Multidrug resistance-reversing agents increase vinblastine distribution in normal tissues expressing the P-glycoprotein but do not enhance drug penetration in brain and testis

The aim of this study was to assess whether P-glycoprotein (Pgp) inhibitors altered the blood-brain barrier and enhanced vinblastine (VBL) distribution in brain, testis and other Pgp-expressing tissues. Trifluoperazine, cyclosporin A, amiodarone, quinidine, the nifedipine analog Bay K8644 and verapamil were selected among Pgp inhibitors and were administered intraperitoneally 1 hr before an intravenous dose of 10 mg/kg VBL. Trifluoperazine and cyclosporin A were also administered intraperitoneally for 7 days before VBL. VBL and its metabolite O4-deacetylvinblastine were measured in tissues by high-performance liquid chromatography assay. None of the reversing agents (RA) appreciably raised VBL concentrations in brain and testis, whereas all except quinidine significantly enhanced VBL distribution in liver and kidney; the most effective were trifluoroperazine and cyclosporin A. In mice treated with RA and VBL combined, O4-deacetylvinblastine levels in liver and kidney reached either the same or higher levels than in mice treated with VBL alone, indicating that the increase in VBL levels is not due to inhibition of its metabolism. The main conclusions are that (1) inhibitors of Pgp, even at high doses, do not increase the permeability of the blood-brain barrier in mice, suggesting caution in the clinical use of RA combined with antitumor agents for brain tumors; and (2) several RA achieve high enough concentrations to enhance the distribution of VBL in other normal tissues expressing Pgp, thus potentially increasing VBL toxicity.     

Modulation of the enzymatic activity of papain by interdomain residues remote from the active site

The two main catalytic residues Cys25 and Hisl59 of the monomericcysteine protease papain are located on different walls of acleft formed by two domains. This topology suggests a possiblerelationship between relative domain organization and catalyticmechanism. The effect on enzymatic parameters of structuralmodifications at various locations of the twodomain interfaceof papain was examined by individual or double replacementsby Ala of pairs of interacting residues. Most modificationshad no effect on enzyme activity. However, the enzyme's substrateturnover (k_cat) decreased following simultaneous alterationof the two most conserved residues, forming an apolar contactlocated 15 Å away from the active site. The pH activityprofile of the double mutant was unchanged, indicating a conservedionization state of the active site thiolate-imidazolium ionpair. This state is strongly dependent on the distance separatingthe two residues, thus suggesting that the active site geometryhas not been significantly altered. Efficient enzymatic activityin papain requires more than a correct active site geometryand is influenced by domain packing properties in a region remotefrom the active site.     

Advanced on-board processing for user oriented communication systems

The continuing improvement of RF components, particularly in the field of spot-beam antennas, combined with the steady progress in digital technology, leads us to consider the advantages of a satellite system able to provide full connectivity to ground stations operating at different data rates. For low data rates, two different access methods: continuous TDM and Multi-carrier TDMA, are compared for earth-stations operating at 2Mb/s. The two methods are compared from the point of view of efficiency and adaptability in a non-uniform load environment. Some control criteria are proposed for the Multi-carrier system. Both methods are particularly suited for small users.     

Language disturbances following vascular lesions restricted to the left basal ganglia, thalamus, and white matter.

Examined the relationship between aphasia type and lesion site in 80 subcortical stroke patients. Ss were classified as affected by aphasia, dysarthria, and nonaphasia, nondysarthria. Sites of lesions were identified by means of computerized tomography (CT) scan. No correlation between site of lesions and category group was found. Lesions of the same subcortical structures yielded different neurolinguistic impairment, whereas comparable linguistic patterns were observed with lesions of different deep areas. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serum IgG2 level, Gm(23) allotype and FcgammaRIIa and FcgammaRIIIb receptors in refractory periodontal disease

The purpose of this investigation was to compare the levels of serum IgG2, the frequency of detection of Gm(23)-negative allotype and frequency of detection of FcgammaRIIa and FcgammaRIIIb receptor haplotypes in 32 refractory, 54 successfully treated and 27 periodontally healthy individuals. Refractory subjects showed mean full mouth attachment loss and/or >3 sites with attachment loss >2.5 mm within 1 year after both scaling and root planing, and surgery plus systemically administered tetracycline. Successfully treated subjects showed mean attachment level gain and no sites with attachment loss >2.5 mm 1 year post-therapy. Periodontally healthy subjects exhibited no pocket depth or attachment level >3 mm, and no evidence of progressing disease during 1 year of monitoring. Blood was obtained from each subject at baseline. Serum IgG2 and Gm(23) allotype were determined using radial immunodiffusion. DNA was extracted from whole blood and the FcgammaR genotypes determined using PCR and allele specific oligonucleotide probes. Significance of differences among clinical groups were sought using the Kruskal-Wallis or chi-square tests. Associations between 2 or more variables were tested using regression analysis. Refractory subjects exhibited higher mean attachment loss and pocket depth than successfully treated or periodontally healthy subjects. Smoking status did not differ significantly among groups. No significant differences in serum IgG2 levels and frequency of detection of Gm(23)-negative allotype were observed among the clinical groups. Serum IgG2 level was positively associated with the number of serum antibody responses to subgingival species (r=0.51, p<0.001). Subjects with the Gm(23)-negative allotype exhibited lower mean levels of serum IgG2 (3.06+/-0.3 versus 3.9+/-0.2, p<0.01) and mean number of serum antibodies to subgingival species (17.7+/-1.7 versus 23.3+/-1.4, p<0.05) than allotype positive individuals. No significant differences in FcgammaR haplotype distribution were observed among the 3 clinical groups. Associations of serum IgG2 level, Gm(23) allotype, FcgammaRIIa and FcgammaRIIIb receptor haplotypes and smoking status were weakly related or not related to clinical status. This lack of relationship may have been due to a reality of no relationship, or the inadvertent pooling of subjects where these factors were of primary importance with subjects in whom these factors played a less important role.     

A Web‐based Open‐source Geoinformation Tool for Regional Water Resources Assessment

Water Resources Management - To reduce the impact of droughts and increase the resilience of regional water systems, various competing demands, such as hydropower, supply, irrigation and river...     

BRAF Gene and Melanoma: Back to the Future

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.     

Microstructure Evolution and Tensile Properties of a Selectively Laser Melted CoNi-Base Superalloy

Metallurgical and Materials Transactions A - A high $$\gamma ^{\prime }$$ volume fraction CoNi-base superalloy with roughly equal amounts of cobalt and nickel was successfully processed through...