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. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics.

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 in vitro and retarded SCLC tumor growth in vivo T-3775440 disrupted the interaction between LSD1 and the transcriptional repressor INSM1, thereby inhibiting expression of neuroendocrine-associated genes, such as ASCL1 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. T-3775440 also inhibited proliferation of an SCLC cell line that overexpressed GFI1B, rather than INSM1, by disrupting the interaction between LSD1 and GFI1B. Taken together, our results argue that LSD1 plays an important role in neuroendocrine-associated transcription and cell proliferation of SCLC via interactions with the SNAG domain proteins INSM1 and GFI1B. Targeting these critical interactions with LSD1 inhibitors offers a novel rational strategy to therapeutically manage SCLC. Cancer Res; 77(17); 4652-62. ©2017 AACR.

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. Despite MET's role in resistance and cancer biology, MET TKI monotherapy has yielded disappointing clinical responses. In this study, we describe the biological activity of a selective, oral MET TKI with slow off-rate and its synergistic antitumor effects when combined with an anti-HGF antibody. We evaluated the combined action of simultaneously neutralizing HGF ligand and inhibiting MET kinase activity in two cancer xenograft models that exhibit autocrine HGF/MET activation. The combination therapy results in additive antitumor activity in KP4 pancreatic tumors and synergistic activity in U-87MG glioblastoma tumors. Pharmacodynamic characterization of biomarkers that correlate with combination synergy reveal that monotherapies induce an increase in the total MET protein, whereas combination therapy significantly reduces total MET protein levels and phosphorylation of 4E-BP1. These results hold promise that dual targeting of HGF and MET by combining extracellular ligand inhibitors with intracellular MET TKIs could be an effective intervention strategy for cancer patients who have acquired resistance that is dependent on total MET protein. Mol Cancer Ther; 16(7); 1269-78. ©2017 AACR.

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. Here, we identified a novel and orally available SPT inhibitor, compound-2. Compound-2 showed an anti-proliferative effect in several cancer cell models, reducing the levels of the sphingolipids ceramide and sphingomyelin. In the presence of compound-2, exogenously added S1P partially compensated the intracellular sphingolipid levels through the salvage pathway by partially rescuing compound-2-induced cytotoxicity. This suggested that the mechanism underlying the anti-proliferative effect of compound-2 involved the reduction of sphingolipid levels. Indeed, compound-2 promoted multinuclear formation with reduced endogenous sphingomyelin levels specifically in a compound-2-sensitive cell line, indicating that the effect was induced by sphingolipid reduction. Furthermore, compound-2 showed potent antitumor activity without causing significant body weight loss in the PL-21 acute myeloid leukemia mouse xenograft model. Therefore, SPT may be an attractive therapeutic anti-cancer drug target for which compound-2 may be a promising new drug.

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. Toward this goal, we generated and characterized T-1840383, a small-molecule kinase inhibitor that targets both c-Met and VEGFRs. T-1840383 inhibited HGF-induced c-Met phosphorylation and VEGF-induced VEGFR-2 phosphorylation in cancer epithelial cells and vascular endothelial cells, respectively. It also inhibited constitutively activated c-Met phosphorylation in c-met-amplified cancer cells, leading to suppression of cell proliferation. In addition, T-1840383 potently blocked VEGF-dependent proliferation and capillary tube formation of endothelial cells. Following oral administration, T-1840383 showed potent antitumor efficacy in a wide variety of human tumor xenograft mouse models, along with reduction of c-Met phosphorylation levels and microvessel density within tumor xenografts. These results suggest that the efficacy of T-1840383 is produced by direct effects on tumor cell growth and by an antiangiogenic mechanism. Furthermore, T-1840383 showed profound antitumor activity in a gastric tumor peritoneal dissemination model. Collectively, our findings indicate the therapeutic potential of targeting both c-Met and VEGFRs simultaneously with a single small-molecule inhibitor for the treatment of human cancers.

