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Background/Aim: Pemetrexed (PEM) and bevacizumab (BEV) are commonly used in combination as second or subsequent line regimens and maintenance therapy after platinum + PEM + BEV therapy for advanced non-small cell lung cancer (NSCLC). Median progression-free survival (PFS) for PEM + BEV has been reported to be less than six months in both clinical trials and clinical practice, but in clinical practice, we found that some patients demonstrate long-term PFS. Furthermore, there is a paucity of clinical practice data on whether long-term administration of PEM + BEV causes renal dysfunction. This study aimed to clarify these aspects in clinical practice. Patients and Methods: A retrospective review of patients with advanced NSCLC treated with PEM + BEV between September 2011 and June 2022 at four hospitals was conducted. Long-term PFS in PEM + BEV therapy was defined as ≥12 months. Results: During the study period, 109 patients received PEM + BEV treatment. Of them, 42 (38.5%) achieved long-term PFS ≥12 months. No significant differences in patient characteristics were found between patients with PFS ≥12 months and

BackgroundHepatocellular carcinoma (HCC) is a worldwide health concern because of a continued increase in cases globally; furthermore, the prognosis for patients with HCC remains poor. Transarterial chemoembolization (TACE) has been established as the standard of care for the intermediate stage of HCC; however, no therapeutic agents are available to reduce the high rate of recurrence. ObjectiveThis study aims to evaluate the safety of alpha-fetoprotein (AFP)-derived peptides for patients with HCC post-TACE. MethodsThis will be an open-label, single-arm, multicenter study to evaluate the safety of AFP-derived peptides (AFP 357 and AFP 403), which contain histocompatibility antigen-A24-restricted cytotoxic T lymphocyte epitopes from tumor antigens expressed in HCC and is recognized at a high rate by lymphocytes in patients with HCC. Protocol treatment will consist of six courses of the subcutaneous administration of 3 mg each of AFP 357 and AFP 403. A total of 14 patients will be included in this study, the first 6 as a main analysis target group and an additional 8 as an extended cohort from three institutions in Japan. The primary endpoint will be the occurrence of serious adverse events (safety profile). The secondary endpoints will include time to progression, overall survival, completion rate, and adverse events (efficacy profile). ResultsWe have recruited 14 patients with HCC as of December 2019. The final follow-up will be completed by March 2020. ConclusionsIn this study, we will evaluate the safety profile of AFP-derived peptides for patients with HCC post-TACE. We believe that this study will provide useful information and will help to design a subsequent phase II trial based on the results. Trial RegistrationJapan Registry of Clinical Trials jRCTs041180155; https://jrct.niph.go.jp/latest-detail/jRCTs041180155 International Registered Report Identifier (IRRID)DERR1-10.2196/17082

IMPORTANCE: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. OBJECTIVE: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). DESIGN, SETTING, AND PARTICIPANTS: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. EXPOSURES: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. MAIN OUTCOMES AND MEASURES: Circulating lipid levels and CAD. RESULTS: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. CONCLUSIONS AND RELEVANCE: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.

This is the first report in which crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, reduced an atypical carcinoid tumor with ALK rearrangement. A 70-year-old man developed a tumor in the left lung and multiple metastases to the lung and brain. The pathology of transbronchial biopsied specimens demonstrated an atypical carcinoid pattern. Combined with immunohistochemical findings, we diagnosed the tumor as atypical carcinoid. ALK gene rearrangement was observed by both immunohistochemical (IHC) and fluorescence in situ hybridization. He was treated with chemotherapy as first-line therapy, however, the tumor did not respond to chemotherapy. Thereafter, he was treated with crizotinib, which successfully reduced the tumors.

Rationale: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. Objective: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. Methods and Results: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P

Background Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose–response curve of target perturbation. Objectives The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose–response curve between genetically altered plasma Lp(a) and risk for CHD. Methods We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. Results One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. Conclusions Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.

