Pharmacokinetics and Bioequivalence of Mirogabalin Orally Disintegrating Tablets and Conventional Tablets in Healthy Japanese Participants.

This single-center, randomized, open-label, single-dose, 2-group, 2-stage crossover trial evaluated the bioequivalence of 15 mg of mirogabalin as orally disintegrating tablets (ODTs) with conventional mirogabalin tablets in healthy Japanese men. The trial involved two studies: in Study 1, the ODT formulation was taken without water, and in Study 2, the ODT formulation was taken with water. The conventional tablet was taken with water in both studies. We investigated the pharmacokinetic parameters and bioequivalence of the 2 formulations, including the maximum plasma concentration and the area under the plasma concentration-time curve up to the last quantifiable time. The plasma concentrations of mirogabalin were determined by a validated liquid chromatography with tandem mass spectrometry method. A total of 72 participants were enrolled and completed the trial. The geometric least-squares mean ratios of maximum plasma concentration of the ODT formulation to the conventional formulation were within the prespecified bioequivalence range of 0.80-1.25 (Study 1, 0.995; Study 2, 1.009), as was the area under the plasma concentration-time curve up to the last quantifiable time (Study 1, 1.023; Study 2, 1.035). No serious adverse events were observed. In conclusion, mirogabalin 15-mg ODTs, either with or without water, were bioequivalent to conventional 15-mg tablets.

Visible-Light-Enhanced Antibacterial Activity of Silver and Copper Co-Doped Titania Formed on Titanium via Chemical and Thermal Treatments.

Dental implants made of titanium (Ti) are used in dentistry, but peri-implantitis is a serious associated problem. Antibacterial and osteoconductive Ti dental implants may decrease the risk of peri-implantitis. In this study, titania (TiO2) co-doped with silver (Ag) at 2.5 at.% and copper (Cu) at 4.9 at.% was formed on Ti substrates via chemical and thermal treatments. The Ag and Cu co-doped TiO2 formed apatite in a simulated body fluid, which suggests osteoconductivity. It also showed antibacterial activity against Escherichia coli, which was enhanced by visible-light irradiation. This enhancement might be caused by the synergistic effect of the release of Ag and Cu and the generation of •OH from the sample. Dental implants with such a Ag and Cu co-doped TiO2 formed on their surface may reduce the risk of peri-implantitis.

Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor.

Histone acetylation is a post-translational modification of histones that is catalyzed by histone acetyltransferases (HATs) and plays an essential role in cellular processes. The HAT domain of EP300/CBP has recently emerged as a potential drug target for cancer therapy. Here, we describe the identification of the novel, highly potent, and selective EP300/CBP HAT inhibitor DS-9300. Our optimization efforts using a structure-based drug design approach based on the cocrystal structures of the EP300 HAT domain in complex with compounds 2 and 3 led to the identification of compounds possessing low-nanomolar EP300 HAT inhibitory potency and the ability to inhibit cellular acetylation of histone H3K27. Optimization of the pharmacokinetic properties in this series resulted in compounds with excellent oral systemic exposure, and once-daily oral administration of 16 (DS-9300) demonstrated potent antitumor effects in a castrated VCaP xenograft mouse model without significant body weight loss.

Steric Control in Activator-Induced Nucleophilic Quencher Detachment-Based Probes: High-Contrast Imaging of Aldehyde Dehydrogenase 1A1 in Cancer Stem Cells.

Turn-on fluorescence probes can visualize the enzyme activity with high contrast. We have established a new turn-on mechanism, activator-induced nucleophilic quencher detachment (AiQd), and developed AiQd-based turn-on fluorescence probes for the detection of enzymes. Herein, we demonstrate that the precise steric control efficiently quenches the fluorescence of AiQd-based turn-on probes before the enzymatic transformation. Theoretical calculation appropriately predicted the ratio of the fluorescence-quenched closed-ring form of probes. ßC5S-A, which has a sterically demanding methyl group at the ß-position of a fluorescence-quenching nucleophilic mercapto group, showed a low background signal. ßC5S-A responded to aldehyde dehydrogenase 1A1 (ALDH1A1) with high selectivity, thereby enabling high-contrast live imaging of cancer stem cells (signal-to-noise ratio >10). The ALDH1A1-responsiveness of ßC5S-A was not significantly affected by amino acids and biological thiols, such as cysteine and glutathione.

