of VWF fibers and platelet aggregation in tumor microvessels. Analysis of human blood samples and tumor tissue revealed that a promoted VWF release combined with a local inhibition of proteolytic activity and protein expression of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type I repeats 13) accounts for this procoagulatory milieu. Blocking endothelial cell activation by the low-molecular-weight heparin tinzaparin was accompanied by a lack of VWF networks and inhibited tumor progression in a transgenic mouse model. Our findings implicate a mechanism wherein tumor-derived vascular endothelial growth factor-A (VEGF-A) promotes tumor progression and angiogenesis. Thus, targeting EC activation envisions new therapeutic strategies attenuating tumor-related angiogenesis and coagulation.
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- 2015
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22. von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans
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Bauer, Alexander T., Suckau, Jan, Frank, Kathrin, Desch, Anna, Goertz, Lukas, Wagner, Andreas H., Hecker, Markus, Goerge, Tobias, Umansky, Ludmila, Beckhove, Philipp, Utikal, Jochen, Gorzelanny, Christian, Diaz-Valdes, Nancy, Umansky, Viktor, and Schneider, Stefan W.
- Abstract
Tumor-mediated procoagulatory activity leads to venous thromboembolism and supports metastasis in cancer patients. A prerequisite for metastasis formation is the interaction of cancer cells with endothelial cells (ECs) followed by their extravasation. Although it is known that activation of ECs and the release of the procoagulatory protein von Willebrand factor (VWF) is essential for malignancy, the underlying mechanisms remain poorly understood. We hypothesized that VWF fibers in tumor vessels promote tumor-associated thromboembolism and metastasis. Using in vitro settings, mouse models, and human tumor samples, we showed that melanoma cells activate ECs followed by the luminal release of VWF fibers and platelet aggregation in tumor microvessels. Analysis of human blood samples and tumor tissue revealed that a promoted VWF release combined with a local inhibition of proteolytic activity and protein expression of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type I repeats 13) accounts for this procoagulatory milieu. Blocking endothelial cell activation by the low-molecular-weight heparin tinzaparin was accompanied by a lack of VWF networks and inhibited tumor progression in a transgenic mouse model. Our findings implicate a mechanism wherein tumor-derived vascular endothelial growth factor-A (VEGF-A) promotes tumor progression and angiogenesis. Thus, targeting EC activation envisions new therapeutic strategies attenuating tumor-related angiogenesis and coagulation.
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- 2015
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23. Force-Sensitive Autoinhibition of the von Willebrand Factor Is Mediated by Interdomain Interactions
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Aponte-Santamaría, Camilo, Huck, Volker, Posch, Sandra, Bronowska, Agnieszka K., Grässle, Sandra, Brehm, Maria A., Obser, Tobias, Schneppenheim, Reinhard, Hinterdorfer, Peter, Schneider, Stefan W., Baldauf, Carsten, and Gräter, Frauke
- Abstract
Von Willebrand factor (VWF) plays a central role in hemostasis. Triggered by shear-stress, it adheres to platelets at sites of vascular injury. Inactivation of VWF has been associated to the shielding of its adhesion sites and proteolytic cleavage. However, the molecular nature of this shielding and its coupling to cleavage under shear-forces in flowing blood remain unknown. In this study, we describe, to our knowledge, a new force-sensory mechanism for VWF-platelet binding, which addresses these questions, based on a combination of molecular dynamics (MD) simulations, atomic force microscopy (AFM), and microfluidic experiments. Our MD simulations demonstrate that the VWF A2 domain targets a specific region at the VWF A1 domain, corresponding to the binding site of the platelet glycoprotein Ibα(GPIbα) receptor, thereby causing its blockage. This implies autoinhibition of the VWF for the binding of platelets mediated by the A1-A2 protein-protein interaction. During force-probe MD simulations, a stretching force dissociated the A1A2 complex, thereby unblocking the GPIbαbinding site. Dissociation was found to be coupled to the unfolding of the A2 domain, with dissociation predominantly occurring before exposure of the cleavage site in A2, an observation that is supported by our AFM experiments. This suggests that the A2 domain prevents platelet binding in a force-dependent manner, ensuring that VWF initiates hemostasis before inactivation by proteolytic cleavage. Microfluidic experiments with an A2-deletion VWF mutant resulted in increased platelet binding, corroborating the key autoinhibitory role of the A2 domain within VWF multimers. Overall, autoinhibition of VWF mediated by force-dependent interdomain interactions offers the molecular basis for the shear-sensitive growth of VWF-platelet aggregates, and might be similarly involved in shear-induced VWF self-aggregation and other force-sensing functions in hemostasis.
