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The paper, employing the narratological method, examines and systematises self-referential speeches in Cestopis obsahující cestu do Horní Italie ([Travelogue containing a journey to Upper Italy] 1843) by Ján Kollár (1793 – 1852). Drawing on materials included in the kollar.elte.hu database, it maps typical forms of narrator’s self-referential speeches: the name of the author and his family members in the narration; the use and interpretation of the author’s own works in the narrative; the various forms of the author’s taste manifested in the text; the preferred literary, artistic, and architectural works he encounters or quotes; the presentation of the author’s ecclesiastical, philological, pedagogical, and other activities in the travelogue; and the narrative forms of self-referentiality that provide the narrator with the opportunity to express himself on an ideological level. The article also examines the various narrative roles which can be attributed to self-referential speeches and which point to the existence of an ideological system generally characteristic of the Enlightenment and Romantic periods in Central Europe. In this way, it reveals the characteristic features of Slavic national emblematism in the text and a certain broad system of ideas which can understood as religio triplex, which by merging revealed, natural, and national devoutness provides the narrator with a unified narrative framework.

This paper deals with a specific genre in Kollár’s work, namely the travelogue entitled Journey to Northern Italy (1843), which is an integral piece of central European travelogues of the 19th century. The study focuses on the analysis of the first stretch of the writer´s journey to the territory of the Hungarian Kingdom, specifically on the description of the area Zalavár/Mosaburg which belongs to the well-known early medieval settlements of the Cyril and Methodius era. On the one hand, the author’s focus is on the method of the space organization of the mentioned travelogue rooted in the Baroque era (first of all the phenomena as enfilade or central organization of the space). On the other hand, the author pays attention to Kollár’s efforts to create a modern Slavic cultural space from the old one as well as to the writer´s endeavour to set the Slavic cultural space free from the Hungarian captivity

A harmine-derived beta-carboline, CM16, inhibits cancer cells growth through its effects on protein synthesis, as described in “A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis” (Carvalho et al., 2017)[1]. This data article provides accompanying data on CM16 cytostatic evaluation in cancer cells as well as data related to its effects on transcription and translation. After confirming the cytostatic effect of CM16, we investigated its ability to arrest the cell cycle in the glioma Hs683 and SKMEL-28 melanoma cell lines but no modification was evidenced. According to the global protein synthesis inhibition induced by CM16 [1], transcription phase, a step prior to mRNA translation, evaluated by labelled nucleotide incorporation assay was not shown to be affected under CM16 treatment in the two cell lines. By contrast, mRNA translation and particularly the initiation step were shown to be targeted by CM16 in [1]. To further decipher those effects, we established herein a list of main actors in the protein synthesis process according to literature survey for comparative analysis of cell lines displaying different sensitivity levels to CM16. Finally, one of these proteins, PERK, a kinase regulating eIF2-α phosphorylation and thereby activity, was evaluated under treatment with CM16 in a cell-free system.

Abstract In this study, we evaluated the consequences of reducing Galectin-1 (Gal-1) in the tumor micro-environment (TME) of glioblastoma multiforme (GBM), via nose-to-brain transport. Gal-1 is overexpressed in GBM and drives chemo- and immunotherapy resistance. To promote nose-to-brain transport, we designed siRNA targeting Gal-1 (siGal-1) loaded chitosan nanoparticles that silence Gal-1 in the TME. Intranasal siGal-1 delivery induces a remarkable switch in the TME composition, with reduced myeloid suppressor cells and regulatory T cells, and increased CD4+ and CD8+ T cells. Gal-1 knock-down reduces macrophages’ polarization switch from M1 (pro-inflammatory) to M2 (anti-inflammatory) during GBM progression. These changes are accompanied by normalization of the tumor vasculature and increased survival for tumor bearing mice. The combination of siGal-1 treatment with temozolomide or immunotherapy (dendritic cell vaccination and PD-1 blocking) displays synergistic effects, increasing the survival of tumor bearing mice. Moreover, we could confirm the role of Gal-1 on lymphocytes in GBM patients by matching the Gal-1 expression and their T cell signatures. These findings indicate that intranasal siGal-1 nanoparticle delivery could be a valuable adjuvant treatment to increase the efficiency of immune-checkpoint blockade and chemotherapy.

