TY - JOUR A1 - Bartel, Karin A1 - Pein, Helmut A1 - Popper, Bastian A1 - Schmitt, Sabine A1 - Janaki-Raman, Sudha A1 - Schulze, Almut A1 - Lengauer, Florian A1 - Koeberle, Andreas A1 - Werz, Oliver A1 - Zischka, Hans A1 - Müller, Rolf A1 - Vollmar, Angelika M. A1 - Schwarzenberg, Karin von T1 - Connecting lysosomes and mitochondria – a novel role for lipid metabolism in cancer cell death JF - Cell Communication and Signaling N2 - Background The understanding of lysosomes has been expanded in recent research way beyond their view as cellular trash can. Lysosomes are pivotal in regulating metabolism, endocytosis and autophagy and are implicated in cancer. Recently it was discovered that the lysosomal V-ATPase, which is known to induce apoptosis, interferes with lipid metabolism in cancer, yet the interplay between these organelles is poorly understood. Methods LC-MS/MS analysis was performed to investigate lipid distribution in cells. Cell survival and signaling pathways were analyzed by means of cell biological methods (qPCR, Western Blot, flow cytometry, CellTiter-Blue). Mitochondrial structure was analyzed by confocal imaging and electron microscopy, their function was determined by flow cytometry and seahorse measurements. Results Our data reveal that interfering with lysosomal function changes composition and subcellular localization of triacylglycerids accompanied by an upregulation of PGC1α and PPARα expression, master regulators of energy and lipid metabolism. Furthermore, cardiolipin content is reduced driving mitochondria into fission, accompanied by a loss of membrane potential and reduction in oxidative capacity, which leads to a deregulation in cellular ROS and induction of mitochondria-driven apoptosis. Additionally, cells undergo a metabolic shift to glutamine dependency, correlated with the fission phenotype and sensitivity to lysosomal inhibition, most prominent in Ras mutated cells. Conclusion This study sheds mechanistic light on a largely uninvestigated triangle between lysosomes, lipid metabolism and mitochondrial function. Insight into this organelle crosstalk increases our understanding of mitochondria-driven cell death. Our findings furthermore provide a first hint on a connection of Ras pathway mutations and sensitivity towards lysosomal inhibitors. KW - lysosome KW - V-ATPase KW - mitochondria KW - fission KW - apoptosis KW - lipid metabolism KW - cardiolipin Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221524 VL - 17 ER - TY - JOUR A1 - Rödel, Michaela A1 - Teßmar, Jörg A1 - Groll, Jürgen A1 - Gbureck, Uwe T1 - Tough and Elastic alpha-Tricalcium Phosphate Cement Composites with Degradable PEG-Based Cross-Linker JF - Materials N2 - Dual setting cements composed of an in situ forming hydrogel and a reactive mineral phase combine high compressive strength of the cement with sufficient ductility and bending strength of the polymeric network. Previous studies were focused on the modification with non-degradable hydrogels based on 2-hydroxyethyl methacrylate (HEMA). Here, we describe the synthesis of suitable triblock degradable poly(ethylene glycol)-poly(lactide) (PEG-PLLA) cross-linker to improve the resorption capacity of such composites. A study with four different formulations was established. As reference, pure hydroxyapatite (HA) cements and composites with 40 wt% HEMA in the liquid cement phase were produced. Furthermore, HEMA was modified with 10 wt% of PEG-PLLA cross-linker or a test series containing only 25% cross-linker was chosen for composites with a fully degradable polymeric phase. Hence, we developed suitable systems with increased elasticity and 5-6 times higher toughn ess values in comparison to pure inorganic cement matrix. Furthermore, conversion rate from alpha-tricalcium phosphate (alpha-TCP) to HA was still about 90% for all composite formulations, whereas crystal size decreased. Based on this material development and advancement for a dual setting system, we managed to overcome the drawback of brittleness for pure calcium phosphate cements. KW - dual setting system KW - bending strength KW - calcium phosphate cement KW - composite material KW - HEMA KW - hydroxyapatite KW - free radical polymerization Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226437 VL - 12 IS - 53 ER - TY - JOUR A1 - Sepahi, Ilnaz A1 - Faust, Ulrike A1 - Sturm, Marc A1 - Bosse, Kristin A1 - Kehrer, Martin A1 - Heinrich, Tilman A1 - Grundman-Hauser, Kathrin A1 - Bauer, Peter A1 - Ossowski, Stephan A1 - Susak, Hana A1 - Varon, Raymonda A1 - Schröck, Evelin A1 - Niederacher, Dieter A1 - Auber, Bernd A1 - Sutter, Christian A1 - Arnold, Norbert A1 - Hahnen, Eric A1 - Dworniczak, Bernd A1 - Wang-Gorke, Shan A1 - Gehrig, Andrea A1 - Weber, Bernhard H. F. A1 - Engel, Christoph A1 - Lemke, Johannes R. A1 - Hartkopf, Andreas A1 - Huu Phuc, Nguyen A1 - Riess, Olaf A1 - Schroeder, Christopher T1 - Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women JF - BMC Cancer N2 - Background Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon. Methods