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- 2015
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24. Monitoring wound healing by multiphoton tomography/endoscopy
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Choi, Bernard, Kollias, Nikiforos, Zeng, Haishan, Kang, Hyun Wook, Wong, Brian J. F., Ilgner, Justus F., Nuttal, Alfred, Richter, Claus-Peter, Skala, Melissa C., Dewhirst, Mark W., Tearney, Guillermo J., Gregory, Kenton W., Marcu, Laura, Mandelis, Andreas, Morris, Michael D., König, Karsten, Weinigel, Martin, Bückle, Rainer, Kaatz, Martin, Hipler, Christina, Zens, Katharina, Schneider, Stefan W., and Huck, Volker
- Published
- 2015
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25. Assessing the Invasive Potential of Bladder Cancer: Development and Validation of a New Preclinical Assay.
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Bolenz, Christian, Gorzelanny, Christian, Knauf, Daniel, Keil, Tanja, Steidler, Annette, Halter, Natalia, Martini, Thomas, and Schneider, Stefan W.
- Subjects
BLADDER cancer ,ELECTROPHYSIOLOGY ,TRANSITIONAL cell carcinoma ,MATRIX metalloproteinases ,ELECTRIC resistance ,EPIDERMAL growth factor ,TRANSMIGRATION - Abstract
Purpose: We developed and validated an electrophysiological method for standardized preclinical assessment of the invasive potential of urothelial carcinoma of the bladder. Materials and Methods: Human UMUC-3, RT-112, HT-1197 and T24/83 bladder urothelial carcinoma cells, and UROtsa benign urothelial cells were co-cultivated with high resistance MDCK-C7 cells seeded below a 0.4 μm pore membrane of an insert to avoid physical contact and cellular migration. Transepithelial electrical resistance in Ω cm
2 across the MDCK-C7 monolayer was measured longitudinally. Invasive potential coefficients were calculated based on the secretion of proteolytic factors by invading cells. Results: Consistent transepithelial electrical resistance breakdown patterns were reproduced in 14 or more independent samples of each cell line. Coefficients of invasive potential were significantly higher in bladder urothelial carcinoma than UROtsa cells, including a mean ± SD of 1.5 ± 0.32 vs 9.9 ± 4.97 in UMUC-3, 12.5 ± 6.61 in T24/83, 20.5 ± 4.24 in RT-112 and 21.0 ± 5.15 in HT-1197 cells (p <0.001). No correlation was found between the secretion patterns of matrix metalloproteinase-1, 2 and 9, and invasive potential. Stimulation of UROtsa cells with recombinant human epidermal growth factor up-regulated matrix metalloproteinase-9 secretion and significantly increased invasive potential a mean of 1.3 ± 0.22 vs 14.6 ± 3.28 after stimulation with 10 ng/ml epidermal growth factor (p <0.001). Conclusions: We developed a highly sensitive translational tool to study the initial process of metastatic spread of urothelial carcinoma of the bladder. The presented electrophysiological invasion assay enables reliable quantification of the invasive potential of bladder urothelial carcinoma cells before physical transmigration. It can be used to identify key molecules for bladder urothelial carcinoma invasion and develop new therapeutic strategies. [Copyright &y& Elsevier]- Published
- 2013
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26. Interplay between coagulation and inflammation in cancer: Limitations and therapeutic opportunities.
