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A systematic investigation of the polymerization of representative diphenylacetylenes with TaCl5 and cocatalysts suggested that low-valent Ta species, which are formed by in situ reduction of TaCl5 by the cocatalysts, are involved in the polymerization and that the polymerization reaction proceeds by an insertion ring expansion mechanism via the formation of tantalacyclopentadiene intermediates, rather than the previously considered metathesis mechanism. This polymerization mechanism indicates the production of unprecedented cis-stereoregular cyclic poly(diphenylacetylene)s. Indeed, the possibilities of a cyclic structure and high cis-stereoregularity of the resulting polymers were reasonably supported by the results of their detailed atomic force microscopy (AFM) and NMR analyses, respectively.

In this paper Pd-catalyzed intramolecular dehydrogenative C(sp3)–H amidation for the synthesis of isoindolinones is described. This method features the use of a Pd/C catalyst and the addition of a stoichiometric amount of oxidant is not necessary. A mechanistic study suggested the possible formation of H2 gas during the reaction.

Glutathione S-transferase (GST) is a family of important drug-metabolizing enzymes, conjugating endogenous and exogenous compounds. Genetic polymorphisms result in the inter-individual variability of GST activity in humans. Especially, human GSTT1 and GSTT2 null alleles are associated with toxicity and various cancers derived from chemicals. Cynomolgus macaque, a nonhuman primate species widely used in drug metabolism studies, has molecular and enzymatic similarities of GSTs to the human orthologs; however, genetic polymorphisms have not been investigated in this species. In this study, resequencing of GSTT1 and GSTT2 in 64 cynomolgus and 32 rhesus macaques found 15 nonsynonymous variants and 1 nonsense variant for GSTT1 and 15 nonsynonymous variants for GSTT2. Some of these GSTT variants were distributed differently in Indochinese and Indonesian cynomolgus macaques and rhesus macaques. For analysis of functional relevance of the GSTT variants, 1-iodohexane and dibromomethane were determined to be suitable substrates for cynomolgus GSTT1 and GSTT2. However, the conjugation activities were roughly correlated with GSTT protein levels immunochemically quantified in cynomolgus liver samples with no statistical significances, implying the contributions of the GST genetic variants. Among the GSTT1 variants identified, the animals carrying R76C and D125G mutations showed lower conjugation activities toward dibromomethane than those of the wild-type in liver cytosolic fractions. Moreover, the recombinant R76C/D125G and D125G GSTT variant proteins showed significantly lower 1-iodohexane or dibromomethane conjugation activities than those of the wild-type protein. Therefore, inter-animal variability of GSTT-dependent drug metabolism is at least partly accounted for by GSTT1 and possibly GSTT2 variants in cynomolgus and rhesus macaques.

A facile synthesis of benzo[b]thiophene-3-carboxamides from (ortho-alkynyl)phenyl methoxymethyl sulfides and isocyanates was realized. The method involves a tandem-type, cyclization–addition sequen...

