Metabolic Adaptation as Potential Target in Papillary Renal Cell Carcinomas Based on Their In Situ Metabolic Characteristics

Metabolic characteristics of kidney cancers have mainly been obtained from the most frequent clear cell renal cell carcinoma (CCRCC) studies. Moreover, the bioenergetic perturbances that affect metabolic adaptation possibilities of papillary renal cell carcinoma (PRCC) have not yet been detailed. Therefore, our study aimed to analyze the in situ metabolic features of PRCC vs. CCRCC tissues and compared the metabolic characteristics of PRCC, CCRCC, and normal tubular epithelial cell lines. The protein and mRNA expressions of the molecular elements in mammalian target of rapamycin (mTOR) and additional metabolic pathways were analyzed in human PRCC cases compared to CCRCC. The metabolic protein expression pattern, metabolite content, mTOR, and metabolic inhibitor sensitivity of renal carcinoma cell lines were also studied and compared with tubular epithelial cells, as “normal” control. We observed higher protein expressions of the “alternative bioenergetic pathway” elements, in correlation with the possible higher glutamine and acetate consumption in PRCC cells instead of higher glycolytic and mTOR activity in CCRCCs. Increased expression of certain metabolic pathway markers correlates with the detected differences in metabolite ratios, as well. The lower lactate/pyruvate, lactate/malate, and higher pyruvate/citrate intracellular metabolite ratios in PRCC compared to CCRCC cell lines suggest that ACHN (PRCC) have lower Warburg glycolytic capacity, less pronounced pyruvate to lactate producing activity and shifted OXPHOS phenotype. However, both studied renal carcinoma cell lines showed higher mTOR activity than tubular epithelial cells cultured in vitro, the metabolite ratio, the enzyme expression profiles, and the higher mitochondrial content also suggest increased importance of mitochondrial functions, including mitochondrial OXPHOS in PRCCs. Additionally, PRCC cells showed significant mTOR inhibitor sensitivity and the used metabolic inhibitors increased the effect of rapamycin in combined treatments. Our study revealed in situ metabolic differences in mTOR and metabolic protein expression patterns of human PRCC and CCRCC tissues as well as in cell lines. These underline the importance in the development of specific new treatment strategies, new mTOR inhibitors, and other anti-metabolic drug combinations in PRCC therapy.     

Genetic Biomarkers of Antipsychotic-Induced Prolongation of the QT Interval in Patients with Schizophrenia

Antipsychotics (AP) induced prolongation of the QT interval in patients with schizophrenia (Sch) is an actual interdisciplinary problem as it increases the risk of sudden death syndrome. Long QT syndrome (LQTS) as a cardiac adverse drug reaction is a multifactorial symptomatic disorder, the development of which is influenced by modifying factors (APs’ dose, duration of APs therapy, APs polytherapy, and monotherapy, etc.) and non-modifying factors (genetic predisposition, gender, age, etc.). The genetic predisposition to AP-induced LQTS may be due to several causes, including causal mutations in the genes responsible for monoheme forms of LQTS, single nucleotide variants (SNVs) of the candidate genes encoding voltage-dependent ion channels expressed both in the brain and in the heart, and SNVs of candidate genes encoding key enzymes of APs metabolism. This narrative review summarizes the results of genetic studies on AP-induced LQTS and proposes a new personalized approach to assessing the risk of its development (low, moderate, high). We recommend implementation in protocols of primary diagnosis of AP-induced LQTS and medication dispensary additional observations of the risk category of patients receiving APs, deoxyribonucleic acid profiling, regular electrocardiogram monitoring, and regular therapeutic drug monitoring of the blood APs levels.     

MIL-100(Fe) Sub-Micrometric Capsules as a Dual Drug Delivery System

Nanoparticles of metal–organic frameworks (MOF NPs) are crystalline hybrid micro- or mesoporous nanomaterials that show great promise in biomedicine due to their significant drug loading ability and controlled release. Herein, we develop porous capsules from aggregate of nanoparticles of the iron carboxylate MIL-100(Fe) through a low-temperature spray-drying route. This enables the concomitant one-pot encapsulation of high loading of an antitumor drug, methotrexate, within the pores of the MOF NPs, and the collagenase enzyme (COL), inside the inter-particular mesoporous cavities, upon the formation of the capsule, enhancing tumor treatment. This association provides better control of the release of the active moieties, MTX and collagenase, in simulated body fluid conditions in comparison with the bare MOF NPs. In addition, the loaded MIL-100 capsules present, against the A-375 cancer cell line, selective toxicity nine times higher than for the normal HaCaT cells, suggesting that MTX@COL@MIL-100 capsules may have potential application in the selective treatment of cancer cells. We highlight that an appropriate level of collagenase activity remained after encapsulation using the spray dryer equipment. Therefore, this work describes a novel application of MOF-based capsules as a dual drug delivery system for cancer treatment.     