Discovery of EP300/CBP histone acetyltransferase inhibitors through scaffold hopping of 1,4-oxazepane ring.

EP300 and its paralog CBP play an important role in post-translational modification as histone acetyltransferases (HATs). EP300/CBP inhibition has been gaining attention as an anticancer treatment target in recent years. Herein, we describe the identification of a novel, highly selective EP300/CBP inhibitor, compound 11 (DS17701585), by scaffold hopping and structure-based optimization of a high-throughput screening hit 1. Compound 11 (DS17701585) shows dose-dependent inhibition of SRY-box transcription factor 2 (SOX2) mRNA expression in a human lung squamous cell carcinoma cell line LK2-xenografted mouse model.

Cross-cultural similarities and differences in the theoretical predictors of cyberbullying perpetration: Results from a seven-country study.

The Barlett Gentile cyberbullying model (BGCM) posits that correlated anonymity perceptions and the belief in the irrelevance of muscularity for online bullying (BIMOB) predict positive cyberbullying attitudes to predict subsequent cyberbullying perpetration. Much research has shown the BGCM to be the only published theory that differentiates traditional and cyberbullying while validly predicting cyberbullying. So far, however, the cross-cultural ubiquity has gone understudied. Thus, 1,592 adult participants across seven countries (USA, Australia, Brazil, China, Germany, Japan, and Singapore) completed measures germane to the BGCM. Supporting the BGCM, the variables were significantly correlated for the entire sample, participants from independent cultures, and participants from interdependent cultures. However, the relationship between BIMOB and positive cyberbullying attitudes as well as the relationship between positive cyberbullying attitudes and cyberbullying perpetration were stronger for independent cultures. These results suggest that the BGCM postulates are mostly universal, but several relations appear to be culturally different. Theoretical implications are discussed.

True accuracy of percutaneous pedicle screw placement in thoracic and lumbar spinal fixation with a CT-based navigation system: Intraoperative and postoperative assessment of 763 percutaneous pedicle screws.

PURPOSE: To investigate intraoperative reinsertion of percutaneous pedicle screw (PPS) with intraoperative CT-based navigation and to evaluate the rate of deviation of PPS at postoperative radiographic examination. METHODS: Seven hundred sixty-three screws were inserted in 138 patients. We investigated the rate of occurrence of intraoperative PPS reinsertion after the diagnosis of screw deviation by fluoroscopy and the causes of each screw deviation. The subsequent distribution of PPS deviation was evaluated by postoperative CT. We also assess the difference in variance between the group judged to be PPS misplaced intra-/postoperatively (IOD group/POD group) and appropriate PPS placement (ND group). RESULTS: Among all the screws inserted, 10 (1.3%) were diagnosed as being deviated by fluoroscopy during surgery, and 74 (9.7%) screws were found to be deviated at postoperative CT evaluation. We found more pedicle screw mismatch in the POD group than in the ND group (52.7 vs 11.0%, P < 0.001). The distance between the screw and the reference was greater in the IOD group than that in the ND group (1.4 ± 1.2 vs 2.4 ± 1.1 vertebral levels, P = 0.016). In one patient in the IOD group, a motor function deficit was observed postoperatively. CONCLUSION: PPS fixation under intraoperative CT-based navigation did not prevent screw deviation completely. It is necessary to consider errors that occur during surgery and to confirm placement with real-time assistance such as fluoroscopy even in a surgery performed under CT navigation assistance.

Characterization of a membrane-associated estrogen receptor in breast cancer cells and its contribution to hormone therapy resistance using a novel selective ligand.