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Bauer, Alexander T, Gorzelanny, Christian, Gebhardt, Christoffer, Pantel, Klaus, and Schneider, Stefan W
- Abstract
Advances in understanding the molecular mechanisms of tumor progression have achieved impressive progress in the treatment of cancer and so-called immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Indeed, antibody-based drugs blocking immune escape of tumor cells by modulation of T cell responses are increasingly utilized for a wide range of tumor entities. Nonetheless, response rates remain limited, and the development of secondary resistance is a common problem. In addition, by increasing the immune response a variety of severe side effects are provoked. Next to autoimmune responses, activation of the complement system and skin toxicity, an increased incidence for thrombotic complications has been observed associated with an increased mortality rate. Based on this, it can be postulated that the interplay of coagulation with inflammation in the tumor microenvironment is relevant for each step in the tumor life cycle. This review focuses on the coagulation as central player fostering mechanisms associated with tumor progression. Thus, a better understanding of the molecular pathways involved in the complex interaction of circulating tumor cells, the plasmatic coagulation and immune cells may help to improve therapeutic concepts reducing mortality and morbidity associated with cancer. [ABSTRACT FROM AUTHOR]
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- 2021
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27. Role of vasculature in atopic dermatitis.
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Steinhoff, Martin, Steinhoff, Antje, Homey, Bernhard, Luger, Thomas A., and Schneider, Stefan W.
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SKIN inflammation ,EPITHELIUM ,TISSUES ,SKIN diseases - Abstract
Atopic dermatitis (AD) lesions are characterized by differences in the activation state of endothelial cells and vascular smooth muscle cells and the release of inflammatory mediators by and toward the vasculature. The vascular system, including endothelial cells and smooth muscle cells, is ultimately involved in clinical symptoms of AD, such as erythema, edema, leukocyte recruitment, and white dermographism. Various mediators and bidirectional neurovascular interactions regulate the inflammatory response during AD. T cell–endothelial cell interactions are a crucial component to establish acute AD. Various immune cells, including monocytes and mast cells, communicate with the endothelium by releasing inflammatory mediators, thereby stimulating inflammatory mediator release from activated endothelial cells. The process of adhesion, tethering, and transmigration of infiltrating cells is a highly regulated and an active communication process between endothelial cells and leukocytes. Endothelial cells play a pivotal role in the pathophysiology of AD and represent future targets for the treatment of AD. [Copyright &y& Elsevier]
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- 2006
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28. von Willebrand disease type 2A phenotypes IIC, IID and IIE: A day in the life of shear-stressed mutant von Willebrand factor
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Brehm, Maria A., Huck, Volker, Aponte-Santamaría, Camilo, Obser, Tobias, Grässle, Sandra, Oyen, Florian, Budde, Ulrich, Schneppenheim, Sonja, Baldauf, Carsten, Gräter, Frauke, Schneider, Stefan W., and Schneppenheim, Reinhard
- Published
- 2014
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29. The various states of von Willebrand factor and their function in physiology and pathophysiology
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Huck, Volker, Schneider, Matthias F., Gorzelanny, Christian, and Schneider, Stefan W.
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- 2014
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30. Highly Invasive Melanoma Cells Activate the Vascular Endothelium via an MMP-2/Integrin αvβ5–Induced Secretion of VEGF-A
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Desch, Anna, Strozyk, Elwira A., Bauer, Alexander T., Huck, Volker, Niemeyer, Verena, Wieland, Thomas, and Schneider, Stefan W.