Background: Tobacco is a major public health concern. A 12-week standard smoking cessation program is available in Japan; however, it requires face-to-face clinic visits, which has been one of the key obstacles to completing the program, leading to a low smoking cessation success rate. Telemedicine using internet-based video counseling instead of regular clinic visits could address this obstacle. Objective: This study aimed to evaluate the efficacy and feasibility of an internet-based remote smoking cessation support program compared with the standard face-to-face clinical visit program among patients with nicotine dependence. Methods: This study was a randomized, controlled, open-label, multicenter, noninferiority trial. We recruited nicotine-dependent adults from March to June 2018. Participants randomized to the telemedicine arm received internet-based video counseling, whereas control participants received standard face-to-face clinic visits at each time point in the smoking cessation program. Both arms received a CureApp Smoking Cessation smartphone app with a mobile exhaled carbon monoxide checker. The primary outcome was a continuous abstinence rate (CAR) from weeks 9 to 12. Full analysis set was used for data analysis. Results: We randomized 115 participants with nicotine dependence: 58 were allocated to the telemedicine (internet-based video counseling) arm and 57, to the control (standard face-to-face clinical visit) arm. We analyzed all 115 participants for the primary outcome. Both telemedicine and control groups had similar CARs from weeks 9 to 12 (81.0% vs 78.9%; absolute difference, 2.1%; 95% CI –12.8 to 17.0), and the lower limit of the difference between groups (–12.8%) was greater than the prespecified limit (–15%). Conclusions: The application of telemedicine using internet-based video counseling as a smoking cessation program had a similar CAR from weeks 9 to 12 as that of the standard face-to-face clinical visit program. The efficacy of the telemedicine-based smoking cessation program was not inferior to that of the standard visit–based smoking cessation program. Trial Registration: University Hospital Medical Information Network Clinical Trials Registry: UMIN000031620; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000035975.

In modern supercomputer architectures, thousands of compute nodes can share a dedicated file I/O server. Recent research has shown I/O can become the performance bottleneck due to large number of simultaneous I/O accesses, in particular, file writes. While methods to tackle I/O performance issues for parallel applications have been extensively studied, not much is known about how co-located I/O-intensive applications interfere each other's performance. In this study, we present a novel approach that uses a lightweight profiling tool to capture concurrent applications' competing behaviors. By comparing all application I/O performance profiles during their overlapped runtime, we are able to figure out the underlying reason to unbalanced write throughput when applications of different sizes run side by side, which is then proved to be useful in building performance models in a concurrent execution environment.

次世代スーパーコンピュータの開発に向けて実アプリケーション本位でのシステムデザインを行うためには，アーキテクチャと実アプリケーション実行性能を結びつける標準ベンチマークやパフォーマンスモデルが必要となるが，そのようなものはいまだ実現されていない．本報告では，将来 HPCI システムのあり方の調査研究 「アプリケーション分野」 におけるシステム評価用ベンチマークと性能モデルの作成について紹介する．本研究では，実アプリケーションコードの提供を受けてコードを単純化した 「ミニアプリ」 を作成し，ベンチマーク・性能モデルの基礎とする．また，複数の HPCI システム上で動作する性能評価ツールを用いてベンチマーク結果を収集し，性能モデルを構築するための基礎データとするとともに，性能モデルの構築方法・表現形式について考察する．

Remote GPU execution has been proven to increase GPU occupancy and reduce job waiting time in multi-GPU batch-queue systems, by allowing jobs to utilize remote GPUs when there are not enough unoccupied local GPUs available. However, for GPU communication intensive applications, remote GPU communication overhead may account for more than 70% of the applications' execution times. The need for using a remote GPU exists when there are not enough local GPUs available on a node assigned to the job, but a local GPU could become available afterward. We propose mrCUDA, a middleware for migrating execution on a remote GPU to a local GPU on-demand. Our evaluation shows that for long-running jobs mrCUDA overhead accounts for less than 1% of their total execution times. In addition, by applying mrCUDA to the first-come-first-serve (FCFS) job scheduling algorithm, we could reduce job lifetimes (waiting + execution times) as much as 30% on average without changing the scheduling policy.

