Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties.

BACKGROUND AND PURPOSE: ABC multidrug transporters (MDR-ABC proteins) cause multiple drug resistance in cancer and may be involved in the decreased anti-cancer efficiency and modified pharmacological properties of novel specifically targeted agents. It has been documented that ABCB1 and ABCG2 interact with several first-generation, small-molecule, tyrosine kinase inhibitors (TKIs), including the Bcr-Abl fusion kinase inhibitor imatinib, used for the treatment of chronic myeloid leukaemia. Here, we have investigated the specific interaction of these transporters with nilotinib, dasatinib and bosutinib, three clinically used, second-generation inhibitors of the Bcr-Abl tyrosine kinase activity. EXPERIMENTAL APPROACH: MDR-ABC transporter function was screened in both membrane- and cell-based (K562 cells) systems. Cytotoxicity measurements in Bcr-Abl-positive model cells were coupled with direct determination of intracellular TKI concentrations by high-pressure liquid chromatography-mass spectrometry and analysis of the pattern of Bcr-Abl phosphorylation. Transporter function in membranes was assessed by ATPase activity. KEY RESULTS: Nilotinib and dasatinib were high-affinity substrates of ABCG2, and this protein mediated an effective resistance in cancer cells against these compounds. Nilotinib and dasatinib also interacted with ABCB1, but this transporter provided resistance only against dasatinib. Neither ABCB1 nor ABCG2 induced resistance to bosutinib. At relatively higher concentrations, however, each TKI inhibited both transporters. CONCLUSIONS AND IMPLICATIONS: A combination of in vitro assays may provide valuable preclinical information for the applicability of novel targeted anti-cancer TKIs, even in multidrug-resistant cancer. The pattern of MDR-ABC transporter-TKI interactions may also help to understand the general pharmacokinetics and toxicities of new TKIs.

Fibrous myopathy as a complication of repeated intramuscular injections for chronic headache.

Two cases of fibrous myopathy associated with repeated, long-term intramuscular injections for treatment of chronic temporomandibular joint pain and chronic headache, respectively, are described. Both patients developed severe, function-limiting contractures in upper and lower extremity muscles used as injection sites. In one of the cases, the contractures were painful. Electrophysiological testing, magnetic resonance imaging and muscle biopsy results were all consistent with myopathy and replacement of skeletal muscle with noncontractile fibrous tissue. These cases are presented to increase awareness of fibrous myopathy and to promote surveillance for this serious potential complication of long-term intramuscular injections in chronic headache and other pain patients.

Proteomic analysis of childhood leukemia.

Childhood acute lymphoblastic and myeloid leukemias are stratified into molecular and cytogenetic subgroups important for prognosis and therapy. Studies have shown that gene expression profiles can discriminate between leukemia subtypes. Thus, proteome analysis similarly holds the potential for characterizing different subtypes of childhood leukemia. We used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to analyze cell lysates from childhood leukemia cell lines as well as pretreatment leukemic bone marrow derived from childhood leukemia cases. Comparison of the acute myeloid leukemia (AML) cell line, Kasumi, and the biphenotypic myelomonocytic cell line, MV4;11, with the acute lymphoblastic leukemia (ALL) cell lines, 697 and REH, revealed many differentially expressed proteins. In particular, one 8.3 kDa protein has been identified as a C-terminal truncated ubiquitin. Analysis of childhood leukemia bone marrow showed differentially expressed proteins between AML and ALL, including a similar peak at 8.3 kDa, as well as several proteins that differentiate between the ALL t(12;21) and hyperdiploid subtypes. These results demonstrate the potential for proteome analysis to distinguish between various forms of childhood leukemia. Future analyses are warranted to validate these findings and to investigate the role of the C-terminal truncated ubiquitin in the etiology of ALL.

Comparative microstructural study of the diffusion zone between NiCr alloy and different dental ceramics.

