The role of CD44H molecule in the interactions between human monocytes and pancreatic adenocarcinoma-derived microvesicles

Introduction. CD44H is a transmembrane molecule important for cell-cell and cell-extracellular matrix interactions. In monocytes, CD44H is implicated in phagocytosis of particles coated by hyaluronan (HA). HA fragments were shown to induce chemokine secretion by monocytes. Tumour derived microvesicles (TMVs), which are small membrane fragments derived from tumour cells can carry fragments of HA. The aim of the study was to examine whether monocyte’s CD44H is involved in the engulfment of pancreatic adenocarcinoma-derived microvesicles and in the production of chemokines induced by TMVs. Materials and methods. TMVs engulfment and chemokines’ secretion stimulated with TMVs were determined in control human monocytes and cells incubated with anti-CD44H monoclonal antibody (mAb) by flow cytometry and ELISA, respectively. Phosphorylation of STAT3, transcription factor essential for chemokines’ production and CD44 signal transduction, was determined by Western blotting. Results. Blocking of CD44H by anti-CD44H mAb on monocytes decreased the engulfment of TMVs and thesecretion of CCL4 and CCL5, but had no effect on CCL2, CCL3 and CXCL8. STAT-3 phosphorylation inmonocytes incubated with TMVs after CD44 blocking was also reduced. Conclusion. The results suggest that tumour-derived microvesicles (TMVs) may carry bioactive cargo(s) which induces STAT3 dependent signalling pathway in human monocytes via CD44 molecules

Regulation and novel action of thymidine phosphorylase in non-small cell lung cancer : crosstalk with Nrf2 and HO-1

Proangiogenic enzyme thymidine phosphorylase (TP) is a promising target for anticancer therapy, yet its action in non-small cell lung carcinoma (NSCLC) is not fully understood. To elucidate its role in NSCLC tumor growth, NCI-H292 lung mucoepidermoid carcinoma cells and endothelial cells were engineered to overexpress TP by viral vector transduction. NSCLC cells with altered expression of transcription factor Nrf2 or its target gene heme oxygenase-1 (HO-1) were used to study the regulation of TP and the findings from pre-clinical models were related to gene expression data from clinical NSCLC specimens. Overexpression of Nrf2 or HO-1 resulted in upregulation of TP in NCI-H292 cells, an effect mimicked by treatment with an antioxidant N-acetylcysteine and partially reversed by HO-1 knockdown. Overexpression of TP attenuated cell proliferation and migration in vitro, but simultaneously enhanced angiogenic potential of cancer cells supplemented with thymidine. The latter was also observed for SK-MES-1 squamous cell carcinoma and NCI-H460 large cell carcinoma cells. TP-overexpressing NCI-H292 tumors in vivo exhibited better oxygenation and higher expression of IL-8, IL-1β and IL-6. TP overexpression in endothelial cells augmented their angiogenic properties which was associated with enhanced generation of HO-1 and VEGF. Correlation of TP with the expression of HO-1 and inflammatory cytokines was confirmed in clinical samples of NSCLC. Altogether, the increased expression of IL-1β and IL-6 together with proangiogenic effects of TP-expressing NSCLC on endothelium can contribute to tumor growth, implying TP as a target for antiangiogenesis in NSCLC

Downstream MET-IRSL single-grain distributions in the Mojave River, southern California: Testing assumptions of a virtual velocity model

