Lamivudine treatment in patients with HBV-related hepatocellular carcinoma--using an untreated, matched control cohort.

Lamivudine is widely used to treat patients with hepatitis B. However, the outcomes in patients with hepatocellular carcinoma (HCC) treated with lamivudine have not been established. This study was conducted to evaluate the outcomes of lamivudine treatment for patients with HCC using an untreated, matched control group. Thirty patients with controlled HCC orally received lamivudine. As controls, 40 patients with HCC who were not treated with lamivudine and matched for clinical features were selected. The lamivudine-treated and untreated groups were compared with respect to changes in liver function, HCC recurrence, survival, and cause of death. In the lamivudine-treated group, there was significant improvement in the Child-Pugh score at 24 months after starting treatment, while no improvement was observed in the untreated group. There was no significant difference in the cumulative incidence of HCC recurrence and survival between the groups. However, there was a significant difference in the cumulative incidence of death due to liver failure (P= 0.043). A significant improvement in liver function was achieved by lamivudine treatment, even in patients with HCC. These results suggest that lamivudine treatment for patients with HCC may prevent death due to liver failure. Further prospective randomized studies using a larger number of patients are required.</p

Entecavir Reduces Hepatocarcinogenesis in Chronic Hepatitis B Patients

Chronic hepatitis B (CHB) leads to cirrhosis and hepatocellular carcinoma (HCC). With a cohort of 1,206 CHB patients who visited Okayama University Hospital and related hospitals in 2011 and 2012, we compared the incidence rates of HCC among the patients grouped by age, hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg), and treatment. HCCs were observed in 115 patients with the median observation period of 1,687 days. Among the HCC patients aged &#8805; 35 years, HBV DNA &#8805; 4 log copies/mL and positive HBeAg at diagnosis (n=184), the HCC incidence rate was 8.4% at 5 years in the entecavir (ETV)-treated patients, 21.8% in the lamivudine (LVD)-treated patients, and 26.4% among the patients not treated with drugs. The cumulative HCC incidence was significantly reduced in the ETV-treated patients compared to those treated with LVD or not treated (p=0.013). Among the patients aged &#8805; 35 years with HBV DNA &#8805; 4 log copies/mL and negative HBeAg (n=237), the cumulative HCC incidence was 14.6% in 5 years in ETV group and 13.9% among those not treated with a drug (p>0.05). Only small numbers of HCCs occurred in other patients. In CHB patients aged&#8805;35 years with HBV DNA &#8805;4 log copies/mL and positive HBeAg, ETV treatment is recommended for the suppression of HCC development

Discovery of a gene cluster for the biosynthesis of novel cyclic peptide compound, KK-1, in Curvularia clavata

KK-1, a cyclic depsipeptide with 10 residues produced by a filamentous fungus Curvularia clavata BAUA-2787, is a promising pesticide active compound with high activity against many plant pathogens, especially Botrytis cinerea. As a first step toward the future mass production of KK-1 through synthetic biological approaches, we aimed to identify the genes responsible for the KK-1 biosynthesis. To achieve this, we conducted whole genome sequencing and transcriptome analysis of C. clavata BAUA-2787 to predict the KK-1 biosynthetic gene cluster. We then generated the overexpression and deletion mutants for each cluster gene using our originally developed transformation system for this fungus, and analyzed the KK-1 production and the cluster gene expression levels to confirm their involvement in KK-1 biosynthesis. As a result of these, a region of approximately 71 kb was found, containing 10 open reading frames, which were co-induced during KK-1 production, as a biosynthetic gene cluster. These include kk1B, which encodes nonribosomal peptide synthetase with a domain structure that is consistent with the structural features of KK-1, and kk1F, which encodes a transcription factor. The overexpression of kk1F increased the expression of the entire cluster genes and, consequently, improved KK-1 production, whereas its deletion decreased the expression of the entire cluster genes and almost eliminated KK-1 production, demonstrating that the protein encoded by kk1F regulates the expressions of the other nine cluster genes cooperatively as the pathway-specific transcription factor. Furthermore, the deletion of each cluster gene caused a reduction in KK-1 productivity, indicating that each gene is involved in KK-1 production. The genes kk1A, kk1D, kk1H, and kk1I, which showed a significant decrease in KK-1 productivity due to deletion, were presumed to be directly involved in KK-1 structure formation, including the biosynthesis of the constituent residues. kk1C, kk1E, kk1G, and kk1J, which maintained a certain level of KK-1 productivity despite deletion, were possibly involved in promoting or assisting KK-1 production, such as extracellular transportation and the removal of aberrant units incorporated into the peptide chain

