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Current business trends push transport companies to improve the efficiency of their entrepreneurial activities, what is closely related to costs reduction and revenues increase. Many transport companies achieve it empirically, but some mathematical algorithms, mainly from operational research, can be used to improve the efficiency of railway transport by finding the optimal solution of specific problems. The paper is focused on using of selected methods from applied mathematics in railway transport. These methods are used mainly for improving the operational efficiency of the transport company, what tends to decrease overall operating costs. Major impact is done by efficient use of railway vehicles and train staff. It can be achieved by optimization as a flow network problem or assignment problem, what is further described in the paper. Mathematical approaches can also positively influence the whole logistic process.

Logistics is defined as an interdisciplinary science, which deals with coordination, harmonization, connection and optimization of material, product and service flows including flows of information and finance. The main aim of logistics is to satisfy needs of the customer with importance of quality aspect and optimal costs. The paper is focused on practical logistic problems within the company, its suppliers and customers so overall supply chain is analyzed there. The aim of the paper is to provide practical simulation and calculation of selected logistic examples such as procurement, storage and distribution on case studies. These logistic aspects are analyzed in way, how are they explained to students in university educational process on school subjects that deal with logistics in some case. The simulation of storage process is done with specialized software called Byron, which is also used for educational purposes.

The issue of surface runoff assessment is one of the important and relevant topics of hydrological as well as geographical research. The aim of the paper is therefore to estimate and assess surface runoff on the example of Vyčoma catchment which is located in the Western Slovakia. For this purpose, SCS runoff curve number method, modeling in GIS and remote sensing were used. An important task was the creation of a digital elevation model (DEM), which enters the surface runoff modeling and affects its accuracy. Great attention was paid to the spatial interpretation of land use categories applying aerial imagery from 2013 and hydrological soil groups as well as calculation of maximum daily rainfall with N-year return periods as partial tasks in estimating surface runoff. From the methodological point of view, the importance of the paper can be seen in the use of a simple GIS-based approach to assess the surface runoff conditions in a small catchment.

The most important element in railway passenger transport is a customer – traveller, who requires the transport from one place to another. A basic precondition for accomplishing the main requirement – transport, is making the complete offer which provides not only transport, but also other associated services. Practically, there are many associated criteria of transport, for example safety, duration, price, reliability, comfort and complementary services. Passenger transport is generally considered as an activity, which arises as the consequence of spatial division of places, where people are in exact time and their need to move. Motivators for moving could be commuting – job or education, dealing with personal or working matters, travelling for vacation – hiking, sport, health, cultural and social facilities, visiting relatives and friends. Requirements for transport of passengers originate in the need to move, while the passenger transport is dependent on the willingness of travelling. In passenger transport, there are mostly individual passengers, so it is difficult to determine all transport requirements. The paper is focused on one of the key factors of passenger transportation - connectivity of trains. Connectivity of passenger trains and other means of transport can be distinguished also from temporal and spatial point of view. Temporal connectivity is such sequence of arrivals and departures of different passenger trains and other means of transport, which allows changing the different passenger vehicles easily in regard to necessary time. Spatial connectivity means the distance between two passenger vehicles, among which the passenger is moving. In the paper, there is described the general methodology for calculation of minimum transfer time in the railway station. Railway passenger station is some kind of transport hub – a starting and finishing point for flows of passengers. Passengers have the opportunity to change the train type from long-haul train to regional train or contrariwise or simply enter or leave the system of railway transport. In the methodology, all necessary aspects are taken into account.

Market liberalization is a great contemporary trend in many fields of economy. Liberalized transport market, where the transport demand is meeting with transport offer, is evolving dynamically. Private railway passenger operators want to increase their market share together with national railway passenger transport companies therefore the quality of passenger transportation is getting higher, which positively influences the attractiveness of railway passenger transport. The article is focused on these current trends of liberalization in railway passenger transport market. From operational and economical point of view, there are described some ways, how to make the railway passenger transport system more effective and make the entire transport system more attractive for traveling public.

Main challenge of logistics is delivering right assortment of products in exact amount, to exact place, in exact time, ecologically and for exact price. Logistics deals with freight transport but when the word ‘products’ is changed to ‘passengers’, then many principles can be applied to passenger transport. Railway passenger transport is the key part of passenger transport system, so it is necessary to optimize it on logistics philosophy at first.