Introduction: Multiple myeloma (MM) is a hematological malignancy characterized by proliferation of abnormal plasma cells in bone marrow. Revised-International Staging System (R-ISS) is generally used as a predictor in newly diagnosed MM (NDMM) since 2015. R-ISS combines ISS with chromosomal abnormalities (CA) and serum lactate dehydrogenase (LDH). R-ISS I is defined as ISS I without high risk CA and normal LDH, R-ISS III is defined as ISS III with high risk CA or high level LDH, and R-ISS II includes all of the other possible combinations. Therefore, about 60% of NDMM are classified to R-ISS II. However, MM is a highly heterogeneous disease, so the clinical outcome of MM with R-ISS II also must be heterogeneous. Therefore, factors stratifying the majority of MM is needed. C-reactive protein (CRP) is a commonly used inflammatory marker. In particular, highly sensitive (hs) CRP detects lower concentration of CRP as compared with the conventional method, and has been reported to be associated with mortality of lung, breast, and renal cell cancers. In this study, we evaluated the predicting potential of hs-CRP in MM in the novel agent era to see if hs-CRP can develop the stratifying power of R-ISS. Materials and Methods: The retrospective study examined 80 patients with symptomatic NDMM who had been diagnosed at our institution between April 2006 and September 2019. Patients with infection and/or amyloidosis were excluded. Linkable anonymizing data, including age, gender, immunoglobulin type, symptoms, R-ISS, hs-CRP at diagnosis, time to next treatment (TNT) of the initial treatment, and overall survival (OS) were collected. The concentration of hs-CRP was measured by quantitative latex agglutination turbidimetric immunoassay. The lower detection limit of hs-CRP is 0.01 mg/dL, while that of conventional CRP was 0.10 mg/dL. We analyzed these data using the Kaplan-Meier method, Fisher's exact, multivariate cox proportional hazard models, and log-rank test. P-values ≤0.05 was considered to be statistically significant. This retrospective study was approved by institutional review board in University of Fukui, Japan (No. 20190101). Results: Among 80 patients, 39 (48.8%) were male. Median age at diagnosis was 71 years (range: 36-89 years). IgG, IgA, and BJP types were 56.8%, 25.9%, and 17.3%, respectively. Median follow-up was 29 months (range: 1-120 months). All of the patients were treated with bortezomib and/or lenalidomide-based regimens throughout their clinical courses. R-ISS I, II, and III were 7.3%, 76.4%, and 16.4%, and median OS in patients with R-ISS I, II, and III were unreached, 67, and 15 months, respectively (p0.1 mg/dL, n=38). No significant difference in gender, age, immunoglobulin type was observed between 2 groups according to Fisher's exact test. The levels of hs-CRP appeared to be associated with the presence of bone lesions, not hypercalcemia, renal dysfunction, and anemia. There was not significant correlation between hs-CRP and TNT of the initial treatment, due to the variation of the used regimens. However, Kaplan-Meier curves showed that low hs-CRP group had significantly better OS than high hs-CRP group (64 months vs. 54 months, p=0.0116). Multivariate analysis indicated that both R-ISS (hazard ration (HR), 6.19) and hs-CRP (HR, 7.03) were independent prognostic factors for OS. Moreover, comparing the patients with R-ISS II divided by median hs-CRP, OS was significantly longer in R-ISS II with low hs-CRP than R-ISS II with high hs-CRP (median OS: 81 months vs. 54 months, p=0.0009) (Figure 1). Similarly, in the patients with R-ISS III, OS tended to be longer in low hs-CRP group than high hs-CRP group (median OS: 21 months vs. 5.5 months). All the patients with R-ISS I survived within the follow-up period. Conclusions: Hs-CRP enabled to detect 0.01-0.1 mg/dL, that is not measured by the conventional CRP method. The superiority of hs-CRP contributes to the role as a powerful predictor in MM. The novel staging system that combines hs-CRP and R-ISS may establish better understanding of prognosis in NDMM. Disclosures Yamauchi: Pfizer: Honoraria, Research Funding; Otsuka: Research Funding; Chugai: Honoraria; Abbie: Research Funding; Solasia Pharma: Research Funding; Daiichi Sankyo: Research Funding; Ono Pharmaceutical: Honoraria; Astellas: Research Funding.

The common marmoset is an important primate species used in drug metabolism studies. However, glutathione S-transferases (GSTs), essential drug-metabolizing enzymes involved in the conjugation of various endogenous and exogenous substrates, have not been identified or characterized in this species. In this study, 20 GSTs [including 3 microsomal GSTs (MGSTs)] were identified and characterized in marmosets. Marmoset GSTs had amino acid sequences highly identical (86-99%) to human GSTs, except for GSTA4L, which had lower identities (59-62%) with human GSTAs. Phylogenetic analysis revealed that marmoset GSTs were closely clustered with their human counterparts. Marmoset GSTs had gene and genomic structures generally similar to their human counterparts, with some differences in GSTA, GSTM, and GSTT clusters. Marmoset GST mRNAs exhibited distinct tissue expression patterns: GSTA1, GSTA3, GSTA4L, GSTK1, GSTT1, GSTZ1, and MGST1 mRNAs were expressed most abundantly in liver. Other GST mRNAs were expressed most abundantly in small intestine, lung, brain, or kidney. Expression of GSTT4 and GSTT4L mRNAs was detected only in testis. Among all 20 marmoset GST mRNAs, the most abundant mRNAs were GSTA1 mRNA in liver, small intestine, and kidney; GSTM3 mRNA in testis; and MSGT3 mRNA in brain and lung. All 20 GSTs mediated the conjugation of GST substrates 1-chloro-2,4-dinitrobenzene; 1,2-epoxy-3-(p-nitrophenoxy)propane; styrene 7,8-oxide; and/or 1-iodohexane, but with different activity levels. Kinetic analyses showed that marmoset GSTM2/GSTM5 and GSTM5/GSTT1 effectively conjugated styrene 7,8-oxide and 1-iodohexane, respectively, with the highest affinity. These results suggest that the 20 newly identified marmoset GSTs were functional drug-metabolizing enzymes able to conjugate typical GST substrates.

