RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis

Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC

Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study

Background: Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings. Methods: Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed. Results: In the total population (N = 334),median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211),median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%),anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered. Conclusions: This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC

Kinetic analysis of the abnormal fluorimetric titration behaviour of naphthylamines

The fluorimetric titration behaviour of naphthylamines is abnormal in that the sum of the reduced quantum yields of conjugated acid and base passes through a minimum. Based on fluorescence quantum yield and lifetime measurements, we explain this behaviour by two independent mechanisms: A diabatic quenching of the excited base by protons and a decrease of the excited cation's protolytic dissociation in the hyperacidic region. Though apparently independent processes, their rate constants can be shown to be related to each other by a quasi-thermodynamical equation

Optical and electrical properties of pulsed laser annealed thin Si films

Thin Si films used for solar energy purposes are commonly treated by relatively slow thermal annealing on a time scale of seconds to obtain the proper electrical behavior. We investigated a different approach, in which the films are annealed and/or molten by a frequency doubled Q-switched Nd:YAG laser pulse on a nanosecond time scale. We studied thin polycrystalline Si films of thickness between 43 nm and 250 nm on fused silica and on sapphire substrates. The different thermal conductivities of these substrates lead to different quench rates for the molten Si films. The optical and electrical properties of the Si films were systematically characterized during, respectively after the various annealing conditions. In addition we monitored the solidification process in situ by time-resolved optical measurements. At low energy densities the film is not completely molten by the laser pulse and resolidification takw place at the moving liquidsolid interface. Above a thickness-dependent threshold energy density complete melting is observed and nucleation in the supercooled melt prevails. In the latter case Sameshima and Usui showed that amorphization can be observed far Si films on fused silica up to thicknesses of 36 nm. We found that Si films on sapphire even with a thickness of 80nm can be amorphized. The reproducible threshold values suggest the possibilty of lateral structuring

Validation of a new emotion regulation self-report questionnaire for children

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Objective</jats:title> <jats:p>To examine and validate the self-report Questionnaire on the Regulation of Unpleasant Moods in Children (FRUST), which is a modified and shortened version of the Questionnaire for the Assessment of Emotion Regulation in Children and Adolescents (FEEL-KJ).</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>The data comprised child and parent ratings of a community-screened sample with differing levels of affective dysregulation (AD) (<jats:italic>N</jats:italic> = 391, age: <jats:italic>M</jats:italic> = 10.64, <jats:italic>SD</jats:italic> = 1.33, 56% male). We conducted latent factor analyses to establish a factor structure. Subsequently, we assessed measurement invariance (MI) regarding age, gender, and AD level and evaluated the internal consistencies of the scales. Finally, we examined the convergent and divergent validity of the instrument by calculating differential correlations between the emotion regulation strategy (ERS) scales and self- and parent-report measures of psychopathology.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>A four-factor model, with one factor representing <jats:italic>Dysfunctional Strategies</jats:italic> and the three factors <jats:italic>Distraction</jats:italic>, <jats:italic>Problem-Solving</jats:italic> and <jats:italic>Social Support</jats:italic> representing functional strategies provided the best fit to our data and was straightforward to interpret. We found strong MI for age and gender and weak MI for AD level. Differential correlations with child and parent ratings of measures of psychopathology supported the construct validity of the factors.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>We established a reliable and valid self-report measure for the assessment of ERS in children. Due to the reduced number of items and the inclusion of highly specific regulatory behaviors, the FRUST might be a valuable contribution to the assessment of ER strategies for diagnostic, therapeutic, and research purposes.</jats:p> </jats:sec&gt

ProteomeBinders: planning a European resource of affinity reagents for analysis of the human proteome

ProteomeBinders is a new European consortium aiming to establish a comprehensive resource of well-characterized affinity reagents, including but not limited to antibodies, for analysis of the human proteome. Given the huge diversity of the proteome, the scale of the project is potentially immense but nevertheless feasible in the context of a pan-European or even worldwide coordination