Krüppel-like factors in cancer progression: three fingers on the steering wheel

Kruppel-like factors (KLFs) comprise a highly conserved family of zinc finger transcription factors, that are involved in a plethora of cellular processes, ranging from proliferation and apoptosis to differentiation, migration and pluripotency. During the last few years, evidence on their role and deregulation in different human cancers has been emerging. This review will discuss current knowledge on Kruppel-like transcription in the epithelial-mesenchymal transition (EMT), invasion and metastasis, with a focus on epithelial cancer biology and the extensive interface with pluripotency. Furthermore, as KLFs are able to mediate different outcomes, important influences of the cellular and microenvironmental context will be highlighted. Finally, we attempt to integrate diverse findings on KLF functions in EMT and stem cell biology to fit in the current model of cellular plasticity as a tool for successful metastatic dissemination

Comparative analysis of dynamic cell viability, migration and invasion assessments by novel real-time technology and classic endpoint assays

Background: Cell viability and motility comprise ubiquitous mechanisms involved in a variety of (patho)biological processes including cancer. We report a technical comparative analysis of the novel impedance-based xCELLigence Real-Time Cell Analysis detection platform, with conventional label-based endpoint methods, hereby indicating performance characteristics and correlating dynamic observations of cell proliferation, cytotoxicity, migration and invasion on cancer cells in highly standardized experimental conditions. Methodology/Principal Findings: Dynamic high-resolution assessments of proliferation, cytotoxicity and migration were performed using xCELLigence technology on the MDA-MB-231 (breast cancer) and A549 (lung cancer) cell lines. Proliferation kinetics were compared with the Sulforhodamine B (SRB) assay in a series of four cell concentrations, yielding fair to good correlations (Spearman's Rho 0.688 to 0.964). Cytotoxic action by paclitaxel (0-100 nM) correlated well with SRB (Rho>0.95) with similar IC50 values. Reference cell migration experiments were performed using Transwell plates and correlated by pixel area calculation of crystal violet-stained membranes (Rho 0.90) and optical density (OD) measurement of extracted dye (Rho. 0.95). Invasion was observed on MDA-MB-231 cells alone using Matrigel-coated Transwells as standard reference method and correlated by OD reading for two Matrigel densities (Rho>0.95). Variance component analysis revealed increased variances associated with impedance-based detection of migration and invasion, potentially caused by the sensitive nature of this method. Conclusions/Significance: The xCELLigence RTCA technology provides an accurate platform for non-invasive detection of cell viability and motility. The strong correlations with conventional methods imply a similar observation of cell behavior and interchangeability with other systems, illustrated by the highly correlating kinetic invasion profiles on different platforms applying only adapted matrix surface densities. The increased sensitivity however implies standardized experimental conditions to minimize technical-induced variance

Tumor Cells and Tumor-Associated Macrophages: Secreted Proteins as Potential Targets for Therapy

Inflammatory pathways, meant to defend the organism against infection and injury, as a byproduct, can promote an environment which favors tumor growth and metastasis. Tumor-associated macrophages (TAMs), which constitute a significant part of the tumor-infiltrating immune cells, have been linked to the growth, angiogenesis, and metastasis of a variety of cancers, most likely through polarization of TAMs to the M2 (alternative) phenotype. The interaction between tumor cells and macrophages provides opportunities for therapy. This paper will discuss secreted proteins as targets for intervention

Geochemical heterogeneity of sand deposits and its implications for the provenance determination of Roman glass

During the production of natron glass most features of the raw materials are lost and only some bulk geochemical characteristics have potential as provenance indicators. To determine the primary origin of archaeological glass artefacts, suitable sand raw materials have to be accurately characterised. In this respect, information about the possible variation in geochemical properties within a silica source is also vital to account for potential (partial) overlap of different sources. In this study, it is shown that the variation in major and minor elemental composition of beach sand on a local scale is smaller than the variation in Roman natron glass. Therefore, a single sand deposit can be seen as a relatively homogeneous source of silica for glass production. Nd isotopic signatures are identical for all samples analysed. The isotopic composition of Sr however varies considerably due to local variations in the relative proportions of carbonates and silicates (mostly feldspar).status: publishe

Towards the sequential assimilation of SAR-derived water stages into hydraulic models using the Particle Filter : proof of concept

