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  • 1
    Publication Date: 2018-10-02
    Description: Although more than 100 lipid metabolites have been identified, their bioactivities remain unknown. In a previous study, we discovered that the production of several lipid metabolites in the intestines dramatically changed in colitis. Of these metabolites, 5,6-dihydroxyeicosatetraenoic acid (DiHETE) possesses novel anti-inflammatory activity in the vasculature. In this study, we used mouse and human umbilical vein endothelial cell (HUVEC) models to elucidate the mechanisms underlying the vascular activity of lipid metabolites, particularly those related to the release of histamine, a major proinflammatory mediator that stimulates endothelial cells to produce NO, a mediator of vascular relaxation and hyperpermeability, by activating intracellular Ca 2+ concentration-dependent signaling. In a mouse ear, the administration of 5,6-DiHETE did not induce inflammatory reactions, and pretreatment with 5,6-DiHETE inhibited histamine-induced inflammation, specifically vascular dilation and hyperpermeability. In an isolated mouse aorta, 5,6-DiHETE treatment did not influence vascular contraction but attenuated acetylcholine-induced vascular relaxation. In HUVECs, treatment with 5,6-DiHETE inhibited histamine-induced endothelial barrier disruption and inhibited the production of NO. Most notably, 5,6-DiHETE inhibited histamine-induced increases in intracellular Ca 2+ concentrations in HUVECs. Our findings suggest that 5,6-DiHETE attenuates vascular hyperpermeability during inflammation by inhibiting endothelial Ca 2+ elevation, which might lead to a novel pharmacological strategy against inflammatory diseases.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 2
    Publication Date: 2018-09-08
    Description: Background/Aim: The aim of the study was to evaluate the necessity of gastrectomy including endoscopic submucosal dissection (ESD) scar with margin-negative early gastric cancer (EGC). Patients and Methods: We analyzed 83 patients with EGC who received additional gastrectomy after non-curative ESD and evaluated the risk factors for residual cancer (RC) and lymph node (LN) metastasis. Results: In addition to positive ESD margin, ulceration was a risk factor for RC. Among cases with deep submucosal invasion (sm), 3 were diagnosed as having negative margins in ESD specimens, but the surgical specimens were positive for cancer. The rate of LN metastasis was 12.0%. There was no significant difference in LN metastasis between tumor characteristics. Conclusion: LN dissection is recommended after non-curative ESD. Gastrectomy including the ESD scar should be performed not only for cases with positive margin in ESD, but also for cases with invasion deeper than sm2, even though the margin is negative.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 3
    Publication Date: 2018-01-14
    Description: Background Hyaluronan (HA) metabolism in skin fibroblasts is mediated by HYBID ( HY aluronan B inding protein I nvolved in hyaluronan D epolymerisation, KIAA1199) and HA synthases 1/2 (HAS1/2). However, photoageing-dependent changes in HA and their molecular mechanisms, and the relationship between HA metabolism and clinical symptoms in photoaged skin remain elusive. Objectives We examined amount, size and tissue distribution of HA and expression levels of HYBID and HAS1/2 in photoaged skin, and analysed their relationships to the degree of photoageing. Methods Photoageing-dependent changes of HA were investigated by studying skin biopsies isolated from photoprotected and photoexposed areas of the same donors, and the relationship between HA and photoageing symptoms such as skin wrinkling and sagging was examined. Results Skin biopsy specimens showed that amount and size of HA are decreased in the photoexposed skin compared to the photoprotected skin, and this was accompanied by increased expression of HYBID and decreased expression of HAS1/2 , respectively. Histologically, HA staining in the papillary dermis was decreased in photoexposed skin, showing reverse correlation with HYBID expression. HYBID expression in the photoexposed skin directly correlated with skin roughness and sagging parameters, and reduced HA staining in the papillary dermis in the photoexposed skin positively correlated with these symptoms. Conclusions These data demonstrate that imbalance between HYBID-mediated HA degradation and HAS-mediated HA synthesis may contribute to enhanced HA catabolism in the photoaged skin, and suggest that HYBID-mediated HA reduction in the papillary dermis is related to skin wrinkling and sagging of photoaged skin. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 4