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 ß (PDGFRß). 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. TAK-593 also potently inhibits VEGF-induced tube formation of endothelial cells co-cultured with fibroblasts. Oral administration of TAK-593 exhibited strong anti-tumor effects against various human cancer xenografts along with good tolerability despite a low level of plasma exposure. Even after the blood and tissue concentrations of TAK-593 decreased below the detectable limit, a pharmacodynamic marker (phospho VEGFR2) was almost completely suppressed, indicating that its long duration of enzyme inhibition might contribute to the potent activity of TAK-593. Immunohistochemical staining indicated that TAK-593 showed anti-proliferative and pro-apoptotic effects on tumors along with a decrease of vessel density and inhibition of pericyte recruitment to microvessels in vivo. Furthermore, dynamic contrast-enhanced magnetic resonance imaging revealed that TAK-593 reduced tumor vessel permeability prior to the onset of anti-tumor activity. In conclusion, TAK-593 is an extremely potent VEGFR/PDGFR kinase inhibitor whose potent anti-angiogenic activity suggests therapeutic potential for the treatment of solid tumors.

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). INTERVENTIONS: Ninety-nine diabetic patients divided into 2 groups: group 1 received an intra-aortic balloon pump (IABP) after the induction of anesthesia and group 2 did not. Group 1 received pulsatile perfusion during CPB, and group 2 received nonpulsatile perfusion during CPB. MEASUREMENTS AND MAIN RESULTS: Hemodynamic data (arterial and jugular venous gas values) were measured during CPB. All patients underwent neurologic and neuropsychologic tests the day before surgery and 7 days and 6 months after surgery. The duration of SjvO(2) ≤50% during CPB was shorter in group 1 (13 ± 5 minutes) than in group 2 (20 ± 6 minutes, p < 0.01). No significant differences in the rate of cognitive dysfunction were observed between groups at 7 days and 6 months postoperatively. CONCLUSIONS: Pulsatile perfusion flow generated by the IABP could reduce the decrease in SjvO(2) values during CPB, but amelioration of SjvO(2) values was not associated with short- or long-term postoperative cognitive dysfunction in diabetic patients with impaired CO(2) reactivity.

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.20d potently blocks the VEGF- and PDGF-stimulated cellular phosphorylation (IC(50) = 2.5 and 3.6 nM, respectively) and proliferation of HUVECs and human coronary artery smooth muscle cells with IC(50) values of 2.8 and 9.6 nM, respectively, and potently inhibits the VEGF-induced tube formation of endothelial cells cocultured with fibroblasts (IC(50) = 3.3 nM). Given orally twice daily, comp.20d at the doses of 1.5-6 mg/kg showed antitumor effects in mice bearing various human cancer xenografts. Consistent with the anti-angiogenic mechanism of action, histological examination of tumors from comp. 20d-treated mice indicated a decrease in microvessel density and inhibition of pericyte recruitment to microvessels, and these were concomitant with decreased interstitial fluid pressure that allowed for therapeutic intratumoral uptake of CPT-11 (irinotecan hydrochloride). In conclusion, comp.20d is an extremely potent inhibitor of VEGFR/PDGFR kinases whose activities suggest therapeutic potential for the treatment of solid tumors that rely on angiogenesis for their survival.

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). After the induction of anesthesia and before the start of surgery, cerebrovascular CO(2) reactivity was measured for all patients. Hemodynamic parameters (arterial and jugular venous blood gas values) were measured during cardiopulmonary bypass. All patients underwent a battery of neurological and neuropsychological tests the day before surgery, 7 days after surgery, and 6 months after surgery. RESULTS: At 7 days, the rate of cognitive dysfunction in the impaired CO(2) group was higher than in the other three groups (normal, 30%; medium, 25%; impaired, 57%; *P < 0.01 compared with the other groups). In contrast, at 6 months postoperatively, no significant difference in the rate of cognitive dysfunction was found among the three groups. Age, hypertension, CO(2) reactivity, the duration for which jugular venous oxygen saturation (SjvO(2)) was less than 50%, ascending aorta atherosclerosis, diabetic retinopathy, and insulin therapy were independent predictors of short-term cognitive dysfunction in diabetic patients, and HbA1c, diabetic retinopathy, and insulin therapy were independent predictors of long-term cognitive dysfunction in diabetic patients. CONCLUSIONS: We found that impaired cerebrovascular CO(2) reactivity was associated with postoperative short-term cognitive dysfunction in diabetic patients.

