127 research outputs found

    Absorption and Metabolism of cis-9,trans-11-CLA and of Its Oxidation Product 9,11-Furan Fatty Acid by Caco-2 Cells

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    Furan fatty acids (furan-FA) can be formed by auto-oxidation of conjugated linoleic acids (CLA) and may therefore be ingested when CLA-containing foodstuff is consumed. Due to the presence of a furan ring structure, furan-FA may have toxic properties, however, these substances are toxicologically not well characterized so far. Here we show that 9,11-furan-FA, the oxidation product of the major CLA isomer cis-9,trans-11-CLA (c9,t11-CLA), is not toxic to human intestinal Caco-2 cells up to a level of 100 μM. Oil-Red-O staining indicated that 9,11-furan-FA as well as c9,t11-CLA and linoleic acid are taken up by the cells and stored in the form of triglycerides in lipid droplets. Chemical analysis of total cellular lipids revealed that 9,11-furan-FA is partially elongated probably by the enzymatic activity of cellular fatty acid elongases whereas c9,t11-CLA is partially converted to other isomers such as c9,c11-CLA or t9,t11-CLA. In the case of 9,11-furan-FA, there is no indication for any modification or activation of the furan ring system. From these results, we conclude that 9,11-furan-FA has no properties of toxicological relevance at least for Caco-2 cells which serve as a model for enterocytes of the human small intestine

    Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

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    Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

    Immunohistochemical Profile for Unknown Primary Adenocarcinoma

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    BACKGROUND: Development of tailored treatment based on immunohistochemical profiles (IPs) of tumors for cancers of unknown primary is needed. METHODOLOGY/PRINCIPAL FINDINGS: We developed an algorithm based on primary known adenocarcinoma for testing sensitivity and specificity. Formalin-fixed paraffin-embedded tissue samples from 71 patients of unfavorable subsets of unknown primary adenocarcinoma were obtained. We examined 15 molecular markers using the algorithm incorporating these IPs and classified the tumours into 9 subsets based on the primary tumour site. The sensitivity and specificity of this algorithm were 80.3% and 97.6%, respectively. Apparent primary sites were lung in 17 patients, digestive organs in 13, gynecological organs in 9, prostate in 7, liver or kidney in 6, breast in 4, urothelial organ in 2, biliary tract and pancreatic profile in none, and unclassified in 13. The response rate to chemotherapy was highest for the gynecological IPs. Patients with gynecological or lung cancer IPs had longer median progression-free survival than those with others: 11.2 months for gynecological IPs (p<0.001) and 6.8 months for lung IPs (p = 0.05). Lung, digestive, prostate, and gynecological profiles were associated with significantly longer median survival time than the other profiles. Multivariate analysis confirmed that the IPs were independent prognostic factors for survival. CONCLUSIONS/SIGNIFICANCE: The IPs identified in this study can be used to further stratify patient prognosis for unfavorable subsets of unknown primary adenocarcinoma

    Productive Parvovirus B19 Infection of Primary Human Erythroid Progenitor Cells at Hypoxia Is Regulated by STAT5A and MEK Signaling but not HIFα

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    Human parvovirus B19 (B19V) causes a variety of human diseases. Disease outcomes of bone marrow failure in patients with high turnover of red blood cells and immunocompromised conditions, and fetal hydrops in pregnant women are resulted from the targeting and destruction of specifically erythroid progenitors of the human bone marrow by B19V. Although the ex vivo expanded erythroid progenitor cells recently used for studies of B19V infection are highly permissive, they produce progeny viruses inefficiently. In the current study, we aimed to identify the mechanism that underlies productive B19V infection of erythroid progenitor cells cultured in a physiologically relevant environment. Here, we demonstrate an effective reverse genetic system of B19V, and that B19V infection of ex vivo expanded erythroid progenitor cells at 1% O2 (hypoxia) produces progeny viruses continuously and efficiently at a level of approximately 10 times higher than that seen in the context of normoxia. With regard to mechanism, we show that hypoxia promotes replication of the B19V genome within the nucleus, and that this is independent of the canonical PHD/HIFα pathway, but dependent on STAT5A and MEK/ERK signaling. We further show that simultaneous upregulation of STAT5A signaling and down-regulation of MEK/ERK signaling boosts the level of B19V infection in erythroid progenitor cells under normoxia to that in cells under hypoxia. We conclude that B19V infection of ex vivo expanded erythroid progenitor cells at hypoxia closely mimics native infection of erythroid progenitors in human bone marrow, maintains erythroid progenitors at a stage conducive to efficient production of progeny viruses, and is regulated by the STAT5A and MEK/ERK pathways

    First-Line Matched Related Donor Hematopoietic Stem Cell Transplantation Compared to Immunosuppressive Therapy in Acquired Severe Aplastic Anemia

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    INTRODUCTION: Acquired severe aplastic anemia (SAA) is a rare and progressive disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells is a first-line treatment option if HLA-matched related donors are available. First-line immunosuppressive therapy may be offered as alternative. The aim was to compare the outcome of these patients in controlled trials. METHODS: A systematic search was performed in the bibliographic databases MEDLINE, EMBASE, and The Cochrane Library. To show an overview of various outcomes by treatment group we conducted a meta-analysis on overall survival. We evaluated whether studies reported statistically significant factors for improved survival. RESULTS: 26 non-randomized controlled trials (7,955 patients enrolled from 1970 to 2001) were identified. We did not identify any RCTs. Risk of bias was high except in 4 studies. Young age and recent year of treatment were identified as factors for improved survival in the HSCT group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the IST group. In 19 studies (4,855 patients), summary statistics were sufficient to be included in meta-analysis. Considerable heterogeneity did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies. CONCLUSIONS: Young age and recent year of treatment were identified as factors for improved survival in the transplant group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the immunosuppressive group. Considerable heterogeneity of non-randomized controlled studies did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies

    Tracking SARS-CoV-2 mutations and variants through the COG-UK-Mutation Explorer

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    COG-UK Mutation Explorer (COG-UK-ME, http://sars2.cvr.gla.ac.uk/cog-uk/-last accessed date 16 March 2022) is a web resource that displays knowledge and analyses on SARS-CoV-2 virus genome mutations and variants circulating in the UK, with a focus on the observed amino acid replacements that have an antigenic role in the context of the human humoral and cellular immune response. This analysis is based on more than 2 million genome sequences (as of March 2022) for UK SARS-CoV-2 data held in the CLIMB-COVID centralised data environment. COG-UK-ME curates these data and displays analyses that are cross-referenced to experimental data collated from the primary literature. The aim is to track mutations of immunological importance that are accumulating in current variants of concern and variants of interest that could alter the neutralising activity of monoclonal antibodies (mAbs), convalescent sera, and vaccines. Changes in epitopes recognised by T cells, including those where reduced T cell binding has been demonstrated, are reported. Mutations that have been shown to confer SARS-CoV-2 resistance to antiviral drugs are also included. Using visualisation tools, COG-UK-ME also allows users to identify the emergence of variants carrying mutations that could decrease the neutralising activity of both mAbs present in therapeutic cocktails, e.g. Ronapreve. COG-UK-ME tracks changes in the frequency of combinations of mutations and brings together the curated literature on the impact of those mutations on various functional aspects of the virus and therapeutics. Given the unpredictable nature of SARS-CoV-2 as exemplified by yet another variant of concern, Omicron, continued surveillance of SARS-CoV-2 remains imperative to monitor virus evolution linked to the efficacy of therapeutics

    Gastroprotective activity of chloroform extract of Muntingia calabura and Melastoma malabathricum leaves

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    Context: Muntingia calabura L. (family Muntingiaceae) and Melastoma malabathricum L. (family Melastomaceae) are traditionally used to treat gastric ulcer. Objective: The present study determines the mechanisms of gastroprotective activity of the chloroform extract of leaves obtained from both the plants using several in vitro and in vivo assays. Materials and methods: Phytochemical screening, HPLC analysis, and antioxidant activity of the respective extract were carried out. Gastroprotective activity was determined using ethanol-induced gastric ulcer assay while the mechanisms of gastroprotection were determined using the pyloric ligation assay. The test solutions [8% Tween-80 (vehicle), 20 mg/kg omeprazole, and different doses of extracts (50, 250, or 500 mg/kg] were administered orally once daily for 7 consecutive days before the animals were subjected to ethanol induced gastric ulcers. Results: The chloroform-extracted M. calabura (CEMC) contains tannins, polyphenolics, triterpenes, and steroids while the chloroform-extracted M. malabathricum (CEMM) contains only triterpenes and steroids. CEMC, but not CEMM, exerted remarkably strong antioxidant activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH)- (86% versus 16%) and superoxide- (73% versus 36%) radical scavenging assays. Both extracts demonstrated significant (p < 0.05) gastroprotection with the EC50 value recorded at 192.3 or 297.7 mg/kg, respectively. In the pylorus ligation assay, CEMC and CEMM significantly (p < 0.05) reduced the total and free acidity and volume; while increased the pH of gastric juice as well as the gastric wall mucus content in comparison with the vehicle-treated group. Discussion and conclusion: CEMC and CEMM exert gastroprotective effects in animals with ethanol-induced gastric ulcers via antioxidant and anti-secretory effects

    Effect of Angiogenesis Inhibitor Bevacizumab on Survival in Patients with Cancer: A Meta-Analysis of the Published Literature

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    Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor which has been used in conjunction with other anti-cancer agents in the treatment of patients with many cancers. It remains controversial whether bevacizumab can prolong survival in cancer patients. This meta-analysis was therefore performed to evaluate effect of bevacizumab on survival in cancer patients. PubMed, EMBASE, and Web of Science databases were searched for English-language studies of randomized controlled trials comparing bevacizumab with control therapy published through February 8, 2012. Progression-free survival, overall survival, and one-year survival rate were analyzed using random- or fixed-effects model. Thirty one assessable randomized controlled trials were identified. A significant improvement in progression-free survival in cancer patients was attributable to bevacizumab compared with control therapy (hazard ratio, 0.72; 95% confidence interval, 0.68 to 0.76; p<0.001). Overall survival was also significantly longer in patients were treated with bevacizumab (hazard ratio, 0.87; 95% confidence interval, 0.83 to 0.91; p<0.001). The significant benefit in one-year survival rate was further seen in cancer patients receiving bevacizumab (odds ratio, 1.30; 95% confidence interval, 1.20 to 1.41; p<0.001). Current evidences showed that bevacizumab prolong progression-free survival and overall survival, and increase one-year survival rate in cancer patients as compared with control therapy
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