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Aim To investigate the therapeutic effect of lenvatinib (LEN) in liver disease etiology, especially nonviral hepatocellular carcinoma (HCC). Methods and Results Sixty‐seven patients with unresectable advanced HCC (u‐HCC) treated with LEN and consisting of 26 hepatitis C virus (HCV), 19 hepatitis B virus (HBV), 11 alcohol, and 11 nonalcoholic steatohepatitis (NASH) cases were retrospectively recruited. Univariate and multivariate Cox proportional hazard models were used to determine predictive factors for survival. The objective response rate in the nonviral (alcohol and NASH) group was higher than that in the viral group (59.1% [13/22] vs. 46.7% [21/45]). Progression‐free survival was significantly longer in the nonviral group than in the viral group (13.7 vs. 6.6 months; hazard ratio [HR] 0.324; 95% confidence interval [CI] 0.174–0.602; P, Kaplan–Meier analysis of progression‐free survival among patients with unresectable advanced hepatocellular carcinoma treated with lenvatinib according to etiology. The PFS in the non‐viral group was significantly longer than that in the viral group. Our results suggest that LEN is more effective against non‐viral u‐HCC than against viral u‐HCC.

A primary splenic angiosarcoma is a rare type of soft tissue sarcoma and is associated with an extremely poor prognosis. In this study, we describe the case of a patient who was diagnosed with metastatic primary splenic angiosarcoma and survived for about 2 years. A 62-year-old female was referred to us for the treatment of splenic angiosarcoma with disseminated intravascular coagulation (DIC) and multiple liver and bone metastases. Paclitaxel therapy resulted in recovery from DIC and enabled her to continue sequential treatment through to sixth-line chemotherapy. We reviewed all splenic angiosarcoma case reports which were described as stage IV to date and compared with our case. From these data, we found that the median overall survival was 105 days, and the prognosis of splenic angiosarcoma of stage IV was worse than conventional case series. Splenectomy was performed in more patients than chemotherapy as a treatment. Moreover, various chemotherapeutic regimens were used. These data suggest that administering chemotherapy including paclitaxel to patients with splenic angiosarcoma might improve their prognosis.

Glass transition behavior of carnosine (β-alanyl-L-histidine) and its impact on the storage stability of freeze-dried lactic acid bacteria (LAB) were investigated. Glass transition temperature of anhydrous carnosine was determined to be 99 oC. From the water sorption isotherm and glass transition temperature curve, the water activity where glass transition occurs at 25 oC (typical room temperature) was determined to be 0.28. These values for carnosine were higher than for sucrose, but lower than for trehalose. Effect of carnosine on the viability of freeze-dried LAB (Lactobacillus acidophilus, Lactobacillus reuteri, and Lactobacillus paracasei) before and after storage at 37 oC for 4 weeks was compared with that of other antioxidants (cysteine, glutathione, and ascorbic acid). Carnosine and cysteine strongly ameliorated reductions in cell viability after the storage. Carnosine showed the highest number of viable cells for L. reuteri and L. paracasei. The stabilizing mechanism of carnosine is thought to be attributed to water substitution, glass transition, antioxidation, and optimum pH.

The therapeutic potential of monoacylglycerol lipase (MAGL) inhibitors in central nervous system-related diseases has attracted attention worldwide. However, the availability of reversible-type inhibitor is still limited to clarify the pharmacological effect. Herein, we report the discovery of novel spiro chemical series as potent and reversible MAGL inhibitors with a different binding mode to MAGL using Arg57 and His121. Starting from hit compound 1 and its co-crystal structure with MAGL, structure-based drug discovery (SBDD) approach enabled us to generate various spiro scaffolds like 2a (azetidine-lactam), 2b (cyclobutane-lactam), and 2d (cyclobutane-carbamate) as novel bioisosteres of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl moiety in 1 with higher lipophilic ligand efficiency (LLE). Optimization of the left hand side afforded 4f as a promising reversible MAGL inhibitor, which showed potent in vitro MAGL inhibitory activity (IC50 6.2 nM), good oral absorption, blood-brain barrier penetration, and significant pharmacodynamic changes (2-arachidonoylglycerol increase and arachidonic acid decrease) at 0.3-10 mg/kg, po. in mice.

The gelatin–thrombin matrix, Floseal, is an excellent novel hemostatic agent that is used in various surgical fields. Thrombin is a serine protease, and the conversion of prothrombin to thrombin is an essential step in the coagulation cascade. However, thrombin can induce blood–brain barrier (BBB) disruption and vasogenic brain edema. This report describes two cases of gelatin–thrombin matrix-related cyst formation after cerebral hematoma evacuation. An 82-year-old man with a gelatin–thrombin matrix-related cyst was treated by cyst drainage and fenestration to the lateral ventricle. Histological evaluation of the cyst wall showed a gelatin–thrombin matrix reserve, marked infiltration of inflammatory cells, and foam cell accumulation. In addition, an 85-year-old woman with a gelatin–thrombin matrix-related cyst was treated with steroids and responded well. In both cases, the post-treatment course was uneventful. Cyst shrinkage and no recurrence were observed. The gelatin–thrombin matrix can cause cyst formation with brain edema. This is the first report demonstrating the cyst wall pathology and the steroid responsivity on cyst shrinkage. The mechanism of cyst formation is thought to be thrombin-induced BBB disruption. Excess gelatin–thrombin matrix should be carefully removed from the surgical beds, particularly those having a blinded space from the neurosurgical microscope.

