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  • ItemZeitschriftenaufsatzOpen Access
    Biocompatibility of variable thicknesses of a novel directly printed aligner in orthodontics
    (2025) Bleilöb, Maximilian; Welte-Jzyk, Claudia; Knode, Vanessa; Ludwig, Björn; Erbe, Christina
    Direct printed aligners (DPAs) offer benefits like the ability to vary layer thickness within a single DPA and to 3D print custom-made removable orthodontic appliances. The biocompatibility of appliances made from Tera Harz TA-28 (Graphy Inc., Seoul, South Korea) depends on strict adherence to a standardized production and post-production protocol, including UV curing. Our aim was to evaluate whether design modifications that increase layer thickness require a longer UV curing time to ensure biocompatibility. Specimens with varying layer thickness were printed to high accuracy using Tera Harz TA-28 and the Asiga MAX 3D printer (Asiga SPS ™ technology, Sydney, Australia). UV curing durations were set at 20, 30 and 60 min. Cytotoxicity was evaluated using the AlamarBlue assay on human gingival fibroblasts. Cell viability decreased with increasing specimen thickness (significant for 2 mm [p < 0.001], 4 mm [p < 0.0001], and 6 mm [p < 0.01]) under the manufacturer-recommended 20-min UV curing. Extending the curing time did not improve cell viability. However, cell viability never decreased by more than 30%, meeting EN ISO 10993-5 standards for non-cytotoxicity. The standard 20-minute UV curing protocol ensures the biocompatibility and patient safety of Tera Harz TA-28 for material thicknesses up to 6 mm.
  • ItemZeitschriftenaufsatzOpen Access
    Mantle dynamics in the Mediterranean and plate motion of the Adriatic microplate : insights from 3D thermomechanical modeling
    (2025) Schuler, Christian; Kaus, Boris J. P.; Le Breton, Eline; Riel, Nicolas; Popov, Anton A.
    The motion of the Adriatic microplate is thought to be highly sensitive to the surrounding subduction zones and the convergence of Africa and Eurasia. However, our understanding of the mantle dynamics in the Mediterranean region and its effect on plate motion remains incomplete. Here, we present a large set of 3D thermomechanical models of the entire Mediterranean region over the last 35 Myr to understand what controls the motion of the Adriatic microplate. The simulations take the convergence of the African and Arabian plates with the Eurasian plate into account, along with the dynamics of the subduction systems in the western (Apennines-Calabria), central (Dinarides-Hellenides) Mediterranean and in the Alpine-Carpathian region. Our results demonstrate that the subduction systems around Adria are highly coupled, which gives rise to complex asthenospheric flow in the central Mediterranean. We find that the plate motion of the Adriatic microplate over the last 35 Myr is controlled by the interplay of three main factors: (a) the convergence between the African and Eurasian plates, (b) the retreat of the Alpine subduction zone to the north of Adria, and (c) the distance between the Calabrian and Hellenic subduction zones around Adria. Furthermore, in a system characterized by active convergence between Africa and Eurasia, the slab pull exerted by nearby subduction zones can only notably influence the motion of the Adriatic microplate if these subduction zones are located within a few hundred kilometers of Adria.
  • ItemZeitschriftenaufsatzOpen Access
    Adaptive evolution of SARS-CoV-2 during a persistent infection for 521 days in an immunocompromised patient
    (2025) Schmidt, Hanno; Schick, Lea; Podlech, Jürgen; Renzaho, Angélique; Lieb, Bettina; Diederich, Stefan; Hankeln, Thomas; Plachter, Bodo; Kriege, Oliver
    Immunocompromised patients struggle to adequately clear viral infections, offering the virus the opportunity to adapt to the immune system in the host. Here we present a case study of a patient undergoing allogeneic hematopoietic stem cell transplantation with a 521-day follow-up of a SARS-CoV-2 infection with the BF.7.21 variant. Virus samples from five time points were submitted to whole genome sequencing. Between the first detection of SARS-CoV-2 infection and its clearance, the patient’s virus population acquired 34 amino acid substitutions and 8 deletions in coding regions. With 11 amino acid substitutions in the receptor binding domain of the virus’ spike protein, substitutions were 15 times more abundant than expected for a random distribution in this highly functional region. Amongst them were the substitutions S:K417T, S:N440S, S:K444R, S:V445A, S:G446N, S:L452Q, S:N460K, and S:E484V at positions that are notorious for their resistance-mediating effects. The substitution patterns found indicate ongoing adaptive evolution.
  • ItemZeitschriftenaufsatzOpen Access
    “Lost in translation?” Animal research in the era of precision medicine
    (2025) Frühwein, Hamideh; Paul, Norbert W.
