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Chronic hepatitis C virus (HCV) infection affects approximately 71 million people worldwide, resulting in an estimated 399,000 deaths annually from HCV-related causes such as cirrhosis and hepatocellular carcinoma. The development of direct-acting antiviral agents (DAA) has resulted in a substantial breakthrough in anti-HCV treatments....

This study aimed to identify a biomarker for predicting the response to sorafenib in patients with hepatocellular carcinoma (HCC). Of 100 patients with unresectable HCC who received sorafenib treatment in our institute (Cohort A), 48 had stored plasma samples collected within 28 days before the start of treatment (Cohort B). Concentrations of 18 plasma cytokines were measured in plasma samples using a sandwich immunoassay with multiplexed fluorescent bead-based technology. Among 27 patients with follow-up plasma samples taken at 5–10 days of treatment (Cohort C), changes in the 18 cytokines were also evaluated. In Cohort A, progressive disease (PD) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) was associated with poor overall survival by multivariate analysis (p = 0.024). In Cohort B, no significant differences in baseline concentrations of α-fetoprotein, des-γ-carboxy prothrombin, or the 18 cytokines were found between patients with PD and those with stable disease (SD) or partial response (PR). In Cohort C, the increase in interleukin-8 and tumor necrosis factor-α (TNF-α) was significant in the PD group (p = 0.0063 and p

A diastereo- and enantioselective total synthesis of diocollettines A with an unusual oxygen-containing tricyclic ring system has been achieved in 63% overall yield from commercially available 3-phenylpropanal via four steps. The key feature of the present synthesis is an exclusively diastereoselective cascade sequence composed of a trans-selective oxa-Michael addition of 1,3-dihydroxyacetone to a 2,3-dihydropyrylium ion intermediate, intramolecular aldol-type reaction, and intramolecular acetalization.

A bioinspired seven-step total synthesis of delitschiapyrone A was accomplished in 32% overall yield from commercially available 4-bromo-3,5-dimethoxybenzoic acid. The key step of the synthesis is an exclusively regioselective and diastereoselective reaction cascade consisting of the Diels-Alder reaction, α-ketol rearrangement, and cyclic hemiacetalization, achieved by simply stirring a heterogeneous mixture of two Diels-Alder substrates (putative biosynthetic intermediates) and water at 35 °C, directly furnishing the pentacyclic natural product in 75% yield.

Various positron emission tomography (PET) probes have been developed to assess in vivo activities in humans of drug transporters, which aid in the prediction of pharmacokinetic properties of drugs and the impact of drug-drug interactions. We developed a new PET probe, sodium (3R, 5R)-3, 5-dihydroxy-7-((1S, 2S, 6S, 8S)-6-hydroxy-2-methyl-8- ((1-[11C]-(E)-2-methyl-but-2-enoyl) oxy) -1, 2, 6, 7, 8, 8a-hexahydronaphthalen-1-yl) heptanoate ([11C]DPV), and demonstrated its usefulness for the quantitative investigation of Oatps (gene symbol SLCO) and Mrp2 (gene symbol ABCC2) in rats. To further analyze the species differences and verify the pharmacokinetic parameters in humans, serial PET scanning of the abdominal region with [11C]DPV was performed in six healthy volunteers with and without an OATP1Bs and MRP2 inhibitor, rifampicin (600 mg, oral), in a crossover fashion. After intravenous injection, [11C]DPV rapidly distributed to the liver and kidney followed by secretion into the bile and urine. Rifampicin significantly reduced the liver distribution of [11C]DPV 3-fold, resulting in a 7.5-fold reduced amount of excretion into the bile and the delayed elimination of [11C]DPV from the blood circulation. The hepatic uptake clearance (CLuptake, liver) and canalicular efflux clearance (CLint, bile) of [11C]DPV (544 ± 204 and 10.2 ± 3.5 µl/min per gram liver, respectively) in humans were lower than the previously reported corresponding parameters in rats (1800 and 298 µl/min per gram liver, respectively) (Shingaki et al., 2013). Furthermore, rifampicin treatment significantly reduced CLuptake, liver and CLint, bile by 58% and 44%, respectively. These results suggest that PET imaging with [11C]DPV is an effective tool for quantitatively characterizing the OATP1Bs and MRP2 functions in the human hepatobiliary transport system.

Aim The optimal combination of two currently available agents with different mechanisms of action, a nucleos(t)ide analog and pegylated interferon-α (PegIFNα), must be determined to improve treatment of chronic hepatitis B (CHB). Methods In this study, 24 patients with CHB (14 hepatitis B envelope antigen [HBeAg]-positive patients and 10 HBeAg-negative patients) received entecavir for 36-52 weeks, followed by entecavir plus Peg-IFNα2a for 4 weeks, and finally by PegIFNα-2a alone for 44 weeks. Results A sustained biochemical, virologic, and serologic response was obtained in 7/24 (29%) patients at 48 weeks post-treatment (2/14 [14%] in HBeAg-positive vs 5/10 [50%] in HBeAg-negative patients, P = 0.085). At baseline, patients with a sustained response had a significantly lower γ-glutamyl transferase level (P = 0.0023), a lower aspartate aminotransferase-to-platelet ratio index (P = 0.049), and a lower α-fetoprotein level (P = 0.042) than those without a sustained response. The decline in hepatitis B surface antigen (HBsAg) levels during the first 24 weeks of PegIFNα-2a treatment in patients with a sustained response was greater than that in patients without (P = 0.017). Additionally, HBsAg seroclearance was achieved in two patients (8.3%): one HBeAg-positive and one HBeAg-negative patient. Conclusion The outcomes of sequential therapy involving an early switch from entecavir to PegIFNα-2a were unsatisfactory in Japanese patients with CHB. In addition to viral factors, host metabolic characteristics and liver fibrosis/tumor markers can be used for prediction of a sustained response to therapy, but accurate prediction of the therapeutic response is difficult.