© 2015 Elsevier B.V.We use samples from a prior study (McGuire and Rhodes, 2015) to investigate the bleaching trend of Mojave River sand in more detail. We present new single grain data which provides insight into how previously presented multiple-grain luminescence signals decrease downriver. The single grain dose distributions allow for a test of the assumption that multiple-grain equivalent dose (De) is representative of fluvial transport down the Mojave River. For samples at the Forks, Victorville and Barstow, with laboratory luminescence sample codes J0262, J0267 and J0265, respectively, inspection of the kernel density estimate (KDE)-generated probability density function supports the assumption, though is does not prove it directly. Implementing a Kolmogorov-Smirnov (K-S) test shows that the downriver samples are statistically different from each other, suggesting bleaching as the primary mechanism for changes is dose distribution downriver. Single-grain dose distributions show that the De of the Afton Canyon sample (J0260) is not representative of grain travel from source to sink, but instead likely a result of local mixing of sediment populations. This result is confirmed by visual inspection of the KDE, and quantitatively using the K-S test. As has been noted by several authors, the single-grain dose distribution in active channels of rivers may represent a worst case in terms of poor bleaching, due to mixing of older-age populations (Cunningham et al., 2014; Jain et al., 2004). This observation holds for our data set and presents an opportunity to test and develop luminescence techniques to determine provenance. In particular, future sampling in the vicinity of the Afton Canyon site has the potential to identify the entry point of a poorly-bleached population

Assessing the effects of spatial discretization on large-scale flow model performance and prediction uncertainty

Large-scale physically-based and spatially-distributed models (>100 km2) constitute useful tools for water management since they take explicitly into account the heterogeneity and the physical processes occurring in the subsurface for predicting the evolution of discharge and hydraulic heads for several predictive scenarios. However, such models are characterized by lengthy execution times. Therefore, modelers often coarsen spatial discretization of large-scale physically-based and spatially-distributed models for reducing the number of unknowns and the execution times. This study investigates the influence of such a coarsening of model grid on model performance and prediction uncertainty. The improvement of model performance obtained with an automatic calibration process is also investigated. The results obtained show that coarsening spatial discretization mainly influences the simulation of discharge due to a poor representation of surface water network and a smoothing of surface slopes that prevents from simulating properly surface water-groundwater interactions and runoff processes. Parameter sensitivities are not significantly influenced by grid coarsening and calibration can compensate, to some extent, for model errors induced by grid coarsening. The results also show that coarsening spatial discretization mainly influences the uncertainty on discharge predictions. However, model prediction uncertainties on discharge only increase significantly for very coarse spatial discretizations.Peer reviewe

A Potential New Pathway for Staphylococcus aureus Dissemination: The Silent Survival of S. aureus Phagocytosed by Human Monocyte-Derived Macrophages

Although considered to be an extracellular pathogen, Staphylococcus aureus is able to invade a variety of mammalian, non-professional phagocytes and can also survive engulfment by professional phagocytes such as neutrophils and monocytes. In both of these cell types S. aureus promptly escapes from the endosomes/phagosomes and proliferates within the cytoplasm, which quickly leads to host cell death. In this report we show that S. aureus interacted with human monocyte-derived macrophages in a very different way to those of other mammalian cells. Upon phagocytosis by macrophages, S. aureus persisted intracellularly in vacuoles for 3–4 days before escaping into the cytoplasm and causing host cell lysis. Until the point of host cell lysis the infected macrophages showed no signs of apoptosis or necrosis and were functional. They were able to eliminate intracellular staphylococci if prestimulated with interferon-γ at concentrations equivalent to human therapeutic doses. S. aureus survival was dependent on the alternative sigma factor B as well as the global regulator agr, but not SarA. Furthermore, isogenic mutants deficient in α-toxin, the metalloprotease aureolysin, protein A, and sortase A were efficiently killed by macrophages upon phagocytosis, although with different kinetics. In particular α-toxin was a key effector molecule that was essential for S. aureus intracellular survival in macrophages. Together, our data indicate that the ability of S. aureus to survive phagocytosis by macrophages is determined by multiple virulence factors in a way that differs considerably from its interactions with other cell types. S. aureus persists inside macrophages for several days without affecting the viability of these mobile cells which may serve as vehicles for the dissemination of infection

Exceedance probability of selected low characteristic flows in mountain catchments