- Abstract
Tumor cell extravasation is a critical step in the metastatic cascade and requires interaction between the tumor cell and the endothelium. Although cancer progression depends on a complex network of mechanisms, including inflammation and coagulation, the involvement of tumor-induced endothelium activation and the subsequent release of procoagulatory factors in this process are not well understood. Using tissue sections from patients with malignant melanoma, immunofluorescence studies for the presence of von Willebrand factor (VWF) clearly demonstrated endothelium activation and the formation of ultra-large VWF fibers in these patients. In vitroanalyses revealed that supernatants from highly invasive melanoma cells induced an acute endothelium activation measured by VWF, P-selectin, and angiopoietin-2 release. Proteome profiling identified vascular endothelial growth factor A (VEGF-A) as the main mediator of endothelium activation. Inhibition and knock-down of VEGF-A in melanoma cells led to a rigorous decrease in VWF exocytosis. Selective small-interfering RNA to matrix metalloproteinase-2 (MMP-2) inhibited endothelium activation, and this effect correlated with reduced VEGF-A content in the supernatants of melanoma cells. Further experiments showed that active MMP-2 regulates VEGF-A in melanoma cells on a transcriptional level via an integrin αvβ5/phosphoinositide-3-kinase–dependent pathway. In conclusion, these results indicate an important role of VEGF-A in acute endothelium activation and provide clear evidence that MMP-2 plays a pivotal role in the autocrine regulation of VEGF-A expression in melanoma cells.
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- 2012
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31. Intravital multiphoton tomography as an appropriate tool for non-invasive in vivo analysis of human skin affected with atopic dermatitis
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Huck, Volker, Gorzelanny, Christian, Thomas, Kai, Mess, Christian, Dimitrova, Valentina, Schwarz, Martin, Riemann, Iris, Niemeyer, Verena, Luger, Thomas A., König, Karsten, and Schneider, Stefan W.
- Abstract
Increasing incidence of inflammatory skin diseases such as Atopic Dermatitis (AD) has been noted in the past years. According to recent estimations around 15% of newborn subjects are affected with a disease severity that requires medical treatment. Although its pathogenesis is multifactorial, recent reports indicate that an impaired physical skin barrier predispose for the development of AD. The major part of this barrier is formed by the stratum corneum (SC) wherein corneocytes are embedded in a complex matrix of proteins and lipids. Its components were synthesized in the stratum granulosum (SG) and secreted via lamellar bodies at the SC/SG interface. Within a clinical in vivo study we focused on the skin metabolism at the SC/SG interface in AD affected patients in comparison to healthy subjects. Measurement of fluorescence life-time of NADH provides access to the metabolic state of skin. Due to the application of a 5D intravital tomographic skin analysis we facilitate the non-invasive investigation of human epidermis in the longitudinal course of AD therapy. We could ascertain by blinded analysis of 40 skin areas of 20 patients in a three month follow-up that the metabolic status at the SC/SG interface was altered in AD compromised skin even in non-lesional, apparent healthy skin regions. This illustrates an impaired skin barrier formation even at non-affected skin of AD subjects appearing promotive for the development of acute skin inflammation. Therefore, our findings allow a deeper understanding of the individual disease development and the improved management of the therapeutic intervention in clinical application.
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- 2011
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32. von Willebrand factor promotes leukocyte extravasation
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Petri, Björn, Broermann, Andre, Li, Hang, Khandoga, Alexander G., Zarbock, Alexander, Krombach, Fritz, Goerge, Tobias, Schneider, Stefan W., Jones, Claire, Nieswandt, Bernhard, Wild, Martin K., and Vestweber, Dietmar
- Abstract
von Willebrand factor (VWF) is an important player in hemostasis but has also been suggested to promote inflammatory processes. Gene ablation of VWF causes a simultaneous defect in P-selectin expression making it difficult to identify VWF-specific functions. Therefore, we analyzed whether blocking antibodies against VWF would be able to interfere with neutrophil extravasation. We found that these antibodies inhibited neutrophil recruitment into thioglycollate-inflamed peritoneum and KC-stimulated cremaster by approximately 50%. Whereas platelet-VWF was not involved, the contribution of VWF to granulocyte recruitment was strictly dependent on the presence of platelets and the accessibility of their VWF-receptor glycoprotein Ib. Surprisingly, platelet P-selectin was largely dispensable for leukocyte extravasation, in agreement with our observation that anti-VWF antibodies did not affect leukocyte rolling and adhesion. Searching for possible effects downstream of leukocyte capture, we found that anti-VWF antibodies significantly inhibited thioglycollate-induced vascular permeability. The increase of permeability was independent of circulating granulocytes, showing that it was not a side effect of neutrophil diapedesis. Collectively, our results demonstrate that VWF-associated platelets strongly support neutrophil extravasation at a step downstream of leukocyte docking to the vessel wall. This step could be related to leukocyte diapedesis facilitated by destabilization of the endothelial barrier.
