Post-marketing surveillance of carfilzomib in Japanese patients with relapsed or refractory multiple myeloma.

Aim: To evaluate the safety and effectiveness of carfilzomib in a real-world setting. Methods: A post-marketing surveillance of Japanese patients with relapsed or refractory multiple myeloma who received carfilzomib treatment was performed. Results: Overall incidences of adverse events of any grade, ≥grade 3 treatment-related adverse events and serious adverse events were 63.5, 44.6 and 37.7% of patients, respectively. No new safety findings were observed. Treatment-related adverse events of special interest (≥5%) were hematological toxicities, infectious disease, cardiac disorders (including cardiac failure, myocardial infarction and QT prolongation), renal disorders, liver failure or liver dysfunction, and hypertension or hypertensive crisis. The overall response rate was 46.5%. Conclusion: Carfilzomib was found to be a safe and effective treatment for relapsed or refractory multiple myeloma in Japanese patients.

Carfilzomib is a medicine that was recently approved for the treatment of cancer of bone marrow (multiple myeloma) that comes back or does not respond to previous treatment (relapsed or refractory). Data gathered from the hospitals, where the medicine is commonly used, was used to generate evidence. We looked at how well carfilzomib works in Japanese participants and if it is safe. Overall, 63.5% of participants treated with carfilzomib had side effects and 37.7% had serious side effects. Death occurred in 3.1% of participants during the study. Decrease in bone marrow and blood cells, infections, heart and kidney disorder, liver failure or dysfunction, and high blood pressure occurred in 5% or more participants. In 46.5% of participants the tumors had disappeared or shrank. In Japanese participants, carfilzomib was found to be safe and effective treatment for cancer of bone marrow that comes back or does not respond to previous treatment.

Synthesis of new fluorescent molecules having an aggregation-induced emission property derived from 4-fluoroisoxazoles.

Fluorescent molecules based on a fluorinated isoxazole scaffold were synthesized and investigated for their photochemical properties. The introduction of a fluorine substituent into 3,5-diarylisoxazoles led to an increase of fluorescence intensity and exhibited a redshift in the emission intensity. α-Fluorinated boron ketoiminates (F-BKIs) were also synthesized via a ring-opening reaction of 4-fluoroisoxazoles and exhibited highly fluorescent luminescence and aggregation-induced emission (AIE), showing promise as a new fluorophore.

Wnts are dispensable for differentiation and self-renewal of adult murine hematopoietic stem cells.

Wnt signaling controls early embryonic hematopoiesis and dysregulated ß-catenin is implicated in leukemia. However, the role of Wnts and their source in adult hematopoiesis is still unclear, and is clinically important as upstream Wnt inhibitors enter clinical trials. We blocked Wnt secretion in hematopoietic lineages by targeting Porcn, a membrane-bound O-acyltransferase that is indispensable for the activity and secretion of all vertebrate Wnts. Surprisingly, deletion of Porcn in Rosa-CreER(T2)/Porcn(Del), MX1-Cre/Porcn(Del), and Vav-Cre/Porcn(Del) mice had no effects on proliferation, differentiation, or self-renewal of adult hematopoietic stem cells. Targeting Wnt secretion in the bone marrow niche by treatment with a PORCN inhibitor, C59, similarly had no effect on hematopoiesis. These results exclude a role for hematopoietic PORCN-dependent Wnts in adult hematopoiesis. Clinical use of upstream Wnt inhibitors is not likely to be limited by effects on hematopoiesis.

Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide. In the heterogeneous group of hepatocellular carcinomas, those with characteristics of embryonic stem-cell and progenitor-cell gene expression are associated with the worst prognosis. The oncofetal gene SALL4, a marker of a subtype of hepatocellular carcinoma with progenitor-like features, is associated with a poor prognosis and is a potential target for treatment. METHODS: We screened specimens obtained from patients with primary hepatocellular carcinoma for the expression of SALL4 and carried out a clinicopathological analysis. Loss-of-function studies were then performed to evaluate the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. To assess the therapeutic effects of a peptide that targets SALL4, we used in vitro functional and in vivo xenograft assays. RESULTS: SALL4 is an oncofetal protein that is expressed in the human fetal liver and silenced in the adult liver, but it is reexpressed in a subgroup of patients who have hepatocellular carcinoma and an unfavorable prognosis. Gene-expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4-positive hepatocellular carcinomas. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN (the phosphatase and tensin homologue protein) and inhibited tumor formation in xenograft models in vivo. CONCLUSIONS: SALL4 is a marker for a progenitor subclass of hepatocellular carcinoma with an aggressive phenotype. The absence of SALL4 expression in the healthy adult liver enhances the potential of SALL4 as a treatment target in hepatocellular carcinoma. (Funded by the Singapore National Medical Research Council and others.).

