Analysis of the Complete Open Reading Frame of Genotype 2b Hepatitis C Virus in Association with the Response to Peginterferon and Ribavirin Therapy

BACKGROUND AND AIMS: Patients infected with genotype 2b hepatitis C virus (HCV) generally can achieve favorable responses to pegylated-interferon plus ribavirin therapy (PEG-IFN/RBV). However, a proportion of patients show poorer responses and the correlation between viral sequence variation and treatment outcome remains unclear. METHODS: The pretreatment complete open reading frame (ORF) sequences of genotype 2b HCV determined by direct sequencing were investigated for correlation with the final outcome in a total of 60 patients. RESULTS: In this study group, 87.5% (14/16) of non-sustained virological response (non-SVR) patients (n = 16) were relapsers. Compared to sustained virological response (SVR) patients (n = 44), non-SVR patients were older and could not achieve prompt viral clearance after the therapy induction. Comparing each viral protein between the two groups, viral sequences were more diverse in SVR patients and that diversity was found primarily in the E1, p7, and NS5A proteins. In searching for specific viral regions associated with the final outcome, several regions in E2, p7, NS2, NS5A, and NS5B were extracted. Among these regions, part of the interferon sensitivity determining region (ISDR) was included. In these regions, amino acid substitutions were associated with the final outcome in an incremental manner, depending upon the number of substitutions. CONCLUSIONS: Viral sequences are more diverse in SVR patients than non-SVR patients receiving PEG-IFN/RBV therapy for genotype-2b HCV infection. Through systematic comparison of viral sequences, several specific regions, including part of the ISDR, were extracted as having significant correlation with the final outcome

In vitro anticancer effects of a RAGE inhibitor discovered using a structure-based drug design system.

金沢大学医薬保健研究域医学系Receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in the pathogenesis of certain types of cancer. In the present study, papaverine was identified as a RAGE inhibitor using the conversion to small molecules through optimized‑peptide strategy drug design system. Papaverine significantly inhibited RAGE‑dependent nuclear factor κ‑B activation driven by high mobility group box‑1, a RAGE ligand. Using RAGE‑ or dominant‑negative RAGE‑expressing HT1080 human fibrosarcoma cells, the present study revealed that papaverine suppressed RAGE‑dependent cell proliferation and migration dose‑dependently. Furthermore, papaverine significantly inhibited cell invasion. The results of the present study suggested that papaverine could inhibit RAGE, and provided novel insights into the field of RAGE biology, particularly anticancer therapies.Embargo Period 6 month

イミ カクチョウ シュタイカ ドウシカ

京都大学0048新制・課程博士博士(人間・環境学)甲第11839号人博第300号新制||人||74(附属図書館)17||D||159(吉田南総合図書館)23599UT51-2005-K505京都大学大学院人間･環境学研究科人間･環境学専攻(主査)教授 山梨 正明, 教授 大木 充, 助教授 河﨑 靖学位規則第4条第1項該当Doctor of Human and Environmental StudiesKyoto UniversityDA

Anticancer effects of a non-narcotic opium alkaloid medicine, papaverine, in human glioblastoma cells.

The interaction between high-mobility group box 1 protein (HMGB1) and receptor for advanced glycation end products (RAGE) is important for tumor cell growth. We investigated the tumor biological effects of HMGB1 and RAGE interaction. Previously, we identified an inhibitor of HMGB1/RAGE interaction, papaverine (a non-narcotic opium alkaloid), using a unique drug design system and drug repositioning approach. In the present study, we examined the anticancer effects of papaverine in human glioblastoma (GBM) temozolomide (TMZ; as a first-line anticancer medicine)-sensitive U87MG and TMZ-resistant T98G cells. HMGB1 supplementation in the culture medium promoted tumor cell growth in T98G cells, and this effect was canceled by papaverine. In addition, papaverine in T98G cells suppressed cancer cell migration. As an HMGB1/RAGE inhibitor, papaverine also significantly inhibited cell proliferation in U87MG and T98G cells. The effects of papaverine were evaluated in vivo in a U87MG xenograft mouse model by determining tumor growth delay. The results indicate that papaverine, a smooth muscle relaxant, is a potential anticancer drug that may be useful in GBM chemotherapy

