Safety and Effectiveness of Elotuzumab in Japanese Patients with Relapsed/Refractory Multiple Myeloma: A Post-marketing Surveillance Study.

Objective Elotuzumab plus lenalidomide and dexamethasone (ELd) was approved in Japan in 2016 for the treatment of relapsed/refractory multiple myeloma (RRMM). This post-marketing surveillance study evaluated the safety and effectiveness of ELd in RRMM patients during routine clinical practice in Japan. Methods Elotuzumab safety was assessed by evaluating adverse drug reactions (ADRs), and effectiveness was assessed primarily by the best overall response. Patients The study enrolled patients with RRMM who received ELd therapy between November 18, 2016, and June 18, 2017. The safety and effectiveness analysis sets included 831 and 755 patients, respectively. Results In the safety analysis set, patients received a median (range) of 12 (1-40) elotuzumab administrations over 108 (1-728) days of treatment. The relative dose intensity of elotuzumab was ≥90% in 74.1% of patients. ADRs and serious ADRs were reported in 41.2% and 15.2% of the patients, respectively. The most common ADR was infection (12.0%), followed by lymphocytopenia (10.1%), infusion reactions (7.5%), secondary malignancies (e.g. gastric cancer and pancreatic carcinoma), cataracts, and interstitial lung disease (0.2% each). While most patients with ADRs recovered, 71 discontinued treatment, and 14 deaths were reported. The presence of comorbidities, particularly cardiovascular disorders, significantly affected the safety. The overall response rate was 41.1%. Conclusion This all-case post-marketing surveillance study showed that ELd had an acceptable tolerability profile and promising clinical activity in Japanese patients with RRMM.

Quantitative Characterization of the Affected Zones in a Single Crystal Fe-6Si Steel Sheet by Fine Piercing.

An iron loss in the motor core was often enhanced by formation of plastically affected zones in piercing the electrical steel sheets. A platform methodology to carry out quantitative evaluation of these affected zones in the pierced electrical steel sheets was proposed to search for the way to minimize the affected zone widths. A coarse-grained electrical steel sheet was employed as a work material for a fine piercing experiment under the narrowed clearance between the plasma-nitrided SKD11 punch and core-die. The shearing behavior by the applied loading for piercing was described by in situ measurement of the load-stroke relationship. The plastic straining in the single-crystal electrical steel sheet was characterized by SEM (scanning electron microscopy) and EBSD (electron back-scattering diffraction) to define the affected zone size and to analyze the rotation of crystallographic orientations by the induced plastic distortion during piercing. Integral and differentiation of spin rotation measured the affected zones. The effect of punch edge sharpness on these spin-rotation measures was also discussed using the nitrided and ion-milled SKD11 punch and core-die.

Micro-/Nano-Texturing onto Plasma-Nitrided Tool Surface by Laser Printing for CNC Imprinting and Piercing.

A new data transformation method for micro-manufacturing using a topological model for a micro-/nano-texture was proposed for a surface-decorated product. Femtosecond laser printing was utilized to form the micro-/nano-textures into the hardened thick layer of dies by plasma nitriding. At first, the plasma-nitrided AISI316L flat substrate was laser-printed as a punch to imprint the tailored nano-textures onto the AA1060 aluminum plate for its surface decoration with topological emblems. Second, the plasma-nitrided SKD11 cylindrical punch was laser-trimmed to form the nanostructures on its side surface. This nano-texture was imprinted onto the hole surface concurrently with piercing a circular hole into electrical steel sheet. The fully burnished surface had a shiny, metallic quality due to the nano-texturing. The plasma nitriding, the laser printing and the CNC (computer numerical control) imprinting provided a way of transforming the tailored textures on the metallic product.

Femtosecond Laser Trimming with Simultaneous Nanostructuring to Fine Piercing Punch to Electrical Amorphous Steel Sheets.

