524 research outputs found

    A Novel Predictor Tool of Biochemical Recurrence after Radical Prostatectomy Based on a Five-MicroRNA Tissue Signature

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    Within five to ten years after radical prostatectomy (RP), approximately 15-34% of prostate cancer (PCa) patients experience biochemical recurrence (BCR), which is defined as recurrence of serum levels of prostate-specific antigen >0.2 µg/L, indicating probable cancer recurrence. Models using clinicopathological variables for predicting this risk for patients lack accuracy. There is hope that new molecular biomarkers, like microRNAs (miRNAs), could be potential candidates to improve risk prediction. Therefore, we evaluated the BCR prognostic capability of 20 miRNAs, which were selected by a systematic literature review. MiRNA expressions were measured in formalin-fixed, paraffin-embedded (FFPE) tissue RP samples of 206 PCa patients by RT-qPCR. Univariate and multivariate Cox regression analyses were performed, to assess the independent prognostic potential of miRNAs. Internal validation was performed, using bootstrapping and the split-sample method. Five miRNAs (miR-30c-5p/31-5p/141-3p/148a-3p/miR-221-3p) were finally validated as independent prognostic biomarkers. Their prognostic ability and accuracy were evaluated using C-statistics of the obtained prognostic indices in the Cox regression, time-dependent receiver-operating characteristics, and decision curve analyses. Models of miRNAs, combined with relevant clinicopathological factors, were built. The five-miRNA-panel outperformed clinically established BCR scoring systems, while their combination significantly improved predictive power, based on clinicopathological factors alone. We conclude that this miRNA-based-predictor panel will be worth to be including in future studies

    Circular RNAs in Clear Cell Renal Cell Carcinoma: Their Microarray-Based Identification, Analytical Validation, and Potential Use in a Clinico-Genomic Model to Improve Prognostic Accuracy

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    Circular RNAs (circRNAs) may act as novel cancer biomarkers. However, a genome-wide evaluation of circRNAs in clear cell renal cell carcinoma (ccRCC) has yet to be conducted. Therefore, the objective of this study was to identify and validate circRNAs in ccRCC tissue with a focus to evaluate their potential as prognostic biomarkers. A genome-wide identification of circRNAs in total RNA extracted from ccRCC tissue samples was performed using microarray analysis. Three relevant differentially expressed circRNAs were selected (circEGLN3, circNOX4, and circRHOBTB3), their circular nature was experimentally confirmed, and their expression-along with that of their linear counterparts-was measured in 99 malignant and 85 adjacent normal tissue samples using specifically established RT-qPCR assays. The capacity of circRNAs to discriminate between malignant and adjacent normal tissue samples and their prognostic potential (with the endpoints cancer-specific, recurrence-free, and overall survival) after surgery were estimated by C-statistics, Kaplan-Meier method, univariate and multivariate Cox regression analysis, decision curve analysis, and Akaike and Bayesian information criteria. CircEGLN3 discriminated malignant from normal tissue with 97% accuracy. We generated a prognostic for the three endpoints by multivariate Cox regression analysis that included circEGLN3, circRHOBT3 and linRHOBTB3. The predictive outcome accuracy of the clinical models based on clinicopathological factors was improved in combination with this circRNA-based signature. Bootstrapping as well as Akaike and Bayesian information criteria confirmed the statistical significance and robustness of the combined models. Limitations of this study include its retrospective nature and the lack of external validation. The study demonstrated the promising potential of circRNAs as diagnostic and particularly prognostic biomarkers in ccRCC patients

    miR-199a-3p and miR-214-3p improve the overall survival prediction of muscle- invasive bladder cancer patients after radical cystectomy

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    To improve the clinical decision-making regarding further treatment management and follow-up scheduling for patients with muscle-invasive bladder cancer (MIBC) after radical cystectomy (RC), a better prediction accuracy of prognosis for these patients is urgently needed. The objective of this study was to evaluate the validity of differentially expressed microRNAs (miRNAs) based on a previous study as prognostic markers for overall survival (OS) after RC in models combined with clinicopathological data. The expression of six miRNAs (miR-100-5p, miR-130b-3p, miR-141-3p, miR-199a-3p, miR-205-5p, and miR-214-3p) was measured by RT-qPCR in formalin-fixed, paraffin-embedded tissue samples from 156 MIBC patients who received RC in three urological centers. Samples from 2000 to 2013 were used according to their tissue availability, with follow-up until June 2016. The patient cohort was randomly divided into a training (n = 100) and test set (n = 56). Seventy-three samples from adjacent normal tissue were used as controls. Kaplan–Meier, univariate and multivariate Cox regression, and decision curve analyses were carried out to assess the association of clinicopathological variables and miRNAs to OS. Both increased (miR-130b-3p and miR-141-3p) and reduced (miR-100-5p, miR-199a- 3p, and miR-214-3p) miRNA expressions were found in MIBC samples in comparison to nonmalignant tissue samples (P < 0.0001). miR-199a-3p and miR-214-3p were independent markers of OS in Cox regression models with the significant clinicopathological variables age, tumor status, and lymph node status. The prediction model with the clinicopathological variables was improved by these two miRNAs in both sets. The predictive benefit was confirmed by decision curve analysis. In conclusion, the inclusion of both miRNAs into models based on clinical data for the outcome prediction of MIBC patients after RC could be a valuable approach to improve prognostic accuracy