It is unclear whether multiple nonstructural (NS) 5A resistance-associated substitutions (RASs) correlate with the outcome of sofosbuvir (SOF) and ledipasvir (LDV) therapy. We investigated the effects of multiple NS5A RASs in NS5A inhibitor-naive patients with chronic hepatitis C virus genotype 1b infection treated with SOF/LDV. In 313 patients treated with SOF/LDV, we assessed the effects of multiple NS5A RASs on the sustained virological response (SVR). RASs at L28, R30, L31, Q54, P58, Q62, A92, and Y93 in the NS5A region were examined by direct sequencing. The prevalence of RASs was as follows: 2.6% at L28, 8.7% at R30, 6.1% at L31, 48.7% at Q54, 9.9% at P58, 9.9% at Q62, 5.1% at A92, 13.8% at Y93, and 19.2% at L31 or Y93. A total of 133 patients had no RASs. SVR was achieved in 98.7% of the patients. SVR rates significantly differed between patients with and without the L31 or Y93 RAS (93.0% [53/57] vs 100% [250/250], P = .0011). In addition, among patients with the L31 or Y93 RAS, 29.8%, 45.6% and 24.6% had one, two and three or more NS5A RASs, respectively. The SVR rate was significantly lower in patients with the L31 or Y93 RAS with more than three NS5A RASs compared to those with fewer than three NS5A RASs (71.4% [10/14] vs 100% [43/43], P = .0025). Although the prevalence of multiple NS5A RASs at baseline was low in NS5A inhibitor-naive patients, the presence of multiple NS5A RASs was associated with the effectiveness of SOF/LDV therapy.

The asymmetric total synthesis of (–)-rossinone A, a meroterpene exhibiting a range of pharmacologically important biological activities, has been accomplished for the first time from geraniol by a concise eight-step sequence that involves the Horner–Wadsworth–Emmons reaction of an aldehyde derived from a geranylated hydroquinone intermediate with a chiral phosphonate prepared via the highly diastereoselective Davis oxidation of a known oxazolidinone derivative.

Hepatitis B virus (HBV) infection is the major cause of cirrhosis worldwide. The ultimate goal of current antiviral treatments for chronic hepatitis B (nucleos(t)ide analogs and interferon-α) is to prevent the development of end-stage liver diseases. Areas covered: We present a review of the current literature on antiviral therapy in patients with chronic hepatitis B and cirrhosis. Medline search was performed to identify relevant literature from 1993 through January of 2017. Expert commentary: One randomized controlled trial and a number of observational studies have shown that nucleos(t)ide analogs can decrease the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B patients with advanced fibrosis. Data from clinical trials of entecavir and tenofovir have shown that histological improvement and regression of fibrosis can be achieved in the majority of patients with chronic hepatitis B by successful viral suppression. Entecavir and tenofovir are the preferred antiviral agents for treatment of chronic hepatitis B in patients with cirrhosis due to their high antiviral potency and high genetic barrier to resistance. Pegylated interferon-α is another therapeutic option for chronic hepatitis B patients with well-compensated cirrhosis. However, interferon therapy is contraindicated in patients with decompensated cirrhosis, and evidence for reduced HCC is currently insufficient.

Background and Aim It is unclear whether polymorphism in the inosine triphosphatase (ITPA) gene correlates with the reduction in hemoglobin (Hb) concentrations during sofosbuvir (SOF) and ribavirin (RBV) therapy. We investigated the effects of the ITPA polymorphism in Japanese patients with chronic hepatitis C virus genotype 2 infection treated with SOF/RBV therapy. Methods In 106 patients treated with SOF/RBV therapy, we assessed the effects of the ITPA polymorphism (rs1127354) on anemia, RBV dose reduction, and sustained virological response (SVR). Results Of the 106 patients, 80 had the CC genotype, whereas 26 had a non-CC genotype in ITPA. Patients with the CC genotype had significantly larger reductions in Hb concentrations than those with a non-CC genotype throughout the treatment course. RBV dose reduction was required in 18/106 (17.0%) patients, with a significantly higher frequency in patients with the CC genotype than in those with a non-CC genotype (p = 0.010). In multivariate analysis, age ≥ 65 years (p = 0.011) and the ITPA CC genotype (p

This prospective cohort study searched for factors associated with a response to nucleos(t)ide analogue/peg-interferon (NUC/peg-IFN) sequential therapy. A total of 95 patients with chronic hepatitis B being treated with NUCs were enrolled. Immediately following NUC cessation, peg-IFN was administered at 180 µg/dose weekly for 48 weeks. Twenty-six patients (27%) were judged to be responders at 48 weeks after the completion of peg-IFN. Analysis of baseline factors revealed that hepatitis B surface antigen (HBsAg)

The first enantioselective total synthesis of JBIR-03 and asporyzin C, indole diterpenoids of fungal origin exhibiting a range of pharmacologically important biological activities, has been accomplished from a known bicyclic keto alcohol in 13 and 14 steps, respectively. A hydroxy-directed cyclopropanation and Pd(II)-mediated indole ring formation were exploited as the key steps to obtain a pivotal pentacylic intermediate, which was converted into asporyzin C via chain elongation using cross-metathesis and then into JBIR-03 by Pd(II)-catalyzed tetrahydrofuran ring formation in an exclusively diastereoselective manner.

Direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection patients (CH) results in a sustained viral response (SVR) in over 95% of patients. However, hepatocellular carcinoma (HCC) occurs in 1&ndash, 5% of patients who achieved an SVR after treatment with interferon. We attempted to develop a minimally invasive and highly reliable method of predicting the occurrence and recurrence of HCC in patients who achieved an SVR with DAA therapy. The exosomal miRNA expression patterns of 69 CH patients who underwent HCC curative treatment and 70 CH patients were assessed using microarray analysis. We identified a miRNA expression pattern characteristic of SVR-HCC by using machine learning. Twenty-five of 69 patients had HCC recurrence. The expression of four exosomal miRNAs predicted HCC recurrence with 85.3% accuracy. Fifteen of 70 patients had HCC occurrence. The expression of four exosomal miRNAs predicted the onset of HCC with 85.5% accuracy. The expression patterns of miR-4718, 642a-5p, 6826-3p, and 762 in exosomes were positively correlated with those in the liver, and downregulation of these miRNAs induced cell proliferation and prevented apoptosis in vitro. Aberrant expression of four miRNAs, which was used for prediction, was associated with HCC onset after HCV eradication. Expression patterns of exosomal miRNAs are a promising tool to predict SVR-HCC.

研究グループは、肝障害を改善する可能性が期待されているサイトグロビンが酸化ストレスで生じるDNA損傷から細胞を保護する役割があることを明らかにしました。ウイルスや飲酒、肥満が原因で生じる肝線維化は難治性疾患であり、治療をしなかった場合は肝硬変へと進展し、その2~8％は肝がんを発症します。先行研究にてサイトグロビンに肝障害を改善する可能性があることは報告されていますが、肝線維化との関連については明らかにされていませんでした。そこで本研究では、脂肪肝患者の肝線維化とサイトグロビンの発現変動を調べたところ、肝線維化の進展に伴い、線維化促進因子であるtransforming growth factor(TGF)-βの過剰産生とサイトグロビンの発現量の減少が観察されました。また、サイトグロビン発現の低い患者では、酸化的DNA損傷が増加することを発見しました。この結果は、サイトグロビンが肝線維化の早期診断指標になる可能性を示唆しており、初期段階から治療に取り組むことが可能になるだけでなく、今後サイトグロビンの発現誘導剤を用いた新たな治療法の開発につながる大きな成果といえます。, Cytoglobin (CYGB) is a respiratory protein that acts as a scavenger of reactive oxygen species and protects cells from oxidative DNA damage. Herein, we show that the cytokine TGF-β1 downregulates human CYGB expression. This leads to oxidative DNA damage in activated hepatic stellate cells. Our findings provide new insights into the relationship between CYGB expression and the pathophysiology of fibrosis in patients with non-alcoholic steatohepatitis.

BackgroundPatients on oral antiviral (OAV) therapy remain at hepatocellular carcinoma (HCC) risk. Risk prediction tools distinguishing treated patients with residual HCC risk are limited. The aim of this study was to develop an accurate, precise, simple-to-use HCC risk score using routine clinical variables among a treated Asian cohort.MethodsAdult Asian chronic hepatitis B (CHB) patients on OAV were recruited from 25 centers in the United States and the Asia-Pacific region. Excluded persons were coinfected with hepatitis C, D, or human immunodeficiency virus, had HCC before or within 1 year of study entry, or their follow-up was ResultsA total of 8048 patients were randomized to the derivation (n = 5365) or validation group (n = 2683). The REAL-B model included 7 variables (male gender, age, alcohol use, diabetes, baseline cirrhosis, platelet count, and alpha fetoprotein), and scores were categorized as follows: 0–3 low risk, 4–7 moderate risk, and 8–13 high risk. Area under receiver operating characteristics were >0.80 for HCC risk at 3, 5, and 10 years, and these were significantly higher than other risk models (p < .001).ConclusionsThe REAL-B score provides 3 distinct risk categories for HCC development in Asian CHB patients on OAV guiding HCC surveillance strategy.

Aims We assessed the problems and efficacy of glecaprevir + pibrentasvir (GLE/PIB) therapy for patients infected with hepatitis C virus (HCV) in the real world. Method A total of 423 patients infected with HCV who started treatment at eight different centers in Japan were enrolled in the study. Glecaprevir (300 mg) and pibrentasvir (120 mg) were given once daily for 8 weeks to 246 non-cirrhotic direct-acting antiviral (DAA)-naive patients with HCV genotype (GT)-1 or -2, and for 12 weeks to patients who: were DAA-naive cirrhotic (n = 55), had experienced DAA failure (n = 78), were cirrhotic and had DAA failure (n = 37), and were other GT-1/2 (n = 7). Anti-HCV efficacy was defined as a sustained virologic response 12 weeks post-treatment (SVR12). The evaluation was undertaken in an intention-to-treat (ITT) population and in patients who were assessed at SVR12 (modified ITT population). Results In the ITT population, 220 (89%) patients on the 8-week regimen and 164 (93%) patients on the 12-week regimen achieved SVR12. The 30 dropout patients were predominantly men and with GT-2. All other DAA-naive GT-1 patients achieved SVR12. The 12-week regimen resulted in 100% SVR12 in 41 GT-2 patients. Nine patients did not achieve SVR12: two DAA naive with GT-2a, two GT-3b patients, two GT-1 patients with discontinuation, and three other GT-1 patients with a history of DAA failure. Four of seven patients who discontinued treatment due to severe adverse effects were more than 75 years old. Conclusions Glecaprevir + pibrentasvir had a remarkable anti-HCV effect in GT-1 and GT-2 patients, but not in GT-3b patients. Although this therapy was reasonably safe, it is necessary to carefully consider elderly and dropout patients.