Post-marketing surveillance of the safety and effectiveness of nivolumab for classic Hodgkin lymphoma in Japan.

Nivolumab was approved for relapsed/refractory classic Hodgkin lymphoma (cHL) in Japan in 2016. After its approval, a prospective, non-interventional, observational post-marketing surveillance was initiated to evaluate the safety and effectiveness of nivolumab treatment for up to 12 months in patients with relapsed/refractory cHL. Of 304 registered patients, 288 were included in safety analyses and 282 in effectiveness analyses. There were 191 (66.3%) male patients, median age was 64.0 years, and 54 patients (18.8%) had performance status ≥ 2. Treatment-related adverse events (TRAEs) were reported in 183 (63.5%) patients, with grade 3-5 TRAEs in 86 (29.9%). The most common TRAEs were infusion reaction (14.6%), hepatic function abnormal (5.9%), interstitial lung disease (ILD) (5.6%), and hypothyroidism (5.2%). TRAEs of special interest in ≥ 5% of patients were infusion reaction (15.6%), hepatic failure/hepatic dysfunction/hepatitis/cholangitis sclerosing (13.2%), thyroid dysfunction (9.7%), and ILD (7.3%). In multivariable analyses, prior allogeneic hematopoietic stem cell transplantation was a risk factor for hepatic failure/hepatic dysfunction/hepatitis/cholangitis sclerosing, and prior thyroid gland disorders was a risk factor for thyroid dysfunction. The overall response rate was 61.7%. In conclusion, nivolumab showed a similar safety profile and comparable effectiveness to that reported in clinical trials for relapsed/refractory cHL (CheckMate 205, ONO-4538-15).

Unprecedented simultaneous enhancement in strain tolerance, toughness and strength of Al2O3 ceramic by multiwall-type failure of a high loading of carbon nanotubes.

Carbon nanotubes (CNTs) have a remarkable load-bearing ability. Recently, however, multi-walled CNTs (MWCNTs) have been shown to possess dramatically higher load-bearing ability when intimately embedded in an oxide ceramic (Al2O3), because the load could be transferred not to only their outermost walls but also their generally unloaded inner walls via the strong interwall shear resistance originating from residual compressive stresses. This phenomenon is characterized by an uncommon, highly energy-dissipating, multiwall-type failure of individual MWCNTs during hybrid fracture, with no evidence of pullout. Here, we demonstrate that this nanoscale in-MWCNT load-transfer process, at an optimized, high loading of MWCNTs (10 vol%) and in a pore-free and uniform platform, leads to unprecedented, dramatic simultaneous enhancement in strain tolerance (81%), fracture toughness (52.2%), and flexural strength (22%) of the Al2O3 ceramic matrix. The extent of toughening by this mechanism is also the highest ever reported. This unprecedented performance by using a high loading of functional MWCNTs, namely, toughening, strengthening, softening and lightening, simultaneously and at this level, has implications for many functional and structural applications.

Dual-nanoparticulate-reinforced aluminum matrix composite materials.

Aluminum (Al) matrix composite materials reinforced with carbon nanotubes (CNT) and silicon carbide nanoparticles (nano-SiC) were fabricated by mechanical ball milling, followed by hot-pressing. Nano-SiC was used as an active mixing agent for dispersing the CNTs in the Al powder. The hardness of the produced composites was dramatically increased, up to eight times higher than bulk pure Al, by increasing the amount of nano-SiC particles. A small quantity of aluminum carbide (Al(4)C(3)) was observed by TEM analysis and quantified using x-ray diffraction. The composite with the highest hardness values contained some nanosized Al(4)C(3). Along with the CNT and the nano-SiC, Al(4)C(3) also seemed to play a role in the enhanced hardness of the composites. The high energy milling process seems to lead to a homogeneous dispersion of the high aspect ratio CNTs, and of the nearly spherical nano-SiC particles in the Al matrix. This powder metallurgical approach could also be applied to other nanoreinforced composites, such as ceramics or complex matrix materials.

Effective load transfer by a chromium carbide nanostructure in a multi-walled carbon nanotube/copper matrix composite.

