A covalently bound photoisomerizable agonist. Comparison with reversibly bound agonists at electrophorus electroplaques

After disulphide bonds are reduced with dithiothreitol, trans-3-(alpha-bromomethyl)-3’-[alpha-(trimethylammonium)methyl]azobenzene (trans-QBr) alkylates a sulfhydryl group on receptors. The membrane conductance induced by this “tethered agonist” shares many properties with that induced by reversible agonists. Equilibrium conductance increases as the membrane potential is made more negative; the voltage sensitivity resembles that seen with 50 [mu]M carbachol. Voltage- jump relaxations follow an exponential time-course; the rate constants are about twice as large as those seen with 50 mu M carbachol and have the same voltage and temperature sensitivity. With reversible agonists, the rate of channel opening increases with the frequency of agonist-receptor collisions: with tethered trans-Qbr, this rate depends only on intramolecular events. In comparison to the conductance induced by reversible agonists, the QBr-induced conductance is at least 10-fold less sensitive to competitive blockade by tubocurarine and roughly as sensitive to “open-channel blockade” bu QX-222. Light-flash experiments with tethered QBr resemble those with the reversible photoisomerizable agonist, 3,3’,bis-[alpha-(trimethylammonium)methyl]azobenzene (Bis-Q): the conductance is increased by cis {arrow} trans photoisomerizations and decreased by trans {arrow} cis photoisomerizations. As with Bis-Q, ligh-flash relaxations have the same rate constant as voltage-jump relaxations. Receptors with tethered trans isomer. By comparing the agonist-induced conductance with the cis/tans ratio, we conclude that each channel’s activation is determined by the configuration of a single tethered QBr molecule. The QBr-induced conductance shows slow decreases (time constant, several hundred milliseconds), which can be partially reversed by flashes. The similarities suggest that the same rate-limiting step governs the opening and closing of channels for both reversible and tethered agonists. Therefore, this step is probably not the initial encounter between agonist and receptor molecules

Report and preliminary results of SONNE cruise SO175, Miami - Bremerhaven, 12.11 - 30.12.2003 : (GAP, Gibraltar Arc Processes)

Expedition SO175 using FS Sonne aimed for a multidisciplinerary geoscientific approach with an international group of researchers. Methods covered the entire span from geophysical data acquisition (seafloor mapping, echography, seismic reflection), sediment coring at sites of active fluid venting, in situ heat flow measurements across the entire length of the Gibraltar thrust wedge, the deformation front, landslide bodies, and mud volcanoes, and finally the deployment of a long-term pore pressure probe. Video-supported operations helped to identify fluid vent sites, regions with tectonic activity, and other attractive high priority targets. Qualitative and quantitative examinations took place on board and are continued on land with respect to pore pressure variation, geomicrobiology, sediment- and fluid mobilization, geochemical processes, faunal assemblages (e.g. cold water corals), and gas hydrates (flammable methane-ice-crystals). Main focus of the expedition has been a better understanding of interaction between dynamic processes in a seismically active region region with slow plate convergence. In the context of earthquake nucleation and subduction zone processes, the SO175 research programme had a variety of goals, such as: • To test the frictional behaviour of the abyssal plain sediments. • To explore the temperature field of the 1755 thrust earthquake event via heat flow measurements. • To assess the role of fluid venting and gas hydrate processes control slope stability and mud volcanic activity along the Iberian continental margin. • To measure isotope geochemistry of pore waters and carbonates of deep fluids. • To quantify microbial activity in Gibraltar wedge sediments. • To test whether microseismicity in the area corresponds to in situ pore pressure changes. • To find out if enhanced heat flow max be indicative of active subduction. Initial tentative results during the cruise suggest that there is a component of active thrusting at the base of the wedge, as attested by heat flow data. Based on mostly geochemical evidence, mud volcanism was found less active than previously assumed. Highlights from post-cruise research include the successful deployment of the long-term station and high frictional resistance of all incoming sediment on the three abyssal plains

Modified transarterial chemoembolization with locoregional administration of sorafenib for treating hepatocellular carcinoma: feasibility, efficacy, and safety in the VX-2 rabbit liver tumor model

PURPOSE:We aimed to assess the feasibility, efficacy and safety of a local application of sorafenib within a conventional transarterial chemoembolization in the VX-2 tumor-bearing rabbit model.METHODS:VX-2 tumors were induced in the left liver lobe of 10 New Zealand White rabbits. After two weeks, growth was verified by contrast-enhanced computed tomography (CT). Five rabbits were treated by transarterial chemoembolization using an emulsion of sorafenib and ethiodized oil (referred to as SORATACE; n=5). Rabbits receiving oral sorafenib for two weeks (n=2) and untreated rabbits (n=3) served as controls. After two weeks, contrast-enhanced CT was performed, followed by animal necropsy.RESULTS:The change in tumor diameter between baseline and follow-up was significantly different in the SORATACE group compared with the other groups; tumor shrinkage was observed in the SORATACE group only (P = 0.016). In both control groups, preserved hypervascularity was seen in the follow-up CT in all but one tumor. All tumors in the SORATACE group were devascularized in the follow-up CT. Importantly, substantial parenchymal damage in nontargeted areas of the tumor-bearing liver lobe was seen in rabbits treated with SORATACE.CONCLUSION:SORATACE demonstrated high efficacy in the treatment of experimental VX-2 liver tumors but was also associated with substantial liver parenchymal toxicity

Impact of Eukaryotic Translation Initiation Factors on Breast Cancer: Still Much to Investigate

Breast carcinoma (BC) remains one of the most serious health problems. It is a heterogeneous entity, and mainly classified according to receptor status for estrogen (ER), progesterone (PR) and egf (HER2/Neu), as well as the proliferation marker ki67. Gene expression in eukaryotes is regulated at the level of both gene transcription and translation, where eukaryotic initiation factors (eIFs) are key regulators of protein biosynthesis. Aberrant translation results in an altered cellular proteome, and this clearly effects cell growth supporting tumorigenesis. The relationship between various eIFs and BC entities, as well as the related regulatory mechanisms, has meanwhile become a focus of scientific interest. Here, we give an overview on the current research state of eIF function, focusing on BC

Curcumin blocks interleukin-1 signaling in chondrosarcoma cells.

Interleukin (IL)-1 signaling plays an important role in inflammatory processes, but also in malignant processes. The essential downstream event in IL-1 signaling is the activation of nuclear factor (NF)-κB, which leads to the expression of several genes that are involved in cell proliferation, invasion, angiogenesis and metastasis, among them VEGF-A. As microenvironment-derived IL-1β is required for invasion and angiogenesis in malignant tumors, also in chondrosarcomas, we investigated IL-1β-induced signal transduction and VEGF-A expression in C3842 and SW1353 chondrosarcoma cells. We additionally performed in vitro angiogenesis assays and NF-κB-related gene expression analyses. Curcumin is a substance which inhibits IL-1 signaling very early by preventing the recruitment of IL-1 receptor associated kinase (IRAK) to the IL-1 receptor. We demonstrate that IL-1 signaling and VEGF-A expression are blocked by Curcumin in chondrosarcoma cells. We further show that Curcumin blocks IL-1β-induced angiogenesis and NF-κB-related gene expression. We suppose that IL-1 blockade is an additional treatment option in chondrosarcoma, either by Curcumin, its derivatives or other IL-1 blocking agents