MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer

Cataloged from PDF version of article.Tamoxifen is an endocrine therapy which is administered to up to 70% of all breast cancer patients with oestrogen receptor alpha (ERα) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate genes. Although the role of a few miRNAs has been described in tamoxifen resistance at the single gene/target level, little is known about how concerted actions of miRNAs targeting biological networks contribute to resistance. Here we identified the miRNA cluster, C19MC, which harbours around 50 mature miRNAs, to be up-regulated in resistant cells, with miRNA-519a being the most highly up-regulated. We could demonstrate that miRNA-519a regulates tamoxifen resistance using gain- and loss-of-function testing. By combining functional enrichment analysis and prediction algorithms, we identified three central tumour-suppressor genes (TSGs) in PI3K signalling and the cell cycle network as direct target genes of miR-519a. Combined expression of these target genes correlated with disease-specific survival in a cohort of tamoxifen-treated patients. We identified miRNA-519a as a novel oncomir in ER+ breast cancer cells as it increased cell viability and cell cycle progression as well as resistance to tamoxifen-induced apoptosis. Finally, we could show that elevated miRNA-519a levels were inversely correlated with the target genes' expression and that higher expression of this miRNA correlated with poorer survival in ER+ breast cancer patients. Hence we have identified miRNA-519a as a novel oncomir, co-regulating a network of TSGs in breast cancer and conferring resistance to tamoxifen. Using inhibitors of such miRNAs may serve as a novel therapeutic approach to combat resistance to therapy as well as proliferation and evasion of apoptosis in breast cancer. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Опыт применения криохирургии в гинекологии

Приведены результаты применения низких температур для лечения ряда гинекологических заболеваний и обоснована необходимость широкого внедрения криогенного метода лечения в клиническую практику.The results of low temperature application in treatment of a number of gynecological diseases are presented, the necessity of wide introduction of cryogenic treatment into clinical practice is substantiated

Computational and experimental analysis identified 6-diazo-5-oxonorleucine as a potential agent for treating infection by Plasmodium falciparum

Plasmodium falciparum (PF) is the most severe malaria parasite. It is developing resistance quickly to existing drugs making it indispensable to discover new drugs. Effective drugs have been discovered targeting metabolic enzymes of the parasite. In order to predict new drug targets, computational methods can be used employing database information of metabolism. Using this data, we performed recently a computational network analysis of metabolism of PF. We analyzed the topology of the network to find reactions which are sensitive against perturbations, i.e., when a single enzyme is blocked by drugs. We now used a refined network comprising also the host enzymes which led to a refined set of the five targets glutamyl–tRNA (gln) amidotransferase, hydroxyethylthiazole kinase, deoxyribose–phophate aldolase, pseudouridylate synthase, and deoxyhypusine synthase. It was shown elsewhere that glutamyl– tRNA (gln) amidotransferase of other microorganisms can be inhibited by 6-diazo-5-oxonorleucine. Performing a half maximal inhibitory concentration (IC50) assay, we showed, that 6-diazo-5-oxonorleucine is also severely affecting viability of PF in blood plasma of the human host. We confirmed this by an in vivo study observing Plasmodium berghei infected mice

Populações de plantas e estratégias de manejo de irrigação na cultura da soja.

Este trabalho teve por objetivo verificar o efeito do manejo da irrigação e da população de plantas sobre o rendimento de grãos em soja semeada após a época recomenda. O experimento foi conduzido de janeiro a maio de 2005 na Universidade Federal de Santa Maria. O delineamento experimental utilizado foi blocos ao acaso com parcelas subdivididas e quatro repetições. Nas parcelas principais foram distribuídos três manejos de irrigação: 1) não-irrigado; 2) irrigado todo o ciclo; e 3) irrigado nos períodos críticos. Nas subparcelas foram distribuídas duas populações de plantas (250.000 e 400.000 plantas ha-1). Para as plantas irrigadas todo o ciclo ou somente nos períodos críticos, o rendimento de grãos não diferiu entre as populações testadas. O rendimento de grãos das plantas não-irrigadas teve um incremento de 21% com o aumento da população de plantas para 400.000 plantas ha-1