In this article, we aim at the prediction of possible locations of already defunct historical objects with a defensive function (HODFs) in Slovakia, which have not been found and documented so far, using three machine learning methods. Specifically, we used the support vector machine, k-nearest neighbors, and random forest algorithms, which were trained based on the following five factors influencing the possible occurrence of HODFs: elevation, distance from a river, distance from a settlement, lithological rock type, and type of representative geoecosystems. Training and testing datasets were based on a database of already documented 605 HODFs, which were divided into 70% of training samples and 30% of testing samples. All of the three models reached the AUC-ROC value over 0.74 based on the testing dataset. The best performance was recorded by the random forest predictive model with the AUC-ROC value equal to 0.79. The results of the random forest model were also validated with the recently documented HODFs via the archeological research., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Compounds with a heterocyclic isoxazole ring are well known for their diverse biologic activities encompassing antimicrobial, antipsychotic, immunosuppressive, antidiabetic and anticancer effects. Recent studies on hematological malignancies have also shown that some of the isoxazole-derived compounds feature encouraging cancer selectivity, low toxicity to normal cells and ability to overcome cancer drug resistance of conventional treatments. These characteristics are particularly promising because patients with hematological malignancies face poor clinical outcomes caused by cancer drug resistance or relapse of the disease. This review summarizes the knowledge on isoxazole-derived compounds toward hematological malignancies and provides clues on their mechanism(s) of action (apoptosis, cell cycle arrest, ROS production) and putative pharmacological targets (c-Myc, BET, ATR, FLT3, HSP90, CARM1, tubulin, PD-1/PD-L1, HDACs) wherever known., (Copyright © 2024. Published by Elsevier Ltd.)

Cisplatin (cDDP) resistance is a matter of concern in triple-negative breast cancer therapeutics. We measured the metabolic response of cDDP-sensitive (S) and -resistant (R) MDA-MB-231 cells to Pd 2 Spermine(Spm) (a possible alternative to cDDP) compared to cDDP to investigate (i) intrinsic response/resistance mechanisms and (ii) the potential cytotoxic role of Pd 2 Spm. Cell extracts were analyzed by untargeted nuclear magnetic resonance metabolomics, and cell media were analyzed for particular metabolites. CDDP-exposed S cells experienced enhanced antioxidant protection and small deviations in the tricarboxylic acid cycle (TCA), pyrimidine metabolism, and lipid oxidation (proposed cytotoxicity signature). R cells responded more strongly to cDDP, suggesting a resistance signature of activated TCA cycle, altered AMP/ADP/ATP and adenine/uracil fingerprints, and phospholipid biosynthesis (without significant antioxidant protection). Pd 2 Spm impacted more markedly on R/S cell metabolisms, inducing similarities to cDDP/S cells (probably reflecting high cytotoxicity) and strong additional effects indicative of amino acid depletion, membrane degradation, energy/nucleotide adaptations, and a possible beneficial intracellular γ-aminobutyrate/glutathione-mediated antioxidant mechanism.

This work compared the metabolic profile of a parental MDA-MB-231 cisplatin-sensitive triple negative breast cancer (TNBC) cell line with that of a derived cisplatin-resistant line, to characterize inherent metabolic adaptations to resistance, as a means for marker and new TNBC therapies discovery. Supported by cytotoxic, microscopic and biochemical characterization of both lines, Nuclear Magnetic Resonance (NMR) metabolomics was employed to characterize cell polar extracts for the two cell lines, as a function of time (0, 24 and 48 h), and identify statistically relevant differences both between sensitive and resistant cells and their time course behavior. Biochemical results revealed a slight increase in activation of the NF-κB pathway and a marked decrease of the ERK signaling pathway in resistant cells. This was accompanied by lower glycolytic and glutaminolytic activities, possibly linked to glutamine being required to increase stemness capacity and, hence, higher survival to cisplatin. The TCA cycle dynamics seemed to be time-dependent, with an apparent activation at 48 h preferentially supported by anaplerotic aromatic amino acids, leucine and lysine. A distinct behavior of leucine, compared to the other branched-chain-amino-acids, suggested the importance of the recognized relationship between leucine and in mTOR-mediated autophagy to increase resistance. Suggested markers of MDA-MB-231 TNBC cisplatin-resistance included higher phosphocreatine/creatine ratios, hypotaurine/taurine-mediated antioxidant protective mechanisms, a generalized marked depletion in nucleotides/nucleosides, and a distinctive pattern of choline compounds. Although the putative hypotheses generated here require biological demonstration, they pave the way to the use of metabolites as markers of cisplatin-resistance in TNBC and as guidance to develop therapies., (© 2023. The Author(s).)

Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer and constitutes 10-20% of all breast cancer cases. Even though platinum-based drugs such as cisplatin and carboplatin are effective in TNBC patients, their toxicity and development of cancer drug resistance often hamper their clinical use. Hence, novel drug entities with improved tolerability and selectivity profiles, as well as the ability to surpass resistance, are needed. The current study focuses on Pd(II) and Pt(II) trinuclear chelates with spermidine (Pd 3 Spd 2 and Pt 3 Spd 2 ) for evaluating their antineoplastic activity having been assessed towards (i) cisplatin-resistant TNBC cells (MDA-MB-231/R), (ii) cisplatin-sensitive TNBC cells (MDA-MB-231) and (iii) non-cancerous human breast cells (MCF-12A, to assess the cancer selectivity/selectivity index). Additionally, the complexes' ability to overcome acquired resistance (resistance index) was determined. This study revealed that Pd 3 Spd 2 activity greatly exceeds that displayed by its Pt analog. In addition, Pd 3 Spd 2 evidenced a similar antiproliferative activity in both sensitive and resistant TNBC cells (IC 50 values 4.65-8.99 µM and 9.24-13.34 µM, respectively), with a resistance index lower than 2.3. Moreover, this Pd compound showed a promising selectivity index ratio: >6.28 for MDA-MB-231 cells and >4.59 for MDA-MB-231/R cells. Altogether, the data presently gathered reveal Pd 3 Spd 2 as a new, promising metal-based anticancer agent, which should be further explored for the treatment of TNBC and its cisplatin-resistant forms.

The article focuses on the mapping and assessment of fluvial flood risk at municipal level of Slovakia. The fluvial floods risk index (FFRI), composed of a hazard component and a vulnerability component, was computed for 2927 municipalities using spatial multicriteria analysis and geographic information systems (GIS). The fluvial flood hazard index (FFHI) was computed based on eight physical-geographical indicators and land cover representing the riverine flood potential and also the frequency of flood events in individual municipalities. The fluvial flood vulnerability index (FFVI) was calculated using seven indicators representing the economic and social vulnerability of municipalities. All of the indicators were normalized and weighted using the rank sum method. By aggregating the weighted indicators, we obtained the FFHI and FFVI in each municipality. The final FFRI is a result of a synthesis of the FFHI and FFVI. The results of this study can be used mainly in the framework of flood risk management at national spatial scale, but also for local governments and periodic update of the Preliminary Flood Risk Assessment document, which is carried out at the national level under the EU Floods Directive., (© 2023. The Author(s).)

Cisplatin (cDDP)-based chemotherapy is often limited by severe deleterious effects (nephrotoxicity, hepatotoxicity and neurotoxicity). The polynuclear palladium(II) compound Pd 2 Spermine (Pd 2 Spm) has emerged as a potential alternative drug, with favorable pharmacokinetic/pharmacodynamic properties. This paper reports on a Nuclear Magnetic Resonance metabolomics study to (i) characterize the response of mice brain and liver to Pd 2 Spm, compared to cDDP, and (ii) correlate brain-liver metabolic variations. Multivariate and correlation analysis of the spectra of polar and lipophilic brain and liver extracts from an MDA-MB-231 cell-derived mouse model revealed a stronger impact of Pd 2 Spm on brain metabolome, compared to cDDP. This was expressed by changes in amino acids, inosine, cholate, pantothenate, fatty acids, phospholipids, among other compounds. Liver was less affected than brain, with cDDP inducing more metabolite changes. Results suggest that neither drug induces neuronal damage or inflammation, and that Pd 2 Spm seems to lead to enhanced brain anti-inflammatory and antioxidant mechanisms, regulation of brain bioactive metabolite pools and adaptability of cell membrane characteristics. The cDDP appears to induce higher extension of liver damage and an enhanced need for liver regeneration processes. This work demonstrates the usefulness of untargeted metabolomics in evaluating drug impact on multiple organs, while confirming Pd 2 Spm as a promising replacement of cDDP.

Corema (C.) album belongs to the family Ericaceae and can be found in the Iberian Peninsula, especially on the coastal areas facing the Atlantic coast. C. album berries have been used for centuries in traditional medicine. Recent studies have revealed that not only the berries but also the leaves have relevant antioxidant, antiproliferative, and anti-inflammatory properties, bringing this plant to the forefront of discussion. A systematic review of the literature was carried out to summarize the phenolic compounds and bioactive properties identified in C. album berries and leaves and to search for research gaps on this topic. The search was conducted in three electronic databases (PubMed, SCOPUS, and Web of Science) using PRISMA methodology. The inclusion criteria were the chemical compositions of the berries, leaves, or their extracts and their bioactive properties. The exclusion criteria were agronomic and archaeological research. The number of studies concerning phenolic compounds' composition and the bioactive properties of C. album berries and leaves is still limited (11 articles). However, the variety of polyphenolic compounds identified make it possible to infer new insights into their putative mechanism of action towards the suppression of NF-kB transcription factor activation, the modulation of inflammatory mediators/enzymes, the induction of apoptosis, the modulation of mitogen activated protein kinase, cell cycle arrest, and the reduction of oxidative stress. These factors can be of major relevance concerning the future use of C. album as nutraceuticals, food supplements, or medicines. Nevertheless, more scientific evidence concerning C. album's bioactivity is required.

