Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents.

We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content.

LSD1 Inhibitor T-3775440 Inhibits SCLC Cell Proliferation by Disrupting LSD1 Interactions with SNAG Domain Proteins INSM1 and GFI1B.

T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1, which exerts antiproliferative effects by disrupting the interaction between LSD1 and GFI1B, a SNAG domain transcription factor, inducing leukemia cell transdifferentiation. Here, we describe the anticancer effects and mechanism of action of T-3775440 in small-cell lung cancer (SCLC). T-3775440 inhibited proliferation of SCLC cells and retarded SCLC tumor growth T-3775440 disrupted the interaction between LSD1 and the transcriptional repressor INSM1, thereby inhibiting expression of neuroendocrine-associated genes, such as INSM1 silencing phenocopied the effects of T-3775440 on gene expression and cell proliferation, consistent with the likelihood T-3775440 mediated its effects in SCLC by inhibiting INSM1.

MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody.

Receptor tyrosine kinase therapies have proven to be efficacious in specific cancer patient populations; however, a significant limitation of tyrosine kinase inhibitor (TKI) treatment is the emergence of resistance mechanisms leading to a transient, partial, or complete lack of response. Combination therapies using agents with synergistic activity have potential to improve response and reduce acquired resistance. Chemoreagent or TKI treatment can lead to increased expression of hepatocyte growth factor (HGF) and/or MET, and this effect correlates with increased metastasis and poor prognosis.

Antitumor activity of a novel and orally available inhibitor of serine palmitoyltransferase.

Metabolic reprogramming is an essential hallmark of neoplasia. Therefore, targeting cancer metabolism, including lipid synthesis, has attracted much interest in recent years. Serine palmitoyltransferase (SPT) plays a key role in the initial and rate-limiting step of de novo sphingolipid biosynthesis, and inhibiting SPT activity prevents the proliferation of certain cancer cells.

A novel inhibitor of c-Met and VEGF receptor tyrosine kinases with a broad spectrum of in vivo antitumor activities.

The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are dysregulated in a wide variety of human cancers and are linked with tumorigenesis and metastatic progression. VEGF also plays a key role in tumor angiogenesis and progression by stimulating the proangiogenic signaling of endothelial cells via activation of VEGF receptor tyrosine kinases (VEGFR). Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel therapeutic approach for treating patients with a broad spectrum of tumors.

Anti-angiogenic and anti-tumor effects of TAK-593, a potent and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinase.

We recently reported that TAK-593, a novel imidazo[1,2-b]pyridazine derivative, is a highly potent and selective inhibitor of the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptor tyrosine kinase families. Moreover, TAK-593 exhibits a uniquely long-acting inhibitory profile towards VEGF receptor 2 (VEGFR2) and PDGF receptor β (PDGFRβ). In this study, we demonstrated that TAK-593 potently inhibits VEGF- and PDGF-stimulated cellular phosphorylation and proliferation of human umbilical vein endothelial cells and human coronary artery smooth muscle cells.

Effects of balloon-induced pulsatile perfusion on postoperative short- and long-term cognitive dysfunction in diabetic patients with impaired cerebrovascular carbon dioxide reactivity.

Objectives: The purpose of this study was to identify whether reduced jugular venous oxygen saturation (SjvO(2)) in diabetic patients with impaired cerebrovascular carbon dioxide (CO(2)) reactivity could be improved by pulsatile perfusion during cardiopulmonary bypass (CPB) and whether improved SjvO(2) could improve postoperative cognitive dysfunction after coronary artery bypass graft surgery.

Setting: A prospective, observational study.

Participants: Ninety-nine diabetic patients with impaired CO(2) reactivity (< 3%/mmHg).

A novel pyrrolo[3, 2-d]pyrimidine derivative, as a vascular endothelial growth factor receptor and platelet-derived growth factor receptor tyrosine kinase inhibitor, shows potent antitumor activity by suppression of tumor angiogenesis.

We recently reported that compound 20d (comp.20d), a novel pyrrolo[3, 2-d]pyrimidine derivative, is a potent and selective inhibitor of tumor angiogenesis-related kinases, including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). In this study, we show that comp.

Association between cerebrovascular carbon dioxide reactivity and postoperative short-term and long-term cognitive dysfunction in patients with diabetes mellitus.