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- 2010
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33. von Willebrand factor promotes leukocyte extravasation
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Petri, Björn, Broermann, Andre, Li, Hang, Khandoga, Alexander G., Zarbock, Alexander, Krombach, Fritz, Goerge, Tobias, Schneider, Stefan W., Jones, Claire, Nieswandt, Bernhard, Wild, Martin K., and Vestweber, Dietmar
- Abstract
von Willebrand factor (VWF) is an important player in hemostasis but has also been suggested to promote inflammatory processes. Gene ablation of VWF causes a simultaneous defect in P-selectin expression making it difficult to identify VWF-specific functions. Therefore, we analyzed whether blocking antibodies against VWF would be able to interfere with neutrophil extravasation. We found that these antibodies inhibited neutrophil recruitment into thioglycollate-inflamed peritoneum and KC-stimulated cremaster by approximately 50%. Whereas platelet-VWF was not involved, the contribution of VWF to granulocyte recruitment was strictly dependent on the presence of platelets and the accessibility of their VWF-receptor glycoprotein Ib. Surprisingly, platelet P-selectin was largely dispensable for leukocyte extravasation, in agreement with our observation that anti-VWF antibodies did not affect leukocyte rolling and adhesion. Searching for possible effects downstream of leukocyte capture, we found that anti-VWF antibodies significantly inhibited thioglycollate-induced vascular permeability. The increase of permeability was independent of circulating granulocytes, showing that it was not a side effect of neutrophil diapedesis. Collectively, our results demonstrate that VWF-associated platelets strongly support neutrophil extravasation at a step downstream of leukocyte docking to the vessel wall. This step could be related to leukocyte diapedesis facilitated by destabilization of the endothelial barrier.
- Published
- 2010
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34. Livedoid Vasculopathy in a Pediatric Patient With Elevated Lipoprotein(a) Levels: Prompt Response to Continuous Low-Molecular-Weight Heparin
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Goerge, Tobias, Weishaupt, Carsten, Metze, Dieter, Nowak-Göttl, Ulrike, Sunderkötter, Cord, Steinhoff, Martin, and Schneider, Stefan W.
- Published
- 2010
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35. Soluble plasma-derived von Willebrand factor assembles to a haemostatically active filamentous network
- Author
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Barg, Alexej, Ossig, Rainer, Goerge, Tobias, Schneider, Matthias F., Schillers, Hermann, Oberleithner, Hans, and Schneider, Stefan W.
- Published
- 2007
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36. Microfluidic reveals generation of platelet-strings on tumoractivated endothelium
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Goerge, Tobias, Kleinerüschkamp, Felix, Barg, Alexej, Schnaeker, Eva-Maria, Huck, Volker, Schneider, Matthias F., Steinhoff, Martin, and Schneider, Stefan W.
- Published
- 2007
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37. Infliximab-Induced Lupus Erythematosus Tumidus in a Patient With Rheumatoid Arthritis
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Schneider, Stefan W., Staender, Sonja, Schlüter, Bernhard, Luger, Thomas A., and Bonsmann, Gisela
- Published
- 2006
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38. The electrical resistance breakdown assay determines the role of proteinases in tumor cell invasion
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Ludwig, Thomas, Ossig, Rainer, Graessel, Susanne, Wilhelmi, Marianne, Oberleithner, Hans, and Schneider, Stefan W.