    Preclinical animal research has long been a cornerstone in evaluating the efficacy, toxicity, and safety of potential drug treatments before they proceed to human clinical trials. However, given the intricate nature of human physiology and the complexities of diseases such as cancer, this paper critically examines the role of animal experimentation in translational research, both from epistemological and ethical viewpoints. We argue that the ethical obligation to protect animals extends beyond their instrumental value for human benefit; it is rooted in the intrinsic value of their well-being. Consequently, we advocate for a paradigm shift in medical research: the adoption of new approach methodologies (NAMs) not merely as supplementary tools but as complete replacements for animal use in medical studies. In this context, replacement emerges as the key principle—an imperative that should be prioritized over all other considerations.
  • ItemZeitschriftenaufsatzOpen Access
    Improving organ dose sparing in left-sided breast cancer with yaw-limited volumetric modulated arc therapy : a dosimetric comparison to conventional and intensity modulated radiation therapy approaches
    (2025) Pollul, Gerhard; Grossmann, Sascha; Karle, Heiko; Bostel, Tilman; Schmidberger, Heinz
    Background: To assess the dose-sparing capabilities of a yaw-limited volumetric modulated arc therapy (YL_VMAT) beam setup for adjacent organs at risk (OAR) in comparison with 3D-conventional radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT) and conventional VMAT for radiation therapy in left-sided breast cancer patients. Methods: In total, 80 treatment plans for 20 patients, of which 10 patients underwent CT-scans in deep inspiration breath-hold (DIBH) and 10 patients in free-breathing (FB) technique. Besides generally tangential-weighted static and IMRT beams, VMAT treatment plans with approximately 270° arc length have been compared and analyzed to a multi-field, yaw-adapted, unconventional partial VMAT technique retrospectively. The prescription dose was set to 40.05 Gy in 15 fractions. Results: We achieved a more pronounced steeper dose falloff directed from the thoracic wall to the adjacent lung tissue resulting in a significantly better ipsilateral lung and considerably cardiac dose sparing using the YL_VMAT method in general. Compared with standard techniques (IMRT, VMAT, 3D-CRT), YL-VMAT in combination with DIBH can achieve lower mean doses for the heart (1.05 Gy vs. 1.73 Gy, 2.16 Gy and 1.44 Gy), the left anterior descending (LAD) artery (3.68 Gy vs. 6.53 Gy, 5.13 Gy and 8.64 Gy) and the left lung (3.59 Gy vs. 5.39 Gy, 4.79 Gy and 5.87 Gy), respectively. Also with FB, the corresponding mean doses for the left lung and cardiac structures were lower with the YL-VMAT method than with IMRT (heart: 1.70 Gy vs. 2.44 Gy; LAD: 6.50 Gy vs. 11.97 Gy; left lung: 3.10 Gy vs. 4.72 Gy), VMAT (heart: 1.70 Gy vs. 2.52 Gy; LAD: 6.50 Gy vs. 9.06 Gy; left lung: 3.10 Gy vs. 4.46 Gy) and 3D-CRT (heart: 1.70 Gy vs. 2.78 Gy; LAD: 6.50 Gy vs. 15.09 Gy; left lung: 3.10 Gy vs. 5.77 Gy). In addition, we found out superiority of YL_VMAT for the V5, V10, and V20 Gy to the left lung. For DIBH and FB, all differences for the left lung were significant, with p < 0.05. Conclusions: With the YL_VMAT technique, dose exposures to radiosensitive OARs like the lung, heart and LAD artery can be reduced considerably to very low values in comparison to already established planning methods. The benefits must be weighed against the potential risks induced by an increased dose exposure to the contralateral breast.
  • ItemZeitschriftenaufsatzOpen Access
    Pre-analytical pitfalls : how blood collection tubes influence exercise-induced cell-free DNA concentrations
    (2025) Enders, Kira; Hillen, Barlo; Haller, Nils; Brahmer, Alexandra; Weber, Vincent; Simon, Perikles; Neuberger, Elmo W. I.