We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways. Results Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00–27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05. Conclusions To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results. KW - breast cancer KW - age at onset KW - DNA-repair genes KW - next-generation-sequencing KW - panel sequencing KW - extreme phenotypes KW - hereditary breast and ovarian cancer KW - BRCA1 KW - DNA-repair Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237676 VL - 19 ER - TY - JOUR A1 - Ebner, Florian A1 - Wöckel, Achim A1 - Schwentner, Lukas A1 - Blettner, Maria A1 - Janni, Wolfgang A1 - Kreienberg, Rolf A1 - Wischnewsky, Manfred T1 - Does the number of removed axillary lymphnodes in high risk breast cancer patients influence the survival? JF - BMC Cancer N2 - Background The decision making process for axillary dissection has changed in recent years for patients with early breast cancer and positive sentinel lymph nodes (LN). The question now arises, what is the optimal surgical treatment for patients with positive axillary LN (pN+). This article tries to answer the following questions: (1) Is there a survival benefit for breast cancer patients with 3 or more positive LN (pN3+) and with more than 10 removed LN? (2) Is there a survival benefit for high risk breast cancer patients (triple negative or Her2 + breast cancer) and with 3 or more positive LN (pN3+) with more than 10 removed LN? (3) In pN + patients is the prognostic value of the lymph node ratio (LNR) of pN+/pN removed impaired if 10 or less LN are removed? Methods A retrospective database analysis of the multi center cohort database BRENDA (breast cancer under evidence based guidelines) with data from 9625 patients from 17 breast centers was carried out. Guideline adherence was defined by the 2008 German National consensus guidelines. Results 2992 out of 9625 patients had histological confirmed positive lymph nodes. The most important factors for survival were intrinsic sub types, tumor size and guideline adherent chemo- and hormonal treatment (and age at diagnosis for overall survival (OAS)). Uni-and multivariable analyses for recurrence free survival (RFS) and OAS showed no significant survival benefit when removing more than 10 lymph nodes even for high-risk patients. The mean and median of LNR were significantly higher in the pN+ patients with ≤10 excised LN compared to patients with > 10 excised LN. LNR was in both, uni-and multivariable, analysis a highly significant prognostic factor for RFS and OAS in both subgroups of pN + patients with less respective more than 10 excised LN. Multivariable COX regression analysis was adjusted by age, tumor size, intrinsic sub types and guideline adherent adjuvant systemic therapy. Conclusion The removal of more than 10 LN did not result in a significant survival benefit even in high risk pN + breast cancer patients. KW - advanced breast cancer KW - axillary dissection KW - lymph nodes KW - number of KW - sentinel KW - survival KW - guideline adherent treatment Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226445 VL - 19 ER - TY - JOUR A1 - Kolb-Mäurer, Annette A1 - Sunderkötter, Cord A1 - Kukowski, Borries A1 - Meuth, Sven G. T1 - An update on Peginterferon beta-1a Management in Multiple Sclerosis: results from an interdisciplinary Board of German and Austrian Neurologists and dermatologists JF - BMC Neurology N2 - Background: Interferon (IFN) beta drugs have been approved for the treatment of relapsing forms of multiple sclerosis (RMS) for more than 20years and are considered to offer a favourable benefit-risk profile. In July 2014, subcutaneous (SC) peginterferon beta-1a 125g dosed every 2weeks, a pegylated form of interferon beta-1a, was approved by the EMA for the treatment of adult patients with RRMS and in August 2014 by the FDA for RMS. Peginterferon beta-1a shows a prolonged half-life and increased systemic drug exposure resulting in a reduced dosing frequency compared to other available interferon-based products in MS. In the Phase 3 ADVANCE trial peginterferon beta-1a demonstrated significant positive effects on clinical and MRI outcome measures versus placebo after one year. Furthermore, in the ATTAIN extension study, sustained efficacy with long-term treatment for nearly 6years was shown. Main text In July 2016, an interdisciplinary panel of German and Austrian experts convened to discuss the management of side effects associated with peginterferon beta-1a and other interferon beta-based treatments in MS in daily practice. The panel was composed of experts from university hospitals and private clinics comprised of neurologists, dermatologists, and an MS nurse. In this paper we report recommendations regarding best practices for adverse event management, focussing on peginterferon beta-1a. Injection site reactions (ISRs) and influenza-like illness are the most common adverse effects of interferon beta therapies and can present a burden for MS patients leading to non-adherence