Purpose: Our intent was to identify whether cerebrovascular CO(2) reactivity in diabetic patients is a risk factor for postoperative cognitive dysfunction after coronary artery bypass graft (CABG) surgery.

Methods: One hundred twenty-four diabetic patients undergoing elective CABG were studied and analyzed. Diabetic patients were divided into three groups: normal CO(2) reactivity group (above 5%/mmHg), medium CO(2) reactivity group (between 5 and 3%/mmHg), or impaired CO(2) reactivity group (below 3%/mmHg).

Time course of changes in cerebral blood flow velocity after tourniquet deflation in patients with diabetes mellitus or previous stroke under sevoflurane anesthesia.

We observed an increase in mean middle cerebral artery blood flow velocity (V(mca)) after tourniquet deflation during orthopedic surgery under sevoflurane anesthesia in patients with diabetes mellitus or previous stroke. Eight controls, seven insulin-treated diabetic patients, and eight previous stroke patients were studied. Arterial blood pressure, heart rate, V(mca), arterial blood gases, and plasma lactate levels were measured every minute for 10 min after tourniquet release in all patients.

Use of imaging agent to determine postoperative indwelling epidural catheter position.

Background: Epidural anesthesia is widely used to provide pain relief, whether for surgical anesthesia, postoperative analgesia, treatment of chronic pain, or to facilitate painless childbirth. In many cases, however, the epidural catheter is inserted blindly and the indwelling catheter position is almost always uncertain.

Methods: In this study, the loss-of-resistance technique was used and an imaging agent was injected through the indwelling epidural anesthesia catheter to confirm the position of its tip and examine the migration rate.

Preoperative depression is a risk factor for postoperative short-term and long-term cognitive dysfunction in patients with diabetes mellitus.

Purpose: To identify whether the presence of preoperative depression in patients with diabetes mellitus is a risk factor for postoperative cognitive dysfunction after coronary artery bypass graft (CABG) surgery.

Methods: Data from 90 patients with diabetes mellitus undergoing elective CABG were analyzed. Hemodynamic data (arterial and jugular venous blood gas values) were measured during cardiopulmonary bypass.

Two-spherical-wave ultraviolet interferometer for making an antireflective subwavelength periodic pattern on a curved surface.

An ultraviolet two-spherical-wave interferometer was developed in order to make a subwavelength structured surface on a curved surface. The change in fringe period on the curved surface was significantly suppressed compared with the two-plane-wave interferometer. The optical setup method for suppressing the change in fringe period is described.

Differential effects of hyperventilation on cerebral blood flow velocity after tourniquet deflation during sevoflurane, isoflurane, or propofol anesthesia.

The purpose of this study was to compare the degree of increase in middle cerebral artery (MCA) blood flow velocity after tourniquet deflation when modulating hyperventilation during orthopedic surgery under sevoflurane, isoflurane, or propofol anesthesia. Twenty-four patients undergoing elective orthopedic surgery were randomly divided into sevoflurane, isoflurane, and propofol groups. Anesthesia was maintained with sevoflurane, isoflurane, or propofol administration with 33% oxygen and 67% nitrous oxide at anesthetic drug concentrations adequate to maintain bispectral values between 45 and 50.

Comparison of the effects of vasopressin and norepinephrine on organ perfusion during septic shock in streptozotocin-induced diabetic rats.

Purpose: The purpose of this study was to compare the effects of norepinephrine (NE) and vasopressin on systemic hemodynamics, renal and mesenteric artery blood flow, inflammatory response and inducible nitric oxide synthase (iNOS) activity during endotoxin shock in streptozotocin-induced diabetic rats.

Methods: The study was designed to include three sets of experiments: (1) measurement of changes in systemic hemodynamics and mesenteric and renal artery blood flow; (2) measurement of biochemical variables; and (3) measurement of iNOS activity in the mesenteric artery. Systemic hemodynamics, regional artery blood flow changes and biochemical variables were assessed before treatment and 1, 2 and 3 h after treatment.

Numerical study on a micro prism and micro lenses with metal-dielectric multilayered structures.

A micro optical prism and micro lenses with metal-and-dielectric multilayered subwavelength structure (MDMS) are discussed. The MDMS prism has a highly dispersive optical property. Light waves do not spread out in the small prism because of the restriction of propagation direction of light.

