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• A retrospective study was conducted to evaluate the safety of extending dose intervals for nivolumab and pembrolizumab. • Most patients were able to continue ICI therapy after an extended dosing interval. • Patients who received an extended-interval dosing schedule for the first time or with pre-existing antibodies are likely to experience immune-related adverse effects after starting extended dosing intervals. In addition to 2-weekly nivolumab 240 mg or 3-weekly pembrolizumab 200 mg, extended dosing intervals of 4-weekly nivolumab 480 mg or 6-weekly pembrolizumab 200 mg were approved. To date, the clinical safety of the extended dosing schedules of immune checkpoint inhibitors (ICIs) has not been adequately investigated in patients with solid tumors. This real-world study enrolled patients with solid tumors who received nivolumab 480 mg every 4 weeks or pembrolizumab 400 mg every 6 weeks at the Kyoto Prefectural University of Medicine in Japan, between August 2020 and December 2021. Sixty-nine patients with solid tumors received an extended-interval dosing schedule during this period. Among them, 60 received it during treatment (cohort A), and nine received it for the first time (cohort B). After the extended dosing interval of ICIs in cohort A, 13 (21.7%) patients developed immune-related adverse events (irAEs). Seven of the 13 patients (53.8%) developed irAEs during the first cycle of the extended dosing interval. All patients who developed irAEs during the first cycle of the extended dosing interval had pre-existing antibodies. Multivariate analysis indicated that patients with pre-existing anti-thyroid antibodies had a significantly higher irAE incidence after starting extended dosing intervals (odds ratio: 6.41; 95% confidence interval: 1.46–28.2, p = 0.01). Most patients were allowed to continue ICI therapy after an extended dosing interval. Patients with pre-existing antibodies, particularly anti-thyroid antibodies, may be prone to developing irAEs after starting extended dosing intervals and should be treated with caution. [ABSTRACT FROM AUTHOR]

A newly isolated bacterium, Cellulomonas parahominis MB426, produced l-ribose isomerase (CeLRI) on a medium containing l-ribose as a sole carbon source. A 32 kDa protein isomerizing l-ribose to l-ribulose was purified to homogeneity from this bacterium. A set of degenerated primers were synthesized based on amino acid sequences of the purified CeLRI, and a 747 bp gene encoding CeLRI was cloned, sequenced and overexpressed in Escherichia coli. This gene encoded a 249 amino acid protein with a calculated molecular mass of 27,435. The deduced amino acid sequence of this gene showed the highest identity with l-ribose isomerase from Acinetobacter calcoaceticus DL-28 (71%). The recombinant l-ribose isomerase (rCeLRI) was optimally active at pH 9.0 and 40°C, and was stable up to 40°C for 1 h and not dependent for metallic ions for its activity. The rCeLRI showed widely substrate specificity for the rare sugar which involved l-erythro form such as l-ribose, d-lyxose, d-talose, d-mannose, l-gulose, and l-allose. [Copyright &y& Elsevier]

Abstract: This paper describes the development of a sinking EDM simulation method by determining discharge locations. The simulation repeats the routine modelling of the process of each discharge consisting of determination of discharge location, removal of electrodes, generation and displacement of debris particles, and tool electrode feeding. The spot with the shortest discharge delay time calculated probabilistically assuming that an exponential distribution applies is searched for and this is determined to be the discharge location. The tool electrode feed is also determined based on discharge delay time like actual feed control. Electrode shapes and gap width distributions simulated for different working surface areas agreed with experimental results. [Copyright &y& Elsevier]

Abstract: l-Rhamnose isomerase (l-RhI) from Pseudomonas stutzeri LL172 can convert d-psicose to d-allose. Partially purified recombinant l-RhI from Escherichia coli was immobilized on BCW-2510 Chitopearl beads and utilized to produce d-allose. Total 20,000 units of immobilized enzyme converted d-psicose to d-allose without remarkable decrease in the enzyme activity over 17 days. When 50% d-psicose (w/w) was applied to a column with a flow rate of 0.8ml/min at 42°C, approximately 30% d-psicose was isomerized to d-allose for 17 days. However, by reducing the flow rate to 0.4ml/min after 17 days, d-allose was transformed at the same rate for 13 days. The total of 27l reaction mixture was separated by Simulated-Moving-Bed Chromatograph system. Approximately 2.2l/d of 50% (w/w) reaction mixture was separated continuously. After separation, d-allose and d-psicose fractions were 3l of approximately 10% (w/w) with 95% purity and 10l of approximately 8% (w/w) with 95% purity per day, respectively. The separated d-allose solution was concentrated up to about 50% and crystallized gradually by being kept at room temperature. Crystals of d-allose were separated from the syrup by filtration and 1.65kg crystals of 100% purity were obtained. The d-allose crystal yield from the d-psicose substrate was approximately 10%. [Copyright &y& Elsevier]