    Circulating cell-free DNA (cfDNA) is a promising biomarker for physiological stress, including exercise-induced responses. However, the lack of standardization in blood collection tubes (BCTs) for quantification of cfDNA hampers inter-study comparisons. In this study, we assessed the impact of different BCTs on exercise-induced cfDNA dynamics. Eleven participants [25 (SD 2.3) years of age] performed three different treadmill exercise protocols, including an all-out test and combinations of constant and interval load. Blood samples were collected before, 5 min and 30 min post-exercise using EDTA, lithium–heparin (LH) and serum BCTs. Concentrations of cfDNA were quantified using quantitative PCR. The cfDNA increased significantly across all protocols and BCTs. A significant effect of BCT on cfDNA concentrations (P = 0.034) was found, with serum showing higher concentrations than EDTA and LH. Although absolute differences from pre- to post-exercise were comparable across BCTs (P = 0.476), fold changes differed significantly (P = 0.012), with the highest observed in EDTA and the lowest in serum. Bland–Altman analyses demonstrated better agreement between EDTA and LH compared with serum. Significant correlations of cfDNA with energy expenditure and peak oxygen uptake were found. These correlations were stronger in EDTA and LH than in serum. Our findings highlight the crucial influence of BCT choice on cfDNA measurements in exercise settings. Given that EDTA and LH reflected exercise load better, they could be preferred for exercise physiology research. This work underscores the need to account for the choice of BCT to improve data comparability across studies. Additionally, these findings might have broader implications for clinical settings where cfDNA is used as a biomarker.
  • ItemZeitschriftenaufsatzOpen Access
    Differences in tooth development in patients with unilateral cleft lip and palate
    (2025) Schwarting, Marie; Wehrbein, Heinrich; Schmidtmann, Irene; Erbe, Christina; Wriedt, Susanne
    Objectives: The aim of this study was to investigate tooth development in patients with unilateral cleft lip and palate (UCLP) and unilateral cleft lip and alveolus (UCLA). Material and Methods: A retrospective case–control study was carried out; 180 panoramic radiographs (OPGs) from non-syndromic patients (160 UCLP, 20 UCLA) treated at the University Medical Center Mainz (2019–2022) were analyzed. Patients were matched to a control group by calendar age, gender, and ethnicity. Inclusion criteria were verified through clinical data, photographs, and radiographs. No follow-up was conducted for this study. Results: The cleft group showed a significantly lower dental age compared to the control group (10.72 ± 2.65 vs. 11.41 ± 2.79; p = 0.017), with a mean difference of 0.69 years (95% CI: 0.13–1.25 years). Tooth development was slower on the cleft side (p = 0.001), and maxillary teeth lagged behind mandibular teeth (p < 0.001). The difference in the control group was somewhat smaller, with a mean difference of 0.11 degrees of mineralization in the control group compared to 0.25 degrees of mineralization in the cleft group. In UCLP patients, significant mineralization differences were noted for the lateral incisors (p = 0.004), the central incisor (p = 0.047), and canine (p = 0.030). Conclusions: Patients with unilateral clefts show delayed tooth development and dental age, particularly in the affected quadrant. In everyday treatment, attention should be paid to a later start of orthodontic tooth movement to avoid damaging the slower developing roots.
  • ItemZeitschriftenaufsatzOpen Access
    Exploring the effects of gut microbiota on cholangiocarcinoma progression by patient-derived organoids
    (2025) Lederer, Ann-Kathrin; Görrissen, Nele; Nguyen, Tinh Thi; Kreutz, Clemens; Rasel, Hannah; Bartsch, Fabian; Lang, Hauke; Endres, Kristina
    Background Recent research indicates a role of gut microbiota in development and progression of life-threatening diseases such as cancer. Carcinomas of the biliary ducts, the so-called cholangiocarcinomas, are known for their aggressive tumor biology, implying poor prognosis of affected patients. An impact of the gut microbiota on cholangiocarcinoma development and progression is plausible due to the enterohepatic circulation and is therefore the subject of scientific debate, however evidence is still lacking. This review aimed to discuss the suitability of complex cell culture models to investigate the role of gut microbiota in cholangiocarcinoma progression. Main body Clinical research in this area is challenging due to poor comparability of patients and feasibility reasons, which is why translational models are needed to understand the basis of tumor progression in cholangiocarcinoma. A promising approach to investigate the influence of gut microbiota could be an organoid model. Organoids are 3D cell models cultivated in a modifiable and controlled condition, which can be grown from tumor tissue. 3D cell models are able to imitate physiological and pathological processes in the human body and thus contribute to a better understanding of health and disease. Conclusion The use of complex cell cultures such as organoids and organoid co-cultures might be powerful and valuable tools to study not only the growth behavior and growth of cholangiocarcinoma cells, but also the interaction with the tumor microenvironment and with components of the gut microbiota.
