Radioembolization in the Treatment of Neuroendocrine Tumor Metastases to the Liver

Surgical excision remains the preferred treatment for resectable hepatic metastases of neuroendocrine tumors. In cases of more disseminated hepatic disease, transarterial radioembolization with Yttrium-90- (90Y-) labeled microspheres has been demonstrated as a viable option for symptom and locoregional tumor control. On an outpatient basis, radioembolization can be utilized from early line to salvage phases, in various combinations with systemic therapies. Review of available data shows encouraging safety and efficacy profiles for the intraarterial application of 90Y for the treatment of mNETs of the liver. Symptom control and decrease in somatostatin analog use can be achieved, as well as prolonged survival

Cost analysis for support and maintenance

Tato diplomová práce se zaměřuje na analýzu nákladů souvisejících s údržbou a podporou softwaru. Téma bylo navrženo společností Diebold Nixdorf, která měla zájem zjistit více informací o složení nákladů na incidenty. Práce obsahuje stručné představení společnosti a představení pojmů souvisejících s vývojem softwaru. Dále je popsán životní cyklus softwaru (SDLC), který zahrnuje údržbu a podporu. V další části je podrobně rozebrána údržba, včetně jejích fází a popisu nákladů. Následuje sekce věnovaná rámci ITIL, který autor již představil ve své bakalářské práci, ale tentokrát se zaměřuje na nejnovější, čtvrtou verzi. V praktické části je představena současná metoda odhadu nákladů společnosti a proveden statistický výzkum na poskytnutých datech. Byly navrženy čtyři metody pro klasifikaci úsilí (celkového času stráveného na incidentu), na základě kterých společnost vypočítává náklady. Součástí práce je také vytvořená aplikace, která na základě zadaných parametrů incidentu klasifikuje toto úsilí a předpovídá celkové úsilí vynaložené na zákazníka. Výsledky výzkumu identifikovaly faktory, které nejvíce ovlivňují klasifikaci úsilí, a jako nejvhodnější metoda pro jeho klasifikaci a odhad celkového úsilí byla vybrána metoda strojového učení nazvaná náhodný les (RF). Společnost projevila zájem o ukázku aplikace a navržených metod. Do budoucna lze na téma diplomové práce navázat vypracováním podrobnější studie metod strojového učení včetně jejich návrhu.ObhájenoThis master's thesis focuses on the cost analysis related to software maintenance and support. The topic was suggested by Diebold Nixdorf, which was interested in finding out more about the composition of incident costs. The thesis includes a brief introduction to the company and an introduction to concepts related to software development. Furthermore, the software development life cycle (SDLC), which includes maintenance and support, is described. In the next section, maintenance is discussed in detail, including its phases and cost breakdown. This is followed by a section devoted to the ITIL framework, which the author has already introduced in his bachelor's thesis, but this time focuses on the latest, fourth version. In the practical part, the current method of estimating company costs is presented, and statistical research is performed on the provided data. Four methods have been proposed to classify the effort (total time spent on an incident) on the basis of which the company calculates the cost. The work also includes the development of an application that classifies this effort and predicts the total effort spent per customer based on the given incident parameters. The results of the research identified the factors that most affect the classification of the effort, and a machine learning method called Random Forest (RF) was selected as the most appropriate method to classify the effort and estimate the total effort. The company expressed interest in demonstrating the application and the proposed methods. In the future, the thesis topic can be followed up by a more detailed study of machine learning methods, including their design

Plasticity-dependent, full detonation at hippocampal mossy fiber–CA3 pyramidal neuron synapses

Mossy fiber synapses on CA3 pyramidal cells are 'conditional detonators' that reliably discharge postsynaptic targets. The 'conditional' nature implies that burst activity in dentate gyrus granule cells is required for detonation. Whether single unitary excitatory postsynaptic potentials (EPSPs) trigger spikes in CA3 neurons remains unknown. Mossy fiber synapses exhibit both pronounced short-term facilitation and uniquely large post-tetanic potentiation (PTP). We tested whether PTP could convert mossy fiber synapses from subdetonator into detonator mode, using a recently developed method to selectively and noninvasively stimulate individual presynaptic terminals in rat brain slices. Unitary EPSPs failed to initiate a spike in CA3 neurons under control conditions, but reliably discharged them after induction of presynaptic short-term plasticity. Remarkably, PTP switched mossy fiber synapses into full detonators for tens of seconds. Plasticity-dependent detonation may be critical for efficient coding, storage, and recall of information in the granule cell–CA3 cell network