The estrogen receptor (ER) plays a role in the progression of hormone-dependent breast cancer and is a hormone therapy target. Estrogen acts as a transcription factor (genomic action) and also produces a quick non-genomic reaction through intracellular signaling pathways. The membrane associated ER (mER) may regulate both these signals and hormone therapy resistance. However, the details remain unclear because a reliable method to distinguish the signals induced by the estradiol (E2)-mER and E2-nuclear ER complex has not been established. In the present study, we prepared the novel ligand Qdot-6-E2, selective for mER, by coupling E2 with insoluble quantum dot nano-beads. We investigated the characteristics of mER signaling pathways and its contribution to hormone therapy resistance using different cell lines including estrogen depletion resistant (EDR) cells with different mechanisms. Qdot-6-E2 stimulated proliferation of nuclear ER-positive cells, but nuclear ER-negative cells showed no response. In addition, Qdot-6-E2 indirectly activated nuclear ER and increased mRNA expression of target genes. We confirmed that E2 was not dissociated from Qdot-6-E2 using a mammalian one-hybrid assay. We visually demonstrated that Qdot-6-E2 acts from the outside of cells. The gene expression profile induced by Qdot-6-E2-mER was different from that induced by E2-nuclear ER. The effect of anti-ER antibody, the GFP-ER fusion protein localization, and the effect of palmitoyl acyltransferase inhibitor also indicated the existence of mER. Regarding intracellular phosphorylation signaling pathways, the MAPK (Erk 1/2) and the PI3K/Akt pathways were both activated by Qdot-6-E2. In EDR cells, only nuclear ER-positive cells showed increased cell proliferation with increased localization of ERα to the membrane fraction. These findings suggested that Qdot-6-E2 reacts with ERα surrounding the cell membrane and that mER signals help the cells to survive under estrogen-depleted conditions by re-localizing the ER to use trace amounts of E2 more effectively. We expect that Qdot-6-E2 is a useful tool for studying the mER.

A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model.

Gliomas are the second most common primary brain tumors in adults. They are treated with combination therapies, including surgery, radiotherapy, and chemotherapy. There are currently limited treatment options for recurrent gliomas, and new targeted therapies need to be identified, especially in glioblastomas, which have poor prognosis. Isocitrate dehydrogenase (IDH) mutations are detected in various tumors, including gliomas. Most patients with IDH mutant glioma harbor the IDH1R132H subtype. Mutant IDH catalyzes the conversion of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), which induces aberrant epigenetic status and contributes to malignant progression, and is therefore a potential therapeutic target for IDH mutant tumors. The present study describes a novel, orally bioavailable selective mutant IDH1 inhibitor, DS-1001b. The drug has high blood-brain barrier (BBB) permeability and inhibits IDH1R132H. Continuous administration of DS-1001b impaired tumor growth and decreased 2-HG levels in subcutaneous and intracranial xenograft models derived from a patient with glioblastoma with IDH1 mutation. Moreover, the expression of glial fibrillary acidic protein was strongly induced by DS-1001b, suggesting that inhibition of mutant IDH1 promotes glial differentiation. These results reveal the efficacy of BBB-permeable DS-1001b in orthotopic patient-derived xenograft models and provide a preclinical rationale for the clinical testing of DS-1001b in recurrent gliomas.

Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity.

We report the discovery of a potent and isozyme-selective MTHFD2 inhibitor, DS18561882 (2). Through investigation of the substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one), MTHFD2 inhibitory activity was shown to be elevated by incorporating an amine moiety at the 8-position and a methyl group at the 7-position of the initial lead 1. X-ray structure analysis revealed that a key interaction for enhanced potency was salt bridge formation between the amine moiety and the diphosphate linker of an NAD+ cofactor. Furthermore, ortho-substituted sulfonamide in place of benzoic acid of 1 significantly improved cell permeability and cell-based growth inhibition against a human breast cancer cell line. The thus-optimized DS18561882 showed the strongest cell-based activity (GI50 = 140 nM) in the class, a good oral pharmacokinetic profile, and thereby tumor growth inhibition in a mouse xenograft model upon oral administration.

Sensory processing in children with autism spectrum disorder and the mental health of primary caregivers.

