Influence of Previous Therapy for Neutropenia Caused by Combination Therapy of Ramucirumab and Docetaxel.

In the present study, the influence of previous immune checkpoint inhibitor (ICI) therapy with ramucirumab (RAM) + docetaxel (DTX) therapy on the occurrence of severe neutropenia in patients with non-small cell lung cancer (NSCLC) was evaluated, taking into account the influences of cytotoxic chemotherapy used in pretreatment. The study participants included patients who received a combination therapy of RAM and DTX as cancer chemotherapy for NSCLC. The influences of previous ICI treatment and pretreatment with cytotoxic anticancer agents on the development of grade ≥ 3 neutropenia were analysed. A total of 89 patients, including 50 with and 39 without a history of ICI treatment, were analysed. Kaplan-Meier curves showed a significant difference in the influence of previous ICI treatment on the development of grade ≥ 3 neutropenia (p = 0.006). Moreover, Cox regression analysis identified a history of ICI treatment and prophylactic administration of G-CSF as factors associated with the development of grade ≥ 3 neutropenia (p = 0.018 and p < 0.001, respectively). This study found that previous treatment with ICIs reduced the incidence of grade ≥ 3 neutropenia after RAM + DTX therapy in patients with NSCLC, regardless of the influences of pretreatment with cytotoxic anticancer agents.

[Examination of Analytical Method for Tris(2,3-dibromopropyl)phosphate and Bis(2,3-dibromopropyl)phosphate to Revise the Official Methods Based on "Act on the Control of Household Products Containing Harmful Substances"].

In Japan, the use of frame retardants [tris(2,3-dibromopropyl)phosphate: TDBPP and bis(2,3-dibromopropyl)phosphate: BDBPP] in several household textile products is banned under the "Act on the Control of Household Products Containing Harmful Substances." As the official analytical methods for testing these substances have not been revised for over 42 years, several issues such as the using of harmful reagents, have been pointed out. Therefore, we developed a new method to revise the official method in our previous study. In this study, the validity of the developed test method is evaluated at six laboratories using two types of textile samples spiked with TDBPP and BDBPP at three concentrations (4, 8, and 20 µg/g). TDBPP and BDBPP are extracted under reflux using methanol containing hydrochloric acid. TDBPP is analyzed using GC-MS, and BDBPP is also analyzed using GC-MS after methylation with trimethylsilyl diazomethane. Although the accuracy (70-120%), repeatability (<10%), and reproducibility (<15%) of a few samples, mainly low concentration samples, are out of range, overall, the concentration level of detection limits of TDBPP and BDBPP (8 and 10 µg/g) in official analytical methods are quantifiable with sufficient precision using the proposed method. Furthermore, harmful reagents are not used in this method. Thus, the method validated in this study is effective as a revised method for the testing of TDBPP and BDBPP in household textile products.

[Inter-laboratory Study on the Modified Methods for Analyzing Bisphenol A Content for Migration Tests from Polycarbonate Food Apparatuses, Containers, and Packaging].

An inter-laboratory study involving 24 laboratories was conducted to validate the modified analytical method for the migration solution of heptane for the determination of bisphenol A migrating from polycarbonate food processing materials. In this study, two concentrations of samples were blindly coded. Each laboratory determined the analyte (bisphenol A, phenol and p-tert-butylphenol) concentration in each sample according to the established protocol. The obtained values were analyzed statistically using internationally accepted guidelines. Horwitz ratios were calculated based on the reproducibility relative standard deviation (RSDR), which was estimated from the inter-laboratory study, and predicted RSDR, which was calculated using the Horwitz/Thompson equation. Horwitz ratios of the two samples ranged from 0.15 to 0.37 for the three compounds, meeting the performance criteria of less than 2 set by the Codex Alimentarius for analytical method approval. These results showed that this modified analytical method shows good performance as an analytical method for the migration solution of heptane.

[Validation Study on Developed Methods for Anions and Bromic Acid in Various Mineral Waters by Ion Chromatography].

