The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma

Multiple myeloma (MM) is characterized by remarkable cytogenetic/molecular heterogeneity among patients and intraclonal diversity even in a single patient. We previously demonstrated that PDPK1, the master kinase of series of AGC kinases, is universally active in MM, and plays pivotal roles in cell proliferation and cell survival of myeloma cells regardless of the profiles of cytogenetic and genetic abnormalities. This study investigated the therapeutic efficacy and mechanism of action of dual blockade of two major PDPK1 substrates, RSK2 and AKT, in MM. The combinatory treatment of BI-D1870, an inhibitor for N-terminal kinase domain (NTKD) of RSK2, and ipatasertib, an inhibitor for AKT, showed the additive to synergistic anti-tumor effect on human MM-derived cell lines (HMCLs) with active RSK2-NTKD and AKT, by enhancing apoptotic induction with BIM and BID activation. Moreover, the dual blockade of RSK2 and AKT exerted robust molecular effects on critical gene sets associated with myeloma pathophysiologies, such as those with MYC, mTOR, STK33, ribosomal biogenesis, or cell-extrinsic stimuli of soluble factors, in HMCLs. These results provide the biological and molecular rationales for the dual-targeting strategy for RSK2 and AKT, which may overcome the therapeutic difficulty due to cytogenetic/molecular heterogeneity in MM.     

Fractionation and Characterization of the Macromolecular Meaty Flavor Enhancer from Beef Meat Extract

ABSTRACT: Macromolecular meaty flavor enhancer was fractionated from a commercial beef extract. The macromolecular fraction was obtained by dialysis and separated by anion-exchange chromatography, Cu²⁺-chelate chromatography, and gel filtration chromatography. Two fractions were isolated as active meaty flavor enhancers. To elucidate the partial structures, the active fractions were treated with endoprotease Glu-C followed by high-performance liquid chromatography (HPLC) separation of the peptide fragments. Determinations of the amino acid compositions and amino acid sequences of the isolated fragments showed that the 2 active fractions consisted of collagen and tropomyosin. The macromolecular material obtained from heated collagen and tro-pomyosin in the low-molecular-weight fraction of beef soup stock enhanced the meaty flavor. These results suggested that collagen and tropomyosin were precursors of the macromolecular meaty flavor enhancer.     

Features of Mechanical Properties and Fabric Handle of Silk Weaves

Basic mechanical properties such as tensile, bending, shearing, compressional, and surface properties of each classified silk weave were measured by the KES-FB system, and fabric handle was obtained by the objective-evaluation method developed by Kawabata and Niwa. These values were examined and compared with those of typical thin dress fabrics. The discriminant analysis was used to distinguish each silk group clearly by primary hand values. The main features of fabric handle of each classified silk weave are as follows. Silk Habutae has high KOSHI and KISHIMI and low SHARI. Silk Dechine shows high SHINAYAKASA and low HARI. Silk Georgette has good SHINAYAKASA, but poor HARI and FUKURAML. Silk Fujiginu has a slightly high KISHIMI and a slightly low SHARI. High KOSHI and HARI with low SHINAYAKASA are distinctive features of silk Chirimen. Silk Shantung has higher KOSHI and HARI and lower SHINAYAKASA.     

Carrier properties of B atomic-layer-doped Si films grown by ECR Ar plasma-enhanced CVD without substrate heating

Abstract

The atomic-layer (AL) doping technique in epitaxy has attracted attention as a low-resistive ultrathin semiconductor film as well as a two-dimensional (2-D) carrier transport system. In this paper, we report carrier properties for B AL-doped Si films with suppressed thermal diffusion. B AL-doped Si films were formed on Si(100) by B AL formation followed by Si cap layer deposition in low-energy Ar plasma-enhanced chemical-vapor deposition without substrate heating. After fabrication of Hall-effect devices with the B AL-doped Si films on unstrained and 0.8%-tensile-strained Si(100)-on-insulator substrates (maximum process temperature 350°C), carrier properties were electrically measured at room temperature. Typically for the initial B amount of 2?×?10¹⁴ cm^?2 and 7?×?10¹⁴ cm^?2, B concentration depth profiles showed a clear decay slope as steep as 1.3 nm/decade. Dominant carrier was a hole and the maximum sheet carrier densities as high as 4?×?10¹³ cm^?2 and 2?×?10¹³ cm^?2 (electrical activity ratio of about 7% and 3.5%) were measured respectively for the unstrained and 0.8%-tensile-strained Si with Hall mobility around 10–13 cm² V^?1 s^?1. Moreover, mobility degradation was not observed even when sheet carrier density was increased by heat treatment at 500–700 °C. There is a possibility that the local carrier (ionized B atom) concentration around the B AL in Si reaches around 10²¹ cm^?3 and 2-D impurity-band formation with strong Coulomb interaction is expected. The behavior of carrier properties for heat treatment at 500–700 °C implies that thermal diffusion causes broadening of the B AL in Si and decrease of local B concentration.     

Blade geometry effects on initial dispersion of chopped glass fibers

The effects of blade geometry on the initial dispersion of chopped glass fiber bundles in polystyrene during batch mixing are investigated. Roller, banbury, cam, and sigma blades are evaluated for dispersive efficiency and differences in mechanism. Processed samples are characterized by image analysis to focus upon the initial stages of dispersion. Sigma blades are found to be the most effective blades for initial chopped glass dispersion, while banbury blades prove the least effective. Analytical treatment based on the average time for a volume to pass through high stress regions does not explain the results; chopped glass fiber dispersion does not depend solely upon passage through narrow-gap, high-stress regions.     

