Pharmacokinetics of Weekly Paclitaxel and Feasibility of Dexamethasone Taper in Japanese Patients with Advanced Non–small Cell Lung Cancer

AbstractPurposeWeekly paclitaxel combined with a platinum-based agent has been advocated as an alternative regimen for patients with advanced non–small cell lung cancer (NSCLC). Limited studies exist on the tolerability of weekly paclitaxel in Japanese patients with advanced NSCLC. Furthermore, the feasibility of dexamethasone taper in the premedication regimen for weekly paclitaxel has not been examined in these patients. To address this issue, we assessed the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of weekly paclitaxel in Japanese patients with advanced NSCLC in a dose-escalation Phase I trial and examined the feasibility of dexamethasone taper in these patients.MethodsWeekly 1-hour infusions of paclitaxel were administered at doses of 80 to 120 mg/m2 (dose escalation of 20 mg/m2). The 7-week treatment cycle consisted of 6 infusions followed by a 2-week treatment interval. Pharmacokinetics were assessed during the first cycle. Dexamethasone was commenced at 16 mg and doses were successively halved if hypersensitivity reactions were absent.FindingsA total of 15 patients with either Stage IIIB or IV NSCLC were enrolled. Although no dose-limiting toxicity was observed at 120 mg/m2, 4 of 6 patients with peripheral neuropathy required discontinuation of treatment. The maximum accepted dose and the recommended dose were 120 and 100 mg/m2, respectively. No grade ≥3 adverse events were observed at 100 mg/m2. The maximum drug concentration and AUC correlated with dose escalation. The pharmacokinetic parameters after the first and sixth infusions were similar, indicating that repeated administration of paclitaxel did not result in drug accumulation or affect its pharmacokinetic profile. Partial response was observed in 3 of 15 patients. Plasma adrenocorticotropic hormone and cortisol levels decreased during treatment but approached baseline levels after a dexamethasone-free interval.ImplicationsWeekly paclitaxel at 100 mg/m2 given as a 1-hour infusion for 6 weeks followed by a 2-week treatment interval was well tolerated by Japanese patients with advanced NSCLC. Dexamethasone taper was feasible in these patients, and no clear trend in plasma adrenocorticotropic hormone or cortisol levels was observed

Effectiveness of spatial analysis in Cryptomeria japonica D. Don (sugi) forward selection revealed by validation using progeny and clonal tests

International audienceAbstractKey messageAccurate evaluation of genetic performances of trees is crucial in order to improve the efficiency of forest tree breeding. We revealed that spatial analysis is effective for predicting individual tree breeding values at the forward selection stage ofCryptomeria japonicaD. Don (sugi) breeding program by using a novel validation approach.ContextIn the process of selecting genetically superior trees for breeding, appropriate handling of environmental effects is important in order to precisely evaluate candidate trees. Spatial analysis has been an effective statistical approach for genetic evaluation at sites with heterogeneous microenvironments. However, the efficiency of spatial analysis on forward selection has not been validated on a practical scale to date.AimsThis study aimed to reveal the effectiveness of spatial analysis, which incorporates spatially autocorrelated residuals into mixed models, for the prediction of breeding values at the forward selection stage by validation using progeny or clonal tests of forward-selected individuals.MethodsTree height was analyzed by ordinary randomized complete block design models and spatial models incorporating spatially autocorrelated residuals in a linear mixed model framework, and model selection was conducted at thirty Cryptomeria japonica D. Don breeding population sites having various topographical ruggedness. For validation, three clonal tests and one progeny test of individuals selected from three and four breeding populations, respectively, were used. The effectiveness of forward selection using the two models was evaluated based on the correlation between individual breeding values at the stage of forward selection and genotypic and breeding values that were estimated by clonal and progeny tests.ResultsSpatial models were more predictive than ordinary models in all cases. Spatial correlation parameters tend to increase with the topographical ruggedness index of each site. The correlation coefficients between breeding values at the time of forward selection and genotypic or breeding values evaluated in succeeding clonal and progeny tests were significantly higher in spatial models than in ordinary models in six out of nine cases.ConclusionValidation using progeny and clonal tests of forward-selected individual trees revealed that spatial analysis is more effective for the evaluation of genetic performance of individuals at the stage of forward selection in Cryptomeria japonica

一抗体免疫法によるPorphyromonas. gingivalis SODの定量(プレリミナリーレポート)

Superoxide dismutase (SOD) as a free radical scavenger in Porphyromonas gingivalis is well documented. The aim of this work was to develop an enzyme-linked immunosorbent assay using recombinant P. gingivalis SOD as an antigen. The sandwich complex was detected using a secondary antibody conjugated to β-D-galactosidase. Under optimum conditions, the sensitivity and the limit of detection were determined from 25pg to 500pg. In future, the application will be extended to the expression of SOD from P. gingivalis under various growing conditions