Systems glycobiology aims to provide models and analysis tools that account for the biosynthesis, regulation, and interactions with glycoconjugates. To facilitate these methods, there is a need for a clear glycan representation accessible to both computers and humans. Linear Code, a linearized and readily parsable glycan structure representation, is such a language. For this reason, Linear Code was adapted to represent reaction rules, but the syntax has drifted from its original description to accommodate new and originally unforeseen challenges. Here, we delineate the consensuses and inconsistencies that have arisen through this adaptation. We recommend options for a consensus-based extension of Linear Code that can be used for reaction rule specification going forward. Through this extension and specification of Linear Code to reaction rules, we aim to minimize inconsistent symbology thereby making glycan database queries easier. With a clear guide for generating reaction rule descriptions, glycan synthesis models will be more interoperable and reproducible thereby moving glycoinformatics closer to compliance with FAIR standards. Here, we present Linear Code for Reaction Rules (LiCoRR), version 1.0, an unambiguous representation for describing glycosylation reactions in both literature and code.

Background: Although mechanical thrombectomy is a standard endovascular therapy for patients with acute ischemic stroke (AIS), the incidence of and risk factors for contrast-induced nephropathy (CIN) following mechanical thrombectomy are infrequently reported. Objectives: The aim of this study was to investigate the incidence and risk factors for CIN following mechanical thrombectomy for AIS, and whether the incidence of CIN is related to a poor prognosis. Methods: We examined consecutive patients who underwent a mechanical thrombectomy in the period from January 2014 to March 2018. The patients’ clinical backgrounds, treatments, and clinical prognoses were analyzed. CIN was defined as an increase in the serum creatinine level of ≥44.2 μmol/L (0.5 mg/dL) or 25% above baseline within 72 h after exposure to the contrast medium. Results: In total, 80 patients (46 men and 34 women aged 74.5 ± 11.5 years) who met our inclusion criteria were analyzed. CIN occurred in 8.8% (7/80) of the patients following mechanical thrombectomy. Although no patients needed permanent dialysis, 1 required temporary dialysis. The median amount of contrast medium was 109 mL. A comparison between the groups with and without CIN showed a significant difference in white blood cell (WBC) count at the time of admission (11.6 ± 2.7 × 103/μL and 8.1 ± 2.7 × 103/μL; p < 0.01) and the cut-off value was 9.70 × 103/μL. In multivariate analysis, contrast volume/estimated glomerular filtration rate by creatinine and WBC count were significantly associated with the incidence of CIN, with odds ratios of 1.64 (95% CI 1.02–2.65; p = 0.04) and 1.61 (95% CI 1.15–2.25; p < 0.01), respectively. Conclusions: This study found that CIN occurred in 8.8% of patients with AIS following mechanical thrombectomy. High WBC count was associated with an increased risk of CIN and may be helpful for predicting CIN.

The effects of the glass transition and the operating process on the hardness of thermally compressed maltodextrin were investigated. The hardness of compressed maltodextrin increased significantly when it was compressed above the glass transition temperature (Tg). Maltodextrin compressed before heating showed much higher fractural stress than that compressed after heating due to the difference in force required for constant deformation. There was no effect of the decompression temperature being above or below Tg. Furthermore, the effect of crystalline additives (NaCl, monosodium glutamate monohydrate, sucrose, lactose monohydrate, lauric acid, and stearic acid) on the hardness of maltodextrin compressed above Tg was investigated. The hardness of compressed maltodextrin decreased with increasing crystalline additives except for hydrate crystals at a low-additive fraction. Since crystalline additives existed as dispersions in amorphous maltodextrin, the compressed maltodextrin became fragile by the addition of crystalline materials. In the case of hydrate crystals, it is thought that the hydrate crystals melted at the interface, releasing water molecules that formed an intermolecular binding layer. Stearic acid formed a solid by itself. Stearic acid has an intrinsically much lower melting temperature than the other crystals, and interfacial melting would have occurred in the compressed stearic acid itself.

Owing to the large contact surface area in geometry, disc-shaped polymer particles and their fascinating properties compared to those of spherical particles have received increasing attention. Alth...

The efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line LEN treatment, investigated the sensitivity of a SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and assessed their signal transduction pathways by protein array analysis. We retrospectively enrolled 57 patients with unresectable HCC. Fifty-three radiologically evaluated patients comprised 34 molecular-targeted agent (MTA)-naive (first-line), nine intolerant to SOR (second-line), and 10 resistant to regorafenib (third-line). The objective response rates (ORRs) were 61.8% in first-line, 33.3% in second-line, and 20.0% in third-line groups. The overall survival (OS) in the first-line was significantly longer than that in the third-line group (p < 0.05). Patients with better liver functional reserves (child score, ALBI grade) exhibited higher ORR and longer OS. The IC50 of LEN against PLC/PRF5-R2 was significantly higher than that against PLC/PRF5. LEN significantly inhibited more LEN-related signal transduction pathways in PLC/PRF5 than in PLC/PRF5-R2 cells. This suggests that LEN is active and safe as a second/third-line treatment for unresectable HCC. LEN seems more effective for patients with HCC with better hepatic reserve functions or before MTA-resistance is acquired because of the partial cross-resistance to SOR.