- Abstract
The electrical resistance breakdown of the Madin-Darby canine kidney (MDCK) cell monolayer provides a continuous assay system for cancer invasion that detects functional changes before morphological alterations. In this study, we address the question of whether physical contact between tumor cell and epithelial monolayer is a prerequisite for tumor cell invasion. When human melanoma cells were seeded directly (i.e., physical contact) on top of an electrically tight epithelial cell layer (5,800 ± 106 Ω · cm2), electrical monolayer leakage led to an 18 ± 3% reduction of transepithelial electrical resistance within 24 h. However, when melanoma cells were seeded close to the basolateral surface of the epithelial cell monolayer but separated by a filter membrane (i.e., no physical contact), electrical leakage occurred even more quickly (42 ± 3% reduction in 24 h). Atomic force microscopy detected discrete structural changes between cells. Electrical leakage was effectively blocked by α2-macroglobulin or ilomastat, inhibitors of matrix metalloproteinases. We conclude that exocytosis of soluble proteases causes electrical breakdown of the MDCK monolayer, independently of physical contact between tumor cells and the monolayer.
- Published
- 2002
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39. Prompt response of refractory Schnitzler syndrome to treatment with anakinra.
- Author
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Schneider, Stefan W., Gaubitz, Markus, Luger, Thomas A., and Bonsmann, Gisela
- Published
- 2007
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40. RAPID ALDOSTERONE-INDUCED CELL VOLUME INCREASE OF ENDOTHELIAL CELLS MEASURED BY THE ATOMIC FORCE MICROSCOPE
- Author
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SCHNEIDER, STEFAN W., YANO, YOSHIKO, SUMPIO, BAUER E., JENA, BHANU P., GEIBEL, JOHN P., GEKLE, MICHAEL, and OBERLEITHNER, HANS
- Abstract
Atomic force microscopy (AFM) is a useful technique for imaging the surface of living cells in three dimensions. The authors applied AFM to obtain morphological information of individual cultured endothelial cells of bovine aorta under stationary and strain conditions and to simultaneously measure changes in cell volume in response to aldosterone. This mineralocorticoid hormone is known to have acute, non-genomic effects on intracellular pH, intracellular electrolytes and inositol-1,4,5-triphosphate production. In this study whether endothelial cells under tension change their volume in response to aldosterone was tested. Such changes were already shown in human leukocytes measured by Coulter counter. In contrast to leukocytes that are more or less spherical and live in suspension, endothelial cells exhibit a complex morphology and adhere to a substrate. Thus, measurements of discrete cell volume changes in endothelial cells under physiological condition is only feasible with more sophisticated techniques. By using AFM we could precisely measure the absolute cell volume of individual living endothelial cells. Before the addition of aldosterone the cell volume of mechanically stressed endothelial cells mimicking arterial blood pressure was 1827±172fl. Cell volume was found to increase by 28% 5min after hormone exposure. Twenty-five minutes later cell volume was back to normal despite the continuous presence of aldosterone in the medium. Amiloride, a blocker of the plasma membrane Na+/H+exchanger prevented the initial aldosterone-induced volume increase. Taken together, AFM disclosed a transient swelling of endothelial cells induced by the activation of an aldosterone sensitive plasma membrane Na+/H+exchanger.
- Published
- 1997
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41. Gain-of-Function Variant p.Pro2555Arg of von Willebrand Factor Increases Aggregate Size through Altering Stem Dynamics
- Author
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Huck, Volker, Chen, Po-Chia, Xu, Emma-Ruoqi, Tischer, Alexander, Klemm, Ulrike, Aponte-Santamaría, Camilo, Mess, Christian, Obser, Tobias, Kutzki, Fabian, König, Gesa, Denis, Cécile V., Gräter, Frauke, Wilmanns, Matthias, Auton, Matthew, Schneider, Stefan W., Schneppenheim, Reinhard, Hennig, Janosch, and Brehm, Maria A.
- Published
- 2021
- Full Text
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42. Pathogenic Activation and Therapeutic Blockage of Fc Alpha Receptor-Expressing Polymorphonuclear Leukocytes in IgA Pemphigus
- Author
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Emtenani, Shirin, Ghorbanalipoor, Saeedeh, Mayer-Hain, Sarah, Kridin, Khalaf, Komorowski, Lars, Probst, Christian, Hashimoto, Takashi, Pas, Hendri H., Męcińska-Jundziłł, Kaja, Czajkowski, Rafał, Recke, Andreas, Sunderkötter, Cord, Schneider, Stefan W., Hundt, Jennifer E., Zillikens, Detlef, Schmidt, Enno, Ludwig, Ralf J., and Hammers, Christoph M.