Less than one percent of marine natural products characterized since 1963 have been obtained from the phylum Bryozoa which, therefore, still represents a huge reservoir for the discovery of bioactive metabolites with its ~6000 described species. The current review is designed to highlight how bryozoans use sophisticated chemical defenses against their numerous predators and competitors, and which can be harbored for medicinal uses. This review collates all currently available chemoecological data about bryozoans and lists potential applications/benefits for human health. The core of the current review relates to the potential of bryozoan metabolites in human diseases with particular attention to viral, brain, and parasitic diseases. It additionally weighs the pros and cons of total syntheses of some bryozoan metabolites versus the synthesis of non-natural analogues, and explores the hopes put into the development of biotechnological approaches to provide sustainable amounts of bryozoan metabolites without harming the natural environment.

Eight new (1−8) structurally diverse diterpenes featuring five different carbocycles were isolated from the organic extracts of the red alga Sphaerococcus coronopifolius collected from the coastline of the Ionian Sea in Greece. The structures of the new natural products, seven of which were halogenated, and the relative configuration of their stereocenters were determined on the basis of comprehensive spectroscopic analyses, including NMR and HRMS data. Compounds 5 and 8 were found to possess in vitro antitumor activity against one murine and five human cancer cell lines with mean IC50 values 15 and 16 μM, respectively.

Marine fungi are known to produce structurally unique secondary metabolites, and more than 1000 marine fungal-derived metabolites have already been reported. Despite the absence of marine fungal-derived metabolites in the current clinical pipeline, dozens of them have been classified as potential chemotherapy candidates because of their anticancer activity. Over the last decade, several comprehensive reviews have covered the potential anticancer activity of marine fungal-derived metabolites. However, these reviews consider the term “cytotoxicity” to be synonymous with “anticancer agent”, which is not actually true. Indeed, a cytotoxic compound is by definition a poisonous compound. To become a potential anticancer agent, a cytotoxic compound must at least display (i) selectivity between normal and cancer cells (ii) activity against multidrug-resistant (MDR) cancer cells; and (iii) a preferentially non-apoptotic cell death mechanism, as it is now well known that a high proportion of cancer cells that resist chemotherapy are in fact apoptosis-resistant cancer cells against which pro-apoptotic drugs have more than limited efficacy. The present review thus focuses on the cytotoxic marine fungal-derived metabolites whose ability to kill cancer cells has been reported in the literature. Particular attention is paid to the compounds that kill cancer cells through non-apoptotic cell death mechanisms.

Bastadins-6, -9 and -16 isolated from the marine sponge Ianthella basta displayed in vitro cytostatic and/or cytotoxic effects in six human and mouse cancer cell lines. The in vitro growth inhibitory effects of these bastadins were similar in cancer cell lines sensitive to pro-apoptotic stimuli versus cancer cell lines displaying various levels of resistance to pro-apoptotic stimuli. While about ten times less toxic than the natural cyclic bastadins, the synthetically derived 5,5'-dibromohemibastadin-1 (DBHB) displayed not only in vitro growth inhibitory activity in cancer cells but also anti-angiogenic properties. At a concentration of one tenth of its in vitro growth inhibitory concentration, DBHB displayed actual antimigratory effects in mouse B16F10 melanoma cells without any sign of cytotoxicity and/or growth inhibition. The serum concentration used in the cell culture media markedly influenced the DBHB-induced antimigratory effects in the B16F10 melanoma cell population. We are currently developing a specific inhalation formulation for DBHB enabling this compound to avoid plasmatic albumin binding through its direct delivery to the lungs to combat primary as well as secondary (metastases) tumors.