In Polish hydrology and water management the term characteristic flow exists denoting a specific value of flow at the given cross-section of a river calculated as the long-term minimum, mean, median or maximum calculated using the annual minimum, mean, median or maximum flow taken for each year from a series of (usually) daily flows. Some of these characteristic flows are used to define the low-flow (o drought) periods while the another criterion: a percentage flow Qp taken from the long-term flow duration curve is also widely used. In the paper the study on the frequency structure the empirical exceedance probability of a given characteristic flow made for some low and average characteristic flows (SNQ, WNQ, NSQ and SSQ) is presented. The results show that the exceedance probability of a given characteristic flow is variable, and the amount of this variability may be large, as is the case of WNQ and NSQ. So assigning a characteristic flow to a single FDC quantile value Qp (as can be find in the literature) cannot be justified. Correlation analysis made for the pairs (P. , characteristic flow), ( P., catchment area) and (P. , gauging station elevation) revealed some significant correlations. Only for SNQ is not correlated at all; correlation for other characteristic flows is statistically significant for at least one of the cases. The highest correlations (greater than 0.4 in absolute values) were found for the pairs ( P, gauging station elevation) for NSQ and, for SSQ, ( P, SSQ) and ( P, catchment area)

The efficiency of some forecasting methods applied to annual minimum flow series

Four methods of forecasting: „no-change", LOESS, local linear regression and Holt-Winters were applied to annual minimum water levels observed at ten cross-sections of two tributaries of the Vistula river. The 1-, 2-, ..., 5-year forecasts were made for each year after some initial year, and four quality measures: bias, root mean square error, mean absolute error and maximum absolute error were calculated for each time series and lead time. The naïve model turned out to be always the worst in it bias and almost always very good, sometimes the best regarding the other measures

On the correctness of the Chomicz equations for design rainfall calculations

Stosowany głównie jako model porównawczy, wzór Chomicza z 1953 r. na miarodajną wysokość opadu w zależności od czasu trwania oparty został na nie całkiem adekwatnych danych, a przedstawione podejście nie zostało wystarczająco uzasadnione, co rodzi wątpliwości dotyczące wiarygodności metody. Niezależnie bowiem od skromności i adekwatności baz danych opadowych z połowy zeszłego stulecia, należy podnieść istotne zastrzeżenia dotyczące poprawności modelu opadu miarodajnego opracowanego dla prawdopodobieństw przewyższenia 10%, 20%, 50% i 100%. Najważniejsze zastrzeżenie dotyczy poprawności przyjętej przez Chomicza metody przedłużania opadu poza zmierzony czas trwania. Metoda ta jest trudna do zaakceptowania, gdyż zakłada, że najwyższe przedziałowe natężenie opadu przypada na koniec zdarzenia opadowego, czego obserwacje nie uzasadniają. Ponadto liczba przedłużonych w ten sposób opadów, czyli liczba półempirycznych danych opadowych, zastosowanych do budowy modelu opadu miarodajnego silnie rośnie z czasem trwania tego opadu przewyższając w skrajnym przypadku, dla najdłuższego czasu trwania 180 minut, aż dwukrotnie liczbę danych oryginalnych. Brak jest również uzasadnienia przyjętego kryterium granicy przedłużania opadu.The Chomicz model of 1953 for DDF curves, used in Poland mainly as a comparative model, is based on not quite adequate data and the approach presented by Chomicz was not substantiated enough, which raises serious doubts on the correctness of the method. Of course, the scarcity and relevance of the then data bases should be taken into account. However, independently of that problem, there are substantial reservations about the correctness of the design rainfalls developed by Chomicz for exceedance probabilities 10%, 20%, 50% and 100%. The most significant reservation concerns the correctness of the method of extending measured rainfall depth over its measured duration. The method can hardly be accepted, because it assumes that that the greatest rainfall interval intensity occurs in the end of the rainfall event, which is not supported by observations. Moreover, the number of extended rainfall depths, i.e., the number of semi-empirical values, used to develop the model of design rainfall, increases strongly with rainfall duration doubling the number of original data in the extreme case of the longest duration of 180 minutes. Also, no rationale is given for adopted criterion for the time limit of rainfall extension over the measured duration