Targeting malignant melanoma with physical plasmas

Melanoma is the deadliest form of cutaneous neoplasia. With a five-year survival rate of only 5–19%, metastatic melanoma presents severe challenges in clinical therapies. In addition, palliation is often problematic due to large numbers of fast growing metastasis. This calls for new therapeutic avenues targeting highly aggressive melanoma in palliative patients. One recently suggested innovative approach for eradication of topical tumor lesions is the application of cold physical plasma. This partially ionized gas emits a cocktail of reactive oxygen and nitrogen species (ROS/RNS). ROS/RNS have been shown to be a double-edged sword in fueling cancer growth at low doses but abrogating it at higher doses. The ROS/RNS output of plasma devices is tunable, and many studies have successfully decreased cancer cell growth in vitro and tumor burden in vivo. In general, increasing numbers of clinical trials suggest combination therapies to outperform monotherapies with regard to prognosis in patients. This review describes current challenges in melanoma treatment and highlights the concept of plasma therapy in experimental studies performed in melanoma research. Future perspectives are given that combine the usage of physical plasma with e.g. chemotherapy, immunotherapy, and ionizing radiation in melanoma medical oncology

Beliefs-oriented subject-matter didactics

This paper presents a modified approach to subject-matter didactics, in which the focus is not on the content itself, but on the students' view of the content. The introduction deals with an overview of subject-matter didactics and the notion of beliefs used in this paper. The main portion of the paper deals with presenting the concepts of a book and a seminar based on the student-centered subject-matter didactics approach. For the first qualitative evaluation, selected reflections of students are analyzed. Finally, initial findings are summarized and an outlook is provided

Eine „neue“ Präsenz? Lehren und Lernen an der Hochschule in Zeiten von Kontaktbeschränkungen – und danach – wirksam gestalten

Anknüpfend an den Beitrag von Hans-Georg Weigand in den Mitteilungen der GDM Nr. 109 soll in diesem Beitrag diskutiert werden, inweit die Möglichkeiten und Herausforderungen digitaler (Hochschul-)Lehre das Verständnis von Präsenz auch über die Pandemie hinaus verändern können. Diskussionsleitend sind dabei die folgenden zwei Fragen:Wie können Lehrende und Lernende in dieser Situation „Präsenz zeigen“?Wie kann Präsenz strukturiert und effizient gestaltet werden

Ex Vivo Exposure of Human Melanoma Tissue to Cold Physical Plasma Elicits Apoptosis and Modulates Inflammation

Cutaneous melanoma is the most aggressive type of skin cancer with a not-sufficient clinical outcome. High tumor mutation rates often hamper a remedial treatment, creating the need for palliative care in many patients. To reduce pain and burden, local palliation often includes cryo-ablation, immunotherapy via injection of IL2, or electrochemotherapy. Yet, a fraction of patients and lesions do not respond to those therapies. To reach even these resistances in a redox-mediated way, we treated skin biopsies from human melanoma ex vivo with cold physical plasma (kINPen MED plasma jet). This partially ionized gas generates a potent mixture of reactive oxygen species (ROS). Physical plasmas have been shown to be potent antitumor agents in preclinical melanoma and clinical head and neck cancer research. The innovation of this technology lies in its ease-of-use without anesthesia, as the “cold” plasma temperature of the kINPen MED does not exceed 37 °C. In metastatic melanoma skin biopsies from six patients, we identified a marked increase of apoptosis with plasma treatment ex vivo. This had an impact on the chemokine/cytokine profile of the cultured biopsies, e.g., three of six patient-derived biopsy supernatants showed an apparent decrease in VEGF compared to non-plasma treated specimens. Moreover, the baseline release levels of 24 chemokines/cytokines investigated may serve as a useful tool for future research on melanoma skin biopsy treatments. Our findings suggest a clinically useful role of cold physical plasma therapy in palliation of cutaneous melanoma lesions, possibly in a combinatory setting with other immune therapies

Mathematik digital erleben - Diskussion aktueller Projekte

Wichtige Basis für vielen Forschungsarbeiten und Lehrtätigkeiten der Mathematikdidaktik der Universität Siegen ist die Bedeutung von Auffassungen von Mathematik für die Entwicklung und Vermittlung mathematischen Wissens. Dabei beziehen wir uns insbesondere auf Arbeiten von Burscheid & Struve (2020), Tall (2013) und Schoenfeld (1985). Weniger Untersuchungen in Zusammenhang mit digitalen Medien und Werkzeugen im Mathematikunterricht beschäftigen sich derzeit mit den Beliefs von angehenden Lehrkräften, Studierenden oder Schüler/-innen.Projekte zu Mathematik digital erleben an der Universität Siegen nehmen diese Adressatengruppen besonders in den Blick. Diese wollen wir an dieser Stelle der Community zur Diskussion stellen und auf interessante Weiterentwicklungen aufmerksam machen

xCT (SLC7A11) expression confers intrinsic resistance to physical plasma treatment in tumor cells

