Learning foreign language vocabulary with gestures and pictures enhances vocabulary memory for several months post-learning in eight-year-old school children

Funding Information: This work was funded by the German Research Foundation grant KR 3735/3-1, a Schulbezogene Forschung grant from the Saxony Zentrum für Lehrerbildung und Schulforschung (ZLS), and an Erasmus Mundus Postdoctoral Fellowship in Auditory Cognitive Neuroscience. B.M. is also supported by the European Research Council Consolidator Grant SENSOCOM 647051 to K.v.K. Acknowledgments Open access funding provided by Projekt DEAL. We thank Julia Schwerin for assistance with planning and preparing the study, as well as serving as a teacher to the children in two experiments.Peer reviewedPublisher PD

MicroRNA expression after ionizing radiation in human endothelial cells

<p>Abstract</p> <p>Background</p> <p>Endothelial cells (EC) in tumor and normal tissue constitute critical radiotherapy targets. MicroRNAs have emerged as master switchers of the cellular transcriptome. Here, we seek to investigate the role of miRNAs in primary human dermal microvascular endothelial cells (HDMEC) after ionizing radiation.</p> <p>Methods</p> <p>The microRNA status in HDMEC after 2 Gy radiation treatment was measured using oligo-microarrays covering 361 miRNAs. To functionally analyze the role of radiation-induced differentially regulated miRNAs, cells were transfected with miRNA precursor or inhibitor constructs. Clonogenic survival and proliferation assays were performed.</p> <p>Results</p> <p>Radiation up-regulated miRNA expression levels included let-7g, miR-16, miR-20a, miR-21 and miR-29c, while miR-18a, miR-125a, miR-127, miR-148b, miR-189 and miR-503 were down-regulated. We found that overexpression or inhibition of let-7g, miR-189, and miR-20a markedly influenced clonogenic survival and cell proliferation per se. Notably, the radiosensitivity of HDMEC was significantly influenced by differential expression of miR-125a, -127, -189, and let-7g. While miR-125a and miR-189 had a radioprotective effect, miR-127 and let-7g enhanced radiosensitivity in human endothelial cells.</p> <p>Conclusion</p> <p>Our data show that ionizing radiation changes microRNA levels in human endothelial cells and, moreover, exerts biological effects on cell growth and clonogenicity as validated in functional assays. The data also suggest that the miRNAs which are differentially expressed after radiation modulate the intrinsic radiosensitivity of endothelial cells in subsequent irradiations. This indicates that miRNAs are part of the innate response mechanism of the endothelium to radiation.</p

Oncogene addiction and radiation oncology: effect of radiotherapy with photons and carbon ions in ALK-EML4 translocated NSCLC

Background: Patients with Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) positive lung cancer are sensitive to ALK-kinase inhibitors. TAE684 is a potent second generation ALK inhibitor that overcomes Crizotinib resistance. Radiotherapy is an integral therapeutic component of locally advanced lung cancer. Therefore, we sought to investigate the effects of combined radiotherapy and ALK-inhibition via TAE684 in ALK-positive vs. wild type lung cancer cells. Methods: Human non-small cell lung cancer (NSCLC) cell lines harboring wild-type ALK (A549), EML4-ALK translocation (H3122) and murine Lewis Lung Cancer (LLC) cells were investigated. Cells were irradiated with 1–4 Gy X-Rays (320 keV) and carbon ions (Spread-out Bragg Peak, SOBP (245.4–257.0 MeV/u)) at Heidelberg Ion Therapy center. TAE684 was administered at the dose range 0–100 nM. Clonogenic survival, proliferation and apoptosis via caspase 3/7 expression level were assessed in all three cell lines using time-lapse live microscopy. Results: TAE684 inhibited the proliferation of H3122 cells in a dose-dependent manner with a half maximal inhibitory concentration (IC50) of ~ 8.2 nM. However, A549 and LLC cells were relatively resistant to TAE684 and IC50 was not reached at concentrations tested (up to 100 nM) in proliferation assay. The antiproliferative effect of TAE684 was augmented by radiotherapy in H3122 cells. TAE684 significantly sensitized H3122 cells to particle therapy with carbon ions (sensitizer enhancement ratio ~1.61, p &lt; 0.05). Caspase 3/7 activity was evidently enhanced after combination therapy in H3122 cells. Conclusions: This is the first report demonstrating synergistic effects of combined TAE684 and radiotherapy in EML4-ALK positive lung cancer cells. In addition to conventional photon radiotherapy, ALK-inhibition also enhanced the effects of particle irradiation using carbon ions. Our data indicate beneficial effects of combined ALK-inhibition and radiotherapy in treatment of this distinct subpopulation of NSCLC that warrant further evaluation