Along with the tumor progression, the bone marrow microenvironment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-β-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 to decrease the expression of critical mediators for MM growth and survival, including PIM2, MYC, Mcl-1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSCs) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-Β ligand (RANKL) expression by BMSCs. TAK1 inhibition effectively impaired MM cell adhesion to BMSCs to disrupt the support of MM cell growth and survival by BMSCs. Furthermore, TAK1 inhibition suppressed osteoclastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM.

This study was conducted to evaluate the regulation mechanism of influenza virus replication following treatment of Madin-Darby canine kidney cells with the soy isoflavone daidzein. We performed comparative qualitative and quantitative analyses of lipid peroxide between mock-infected and virus-infected cells treated with or without daidzein, as it had been reported that daidzein was an antioxidant and lipid peroxide levels increased upon virus infection. Contrary to our belief, lipid peroxides were not elevated in virus-infected cells and no decrease in lipid peroxides was observed in daidzein-treated cells. In daidzein-treated cells, 5-hydroxyeicosatetraenoic acid, the 5-lipoxygenase product derived from arachidonate, was significantly elevated compared to other lipid peroxides. Zileuton (5-lipoxygenase inhibitor) and 5-lipoxygenase knockdown reduced the daidzein-induced antiviral effect. Moreover, virus replication was regulated by treatment with 5-hydroperoxyeicosatetraenoic acid, a precursor of 5-hydroxyeicosatetraenoic acid and 5-lipoxygenase primary product. These results suggest that daidzein regulates virus replication via signal transduction through 5-lipoxygenase products.

Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects. Here, we report the pharmacological characteristics of a novel AMPA-R potentiator, TAK-653, which exhibits minimal agonistic properties. TAK-653 bound to the ligand binding domain of recombinant AMPA-R in a glutamate-dependent manner. TAK-653 strictly potentiated a glutamate-induced Ca2+ influx in hGluA1i-expressing CHO cells through structural interference at Ser743 in GluA1. In primary neurons, TAK-653 augmented AMPA-induced Ca2+ influx and AMPA-elicited currents via physiological AMPA-R with little agonistic effects. Interestingly, TAK-653 enhanced electrically evoked AMPA-R-mediated EPSPs more potently than AMPA (agonist) or LY451646 (AMPA-R potentiator with a prominent agonistic effect) in brain slices. Moreover, TAK-653 improved cognition for both working memory and recognition memory, while LY451646 did so only for recognition memory, and AMPA did not improve either. These data suggest that the facilitation of phasic AMPA-R activation by physiologically-released glutamate is the key to enhancing synaptic and cognitive functions, and nonselective activation of resting AMPA-Rs may negatively affect this process. Importantly, TAK-653 had a wide safety margin against convulsion; TAK-653 showed a 419-fold (plasma Cmax) and 1017-fold (AUC plasma) margin in rats. These findings provide insight into a therapeutically important aspect of AMPA-R potentiation.

Silver bismuth diselenide (AgBiSe2) is an n-type thermoelectric material that exhibits a complex structural phase transition from the hexagonal to cubic phase, while silver antimony diselenide (AgS...

This study described the effect of water content on the glass transition temperature (Tg) of a soup powder and the hardness of a soup solid compressed at various temperatures above and below the Tg. Although differential scanning calorimetry showed indistinct glass transition, thermal rheological analysis revealed a clear mechanical glass transition. The mechanical Tg decreased as water activity (or water content) increased because of a water-plasticizing effect. Since X-ray diffraction showed peaks reflecting crystalline NaCl, lactose, and sucrose, the amorphous region in the soup powder likely consisted mainly of vegetable, yeast, beef, and chicken extracts. The fractural stress of the thermally compressed soup solid increased with water activity of the samples, compressed height (density), and temperature. The results showed that the fractural stress of the soup solid increased dramatically when it was compressed at a temperature above the mechanical Tg.

Immunotherapy is revolutionizing the treatment paradigm for multiple myeloma (MM). Interferon (IFN)-γ is essential for immune responses, whereas immune checkpoint molecules, such as programmed cell death-1 ligand-1 (PD-L1), mitigate the beneficial anti-tumor immune responses. As HDAC inhibitors alter the immunogenicity and anti-tumor immune responses, we here explored the regulation of PD-L1 expression in MM cells by the clinically available HDAC inhibitor panobinostat in the presence of IFN-γ. IFN-γ activated the STAT1-IRF1 pathway to upregulate PD-L1 expression in MM cells, and panobinostat was able to upregulate their PD-L1 expression without activating the STAT1-IRF1 pathway. Of note, panobinostat enhanced IFN-γR1 expression, which substantially increased the total and phosphorylated levels of STAT1 protein but reduced IRF1 protein levels through proteasomal degradation in the presence of IFN-γ. Panobinostat further enhanced the IFN-γ-mediated durable STAT1 activation in MM cells; STAT1 gene silencing abolished the PD-L1 upregulation by panobinostat and IFN-γ in combination, indicating a critical role for STAT1. These results suggest that panobinostat enhances PD-L1 expression by facilitating the IFN-γ-STAT1 pathway in a ligand-dependent manner in MM cells with ambient IFN-γ. PD-L1 upregulation should be taken into account when combining immunotherapies with panobinostat.