and discontinuation of therapy. Peginterferon beta-1a shows improved pharmacological properties. In clinical trials, the adverse event (AE) profile of peginterferon beta-1a was similar to other interferon beta formulations. The most common AEs were mild to moderate ISRs, influenza-like illness, pyrexia, and headache. Current information on the underlying cause of skin reactions associated with SC interferon treatment, and the management strategies for these AEs are limited. In pivotal trials, ISRs were mainly characterized and classified by neurologists, while dermatologists were only rarely consulted. Conclusions This report addresses expert recommendations on the management of most relevant adverse effects related to peginterferon beta-1a and other interferon betas, based on literature and interdisciplinary experience. KW - multiple sclerosis KW - peginterferon bet-1a KW - interferon beta KW - flu-like symptoms KW - injection site reactions KW - management Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224646 VL - 19 ER - TY - JOUR A1 - Rasche, Leo A1 - Kortüm, K. Martin A1 - Raab, Marc S. A1 - Weinhold, Niels T1 - The impact of tumor heterogeneity on diagnostics and novel therapeutic strategies in multiple myeloma JF - International Journal of Molecular Sciences N2 - Myeloma is characterized by extensive inter-patient genomic heterogeneity due to multiple different initiating events. A recent multi-region sequencing study demonstrated spatial differences, with progression events, such as TP53 mutations, frequently being restricted to focal lesions. In this review article, we describe the clinical impact of these two types of tumor heterogeneity. Target mutations are often dominant at one site but absent at other sites, which poses a significant challenge to personalized therapy in myeloma. The same holds true for high-risk subclones, which can be locally restricted, and as such not detectable at the iliac crest, which is the usual sampling site. Imaging can improve current risk classifiers and monitoring of residual disease, but does not allow for deciphering the molecular characteristics of tumor clones. In the era of novel immunotherapies, the clinical impact of heterogeneity certainly needs to be re-defined. Yet, preliminary observations indicate an ongoing impact of spatial heterogeneity on the efficacy of monoclonal antibodies. In conclusion, we recommend combining molecular tests with imaging to improve risk prediction and monitoring of residual disease. Overcoming intra-tumor heterogeneity is the prerequisite for curing myeloma. Novel immunotherapies are promising but research addressing their impact on the spatial clonal architecture is highly warranted. KW - multiple myeloma KW - spatial heterogeneity KW - risk stratification KW - minimal residual disease KW - targeted therapy KW - clinical imaging KW - immunotherapy KW - daratumumab Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285402 SN - 1422-0067 VL - 20 IS - 5 ER - TY - JOUR A1 - Radchuk, Volodymyr A1 - Rajiv, Sharma A1 - Potokina, Elena A1 - Radchuk, Ruslana A1 - Weier, Diana A1 - Munz, Eberhard A1 - Schreiber, Miriam A1 - Mascher, Martin A1 - Stein, Nils A1 - Wicker, Thomas A1 - Kilian, Benjamin A1 - Borisjuk, Ljudmilla T1 - The highly divergent \(Jekyll\) genes, required for sexual reproduction, are lineage specific for the related grass tribes Triticeae and Bromeae JF - Plant Journal N2 - Phylogenetically related groups of species contain lineage-specific genes that exhibit no sequence similarity to any genes outside the lineage. We describe here that the Jekyll gene, required for sexual reproduction, exists in two much diverged allelic variants, Jek1 and Jek3. Despite low similarity, the Jek1 and Jek3 proteins share identical signal peptides, conserved cysteine positions and direct repeats. The Jek1/Jek3 sequences are located at the same chromosomal locus and inherited in a monogenic Mendelian fashion. Jek3 has a similar expression as Jek1 and complements the Jek1 function in Jek1-deficient plants. Jek1 and Jek3 allelic variants were almost equally distributed in a collection of 485 wild and domesticated barley accessions. All domesticated barleys harboring the Jek1 allele belong to single haplotype J1-H1 indicating a genetic bottleneck during domestication. Domesticated barleys harboring the Jek3 allele consisted of three haplotypes. Jekyll-like sequences were found only in species of the closely related tribes Bromeae and Triticeae but not in other Poaceae. Non-invasive magnetic resonance imaging revealed intrinsic grain structure in Triticeae and Bromeae, associated with the Jekyll function. The emergence of Jekyll suggests its role in the separation of the Bromeae and Triticeae lineages within the Poaceae and identifies the Jekyll genes as lineage-specific. KW - gene alleles KW - lineage-specific genes KW - Triticeae KW - Hordeum vulgare KW - Triticum aestivum KW - gene family evolution KW - plant reproduction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224769 