Lipophilic Allergens, Different Modes of Allergen-Lipid Interaction and Their Impact on Asthma and Allergy

Molecular allergology research has provided valuable information on the structure and function of single allergenic molecules. There are several allergens in food and inhalant allergen sources that are able to interact with lipid ligands via different structural features: hydrophobic pockets, hydrophobic cavities, or specialized domains. For only a few of these allergens information on their associated ligands is already available. Several of the allergens are clinically relevant, so that it is highly probable that the individual structural features with which they interact with lipids have a direct effect on their allergenic potential, and thus on allergy development. There is some evidence for a protective effect of lipids delaying the enzymatic digestion of the peanut (Arachis hypogaea) allergen Ara h 8 (hydrophobic pocket), probably allowing this molecule to get to the intestinal immune system intact (sensitization). Oleosins from different food allergen sources are part of lipid storage organelles and potential marker allergens for the severity of the allergic reaction. House dust mite (HDM), is more often associated with allergic asthma than other sources of inhalant allergens. In particular, lipid-associated allergens from Dermatophagoides pteronyssinus which are Der p 2, Der p 5, Der p 7, Der p 13, Der p 14, and Der p 21 have been reported to be associated with severe allergic reactions and respiratory symptoms such as asthma. The exact mechanism of interaction of these allergens with lipids still has to be elucidated. Apart from single allergens glycolipids have been shown to directly induce allergic inflammation. Several—in parts conflicting—data exist on the lipid (and allergen) and toll-like receptor interactions. For only few single allergens mechanistic studies were performed on their interaction with the air-liquid interface of the lungs, in particular with the surfactant components SP-A and SP-D. The increasing knowledge on protein-lipid-interaction for lipophilic and hydrophobic food and inhalant allergens on the basis of their particular structure, of their capacity to be integral part of membranes (like the oleosins), and their ability to interact with membranes, surfactant components, and transport lipids (like the lipid transfer proteins) are essential to eventually clarify allergy and asthma development

Determination of habitat requirements of the glacial relict Nuphar pumila as basis for successful (re-)introductions

Nuphar pumila is a glacial relict, which is nowadays rare throughout Europe and red-listed in most European regions. In Switzerland only three autochthonous populations and one population of the hybrid with N. lutea (N. ×spenneriana) have survived to date, one of them in the canton of Zurich. To protect this species regionally, the canton of Zurich has commissioned the ex situ propagation of speci-mens, which then had been introduced to 37 water bodies in protected areas, including one known former site. Since only about 10% of these introductions had been successful, there was a wish to identify causes of this lack of success. To this end, we compared the vegetation and physical-chemical parameters of the four natural sites in Switzerland with the successful and unsuccessful introduction sites. Additionally, for a subset of sites, we assessed diatom genus composition as a proxy of water quality. Moreover, we derived vegetation plots of N. pumila and N. lutea from across Europe from the European Vegetation Archive (EVA) to compare their site conditions, using mean ecological indicator values and bioclimatic variables of the localities. We found that inside Switzerland the main differences were between the natural sites and all introduction sites, while successful and unsuccessful introduction sites hardly differed in the determined parameters. Natural sites had cooler water with lower magnesi-um content, and according to mean ecological indicator values, also lower nutrient status. The diatom data, though limited in amount, point into the same direction. The EVA data demonstrate that stands of N. pumila are mainly more oligotrophic, but also cooler and more acidic than those of N. lutea. We could not find any factor that explains the success vs. lack of success of plantations of N. pumila in multiple sites in the canton of Zurich, but our results rather indicate that due to the relatively warm climate, the high atmogenic nitrogen input and the predominantly base-rich bedrock, the sites in the canton are generally not particularly well suited for N. pumila. We consider it therefore more promising to protect and possibly (re-)introduce N. pumila in other cantons with higher elevation, base-poor bedrock and lower atmogenic nitrogen input