The first chemical study of the Indo-Pacific dorid nudibranch Aldisa andersoni resulted in the isolation of five chlorinated phenyl-pyrrolyloxazoles belonging to the phorbazole series. Two new molecules, 9-chloro-phorbazole D and N1-methyl-phorbazole A, co-occurring with known phorbazoles A, B and D, have been characterized. Phorbazoles were found to be present mainly in the external part of the mollusc. The structures of the new compounds were determined by interpretation of spectroscopic data, mainly NMR and mass spectrometry and by comparison with the literature data. Evaluation of feeding-deterrence activity as well as in vitro growth inhibitory properties in human cancer cells was also carried out.

The study deals with one of the central motifs of Ján Kollár’s work Slávy dcera, namely with the history of the figure of Complaining Slavia. Kollár derives the motif from Velius’s epistle entitled Querela Austriae (1527). The motif entered Hungary’s Latin-language literature becoming an important topos in Late Humanist and Baroque writing. With the Querela Hungariae topos other content elements became associated: description of the country’s riches (‘fertilitas Hungariae’) and comparison of the happiness of earlier times with the misery of conditions in Kollár’s own day. The literariness of Kollár was rooted deeply in Hungary’s Latin-language and Slavic-language cultures. His Latin-language didactic poem Deploratio praesentis status Hungariae proves that the author was familiar with the Querela Hungariae topos from his secondary-school years onwards. At the same time, in the Prologue to his Slávy dcera and in many of his sonnets, Kollár reinterpreted the topos according to the ideological requirements of the national movements of his time, changing Complaining Hungary into Complaining Slavia. In his Prologue to Slávy dcera, Kollár retained the metrical form of Latin didactic poetry (elegiac couplets), but at the same time refashioned it in accordance with the aesthetic demands of Classicism and Romanticism. There are in early 19th-century literature some areas that attempt to depict a nation emblematically. Of these, emblematic geography, ethnography, zoography, and phytography are investigated in this study. Through his works, in which famous mountain ranges (the Tatras, the Giant Mountains, the Urals), waters (the Danube, the Elbe, the Baltic Sea), cities (Prague, Moscow), and so forth are invested with surplus meaning, Kollár contributed to the depiction of the Slav (Czech and Slovak) nations. Together with their connotations, these places became parts of modern national mythology. This occurred during a several-decades-long canonisation process, at the end of which a given geographical place-name could lay claim to the status of ‘Slavic holy place’. It was in his 1821 volume entitled Básně (‘Verses’) that Kollár first pointed out geographical locations of importance from the national point of view, although these were at that time still at a rather low level of sacrality. Works published by Kollár in the mid-1820s – Čítanka (‘A Reader’) and the 1824 edition of Slávy dcera – were like maps from the Age of Discovery on which the coastlines of newly discovered continents already featured but where the land within still featured as white space. In the 1832 edition of Slávy dcera and in the Explanations (Vysvětlivky) he wrote for this work, Kollár ‘populated’ the three continents where Slavs lived. With the help of emblematic national topography, he created an imaginary Slavic country which ignored the status quo then prevailing in Europe. Kollár reached his highest degree of sacralisation of the nation with two songs published in his 1832 edition of Slávy dcera. In these, which presented a Slavic Heaven and a Slavic Purgatory, he enriched the emblematic national geography with the dimension of the life to come. In his Cestopis (‘Travelogue’), he launched a linguistic, historical and cultural crusade for the re-conquest of Northern Italy as a Slavic Holy Land.

The motifs of national exodus in Ján Kollár´s works Róbert K i s s S z e m á n, University Lóranda Eötvösa, Budapest, Hungary The study tries to grasp a phenomenon of the early 19th century when the Slovak nation and national literature separated from the Hungarian cultural tradition. However, many of its traditional features continued to exist in modern national literatures. The author focuses on the phenomenon of exodus as one of the defining organizational factors of Kollár´s life. He tries to reconstruct Kollár´s relationship with the world in his childhood and youth from individual chapters of his memoirs Paměti z mladších let života (Momoirs of my life´s younger years), she mentions his priesthood in Pešť, whose most important moment was Slovak church´s independence struggle against the German majority. The parts dealing with Kollár´s Čítanka demonstrate the impact of exodus on his personal life and priest´s and teacher´s careers. The concept of Panslavism in his works is interpreted as an imaginary home, which refers to Old Testament´s paradigm system of Promised land. There is some symbolism in Kollár´s travels around Italy, which played an important role in Slovak national exodus. This phenomenon is naturally associated with many sonnets in Slávy dcéra (Fame´s daughter), which by activating the Old Testament´s symbolism in a creative way also played a major role in establishing new Czech and Slovak ethnographies.

