Aurora A kinase (AURKA), a member of the serine/threonine kinase family, plays a critical role in cell division, and it is widely overexpressed in a variety of tumors including glioblastoma (GBM). ...Alisertib (MLN8237) is an orally administered selective AURKA inhibitor with potent antiproliferative activity, currently undergoing clinical testing in different tumor types. In vitro evaluation of alisertib against the primary GBM lines, GBM6, GBM10, GBM12 and GBM39 showed significant antitumor activity with IC
50s
ranging between 30 and 95 nM. Orthotopic xenografts of GBM10 and the bevacizumab resistant lines GBM6 and GBM39 were established by implantating 3 × 10
5
cells in the caudate nucleus of nude mice; animals were randomized to treatment with either alisertib 30 mg/kg/day or vehicle. In all three models, treatment with alisertib resulted in a statistically significant prolongation of survival (p < 0.0001). In addition, alisertib administration in these mice decreased phosphorylated aurora-A, induced mitotic arrest and significantly decreased histone H3 phosphorylation in tumors. In conclusion, alisertib displays significant antitumor activity against primary GBM lines and xenografts, including patient derived GBM lines resistant to bevacizumab; these data support clinical translation in GBM.
Japan is currently facing serious issues associated with an aging society and negative population growth. Urban structures, remnants of economic prosperity, are now hindrances to sustainable urban ...development, driving municipalities to seek efficient methods to manage this growth. Japanese municipalities continuously conduct surveys to collect data for urban planning purposes. However, lack of standardization and poor visualization tools prevent coordination and consensus-building among stakeholders during the planning process. The "i-Urban Revitalization" (i-UR) is an information infrastructure promoted by the Japanese government expected to enable municipalities to analyze and visualize their goals related to that process.This paper presents the implementation of i-UR. One approach employed for data standardization is to develop a CityGML Application Domain Extension (ADE) for urban planning that covers detailed attributes of city objects and mechanisms for global representation and analysis necessary for urban planning. The effectiveness of this ADE is being evaluated through data implementation and visualization experiments conducted in three municipalities in Japan. A prototype for the proposed "AR Consensus-formation system" is being developed for further utilization of the ADE. In addition, Ideathon events are being held to develop human resources in municipalities to promote urban revitalization and facilitate i-UR use. The ADE and i-UR tools described in this paper are expected to evolve based on feedback from users and experimental results.
Oncolytic measles virus (MV) strains have demonstrated broad spectrum preclinical anti-tumor efficacy, including breast cancer. Aurora A kinase controls mitotic spindle formation and has a critical ...role in malignant transformation. We hypothesized that the Aurora A kinase inhibitor MLN8237 (alisertib) can increase MV oncolytic effect and efficacy by causing mitotic arrest. Alisertib enhanced MV oncolysis in vitro and significantly improved outcome in vivo against breast cancer xenografts. In a disseminated MDA-231-lu-P4 lung metastatic model, the MV/alisertib combination treatment markedly increased median survival to 82.5 days with 20% of the animals being long-term survivors versus 48 days median survival for the control animals. Similarly, in a pleural effusion model of advanced breast cancer, the MV/alisertib combination significantly improved outcome with a 74.5 day median survival versus the single agent groups (57 and 40 days, respectively). Increased viral gene expression and IL-24 upregulation were demonstrated, representing possible mechanisms for the observed increase in anti-tumor effect. Inhibiting Aurora A kinase with alisertib represents a novel approach to enhance MV-mediated oncolysis and antitumor effect. Both oncolytic MV strains and alisertib are currently tested in clinical trials, this study therefore provides the basis for translational applications of this combinatorial strategy in the treatment of patients with advanced breast cancer.
Summary
The impact of excess body fat on bone remodeling was evaluated in overweight, obese, and extremely obese adolescents. In adolescents with excess weight, it was observed that the higher the ...bone mineral content and bone mineral density values, the lower the levels of the biomarkers. Nutritional imbalances by excess had a negative effect on bone formation in this stage of life.
Introduction
The aim of this study was to investigate the impact of excess body fat on bone remodeling in adolescents.
Methods
Body weight, height, and body mass index were determined in 391 adolescents classified as normal weight, overweight, obese, and extremely obese. Bone age was obtained and bone mineral content and bone mineral density were evaluated in the lumbar spine, proximal femur, and total and subtotal body. Blood samples were collected for evaluation of the following bone biomarkers: osteocalcin, bone alkaline phosphatase (BAP), and serum carboxy-terminal telopeptide (S-CTx). The data were analyzed according to nutritional status and age.
Results
In girls with excess weight, the biomarkers were higher in the 10 to 13-year age group and no significant differences were observed between groups according to nutritional status. In boys, the levels were higher in those aged 13 to 15 years. According to nutritional status, significant differences were only observed in mean S-CTx for the age groups of 10–15 years, with higher levels between overweight and obese adolescents aged 10–12 years and between obese and extremely obese adolescents aged 13–15 years. In girls, significant negative correlations were observed between lean mass, fat mass, and fat percentage and each of the three bone markers studied. There was no correlation between lean mass or fat mass and the three biomarkers in boys. The biomarker trends demonstrated across the age groups follow the age trends for growth velocity.
Conclusions
The higher the fat percentage and fat mass in girls, the lower the levels of the biomarkers, indicating that excess body fat has a negative effect on the evolution of these markers during adolescence.