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. V(mca) was measured using a transcranial Doppler probe. V(mca) in all three groups increased after tourniquet deflation, the increase lasting for 4 or 5 min. However, the degree of increase in V(mca) in the diabetic patients was smaller than that in the other two groups after tourniquet deflation (at 2 min after tourniquet deflation: control 58.5 ± 3.3, previous stroke 58.4 ± 4.6, diabetes 51.7 ± 2.3; P < 0.05 compared with the other two groups). In conclusion, the degree of increase in V (mca) in diabetic patients is smaller than that in controls and patients with previous stroke.

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. Preoperatively, all patients were given the 21-item Beck depression inventory to identify the presence of depression. In addition, all patients underwent a battery of neurological and neuropsychological tests the day before surgery, 7 days after surgery, and 6 months after surgery. RESULTS: The rate of cognitive dysfunction was 50% at 7 days and 23% at 6 months after surgery. Age, hypertension, presence of depression, duration of SjvO(2) ≤ 50%, ascending aorta atherosclerosis, diabetic retinopathy, and insulin therapy were independent predictors of short-term cognitive dysfunction, whereas HbA1c, diabetic retinopathy, insulin therapy, and presence of depression were independent predictors of long-term cognitive dysfunction. CONCLUSIONS: We found that the presence of depression preoperatively is associated with short-term and long-term postoperative cognitive dysfunction in patients with diabetes mellitus.

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. The effect of the two-spherical-wave interferometer was investigated by numerical simulations. In an experimental demonstration for a concave spherical surface with 11.1 mm radius of curvature and 10 mm diameter, the change in period of the photoresist pattern was reduced to 12 nm for the target period of 250 nm.

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. A 2.0-MHz transcranial Doppler probe was attached to the patient's head at the temporal window, and mean blood flow velocity in the MCA (V (mca)) was continuously measured. The extremity was exsanguinated with an Esmarch bandage, and the pneumatic tourniquet was inflated to a pressure of 450 mmHg. Arterial blood pressure, heart rate, V (mca) and arterial blood gases were measured every minute for 10 min after release of the tourniquet in all three groups. Immediately after tourniquet release, the patients' respiratory rates were increased to tightly maintain end-tidal carbon dioxide (PetCO(2)) at 35 mmHg. No change in partial pressure of carbon dioxide in arterial blood (PaCO(2)) was observed pre- and posttourniquet deflation in any of the three groups. Increase in V (mca) in the isoflurane group was greater than that in the other two groups after tourniquet deflation. In addition, during the study period, no difference in V (mca) after tourniquet deflation was observed between the propofol and sevoflurane groups. Hyperventilation could prevent an increase in V (mca) in the propofol and sevoflurane groups after tourniquet deflation. However, hyperventilation could not prevent an increase in V (mca) in the isoflurane group.

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. RESULTS: Vasopressin, but not NE, prevented the decreases in aortic blood flow, but did not restore mesenteric artery blood flow. In addition, vasopressin partially restored renal artery blood flow in diabetic rats. Plasma nitrite levels and iNOS activity in the mesenteric artery were elevated after intravenous LPS in diabetic rats. Endotoxin-induced decreases in mesenteric arterial blood flow were partially restored by vasopressin with nonselective NOS inhibitor, N G-nitro-l-arginine methyl ester (l-NAME), in diabetic rats. Moreover, l-NAME prevented increases in plasma nitrite levels and iNOS activity in the mesenteric artery. In contrast, endotoxin-induced decreases in renal arterial blood flow were partially restored by vasopressin with l-NAME, but not by NE in diabetic rats. CONCLUSIONS: Nitric oxide may be one possible contributor to reduced sensitivity of the mesenteric and renal arteries to vasopressin during septic shock in streptozotocin-induced diabetic rats.

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. Optical properties of a curved MDMS prism were investigated by theoretical analysis and numerical simulations. The curved MDMS prism with a structure period of 0.4 microm and an apex angle of 90 degrees had angular dispersion of 0.11 degrees /nm for light of 1.5 microm wavelength. A convexo-plane MDMS lens and a gradient-index MDMS lens were also investigated, and the optical behavior for the curved prism with the convexo-plane lens was demonstrated by a numerical simulation.