Glioblastoma (GBM) is the most frequent malignant glioma. Treatment of GBM patients is multimodal with maximum surgical resection, followed by concurrent radiation and chemotherapy with the alkylating drug temozolomide (TMZ). The present study aims to identify genes implicated in the acquired resistance of two human GBM cells of astrocytic origin, T98G and U373, to TMZ. Resistance to TMZ was induced by culturing these cells in vitro for months with incremental TMZ concentrations up to 1 mM. Only partial resistance to TMZ has been achieved and was demonstrated in vivo in immunocompromised mice bearing orthotopic U373 and T98G xenografts. Our data show that long-term treatment of human astroglioma cells with TMZ induces increased expression of facilitative glucose transporter/solute carrier GLUT/SLC2A family members, mainly GLUT-3, and of the AKR1C family of proteins. The latter proteins are phase 1 drug-metabolizing enzymes involved in the maintenance of steroid homeostasis, prostaglandin metabolism, and metabolic activation of polycyclic aromatic hydrocarbons. GLUT-3 has been previously suggested to exert roles in GBM neovascularization processes, and TMZ was found to exert antiangiogenic effects in experimental gliomas. AKR1C1 was previously shown to be associated with oncogenic potential, with proproliferative effects similar to AKR1C3 in the latter case. Both AKR1C1 and AKR1C2 proteins are involved in cancer pro-proliferative cell chemoresistance. Selective targeting of GLUT-3 in GBM and/or AKR1C proteins (by means of jasmonates, for example) could thus delay the acquisition of resistance to TMZ of astroglioma cells in the context of prolonged treatment with this drug.

NAD+-dependent histone deacetylases (sirtuins) are implicated in cellular processes such as proliferation, DNA repair, and apoptosis by regulating gene expression and the functions of numerous proteins. Due to their key role in cells, the discovery of small molecule sirtuin modulators has been of significant interest for diverse therapeutic applications. In particular, it has been shown that inhibition of sirtuin 1 and 2 activities is beneficial for cancer treatment. Here, we demonstrate that the fungal metabolite eurochevalierine from the fungus Neosartorya pseudofischeri inhibits sirtuin 1 and 2 activities (IC50 about 10 µM) without affecting sirtuin 3 activity. The binding modes of the eurochevalierine for sirtuin 1 and 2 have been identified through computational docking analyses. Accordingly, this sequiterpene alkaloid induces histone H4 and α-tubulin acetylation in various cancer cell models in which it induces strong cytostatic effects without affecting significantly the viability of healthy PBMCs. Importantly, eurochevalierine targets preferentially cancer cell proliferation (selectivity factor ≫ 7), as normal human primary CD34+ stem/progenitor cells were less affected by the treatment. Finally, eurochevalierine displays suitable drug-likeness parameters and therefore represent a promising scaffold for lead molecule optimization to study the mechanism and biological roles of sirtuins and potentially a basis for development into therapeutics.