Our knowledge on the bonding mechanisms between the metal and ceramic parts of dental systems is very limited. This work tested the hypothesis that the details of the interface processes can be described in the framework of a chemical diffusion model. The development of interfacial phases was investigated by cross-sectional analytical transmission electron microscopy between a NiCr (Wiron 99) alloy and three different dental ceramics (Carat, Vita VMK 95, and Vision). All systems were investigated at normal firing conditions (suggested by the manufacturer) and at increased firing times as well. The conclusions are based on the results that the formation of a nanocrystalline Cr(2)O(3) layer and amorphous silicon oxide inclusions were detected in the early stage of the firing process in all investigated systems, and that, in the case of Carat and Vision ceramics, formation of complex NiCr and NiCrTi oxides was also observed at longer annealing times.

Accuracy of in vivo carotid B-mode ultrasound compared with pathological analysis: intima-media thickening, lumen diameter, and cross-sectional area.

BACKGROUND AND PURPOSE: This study aimed to determine the correlation of in vivo ultrasound measurements of intima-media thickening (IMT), lumen diameter, and cross-sectional area of the common carotid artery (CCA) with corresponding measurements obtained by gross pathology and histology. METHODS: Sixty-six moribund neurological patients (mean age 71 years) underwent B-mode ultrasound of the CCA a few days before death. During autopsy, carotid specimens were removed in toto. Carotid arteries were ligated and cannulated for injection of a hydrophilic embedding material under standardized conditions. The carotid bifurcation was frozen and cut manually in 3-mm cross slices. Digital image analysis was carried out to determine the diameter and the cross-sectional area of the frozen slices of the CCA. IMT was assessed by light microscope. Ultrasonic and planimetric data were compared. RESULTS: Mean measurements of lumen diameter and cross-sectional area were 7.13+/-1.27 mm and 0.496+/-0.167 cm(2), respectively, by ultrasound, and 7.81+/-1.45 mm and 0.516+/-0.194 cm(2), respectively, by planimetric analysis of the unfixed redistended carotid arteries (R(2)=0.389 and 0.497). The mean IMT was 1.005+/-0.267 mm by ultrasound and 0.67+/-0.141 mm histologically, resulting in a mean difference of -31%. CONCLUSIONS: Transcutaneous B-mode ultrasound provides a reliable approach for in vivo measurements of the cross-sectional area and, less exactly, of the lumen diameter of the CCA. Compared with histological results, in vivo ultrasound measurements of the IMT are systematically larger.

A novel method of macropathologic and arteriographic examination of carotid specimens obtained from autopsy.

Twenty carotid bifurcations were examined. During autopsy, carotid bifurcations were removed in toto. Unfixed carotids were ligated and cannulated for injection of an angiographic contrast medium followed by injection of a tissue-embedding medium at physiologic pressure and temperature. The carotid bifurcation was frozen and cut manually in 3-mm cross-sections. Photographs were then taken of every slice. Angiography, filling with tissue-embedding material, and sectioning were successful in all cases. In the macropathologic sections, the extent, configuration and location of atherosclerotic lesions could be identified.

3D reconstruction based on hard tissue microtome cross-section pictures in dentistry.

The aim of this study was to examine the accuracy of the computerized 3D surface analyzing and volume measuring method in dentistry. Two different types of test objects were used in the first part of the measurements. Each sample of the two groups was cross-sectioned using a hard tissue microtome. The sections were photographed on both sides and were projected on a graphical tablet and analyzed using a computer program. The measured and calculated parameters were compared. In the second part, 200 microm thick horizontal sections were prepared from 11 human incisor roots using the hard tissue microtome. This way, five sections were prepared from the apical 2 mm of each root. The effects of section thickness and number were modeled by decreasing the inclusion rate of the obtained number of sections from 10 to 2 and its influence on the calculated results was determined. This method was suitable for the approximation and analysis of 3D parameters. The results indicated that using 200-300 microm section thickness, the measured values were approximately 8-21% lower than the real parameters.

[Examination of silane ceramic systems by differential thermoanalysis]. / Fogászatban alkalmazott szilánkerámia rendszerek differenciál termoanalitikai vizsgálata.

In the present study two silane adhesive agents (Silicoup, Heraeus/Kulzer, and Monobond-S, Vivadent) and one type ceramic (VITA VKM 68) and their interface reactions were tested by thermo-analysis. The ceramic powder is thermally inactive. Using the two different silane solutions with the same ceramic type different thermical characteristics were found despite the same base material (gamma-methacryloxi-propyl-trimethoxi-silane). This can probably be attributed to the different configurations of the polycondensates.