    Fast and slow Kelvin waves in the Madden-Julian Oscillation of a GCM

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    The structure of the Madden-Julian Oscillation (MJO) in an 1800-day integration of the Hadley Centre Unified Model was analysed, and interpreted within a Kelvin wave framework. The model was forced with constant equinoctial (March) boundary conditions so that a ``clean'' MJO signal could be separated from the effects of the seasonal cycle and forced interannual variability. The simulated MJO was fairly realistic in terms of its large-scale spatial structure and propagation characteristics, although its period of 30 days (corresponding to an average phase speed of 15 \mps) was shorter than that observed. The signal in deep convection was less coherent than in observations, and appeared to move eastward as a sequence of discrete convective anomalies, rather than by a smooth eastward propagation. Both ``fast'' and ``slow'' equatorial Kelvin waves appeared to play an important role in the eastward propagation of the simulated MJO. Enhanced convection over the Indian Ocean was associated with a ``fast'' equatorial Kelvin wave that propagated eastward at 55 m s-1 over the Pacific. On reaching the west coast of South America, a component of this Kelvin wave propagated northward and southward as a trapped wave along the mountain ranges of Central America and the Andes, in agreement with observations. The anomalous surface easterlies over the tropical eastern Pacific associated with this fast Kelvin wave enhanced the climatological mean easterlies and led to positive convective anomalies over the eastern Pacific consistent with the WISHE mechanism. However, WISHE was not able to account for the eastward development of the convective anomalies over the Indian Ocean/western Pacific region. By splitting the equatorial divergence anomalies of the simulated MJO into their du/dx and dv/dy components, the role of Kelvin wave dynamics in the ``slow'' (15 m s-1) average eastward propagation of the simulated MJO was examined. Although the two components were of comparable magnitude, the \dudx\ component exhibited a pronounced eastward propagation which tended to be disrupted by the \dvdy\ component, thus supporting the paradigm of an underlying, but strongly modified, Kelvin wave mechanism

    North American monsoon and convectively coupled equatorial waves simulated by IPCC AR4 coupled GCMs

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    This study evaluates the fidelity of North American monsoon and associated intraseasonal variability in the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4) coupled general circulation models (CGCMs). Twenty years of monthly precipitation data from each of the 22 models' twentieth-century climate simulations, together with the available daily precipitation data from 12 of them, are analyzed and compared with Global Precipitation Climatology Project (GPCP) monthly and daily precipitation. The authors focus on the seasonal cycle and horizontal pattern of monsoon precipitation in conjunction with the two dominant convectively coupled equatorial wave modes: the eastward-propagating Madden-Julian oscillation (MJO) and the westward-propagating easterly waves. The results show that the IPCC AR4 CGCMs have significant problems and display a wide range of skill in simulating the North American monsoon and associated intraseasonal variability. Most of the models reproduce the monsoon rainbelt, extending from southeast to northwest, and its gradual northward shift in early summer, but overestimate the precipitation over the core monsoon region throughout the seasonal cycle and fail to reproduce the monsoon retreat in the fall. Additionally, most models simulate good westward propagation of the easterly waves, but relatively poor eastward propagation of the MJO and overly weak variances for both the easterly waves and the MJO. There is a tendency for models without undiluted updrafts in their deep convection scheme to produce better MJO propagation.open221

    miR-9-5p in Nephrectomy Specimens is a Potential Predictor of Primary Resistance to First-Line Treatment with Tyrosine Kinase Inhibitors in Patients with Metastatic Renal Cell Carcinoma

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    Approximately 20-30% of patients with metastatic renal cell carcinoma (mRCC) in first-line treatment with tyrosine kinase inhibitors (TKIs) do not respond due to primary resistance to this drug. At present, suitable robust biomarkers for prediction of a response are not available. Therefore, the aim of this study was to evaluate a panel of microRNAs (miRNAs) in nephrectomy specimens for use as predictive biomarkers for TKI resistance. Archived formalin-fixed, paraffin embedded nephrectomy samples from 60 mRCC patients treated with first-line TKIs (sunitinib, n = 51; pazopanib, n = 6; sorafenib, n = 3) were categorized into responders and non-responders. Using the standard Response Evaluation Criteria in Solid Tumors, patients with progressive disease within 3 months after the start of treatment with TKI were considered as non-responders and those patients with stable disease and complete or partial response under the TKI treatment for at least 6 months as responders. Based on a miRNA microarray expression profile in the two stratified groups of patients, seven differentially expressed miRNAs were validated using droplet digital reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) assays in the two groups. Receiver operating characteristic curve analysis and binary logistic regression of response prediction were performed. MiR-9-5p and miR-489-3p were able to discriminate between the two groups. MiR-9-5p, as the most significant miRNA, improved the correct prediction of primary resistance against TKIs in comparison to that of conventional clinicopathological variables. The results of the decision curve analyses, Kaplan-Meier analyses and Cox regression analyses confirmed the potential of miR-9-5p in the prediction of response to TKIs and the prediction of progression-free survival after the initiation of TKI treatment