Gliomas account for more than 50% of all primary brain tumors. The worst prognosis is associated with gliomas of astrocytic origin, whereas gliomas with an oligodendroglial origin offer higher sensitivity to chemotherapy, especially when oligodendroglioma cells display 1p19q deletions. Temozolomide (TMZ) provides therapeutic benefits and is commonly used with radiotherapy in highly malignant astrocytic tumors, including glioblastomas. The actual benefits of TMZ during long-term treatment in oligodendroglioma patients have not yet been clearly defined. In this study, we have investigated the effects of such a long-term TMZ treatment in the unique Hs683 oligodendroglioma model. We have observed increased TMZ sensitivity of Hs683 orthotopic tumors that were previously treated in vitro with months of progressive exposure to increasing TMZ concentrations before being xenografted into the brains of immunocompromised mice. Whole-genome and proteomic analyses have revealed that this increased TMZ sensitivity of Hs683 oligodendroglioma cells previously treated for long periods with TMZ can be explained, at least partly, by a TMZ-induced p38-dependant dormancy state, which in turn resulted in changes in amino acid metabolism balance, in growth delay, and in a decrease in Hs683 oligodendroglioma cell-invasive properties. Thus, long-term TMZ treatment seems beneficial in this Hs683 oligodendroglioma model, which revealed itself unable to develop resistance against TMZ.

We have previously reported that galectin 1 (Gal-1) plays important biological roles in astroglial as well as in oligodendroglial cancer cells. As an oligodendroglioma model, we make use of the Hs683 cell line that has been previously extensively characterized at cell biology, molecular biology, and genetic levels. Galectin 1 has been shown to be involved in Hs683 oligodendroglioma chemoresistance, neoangiogenesis, and migration. Down-regulating Gal-1 expression in Hs683 cells through targeted small interfering RNA provokes a marked decrease in the expression of the brain-expressed X-linked gene: BEX2. Accordingly, the potential role of BEX2 in Hs683 oligodendroglioma cell biology has been investigated. The data presented here reveal that decreasing BEX2 expression in Hs683 cells increases the survival of Hs683 orthotopic xenograft-bearing mice. Furthermore, this decrease in BEX2 expression impairs vasculogenic mimicry channel formation in vitro and angiogenesis in vivo, and modulates glioma cell adhesion and invasive features through the modification of several genes previously reported to play a role in cancer cell migration, including MAP2, plexin C1, SWAP70, and integrin β6. We thus conclude that BEX2 is implicated in oligodendroglioma biology.

Purpose: The aims of the present work were to investigate the in vitro and in vivo antiangiogenic effects of chronic temozolomide treatment on various glioma models and to demonstrate whether bevacizumab (Avastin) increased the therapeutic benefits contributed by temozolomide in glioma. Experimental Design: The expression levels of various antiangiogenic factors in four glioma cell lines were evaluated after chronic in vitro treatment with temozolomide by Western blot. Proliferation and migration assays were performed on human endothelial cells incubated with supernatants of glioma cells treated with and without temozolomide. Orthotopic glioma models were used to evaluate the antiangiogenic effects of temozolomide in vivo and the therapeutic benefits of different temozolomide treatment schedules used alone or in combination with bevacizumab. Results: Temozolomide, a proautophagic and proapoptotic drug, decreased the expression levels of HIF-1α, ID-1, ID-2, and cMyc in the glioma models investigated, all of which playing major roles in angiogenesis and the switch to hypoxic metabolism. These changes could be, at least partly, responsible for the impairment of angiogenesis observed in vitro and in vivo. Moreover, combining bevacizumab with temozolomide increased the survival of glioma-bearing mice in comparison to each compound administered alone. Conclusions: In addition to the numerous mechanisms of action already identified for temozolomide, we report here that it also exerts antitumor effects by impairing angiogenic processes. We further emphasize that bevacizumab, which is an antiangiogenic drug with a different mechanism of action, could be useful in combination with temozolomide to increase the latter's therapeutic benefit in glioma patients.

