Michael P. Schön

Deadly allies: the fatal interplay between platelets and metastasizing cancer cells

The general notion that functional platelets are important for successful hematogenous tumor metastasis has been inaugurated more than 4 decades ago and has since been corroborated in numerous experimental settings. Thorough preclinical investigations have, at least in part, clarified some specifics regarding the involvement of platelet adhesion receptors, such as thrombin receptors or integrins, in the metastasis cascade. Pivotal preclinical experiments have demonstrated that hematogenous tumor spread was dramatically diminished when platelets were depleted from the circulation or when functions of platelet surface receptors were inhibited pharmacologically or genetically. Such insight has inspired researchers to devise novel antitumoral therapies based on targeting platelet receptors. However, several mechanistic aspects underlying the impact of platelet receptors on tumor metastasis are not fully understood, and agents directed against platelet receptors have not yet found their way into the clinic. In addition, recent results suggesting that targeted inhibition of certain platelet surface receptors may even result in enhanced experimental tumor metastasis have demonstrated vividly that the role of platelets in tumor metastasis is more complex than has been anticipated previously. This review gives a comprehensive overview on the most important platelet receptors and their putative involvement in hematogenous metastasis of malignant tumors.

Imiquimod, a Topical Immune Response Modifier, in the Treatment of Cutaneous Metastases of Malignant Melanoma

Background: Imiquimod 5% cream (Aldara®), a novel topical immune response modifier, has been approved for the topical treatment of anogenital HPV-induced warts. In addition, several studies have demonstrated antitumoral activity in solar keratoses, superficial basal cell carcinomas and Bowen’s disease. Aim: Given the convincing therapeutic results of imiquimod when used for treating selected types of epithelial skin cancer, we became interested to study imiquimod as an adjuvant for treating cutaneous metastases of malignant melanoma. Methods: Three patients with multiple, i.e. more than 15, cutaneous in-transit metastases of malignant melanoma in unilateral localization on the leg were treated topically with imiquimod 5% cream. Results: Twice daily application under occlusive conditions for a period of 21–28 weeks resulted in >90% regression of cutaneous metastases in 2 patients. The third patient showed marked response only when topical imiquimod was intermittently supplemented by intralesional interleukin (IL)-2 for 2 weeks. Unwanted side effects were mild in all patients. Conclusion: Overall, imiquimod as a single agent or in combination with intralesional IL-2 may be a promising immunomodulatory compound for the adjuvant topical treatment of patients with multiple cutaneous metastases of malignant melanoma.

Managing comorbid disease in patients with psoriasis

#### Summary points Psoriasis is a common, chronic inflammatory skin disease that typically presents with sharply demarcated, red scaly dermatological plaques that may be painful and stigmatising (fig 1⇓). It causes a high burden of disease, comparable to that of cancer or diabetes mellitus.1 In about a quarter of people with psoriasis the condition is severe enough for them to need ultraviolet light therapy, systemic drug treatment, or hospital admission. Fig 1 Patient with severe psoriasis: red scaly plaques cover more than 10% of the body surface area; this patient also has a body mass index >25 Three recent developments have changed our understanding of psoriasis substantially. Firstly, researchers identified “Th17 cells” (a new type of lymphocyte) as important effector cells in autoimmune diseases.2 Indeed, the first drug that interferes with the functions of Th17 cells was approved in 2009, its first indication being psoriasis.3 Secondly, psoriasis is now confirmed as a systemic disease, as serum biomarkers for inflammation are raised in patients with psoriasis.4 Finally, psoriasis frequently occurs alongside other diseases.5 This review focuses on comorbid …

Alleviation of chronic venous leg ulcers with a hand-held dielectric barrier discharge plasma generator (PlasmaDerm® VU-2010): results of a monocentric, two-armed, open, prospective, randomized and controlled trial (NCT01415622)

Cold atmospheric plasma (CAP, i.e. ionized air) is an innovating promising tool in reducing bacteria.

Is psoriasis a T-cell disease?