Corema (C.) album is a shrub endemic to the Atlantic coast and has been described as yielding beneficial effects for human health. Nevertheless, studies concerning the bioactivity of C. album leaves are scarce. This study aims at investigating the anticancer potential and mode of action, of an hydroethanolic extract of C. album leaves (ECAL) on triple-negative breast cancer. This is a poor survival breast cancer subtype, owing to its high risk of distant reappearance, metastasis rates and the probability of relapse. The ECAL ability to prevent tumor progression through (i) the inhibition of cell proliferation (cell viability); (ii) the induction of apoptosis (morphological changes, TUNEL assay, caspase-3 cleaved) and (iii) the induction of DNA damage (PARP1 and γH2AX) with (iv) the involvement of NF-κB and of ERK1/2 pathways (AlphaScreen assay) was evaluated. ECAL activated the apoptotic pathway (through caspase-3) along with the inhibition of ERK and NF-κB pathways causing DNA damage and cell death. The large polyphenolic content of ECAL was presumed to be accountable for these effects. The extract of C. album leaves can target multiple pathways and, thus, can block more than one possible means of disease progression, evidencing the anticancer therapeutic potential from a plant source.

The new palladium agent Pd 2 Spermine (Spm) has been reported to exhibit promising cytotoxic properties, while potentially circumventing the known disadvantages associated to cisplatin therapeutics, namely acquired resistance and high toxicity. This work presents a nuclear magnetic resonance (NMR) metabolomics study of brain extracts obtained from healthy mice, to assess the metabolic impacts of the new Pd 2 Spm complex in comparison to that of cisplatin. The proton NMR spectra of both polar and nonpolar brain extracts were analyzed by multivariate and univariate statistics, unveiling several metabolite variations during the time course of exposition to each drug (1-48 h). The distinct time-course dependence of such changes revealed useful information on the drug-induced dynamics of metabolic disturbances and recovery periods, namely regarding amino acids, nucleotides, fatty acids, and membrane precursors and phospholipids. Putative biochemical explanations were proposed, based on existing pharmacokinetics data and previously reported metabolic responses elicited by the same metal complexes in the liver of the same animals. Generally, results suggest a more effective response of brain metabolism towards the possible detrimental effects of Pd 2 Spm, with more rapid recovery back to metabolites' control levels and, thus, indicating that the palladium drug may exert a more beneficial role than cDDP in relation to brain toxicity.

Pd 2 Spm is a dinuclear palladium(II)-spermine chelate with promising anticancer properties against triple-negative breast cancer (TNBC), a breast carcinoma subset with poor prognosis and limited treatment options. The present study evaluated the in vitro and in vivo anticancer effects of Pd 2 Spm compared to the reference metal-based drug cisplatin. Triple-negative breast cancer MDA-MB-231 cells, non-cancerous MCF-12A breast cells and chorioallantoic membrane (CAM) assay were used for antiproliferative, antimigratory and antiangiogenic studies. For an in vivo efficacy study, female CBA nude mice with subcutaneously implanted MDA-MB-231 breast tumors were treated with Pd 2 Spm (5 mg/kg/day) or cisplatin (2 mg/kg/day) administered intraperitoneally during 5 consecutive days. Promising selective antiproliferative activity of Pd 2 Spm was observed in MDA-MB-231 cells (IC 50 values of 7.3-8.3 µM), with at least 10-fold lower activity in MCF-12A cells (IC 50 values of 89.5-228.9 µM). Pd 2 Spm inhibited the migration of MDA-MB-231 cells, suppressed angiogenesis in CAM and decreased VEGF secretion from MDA-MB-231 cells with similar potency as cisplatin. Pd 2 Spm-treated mice showed a significant reduction in tumor growth progression, and tumors evidenced a reduction in the Ki-67 proliferation index and number of mitotic figures, as well as increased DNA damage, similar to cisplatin-treated animals. Encouragingly, systemic toxicity (hematotoxicity and weight loss) observed in cisplatin-treated animals was not observed in Pd 2 Spm-treated mice. The present study reports, for the first time, promising cancer selectivity, in vivo antitumor activity towards TNBC and a low systemic toxicity of Pd 2 Spm. Thus, this agent may be viewed as a promising Pd(II) drug candidate for the treatment of this type of low-prognosis neoplasia.