VL - 98 IS - 6 ER - TY - JOUR A1 - Reinermann, Sophie A1 - Gessner, Ursula A1 - Asam, Sarah A1 - Kuenzer, Claudia A1 - Dech, Stefan T1 - The Effect of Droughts on Vegetation Condition in Germany: An Analysis Based on Two Decades of Satellite Earth Observation Time Series and Crop Yield Statistics JF - Remote Sensing N2 - Central Europe experienced several droughts in the recent past, such as in the year 2018, which was characterized by extremely low rainfall rates and high temperatures, resulting in substantial agricultural yield losses. Time series of satellite earth observation data enable the characterization of past drought events over large temporal and spatial scales. Within this study, Moderate Resolution Spectroradiometer (MODIS) Enhanced Vegetation Index (EVI) (MOD13Q1) 250 m time series were investigated for the vegetation periods of 2000 to 2018. The spatial and temporal development of vegetation in 2018 was compared to other dry and hot years in Europe, like the drought year 2003. Temporal and spatial inter- and intra-annual patterns of EVI anomalies were analyzed for all of Germany and for its cropland, forest, and grassland areas individually. While vegetation development in spring 2018 was above average, the summer months of 2018 showed negative anomalies in a similar magnitude as in 2003, which was particularly apparent within grassland and cropland areas in Germany. In contrast, the year 2003 showed negative anomalies during the entire growing season. The spatial pattern of vegetation status in 2018 showed high regional variation, with north-eastern Germany mainly affected in June, north-western parts in July, and western Germany in August. The temporal pattern of satellite-derived EVI deviances within the study period 2000-2018 were in good agreement with crop yield statistics for Germany. The study shows that the EVI deviation of the summer months of 2018 were among the most extreme in the study period compared to other years. The spatial pattern and temporal development of vegetation condition between the drought years differ. KW - drought KW - time series KW - heat wave KW - agriculture KW - climate extremes KW - climate change KW - crop statistics KW - MODIS KW - Germany Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225165 VL - 11 IS - 15 ER - TY - JOUR A1 - Schlottmann, Elisabeth A1 - Schicke, David A1 - Krüger, Felix A1 - Lingnau, Benjamin A1 - Schneider, Christian A1 - Höfling, Sven A1 - Lüdge, Kathy A1 - Porte, Xavier A1 - Reitzenstein, Stephan T1 - Stochastic polarization switching induced by optical injection in bimodal quantum-dot micropillar lasers JF - Optics Express N2 - Mutual coupling and injection locking of semiconductor lasers is of great interest in non-linear dynamics and its applications for instance in secure data communication and photonic reservoir computing. Despite its importance, it has hardly been studied in microlasers operating at mu W light levels. In this context, vertically emitting quantum dot micropillar lasers are of high interest. Usually, their light emission is bimodal, and the gain competition of the associated linearly polarized fundamental emission modes results in complex switching dynamics. We report on selective optical injection into either one of the two fundamental mode components of a bimodal micropillar laser. Both modes can lock to the master laser and influence the non-injected mode by reducing the available gain. We demonstrate that the switching dynamics can be tailored externally via optical injection in very good agreement with our theory based on semi-classical rate equations. (C) 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement KW - Nonlinear Dynamics KW - Bistability KW - Generation KW - Subject KW - Regimes KW - Physics KW - Vcsels Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228603 VL - 27 IS - 20 ER - TY - JOUR A1 - Radeva, Mariya Y. A1 - Walter, Elias A1 - Stach, Ramona Alexandra A1 - Yazdi, Amir S. A1 - Schlegel, Nicolas A1 - Sarig, Ofer A1 - Sprecher, Eli A1 - Waschke, Jens T1 - ST18 Enhances PV-IgG-Induced Loss of Keratinocyte Cohesion in Parallel to Increased ERK Activation JF - Frontiers in Immunology N2 - Pemphigus is an autoimmune blistering disease targeting the desmosomal proteins desmoglein (Dsg) 1 and Dsg3. Recently, a genetic variant of the Suppression of tumorigenicity 18 (ST18) promoter was reported to cause ST18 up-regulation, associated with pemphigus vulgaris (PV)-IgG-mediated increase in cytokine secretion and more prominent loss of keratinocyte cohesion. Here we tested the effects of PV-IgG and the pathogenic pemphigus mouse anti-Dsg3 antibody AK23 on cytokine secretion and ERK activity in human keratinocytes dependent on ST18 expression. Without ST18 overexpression, both PV-IgG and AK23 induced loss of keratinocyte cohesion which was accompanied by prominent fragmentation of Dsg3 immunostaining along cell borders. In contrast, release of pro-inflammatory cytokines such as IL-1 alpha, IL-6, TNF alpha, and IFN-gamma was not altered