体内無給電型人工心臓駆動用磁気式アクチュエータの性能向上

研究種目:科学研究費補助金基盤研究(C)報告年度:2001年度研究課題番号:11650280研究概要:本研究は,平成11年度から3カ年に亘って遂行したものであり,平成13年度は,以下の研究業績を得た。1.アクチュエータ出力向上を目的とした磁石ヨークの検討本アクチュエータの機構上,金属磁石に隣接させるヨークの磁化特性がアクチュエータの磁気力を左右させ,その結果としてこれがアクチュエータ出力を決定する要因の一つとなっており,珪素鋼鈑を含む複数のヨークに対して,最もアクチュエータ出力が得られるヨークを決定した。ヨーク厚としては,1.6mmから6mmまでを検討した。また,ヨークの体積軽減を図り,アクチュエータの軽量化実現のため,金属磁石ヨークを空洞化して,その内径について検討した。シミュレーションにより金属磁石間に働く磁力を計算し,シリンダ行程を最大限取れるヨーク厚およびヨーク内径を求めた。2.アクチュエータ出力向上を目的とした構造設計法の確立アクチュエータによって駆動されるポンプのシリンダ行程およびシリンダへの電磁力仕様から,金属磁石の内径寸法を決定するアルゴリズムを構築した。本アクチュエータを人工心臓駆動用ポンプへ適用する場合を想定し,ヒトの循環器系の最高血圧からポンプの最大圧力出力を仕様として定め,一方,シリンダ行程の最大状態からポンプ動作が可能な磁石間距離を求めてこれもポンプ設計上の仕様と定めた。これらの仕様および金属磁石の磁化特性からポンプ出力を最大とするシリンダ行程および磁石間距離を定めるアルゴリズムを構築した

Detection of matrilysin (MMP-7) activity using polypeptide functionalized reduced graphene oxide field-effect transistor sensor.

A novel approach for rapid and sensitive detection of matrilysin (MMP-7, a biomarker involved in the degradation of vari-ous macromolecules) based on polypeptide (JR2EC) functionalized reduced graphene oxide (rGO) field effect transistor (FET) is reported. MMP-7 specifically digests negatively charged JR2EC immobilized on rGO, thereby modulating the con-ductance of rGO-FET. The proposed assay enabled detection of MMP-7 at clinically relevant concentrations with a limit of detection (LOD) of 10 ng/mL (400 pM), attributed to the significant reduction of the net charge of JR2EC upon digestion by MMP-7. Quantitative detection of MMP-7 in human plasma was further demonstrated with a LOD of 40 ng/mL, illustrating the potential for the proposed methodology for tumor detection and carcinoma diagnostic (e.g. lung cancer and salivary gland cancer). Additionally, excellent specificity of the proposed assay was demonstrated using matrix metallopeptidase 1 (MMP-1), a protease of the same family. With appropriate selection and modification of polypeptides, the proposed assay could be extended for detections of other enzymes with polypeptide digestion capability

Additional file 1 of Drug-target interaction prediction based on spatial consistency constraint and graph convolutional autoencoder

Additional file 1. Novel DTIs predicted by SDGAE.xlsx: it contains 30 candidate targets for all drugs in the dataset. The candidate targets for each drug are sorted in descending order according to their prediction scores

