Different tumoricidal effects of interferon subclasses and p53 status on hepatocellular carcinoma development and neovascularization.

Interferon (IFN) is known as a multifunctional cytokine. The aim of this study was to examine the different effects of IFN subclass; namely, IFN-α and IFN-β, on hepatocellular carcinoma (HCC) growth especially in conjunction with angiogenesis that is known to play a pivotal role in the tumor growth. Furthermore, we also examined whether the p53 status in the tumor would alter the anti-tumoral effect of IFN against HCC growth since the p53 status reportedly affected the therapeutic effect of anti-angiogenic agents against cancer. When compared with IFN-α, IFN-β exerted a more potent inhibitory effect on HCC growth, even after the tumor was established, along with suppression of neovascularization in the tumor. A single treatment with clinically comparable low doses of IFN-β significantly inhibited HCC growth whereas the same dose of IFN-α did not. IFN-β also significantly suppressed the tumor growth both in the p53-wild and p53-mutant HCC cells. Our in vitro study revealed that IFN-β showed a more potent inhibitory effect on the endothelial cell proliferation than IFN-α as in the in vivo study. Collectively, IFN may be an alternative anti-angiogenic agent against HCC since it exerted a significant tumoricidal effect regardless of the host p53 status even at a low dose. A cautious approach may be also required in the clinical practice since even in a same IFN subclass (class-I), IFN-α and IFN-β exert tumoricidal effects of different magnitudes on HCC

The vascular endothelial growth factor (VEGF) receptor-2 is a major regulator of VEGF-mediated salvage effect in murine acute hepatic failure

Although administration of the vascular endothelial growth factor (VEGF), a potent angiogenic factor, could improve the overall survival of destroyed sinusoidal endothelial cells (SEC) in chemically induced murine acute hepatic failure (AHF), the mechanistic roles of the VEGF receptors have not been elucidated yet. The respective roles of VEGF receptors; namely, Flt-1 (VEGFR-1: R1) and KDR/Flk-1 (VEGFR-2: R2), in the D-galactosamine (Gal-N) and lipopolysaccharide (LPS)-induced AHF were elucidated with specific neutralizing monoclonal antibody against R1 and R2 (R1-mAb and R2-mAb, respectively). The serum ALT elevation, with a peak at 24 h after Gal-N+LPS intoxication, was markedly augmented by means of the R1-mAb and R2-mAb. The aggregative effect of R2-mAb was more potent than that of R1-mAb, and the survival rate was 70% in the R2-mAb-treated group and 100% in the other groups. The results of SEC destruction were almost parallel to those of the ALT changes. Our in-vitro study showed that R1-mAb and R2-mAb significantly worsened the Gal-N+LPS-induced cytotoxicity and apoptosis of SEC mediated by caspase-3, which were almost of similar magnitude to those in the in-vivo study. In conclusion, these results indicated that R2 is a major regulator of the salvage effect of VEGF on the maintenance of SEC architecture and the anti-apoptotic effects against chemically-induced murine AHF

AIR-COOLED MAGNETIC ALLOY CAVITY FOR J-PARC DOUBLED REP.-RATE SCENARIO

Abstract The upgrade project of the J-PARC MR (Main Ring) based on doubled repetition-rate scenario is in progress to deliver the beam power of 750 kW. The present RF section will be occupied by 9 sets of new magnetic alloy, FT3L, cavities using the direct water cooling scheme. The direct water cooling is the efficient scheme to cool the magnetic alloy core although it requires dedicated high-quality cooling water which does not contain copper oxide and copper ions because copper ions may cause the severe corrosion damage on the magnetic alloy cores. These cavities will be used for the fundamental RF for acceleration which requires high duty operation. The second harmonic RF is necessary to increase the bunch length. This allows to enlarge the beam current because it relaxes the space charge effects during the injection. Thanks to the high impedance FT3L and low duty operation of the second harmonic RF, the power loss in the second harmonic RF system becomes moderate. The air cooled cavity is designed to fit in any locations in the MR where the dedicated high-quality water is not available. This paper reports the design of the second RF system, technical issues to produce the magnetic alloy cores to fit the air cooling, and construction of the system

PERFORMANCE OF MULTI-HARMONIC RF FEEDFORWARD SYSTEM FOR BEAM LOADING COMPENSATION IN THE J-PARC RCS

Abstract The beam loading compensation is a key part for acceleration of high intensity proton beams in the J-PARC RCS. In the wide-band MA-loaded RF cavity, the wake voltage consists of not only the accelerating harmonic component but also the higher harmonics. The higher harmonic components cause the RF bucket distortion. We employ the RF feedforward method to compensate the multi-harmonic beam loading. The full-digital feedforward system is developed, which compensates the first three harmonic components of the beam loading. We present the results of the beam test with a high intensity proton beam (2.5 × 10 13 ppp). The impedance seen by the beam is greatly reduced, the impedance of the fundamental accelerating harmonic is reduced to less than 25 Ω in a full accelerating cycle, while the shunt resistance of the cavity is in the order of 800 Ω. The performance of the feedforward system is promising for achievement of the design beam power, 1 MW, in the future

Dual-harmonic auto voltage control for the rapid cycling synchrotron of the Japan Proton Accelerator Research Complex

The dual-harmonic operation, in which the accelerating cavities are driven by the superposition of the fundamental and the second harmonic rf voltage, is useful for acceleration of the ultrahigh intensity proton beam in the rapid cycling synchrotron (RCS) of Japan Proton Accelerator Research Complex (J-PARC). However, the precise and fast voltage control of the harmonics is necessary to realize the dual-harmonic acceleration. We developed the dual-harmonic auto voltage control system for the J-PARC RCS. We describe details of the design and the implementation. Various tests of the system are performed with the RCS rf system. Also, a preliminary beam test has been done. We report the test results