Safety, tolerability, pharmacokinetics, and pharmacodynamics of the afucosylated, humanized anti-EPHA2 antibody DS-8895a: a first-in-human phase I dose escalation and dose expansion study in patients with advanced solid tumors

BACKGROUND:Erythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface in many cancers and predicts poor prognosis. DS-8895a is a humanized anti-EPHA2 IgG1 monoclonal antibody afucosylated to enhance antibody-dependent cellular cytotoxicity activity. We conducted a two-step, phase I, multicenter, open-label study to determine the safety, tolerability, and pharmacokinetics of DS-8895a in patients with advanced solid tumors.METHODS:Step 1 was a dose escalation cohort in advanced solid tumor patients (six dose levels, 0.1-20 mg/kg) to determine Step 2 dosing. Step 2 was a dose expansion cohort in EPHA2-positive esophageal and gastric cancer patients. DS-8895a was intravenously administered every 2 weeks for the duration of the study, with a 28-day period to assess dose-limiting toxicity (DLT). Safety, pharmacokinetics, tumor response, and potential biomarkers were evaluated.RESULTS:Thirty-seven patients (Step 1: 22, Step 2: 15 [9: gastric cancer, 6: esophageal cancer]) were enrolled. Although one DLT (Grade 4 platelet count decreased) was observed in Step 1 (dose level 6, 20 mg/kg), the maximum tolerated dose was not reached; the highest dose (20 mg/kg) was used in Step 2. Of the 37 patients, 24 (64.9%) experienced drug-related adverse events (AEs) including three (8.1%) with Grade ≥ 3 AEs. Infusion-related reactions occurred in 19 patients (51.4%) but were manageable. All patients discontinued the study (evident disease progression, 33; AEs, 4). Maximum and trough serum DS-8895a concentrations increased dose-dependently. One gastric cancer patient achieved partial response and 13 patients achieved stable disease. Serum inflammatory cytokines transiently increased at completion of and 4 h after the start of DS-8895a administration. The proportion of CD16-positive natural killer (NK) cells (CD3-CD56+CD16+) decreased 4 h after the start of DS-8895a administration, and the ratio of CD3-CD56+CD137+ to CD3-CD56+CD16+ cells increased on day 3.CONCLUSIONS:Twenty mg/kg DS-8895a infused intravenously every 2 weeks was generally safe and well tolerated in patients (n = 21) with advanced solid tumors. The exposure of DS-8895a seemed to increase dose-dependently and induce activated NK cells

電子メディア教材における画質高度化の必要性について : 高品位映像教材の開発について(その1)

We examined the difference of the effects of different format video media to the human brain function by means of brain electric activity measuring method we have developed. As the visual materials for evaluation, three materials recorded by high definition (HD) video format, which has the highest visual quality now in practical use, were chosen and edited to the test pieces. Subsequently, they were down-converted to NTSC video format. On the presentation of visual images, we set three sound condition ; the music rich in natural high frequency components above the audible range (full-range sound), the same sound but from which high frequency components above 26kHz were eliminated (high-cut sound), and no sound. As a resullt, when the HD video were presented, the average of α-EEG (electroence-phalogram) potentials were significantly higher than NTSC video (p<0.05, post hoc test with Fisher\u27s PLSD). When we used the video of natural materials, the difference of a-EEG potential between HD presentation and NTSC presentation showed statistically significance. Although no significant difference in α-EEG was observed by using the more artificial visual material. When the video were presented with full-range sound, the average of α-EEG potential were significantly higher than the presentation with high-cut sound as well as no sound. These results showed that the quality of electric visual information could be evaluated by the α-EEG potential, which is the physiological and quantitative index of brain activity. It was also suggested that the improvement of the audio-visual format would be effective for the higher education

放送大学におけるデジタル・リテラシー教育の展開と成果

　放送大学では、自宅や職場で学習する多様な学生のニーズに応えるため、Webによる授業配信、オンライン履修登録、電子図書館サービスを含むICTを活用した学生サービスを提供しているが、十分な利用には至っていない。これは、放送大学にパソコンやインターネットの利用経験が少ない高齢学生が在籍するためだと思われる。そこで、学生によるICT環境の学習への活用を促進しWebを通じた学習の機会を拡張すべく、面接授業「初歩からのパソコン」を2010年度２学期から全国50箇所の学習センターで毎年少なくとも年１回開設し、共通シラバス、共通テキストを用いた実習を含む12時間の集中授業を、アシスタントの協力を得て本部教員が担当した。FDセミナーや実践報告の共有を含むPDCAサイクルを通じた教材と授業内容の改訂により、授業改善を行ってきた。各学生の学習目標の達成度と自己効力感を測るため、事前・事後に記入してもらったチェックリストによる学習効果を測定した結果、一定の学習効果が認められた。また、事前に記入してもらったチェックリストを年齢により比較した結果、高齢学生のICTスキルが低い傾向が認められた。この授業の受講を希望する学生が許容できる人数を超えたことにより、年に複数回開設して学習センターの非常勤講師が担当するケースも生じている。また、本部教員が地域に学習共同体を構築するのが困難なことにより、2013年２学期以降は主に各学習センターの非常勤講師がこの授業を担当している