A CVD (Chemical Vapor Deposition) diamond coated tungsten carbide (WC) and cobalt (Co) sintered alloy punch was trimmed by the femtosecond laser machining to sharpen its edge with about 2 µm and to simultaneously make nanostructuring to its side surface. In addition to the sharpened edge, its edge profile was formed to be homogeneous enough to reduce the damage layer width by piercing the electrical amorphous steel sheet stack. Each brittle sheet in the stacked work was damaged to have three kinds of defects by piercing; e.g., the droop-like cracking in the thickness and at the vicinity of hole, the wrinkling in peak-to-valley with partial cracking on the peaks, and the circumferential cracking. When using the WC (Co) punch with the inhomogeneous edge profile in the sharpened edge width, these three damages were induced into each sheet and the maximum damage width exceeded 80 µm. When using the punch with the sharpened edge and homogeneous edge profile, the wrinkling mode was saved and the total affected layer width was significantly reduced to less than 20 µm. Through the precise embossing experiments, this effect of punch edge profile condition to the induced damages was discussed with a statement on the nanostructuring effect on the reduction of damaged width in electrical amorphous steel sheets. The developed tool with the sharpened edge and homogenous edge condition contributes to the realization of a low iron loss motor with a reduced affected layer width.

Free-Forging of Pure Titanium with High Reduction of Thickness by Plasma-Carburized SKD11 Dies.

A tool steel type SKD11 punch was plasma carburized at 673 K for 14.4 ks at 70 Pa to make carbon supersaturation. This carburized SKD11 punch was employed for upsetting the pure titanium wire with the diameter of 1.00 mm up to the reduction of thickness by 70% in a single shot. Its contact interface to titanium work was analyzed to describe the anti-galling behavior in this forging. Little trace of titanium proved that the galling process was suppressed by the in situ solid lubrication. The isolated free carbon agglomerates are wrought as a solid lubricant to sustain the galling-free forging process. This anti-galling upsetting reduced the residual strains in the forged wires. A long titanium wire with a length of 45 mm was incrementally upset to yield the titanium ribbon with a thickness of 0.3 mm, the width of 2.3 mm, and the length of 50 mm. The grain size of original pure titanium was much reduced to 2 µm on average. A micro-pillared microtexture was imprinted onto this forged titanium ribbon.

Dry Cold Forging of Pure Titanium Wire to Thin Plate with Use of ß-SiC Coating Dies.

Dense ß-SiC coating with 3C-structure was utilized as a dry cold forging punch and core-die. Pure titanium T328H wires of industrial grade II were employed as a work material. No adhesion or galling of metallic titanium was detected on the contact interface between this ß-SiC die and titanium work, even after this continuous forging process, up to a reduction in thickness by 70%. SEM (Scanning Electron Microscopy) and EDX (Electron Dispersive X-ray spectroscopy) were utilized to analyze this contact interface. A very thin titanium oxide layer was in situ formed in the radial direction from the center of the contact interface. Isolated carbon from ß-SiC agglomerated and distributed in dots at the center of the initial contact interface. Raman spectroscopy was utilized, yielding the discovery that this carbon is unbound as a free carbon or not bound in SiC or TiC and that intermediate titanium oxides are formed with TiO2 as a tribofilm.

Evolution of acoustic softening effect on ultrasonic-assisted micro/meso-compression behavior and microstructure.

