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Im Rahmen dieser publikationsbasierten Dissertation wurden drei wissenschaftliche Arbeiten veröffentlicht. Als Erstautorenschaft wurde 2022 die Arbeit “Effectiveness of High-intensity Focused Ultrasound (HIFU) Therapy of Solid and Complex Benign Thyroid Nodules - A Long-term Follow up Two-center Study.” im Journal “Experimental and Clinical Endocrinology & Diabetes” veröffentlicht. Im Folgenden wird der Inhalt dieser Arbeit dargelegt. Ein kurzer Überblick über die Ergebnisse der anderen beiden mitpublizierten Arbeiten findet sich im Kapitel „Weitere Ergebnisse der Arbeitsgruppe“.
Durch die hohe Prävalenz benigner Schilddrüsenknoten sind deren Behandlungsalternativen von großem wissenschaftlichem Interesse. Dabei bildet die nebenwirkungsarme, minimalinvasive Thermoablation mittels high-intensity focused ultrasound (HIFU) eine attraktive Alternative zu herkömmlichen Verfahren wie der Schilddrüsenchirurgie oder der Radioiodtherapie. Bei der HIFU-Echotherapie werden die Schilddrüsenknoten auf 80 - 90 Grad Celsius erhitzt, sodass eine irreversible Koagulationsnekrose entsteht. Um den Therapieprozess und die Indikationsstellung von HIFU bei benignen Schilddrüsenknoten zu optimieren, ist es notwendig, genaue Studien durchzuführen.
Ziel der vorliegenden bizentrischen Langzeitstudie war, die Effektivität von HIFU-Echotherapien bei benignen Schilddrüsenknoten zu evaluieren und erstmalig den Einfluss der Knotenmorphologie auf den Therapieerfolg zu untersuchen. Vor der Therapie und in regelmäßigen Intervallen nach der Therapie wurden die Größe und die Morphologie der Schilddrüsenknoten mittels Ultraschall dokumentiert. In der retrospektiven Studie wurden Daten von 58 Patienten ausgewertet. Dabei wurde die Gesamtpopulation in eine Gruppe mit soliden und in eine Gruppe mit komplexen Knoten eingeteilt. Die durchschnittliche prozentuale Volumenreduktion in jeder Gruppe wurde mit dem Wilcoxon-Signed-Rank Test statistisch analysiert.
Die Gesamtpopulation zeigte eine Volumenreduktion der zuvor abladierten Knoten von 38.86 % nach 3 Monaten (Spannweite: 4.03 % - 91.16 %, p < 0.0001, n = 25), 42.7 % nach 6 Monaten (Spannweite: 7.36 % - 93.2 %, p < 0.0001, n = 18), 62.21 % nach 9 Monaten (Spannweite: 12.88 % - 93.2 %, p = 0.0078, n = 8) und 61.42 % nach 12 Monaten (Spannweite: 39.39 % - 93.2 %, p > 0.05, n = 4). Die soliden Knoten hatten eine Volumenreduktion von 49.98 % nach 3 Monaten (Spannweite: 4.03 % - 91.16 %, p = 0.0001, n = 15), 46.40 % nach 6 Monaten (Spannweite: 7.36 % - 93.2 %, p = 0.001, n = 11), 65.77 % nach 9 Monaten (Spannweite: 39.39 % - 93.2 %, p = 0.0156, n = 7) und 63.88 % nach 12 Monaten (Spannweite: 39.39 % - 93.2%, p > 0.05, n = 2). Komplexe Knoten hatten eine Volumenreduktion von 35.2 % nach 3 Monaten (Spannweite: 5.85 % - 68.63 %, p = 0.002, n = 10), 36.89 % nach 6 Monaten (Spannweite: 12.23 % - 68.63 %, p = 0.0156, n = 7) und 63.64 % nach 12 Monaten (Spannweite: 52,38 % - 73.91 %, p > 0.05, n = 2).
In der vorliegenden bizentrischen Langzeitstudie wurde deutlich, dass HIFU-Echotherapie eine effektive Behandlungsoption benigner Schilddrüsenknoten ist. Erstmalig gezeigt wurde der Trend, dass solide Knoten besser auf HIFU-Echotherapie ansprechen als komplexe Knoten.
