Biological Risk Assessment of Three Dental Composite Materials following Gas Plasma Exposure

Gas plasma is an approved technology that generates a plethora of reactive oxygen species, which are actively applied for chronic wound healing. Its particular antimicrobial action has spurred interest in other medical fields, such as periodontitis in dentistry. Recent work has indicated the possibility of performing gas plasma-mediated biofilm removal on teeth. Teeth frequently contain restoration materials for filling cavities, e.g., resin-based composites. However, it is unknown if such materials are altered upon gas plasma exposure. To this end, we generated a new in-house workflow for three commonly used resin-based composites following gas plasma treatment and incubated the material with human HaCaT keratinocytes in vitro. Cytotoxicity was investigated by metabolic activity analysis, flow cytometry, and quantitative high-content fluorescence imaging. The inflammatory consequences were assessed using quantitative analysis of 13 different chemokines and cytokines in the culture supernatants. Hydrogen peroxide served as the control condition. A modest but significant cytotoxic effect was observed in the metabolic activity and viability after plasma treatment for all three composites. This was only partially treatment time-dependent and the composites alone affected the cells to some extent, as evident by differential secretion profiles of VEGF, for example. Gas plasma composite modification markedly elevated the secretion of IL6, IL8, IL18, and CCL2, with the latter showing the highest correlation with treatment time (Pearson’s r > 0.95). Cell culture media incubated with gas plasma-treated composite chips and added to cells thereafter could not replicate the effects, pointing to the potential that surface modifications elicited the findings. In conclusion, our data suggest that gas plasma treatment modifies composite material surfaces to a certain extent, leading to measurable but overall modest biological effects

SimbaML: Connecting Mechanistic Models and Machine Learning with Augmented Data

Training sophisticated machine learning (ML) models requires large datasets that are difficult or expensive to collect for many applications. If prior knowledge about system dynamics is available, mechanistic representations can be used to supplement real-world data. We present SimbaML (Simulation-Based ML), an open-source tool that unifies realistic synthetic dataset generation from ordinary differential equation-based models and the direct analysis and inclusion in ML pipelines. SimbaML conveniently enables investigating transfer learning from synthetic to real-world data, data augmentation, identifying needs for data collection, and benchmarking physics-informed ML approaches. SimbaML is available from https://pypi.org/project/simba-ml/.Comment: 6 pages, 1 figur

Molecular mechanisms of the efficacy of cold atmospheric pressure plasma (CAP) in cancer treatment

Recently, the potential use of cold atmospheric pressure plasma (CAP) in cancer treatment has gained increasing interest. Especially the enhanced selective killing of tumor cells compared to normal cells has prompted researchers to elucidate the molecular mechanisms for the efficacy of CAP in cancer treatment. This review summarizes the current understanding of how CAP triggers intracellular pathways that induce growth inhibition or cell death. We discuss what factors may contribute to the potential selectivity of CAP towards cancer cells compared to their non-malignant counterparts. Furthermore, the potential of CAP to trigger an immune response is briefly discussed. Finally, this overview demonstrates how these concepts bear first fruits in clinical applications applying CAP treatment in head and neck squamous cell cancer as well as actinic keratosis. Although significant progress towards understanding the underlying mechanisms regarding the efficacy of CAP in cancer treatment has been made, much still needs to be done with respect to different treatment conditions and comparison of malignant and non-malignant cells of the same cell type and same donor. Furthermore, clinical pilot studies and the assessment of systemic effects will be of tremendous importance towards bringing this innovative technology into clinical practice. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Molecular Mechanisms of the Efficacy of Cold Atmospheric Pressure Plasma (CAP) in Cancer Treatment

Recently, the potential use of cold atmospheric pressure plasma (CAP) in cancer treatment has gained increasing interest. Especially the enhanced selective killing of tumor cells compared to normal cells has prompted researchers to elucidate the molecular mechanisms for the efficacy of CAP in cancer treatment. This review summarizes the current understanding of how CAP triggers intracellular pathways that induce growth inhibition or cell death. We discuss what factors may contribute to the potential selectivity of CAP towards cancer cells compared to their non-malignant counterparts. Furthermore, the potential of CAP to trigger an immune response is briefly discussed. Finally, this overview demonstrates how these concepts bear first fruits in clinical applications applying CAP treatment in head and neck squamous cell cancer as well as actinic keratosis. Although significant progress towards understanding the underlying mechanisms regarding the efficacy of CAP in cancer treatment has been made, much still needs to be done with respect to different treatment conditions and comparison of malignant and non-malignant cells of the same cell type and same donor. Furthermore, clinical pilot studies and the assessment of systemic effects will be of tremendous importance towards bringing this innovative technology into clinical practice. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Onset and progression of diabetes in kidney transplant patients receiving everolimus or cyclosporine therapy: an analysis of two randomized, multicenter trials