Effects of Five Amino Acids (Serine, Alanine, Glutamate, Aspartate, and Tyrosine) on Mental Health in Healthy Office Workers: A Randomized, Double-Blind, Placebo-Controlled Exploratory Trial

Background: The importance of maintaining good mental health with overall well-being has recently drawn attention from various spheres of academics and the working population. Amino acid intake has been reported to reduce depression symptoms and other mental health problems. However, the effectiveness of amino acid intake (i.e., single or combined) remains unknown. In this study, we assessed a combination of five amino acids (serine, alanine, glutamate, aspartate, and tyrosine; SAGAT) reported to regulate mental health. Methods: A randomized, double-blind, placebo-controlled exploratory trial was conducted. Participants, aged between 20 and 65 years with fatigue sensation, were randomized to receive either SAGAT or the placebo and ingested them for four weeks. A transient mental work was loaded at day 0 and after four weeks of intervention. As the primary outcomes, the fatigue sensation was assessed. The mood status, cognitive function, work efficiency, and blood marker were also measured as secondary outcomes. Results: The number of participants analyzed for the efficacy evaluation were 20 in SAGAT and 22 in the placebo. There were no significant differences in the primary outcomes. However, as the secondary outcomes, the SAGAT group showed a significant improvement in motivation and cognitive function in the recovery period after mental work loaded in a four-week intervention compared to the placebo. Conclusion: The current findings suggest that SAGAT contributes to maintaining proper motivation and cognitive function. Clinical Trial Registration: University Hospital Medical Information Network Clinical Trial Registry (ID: UMIN 000041221)

Deep Sequencing of Cancer-Related Genes Revealed <i>GNAS</i> Mutations to Be Associated with Intraductal Papillary Mucinous Neoplasms and Its Main Pancreatic Duct Dilation

<div><p>Background</p><p>To clarify the genetic mutations associated with intraductal papillary mucinous neoplasms (IPMN) and IPMN-related pancreatic tumours, we conducted cancer-related gene profiling analyses using pure pancreatic juice and resected pancreatic tissues.</p><p>Methods</p><p>Pure pancreatic juice was collected from 152 patients [nine with a normal pancreas, 22 with chronic pancreatitis (CP), 39 with pancreatic ductal adenocarcinoma (PDAC), and 82 with IPMN], and resected tissues from the pancreas were collected from 48 patients (six IPMNs and 42 PDACs). The extracted DNA was amplified by multiplexed polymerase chain reaction (PCR) targeting 46 cancer-related genes containing 739 mutational hotspots. The mutations were analysed using a semiconductor-based DNA sequencer.</p><p>Results</p><p>Among the 46 cancer-related genes, <i>KRAS</i> and <i>GNAS</i> mutations were most frequently detected in both PDAC and IPMN cases. In pure pancreatic juice, <i>GNAS</i> mutations were detected in 7.7% of PDAC cases and 41.5% of IPMN cases (<i>p</i><0.001 vs. others). All PDAC cases with <i>GNAS</i> mutations (n = 3) were accompanied by IPMN. Multivariate analysis revealed that <i>GNAS</i> mutations in IPMN cases were associated with dilated main pancreatic ducts (MPD, <i>p</i> = 0.016), while no statistically independent associations with clinical variables were observed for <i>KRAS</i> mutations. In the resected pancreatic tissues, <i>GNAS</i> mutations were detected in 50% of PDAC cases concomitant with IPMN, 33.3% of PDAC cases derived from IPMN, and 66.7% of IPMN cases, while no <i>GNAS</i> mutations were detected in cases of PDAC without IPMN.</p><p>Conclusions</p><p>The <i>GNAS</i> mutation was specifically found in the cases with IPMN and it was speculated that some PDACs might be influenced by the concomitant but separately-located IPMN in their pathogenic mechanism. Furthermore, the <i>GNAS</i> mutation was significantly associated with MPD dilatation in IPMN cases, suggesting its role in mucus hypersecretion.</p></div