Narrow safety range of intraoperative rectal irradiation exposure volume for avoiding bleeding after seed implant brachytherapy

<p>Abstract</p> <p>Background & Purpose</p> <p>Rectal toxicity is less common after ¹²⁵I seed implant brachytherapy for prostate cancer, and intraoperative rectal dose-volume constraints (the constraint) is still undetermined in pioneering studies. As our constraint failed to prevent grade 2 or 3 rectal bleeding (bled-pts) in 5.1% of patients, we retrospectively explored another constraint for the prevention of rectal bleeding.</p> <p>Materials and methods</p> <p>The study population consisted of 197 patients treated with the brachytherapy as monotherapy using real-time intraoperative transrectal ultrasound (US)-guided treatment at a prescribed dose of 145 Gy. Post-implant dosimetry was performed on Day 1 and Day 30 after implantation using computed tomography (CT) imaging. Rectal bleeding toxicity was classified by CTC-AE ver. 3.0 during a mean 29-month (range, 12-48 months) period after implantation. The differences in rV100s were compared among intraoperative, Day 1 and Day 30 dosimetry, and between that of patients with grade 2 or 3 rectal bleeding (the bled-pts) and of the others (the spared-pts). All patients were divided into groups based on provisional rV100s that were increased stepwise in 0.1-cc increments from 0 to 1.0 cc. The difference in the ratios of the bled-pts to the spared-pts was tested by chi-square tests, and their odds ratios were calculated (bled-OR). All statistical analyses were performed by <it>t</it>-tests.</p> <p>Results</p> <p>The mean values of rV100us, rV100CT_1, and rV100CT_30 were 0.31 ± 0.43, 0.22 ± 0.36, and 0.59 ± 0.68 cc, respectively. These values temporarily decreased (p = 0.020) on Day 1 and increased (p = 0.000) on Day 30. There was no significant difference in rV100s between the bled-pts and spared-pts at any time of dosimetry. The maximum bled-OR was identified among patients with an rV100us value above 0.1 cc (p = 0.025; OR = 7.8; 95% CI, 1.4-145.8); an rV100CT_1 value above 0.3 cc (p = 0.014; OR = 16.2; 95% CI, 3.9-110.7), and an rV100CT_30 value above 0.5 cc (p = 0.019; OR = 6.3; 95% CI, 1.5-42.3).</p> <p>Conclusion</p> <p>By retrospective analysis exploring rV100 as intraoperative rectal dose-volume thresholds in ¹²⁵I seed implant brachytherapy for prostate cancer, it is proved that rV100 should be less than 0.1 cc for preventing rectal bleeding.</p

A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis.

