@article{VikukFuchsKrischkeetal.2020, author = {Vikuk, Veronika and Fuchs, Benjamin and Krischke, Markus and Mueller, Martin J. and Rueb, Selina and Krauss, Jochen}, title = {Alkaloid Concentrations of Lolium perenne Infected with Epichlo{\"e} festucae var. lolii with Different Detection Methods—A Re-Evaluation of Intoxication Risk in Germany?}, series = {Journal of Fungi}, volume = {6}, journal = {Journal of Fungi}, number = {3}, issn = {2309-608X}, doi = {10.3390/jof6030177}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213171}, year = {2020}, abstract = {Mycotoxins in agriculturally used plants can cause intoxication in animals and can lead to severe financial losses for farmers. The endophytic fungus Epichlo{\"e} festucae var. lolii living symbiotically within the cool season grass species Lolium perenne can produce vertebrate and invertebrate toxic alkaloids. Hence, an exact quantitation of alkaloid concentrations is essential to determine intoxication risk for animals. Many studies use different methods to detect alkaloid concentrations, which complicates the comparability. In this study, we showed that alkaloid concentrations of individual plants exceeded toxicity thresholds on real world grasslands in Germany, but not on the population level. Alkaloid concentrations on five German grasslands with high alkaloid levels peaked in summer but were also below toxicity thresholds on population level. Furthermore, we showed that alkaloid concentrations follow the same seasonal trend, regardless of whether plant fresh or dry weight was used, in the field and in a common garden study. However, alkaloid concentrations were around three times higher when detected with dry weight. Finally, we showed that alkaloid concentrations can additionally be biased to different alkaloid detection methods. We highlight that toxicity risks should be analyzed using plant dry weight, but concentration trends of fresh weight are reliable.}, language = {en} } @article{BrachnerFragouliDuarteetal.2020, author = {Brachner, Andreas and Fragouli, Despina and Duarte, Iola F. and Farias, Patricia M. A. and Dembski, Sofia and Ghosh, Manosij and Barisic, Ivan and Zdzieblo, Daniela and Vanoirbeek, Jeroen and Schwabl, Philipp and Neuhaus, Winfried}, title = {Assessment of human health risks posed by nano-and microplastics is currently not feasible}, series = {International Journal of Environmental Research and Public Health}, volume = {17}, journal = {International Journal of Environmental Research and Public Health}, number = {23}, issn = {1660-4601}, doi = {10.3390/ijerph17238832}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219423}, year = {2020}, abstract = {The exposure of humans to nano-and microplastic particles (NMPs) is an issue recognized as a potential health hazard by scientists, authorities, politics, non-governmental organizations and the general public. The concentration of NMPs in the environment is increasing concomitantly with global plastic production and the usage of plastic materials. NMPs are detectable in numerous aquatic organisms and also in human samples, therefore necessitating a risk assessment of NMPs for human health. So far, a comprehensive risk assessment of NMPs is hampered by limited availability of appropriate reference materials, analytical obstacles and a lack of definitions and standardized study designs. Most studies conducted so far used polystyrene (PS) spheres as a matter of availability, although this polymer type accounts for only about 7\% of total plastic production. Differently sized particles, different concentration and incubation times, and various biological models have been used, yielding hardly comparable data sets. Crucial physico-chemical properties of NMPs such as surface (charge, polarity, chemical reactivity), supplemented additives and adsorbed chemicals have been widely excluded from studies, although in particular the surface of NMPs determines the interaction with cellular membranes. In this manuscript we give an overview about the critical parameters which should be considered when performing risk assessments of NMPs, including novel reference materials, taking into account surface modifications (e.g., reflecting weathering processes), and the possible role of NMPs as a substrate and/or carrier for (pathogenic) microbes. Moreover, we make suggestions for biological model systems to evaluate immediate toxicity, long-term effects and the potential of NMPs to cross biological barriers. We are convinced that standardized reference materials and experimental parameters along with technical innovations in (nano)-particle sampling and analytics are a prerequisite for the successful realization of conclusive human health risk assessments of NMPs.