Several naphthalimides have been evaluated clinically as potential anticancer agents. UNBS3157, a naphthalimide that belongs to the same class as amonafide, was designed to avoid the specific activating metabolism that induces amonafide’s hematotoxicity. The current study shows that UNBS3157 rapidly and irreversibly hydrolyzes to UNBS5162 without generating amonafide. In vivo UNBS5162 after repeat administration significantly increased survival in orthotopic human prostate cancer models. Results obtained by the National Cancer Institute (NCI) using UNBS3157 and UNBS5162 against the NCI 60 cell line panel did not show a correlation with any other compound present in the NCI database, including amonafide, thereby suggesting a unique mechanism of action for these two novel naphthalimides. Affymetrix genome-wide microarray analysis and enzyme-linked immunosorbent assay revealed that in vitro exposure of PC-3 cells to UNBS5162 (1 μM for 5 successive days) dramatically decreased the expression of the proangiogenic CXCL chemokines. Histopathology additionally revealed antiangiogenic properties in vivo for UNBS5162 in the orthotopic PC-3 model. In conclusion, the present study reveals UNBS5162 to be a pan-antagonist of CXCL chemokine expression, with the compound displaying antitumor effects in experimental models of human refractory prostate cancer when administered alone and found to enhance the activity of taxol when coadministered with the taxoid.

Purpose. To review the involvement of the ion transporter Na+/K+-ATPase (NaK) in the migration and proliferation of glioma cells. Preliminary studies indicate that NaK α1 subunits seem to be upregulated in a proportion of glioblastomas but not in normal brain tissues. Design. The present review focuses on (1) the natural resistance of migrating malignant glioma cells to apoptosis, (2) autophagic cell death as an alternative to combat malignant gliomas, (3) the fact that reducing the levels of malignant glioma cell motility can restore proapoptotic drug sensitivity, and (4) on the observation that inhibiting the NaK activity reduces both glioma cell proliferation and migration. Results. The natural ligands of the NaK are the cardiotonic steroids. A hemisynthetic derivative of 2″-oxovoruscharin (UNBS1450), a novel cardenolide, displays unique structural features, making its binding affinity to NaK α subunits (including α1) 10 to 100 times higher than that of other cardenolides. UNBS1450 markedly decreases intracellular ATP concentration in glioma cells, disorganizes the actin cytoskeleton, and leads to autophagic cell death in NaK α1 over-expressing glioma cells. Conclusions. Glioblastoma patients who do not respond to chemotherapy and whose tumors over-express NaK α1 subunits could benefit from a treatment using ligands with marked binding affinity for the NaK α1 subunit.

Our study has shown that the Amaryllidaceae isocarbostyril narciclasine induces marked apoptosismediated cytotoxic effects in human cancer cells but not in normal fibroblasts by triggering the activation of the initiator caspases of the death receptor pathway (caspase-8 and caspase-10) at least in human MCF-7 breast and PC-3 prostate carcinoma cells. The formation of the Fas and death receptor 4 (DR4) death-inducing signaling complex was clearly evidenced in MCF-7 and PC-3 cancer cells. Caspase-8 was found to interact with Fas and DR4 receptors on narciclasine treatment. However, narciclasine-induced downstream apoptotic pathways in MCF-7 cells diverged from those in PC-3 cells, where caspase-8 directly activated effector caspases such as caspase-3 in the absence of any further release of mitochondrial proapoptotic effectors. In contrast, in MCF-7 cells, the apoptotic process was found to require an amplification step that is mitochondria-dependent, with Bid processing, release of cytochrome c, caspase-9 activation. It is postulated that the high selectivity of narciclasine to cancer cells might be linked, at least in part, to this activation of the death receptor pathway. Normal human fibroblasts appear approximately 250-fold less sensitive to narciclasine, which does not induce apoptosis in these cells probably due to the absence of death receptor pathway activation.