  • ItemZeitschriftenaufsatzOpen Access
    Simulator training in focus assessed transthoracic echocardiography (FATE) for undergraduate medical students : results from the FateSim randomized controlled trial
    (2025) Weimer, Johannes Matthias; Sprengart, Franziska Marietta; Vieth, Thomas; Göbel, Sebastian; Dionysopoulou, Anna; Krüger, Rebecca; Beer, Jan; Weimer, Andreas Michael; Buggenhagen, Holger; Kloeckner, Roman; Pillong, Lukas; Helfrich, Johanna; Waezsada, Elias; Wand, Philipp; Weinmann-Menke, Julia
    Introduction Ultrasound is important in heart diagnostics, yet implementing effective cardiac ultrasound requires training. While current strategies incorporate digital learning and ultrasound simulators, the effectiveness of these simulators for learning remains uncertain. This study evaluates the effectiveness of simulator-based versus human-based training in Focused Assessed with Transthoracic Echocardiography (FATE). Materials and methods This single-centre, prospective, randomised controlled study was conducted during an extracurricular FATE workshop (approximately 420 min) for third-year medical students. Participants were randomly assigned to the study group (training solely on simulators) or the control group (training on human subjects). Both groups completed a theory test and a self-assessment questionnaire before the course (T1) and at the end of the training (T2). At T2, all participants also completed two Direct Observation of Procedural Skills (DOPS) tests—one on the simulator (DOPSSim) and one on humans (DOPSHuman). Results Data from 128 participants were analysed (n = 63 study group; n = 65 control group). Both groups exhibited increased competency between the T1 and T2 self-assessments and theory tests (p < 0.01). In the DOPSHuman assessment at T2, the control group performed significantly better (p < 0.001) than the study group. While motivation remained consistently high among both groups, the study group rated their “personal overall learning experience” and the “realistic nature of the training” significantly worse than the control group (p < 0.0001). Both groups supported the use of ultrasound simulators as a “supplement to human training” (study: 1.6 ± 1.1 vs. control: 1.7 ± 1.2; p = 0.38), but not as a “replacement for human training” (study: 5.0 ± 2.3 vs. control: 5.4 ± 2.1; p = 0.37). Conclusion Both simulator- and human-based training effectively developed theoretical and practical skills in FATE. However, the simulator group demonstrated significantly poorer performance when applying their skills to human subjects, indicating limitations in the transferability of this simulator-based training to real-life patient care. These limitations of simulator-based ultrasound training should be considered in future training concepts.
  • ItemZeitschriftenaufsatzOpen Access
    Is it safe to omit any chest X-ray before removing the chest drain after elective, non-cardiac thoracic surgery? A single-center, retrospective, case–control study
    (2025) Karampinis, Ioannis; Reker, Carolin; Grifone, Laura; Souschek, Fabio; Galata, Christian; Stamenovic, Davor; Roessner, Eric
    Background: Every patient undergoing non-cardiac thoracic surgery will receive several chest X-rays through the perioperative period. The patient might receive a preoperative X-ray as a baseline as well as several X-rays before and after drain removal. This routine has several disadvantages, for the patient, the health care system and the medical staff. Purpose of this study was to examine if all X-rays before removal of the drain can be omitted. Methods: Two hundred fifty-five patients who underwent elective thoracic surgery were included in this retrospective analysis. Patients undergoing urgent procedures or empyema surgery, as well as patients with symptoms requiring further diagnostic measures or patients who required clamping of the drain before removal, were excluded. Results: Forty-five patients received an X-ray before removal of the drain, and 210 patients did not. The X-ray group developed significantly more minor complications than the no X-ray group. 46.7% of the X-rays before drain removal (X-ray group) were reported with abnormalities. However, these abnormalities never led to a change in patient care. Drainage time and postoperative hospital stay were significantly longer in the X-ray group. Conclusions: Omitting any X-ray between surgery and removal of the chest drain appears to be safe in our retrospective patient cohort. The proposed benefits of omitting the X-ray are very relevant for the health care system, the medical and nursing teams, and, more importantly, for the patients. Evidence suggests that X-ray of patients regularly do not exist. It is therefore reasonable to consider exploring this question in a formal prospective trial.
  • ItemZeitschriftenaufsatzOpen Access
    The football effect : comparing European identity between fans and non-fans
    (2025) Finger, Tobias; Biel, Jonas; Stockemer, Daniel; Niemann, Arne; Reinke, Vincent; Jungblut, Jens; Kossakowski, Radosław; Llopis-Goig, Ramon; Mańkowski, Dobrosław
    The formation of European identities is a pivotal issue for the cohesion of the European community in times of multiple crises. Based on theories of identity formation through habitualisation, we posit that football fandom—a ubiquitous, emotional, strongly Europeanised activity in everyday life—holds unique potential for fostering a sense of a shared European identity. Football fandom provides habitual contact, interaction and experiences of Europe, shaping fans' European identity formations. We use new representative survey data from four European countries (Germany, Norway, Poland, and Spain) to examine the relationship between football fandom and various dimensions of European identity. The results largely support our hypotheses, demonstrating that football fans exhibit stronger attachments to Europe and the EU, greater support for European integration and a more positive assessment of EU membership than non-fans.