Curvature of the Localized Surface Plasmon Resonance Peak

Localized surface plasmon resonance (LSPR) occurring in noble metal nanoparticles (e.g., Au) is a widely used phenomenon to report molecular interactions. Traditional LSPR sensors typically monitor shifts in the peak position or extinction in response to local refractive index changes in the close vicinity of the nanoparticle surface. The ability to resolve minute shifts/extinction changes is to a large extent limited by instrumental noise. A new strategy to evaluate LSPR responses utilizing changes in the shape of the extinction spectrum (the curvature) is proposed. The response of curvature to refractive index changes is investigated theoretically using Mie theory and an analytical expression relating the curvature to the refractive index is presented. The experimentally derived curvatures for 13 nm spherical gold nanoparticles (AuNPs) exposed to solvents with different bulk refractive indices confirm the theoretical predictions. Moreover, both the calculated and experimental findings suggest that the curvature is approximately a linear function of refractive index in regimes relevant to bio and chemical sensing. We demonstrate that curvature is superior over peak shift and extinction both in terms of signal-to-noise (S/N) ratio and reliability of LSPR sensors. With a curvature, one could readily monitor submonolayer adsorption of a low molecular weight thiol molecule (<i>M</i>_w = 458.6) onto 13 nm AuNPs. It is also worthwhile mentioning that curvature is virtually insensitive to instrumental instabilities and artifacts occurring during measurement. Instabilities such as baseline tilt and shift, shift in peak position as well as sharp spikes/steps in the extinction spectra do not induce artifacts in the sensorgrams of curvature

Phosphine-Catalyzed Asymmetric Synthesis of α‑Quaternary Amine via Umpolung γ‑Addition of Ketimines to Allenoates

A first phosphine-catalyzed enantioselective umpolung γ-addition of ketimines to allenoates has been developed that provides efficient access to optically active γ,δ-unsaturated α-amino esters and δ-amino esters with a chiral tertiary stereocenter under mild conditions. The salient features of this reaction include general substrate scope, mild conditions, good yields, high enantioselectivity, ease of scale-up to gram scale, and further transformations

Distinguishing Direct and Indirect Photoelectrocatalytic Oxidation Mechanisms Using Quantitative Single-Molecule Reaction Imaging and Photocurrent Measurements

Light-driven semiconductor-catalyzed oxidation reactions are of fundamental importance in photocatalysis and photoelectrocatalysis for removing organic contaminants in wastewater, solar energy conversion, and fine chemical synthesis. The underlying reaction mechanism is often unclear because it is difficult to measure directly and specifically the semiconductor-catalyzed reaction rates. For example, an organic molecule could be oxidized “directly” by photogenerated holes that are transported from the semiconductor interior to the semiconductor–electrolyte interface or “indirectly” by photogenerated intermediates (e.g., hydroxyl radical, superoxide anion, or hydrogen peroxide) that are produced at the semiconductor surface in aqueous solution. New experimental approaches that can distinguish these pathways are thus desirable. Here we introduce quantitative single-molecule, single-particle fluorescence imaging to measure the photoelectrocatalytic oxidation rate of a model organic substrate, amplex red, on the surface of individual rutile TiO₂ nanorods. Our approach probes the oxidation product selectively before it becomes further degraded (which complicates bulk reaction kinetics measurements) while also avoiding interparticle charge transfer kinetics. By examining the reaction rate scaling relations versus light intensity at fixed potential and versus potential at fixed light intensity, together with the corresponding photocurrent scaling reactions, we demonstrate that amplex red oxidation on a TiO₂-nanorod photoanode proceeds via an indirect mechanism

Image1_First-line tremelimumab plus durvalumab and chemotherapy versus chemotherapy alone for metastatic non-small cell lung cancer: a cost-effectiveness analysis in the United States.pdf