Isotropic pitch-based carbon fiber has been utilized for various applications such as thermal insulation materials for high-temperature furnace and additives for slide member, but the structure of the carbon fiber is still under debate. This is because the precursor pitch contains various aromatic compounds in addition to the complicated oxidation and carbonization reaction during production process of carbon fiber. In this work, oxidation processes of model compounds of pitch such as pyrene (sp2C H with zigzag-like edges), triphenylene (sp2C H with armchair edges), fluorene (pentagon with sp3CH2), and 9-methylanthracene (hexagon with sp3CH3) were analyzed using mass spectrometry, elemental analysis, infrared (IR), Raman, and X-ray photoelectron spectroscopy (XPS) in addition to calculation such as molecular dynamic simulation with a reactive force field (ReaxFF) and simulation of IR, Raman, and XPS spectra (Gaussian09). Combination of calculations and experiments revealed that oxidation proceeded in the order of zigzag-like edges > sp3CH3 > sp2CH2 > armchair edges, and the quinone formed by oxidation worked as a precursor for a crosslinking reaction. It is expected that the results of this work, which revealed the origin of the crosslinking, could lead to improve properties as well as to estimate the detailed structures of isotropic pitch-based carbon fiber.

The effect of polymers (gelatin, starch, and maltodextrin) on the physical properties of freeze-dried model soup (sodium chloride, sucrose, and monosodium glutamate) was investigated. The polymers were added to the soup solution at 1 or 3% (w/v), which was then freeze-dried at 25 or 50 °C. Gelatin and maltodextrin prevented crystallization of sodium chloride to a greater extent than starch under freezing. Freeze-drying was conducted above the freeze-concentrated glass transition temperature. Polymer addition prolonged drying time, but prevented structural deformation. Gelatin enhanced the physical strength of the freeze-dried solid more than starch and maltodextrin because of its gel-network. In a dissolution test, 1% gelatin, and 1 and 3% maltodextrin exhibited greater dissolution than the other samples. The drying rate was lower at 50 °C, with minor modifications to the other properties. From these results, it was concluded that 1% gelatin was useful as a physical stabilizer for freeze-dried soup. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-021-05161-x.

Quantum computing is suggested as a new tool to deal with large data set for machine learning applications. However, many quantum algorithms are too expensive to fit into the small-scale quantum hardware available today and the loading of big classical data into small quantum memory is still an unsolved obstacle. These difficulties lead to the study of quantum-inspired techniques using classical computation. In this work, we propose a new classification method based on support vectors from a DBSCAN–Deutsch–Jozsa ranking and an Ising prediction model. The proposed algorithm has an advantage over standard classical SVM in the scaling with respect to the number of training data at the training phase. The method can be executed in a pure classical computer and can be accelerated in a hybrid quantum–classical computing environment. We demonstrate the applicability of the proposed algorithm with simulations and theory.

D-amino acid oxidase (DAO) is a flavoenzyme catalyzing the oxidation of D-amino acid (AA)s. In the kidney, its expression is detected in proximal tubules, and DAO is considered to play a role in the conversion of D-form AAs to α-keto acids. LLC-PK1 cells, a pig renal proximal tubule cell line, were used to elucidate the regulation of DAO protein synthesis and degradation. In this study, we showed that trypsinization of LLC-PK1 cells in culture system rapidly reduced the intracellular DAO protein level to ∼33.9% of that before treatment, even within 30 min. Furthermore, we observed that the DAO protein level was decreased when LLC-PK1 cells were subjected to AA starvation. To determine the degradation pathway, we treated the cells with chloroquine and MG132. DAO degradation was found to be inhibited by chloroquine, but not by MG132 treatment. We next examined whether or not DAO was degraded by autophagy. We found that AA starvation led to an increased accumulation of LC3-II, suggesting that DAO protein is degraded by autophagy due to AA starvation conditions. Furthermore, treatment with cycloheximide inhibited DAO protein degradation. Taken together, DAO protein is degraded by autophagy under starvation. The present study revealed the potential dynamics of DAO correlated with renal pathophysiology.

AIM The optimal choice between sorafenib (SOR) or lenvatinib (LEN) as the first-line treatment for unresectable hepatocellular carcinoma (u-HCC) remains debatable. Using propensity score matching, this study compares the outcomes of SOR and LEN in the molecular-targeted agent (MTA) sequential treatment of u-HCC patients. METHODS This retrospective, multicenter, observational study recruited 137 u-HCC patients who underwent primary treatment with LEN (n = 52) or SOR (n = 85) between June 2017 and June 2020 after regorafenib was approved as the secondary treatment for u-HCC. Propensity score matching was used to reduce confounding, resulting in the selection of 104 patients (n = 52 for the SOR and LEN cohorts). RESULTS The median overall survival was 21.8 months for LEN and 20.4 months for SOR. LEN exhibited significantly greater therapeutic efficacy as compared to SOR (objective response rate: 3.8% [SOR] vs. 42.3% [LEN], p

Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate and NADH to NAD+; it has two isoforms, LDHA and LDHB. LDHA is a promising target for cancer therapy, whereas LDHB is necessary for basal autophagy and cancer cell proliferation in oxidative and glycolytic cancer cells. To the best of our knowledge, selective inhibitors for LDHB have not yet been reported. Here, we developed a high-throughput mass spectrometry screening system using an LDHB enzyme assay by detecting NADH and NAD+. As a result, we identified a small-molecule LDHB selective inhibitor AXKO-0046, an indole derivative. This compound exhibited uncompetitive LDHB inhibition (EC50 = 42 nM). X-ray crystallography revealed that AXKO-0046 bound to the potential allosteric site away from the LDHB catalytic active site, suggesting that targeting the tetramerisation interface of the two dimers is critical for the enzymatic activity. AXKO-0046 and its derivatives can be used to validate LDHB-associated pathways in cancer metabolism.