Cold physical plasma is a partially ionized gas investigated as a new anticancer tool in selectively targeting cancer cells in monotherapy or in combination with therapeutic agents. Here, we investigated the intrinsic resistance mechanisms of tumor cells towards physical plasma treatment. When analyzing the dose-response relationship to cold plasma-derived oxidants in 11 human cancer cell lines, we identified four 'resistant' and seven 'sensitive' cell lines. We observed stable intracellular glutathione levels following plasma treatment only in the 'resistant' cell lines indicative of altered antioxidant mechanisms. Assessment of proteins involved in GSH metabolism revealed cystine-glutamate antiporter xCT (SLC7A11) to be significantly more abundant in the 'resistant' cell lines as compared to 'sensitive' cell lines. This decisive role of xCT was confirmed by pharmacological and genetic inhibition, followed by cold physical plasma treatment. Finally, microscopy analysis of ex vivo plasma-treated human melanoma punch biopsies suggested a correlation between apoptosis and basal xCT protein abundance. Taken together, our results demonstrate that xCT holds the potential as a biomarker predicting the sensitivity of tumor cells towards plasma treatment

Correlation of tumor PD-L1 expression in different tissue types and outcome of PD-1-based immunotherapy in metastatic melanoma – analysis of the DeCOG prospective multicenter cohort study ADOREG/TRIM

Background PD-1-based immune checkpoint inhibition (ICI) is the major backbone of current melanoma therapy. Tumor PD-L1 expression represents one of few biomarkers predicting ICI therapy outcome. The objective of the present study was to systematically investigate whether the type of tumor tissue examined for PD-L1 expression has an impact on the correlation with ICI therapy outcome. Methods Pre-treatment tumor tissue was collected within the prospective DeCOG cohort study ADOREG/TRIM (CA209-578; NCT05750511) between February 2014 and May 2020 from 448 consecutive patients who received PD-1-based ICI for non-resectable metastatic melanoma. The primary study endpoint was best overall response (BOR), secondary endpoints were progression-free (PFS) and overall survival (OS). All endpoints were correlated with tumor PD-L1 expression (quantified with clone 28–8; cutoff ≥5%) and stratified by tissue type. Findings Tumor PD-L1 was determined in 95 primary tumors (PT; 36.8% positivity), 153 skin/subcutaneous (34.0% positivity), 115 lymph node (LN; 50.4% positivity), and 85 organ (40.8% positivity) metastases. Tumor PD-L1 correlated with BOR if determined in LN (OR = 0.319; 95% CI = 0.138–0.762; P = 0.010), but not in skin/subcutaneous metastases (OR = 0.656; 95% CI = 0.311–1.341; P = 0.26). PD-L1 positivity determined on LN metastases was associated with favorable survival (PFS, HR = 0.490; 95% CI = 0.310–0.775; P = 0.002; OS, HR = 0.519; 95% CI = 0.307–0.880; P = 0.014). PD-L1 positivity determined in PT (PFS, HR = 0.757; 95% CI = 0.467–1.226; P = 0.27; OS; HR = 0.528; 95% CI = 0.305–0.913; P = 0.032) was correlated with survival to a lesser extent. No relevant survival differences were detected by PD-L1 determined in skin/subcutaneous metastases (PFS, HR = 0.825; 95% CI = 0.555–1.226; P = 0.35; OS, HR = 1.083; 95% CI = 0.698–1.681; P = 0.72). Interpretation For PD-1-based immunotherapy in melanoma, tumor PD-L1 determined in LN metastases was stronger correlated with therapy outcome than that assessed in PT or organ metastases. PD-L1 determined in skin/subcutaneous metastases showed no outcome correlation and therefore should be used with caution for clinical decision making. Funding Bristol-Myers Squibb (ADOREG/TRIM, NCT05750511); German Research Foundation (DFG; Clinician Scientist Program UMEA); Else Kröner-Fresenius-Stiftung (EKFS; Medical Scientist Academy UMESciA)

A skin cancer prevention facial-aging mobile app for secondary schools in Brazil : appearance-focused interventional study.