BACKGROUND: Sensory processing difficulties, which commonly occur in autism spectrum disorder (ASD), are expected to have negative effects on the primary caregiver's mental health. The aim of this study was to examine the association between sensory processing difficulties in children with ASD and the mental health of primary caregivers. METHODS: A total of 707 primary caregivers (mothers in the present study) and their children with ASD (4-18 years of age) participated in this study. Sensory processing difficulties were indexed using the Short Sensory Profile (SSP). The mental health of primary caregivers was indexed using the General Health Questionnaire (GHQ12). RESULTS: Higher scores on Auditory Filtering as measured with the SSP were associated with poorer mental health of primary caregivers, even after an adjustment for ASD symptom severity. Analyses of two age sub-groups, a young (4-10 years) and an old age group (11-18 years), revealed that higher scores on Tactile Sensitivity and Auditory Filtering were associated with poorer mental health of primary caregivers in younger children, whereas only higher scores on Auditory Filtering were associated with poorer mental health of primary caregivers in older children. CONCLUSIONS: Our findings suggest that practitioners who support primary caregivers of children with ASD need to focus not only on the social and communication-related symptoms of the child but also on their specific sensory processing difficulties.

Media Violence and Other Aggression Risk Factors in Seven Nations.

Cultural generality versus specificity of media violence effects on aggression was examined in seven countries (Australia, China, Croatia, Germany, Japan, Romania, the United States). Participants reported aggressive behaviors, media use habits, and several other known risk and protective factors for aggression. Across nations, exposure to violent screen media was positively associated with aggression. This effect was partially mediated by aggressive cognitions and empathy. The media violence effect on aggression remained significant even after statistically controlling a number of relevant risk and protective factors (e.g., abusive parenting, peer delinquency), and was similar in magnitude to effects of other risk factors. In support of the cumulative risk model, joint effects of different risk factors on aggressive behavior in each culture were larger than effects of any individual risk factor.

4-Anilino-pyrimidine, novel aldosterone synthase (CYP11B2) inhibitors bearing pyrimidine structures.

2,2,2-Trifluoro-1-{4-[(4-fluorophenyl)amino]pyrimidin-5-yl}-1-[1-(methylsulfonyl)piperidin-4-yl]ethanol 1 was identified as a novel potent aldosterone synthase inhibitor. Despite large species differences, compound 1 inhibits both human and rodent CYP11B2 in a nano-molar range.

Estrogen receptor activation by tobacco smoke condensate in hormonal therapy-resistant breast cancer cells.

The relationship between tobacco smoke and breast cancer incidence has been studied for many years, but the effect of smoking on hormonal therapy has not been previously reported. We investigated the effect of smoking on hormonal therapy by performing in vitro experiments. We first prepared tobacco smoke condensate (TSC) and examined its effect on estrogen receptor (ER) activity. The ER activity was analyzed using MCF-7-E10 cells into which the estrogen-responsive element (ERE)-green fluorescent protein (GFP) reporter gene had been stably introduced (GFP assay) and performing an ERE-luciferase assay. TSC significantly activated ERs, and upregulated its endogenous target genes. This activation was inhibited by fulvestrant but more weakly by tamoxifen. These results suggest that the activation mechanism may be different from that for estrogen. Furthermore, using E10 estrogen depletion-resistant cells (EDR cells) established as a hormonal therapy-resistant model showing estrogen-independent ER activity, ER activation and induction of ER target genes were significantly higher following TSC treatment than by estradiol (E2). These responses were much higher than those of the parental E10 cells. In addition, the phosphorylation status of signaling factors (ERK1/2, Akt) and ER in the E10-EDR cells treated with TSC increased. The gene expression profile induced by estrogenic effects of TSC was characterized by microarray analysis. The findings suggested that TSC activates ER by both ligand-dependent and -independent mechanisms. Although TSC constituents will be metabolized in vivo, breast cancer tissues might be exposed for a long period along with hormonal therapy. Tobacco smoke may have a possibility to interfere with hormonal therapy for breast cancer, which may have important implications for the management of therapy.

