Search

Background/Aims: Vedolizumab is indicated for moderately-to-severely active ulcerative colitis (UC) and Crohn’s disease (CD). Because multiple factors may result in different pharmacokinetics and clinical efficacies, understanding determinants of vedolizumab clearance may enhance dose and treatment strategies. The aim was to characterize vedolizumab pharmacokinetics in Asian and non-Asian UC and CD patients.Methods: Population pharmacokinetic analysis for repeated measures, using data from 5 studies, was conducted using nonlinear mixed-effects modeling. A Bayesian estimation approach in NONMEM 7.3 was utilized to leverage the predominantly sparse data available for this analysis with results from a prior population pharmacokinetic analysis of vedolizumab.Results: Vedolizumab pharmacokinetics were described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half life of vedolizumab was 24.7 days for anti-vedolizumab antibody (AVA)-negative patients and 18.1 days for AVA-positive patients; linear clearance (CLL) was 0.165 L/day for AVA-negative patients and 0.246 L/day for AVA-positive patients; central (Vc) and peripheral compartment volumes of distribution were 3.16 L and 1.84 L, respectively. Interindividual variabilities (percent coefficient of variation) were 30.8% for CLL and 19% for Vc; interoccasion variability on CLL was 20.3%; residual variance was 17.8%. For albumin, body weight and AVA, only extreme values were identified as potentially clinically important predictors of CLL. The effect of race (Asian/non-Asian) and diagnosis (UC/CD) on CLL was negligible and likely not of clinical importance.Conclusions: Pharmacokinetic parameters were similar in Asian and non-Asian patients with moderately-to-severely active UC and CD. This analysis supports use of vedolizumab flat-fixed dosing in these patients. (Clinicaltrials.gov Identifiers: NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2). CCT 101; NCT02039505 and CCT-001; NCT02038920)

Additional file 3. Supplementary Table 2: The relative error between manual and automatic delineation volume at each organ.

Additional file 4. Supplementary Table 3: The Pearson's correlation coefficient between three similarity indexes and volumes at each site of head and neck cancer patients.

Authors’ original file for figure 2

Authors’ original file for figure 3

Authors’ original file for figure 1

Additional file 2. Supplementary Table 1: The Pearson's correlation coefficient r of volume and metrics in the bladder and rectum for the atlas-based segmentation and the AI-based segmentation.

Additional file of A second generation genetic linkage map of Japanese flounder (Paralichthys olivaceus)

Additional file 1. Supplementary Figure 1: The workflow of the atlas-based segmentation.

Table S2. Assessed categories in the central review. (DOCX 16 kb)

Figure S1. DVH criteria and the box-plots with a bar of range for 94 treatment plans in two cases: Case 1: (a) and (b), Case 2: (c) and (d). 100% of dose and volume means the prescribed dose of 50.4â Gy and a whole volume of a structure, respectively (DOCX 46 kb)

Kase, Y., Kanai, T., Matsumoto, Y., Furusawa, Y., Okamoto, H., Asaba, T., Sakama, M. and Shinoda, H. Microdosimetric Measurements and Estimation of Human Cell Survival for Heavy-Ion Beams. Radiat. Res. 166, 629–638 (2006). The microdosimetric spectra for high-energy beams of photons and proton, helium, carbon, neon, silicon and iron ions (LET = 0.5–880 keV/μm) were measured with a spherical-walled tissue-equivalent proportional counter at various depths in a plastic phantom. Survival curves for human tumor cells were also obtained under the same conditions. Then the survival curves were compared with those estimated by a microdosimetric model based on the spectra and the biological parameters for each cell line. The estimated α terms of the liner-quadratic model with a fixed β value reproduced the experimental results for cell irradiation for ion beams with LETs of less than 450 keV/μm, except in the region near the distal peak.

Based on a new concept, a low power electrostatic thruster is being developed for its application to 50 kg class satellite, which is named “Microwave Engine”. The proto-model (PM) of the microwave engine was manufactured and the qualification test (QT) was conducted. The estimated performances are 1250 seconds in specific impulse, 0.36mN in thrust and 10% in thrust efficiency when it is operated at 26.6W. To evaluate the feasibility of its accelerating mechanism, the flight demonstration of a plasma thruster is implemented under microgravity. The demonstrated thruster has an aperture of 19 mm in diameter. The same accelerating mechanism as Microwave Engine is applied to the plasma thruster although there is a difference in the mechanism of generating plasma. The flight demonstrator utilizes the glow discharge while the microwave discharge is applied to Microwave Engine. In this study, the thrust is estimated based on the flight path of the plasma thruster under microgravity, the swing of its pendulum under 1G and the beam theory of its copper wires. These corresponding thrusts are 0.36 mN, 0.20 mN and 0.11 mN, respectively. In addition, a series of its flight images is shown in this paper. As a result, the reasonable flight performance validates the accelerating mechanism of Microwave Engine.

We have begun the feasibility study to build a small satellite in the 3kg mass range and in the power range less than 30W since October in 1998, sponsored by National Space Development Agency of Japan (NASDA). This satellite installs three reaction wheels for an attitude control and camera which will demonstrate optical navigation experiment by using image processing. The BBM design status is described in this paper. The components such as a small reaction wheel, electric flash and onboard computer were built. Mothership - daughtership technology and formation flying experiments are planned. New electric propulsion is being developed for small satellite.

Indium inserted effect to electrical properties of Nb 3 Te 4 has been studied in the temperature range from 0.5 to 250 K . With addition of In, the resistivity remains largely unchanged, but shows resistivity anomaly at T R >100 K , around 84 K and near 49 K depending upon to In concentration. The superconducting transition temperature is enhanced from 1.8 to 3.3 K by addition of In and the coherence length ξ parallel to the c -axis increases sharply at x =0.2, but ξ perpendicular to the c -axis is insensitive to In concentration.

Melatonin receptors (MT1 and MT2) transduce inhibitory signaling by melatonin (N-acetyl-5-methoxytryptamine), which is associated with sleep induction and circadian rhythm modulation. Although recently reported crystal structures of ligand-bound MT1 and MT2 elucidated the basis of ligand entry and recognition, the ligand-induced MT1 rearrangement leading to Gi-coupling remains unclear. Here we report a cryo-EM structure of the human MT1–Gi signaling complex at 3.3 A resolution, revealing melatonin-induced conformational changes propagated to the G-protein-coupling interface during activation. In contrast to other Gi-coupled receptors, MT1 exhibits a large outward movement of TM6, which is considered a specific feature of Gs-coupled receptors. Structural comparison of Gi and Gs complexes demonstrated conformational diversity of the C-terminal entry of the Gi protein, suggesting loose and variable interactions at the end of the α5 helix of Gi protein. These notions, together with our biochemical and computational analyses, highlight variable binding modes of Gαi and provide the basis for the selectivity of G-protein signaling. A cryo-EM structure of the active human melatonin receptor in complex with Gi reveals conformational changes upon activation and the molecular basis for G-protein selectivity.