Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use.

Deregulating fibroblast growth factor receptor (FGFR) signaling is a promising strategy for cancer therapy. Herein, we report the discovery of compound (TAS-120, futibatinib), a potent and selective covalent inhibitor of FGFR1-4, starting from a unique dual inhibitor of mutant epidermal growth factor receptor and FGFR (compound ). Compound inhibited all four families of FGFRs in the single-digit nanomolar range and showed high selectivity for over 387 kinases.

Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors.

FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with IC values of 1.

A Clinical Association between an Increasing Renal Resistive Index and the Atherosclerotic Burden in Patients with a Preserved Renal Function.

Objective A positive correlation is observed between the progression of renal impairment and the increasing risk of cardiovascular disease. Our aim was to examine the relationship between the renal resistive index (RRI) assessed by duplex sonography and the extent of atherosclerosis in patients without renal impairment undergoing vascular imaging studies. Methods The RRI was evaluated pre-procedurally among 106 outpatients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.

Protective activity of anti-lipoteichoic acid monoclonal antibody in single or combination therapies in methicillin-resistant Staphylococcus aureus-induced murine sepsis models.

Previously, we generated and screened a panel of monoclonal antibodies (mAbs) against methicillin-resistant Staphylococcus aureus (MRSA) to identify protective mAbs in mouse infection models. One of these mAbs, ZBIA3H, bound to lipoteichoic acid (LTA) and exerted protective effects in a mouse sepsis model. To reinforce the ability of the mAb to protect against infection, combination therapies with the mAb and antibiotics need to be examined.

TAS-121, A Selective Mutant EGFR Inhibitor, Shows Activity Against Tumors Expressing Various Mutations Including T790M and Uncommon Mutations G719X.

TAS-121 is a novel orally active selective covalent inhibitor of the mutant EGFR. We performed preclinical characterization of TAS-121 and compared its efficacy and selectivity for common mutations (Ex19del and L858R), first- and second- generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance mutation (T790M), and uncommon mutations (G719X and L861Q) with those of other EGFR-TKIs. We also commenced investigation of the clinical benefits of TAS-121.

Protective effect of pre- and post-vitamin C treatments on UVB-irradiation-induced skin damage.

Several studies have reported the effects of vitamin C (L-ascorbic acid, AA) on ultraviolet B (UVB)-induced cell damage using cultured keratinocytes. However, the epidermis consists of multiple cell layers, and the effect of AA on UVB-induced damage to the human epidermis remains unclear. Therefore, we investigated the effect of AA on UVB-induced skin damage using reconstituted human epidermis.

TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations.

Activating mutations in the gene are important targets in cancer therapy because they are key drivers of non-small cell lung cancer (NSCLC). Although almost all common EGFR mutations, such as exon 19 deletions and the L858R point mutation in exon 21, are sensitive to EGFR-tyrosine kinase inhibitor (TKI) therapies, NSCLC driven by EGFR exon 20 insertion mutations is associated with poor clinical outcomes due to dose-limiting toxicity, demonstrating the need for a novel therapy. TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR.

Successful selection of an infection-protective anti-Staphylococcus aureus monoclonal antibody and its protective activity in murine infection models.

Recent clinical trials to develop anti-methicillin-resistant Staphylococcus aureus (MRSA) therapeutic antibodies have met unsuccessful sequels. To develop more effective antibodies against MRSA infection, a panel of mAbs against S. aureus cell wall was generated and then screened for the most protective mAb in mouse infection models.

[Clinical evaluation of intraoperative cardiac output measurement by a new arterial pressure waveform analysis method( FloTrac/Vigileo) in open heart surgery].

We retrospectively evaluated the initial clinical experience of intraoperative cardiac output measurement by a new arterial pressure-based cardiac output (APCO:FloTrac/Vigileo) analysis in patients undergoing open heart surgery. Thirty-two patients (mean age 76.4, range 59 to 90)who underwent cardiac surgery under cardiopulmonary bypass( CPB) from July 2008 to September 2009 in our institute were enrolled in this study.

In vivo evaluation of the "TinyPump" as a pediatric left ventricular assist device.

Pediatric patients with end-stage heart failure require mechanical circulatory support (MCS) just as adults do. In order to meet the special requirements for neonates' and infants' MCS, pediatric circulatory support devices must be compact with low priming volume, easily controllable with low flow, less traumatic for blood cells and tissues, and biocompatible with minimum anticoagulation. We have designed and developed a miniature rotary centrifugal blood pump, "TinyPump," with a priming volume of 5 mL, which has already demonstrated its controllable performance for low flow and durability in vitro.

Is there a difference between the effects of single and triple indirect moxibustion stimulations on skin temperature changes of the posterior trunk surface?

Objectives: To determine whether any difference exists in responses to indirect moxibustion (IM) relative to thermal stimulation duration.

Methods: In experiment 1, 9 subjects attended two experimental sessions consisting of single stimulation with IM or triple stimulation with IM, using a crossover design. A K-type thermocouple temperature probe was fixed on the skin surface at the GV14 acupuncture point.

Structures of the PKC-iota kinase domain in its ATP-bound and apo forms reveal defined structures of residues 533-551 in the C-terminal tail and their roles in ATP binding.

