Synergistic Effect of Geranylgeranyltransferase Inhibitor, GGTI, and Docetaxel on the Growth of Prostate Cancer Cells

Most advanced prostate cancers progress to castration resistant prostate cancer (CRPC) after a few years of androgen deprivation therapy and the prognosis of patients with CRPC is poor. Although docetaxel and cabazitaxel can prolong the survival of patients with CRPC, inevitable progression appears following those treatments. It is urgently required to identify better or alternative therapeutic strategies. The purpose of this study was to confirm the anti-cancer activity of zoledronic acid (Zol) and determine whether inhibition of geranylgeranylation in the mevalonate pathway could be a molecular target of prostate cancer treatment. We examined the growth inhibitory effect of Zol in prostate cancer cells (LNCaP, PC3, DU145) and investigated a role of geranylgeranylation in the anticancer activity of Zol. We, then, evaluated the growth inhibitory effect of geranylgeranyltransferase inhibitor (GGTI), and analyzed the synergy of GGTI and docetaxel by combination index and isobolographic analysis. Zol inhibited the growth of all prostate cancer cell lines tested in a dose-dependent manner through inhibition of geranylgeranylation. GGTI also inhibited the prostate cancer cell growth and the growth inhibitory effect was augmented by a combination with docetaxel. Synergism between GGTI and docetaxel was observed across a broad range of concentrations. In conclusion, our results demonstrated that GGTI can inhibit the growth of prostate cancer cells and has synergistic effect with docetaxel, suggesting its potential role in prostate cancer treatment

Coradion calendula, a new butterflyfish from Australia (Teleostei: Chaetodontidae)

The new butterflyfish, Coradion calendula, is described on the basis of 44 specimens collected off Western Australia, the Northern Territory, and north Queensland, Australia. The new species is most similar to Coradion chrysozonus, with which it shares IX dorsal-fin spines, a single ocellated spot on the soft-rayed portion of the dorsal-fin, and a single dark band on the frontal surface of the thorax. The new species is distinguished from C. chrysozonus by slightly higher ranges of dorsal-fin soft rays 28–32, mode 29 (vs. 27–30, mode 28) and anal-fin soft rays 20–22, mode 21 (vs. 18–21, mode 20); an orange band on the caudal peduncle in fresh specimens (lost after preservation) with a saddle-like blackish dorsal streak (vs. a broad brown -to-black circumpeduncular band in both fresh and preserved specimens); a sharply pointed pelvic fin with an almost straight posterior contour when spread (vs. a rounded pelvic fin with an expanded posterior contour); and a dark band on each interopercle joining on the ventral midline, with their anterior margins forming a sharply pointed “V” in ventral view (vs. separated by a relatively wide interspace). Despite well-defined morphological and coloration differences, the mtDNA difference between the two species was relatively low, 0.8–1.9% (mean 1.3%) and 2.9–7.5% (mean 4.8%) pairwise sequence difference in COI and control region genes, respectively. Morphological and color-pattern characters and mtDNA lineage were not concordant in some specimens from northern Australia, where the two species overlap, suggesting that the two species hybridize at their common biogeographic borders

Trial of Brain Redox Imaging and Estimation of Radiation-Induced Redox Change in Mouse Brain

The in vivo T1-weighted contrasting abilities and signal decay behaviors of several nitroxyl contrast agents, which have been used as redox responsive contrast agents in several magnetic resonance-based imaging modalities, in mouse brain were compared. In addition, daily variations of redox behavior in mouse brain after irradiation of X-ray or carbon-ion beams (C-beam) were tried to estimate based on the in vivo reduction rate of amphiphilic nitroxyl contrast agents.Injection solutions of five types of five-membered-ring nitroxyl contrast agents, i.e. 3-carboxy-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CxP), 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CmP), 3-methoxy-carbonyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (MCP), acetoxymethyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl-3-carboxylate (CxP-AM), and 4-(N-methylpiperidine)-2,2,5,5-tetramethylpyrroline-N-oxyl (23c), and a six-membered-ring nitroxyl contrast agent, i.e. 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL), were prepared. The nitroxyl contrast agent was i.v. injected to a mouse through tail vein. Then, the distributions and pharmacokinetics of nitroxyl contrast agents were compared based on the time course of T1-weighted MRI. The MRI experiments using CMP or TEMPOL were repeated for mice irradiated by X-ray or C-beam to their head on several deferent timings, i.e. 1, 2, 4, 8 day(s) after irradiation. C-beam was irradiated at Heavy-Ion Medical Accelerator in Chiba (HIMAC, National Institute of Radiological Sciences/ National Institutes for Quantum and Radiological Science and Technology).The blood-brain-barrier (BBB)-impermeable CxP could not be distributed in the brain. The slightly lipophilic CmP showed slight distribution only in the ventricle, but not in the medulla and cortex. The amphiphilic MCP and TEMPOL had good initial uniform distribution in the brain and showed typical 2-phase signal decay profiles. A brain-seeking nitroxyl probe, CxP-AM, showed an accumulating phase, and then its accumulation was maintained in the medulla and ventricle regions, but not in the cortex. The lipophilic 23c was well distributed in the cortex and medulla, but slightly in the ventricle, and showed relatively rapid linear signal decay.Decay rates of MCP in mouse brain after irradiation of 8 Gy X-ray, 8 Gy C-beam or 16 Gy C-beams did not show marked clear changes, however relatively little decreasing were observed at day 1 and day 2 after irradiation. Decay rates of TEMPOL was increased 1 after irradiation then gradually recovered to the control level. MCP and TEMPOL showed opposite responses but the timing of redox change may be 1 or 2 days after irradiation.Nitroxyl contrast agents equipped with a suitable lipophilic substitution group could be BBB-permeable functional contrast agents. MR redox imaging, which can estimate not only the redox characteristics but also the detailed distribution of the contrast agents, is a good candidate for a theranostic tool. Irradiation of ionized radiation to head could cause alternation of redox status in the brain. Detail of redox mechanisms were still in progress.第7回国際放射線神経生物学会大