高性能計算機の規模は年々大きくなっている．大規模化に伴う故障率の増加により，Silent Data Corruption (SDC) と呼ばれる問題が深刻になると予想されている．SDC はアプリケーションが異常な結果を出力するが，停止には至らないため計算結果の誤りを検知できない障害である．SDC に対処するため多くの研究が行われたが，計算機の変化とともに故障の種類や発生傾向も変化しており，新たな耐故障手法が求められている．本研究は連続したメモリデータの破壊または複数のビットエラーが DRAM 上に発生した際に，NAS Parallel Benchmark の CG カーネルに現れる SDC の調査を目的とする．またそのために，DRAM に特定の故障パターンを注入する故障発生器を，仮想マシンエミュレータである QEMU を拡張して作成した．これにより，SDC が発生しうること，アプリケーションの特性により SDC の発生割合が約 5%減少することを確認した．また連続したデータ破壊が発生したとき，アプリケーションは約 80%の割合で正常な結果を返すが，同じビット数のビットエラーを注入した際には約 90%の割合で異常終了することを確認した．

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals fromstudies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2×10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3× 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7× 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in exvivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8× 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8× 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

The aim of this paper is to examine about the lesson construction for enhancing the learning motivation through analyzing teaching practices by excellent elementary teachers. The result of analyzing is the following three. 1) Teacher must develop the lesson plan for enhancing the learning motivation. Because, this is one of the objectives and important goal of self- learning in classroom. 2) Teacher need to prepare the instructional material and questions for enhancing the learning motivation in classroom lesson. 3) In the lesson, teacher must make the learning environment and cooperative formation and activities by children.

我々は既に MPI 3.0 において規格化される予定の非ブロッキング集団通信を高速に実行する手法 KACC を提案した．KACC は集団通信の進捗処理を OS カーネル上に実装することによって，従来手法では問題となっていたオーバヘッドの問題と実行タイミングの問題を解決している．本報告では，KACC が OS カーネル上に進捗処理を実装することに起因する負荷分散に関する問題点と，その解決法を示す．KACC のテスト実装において CPU 時間の消費および通信アルゴリズムの実行時間の 2 点について従来手法と比較し，解決法の妥当性を評価する．We have proposed a new method, called KACC, to execute non-blocking collective communications, which will be introduced in MPI 3.0, efficiently. KACC resolves overhead and timing problems in former methods by implementing progression of collective communications in the OS kernel. In this paper, we describe the load-balancing problem, which is caused by implementing progression in OS kernel, and its solution. We evaluate CPU time consumption and execution time of collective communications among several implementations.

ジョブのメモリおよびネットワーク負荷の統計情報があらかじめ取得されているジョブ群において、 NUMA 並列型クラスタ上での効率的なバッチジョブスケジューリング手法を提案する。本提案手法では、単純なメモリや I/O のリクエスト数をスケジューリング指標とする代わりに、同時実行したメモリ、 I/O アクセスを行うベンチマークの速度低下を指標として用いる。 NAS Parallel Benchmarks タスクセットでは、従来手法より良いスケジューリングを行うことができることを確認した。We propose a new algorithm to schedule jobs on a cluster of NUMA machines. Instead of using simple memory or I/O request rate as the scheduling metrics, we use degradation of performance rate in memory and I/O benchmarks concurrently executed with the task as an indicator. We confirm the proposed scheduler using the NAS Parallel Benchmarks.