Although the molecular function of cr receptors has not been fully defined and the natural ligand(s) is still not known, there is increasing evidence that these receptors and their ligands might play a significant role in cancer biology. 4-(N-tibenzylpiperidin-4-yl)-4iodobenzamide (4-IBP), a selective σ1, agonist, has been used to investigate whether this compound is able to modify: 1) in vitro the migration and proliferation of human cancer cells; 2) in vitro the sensitivity of human glioblastoma cells to cytotoxic drugs; and 3) in vivo in orthotopic glioblastoma and non-small cell lung carcinoma (NSCLC) models the survival of mice coadministered cytotoxic agents. 4-IBP has revealed weak anti proliferative effects on human U373-MG glioblastoma and C32 melanoma cells but induced marked concentration-dependent decreases in the growth of human A549 NSCLC and PC3 prostate cancer cells. The compound was also significantly antimigratory in all four cancer cell lines. This may result, at least in U373-MG cells, from modifications to the actin cytoskeleton. 4-IBP modified the sensitivity of U373-MG cells in vitro to proapoptotic lomustin and proautophagic temozolomide, and markedly decreased the expression of two proteins involved in drug resistance: glucosylceramide synthase and Rho guanine nucleotide dissociation inhibitor. In vivo, 4-IBP increased the antitumor effects of temozolomide and irinotecan in immunodeficient mice that were orthotopically grafted with invasive cancer cells.

Background: While the neurotensin (NT) roles in pancreatic cancer growth are well documented, its effects on pancreatic cancer cell migration have not been described. Methods: The NT-induced effects on the migration process of human pancreatic ductal adenocarcinoma cells (PDACs) were characterized by means of various assays including computer-assisted video-microscopy, fluorescence microscopy, ELISA-based, small GTPase pull-down and phosphorylation assays. Results: The NT-induced modifications on in vitro PDACs migration largely depended on the extra-cellular matrix environment and cell propensity to migrate collectively or individually. While NT significantly reduced the level of migration of collectively migrating PDACs on vitronectin, it significantly increased the level of individually migrating PDACs. These effects were mainly mediated through the sortilin/NTR3 receptor. Neurotensin both induced altered expression of αV and β5 integrin subunits in PDACs cultured on vitronectin resulting in modified adhesion abilities, and caused modifications to the organization of the actin cytoskeleton through the NT-mediated activation of small Rho GTPases. While the NT effects on individually migrating PDACs were mediated at least through the EGFR/ERK signaling pathways, those on collectively migrating PDACs appeared highly dependent on the PI 3-kinase pathway. Conclusion: This study strongly suggests the involvement of neurotensin in the modulation of human PDAC migration.

Non-small cell lung cancers (NSCLCs) are the leading cause of cancer deaths in most developed countries. Targeting heat shock protein 70 (Hsp70) expression and function, together with the induction of lysosomal membrane permeabilization (LMP), could overcome the multiple anti-cell death mechanisms evidenced in NSCLCs that are responsible for the failure of currently used chemotherapeutic drugs. Because cardenolides bind to the sodium pump, they affect multiple signaling pathways and thus have a number of marked effects on tumor cell behavior. The aim of the present study was to characterize in vitro and in vivo the antitumor effects of a new cardenolide (UNBS1450) on experimental human NSCLCs. UNBS1450 is a potent source of in vivo antitumor activity in the case of paclitaxeland oxaliplatin-resistant subcutaneous human NCIH727 and orthotopic A549 xenografts in nude mice. In vitro UNBS1450-mediated antitumor activity results from the induction of nonapoptotic cell death. UNBS1450 mediates the decrease of Hsp70 at both mRNA and protein levels, and this is at least partly due to UNBS1450-induced downregulation of NFAT5/ TonEBP (a factor responsible for the transcriptional control of Hsp70). These effects were paralleled by the induction of LMP, as evidenced by acridine orange staining and immunofluorescence analysis for cathepsin B accumulation.

The effects of gastrin (G17) on the growth and migration factors of four human melanoma cell lines (HT-144, C32, G-361, and SKMEL-28) were investigated. The expression patterns of cholecystokinin (CCK)A CCKB, and CCKC gastrin receptors were investigated in these cells and in seven clinical samples by means of reverse transcription polymerase chain reaction. Melanoma cells appear to express mRNA for CCKc receptors, but not for CCKA or CCKB receptors. Although gastrin does not significantly modify the growth characteristics of the cell lines under study, it significantly modifies their cell migration characteristics. These modifications occur at adhesion level by modifying the expression levels of αv and β3 integrins, at motility level by modifying the organization of the actin cytoskeleton, and at invasion level by modifying the expression levels of matrix metal loproteinase 14. We recently demonstrated the presence of CCKB receptors in mouse endothelial cells involved in glioblastoma neoangiogenesis. Chronic in vivo administration of a selective CCKB receptor antagonist to mice bearing xenografts of human C32 melanoma cells significantly decreased levels of neoangiogenesis, resulting in considerable delays in the growth of these C32 xenografts. In conclusion, our study identifies the pleiotropic effects of gastrin on melanoma cell biology.

