Clinically relevant concentrations of lidocaine and ropivacaine inhibit TNFα-induced invasion of lung adenocarcinoma cells in vitro by blocking the activation of Akt and focal adhesion kinase

BACKGROUND Matrix-metalloproteinases (MMP) and cancer cell invasion are crucial for solid tumour metastasis. Important signalling events triggered by inflammatory cytokines, such as tumour necrosis factor α (TNFα), include Src-kinase-dependent activation of Akt and focal adhesion kinase (FAK) and phosphorylation of caveolin-1. Based on previous studies where we demonstrated amide-type local anaesthetics block TNFα-induced Src activation in malignant cells, we hypothesized that local anaesthetics might also inhibit the activation and/or phosphorylation of Akt, FAK and caveolin-1, thus attenuating MMP release and invasion of malignant cells. METHODS NCI-H838 lung adenocarcinoma cells were incubated with ropivacaine or lidocaine (1 nM-100 µM) in absence/presence of TNFα (20 ng ml(-1)) for 20 min or 4 h, respectively. Activation/phosphorylation of Akt, FAK and caveolin-1 were evaluated by Western blot, and MMP-9 secretion was determined by enzyme-linked immunosorbent assay. Tumour cell migration (electrical wound-healing assay) and invasion were also assessed. RESULTS Ropivacaine (1 nM-100 μM) and lidocaine (1-100 µM) significantly reduced TNFα-induced activation/phosphorylation of Akt, FAK and caveolin-1 in NCI-H838 cells. MMP-9 secretion triggered by TNFα was significantly attenuated by both lidocaine and ropivacaine (half-maximal inhibitory concentration [IC50]=3.29×10(-6) M for lidocaine; IC50=1.52×10(-10) M for ropivacaine). The TNFα-induced increase in invasion was completely blocked by both lidocaine (10 µM) and ropivacaine (1 µM). CONCLUSIONS At clinically relevant concentrations both ropivacaine and lidocaine blocked tumour cell invasion and MMP-9 secretion by attenuating Src-dependent inflammatory signalling events. Although determined entirely in vitro, these findings provide significant insight into the potential mechanism by which local anaesthetics might diminish metastasi

The Effects of Postfire Salvage Logging on Aquatic Ecosystems in the American West

Recent changes in the forest policies, regulations, and laws affecting public lands encourage postfire salvage logging, an activity that all too often delays or prevents recovery. In contrast, the 10 recommendations proposed here can improve the condition of watersheds and aquatic ecosystems

A review of research on the role and effectiveness of business incubation for technology-based start-ups

The aim of this paper is to provide an overview of current knowledge on the role and effectiveness of business incubation in supporting the development of new firms with high growth potential. The quantitative and qualitative literature published by the academic and practitioner communities is reviewed. From analysis of this literature, the following conclusions are drawn: • In academic and practitioner publications alike there is widespread definitional and conceptual ambiguity in relation to business incubation. • Given the variety of business incubator strategies, business models, stakeholders, et al., there is no standard measure for assessing incubator performance. The validity, comparability and generalisability of published findings of incubator performance need to be carefully considered. • As the incubation industry has matured so understanding of its core purpose has become more sophisticated. • Research on business incubation needs to be considered in the context of other bodies of knowledge; in particular cluster theory, regional innovation systems, entrepreneurship, investment, and firm growth. These conclusions point to areas of further research including the development of comparable performance indicators – not absolute performance measures – for business incubation; the need to integrate incubation research more effectively within established areas of research; the linking the activities of business incubation to new ventures in emerging industries; and research on the provision of incubation services for device-based or other physical productbased start-ups