R-268712, an orally active transforming growth factor-ß type I receptor inhibitor, prevents glomerular sclerosis in a Thy1 nephritis model.

R-268712 is a novel and specific inhibitor of activin receptor-like kinase 5 (ALK5), a transforming growth factor ß (TGF-ß) type I receptor. Evaluation of in vitro inhibition indicated that R-268712 is a potent and selective inhibitor of ALK5 with an IC50 of 2.5nM, an approximately 5000-fold more selectivity for ALK5 than p38 mitogen-activated protein kinase (MAPK). Oral administration of R-268712 at doses of 1, 3 and 10mg/kg also inhibited the development of renal fibrosis in a dose-dependent manner in a unilateral ureteral obstruction (UUO) model. Additionally, we evaluated the efficacy of R-268712 in a heminephrectomized anti-Thy1 glomerulonephritis model at doses of 0.3 and 1mg/kg. R-268712 reduced proteinuria and glomerulosclerosis significantly with improvement of renal function. Collectively, these results suggested that R-268712 and other ALK5 inhibitors could suppress glomerulonephritis as well as glomerulosclerosis by an inhibitory mechanism that involves suppression of TGF-ß signaling.

Long-term relations among prosocial-media use, empathy, and prosocial behavior.

Despite recent growth of research on the effects of prosocial media, processes underlying these effects are not well understood. Two studies explored theoretically relevant mediators and moderators of the effects of prosocial media on helping. Study 1 examined associations among prosocial- and violent-media use, empathy, and helping in samples from seven countries. Prosocial-media use was positively associated with helping. This effect was mediated by empathy and was similar across cultures. Study 2 explored longitudinal relations among prosocial-video-game use, violent-video-game use, empathy, and helping in a large sample of Singaporean children and adolescents measured three times across 2 years. Path analyses showed significant longitudinal effects of prosocial- and violent-video-game use on prosocial behavior through empathy. Latent-growth-curve modeling for the 2-year period revealed that change in video-game use significantly affected change in helping, and that this relationship was mediated by change in empathy.

Antitumor effects of novel highly hydrophilic and non-ATP-competitive MEK1/2 inhibitor, SMK-17.

The mitogen-activated protein kinase (MAPK) signal pathway plays a central role in regulating tumor cell proliferation, survival, and differentiation. The components of this pathway, Ras/Raf/MEK/ERK, are frequently activated in human cancers. Targeting this pathway is considered to be a promising anticancer strategy. In particular, MEK is an attractive drug target because of its high selectivity to ERK. We can expect potent growth inhibitory and proapoptotic effects by inhibiting MEK. Here, we report derivatives of N-[2-(2-chloro-4-iodo-phenylamino)-3,4-difluorophenyl]-methanesulfonamide as novel MEK1/2 inhibitors. Among these compounds, we found SMK-17 to be a potent MEK1/2 inhibitor with high aqueous solubility. The in-silico docking study suggested that SMK-17 is bound to an allosteric pocket of MEK1. The kinetic study and the kinase profiler analysis confirmed the allosteric nature of SMK-17. SMK-17 inhibited MEK1 kinase activity in a non-ATP-competitive manner and it was highly selective to MEK1 and 2. SMK-17 inhibited the growth of tumor cell lines in vitro. Especially, it seemed that cell lines harboring highly phosphorylated MEK1/2 and ERK1/2 were highly sensitive to SMK-17. Moreover, unlike previously reported MEK inhibitors, PD184352 or U0126, SMK-17 did not inhibit the phosphorylation of ERK5. In vivo, SMK-17 exhibited potent antitumor activity in animal models on oral administration. SMK-17 selectively blocked the MAPK pathway signaling without affecting other signal pathways, which resulted in significant antitumor efficacy without notable side effects. These findings suggest that SMK-17, an exquisitely selective, orally available MEK1/2 inhibitor, is a useful chemical biology tool for characterizing the function of MEK/MAPK signaling both in vitro and in vivo.