Activation of sensory neurons reduces ischemia/reperfusion-induced acute renal injury in rats.

Background: Prostaglandin I2 (PGI2) produced by endothelial cells improves ischemia/reperfusion-induced acute renal injury by inhibiting leukocyte activation in rats. However, the underlying mechanism(s) of increased PGI2 production is not fully understood. Activation of sensory neurons increases endothelial PGI2 production by releasing calcitonin gene-related peptide (CGRP) in rats with hepatic ischemia or reperfusion.

Ray tracing of an aspherical lens with antireflective subwavelength structured surfaces.

A method of ray tracing for an aspherical lens with subwavelength periodic structured surfaces has been developed. The ray tracing in the antireflective subwavelength structure is based on the group velocity of the Bloch wave. Transmittance and phase delay for the surface structure are determined with rigorous coupled wave analysis.

Pulmonary changes in a mouse model of combined burn and smoke inhalation-induced injury.

The morbidity and mortality of burn victims increase when burn injury is combined with smoke inhalation. The goal of the present study was to develop a murine model of burn and smoke inhalation injury to more precisely reveal the mechanistic aspects of these pathological changes. The burn injury mouse group received a 40% total body surface area third-degree burn alone, the smoke inhalation injury mouse group received two 30-s exposures of cotton smoke alone, and the combined burn and smoke inhalation injury mouse group received both the burn and the smoke inhalation injury.

High transmission recovery of slow light in a photonic crystal waveguide using a hetero groupvelocity waveguide.

High transmission of slow-light in a photonic crystal (PC) waveguide (WG) using a hetero group-velocity (Ht-V(g)) PC-WG was proposed and experimentally investigated. The Ht-V(g) WG, which comprises a low-group-velocity (L-V(g)) PC-WG section between two identical high-group- velocity (H-V(g)) PC-WGs, is designed to decrease the impedance mismatch of the L-V(g) PC-WG. The increase in transmittance of a propagating pulse was confirmed in the Ht-V(g) PC-WG even in the vicinity of the band-gap, whereas the homogeneous PC-WG showed a gradual decrease in transmittance with the pulse wavelength approaching the band-gap.

Broadband waveguide intersection with low crosstalk in two-dimensional photonic crystal circuits by using topology optimization.

Topology optimization has been used to design intersections in two-dimensional photonic crystal slab waveguides. We have experimentally confirmed that the optimized intersection displays high-transmittance with low-crosstalk for the straightforward beam-propagation line.

Recombinant human activated protein C improves pulmonary function in ovine acute lung injury resulting from smoke inhalation and sepsis.

Objective: To investigate the effects of recombinant human activated protein C (rhAPC) on pulmonary function in acute lung injury (ALI) resulting from smoke inhalation in association with a bacterial challenge.

Design: Prospective, randomized, controlled, experimental animal study with repeated measurements.

Setting: Investigational intensive care unit at a university hospital.

Estimation method for the light extraction efficiency of light-emitting elements with a rigorous grating diffraction theory.

The light extraction efficiency of a light-emitting element with microstructured surface is analyzed with a rigorous grating diffraction theory. The grating theory reveals an improvement of extraction efficiency due to diffraction of light by the surface microstructure. The simulation results show that the improvement of extraction efficiency is due mainly to the reflected diffraction rather than to the transmitted diffraction.

Reduced wavelength-dependent quarter-wave plate fabricated by a multilayered subwavelength structure.

We developed a novel fabrication method of a reduced wavelength-dependent quarter-wave plate (QWP) based on form birefringence of a multilayered subwavelength structure. The multilayered structure was constructed by depositing a high-refractive-index thin film on a subwavelength-structured substrate with a low refractive index. The surface structure of the substrate was shallow enough to be formed by a mass replication technology.

Olprinone reduces ischemia/reperfusion-induced acute renal injury in rats through enhancement of cAMP.

Activated leukocytes are implicated in development of ischemia/reperfusion (I/R)-induced organ injuries. Phosphodiesterase 3 inhibitors have anti-inflammatory effects by preventing cyclic adenosine monophosphate (cAMP) degradation. We examined the effects of olprinone, a specific phosphodiesterase 3 inhibitor, on I/R-induced acute renal injury model in rats.