}, language = {en} } @article{DiefenhardtMartinLudmiretal.2022, author = {Diefenhardt, Markus and Martin, Daniel and Ludmir, Ethan B. and Fleischmann, Maximilian and Hofheinz, Ralf-Dieter and Ghadimi, Michael and Kosmala, Rebekka and Polat, B{\"u}lent and Friede, Tim and Minsky, Bruce D. and R{\"o}del, Claus and Fokas, Emmanouil}, title = {Development and validation of a predictive model for toxicity of neoadjuvant chemoradiotherapy in rectal cancer in the CAO/ARO/AIO-04 phase III trial}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {18}, issn = {2072-6694}, doi = {10.3390/cancers14184425}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288081}, year = {2022}, abstract = {Background: There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer. Patient and Methods: The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3-4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated. Results: In the development cohort, 155 patients developed grade 3-4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (p < 0.001). Rates of toxicity (p = 0.001) and low treatment adherence (p = 0.007) remained significantly different in the validation cohort, whereas discrimination ability was not significantly worse (DeLong test 0.09). Conclusion: We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making.}, language = {en} } @article{ToppvanMeertenHouotetal.2021, author = {Topp, Max S. and van Meerten, Tom and Houot, Roch and Minnema, Monique C. and Bouabdallah, Krimo and Lugtenburg, Pieternella J. and Thieblemont, Catherine and Wermke, Martin and Song, Kevin W. and Avivi, Irit and Kuruvilla, John and D{\"u}hrsen, Ulrich and Zheng, Yan and Vardhanabhuti, Saran and Dong, Jinghui and Bot, Adrian and Rossi, John M. and Plaks, Vicki and Sherman, Marika and Kim, Jenny J. and Kerber, Anne and Kersten, Marie Jos{\´e}}, title = {Earlier corticosteroid use for adverse event management in patients receiving axicabtagene ciloleucel for large B-cell lymphoma}, series = {British Journal of Haematology}, volume = {195}, journal = {British Journal of Haematology}, number = {3}, doi = {10.1111/bjh.17673}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258342}, pages = {388-398}, year = {2021}, abstract = {Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel-related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93\% and 61\%, respectively (grade ≥ 3, 2\% and 17\%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73\% and 51\%, respectively, and 51\% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel.}, language = {en} } @article{KraussVikukYoungetal.2020, author = {Krauss, Jochen and Vikuk, Veronika and Young, Carolyn A. and Krischke, Markus and Mueller, Martin J. and Baerenfaller, Katja}, title = {Epichlo{\"e} endophyte infection rates and alkaloid content in commercially available grass seed mixtures in Europe}, series = {Microorganisms}, volume = {8}, journal = {Microorganisms}, number = {4}, issn = {2076-2607}, doi = {10.3390/microorganisms8040498}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203323}, pages = {498}, year = {2020}, abstract = {Fungal endophytes of the genus Epichlo{\"e} live symbiotically in cool season grass species and can produce alkaloids toxic to insects and vertebrates, yet reports of intoxication of grazing animals have been rare in Europe in contrast to overseas. However, due to the beneficial resistance traits observed in Epichlo{\"e} infected grasses, the inclusion of Epichlo{\"e} in seed mixtures might become increasingly advantageous. Despite the toxicity of fungal alkaloids, European seed mixtures are rarely tested for Epichlo{\"e} infection and their infection status is unknown for consumers. In this study, we tested 24 commercially available seed mixtures for their infection rates with Epichlo{\"e} endophytes and measured the concentrations of the alkaloids ergovaline, lolitrem B, paxilline, and peramine. We detected Epichlo{\"e} infections in six seed mixtures, and four contained vertebrate and insect toxic alkaloids typical for Epichlo{\"e} festucae var. lolii infecting Lolium perenne. As Epichlo{\"e} infected seed mixtures can harm livestock, when infected grasses become dominant in the seeded grasslands, we recommend seed producers to test and communicate Epichlo{\"e} infection status or avoiding Epichlo{\"e} infected seed mixtures.}, language = {en} } @article{KochPetzoldWesselyetal.2022, author = {Koch, Elias A. T. and Petzold, Anne and Wessely, Anja and Dippel, Edgar and Gesierich, Anja and Gutzmer, Ralf and Hassel, Jessica C. and Haferkamp, Sebastian and K{\"a}hler, Katharina C. and Knorr, Harald and Kreuzberg, Nicole and Leiter, Ulrike and Loquai, Carmen and Meier, Friedegund and Meissner, Markus and Mohr, Peter and Pf{\"o}hler, Claudia and Rahimi, Farnaz and Schadendorf, Dirk and Schell, Beatrice and Schlaak, Max and Terheyden, Patrick and Thoms, Kai-Martin and Schuler-Thurner, Beatrice and Ugurel, Selma and Ulrich, Jens and Utikal, Jochen and Weichenthal, Michael and Ziller, Fabian and Berking, Carola and Heppt, Markus V.