Secondary xylem maturation evaluated by modeling radial variations in anatomical characteristics and wood properties of Shorea macrophylla (De Vr.) Ashton planted in Sarawak, Malaysia

Radial variations in anatomical characteristics and wood properties were investigated in 23-year-old Shorea macrophylla (engkabang) trees planted in Sarawak, Malaysia. The efects of radial growth rates on anatomical characteristics and wood properties and the manner of xylem maturation were determined based on selected mixed-efects models. The best models of radial variation were ftted by linear functions for wood fber length, wood fber wall thickness, basic density, and compressive strength. Logarithmic functions were applied for vessel element length and vessel frequency, and quadratic functions were applied for vessel diameter and wood fber diameter. Vessel diameter and wood fber length were afected by radial growth rates although these efects on the other properties were minimal. In the fxed part of the models, the results showed small mean absolute error values of radial variation in relation to the distance from the pith according to vessel frequency and vessel diameter. In contrast, in relation to the estimated cambial age, smaller mean absolute error values were obtained for cell length, wood fber traits, and basic density, suggesting that all properties varied from pith to bark in relation to the cambial age, except for vessel traits. Thus, in S. macrophylla, xylem maturation in cell length, wood fber traits, and basic density were due to cambial age rather than diameter growth, but xylem maturation in vessel traits depended on diameter growth

Potential of Genome-Wide Studies in Unrelated Plus Trees of a Coniferous Species, Cryptomeria japonica (Japanese Cedar)

A genome-wide association study (GWAS) was conducted on more than 30,000 single nucleotide polymorphisms (SNPs) in unrelated first-generation plus tree genotypes from three populations of Japanese cedar Cryptomeria japonica D. Don with genomic prediction for traits of growth, wood properties and male fecundity. Among the assessed populations, genetic characteristics including the extent of linkage disequilibrium (LD) and genetic structure differed and these differences are considered to be due to differences in genetic background. Through population-independent GWAS, several significant SNPs found close to the regions associated with each of these traits and shared in common across the populations were identified. The accuracies of genomic predictions were dependent on the traits and populations and reflected the genetic architecture of traits and genetic characteristics. Prediction accuracies using SNPs selected based on GWAS results were similar to those using all SNPs for several combinations of traits and populations. We discussed the application of genome-wide studies for C. japonica improvement

Porphyromonas gingivalis SOD における活性中心近傍に局在するアミノ酸残基の金属特異的活性における関与：Leu ₇2 Trp およびLeu ₇6 Phe の2残基変異による検討

The role of superoxide dismutase (SOD) as a radical scavenger in Porphyromonas gingivalis is well documented. P. gingivalis SOD (Pg SOD), which is characterized by a metal–tolerant activity, can use either iron or manganese as a cofactor. Leu ₇2 and Leu ₇6, located near the active–site metal, are characteristic amino acid sequences of Pg SOD proteins, although they are substituted to Trp in the ₇2 position and Phe in the ₇6 position in most iron–containing SOD (Fe–SOD) proteins. In the present study, we constructed a mutant of the enzyme with changes from Leu ₇2 to Trp and Leu ₇6 to Phe. This mutant SOD was examined with respect to its metal–dependent activity and structural characterization. We herein conclude the integrity of Leu ₇2 and Leu ₇6 is a necessary requisite for the metal–tolerant activity of Pg SOD

Porphyromonas gingivalis スーパーオキシドジスムターゼの構造における72位Leu をTrp に置換した影響

Porphyromonas gingivalis contains a single constitutive superoxide dismutase (SOD) that is active with either iron or manganese at the active site. The aim of this work was to evaluate the effect of the Leu ₇2 to Trp mutation on the structure of P. gingivalis SOD (Pg SOD) using lectrophoretic characterization. Leu ₇2, which is located near the active site metal, is substituted with Trp in aligned amino acid sequences of iron–containing SOD. The results of electrophoretic characterization and the expressed activity of mutant SOD suggest that mutant SOD have the same gross structure as wild–type SOD. We herein conclude that the integrity of Leu ₇2 is a necessary requisite for the metal–tolerant activity of Pg SOD

Initial validations for pursuing irradiation using a gimbals tracking system.

Our newly designed image-guided radiotherapy (IGRT) system enables the dynamic tracking irradiation with a gimbaled X-ray head and a dual on-board kilovolt imaging subsystem for real-time target localization. Examinations using a computer-controlled three-dimensionally movable phantom demonstrated that our gimbals tracking system significantly reduced motion blurring effects in the dose distribution compared to the non-tracking state