significantly in both HaCaT and primary NHEK cells. These experiments indicate that cytokine expression is not strictly required for loss of keratinocyte cohesion. Upon ST18 overexpression, fragmentation of cell monolayers increased significantly in response to autoantibody incubation. Furthermore, production of IL-1 alpha and IL-6 was enhanced in some experiments but not in others whereas release of TNF-alpha dropped significantly upon PV-IgG application in both EV- and ST18-transfected HaCaT cells. Additionally, in NHEK, application of PV-IgG but not of AK23 significantly increased ERK activity. In contrast, ST18 overexpression in HaCaT cells augmented ERK activation in response to both c-IgG and AK23 but not PV-IgG. Because inhibition of ERK by U0126 abolished PV-IgG- and AK23-induced loss of cell cohesion in ST18-expressing cells, we conclude that autoantibody-induced ERK activation was relevant in this scenario. In summary, similar to the situation in PV patients carrying ST18 polymorphism, overexpression of ST18 enhanced keratinocyte susceptibility to autoantibody-induced loss of cell adhesion, which may be caused in part by enhanced ERK signaling. KW - pemphigus KW - desmosome KW - desmoglein KW - ST18 KW - ERK KW - cytokines Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224910 VL - 10 ER - TY - JOUR A1 - Thölken, Clemens A1 - Thamm, Markus A1 - Erbacher, Christoph A1 - Lechner, Marcus T1 - Sequence and structural properties of circular RNAs in the brain of nurse and forager honeybees (Apis mellifera) JF - BMC Genomics N2 - Background The honeybee (Apis mellifera) represents a model organism for social insects displaying behavioral plasticity. This is reflected by an age-dependent task allocation. The most protruding tasks are performed by young nurse bees and older forager bees that take care of the brood inside the hive and collect food from outside the hive, respectively. The molecular mechanism leading to the transition from nurse bees to foragers is currently under intense research. Circular RNAs, however, were not considered in this context so far. As of today, this group of non-coding RNAs was only known to exist in two other insects, Drosophila melanogaster and Bombyx mori. Here we complement the state of circular RNA research with the first characterization in a social insect. Results We identified numerous circular RNAs in the brain of A. mellifera nurse bees and forager bees using RNA-Seq with exonuclease enrichment. Presence and circularity were verified for the most abundant representatives. Back-splicing in honeybee occurs further towards the end of transcripts and in transcripts with a high number of exons. The occurrence of circularized exons is correlated with length and CpG-content of their flanking introns. The latter coincides with increased DNA-methylation in the respective loci. For two prominent circular RNAs the abundance in worker bee brains was quantified in TaqMan assays. In line with previous findings of circular RNAs in Drosophila, circAmrsmep2 accumulates with increasing age of the insect. In contrast, the levels of circAmrad appear age-independent and correlate with the bee's task. Its parental gene is related to amnesia-resistant memory. Conclusions We provide the first characterization of circRNAs in a social insect. Many of the RNAs identified here show homologies to circular RNAs found in Drosophila and Bombyx, indicating that circular RNAs are a common feature among insects. We find that exon circularization is correlated to DNA-methylation at the flanking introns. The levels of circAmrad suggest a task-dependent abundance that is decoupled from age. Moreover, a GO term analysis shows an enrichment of task-related functions. We conclude that circular RNAs could be relevant for task allocation in honeybee and should be investigated further in this context. KW - circRNA KW - circular transcriptome sequencing KW - honeybee KW - brain KW - neuronal KW - Methylation KW - CpG KW - alternative splicing KW - behavioral plasticity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241302 VL - 20 ER - TY - JOUR A1 - Grebinyk, Anna A1 - Prylutska, Svitlana A1 - Grebinyk, Sergii A1 - Prylutskyy, Yuriy A1 - Ritter, Uwe A1 - Matyshevska, Olga A1 - Dandekar, Thomas A1 - Frohme, Marcus T1 - Complexation with C\(_{60}\) fullerene increases doxorubicin efficiency against leukemic cells in vitro JF - Nanoscale Research Letters N2 - Conventional anticancer chemotherapy is limited because of severe side effects as well as a quickly evolving multidrug resistance of the tumor cells. To address this problem, we have explored a C\(_{60}\) fullerene-based nanosized system as a carrier for anticancer drugs for an optimized drug delivery to leukemic cells.Here, we studied the physicochemical properties and anticancer activity of C\(_{60}\) fullerene noncovalent complexes with the commonly used anticancer drug doxorubicin. C\(_{60}\)-Doxorubicin complexes in a ratio 1:1 and 2:1 were characterized with UV/Vis spectrometry, dynamic light