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The biophysical fine-tuning of cancer cell plasticity is crucial for tumor progression but remains largely enigmatic. Although vascular cell adhesion molecule-1 (VCAM-1/CD106) has been implicated in melanoma progression, here its presentation on endothelial cells was associated with diminished melanoma cell spreading. Using a specific nanoscale modulation of VCAM-1 (tunable from 70 to 670 ligands/μm²) next to integrin ligands (RGD motifs) in a bifunctional system, reciprocal regulation of integrin α4 (ITGA4/VLA-4/CD49d)-dependent adhesion and spreading of melanoma cells was found. As the VCAM-1/VLA-4 receptor pair facilitated adhesion, while at the same time antagonizing RGD-mediated spreading, melanoma cell morphogenesis on these bifunctional matrices was directly regulated by VCAM-1 in a dichotomic and density-dependent fashion. This was accompanied by concordant regulation of F-actin cytoskeleton remodeling, Rac1-expression, and paxillin-related adhesion formation. The novel function of VCAM-1 was corroborated in vivo using two murine models of pulmonary metastasis. The regulation of melanoma cell plasticity by VCAM-1 highlights the complex regulation of tumor–matrix interactions. Implications: Nanotechnology has revealed a novel dichotomic function of the VCAM-1/VLA-4 interaction on melanoma cell plasticity, as nanoscale tuning of this interaction reciprocally determines adhesion and spreading in a ligand density-dependent manner. Mol Cancer Res; 16(3); 528–42. ©2017 AACR.

Given that local elevated protease activity (EPA) has been implicated in impaired wound healing, a prospective single-center study was conducted to assess protease activity in various wound types.Protease activity was determined using an easy-to-use test system (Woundchek Protease Status Test Kit; Systagenix, Gatwick, United Kingdom) in 160 wounds in 143 patients. The assay detects the combined activity of inflammatory proteases, mainly matrix metalloproteinases 8 and 9 and human neutrophil elastase.Local EPA was detected in 29 of 153 validly tested wounds (18.95%). No difference was detected between acute and chronic wounds, regardless of associated or causative conditions, with the sole exception of surgical wounds. Surgical wounds showed EPA significantly less frequently than nonsurgical wounds. Among nonsurgical wounds, EPA was detected more frequently in acute compared with chronic wounds. Wounds with signs of unimpeded healing (granulation or epithelialization) showed EPA less often than wounds covered with necrotic tissue or a fibrin layer. However, 14% of wounds with epithelialization or granulation exhibited EPA potentially impeding wound healing. Wounds treated with moisture-retentive wound dressings showed EPA significantly less frequently compared with wounds bandaged with dressings with less moisture-retentive properties. Remarkably, none of the wounds treated with collagen/oxidized regenerated cellulose/silver, which is a protease-modulating dressing, showed EPA.To the study authors' knowledge, this is the largest study assessing EPA in various wound types. The convenient applicability of the test system provides a basis for future studies assessing the pathophysiologic relevance of EPA. In some unsuspicious wounds, early detection of EPA might precede impaired healing and prompt protease-modulating treatment before failure to heal becomes apparent.

Background: Palmoplantar pustulosis (PPP) is arecalcitrant chronic inflammatory skin disease. Datarelevant for the medical care of patients with PPP arescarce. Thus, the aim of this work was to investigatethe disease burden, clinical characteristics, andcomorbidity of PPP patients in Germany. Patientsand Methods: PPP patients were examined in a crosssectionalstudy at seven specialized psoriasis centersin Germany. Results: Of the 172 included patients withPPP, 79.1% were female and 69.8% were smokers.In addition, 25.0% suffered from psoriasis vulgaris,28.2% had documented psoriatic arthritis, and 30.2%had a family history of psoriasis. In 77 patients themean Dermatology Life Quality Index (DLQI) was 12.2± 7.7 (mean ± SD). The mean Psoriasis PalmoplantarPustulosis Area and Severity Index (PPPASI) was 12.6 ±8.6. Mean body mass index was above average at 27.1± 5.5. The PPP patients had previously received anaverage of 2.6 ± 2.1 different anti-psoriatic systemicdrugs or UV-therapies. The systemic drugs that hadbeen used most frequently were corticosteroids in40.1% of patients, followed by acitretin (37.8%), andmethotrexate (27.9%). The PPPASI was 13.4 ± 8.9 inpatients without current systemic therapy and 10.4 ±7.9 in patients with systemic therapy. Conclusion: ManyPPP patients had a concomitant diagnosis of psoriasisvulgaris and/or psoriatic arthritis or had a familyhistory of psoriasis. Despite the fact that many of thepatients were using anti-psoriatic therapies, there wasstill a high burden of disease within this PPP cohort.This insufficient control of symptoms demonstratesthe urgent need for new PPP treatments.

Given that metastasized melanoma is a fatal disease in most cases, it is tempting to develop strategies to a priori prevent metastasis. We have stimulated the pulmonary innate immune system by macrophage-activating lipopeptide-2 (MALP-2), a specific agonist at Toll-like receptor (TLR) 2/6, and investigated its impact on experimental melanoma metastasis. In C57BL/6 mice, intratracheal application of MALP-2 induced a profound influx of neutrophils and macrophages into the lung, which peaked after 24 h (sixfold increase) and returned to baseline within 72 h. Further analysis revealed that MALP-2 also markedly induced VCAM-1 expression on pulmonary blood vessels. In vitro experiments demonstrated that this adhesion molecule mediates binding of B16F10 melanoma cells. Furthermore, in vivo or in vitro treatment with MALP-2 did not significantly affect the ability of immune cells to lyse melanoma cells. As a consequence, notwithstanding the profound pulmonary immune response induction and in contrast to conclusions drawn from some previous publications, the net extent of experimental metastasis did not change significantly, regardless of the application regimen of MALP-2 prior to, concomitant with or after tumor cell inoculation. Melanoma cells stably transfected with green fluorescent protein allowed tracking of early events after tumor cell dissemination and showed that MALP-2-mediated TLR2/6 activation did not interfere with pulmonary melanoma cell arrest. Likewise, boosting the immune induction after establishment of metastases did not change the clinical outcome. These unexpected results vividly counsel caution regarding predictions of immunomodulating therapies, as multiple intertwined effects may influence the net outcome.