Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study) : A multicentre, open-label, dose-escalation phase 1 trial

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of motor neurons, and development of effective medicines is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified the Src/c-Abl inhibitor bosutinib, which is approved for the treatment of chronic myelogenous leukemia (CML), as a candidate for the molecular targeted therapy of ALS. Methods: An open-label, multicentre, dose-escalation phase 1 study using a 3 + 3 design was conducted in 4 hospitals in Japan to evaluate the safety and tolerability of bosutinib in patients with ALS. Furthermore, the exploratory efficacy was evaluated using Revised ALS Functional Rating Scale (ALSFRS-R), predictive biomarkers including plasma neurofilament light chain (NFL) were explored, and single-cell RNA sequencing of iPSC-derived motor neurons was conducted. Patients, whose total ALSFRS-R scores decreased by 1–3 points during the 12 week, received escalating doses starting from 100 mg quaque die (QD) up to 400 mg QD based on dose-limiting toxicity (DLT) occurrence, and all participants who received one dose of the study drug were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT04744532, as Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic Lateral Sclerosis Medicine (iDReAM) study. Findings: Between March 29, 2019 and May 7, 2021, 20 patients were enrolled, 13 of whom received bosutinib treatment and 12 were included in the safety and efficacy analyses. No DLTs were observed up to 300 mg QD, but DLTs were observed in 3/3 patients of the 400 mg QD cohort. In all patients receiving 100 mg–400 mg, the prevalent adverse events (AEs) were gastrointestinal AEs in 12 patients (92.3%), liver function related AEs in 7 patients (53.8%), and rash in 3 patients (23.1%). The safety profile was consistent with that known for CML treatment, and ALS-specific AEs were not observed. A subset of patients (5/9 patients) was found to respond well to bosutinib treatment over the 12-week treatment period. It was found that the treatment-responsive patients could be distinguished by their lower levels of plasma NFL. Furthermore, single-cell RNA sequencing of iPSC-derived motor neurons revealed the pathogenesis related molecular signature in patients with ALS showing responsiveness to bosutinib. Interpretation: This is the first trial of a Src/c-Abl inhibitor, bosutinib, for patients with ALS. The safety and tolerability of bosutinib up to 300 mg, not 400 mg, in ALS were described, and responsiveness of patients on motor function was observed. Since this was an open-label trial within a short period with a limited number of patients, further clinical trials will be required

Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial

筋萎縮性側索硬化症（ALS）患者さんを対象とした ボスチニブ第1相試験；iDReAM試験の成果報告 （論文発表）. 京都大学プレスリリース. 2022-10-26.Phase I clinical trial of bosutinib for amyotrophic lateral sclerosis (ALS); iDReAM study. 京都大学プレスリリース. 2022-11-28.[Background] Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of motor neurons, and development of effective medicines is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified the Src/c-Abl inhibitor bosutinib, which is approved for the treatment of chronic myelogenous leukemia (CML), as a candidate for the molecular targeted therapy of ALS. [Methods] An open-label, multicentre, dose-escalation phase 1 study using a 3 + 3 design was conducted in 4 hospitals in Japan to evaluate the safety and tolerability of bosutinib in patients with ALS. Furthermore, the exploratory efficacy was evaluated using Revised ALS Functional Rating Scale (ALSFRS-R), predictive biomarkers including plasma neurofilament light chain (NFL) were explored, and single-cell RNA sequencing of iPSC-derived motor neurons was conducted. Patients, whose total ALSFRS-R scores decreased by 1–3 points during the 12-week, received escalating doses starting from 100 mg quaque die (QD) up to 400 mg QD based on dose-limiting toxicity (DLT) occurrence, and all participants who received one dose of the study drug were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT04744532, as Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic Lateral Sclerosis Medicine (iDReAM) study. [Findings] Between March 29, 2019 and May 7, 2021, 20 patients were enrolled, 13 of whom received bosutinib treatment and 12 were included in the safety and efficacy analyses. No DLTs were observed up to 300 mg QD, but DLTs were observed in 3/3 patients of the 400 mg QD cohort. In all patients receiving 100 mg–400 mg, the prevalent adverse events (AEs) were gastrointestinal AEs in 12 patients (92.3%), liver function related AEs in 7 patients (53.8%), and rash in 3 patients (23.1%). The safety profile was consistent with that known for CML treatment, and ALS-specific AEs were not observed. A subset of patients (5/9 patients) was found to respond well to bosutinib treatment over the 12-week treatment period. It was found that the treatment-responsive patients could be distinguished by their lower levels of plasma NFL. Furthermore, single-cell RNA sequencing of iPSC-derived motor neurons revealed the pathogenesis related molecular signature in patients with ALS showing responsiveness to bosutinib. [Interpretation] This is the first trial of a Src/c-Abl inhibitor, bosutinib, for patients with ALS. The safety and tolerability of bosutinib up to 300 mg, not 400 mg, in ALS were described, and responsiveness of patients on motor function was observed. Since this was an open-label trial within a short period with a limited number of patients, further clinical trials will be required

Relationship Between Mobile Device Use and Self-Regulation in Early Childhood : Examination by Nursery School Survey

