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In patients with metastatic melanoma the advent of targeted therapy and immune checkpoint inhibitors has transformed the management of advanced and metastatic disease, resulting in improved outcomes. Neopterin is a biomarker of immune activation increased in cancer as well as in other conditions associated with immune activation. We present a case of a patient with advanced metastatic melanoma responding to the combination targeted therapy with dabrafenib and trametinib. The treatment was complicated by a fever that was accompanied by a marked rise in serum and urinary neopterin concentrations. Present case report illustrates not only the efficacy of combined targeted therapy, but also the utilization of neopterin measurements in the diagnosis and monitoring of pyrexia in patients with metastatic malignant melanoma.

Creativity in the arts has been influenced by an environment where the integral parts are state provisions, which directly and indirectly support the development of the independent arts sector. The past decades have seen a change in the field of arts and the support thereof as part of creative branches. The paper focuses on new approaches of non-profit arts organizations to receive support for their activities using the principles of cultural entrepreneurship. The research was performed in the Czech Republic in the monitored period of 2008-2016. The theoretical part of the research is concluded by a proposal for a new definition of cultural entrepreneurship of non-profit cultural and arts organizations and is then implemented in the practical part. The practical part includes outputs of the author’s research in the field of crowdfunding platforms in the Czech Republic, outputs from the focus groups analysis and a selective survey. Apart from the research, there are outputs of three case studies from the field of non-profit arts, observing their economic behaviour as seen by cultural entrepreneurship. In the end, the paper presents a proposal for recommendations for the non-profit arts sector and the extent of strategic measures at the state level.

The Žerotice Formation recognised in a confined area NE–SE of Znojmo represents a basal member of the sedimentary succession of the southwestern margin of the Carpathian Foredeep in Moravia (Czech Republic). Two facies associations were recognised within the formation. The first one mantles the pre-Neogene basement with an irregular unconformity, reflects arid climatic conditions and deposition of episodic shallow, high-energy stream flows and/or mass flows (alluvial to fluvial deposits). The second facies association is interpreted as lagoonal to distal flood plain deposits. The barren unfossiliferous deposits of the Žerotice Formation are covered by nearshore marine Eggenburgian deposits. The boundary between these deposits represents a sequence boundary (i.e. the basal forebulge unconformity). Detailed provenance studies of successive beds below and above this sequence boundary showed differences in the source area and paleodrainage. Both the local primary crystalline rocks (Moravian and Moldanubian Unit, Thaya Batholith) and older sedimentary cover (especially Permo–Carboniferous sedimentary rocks) form the source of the Žerotice Formation. All these geological units are located only a few km away from the preserved areal extent of the deposits of the Žerotice Formation (short transport and a local source). The source areas of the overlying marine Eggenburgian beds are located far more to the W and NW in the Moldanubian and Moravian Units (longer transport, extended source area). Local confined preservation of the Žerotice Formation is preliminarily explained as connected with a tectonically predisposed paleovalley.

The fossil assemblages of the foraminifers, bryozoans, molluscs, corals, decapods, sharks and teleosteans were analysed from the Litenčice sand pit in the middle part of the Carpathian Foredeep. The section can be assigned to the Karpatian Stage of the Central Paratethys regional stratigraphy (uppermost Lower Miocene) on the basis of species Uvigerina graciliformis Papp et Turn., Lampanyctus carpaticus (Brz.) and Agapilia pachii (Hoern.). Rich and diversified assemblages indicate mainly shallow water marine environment. Foraminifers and molluscs indicate salinity perturbations. Bryozoans and also molluscs document environment with relatively high dynamics and depth of water about 100 m. Foraminifers, fishes and sharks represent deeper water taxa and indicate a possible reworking of shallow-water elements. The studied sands and gravels of the Holešov Member of the Kroměříž Formation are interpreted as sediments of gravitational currents, more precisely dense turbidity currents (high-density turbidity currents) in the sense of Lowe (1982). The deposition environment can probably be placed on the submarine slope of the coarse-grained delta of the Gilbert type (so-called foresets). This study provided evidence of a number of fossil groups that occur at the site.