Albumin has reportedly enhanced cytochrome P450 (P450)-mediated drug oxidation rates in human liver microsomes. Consequently, measurements of clearances and fractions metabolized could vary depending on the experimental albumin concentrations used. In this study, the oxidation rates of diclofenac and warfarin by human liver microsomes were significantly enhanced in the presence of 0.10% (w/v) bovine serum albumin, whereas those of tolbutamide and phenytoin required 1.0% and 2.0% of albumin for significant enhancement. Values of the fractions metabolized by P450 2C9 for four substrates did not markedly change in the presence of albumin at the above-mentioned concentrations. The oxidation rates of bupropion, omeprazole, chlorzoxazone and phenacetin in human liver microsomes were reportedly enhanced by 0.5%, 1%, 2% and 2% of albumin, respectively. Analysis of reported intrinsic clearance values and suitable albumin concentrations for the currently analyzed substrates and the reported substrates revealed an inverse correlation, with warfarin as an outlier. Suitable albumin concentrations were multivariately correlated with physicochemical properties, that is, the plasma unbound fractions, octanol-water partition coefficient and acid dissociation constant (r = 0.98, p

Tributyltin (TBT), a common organotin environmental pollutant, has been widely used as a component of marine antifouling paints. We previously reported that exposure to TBT inhibits the expression and DNA binding of nuclear respiratory factor-1 (NRF-1) and causes neurotoxicity. In the present study, we focused on the epigenetic effects of TBT and investigated whether TBT decreases NRF-1 expression via epigenetic modifications in SH-SY5Y human neuroblastoma cells. First, we found that exposure to 300 nM TBT decreases NRF-1 expression. We examined epigenetic changes induced by TBT, and showed that TBT causes hypermethylation of the NRF-1 promoter region, increases the amount of methyl-CpG-binding protein 2 (MeCP2) bound to the NRF-1 promoter, and alters the expression of DNA methyltransferases and ten-eleven translocation (TET) demethylation enzymes. These results suggest that epigenetic changes play an important role in regulation of NRF-1 expression. Next, we investigated effect of NRF-1 expression decrease on cells, and TBT reduces mitochondrial membrane potential and overexpression of NRF-1 rescued this reduction in membrane potential. Thus, we suggested that NRF-1 is important for maintaining mitochondrial membrane potential. Our study indicates that TBT causes epigenetic changes such as hypermethylation, which increases recruitment of MeCP2 to the NRF-1 promoter and probably lead to decreased of NRF-1 expression and mitochondrial membrane potential. Therefore, this research provides new evidence of the epigenetic action caused by organotin.

Time-resolved luminescent spectra of ionic liquids of 1-butyl-3-methylimidazolium dicyanoaurate ([C4mim][Au(CN)2]) and N-butyl-N-methylpyrrolidinium dicyanoaurate ([P14][Au(CN)2]) at different excitation wavelengths (310 and 340nm) were measured using a streak camera. Immediately after photoexcitation, an intense luminescence band appeared at ~380nm that rapidly decayed with a time constant of 31 ps for [C4mim][Au(CN)2] and 71 ps for [P14][Au(CN)2]. With the decay of this band, another luminescent band appeared at ~460nm that slowly decayed (88ns for [C4mim][Au(CN)2] and 1.2μs for [P14][Au(CN)2]). The peak position of this second band shifted to a longer wavelength over time for both ionic liquids. The time profile of the peak showed a multi-exponential decay and depended on the excitation wavelength and the cation species. The peak shift is discussed in terms of the aggregation of anions. The excitation wavelength dependence was supposed to reflect the distribution of the larger oligomer in the ground state and the structural heterogeneity of the ionic liquids. The difference as a result of the cation is discussed in relation to the viscosity and the structure of the ionic liquids.