本研究の目的は，幼少期の子どものモバイル端末利用と自己制御の関連を検討することであった。自己制御は，気質的側面であり子どもの養育者によって測定されるエフォートフル・コントロール（EC）と，認知的側面であり子どもへの課題の実施によって測定される実行機能の2つの観点から捉え，モバイル端末利用頻度や利用規則との相関係数を算出した。その結果，幼少期の子どものモバイル端末利用頻度は，自己制御の低さと関連することが示された。This study examined whether mobile device use was associated with self-regulation in early childhood. Self-regulation was assessed by two aspects: effortful control (i.e., a temperamental aspect and evaluated by the caregiver) and executive function, (i.e., a cognitive aspect and measured by performing tasks on children). We calculated the correlation coefficient between mobile device use and self-regulation. We found that the frequency of mobile device use was associated with lower levels of executive function among infants

Relationship Between Mobile Device Use and Self-Regulation in Early Childhood : Examination by Internet and Nursery School Surveys

本研究の目的は，幼少期の子どものモバイル端末利用と自己制御の関連を検討することであった。研究1ではインターネット調査，研究2では保育園調査を実施した。自己制御を，気質的側面であり養育者により評定がなされるエフォートフル・コントロール（EC）と，認知的側面であり子どもへの課題の実施により測定される実行機能の2側面からとらえ，モバイル端末利用頻度や利用規則との相関係数を算出した。その結果，幼少期の子どものモバイル端末利用頻度は自己制御の低さと関連がある一方で，利用規則は自己制御の高さと関連していた。幼少期の子どものモバイル端末利用について，自己制御の観点からも長時間利用を避けることや利用規則を設けることの重要性が示唆された。The purpose of this study was to examine whether mobile device use was associated with self-regulation in early childhood.Study 1 was an internet survey and Study 2 was a nursery school survey. Self-regulation was examined in two aspects:effortful control (EC), which is a temperamental aspect and evaluated by the caregiver, and executive function, which is a cognitive aspect and measured by performing tasks on children. We calculated the correlation coefficient between mobile device use and self-regulation. In our results, the frequency of mobile device use by children in early childhood was associated with low self-regulation, while usage rules were associated with high self-regulation. In other words, it was suggested that it is important to avoid long-term use and to establish rules for mobile device use among young children from the viewpoint of self-regulation

心理学科における高等学校公民の教科教育

高等学校の教員免許状は教科毎の免許状となる。教員を目指す者は、教員の免許状授与の所要資格を得させるための大学の課程（以後、「教職課程」と略す）において、教育職員免許法及び教育職員免許法施行規則の定める科目を履修しなければならない。すなわち、「教科に関する科目」「教科又は教職に関する科目」「教職に関する科目」より必要な単位数を取得する必要がある。本稿では、「教科に関する科目」に注目し、久留米大学文学部心理学科の高等学校公民の教員養成における「教科に関する科目」のあり方について検討し、2018年度からのカリキュラムの見直しについて報告する

Effects of infection by Turnip mosaic virus on the population growth of generalist and specialist aphid vectors on turnip plants.

Recent studies have revealed that relationships between plant pathogens and their vectors differ depending on species, strains and associated host plants. Turnip mosaic virus (TuMV) is one of the most important plant viruses worldwide and is transmitted by at least 89 aphid species in a non-persistent manner. TuMV is fundamentally divided into six phylogenetic groups; among which Asian-BR, basal-BR and world-B groups are known to occur in Japan. In Kyushu Japan, basal-BR has invaded approximately 2000 and immediately replaced the predominant world-B virus group. To clarify the relationships between TuMV and vector aphids, we examined the effects of the TuMV phylogenetic group on the population growth of aphid vectors in turnip plants. The population growth of a generalist aphid, Myzus persicae, was not significantly different between non-infected and TuMV-infected treatments. The population growth of a specialist aphid, Lipaphis erysimi, was higher in TuMV-infected plants than non-infected ones. Similar results were obtained in experiments using world-B and basal-BR groups of TuMV. Therefore, we conclude that L. erysimi is more mutualistic with TuMV than M. persicae, and differences in TuMV phylogenetic groups do not affect the growth of aphid vectors on turnip plants

Suzaku observations of γ\gamma-ray bright radio galaxies : origin of the X-ray emission and broadband modeling

We performed a systematic X-ray study of eight nearby $\gamma$-ray bright radio galaxies with Suzaku in order to understand the origins of their X-ray emissions. The Suzaku spectra for five of those have been presented previously, while the remaining three (M87, PKS 0625–354, and 3C 78) are presented here for the first time. Based on the Fe-K line strength, X-ray variability, and X-ray power-law photon indices, and using additional information on the [O III] line emission, we argue for a jet origin of the observed X-ray emission in these three sources. We also analyzed five years of Fermi Large Area Telescope (LAT) GeV gamma-ray data on PKS 0625–354 and 3C 78 to understand these sources within the blazar paradigm. We found significant $\gamma$-ray variability in the former object. Overall, we note that the Suzaku spectra for both PKS 0625–354 and 3C 78 are rather soft, while the LAT spectra are unusually hard when compared with other $\gamma$-ray detected low-power (FR I) radio galaxies. We demonstrate that the constructed broadband spectral energy distributions of PKS 0625–354 and 3C 78 are well described by a one-zone synchrotron/synchrotron self-Compton model. The results of the modeling indicate lower bulk Lorentz factors compared to those typically found in other BL Lacertae (BL Lac) objects, but consistent with the values inferred from modeling other LAT-detected FR I radio galaxies. Interestingly, the modeling also implies very high peak ( $\sim 10^{16}Hz$) synchrotron frequencies in the two analyzed sources, contrary to previously suggested scenarios for Fanaroff-Riley (FR) type I/BL Lac unification. We discuss the implications of our findings in the context of the FR I/BL Lac unification schemes