Dysregulated Aire expression and autoimmunity

Deficiency for AIRE/Aire in both humans and mice results in the development of organ-specific autoimmune disease. We tested whether augmented and/or dysregulated AIRE/Aire expression might be also prone to the breakdown of self-tolerance. To define the effect of augmented Aire expression on the development of autoimmunity, antigen-specific clonal deletion and production of clonotypic regulatory T cells (Tregs) in the thymus were examined using mice expressing two additional copies of Aire in a heterozygous state (3xAire-knockin mice: 3xAire-KI). We found that both clonal deletion of autoreactive T cells and production of clonotypic Tregs in the thymus from 3xAire-KI were impaired in a T-cell receptor-transgenic system. Furthermore, 3xAire-KI females showed higher scores of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein than wild-type littermates, suggesting that augmented Aire expression exacerbates organ-specific autoimmunity under disease-prone conditions. In humans, we found that one patient with amyopathic dermatomyositis showed CD3–CD19– cells expressing AIRE in the peripheral blood before the treatment but not during the remission phase treated with immunosuppressive drugs. Thus, not only loss of function of AIRE/Aire but also augmented and/or dysregulated expression of AIRE/Aire should be considered for the pathogenesis of organ-specific autoimmunity. We suggest that further analyses should be pursued to establish a novel link between organ-specific autoimmune disease and dysregulated AIRE expression in clinical settings

Development of a folding arm on an articulated mobile robot for plant disaster prevention

In this work, we develop a folding arm on an articulated mobile robot to inspect an industrial plant. The design targets of the arm, its operations, measurement ability, and mobility, were set for the task of inspecting an industrial plant. To accomplish the targets, we designed the folding arm considering both accessibility to high locations and the mobility of the articulated mobile robot to which it is attached. The arm has links, joints, dummy wheels, and sensors and enables the robot to which it is attached to manipulate objects, e.g. rotating valves, opening a door, or inspecting by accessing high locations. In addition, changing the posture of the arm and touching the dummy wheel in the arm to the surrounding terrain can reduce any negative effect of the arm on the robot\u27s mobility when it encounters narrow spaces, stairs, steps, and trenches. The arm is controlled as a six degrees-of-freedom manipulator without redundancy by an operator who directly sets two joint angles. The effectiveness of the developed arm was demonstrated not only through experiments in a laboratory but also in a field test at the Plant Disaster Prevention Challenge of the World Robot Summit 2018

Anxiolytic-like effects of hochuekkito in lipopolysaccharide-treated mice involve interleukin-6 inhibition

Hochuekkito (HET) is a Kampo medicine used to treat postoperative and post-illness general malaise and decreased motivation. HET is known to regulate immunity and modulate inflammation. However, the precise mechanism and effects of HET on inflammation-induced central nervous system disorders remain unclear. This study aimed to assess the effect of HET on inflammation-induced anxiety-like behavior and the mechanism underlying anxiety-like behavior induced by lipopolysaccharide (LPS). Institute of Cancer Research mice were treated with LPS (300 mu g/kg, intraperitoneally), a bacterial endotoxin, to induce systemic inflammation. The mice were administered HET (1.0 g/kg, orally) once a day for 2 weeks before LPS treatment. The light-dark box test and the hole-board test were performed 24 h after the LPS injection to evaluate the effects of HET on anxiety-like behaviors. Serum samples were obtained at 2, 5, and 24 h after LPS injection, and interleukin-6 (IL-6) levels in serum were measured. Human and mouse macrophage cells (THP-1 and RAW264.7 cells, respectively) were used to investigate the effect of HET on LPS-induced IL-6 secretion. The repeated administration of HET prevented anxiety-like behavior and decreased serum IL-6 levels in LPS-treated mice. HET significantly suppressed LPS-induced IL-6 secretion in RAW264.7 and THP-1 cells. Similarly, glycyrrhizin, one of the chemical constituents of HET, suppressed LPS-induced anxiety-like behaviors. Our study revealed that HET ameliorated LPS-induced anxiety-like behavior and inhibited IL-6 release in vivo and in vitro. Therefore, we postulate that HET may be useful against inflammation-induced anxiety-like behavior

Development and field test of the articulated mobile robot T2 Snake-4 for plant disaster prevention

In this work, we develop an articulated mobile robot that can move in narrow spaces, climb stairs, gather information, and operate valves for plant disaster prevention. The robot can adopt a tall position using a folding arm and gather information using sensors mounted on the arm. In addition, this paper presents a stair climbing method using a single backward wave. This method enables the robot to climb stairs that have a short tread. The developed robot system is tested in a field test at the World Robot Summit 2018, and the lessons learned in the field test are discussed