Multi-walled carbon nanotube (MWCNT) reinforced copper (Cu) matrix composites, which exhibit chromium (Cr) carbide nanostructures at the MWCNT/Cu interface, were prepared through a carbide formation using CuCr alloy powder. The fully densified and oriented MWCNTs dispersed throughout the composites were prepared using spark plasma sintering (SPS) followed by hot extrusion. The tensile strengths of the MWCNT/CuCr composites increased with increasing MWCNTs content, while the tensile strength of MWCNT/Cu composite decreased from that of monolithic Cu. The enhanced tensile strength of the MWCNT/CuCr composites is a result of possible load-transfer mechanisms of the interfacial Cr carbide nanostructures. The multi-wall failure of MWCNTs observed in the fracture surface of the MWCNT/CuCr composites indicates an improvement in the load-bearing capacity of the MWCNTs. This result shows that the Cr carbide nanostructures effectively transferred the tensile load to the MWCNTs during fracture through carbide nanostructure formation in the MWCNT/Cu composite.

Effects of arsenic compound amendment on arsenic speciation in rice grain.

Rice consumption is a major source of arsenic for Asian populations. Arsenic is present in rice grain both as inorganic arsenic and as dimethylarsinic acid (DMA). It is unclear whether DMA in rice is taken up from the soil or synthesized in planta. We investigated the effect of DMA, methylarsonic acid (MMA) and arsenite amendment on arsenic speciation in rice grain grown in soil and in solution culture. We also investigated the methylation of arsenic in solution culture under suppression of bacterial activity. When rice was grown under flooded conditions after the heading stage, DMA amendment to the soil resulted in higher DMA concentration in brown rice and rice straw. In the solution culture, not only DMA amendment but also MMA or arsenite amendment increased the DMA concentration in brown rice and rice straw. DMA was detected in the solution amended by MMA or arsenite with young rice plants. When the solution included the antibacterial agent chloramphenicol, DMA concentration in the solution decreased dramatically. When only the soil was incubated with MMA or arsenite, only a slight amount of DMA was detected in the soil. These results suggest that rice rhizosphere associated bacteria would be involved in the formation of DMA in brown rice.

Carbon nanofiber reinforced aluminum matrix composite fabricated by combined process of spark plasma sintering and hot extrusion.

Spark plasma sintering and hot extrusion processes have been employed for fabricating carbon nanofiber (CNF)-aluminum (Al) matrix bulk materials. The Al powder and the CNFs were mixed in a mixing medium of natural rubber. The CNFs were well dispersed onto the Al particles. After removal of the natural rubber, the Al-CNF mixture powders were highly densified. From the microstructural viewpoint, the composite materials were observed by optical, field-emission scanning electron, and high-resolution transmission electron microscopies. The CNFs were found to be located on every grain boundary and aligned with the extrusion direction of the Al-CNF bulk materials. Some Al carbides (Al4C3) were also observed at the surface of the CNFs. This carbide was created by a reaction between the Al and the disordered CNF. The CNFs and the formation of Al4C3 play an important role in the enhancement of the mechanical properties of the Al-CNF bulk material. The CNFs can also be used for engineering reinforcement of other matrix materials such as ceramics, polymers and more complex matrices.

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine.

Naldemedine is a peripherally acting µ-opioid-receptor antagonist for the treatment of opioid-induced constipation. Two phase 1 single-dose studies investigated the pharmacokinetics and safety of a 0.2-mg oral dose of naldemedine in subjects with renal impairment (mild, n = 9; moderate, n = 9; severe, n = 6; and end-stage renal disease, n = 8) or hepatic impairment (mild or moderate, n = 8 each) and demographically matched healthy subjects with normal renal and hepatic function (n = 8, both studies). Pharmacokinetic assessments indicate that dose adjustments for naldemedine are not necessary for subjects with any degree of renal impairment or for subjects with mild or moderate hepatic impairment. In subjects with renal impairment compared with healthy subjects with normal renal function, the geometric mean ratios of naldemedine area under the concentration-time curve (AUC0-inf ) ranged from 82.8% (90%CI 69.5% to 98.6%) to 137.8% (90%CI 114.0% to 166.5%). Renal clearance decreased with reduced renal function (normal function 1.3 L/h; mild impairment 1.1 L/h; moderate impairment 1.0 L/h; severe impairment 0.5 L/h), and only 2.7% of naldemedine was removed by hemodialysis. In subjects with hepatic impairment compared with healthy subjects with normal hepatic function, the geometric mean ratio of AUC0-inf ranged from 82.8% (90%CI 65.7% to 104.5%) to 105.2% (90%CI 83.4% to 132.6%). Naldemedine was well tolerated in both healthy subjects and subjects with renal or hepatic impairment, and reported adverse events were generally consistent with the known safety profile.

