@article{SalmanHaiderSchreinerKendletal.2019, author = {Salman Haider, Malik and Schreiner, Jochen and Kendl, Sabine and Kroiss, Matthias and Luxenhofer, Robert}, title = {A Micellar Mitotane Formulation with High Drug-Loading and Solubility: Physico-Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models}, series = {Macromolecular Bioscience}, volume = {20}, journal = {Macromolecular Bioscience}, number = {1}, doi = {10.1002/mabi.201900178}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206224}, pages = {1900178}, year = {2019}, abstract = {Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14-20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT-loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI-H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.}, language = {en} } @article{BrillSchwab2019, author = {Brill, Michael and Schwab, Frank}, title = {A mixed-methods approach using self-report, observational time series data, and content analysis for process analysis of a media reception phenomenon}, series = {Frontiers in Psychology}, volume = {10}, journal = {Frontiers in Psychology}, doi = {10.3389/fpsyg.2019.01666}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201380}, pages = {1666}, year = {2019}, abstract = {Due to the complexityof research objects, theoretical concepts, and stimuli in media research, researchers in psychology and communications presumably need sophisticated measures beyond self-report scales to answer research questions on media use processes. The present study evaluates stimulus-dependent structure in spontaneous eye-blink behavior as an objective, corroborative measure for the media use phenomenon of spatial presence. To this end, a mixed methods approach is used in an experimental setting to collect, combine, analyze, and interpret data from standardized participant self-report, observation of participant behavior, and content analysis of the media stimulus. T-pattern detection is used to analyze stimulus-dependent blinking behavior, and this structural data is then contrasted with self-report data. The combined results show that behavioral indicators yield the predicted results, while self-report data shows unpredicted results that are not predicted by the underlying theory. The use of a mixed methods approach offered insights that support further theory development and theory testing beyond a traditional, mono-method experimental approach.}, language = {en} } @article{LoefflerWirthKreuzHoppetal.2019, author = {Loeffler-Wirth, Henry and Kreuz, Markus and Hopp, Lydia and Arakelyan, Arsen and Haake, Andrea and Cogliatti, Sergio B. and Feller, Alfred C. and Hansmann, Martin-Leo and Lenze, Dido and M{\"o}ller, Peter and M{\"u}ller-Hermelink, Hans Konrad and Fortenbacher, Erik and Willscher, Edith and Ott, German and Rosenwald, Andreas and Pott, Christiane and Schwaenen, Carsten and Trautmann, Heiko and Wessendorf, Swen and Stein, Harald and Szczepanowski, Monika and Tr{\"u}mper, Lorenz and Hummel, Michael and Klapper, Wolfram and Siebert, Reiner and Loeffler, Markus and Binder, Hans}, title = {A modular transcriptome map of mature B cell lymphomas}, series = {Genome Medicine}, volume = {11}, journal = {Genome Medicine}, doi = {10.1186/s13073-019-0637-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237262}, year = {2019}, abstract = {Background Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. Conclusions The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.}, language = {en} } @article{UereyenKuenzer2019, author = {Uereyen, Soner and Kuenzer, Claudia}, title = {A review of earth observation-based analyses for major river basins}, series = {Remote Sensing}, volume = {11}, journal = {Remote Sensing}, number = {24}, issn = {2072-4292}, doi = {10.3390/rs11242951}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193849}, pages = {2951}, year = {2019}, abstract = {Regardless of political boundaries, river basins are a functional unit of the Earth's land surface and provide an abundance of resources for the environment and humans. They supply livelihoods supported by the typical characteristics of large river basins, such as the provision of freshwater, irrigation water, and transport opportunities. At the same time, they are impacted i.e., by human-induced environmental changes, boundary conflicts, and upstream-downstream inequalities. In the framework of water resource management, monitoring of river basins is therefore of high importance, in particular for researchers, stake-holders and decision-makers. However, land surface and surface water properties of many major river basins remain largely unmonitored at basin scale. Several inventories exist, yet consistent spatial databases describing the status of major river basins at global scale are lacking. Here, Earth observation (EO) is a potential source of spatial information providing large-scale data on the status of land surface properties. This review provides a comprehensive overview of existing research articles analyzing major river basins primarily using EO. Furthermore, this review proposes to exploit EO data together with relevant open global-scale geodata to establish a database and to enable consistent spatial analyses and evaluate past and current states of major river basins.