scattering, and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The obtained analytical data indicated that the 140-nm complexes were stable and could be used for biological applications. In leukemic cell lines (CCRF-CEM, Jurkat, THP1 and Molt-16), the nanocomplexes revealed 3.5 higher cytotoxic potential in comparison with the free drug in a range of nanomolar concentrations. Also, the intracellular drug's level evidenced C\(_{60}\) fullerene considerable nanocarrier function.The results of this study indicated that C\(_{60}\) fullerene-based delivery nanocomplexes had a potential value for optimization of doxorubicin efficiency against leukemic cells. KW - C-60 fullerene KW - doxorubicin KW - noncovalent complex KW - leukemic cells KW - cytotoxicity KW - accumulation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228257 VL - 14 IS - 61 ER - TY - JOUR A1 - Richter, Julia A1 - Hüttmann, Andreas A1 - Rekowski, Jan A1 - Schmitz, Christine A1 - Gärtner, Selina A1 - Rosenwald, Andreas A1 - Hansmann, Martin-Leo A1 - Hartmann, Sylvia A1 - Möller, Peter A1 - Wacker, Hans-Heinrich A1 - Feller, Alfred A1 - Thorns, Christoph A1 - Müller, Stefan A1 - Dührsen, Ulrich A1 - Klapper, Wolfram T1 - Molecular characteristics of diffuse large B-cell lymphoma in the Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin lymphomas (PETAL) trial: correlation with interim PET and outcome JF - Blood Cancer Journal N2 - No abstract available KW - Cancer genetics KW - Medical research KW - Translational research Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226185 VL - 9 ER - TY - JOUR A1 - Akshat, Puri A1 - Aaboud, M. A1 - Aad, G. A1 - Abbott, B. A1 - Abdinov, O. A1 - Abeloos, B. A1 - Abhayasinghe, D. K. A1 - Abidi, S. H. A1 - Abou Zeid, O. S. A1 - Abraham, N. L. A1 - Abramowicz, H. A1 - Abreu, H. A1 - Abulaiti, Y. A1 - Acharya, B. S. A1 - Adachi, S. A1 - Adam, L. A1 - Adamczyk, L. A1 - Adelman, J. A1 - Adersberger, M. A1 - Adiguzel, A. A1 - Adye, T. A1 - Affolder, A. A. A1 - Afik, Y. A1 - Agheorghiesei, C. A1 - Aguilar-Saavedra, J. A. A1 - Ahmadov, F. A1 - Aiellil, G. A1 - Akatsuka, S. A1 - Akesson, T. P. A. A1 - Akilli, E. A1 - Akimov, A. V. A1 - Alberghi, G. L. A1 - Albert, J. A1 - Albicocco, P. A1 - Alconada Verzini, M. J. A1 - Alderweireld, S. A1 - Aleksa, M. A1 - Aleksandrov, I. N. A1 - Alexa, C. A1 - Alexopoulos, T. A1 - Alhroob, M. A1 - Ali, B. A1 - Alimonti, G. A1 - Alison, J. A1 - Andre, S. P. A1 - Allaire, C. A1 - Allbrooke, B. M. M. A1 - Allen, B. W. A1 - Allport, P. P. A1 - Aloisio, A. A1 - Alonso, A. A1 - Alonso, F. A1 - Alpigiani, C. A1 - Alshehri, A. A. A1 - Alstaty, M. I. A1 - Alvarez, Gonzalez B. A1 - Alvarez Piqueras, D. A1 - Alviggi, M. G. A1 - Amadio, B. T. A1 - Amaral, Coutinho, Y. A1 - Ambler, A. A1 - Ambroz, L. A1 - Amelung, C. A1 - Amidei, D. A1 - Amor Dos Santos, S. P. A1 - Amoroso, S. A1 - Amrouche, C. S. A1 - Anastopoulos, C. A1 - Ancu, L. S. A1 - Andari, N. A1 - Andeen, T. A1 - Anders, C. F. A1 - Anders, J. K. A1 - Anderson, K. J. A1 - Andreazza, A. A1 - Andrei, V. A1 - et al, T1 - Measurement of angular and momentum distributions of charged particles within and around jets in Pb plus Pb and pp collisions at root s(NN)=5.02 TeV with ATLAS at the LHC : XXVIIth International Conference on Ultrarelativistic Nucleus-Nucleus Collisions (Quark Matter 2018) JF - Nuclear Physics A N2 - Studies of the fragmentation of jets into charged particles in heavy-ion collisions can help in understanding the mechanism of jet quenching by the hot and dense QCD matter created in such collisions, the quark-gluon plasma. These proceedings present a measurement of the angular distribution of charged particles around the jet axis in root s(NN) = 5.02 TeV Pb+Pb and pp collisions, done using the ATLAS detector at the LHC. The measurement is performed inside jets reconstructed with the anti-k(t) algorithm with radius parameter R = 0.4, and is extended to regions outside the jet cone. Results are presented as a function of Pb+Pb collision centrality, and both jet and charged-particle transverse momenta. KW - jets KW - fragmentation functions KW - jet shapes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224703 VL - 982 IS - 2 ER - TY - JOUR A1 - Rademaker, Manuel E. A1 - Schuberth, Florian A1 - Dijkstra, Theo K. T1 - Measurement error correlation within blocks of indicators in consistent partial least squares : Issues and remedies JF - Internet Research N2 - Purpose The purpose of this paper is to enhance consistent partial least squares (PLSc) to yield consistent parameter estimates for population models whose indicator blocks contain a subset of correlated measurement errors. Design/methodology/approach Correction for attenuation as originally applied by PLSc is modified to include a priori assumptions on the structure of the measurement error correlations within blocks of indicators. To assess the efficacy of the modification, a Monte Carlo simulation is conducted. Findings In the presence of population measurement error correlation, estimated parameter bias is