No controlled trial in patients with chronic hepatitis B virus (HBV) infection on long-term entecavir (ETV) treatment, comparing switching to tenofovir disoproxil fumarate (TDF) with continuing the therapy, has been reported. Twenty-seven nucleos(t)ide-naive patients with chronic HBV who underwent ETV therapy for ≥5 years and maintained virological response were included and randomized into two groups: one group continued ETV, and the other switched to TDF, in a 1:2 ratio. The primary endpoint was changed from baseline in serum hepatitis B surface antigen (HBsAg) level at week 48. The baseline characteristics were not different between nineteen patients in the TDF group and eight patients in the ETV group. Mean decreases in HBsAg level at week 48 were 0.023 and 0.042 log10 IU/mL in the TDF and ETV groups, respectively (P = 0.94). The mean drops in hepatitis B core-related antigens were also not different between the TDF and ETV groups at week 48 (P = 0.80). HBV DNA was sustainedly

A thermophilic bacterium Thermosporothrix hazakensis NBRC 105916 which belongs to the class Ktedonobacteria was investigated to explore its biosynthetic potential of secondary metabolites. UV-guided fractionation led to the identification of a new benzenoid metabolite designated ktedonoketone (6) and an α-diketone metabolite 2’-oxosattabacin (7) along with five known compounds. Compound 7 was previously described as a synthetic compound, but this is the first finding as a natural product. Compound 7 induced adipocyte differentiation at 10–20 μM and autophagy at 1–10 μM. Compound 6 showed weak inducing activity of adipocyte differentiation. The biosynthetic origin of hazakacin (3), an acyloin-type compound, was elucidated by 13C-labeled precursor-feeding experiments.

The cell wall integrity signaling (CWIS) pathway is involved in fungal cell wall biogenesis. This pathway is composed of sensor proteins, protein kinase C (PKC), and the mitogen-activated protein kinase (MAPK) pathway, and it controls the transcription of many cell wall-related genes. PKC plays a pivotal role in this pathway; deficiencies in PkcA in the model filamentous fungus Aspergillus nidulans and in MgPkc1p in the rice blast fungus Magnaporthe grisea are lethal. This suggests that PKC in filamentous fungi is a potential target for antifungal agents. In the present study, to search for MgPkc1p inhibitors, we carried out in silico screening by three-dimensional (3D) structural modeling and performed growth inhibition tests for M. grisea on agar plates. From approximately 800,000 candidate compounds, we selected Z-705 and evaluated its inhibitory activity against chimeric PKC expressed in Saccharomyces cerevisiae cells in which the kinase domain of native S. cerevisiae PKC was replaced with those of PKCs of filamentous fungi. Transcriptional analysis of MLP1, which encodes a downstream factor of PKC in S. cerevisiae, and phosphorylation analysis of the mitogen-activated protein kinase (MAPK) Mpk1p, which is activated downstream of PKC, revealed that Z-705 specifically inhibited PKCs of filamentous fungi. Moreover, the inhibitory activity of Z-705 was similar to that of a well-known PKC inhibitor, staurosporine. Interestingly, Z-705 inhibited melanization induced by cell wall stress in M. grisea. We discuss the relationships between PKC and melanin biosynthesis. IMPORTANCE A candidate inhibitor of filamentous fungal protein kinase C (PKC), Z-705, was identified by in silico screening. A screening system to evaluate the effects of fungal PKC inhibitors was constructed in Saccharomyces cerevisiae. Using this system, we found that Z-705 is highly selective for filamentous fungal PKC in comparison with S. cerevisiae PKC. Analysis of the AGS1 mRNA level, which is regulated by Mps1p mitogen-activated protein kinase (MAPK) via PKC, in the rice blast fungus Magnaporthe grisea revealed that Z-705 had a PKC inhibitory effect comparable to that of staurosporine. Micafungin induced hyphal melanization in M. grisea, and this melanization, which is required for pathogenicity of M. grisea, was inhibited by PKC inhibition by both Z-705 and staurosporine. The mRNA levels of 4HNR, 3HNR, and SCD1, which are essential for melanization in M. grisea, were suppressed by both PKC inhibitors.

An enantioselective synthesis of the tricyclic core structure of (+)-strigol, a potent seed germination stimulant for root parasitic weeds, has been achieved from 2-iodo-4,4-dimethyl-2-cyclohexen-1-one in 14 steps. The key steps include a CBS reduction of an iodo enone to obtain a cyclohexenol derivative of high enantiomeric excess, regioselective epoxide ring opening with a Grignard reagent in a low-polarity solvent, highly diastereoselective addition of vinyllithium to a ketone, and Lewis acid-promoted installation an acetate unit onto a bicyclic allylic acetate intermediate.

Simeprevir (SMV) is a potent, macrocyclic hepatitis C virus (HCV) non-structural 3/4 A protease inhibitor. This prospective study compared the efficacy and safety of SMV in combination with peginterferon α2a + ribavirin (P2aR) and with peginterferon α2b + ribavirin (P2bR) in Japanese patients with HCV genotype 1b infection. Methods Hepatitis C virus genotype 1b patients were randomly assigned to receive SMV (100 mg QD) with P2aR for 12 weeks, then P2aR alone for 12 or 36 weeks; or SMV (100 mg QD) with P2bR for 12 weeks, then P2bR alone for 12 or 36 weeks. The primary endpoint was a sustained virologic response 24 weeks after completing treatment (SVR24). Results In total, 151 patients were randomly assigned to the P2aR (n = 76) or P2bR group (n = 75). Six patients dropped out. Sustained virologic response 24 weeks after completing treatment was achieved in 55 (75.3%) of 73 P2aR patients and 55 (76.4%) of 72 P2bR patients. There was no difference in the rate of SVR24 between the two groups (P = 0.88). No differences in the proportion of patients who became HCV RNA-negative were detected between the P2aR and P2bR groups. The two groups had comparable numbers of adverse events, which led to the discontinuation of treatment in 9.6% and 8.3% of participants in the P2aR and P2bR groups, respectively. Conclusion Peginterferon α2a or α2b in combination with SMV + ribavirin therapy showed identical antiviral effects in patients with chronic hepatitis C. Also, the incidence of adverse events was identical for both regimens.