    Assistenzsystem für die Prüfung von Blechbauteilen mit Mehrkomponenten-Streifenprojektionssystemen unter Anwendung der „virtuellen Rückdeformation“

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    Fringe Projection Systems are increasingly used for dimensional inspection. They are especially suited for the cycle time compatible inspection of lightweight structures – that are deformed due to internal stress – without clamping by use of ‘virtual reverse deformation’. However, the inspection sequence has to be determined under consid-eration of inspection task, measurement uncertainty and minimal inspection effort. Today this complex planning is performed unmethodically. Consequences are long planning time, high inspection costs and the risk of unsuitably planned inspections. This work introduces an approach for the elimination of these shortcomings by use of a simulation-based assistance system that supports the inspection planner when set-ting up a task-sensitive inspection sequence. It is based on a model for the simulation of planned measurements, including a GUM-compatible forecast of the local mea-surement uncertainty. Herewith, the quality of a planned inspection sequence can be determined and optimized task-sensitively by use of elaborated automatic algorithms. The scientific fundamentals are stated universally and realized in a prototype of such assistance system. The model for simulation of measurements and the automatic inspection planning methods are successfully verified.Streifenprojektionssysteme werden zunehmend in der dimensionellen Bauteilprüfung eingesetzt. Insbesonders sind sie geeignet um flächige und durch Eigenspannungen deformierte Leichtbauteile unter Anwendung der „virtuellen Rückdeformation“ takt-zeitgerecht ohne Aufspannung zu prüfen. Zur Durchführung der Bauteilprüfung muss der Prüfablauf optimal geplant werden. Diese komplexe, multikriterielle Planung – bei der u.a. zu prüfende Merkmale, die akzeptable Messunsicherheit und wirtschaftliche Aspekte zu berücksichtigen sind – erfolgt bislang unmethodisch und subjektiv. Die Folgen sind lange Planungs- und Prüfzeiten, hohe Prüfkosten und die Gefahr man-gelhafter Prüfergebnisse aufgrund nicht aufgabenorientiert geplanter Prüfstrategien. Die vorliegende Arbeit zeigt einen Ansatz zur Beseitigung dieser Defizite mittels ei-nes simulationsbasierten Assistenzsystems zur Unterstützung des Prüfplaners bei der Ermittlung eines aufgabengerechten Prüfablaufplans. Er basiert auf einem physikalischen Modell zur Simulation der Streifenprojektionsmessung, inklusive der GUM-konformen Prognose der lokal auftretenden Messunsicherheit. Auf dieser Basis kann die Güte eines geplanten Prüfablaufs abgeschätzt und diese mittels erarbeiteter Algorithmen weitgehend automatisch, multikriteriell und toleranzgerecht optimiert wer-den. Die wissenschaftlichen Grundlagen werden allgemein beschrieben und in einem Prototyp realisiert. Die Güte des Modells zur Simulation von Messungen und die Wirksamkeit der automatischen Prüfablaufplanung werden experimentell verifiziert

    Jugendverbände in Berlin

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    JUGENDVERBÄNDE IN BERLIN Jugendverbände in Berlin / Weickmann, Tilmann (Rights reserved) ( -

    The impacts of convective parameterization and moisture triggering on AGCM-simulated convectively coupled equatorial waves

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    This study examines the impacts of convective parameterization and moisture convective trigger on convectively coupled equatorial waves simulated by the Seoul National University (SNU) atmospheric general circulation model (AGCM). Three different convection schemes are used, including the simplified Arakawa-Schubert (SAS) scheme, the Kuo (1974) scheme, and the moist convective adjustment (MCA) scheme, and a moisture convective trigger with variable strength is added to each scheme. The authors also conduct a "no convection" experiment with deep convection schemes turned off. Space-time spectral analysis is used to obtain the variance and phase speed of dominant convectively coupled equatorial waves, including the Madden-Julian oscillation (MJO), Kelvin, equatorial Rossby (ER), mixed Rossby-gravity (MRG), and eastward inertio-gravity (EIG) and westward inertio-gravity (WIG) waves. The results show that both convective parameterization and the moisture convective trigger have significant impacts on AGCM-simulated, convectively coupled equatorial waves. The MCA scheme generally produces larger variances of convectively coupled equatorial waves including the MJO, more coherent eastward propagation of the MJO, and a more prominent MJO spectral peak than the Kuo and SAS schemes. Increasing the strength of the moisture trigger significantly enhances the variances and slows down the phase speeds of all wave modes except the MJO, and usually improves the eastward propagation of the MJO for the Kuo and SAS schemes, but the effect for the MCA scheme is small. The no convection experiment always produces one of the best signals of convectively coupled equatorial waves and the MJO.open585
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