Abstract: The efficient isomerization of l-rhamnose [the only cheaply available deoxy hexose] to 1-deoxy-l-psicose, 1-deoxy-d-psicose, 1-deoxy-l-fructose, 1-deoxy-d-fructose, 1-deoxy-l-tagatose, 6-deoxy-l-psicose, 6-deoxy-d-psicose, 6-deoxy-l-fructose, 6-deoxy-d-fructose, and 6-deoxy-l-tagatose is described. The conversion of rhamnose to ten of the sixteen 1- and 6-deoxyketohexoses is accomplished in water in three steps. The range of substrates for d-tagatose-3-epimerase (DTE) is extended to 1- and 6-deoxyketoses. An authentic sample of 6-deoxy-d-psicose is prepared from d-psicose. [Copyright &y& Elsevier]

Abstract: A novel facultative thermophilic bacterium capable of producing rare ketoses from polyols was isolated from soil and identified as Bacillus pallidus Y25. We have employed this isolated strain for the production of l-xylulose, a rare ketopentose, from xylitol by a resting cell reaction at 50°C. After optimization of culture conditions and reaction states, l-xylulose was produced at up to 85% yield when 2% xylitol was utilized. The key enzyme responsible for the interconversion of xylitol and l-xylulose was purified to homogeneity and identified as NAD-dependent xylitol dehydrogenase (XDH-Y25), with a molecular mass of 28kDa as determined by SDS-PAGE. XDH-Y25 is most active in glycine–NaOH buffer (pH 10) at 40°C and its substrate specificity is restricted to d-threitol, xylitol and d-iditol. This suggested that the enzyme is specific for polyols that have a hydroxyl group at the C-2 and C-3 positions in the l- and d-sides, respectively, in the Fischer projection. N-terminal amino acid sequencing of XDH-Y25 revealed low homology to any known dehydrogenases. To our knowledge, this is the first report on the characterization of xylitol dehydrogenase from a Bacillus species. [Copyright &y& Elsevier]

Abstract: Xylitol was used as a raw material for production of l-xylose and l-lyxose using Alcaligenes 701B strain and immobilized l-rhamnose isomerase enzyme. Alcaligenes 701B converted xylitol to l-xylulose with a yield of 34% in the bioreactor. l-Xylulose was converted to l-xylose and l-lyxose using immobilized l-rhamnose isomerase enzyme. The final equilibrium between l-xylulose, l-xylose and l-lyxose was 53:26:21. The enzyme assays indicated that Alcaligenes 701B strain has an NAD-dependent xylitol dehydrogenase enzyme responsible for l-xylulose production. Furthermore, NAD(P)H-dependent l-xylulose reductase enzyme was active during conversion of xylitol to l-xylulose. The highest l-xylulose production rate corresponded with the highest growth rate. The Alcaligenes 701B strain used d-xylose for biomass growth, but xylitol was used only for l-xylulose production during conversion phase. [Copyright &y& Elsevier]

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC) harboring ALK- rearrangements. However, a small population of tumor cells survives due to adaptive resistance under drug pressure and ultimately acquires drug resistance. Thus, it is necessary to elucidate the mechanisms underlying the prevention of drug resistance to improve the prognosis of patients with ALK-rearranged NSCLC. We identified novel adaptive resistance, generated through c-Jun N-terminal kinase (JNK)/c-Jun signaling, to initial ALK-TKIs-alectinib and brigatinib-in ALK-rearranged NSCLC. Inhibition of JNK/c-Jun axis showed suppression of growth and promotion of apoptosis induced by ALK-TKIs in drug-tolerant cells. JNK inhibition, in combination with the use of ALK-TKIs, increased cell apoptosis through repression of the Bcl-xL proteins, compared with ALK-TKI monotherapy. Importantly, combination therapy targeting JNK and ALK significantly delayed the regrowth following cessation of these treatments. Together, our results demonstrated that JNK pathway activation plays a pivotal role in the intrinsic resistance to ALK-TKIs and the emergence of ALK-TKI-tolerant cells in ALK-rearranged NSCLC, thus indicating that optimal inhibition of tolerant signals combined with ALK-TKIs may potentially improve the outcome of ALK-rearranged NSCLC. [ABSTRACT FROM AUTHOR]