Background: Conversion from calcineurin inhibitor (CNI) therapy to a mammalian target of rapamycin (mTOR) inhibitor following kidney transplantation may help to preserve graft function. Data are sparse, however, concerning the impact of conversion on posttransplant diabetes mellitus (PTDM) or the progression of pre-existing diabetes. Methods: PTDM and other diabetes-related parameters were assessed post hoc in two large open-label multicenter trials. Kidney transplant recipients were randomized (i) at month 4.5 to switch to everolimus or remain on a standard cyclosporine (CsA)-based regimen (ZEUS, n = 300), or (ii) at month 3 to switch to everolimus, remain on standard CNI therapy or convert to everolimus with reduced-exposure CsA (HERAKLES, n = 497). Results: There were no significant differences in the incidence of PTDM between treatment groups (log rank p = 0.97 [ZEUS], p = 0.90 [HERAKLES]). The mean change in random blood glucose from randomization to month 12 was also similar between treatment groups in both trials for patients with or without PTDM, and with or without pre-existing diabetes. The change in eGFR from randomization to month 12 showed a benefit for everolimus versus comparator groups in all subpopulations, but only reached significance in larger subgroups (no PTDM or no pre-existing diabetes). Conclusions: Within the restrictions of this post hoc analysis, including non-standardized diagnostic criteria and limited glycemia laboratory parameters, these data do not indicate any difference in the incidence or severity of PTDM with early conversion from a CsA-based regimen to everolimus, or in the progression of pre-existing diabetes. Trial registration: clinicaltrials.gov , NCT00154310 (registered September 2005) and NCT00514514 (registered August 2007); EudraCT ( 2006-007021-32 and 2004-004346-40 )

Plasma medical oncology: Immunological interpretation in head and neck squamous cell carcinoma

Over the past several years, various important articles focusing on cancer therapy approaches in head and neck squamous cell carcinomas (HNSCCs) using cold atmospheric plasma (CAP) have been published (SEMMLER et al. 2020 [53], METELMANN et al. 2018 [44], KEIDAR et al. 2011 [33]). This doctoral thesis presents selected results from a prospective observational clinical study in CAP therapy of palliative HNSCC patients, carried out at the Department of Oral and Maxillofacial Surgery/Plastic Surgery of the Greifswald University Medicine. For oral and maxillofacial surgeons, ulcerated surfaces of locally advanced head and neck squamous cell carcinomas (UICC IV) offer a challenging treatment assignment with microbial contamination and tumour progression. The clinical attempt appears to eradicate microbial contamination and to initiate tumour regression. This doctoral thesis will describe the processes of human tumour biology and tumour immunology in HNSCCs and the extent of present knowledge concerning plasma medical oncology as an anticancer modality. In the introduction of the doctoral thesis clinical results of plasma therapy in locally advanced HNSCCs (UICC IV) are set out. This mainly includes the investigation of a therapeutic concept, the treatment phases, the tumour size development and the morphological changes of the infected tumour surface following cold atmospheric plasma therapy. In the main part, a detailed immunological interpretation is proposed on the basis of present preclinical and clinical immunological knowledge. Finally, unexplored questions in plasma medical oncology are highlighted. This is highly significant for future plasma research and clinical anticancer therapy

Biological Risk Assessment of Three Dental Composite Materials following Gas Plasma Exposure