    Publication Date: 2018-05-31
    Description: Background/Aim: The purpose of this study was to consider appropriate application of liquid and re-biopsy through analysis of current status in practice. Patients and Methods: We performed a retrospective analysis of 22 patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer who exhibited 1st/2nd generation EGFR-tyrosine kinase inhibitors resistance. The cobas® method was used to detect T790M with re-biopsy and the mutation-biased PCR and quenched probe method was used with liquid biopsy. Results: T790M detection rate was 52% with re-biopsy and 58% with liquid biopsy. The concordance between tissue and plasma was 58%. One patient who was T790M-positive with liquid biopsy showed heterogeneity among metastatic lesions in terms of osimertinib efficacy, as revealed by T790M detection with re-biopsy. Conclusion: Liquid biopsy reflects the whole body, whereas re-biopsy is useful for spatial diagnosis. Considering these characteristics, a combination of liquid and re-biopsy contribute to enhanced treatment.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 5
    Publication Date: 2018-04-02
    Description: Although several studies have revealed the role of different lipid mediators in colitis, the comprehensive analysis of their production across different phases of colitis remained unclear. Here, we performed the following analysis in the dextran sodium sulfate (DSS)-induced colitis model using LC-MS/MS. Oral administration of 2% DSS in mice for 4 days resulted in severe intestinal inflammation by day 7, which gradually subsided by day 18. Based on the disease scoring index (assigned on the basis of fecal condition and weight loss), we defined the phases of colitis as induction (days 0–4), acute inflammation (days 4–7), recovery (days 7–9), and late recovery (days 9–18). Across all phases, 58 lipid mediators were detected in the inflamed colon tissue. In the induction phase, the production of n-6 fatty acid-derived prostaglandin E 2 and thromboxane B 2 increased by ~2-fold. In the acute inflammation phase, the production of n-6 fatty acid-derived leukotrienes increased by 〉10-fold, while that of n-3 fatty acid-derived hydroxyeicosapentaenoic acids and dihydroxyeicosatetraenoic acids decreased. In the recovery phase, a precursor of protectin D1 (17-hydroxydocosahexaenoic acid) increased over 3-fold. These observations suggested dynamic changes in the production of lipid mediators across different phases of the disease and their potential regulation in healing colitis.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 6
    Publication Date: 2018-03-30
    Description: Background/Aim: Although there are a few reports recommending gastrectomy for unresectable gastric cancer (UGC) to improve survival, the advantage of gastrectomy remains unclear. The objective of this study was to assess the meanings of the surgical intervention. Patients and Methods: Therapeutic outcomes were retrospectively evaluated in 127 patients with UGC. All patients had chemotherapy and 47 patients underwent gastrectomy. Patients were classified to three groups according to the treatment. Results: Multivariate analysis showed that gastrectomy was in independent favorable prognosis factor (p〈0.001) as well as performance status 0/1, differentiated type, absence of distant organ metastasis, and second line chemotherapy for UGC. Among the patients with gastrectomy, R0 resection was an independent prognostic factor (p=0.011). R0 resection was mainly achieved when there was a single non-curable factor and no distant organ metastasis (p=0.007 and p=0.024, respectively). Conclusion: Gastrectomy has an advantage in improving the survival in selected cases among UGC. If chemotherapy enables to control the non-curable factors, gastrectomy should be considered.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 7
    Publication Date: 2018-05-17