Anhand der gewonnenen Ergebnisse und der neuen Erkenntnisse zum Einfluss der Knotenmorphologie auf die HIFU-Echotherapie benigner Schilddrüsenknoten kann HIFU als Therapieoption besser bewertet werden. Eine differenziertere Indikationsstellung in Bezug auf solide und komplexe Knoten wird ermöglicht und die HIFU-Echotherapie kann gegen andere thermoablative Verfahren abgewogen werden.
Highlights
• An airport can result in high particle concentrations in a distant residential area.
• The particle size distribution indicated the airport as the main source of particles.
• Lower air traffic during the COVID-19 pandemic lead to lower particle concentrations.
• The particle concentration showed high temporal variations.
Abstract
Exposure to ultrafine particles has a significant influence on human health. In regions with large commercial airports, air traffic and ground operations can represent a potential particle source. The particle number concentration was measured in a low-traffic residential area about 7 km from Frankfurt Airport with a Condensation Particle Counter in a long-term study. In addition, the particle number size distribution was determined using a Fast Mobility Particle Sizer.
The particle number concentrations showed high variations over the entire measuring period and even within a single day. A maximum 24 h-mean of 24,120 cm−3 was detected. Very high particle number concentrations were in particular measured when the wind came from the direction of the airport. In this case, the particle number size distribution showed a maximum in the particle size range between 5 and 15 nm. Particles produced by combustion in jet engines typically have this size range and a high potential to be deposited in the alveoli. During a period with high air traffic volume, significantly higher particle number concentrations could be measured than during a period with low air traffic volume, as in the COVID-19 pandemic.
A large commercial airport thus has the potential to lead to a high particle number concentration even in a distant residential area. Due to the high particle number concentrations, the critical particle size, and strong concentration fluctuations, long-term measurements are essential for a realistic exposure analysis.
Highlights
• Currently, China has the most publications, ahead of the USA and European countries.
• Research focuses are strictly separated into ecological and material science topics.
• Russia and Ukraine are among the frontrunners with a clear focus on materials science.
• The focus in PFAS research is shifting toward ecological issues.
• A national imbalance can be observed that leaves the low economies behind.
Abstract
The European Commission's current efforts to launch the largest proposal to restrict per- and polyfluoroalkyl substances (PFAS) in history reflect the dire global plight of PFAS accumulation in the environment and their health impacts. While there are existing studies on PFAS research, there is a lack of comprehensive analysis that both covers the entire research period and provides deep insights into global research patterns, incentives, and barriers based on various parameters. We have been able to demonstrate the increasing interest in PFAS research, although citation numbers are declining prematurely. Policy regulations based on proving and establishing the toxicity of PFASs have stimulated research in developed countries and vice versa, with increasing emphasis on ecological aspects. China, in particular, is investing increasingly in PFAS research, but without defining or implementing regulations - with devastating effects. The separation of industrial and environmental research interests is clear, with little involvement of developing countries, even though their exposure to PFAS is devastating. It, therefore, requires increased globally networked and multidisciplinary approaches to address PFAS contamination challenges.
Koch, Benjamin Florian ; Filzmayer, Maximilian ; Patyna, Ralf Sammy ; Wetzstein, Nils ; Lampe, Sebastian ; Schmid, Tobias ; Geiger, Helmut ; Baer, Patrick C. ; Dolnik, Olga
Highligthts
• Marburg virus infects and replicates in primary human proximal tubular cells (PTC).
• Transcriptome analyses at multiple time points revealed a profound inflammatory response by IFNα, -y and TNFα signaling.
• Among the strongly downregulated gene sets were targets of the transcription factors MYC and E2F, the G2M checkpoint, as well as oxidative phosphorylation.
• Importantly, the downregulated factors comprise PGC-1α, a key factor in mitochondrial biogenesis and renal energy homeostasis, to be substantially downregulated in MARV-infected PTC.
• Our results suggest inflammation-induced changes in tubular energy metabolism as a possible factor in MARV-associated tubular dysfunction.