Abstract: The etiology and pathogenesis of psoriasis – one of the most common chronic, inflammatory, hyperproliferative skin disorders of man – have long fascinated dermatologists, pathologists and biologists alike. Here, we have a model disease that offers to study neuroectodermal‐mesenchymal interactions in the widest sense possible. Epithelial, endothelial, and hematopoietic cells as well as neurons projecting into the skin apparently all interact with each other to generate the characteristic psoriatic lesion. For decades, the ongoing controversy on the molecular nature, choreography and hierarchy of these complex interactions e.g. between epidermal keratinocytes, T cells, neurotrophils, endothelial cells and sensory nerves has served as a driving force propelling investigative dermatology to ever new horizons. This debate has not only been at the heart of our quest to develop more effective forms of therapy for this socially crippling disease, but it also has profoundly influenced how we view the skin as a whole: the numerous competing theories on the pathogenesis of psoriasis published so far also are reflections on the evolution of mainstream thought in skin biology over the last decades. These days, conventional wisdom – infatuated with a T‐cell‐centered approach to inflammatory skin diseases – portrays psoriasis as an autoimmune disease, where misguided T lymphocyte activities cause secondary epithelial abnormalities. And yet, as this CONTROVERSIES feature reminds us, some authoritative “pockets of academic resistance” are still quite alive, and interpret psoriasis e.g. as a genetically determined, abnormal epithelial response pattern to infectious and/or physicochemical skin insults. Weighing the corresponding lines of argumentation is not only an intriguing, clinically relevant intellectual exercise, but also serves as a wonderful instrument for questioning our own views of the skin universe and its patterns of deviation from a state of homeostasis.

Monocytes/macrophages prevent healing defects and left ventricular thrombus formation after myocardial infarction

Myocardial infarction (MI) leads to rapid necrosis of cardiac myocytes. To achieve tissue integrity and function, inflammatory cells are activated, including monocytes/macrophages. However, the effect of monocyte/macrophage recruitment after MI remains poorly defined. After experimental MI, monocytes and macrophages were depleted through serial injections of clodronate‐containing liposomes. Monocyte/macrophage infiltration was reduced in the myocardium after MI by active treatment. Mortality was increased due to thromboembolic events in monocyte‐ and macrophage‐depleted animals (92 vs. 33%; P<0.01). Left ventricular thrombi were detectable as early as 24 h after MI; this was reproduced in a genetic model of monocyte/macrophage ablation. A general prothrombotic state, increased infarct expansion, and deficient neovascularization were not observed. Severely compromised extracellular matrix remodeling (collagen I, placebo liposome vs. clodronate liposome, 2.4±0.2 vs. 0.8±0.2 arbitrary units; P<0.001) and locally lost integrity of the endocardium after MI are potential mechanisms. Patients with a left ventricular thrombus had a relative decrease of CD14+CD16+ monocyte/macrophage subsets in the peripheral blood after MI (no thrombus vs. thrombus, 14.2±0.9 vs. 7.80±0.4%; P<0.05). In summary, monocytes/macrophages are of central importance for healing after MI. Impaired monocyte/macrophage function appears to be an unrecognized new pathophysiological mechanism for left ventricular thrombus development after MI.—Frantz, S., Hofmann, U., Fraccarollo, D., Schäfer, A., Kranepuhl, S., Hagedorn, I., Nieswandt, B., Nahrendorf, M., Wagner, H., Bayer, B., Pachel, C., Schön, M.P., Kneitz, S., Bobinger, T., Weidemann, F., Ertl, G., Bauersachs, J. Monocytes/macrophages prevent healing defects and left ventricular thrombus formation after myocardial infarction. FASEB J. 27, 871–881 (2013). www.fasebj.org

Involvement of IL-9 in Th17-Associated Inflammation and Angiogenesis of Psoriasis

It is thought that a Th1/Th17-weighted immune response plays a predominant role in the pathogenesis of psoriasis. Our findings now indicate a link between IL-9, a Th2 and Th9 cytokine, and Th17 pathway in psoriasis. In K5.hTGF-β1 transgenic mice, exhibiting a psoriasis-like phenotype, we found increased IL-9R and IL-9 expression in the skin and intradermal IL-9 injection induced Th17-related inflammation. IL-9 also promoted angiogenesis and VEGF and CD31 overexpression in mice in vivo and increased tube formation of human endothelial cells in vitro. Injecting anti-IL-9 antibody into K5.hTGF-β1 transgenic mice not only diminished inflammation (including skin infiltration by T cells, monocytes/macrophages, and mast cells) and angiogenesis but also delayed the psoriasis-like skin phenotype. Notably, injection of anti-psoriatic acting anti-IL-17 antibody reduced skin IL-9 mRNA and serum IL-9 protein levels in K5.hTGF-β1 transgenic mice and prevented IL-9-induced epidermal hyperplasia and inflammation of the skin of wild type mice. In addition, we observed that IL-9R expression in lesional skin from psoriasis patients was markedly higher than in healthy skin from control subjects. Moreover, IL-9 significantly enhanced IL-17A production by cultured human peripheral blood mononuclear cells or CD4+ T cells, especially in psoriasis patients. Thus, IL-9 may play a role in the development of psoriatic lesions through Th17-associated inflammation and angiogenesis.

