In order to improve the bioavailability, it is desired to obtain the polymorph which has the higher solubility of indomethacin (IMC α-form). However, when α-form crystals were obtained by ...conventional anti-solvent crystallization, the stirring operation could not be continued because cotton agglomerates were formed in the solution. In order to simultaneously satisfy the bioavailability of IMC and the operability of IMC production, the modification of the morphology (external shape) of α-form agglomerates is important. So, the purpose of this present study is the development of the crystallization method. In order to modify the cotton agglomerates, the anti-solvent crystallization was carried out by using electrolyte aqueous solution (NaCl aq. solution) as the anti-solvent. By using the electrolyte aqueous solution, the liquid–liquid phase separation (LLPS) was observed depending on the solution composition. From the experimental results, under the condition both of high electrolyte concentration and of high stirring speed, dispersion of droplets was obtained, and spherical agglomerates of α-form were formed in the slurry. The stirring operation could be continued in the slurry because the modification of α-form cotton agglomerates was achieved. So, the simultaneous control method of the polymorphism and the morphology in IMC crystallization was realized.
•Anti-solvent crystallization was carried out for indomethacin (IMC).•Dispersion of droplets was obtained by using NaCl aq. solution as the anti-solvent.•IMC cotton agglomerates was modified by using the dispersion of droplets.•Simultaneous control method of polymorphism and morphology for IMC was proposed.
Aim
This study aimed to describe the real‐world efficacy and safety of sofosbuvir (SOF) + ribavirin (RBV) for chronic hepatitis C, genotype 2.
Methods
This was a retrospective analysis of a ...nationwide, multicenter registry including 914 hepatitis C genotype 2 Japanese patients treated with SOF + RBV for 12 weeks. The rate of sustained virologic response at 12 weeks after treatment (SVR12), incidence of adverse events, and changes in serological parameters were analyzed.
Results
Treatment was completed in 98.9% of patients. Ribavirin dose reduction was required in 29.7% of patients. The SVR12 rate was 96.8% in the intention‐to‐treat population and 97.6% in the per‐protocol population. Factors associated with SVR12 were absence of advanced fibrosis (odds ratio, 5.76, P = 0.003) and interferon‐treatment‐naïve status (odds ratio, 4.79, P = 0.017). Dose reduction or total adherence of RBV was not associated with SVR. The resistance‐associated substitution S282 T in NS5B was not detected in any patient at virologic failure. Serum albumin levels significantly increased, and the degree of increase was greater in patients with advanced fibrosis than in those without (0.21 ± 0.32 vs. 0.05 ± 0.29, P < 0.0001). Alpha‐fetoprotein decreased significantly at end of treatment (P < 0.0001), and the degree of decrease was greater in patients with advanced fibrosis than in those without (21.7 ± 60.8 vs. 2.5 ± 15.5, P < 0.001). The most commonly reported adverse event was anemia (13.7%).
Conclusions
Treatment with SOF + RBV was highly effective and safe in Japanese patients with HCV genotype 2 infection.
KDM5 family members (A, B, C and D) that demethylate H3K4me3 have been shown to be involved in human cancers. Here we performed screening for KDM5A inhibitors from chemical libraries using the ...AlphaScreen method and identified a battery of screening hits that inhibited recombinant KDM5A. These compounds were further subjected to cell-based screening using a reporter gene that responded to KDM5A inhibition and 6 compounds were obtained as candidate inhibitors. When further confirmation of their inhibition activity on cellular KDM5A was made by immunostaining H3K4me3 in KDM5A-overexpressing cells, ryuvidine clearly repressed H3K4me3 demethylation. Ryuvidine prevented generation of gefitinib-tolerant human small-cell lung cancer PC9 cells and also inhibited the growth of the drug-tolerant cells at concentrations that did not affect the growth of parental PC9 cells. Ryuvidine inhibited not only KDM5A but also recombinant KDM5B and C; KDM5B was the most sensitive to the inhibitor. These results warrant that ryuvidine may serve as a lead compound for KDM5 targeted therapeutics.