}, title = {Immune checkpoint blockade for metastatic uveal melanoma: re-induction following resistance or toxicity}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {3}, issn = {2072-6694}, doi = {10.3390/cancers14030518}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254814}, year = {2022}, abstract = {Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95\% CI: 11.1-23.8) versus 9.4 months (cohort B, 95\% CI: 6.1-14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities.}, language = {en} } @article{WagenbrennerHeinzHorasetal.2020, author = {Wagenbrenner, Mike and Heinz, Tizian and Horas, Konstantin and Jakuscheit, Axel and Arnholdt, Joerg and Mayer-Wagner, Susanne and Rudert, Maximilian and Holzapfel, Boris M. and Weißenberger, Manuel}, title = {Impact of Tranexamic Acid on Chondrocytes and Osteogenically Differentiated Human Mesenchymal Stromal Cells (hMSCs) In Vitro}, series = {Journal of Clinical Medicine}, volume = {9}, journal = {Journal of Clinical Medicine}, number = {12}, issn = {2077-0383}, doi = {10.3390/jcm9123880}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219410}, year = {2020}, abstract = {The topical application of tranexamic acid (TXA) helps to prevent post-operative blood loss in total joint replacements. Despite these findings, the effects on articular and periarticular tissues remain unclear. Therefore, this in vitro study examined the effects of varying exposure times and concentrations of TXA on proliferation rates, gene expression and differentiation capacity of chondrocytes and human mesenchymal stromal cells (hMSCs), which underwent osteogenic differentiation. Chondrocytes and hMSCs were isolated and multiplied in monolayer cell cultures. Osteogenic differentiation of hMSCs was induced for 21 days using a differentiation medium containing specific growth factors. Cell proliferation was analyzed using ATP assays. Effects of TXA on cell morphology were examined via light microscopy and histological staining, while expression levels of tissue-specific genes were measured using semiquantitative RT-PCR. After treatment with 50 mg/mL of TXA, a decrease in cell proliferation rates was observed. Furthermore, treatment with concentrations of 20 mg/mL of TXA for at least 48 h led to a visible detachment of chondrocytes. TXA treatment with 50 mg/mL for at least 24 h led to a decrease in the expression of specific marker genes in chondrocytes and osteogenically differentiated hMSCs. No significant effects were observed for concentrations beyond 20 mg/mL of TXA combined with exposure times of less than 24 h. This might therefore represent a safe limit for topical application in vivo. Further research regarding in vivo conditions and effects on hMSC functionality are necessary to fully determine the effects of TXA on articular and periarticular tissues.}, language = {en} } @article{RadeloffRadeloffTiradoetal.2019, author = {Radeloff, Katrin and Radeloff, Andreas and Tirado, Mario Ramos and Scherzad, Agmal and Hagen, Rudolf and Kleinsasser, Norbert H. and Hackenberg, Stephan}, title = {Long-Term Impact of Zinc Oxide Nanoparticles on Differentiation and Cytokine Secretion of Human Adipose-Derived Stromal Cells}, series = {Materials}, volume = {12}, journal = {Materials}, number = {1823}, doi = {10.3390/ma12111823}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224779}, pages = {1-14}, year = {2019}, abstract = {Zinc oxide nanoparticles (ZnO-NPs) are widely utilized, for example in manufacturing paints and in the cosmetic industry. In addition, there is raising interest in the application of NPs in stem cell research. However, cytotoxic, genotoxic and pro-inflammatory effects were shown for NPs. The aim of this study was to evaluate the impact of ZnO-NPs on cytokine secretion and differentiation properties of human adipose tissue-derived stromal cells (ASCs). Human ASCs were exposed to the subtoxic concentration of 0.2 mu g/mL ZnO-NPs for 24 h. After four weeks of cultivation, adipogenic and osteogenic differentiation procedures were performed. The multi-differentiation potential was confirmed histologically and using polymerase chain reaction (PCR). In addition, the gene expression of IL-6, IL-8, vascular endothelial growth factor (VEGF) and caspase 3 was analyzed. Over the course of four weeks after ZnO-NPs exposure, no significant differences were detected in the gene expression of IL-6, IL-8, VEGF and caspase 3 compared to non-exposed cells. The differentiation was also not affected by the ZnO-NPs. These findings underline the fact, that functionality of ASCs is likely to be unaffected by ZnO-NPs, despite a long-term disposition of NPs in the cells, supposing that the starting concentration was safely in the non-toxic range. This might provide important information for single-use nanomedical applications of ZnO-NPs.