With the onset of new satellite radar constellations (e.g. Sentinel-1) and advances in computational science (e.g. grid computing) enabling the supply and processing of multimission satellite data at a temporal frequency that is compatible with real-time flood forecasting requirements, this study presents a new concept for the sequential assimilation of Synthetic Aperture Radar (SAR)-derived water stages into coupled hydrologic-hydraulic models. The proposed methodology consists of adjusting storages and fluxes simulated by a coupled hydrologic-hydraulic model using a Particle Filterbased data assimilation scheme. Synthetic observations of water levels, representing satellite measurements, are assimilated into the coupled model in order to investigate the performance of the proposed assimilation scheme as a function of both accuracy and frequency of water level observations. The use of the Particle Filter provides flexibility regarding the form of the probability densities of both model simulations and remote sensing observations. We illustrate the potential of the proposed methodology using a twin experiment over a widely studied river reach located in the Grand-Duchy of Luxembourg. The study demonstrates that the Particle Filter algorithm leads to significant uncertainty reduction of water level and discharge at the time step of assimilation. However, updating the storages of the model only improves the model forecast over a very short time horizon. A more effective way of updating thus consists in adjusting both states and inputs. The proposed methodology, which consists in updating the biased forcing of the hydraulic model using information on model errors that is inferred from satellite observations, enables persistent model improvement. The present schedule of satellite radar missions is such that it is likely that there will be continuity for SAR-based operational water management services. This research contributes to evolve reactive flood management into systematic or quasi-systematic SAR-based flood monitoring services

Recent developments in the treatment of small cell lung cancer

Small cell lung cancer (SCLC) comprises about 15% of all lung cancers. It is an aggressive disease, with early metastasis and a poor prognosis. Until recently, SCLC treatment remained relatively unchanged, with chemotherapy remaining the cornerstone of treatment. In this overview we will highlight the recent advances in the field of staging, surgery, radiotherapy and systemic treatment. Nevertheless, the prognosis remains dismal and there is a pressing need for new treatment options. We describe the progress that has been made in systemic treatment by repurposing existing drugs and the addition of targeted treatment. In recent years, immunotherapy entered the clinic with high expectations of its role in the treatment of SCLC. Unravelling of the genomic sequence revealed new possible targets that may act as biomarkers in future treatment of patients with SCLC. Hopefully, in the near future, we will be able to identify patients who may benefit from targeted therapy or immunotherapy to improve prognoses

Assimilating SAR-derived water level data into a hydraulic model: a case study

Satellite-based active microwave sensors not only provide synoptic overviews of flooded areas, but also offer an effective way to estimate spatially distributed river water levels. If rapidly produced and processed, these data can be used for updating hydraulic models in near real-time. The usefulness of such approaches with real event data sets provided by currently existing sensors has yet to be demonstrated. In this case study, a Particle Filter-based assimilation scheme is used to integrate ERS-2 SAR and ENVISAT ASAR-derived water level data into a one-dimensional (1-D) hydraulic model of the Alzette River. Two variants of the Particle Filter assimilation scheme are proposed with a global and local particle weighting procedure. The first option finds the best water stage line across all cross sections, while the second option finds the best solution at individual cross sections. The variant that is to be preferred depends on the level of confidence that is attributed to the observations or to the model. The results show that the Particle Filter-based assimilation of remote sensing-derived water elevation data provides a significant reduction in the uncertainty at the analysis step. Moreover, it is shown that the periodical updating of hydraulic models through the proposed assimilation scheme leads to an improvement of model predictions over several time steps. However, the performance of the assimilation depends on the skill of the hydraulic model and the quality of the observation data

Expression profiling of migrated and invaded breast cancer cells predicts early metastatic relapse and reveals Krüppel-like factor 9 as a potential suppressor of invasive growth in breast cancer

Cell motility and invasion initiate metastasis. However, only a subpopulation of cancer cells within a tumor will ultimately become invasive. Due to this stochastic and transient nature, in an experimental setting, migrating and invading cells need to be isolated from the general population in order to study the gene expression profiles linked to these processes. This report describes microarray analysis on RNA derived from migrated or invaded subpopulations of triple negative breast cancer cells in a Transwell set-up, at two different time points during motility and invasion, pre-determined as “early” and “late” in real-time kinetic assessments. Invasion- and migration-related gene expression signatures were generated through comparison with non-invasive cells, remaining at the upper side of the Transwell membranes. Late-phase signatures of both invasion and migration indicated poor prognosis in a series of breast cancer data sets. Furthermore, evaluation of the genes constituting the prognostic invasion-related gene signature revealed Krüppel-like factor 9 (KLF9) as a putative suppressor of invasive growth in breast cancer. Next to loss in invasive vs non-invasive cell lines, KLF9 also showed significantly lower expression levels in the “early” invasive cell population, in several public expression data sets and in clinical breast cancer samples when compared to normal tissue. Overexpression of EGFP-KLF9 fusion protein significantly altered morphology and blocked invasion and growth of MDA-MB-231 cells in vitro. In addition, KLF9 expression correlated inversely with mitotic activity in clinical samples, indicating anti-proliferative effects