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. Study subjects were patients scheduled to undergo surgery using general anesthesia combined with epidural anesthesia. Placement of the epidural catheter was confirmed postoperatively by injection of an imaging agent and X-ray imaging. RESULTS: The indwelling epidural catheter was placed between upper thoracic vertebrae (n = 83; incorrect placement, n = 5), lower thoracic vertebrae (n = 123; incorrect placement, n = 5), and lower thoracic vertebra-lumbar vertebra (n = 46; incorrect placement, n = 7). In this study, a relatively high frequency of incorrectly placed epidural catheters using the loss-of-resistance technique was observed, and it was found that incorrect catheter placement resulted in inadequate analgesia during surgery. CONCLUSIONS: Although the loss-of-resistance technique is easy and convenient as a method for epidural catheter placement, it frequently results in inadequate placement of epidural catheters. Care should be taken when performing this procedure.

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. We examined here whether activation of sensory neurons increases PGI2 endothelial production, thereby reducing ischemia/reperfusion-induced acute renal injury. METHODS: Anesthetized rats were subjected to 45 min of renal ischemia/reperfusion. Rats were pretreated with CGRP, capsazepine (a vanilloid receptor-1 antagonist), CGRP(8-37) (a CGRP receptor antagonist), or indomethacin (a cyclooxygenase inhibitor), or subjected to denervation of primary sensory nerves before ischemia/reperfusion. RESULTS: Renal tissue levels of CGRP and 6-keto-prostaglandin F1alpha, a stable metabolite of PGI2, increased after renal ischemia/reperfusion, peaking at 1 h after reperfusion. Overexpression of CGRP was also noted at 1 h after reperfusion. Increases in renal tissue levels of 6-keto-prostaglandin F1alpha at 1 h after reperfusion were significantly inhibited by pretreatment with capsazepine, CGRP(8-37), and indomethacin. Pretreatment with capsazepine, CGRP(8-37), indomethacin, and denervation of primary sensory nerves significantly increased blood urea nitrogen and serum creatinine levels, renal vascular permeability, renal tissue levels of myeloperoxidase activity, cytokine-induced neutrophil chemoattractant, and tumor necrosis factor-alpha, and decreased renal tissue blood flow. However, pretreatment with CGRP significantly improved these changes. CONCLUSIONS: Our results suggest activation of sensory neurons in the pathologic process of ischemia/reperfusion-induced acute renal injury. Such activation reduces acute renal injury by attenuating inflammatory responses through enhanced endothelial PGI2 production.

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. Calculated wavefront aberration was smaller than 20 mlambda for an aspherical lens with numerical aperture of 0.6. For a lens with a higher numerical aperture, the wavefront aberrations increase drastically.

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. Animal survival was monitored for 120 h. Survival rates in the burn injury group, the smoke inhalation injury group, and the combined injury group were 70%, 60%, and 30%, respectively. Mice that received combined burn and smoke injury developed greater lung damage as evidenced by histological changes (septal thickening and interstitial edema) and higher lung water content. These mice also displayed more severely impaired pulmonary gas exchange [arterial PO2 (PaO2)/inspired O2 fraction (FiO2)<200]. Lung myeloperoxidase activity was significantly higher in burn and smoke-injured animals compared with the other three experimental groups. Plasma NO2-/NO3-, lung inducible nitric oxide synthase (iNOS) activity, and iNOS mRNA increased with injury; however, the burn and smoke injury group exhibited a higher response. Severity of burn and smoke inhalation injury was associated with more pronounced production of nitric oxide and accumulation of activated leukocytes in lung tissue. The murine model of burn and smoke inhalation injury allows us to better understand pathophysiological mechanisms underlying cardiopulmonary morbidity secondary to burn and 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. The group index (n(g)) of the L-V(g) region in the Ht-V(g) PC-WG was measured by the cross-correlation method and attained a value above 20. On the other hand, the transmittance of the Ht-V(g) structure recovered approximately 16dB compared to the homogeneous L-V(g) WG having same n(g), 17. This recovery is mainly dominated by the coupling improvement due to the Ht-V(g) structure, around 12dB. These results indicate the effectiveness of the Ht-V(g) structure to use slow light in a PC-WG, which leads to various applications in PC-based optical devices.