Primordial germ cells (PGCs) arise from cells of the post-implantation epiblast in response to cytokine signaling. PGC development can be recapitulated in vitro by differentiating epiblast-like cells (EpiLCs) into PGC-like cells (PGCLCs) through cytokine exposure. Interestingly, the cytokine requirement for PGCLC induction can be bypassed by enforced expression of the transcription factor (TF) NANOG. However, the underlying mechanisms are not fully elucidated. Here, we show that NANOG mediates Otx2 downregulation in the absence of cytokines and that this is essential for PGCLC induction by NANOG. Moreover, the direct NANOG target gene Esrrb, which can substitute for several NANOG functions, does not downregulate Otx2 when overexpressed in EpiLCs and cannot promote PGCLC specification. However, expression of ESRRB in Otx2 +/- EpiLCs rescues emergence of PGCLCs. This study illuminates the interplay of TFs occurring at the earliest stages of PGC specification., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The interest in palladium(II) compounds as potential new anticancer drugs has increased in recent years, due to their high toxicity and acquired resistance to platinum(II)-derived agents, namely cisplatin. In fact, palladium complexes with biogenic polyamines (e.g., spermine, Pd 2 Spm) have been known to display favorable antineoplastic properties against distinct human breast cancer cell lines. This study describes the in vivo response of triple-negative breast cancer (TNBC) tumors to the Pd 2 Spm complex or to cisplatin (reference drug), compared to tumors in vehicle-treated mice. Both polar and lipophilic extracts of tumors, excised from a MDA-MB-231 cell-derived xenograft mouse model, were characterized through nuclear magnetic resonance (NMR) metabolomics. Interestingly, the results show that polar and lipophilic metabolomes clearly exhibit distinct responses for each drug, with polar metabolites showing a stronger impact of the Pd(II)-complex compared to cisplatin, whereas neither drug was observed to significantly affect tumor lipophilic metabolism. Compared to cisplatin, exposure to Pd 2 Spm triggered a higher number of, and more marked, variations in some amino acids, nucleotides and derivatives, membrane precursors (choline and phosphoethanolamine), dimethylamine, fumarate and guanidine acetate, a signature that may be relatable to the cytotoxicity and/or mechanism of action of the palladium complex. Putative explanatory biochemical hypotheses are advanced on the role of the new Pd 2 Spm complex in TNBC metabolism.

Retroelement silencing factor 1 (RESF1) interacts with the key regulators of mouse embryonic stem cells (ESCs) OCT4 and NANOG, and its absence results in sterility of mice. However, the function of RESF1 in ESCs and germline specification is poorly understood. In this study, we used Resf1 knockout cell lines to determine the requirements of RESF1 for ESC self-renewal and for in vitro specification of ESCs into primordial germ cell-like cells (PGCLCs). We found that deletion of Resf1 in ESCs cultured in serum and LIF reduces self-renewal potential, whereas episomal expression of RESF1 has a modest positive effect on ESC self-renewal. In addition, RESF1 is not required for the capacity of NANOG and its downstream target ESRRB to drive self-renewal in the absence of LIF. However, Resf1 deletion reduces the efficiency of PGCLC differentiation in vitro. These results identify Resf1 as a novel player in the regulation of pluripotent stem cells and germ cell specification., (© 2021 Vojtek and Chambers.)

G-protein-coupled receptors (GPCRs) comprise a large protein superfamily divided into six classes, rhodopsin-like (A), secretin receptor family (B), metabotropic glutamate (C), fungal mating pheromone receptors (D), cyclic AMP receptors (E) and frizzled (F). Until recently, GPCRs signaling was thought to emanate exclusively from the plasma membrane as a response to extracellular stimuli but several studies have challenged this view demonstrating that GPCRs can be present in intracellular localizations, including in the nuclei. A renewed interest in GPCR receptors' superfamily emerged and intensive research occurred over recent decades, particularly regarding class A GPCRs, but some class B and C have also been explored. Nuclear GPCRs proved to be functional and capable of triggering identical and/or distinct signaling pathways associated with their counterparts on the cell surface bringing new insights into the relevance of nuclear GPCRs and highlighting the nucleus as an autonomous signaling organelle (triggered by GPCRs). Nuclear GPCRs are involved in physiological (namely cell proliferation, transcription, angiogenesis and survival) and disease processes (cancer, cardiovascular diseases, etc.). In this review we summarize emerging evidence on nuclear GPCRs expression/function (with some nuclear GPCRs evidencing atypical/disruptive signaling pathways) in non-communicable disease, thus, bringing nuclear GPCRs as targets to the forefront of debate.