Five kinds of anions namely fluoride, chlorate, chlorite, nitrate and nitrite ions, and bromic acid were determined in various mineral waters (MWs), and the methods were validated. MWs are varying in the degree of hardness and contents of carbonate. When the five anions were measured based on the official method of tap water, the peak shape of fluoride ion in MWs with high degree of hardness was different from the standard solution, making it difficult to determine. The same phenomenon was also observed when bromic acid was measured. In order to achieve accurate determination, five-fold dilution with ultrapure water was carried out on the samples. With the additional step, the abnormal peak of both analytes was improved, and no difference in the retention times between standard and sample solutions was observed. The validation tests were performed using the developed methods with the additional diluting step, and the results of all target substances met the criteria of the guideline on analytical method validation for MW in Japan. Our results suggested that the methods we developed could be useful for the accurate determination of the anions and bromic acid in various MWs on the market.

Hydrated Ionic Liquids: Perspective for Bioscience.

Hydrated ionic liquid (IL) is a simple mixture of IL and water. Unique aqueous electrolyte solution can be designed by mixing IL with limited amount of water. In most hydrated ILs, there are no free water and all are strongly interacted with ions. The properties of hydrated ILs, such as polarity, viscosity, ion mobility, and hydrogen bonding ability, can therefore be controlled simply by water content. This mixture is expected to provide similar environment to that of living cell, and is desired to be effective solvents for biomolecules. In this account, we would like to survey the basic properties, recent results, and future aspects of the hydrated ILs.

Applications of Zwitterions and Zwitterionic Polymers for Li-Ion Batteries.

A zwitterion is a neutral compound that has both a cation and an anion in the same molecule. Quaternary ammonium cations are frequently used for zwitterions. Zwitterions with quaternary ammonium cations are also common in biological molecules, such as phospholipids, which are the main components of cell membranes. Chemically, they have broad applicability because they are dielectric, non-volatile, and highly polar compounds with a large dipole moment. In addition, after salt addition, ion exchange does not occur in the presence of zwitterions. Owing to these characteristics, zwitterions have been applied as novel electrolyte materials targeting high ionic conductivity. In this review, application of zwitterions and their polymers for Li-ion batteries is addressed.

[Validation Study on Migration Test for Plastic Food Utensils, Containers, and Packaging].

Migration test of food utensils, containers, and packaging is an important test method for confirming the safety and their compliance to the standards. However, there is little report on inter-laboratory study which was performed to evaluate the entire migration test, including migration operations and quantification. An interlaboratory study was performed participating 22 laboratories using 8 types of model synthetic resin samples containing 10 substances with a wide range of Log Pow values to evaluate the accuracy of the entire migration test. As a result, most of HorRat (r) values met the target criteria (0.3

[Inter-laboratory Study on the Modified Method Assessment for the Determining Methanol Content in Kitchen Detergents].

We modified a method for determining methanol content in detergents used in kitchens. Furthermore, an inter-laboratory study was conducted in 10 laboratories to validate the modified method. In this study, two concentrations of samples were blindly coded. Each laboratory determined the methanol content in each sample according to a protocol. The determined values were statistically analyzed according to an international harmonized guideline. HorRat values were calculated based on the reproducibility relative standard deviation (RSDR) which was estimated from the interlaboratory study, and predicted RSDR calculated from the Horwitz/Thompson equation. The HorRat values of the two samples were 0.8 and 1.8, meeting the performance criteria of less than 2 set by the Codex Alimentarius for analytical method approval. These results confirm that this modified analytical method shows good performance as an analytical method for determining methanol content in kitchen detergents.

Inhalation exposure to 2-ethyl-1-hexanol causes hepatomegaly and transient lipid accumulation without induction of peroxisome proliferator-activated receptor alpha in mice.

2-Ethyl-1-hexanol (2EH) is a volatile organic compound known to cause sick building syndrome. However, 2EH-induced hepatotoxicity has been mainly evaluated in experiments orally administering 2EH as a metabolite of di(2-ethylhexyl) phthalate. To evaluate the hepatotoxicity risk of 2EH as an indoor air pollutant, we exposed 10-wk-old male ICR mice to 2EH by inhalation for 8 h/d, 5 d/wk for 3 months (0, 20, 60, or 150 ppm) or 6 months (0, 0.5, 10, or 100 ppm). In both experiments, relative liver weights significantly increased in the highest exposure groups. The 3-month exposure increased histopathological lipid droplets in the liver in a dose-dependent manner, hepatic triglyceride at all exposure levels, hepatic phospholipid at 150 ppm, and microsomal triglyceride transfer protein at 60 and 150 ppm; however, these changes were not observed following the 6-month of exposure. Following the 3-month exposure, alanine transaminase and peroxisomal bifunctional proteins, known markers of liver injury and peroxisome proliferation, respectively, remained unaltered. Therefore, in the present study, the inhalation concentration range of 2EH induced a toxic hypertrophic change, revealing a limited role of peroxisome proliferator-activated receptor alpha (PPARα). The liver weights may have presumably increased via a mechanism independent of PPARα activation.