Seiridiasteriscane A (1), pestalotiopsins L-N (2–4), and 2-O-deacetylpestalotiopsin A (5) were isolated along with known pestalotiopsins A (7), B (6), and fuscoatrol A (8) from Seiridium sp. KT3957. Their relative structures were elucidated by extensive NMR analysis and verified using DFT (density functional theory) chemical shift calculations. The absolute configurations were determined by reproducing their experimental ECD spectra based on DFT calculations. Although 3 and 4 existed as conformational mixtures in CDCl3, DFT-based 13C chemical shift calculations were useful for evaluating each conformer. Simultaneous isolation of seiridiasteriscane A (1) and pestalotiopsins 2–8 suggested a plausible route for the biosynthesis of 1 involving the expansion of the cyclobutane moiety into a cyclopentane ring.

Terfestatin A, a specific inhibitor of auxin signaling, has been synthesized from a known aromatic aldehyde in 21% overall yield via five steps. The first total synthesis of terfestatin B with potent neuroprotective activity has also been accomplished in eight steps from the same aromatic aldehyde in 30% overall yield through a common intermediate. The key feature of this synthesis is the utilization of the aldehyde functionality of the starting material both as a directing group for regioselective O-protection and as a masked hydroxy group.

The first total synthesis of (S)-ktedonoketone has been accomplished in 16% overall yield from (R)-2-hydroxybutyric acid by an eight-step sequence that features a highly diastereoselective methallylation of a chiral dioxolanone and a nucleophilic addition of α-lithiostyrene to a Weinreb’s amide intermediate followed by ring-closing metathesis of the resulting enone to construct an α,β-disubstituted cyclopentenone ring system. The sign of specific rotation of synthetic (S)-ktedonoketone was opposite to that reported for the natural product.

The microwave-assisted heating reaction of N-acetyl glucosamine (GlcNAc) in sulfolane is described. The reaction produces two major products that are assignable to 1,6-anhydro-2-acetamido-2-deoxy-β-d-glucopyranose (AGPNAc) and 1,6-anhydro-2-acetamido-2-deoxy-β-d-glucofuranose (AGFNAc). In order to reveal a general feature of the system, the 3, 5, and 10 min reactions were performed at 140, 160, 180, 200, and 220 °C to clarify the time course changes in the conversion of GlcNAc and the yields of the two produced 1,6-anhydrosugars. Temperature is a crucial factor that significantly affects the conversion of GlcNAc. The yields of AGPNAc and AGFNAc are also drastically changed depending on the reaction conditions. The 5-min reaction at 200 °C is shown to be the optimal condition to generate the 1,6-anhydrosugars with a high efficiency in which AGPNAc and AGFNAc are produced in the yields of 21% and 44%, respectively. Consequently, the microwave-assisted heating reaction of GlcNAc in sulfolane is shown to be a simple and promising pathway to generate 1,6-anhydrosugars consisting of amino monosaccharide backbones, which have high potentials as raw materials leading to biological oligosaccharides and biomimetic polysaccharides.

Recently, three tyrosine kinase inhibitors (TKIs) have become available for treatment of unresectable hepatocellular carcinoma (HCC). We herein report a case of a 59-year-old man with interstitial pneumonia that was suspected during regorafenib administration and was exacerbated by subsequent lenvatinib treatment for advanced HCC. After sorafenib was discontinued due to progressive HCC, regorafenib treatment was started. Progressive HCC was again noted and reticular shadows were suspected in both lower lung fields at 2 months after starting regorafenib administration. Subsequent treatment with lenvatinib obtained a partial response for HCC, but the reticular shadows became marked and dyspnea on effort emerged, followed by hypoxemia and an increased Krebs von den Lungen-6 (KL-6) value. Because we suspected acute interstitial pneumonia, due to these TKIs, intravenous pulse steroid therapy was started immediately after discontinuing lenvatinib. Within 1 week after starting steroid therapy, the patient’s respiratory condition and hypoxemia gradually began improving. No previous case of pulmonary interstitial changes that appeared in association with regorafenib administration for HCC and that were exacerbated by subsequent treatment with lenvatinib has been reported. This case emphasizes that it is necessary to observe the patient’s respiratory condition and to perform imaging examinations to monitor for adverse events during TKI treatment.

There have been a few reports on the treatment of patients infected with recombinant hepatitis C virus (HCV) genotype 2/1 strains with direct-acting antivirals (DAAs). We experienced three patients, with genotype 2/1 recombinant HCV, treated with DAAs successfully. The first, a 39-year-old man, was infected with recombinant HCV genotype 2a/1b, a rare variant. The sequence of the relapsed virus showed chimeric HCV 2a/1b with the recombinant breakpoint found at nucleotide +49 from the start of the NS3 region. Sofosbuvir plus ribavirin, a regimen recommended for HCV genotype 2, did not lead to a sustained viral response (SVR). Retreatment with grazoprevir plus elbasvir resulted in an SVR. The second case, a 70-year-old woman, was infected with recombinant HCV genotype 2b/1b. DAA therapy with sofosbuvir plus ledipasvir resulted in an SVR. The third case, a 48-year-old woman, was also infected with recombinant HCV genotype 2b/1b. DAA therapy with daclatasvir plus asunaprevir resulted in an SVR. The baseline sequences of the viruses from both the second and third cases showed chimeric HCV 2b/1b with the recombinant breakpoint found at nucleotide +10 from the NS3 start. We report three cases with 2/1 chimeras and discuss the prevalence and response to therapy.