  • ItemZeitschriftenaufsatzOpen Access
    Harnessing orbital Hall effect in spin-orbit torque MRAM
    (2025) Gupta, Rahul; Bouard, Chloé; Kammerbauer, Fabian; Ledesma-Martin, J. Omar; Bose, Arnab; Kononenko, Iryna; Martin, Sylvain; Usé, Perrine; Jakob, Gerhard; Drouard, Marc; Kläui, Mathias
    Spin-Orbit Torque (SOT) Magnetic Random-Access Memory (MRAM) devices offer improved power efficiency, nonvolatility, and performance compared to static RAM, making them ideal, for instance, for cache memory applications. Efficient magnetization switching, long data retention, and high-density integration in SOT MRAM require ferromagnets (FM) with perpendicular magnetic anisotropy (PMA) combined with large torques enhanced by Orbital Hall Effect (OHE). We have engineered a PMA [Co/Ni]3 FM on selected OHE layers (Ru, Nb, Cr) and investigated the potential of theoretically predicted larger orbital Hall conductivity (OHC) to quantify the torque and switching current in OHE/[Co/Ni]3 stacks. Our results demonstrate a ~30% enhancement in damping-like torque efficiency with a positive sign for the Ru OHE layer compared to a pure Pt layer, accompanied by a ~20% reduction in switching current for Ru compared to pure Pt across more than 250 devices, leading to more than a 60% reduction in switching power. These findings validate the application of Ru in devices relevant to industrial contexts, supporting theoretical predictions regarding its superior OHC. This investigation highlights the potential of enhanced orbital torques to improve the performance of orbital-assisted SOT-MRAM, paving the way for next-generation memory technology.
  • ItemZeitschriftenaufsatzOpen Access
    Transcatheter edge-to-edge repair of atrial secondary mitral regurgitation positively influences atrial remodelling
    (2025) Petrescu, Aniela; Geyer, Martin; Gelves Meza, Julian Andres; Hahad, Omar; Ruf, Tobias; de Luca, Valeria Maria; Hobohm, Lukas; Gößler, Theresa; Kreidel, Felix; Lurz, Philipp; von Bardeleben, Ralph Stephan
    Background: Atrial secondary mitral valve regurgitation (ASMR) is a distinct anatomical subset of secondary mitral regurgitation (SMR). Evidence of the effect of transcatheter edge-to-edge repair (TEER) on left atrial (LA) anatomy and function, especially reverse remodelling (LARR), is still sparse. Methods and results: We retrospectively evaluated all consecutive patients treated with TEER for mitral regurgitation (MR) in our centre between January 2013 and October 2023. Of the 597 patients with SMR, 103 patients (17.3%) met the inclusion criteria for ASMR. All patients in the ASMR group (mean age 79.4 ± 6.8 years, 71% female) were symptomatic (89% NYHA ≥ III) and had a mean logistic EuroScore of 22.5 ± 12.4%. TEER was successfully performed in all patients, and invasive LA mean pressures decreased intraprocedurally from 17.8 ± 5.7 to 13.1 ± 4.8 mmHg (P < 0.001). At hospital discharge, 94% of patients had mild residual or non/trace MR. At 1YFUP, the prevalence of residual moderate MR was 7% and 1% had severe MR. A significant reduction in LA volume compared with baseline, both at end-systole (151.4 ± 64 vs. 113 ± 64 mL, P < 0.001) and at end-diastole (119.8 ± 56 vs. 91.2 ± 56.9 mL, P < 0.001) could be observed. Seventy per cent of patients had a sustained decrease in NYHA class ≤ II. LARR, defined as LAESV decrease ≥15% at 1YFUP, was documented in 59% of patients. These patients were more likely to have lower post-interventional mitral valve mean pressure gradients (2.2 ± 0.8 mmHg vs. 2.8 ± 1.1 mmHg, P = 0.02) and lower BNP at discharge and at 1 month follow-up [319 (197.8 to 526) vs. 560 (279.3 to 929), P = 0.07, and 287.5 (191.3 to 386.3) vs. 506.5 (223.3 to 935.5), P = 0.06, respectively]. A multivariate logistic regression analysis identified pre-procedural MPG (P = 0.06, OR 0.92, CI 95% 0.85–1.00) and BNP at discharge (P = 0.11, OR 0.99, CI 95% 0.99–1.00) as independent predictors for the occurrence of LARR at 1 year. Conclusions: Transcatheter mitral valve repair by edge-to-edge therapy represents a safe and effective therapeutic option in symptomatic patients with atrial secondary mitral regurgitation and might have the potential to induce left atrial reverse remodelling.
