Investigation of drugs for the prevention of doxorubicin-induced cardiac events using big data analysis

Aim: Doxorubicin, an anthracycline anti-tumour agent, is an essential chemotherapeutic drug; however, the adverse events associated with doxorubicin usage, including cardiotoxicity, prevent patients from continuing treatment. Here, we used databases to explore existing approved drugs with potential preventative effects against doxorubicin-induced cardiac events and examined their efficacy and mechanisms. Methods: The Gene Expression Omnibus (GEO), Library of Integrated Network-based Cellular Signatures (LINCS), and Food and Drug Administration Adverse Events Reporting System (FAERS) databases were used to extract candidate prophylactic drugs. Mouse models of doxorubicin-induced cardiac events were generated by intraperitoneal administration of 20 mg/kg of doxorubicin on Day 1 and oral administration of prophylactic candidate drugs for 6 consecutive days beginning the day before doxorubicin administration. On Day 6, mouse hearts were extracted and examined for mRNA expression of apoptosis-related genes. Results: GEO analysis showed that doxorubicin administration upregulated 490 genes and downregulated 862 genes, and LINCS data identified sirolimus, verapamil, minoxidil, prednisolone, guanabenz, and mosapride as drugs capable of counteracting these genetic alterations. Examination of the effects of these drugs on cardiac toxicity using FAERS identified sirolimus and mosapride as new prophylactic drug candidates. In model mice, mosapride and sirolimus suppressed the Bax/Bcl-2 mRNA ratio, which is elevated in doxorubicin-induced cardiotoxicity. These drugs also suppressed the expression of inflammatory cytokines Il1b and Il6 and markers associated with myocardial fibrosis, including Lgal3 and Timp1. Conclusion: These findings suggest that doxorubicin-induced cardiac events are suppressed by the administration of mosapride and sirolimus

The difference of ground reaction force during anterior step motion in collegiate male long-distance runners between with or without a history of medial tibial stress syndrome

本研究は代表的なランニング障害の一つである内側脛骨過労性骨膜炎（MTSS）を発症したアスリートのリハビリテーションや再発予防の一助とするために、MTSSの既往がある男子長距離ランナーにおける前方ステップ動作中の着地衝撃パターンを明らかにすることを目的とした。対象は大学男子長距離ランナー15名とした。自記式アンケートを用いて基本属性に関する情報を得た。最大一歩幅の距離をステップ幅とした前方ステップ時の片脚着地動作（前方ステップ動作）を行わせ、最大垂直床反力（pVGRF）、初期接地からpVGRFまでの時間、loading rate 、およびfree moment（FM）を計測、算出した。対象をMTSS既往あり群（4名6脚）とMTSS既往なし群（13名24脚）に分け、床反力パラメータを群間で比較した。MTSS既往なし群と比較してMTSS既往あり群のpVGRFとFMは有意に小さかった。省スペースで動作の評価が可能な前方ステップ動作において、MTSSの既往がある男子長距離ランナーと既往がない男子長距離ランナーの前方ステップ動作中の床反力パターンに違いがみられた。このことはMTSSの発症予防に向けた動作指導に役立つ可能性があるが、本研究の結果がMTSSの発症要因となるか、MTSSを発症した結果生じた動作戦略であるかは不明である。東京都立大学学位論乙第254号　副論文journal articl

Picosecond time-resolved fluorescence spectroscopy of hematoporphyrin derivative

The picosecond time-resolved fluorescence decays I(t) and spectra I(λ, t) for hematoporphyrin derivative (HPD) in a phosphate buffer saline aqueous solution at different concentrations (8.4 x 10^[-6] ～ 8.4 x 10^[-3] M) are measured by a two-dimensional synchroscan streak camera with a mode-locked CW dye laser, and a new emission band (which we call the Y-band) is found at high concentration. It is shown that the fluorescence decays composed of fast and slow components at high concentration are due to the Y-band (120 ps lifetime) from head-to-tail aggregates including equilibrium dimer and stable dimer, and the usual band (3.6 ns lifetime) from monomer, respectively, and the latter band is dynamically quenched by the Förster type resonance energy transfer from the monomer to the aggregate. Furthermore, the measurement of static fluorescence spectra from human gastric cancers and the surrounding in vivo after HPD injection shows that a band corresponding to the Y-band from the aggregate appears at only the cancerous cells

Picosecond time-resolved fluorescence spectroscopy of hematoporphyrin derivative

The picosecond time-resolved fluorescence decays I(t) and spectra I(λ, t) for hematoporphyrin derivative (HPD) in a phosphate buffer saline aqueous solution at different concentrations (8.4 x 10^[-6] ～ 8.4 x 10^[-3] M) are measured by a two-dimensional synchroscan streak camera with a mode-locked CW dye laser, and a new emission band (which we call the Y-band) is found at high concentration. It is shown that the fluorescence decays composed of fast and slow components at high concentration are due to the Y-band (120 ps lifetime) from head-to-tail aggregates including equilibrium dimer and stable dimer, and the usual band (3.6 ns lifetime) from monomer, respectively, and the latter band is dynamically quenched by the Förster type resonance energy transfer from the monomer to the aggregate. Furthermore, the measurement of static fluorescence spectra from human gastric cancers and the surrounding in vivo after HPD injection shows that a band corresponding to the Y-band from the aggregate appears at only the cancerous cells

Green Forging of Titanium and Titanium Alloys by Using the Carbon Supersaturated SKD11 Dies

The carbon-supersaturated SKD11 punch was proposed as a green, or, a galling-free, long-life and low energy-consuming forging tool of pure titanium and β-titanium alloy that works with low friction and less work hardening and without galling. The reduction in thickness was increased up to 50% to investigate the friction process on the contact interface and the work-hardening behavior. The nitrogen-supersaturated SKD11 punch was utilized as a reference tool for this forging experiment. Three-dimensional finite element analysis was employed to derive the regression curve between the contact interface width and the friction coefficient. The friction coefficient was estimated in forging the pure titanium wires by using the regression curves. The work-hardening process was analyzed by the hardness mapping on the cross-section of forged wires. The SEM-EDX analysis on the contact interface proved that no adhesion of fresh metallic titanium and titanium oxide debris was seen on the interface between the carbon-supersaturated SKD11 punch and the titanium work. In particular, the work hardening is suppressed without shear localization in forging the β-titanium. Finally, the uniform carbon layer was derived from the supersaturated carbon solute from the punch matrix and wrought as a friction film on the contact interface to reduce the friction and the work hardening as well as suppress the chemical galling. This in situ carbon lubrication must be essential in green forging to highly qualify the titanium and titanium alloy products and to prolong the punch-and-die lives in practical operation