An amperometric biosensor of L-fucose in urine for the first screening test of cancer.

Quantitative routine detection of fucose, which is a cancer marker, in urine is effective for the preliminary screening of cancer. Amperometric biosensing methods have the advantage of being simple, rapid, and precise for urinalysis. However, coexisting electroactive interferences such as ascorbic acid (AA), dopamine (DA), and uric acid (UA) prevent accurate measurements. In this work, an amperometric l-fucose biosensor unaffected by interferences was developed and utilizes direct electron transfer type bioelectrocatalysis of pyrroloquinoline quinone (PQQ)-dependent pyranose dehydrogenase from Coprinopsis cinerea (CcPDH). The isolated PQQ domain from CcPDH was immobilized on gold nanoparticle (AuNP)-modified electrodes, which obtained a catalytic current at a lower potential than the oxidation potential of the interfering compounds. Applying an operating potential of -0.1 V vs. Ag|AgCl (3 M NaCl) enabled the detection of l-fucose while completely eliminating the oxidation of AA, DA, and UA on the electrodes. The increase in the specific area of the electrodes by increasing the AuNP drop-casting time resulted in an improvement in the sensor performance. The biosensor exhibited a linear range for l-fucose detection between 0.1 mM and 1 mM (R2 = 0.9996), including a cut-off value, the sensitivity was 3.12 ± 0.05 µA mM-1 cm-2, and the detection limit was 13.6 µM at a signal-to-noise ratio of three. The biosensor can be used to quantify the concentration of l-fucose at physiological levels and does not require urine preprocessing, making it applicable to practical use for point-of-care testing with urine.

[Validation Study on Developed Methods for Total Organic Carbon in Some Kinds of Mineral Water].

Total organic carbon (TOC) was measured in some kinds of mineral water, and the method was validated. In mineral water, there are many kinds of elements such as carbon dioxide and a wide range of hardness. The official method for amount of TOC in tap water was validated in non-carbonated mineral water regardless of the degree of hardness. However, the amount of TOC was not accurately measured in two kinds of carbonated mineral water with medium or high degree of hardness. In our method of this study, the removal of carbon dioxide from the two kinds of mineral water was achieved by making bubbling time longer and additive rate of HCl upper than the official condition of tap water. And then, the method we developed was validated in the two kinds of mineral water. Our results suggested that the method we developed could be useful to measure the amount of TOC in many kinds of mineral water on the market.

Effect of the cation structure on cellulose dissolution in aqueous solutions of organic onium hydroxides.

The solubility of cellulose was systematically assessed in organic onium/inium hydroxide aqueous solutions (OHAS) having assorted cations, such as phosphonium, ammonium, piperidinium, morpholinium, pyrrolidinium, and cholinium. From a dissolution test of cellulose in OHAS, it was confirmed that the single most important factor in the dissolution is the high concentration of OHAS. In addition, having a weaker hydrogen bond network around OH and H2O was found to be important to facilitate the cellulose dissolution. In NMR analysis, the OHAS with an excellent cellulose solubility, such as tetrabutylphosphonium hydroxide ([P4444]OH), exhibited a chemical shift of water (δH2O) integrated with that of OH in the low frequency region (∼4.9 ppm), while choline hydroxide ([Ch]OH) with poor cellulose solubility showed δH2O higher than 5.2 ppm. A higher δH2O means that the protons are deshielded due to a stronger hydrogen bond network around H2O and OH, which indicates a strong self-associating property of OHAS that is unfavourable for the cellulose dissolution. Assuming that the strong self-associating property can be reduced by improving the hydrophobicity of organic cations, the methyl group in N-butyl-N-methylmorpholinium hydroxide ([Mor14]OH) was replaced by a butyl chain to shield the positive charge. While [Mor14]OH dissolved only 5 wt% of cellulose, the solubility in the synthesised OHAS, N,N-dibutylmorpholinium hydroxide ([Mor44]OH), was successfully improved to 20 wt%. In the present paper, cellulose solubility was also analysed in relation to the Kamlet-Taft parameters.