- Abstract
Pathomechanisms in IgA pemphigus are assumed to rely on Fc-dependent cellular activation by antigen-specific IgA autoantibodies, however, models for disease and more detailed pathophysiologic data are lacking. We here aimed to establish in vitromodels of disease for IgA pemphigus, allowing to study effects of the interaction of anti-keratinocyte IgA with cell-surface Fc alpha receptors. Employing multiple in vitroassays, such as a skin cryosection assay and a human skin organ culture model, we here present mechanistic data for the pathogenesis of IgA pemphigus, mediated by anti-desmoglein 3 IgA autoantibodies. Our results reveal that this disease is dependent on Fc alpha receptor-mediated activation of leukocytes in the epidermis. Importantly, this cell-dependent pathology can be dose-dependently abrogated by peptide-mediated inhibition of Fc alpha receptor:IgA interaction, as confirmed in an additional model for IgA-dependent disease, i.e., IgA vasculitis. These data suggest that IgA pemphigus can be modeled in vitro, and IgA pemphigus and IgA vasculitis are Fc alpha receptor-dependent disease entities that can be specifically targeted in these experimental systems.
- Published
- 2021
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43. Functional and Structural Properties of the 2nd Gain-of-Function Variant in the C4 Domain of von Willebrand Factor
- Author
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Brehm, Maria A., König, Gesa, Obser, Tobias, Huck, Volker, Schneider, Stefan W., and Schneppenheim, Reinhard
- Published
- 2020
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44. Ichthyosis Prematurity Syndrome Caused by a Novel Fatty Acid Transport Protein 4 Gene Mutation in a German Infant
- Author
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Inhoff, Oliver, Hausser, Ingrid, Schneider, Stefan W., Khnykin, Denis, Jahnsen, Frode L., Sartoris, Johann, Goerdt, Sergij, and Peitsch, Wiebke K.
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- 2011
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45. The Von Willebrand Factor Tyr2561 Allele Is a Gain-of-Function Variant and a Potential Risk Factor for Early Myocardial Infarction
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Schneppenheim, Reinhard, Hellermann, Natalie, Brehm, Maria Alexandra, Klemm, Ulrike, Obser, Tobias, Huck, Volker, Schneider, Stefan W, Denis, Cecile V., Tischer, Alexander, Auton, Matthew, Maerz, Winfried, Xu, Emma-Ruoqi, Wilmanns, Matthias, and Zotz, Rainer B.
- Abstract
Schneppenheim: SHIRE: Consultancy; CSL Behring: Consultancy.
- Published
- 2018
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46. The Von Willebrand Factor Tyr2561 Allele Is a Gain-of-Function Variant and a Potential Risk Factor for Early Myocardial Infarction
- Author
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Schneppenheim, Reinhard, Hellermann, Natalie, Brehm, Maria Alexandra, Klemm, Ulrike, Obser, Tobias, Huck, Volker, Schneider, Stefan W, Denis, Cecile V., Tischer, Alexander, Auton, Matthew, Maerz, Winfried, Xu, Emma-Ruoqi, Wilmanns, Matthias, and Zotz, Rainer B.
- Abstract
The frequent von Willebrand factor (VWF) variant p.Phe2561Tyr is located within the C4 domain, which also harbors the platelet GPIIb/IIIa-binding RGD sequence. To investigate its potential effect on hemostasis, we genotyped 865 patients with coronary artery disease (CAD), 915 with myocardial infarction (MI) and 417 controls (Ludwigshafen Risk and Cardiovascular Health Study (LURIC)) and performed functional studies of this variant. A univariate analysis of male and female carriers of the Tyr2561 allele ≤55 years revealed an elevated risk for repeated MI (Odds ratio: 2.53, 95% CI:1.07-5.98). The Odds ratio was even higher in females ≤55 years at a value of 5.93 (95% CI:1.12-31.24). Cone and plate aggregometry showed, that compared to Phe2561, Tyr2561 was associated with increased platelet aggregate size, both in probands' blood and with the recombinant variants. Inhibition of the VWF-GPIIb/IIIa interaction abrogated the effect. Microfluidic assays revealed that the critical shear rate for inducing aggregate formation was decreased to 50% by Tyr2561 compared to Phe2561. Differences in C-domain circular dichroism spectra resulting from Tyr2561 suggest an increased shear sensitivity of VWF, as a result of altered association of the C-domains that disrupts the normal dimer interface. In summary, our data emphasize the functional impact of the VWF C4-domain for VWF-mediated platelet aggregation in a GPIIb/IIIa-dependent manner and provide the first evidence that a functional variant of VWF plays a role in arterial thromboembolism.