Multiscale Drivers of Water Chemistry of Boreal Lakes and Streams

The variability in surface water chemistry within and between aquatic ecosystems is regulated by many factors operating at several spatial and temporal scales. The importance of geographic, regional-, and local-scale factors as drivers of the natural variability of three water chemistry variables representing buffering capacity and the importance of weathering (acid neutralizing capacity, ANC), nutrient concentration (total phosphorus, TP), and importance of allochthonous inputs (total organic carbon, TOC) were studied in boreal streams and lakes using a method of variance decomposition. Partial redundancy analysis (pRDA) of ANC, TP, and TOC and 38 environmental variables in 361 lakes and 390 streams showed the importance of the interaction between geographic position and regional-scale variables. Geographic position and regional-scale factors combined explained 15.3% (streams) and 10.6% (lakes) of the variation in ANC, TP, and TOC. The unique variance explained by geographic, regional, and local-scale variables alone was <10%. The largest amount of variance was explained by the pure effect of regional-scale variables (9.9% for streams and 7.8% for lakes), followed by local-scale variables (2.9% and 5.8%) and geographic position (1.8% and 3.7%). The combined effect of geographic position, regional-, and local-scale variables accounted for between 30.3% (lakes) and 39.9% (streams) of the variance in surface water chemistry. These findings lend support to the conjecture that lakes and streams are intimately linked to their catchments and have important implications regarding conservation and restoration (management) endeavors

Genome-Wide Analysis of GLD-1–Mediated mRNA Regulation Suggests a Role in mRNA Storage

Translational repression is often accompanied by mRNA degradation. In contrast, many mRNAs in germ cells and neurons are “stored" in the cytoplasm in a repressed but stable form. Unlike repression, the stabilization of these mRNAs is surprisingly little understood. A key player in Caenorhabditis elegans germ cell development is the STAR domain protein GLD-1. By genome-wide analysis of mRNA regulation in the germ line, we observed that GLD-1 has a widespread role in repressing translation but, importantly, also in stabilizing a sub-population of its mRNA targets. Additionally, these mRNAs appear to be stabilized by the DDX6-like RNA helicase CGH-1, which is a conserved component of germ granules and processing bodies. Because many GLD-1 and CGH-1 stabilized mRNAs encode factors important for the oocyte-to-embryo transition (OET), our findings suggest that the regulation by GLD-1 and CGH-1 serves two purposes. Firstly, GLD-1–dependent repression prevents precocious translation of OET–promoting mRNAs. Secondly, GLD-1– and CGH-1–dependent stabilization ensures that these mRNAs are sufficiently abundant for robust translation when activated during OET. In the absence of this protective mechanism, the accumulation of OET–promoting mRNAs, and consequently the oocyte-to-embryo transition, might be compromised

Spatial distribution of bivalves in relation to environmental conditions (middle Danube catchment, Hungary)

The spatial distribution of bivalves in relation to environmental conditions was studied along a second- and third order stream – medium-sized river (River Ipoly) – large river (River Danube) continuum in the Hungarian Danube River system. Quantitative samples were collected four times in 2007 and a total of 1662 specimens, belonging to 22 bivalve species were identified. Among these species, two are endangered (Pseudanodonta complanata, Unio crassus) and five are invasive (Dreissena polymorpha, D. rostriformis bugensis, Corbicula fluminea, C. fluminalis, Anodonta woodiana) in Hungary. The higher density presented by Pisidium subtruncatum, P. supinum, P. henslowanum and C. fluminea suggests that these species may have a key role in this ecosystem. Three different faunal groups were distinguished but no significant temporal change was detected. The lowest density and diversity with two species (P. casertanum and P. personatum) occurred in streams. The highest density and diversity was found in the River Ipoly, in the side arms of the Danube and in the main arm of the Danube with sand and silt substrate, being dominated by P. subtruncatum and P. henslowanum. Moderate density and species richness were observed in the main arm of the Danube with pebble and stone substrate, being dominated by C. fluminea and S. rivicola. Ten environmental variables were found to have significant influence on the distribution of bivalves, the strongest explanatory factors being substrate types, current velocity and sedimentological characteristics.The project was financially supported by the Hungarian Scientific Research Fund under the contract No. OTKA T/046180. Special thanks to the DanubeIpoly National Park for the help in field work.info:eu-repo/semantics/publishedVersio