8-Methoxypsoralen Plus Ultraviolet A Therapy Acts via Inhibition of the IL-23/Th17 Axis and Induction of Foxp3+ Regulatory T Cells Involving CTLA4 Signaling in a Psoriasis-Like Skin Disorder

To elucidate the molecular action of 8-methoxypsoralen plus UVA (PUVA), a standard dermatological therapy, we used K5.hTGF-β1 transgenic mice exhibiting a skin phenotype and cytokine abnormalities with strong similarities to human psoriasis. We observed that impaired function of CD4+CD25+ regulatory T cells (Tregs) and increased cytokine levels of the IL-23/Th17 pathway were responsible for the psoriatic phenotype in this mouse model. Treatment of K5.hTGF-β1 transgenic mice with PUVA suppressed the IL-23/Th17 pathway, Th1 milieu, as well as transcription factors STAT3 and orphan nuclear receptor RORγt. PUVA induced the Th2 pathway and IL-10–producing CD4+CD25+Foxp3+Tregs with disease-suppressive activity that was abolished by anti-CTLA4 mAb treatment. These findings were paralleled by macroscopic and microscopic clearance of the diseased murine skin. Anti–IL-17 mAb treatment also diminished the psoriatic phenotype of the mice. This indicated that both induced Tregs involving CTLA4 signaling and inhibition of the IL-23/Th17 axis are central for the therapeutic action of PUVA.

Comparative study of human-induced pluripotent stem cells derived from bone marrow cells, hair keratinocytes, and skin fibroblasts

AIMS Induced pluripotent stem cells (iPSCs) provide a unique opportunity for the generation of patient-specific cells for use in disease modelling, drug screening, and regenerative medicine. The aim of this study was to compare human-induced pluripotent stem cells (hiPSCs) derived from different somatic cell sources regarding their generation efficiency and cardiac differentiation potential, and functionalities of cardiomyocytes. METHODS AND RESULTS We generated hiPSCs from hair keratinocytes, bone marrow mesenchymal stem cells (MSCs), and skin fibroblasts by using two different virus systems. We show that MSCs and fibroblasts are more easily reprogrammed than keratinocytes. This corresponds to higher methylation levels of minimal promoter regions of the OCT4 and NANOG genes in keratinocytes than in MSCs and fibroblasts. The success rate and reprogramming efficiency was significantly higher by using the STEMCCA system than the OSNL system. All analysed hiPSCs are pluripotent and show phenotypical characteristics similar to human embryonic stem cells. We studied the cardiac differentiation efficiency of generated hiPSC lines (n = 24) and found that MSC-derived hiPSCs exhibited a significantly higher efficiency to spontaneously differentiate into beating cardiomyocytes when compared with keratinocyte-, and fibroblast-derived hiPSCs. There was no significant difference in the functionalities of the cardiomyocytes derived from hiPSCs with different origins, showing the presence of pacemaker-, atrial-, ventricular- and Purkinje-like cardiomyocytes, and exhibiting rhythmic Ca2+ transients and Ca2+ sparks in hiPSC-derived cardiomyocytes. Furthermore, spontaneously and synchronously beating and force-developing engineered heart tissues were generated. CONCLUSIONS Human-induced pluripotent stem cells can be reprogrammed from all three somatic cell types, but with different efficiency. All analysed iPSCs can differentiate into cardiomyocytes, and the functionalities of cardiomyocytes derived from different cell origins are similar. However, MSC-derived hiPSCs revealed a higher cardiac differentiation efficiency than keratinocyte- and fibroblast-derived hiPSCs.

A Role for Caspase-1 in Heart Failure

Apoptosis of cardiomyocytes is increased in heart failure and has been implicated in disease progression. The activation of “proapoptotic” caspases represents a key step in cardiomyocyte apoptosis. In contrast, the role of “proinflammatory” caspases (caspases 1, 4, 5, 11, 12) is unclear. Here, we study the cardiac function of caspase-1. Gene array analysis in a murine heart failure model showed upregulation of myocardial caspase-1. In addition, we found increased expression of caspase-1 protein in murine and human heart failure. Mice with cardiomyocyte-specific overexpression of caspase-1 developed heart failure in the absence of detectable formation of interleukin (IL)-1&bgr; or IL-18 and inflammation. Transgenic caspase-1 induced primary cardiomyocyte apoptosis before structural and molecular signs of myocardial remodeling occurred. In contrast, deletion of endogenous caspase-1 was beneficial in the setting of myocardial infarction–induced heart failure. Furthermore, caspase-1–deficient mice were protected from ischemia/reperfusion-induced cardiomyocyte apoptosis. Studies in primary rat cardiomyocytes indicated that caspase-1 induces cardiomyocyte apoptosis primarily through activation of caspases-3 and -9. In contrast to previous findings, which imply a proinflammatory role of caspase-1, these data suggest a primary proapoptotic role for caspase-1 in cardiomyocytes. Our findings support a functional role for caspase-1–mediated myocardial apoptosis contributing to the progression of heart failure.