Takanobu Sato

Key Roles for the Lipid Signaling Enzyme Phospholipase D1 in the Tumor Microenvironment During Tumor Angiogenesis and Metastasis

Genetic ablation or pharmacological inhibition of a lipid signaling enzyme attenuates tumor growth and metastasis. Targeting the Tumor Microenvironment Phospholipase D (PLD) is an enzyme that produces the signaling lipid phosphatidic acid and promotes the proliferation, survival, invasion, and metastasis of cancer cells. Chen et al. examined the role of the PLD isoforms PLD1 and PLD2 in the tumor environment. They found that compared to wild-type mice, mice deficient in PLD1 developed smaller, less vascularized tumors as well as fewer lung metastases in a xenograft model. Furthermore, mice treated with an inhibitor of PLD1 also developed smaller tumors and fewer metastases. These results suggest that PLD1 inhibitors could be developed to treat cancer. Angiogenesis inhibitors, which target tumor cells, confer only short-term benefits on tumor growth. We report that ablation of the lipid signaling enzyme phospholipase D1 (PLD1) in the tumor environment compromised the neovascularization and growth of tumors. PLD1 deficiency suppressed the activation of Akt and mitogen-activated protein kinase signaling pathways by vascular endothelial growth factor in vascular endothelial cells, resulting in decreased integrin-dependent cell adhesion to, and migration on, extracellular matrices, as well as reduced tumor angiogenesis in a xenograft model. In addition, mice lacking PLD1 incurred fewer lung metastases than did wild-type mice. Bone marrow transplantation and binding studies identified a platelet-derived mechanism involving decreased tumor cell–platelet interactions, in part because of impaired activation of αIIbβ3 integrin in platelets, which decreased the seeding of tumor cells into the lung parenchyma. Treatment with a small-molecule inhibitor of PLD1 phenocopied PLD1 deficiency, efficiently suppressing both tumor growth and metastasis in mice. These findings reveal that PLD1 in the tumor environment promotes tumor growth and metastasis and, taken together with previous reports on the roles of PLD in tumor cell–intrinsic adaptations to stress, suggest the potential use of PLD inhibitors as cancer therapeutics.

Fabrication and characterization of HfC coated Si field emitter arrays

We fabricated hafnium carbide (HfC) coated Si field emitter arrays (HfC FEAs) with an extraction-gate electrode to improve the emission characteristics of Si FEAs. Hafnium carbide thin film was deposited by inductively coupled plasma-assisted magnetron sputtering. The HfC film was characterized by x-ray photoelectron spectroscopy and x-ray diffraction measurement, and was found to be (111)-oriented polycrystalline film. The HfC FEAs exhibited superior performance. An emission of more than 10 mA could be obtained from the 16 000 tip array, which is 20 times higher than that for Si FEAs. The operational voltage for emission of 1 μA decreased from 61 to 45 V due to the HfC coating. The long-term emission characteristics were also measured. Si FEAs degraded rapidly even in an ultrahigh vacuum chamber. However, the emission degradation in the HfC FEAs was much slower. The number of active tips was counted using an electrostatic-lens projector, and the results revealed that the HfC FEAs had six times as many ti...

Molecular Mechanisms of N-Formyl-Methionyl-Leucyl-Phenylalanine-Induced Superoxide Generation and Degranulation in Mouse Neutrophils: Phospholipase D Is Dispensable

ABSTRACT Phospholipase D (PLD), which produces the lipid messenger phosphatidic acid (PA), has been implicated in superoxide generation and degranulation in neutrophils. The basis for this conclusion is the observation that primary alcohols, which interfere with PLD-catalyzed PA production, inhibit these neutrophil functions. However, off-target effects of primary alcohols cannot be totally excluded. Here, we generated PLD−/− mice in order to reevaluate the involvement of PLD in and investigate the molecular mechanisms of these neutrophil functions. Surprisingly, N-formyl-methionyl-leucyl-phenylalanine (fMLP) induced these functions in PLD−/− neutrophils, and these functions were suppressed by ethanol. These results indicate that PLD is dispensable for these neutrophil functions and that ethanol nonspecifically inhibits them, warning against the use of primary alcohols as specific inhibitors of PLD-mediated PA formation. The calcium ionophore ionomycin and the membrane-permeative compound 1-oleoyl-2-acetyl-sn-glycerol (OADG) synergistically induced superoxide generation. On the other hand, ionomycin alone induced degranulation, which was further augmented by OADG. These results demonstrate that conventional protein kinase C (cPKC) is crucial for superoxide generation, and a Ca2+-dependent signaling pathway(s) and cPKC are involved in degranulation in mouse neutrophils.

Fabrication of Polycrystalline Silicon Field Emitter Arrays with Hafnium Carbide Coating for Thin-Film-Transistor Controlled Field Emission Displays

Hafnium Carbide (HfC)-coated polycrystalline silicon (poly-Si) field emitter arrays (FEAs) were fabricated on an oxidized silicon wafer. The HfC coating layer was deposited by inductively coupled plasma-assisted magnetron sputtering. The effect of the HfC thickness on the emission characteristics was investigated by depositing 15-nm- and 30-nm-thick HfC on the tip. The thinner HfC could effectively improve the emission characteristics of poly-Si FEA, while the thicker one degrades the emission. Two methods of tip sharpening were also investigated: one is thermal oxidation sharpening which is commonly used for Si FEA fabrication, and the other is Ar ion sputtering. The apex radius of the thermally oxidized FEA was much smaller than that of the sputter-sharpened one. However, some irregularly shaped tips were found in the oxidized FEA, which are responsible for gate current. The detailed fabrication and emission characteristics, including gate current, will be reported.