Crystal Structure of the Catalytic and Cytochrome b Domains in a Eukaryotic Pyrroloquinoline Quinone-Dependent Dehydrogenase.

Pyrroloquinoline quinone (PQQ) was discovered as a redox cofactor of prokaryotic glucose dehydrogenases in the 1960s, and subsequent studies have demonstrated its importance not only in bacterial systems but also in higher organisms. We have previously reported a novel eukaryotic quinohemoprotein that exhibited PQQ-dependent catalytic activity in a eukaryote. The enzyme, pyranose dehydrogenase (PDH), from the filamentous fungus Coprinopsis cinerea (CcPDH) of the Basidiomycete division, is composed of a catalytic PQQ-dependent domain classified as a member of the novel auxiliary activity family 12 (AA12), an AA8 cytochrome b domain, and a family 1 carbohydrate-binding module (CBM1), as defined by the Carbohydrate-Active Enzymes (CAZy) database. Here, we present the crystal structures of the AA12 domain in its apo- and holo-forms and the AA8 domain of this enzyme. The crystal structures of the holo-AA12 domain bound to PQQ provide direct evidence that eukaryotes have PQQ-dependent enzymes. The AA12 domain exhibits a six-blade ß-propeller fold that is also present in other known PQQ-dependent glucose dehydrogenases in bacteria. A loop structure around the active site and a calcium ion binding site are unique among the known structures of bacterial quinoproteins. The AA8 cytochrome domain has a positively charged area on its molecular surface, which is partly due to the propionate group of the heme interacting with Arg181; this feature differs from the characteristics of cytochrome b in the AA8 domain of the fungal cellobiose dehydrogenase and suggests that this difference may affect the pH dependence of electron transfer.IMPORTANCE Pyrroloquinoline quinone (PQQ) is known as the "third coenzyme" following nicotinamide and flavin. PQQ-dependent enzymes have previously been found only in prokaryotes, and the existence of a eukaryotic PQQ-dependent enzyme was in doubt. In 2014, we found an enzyme in mushrooms that catalyzes the oxidation of various sugars in a PQQ-dependent manner and that was a PQQ-dependent enzyme found in eukaryotes. This paper presents the X-ray crystal structures of this eukaryotic PQQ-dependent quinohemoprotein, which show the active site, and identifies the amino acid residues involved in the binding of the cofactor PQQ. The presented X-ray structures reveal that the AA12 domain is in a binary complex with the coenzyme, clearly proving that PQQ-dependent enzymes exist in eukaryotes as well as prokaryotes. Because no biosynthetic system for PQQ has been reported in eukaryotes, future research on the symbiotic systems is expected.

Dimension control of ionic liquids.

Ionic liquids have established themselves as promising soft compounds for bringing innovation to materials science. For further developing functions and abilities of ionic liquids, one of the most important challenges is to organize ionic liquids into dimensionally ordered states. In this feature article, we will present the organization of ionic liquids by endowing them with liquid-crystalline properties. In particular, focusing on the specific abilities and properties of functional ionic liquids, a variety of nanostructured ionic materials have been developed and their unique and enhanced functions have been revealed. Some potential uses of organized ionic liquids have also been mentioned.

Effects of charge balance and hydrophobicity of the surface of cytochrome c on the distribution behaviour in an ionic liquid/buffer biphasic system.

Factors contributing to the different distribution behaviour of cytochrome c were investigated in a biphasic tetrabutylphosphonium 2,4,6-trimethylbenzenesulfonate and potassium phosphate buffer system, which shows a lower critical solution temperature. To change charge balance and hydrophobicity of cytochrome c, surface modification with a few modifier molecules was applied. Surface charge and hydrophobicity affected the distribution behavior of chemically modified cytochrome c in the tetrabutylphosphonium 2,4,6-trimethylbenzenesulfonate and potassium phosphate buffer biphasic system. The distribution ratio into tetrabutylphosphonium 2,4,6-trimethylbenzenesulfonate decreased with decreasing isoelectric point of cytochrome c. Furthermore, cytochrome c possessing a low isoelectric point showed different distribution ratio depending on surface hydrophobicity. Taken together, these findings indicate that isoelectric point and surface hydrophobicity of cytochrome c are important factors controlling the distribution behavior in temperature sensitive biphasic systems.