In 2018 an excavation of 20 × 20 m large and up to 5 m thick calcareous clays of the Langhian age was found. Rich and diversified assemblages of foraminifers with species Orbulina suturalis Brön. and Martinotiella karreri (Cush.) indicate early Badenian (in sense of the Central Paratethys regional stratigraphy) age of the sediments, zone M5b sensu Berggren et al. (1995). Variously deformed lenses and layers of fine-grained sand with several blocks of white calcareous silts and with two layers of clayey sediments with pebbles were found. The identified outcrop is part of a large landslide situated at the western margin of the Carpathian Foredeep. Samples determining the age of the landslide movements were taken from Badenian clays and from slope sediments with pebbles for study of palynomorphs. Very rich and diversified fauna was described mainly from the fine-grained sand creating layers in calcareous clays. The assemblage contained tests of foraminifers, spines of the echinoids, fragments of sponge spicules, rich fragments of molluscs and zoarias of bryozoas, worms – Ditrupa cornea (Linnaeus, 1758), Serpula sp., ?Serpulidae indet., fragments of brachiopods, arthropods, coral, ostracods, teleostei etc.The findings from the Badenian and Quaternary periods were mixed by slope movements. Large landslide in the Middle Pleistocene was the terminal gravity proces in the area of Viničné Šumice.

The entrenched Odra palaeovalley, cut into the bedrock of the distal margin (forebulge basal unconformity) of the Moravian Carpathian Foredeep (peripheral foreland basin) is filled with an almost 300 m thick pile of Miocene deposits. The directon of the valley (NW–SE to NNW–SSE) has been controlled by faults subparallel with the system of “sudetic faults“. The sedimentary succession consists of 5 facies associations/depositional environments, which are interpreted (from bottom to top, i.e. from the oldest to the youngest) as: 1 – colluvial deposits to deposits of alluvial fan, 2 – deposits of alluvial fan, 3 – fan-delta deposits, 4 – shallow water delta to nearshore deposits and 5 – open marine deposits. This fining-up and deepening-up succession reveals the following: the formation of the new flexural shape of the basin; deep erosion connected with uplift and tilting of the forebulge and reactivation of the NW–SE trending basement faults; the Early/Middle Miocene sea level fall; alluvial deposition mostly driven by tectonics and morphology; forebulge flexural retreat; Middle-Miocene sea level rise; back-stepping of valley infill; marine invasion during the Early Badenian with shift of the coastline further landward of the pallaeovalley. Tectonics related to contemporary thrusting processes in the Western Carpathians are assumed to be the dominating factor of the studied deposition at the expense of eustatic sea level changes. Provenance studies have proven that the pre-Neogene basement (i.e. the Early Carboniferous clastic “Culmian facies” of the Moravian-Silesian Paleozoic) represents an important source for the conglomerates and sands, which volumetrically dominate in the palaeovalley infill. However, they also showed, that the deposits of the earlier Carpathian Foredeep Basin sedimentary stage (Karpatian in age?) covered the area under study and were eroded and resedimented into the palaeovalley infill.

Lower Badenian sediments were studied on the locality Hvozdíkova at the Diviš district, Brno. There were interpreted 4 lithofacies of Neogene (Lower Badenian) sediments (lithofacies M1, M2, Sl, and SGl). Occurrence of basal Lower Badenian clastics is connected with existence of coarse-grained delta (foreset). Overlying pelites document pelagic sedimentation of open sea. Garnet dominates in assemblage of heavy translucent minerals.Rich assemblages of foraminifers, molluscs, spines of echinoids, ostracods and shark fauna were discovered in sediments. Diversified assemblages are dominated by plankton specimens. Species Orbulina suturalis Brön., Praeorbulina glomerosa circularis (Blow) and Globigerinoides bisphericus Todd. indicate the Lower Badenian age.From the point of view of the shark fauna diversity the locality Hvozdíkova is unique; shark fauna is very rare in Lower Badenian clays, and the genera of Squaliolus and Paraetmopterus are identified for the first time. Oysters – especially species Neopycnodonte navicularis (Brocchi) – dominate in Lower Badenian sediments. Small gastropods (for example Cancellaria sp., ?Tornus sp., Rissoa sp., Alvania sp.) probably represent fossils reworked from shallow littoral area.

Sedimentary and stratigraphic developments with tectonic settings of Paleogene and Neogene sediments in individual Central Europe basins.