The application of ultrasonic vibration is an effective method to overcome the processing problems in micro/meso-forming. Previously it was observed that ultrasonic vibration could reduce flowing stress in the forming process, called ultrasonic volume effect. The volume effect contains multi-mechanisms such as stress superposition leading to apparent average stress reduction, acoustic softening and ultrasonic impact leading to real stress reductin. However, the evolutional characteristics and the mechanism of acoustic softening on material deformation is still not clear. And in most previous studies only the average stress but not the oscillatory stress was measured due to the convenience of dynamic force sensing system, which confused the different ultrasonic volume effects, acoustic softening, stress superposition and ultrasonic impact. The purpose of this study is to investigate the effects of acoustic softening on micro/meso-compression behavior and microstructure evolution. An ultrasonic-assisted compression test system with dynamic force sensing technology was developed. And a series of ultrasonic-assisted micro/meso-compression tests at different amplitudes were carried out on pure copper C1100O combining the microstructure analysis by EBSD technique. By analyzing the waveform of the oscillatory stress in the process, acoustic softening was successfully separated from the stress superposition and it was found that the deformation strain plays an important role on the effect of acoustic softening. The stress reduction by acoustic softening increases with the flowing strain or ultrasonic amplitude increasing. Besides, there is an evolutionary transition of acoustic softening ratio between small strain and large strain. When acoustic softening occurs, the low-angle grain boundaries distribute randomly in grains, compared to the piled distribution without ultrasonic assistance, implying motions of the low-angle grain boundaries or dislocation is improved by acoustic softening, resulting in the real stress reduction. In addition, with small deformation strain, the elongated grain becomes equiaxed and dislocation density is significantly reduced, which may be the result of the increased dislocation annihilation due to ultrasonic-induced dynamic recovery. However, with the deformation strain increasing to some extent, acoustic hardening gradually becomes significant, leading to much less effectiveness of acoustic softening on dislocation density reduction. The findings of this study provide an instructive understanding of the underlying mechanisms of acoustic softening in ultrasonic-assisted micro/meso-forming.

Multiple proteins are involved in the protein-DNA complex in the proximal promoter of the human alpha1(III) collagen gene (COL3A1).

We have characterized the proximal promoter of the human alpha1(III) collagen gene (COL3A1). Transient transfection assays using a series of chimeric constructs linked to the luciferase gene indicated that the segment from -96 to -34 is necessary to activate transcription. Electrophoretic mobility shift assays (EMSAs) showed that the multiple proteins form the DNA-protein complex in different combinations depending on the cell types. A competition assay using mutant oligonucleotides showed that the sequence 5'-GCTCTCATATTTCAGAA-3' (-79 to -63 bp) is critical for DNA-protein complex formation. This sequence is contained in the B element of mouse alpha1(III) collagen gene (Col3a1) reported by Ruteshouse and de Crombrugghe (J. Biol. Chem., 1993). In the rhabdomyosarcoma cell line, A204, at least two proteins of 92-118 kDa and 40-52 kDa are involved in the DNA-protein complex bound to this motif.

Preparation and characterization of chitosan microspheres containing doxifluridine.

Chitosan microspheres containing 5-fluorouracil (5-FU), tegafur (FT), and doxifluridine (DFUR) were prepared by the dry-in-oil method using silicone oil with no surfactant as a dispersion medium. For DFUR-containing chitosan microspheres (DFUR-M), reacetylation with acetic anhydride or coating using chitosan and glutaraldehyde was performed. DFUR-M, reacetylated DFUR-M, and chitosan-coated DFUR-M were investigated on in vitro drug release, and the former two microspheres were examined for in vivo degradation after subcutaneous (s.c.) implantation in mice, and in vivo plasma concentration-time profiles after s.c. implantation in rats. The present method gave fairly large microspheres purely composed of chitosan and drug because of no use of surfactant, which showed the mean particle diameters of 300-900 microm and the drug contents of 4-22% (w/w). Encapsulation efficiency of DFUR was higher than that of 5-FU and FT. DFUR-M and reacetylated DFUR-M exhibited spherical shape except chitosan-coated DFUR-M. DFUR-M showed high initial rapid release, which was suppressed to some extent by reacetylation or chitosan coating. DFUR-M and reacetylated DFUR-M subcutaneously implanted were gradually degraded, and approximately half or a little more of the microspheres disappeared from the implanted site at 3 weeks postimplantation. DFUR-M and reacetylated DFUR-M implanted subcutaneously gave similar plasma concentration-time profiles of DFUR, which did not indicate prolonged release in vivo. DFUR-containing chitosan microspheres with fairly large size and good drug content could be obtained by the present preparation but remained to be improved for drug release properties.