    Description: Mammalian CST (CTC1-STN1-TEN1) complex fulfills numerous functions including rescue of the stalled replication forks and termination of telomerase action. In fission yeast lacking the CTC1 ortholog, the Stn1-Ten1 complex restricts telomerase action via its sumoylation-mediated interaction with Tpz1 TPP1 . We identify a small ubiquitin-like modifier (SUMO)–interacting motif (SIM) in the carboxyl-terminal part of Stn1 and show that this domain is crucial for SUMO and Tpz1-SUMO interactions. Point mutations in the SIM (Stn1-226) lead to telomere elongation, impair Stn1-Ten1 recruitment to telomeres, and enhance telomerase binding, revealing that Stn1 SIM domain contributes to the inhibition of telomerase activity at chromosome ends. Our results suggest that Stn1-Ten1 promotes DNA synthesis at telomeres to limit single-strand DNA accumulation. We further demonstrate that Stn1 functions in the replication of telomeric and subtelomeric regions in a Taz1-independent manner. Genetic analysis reveals that misregulation of origin firing and/or telomerase inhibition circumvents the replication defects of the stn1-226 mutant. Together, our results show that the Stn1-Ten1 complex has a dual function at telomeres by limiting telomerase action and promoting chromosome end replication.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 8
    Publication Date: 2018-05-31
    Description: Background/Aim: In patients with soft tissue sarcoma (STS), distinguishing small metastatic pulmonary nodules from benign ones remains difficult. This study aimed to determine the accuracy of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in detecting pulmonary metastasis and identify factors affecting sensitivity with STS. Materials and Methods: The clinical records and chest CT and FDG-PET/CT scans of 102 patients with STS were reviewed to determine the presence of pulmonary nodules. Results: A significant relationship was observed between nodule size and maximum standardized uptake value (SUV max ). For nodules smaller than 5 mm, only 10 out of 76 metastatic pulmonary nodules exhibited FDG accumulation, showing a weak correlation between nodule size and SUV max . Conclusion: The role of FDG-PET/CT in differentiating metastatic from benign pulmonary nodules was unsatisfactory, especially for small nodules. Careful follow-up using CT scan may still be appropriate for diagnosing pulmonary nodules smaller than 5 mm.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 9
    Publication Date: 2018-04-03
    Description: Clinical PET studies using 18 F-THK5351 have demonstrated significant tracer retention in sites susceptible to tau burden in Alzheimer disease (AD). However, the in vivo PET signal to reflect tau aggregates remains controversial. Methods: We examined the spatial pattern of tracer binding, amyloid-β, tau, and gliosis in an autopsy-confirmed AD patient who underwent 18 F-THK5351 and 11 C-Pittsburgh compound B PET before death. Results: Regional in vivo 18 F-THK5351 retention was significantly correlated with the density of tau aggregates in the neocortex and monoamine oxidase-B in the whole brain, but not correlated with that of insoluble amyloid-β. Furthermore, significant association was observed between the density of tau aggregates, monoamine oxidase-B, and glial fibrillary acidic protein, suggesting that neocortical tau would strongly influence the formation of reactive astrocytes. Conclusion: 18 F-THK5351 PET may have limited utility as a biomarker of tau pathology in AD; however, it could be used to monitor the neuroinflammatory processes in the living brain.
    Print ISSN: 0022-3123
    Topics: Medicine
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  • 10
    Publication Date: 2018-10-19
    Description: Human in vitro gametogenesis may transform reproductive medicine. Human pluripotent stem cells (hPSCs) have been induced into primordial germ cell–like cells (hPGCLCs); however, further differentiation to a mature germ cell has not been achieved. Here, we show that hPGCLCs differentiate progressively into oogonia-like cells during a long-term in vitro culture (approximately 4 months) in xenogeneic reconstituted ovaries with mouse embryonic ovarian somatic cells. The hPGCLC-derived oogonia display hallmarks of epigenetic reprogramming—genome-wide DNA demethylation, imprint erasure, and extinguishment of aberrant DNA methylation in hPSCs—and acquire an immediate precursory state for meiotic recombination. Furthermore, the inactive X chromosome shows a progressive demethylation and reactivation, albeit partially. These findings establish the germline competence of hPSCs and provide a critical step toward human in vitro gametogenesis.
    Keywords: Development
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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