Abstract
Marburg virus, a member of the Filoviridae, is the causative agent of Marburg virus disease (MVD), a hemorrhagic fever with a case fatality rate of up to 90 %. Acute kidney injury is common in MVD and is associated with increased mortality, but its pathogenesis in MVD remains poorly understood. Interestingly, autopsies show the presence of viral proteins in different parts of the nephron, particularly in proximal tubular cells (PTC). These findings suggest a potential role for the virus in the development of MVD-related kidney injury. To shed light on this effect, we infected primary human PTC with Lake Victoria Marburg virus and conducted transcriptomic analysis at multiple time points. Unexpectedly, infection did not induce marked cytopathic effects in primary tubular cells at 20 and 40 h post infection. However, gene expression analysis revealed robust renal viral replication and dysregulation of genes essential for different cellular functions. The gene sets mainly downregulated in PTC were associated with the targets of the transcription factors MYC and E2F, DNA repair, the G2M checkpoint, as well as oxidative phosphorylation. Importantly, the downregulated factors comprise PGC-1α, a well-known factor in acute and chronic kidney injury. By contrast, the most highly upregulated gene sets were those related to the inflammatory response and cholesterol homeostasis. In conclusion, Marburg virus infects and replicates in human primary PTC and induces downregulation of processes known to be relevant for acute kidney injury as well as a strong inflammatory response.
Highlights
• High resolution profile of C. pipiens' sugar diet has been obtained using UHPLC-MS.
• Artificial feeding using ornamental plants provides similar sugar profiles as observed in field collected mosquitoes.
• Metabolomic profiling found secondary metabolites and pollutants of anthropogenic use.
Abstract: Culex pipiens (Linnaeus, 1758) mosquitoes search plant sources of sugars to cope with the energetic demand of various physiological processes. The crop as part of the digestive system is devoted to the storage of sugar-based meal obtained from various nectars sources. The profiling of sugars and metabolites in the Culex pipiens’ crop is scarce, and only few studies used Liquid Chromatography – Mass Spectrometry (LC-MS), which provides broad detection for biomonitoring environmental substances and even contaminants in the sugar diet of mosquitoes populations.
Therefore, sugar and metabolite profiling were performed on crops obtained from mosquitoes exposed to plant nectar under laboratory or natural conditions by Ultra High-Performance LC-MS (UHPLC-MS). This method allowed us a precise quantitative and qualitative identification of sugar diet and associated environmental compounds in the crop of the mosquito C. pipiens. Under laboratory condition, mosquitoes were allowed to feed on either glucose solution, commercially-available flowers or field collected flowers. In addition, we collected mosquitoes from the field to compare those crop metabolomes with metabolome patterns occurring after nectar feeding in the lab.
The sugar quantities and quality obtained from the crops of mosquitoes collected in the field were similar to those crops obtained from mosquitoes that fed on commercially-available flowers and from field collected flowers with a limit of detection of 10 μg/L for sucrose, glucose and sucrose. Next to sugar compounds, we identified 2 types of amino acids, 12 natural products, and 9 pesticides.
Next to the diversity of sugar compounds, we could confirm that secondary metabolites and environmental pollutants are typically up taken from floral nectar sources by C. pipiens. The in-depth knowledge on mosquito–plant interactions may inspire the development and further optimization of mosquito trap systems and arboviral surveillance systems.
Naeem, Zumer ; Zukunft, Sven ; Huard, Arnaud ; Hu, Jiong ; Hammock, Bruce D. ; Weigert, Andreas ; Frömel, Timo ; Fleming, Ingrid
The lipid content of skin plays a determinant role in its barrier function with a particularly important role attributed to linoleic acid and its derivatives. Here we explored the consequences of interfering with the soluble epoxide hydrolase (sEH) on skin homeostasis. sEH; which converts fatty acid epoxides generated by cytochrome P450 enzymes to their corresponding diols, was largely restricted to the epidermis which was enriched in sEH-generated diols. Global deletion of the sEH increased levels of epoxides, including the linoleic acid-derived epoxide; 12,13-epoxyoctadecenoic acid (12,13-EpOME), and increased basal keratinocyte proliferation. sEH deletion (sEH-/- mice) resulted in thicker differentiated spinous and corneocyte layers compared to wild-type mice, a hyperkeratosis phenotype that was reproduced in wild-type mice treated with a sEH inhibitor. sEH deletion made the skin sensitive to inflammation and sEH-/- mice developed thicker imiquimod-induced psoriasis plaques than the control group and were more prone to inflammation triggered by mechanical stress with pronounced infiltration and activation of neutrophils as well as vascular leak and increased 12,13-EpOME and leukotriene (LT) B4 levels. Topical treatment of LTB4 antagonist after stripping successfully inhibited inflammation and neutrophil infiltration both in wild type and sEH-/- skin. While 12,13-EpoME had no effect on the trans-endothelial migration of neutrophils, like LTB4, it effectively induced neutrophil adhesion and activation. These observations indicate that while the increased accumulation of neutrophils in sEH-deficient skin could be attributed to the increase in LTB4 levels, both 12,13-EpOME and LTB4 contribute to neutrophil activation. Our observations identify a protective role of the sEH in the skin and should be taken into account when designing future clinical trials with sEH inhibitors.