Background & Aims: The effect of hepatocellular carcinoma (HCC) on the response to interferon-free direct-acting antiviral (DAA) therapy in patients with chronic hepatitis C (CHC) infection remains unclear. Using a systematic review and meta-analysis approach, we aimed to investigate the effect of DAA therapy on sustained virologic response (SVR) among patients with CHC and either active, inactive or no HCC. Methods: PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from 1/1/2013 to 9/24/2018. The pooled SVR rates were computed using DerSimonian-Laird random-effects models. Results: We included 49 studies from 15 countries, comprised of 3,341 patients with HCC and 35,701 without HCC. Overall, the pooled SVR was lower in patients with HCC than in those without HCC (89.6%, 95% CI 86.8–92.1%, I2 = 79.1% vs. 93.3%, 95% CI 91.9–94.7%, I2 = 95.0%, p = 0.0012), translating to a 4.8% (95% CI 0.2–7.4%) SVR reduction by meta-regression analysis. The largest SVR reduction (18.8%) occurred in patients with active/residual HCC vs. inactive/ablated HCC (SVR 73.1% vs. 92.6%, p = 0.002). Meanwhile, patients with HCC who received a prior liver transplant had higher SVR rates than those who did not (p

BACKGROUND AND AIMS It remains unclear whether there is an association between single-nucleotide polymorphisms (SNPs) and development of hepatocellular carcinoma (HCC) during entecavir (ETV) treatment in nucleos(t)ide analog-naive patients with chronic hepatitis B virus infection. We investigated the risk factors for HCC, especially host factors, during ETV treatment. METHODS A total of 127 Japanese patients undergoing ETV treatment were enrolled in this study. Univariate and multivariate analyses for clinical factors, hepatic fibrosis markers, and SNPs associated with HCC development were analyzed. RESULTS A total of 10 patients developed HCC during the follow-up period (median duration, 3.3 years). The 3-, 5-, and 7-year cumulative rates of HCC development were 4.8%, 10.6%, and 13.6%, respectively. Liver fibrosis (cirrhosis; P = 0.0005), age (≥ 49 years; P = 0.0048), platelet count (≤ 115 × 10/mm3 ; P = 0.0007), α-fetoprotein (≥ 8.0 ng/mL; P = 0.030), type IV collagen (≥ 200 ng/mL; P = 0.043), fibrosis-4 index (≥ 4.14; P = 0.0006), and human leukocyte antigen (HLA)-DQA1/DRB1-SNP (AA genotype; P = 0.0092) were significantly associated with HCC development according to the log-rank test. In multivariate analysis, AA genotype in the HLA-DQA1/DRB1 gene (P = 0.013; hazard ratio 4.907; 95% confidence interval 1.407-17.113) and cirrhosis (P = 0.019; hazard ratio 4.789; 95% confidence interval 1.296-17.689) were significantly associated with HCC development. CONCLUSIONS Our findings suggested that patients with AA genotype in the HLA-DQA1/DRB1 gene or cirrhosis should be carefully followed up as a population potentially at higher risk of HCC during ETV treatment.

【概要】C型慢性肝炎に対するDAA治療後の肝病理組織所見の検討は、これまで十分になされていませんでした。本研究ではDAA治療によってウイルス排除に成功し、かつ血液検査で異常が見られなかった51症例に対し肝生検を行い、炎症、線維化、鉄沈着、脂肪化などの項目について調べました。その結果、ほとんどの症例で肝組織の改善が見られました。また、同時に約2割程度の症例に有意な炎症が残存していることがわかりました。DAAによってC型肝炎ウイルスを排除することにより、血液検査のみならず肝生検結果の改善も見られたことから、治療によって将来的には肝硬変や肝臓がんへの進展が予防できることが期待されます。一方、炎症が残存していた症例の少なくとも一部は脂肪肝炎が原因であったことから、治療後もアルコール多飲や肥満などを避けて生活習慣に注意する必要があると考えられます。, Background: Interferon-free, direct-acting antiviral (DAA) treatments can result in a sustained virologic response (SVR) in nearly 100% of patients with chronic hepatitis C virus (HCV) infection. / Aims: To evaluate histological improvement after achieving an SVR to DAA treatments in patients with chronic hepatitis C. / Methods: Among 691 patients with chronic hepatitis C who achieved an SVR to DAAs, 51 underwent liver biopsy 41 ± 20 weeks after the end of treatment despite normal transaminase levels. In 20 patients, liver biopsy specimens obtained a median of 1.2 years before the start of treatment were available....