放送大学におけるデジタル・リテラシー教育 : 習得スキルの定着

　本研究は、面接授業「初歩からのパソコン」の受講で習得した放送大学生のデジタル・リテラシー・スキル（以下「DLスキル」）の定着状況把握を目的に実施した。この授業を2010年度２学期から2013年度１学期の間に受講した在学生に2013年11月に郵送アンケートを実施した。調査結果は、DLスキルの種類により、定着したもの、低下したもの、向上したものがあること、DLスキルの定着には、受講生の年齢、受講生のパソコン・インターネットの利用頻度が影響を及ぼしていること、DLスキルの向上とパソコン・インターネット利用頻度の間に相関があること、DLスキルの定着には、受講生のその後の学習方法が影響を及ぼしていることを示した。受講直後から本調査の期間に低下したDLスキルについて、授業後のスキル活用の機会を増加させる必要性が示唆された。また、定着効果のあるテレビ授業「遠隔学習のためのパソコン活用」の受講と同好会等への参加を促す必要性が示唆された

Changing patterns of perceived ICT skill levels of elderly learners in a digital literacy training course

Background. In 2010, the Open University of Japan began offering a one-semester face-to-face digital literacy (DL) training course at each of its 50 study centers to help elderly students use personal computers (PC) and the Internet for study. A series of checklists was completed by students before and after each DL training course to assess their achievement. Objectives. This study identified the degree to which students’ perceived information and communication technology (ICT) skills had changed one to three years after completion of the DL training course. It revealed which skills were retained and which skills declined. Methods. A survey questionnaire was sent to 2,112 students who took the DL training course and we received 1,153 responses. Questions focused on students’ daily use of a PC and the Internet, and opportunities to learn DL skills after the training course. The same items were used in a checklist to assess ICT skills, and the two sets of data were compared to identify the level of retention of 18 ICT skills. Results. Overall, scores for 16 of the 18 ICT skills declined. It was found that students who used a PC and the Internet more frequently and those who continued learning by self-instruction or peer learning in the community retained their ICT skills. Contributions. Visualization of changing patterns in ICT skills helped identify insufficient elements of the DL training course. This information is useful in refining course content and in planning post-course support for DL training attendees.Published versio

Frequencies of Inaudible High-Frequency Sounds Differentially Affect Brain Activity: Positive and Negative Hypersonic Effects

<div><p>The hypersonic effect is a phenomenon in which sounds containing significant quantities of non-stationary high-frequency components (HFCs) above the human audible range (max. 20 kHz) activate the midbrain and diencephalon and evoke various physiological, psychological and behavioral responses. Yet important issues remain unverified, especially the relationship existing between the frequency of HFCs and the emergence of the hypersonic effect.</p><p>In this study, to investigate the relationship between the hypersonic effect and HFC frequencies, we divided an HFC (above 16 kHz) of recorded gamelan music into 12 band components and applied them to subjects along with an audible component (below 16 kHz) to observe changes in the alpha2 frequency component (10–13 Hz) of spontaneous EEGs measured from centro-parieto-occipital regions (Alpha-2 EEG), which we previously reported as an index of the hypersonic effect.</p><p>Our results showed reciprocal directional changes in Alpha-2 EEGs depending on the frequency of the HFCs presented with audible low-frequency component (LFC). When an HFC above approximately 32 kHz was applied, Alpha-2 EEG increased significantly compared to when only audible sound was applied (positive hypersonic effect), while, when an HFC below approximately 32 kHz was applied, the Alpha-2 EEG decreased (negative hypersonic effect). These findings suggest that the emergence of the hypersonic effect depends on the frequencies of inaudible HFC.</p></div

Results of Experiment 2: detailed examinations of frequency dependency of the hypersonic effect.

<p>A: Mean (+SE) values of ΔAlpha-2 EEG across the subjects in each of twelve sub-experiments. The frequencies indicate the frequency range of HFC that were applied together with LFC ([LFC+HFC]) in comparison with the control ([LFC] alone). ΔAlpha-2 EEG is calculated by subtracting Alpha-2 EEG obtained during [LFC] from those during [LFC+HFC] in each subject. Univariate ANOVA showed the main effect of the frequency of HFC (<i>p</i><0.05). Tukey's post-hoc tests showed a significant difference between ΔAlpha-2 EEG obtained with [LFC+HFC_16-24] and that obtained with [LFC+HFC_80–88] (<i>p</i><0.05). B: Comparison of ΔAlpha-2 EEG between two groups of pooled data obtained in the sub-experiments using HFC below 32 kHz and those obtained in the sub-experiments using HFC above 32 kHz. Unpaired t-tests showed significant difference between the two groups and 1-sampled t-tests showed significant difference from zero for each group, that is, ΔAlpha-2 EEG obtained by using HFC below 32 kHz was significantly negative (<i>p</i><0.01), while those obtained by using HFC above 32 kHz was significantly positive (<i>p</i><0.001).</p

Results of Experiment 1: broad examination of frequency dependency of the hypersonic effect.

<p>A: Scalp distribution of electroencephalographic activity during application of different HFC frequencies. To overview the spatial distribution of the equivalent potential of alpha2 frequency band (10–13 Hz) of EEGs, colored contour line maps were constructed by using 2,565 scalp grid points computed by linear interpolation and extrapolation of alpha2 components from 12 electrodes <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095464#pone.0095464-Ueno1" target="_blank">[33]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095464#pone.0095464-Duffy1" target="_blank">[34]</a>. Darker red indicates higher alpha2. Note that the alpha2 in the occipital region changed depending on the frequency of the HFC. B: Mean (+SE) value of Alpha-2 EEGs. Potential of alpha2 frequency band recorded from 7 electrodes in the centro-parieto-occipital region (C3, C4, T5, Pz, T6, O1 and O2) for the last 100 sec of sound application was averaged across all subjects. Analysis of variance (ANOVA) revealed the main effect of HFC to be significant, and Tukey's post-hoc test found significant difference between [LFC+HFC_16-48] and [LFC+HFC_48<].</p