Background: The incidence of melanoma is increasing faster than any other major cancer both in Brazil and worldwide. Southeast Brazil has especially high incidences of melanoma, and early detection is low. Exposure to ultraviolet (UV) radiation is a primary risk factor for developing melanoma. Increasing attractiveness is a major motivation among adolescents for tanning. A medical student-delivered intervention that takes advantage of the broad availability of mobile phones and adolescents? interest in their appearance indicated effectiveness in a recent study from Germany. However, the effect in a high-UV index country with a high melanoma prevalence and the capability of medical students to implement such an intervention remain unknown. Objective: In this pilot study, our objective was to investigate the preliminary success and implementability of a photoaging intervention to prevent skin cancer in Brazilian adolescents. Methods: We implemented a free photoaging mobile phone app (Sunface) in 15 secondary school classes in southeast Brazil. Medical students ?mirrored? the pupils? altered 3-dimensional (3D) selfies reacting to touch on tablets via a projector in front of their whole grade accompanied by a brief discussion of means of UV protection. An anonymous questionnaire capturing sociodemographic data and risk factors for melanoma measured the perceptions of the intervention on 5-point Likert scales among 356 pupils of both sexes (13-19 years old; median age 16 years) in grades 8 to 12 of 2 secondary schools in Brazil. Results: We measured more than 90% agreement in both items that measured motivation to reduce UV exposure and only 5.6% disagreement: 322 (90.5%) agreed or strongly agreed that their 3D selfie motivated them to avoid using a tanning bed, and 321 (90.2%) that it motivated them to improve their sun protection; 20 pupils (5.6%) disagreed with both items. The perceived effect on motivation was higher in female pupils in both tanning bed avoidance (n=198, 92.6% agreement in females vs n=123, 87.2% agreement in males) and increased use of sun protection (n=197, 92.1% agreement in females vs n=123, 87.2% agreement in males) and independent of age or skin type. All medical students involved filled in a process evaluation revealing that they all perceived the intervention as effective and unproblematic, and that all pupils tried the app in their presence. Conclusions: The photoaging intervention was effective in changing behavioral predictors for UV protection in Brazilian adolescents. The predictors measured indicated an even higher prospective effectiveness in southeast Brazil than in Germany (>90% agreement in Brazil vs >60% agreement in Germany to both items that measured motivation to reduce UV exposure) in accordance with the theory of planned behavior. Medical students are capable of complete implementation. A randomized controlled trial measuring prospective effects in Brazil is planned as a result of this study

Untersuchungen zur Kryokonservierung humaner Adipozyten zur mehrzeitigen autologen Transplantation

The autologous transplantation of cryopreserved human adipocytes is a usual technique in Plastic Surgery, up to now. There are no evidences, that these cells have normal vitality and a complete integrity of their membranes, at the moment of the transplantation. Aim of this work was, to make a quantitative statement about the cell-vitality and cell-integrity of mature human adipocytes, by using an enzyme-based test-system. Therefore, the existing MTT-, XTT- and GPDH-tests were modified for the use of human adipocytes. For the protection of human cells, during cryopreservation, cryoprotective agents are a common group of chemical substances, in science. In this work we used hydroxyethylstarch, glycerol and a mixture of glycerol, dextran and polyvinylpyrrolidone. The vitality of the cells was measured before the cryopreservation, at -20°C and -80°C, and after 2, 7 and 14 days as well as after 1, 6 and 12 month. As an intermediate-result we ascertained, that a cryopreservation of human adipocytes for 48 hours, without using a cryoprotective agent, leads to a vitality-loss of 94,9% (MTT-test, -20°C) and after one year of cryostorage to a vitality-loss of 97,4% (MTT-test, -20°C). Comparable results were detected in the XTT- and GPDH-test as well as by using -80°C as cryopreservation temperature. The use of the selected cryoprotectives was able to reduce the loss of cell-vitality and the cell-membrane damage, which was measured by using the GPDH-test. The best quantitative result was achieved by using the cryoprotective mixture. After one year of cryopreservation the cell-vitality was increased up to 30% in the MTT-test and up to 60% in the XTT-test; the GPDH-test could prove a reduction of the loss of cell-integrity up to 50%.1. The inset of cryopreserved human adipocytes, without using a cryoprotective agent, should be no subject of practical use in medicine.2. Through the addition of cryoprotective agents, it is possible to improve the vitality and integrity of human adipocytes high significantly, in comparison with the non-use.3. The suitable cryoprotective was a mixture of one intracellular (Glycerol) and two extracellular (Dextran and Polyvinylpyrrolidone) protectives