  • ItemZeitschriftenaufsatzOpen Access
    A subcellular sampling instrument allows spatial resolution of amyloid deposit-derived organelle-specific effects in microglia
    (2025) Subirana Slotos, Robert; Nguyen, Tinh Thi; Fiska, Ledjona; Friedland, Kristina; Endres, Kristina
    Methodological developments in biomedical research are currently moving towards single-cell approaches. This allows for a much better spatial and functional characterization of, for example, the deterioration of cells within a tissue in response to noxae. However, subcellular resolution is also essential to elucidate whether observed impairments are driven by an explicit organelle. Here, we use the Single Cellome™ System SS2000 (Yokogawa) to investigate the local effects of Aβ plaque-like deposits (characteristic for Alzheimer’s disease) on mitochondria in the mouse microglial cell line SIM-A9. First, the specificity of subcellular extraction is demonstrated by detecting subcellular staining and RT-qPCR concerning marker genes by comparing nuclear and mitochondrial samples. Oxygen consumption and gene expression is then assessed in cells near and far from peptide deposits. Mostly, all analyses confirm the high specificity and integrity of the sampled material. In addition, impact of the peptide deposits occur concerning spatial distribution of the cells: e.g., oxygen consumption is only reduced in cells close to Aβ deposits but not in proximity to deposits of biologically inactive Aβ (scrambled) or in far distance. Moreover, a distance-related gene expression pattern occurs, demonstrating the local initiation of mitochondrial changes of microglia when approaching toxic peptide deposits.
  • ItemZeitschriftenaufsatzOpen Access
    First- vs. second-generation autologous platelet concentrates and their implications for wound healing : differences in proteome and secretome
    (2024) Stiller, Hanna L.; Perumal, Natarajan; Manicam, Caroline; Trzeciak, Emily R.; Todt, Julia; Jurk, Kerstin; Tuettenberg, Andrea; Schumann, Sven; Schiegnitz, Eik; Blatt, Sebastian
    Differences in cell count and growth factor expression between first- and second-generation autologous platelet concentrates (APCs) have been well described. The debate over which formula best supports wound healing in various surgical procedures is still ongoing. This study aims to assess the whole proteome assembly, cell content, immunological potential and pro-angiogenic potential of second-generation APC, Platelet-Rich Fibrin (PRF) vs. first-generation APC, Platelet-Rich Plasma (PRP). The global proteome of the APCs was analyzed using nano-liquid chromatography mass spectrometry. Blood cell concentrations were determined by an automated cell counter. The effect of APCs on macrophage polarization was analyzed by flow cytometry. A yolk sac membrane (YSM) assay was used to monitor the neo-vessel formation and capillary branching in vivo. Cell count analysis revealed a higher number/concentration of leukocytes in PRF vs. PRP. Incubation of macrophages with PRP or platelet-free plasma (PFP) did not induce a significant pro-inflammatory state but led to a shift to the M0/M2 phenotype as seen in wound healing for all tested formulas. Label-free proteomics analysis identified a total of 387 proteins from three biological replicates of the respective designated groups. PRF induced increased formation of neo-vessels and branching points in vivo in comparison to PRP and PFP (each p < 0.001), indicating the enhanced pro-angiogenic potential of PRF. Overall, PRF seems superior to PRP, an important representative of first-generation formulas. Inclusion of leucocytes in PRF compared to PRP suggested rather an anti-inflammatory effect on macrophages. These results are important to support the versatile clinical applications in regenerative medicine for second-generation autologous platelet concentrates to optimize wound healing.
  • ItemZeitschriftenaufsatzOpen Access
    Assessing cytotoxicity : a comparative analysis of biodegradable and conventional 3D-printing materials post-steam sterilization for surgical guides
    (2024) Gielisch, Matthias W.; Thiem, Daniel G. E.; Ritz, Ulrike; Bösing, Christoph; Al- Nawas, Bilal; Kämmerer, Peer W.