- Published
- 2018
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47. Mechanosensitive Von Willebrand Factor Protein-Protein Interactions Regulate Hemostasis
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Aponte Santamaría, Camilo A., Huck, Volker, Posch, Sandra, Bronowska, Agnieszka K., Grässle, Sandra, Brehm, Maria A., Obser, Tobias, Schneppenheim, Reinhard, Hinterdorfer, Peter, Schneider, Stefan W., Baldauf, Carsten, and Gräter, Frauke
- Published
- 2015
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48. Efficacy of tacrolimus 0.1% ointment in cutaneous lupus erythematosus: A multicenter, randomized, double-blind, vehicle-controlled trial.
- Author
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Kuhn, Annegret, Gensch, Kristina, Haust, Merle, Schneider, Stefan W., Bonsmann, Gisela, Gaebelein-Wissing, Noemi, Lehmann, Percy, Wons, Annette, Reitmeir, Peter, Ruland, Vincent, Luger, Thomas A., and Ruzicka, Thomas
- Abstract
Background: Topical calcineurin inhibitors are licensed for the treatment of atopic dermatitis; however, the efficacy of tacrolimus in cutaneous lupus erythematosus (CLE) has only been shown in single case reports. Objective: In a multicenter, randomized, double-blind, vehicle-controlled trial, we sought to evaluate the efficacy of tacrolimus 0.1% ointment for skin lesions in CLE. Methods: Thirty patients (18 female, 12 male) with different subtypes of CLE were included, and two selected skin lesions in each patient were treated either with tacrolimus 0.1% ointment or vehicle twice daily for 12 weeks. The evaluation included scoring of clinical features, such as erythema, hypertrophy/desquamation, edema, and dysesthesia. Results: Significant improvement (P < .05) was seen in skin lesions of CLE patients treated with tacrolimus 0.1% ointment after 28 and 56 days, but not after 84 days, compared with skin lesions treated with vehicle. Edema responded most rapidly to tacrolimus 0.1% ointment and the effect was significant (P < .001) in comparison to treatment with vehicle after 28 days. Clinical score changes in erythema also showed remarkable improvement (P < .05) after 28 days, but not after 56 and 84 days. Moreover, patients with lupus erythematosus tumidus revealed the highest degree of improvement. None of the patients with CLE demonstrated any major side effects. Limitations: The study was limited by the small sample size. Conclusion: Explorative subgroup analyses revealed that topical application of tacrolimus 0.1% ointment may provide at least temporary benefit, especially in acute, edematous, non-hyperkeratotic lesions of CLE patients, suggesting that calcineurin inhibitors may represent an alternative treatment for the various disease subtypes. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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49. Uptake Kinetics, Uptake Pathways and Cytotoxicity of SiO2-Nanoparticles Interacting with HeLa and HUVEC Cells
- Author
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Blechinger, Julia, Torrano, Adriano A., Herrmann, Rudolf, Bauer, Alexander T., Schneider, Stefan W., Reller, Armin, and Bräuchle, Christoph
- Published
- 2011
- Full Text
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50. ChemInform Abstract: Nanomedicine—Challenge and Perspectives
- Author
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Riehemann, Kristina, Schneider, Stefan W., Luger, Thomas A., Godin, Biana, Ferrari, Mauro, and Fuchs, Harald
- Abstract
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
- Published
- 2009
- Full Text
- View/download PDF
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