The present paper reports our experience with, and our opinion of static telepathology as applied to neuropathology by means of the PHAROS acquisition system and conventional telephone data transmission (modem). The classical procedure of expert consultation based on surface mailing of histological slides is routinely performed, especially in highly specialized fields of pathology. Telepathology is an easy means of sharing scientific expertise at international level and could thus improve diagnosis particularly in neuropathology, where certain tumor types are very rare and complex to diagnose. Dynamic telepathology allows the referring pathologist to capture by himself images supporting their diagnosis. Using static telepathology the pathologist could be limited in diagnosis by problems in fields selection.

Using a series of 105 renal cell carcinomas (RCCs) we investigated whether features quantitatively describing the appearance of Feulgen‐stained nuclei and, more particularly, of their chromatin (on the basis of computer‐assisted microscopy) can contribute any significant prognostic information. Thirty morphonuclear and 8 nuclear DNA content‐related variables were thus generated. The actual prognostic values of this set of cytometric variables was compared (by means of discriminant statistical analysis) to conventional diagnostic and/or prognostic markers including histopathological grades, tumour invasion levels and the presence or absence of metastases. We obtained complete clinical follow‐ups for 49 of the 105 RCC patients under study, making it possible to define a subset of patients with a bad prognosis (i.e., who died in the 12 months following nephrectomy) and a subset of patients with a good prognosis (i.e., who survived at least 24 months following nephrectomy). An original method of data analysis related to artificial intelligence (decision tree induction) enabled a strong prognostic model to be set up. In the case of 10 new patients, this model identified all the dead patients as having a bad survival status, with a total of 8 correct predictions. Another prognostic model similarly generated enabled the correct predictions to be confirmed.

Marine invertebrates provide a rich source of metabolites with anticancer activities and several marine-derived agents have been approved for the treatment of cancer. However, the limited supply of promising anticancer metabolites from their natural sources is a major hurdle to their preclinical and clinical development. Thus, the lack of a sustainable large-scale supply has been an important challenge facing chemists and biologists involved in marine-based drug discovery. In the current review we describe the main strategies aimed to overcome the supply problem. These include: marine invertebrate aquaculture, invertebrate and symbiont cell culture, culture-independent strategies, total chemical synthesis, semi-synthesis, and a number of hybrid strategies. We provide examples illustrating the application of these strategies for the supply of marine invertebrate-derived anticancer agents. Finally, we encourage the scientific community to develop scalable methods to obtain selected metabolites, which in the authors’ opinion should be pursued due to their most promising anticancer activities.

Abstract Background Although the number of point-of-care ultrasound devices available in Hungarian primary care practices are increasing due to government funding, their use in day-to-day patient care is limited and unregulated. Our study aimed to evaluate the attitudes and needs of general practitioners (GPs) and patients in Hungary regarding the introduction of bedside ultrasonography in primary care practices. Methods As a part of a cross-sectional study, an anonymous, self-administered questionnaire was distributed to GPs and patients on a social media platform. Data collection was carried out from August 2023 to October 2023. Chi-square test was used to determine the associations between categorical variables. Results The survey was completed by 415 GPs (mean age 53.8 ± 11.1 years, 54.9% female, mean 19.5 ± 11.9 years of practice) and 693 patients (mean age 45.5 ± 12.3 years, 95.2% female). There was a statistically significant increase in interest in PoCUS among young and middle-aged GPs (age 28–59; p = 0.02). In addition, this population of GPs was also more likely to undertake training in PoCUS than their older colleagues (p