The aim of the present study was to examine the changes in intima-media thickness (IMT) and myocardial perfusion in association with other laboratory risk factors for atherosclerosis in patients treated with therapy that targeted vascular endothelial growth factor (VEGF). IMT, myocardial perfusion and laboratory risk factors of atherosclerosis were studied in 58 patients with metastatic colorectal carcinoma or metastatic renal cell carcinoma prior to and at 3-monthly intervals during anti-VEGF treatment. Compared with the pretreatment IMT, the results indicated that the IMT was consistently increased during therapy in the two patient groups. Patient blood pressure and concentration of troponin T increased transiently. An increase in the concentration of high-density lipoprotein cholesterol and decrease in the concentrations of C-reactive protein and homocysteine were also observed. Novel myocardial ischemia was evident in individual patients. In conclusion, anti-VEGF therapy affects the laboratory risk factors of atherosclerosis and results in an acceleration of atherosclerosis, as demonstrated by increased IMT.

The aim of the present study was to evaluate the correlations of peripheral blood cell count (PBC)-derived ratios with neopterin concentration and biomarkers of atherosclerosis risk in patients with history of breast cancer. Neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR) and platelet-to-lymphocyte ratio (PLR) were calculated in three cohorts of patients with a history of breast cancer and in controls. Significant differences were observed between PBC-derived ratios obtained from automated and manual counts. NLR and PLR were significantly higher and LMR was significantly lower in patients. NLR and PLR correlated positively with each other and negatively with LMR. NLR exhibited a significant correlation with age, glucose and C-reactive protein (CRP) concentrations, whereas LMR correlated negatively with CRP. With the exception of a correlation between LMR and urinary or serum neopterin concentrations in controls, no other correlation between neopterin concentrations and PBC-derived ratios was observed. NLR ≥3 was a significant predictor of poor survival, but neither urinary neopterin ≥205 μmol/mol creatinine, NLR ≥150 nor LMR ≥4.25 was significantly associated with survival. In conclusion, no consistent correlation was observed between urinary and serum neopterin concentrations and any of the PBC-derived ratios. In a cohort of breast cancer patients, a higher NLR predicted poor survival.

The aim of the present study was to evaluate the prevalence of the risk factor of atherosclerosis in patients with history of breast cancer. C-reactive protein, lipoprotein (a), cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, triglycerides, homocysteine, fibrinogen, glucose, magnesium, uric acid, and urinary albumin were determined by routine methods in 61 patients with history of breast cancer and 74 control subjects. Urinary neopterin and creatinine concentrations were measured by high-performance liquid chromatography, and intima-media thickness was determined sonographically. Breast cancer patients were significantly older and also had higher systolic blood pressure, glycosylated hemoglobin, lipoprotein (a), serum neopterin, and intima-media thickness. Serum HDL cholesterol and magnesium concentrations were significantly higher in controls compared with patients. Differential patterns of associations between the risk factors of atherosclerosis were observed in patients with history of breast cancer compared with controls. In conclusion, the prevalence of risk factors of atherosclerosis is high in patients with history of breast cancer. Differential associations between risk factors suggest possible differences in the pathogenesis of atherosclerosis in breast cancer patients and controls.

Colonization by marine organisms such as foraminifers, molluscs, bryozoans, brachiopods and red algae during the Middle Miocene (Early Badenian) transgression near Přemyslovice (Carpathian Foredeep) was initially affected by a cool water current of unclear origin. However, shortly afterwards, fallout of volcanic material caused a total termination of the biota. After this catastrophe, the biota started recolonize the area. The succeeding association, adopted to warm-water input, is characteristic of the climatic optimum during the Early Badenian and is comparable with those of other sections referred to this interval in the Carpathian Foredeep (such as Kralice nad Oslavou, Podbřežice, and Hluchov).