Importance: In the open-label phase III POSEIDON randomized clinical trial (RCT), a limited course of tremelimumab plus durvalumab and chemotherapy (T + D + CT) indicated in the first-line treatment of metastatic non-small cell lung cancer (mNSCLC), progression-free survival, and overall survival (OS) were substantially improved without significant additional tolerance burden compared to chemotherapy (CT). However, given the high cost of T + D + CT, its value needs to be evaluated in terms of both potency and cost.Objective: To evaluate the cost-effectiveness of T + D + CT versus CT in individuals with previously untreated mNSCLC from a U.S. payer perspective.Design, setting, and participants: A three-state Markov model was adopted to weigh the lifetime costs and effectiveness of T + D + CT versus CT for the treatment of first-line mNSCLC, according to the results of the POSEIDON phase III RCT involving 675 individuals with mNSCLC. Individuals were simulated to undergo either T + D + CT for up to four 21-day cycles, followed by durvalumab once every 4 weeks until disease progression or unacceptable toxic effects and one additional tremelimumab dose, or CT for up to six 21-day cycles (with or without pemetrexed maintenance; all groups) in the analysis.Main outcomes and measures: Lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were evaluated with a willingness-to-pay (WTP) threshold of $100,000 to$ 150,000 per QALY. The uncertainty of the model was investigated using univariate and probabilistic sensitivity analysis.Results: T + D + CT produced additional 0.36 QALYs with additional costs of $217,694, compared to CT, giving rise to ICERs of$ 608,667.86/QALY. The univariate sensitivity analysis demonstrated that the outcomes were most sensitive to the cost of durvalumab. Other variables with a large or moderate influence were the utility of progression-free survival state, utility of progressive disease state, and cost of tremelimumab. Probability sensitivity analysis revealed that T + D + CT had a 0% probability of cost-effectiveness in individuals with mNSCLC at a willingness-to-pay threshold of $100,000 to$ 150,000 per QALY.Conclusion and relevance: In this model, T + D + CT was estimated to be less cost-effective than CT for patients with mNSCLC at a WTP threshold of $100,000 to$ 150,000 per QALY in the United States. When new combination therapies with remarkable effect become pivotal in the first-line treatment, the price reduction of durvalumab and tremelimumab may be necessary to achieve cost-effectiveness in future possible context.</p

Data_Sheet_1_Cost-effectiveness of first-line versus second-line use of brigatinib followed by lorlatinib in patients with ALK-positive non-small cell lung cancer.PDF

BackgroundThe ALTA-1 L trial and EXP-3B arm of NCT01970865 trial found that both brigatinib and lorlatinib showed durable and robust responses in treating ALK-positive non-small cell lung cancer (NSCLC) patients. However, brigatinib and lorlatinib treatments are costly and need indefinite administration until the disease progression. Thus, it remains uncertain whether using brigatinib followed by lorlatinib before chemotherapy is cost-effective compared to reserving these two drugs until progression after chemotherapy.MethodsWe used a Markov model to assess clinical outcomes and healthcare costs of treating ALK-positive NSCLC individuals with brigatinib followed by lorlatinib before chemotherapy versus a strategy of reserving these drugs until progression after chemotherapy. Transition probabilities were estimated using parametric survival modeling based on multiple clinical trials. The drug acquisition costs, adverse events costs, administration costs were extracted from published studies before and publicly available data. We calculated lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from the perspective of a United States payer.ResultsOur base-case analysis indicated that the incremental cost-effectiveness ratios of using first-line brigatinib followed by lorlatinib compared with second-line brigatinib followed by lorlatinib is $-400,722.09/QALY which meant that second-line brigatinib followed by lorlatinib had less costs and better outcomes. Univariate sensitivity analysis indicated the results were most sensitive to the cost of brigatinib. Probability sensitivity analysis revealed that using brigatinib followed by lorlatinib before chemotherapy had a 0$150,000 per QALY. Sensitivity analyses conducted revealed the robustness of this result, as incremental cost-effectiveness ratios never exceeded the willingness-to-pay threshold.ConclusionUsing brigatinib as first-line treatment followed by lorlatinib for ALK-positive NSCLC may not be cost-effective given current pricing from the perspective of a United States payer. Delaying brigatinib followed by lorlatinib until subsequent lines of treatment may be a reasonable strategy that could limit healthcare costs without affecting clinical outcomes. More mature data are needed to better estimate cost-effectiveness in this setting.</p

Table1_First-line tremelimumab plus durvalumab and chemotherapy versus chemotherapy alone for metastatic non-small cell lung cancer: a cost-effectiveness analysis in the United States.doc