Compromised oral health can alter food choices. Poor masticatory function leads to imbalanced food intake and undesirable nutritional status. The associations among nutritional status, oral health behavior, and self-assessed oral functions status were investigated using a community-based survey. In total, 701 subjects more than 50 years old living Ebina city located southwest of the capital Tokyo were investigated. The number of remaining teeth was counted by dental hygienists. Oral health behavior and self-assessed oral functions were evaluated by oral frailty checklist. Nutritional status was evaluated by the brief-type self-administered diet history questionnaire using Dietary Reference Intakes for Japanese as reference. More than 80% of subjects&rsquo, intakes of vitamin B12, pantothenic acid, copper, and proteins were sufficient. In contrast, only 19% of subjects&rsquo, intake of vitamin A was sufficient and 35.5% for vitamin B1. More than 90% of subjects&rsquo, intakes of vitamin D and vitamin K were sufficient. Only 35.5% of subjects&rsquo, intakes of dietary fiber were sufficient. Overall, 88.9% of subjects had excess salt. The number of remaining teeth was not correlated with nutritional intakes. Oral health behavior significantly correlated with nutritional intakes. Oral functions are important for food choice, however, oral functions were not directly correlated with nutritional intakes. Comprehensive health instructions including nutrition and oral health education is necessary for health promotion.

Background and Aim Currently, there is no molecular‐targeted agent that has demonstrated evidence of efficacy in patients with unresectable hepatocellular carcinoma (u‐HCC) who have developed resistance to treatment with lenvatinib (LEN). In this real‐world study, we aimed to investigate the therapeutic effect and safety of sorafenib (SOR) in patients with u‐HCC after progression on treatment with LEN. Methods (Patients) and Results A total of 13 patients with u‐HCC (12 males and 1 female), who were treated with SOR after progression on LEN, were enrolled in this retrospective study. Therapeutic efficacy was evaluated via contrast‐enhanced computerized tomography at 8 weeks after the initiation of SOR therapy according to modified response evaluation criteria in solid tumors (mRECIST) and RECIST. According to mRECIST, the objective response rate (ORR) and disease control rate (DCR) were 15.3% (2/13) and 69.2% (9/13), respectively. According to RECIST, the ORR and DCR were 0% (0/13) and 69.2% (9/13), respectively. The median progression‐free survival was 4.1 months. The median albumin‐bilirubin scores did not deteriorate significantly at 4, 6, and 8 weeks after initiation of SOR, compared with the scores at the baseline. The most frequent grade 1 or 2 adverse events (AEs) were palmar–plantar erythrodysesthesia, fatigue, diarrhea, and hypertension. There was no incidence of grade 3 AEs. Conclusion Treatment with SOR may be effective for u‐HCC after failure on LEN and may not worsen the liver reserve., We demonstrated that treatment with sorafenib after lenvatinib failure could be useful for unresectable hepatocellular carcinoma. In addition, this treatment strategy may not worsen the liver reserve.

Mannosylerythritol lipids (MELs) are glycolipid biosurfactants produced by various yeasts. Mmf1, a putative transporter of MELs, is conserved in the MEL biosynthesis gene clusters of diverse MEL producers, including the genera Ustilago, Pseudozyma, Moesziomyces, and Sporisorium. To clarify the function of Mmf1, we generated the gene-deleted strain of P. tsukubaensis ΔPtMMF1 and evaluated its MEL production. Using thin-layer chromatography analyses, we detected most MELs produced by ΔPtMMF1 in the culture supernatant. The spot size of diacylated MEL-B (the only product of the parental strain) was significantly smaller for strain ΔPtMMF1 than for the parental strain, and a mono-acylated MEL-D spot was detected. In addition, an unknown glycolipid was detected in the sample extracted from strain ΔPtMMF1. Liquid chromatography–mass spectrometry and nuclear magnetic resonance analyses revealed that the unknown glycolipid was a novel MEL homologue, mono-acylated MEL-B. • P. tsukubaensis is able to secrete MELs without PtMMF1p. • Strain ΔPtMMF1 mainly produced mono-acylated MELs.

The accumulation of β-amyloid (Aβ) aggregates in the brain occurs early in the progression of Alzheimer's disease (AD), and non-fibrillar soluble Aβ oligomers are particularly neurotoxic. During binding to Aβ fibrils, curcumin, which can exist in an equilibrium state between its keto and enol tautomers, exists predominantly in the enol form, and binding activity of the keto form to Aβ fibrils is much weaker. Here we described the strong binding activity the keto form of curcumin derivative Shiga-Y51 shows for Aβ oligomers and its scant affinity for Aβ fibrils. Furthermore, with imaging mass spectrometry we revealed the blood-brain barrier permeability of Shiga-Y51 and its accumulation in the cerebral cortex and the hippocampus, where Aβ oligomers were mainly localized, in a mouse model of AD. The keto form of curcumin derivatives like Shiga-Y51 could be promising seed compounds to develop imaging probes and therapeutic agents targeting Aβ oligomers in the brain.