Several recent studies aim at the detection of biological parameters that enable more precise diagnostics and stratification of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). The objective of our study was to assess the potential contribution of serum levels of Dickkopf-1 (DKK-1) in MGUS and MM from the point of more specific differentiation of both conditions, and the relationship of DKK-1 to selected laboratory parameters, individual forms and clinical stages of both conditions.The analyzed cohort consisted of 46 individuals with MGUS and 152 patients with MM at the time of diagnosis. For the assessment of serum levels of DKK-1 we used ELISA method. We assessed also serum levels of free light chains (FLC) κ and λ using the Freelite system, and β2-microglobulin (β2-M) using the Immulite 1000 method. For statistical estimation we used: Pearson χ2-test, U-test according to Mann-Whitney and Kruskal-Wallis test. Our analysis revealed that there was no significant difference between the levels of DKK-1 in MGUS risk groups (0-3) and between the states with different FLC concentration including the κ/λ index of monoclonality. In MM there was a significant relationship of DKK-1 to the level of hemoglobin (p0.008) but not to the levels of FLC, creatinine or β2-microglobulin. Within the Durie-Salmon staging system, there were significant differences of DKK-1 between the stages I vs. III (p=0.001) and I vs. II+III (p=0.002). In the International Staging System (ISS) there were significant differences only between stages 1 vs. 2+3 (p=0.045). Although there was no overall significant difference of DKK-1 levels between MGUS and MM, there was a difference between MGUS vs stage III (p=0.001) and II+III (p=0.001) according to Durie-Salmon, and also MGUS vs. stage 2 (p=0.005) and vs. stages 2+3 (p=0,012) according to ISS. There were no significant differences in DKK-1 between MGUS and initial/asymptomatic form of MM (stage I).Although there was a significant difference of serum levels of DKK-1 between MGUS and initial/asymptomatic stage of MM when compared to advanced stage MM, and in patients with different Hb levels, we do not find the evaluation of serum levels of DKK-1 useful for routine discrimination of MGUS and MM, and for the specification of temporary stratification systems.

Glycosyltransferases are key enzymes involved in biosynthesis of oligosaccharides. Nucleotide-sugars, the glycosyltransferase substrates, serve as activated donors of sugar residues during the enzymatic reaction Although very little is known about the catalytic mechanism of these enzymes, it appears that the catalytic activity in most glycosyltransferases is dependent upon the presence of a divalent cation, for example Mn2+ or Mg2+. It is not known whether the ion is bound to the enzyme before its interaction with the substrate, or if it binds the substrate before the enzymatic reaction to modify its conformation to fit better the active site of the enzyme. We have inspected the latter possibility by running four 2-ns molecular dynamics trajectories on fully solvated UDP-glucose in the presence of Mg2+ ions. Our results indicate that the divalent cation interacts strongly with the nucleotide-sugar in solution, and that it can alter its conformational behavior. It is also shown that a conformation of the pyrophosphate moiety that results in an eclipsed or almost eclipsed orientation of two of the oxygen atoms, and which is found in protein interacting with a nucleotide di- or tri-phosphate X-ray data, is energetically favored. The results are also discussed in light of existing NMR data, and are found to be in a good agreement with them.

Glycosyl esters of nucleoside di or mono-phosphates, generally referred to as “sugar nucleotides”, serve as a sugar donors during the biosynthesis of oligo- and polysaccharides; they are therefore of a primary importance in carbohydrate metabolism in the living world. Molecular dynamics simulations were used to explore the conformational flexibility of one nucleotide sugar, UDP-glucose (UDP-Glc). The AMBER program package was used with some new parameters especially developed for nucleotide sugars. Several simulations on this molecule in aqueous solution, each of 2 ns duration, were carried out for increasing concentrations of monovalent K+ and divalent Mg2+ ions. For the monovalent ion, it is revealed that its presence and concentration is crucial for the conformational behavior, resulting in the stabilization of the extended conformation. The preferred location of K+ is in close proximity to the negatively charged phosphate oxygens, but the ion moves freely and can occupy other sites. Since the...

Glycosyl esters of nucleoside di- or monophosphates, generally referred to as “sugar nucleotides”, serve as a sugar donor during the biosynthesis of oligo- and polysaccharides. Therefore, they are of primary importance in carbohydrate metabolism in the living world. Not only the molecules themselves but especially their complexes with proteins are of interest in structural glycobiology. For computational studies on these molecules, it is necessary to have access to empirical methods with appropriate force field parametrization. In this work, we propose a set of parameters, developed using ab initio calculations with the 6-31G* basis set at the SCF level on model compounds, for the commonly used AMBER force field. By implementation of the new parameter set together with the CICADA conformational search program, we have obtained a semiquantitative description of conformational space, showing that nucleotide sugars can adopt several conformational families. The majority of them exhibit a “folded” rather than...