Background: Lenvatinib (LEN) has been approved for patients with unresectable hepatocellular carcinoma (u-HCC) since March 2018 in Japan. We performed a retrospective nationwide multicenter study to ...clarify the clinical characteristics of LEN in real-world practice. Methods: A total of 343 u-HCC patients who received LEN from March 2018 to May 2020 at 23 sites in Japan were registered. Results: During the median observation period of 10.5 months, 143 patients died. In Child-Pugh A (n = 276) and Child-Pugh B (n = 67) patients, the median overall survival (OS) was 21.0 and 9.0 months. The median progression-free survival (PFS) was 8.8 months in Child-Pugh A patients. The objective response rate (ORR) and disease control rate (DCR) according to modified response evaluation criteria in solid tumors (RECIST criteria) were 42.1% and 82.1%. The independent pretreatment factors associated with mortality in all patients were AFP ≥ 400 ng/mL (hazard ratio (HR) 2.00, 95% confidential interval (95% CI) 1.08–2.09, p < 0.0001), modified albumin-bilirubin (ALBI) grade 2b or 3 (HR 1.56, 95% CI 1.09–2.17, p = 0.012), major vascular invasion (HR 1.91, 95% CI 1.26–2.89, p = 0.0022), PS > 0 (HR 1.50, 95% CI 1.09–2.08, p = 0.014), and MTT (molecular targeted therapy) experience (HR 2.22, 95% CI 1.56–3.13, p = 0.00038). In the MTT naïve patients with ALBI grade 1 or modified ALBI 2a and BCLC stage B (n = 68), median OS and PFS were 25.3 and 12.3 months. Liver-related adverse events during LEN were the only significant adverse event associated with OS (HR 2.74, 95% CI 1.93–3.88, p < 0.0001). Among the Child-Pugh A patients with extrahepatic metastasis and no major vascular invasion, median PFS in the patients with bone metastasis was significantly shorter than those with lung or adrenal grand metastasis (6.3 vs. 12.5 months, p = 0.0025). Conclusion: LEN showed a high response rate in real-world practice. Pretreatment factors, including ALBI score, AFP, and major vascular invasion are important in making a treatment strategy for patients with u-HCC. The patients with bone metastasis would be candidates for new therapeutic approaches.
Aim
Past hepatitis B virus (HBV) infection is considered a risk factor for hepatocarcinogenesis, but the clinicopathological characteristics of non‐B non‐C hepatocellular carcinoma (NBNC‐HCC) ...excluding past HBV infection have not been investigated. This study aimed to clarify the clinicopathological features of strictly defined NBNC‐HCC.
Methods
Among HCC patients who underwent surgical resection at our affiliated hospitals in Nagano prefecture, Japan, between 1996 and 2012, 77 were negative for serum anti‐HBV core/surface antibodies in addition to HBV surface antigen and anti‐hepatitis C virus antibody without signs of autoimmune liver disease, Wilson disease, or hemochromatosis. These patients were divided into the alcohol intake‐positive group (ethanol intake >20 g/day, n = 31), non‐alcoholic fatty liver group (steatosis >5% and ethanol intake <20 g/day, n = 30), and cryptogenic group (no ethanol intake or steatosis, n = 16). Preoperative clinical parameters, tumor and background liver pathology, and prognosis were analyzed.
Results
Advanced fibrosis and steatosis were detected in 64% and 60% of all patients, respectively. Approximately 85% of the alcohol intake‐positive patients had advanced fibrosis. Non‐alcoholic fatty liver HCC subjects had the highest body mass index and prevalence of diabetes, but 30–40% had none to mild fibrosis. The cryptogenic group of HCC patients had the lowest incidence of accompanying hepatic inflammation/fibrosis but the largest tumor size. Recurrence/survival rates were comparable among the groups.
Conclusions
Liver fibrosis and steatosis are risk factors of HCC regardless of past HBV infection and ethanol consumption. The present results also indicate the possibility of hepatocarcinogenesis independent of hepatic steatosis, inflammation and fibrosis, ethanol intake, and past HBV infection.
Pancreatic panniculitis is a rare skin manifestation in pancreatic disease patients that most frequently develops on the lower legs. We report the unique case of a 68-year-old man who suffered from ...pancreatic panniculitis on his trunk associated with acute pancreatitis due to an intraductal papillary mucinous neoplasm.
A 68-year-old man complained of a 2-day history of a tender subcutaneous nodule on his trunk. Laboratory tests and abdominal contrast computed tomography were consistent with acute pancreatitis due to an intraductal papillary mucinous neoplasm. A skin biopsy of the nodule histologically displayed lobular panniculitis with characteristic "ghost cells", which indicated pancreatic panniculitis.
In order to avoid a missed or delayed diagnosis, clinicians should bear in mind that pancreatic panniculitis can be the first manifestation of pancreatic disease when encountering subcutaneous nodules on the trunk.