Systems glycobiology aims to provide models and analysis tools that account for the biosynthesis, regulation, and interactions with glycoconjugates. To facilitate these methods, there is a need for a clear glycan representation accessible to both computers and humans. Linear Code, a linearized and readily parsable glycan structure representation, is such a language. For this reason, Linear Code was adapted to represent reaction rules, but the syntax has drifted from its original description to accommodate new and originally unforeseen challenges. Here, we delineate the consensuses and inconsistencies that have arisen through this adaptation. We recommend options for a consensus-based extension of Linear Code that can be used for reaction rule specification going forward. Through this extension and specification of Linear Code to reaction rules, we aim to minimize inconsistent symbology thereby making glycan database queries easier. With a clear guide for generating reaction rule descriptions, glycan synthesis models will be more interoperable and reproducible thereby moving glycoinformatics closer to compliance with FAIR standards. Here, we present Linear Code for Reaction Rules (LiCoRR), version 1.0, an unambiguous representation for describing glycosylation reactions in both literature and code.

During muscle regeneration, extracellular signal-regulated kinase (ERK) promotes both proliferation and migration. However, the relationship between proliferation and migration is poorly understood in this context. To elucidate this complex relationship on a physiological level, we established an intravital imaging system for measuring ERK activity, migration speed, and cell-cycle phases in mouse muscle satellite cells. We found that in vivo, ERK was maximally activated in satellite cells two days after injury, and this is then followed by increases in cell number and motility. With limited effects of immediate ERK activity on migration, we hypothesized that ERK increases migration speed in the later phase by promoting cell-cycle progression. Our cell-cycle analysis further revealed that in satellite cells, ERK activity is critical for the G1/S transition, and cells migrate more rapidly in the S/G2 phase three days after injury. Finally, migration speed of satellite cells was suppressed after CDK1/2, but not CDK1, inhibitor treatment, demonstrating a critical role of CDK2 in satellite cell migration. Overall, our study demonstrates that in satellite cells, the ERK-CDK2 axis not only promotes the G1/S transition, but also migration speed, which may provide a novel mechanism for efficient muscle regeneration.

The extent of liver fibrosis predicts prognosis and is important for determining treatment strategies for chronic hepatitis. During the fibrosis progression, serum levels of Mac2 binding protein (M2BP) increase and the N-glycan structure changes to enable binding to Wisteria floribunda agglutinin (WFA) lectin. As a novel diagnostic marker, glycosylation isomer of M2BP (M2BPGi) has been developed. However, its glycan structures recognized by WFA are unclear. In this study, we analyzed site-specific N-glycan structures of serum M2BP using Glyco-RIDGE (Glycan heterogeneity-based Relational IDentification of Glycopeptide signals on Elution profile) method. We evaluated five sample types: (1) M2BP immunoprecipitated from normal healthy sera (NHS-IP(+)), (2) M2BP immunoprecipitated from sera of patients with liver cirrhosis (stage 4; F4-IP(+)), (3) M2BP captured with WFA from serum of patients with liver cirrhosis (stage 4; F4-WFA(+)), (4) recombinant M2BP produced by HEK293 cells (rM2BP) and (5) WFA-captured rM2BP (rM2BP-WFA(+)). In NHS-IP(+) M2BP, bi-antennary N-glycan was the main structure, and LacNAc extended to its branches. In F4-IP(+) M2BP, many branched structures, including tri-antennary and tetra-antennary N-glycans, were found. F4-WFA(+) showed a remarkable increase in branched structures relative to the quantity before enrichment. In recombinant M2BP, both no sialylated-LacdiNAc and -branched LacNAc structures were emerged. The LacdiNAc structure was not found in serum M2BP. Glycosidase-assisted HISCL assays suggest that reactivity with WFA of both serum and recombinant M2BP depends on unsialylated and branched LacNAc and in part of recombinant depends on LacdiNAc. On M2BPGi, the highly branched LacNAc, probably dense cluster of LacNAc, would be recognized by WFA.

Receptor activator of NF-&kappa, B ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells, however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox&rsquo, s anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage.

Human D-amino acid oxidase (DAO) is a flavoenzyme that is implicated in neurodegenerative diseases. We investigated the impact of replacement of proline with leucine at Position 219 (P219L) in the active site lid of human DAO on the structural and enzymatic properties, because porcine DAO contains leucine at the corresponding position. The turnover numbers (kcat) of P219L were unchanged, but its Km values decreased compared with wild-type, leading to an increase in the catalytic efficiency (kcat/Km). Moreover, benzoate inhibits P219L with lower Ki value (0.7–0.9 µM) compared with wild-type (1.2–2.0 µM). Crystal structure of P219L in complex with flavin adenine dinucleotide (FAD) and benzoate at 2.25 Å resolution displayed conformational changes of the active site and lid. The distances between the H-bond-forming atoms of arginine 283 and benzoate and the relative position between the aromatic rings of tyrosine 224 and benzoate were changed in the P219L complex. Taken together, the P219L substitution leads to an increase in the catalytic efficiency and binding affinity for substrates/inhibitors due to these structural changes. Furthermore, an acetic acid was located near the adenine ring of FAD in the P219L complex. This study provides new insights into the structure–function relationship of human DAO.