Background Hepatocellular carcinoma (HCC) develops in some patients who achieve sustained virological response (SVR) against hepatitis C virus (HCV) infection via anti-HCV therapy. To examine the pathogenesis of HCC development after HCV eradication, histopathological changes and clinical markers were evaluated in SVR patients. Methods Of 654 SVR patients treated with interferon (IFN)-based therapies, 34 patients who had undergone liver biopsy before initiating IFN therapy and after SVR achievement were enrolled: 11 patients with HCC and 23 patients without HCC (male/female, 9/2 and 8/15, respectively: age, 58 ± 5 and 54 ± 11 years, respectively). We compared the clinical and histopathological factors between the two groups. Immunohistochemistry for Cytoglobin (CYGB) and α smooth muscle actin (α-SMA) was also performed. Results At baseline, prior to initiating the IFN-based therapy, there were significant differences between the SVR-non-HCC and SVR-HCC groups in the male gender, HBc antibody positivity, prothrombin activity, and histological inflammatory grade. Histopathological evaluation, using the new Inuyama classification system, revealed an improvement in the inflammatory grade, from 2.1 ± 0.6 to 1.0 ± 0.6 (p < 0.0001), whereas the fibrosis stage remained unchanged, from 2.3 ± 0.9 to 2.0 ± 1.2 (p = 0.2749), during the 97 ± 72-month observation period in the SVR-HCC group. Both the grade and stage scores were significantly improved in the SVR-non-HCC group. The area of collagen deposition, evaluated using Sirius red staining, showed a marked decrease, from 18.6 ± 7.6% to 7.7 ± 4.6%, in the SVR-non-HCC group, with no change in the SVR-HCC group. CYGB- and α-SMA-positive hepatic stellate cells (HSCs), indicative of the HSC activated phenotype, remained in the fibrotic tissue of livers among patients in the SVR-HCC group. Conclusion Stagnation of fibrosis regression is associated with a high risk for HCC after SVR. HSC activation may inhibit improvement in fibrosis after SVR and potentially contribute to hepatocarcinogenesis.

Aim Hepatocellular carcinoma (HCC) develops in up to 5% of patients after the successful treatment of chronic hepatitis C virus (HCV) infection using interferon therapy. The aim of this study was to characterize miRNA expression in liver tissues from patients who achieved a sustained viral response (SVR). Methods Seventy-one patients with resected HCC were enrolled into the present study: 61 HCC from patients with continuously infected HCV (HCV-HCC) and 10 from patients who had achieved SVR (SVR-HCC). We also included non-tumor tissues (SVR-NT) from four patients with SVR-HCC, and liver tissue (SVR-CH) from four SVR patients without HCC. Total RNA was extracted from liver samples. The miRNA expression patterns were analyzed using microarrays. In addition, target gene expression was quantified after miRNA overexpression in HEK293 cells. Results We could discriminate between SVR-HCC and HCV-HCC with 75.36% accuracy using the expression pattern of six specific miRNA. The expression levels of 37 miRNA were significantly lower in HCV-HCC than in SVR-HCC, whereas the expression of 25 miRNA was significantly higher in HCV-HCC than SVR-HCC (P

The enantio- and diastereoselective total synthesis of amicoumacin C was achieved from l -phenylalanine in 17% overall yield through 13 steps via condensation between an amine and an acid segment. The amine segment was prepared from l -leucine in 42% yield by a 7-step sequence involving a diastereoselective reduction of an α-dibenzylamino ketone intermediate, while the acid segment was obtained from l -phenylalanine by using acidic hydrolysis of an acetonide-protected amide accompanied by concomitant lactonization as a key step.

Aim. Anemia is the most common adverse event in patients with chronic hepatitis C virus (HCV) treated with telaprevir (TVR) combined triple therapy. We examined the effects of drug dose adjustment on anemia and a sustained viral response (SVR) during combination therapy. Material and methods. This study enrolled 62 patients treated with TVR (2,250 mg) for 12 weeks plus pegylated interferon-alpha-2b and ribavirin for 24 weeks. The patients were assigned randomly to the TVR-standard or -reduced groups before treatment. At the occurrence of anemia (hemoglobin < 12 g/dL), the TVR-reduced group received 1500 mg TVR plus the standard dose of ribavirin, whereas the TVR-standard group received the standard TVR dose (2,250 mg) and a reduced dose of ribavirin (200 mg lower than prescribed originally). The safety and SVR at 24 weeks were compared between the TVR-standard (n = 28) and TVR-reduced (n = 25) groups. Results. No differences in the proportion of patients who became HCV RNA-negative were detected between the TVRstandard and -reduced groups (72 and 72% at week 4, 79 and 84% at the end of treatment, and 76 and 80% at SVR24, respectively). Two groups had comparable numbers of adverse events, which led to the discontinuation of TVR in 14 patients of TVR-standard group and in 14 of TVR-reduced group. A lower incidence of renal impairment was observed in the TVR-reduced group (6%) than the TVR-standard group (11%, not statistically significant). Conclusions. TVR dose adjustment could prevent anemia progression without weakening the anti-viral effect during triple therapy in HCV-patients.

The first synthesis of bacilosarcin C, a member of amicoumacin family of natural product isolated from the culture broth of a marine bacterium, has been achieved in 2 steps by diastereoselective reductive amination of amicoumacin C with 2,3-butanedione followed by hydrolysis of the resulting N -alkylated lactone intermediate. Ammonolysis of the intermediate, on the other hand, led to an improved synthesis of bacilosarcin B, an amide congener of bacilosarcin C.

An enantio- and diastereoselective synthesis of the C17–C29 fragment of amphidinolide N, an extremely potent macrocyclic cytotoxin of marine origin, has been accomplished from a known olefinic ester by a 10-step sequence that involves a ring opening of a chiral epoxide with a dithiane derivative to construct the full carbon skeleton, a highly diastereoselective reduction of a β-hydroxy ketone intermediate to install the C21 asymmetric center, and a one-pot Sharpless AD/cyclization sequence to form a trans -substituted tetrahydrofuran ring system.