Peracetic acid as a single endodontic irrigant: effects on microhardness,roughness and erosion of root canal dentin

The aim was to assess the effects of 1% peracetic acid (PAA) as a single endodontic irrigant on microhardness, roughness, and erosion of root canal dentin, compared with 2.5% sodium hypochlorite (NaOCl) and with 2.5% NaOCl combined with 17% EDTA. Forty human, single‐rooted tooth hemisections were submitted to Knoop microhardness test, before and after the following irrigation protocols: PAA = 1% PAA; NaOCl = 2.5% NaOCl; NaOCl‐EDTA‐NaOCl = 2.5% NaOCl +17% EDTA +2.5% NaOCl; and SS = saline. Another 40 roots were instrumented, irrigated with the same protocols, and sectioned longitudinally. The roughness analysis was performed on the mesial section using a confocal laser scanning microscope, whereas erosion was analyzed on each third of the distal section, using a scanning electron microscope. The data were analyzed using ANOVA and Tukey post‐tests, and Kruskal‐Wallis and Dunn post‐tests (α = .05). The PAA and NaOCl‐EDTA‐NaOCl groups showed no significant differences (p > .05); both promoted reduction in microhardness and increase in roughness, compared with the NaOCl and SS groups (p < .05). NaOCl‐EDTA‐NaOCl promoted higher erosion in the cervical and middle thirds than the other groups (p < .05); there was no difference among PAA, NaOCl, and SS (p > .05). There was also no difference among the groups regarding the apical third (p > .05). PAA used as a single endodontic irrigant caused reduction in root canal dentin microhardness and increase in roughness in a similar way to NaOCl‐EDTA‐NaOCl; however, PAA caused less erosion than NaOCl‐EDTA‐NaOCl.     

Study of the sorption and acidic properties of MTW-type zeolite

The acidity of H-MTW-type zeolite has been investigated using infrared spectroscopy of adsorbed pyridine. Pore volume has been measured by nitrogen andn-hexane adsorption. The zeolite exhibits infrared signals at 3612 and 3580 cm^–1 tentatively attributed to bridging hydroxyl groups vibrating in the main channel and in the six-membered rings of the structure, respectively. Both hydroxyl groups possess high acid strength and are readily accessible to pyridine. H-MTW shows an-hexane cracking activity at 350°C comparable to that obtained with MFI and BEA-type materials with a product selectivity between medium and large pore structural types.     

Microbiological water quality along the Danube River: Integrating data from two whole-river surveys and a transnational monitoring network

The River Danube is with 2780 km the second longest river in Europe. Its catchment area covers 801 500 km², with approximately 81 million inhabitants in 19 countries. River water for anthropogenic use, transportation and recreation is of major importance in all of these countries. Microbiological contamination from faecal pollution by anthropogenic sources is considered to be a crucial problem throughout the Danube River basin. Thus, detailed knowledge on the extent and the origin of microbial pollution is essential for watershed management. The determination of faecal indicator concentrations along the Danube and its major tributaries during two whole-river surveys and 16 permanent stations allowed for the first time to draw a clear picture of the faecal pollution patterns along the whole longitudinal profile of this important international river. By including a variety of environmental variables in statistical analysis, an integrative picture of faecal pollution in the Danube River basin could be evolved. Four hot spots and six stretches of differing faecal pollution were identified, mainly linked with input from large municipalities. Significant decline of microbiological pollution was observed in the upper and lower Danube stretches over the investigation period. In contrast, a significant increase in the middle part was evident. The planned implementation of new wastewater treatment plants and advanced wastewater treatment measures according to the European Union urban wastewater directive will have a great potential to reduce microbial faecal pollution in the Danube and thus improving water quality.     

Effect of in‐office bleaching agents on the surface roughness and morphology of different dental composites: An AFM study

The aim of this study was to evaluate, using atomic force microscopy, the effect of two different bleaching agents on the modification of dental composites materials. This modification will be judged by analyzing the variation of surface roughness and surface morphology of two different composites: one containing nanoparticles and other consisting of microhybrid resin. The bleaching was performed by using two different concentrations of hydrogen peroxide: HP Blue (20% hydrogen peroxide) and Whiteness HP Maxx (35% hydrogen peroxide). Disks of Esthet X and Filtek? Z350 composites were used. Atomic force microscopy was used for analyses of the same place of the sample before and after treatment. A total of 12 analyses were performed per group (n = 12). The samples were analyzed qualitatively by evaluating morphological changes in the images and quantitatively by using roughness parameters (Ra). Data were analyzed statistically using Kruskal–Wallis, Mann–Whitney, and Friedman tests (P < 0.05). Changes were observed both qualitatively and quantitatively only in the groups where Esthet X resin was used. The use of hydrogen peroxide bleaching agents caused changes only in the surface of microhybrid composites, with no changes being observed in the composite containing nanoparticles. Despite being even significant, these alterations are clinically slight and can be eliminated by polishing them. Microsc. Res. Tech. 76:481–485, 2013. © 2013 Wiley Periodicals, Inc.     

Prior detection of genetic algorithm significant parameters: Coupling factorial design technique to genetic algorithm

This work presents an extension of a previous proposed procedure [Costa, C.B.B., Wolf Maciel, M.R., Maciel Filho, R., 2005. Factorial design technique applied to genetic algorithm parameters in a batch cooling crystallization optimization. Computers and Chemical Engineering 29, 2229-2241] to be adopted as a prior analysis in optimization problems to be solved using genetic algorithm (GA). Chemical engineering problems are commonly highly non-linear and possess a large number of variables, sometimes with significant interactions among them. Such characteristics make the optimization problems really difficult to be solved by deterministic methods. GA is an increasing tool for solving this sort of problems. However, no systematic approach to establish the best set of GA parameters for any problem was found in the literature and a relatively easy to use and meaningful approach is proposed and proved to be of general application. The proposed approach consists of applying factorial design, a well-established statistical technique to identify the most meaningful information about the influences of factors on a specific problem, as a support tool to identify the GA parameters with significant effect on the optimization problem. This approach is very useful in conducting further optimization works, since it discharges GA parameters that are not statistically significant for the evolutionary search for the optimum, saving time and computation burden in evolutionary optimization studies.