Background & AimsThe efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line treatment of LEN, investigated the sensitivity of SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and their signal transduction pathway by protein array analysis.MethodsWe retrospectively enrolled 57 unresectable HCC patients. Radiologic responses in 53 patients were evaluated by modified Response Evaluation Criteria in Solid Tumors. Active signal transduction pathways in cells were identified by protein array analysis, including 1205 proteins.ResultsPatients comprised 34 tyrosine kinase inhibitor (TKI)-naive (first-line), nine SOR-intolerant (second-line), and ten resistant to regorafenib (third-line). Objective response rates (ORRs) were 61.8% (21/34) in TKI-naive, 33.3% (3/9) in second-line, and 20.0% (2/10) in third-line groups. The overall survival (OS) and the progression free survival (PFS) in the first-line was significantly longer than those in third-line group (p50 value of LEN against PLC/PRF5-R2 cells (30 μM) was significantly higher than that against PLC/PRF5 cells (6.4 μM). LEN inhibited significantly more signal transduction pathways related to FRS2, a crucial FGFR downstream molecule, in PLC/PRF5 than PLC/PRF5-R2 cells.ConclusionsLEN was active and safe as a second/third-line treatment for unresectable HCC. LEN seems to be more effective for HCC patients with better hepatic reserve function or before TKI-resistance is acquired because of partial cross-resistance to SOR.

Background Hepatitis B virus (HBV), which causes hepatitis, liver cirrhosis, and hepatocellular carcinoma, is a global human health problem. HBV contains three envelope proteins, S-, M-, and L-hepatitis B surface antigen (HBsAg). We recently found that O-glycosylated M-HBsAg, reactive with jacalin lectin, is one of the primary components of HBV DNA-containing virus particles. Thus, we aimed to analyze and target the glycosylation of HBsAg. Methods HBsAg prepared from the serum of Japanese patients with HBV were analyzed using mass spectrometry. The glycopeptide modified with O-glycan was generated and used for immunization. The specificity of the generated antibody and the HBV infection inhibition activity was examined. Results Mass spectrometry analysis revealed that T37 and/or T38 on M-HBsAg of genotype C were modulated by ±NeuAc(α2,3)Gal(β1,3)GalNAc. Chemically and enzymatically synthesized O-glycosylated peptide (Glyco-PS2) induced antibodies that recognize mainly PreS2 in M-HBsAg not in L-HBsAg, whereas the non-glycosylated peptide (PS2) induced antisera recognizing L-HBsAg but not O-glycosylated M-HBsAg. The removal of O-glycan from M-HBsAg partly decreased the reactivity of the Glyco-PS2 antibody, suggesting that peptide part was also recognized by the antibody. The antibody further demonstrated the inhibition of HBV infection in human hepatic cells in vitro. Conclusions Glycosylation of HBsAg occurs differently in different HBsAgs in a site-specific manner. The new Glyco-PS2 antibody, recognizing O-glycosylated M-HBsAg of genotype C, could inhibit HBV infection. General significance The detailed analysis of HBsAg identified different glycosylations of HBV surface. The glycosylated peptide based on mass spectrometry analysis showed higher potential to induce functional antibody against HBV.

The thermostable endo-1,5-α-L-arabinanase fromBacillus thermodenitrificansTS-3 (ABN-TS) hydrolyzes the α-1,5-L-arabinofuranoside linkages of arabinan. In this study, the crystal structures of inactive ABN-TS mutants, D27A and D147N, were determined in complex with arabino-oligosaccharides. The crystal structures revealed that ABN-TS has at least six subsites in the deep V-shaped cleft formed across one face of the propeller structure. The structural features indicate that substrate recognition is profoundly influenced by the remote subsites as well as by the subsites surrounding the active center. The `open' structure of the substrate-binding cleft of the endo-acting ABN-TS is suitable for the random binding of several sugar units in polymeric substrates.

This study aimed to examine the effects of porous structure and water plasticization on the mechanical glass transition temperature ( T g ) of freeze-dried trehalose solid and cookie. The thermal T g and mechanical T g were evaluated by differential scanning calorimetry (DSC) and thermal rheological analysis (TRA), respectively. The mechanical T g of the porous trehalose sample was slightly higher than that of the pellet sample. The mechanical T g s for pellet and porous trehalose samples were higher than thermal T g . Although pellet, crust, and crumb cookie samples showed indistinct glass transition behavior in the DSC thermosgrams, TRA revealed a clear glass transition. There were little differences in the mechanical T g of the cookie samples. The mechanical T g decreased with an increase in water content, and mechanically and thermally critical water contents (water content at T g = 25 °C) were evaluated. Fracture properties of the cookie sample changed discontinuously at the thermally critical water content.

Aggregation of tau into neurofibrillary tangles (NFTs) is characteristic of tauopathies, including Alzheimer's disease. Recent advances in tau imaging have attracted much attention because of its potential contributions to early diagnosis and monitoring of disease progress. Fluorine-19 magnetic resonance imaging (19F-MRI) may be extremely useful for tau imaging once a high-quality probe has been formulated. In this investigation, a novel fluorine-19–labeling compound has been developed as a probe for tau imaging using 19F-MRI. This compound is a buta-1,3-diene derivative with a polyethylene glycol side chain bearing a CF3 group and is known as Shiga-X35. Female rTg4510 mice (a mouse model of tauopathy) and wild-type mice were intravenously injected with Shiga-X35, and magnetic resonance imaging of each mouse's head was conducted in a 7.0-T horizontal-bore magnetic resonance scanner. The 19F-MRI in rTg4510 mice showed an intense signal in the forebrain region. Analysis of the signal intensity in the forebrain region revealed a significant accumulation of fluorine-19 magnetic resonance signal in the rTg4510 mice compared with the wild-type mice. Histological analysis showed fluorescent signals of Shiga-X35 binding to the NFTs in the brain sections of rTg4510 mice. Data collected as part of this investigation indicate that 19F-MRI using Shiga-X35 could be a promising tool to evaluate tau pathology in the brain. © 2017 Wiley Periodicals, Inc.