    Introduction. Ecological concerns and the depletion of petroleum resources have driven the exploration of biodegradable 3D-printing materials derived from bio-renewable sources, such as polylactic acid (PLA) and polyhydroxyalkanoates (PHA). This study aimed to compare the potential cytotoxic effects of a biodegradable PLA/PHA blend filament, a conventional photopolymer (MED610), and a combination of MED610 with a support material (SUP705) before and after steam sterilization in vitro, with a focus on their application in the production of surgical guides. Materials and Methods. PLA/PHA, MED610, and SUP705 (both in their pure and steam-sterilized forms; n = 6 per group) were assessed for their cytotoxic effects on human fibroblasts using the neutral red uptake assay. Positive controls included zinc diethyldithiocarbamate and zinc dibutyldithiocarbamate, while high-density polyethylene served as a negative control. A stock solution of the extraction medium was used as the vehicle control (VC). Results. Significant differences in cell viability were observed between pure PLA/PHA (1.2 ± 0.24) and MED610 (0.94 ± 0.08) (p = 0.005). However, both materials exhibited non-cytotoxicity, with cell viability exceeding 70% compared to VCs. SUP705 (0.58 ± 0.42) demonstrated significantly reduced cell viability compared to PLA/PHA (p = 0.001) and MED610 (p = 0.007). After steam sterilization, no significant difference in cell viability was noted between MED610 (1.0 ± 0.08) and PLA/PHA (1.2 ± 0.25) (p = 0.111). While both materials remained non-cytotoxic after sterilization, SUP705 (0.60 ± 0.45) exhibited cytotoxic effects compared to MED610 (p = 0.006) and PLA/PHA (p < 0.001). Steam sterilization did not induce significant cytotoxic effects in the investigated materials (p = 0.123). Conclusion. Pure and steam-sterilized PLA/PHA and MED610 were not cytotoxic, supporting their potential use in the production of surgical guides. However, the observed cytotoxicity of SUP705 suggests caution in scenarios requiring sterile conditions, as the removal of support material from complex printed parts may be challenging. The consideration of PLA/PHA is recommended in such settings to ensure biocompatibility.
  • ItemZeitschriftenaufsatzOpen Access
    A 3D-printed dummy for training distal phalanx amputation in mice
    (2024) Heuser, Miriam; Gonzalez-Uarquin, Fernando; Nuber, Maximilian; Brockmann, Marc A.; Baumgart, Jan; Baumgart, Nadine
    The development of realistic dummies for training the distal phalanx amputation (DPA) technique in mouse pups is a promising alternative to reduce and replace animals in training for research and teaching. To test this, we obtained micro-CT data from postnatal day-five mouse pups, meticulously segmented them, and converted them into a 3D mesh format suitable for 3D printing. Once the dummy was printed, it was evaluated during actual training courses in two different groups: in the first group, users received no dummies to train the DPA, and in the second group, users were trained with three dummies. To assess the effectiveness of the dummy, we conducted a survey followed by an expert veterinarian evaluation. Our results showed that DPA is a complex procedure, and it is commonly poorly performed. When implementing the dummies, users who were not provided with dummies to practice only had an 8.3% success rate in DPA, while users provided with three dummies had a 45.5% success rate, respectively. Despite additional research being needed, our dummy offered improved practical training by providing a safe and effective alternative in line with ethical considerations while demonstrating the feasibility of using 3D printing technology to promote the 3Rs in experimental research.
  • ItemZeitschriftenaufsatzOpen Access
    Growth of renal cancer cell lines is strongly inhibited by synergistic activity of low-dosed amygdalin and sulforaphane
    (2024) Markowitsch, Sascha D.; Pham, Thao; Rutz, Jochen; Chun, Felix K.-H.; Haferkamp, Axel; Tsaur, Igor; Juengel, Eva; Ries, Nathalie; Thomas, Anita; Blaheta, Roman A.
