Laurenz Schmitt

Synthesis of a Sulfonimidamide-Based Analog of Tasisulam and Its Biological Evaluation in the Melanoma Cell Lines SKMel23 and A375

Tasisulam is a promising antitumor agent with complex pharmacology, which is used as an antiproliferative agent in patients with metastatic melanoma and other solid tumors. Phase 2 melanoma studies showed promising results but had to be stopped because of insufficient tasisulam clearance leading to toxic side effects. To reduce the negative effects of tasisulam, we synthesized a novel sulfonimidamide-based analog to evaluate its antiproliferative effects in comparison to the original compound by performing a cell proliferation assay in melanoma cell lines SKMel23 and A375. The results revealed that the analog had inhibitory effects on the proliferation comparable to tasisulam in both investigated cell lines. These results could contribute to a reduced toxicity of tasisulam and lead to further clinical trials in metastatic melanoma.

Effects of a ceramide-containing water-in-oil ointment on skin barrier function and allergen penetration in an IL-31 treated 3D model of the disrupted skin barrier

Atopic dermatitis (AD) is a chronically relapsing, pruritic inflammation of the skin with dryness and disturbed skin barrier function. Recently, we established that IL‐31 treatment of human 3D skin models resulted in a disrupted skin barrier phenotype resembling AD. In this model, we found that IL‐31 interferes with the differentiation of keratinocytes and inhibits the expression of terminal differentiation markers. In the present study, we investigated the effects of a ceramide‐containing water‐in‐oil skin care ointment on the physical skin barrier structure and function in disrupted skin barrier models, generated either by using primary normal human epidermal keratinocytes (NHEK) or HaCaT cells. We observed that the physical skin barrier of the models recovered after daily topical treatment with the ceramide‐containing ointment. Topical application of the ointment prevented downregulation of filaggrin and disorganization of other differentiation markers, such as keratin 10 and β4‐integrin, as demonstrated by immunohistological analysis. The expression of Ki67 was also upregulated in response to the ointment. Furthermore, functional studies revealed that local application of the ointment diminished the increased uptake of fluorescently labelled recombinant allergens of timothy grass (phl p1) in our model. In conclusion, our data revealed that topical application of a ceramide‐containing skin care ointment reduced IL‐31 induced impairments of the physical skin barrier and skin barrier function in an in vitro model of the disrupted skin barrier. This standardized model can be utilized in the future to monitor ex vivo effects of various topical therapies on skin morphology, physiology, and gene expression.

Effectiveness and Safety of Surgical Excision in the Treatment of Digital Mucoid Cysts

BACKGROUND Digital mucoid cysts have a tendency for recurrence after operative intervention. Several procedures are in use. OBJECTIVE Retrospective evaluation for effectiveness, safety and patient satisfaction by using a questionnaire after treatment for digital mucoid cysts with targeted surgical excision and closure by flap-design. MATERIALS AND METHODS All patients treated with surgical excision for digital mucoid cysts at the Dermatology Department of the Ludwigshafen City Hospital between 2007 and 2011 were evaluated using a specially designed questionnaire. RESULTS We evaluated 31 patients. The patient group consisted of 65% women, the median age was 61 years. Seventy-eight percent of patients with nail involvement had a marked improvement or complete resolution of this complaint after surgery. A few complications (e.g., redness, pain or hematoma) were observed after treatment, but no patients required oral antibiotics. Patient evaluation of cosmetic outcome revealed high satisfaction with the procedure, nevertheless recurrence of the digital mucoid cysts was observed in 22.5% of all cases. CONCLUSION Surgical excision in treatment of digital mucoid cysts was shown to be effective and safe. However, possible advantages and disadvantages of this treatment option should be discussed with the patients before a decision on the kind of therapy is reached.

Comprehensive molecular characterization of microneedling therapy in a human three‐dimensional skin model

Background and objectives Microneedling therapy is a widely used technique in dermatology. However, little is known about the underlying molecular effects of this therapy on extracellular matrix remodeling, wound healing, and inflammation. The aim of this study was to examine morphological and molecular changes caused by microneedling treatment in a standardized in vitro full-thickness 3D model of human skin. Materials and methods A microneedling device was used to treat full-thickness 3D skin models. Specimens were harvested at specified time points and qRT-PCR and microarray studies were performed. Frozen sections were examined histologically. Results Microneedling treatment caused morphological changes in the skin model resulting in an almost complete recovery of the epidermis five days after treatment. Microarray analysis identified an upregulation of genes that are associated with tissue remodeling and wound healing (e.g. COL3A1, COL8A1, TIMP3), epithelial proliferation and differentiation (KRT13, IGF1), immune cell recruitment (CCL11), and a member of the heat shock protein family (HSPB6). On the other hand, we detected a downregulation of pro-inflammatory cytokines (e.g. IL1α, IL1β, IL24, IL36γ, IL36RN), and antimicrobial peptides (e.g. S100A7A, DEFB4). These data were confirmed by independent RT-PCR analyses. Conclusion We present for the first time the direct molecular effects of microneedling therapy on epidermal keratinocytes and dermal fibroblasts using a standardized 3D skin model. Treatment resulted in histological alterations and changed the expression of various genes related to epidermal differentiation, inflammation, and dermal remodeling. This data suggests that skin microneedling plays a role in dermal remodeling, increases epidermal differentiation, and might also have a direct effect on collagen synthesis. These findings may increase our understanding of the molecular mechanisms of human skin repair induced by microneedling therapy and will allow comparisons with competing applications, such as ablative laser therapies.

Surgical Approaches for Melanocytic Nevi and Malignant Melanoma of the Umbilicus

Surgical approaches for melanocytic nevi and malignant melanoma of the umbilicus differ in the extent of the procedures. Whenever appropriate, umbilical nevi should be removed with minimal trauma and preservation of the tissue for unimpaired histological investigation. Simple strategies for successful outpatient procedures will be introduced. In the rare case of a proven umbilical melanoma, surgery has to be extensive to ensure necessary margins. Since accidental opening of the abdomen can be a risk after previous surgery or occult umbilical hernia, strict hygiene has to be guaranteed and necessary precautions should to be taken.

Contents Vol. 29, 2016

N. Ahmad, Madison, Wis. C. Antoniou, Athens J.M. Baron, Aachen E. Benfeldt, Roskilde E. Berardesca, Rome K. De Paepe, Brussels P. Elsner, Jena A. Farkas, Zurich N. Garcia Bartels, Berlin M.W. Greaves, London R.H. Guy, Bath S. Hedtrich, Berlin E.M. Jackson, Bonney Lake, Wash. H. Kandárová, Ashland, Mass. L. Kemeny, Szeged J. Kresken, Viersen J. Krutmann, Düsseldorf B. Lange-Asschenfeldt, Klagenfurt am Wörthersee R. Neubert, Halle T. Ruzicka, Munich M. Schäfer-Korting, Berlin M. Schmuth, Innsbruck S. Seidenari, Modena P.W. Wertz, Iowa City, Iowa J. Wohlrab, Halle L. Zastrow, Monaco Journal of Pharmacological and Biophysical Research