Palladium-based compounds are regarded as potential analogs to platinum anticancer drugs with improved properties. The present study assessed the pharmacokinetics and biodistribution of a dinuclear palladium(II)-spermine chelate (Pd 2 Spm), which has previously been shown to possess promising in vitro activity against several therapy-resistant cancers. Using inductively coupled plasma-mass spectrometry, the kinetic profiles of palladium/platinum in serum, serum ultrafiltrate and tissues (kidney, liver, brain, heart, lungs, ovaries, adipose tissue and mammary glands) were studied in healthy female Balb/c mice after a single intraperitoneal bolus injection of Pd 2 Spm (3 mg/kg bw) or cisplatin (3.5 mg/kg bw) between 0.5 and 48 h post-injection. Palladium in serum exhibited biphasic kinetics with a terminal half-life of 20.7 h, while the free palladium in serum ultrafiltrate showed a higher terminal half-life than platinum (35.5 versus 31.5 h). Palladium was distributed throughout most of the tissues except for the brain, with the highest values in the kidney, followed by the liver, lungs, ovaries, adipose tissue and mammary glands. The in vitro cellular accumulation was also evaluated in breast cancer cells, evidencing a passive diffusion as a mechanism of Pd 2 Spm's cellular entry. This study reports, for the first time, the favorable pharmacokinetics and biodistribution of Pd 2 Spm, which may become a promising pharmacological agent for cancer treatment.

Pd(II)-compounds are presently regarded as promising anticancer drugs, as an alternative to Pt(II)-based drugs (e.g., cisplatin), which typically trigger severe side-effects and acquired resistance. Dinuclear Pd(II) complexes with biogenic polyamines such as spermine (Pd 2 Spm) have exhibited particularly beneficial cytotoxic properties, hence unveiling the importance of understanding their impact on organism metabolism. The present study reports the first nuclear magnetic resonance (NMR)-based metabolomics study to assess the in vivo impact of Pd 2 Spm on the metabolism of healthy mice, to identify metabolic markers with possible relation to biotoxicity/side-effects and their dynamics. The changes in the metabolic profiles of both aqueous and lipophilic extracts of mice kidney, liver, and breast tissues were evaluated, as a function of drug-exposure time, using cisplatin as a reference drug. A putative interpretation was advanced for the metabolic deviations specifically triggered by Pd 2 Spm, this compound generally inducing faster metabolic response and recovery to control levels for all organs tested, compared to cisplatin (except for kidney lipid metabolism). These results constitute encouraging preliminary metabolic data suggestive of potential lower negative effects of Pd 2 Spm administration.

Palladium-(Pd)-based drugs are emerging as alternatives to platinum (Pt) anticancer chemotherapeutics, which increases the need for efficient and suitable procedures of Pd analysis in reduced amounts of pre-clinical animal samples. Herein, an ICP-MS (inductively coupled plasma-mass spectrometry) method was developed and validated for simple and fast analysis of Pd/Pt-based drugs in 11 distinct biological matrices (adipose tissue, muscle, liver, kidney, spleen, testis, heart, lungs, brain, blood and serum). The critical variables affecting sample preparation and Pd/Pt extraction were optimized using two-level (2 k ) factorial and central composite designs. Biological samples (50 mg) were digested in closed tubes with a screw cap, using a 3 : 1 (v/v) mixture of nitric acid (900 μL) and hydrochloric acid (300 μL) for 60 min in a 90 °C water bath. Full method validation using in-house materials showed a LOD of 0.001 μg L -1 , linear dynamic range from 0.025-10 μg L -1 (R 2 = 0.9999 for Pd; R 2 = 0.9998 for Pt), good repeatability (CV: 0.02-1.9%) and intermediate precision (CV: 0.52-1.53%) for both the studied metals. The accuracy ranged from 83.5-105.1% considering microwave-assisted digestion as the reference method. The developed and validated method allows the processing of hundreds of biological samples simultaneously, with low reagent and sample consumption. Therefore, the method is highly suitable for analysis of novel Pd/Pt-based drugs in pharmaco-toxicokinetic and biodistribution animal studies that involve a large number of multi-organ samples.