TableButler – a Windows based tool for processing large data tables generated with high-throughput methods

<p>Abstract</p> <p>Background</p> <p>High-throughput "omics" based data analysis play emerging roles in life sciences and molecular diagnostics. This emphasizes the urgent need for user-friendly windows-based software interfaces that could process the diversity of large tab-delimited raw data files generated by these methods. Depending on the study, dozens to hundreds of these data tables are generated. Before the actual statistical or cluster analysis, these data tables have to be combined and merged to expression matrices (e.g., in case of gene expression analysis). Gene annotations as well as information concerning the samples analyzed may be appended, renewed or extended. Often additional data values shall be computed or certain features must be filtered out.</p> <p>Results</p> <p>In order to perform these tasks, we have developed a Microsoft Windows based application, "<b><it>TableButler</it></b>", which allows biologists or clinicians without substantial bioinformatics background to perform a plethora of data processing tasks required to analyze the large-scale data.</p> <p>Conclusion</p> <p><b><it>TableButler </it></b>is a monolithic Windows application. It is implemented to handle, join and preprocess large tab delimited ASCII data files. The intuitive user interface enables scientists (e.g. biologists, clinicians or others) to setup workflows for their specific problems by simple drag-and drop like operations.</p> <p>For more details about <b><it>TableButler</it></b>, visit <url>http://www.OncoExpress.org/software/tablebutler</url>.</p

Retrospective Analysis of Treatment Pathways in Patients With BRAFV600E-mutant Metastatic Colorectal Carcinoma - MORSECRC.

BACKGROUND/AIM Metastatic colorectal cancer (mCRC) is a heterogeneous disease with distinct molecular subtypes. The BRAFV600E-mutation found in approximately 8-12% of mCRC patients is associated with poor prognosis. Guideline recommendations for this population are mostly based on small cohorts due to lack of clinical data. This retrospective analysis was designed to evaluate (approved) therapeutic approaches and algorithms in BRAFV600E-mutant mCRC prior to approval of the targeted combination encorafenib plus cetuximab in Germany, Austria, and Switzerland. PATIENTS AND METHODS Anonymized data from BRAFV600E-mutant mCRC patients were analyzed retrospectively regarding 1st-, 2nd- and 3rd-line treatment using descriptive statistics. RESULTS Forty-two patients were eligible for analysis (mean age 62.1 years, 47.6% female). At initial diagnosis, 20 patients (47.6%) were documented with right-sided tumors. Most patients (81.0%) were tested for BRAF before 1st-line. Four patients (9.5%) showed high microsatellite instability (MSI-H). Based on 94 treatment lines, chemotherapy combined with targeted therapy (TT) was used mostly (61.7%), followed by chemotherapy alone (19.1%). Backbone therapies were most frequently FOLFOXIRI (27.7%), FOLFOX/CAPOX (22.3%), or FOLFIRI (20.2%). Anti-VEGF/VEGFR and anti-EGFR-treatments were used in 45.7% and 23.4% of patients, respectively. Across all treatment lines and types, the predominantly documented reason for discontinuation was lack of efficacy. CONCLUSION Combined chemotherapy+TT (anti-VEGF/VEGFR and anti-EGFR) played a predominant role in BRAFV600E-mutated mCRC treatment prior to approval of the targeted combination encorafenib plus cetuximab. Since lack of efficacy was the major reason for treatment discontinuation, newly approved therapies including encorafenib plus cetuximab and - for MSI-H tumors - pembrolizumab represent urgently needed options for future mCRC patients

The impact of tumor metabolic activity assessed by 18^{18}F-FET amino acid PET imaging in particle radiotherapy of high-grade glioma patients

Selective uptake of (18)F-fluoro-ethyl-tyrosine ($^{18}$F-FET) is used in high-grade glioma (HGG) to assess tumor metabolic activity via positron emission tomography (PET). We aim to investigate its value for target volume definition, as a prognosticator, and associations with whole-blood transcriptome liquid biopsy (WBT lbx) for which we recently reported feasibility to mirror tumor characteristics and response to particle irradiation in recurrent HGG (rHGG)

