Wechselwirkung des Transkriptionsfaktors Nuclear factor E2-related factor 2 (Nrf2) mit TGF-β1 sowie deren Einfluss auf malignitätsassoziierte Eigenschaften in Pankreasgangepithelzellen

Die inflammatorische Karzinogenese des PDAC ist ein komplexes Netzwerk aus intrazellulären Signalkaskaden und zellulären Vorgängen. Einen wichtigen Beitrag dazu leisten TGF-β1 und mutiertes K-ras. Diese Arbeit liefert neue Erkenntnisse über die Rolle von Nrf2 im funktionellen Wechsel von TGF-β1 vom Tumorsuppressor zum Tumorpromoter, welcher anscheinend bereits früh in der pankreatischen Karzinogenese seinen Ursprung nimmt. Während beide Faktoren allein unter physiologischen und akut entzündlichen Bedingungen die Zellhomöostase maßgeblich regulieren, führt ihre gleichzeitige und dauerhaft erhöhte Präsenz zur gegenseitigen Initiierung protumorigener Zelleigenschaften. So konnte im Rahmen dieser Arbeit gezeigt werden, dass gegenseitige Wechselwirkungen zu einer Steigerung des Zellwachstums und -überlebens von benignen und prämalignen Pankreasgangepithelzellen führte. Dies steht stellvertretend für die Entkopplung von den zellzyklusregulierenden Eigenschaften des TGF-β1 sowie die Verstärkung der TGF-β1-vermittelten Apoptoseresistenz durch Nrf2. Die Interaktion spiegelt sich auf Signaltransduktionsebene in einer verminderten TGF-β1-vermittelten Aktivierung von Smad3 sowie der MAPK p38 wider. Das mutierte Onkogen K-ras erhöht zwar die Aktivität von Nrf2 in HPDE Zellen, eine Steigerung der zuvor beschriebenen Nrf2-abhängigen Effekte machte sich dadurch jedoch nicht bemerkbar. Die TGF-β1-vermittelte EMT benigner Pankreasgangepithelzellen zeigte sich weitgehend unabhängig von Nrf2

Extensive alterations of the whole-blood transcriptome are associated with body mass index: results of an mRNA profiling study involving two large population-based cohorts

Background: Obesity, defined as pathologically increased body mass index (BMI),is strongly related to an increased risk for numerous common cardiovascular and metabolic diseases. It is particularly associated with insulin resistance, hyperglycemia, and systemic oxidative stress and represents the most important risk factor for type 2 diabetes (T2D). However, the pathophysiological mechanisms underlying these associations are still not completely understood. Therefore, in order to identify potentially disease-relevant BMI-associated gene expression signatures, a transcriptome-wide association study (TWAS) on BMI was performed. Methods: Whole-blood mRNA levels determined by array-based transcriptional profiling were correlated with BMI in two large independent population-based cohort studies (KORA F4 and SHIP-TREND) comprising a total of 1977 individuals. Results: Extensive alterations of the whole-blood transcriptome were associated with BMI: More than 3500 transcripts exhibited significant positive or negative BMI-correlation. Three major whole-blood gene expression signatures associated with increased BMI were identified. The three signatures suggested: i) a ratio shift from mature erythrocytes towards reticulocytes, ii) decreased expression of several genes essentially involved in the transmission and amplification of the insulin signal, and iii) reduced expression of several key genes involved in the defence against reactive oxygen species (ROS). Conclusions: Whereas the first signature confirms published results, the other two provide possible mechanistic explanations for well-known epidemiological findings under conditions of increased BMI, namely attenuated insulin signaling and increased oxidative stress. The putatively causative BMI-dependent down-regulation of the expression of numerous genes on the mRNA level represents a novel finding. BMI-associated negative transcriptional regulation of insulin signaling and oxidative stress management provide new insights into the pathogenesis of metabolic syndrome and T2D

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING: For detailed information per study, see Acknowledgments.This work was supported by a grant from the US National Heart, Lung, and Blood Institute (N01-HL-25195; R01HL 093328 to RSV), a MAIFOR grant from the University Medical Center Mainz, Germany (to PSW), the Center for Translational Vascular Biology (CTVB) of the Johannes Gutenberg-University of Mainz, and the Federal Ministry of Research and Education, Germany (BMBF 01EO1003 to PSW). This work was also supported by the research project Greifswald Approach to Individualized Medicine (GANI_MED). GANI_MED was funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg, West Pomerania (contract 03IS2061A). We thank all study participants, and the colleagues and coworkers from all cohorts and sites who were involved in the generation of data or in the analysis. We especially thank Andrew Johnson (FHS) for generation of the gene annotation database used for analysis. We thank the German Center for Cardiovascular Research (DZHK e.V.) for supporting the analysis and publication of this project. RSV is a member of the Scientific Advisory Board of the DZHK. Data on CAD and MI were contributed by CARDIoGRAMplusC4D investigators. See Supplemental Acknowledgments for consortium details. PSW, JFF, AS, AT, TZ, RSV, and MD had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis

Light weight car seat

Den här rapporten handlar om framtagningen av en bilstoldesign inom lättkonstruktioner. Stolen i fråga är anpassad efter ett steer-by-wire system, vilket innebär en datoriserad koppling mellan ratt, pedaler, motor och hjul. Rapporten behandlar vår arbetsgång med beräkningar, kravspecifikationer, labborationsresultat och materialforskning som ledde oss fram till vår slutliga produkt. Längst bak i rapporten finns alla bilagor. T.ex. den fullständiga kravspecifikationen, uppdraget som var givet från början samt beräkningar och koder. Stolen ska installeras i KTHs RCV och förhoppningen är att den även kommer användas i framtida koncept där hela störtbågen och chassit är anpassat utifrån viktoptimering

SOCIUS Mentoring—A Novel Course to Encourage Students for a Career as Surgical Oncologists

Surgical disciplines are affected by an increasing shortage of young doctors. Studies show that formerly interested students decide against a career in surgical disciplines at the end of their studies or during practical year. Measures to counteract this development are urgently needed. As a joint project between gynecology, urology, and general surgery, SOCIUS mentoring was designed to prepare and encourage students for a career in surgical oncology. The structured curriculum of SOCIUS mentoring contains six modules, including surgical skills, soft skills, mentoring, theory, clinical visitation, and congress participation and runs over one year. Effects on confidence towards physician skills and plans for a future career were evaluated with questionnaires. After participation, students reported increased confidence in surgical and soft skills. In addition, participants noted that they have specified their career goals and gained more confidence in surgery, as well as seeing more development potential for a career in surgery. We describe the implementation of a novel extracurricular program for motivated students that combines individual mentoring with surgical and soft skills training. Due to its modular structure, this concept can easily be transferred to other disciplines. SOCIUS mentoring, with its combination of mentoring and skills training, is a promising measure to prepare and motivate students for their surgical career and thus counteract the shortage of young talent

A FDG-PET radiomics signature detects esophageal squamous cell carcinoma patients who do not benefit from chemoradiation

Detection of patients with esophageal squamous cell carcinoma (ESCC) who do not benefit from standard chemoradiation (CRT) is an important medical need. Radiomics using 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a promising approach. In this retrospective study of 184 patients with locally advanced ESCC. 152 patients from one center were grouped into a training cohort (n = 100) and an internal validation cohort (n = 52). External validation was performed with 32 patients treated at a second center. Primary endpoint was disease-free survival (DFS), secondary endpoints were overall survival (OS) and local control (LC). FDG-PET radiomics features were selected by Lasso-Cox regression analyses and a separate radiomics signature was calculated for each endpoint. In the training cohort radiomics signatures containing up to four PET derived features were able to identify non-responders in regard of all endpoints (DFS p < 0.001, LC p = 0.003, OS p = 0.001). After successful internal validation of the cutoff values generated by the training cohort for DFS (p = 0.025) and OS (p = 0.002), external validation using these cutoffs was successful for DFS (p = 0.002) but not for the other investigated endpoints. These results suggest that pre-treatment FDG-PET features may be useful to detect patients who do not respond to CRT and could benefit from alternative treatment

Rilke's Novel Die Aufzeichungen des Malte Laurids Brigge in Czech Translations

The diploma thesis deals with two translations of Rilke's novel Die Aufzeichnungen des Malte Laurids Brigge. Each translation is not only conceived as a final product, but also as a communication process, influenced by a number of cultural and socio-political factors. The thesis therefore attempts to capture changes in Rilke's reception in relation to the literary paradigm and - with regards to the political situation - to the contemporary publisher policy, because during the period of socialism Rilke's work, which was highly valued in the thirties, came back into general awareness quite slowly in connection with the gradual liberation of cultural and political situation. The goal of the thesis is to map the problems of the translations' genesis with regards to the period and cultural environment and to the translators' poetic style. Part of the thesis addresses a translatological analysis, which is the base for defining both of the translators' methods

Estimation of the pKa values of water ligands in transition metal complexes using density functional theory with polarized continuum model solvent corrections

The deprotonation energies of the water ligands in a set of 40 d-block metal complexes have been calculated using density functional theory with polarized continuum model solvent corrections. The complexes include 13 aqua ions [M(OH2)n]2+/3+ and a variety of aqua complexes with organic co-ligands, whose experimental pKa values have been reported in the literature. For comparison, the deprotonation energies of a set of 60 organic and inorganic molecules with experimental pKa values ranging from -25 (HSbF6) to +52 (C2H6) have also been calculated. Three different classes of acids are identified as giving different slopes in plots of pKaversus deprotonation energies; namely non-hydroxy acids, hydroxy acids, and the metal complexes. The correlation coefficients for the straight lines obtained for these three classes are 0.96, 0.97 and 0.92 respectively. Better correlations are found for sub-sets of the complexes, such as the 31 first row complexes (correlation coefficient 0.95).For several of the complexes, comparison of the calculated and observed pKa values, together with changes in the geometry upon optimization, offer new insights into the possible solution structures. It is concluded that DFT calculations incorporating solvent corrections can be used to give reasonable estimates of pKa values for the aqua ligands in a range of complex types

<i>Eigen-R²</i> results for SHIP-TREND, KORA F4 and GHS.

*<p><i>Storage time</i>: <i>Time between blood donation and RNA isolation</i> (SHIP-TREND and KORA F4) or <i>time between RNA isolation and RNA amplification</i> (GHS).</p><p>The first six lines of the Table represent technical parameters. A dash indicates that the parameter was not available in the cohort.</p