Influence of magnetic susceptibility and volume on MRI artifacts produced by low magnetic susceptibility Zr-14Nb alloy and dental alloys.

The artifact volume generated in magnetic resonance (MR) images was quantitatively evaluated to investigate how artifact behavior correlates to the magnetic susceptibility and volume of an implanted metal device. For this, a new low-magnetic-susceptibility Zr-14Nb alloy was compared with two conventional dental alloys, Ti-6Al-7Nb alloy and Co-Cr-Mo alloy, using spherical specimens of each alloy prepared with four different diameters. Then, MR images were recorded under fast spin echo and gradient echo conditions, from which the artifact volume was measured. The artifact volume decreased with the magnetic susceptibility, volume, and mass of the specimens, and significant linear correlations were observed. The artifact volume can be estimated by the equations presented here; nevertheless, further studies are necessary to interpret the influence of some important factors (e.g., imaging conditions, shape, and orientation) to predict the artifact volume more precisely.

Liquid-Phase Assisted Engineering of Highly Strong SiC Composite Reinforced by Multiwalled Carbon Nanotubes.

Despite the ultrahigh intrinsic strength of multiwalled carbon nanotube (MWCNT), the strengthening effect on ceramic matrix composite remains far from expectation mainly due to the weak load transfer between the reinforcement and ceramic matrix. With the assistance of the in situ pullout test, it is revealed that the liquid-phase sintering (LPS) can serve as a novel strategy to achieve effective load transfer in MWCNT reinforced ceramic matrix composites. The YAlO3 formed liquid phase during spark plasma sintering of SiC composite greatly facilitates radical elastic deformation of MWCNT, leading to highly increased interfacial shear strength (IFSS) as well as interlayer shear resistance (ISR) of nested walls. The liquid phase with superior wettability can even penetrate into the defects of MWCNT, which further increases the ISR of MWCNT. Moreover, the first-principles calculation indicates that the oxygen terminated YAlO3 phase displays much stronger bonding compared with SiC matrix, which is also responsible for the large IFSS in the composite. As a result, as high as 30% improvement of bending strength is achieved in the composite with only 3 wt% MWCNT in comparison to the monolithic ceramic, manifesting the unprecedented strengthening effect of MWCNT assisted by LPS.

Root-to-shoot Cd translocation via the xylem is the major process determining shoot and grain cadmium accumulation in rice.

Physiological properties involved in divergent cadmium (Cd) accumulation among rice genotypes were characterized using the indica cultivar 'Habataki' (high Cd in grains) and the japonica cultivar 'Sasanishiki' (low Cd in grains). Time-dependence and concentration-dependence of symplastic Cd absorption in roots were revealed not to be responsible for the different Cd accumulation between the two cultivars because root Cd uptake was not greater in the Cd-accumulating cultivar 'Habataki' compared with 'Sasanishiki'. On the other hand, rapid and greater root-to-shoot Cd translocation was observed in 'Habataki', which could be mediated by higher abilities in xylem loading of Cd and transpiration rate as a driving force. To verify whether different abilities in xylem-mediated shoot-to-root translocation generally account for the genotypic variation in shoot Cd accumulation in rice, the world rice core collection, consisting of 69 accessions which covers the genetic diversity of almost 32,000 accessions of cultivated rice, was used. The results showed strong correlation between Cd levels in xylem sap and shoots and grains among the 69 rice accessions. Overall, the results presented in this study revealed that the root-to-shoot Cd translocation via the xylem is the major and common physiological process determining the Cd accumulation level in shoots and grains of rice plants.

Extrusion of spark plasma sintered aluminum-carbon nanotube composites at various sintering temperatures.

The combined processes of spark plasma sintering and hot extrusion were used to fabricate a multi-walled carbon nanotube (MWCNT) reinforced aluminum (Al) matrix composite. The structural defects of carbon nanotubes (CNT) at various sintering temperatures were investigated by Raman spectroscopy. A small amount of Al liquid phase was generated and it reacted with disordered CNTs, even during the solid-state spark plasma sintering process. The influence of Al carbides generated by the reaction between Al and disordered CNTs is discussed from a microstructural viewpoint and in relation to tensile strength. We conclude that structurally controlled CNTs could potentially be attractive for metal matrix applications, and could significantly improve the mechanical properties of AI-CNT composites.

Aluminum/Carbon Composites Materials Fabricated by the Powder Metallurgy Process.