An atomic force microscopy study on the effect of bleaching agents on enamel surface.

OBJECTIVES: The aim of the present study was to evaluate the effect of three peroxide-containing bleaching agents, Opalescence, Nite White and a 30% hydrogen peroxide solution, on enamel surfaces using Atomic Force Microscopy (AFM). METHODS: Fifteen non-carious human incisors (ten maxillary and five mandibular, extracted for periodontal reasons) were used. The teeth were divided randomly into three groups of five, according to the bleaching agents. The labial surface of each tooth was imaged by AFM before and after treatment. Each bleaching agent was applied for a total of 28 h (in individual 4 h treatments). The specimens were examined only after 28 h of treatment. RESULTS: On comparing the AFM images of untreated and treated enamel, surface alterations were observed after 28 h of treatment with Opalescence, Nite White and 30% hydrogen peroxide solution. Several grooves present in the enamel surface of untreated teeth became deeper after the bleaching procedure. The depths of the grooves increased in each case. The increase in the depth of grooves was more pronounced in the case of the 30% H2O2 solution. CONCLUSION: Home-use bleaching agents are capable of causing enamel surface alterations. It is hypothesized that the peroxide-containing bleaching agents affect the organic phase of enamel. Peroxides can affect not only the surface but also the inner structure of enamel. As a result of its low molecular weight, hydrogen peroxide can penetrate into the enamel. Thus, inner oxidative effects are more likely to occur in the subsurface enamel where more organic material is present and oxidation is capable of altering the outer enamel and the surface.

[Interface between Ni-Cr alloy and ceramic studied by scanning electron microscopy]. / Ni-Cr ötvözet és kerámia határfelület pásztázó elektronmikroszkópos (PEM) vizsgálata.

In this investigation we observed the interface between Wiron 99 (Bego) dental Ni-Cr alloy and Vision (Wohlwend AG) ceramic opaquer with SEM. In the system there are intermediate phases coming from a solid phase rection which play an essential role in the metal-ceramic bond. The analytical methods showed that in this phases the content of Ni and Cr charge not monotonously from alloy to ceramic which shows strong chemical effects (the selective affinity of Cr and Ni). The concentration of Cr after the alloy surface increases in a 1-1.5 microns layer, where its concentration is higher than at the alloy, while the concentration of Ni decrease in this layer. Than at the ceramic side of the reaction zone the concentration of Ni increases in a 1-1.5 microns wide layer where its concentration is near upon that one in the alloy.

[Typical symptoms of methyl acylate sensitivity in wearers of acylate dentures]. / Metil-metakrilát-érzékenység jellegzetes tünetei akrilát fogsort viselöknél.

Between 1986. and 1995. 150 patients were patch tested who had developed allergic reactions to their prosthesis made from acrylate. Three patients are described, whose history and patch test results confirmed the hypersensitivity to methylmetacrylate. The typical symptoms of acrylate sensitivity are discussed. After the removal of acrylate prosthesis and replacement with polyamide base (Valplast) prosthesis, the symptoms disappeared. Because the number of allergic reactions increases, the authors emphasize the necessity of prescreening in suspected cases of acrylate allergy.

[Computer tomography in implantology]. / Komputertomográfiás vizsgálat az implantológiai diagnosztikában.

During the planning of implantation the CT method helps in determining the location of the implant and aids in choosing the right implant. It provides the following measurable information about the jaw-bones: height and width; exact location of bone deficiencies; the orovestibular shape of the alveolar process; the course of the mandibular canal; the location of the mental foramen; the location and size of the canalis incisivus; the area of the nasal cavity and the maxillary sinus; the quality of the bones and the relationship between cortical and spongious bone. In comparison to the X-ray examinations possession of these informations increase significantly the safety of planning before surgery.

[Scanning electron microscopy in the study of surface treatment methods used in the repair of porcelain-fused-to-metal restorations]. / A fémre égetett kerámiapótlás javításánál használatos felszínérdesítési eljárások pásztázó elektronmikroszkópos (SEM) vizsgálata.