Although concurrent chemoradiotherapy (CCRT) followed by durvalumab is the standard treatment for patients with stage III non-small cell lung cancer (NSCLC), only half of the patients are allowed to receive CCRT in real-world settings. We evaluated the efficacy and safety of durvalumab after radiation monotherapy for NSCLC patients who are ineligible for chemoradiotherapy. A single-arm, prospective, open-label, multicenter phase II trial was conducted in Japan. The patients received radiation (54–66 Gy) followed by durvalumab (10 mg/kg every 2 weeks for up to 12 months). The primary endpoint was the 1-year progression-free survival (PFS) rate. The secondary endpoints were the objective response rate (ORR), PFS, overall survival (OS), and safety. Between September 2019 and April 2021, 33 patients were enroled from eight institutions. The median patient age was 79 years, and the majority of patients were male (78.8%). The 1-year PFS rate was 39.1% (90% confidence interval [CI]: 24.7–54.6%). Three patients (9.1%) had a performance status of 2. The ORR was 42.4% (95% CI: 27.2–59.2%). The median PFS and OS were 8.9 (95% CI: 7.4–19.4) and 20.8 (95% CI: 15.8–not estimable) months, respectively. The most common adverse event was radiation pneumonitis (51.5%). The median treatment duration was 6.4 (range: 0.50–12.0) months for durvalumab. At the endpoint, 30.3% (10/33) of the patients had completed 1 year of durvalumab therapy. Durvalumab is an effective treatment with tolerable toxicity following radiation monotherapy in stage III NSCLC patients who are ineligible for chemoradiotherapy. JMA-IIA00434 (jRCT). • The SPIRAL-RT study first evaluated durvalumab after radiation monotherapy. • Patients with NSCLC ineligible for stage III chemoradiotherapy were enroled. • The 1-year PFS rate was 39.1%, thereby meeting the primary endpoint. • The median PFS and OS were 8.9 and 20.8 months, respectively. • Durvalumab is effective and can be safely administered following radiotherapy. [ABSTRACT FROM AUTHOR]

We report the discovery of a novel series of influenza Cap-dependent EndoNuclease (CEN) inhibitors based on the 4-pyridone-carboxylic acid (PYXA) scaffold, which were found from our chelate library. Our SAR research revealed the lipophilic domain to be the key to CEN inhibition. In particular, the position between the chelate and the lipophilic domain in the derivatives was essential for enhancing the potency. Our study, based on virtual modeling, led to the identification of 2y as a potent CEN inhibitor with an IC 50 of 5.12 nM. [ABSTRACT FROM AUTHOR]

Abstract: 2-Deoxy-d-glucitol and 2-deoxy-d-allitol, both prepared as crystalline polyols from d-erythronolactone, are oxidized by Gluconobacter thailandicus NBRC 3254 to 5-deoxy-d-threo-hexulose [5-deoxy-d-fructose=5-deoxy-l-sorbose] and 5-deoxy-d-erythro-hexulose [5-deoxy-l-psicose=5-deoxy-d-tagatose], respectively. d-Tagatose-3-epimerase (DTE) equilibrates 5-deoxy-d-fructose to 5-deoxy-d-psicose and 5-deoxy-l-psicose to 5-deoxy-l-fructose, providing substrates for the preparation of all eight d- and l-5-deoxy aldohexoses by aldose isomerases. This combination of chemical and biotechnological methods allows a concise approach to the synthesis of all twelve 5-deoxy hexoses and further demonstrates the range of deoxy sugar substrates on which DTE is active. NMR studies show that 5-deoxy-d-fructose exists solely as the β-pyranose form whereas both pyranoses of 5-deoxy-d-fructose [α:β. 22:78] are observed. [For the sake of clarity, all ketoses in this Letter are shown in blue, alditols in red and aldoses in purple.] [Copyright &y& Elsevier]

Abstract: The Kiliani synthesis on the 4 readily accessible ketohexoses (d-fructose, d-tagatose, l-sorbose, d-psicose) allows access to 4 diastereomeric 2-C-methyl-aldohexoses (2-C-methyl-d-mannose, 2-C-methyl-d-talose, 2-C-methyl-l-gulose, 2-C-methyl-d-allose) and 4 diastereomeric 2-C-methyl-alditols (2-C-methyl-d-mannitol, 2-C-methyl-d-talitol, 2-C-methyl-l-gulitol, 2-C-methyl-d-allitol). Microbial oxidation of 2-C-methyl-d-mannitol and 2-C-methyl-l-gulitol gave 5-C-methyl-d-fructose; microbial oxidation of 2-C-methyl-d-talitol afforded 5-C-methyl-d-psicose, whereas 2-C-methyl-d-allitol formed 5-C-methyl-l-psicose. Both enantiomers of 5-C-methyl-fructose were equilibrated by d-tagatose-3-epimerase (DTE) with both enantiomers of 5-C-methyl-psicose. These transformations demonstrate that polyol dehydrogenases and DTE act on branched synthetic sugars. Full NMR analyses show that 5-C-methyl-d-fructose is present as the β-pyranose and β-furanose forms in a ratio of 90:10; all pyranose and furanose forms of 5-C-methyl-d-psicose are present in solution. The combination of chemical and biological procedures allows the environmentally friendly generation of a new family of branched monosaccharides. [Copyright &y& Elsevier]