Importance: In the open-label phase III POSEIDON randomized clinical trial (RCT), a limited course of tremelimumab plus durvalumab and chemotherapy (T + D + CT) indicated in the first-line treatment of metastatic non-small cell lung cancer (mNSCLC), progression-free survival, and overall survival (OS) were substantially improved without significant additional tolerance burden compared to chemotherapy (CT). However, given the high cost of T + D + CT, its value needs to be evaluated in terms of both potency and cost.Objective: To evaluate the cost-effectiveness of T + D + CT versus CT in individuals with previously untreated mNSCLC from a U.S. payer perspective.Design, setting, and participants: A three-state Markov model was adopted to weigh the lifetime costs and effectiveness of T + D + CT versus CT for the treatment of first-line mNSCLC, according to the results of the POSEIDON phase III RCT involving 675 individuals with mNSCLC. Individuals were simulated to undergo either T + D + CT for up to four 21-day cycles, followed by durvalumab once every 4 weeks until disease progression or unacceptable toxic effects and one additional tremelimumab dose, or CT for up to six 21-day cycles (with or without pemetrexed maintenance; all groups) in the analysis.Main outcomes and measures: Lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were evaluated with a willingness-to-pay (WTP) threshold of $100,000 to$ 150,000 per QALY. The uncertainty of the model was investigated using univariate and probabilistic sensitivity analysis.Results: T + D + CT produced additional 0.36 QALYs with additional costs of $217,694, compared to CT, giving rise to ICERs of$ 608,667.86/QALY. The univariate sensitivity analysis demonstrated that the outcomes were most sensitive to the cost of durvalumab. Other variables with a large or moderate influence were the utility of progression-free survival state, utility of progressive disease state, and cost of tremelimumab. Probability sensitivity analysis revealed that T + D + CT had a 0% probability of cost-effectiveness in individuals with mNSCLC at a willingness-to-pay threshold of $100,000 to$ 150,000 per QALY.Conclusion and relevance: In this model, T + D + CT was estimated to be less cost-effective than CT for patients with mNSCLC at a WTP threshold of $100,000 to$ 150,000 per QALY in the United States. When new combination therapies with remarkable effect become pivotal in the first-line treatment, the price reduction of durvalumab and tremelimumab may be necessary to achieve cost-effectiveness in future possible context.</p

Data_Sheet_2_Cost-effectiveness of first-line versus second-line use of brigatinib followed by lorlatinib in patients with ALK-positive non-small cell lung cancer.docx

BackgroundThe ALTA-1 L trial and EXP-3B arm of NCT01970865 trial found that both brigatinib and lorlatinib showed durable and robust responses in treating ALK-positive non-small cell lung cancer (NSCLC) patients. However, brigatinib and lorlatinib treatments are costly and need indefinite administration until the disease progression. Thus, it remains uncertain whether using brigatinib followed by lorlatinib before chemotherapy is cost-effective compared to reserving these two drugs until progression after chemotherapy.MethodsWe used a Markov model to assess clinical outcomes and healthcare costs of treating ALK-positive NSCLC individuals with brigatinib followed by lorlatinib before chemotherapy versus a strategy of reserving these drugs until progression after chemotherapy. Transition probabilities were estimated using parametric survival modeling based on multiple clinical trials. The drug acquisition costs, adverse events costs, administration costs were extracted from published studies before and publicly available data. We calculated lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from the perspective of a United States payer.ResultsOur base-case analysis indicated that the incremental cost-effectiveness ratios of using first-line brigatinib followed by lorlatinib compared with second-line brigatinib followed by lorlatinib is $-400,722.09/QALY which meant that second-line brigatinib followed by lorlatinib had less costs and better outcomes. Univariate sensitivity analysis indicated the results were most sensitive to the cost of brigatinib. Probability sensitivity analysis revealed that using brigatinib followed by lorlatinib before chemotherapy had a 0$150,000 per QALY. Sensitivity analyses conducted revealed the robustness of this result, as incremental cost-effectiveness ratios never exceeded the willingness-to-pay threshold.ConclusionUsing brigatinib as first-line treatment followed by lorlatinib for ALK-positive NSCLC may not be cost-effective given current pricing from the perspective of a United States payer. Delaying brigatinib followed by lorlatinib until subsequent lines of treatment may be a reasonable strategy that could limit healthcare costs without affecting clinical outcomes. More mature data are needed to better estimate cost-effectiveness in this setting.</p