MPI 通信ライブラリの実装の一つである YAMPI を最新の低遅延ネットワークに対応させるため、効率的な通信インタフェースの設計と実装の最適化を行った。新しい通信インタフェースは Myrinet-10G の MX 通信ライブラリに代表されるようなマッチング機構を持った通信デバイスを効率的に扱うことが可能である。また、実装の最適化としては通信状態の管理を行うオブジェクトの確保と解放を高速化し、送受信に必要な命令実行数を削減した。性能評価では最適化によって通信遅延が 1.5 から 1.7 マイクロ秒削減されたことが示された。アプリケーションベンチマークでは最大 4.6% の高速化を達成した一方、まったく効果のないアプリケーションもあった。An implementation called YAMPI is optimized in order to adopt high-speed interconnects, such as Myrinet-10G. We design a new efficient communication interface for the Myrinet network and the overall implementation of YAMPI is optimized by reducing the overhead to allocate and deallocate objects that keeps the statuses of outstanding communication. Results of performance evaluation show that communication latency is reduced by 1.5 to 1.7 microseconds and application benchmarks run faster at most by 4.6%, while some benchmarks show that our optimization has no effect to performance of these benchmarks.

通信パターンによるバンド幅の変化及びパケット再送の遅延を考慮した新しい通信モデル PlogP-BR を提案する．PlogPモデルを拡張し，再送タイムアウトによる遅延とスイッチ内のボトルネックリンクによるバンド幅低下に対応させる．このことによりボトルネックがある通信路や再送制御プロトコルによる遅延が入る通信路でのアルゴリズム実行時間を予測できるようになる．複数のアルゴリズムについて PlogP-BR モデルによる実行時間予測と実際の実行時間を比較することによって，このモデルが従来のモデルよりもより正確に通信の振る舞いを模倣できることを示す．We propose the PlogP-BR communication model which considers the variation of bandwidth brought by communication pattern and the delay of packet retransmission. PlogP model is extended so that it can treat the delay brought by retransmission timeout and bandwidth decreasing caused by bottleneck link in the switch. Execution time is be predicted in the network with bottleneck link or in the network with delay by retransmission control protocol. We show the PlogP-BR model can simulate the behavior of communication more collect than the existing model, by comparing between the expected time based on the model and actual execution time for several algorithms in practice.

In heterogeneous supercomputers such as TSUBAME2.5, GPUs on some nodes in GPU batch queues are left idle even though there are jobs waiting in the queues, this is caused by GPU resource-assignment fragmentation problem. For example, in the case that each node has three GPUs like TSUBAME2.5's, if a node has already been assigned to a job requesting two GPUs per node, that node cannot be assigned to another job requesting more than one GPU per node until the ongoing job finishes, hence, one GPU is left idle on that node. We examine this problem on TSUBAME2.5's GPU batch-queue system and present a scheduling algorithm that assigns rCUDA (a remote CUDA execution technology) to some processes of some jobs. Because rCUDA allows jobs to utilize the idle GPUs, the proposed scheduling algorithm can alleviate the problem. Using a job pattern obtained from a scheduler log of a TSUBAME2.5's GPU queue, our simulation shows that the proposed algorithm can decrease jobs' lifetime (from the time when a job arrives until finishes) by about 5% on average. Moreover, it can reduce the average number of idle GPUs by about 15%. Also, even reducing the number of nodes serving jobs by around 4%, the proposed algorithm can maintain the average jobs' lifetime around the same as the scheduling algorithm currently used in the TSUBAME2.5's GPU queue.

時間制約のあるタスク間の通信の制御について、各メッセージパケット毎に時間制約情報を付加してパケット配送時間をカーネルに明示して保障する方法を提案する。カーネル内で各パケットの送信時間を算出してそれらの時間制約を満たすように送信順序を調整して送出する。これらにより通信の中で起こる優先度逆転現象を解決する。上記機構をLinux上のQdisc（キューイング規則）を用いて実装する。様々な時間制約を持つパケットを混在させた環境でもそれぞれの時間制約を満たす通信が行われることを示す。In the control of communication between tasks whose packet's delivery time has deadline, we propose a new method, telling the delivery time information of each packet to kernel to make these deadline constraints be satisfied. The transmission order is determined based on the delivery time. In this mechanism, the priority inversion problem is resolved in the transmission queue. This mechanism is implemented in Linux using the Qdisc (queuing discipline) framework. We show that the communication is done with various deadline constraints satisfied.