Gas plasma is an approved technology that generates a plethora of reactive oxygen species, which are actively applied for chronic wound healing. Its particular antimicrobial action has spurred interest in other medical fields, such as periodontitis in dentistry. Recent work has indicated the possibility of performing gas plasma-mediated biofilm removal on teeth. Teeth frequently contain restoration materials for filling cavities, e.g., resin-based composites. However, it is unknown if such materials are altered upon gas plasma exposure. To this end, we generated a new in-house workflow for three commonly used resin-based composites following gas plasma treatment and incubated the material with human HaCaT keratinocytes in vitro. Cytotoxicity was investigated by metabolic activity analysis, flow cytometry, and quantitative high-content fluorescence imaging. The inflammatory consequences were assessed using quantitative analysis of 13 different chemokines and cytokines in the culture supernatants. Hydrogen peroxide served as the control condition. A modest but significant cytotoxic effect was observed in the metabolic activity and viability after plasma treatment for all three composites. This was only partially treatment time-dependent and the composites alone affected the cells to some extent, as evident by differential secretion profiles of VEGF, for example. Gas plasma composite modification markedly elevated the secretion of IL6, IL8, IL18, and CCL2, with the latter showing the highest correlation with treatment time (Pearson’s r > 0.95). Cell culture media incubated with gas plasma-treated composite chips and added to cells thereafter could not replicate the effects, pointing to the potential that surface modifications elicited the findings. In conclusion, our data suggest that gas plasma treatment modifies composite material surfaces to a certain extent, leading to measurable but overall modest biological effects

Evaluationsmodul: Förderung und Wohlergehen von Kindern. Endbericht: Studie im Auftrag der Geschäftsstelle für die Gesamtevaluation ehe- und familienbezogener Maßnahmen und Leistungen in Deutschland, Prognos AG, für das Bundesministerium für Familie, Senioren, Frauen und Jugend und das Bundesministerium der Finanzen

In Deutschland gab es im Jahr 2010 156 ehe- und familienbezogene Einzelmaßnahmen, für die mehr als 200 Mrd. Euro aufgewendet wurden. Es ist das Ziel der Bundesregierung, im Rahmen einer umfassenden Evaluation Erkenntnisse über die Wirkung der wichtigsten ehe- und familienorientierten Leistungen in Bezug auf die Ziele einer nachhaltigen Familienpolitik zu gewinnen. Diese Gesamtevaluation der familienbezogenen Leistungen in Deutschland wurde 2009 begonnen und umfasst mehrere Evaluationsmodule, die ausgewählte Leistungen in Bezug auf unterschiedliche Ziele der Familienpolitik untersuchen. Das Evaluationsmodul 'Förderung und Wohlergehen von Kindern' ist Teil dieser Gesamtevaluation und hat zum Ziel, 12 ausgewählte familienorientierte Leistungen hinsichtlich des Ziels Förderung und Wohlergehen von Kindern zu untersuchen. Wirkungen auf weitere familienpolitische Ziele wie z.B. 'wirtschaftliche Stabilität / soziale Teilhabe von Familien', 'Vereinbarkeit von Familie und Beruf' und 'Fertilität / Erfüllung von Kinderwünschen' stehen nicht im Fokus dieses Evaluationsmoduls. Da allerdings die Förderung von Kindern nicht unabhängig von der Erwerbstätigkeit der Mütter gesehen werden kann, treffen wir in diesem Bericht auch Aussagen über die Wirkung der von uns untersuchten Leistungen auf das Arbeitsangebot von Müttern und die wirtschaftliche Stabilität von Familien. [...

Comparative Sample Preparation Using Focused Ion Beam and Ultramicrotomy of Human Dental Enamel and Dentine for Multimicroscopic Imaging at Micro- and Nanoscale

(1) Background: The aim of this study was to systematically compare TEM sections of mineralized human enamel and dentine prepared by focused ion beam (in situ lift-out) technique and ultramicrotomy through a combination of microscopic examination methods (scanning electron microscopy and transmission electron microscopy). In contrast with published studies, we compared the TEM preparation methods using the same specimen blocks as those for the ultramicrotomy and FIB technique. (2) Methods: A further evaluation of TEM sample preparation was obtained by confocal laser scanning microscopy and atomic force microscopy. In addition, ultramicrotome- and focused ion beam-induced artefacts are illustrated. (3) Results: The FIB technique exposed a major difference between non-decalcified enamel and dentine concerning the ultrastructural morphology compared to ultramicrotome-prepared sections. We found that ultramicrotomy was useful for cutting mineralized dentine, with the possibility of mechanical artefacts, but offers limited options for the preparation of mineralized enamel. FIB preparation produced high-quality TEM sections, showing the anisotropic ultrastructural morphology in detail, with minor structural artefacts. Our results show that the solution of artificial saliva and glutardialdehyde (2.5% by volume) is a very suitable fixative for human mineralized tissue. (4) Conclusions: The protocol that we developed has strong potential for the preparation of mineralized biomaterials for TEM imaging and analysis