Across the world, the flood magnitude is expected to increase as well as the damage caused by their occurrence. In this case, the prediction of areas which are highly susceptible to these phenomena becomes very important for the authorities. The present study is focused on the evaluation of flood potential within Trotuș river basin in Romania using six ensemble models created by the combination of Analytical Hierarchy Process (AHP), Certainty Factor (CF) and Weights of Evidence (WOE) on one hand, and Gradient Boosting Trees (GBT) and Multilayer Perceptron (MLP) on the other hand. A number of 12 flood predictors, 172 flood locations and 172 non-flood locations were used. A percentage of 70% of flood and non-flood locations were used as input in models. From the input data, 70% were used as training sample and 30% as validating sample. The highest accuracy was obtained by the MLP-CF model in terms of both training (0.899) and testing (0.889) samples. A percentage between 21.88% and 36.33% of study area is covered with high and very high flood potential. The results validation, performed through the ROC Curve method, highlights that the MLP-CF model provided the most accurate results., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This work describes, to our knowledge, the first NMR metabolomics analysis of mice kidney, liver, and breast tissue in response to cisplatin exposure, in search of early metabolic signatures of cisplatin biotoxicity. Balb/c mice were exposed to a single 3.5 mg/kg dose of cisplatin and then euthanized; organs (kidney, liver, breast tissue) were collected at 1, 12, and 48 h. Polar tissue extracts were analyzed by NMR spectroscopy, and the resulting spectra were studied by multivariate and univariate analyses. The results enabled the identification of the most significant deviant metabolite levels at each time point, and for each tissue type, and showed that the largest metabolic impact occurs for kidney, as early as 1 h post-injection. Kidney tissue showed a marked depletion in several amino acids, comprised in an overall 13-metabolites signature. The highest number of changes in all tissues was noted at 12 h, although many of those recovered to control levels at 48 h, with the exception of some persistently deviant tissue-specific metabolites, thus enabling the identification of relatively longer-term effects of cDDP. This work reports, for the first time, early (1-48 h) concomitant effects of cDDP in kidney, liver, and breast tissue metabolism, thus contributing to the understanding of multi-organ cDDP biotoxicity.

Objective: To evaluate the utility of claudin-4 as a pan-carcinoma marker in cell-blocks of effusion specimens and compare results with Ber-Ep4 staining., Methods: Effusion cell-blocks (n = 284) were stained for claudin-4 and results compared with Ber-Ep4. Cases included 172 metastatic malignancies (137 adenocarcinomas, 20 small cell lung tumours, eight metastatic melanoma, four squamous cell carcinoma, three urothelial cell carcinoma), 49 benign reactive cases and 63 mesotheliomas., Results: All 49 benign effusions were negative. Only 1/63 (1.6%) mesotheliomas was positive for claudin-4. Claudin-4 staining was positive in 131/137 (95.6%) adenocarcinoma cases. Cases negative for claudin-4 included single cases of metastases from breast, colon, stomach, prostate, kidney and ovary. Claudin-4 outperformed Ber-Ep4. Sensitivity (95.6% vs 85.4%), specificity (99.1% vs 86.6%), negative predictive value (94.9% vs 82.9%) and positive predictive value (99.2% vs 88.6%) were all higher for claudin-4 compared with Ber-Ep4, respectively. Only two cases were claudin-4-/Ber-Ep4+. Significantly (P < .0064) more cases of metastatic adenocarcinoma stained positive for claudin-4 (131/137; 95.6%) than Ber-Ep4 (117/137; 86.2%). Claudin-4 staining was present in 15/20 (75%) of neuroendocrine carcinomas, 3/4 (75%) squamous cell carcinoma and 3/3 (100%) urothelial cell carcinoma. All eight cases of melanoma were negative for both claudin-4 and Ber-Ep4., Conclusions: Claudin-4 staining is a useful addition to IHC panels for effusions specimens with superior performance to Ber-Ep4., (© 2019 John Wiley & Sons Ltd.)