Despotovic, Vladimir ; Kim, Sang-Yoon ; Hau, Ann-Christin ; Kakoichankava, Aliaksandra ; Klamminger, Gilbert Georg ; Kleine Borgmann, Felix Bruno ; Frauenknecht, Katrin Barbara Magda ; Mittelbronn, Michel Guy André ; Nazarov, Petr V.
We provide in this paper a comprehensive comparison of various transfer learning strategies and deep learning architectures for computer-aided classification of adult-type diffuse gliomas. We evaluate the generalizability of out-of-domain ImageNet representations for a target domain of histopathological images, and study the impact of in-domain adaptation using self-supervised and multi-task learning approaches for pretraining the models using the medium-to-large scale datasets of histopathological images. A semi-supervised learning approach is furthermore proposed, where the fine-tuned models are utilized to predict the labels of unannotated regions of the whole slide images (WSI). The models are subsequently retrained using the ground-truth labels and weak labels determined in the previous step, providing superior performance in comparison to standard in-domain transfer learning with balanced accuracy of 96.91% and F1-score 97.07%, and minimizing the pathologist's efforts for annotation. Finally, we provide a visualization tool working at WSI level which generates heatmaps that highlight tumor areas; thus, providing insights to pathologists concerning the most informative parts of the WSI.
Higuchi, Takahiro ; Serfling, Sebastian E. ; Leistner, David M. ; Speer, Thimoteus ; Werner, Rudolf A.
PET probes targeting fibroblasts are frequently used for varying applications in oncology. In recent years, the clinical spectrum has been expanded towards cardiovascular medicine, e.g., after myocardial infarction, in aortic stenosis or as a non-invasive read-out of atherosclerosis. We herein provide a brief overview of the current status of this PET radiotracer in the context of cardiovascular disease, including translational and clinical evidence. In addition, we will also briefly discuss future applications, e.g., the use of fibroblast-targeting PET to investigate bilateral organ function along the cardiorenal axis.
• Mexican and German populations of L. sericata differ in their development times.
• Mexican L. sericata had a shorter development time at 20°C than German flies.
• At 30 °C, German L. sericata pupariated and eclosed earlier than the Mexican flies.
• Differences in study design make the comparison of developmental studies difficult.
Abstract
The cosmopolitan blow fly Lucilia sericata is often used in forensic case work for estimating the minimum postmortem interval (PMImin). For this, the age of immature specimens developing on the dead body is calculated by measuring the time taken to reach the sampled developmental stage at a given temperature. To test whether regional developmental data of L. sericata is valid on a global scale, the time taken to reach different developmental stages was compared between a population from Mexico and one from Germany at two different constant temperatures.
The German population of L. sericata was collected in Frankfurt/Main, while the Mexican population originated near Oaxaca de Juarez and was transported to Germany in the larval stage. Only the F1 generation was used to avoid adaption of the Mexican flies. Eggs were immediately placed at 20 °C and 30 °C. Five times 30 freshly eclosed larvae per replicate (n = 5) were then transferred to a cup of minced meat in separate containers. The larvae were checked every 8 h for migration, pupariation or emergence of adult flies. The time at which the first individual and 50 % of the specimens per container entered each of these stages, was recorded.
Significant differences in the time of development between the two populations were observed at both temperatures. At 20 °C, the first specimens of the Mexican population reached all developmental stages a little (< 1 day to < 2 days) earlier than the German L. sericata. At 30 °C, the Mexican flies also reached the post-feeding stage slightly earlier (0.2 days). However, at 30 °C, the German flies started pupariation significantly earlier (after 5 days) than the Mexican flies (6.9 days) and the adults from Germany also emerged earlier (10.5 days compared to 13.1 days). The same pattern was observed when looking at 50 % of the total number of specimens per container. A comparison with previously published developmental studies was difficult as the experimental design varied widely between studies. However, the results were within the range of most studies. Our study has shown that age estimation can vary widely depending on the population on which the reference data used for the calculations are based. This highlights the importance of using local and population-specific developmental data for estimating the age of blow flies in case work.