Methods for the chemical recycling of polycarbonate (PC) wastes in the forms of bisphenol A (BPA) and cyclic heterocarbonates, such as 1,3-dithiolan-2-one (DTO), 1,3-dithiane-2-one (DTA), and cyclic unsymmetric heterocarbonates, were investigated to prove that PC can be utilized as a phosgene equivalent for industrial purposes. Treatment of PC pellets or waste PC compact discs with 1,2-ethanedithiol and a catalytic amount of base (e.g., 1.5 mol % NaOH) in dioxane for a short period at 40°C produced DTO and BPA, both in nearly quantitative yields. The reaction could also be carried out in DTO, which saved the use of conventional solvents. Other cyclic heterocarbonates, that is, DTA, 1,3-oxathiolan-2-one, 1,3-thiazolidine-2-one, and N-methyl-1,3-oxazolidine-2-one, were prepared in high yields under analogous conditions. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 2959–2968, 2003

The Fukushima first nuclear power plant accident was triggered by the Japanese big earthquake in 2011. The main radioactivity concerned after the accident are I-131 (half-life 8.0 days), Cs-134 (2.1 years) and 137 (30 years), Sr-89 (51 days) and 90 (29 years). We are aiming to establish a new detection technique which enables us to realize quantitative evaluation of the strontium radioactivity by means of nondestructive measurement without chemical separation processing, which is concerned to be included inside foods, environmental water and soil around us, in order to prevent us from undesired internal exposure to the radiation.

A new type of a trigger-scintillation counter array designed for the MTV experiment at TRIUMF-ISAC has been developed, which uses aluminum-metallized film tape for wrapping to achieve the required assembling precision of $\pm$0.5 mm. The MTV experiment uses a cylindrical drift chamber (CDC) as the main electron-tracking detector. The barrel-type trigger counter is placed inside the CDC to generate a trigger signal using 1 mm thick, 300 mm long thin plastic scintillation counters. Detection efficiency and light attenuation compared with conventional wrapping materials are studied., Comment: to be published in Nuclear Instruments and Methods A

Gymnopilus junonius is a widely spread mushroom in Japan and well known as a hallucinogenic mushroom. Gymnopilin was purified from the fruiting body of G. junonius and was reported to act on the spinal cord and depolarize motoneurons. This is the only evidence that gymnopilin has a biological effect on animals and no mechanism of the action has been determined at all. In this study, we examined effects of gymnopilin on intracellular Ca(2+) concentrations ([Ca(2+)](i)) of cultured cells isolated from the dorsal root ganglion (DRG) of the rat. The cell culture consisted of neurons and non-neuronal cells. Gymnopilin increased [Ca(2+)](i) in both the types of cells. The gymnopilinevoked [Ca(2+)](i) rise in the non-neuronal cells was inhibited by cyclopiazonic acid and U-73122, inhibitors of Ca(2+)-ATPase of the intracellular Ca(2+) store and phospholipase C, respectively, but not by removal of extracellular Ca(2+). These results indicate that gymnopilin activated phospholipase C and mobilize Ca(2+) from the intracellular Ca(2+) store in non-neuronal cells from the DRG. This is the first report to show that gymnopilin directly acts on cells isolated from the mammalian nervous system.

The Fukushima Daiichi nuclear power plant accident was triggered by the 2011 Great East Japan Earthquake. The main radioactivity concerns after the accident are I-131 (half-life: 8.0 days), Cs-134 (2.1 years), Cs-137 (30 years), Sr-89 (51 days), and Sr- 90 (29 years). We are aiming to establish a new nondestructive measurement and detection technique that will enable us to realize a quantitative evaluation of strontium radioactivity without chemical separation processing. This technique is needed to detect radiation contained in foods, environmental water, and soil, to prevent us from undesired internal exposure to radiation.