Cytidine triphosphate synthase 1 (CTPS1) is an enzyme expressed in activated lymphocytes that catalyzes the conversion of uridine triphosphate (UTP) to cytidine triphosphate (CTP) with ATP-dependent amination, using either L-glutamine or ammonia as the nitrogen source. Since CTP plays an important role in DNA/RNA synthesis, phospholipid synthesis, and protein sialyation, CTPS1-inhibition is expected to control lymphocyte proliferation and size expansion in inflammatory diseases. In contrast, CTPS2, an isozyme of CTPS1 possessing 74% amino acid sequence homology, is expressed in normal lymphocytes. Thus, CTPS1-selective inhibition is important to avoid undesirable side effects. Here, we report the discovery of CTpep-3: Ac-FRLGLLKAFRRLF-OH from random peptide libraries displayed on T7 phage, which exhibited CTPS1-selective binding with a KD value of 210nM in SPR analysis and CTPS1-selective inhibition with an IC50 value of 110nM in the enzyme assay. Furthermore, two fundamentally different approaches, enzyme inhibition assay and HDX-MS, provided the same conclusion that CTpep-3 acts by binding to the amidoligase (ALase) domain on CTPS1. To our knowledge, CTpep-3 is the first CTPS1-selective inhibitor.

Evidence for the Higgs boson, for which the Nobel Prize in physics was awarded in 2013, was discovered by the European Organization for Nuclear Research (CERN) in 2012, using the Large Hadron Collider (LHC). PIXEO BP-S exhibited superior resistance to both radiation and cryogenics and this polymer played a crucial role in the operation of the LHC, thus contributing to the Higgs boson discovery. Herein, we report the synthesis and characterization of various polyester imides for a cryogenic and radiation-resistant polyimide adhesive tape. These polyester imides (3) were synthesized from 2,2-bis(4-hydroxyphenyl)propanedibenzoate-3,3ʹ,4,4ʹ-tetracarboxylic acid anhydride (ESDA) and various diamines (1a–1l). All polymers showed high solubility in various solvents, especially 3a, which was synthesized from ESDA and 4,4ʹ-bis(3-aminophenoxy)diphenyl sulfone and dissolved even in ether solvents such as dioxane and dioxolane. Dynamic mechanical analysis and X-ray diffraction studies indicated that the excluded volume of the polyester imides had a length of 150 A, and that this volume affected the thermoplastic properties and solubilities of the polymers. The degree of imidization of 3a dissolved in dimethyl sulfoxide was examined by 1H-Nuclear magnetic resonance(NMR) imaging utilizing a 15N-enriched amine model compound in conjunction with 1H–15N heteronuclear single quantum coherence 2-dimensional NMR and was found to be 99.5%. PIXEO BP-S tape used for Large Hadron Collider and its chemical structure.

The Ras proteins play roles in cell differentiation, proliferation, and survival. Aberrant signaling through Ras-mediated pathways in tumor cells occurs as a result of several types of mutational damage, which most frequently affects the amino acids G12, G13, and Q61. Recently, KRpep-2d was identified as a K-Ras(G12D) selective inhibitory peptide against the G12D mutant of K-Ras, which is a key member of the Ras protein family and an attractive cancer therapeutic target. In this study, the crystal structure of the human K-Ras(G12D) mutant was determined in complex with GDP and KRpep-2d at 1.25 Å resolution. This structure revealed that the peptide binds near Switch II and allosterically blocks protein-protein interactions with the guanine nucleotide exchange factor. This discovery of a unique binding pocket provides valuable information that will facilitate the design of direct Ras inhibitors.

Hepatitis C virus (HCV) infection remains the main cause of liver disease and can lead to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HCV may also develop extrahepatic manifestations in the skin, eyes, joints, kidneys, nervous system, and immune system. In fact, several studies reported that up to 70% of HCV patients experienced extrahepatic manifestations. Lichen planus (LP), which is an immune system disorder that is triggered by viral infections, allergens, and stress, can affect the skin, mouth, nails, and scalp. The association of LP with HCV has been reported, but the effect of HCV treatment on LP remission is controversial. We encountered a 53-year-old man with HCV genotype 2a and LP that were successfully treated with sofosbuvir and ribavirin for 12 weeks. After treatment, he achieved sustained virological response against HCV and remission of erosive LP lesions on the lip. In the era of interferon (IFN)-based treatment for HCV, exacerbation of autoimmune diseases is a common adverse event. Therefore, use of an IFN-free regimen of direct-acting antivirals for HCV might prevent the extrahepatic manifestation of an immune disorder.

Eukaryotic initiation factor 4A3 (eIF4A3), an ATP-dependent RNA helicase, is a core component of exon junction complex (EJC). EJC has a variety of roles in RNA metabolism such as translation, surveillance, and localization of spliced RNA. It is worthwhile to identify selective eIF4A3 inhibitors with a view to investigating the functions of eIF4A3 and EJC further to clarify the roles of the ATPase and helicase activities in cells. Our chemical optimization of hit compound 2 culminated in the discovery of ATP-competitive eIF4A3 inhibitor 18 with submicromolar ATPase inhibitory activity and excellent selectivity over other helicases. Hence, compound 18 could be a valuable chemical probe to elucidate the detailed functions of eIF4A3 and EJC.