generally small for original and modified PLSc, with the latter outperforming the former for large sample sizes. In terms of the root mean squared error, the results are virtually identical for both original and modified PLSc. Only for relatively large sample sizes, high population measurement error correlation, and low population composite reliability are the increased standard errors associated with the modification outweighed by a smaller bias. These findings are regarded as initial evidence that original PLSc is comparatively robust with respect to misspecification of the structure of measurement error correlations within blocks of indicators. Originality/value Introducing and investigating a new approach to address measurement error correlation within blocks of indicators in PLSc, this paper contributes to the ongoing development and assessment of recent advancements in partial least squares path modeling. KW - Monte Carlo simulation KW - Structural equation modelling KW - Consistent partial least squares KW - Measurement error correlation KW - Model specification Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224901 VL - 29 IS - 3 ER - TY - JOUR A1 - Ruiz, E. Josue A1 - Diefenbacher, Markus E. A1 - Nelson, Jessica K. A1 - Sancho, Rocio A1 - Pucci, Fabio A1 - Chakraborty, Atanu A1 - Moreno, Paula A1 - Annibaldi, Alessandro A1 - Liccardi, Gianmaria A1 - Encheva, Vesela A1 - Mitter, Richard A1 - Rosenfeldt, Mathias A1 - Snijders, Ambrosius P. A1 - Meier, Pascal A1 - Calzado, Marco A. A1 - Behrens, Axel T1 - LUBAC determines chemotherapy resistance in squamous cell lung cancer JF - Journal of Experimental Medicine N2 - Lung squamous cell carcinoma (LSCC) and adenocarcinoma (LADC) are the most common lung cancer subtypes. Molecular targeted treatments have improved LADC patient survival but are largely ineffective in LSCC. The tumor suppressor FBW7 is commonly mutated or down-regulated in human LSCC, and oncogenic KRasG12D activation combined with Fbxw7 inactivation in mice (KF model) caused both LSCC and LADC. Lineage-tracing experiments showed that CC10(+), but not basal, cells are the cells of origin of LSCC in KF mice. KF LSCC tumors recapitulated human LSCC resistance to cisplatin-based chemotherapy, and we identified LUBAC-mediated NF-kappa B signaling as a determinant of chemotherapy resistance in human and mouse. Inhibition of NF-kappa B activation using TAK1 or LUBAC inhibitors resensitized LSCC tumors to cisplatin, suggesting a future avenue for LSCC patient treatment. KW - Solid tumors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227146 VL - 216 IS - 2 ER - TY - JOUR A1 - Robin, Marie A1 - de Wreede, Liesbeth C. A1 - Wolschke, Christine A1 - Schetelig, Johannes A1 - Eikema, Diderik-Jan A1 - Van Lint, Maria Teresa A1 - Knelange, Nina Simone A1 - Beelen, Dietrich A1 - Brecht, Arne A1 - Niederwieser, Dietger A1 - Vitek, Antonin A1 - Bethge, Wolfgang A1 - Arnold, Renate A1 - Finke, Jürgen A1 - Volin, Liisa A1 - Yakoub-Agha, Ibrahim A1 - Nagler, Arnon A1 - Poiré, Xavier A1 - Einsele, Hermann A1 - Chevallier, Patrice A1 - Holler, Ernst A1 - Ljungman, Per A1 - Robinson, Stephen A1 - Radujkovic, Alekxandar A1 - McLornan, Donal A1 - Chalandon, Yves A1 - Kröger, Nicolaus T1 - Long-term outcome after allogeneic hematopoietic cell transplantation for myelofibrosis JF - Haematologica N2 - Allogeneic hematopoietic stem cell transplant remains the only curative treatment for myelofibrosis. Most post-transplantation events Aoccur during the first two years and hence we aimed to analyze the outcome of 2-year disease-free survivors. A total of 1055 patients with myelofibrosis transplanted between 1995 and 2014 and registered in the registry of the European Society for Blood and Marrow Transplantation were included. Survival was compared to the matched general population to determine excess mortality and the risk factors that are associated. In the 2-year survivors, disease-free survival was 64% (60-68%) and overall survival was 74% (71-78%) at ten years; results were better in younger individuals and in women. Excess mortality was 14% (8-21%) in patients aged <45 years and 33% (13-53%) in patients aged >= 65 years. The main cause of death was relapse of the primary disease. Graft-versus-host disease (GvHD) before two years decreased the risk of relapse. Multivariable analysis of excess mortality showed that age, male sex recipient, secondary myelofibrosis and no GvHD disease prior to the 2-year landmark increased the risk of excess mortality. This is the largest study to date analyzing long-term outcome in patients with myelofibrosis undergoing transplant. Overall it shows a good survival in patients alive and in remission at two years. However, the occurrence of late complications, including late relapses, infectious complications and secondary malignancies, highlights the importance of screening and monitoring of long-term survivors. KW - Prognostic scoring system KW - Societe Francaise KW - Gruppo-italiano KW - European group KW - Late mortality KW - Midollo-Osseo KW - LATE DEATHS KW - Survival KW - Blood KW - Ruxolitinib Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226386 VL - 104 IS - 9 ER - TY - JOUR A1 - Radeloff, Katrin A1 - Radeloff, Andreas A1 - Tirado, Mario Ramos A1 - Scherzad, Agmal A1 - Hagen, Rudolf A1 - Kleinsasser, Norbert H. A1 - Hackenberg, Stephan T1 - Long-Term Impact of Zinc Oxide Nanoparticles on Differentiation and Cytokine Secretion of Human Adipose-Derived Stromal Cells JF - Materials N2 - 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. KW - zinc oxide KW - nanoparticles KW - toxicity KW - differentiation potential KW - human adipose-derived stromal cells KW - stem cells Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224779 VL - 12 IS - 1823 ER - TY - JOUR A1 - Rudelius, Martina A1 - Rosenfeldt, Mathias Tillmann A1 - Leich, Ellen A1 - Rauert-Wunderlich, Hilka A1 - Solimando, Antonio Giovanni A1 - Ott, German A1 - Rosenwald, Andreas A1 - Beilhack, Andreas T1 - Inhibition of focal adhesion kinase overcomes resistance of mantle cell lymphoma to ibrutinib in the bone marrow microenvironment JF - Haematologica N2 - Mantle cell lymphoma and other lymphoma subtypes often spread to the bone marrow, and stromal interactions mediated by focal adhesion kinase frequently enhance survival and drug resistance of the lymphoma cells. To study the role of focal adhesion kinase in mantle cell lymphoma, immunohistochemistry of primary cases and functional analysis of mantle cell lymphoma cell lines and primary mantle cell lymphoma cells co-cultured with bone marrow stromal cells (BMSC) using small molecule inhibitors and RNAi-based focal adhesion kinase silencing was performed. We showed that focal adhesion kinase is highly expressed in bone marrow infiltrates of mantle cell lymphoma and in mantle cell lymphoma cell lines. Stroma-mediated activation of focal adhesion kinase led to activation of multiple kinases (AKT, p42/44 and NF-kappa B), that are important for prosurvival and proliferation signaling. Interestingly, RNAi-based focal adhesion kinase silencing or inhibition with small molecule inhibitors (FAKi) resulted in blockage of targeted cell invasion and induced apoptosis by inactivation of multiple signaling cascades, including the classic and alternative NF-kappa B pathway. In addition, the combined treatment of ibrutinib and FAKi was highly synergistic, and ibrutinib resistance of mantle cell lymphoma could be overcome. These data demonstrate that focal adhesion kinase is important for stroma-mediated survival and drug resistance in mantle cell lymphoma, providing indications for a targeted therapeutic strategy. KW - NF-Kappa-B KW - Stromal cells KW - Induced apoptosis KW - Fak regulation KW - Phase- KW - Multiple KW - Activation KW - Mechanisms KW - Migration KW - Pathogenesis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227117 VL - 103 IS - 1 ER - TY - JOUR A1 - Stuckensen, Kai A1 - Lamo-Espinosa, José M. A1 - Muiños-López, Emma A1 - Ripalda-Cemboráin, Purificación A1 - López-Martínez, Tania A1 - Iglesias, Elena A1 - Abizanda, Gloria A1 - Andreu, Ion A1 - Flandes-Iparraguirre, María A1 - Pons-Villanueva, Juan A1 - Elizalde, Reyes A1 - Nickel, Joachim A1 - Ewald, Andrea A1 - Gbureck, Uwe A1 - Prósper, Felipe A1 - Groll, Jürgen A1 - Granero-Moltó, Froilán T1 - Anisotropic cryostructured collagen scaffolds for efficient delivery of RhBMP−2 and enhanced bone regeneration JF - Materials N2 - In the treatment of bone non-unions, an alternative to bone autografts is the use of bone morphogenetic proteins (BMPs), e.g., BMP–2, BMP–7, with powerful osteoinductive and osteogenic properties. In clinical settings, these osteogenic factors are applied using absorbable collagen sponges for local controlled delivery. Major side effects of this strategy are derived from the supraphysiological doses of BMPs needed, which may induce ectopic bone formation, chronic inflammation, and excessive bone resorption. In order to increase the efficiency of the delivered BMPs, we designed cryostructured collagen scaffolds functionalized with hydroxyapatite, mimicking the structure of cortical bone (aligned porosity, anisotropic) or trabecular bone (random distributed porosity, isotropic). We hypothesize that an anisotropic structure would enhance the osteoconductive properties of the scaffolds by increasing the regenerative performance of the provided rhBMP–2. In vitro, both scaffolds presented similar mechanical properties, rhBMP–2 retention and delivery capacity, as well as scaffold degradation time. In vivo, anisotropic scaffolds demonstrated better bone regeneration capabilities in a rat femoral critical-size defect model by increasing the defect bridging. In conclusion, anisotropic cryostructured collagen scaffolds improve bone regeneration by increasing the efficiency of rhBMP–2 mediated bone healing. KW - rhBMP–2 KW - collagen sponge KW - cryostructured scaffolds KW - bone critical size defect Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195966 SN - 1996-1944 VL - 12 IS - 19 ER -