}, language = {en} } @article{VeyKapsnerFuchsetal.2019, author = {Vey, Johannes and Kapsner, Lorenz A. and Fuchs, Maximilian and Unberath, Philipp and Veronesi, Giulia and Kunz, Meik}, title = {A toolbox for functional analysis and the systematic identification of diagnostic and prognostic gene expression signatures combining meta-analysis and machine learning}, series = {Cancers}, volume = {11}, journal = {Cancers}, number = {10}, issn = {2072-6694}, doi = {10.3390/cancers11101606}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193240}, year = {2019}, abstract = {The identification of biomarker signatures is important for cancer diagnosis and prognosis. However, the detection of clinical reliable signatures is influenced by limited data availability, which may restrict statistical power. Moreover, methods for integration of large sample cohorts and signature identification are limited. We present a step-by-step computational protocol for functional gene expression analysis and the identification of diagnostic and prognostic signatures by combining meta-analysis with machine learning and survival analysis. The novelty of the toolbox lies in its all-in-one functionality, generic design, and modularity. It is exemplified for lung cancer, including a comprehensive evaluation using different validation strategies. However, the protocol is not restricted to specific disease types and can therefore be used by a broad community. The accompanying R package vignette runs in ~1 h and describes the workflow in detail for use by researchers with limited bioinformatics training.}, language = {en} } @article{LewitzkiKlementKosmalaetal.2019, author = {Lewitzki, Victor and Klement, Rainer J. and Kosmala, Rebekka and Lisowski, Dominik and Flentje, Michael and Polat, B{\"u}lent}, title = {Accelerated hyperfractionated radiochemotherapy with temozolomide is equivalent to normofractionated radiochemotherapy in a retrospective analysis of patients with glioblastoma}, series = {Radiation Oncology}, volume = {14}, journal = {Radiation Oncology}, doi = {10.1186/s13014-019-1427-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202614}, pages = {227}, year = {2019}, abstract = {Background Current standard of treatment for newly diagnosed patients with glioblastoma (GBM) is surgical resection with adjuvant normofractionated radiotherapy (NFRT) combined with temozolomide (TMZ) chemotherapy. Hyperfractionated accelerated radiotherapy (HFRT) which was known as an option from randomized controlled trials before the temozolomide era has not been compared to the standard therapy in a randomized setting combined with TMZ. Methods Data of 152 patients with newly diagnosed GBM treated from 10/2004 until 7/2018 at a single tertiary care institution were extracted from a clinical database and retrospectively analyzed. Thirty-eight patients treated with NFRT of 60 Gy in 30 fractions (34 with simultaneous and 2 with sequential TMZ) were compared to 114 patients treated with HFRT of 54.0 Gy in 30 fraction of 1.8 Gy twice daily (109 with simultaneous and 3 with sequential TMZ). The association between treatment protocol and other variables with overall survival (OS) was assessed using univariable and multivariable Cox regression analysis; the latter was performed using variables selected by the LASSO method. Results Median overall survival (OS) was 20.3 month for the entire cohort. For patients treated with NFRT median OS was 24.4 months compared to 18.5 months in patients treated with HFRT (p = 0.131). In univariable regression analysis the use of dexamethasone during radiotherapy had a significant negative impact on OS in both patient groups, HR 2.21 (95\% CI 1.47-3.31, p = 0.0001). In multivariable analysis adjusted for O6-methylguanine-DNA methyl-transferase (MGMT) promotor methylation status, salvage treatment and secondary GBM, the use of dexamethasone was still a negative prognostic factor, HR 1.95 (95\% CI 1.21-3.13, p = 0.006). Positive MGMT-methylation status and salvage treatment were highly significant positive prognostic factors. There was no strong association between treatment protocol and OS (p = 0.504). Conclusions Our retrospective analysis supports the hypothesis of equivalence between HFRT and the standard protocol of treatment for GBM. For those patients who are willing to obtain the benefit of shortening the course of radiochemotherapy, HFRT may be an alternative with comparable efficacy although it was not yet tested in a large prospective randomized study against the current standard. The positive influence of salvage therapy and negative impact of concomitant use of corticosteroids should be addressed in future prospective trials. To confirm our results, we plan to perform a pooled analysis with other tertiary clinics in order to achieve better statistical reliability.}, language = {en} } @article{RullmannPreusserPoppitzetal.2019, author = {Rullmann, Michael and Preusser, Sven and Poppitz, Sindy and Heba, Stefanie and Gousias, Konstantinos and Hoyer, Jana and Sch{\"u}tz, Tatjana and Dietrich, Arne and M{\"u}ller, Karsten and Hankir, Mohammed K. and Pleger, Burkhard}, title = {Adiposity Related Brain Plasticity Induced by Bariatric Surgery}, series = {Froniers in Human Neuroscience}, volume = {13}, journal = {Froniers in Human Neuroscience}, doi = {10.3389/fnhum.2019.00290}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227168}, pages = {1-11}, year = {2019}, abstract = {Previous magnetic resonance imaging (MRI) studies revealed structural-functional brain reorganization 12 months after gastric-bypass surgery, encompassing cortical and subcortical regions of all brain lobes as well as the cerebellum. Changes in the mean of cluster-wise gray/white matter density (GMD/WMD) were correlated with the individual loss of body mass index (BMI), rendering the BMI a potential marker of widespread surgery-induced brain plasticity. Here, we investigated voxel-by-voxel associations between surgery-induced changes in adiposity, metabolism and inflammation and markers of functional and structural neural plasticity. We re-visited the data of patients who underwent functional and structural MRI, 6 months (n = 27) and 12 months after surgery (n = 22), and computed voxel-wise regression analyses. Only the surgery-induced weight loss was significantly associated with brain plasticity, and this only for GMD changes. After 6 months, weight loss overlapped with altered GMD in the hypothalamus, the brain's homeostatic control site, the lateral orbitofrontal cortex, assumed to host reward and gustatory processes, as well as abdominal representations in somatosensory cortex. After 12 months, weight loss scaled with GMD changes in right cerebellar lobule VII, involved in language-related/cognitive processes, and, by trend, with the striatum, assumed to underpin (food) reward. These findings suggest time-dependent and weight-loss related gray matter plasticity in brain regions involved in the control of eating, sensory processing and cognitive functioning.}, language = {en} } @article{KarlNandiniColacoSchulteetal.2019, author = {Karl, Franziska and Nandini Cola{\c{c}}o, Maria B. and Schulte, Annemarie and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Affective and cognitive behavior is not altered by chronic constriction injury in B7-H1 deficient and wildtype mice}, series = {BMC Neuroscience}, volume = {20}, journal = {BMC Neuroscience}, doi = {10.1186/s12868-019-0498-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200540}, pages = {16}, year = {2019}, abstract = {Background Chronic neuropathic pain is often associated with anxiety, depressive symptoms, and cognitive impairment with relevant impact on patients` health related quality of life. To investigate the influence of a pro-inflammatory phenotype on affective and cognitive behavior under neuropathic pain conditions, we assessed mice deficient of the B7 homolog 1 (B7-H1), a major inhibitor of inflammatory response. Results Adult B7-H1 ko mice and wildtype littermates (WT) received a chronic constriction injury (CCI) of the sciatic nerve, and we assessed mechanical and thermal sensitivity at selected time points. Both genotypes developed mechanical (p < 0.001) and heat hypersensitivity (p < 0.01) 7, 14, and 20 days after surgery. We performed three tests for anxiety-like behavior: the light-dark box, the elevated plus maze, and the open field. As supported by the results of these tests for anxiety-like behavior, no relevant differences were found between genotypes after CCI. Depression-like behavior was assessed using the forced swim test. Also, CCI had no effect on depression like behavior. For cognitive behavior, we applied the Morris water maze for spatial learning and memory and the novel object recognition test for object recognition, long-, and short-term memory. Learning and memory did not differ in B7-H1 ko and WT mice after CCI. Conclusions Our study reveals that the impact of B7-H1 on affective-, depression-like- and learning-behavior, and memory performance might play a subordinate role in mice after nerve lesion.