Emission statistics for Si and HfC emitter arrays after residual gas exposure

Field emission arrays (FEAs) comprising 100 Si or HfC coated Si emitters have been fabricated. The FEAs emission properties were measured in ultra high vacuum conditions and after being subject to Ar and O2 residual gases with partial pressures in the range 10−6 to 10−4Pa. The influence of residual gases on the FEAs field emission properties has been comparatively assessed using the model parameter extraction method. The array field emission model uses equations that describe the electron emission current from individual emitters of given radius R and work function ϕ together with nonuniform distribution functions giving the dispersion of these parameters within the array. A simplified relationship for the array emission current depending on a single integral instead of a double one has been derived. A nonlinear extraction algorithm using partial derivatives of the objective function is used, which gives fast and accurate results. Both Si and HfC emitters exhibit (to a different degree) tightening of the ...

Characterization of enhanced field emission from HfC-coated Si emitter arrays through parameter extraction

In this paper a HfC coating layer was deposited on the tips resulting in enhanced field emission properties. The field emission temporal evolution was measured in ultra-high vacuum conditions and also in O/sub 2/ and Ar gases of different concentration.

Development of a super-high-sensitivity image sensor using 640×480 pixel active-matrix high-efficiency electron emission device

An extremely high-sensitivity image sensor has been developed with a combination of an active-matrix high-efficiency electron emission device (HEED) array and a high-gain avalanche rushing amorphous photoconductor (HARP) target. Following the description of the requirements for the use of the electron emitter as an image-sensing probe, the characteristics of a fabricated 640×480 pixel active-matrix HEED image sensor with a HARP target are presented by image-pickup experiments under a dark condition. The emission current density of the experimental HEED under an active-matrix drive was 4 A/cm2 corresponding to a practical level. A clear image observed in the prototype compact camera demonstrates that the surface-emitting HEED is useful for image sensing based on HARP with high sensitivity and sufficient definition.

2∕3in. ultrahigh-sensitivity image sensor with active-matrix high-efficiency electron emission device

A 640×480pixel image sensor has been developed for low light imaging with a practical resolution. This image sensor combined an active-matrix high-efficiency electron emission device (HEED) with a high-gain avalanche rushing amorphous photoconductor (HARP) target. To meet the requirement for a scaling of the imaging size, we developed a 2∕3in. image sensor based on an active-matrix HEED with 13.75×13.75μm2pixels. The highly emissive property of 3.8μA∕pixel was comparable to that obtained previously from a 1in. device. The possible effect of the pixel size scaling on the image-pickup sensitivity was compensated by a significant increase in the emission current density. The technological potential of the HEED-HARP image sensing has been further enhanced toward practical use.

Enhanced output current density of an active-matrix high-efficiency electron emission device array with 13.75μmpixels

An active-matrix array of high-efficiency electron emission device (HEED) with a sufficient output density has been developed for the use as imaging probe in a high-gain avalanche rushing amorphous photoconductor target. Previously, it was demonstrated that a prototyped image sensor with 20×20μm2pixels could pick up a high definition image with an ultrahigh sensitivity under low-light-level condition. Based on it, an efficient active-matrix HEED with 13.75×13.75μm2pixels is fabricated for pursuing higher sensitivity and resolution. The improvement in the device isolation method enables to enlarge the relative emitting area, and then the emission current density per pixel reaches 3.6A∕cm2 that is about four times of that obtained from the previous one. The active-matrix HEED array with small pixels is available for application to the compact ultrahigh-sensitivity image sensor without affecting on the image definition.An active-matrix array of high-efficiency electron emission device (HEED) with a sufficient output density has been developed for the use as imaging probe in a high-gain avalanche rushing amorphous photoconductor target. Previously, it was demonstrated that a prototyped image sensor with 20×20μm2pixels could pick up a high definition image with an ultrahigh sensitivity under low-light-level condition. Based on it, an efficient active-matrix HEED with 13.75×13.75μm2pixels is fabricated for pursuing higher sensitivity and resolution. The improvement in the device isolation method enables to enlarge the relative emitting area, and then the emission current density per pixel reaches 3.6A∕cm2 that is about four times of that obtained from the previous one. The active-matrix HEED array with small pixels is available for application to the compact ultrahigh-sensitivity image sensor without affecting on the image definition.

Molecular mechanisms of fMLP-induced superoxide generation and degranulation in mouse neutrophils.

In this manuscript, involvement of PLD in fMLP-induced superoxide generation and degranulation were re-investigated using PLD(-/-) neutrophils, and the molecular mechanisms of these neutrophil functions were examined. Neither PLD1 nor PLD2 is involved in these fMLP-induced neutrophil functions. The results obtained in this study provide evidence that cPKC plays an important role in fMLP-induced superoxide generation. On the other hand, Ca(2+)-dependent signaling pathway and cPKC seem to be involved in degranulation.