    Background: Plant derived isolated compounds or extracts enjoy great popularity among cancer patients, although knowledge about their mode of action is unclear. The present study investigated whether the combination of two herbal drugs, the cyanogenic diglucoside amygdalin and the isothiocyanate sulforaphane (SFN), influences growth and proliferation of renal cell carcinoma (RCC) cell lines. Methods: A498, Caki-1, and KTCTL-26 cells were exposed to low-dosed amygdalin (1 or 5 mg/mL), or SFN (5 µM) or to combined SFN-amygdalin. Tumor growth and proliferation were analyzed by MTT, BrdU incorporation, and clone formation assays. Cell cycle phases and cell cycle-regulating proteins were analyzed by flow cytometry and Western blotting, respectively. The effectiveness of the amygdalin–SFN combination was determined using the Bliss independence model. Results: 1 mg/mL amygdalin or 5 µM SFN, given separately, did not suppress RCC cell growth, and 5 mg/mL amygdalin only slightly diminished A498 (but not Caki-1 and KTCTL-26) cell growth. However, already 1 mg/mL amygdalin potently inhibited growth of all tumor cell lines when combined with SFN. Accordingly, 1 mg/mL amygdalin suppressed BrdU incorporation only when given together with SFN. Clonogenic growth was also drastically reduced by the drug combination, whereas only minor effects were seen under single drug treatment. Superior efficacy of co-treatment, compared to monodrug exposure, was also seen for cell cycling, with an enhanced G0/G1 and diminished G2/M phase in A498 cells. Cell cycle regulating proteins were altered differently, depending on the applied drug schedule (single versus dual application) and the RCC cell line, excepting phosphorylated Akt which was considerably diminished in all three cell lines with maximum effects induced by the drug combination. The Bliss independence analysis verified synergistic interactions between amygdalin and SFN. Conclusions: These results point to synergistic effects of amygdalin and SFN on RCC cell growth and clone formation and Akt might be a relevant target protein. The combined use of low-dosed amygdalin and SFN could, therefore, be beneficial as a complementary option to treat RCC. To evaluate clinical feasibility, the in vitro protocol must be applied to an in vivo model.
  • ItemZeitschriftenaufsatzOpen Access
    Survey of physicians and healers using amygdalin to treat cancer patients
    (2024) Markowitsch, Sascha D.; Binali, Sali; Rutz, Jochen; Chun, Felix K.-H.; Haferkamp, Axel; Tsaur, Igor; Juengel, Eva; Fischer, Nikita D.; Thomas, Anita; Blaheta, Roman A.
    Amygdalin is purported to exhibit anti-cancer properties when hydrolyzed to hydrogen cyanide (HCN). However, knowledge about amygdalin efficacy is limited. A questionnaire evaluating the efficacy, treatment, and dosing protocols, reasons for use, HCN levels, and toxicity was distributed to physicians and healers in Germany, providing amygdalin as an anti-cancer drug. Physicians (20) and healers (18) provided amygdalin over 8 (average) years to nearly 80 annually treated patients/providers. Information about amygdalin was predominantly obtained from colleagues (55%). Amygdalin was administered both intravenously (100%) and orally (32%). Intravenous application was considered to maximally delay disease progression (90%) and relieve symptoms (55%). Dosing was based on recommendations from colleagues (71%) or personal experience (47%). If limited success became apparent after an initial 3g/infusion, infusions were increased to 27g/infusion. Treatment response was primarily monitored with established (26%) and non-established tumor markers (19%). 90% did not monitor HCN levels. Negative effects were restricted to a few dizzy spells and nausea. Only 58% were willing to participate in clinical trials or contribute data for analysis (34%). Amygdalin infusions are commonly administered by healers and physicians with few side effects. The absence of standardized treatment calls for guidelines. Since intravenous application bypasses metabolization, re-evaluation of its mode of action is required.
  • ItemZeitschriftenaufsatzOpen Access
    ALDH1A3 contributes to radiation-induced inhibition of self-renewal and promotes proliferative activity of p53-deficient glioblastoma stem cells at the onset of differentiation
    (2024) Müller, Andreas; Lyubarskyy, Bogdan; Tchoumakov, Jurij; Wagner, Maike; Sprang, Bettina; Ringel, Florian; Kim, Ella L.
    ALDH1A3 is a marker for mesenchymal glioblastomas characterized by a greater degree of aggressiveness compared to other major subtypes. ADH1A3 has been implicated in the regula- tion of stemness and radioresistance mediated by glioblastoma stem cells. Mechanisms by which ALDH1A3 promotes malignant progression of glioblastoma remain elusive posing a challenge for rationalization of ALDH1A3 targeting in glioblastoma, and it is also unclear how ALDH1A3 regulates glioblastoma cells stemness. Usage of different models with diverse genetic backgrounds and often unknown degree of stemness is one possible reason for discrepant views on the role of ALDH1A3 in glioblastoma stem cells. This study clarifies ALDH1A3 impacts on glioblastoma stem cells by modelling ALDH1A3 expression in an otherwise invariable genetic background with consideration of the impacts of inherent plasticity and proliferative changes associated with transitions between cell states. Our main finding is that ALDH1A3 exerts cell-state dependent impact on proliferation of glioblastoma stem cells. We provide evidence that ALDH1A3 augments radiation-induced inhibition of self-renewal and promotes the proliferation of differentiated GSC progenies. Congruent effects ALDH1A3 and radiation on self-renewal and proliferation provides a framework for promoting glioblastoma growth under radiation treatment.