Abstract: Microbial oxidation of 2-C-methyl-d-ribitol and 2-C-methyl-d-arabinitol by Gluconobacter thailandicus NBRC 3254 produces 4-C-methyl-l-ribulose and 4-C-methyl-d-ribulose, respectively. Further, 4-C-methyl-l-ribulose and 4-C-methyl-d-ribulose were equilibrated by d-tagatose-3-epimerase (DTE) with 4-C-methyl-l-xylulose and 4-C-methyl-d-xylulose, respectively. These transformations demonstrate that polyol dehydrogenase and DTE act on branched synthetic sugars. The green preparation of all of the stereoisomers of 4-C-methyl pentuloses illustrates the ability of biotechnology to generate novel branched monosaccharides. [Copyright &y& Elsevier]

Abstract: 1-Deoxy-d-tagatose was produced by the hydrogenation of 6-deoxy-l-galactose (l-fucose) to l-fucitol followed by oxidation with Enterobacter agglomerans 221e; a similar sequence on d-fucose afforded 6-deoxy-d-tagatose. Thus, the polylol dehydrogenase recognizes the d-galacto-configuration of both d-fucitol and l-fucitol. The procedures were conducted in water and show the power of green, environmentally friendly biotechnology in the preparation of new monosaccharides with a potential for novel bioactive properties. 6-Deoxy-d-tagatose was also synthesized from d-tagatose via the efficient formation of 1,2:3,4-di-O-isopropylidene-α-d-tagatofuranose; a difficult final removal of protecting groups by acid makes the biotechnological route more attractive. [Copyright &y& Elsevier]

Abstract: 1-Deoxy-l-fructose, a very rare monosaccharide, was produced by hydrogenation of 6-deoxy-l-mannose (l-rhamnose)—the only cheaply available deoxy sugar—to 1-deoxy-l-mannitol (l-rhamnitol) followed by oxidation with Enterobacter aerogenes IK7. The entire procedure was conducted in water and shows the power of green environmentally friendly chemistry combined with biotechnology in the preparation of new monosaccharides with potential for novel bioactive properties or alternative foodstuffs; the reactions here are reported on a multigram scale but would be reproducible on a very large scale. [Copyright &y& Elsevier]

Abstract: The four 1-deoxy-d-ketohexoses—1-deoxy-d-psicose, 1-deoxy-d-fructose, 1-deoxy-d-sorbose and 1-deoxy-d-tagatose—were synthesised by methyl lithium addition to suitably protected and readily available pentonolactones. The 1-deoxy-l-ketohexoses are available from the enantiomeric lactones. The NMR studies on aqueous solutions of each diastereomer show that the relative amounts of open chain ketones, α- and β-pyranoses, and α- and β-furanoses vary considerably; at least four different species are identifiable from each equilibrium. [Copyright &y& Elsevier]

Escherichia coli strain JM 109 harboring 6× His-tag l-rhamnose isomerase (l-RhI) from Pseudomonas stutzeri allowed a 20-fold increase in the volumetric yield of soluble enzyme compared to the value for the intrinsic yield. Detailed studies on the substrate specificity of the purified His-tagged protein revealed that it catalyzed previously unknown common and rare aldo/ketotetrose, aldo/ketopentose, and aldo/ketohexose substrates in both d- and l-forms, for instance, erythrose, threose, xylose, lyxose, ribose, glucose, mannose, galactose, altrose, tagatose, sorbose, psicose, and fructose. Using a high enzyme–substrate ratio in extended reactions, the enzyme-catalyzed interconversion reactions from which two different products from one substrate were formed: l-lyxose, l-glucose, l-tagatose and d-allose were isomerized to l-xylulose and l-xylose, l-fructose and l-mannose, l-galactose and l-talose, and d-psicose and d-altrose, in that order. Kinetic studies, however, showed that l-rhamnose with Km and Vmax values of 11 mM and 240 U/mg, respectively, was the most preferred substrate, followed by l-mannose, l-lyxose, d-ribose, and d-allose. Based on the observed catalytic mode of action, these new findings reflected a hitherto undetected interrelation between l-RhI and d-xylose isomerase (d-XI). [Copyright &y& Elsevier]