DNA-Methylome based Tumor Hypoxia Classifier Identifies HPV-negative Head & Neck Cancer Patients at Risk for Locoregional Recurrence After Primary Radiochemotherapy

BACKGROUND Tumor hypoxia is a paradigmatic negative prognosticator of treatment resistance in Head and Neck Squamous Cell Carcinoma (HNSCC). The lack of robust and reliable hypoxia classifiers limits the adaptation of stratified therapies. We hypothesized that the tumor DNA methylation landscape might indicate epigenetic reprogramming induced by chronic intratumoral hypoxia. METHODS A DNA methylome-based tumor hypoxia classifier (Hypoxia-M) was trained in the TCGA-HNSCC cohort based on matched assignments using gene expression-based signatures of hypoxia (Hypoxia-GES). Hypoxia-M was validated in a multicenter DKTK-ROG trial consisting of Human Papilloma Virus (HPV)-negative HNSCC patients treated with primary radiochemotherapy (RCHT). RESULTS While hypoxia-GSEs failed to stratify patients in the DKTK-ROG, Hypoxia-M was independently prognostic for local recurrence (LR, HR=4.3, p=0.001) and overall survival (OS, HR=2.34, p=0.03) but not distant metastasis (DM) after RCHT in the both cohorts. Hypoxia-M status was inversely associated with CD8 T-cells infiltration in both cohorts. Hypoxia-M was further prognostic in the TCGA-PanCancer cohort (HR=1.83, p=0.04), underscoring the breadth of this classifier for predicting tumor hypoxia status. CONCLUSIONS Our findings highlight an unexplored avenue for DNA Methylation-based classifiers as biomarkers of tumoral hypoxia for identifying high-risk features in patients with HNSCC tumors. TRIAL REGISTRATION Retrospective observational study from the German Cancer Consortium (DKTK-ROG), not interventional

Investigation of tumor hypoxia using a two-enzyme system for in vitro generation of oxygen deficiency

<p>Abstract</p> <p>Background</p> <p>Oxygen deficiency in tumor tissue is associated with a malign phenotype, characterized by high invasiveness, increased metastatic potential and poor prognosis. Hypoxia chambers are the established standard model for <it>in vitro </it>studies on tumor hypoxia. An enzymatic hypoxia system (GOX/CAT) based on the use of glucose oxidase (GOX) and catalase (CAT) that allows induction of stable hypoxia for <it>in vitro </it>approaches more rapidly and with less operating expense has been introduced recently. Aim of this work is to compare the enzymatic system with the established technique of hypoxia chamber in respect of gene expression, glucose metabolism and radioresistance, prior to its application for <it>in vitro </it>investigation of oxygen deficiency.</p> <p>Methods</p> <p>Human head and neck squamous cell carcinoma HNO97 cells were incubated under normoxic and hypoxic conditions using both hypoxia chamber and the enzymatic model. Gene expression was investigated using Agilent microarray chips and real time PCR analysis. ¹⁴C-fluoro-deoxy-glucose uptake experiments were performed in order to evaluate cellular metabolism. Cell proliferation after photon irradiation was investigated for evaluation of radioresistance under normoxia and hypoxia using both a hypoxia chamber and the enzymatic system.</p> <p>Results</p> <p>The microarray analysis revealed a similar trend in the expression of known HIF-1 target genes between the two hypoxia systems for HNO97 cells. Quantitative RT-PCR demonstrated different kinetic patterns in the expression of carbonic anhydrase IX and lysyl oxidase, which might be due to the faster induction of hypoxia by the enzymatic system. ¹⁴C-fluoro-deoxy-glucose uptake assays showed a higher glucose metabolism under hypoxic conditions, especially for the enzymatic system. Proliferation experiments after photon irradiation revealed increased survival rates for the enzymatic model compared to hypoxia chamber and normoxia, indicating enhanced resistance to irradiation. While the GOX/CAT system allows independent investigation of hypoxia and oxidative stress, care must be taken to prevent acidification during longer incubation.</p> <p>Conclusion</p> <p>The results of our study indicate that the enzymatic model can find application for <it>in vitro </it>investigation of tumor hypoxia, despite limitations that need to be considered in the experimental design.</p