}, language = {en} } @article{KleefeldtBoemmelBroedeetal.2019, author = {Kleefeldt, Florian and B{\"o}mmel, Heike and Broede, Britta and Thomsen, Michael and Pfeiffer, Verena and W{\"o}rsd{\"o}rfer, Philipp and Karnati, Srikanth and Wagner, Nicole and Rueckschloss, Uwe and Erg{\"u}n, S{\"u}leyman}, title = {Aging-related carcinoembryonic antigen-related cell adhesion molecule 1 signaling promotes vascular dysfunction}, series = {Aging Cell}, volume = {2019}, journal = {Aging Cell}, number = {18}, doi = {10.1111/acel.13025}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201231}, pages = {e13025}, year = {2019}, abstract = {Aging is an independent risk factor for cardiovascular diseases and therefore of particular interest for the prevention of cardiovascular events. However, the mechanisms underlying vascular aging are not well understood. Since carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is crucially involved in vascular homeostasis, we sought to identify the role of CEACAM1 in vascular aging. Using human internal thoracic artery and murine aorta, we show that CEACAM1 is upregulated in the course of vascular aging. Further analyses demonstrated that TNF-α is CEACAM1-dependently upregulated in the aging vasculature. Vice versa, TNF-α induces CEACAM1 expression. This results in a feed-forward loop in the aging vasculature that maintains a chronic pro-inflammatory milieu. Furthermore, we demonstrate that age-associated vascular alterations, that is, increased oxidative stress and vascular fibrosis, due to increased medial collagen deposition crucially depend on the presence of CEACAM1. Additionally, age-dependent upregulation of vascular CEACAM1 expression contributes to endothelial barrier impairment, putatively via increased VEGF/VEGFR-2 signaling. Consequently, aging-related upregulation of vascular CEACAM1 expression results in endothelial dysfunction that may promote atherosclerotic plaque formation in the presence of additional risk factors. Our data suggest that CEACAM1 might represent an attractive target in order to delay physiological aging and therefore the transition to vascular disorders such as atherosclerosis.}, language = {en} } @article{MatosMachadoSchartletal.2019, author = {Matos, Isa and Machado, Miguel P. and Schartl, Manfred and Coelho, Maria Manuela}, title = {Allele-specific expression variation at different ploidy levels in Squalius alburnoides}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-40210-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200910}, pages = {3688}, year = {2019}, abstract = {Allopolyploid plants are long known to be subject to a homoeolog expression bias of varying degree. The same phenomenon was only much later suspected to occur also in animals based on studies of single selected genes in an allopolyploid vertebrate, the Iberian fish Squalius alburnoides. Consequently, this species became a good model for understanding the evolution of gene expression regulation in polyploid vertebrates. Here, we analyzed for the first time genome-wide allele-specific expression data from diploid and triploid hybrids of S. alburnoides and compared homoeolog expression profiles of adult livers and of juveniles. Co-expression of alleles from both parental genomic types was observed for the majority of genes, but with marked homoeolog expression bias, suggesting homoeolog specific reshaping of expression level patterns in hybrids. Complete silencing of one allele was also observed irrespective of ploidy level, but not transcriptome wide as previously speculated. Instead, it was found only in a restricted number of genes, particularly ones with functions related to mitochondria and ribosomes. This leads us to hypothesize that allelic silencing may be a way to overcome intergenomic gene expression interaction conflicts, and that homoeolog expression bias may be an important mechanism in the achievement of sustainable genomic interactions, mandatory to the success of allopolyploid systems, as in S. alburnoides.}, language = {en} }