Aluminum matrix composites reinforced with carbon fibers or diamond particles have been fabricated by a powder metallurgy process and characterized for thermal management applications. Al/C composite is a nonreactive system (absence of chemical reaction between the metallic matrix and the ceramic reinforcement) due to the presence of an alumina layer on the surface of the aluminum powder particles. In order to achieve fully dense materials and to enhance the thermo-mechanical properties of the Al/C composite materials, a semi-liquid method has been carried out with the addition of a small amount of Al-Si alloys in the Al matrix. Thermal conductivity and coefficient of thermal expansion were enhanced as compared with Al/C composites without Al-Si alloys and the experimental values were close to the ones predicted by analytical models.

Natural cadmium loading and balance in a non-polluted rice paddy field in Japan.

We determined the natural Cd balance in a cultivated rice paddy field in Japan. The main sources of Cd in the non-polluted paddy field were phosphorus fertilizer and precipitation (annual input of Cd, 2,000 mg ha(-1) and 1,020 mg ha(-1), respectively). These sources account for 95% of the total input of Cd (3,192 mg ha(-1)). The actual increase of Cd in the soil was 0.0016 mg kg(-1), we thus consider Cd in soil increases only slightly as a result of rice culture. This study indicates that it is difficult to reduce Cd loading by irrigation water treatment in a non-polluted paddy field. This further indicates that once a field is polluted by Cd it is difficult to decrease the accumulated Cd by the ordinary cultivation of rice plants.

Safety, Tolerability, and Pharmacokinetics of the Novel Anti-influenza Agent Baloxavir Marboxil in Healthy Adults: Phase I Study Findings.

BACKGROUND AND OBJECTIVE: Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. This first-in-human phase I study evaluated the safety, tolerability, and pharmacokinetics of baloxavir marboxil/baloxavir acid in healthy Japanese volunteers (Study 1), while food effects were evaluated in a separate phase I, crossover study in healthy Japanese volunteers (Study 2). METHODS: Study 1 participants were randomized to single-dose oral baloxavir marboxil (6, 20, 40, 60, or 80 mg; n = 6 per dose) or placebo (n = 10), while Study 2 participants (n = 15) received single-dose oral baloxavir marboxil 20 mg in fasted, fed, and before-meal states. RESULTS: Baloxavir marboxil was well tolerated; there were few treatment-emergent adverse events and no serious adverse events/deaths. The mean plasma baloxavir acid concentration 24 h after single-dose (C24) oral baloxavir marboxil 6 mg was 6.92 ng/mL, exceeding the target C24 (6.85 ng/mL) estimated in nonclinical studies. In Study 1, baloxavir acid exposure demonstrated dose-proportional increases in the fasted state, with maximum plasma concentration generally attained within 3.5 h. Terminal elimination half-life ranged from 49 to 91 h. In Study 2, exposure was decreased and apparent clearance increased in the fed and before-meal states versus the fasted state; however, exposure exceeded the target C24 in all states. CONCLUSION: Single-dose oral baloxavir marboxil was well tolerated, had a favorable safety profile, and had favorable pharmacokinetic characteristics, including a long half-life, supporting single oral dosing. The baloxavir acid area under the plasma concentration-time curve decreased with food intake by approximately 40%.

Correction to: Genetic diversity of arsenic accumulation in rice and QTL analysis of methylated arsenic in rice grains.

The authors of article "Genetic diversity of arsenic accumulation in rice and QTL analysis of methylated arsenic in rice grains" (Kuramata et al. 2013) would like to note that the original version of the article online unfortunately contains the following errors.

Effect of adding support structures for overhanging part on fatigue strength in selective laser melting.

Selective laser melting (SLM) technology was recently introduced to fabricate dental prostheses. However, the fatigue strength of clasps in removable partial dentures prepared by SLM still requires improvement. In this study, we attempted to improve the fatigue strength of clasps by adding support structures for overhanging parts, which can generally be manufactured at an angle to be self-supporting. The results show that the fatigue strength of the supported specimens was more than twice that of unsupported specimens. Electron back-scattered diffraction analysis revealed that the supported specimens exhibited lower kernel average misorientation values than the unsupported specimens, which suggested that the support structure reduced the residual strain during the SLM process and helped to prevent micro-cracks led by thermal distortion. In addition, the supported specimens cooled more rapidly, thereby forming a finer grain size compared to that of the unsupported specimens, which contributed to improving the fatigue strength. The results of this study suggest that the fatigue strength of overhanging parts can be improved by intentionally adding support structures.