}, language = {en} } @article{TamihardjaLawrenzLutyjetal.2022, author = {Tamihardja, J{\"o}rg and Lawrenz, Ingulf and Lutyj, Paul and Weick, Stefan and Guckenberger, Matthias and Polat, B{\"u}lent and Flentje, Michael}, title = {Propensity score-matched analysis comparing dose-escalated intensity-modulated radiation therapy versus external beam radiation therapy plus high-dose-rate brachytherapy for localized prostate cancer}, series = {Strahlentherapie und Onkologie}, volume = {198}, journal = {Strahlentherapie und Onkologie}, number = {8}, doi = {10.1007/s00066-022-01953-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325055}, pages = {735-743}, year = {2022}, abstract = {Purpose Dose-escalated external beam radiation therapy (EBRT) and EBRT + high-dose-rate brachytherapy (HDR-BT) boost are guideline-recommended treatment options for localized prostate cancer. The purpose of this study was to compare long-term outcome and toxicity of dose-escalated EBRT versus EBRT + HDR-BT boost. Methods From 2002 to 2019, 744 consecutive patients received either EBRT or EBRT + HDR-BT boost, of whom 516 patients were propensity score matched. Median follow-up was 95.3 months. Cone beam CT image-guided EBRT consisted of 33 fractions of intensity-modulated radiation therapy with simultaneous integrated boost up to 76.23 Gy (D\(_{Mean}\)). Combined treatment was delivered as 46 Gy (D\(_{Mean}\)) EBRT, followed by two fractions HDR-BT boost with 9 Gy (D\(_{90\\%}\)). Propensity score matching was applied before analysis of the primary endpoint, estimated 10-year biochemical relapse-free survival (bRFS), and the secondary endpoints metastasis-free survival (MFS) and overall survival (OS). Prognostic parameters were analyzed by Cox proportional hazard modelling. Genitourinary (GU)/gastrointestinal (GI) toxicity evaluation used the Common Toxicity Criteria for Adverse Events (v5.0). Results The estimated 10-year bRFS was 82.0\% vs. 76.4\% (p = 0.075) for EBRT alone versus combined treatment, respectively. The estimated 10-year MFS was 82.9\% vs. 87.0\% (p = 0.195) and the 10-year OS was 65.7\% vs. 68.9\% (p = 0.303), respectively. Cumulative 5‑year late GU ≥ grade 2 toxicities were seen in 23.6\% vs. 19.2\% (p = 0.086) and 5‑year late GI ≥ grade 2 toxicities in 11.1\% vs. 5.0\% of the patients (p = 0.002); cumulative 5‑year late grade 3 GU toxicity occurred in 4.2\% vs. 3.6\% (p = 0.401) and GI toxicity in 1.0\% vs. 0.3\% (p = 0.249), respectively. Conclusion Both treatment groups showed excellent long-term outcomes with low rates of severe toxicity.}, language = {en} } @article{SchneiderTautzGruenewaldetal.2012, author = {Schneider, Christof W. and Tautz, J{\"u}rgen and Gr{\"u}newald, Bernd and Fuchs, Stefan}, title = {RFID Tracking of Sublethal Effects of Two Neonicotinoid Insecticides on the Foraging Behavior of Apis mellifera}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {1}, doi = {10.1371/journal.pone.0030023}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131753}, pages = {e30023}, year = {2012}, abstract = {The development of insecticides requires valid risk assessment procedures to avoid causing harm to beneficial insects and especially to pollinators such as the honeybee Apis mellifera. In addition to testing according to current guidelines designed to detect bee mortality, tests are needed to determine possible sublethal effects interfering with the animal's vitality and behavioral performance. Several methods have been used to detect sublethal effects of different insecticides under laboratory conditions using olfactory conditioning. Furthermore, studies have been conducted on the influence insecticides have on foraging activity and homing ability which require time-consuming visual observation. We tested an experimental design using the radiofrequency identification (RFID) method to monitor the influence of sublethal doses of insecticides on individual honeybee foragers on an automated basis. With electronic readers positioned at the hive entrance and at an artificial food source, we obtained quantifiable data on honeybee foraging behavior. This enabled us to efficiently retrieve detailed information on flight parameters. We compared several groups of bees, fed simultaneously with different dosages of a tested substance. With this experimental approach we monitored the acute effects of sublethal doses of the neonicotinoids imidacloprid (0.15-6 ng/bee) and clothianidin (0.05-2 ng/bee) under field-like circumstances. At field-relevant doses for nectar and pollen no adverse effects were observed for either substance. Both substances led to a significant reduction of foraging activity and to longer foraging flights at doses of >= 0.5 ng/bee (clothianidin) and >= 1.5 ng/bee (imidacloprid) during the first three hours after treatment. This study demonstrates that the RFID-method is an effective way to record short-term alterations in foraging activity after insecticides have been administered once, orally, to individual bees. We contribute further information on the understanding of how honeybees are affected by sublethal doses of insecticides.}, language = {en} }