Funder: Japan Foundation for Applied Enzymology; doi: https://doi.org/10.13039/100008695Funder: Pancreas Research Foundation of Japan Collaborative Research Project Program of the Medical Institute of Bioregulation, Kyushu University, Japan Joint Research Program of the Institute for Molecular and Cellular Regulation, Gunma University, Japan Grant for Joint Research Project of the Research Institute for Microbial Diseases Osaka UniversityFunder: European Research Council (ERC (639050) and the Interpark Bio-Convergence Center Grant Program.Frequent mutation of the tumour suppressor RNF43 is observed in many cancers, particularly colon malignancies. RNF43, an E3 ubiquitin ligase, negatively regulates Wnt signalling by inducing degradation of the Wnt receptor Frizzled. In this study, we discover that RNF43 activity requires phosphorylation at a triplet of conserved serines. This phospho-regulation of RNF43 is required for zebrafish development and growth of mouse intestinal organoids. Cancer-associated mutations that abrogate RNF43 phosphorylation cooperate with active Ras to promote tumorigenesis by abolishing the inhibitory function of RNF43 in Wnt signalling while maintaining its inhibitory function in p53 signalling. Our data suggest that RNF43 mutations cooperate with KRAS mutations to promote multi-step tumorigenesis via the Wnt-Ras-p53 axis in human colon cancers. Lastly, phosphomimetic substitutions of the serine trio restored the tumour suppressive activity of extracellular oncogenic mutants. Therefore, harnessing phospho-regulation of RNF43 might be a potential therapeutic strategy for tumours with RNF43 mutations

Synthesis of Amphiphilic Triblock Copolymers by ATRP and Coalescence Suppression Effect in Suspension Polymerization

In this study, the role of amphiphilic triblock copolymers in suppressing the coalescence of the polymers obtained by suspension polymerization was systematically investigated through the preparation of polymer beads using a common monomer (methyl methacrylate). First, a series of amphiphilic triblock copolymers (PAA-b-PS-b-PAA) were synthesized by atom transfer radical polymerization (ATRP). After synthesizing macroinitiators (PS), the corresponding amphiphilic triblock copolymers were prepared with varied numbers of hydrophobic and hydrophilic units. Subsequently, suspension polymerization was conducted to synthesize polymer beads using the obtained amphiphilic triblock copolymers as polymeric surfactants. We clarified the role of the amphiphilic triblock copolymers in suppressing coalescence of each bead, by observing the size of the monomer droplets prior to suspension polymerization and that of the resulting polymer beads with a microscope

Electrorheological Effect of Gold Nanoparticles Coated with Fluorescent Mesogenic Groups Dispersed in Nematic Liquid Crystal

The electrorheological (ER) properties of composite materials consisting of a nematic liquid crystal (LC) and gold nanoparticles (GNPs) coated with bistolane-based mesogenic groups were studied. The GNPs were coated by normal alkyl chains and the fluorescent LC compounds, of which the molecular structure was similar to that of the LC matrix. The dispersity of the GNPs in the nematic LC was investigated by polarizing optical microscopy (POM). In order to improve the ER effect of the composite, a simple strategy was investigated from the viewpoint of a material design in surface-modified GNPs by lateral substitution of the mesogenic groups. The presence of the GNPs in the nematic LC led to a slightly enhanced ER effect compared to that observed for only the nematic LC. This study demonstrates the potential of a hybrid system consisting of LCs and GNPs to yield a larger ER effect

Contamination by neonicotinoid insecticides and their metabolites in Sri Lankan black tea leaves and Japanese green tea leaves

Tea is one of the world's most popular beverages due to health promoting effects. Despite these, there have been concerns about the adverse effects of tea contamination by neonicotinoid insecticides. Only a handful of studies on neonicotinoid insecticides in tea have been carried out and this study was therefore performed to determine the concentrations of seven neonicotinoid insecticides and 20 metabolites in Japanese green tea leaves, and black tea leaves from Sri Lanka; and assess the Maximum Daily Intake (MDI) of neonicotinoid insecticides. From the results, the seven parent compounds were detected in Japanese tea leaves and beverages. Dinotefuran (3004 ng/g) was found at the highest level in green tea leaves. Ten of the 20 metabolites were detected in Japanese tea products. Dinotefuran-urea (92%) and thiacloprid-amide (89%) were most frequently detected in Japanese tea leaves. Clothianidin-urea (100 ng/g) was found at the highest level in green tea leaves. Neonicotinoid insecticides and metabolites were not detected in Sri Lankan black tea leaves. The concentrations and MDI of neonicotinoid insecticides in tea leaves were below the Maximum Residual Levels (MRLs) and Acceptable Daily Intakes (ADIs), respectively