The optimal combination of two currently available agents with different mechanisms of action, a nucleos(t)ide analog and pegylated interferon-α (PegIFNα), must be determined to improve treatment of chronic hepatitis B (CHB).In this study, 24 patients with CHB (14 hepatitis B envelope antigen [HBeAg]-positive patients and 10 HBeAg-negative patients) received entecavir for 36-52 weeks, followed by entecavir plus Peg-IFNα2a for 4 weeks, and finally by PegIFNα-2a alone for 44 weeks.A sustained biochemical, virologic, and serologic response was obtained in 7/24 (29%) patients at 48 weeks post-treatment (2/14 [14%] in HBeAg-positive vs 5/10 [50%] in HBeAg-negative patients, P = 0.085). At baseline, patients with a sustained response had a significantly lower γ-glutamyl transferase level (P = 0.0023), a lower aspartate aminotransferase-to-platelet ratio index (P = 0.049), and a lower α-fetoprotein level (P = 0.042) than those without a sustained response. The decline in hepatitis B surface antigen (HBsAg) levels during the first 24 weeks of PegIFNα-2a treatment in patients with a sustained response was greater than that in patients without (P = 0.017). Additionally, HBsAg seroclearance was achieved in two patients (8.3%): one HBeAg-positive and one HBeAg-negative patient.The outcomes of sequential therapy involving an early switch from entecavir to PegIFNα-2a were unsatisfactory in Japanese patients with CHB. In addition to viral factors, host metabolic characteristics and liver fibrosis/tumor markers can be used for prediction of a sustained response to therapy, but accurate prediction of the therapeutic response is difficult.

The synthesis of aurachin B, an antibiotic that features a C3-oxygen-substituted quinoline N-oxide nucleus bearing a farnesyl side chain at C4, was accomplished in 60% overall yield from o-nitrotoluene by a concise five-step sequence. An enantioselective synthesis of aurachin H was also achieved for the first time in only two steps from an optically active epoxy iodide.

To determine the clinical characteristics of hepatitis B virus (HBV) reactivation in patients undergoing interferon-free antihepatitis C virus (HCV) therapy, we examined HBV DNA in 25 HBV co-infected patients and 765 patients with resolved HBV infection during and after treatment with direct-acting antiviral agents (DAAs). Among those with HCV genotype 1, asunaprevir plus daclatasvir was administered to 160 patients, sofosbuvir (SOF) plus ledipasvir to 438 patients and paritaprevir plus ombitasvir and ritonavir to 25 patients. In total, 167 patients with genotype 2 were treated with SOF plus ribavirin. Three patients with an HBV DNA level ≥2000 IU/mL were treated with entecavir before anti-HCV therapy, without reactivation of HBV. In 3 of 22 (12%) HBV surface antigen (HBsAg)-positive patients with an HBV DNA level

We evaluated the transition of dominant resistance-associated substitutions (RASs) in hepatitis C virus during long-term follow-up after the failure of DAAs (direct acting antivirals)-based therapy. RASs in non-structure (NS)3/4A, NS5A, NS5B, and deletions in NS5A from 20 patients who failed simeprevir/pegylated-interferon/ribavirin (SMV/PEG-IFN/RBV) and 25 patients who failed daclatasvir/asunaprevir (DCV/ASV) treatment were examined by direct sequencing. With respect to SMV/PEG-IFN/RBV treatment, RAS was detected at D168 in NS3/4A but not detected in NS5A and NS5B at treatment failure in 16 of 20 patients. During the median follow-up period of 64 weeks, the RAS at D168 became less dominant in 9 of 16 patients. Among 25 DCV/ASV failures, RASs at D168, L31, and Y93 were found in 57.1%, 72.2%, and 76.9%, respectively. NS5A deletions were detected in 3 of 10 patients treated previously with SMV/PEG-IFN/RBV. The number of RASs in the breakthrough patients exceeded that in relapsers (mean 3.9 vs. 2.7, p < 0.05). RAS at D168 in NS3/4A became less dominant in 6 of 15 patients within 80 weeks. Y93H emerged at the time of relapse, then decreased gradually by 99% at 130 weeks post-treatment. Emerged RASs were associated with the clinical course of treatment and could not be detected during longer follow-up.

Background and Aim 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) may detect primary lesions (PLs) and extrahepatic metastases (EHMs) only in advanced hepatocellular carcinoma (HCC) patients. We investigated the requirement of PET and the optimal timing of PET scanning for accurate staging and treatment planning. Methods We conducted a retrospective investigation of 64 HCC patients who underwent PET (median age, 74 years; male/female, 41/23; etiology, 46 hepatitis C virus/4 hepatitis B virus/4 alcoholic/10 others). To determine the best timing for PET examinations, we analyzed PET result-based recommended treatment changes and characteristics of patients with FDG-avid PLs or EHMs. Results FDG-avid PLs were detected by PET in 22 patients (34%): 18 with hypervascular PL, 11 with serum α-fetoprotein levels ≥ 200 ng/mL, and 11 beyond Milan criteria. EHMs were detected in 21 patients (33%: lymph nodes, 8; lung, 5; abdominal wall, 4; bone, 3; other organs, 4 [including overlapping]). Recommended treatments changed for 16 patients (25%) because of Barcelona Clinic Liver Cancer stage increases based on PET scanning. In multivariate analyses, serum α-fetoprotein levels ≥ 200 ng/mL and beyond Milan criteria were independent factors for FDG-avid PLs and a maximum standardized uptake value (SUVmax) of PLs of ≥ 4.0 was an independent factor for FDG-avid EHMs (P = 0.002, 0.008, and 0.045, respectively). Conclusions PET allows detection of HCC spread in patients with elevated serum α-fetoprotein levels or those beyond Milan criteria and detects EHMs in patients with PLs with high SUVmax values. Optimally timed PET scans can complement conventional imaging for accurate staging and treatment strategy determination.