Purpose:
If a cone-beam computed tomography (CBCT) image can be used for adaptive radiotherapy (ART), an irradiated actual dose distribution can be verified on every treatment day. However, a CBCT ...image is commonly degraded by scattered photons and thus cannot be directly used for dose calculation. The purpose of the present study is to evaluate whether a cross-type carbon fiber antiscatter grid improves CBCT image quality using a Monte Carlo (MC) method for achieving CBCT-based ART.
Methods:
We designed a new carbon fiber (C6H10O5) interspaced grid, which allows the grid ratio to be increased while maintaining the transmission of primary photons. The grid ratio was 20:1, and the grid frequency was 20 lp/cm, with lead strips oriented along the cone beam projections. The MC method was used to simulate a projection data acquisition system of a material phantom (water, lung, bone, cartilage, and adipose) with a bow-tie filter. The parameters used to evaluate the image quality were uniformity, contrast, and contrast-to-noise ratio (CNR). Moreover, to evaluate the accuracy of the CT number, we compared CT numbers between images reconstructed by only primary photons and those obtained using grids.
Results:
The proposed grid had a beneficial impact on the image quality and accuracy of the CT number. The uniformity was improved by approximately 70% compared to the case without the grid. The average contrast and CNR improved by 14.2% and 22.6%, respectively, when using the proposed grid. CT numbers using the proposed grid were most consistent with nominal CT numbers obtained with only primary photons.
Conclusion:
The proposed cross-type carbon fiber grid improves CBCT image quality and achieves an accurate CT number, without increasing the imaging doses. Therefore, the cross-type carbon fiber antiscatter grid should be considered to achieve CBCT-based ART.
This work was supported by Japan Society for the Promotion of Science KAKENHI.
Grant Number 15K19211.
Although oxidative stress and inflammation are important mechanisms in the pathophysiology of preeclampsia and preterm diseases, their contribution to the respiratory prognosis of premature infants ...of hypertensive mothers is not known. Our objective was to determine the levels of oxidative stress and inflammation markers in the airways of premature infants born to hypertensive and normotensive mothers, in the first 72 h of life, and to investigate whether they are predictors of bronchopulmonary dysplasia (BPD)/death. This was a prospective study with premature infants less than 34 weeks' gestation on respiratory support who were stratified into 2 groups: 32 premature infants of hypertensive mothers and 41 of normotensive women, with a mean gestational age of 29 weeks. Exclusion criteria were as follows: diabetes mellitus, chorioamnionitis, malformation, congenital infection, and death within 24 h after birth. The outcome of interest was BPD/death. Malondialdehyde (MDA), nitric oxide (NO), and interleukin 8 (IL-8) were measured in airway aspirates from the first and third days of life and did not differ between the groups. Univariate and multivariate statistical analyses were performed. The concentrations of MDA, NO, and IL-8 were not predictors of BPD/death. Premature infants who developed BPD/death had higher levels of IL-8 in the first days of life. The gestational age, mechanical ventilation, and a small size for gestational age were risk factors for BPD/death. In conclusion, the biomarkers evaluated were not increased in premature infants of hypertensive mothers and were not predictors of BPD/death.
Purpose: To evaluate the feature of our tissue‐equivalent Thermoluminescense and Photoluminescense films for dose distribution measurements of photon and electron, and proton beams. Methods: Thermal ...and light fading, repeatability, and dose linearity (dose proportionality) were evaluated for our tissue‐equivalent Thermoluminescense (TLD) and Photo‐Stimulated luminescense (PSLD) films, which has 18 × 40 cm2 dimension and 0.09 mm thickness. These effects were examined at room temperature and under fluorescent light after irradiation by 6 MV photon. Three‐dimensional dose distributions for photon, electron, and proton beams were also measured. Before the measurements of dose distributions, the irradiation was done to calibrate the response of each film. The readout was performed by 180 oC for TLD and blue LED lights for PSLD films, and generated light was detected with a CCD camera which has 1024 × 1024 pixels (FLIML 1001E‐2, Finger Lakes Instrument). Results: After the irradiation, the fading of signals was 1–5% in one hour. It was observed that the variation for 10 sequent dose measurements at 200 cGy using 6 MV photons was less than 5%. Dose profiles for photon and electrons were obtained as smooth curve after the calibration. For photon measurements, PDDs with the TLD films well reproduced the results with ionization chamber, except for the surface region. The measured dose with TLD at surface is around 15%, which is lower more than 30% comparing to the dose with ionization chamber. Although obtained electron PDDs with TLD showed good agreement with that of ionization chamber, PDDs with PSLD showed slightly deviations from the chamber due to the contamination of high Z material. Conclusion: The characteristics of TLD and PSLD films were evaluated in order to make precise measurements. It is shown that they have the potential to measure the 3D dose distribution including low dose at surface. This work was supported by JSPS KAKENHI Grant Number 23791450.
Dose distributions for photon beam were measured using a Photo-Stimulated Luminescence Dosimeter (PSLD) sheet, which has 18 × 24 cm2 dimension and 0.2 mm thickness. Its density and effective atomic ...number are 1.0 g/cm3 and 7.6, respectively. The read out was performed by blue LED lights for 20 seconds, which was much shorter than the readout time for TLD. The percent depth dose and dose profile were obtained as smooth curve after the calibration and it reproduced the measurements with ionization chamber, except for the tail region in the dose profile. We demonstrated the measurement of the prostate VMAT dose distribution also. The result reproduces the calculation by treatment planning system (TPS) qualitatively. It is shown that the PSLD sheet has the potential to measure the dose distribution.
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