According to the literature the ceramic crowns are damaged in 1%-9% of the cases. In order to repair the damage with polimers, first the exposed surfaces have to be made microretentive. Our aim was to investigate with scanning electronmicroscope how the different surface treatment methods modify the structure of metal and ceramic surfaces. We applied two different methods of grinding: 40 microns grained diamond, K1 burs stone (SILISTOR) for ceramic and metal surfaces. The third surface treatment was the application of HF acid for ceramic surface and the sandblasting for metal surface. To achieve microretention the latter mentioned methods increased the most the retentive surface.

[Contact allergy reactions to Silodent impression material]. / Kontakt allergiás reakciók Silodent lenyomatanyag alkalmazása után.

The silicon based impression materials are often used in dental practice. Recently, we have observed two cases of contact allergic reaction after using Silodent (Ferrokémia) impression material. Epicutaneous test has shown that the allergic reaction is provoked by the catalisator. This hypersensitivity reaction is due to a previous sensibilization (e.g. previous impression taking or environmental hazards). No epicutaneous reaction to the other types of silicon based impression materials was found.

The role of reactive oxygen intermediates in the pathogenesis of chronic apical periodontitis.

The level of malondialdehyde, a stable end product of lipid peroxidation induced by reactive oxygen intermediates and the activity of two potent antioxidant enzymes, superoxide dismutase and glutathione peroxidase, was investigated in tissue homogenates of 22 surgical periapical granuloma specimens. Malondialdehyde levels were significantly higher and glutathione peroxidase activity was significantly lower in periapical granuloma samples than in healthy gingival tissue homogenates, which were used as controls. The activity of superoxide dismutase was similar in periapical granuloma and in control samples. Our results indicate an altered balance between the production and the elimination of toxic oxygen metabolites in chronic apical periodontitis. We hypothesize that reactive oxygen intermediates, which are being produced by activated phagocytic cells abundantly present in periapical granulomas, can contribute to periapical tissue injury and bone loss in this disease.

[Corrosion of NiCr- and CoCr-containing dental alloys in cellulose-based artificial saliva under in vitro conditions]. / NiCr- és CoCr-alapú fogászati ötvözetek korróziója methocelalapú münyálban in vitro körülmények között.

It was found that the CoCr alloy is more resistant to the corrosive effects than NiCr alloy. The artificial saliva developed at our clinic increased the passivation range of the both alloys. The higher value observed in the case of the CoCr alloy makes it more suitable for use in patients with xerostomia or an increased risk of allergy.

[The effect of surface etching on tensile strength]. / A felszínérdesítés hatása a szakítószilárdságra.

The aim of this study was to investigate the effect of different partial size of corundum used by sand blasting on the surface roughness and on the tensile strength. The conclusions of the authors were as follows: 1. The maximum values of tensile strength were measured when 200-250 microns corundum was used. 2. The values of the R(a) and Rmax were grown proportionally with the grain of corundum, but it was not resulted in the same increase of the tensile strength. 3. After the tensile test the residue of the bonding agent on one surface of the test-piece pairs, always remained significantly higher, than on the other, but this phenomenon cannot be explained by the differences between R(a) and Rmax within the test-piece pairs.

[Alpha-1-antitrypsin deficiency and liver diseases]. / Alfa-1-antitripszin-hiány és májbetegség.

Authors studied liver biopsy of hundred infants and young children. 15 livers were normal and three of 85 patients suffering from liver disease had liver changes associated with serious alpha--1-antitrypsin (AAT) deficiency (in two cases with portal fibrosis associated with inflammation, in one case with portal fibrosis associated with moderate active inflammation of reduction of intrahepatic biliary ducts). Typical positive, diastase resistant globules were in the hepatocytes of only one patient, but AAT could be demonstrated in periportal liver cells of all three patients by AAT specific immuneperoxidase method. Of 830 hepatic cirrhosises in adult age, in eight cases PAS positive, diastase-resistant AAT immunreactive globules occurred in periportal hepatocytes, suggesting AAT deficiency; however, the AAT level and fenotype of these patients were not known. Examination of possibility of AAT deficiency should be performed in every case, where the cause of liver disease is unsolved; this examination is especially indicated by the presence of typical PAS positive, diastase-resistant, AAT immunreactive globules in hepatocytes.