Estimation of The Relationship Between The Travel Time of Flood Peaks and Peak Discharge on The Poprad River by Multilinear Flood Routing

The empirical relationship between travel-time of flood peaks and peak discharge was studied on a reach of the Poprad River in Slovakia. The data were fitted by regression and compared with the expected shapes as described in the literature. Further a chain of linear segments has been considered as the model of that relation. The number of segments parameters and the angles between theses in this piecewise linear model were fitted by optimisation of a conceptual multilinear flood routing model performance on a large flood wave with the help of a genetic algorithm. In the setup of the multilinear model the travel-time parameter of the model was allowed to vary with discharge according to the piecewise linear model of the travel time of flood peaks. The discrete state space representation of the Kalinin-Miljukov model was used as the basis for a multilinear discrete cascade flood routing model. The resulting relationship was compared with empirical data on travel times and used to model the variability of the time parameter in the discrete state space representation of the Kalinin and Miljukov model on three verification floods. The modelling results showed that the inclusion of empirical information on the variability of the travel-time with discharge even from one flood enables satisfactory accuracy for the prediction of the flood propagation process

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Surgical excision remains the preferred treatment for resectable hepatic metastases of neuroendocrine tumors. In cases of more disseminated hepatic disease, transarterial radioembolization with Yttrium-90-(90Y-) labeled microspheres has been demonstrated as a viable option for symptom and locoregional tumor control. On an outpatient basis, radioembolization can be utilized from early line to salvage phases, in various combinations with systemic therapies. Review of available data shows encouraging safety and efficacy profiles for the intraarterial application of 90Y for the treatment of mNETs of the liver. Symptom control and decrease in somatostatin analog use can be achieved, as well as prolonged survival

Fast Inhibition of Glutamate-Activated Currents by Caffeine

Background: Caffeine stimulates calcium-induced calcium release (CICR) in many cell types. In neurons, caffeine stimulates CICR presynaptically and thus modulates neurotransmitter release. Methodology/Principal Findings: Using the whole-cell patch-clamp technique we found that caffeine (20 mM) reversibly increased the frequency and decreased the amplitude of miniature excitatory postsynaptic currents (mEPSCs) in neocortical neurons. The increase in mEPSC frequency is consistent with a presynaptic mechanism. Caffeine also reduced exogenously applied glutamate-activated currents, confirming a separate postsynaptic action. This inhibition developed in tens of milliseconds, consistent with block of channel currents. Caffeine (20 mM) did not reduce currents activated by exogenous NMDA, indicating that caffeine block is specific to non-NMDA type glutamate receptors. Conclusions/Significance: Caffeine-induced inhibition of mEPSC amplitude occurs through postsynaptic block of non-NMDA type ionotropic glutamate receptors. Caffeine thus has both pre and postsynaptic sites of action at excitatory synapses

Nanodomain coupling explains Ca^2+ independence of transmitter release time course at a fast central synapse

A puzzling property of synaptic transmission, originally established at the neuromuscular junction, is that the time course of transmitter release is independent of the extracellular Ca2+ concentration ([Ca2+]o), whereas the rate of release is highly [Ca2+]o-dependent. Here, we examine the time course of release at inhibitory basket cell-Purkinje cell synapses and show that it is independent of [Ca2+]o. Modeling of Ca2+-dependent transmitter release suggests that the invariant time course of release critically depends on tight coupling between Ca2+ channels and release sensors. Experiments with exogenous Ca2+ chelators reveal that channel-sensor coupling at basket cell-Purkinje cell synapses is very tight, with a mean distance of 10–20 nm. Thus, tight channel-sensor coupling provides a mechanistic explanation for the apparent [Ca2+]o independence of the time course of release

A pre-docking source for the power-law behavior of spontaneous quantal release: application to the analysis of LTP