Preparation of epoxy resins derived from lignin solubilized in tetrabutylphosphonium hydroxide aqueous solutions.

Organic onium hydroxide aqueous solutions (OHAS) are demonstrated to be potential solvents for the dissolution of lignin and its epoxidation. A series of OHAS has been assessed in terms of the solubility of soda lignin (SL) and Klason lignin (KL), which are moderately and rarely soluble in NaOH aq. soln., respectively. Tetrabutylphosphonium hydroxide ([P4444]OH) aqueous solution was found to exhibit a highest solubility, specifically 40 wt% of SL and 3.0 wt% of KL. The superior solubility of OHAS is comprehended to be due to weak interactions between OH anions and phosphonium cations, and hence OH anions interact effectively with lignin. Epoxidation of SL was achieved by simply adding epichlorohydrin to [P4444]OH aq. dissolving SL. Films of epoxidized SL were prepared by thermal curing with the aid of a crosslinking agent, and the films were found to possess high thermal stability of >250 °C and excellent ductility. The thermal and mechanical properties were controllable by the concentration of [P4444]Cl as an additive.

Hydrated ionic liquids enable both solubilisation and refolding of aggregated concanavalin A.

The dissolution and refolding of aggregated concanavalin A have been achieved, in hydrated ionic liquids containing a limited number of water molecules. Both ammonium and phosphonium salts were examined to find a suitable hydrophobicity of ions and water content for refolding. Recovery of sugar recognition was confirmed as a proof of refolding.

Comprehensive review of 2-ethyl-1-hexanol as an indoor air pollutant.

OBJECTIVES: 2-Ethyl-1-hexanol (2EH), a fragrance ingredient and a raw material for the production of plasticizer di(2-ethylhexyl) phthalate, is responsible for sick building syndrome (SBS). This review aims to clarify the 2EH characteristics as an indoor air pollutant such as indoor air concentration, emission mechanism, toxicity, and clinical effects. METHODS: Scientific publications in English that has been made available on PubMed as of June 2018 and ad hoc publications in regional languages were reviewed. RESULTS: Inhalation exposure to 2EH caused mucous membrane irritation in the eyes, nose, and throat in experimental animals. Studies in human volunteers revealed an increase in olfactory irritation and eye discomfort. There has been increasing evidence of 2EH being present in indoor air in buildings. The primary sources of 2EH emissions are not building materials themselves, but instead the hydrolysis of plasticizers and flooring adhesives. In particular, compounds like di(2-ethylhexyl) phthalate present in polyvinyl chloride flooring materials are hydrolyzed upon contact with alkaline moisture-containing concrete floors. That being said, it may be observed that indoor concentrations of 2EH increased every year during summer. CONCLUSIONS: Unlike other volatile organic compounds that cause SBS, 2EH can be retained in indoor air for long durations, increasing the likelihood of causing undesirable health effects in building occupants exposed to it. As a precautionary measure, it is important to use flooring materials that do not emit 2EH by hydrolysis, or to dry concrete before covering with flooring materials.

Synthesis of Ionic Liquids Originated from Natural Products.

In this chapter, preparation, basic properties, and some applications of ionic liquids composed of naturally-derived ions are summarized. There are many candidate ions in nature suitable for ionic liquid preparation. Physicochemical properties and preparation of some ionic liquids based on carboxylate anions, cholinium cation, and even amino acids are mentioned. Some interesting applications based on these ionic liquids composed of naturally-derived ions are also briefly introduced. Graphical Abstract.

An integrated process for enzymatic catalysis allowing product recovery and enzyme reuse by applying thermoreversible aqueous biphasic systems.

Thermoreversible aqueous biphasic systems (ABS) composed of ammonium-based zwitterions (ZIs) and polymers are here disclosed to act as integrated bioreaction-separation processes. The biocatalytic reaction involving laccase occurs in homogeneous media, after which small changes in temperature induce the formation of two phases and the complete separation of the enzyme from the products in a single-step. These systems also allow the recover and reuse of the enzyme, along with the ZI-rich phase, contributing towards the development of sustainable biocatalytic processes.