Background. A new agent, potassium-competitive acid blocker vonoprazan (VPZ) has potent acid-inhibitory effects and may offer advantages over conventional H. pylori eradication therapies. We aimed to ...compare the eradication rate between VPZ-based treatment and PPI-based one. Methods. This randomized controlled trial was designed to assign 141 patients with H. pylori-positive gastritis to VPZ group (VPZ 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg twice daily for 7 days) or PPI group (rabeprazole 20 mg or lansoprazole 30 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg twice daily for 7 days). Primary endpoints were eradication rates and adverse events. Results. Seventy of 72 patients in VPZ group and 63 of 69 patients in PPI group completed the treatment after 7 days. The eradication rate was significantly higher in VPZ group than PPI group by intention-to-treat analysis (95.8% versus 69.6%, P=0.00003, 95% confidence interval CI 88.3-99.1% versus 57.3-80.1%) and per-protocol analysis (95.7% versus 71.4%, P=0.0002, 95% CI 88.0-99.1% versus 58.7-82.1%). The incidence of adverse events was not different between the groups (26.3% in VPZ group versus 37.7% in PPI group, P=0.15). Conclusion. VPZ-based regimen is more useful than that PPI-based regimen as a first-line H. pylori eradication therapy.
Overexpression of human dynactin-associated protein (dynAP) transforms NIH3T3 cells. DynAP is a single-pass transmembrane protein with a carboxy-terminal region (amino acids 135–210) exposed to the ...outside of the cell possessing one potential
N
-glycosylation site (position 143) and a distal C-terminal region (residues 173–210) harboring a Thr/Ser-rich (T/S) cluster that may be
O
-glycosylated. In SDS–PAGE, dynAP migrates anomalously at ~ 45 kDa, much larger than expected (22.5 kDa) based on the amino acid composition. Using dynAP mutants, we herein showed that the T/S cluster region is responsible for the anomalous migration. The T/S cluster region is required for transport to the cytoplasmic membrane and cell transformation. We produced and purified the extracellular fragment (dynAP135–210) in secreted form and analyzed the attached glycans. Asn143 displayed complex-type glycosylation, suggesting that oligosaccharide transferase may recognize the NXT/S sequon in the secretory form, but not clearly in full-length dynAP. Core I-type
O
-glycosylation (Gal-GalNAc) was observed, but the mass spectrometry signal was weak, clearly indicating that further studies are needed to elucidate modifications in this region.
Polycyclic aromatic hydrocarbons (PAHs) are pollutants that exert harmful effects on marine invertebrates; however, the molecular mechanism underlying PAH action remains unclear. We investigated the ...effect of PAHs on the ascidian
type A (
). First, the influence of PAHs on early
development was evaluated. PAHs such as dibenzothiophene, fluorene, and phenanthrene resulted in formation of abnormal larvae. PAH treatment of swimming larva induced malformation in the form of tail regression. Additionally, we observed the
(
) mRNA expression in swimming larva, mid body axis rotation, and early juvenile stages. The time correlation between PAH action and
mRNA expression suggested that Ci-AhR could be associated with PAH metabolism. Lastly, we analyzed
mRNA localization in
juveniles.
mRNA was localized in the digestive tract, dorsal tubercle, ganglion, and papillae of the branchial sac, suggesting that Ci-AhR is a candidate for an environmental pollutant sensor and performs a neural function. Our results provide basic knowledge on the biological function of Ci-AhR and PAH activity in marine invertebrates.
O-Linked β-
N-acetylglucosaminylation (
O-GlcNAcylation) on the Ser/Thr residue of nucleocytoplasmic proteins is a dynamic post-translational modification found in multicellular organisms. More than ...500 proteins involved in a wide range of cellular functions, including cell cycle, transcription, epigenesis, and glucose sensing, are modified with
O-GlcNAc. Although it has been suggested that
O-GlcNAcylation is involved in the differentiation of cells in a lineage-specific manner, its role in skeletal myogenesis is unknown.
A myogenesis-dependent drastic decrease in the levels of
O-GlcNAcylation was found in mouse C2C12 myoblasts. The global decrease in
O-GlcNAcylation was observed at the earlier stage of myogenesis, prior to myoblast fusion. Genetic or pharmacological inactivation of
O-GlcNAcase blocked both the myogenesis-dependent global decrease in
O-GlcNAcylation and myoblast fusion. Although inactivation of
O-GlcNAcase affected neither cell-cycle exit nor cell survival in response to myogenic stimulus, it perturbed the expression of myogenic regulatory factors. While the expression of
myod and
myf5 in response to myogenic induction was not affected, that of
myogenin and
mrf4 was severely inhibited by the inactivation of
O-GlcNAcase.
These results indicate that the terminal differentiation program of skeletal myogenesis is negatively regulated by
O-GlcNAcylation.
O-GlcNAcylation is involved in differentiation in a cell lineage-dependent manner, and a decrease in
O-GlcNAcylation may have a common role in the differentiation of cells of muscle lineage.
►
O-GlcNAcylation decreases drastically during myogenesis in mouse C2C12 myoblasts. ► The decrease in
O-GlcNAcylation is involved in myoblast fusion. ► The expression of
myogenin and
mrf4 is inhibited by the inactivation of
O-GlcNAcase.
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