Cell surface G-protein-coupled receptors (GPCRs) are targets for ∼ 30% of drugs currently on the market, and are the largest group of gene products targeted by drugs. Until recently, signaling mediated by GPCRs was thought to emanate exclusively from the cell membrane as a response to extracellular stimuli. However, recent research has revealed the existence of nuclear (n)GPCRs with the ability to trigger identical and/or distinct signaling pathways to their respective counterparts on the cell surface. Understanding of the GPCR signaling platform on the nuclear membranes and its involvement in physiology and/or pathophysiology will be important to develop selective pharmacological and pharmaceutical approaches. In this review, we summarize our current understanding of nGPCRs, with emphasis on their potential as novel pharmacological targets., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Adenosinergic system regulates vascular tonicity through the complex system of adenosine, adenosine receptors (ARs) and nucleoside transporters. This work aimed at evaluating the impact of hypertension on adenosine bioavailability and expression/distribution profile of AR subtypes (A 1 , A 2A , A 2B , A 3 ) and equilibrative nucleoside transporters (ENT1, ENT2, ENT3, ENT4). Adenosine was measured in vascular tissue extracts by HPLC (fluorescence detection); immunoreactivities (ARs/ENTs) in mesenteric arteries/veins from normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were analyzed by histomorphometry. Significantly higher adenosine bioavailability occurred in arteries than in veins. Adenosine bioavailability was even more increased in SHR vessels. Expression/distribution of ARs and ENTs observed in all vascular layers (intima, media, adventitia), with more intensified expression in arteries than in veins. In SHR arteries, a downregulation of all ENT along with downregulated and punctuated distribution of A 1 and A 2B receptors occurred comparatively to WKY arteries. By contrast, expressions of ARs and ENTs were unaltered, exception for an A 2A receptor upregulation, and ENT2 downregulation in SHR veins relatively to WKY veins. Our data evidenced clear alterations of adenosinergic dynamics occurring in hypertension, particularly in arterial vessels. An increased adenosine bioavailability was observed, for the first time, in hypertensive vascular tissues.

Treatment of triple-negative breast carcinoma (TNBC) remains an unmet medical need with no targeted therapy available to date. Accounting for 10-30% of all human breast cancer tumors, this mammary carcinoma subtype has a particularly poor prognosis owing to its high metastatic potential, aggressive biology and limited pharmacological treatment options. Platinum chemotherapeutics are the mainstay therapy in patients with TNBC but their clinical use is limited by severe toxicity and acquired resistance. Palladium-based complexes are appealing alternative metal-based drugs because of significant similarities regarding structure and coordination chemistry with the platinum agents. This review summarizes the knowledge gathered so far on 121 Pd(II) complexes, emphasizing their anticancer activity and putative pharmacological targets toward TNBC., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The successful segregation of germ cells from somatic lineages is vital for sexual reproduction and species survival. In the mouse, primordial germ cells (PGCs), precursors of all germ cells, are induced from the post-implantation epiblast 1 . Induction requires BMP4 signalling to prospective PGCs 2 and the intrinsic action of PGC transcription factors 3-6 . However, the molecular mechanisms that connect BMP4 to induction of the PGC transcription factors that are responsible for segregating PGCs from somatic lineages are unknown. Here we show that the transcription factor OTX2 is a key regulator of these processes. Downregulation of Otx2 precedes the initiation of the PGC programme both in vitro and in vivo. Deletion of Otx2 in vitro markedly increases the efficiency of PGC-like cell differentiation and prolongs the period of PGC competence. In the absence of Otx2 activity, differentiation of PGC-like cells becomes independent of the otherwise essential cytokine signals, with germline entry initiating even in the absence of the PGC transcription factor BLIMP1. Deletion of Otx2 in vivo increases PGC numbers. These data demonstrate that OTX2 functions repressively upstream of PGC transcription factors, acting as a roadblock to limit entry of epiblast cells to the germline to a small window in space and time, thereby ensuring correct numerical segregation of germline cells from the soma.

The discovery of the immunoregulatory potential of human amniotic membrane (hAM) propelled several studies focusing on its application for the treatment of immunological disorders. However, there is little information regarding the effects of hAM on distinct activation and differentiation stages of immune cells. Here, we aim to investigate the effect of human amniotic membrane extract (hAME) on the pattern of cytokine production by T cells, monocytes and myeloid dendritic cells (mDCs). For this purpose, peripheral blood mononuclear cells (PBMCs) from eight healthy individuals were stimulated in vitro in the presence or absence of hAME. Mitogen-induced proliferation of PBMCs and cytokine production among the distinct T cell functional compartments, monocyte subpopulations and mDCs were evaluated. hAME displayed an anti-proliferative effect and decreased the frequency of T cells producing tumor necrosis factor (TNF)α, interferon (IFN)γ and interleukin (IL)-2, for all T cell functional compartments. The frequency of IL-17 and IL-9-producing T cells was also reduced. The inhibition of mRNA expression of granzyme B, perforin and NKG2D by CD8 + T cells and γδ T cells and the augment of FoxP3 and IL-10 in CD4 + T cells and IL-10 in regulatory T cells were also observed. Furthermore, hAME inhibited IFNγ-induced protein (IP)-10 expression by classical and non-classical monocytes, without hampering the production of TNFα and IL-6 by monocytes and mDCs. These results suggest that hAME exerts an anti-inflammatory effect on T cells, still at a different extent for distinct T cell functional compartments.