In neurons, power-law behavior with different scaling exponents has been reported at many different levels, including fluctuations in membrane potentials, synaptic transmission up to neuronal network dynamics. Unfortunately in most cases the source of this nonlinear feature remains controversial. Here we have analyzed the dynamics of spontaneous quantal release at hippocampal synapses and characterized their power-law behavior. While in control conditions a fractal exponent greater than zero was rarely observed, its value was greatly increased by α-latrotoxin (α-LTX), a potent stimulator of spontaneous release, known to act at the very last step of vesicle fusion. Based on computer modeling, we confirmed that at an increase in fusion probability would unmask a pre-docking phenomenon with 1/f structure, where α estimated from the release series appears to sense the increase in release probability independently from the number of active sites. In the simplest scenario the pre-docking 1/f process could coincide with the Brownian diffusion of synaptic vesicles. Interestingly, when the effect of long-term potentiation (LTP) was tested, a ∼200% long-lasting increase in quantal frequency was accompanied by a significant increase in the scaling exponent. The similarity between the action of LTP and of α-LTX suggests an increased contribution of high release probability sites following the induction of LTP. In conclusion, our results indicate that the source of the synaptic powerlaw behavior arises before synaptic vesicles dock to the active zone and that the fractal exponent α is capable of sensing a change in release probability independently from the number of active sites or synapses. © 2015 Lamanna, Signorini, Cerutti and Malgaroli

"Der Balkan" in der Krone: Austria between "frontier Orientalism" and amnesiac nationalism

This article traces the “silent inscription” of (former) colonial relations in the European integration project to their re-inflection in an EU-sceptical medium. To do so, this contribution draws on a corpus of data comprising news-coverage, commentaries and readers’ letters published in Austria’s largest newspaper, the Kronen Zeitung, whose reach, influence and leanings are well-known. The analysis considers the Krone’s representations of, and discursive references to, “the Balkans” during the crises-littered period between 2009 and 2017. For analytical purposes this discussion focuses on a sub-sample of invocations of “the Balkans” in the Krone, which have appeared with growing frequency since 2015. Conceptually, the discourse-analytical notion of the topos, or argumentative structure, and anthropological literature on “identity grammars” inform the analysis. The discussion reveals continuities with Austria’s historically long-established representational regimes of South-Eastern Europe, and novel discursive features. A contemporary paternalism is shown to re-appropriate the nineteenth-century topos of Austria’s alleged “civilizing mission” and what André Gingrich (2005) has described as Central Europe’s “frontier Orientalism”. Further, preoccupations with “the Balkan-route” and its closure articulate a topos of external threats tied to recent migration flows. The article reflects on an “amnesiac nationalism”, and its post-imperial entanglements, that are currently re-shaping the European Union

Suppression of Ribosomal Function Triggers Innate Immune Signaling through Activation of the NLRP3 Inflammasome

Some inflammatory stimuli trigger activation of the NLRP3 inflammasome by inducing efflux of cellular potassium. Loss of cellular potassium is known to potently suppress protein synthesis, leading us to test whether the inhibition of protein synthesis itself serves as an activating signal for the NLRP3 inflammasome. Murine bone marrow-derived macrophages, either primed by LPS or unprimed, were exposed to a panel of inhibitors of ribosomal function: ricin, cycloheximide, puromycin, pactamycin, and anisomycin. Macrophages were also exposed to nigericin, ATP, monosodium urate (MSU), and poly I:C. Synthesis of pro-IL-ß and release of IL-1ß from cells in response to these agents was detected by immunoblotting and ELISA. Release of intracellular potassium was measured by mass spectrometry. Inhibition of translation by each of the tested translation inhibitors led to processing of IL-1ß, which was released from cells. Processing and release of IL-1ß was reduced or absent from cells deficient in NLRP3, ASC, or caspase-1, demonstrating the role of the NLRP3 inflammasome. Despite the inability of these inhibitors to trigger efflux of intracellular potassium, the addition of high extracellular potassium suppressed activation of the NLRP3 inflammasome. MSU and double-stranded RNA, which are known to activate the NLRP3 inflammasome, also substantially inhibited protein translation, supporting a close association between inhibition of translation and inflammasome activation. These data demonstrate that translational inhibition itself constitutes a heretofore-unrecognized mechanism underlying IL-1ß dependent inflammatory signaling and that other physical, chemical, or pathogen-associated agents that impair translation may lead to IL-1ß-dependent inflammation through activation of the NLRP3 inflammasome. For agents that inhibit translation through decreased cellular potassium, the application of high extracellular potassium restores protein translation and suppresses activation of the NLRP inflammasome. For agents that inhibit translation through mechanisms that do not involve loss of potassium, high extracellular potassium suppresses IL-1ß processing through a mechanism that remains undefined