In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs

TRAIL/Apo-2L has shown promise as an anti-glioma drug, based on investigations of TRAIL sensitivity in established glioma cell lines, but it is not known how accurately TRAIL signalling pathways of glioma cells in vivo are reproduced in these cell lines in vitro. To replicate as closely as possible the in vivo behaviour of malignant glioma cells, 17 early passage glioma cell lines and 5 freshly resected gliomas were exposed to TRAIL-based agents and/or chemotherapeutic drugs. Normal human hepatocytes and astrocytes and established glioma cell lines were also tested. Cross-linked TRAIL, but not soluble TRAIL, killed both normal cell types and cells from three tumours. Cells from only one glioma were killed by soluble TRAIL, although only inefficiently. High concentrations of cisplatin were lethal to glioma cells, hepatocytes and astrocytes. Isolated combinations of TRAIL and chemotherapy drugs were more toxic to particular gliomas than normal cells, but no combination was generally selective for glioma cells. This study highlights the widespread resistance of glioma cells to TRAIL-based agents, but suggests that a minority of high-grade glioma patients may benefit from particular combinations of TRAIL and chemotherapy drugs. In vitro sensitivity assays may help identify effective drug combinations for individual glioma patients

In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs

Background: Depression is common in individuals with diabetes. The present study is the first randomized controlled trial to test the efficacy of ω-3 ethyl-eicosapentaenoic acid (E-EPA) as adjuvant to antidepressant medication in the treatment of depression in adults with diabetes mellitus. Methods: In the VU University Medical Center, we conducted a 12-week, placebo-controlled, double-blind, parallel-group intervention study of E-EPA (1 g/day) versus placebo in 25 diabetes patients meeting DSM-IV criteria for major depressive disorder, who were already using antidepressant medication. The primary outcome was severity of depressive symptoms, assessed by the Montgomery Åsberg Depression Rating Scale (MADRS) at baseline and 12-week follow-up at two-weekly intervals. Blood samples were collected at baseline and at 12-week follow-up to determine EPA levels in erythrocyte membranes. Data were analyzed with ANOVA for repeated measures. Results: Thirteen participants were randomly assigned to E-EPA; 12 participants were given placebo. At 12-week follow-up, erythrocyte membranes from patients receiving E-EPA contained tripled levels of EPA, while no changes were noted in participants receiving placebo. In both groups, depressive symptoms significantly decreased over time (F = 21.14, p < 0.001), yet no significant differences were found between those treated with E-EPA versus placebo (F = 1.63, p = 0.17). Limitations: Although having sufficient study power, this study had a relatively small sample size. Small effects could not be detected, and dose-dependent effects could not be studied. Conclusions: No evidence was found for the efficacy of adding E-EPA to antidepressants in reducing depressive symptoms in diabetic patients with co-morbid depression. © 2009 Elsevier B.V. All rights reserved

Discovery of Novel MicroRNAs in Female Reproductive Tract Using Next Generation Sequencing

MicroRNAs (miRNAs) are small non-coding RNAs that mediate post-transcriptional gene silencing. Over 700 human miRNAs have currently been identified, many of which are mutated or de-regulated in diseases. Here we report the identification of novel miRNAs through deep sequencing the small RNAome (<30 nt) of over 100 tissues or cell lines derived from human female reproductive organs in both normal and disease states. These specimens include ovarian epithelium and ovarian cancer, endometrium and endometriomas, and uterine myometrium and uterine smooth muscle tumors. Sequence reads not aligning with known miRNAs were each mapped to the genome to extract flanking sequences. These extended sequence regions were folded in silico to identify RNA hairpins. Sequences demonstrating the ability to form a stem loop structure with low minimum free energy (<−25 kcal) and predicted Drosha and Dicer cut sites yielding a mature miRNA sequence matching the actual sequence were considered putative novel miRNAs. Additional confidence was achieved when putative novel hairpins assembled a collection of sequences highly similar to the putative mature miRNA but with heterogeneous 3′-ends. A confirmed novel miRNA fulfilled these criteria and had its “star” sequence in our collection. We found 7 distinct confirmed novel miRNAs, and 51 additional novel miRNAs that represented highly confident predictions but without detectable star sequences. Our novel miRNAs were detectable in multiple samples, but expressed at low levels and not specific to any one tissue or cell type. To date, this study represents the largest set of samples analyzed together to identify novel miRNAs

