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).

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.

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.

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.

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.

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.

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.

The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia.

Acute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique gene expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has the worst prognosis among all subtypes of MLL-rearranged AMLs. SHARP1 is expressed solely in MLL-AF6 AML, and its expression is regulated directly by MLL-AF6/DOT1L. Suppression of SHARP1 induces robust apoptosis of human MLL-AF6 AML cells. Genetic deletion in mice delays the development of leukemia and attenuated leukemia-initiating potential, while sparing normal hematopoiesis. Mechanistically, SHARP1 binds to transcriptionally active chromatin across the genome and activates genes critical for cell survival as well as key oncogenic targets of MLL-AF6. Our findings demonstrate the unique oncogenic role for SHARP1 in MLL-AF6 AML.

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.

Chromium carbide/Carbon Nanotube Hybrid Structure Assisted Copper Composites with Low Temperature Coefficient of Resistance.

In order to explore the possibility of using carbon nanotube (CNT) to introduce and control the temperature coefficient of resistance (TCR) of metal matrix composite, relatively thick and short multi-walled CNTs (MWCNTs) were introduced in the metal matrix with in-situ formation of chromium carbide (Cr7C3) at the CNT/copper (Cu) interface. We demonstrate that incompatible properties such as electrical conductivity and TCR can be achieved simultaneously by introducing MWCNTs in the Cu matrix, with control of the interfacial resistivity using the MWCNT/Cr7C3-Cu system. High electrical conductivity of 94.66 IACS and low TCR of 1,451 10-6 °C-1 are achieved in the 5 vol.% MWCNT-CuCr composite. In-situ formation of Cr7C3 nanostructures at the MWCNT/Cu interface by reaction of diffused Cr atoms and amorphous carbon of MWCNTs would assist in improving the electrical properties of the MWCNT-CuCr composites.

Synthesis of n-type Mg2Si/CNT Thermoelectric Nanofibers.

Magnesium silicide (Mg2Si)/carbon nanotube (CNT) thermoelectric nanofibers for use as a flexible thermoelectric material were successfully synthesized through the combined processes of the sol-gel method, magnesiothermic reduction, and liquid-solid phase reaction. In the resulting product, each CNT was coated with Mg2Si which was an approximately 60-nm-thick single crystal. The synthesized Mg2Si-coated CNTs exhibited n-type thermoelectric behavior confirming that n-type thermoelectric composite nanofibers were successfully obtained.

Fabrication of a Functionally Graded Copper-Zinc Sulfide Phosphor.

Functionally graded materials (FGMs) are compositionally gradient materials. They can achieve the controlled distribution of the desired characteristics within the same bulk material. We describe a functionally graded (FG) metal-phosphor adapting the concept of the FGM; copper (Cu) is selected as a metal and Cu- and Cl-doped ZnS (ZnS:Cu,Cl) is selected as a phosphor and FG [Cu]-[ZnS:Cu,Cl] is fabricated by a very simple powder process. The FG [Cu]-[ZnS:Cu,Cl] reveals a dual-structured functional material composed of dense Cu and porous ZnS:Cu,Cl, which is completely combined through six graded mediating layers. The photoluminescence (PL) of FG [Cu]-[ZnS:Cu,Cl] is insensitive to temperature change. FG [Cu]-[ZnS:Cu,Cl] also exhibits diode characteristics and photo reactivity for 365 nm -UV light. Our FG metal-phosphor concept can pave the way to simplified manufacturing of low-cost and can be applied to various electronic devices.

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.

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

BACKGROUND: Rice is a major source of dietary intake of arsenic (As) for the populations that consume rice as a staple food. Therefore, it is necessary to reduce the As concentration in rice to avoid the potential risk to human health. In this study, the genetic diversity in As accumulation and As speciation in rice grains was investigated using a world rice core collection (WRC) comprising 69 accessions grown over a 3-year period. Moreover, quantitative trait locus (QTL) analysis was conducted to identify QTLs controlling the dimethylarsinic acid (DMA) content of rice grains. RESULTS: There was a 3-fold difference in the grain As concentration of WRC. Concentrations of total-As, inorganic As, and DMA were significantly affected by genotype, year, and genotype-year interaction effects. Among the WRC accessions, Local Basmati and Tima (indica type) were identified as cultivars with the lowest stable total-As and inorganic As concentrations. Using an F2 population derived from Padi Perak (a high-DMA accession) and Koshihikari (a low-DMA cultivar), we identified two QTLs on chromosome 6 (qDMAs6.1 and qDMAs6.2) and one QTL on chromosome 8 (qDMAs8) that were responsible for variations in the grain DMA concentration. Approximately 73% of total phenotypic variance in DMA was explained by the three QTLs. CONCLUSIONS: Based on the results provided, one strategy for developing rice cultivars with a low level of toxic As would be to change the proportion of organic As on the basis of a low level of total As content.

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.).

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.

C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence.

In blood, the transcription factor C/EBPa is essential for myeloid differentiation and has been implicated in regulating self-renewal of fetal liver haematopoietic stem cells (HSCs). However, its function in adult HSCs has remained unknown. Here, using an inducible knockout model we found that C/EBPa-deficient adult HSCs underwent a pronounced increase in number with enhanced proliferation, characteristics resembling fetal liver HSCs. Consistently, transcription profiling of C/EBPa-deficient HSCs revealed a gene expression program similar to fetal liver HSCs. Moreover, we observed that age-specific Cebpa expression correlated with its inhibitory effect on the HSC cell cycle. Mechanistically we identified N-Myc as a downstream target of C/EBPa, and loss of C/EBPa resulted in de-repression of N-Myc. Our data establish C/EBPa as a central determinant in the switch from fetal to adult HSCs.

[Reducing cadmium content of rice grains by means of flooding and a few problems].

The effects of water management in rice paddies on the levels of cadmium (Cd) and arsenic (As) in Japanese rice grains were tested. In order to reduce the Cd concentration in rice grains, flooding for 3 weeks before and after heading was most effective, but this treatment increased As concentration considerably. Aerobic treatment was effective in reducing As concentration in rice grains, but increased Cd concentration markedly. In the pot experiment, flooding treatment after heading was more effective than flooding treatment before heading in reducing both Cd and As concentrations in rice grains. The concentration of dimethylarsinic acid (DMA) in rice grains was very low under aerobic conditions, but increased in the continuous-flooding treatment. In the field experiment, the grain As concentration in the case of flooding for 3 weeks before and after heading was higher than that in the case of intermittent irrigation. The ratios of DMA to the total As concentration were 3-52% in the pot experiment and 7-13% in the field experiment.