Protein kinase C (PKC) plays an essential role in a wide range of cellular functions. Although crystal structures of the PKC-theta, PKC-iota and PKC-betaII kinase domains have previously been determined in complexes with small-molecule inhibitors, no structure of a PKC-substrate complex has been determined. In the previously determined PKC-iota complex, residues 533-551 in the C-terminal tail were disordered.

Neural mechanism of localized changes in skeletal muscle blood flow caused by moxibustion-like thermal stimulation of anesthetized rats.

Moxibustion-like thermal stimulation (MTS) was applied to the gastrocnemius muscle to measure local muscle blood flow (MBF) in the stimulated region and the change in the MBF in the region, and its mechanism was examined. In the experiment, we used urethane-anesthetized rats under artificial respiration and observed the change caused by gastrocnemius MTS using a laser Doppler blood-flow meter. MTS applied to the gastrocnemius muscle caused a two-phase response in blood flow that showed a transient decrease followed by an increase without blood pressure change.

Percutaneous dye image cardioscopy for detection of endocardial lesions.

Endocardial lesions are caused not only by inflammatory processes but also by myocardial ischemia, resulting in endocardial thrombosis and cerebral embolism. We deviced a method for direct visualization of endocardial damages by a novel dye image cardioscopy with Evans blue and examined its feasibility in patients with heart disease. The dye was injected into the left ventricle before and after endomyocardial biopsy.

Angioscopic evaluation of stabilizing effects of bezafibrate on coronary plaques in patients with coronary artery disease.

Background Since long-term administrations of anti-hyperlipidemic agents result in reduction in % stenosis or increase in minimum lumen diameter (MLD) of stenotic coronary segments, it is generally believed that anti-hyperlipidemic agents stabilize vulnerable coronary plaques. However, recent pathologic and angioscopic studies revealed that vulnerability of coronary plaques is not related to severity of stenosis and the rims rather than top of the plaques disrupt, and therefore, angiography is not adequate for evaluation of vulnerability.Angioscopy enables macroscopic pathological evaluation of the coronary plaques.

Chemically induced permanent magnetism in Au, Ag, and Cu nanoparticles: localization of the magnetism by element selective techniques.

We report a direct observation of the intrinsic magnetization behavior of Au in thiol-capped gold nanoparticles with permanent magnetism at room temperature. Two element specific techniques have been used for this purpose: X-ray magnetic circular dichroism on the L edges of the Au and 197Au Mössbauer spectroscopy. Besides, we show that silver and copper nanoparticles synthesized by the same chemical procedure also present room-temperature permanent magnetism.

Neural mechanism of bradycardiac responses elicited by acupuncture-like stimulation to a hind limb in anesthetized rats.

The effects of acupuncture-like stimulation of a hind limb on heart rate were examined in anesthetized rats. An acupuncture needle, having a diameter of either 160 or 340 microm, was inserted into the skin and underlying muscles at a depth of about 5 mm and twisted right and left twice every second for 1 min. Stimulation by a needle with a diameter of either 160 or 340 microm produced a decrease in heart rate.

Regeneration of retinotectal projections after optic tectum removal in adult newts.

Purpose: When injured, the adult newt possesses the remarkable capability to regenerate tissues and organs with return of function and physiology. One example is the newt eye, in which regeneration can restore normal vision if the retina or lens has been removed. We wanted to examine how the retinotectal projections regenerate after removal of the brain's optic tectum and establish this animal as a model for retinal projection as well as a central nervous system regeneration model.

Outcomes and hemodynamics after aortic valve replacement: a comparison of stentless versus mechanical valves.

Purpose: Some investigators suggest that hemodynamic outcomes may be superior with the stentless aortic bioprosthesis when compared with a mechanical valve. The goal of this study was to characterize outcomes and hemodynamic data associated with each type of valve.

Subjects And Methods: Patient outcomes and echocardiographic data were compared between 25 patients with stentless valves and 59 patients with mechanical valves.

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer.

Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m-2 day-1 from days 1 to 14 of a 28-day cycle.

Transbronchial localization of small pulmonary lesions for thoracoscopic resection.

The localization of small lung masses at thoracoscopic operation is very difficult. A 67-year-old female with tiny pulmonary metastases of renal cell carcinoma primary was successfully treated by pulmonary thoracoscopic resection after transbronchial localization using a dye.

[Angina pectoris presenting with unusual form of coronary spasm: a case report].

A 46-year-old male with asthma bronchiale and eosinophilia was admitted to our hospital because of continuous severe chest pain. Electrocardiography showed ST segment elevation in leads II, III and aVF during chest pain. Emergency coronary angiography showed a series of coronary arterial narrowings in segments 1 and 2.

[Study of the echocardiographic diagnosis of acute pulmonary thromboembolism and risk factors for venous thromboembolism].

Objectives: To identify the relationship of risk factors for atherosclerosis with venous thromboembolism (VTE) and the utility of transthoracic echocardiography in acute pulmonary thromboembolism (APTE).

Methods: In 75 patients with VTE (VTE group), 101 patients with suspected VTE (N group), and 50 control subjects (control group), the frequency of atherosclerosis risk factors such as hyperlipidemia, obesity, hypertension, smoking, and diabetes mellitus and the number of risk factors were evaluated. Transthoracic echocardiographic findings such as tricuspid regurgitation, right ventricular dilation, pulmonary hypertension, and right ventricular dysfunction were evaluated in 15 patients with APTE (APTE group) and 38 patients in the N group (NC group).