Crop Updates 2000 - Cereals part 2

This session covers twenty papers from different authors: DISEASE 1. Forecasting aphid and virus risk in cereals, Debbie Thackray, Jenny Hawkes and Roger Jones, Agriculture Western Australia and Centre for Legumes in Mediterranean Agriculture 2. Cereal Diagnostics, Dominie Wright, Agriculture Western Australia 3. The economic returns from spraying for leaf rust in the central wheatbelt in 1999, Peter Carlton, Trials Coordinator, Elders Limited 4. Impact and Management of Yellow Spot and Leaf Rust in the Northern Agricultural Region, Jat Bhathal and Robert Loughman, Agriculture Western Australia 5. Leaf disease management in wheat and barley in the southern agricultural region, K. Jayasena, R. Loughman and J. Majewski, Agriculture Western Australia 6. Root nematode update, R. Loughman1, S. Kelly1, G. Holloway2, N. Venn1 and D. Diepeveen1 1 Agriculture Western Australia, 2Agriculture Victoria WHEAT AGRONOMY 7. Small Grain Screenings in wheat - the agronomic issues, Brenda Shackley, Agriculture Western Australia, 8. Response of New Wheat Varieties to Seed Rate and applied Nitrogen in the North, Darshan Sharma and Wal Anderson, Agriculture Western Australia 9. Seen vigour in wheat, Darshan Sharma and Wal Anderson, Agriculture Western Australia 10. Influence of the Time of Sowing on New Wheat Varieties in the North, Darshan Sharma and Wal Anderson, Agriculture Western Australia 11, Wheat performance in a high disease season on the South Coast. 1. Disease and grain quality on the Esperance sandplain, Mohammad Amjad, Vanessa Dooley and Wal Anderson, Agriculture Western Australia 12. Wheat performance in a high disease season on the South Coast. 2. Leaf area, disease and yield at Gibson and Salmon Gums, Mohammad Amjad, Vanessa Dooley and Wal Anderson, Agriculture Western Australia 13. Agronomic Evaluation of Wheat in the Central Wheatbelt of Western Australia, Peter Burgess and Ashley Bacon, Agritech Crop Research 14. Mechanisms influencing grain susceptibility to black point in wheat, Frances Hoyle, University of Western Australia and Agriculture Western Australia 15. Improving paddock productivity using renovation cropping techniques on heavier soils, Frances Hoyle, Agriculture Western Australia 16. Improving paddock productivity using renovation cropping techniques on sandplain soils, Frances Hoyle and Keith Devenish, Agriculture Western Australia 17. Increasing profit - Is it possible using high input package approach for cereal production? M. Appelbee, IAMA Agri Services 18. Improving wheat yield, soil physical and chemical fertility by a package of deep ripping, gypsum and complete nutrients, M.A. Hamza and W.K. Anderson, Agriculture Western Australia 19. Organic Wheat - Production System Guidelines, Steven McCoy, Centre for New Industries Development 20. Durum wheat obtains a premium over bread wheat, Steven Penny, Agriculture Western Australi

Causal structures and causal boundaries

We give an up-to-date perspective with a general overview of the theory of causal properties, the derived causal structures, their classification and applications, and the definition and construction of causal boundaries and of causal symmetries, mostly for Lorentzian manifolds but also in more abstract settings.Comment: Final version. To appear in Classical and Quantum Gravit

Is the socioeconomic gap in childhood exposure to secondhand smoke widening or narrowing?

Objectiv

TRAIL treatment provokes mutations in surviving cells

Chemotherapy and radiotherapy commonly damage DNA and trigger p53-dependent apoptosis through intrinsic apoptotic pathways. Two unfortunate consequences of this mechanism are resistance due to blockade of p53 or intrinsic apoptosis pathways, and mutagenesis of non-malignant surviving cells which can impair cellular function or provoke second malignancies. Death ligand-based drugs, such as tumor necrosis factor-related apoptosis inducing ligand (TRAIL), stimulate extrinsic apoptotic signaling, and may overcome resistance to treatments that induce intrinsic apoptosis. As death receptor ligation does not damage DNA as a primary mechanism of pro-apoptotic action, we hypothesized that surviving cells would remain genetically unscathed, suggesting that death ligand-based therapies may avoid some of the adverse effects associated with traditional cancer treatments. Surprisingly, however, treatment with sub-lethal concentrations of TRAIL or FasL was mutagenic. Mutations arose in viable cells that contained active caspases, and overexpression of the caspase-8 inhibitor crmA or silencing of caspase-8 abolished TRAIL-mediated mutagenesis. Downregulation of the apoptotic nuclease caspase-activated DNAse (CAD)/DNA fragmentation factor 40 (DFF40) prevented the DNA damage associated with TRAIL treatment. Although death ligands do not need to damage DNA in order to induce apoptosis, surviving cells nevertheless incur DNA damage after treatment with these agents