Fast insertion methods of a double‐array structure

A double‐array is a compact and fast data structure for a trie, but it degrades the speed of insertion for a large set of keys. In this paper, two kinds of methods for improving insertion are presented. The basic functions for retrieval, insertion and deletion are implemented in the C language. Comparing with the original double‐array for large sets of keys, the improved double‐array is about six to 320 times faster than that for insertion. Copyright © 2001 John Wiley & Sons, Ltd.     

Influences of Fe-impurity on the production process of SiC fiber reinforced Al for electric cables

As electrical power demands increase every year, the need becomes stronger for light weight electric cables which have high transmission capacity, high thermal resistance and low sag. We have developed a SiC fiber reinforced aluminum electrical cable to meet this need. Mechanical properties of the SiC/Al composite conductor are very susceptible to iron impurity which becomes mixed in the Al matrix during manufacture of the composite conductor. In this work, we studied the effects of Fe impurity in Al on fracture behavior of the composite conductor. A preformed wire was prepared by dipping a bundle of 1500 pieces of SiC fiber (Si: 63.7, C: 35.8, O: 12.3 mass %) into molten Al in which 0.36 mass % Fe and 0.5 mass % Ti were mixed. The Ti was added to improve the wetting property. Test samples were prepared by bundling seven preformed wires together. A tensile test was carried out for the composite conductor, and pull-out behavior of SiC fiber at the fracture surface was observed by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX) and electron probe micro analysis (EPMA). Pull-out of SiC fiber was observed at the fracture surface of the composite conductor using Fe-free Al. However, pull-out of SiC fiber was not observed at the fracture surface of the composite conductor using Fe-containing Al since Al was combined inseparably with the SiC and Fe. The fracture origin of the Fe-containing sample was a precipitated Fe-compound at the SiC/Al interface. Tensile strength of the Fe-containing sample was a half of that of the Fe-free sample. We propose the following the precipitation mechanism for the Fe compound. In manufacturing of the preformed wire, molten Al solidifies from the surface to the SiC/Al interface because of the low thermal conductivity of the SiC fiber. In the cooling process, Fe-free Ti-compound precipitates in the molten Al by a peritectic reaction. This leads to a higher concentration of Fe in the molten Al near the interface, and finally, FeAl₃ compound precipitates at the SiC/Al interface.     

Crystal growth study using combination of molecular dynamics and Monte Carlo methods

Molecular dynamics method although provides details of energies of the system as a function of time, is not suited to simulate the processes involving activation processes. Therefore, we attempted to combine the molecular dynamics and Monte Carlo methods. Using molecular dynamics, the energies of the system were calculated which were subsequently combined with Monte Carlo method using random numbers, epitaxial growth of (111) plane of copper, silver, and gold. While surface adsorption and surface diffusion for copper, silver, and gold were simulated by use of molecular dynamics method, the relation between the growth rate of thin films and the packing density of atoms were obtained using Monte Carlo simulation. Thus, by combining the results of the molecular dynamics method and the Monte Carlo method the growth process of thin films at elevated temperatures were obtained, which is too tedious to be calculated by molecular dynamics alone.     

Modeling a rectilinearly channeled negative surface discharge

This study presents a new theoretical model for describing a rectilinearly channeled negative discharge generated on PET film (δ = 50 μm) under atmospheric conditions. The channel is modeled using an RC distributed constant circuit with front potential V_t and moving at propagation speed v_t. A conduction equation (∂U/∂t=μ√U∂²U/∂²z), U = V², with V the potential and μ the electron mobility is introduced under the assumption that the generated current consists of only electrons. This equation can be solved using the boundary conditions and the speed condition in which the speed is considered as being proportional to the gradient of U [, β const]. Although it is difficult to solve the conduction equation analytically under the boundary condition and speed condition, using the simplified boundary condition and the length l(t) instead of the speed condition, the conduction equation is solved numerically. The U(z, t) are calculated and compared with the experimental results. I proposed that one of the best approaches to the discussion of the conduction equation is using the solution of the Stefan problem which corresponds to the fusion phenomenon occurring in a column of ice. The solution of the Stefan problem is also compared with the above numerical solution. © 1997 Scripta Technica, Inc. Electr Eng Jpn, 120(4): 7–13, 1997     

Vibration analysis of a 3-phase model transformer core

Noise generated by a transformer core has been reduced by improving material and design, but further reduction is still required. To obtain the reduction, the comprehension of noise generating mechanism is important. It is achieved by detailed investigation of core vibration. A vibration measuring system utilizing a laser Doppler vibration meter was developed, and the vibration of a 3-phase 3-limb transformer core was measured. The following results were obtained. The vibration on the front and back of the core was two or three times higher than the other surfaces. The vibration occurred mainly in the limbs of the core, and the vibration direction was perpendicular to the core surface. The vibration waveforms were out of phase between the center limb and both of the side limbs. These results reveal that the principal cause of the vibration on the core was resonance. On the upper surface of the yoke, the vibration was higher in the right and left part and the middle. It is likely that the vibration on the right and left parts is derived from the magnetostriction of the side limbs. The vibration in the middle was considered to be generated by the magnetostriction under the rotational magnetization which occurs in the T-joint area of a 3-phase transformer core. © 1997 Scripta Technica, Inc. Electr Eng Jpn 119(1): 1–8, 1997