SURVEILLANCE FOR VANCOMYCIN RESISTANT ENTEROCOCCI IN A TERTIARY INSTITUTION IN SOUTH WESTERN NIGERIA

Background. Enterococci are responsible for up to 12% of cases of healthcare associated infections worldwide and cause life threatening infections among critically ill patients. They show intrinsic and acquired resistance to a wide range of antimicrobial agents. Glycopeptide resistance is due to vanA, vanB, vanC, vanD, vanE, vanG and vanL genes. Objectives. To determine the carriage rate of VRE among patients on prolonged hospitalization in LUTH, assess the antimicrobial resistance pattern of VRE, identify factors associated with VRE colonization and describe the genetic determinants of enterococcal resistance to Vancomycin. Methods. VRE were isolated from rectal swabs collected from patients hospitalized for seven days or more in Lagos University Teaching Hospital and identified by Matrix Assisted Laser Desorption Ionization (MALDI) and Polymerase Chain Reaction (PCR). Antimicrobial susceptibility testing was performed by E-test. PCR assay for Vancomycin resistance genes was also performed. Data on demographic and risk factors collected by questionnaire was tested for significance using chi square. Results. Thirteen of 319 patients surveyed were colonized with VRE; one with vanA E. faecium, two with vanB E. faecium, ten with E. gallinarum and one with E. casseliflavus. Univariate analysis for risk factors associated with VRE colonization was only significant for the ward of admission. Only one VRE isolate showed full resistance to vancomycin and Teicoplanin. Three were resistant to Ampicillin and nine to Ciprofloxacin but all were susceptible to Linezolid. High-level resistance to Gentamicin was found in four VRE isolates. Conclusion. There is a low prevalence of VRE in Lagos University Teaching Hospital which may be spreading among patients in affected wards

Proof of principle X-ray reflection mass measurement of the black hole in H1743-322

\ua9 2024 The Author(s). The black hole X-ray binary H1743-322 lies in a region of the Galaxy with high extinction, and therefore it has not been possible to make a dynamical mass measurement. In this paper, we make use of a recent model which uses the X-ray reflection spectrum to constrain the ratio of the black hole mass to the source distance. By folding in a reported distance measurement, we are able to estimate the mass of the black hole to be 12 \ub1 2 M☉ (1σ credible interval). We are then able to revise a previous disc continuum fitting estimate of black hole spin a∗ (previously relying on a population mass distribution) using our new mass constraint, finding a∗ = 0.47 \ub1 0.10. This work is a proof of principle demonstration of the method, showing it can be used to find the mass of black holes in X-ray binaries

Smoking is not linked to the development of anti-peptidylarginine deiminase 4 autoantibodies in rheumatoid arthritis

Background: Defining environmental factors responsible for development of autoimmunity in rheumatoid arthritis (RA) is critical for understanding mechanisms of disease initiation and propagation. Notably, a history of cigarette smoking has been implicated in the genesis of RA and is associated with worse disease outcomes. Antibodies to peptidylarginine deiminase 4 (PAD4) are also associated with more severe RA. A subset of patients who have PAD4 autoantibodies that cross-react with PAD3 (anti-PAD3/4) are at the highest risk for interstitial lung disease, and this risk is augmented by a history of cigarette smoking. It is unclear, however, if smoking is etiologically linked to the development of anti-PAD4 antibodies. Methods: Patients were included in this study if they had physician-diagnosed RA as well as DNA, serum, and a date-matched clinical assessment (n = 274). Anti-PAD4 and anti-CCP antibodies were measured by immunoprecipitation and ELISA, respectively; shared epitope (SE) status was determined by HLA-DRβ1 genotyping. Logistic regression analysis was used to evaluate associations of smoking with PAD4 antibodies, with adjustment for relevant demographic and clinical features. Stratified analyses by disease duration and shared epitope status were also performed. Results: Anti-PAD4 antibodies were present in 25% of RA patients, with 50% of these individuals having anti-PAD3/4 cross-reactive antibodies. Anti-PAD4 antibodies were significantly associated with a longer disease duration, SE alleles, and anti-CCP antibodies. Importantly, there were no significant differences in smoking history between anti-PAD4 positive and negative groups in univariate analyses, stratified analyses, or multivariable models. However, an inverse relationship between smoking and anti-PAD4 antibodies was suggested by a lower prevalence of current smokers among patients with anti-PAD3/4 antibodies compared to antibody negative individuals (p = 0.04). Further, the lowest levels of anti-PAD4 antibodies were observed in current smokers (p = 0.14), and a significant association of SE and anti-PAD4 antibodies was only present among never smokers (p = 0.01). Conclusions: Smoking history was not associated with anti-PAD4 antibodies in patients with RA. The finding that anti-PAD4 antibodies were not associated with smoking suggests that other environmental factors may contribute to the development of autoimmunity to PAD4 in these patients

Transport Spectroscopy of Symmetry-Broken Insulating States in Bilayer Graphene

The flat bands in bilayer graphene(BLG) are sensitive to electric fields E\bot directed between the layers, and magnify the electron-electron interaction effects, thus making BLG an attractive platform for new two-dimensional (2D) electron physics[1-5]. Theories[6-16] have suggested the possibility of a variety of interesting broken symmetry states, some characterized by spontaneous mass gaps, when the electron-density is at the carrier neutrality point (CNP). The theoretically proposed gaps[6,7,10] in bilayer graphene are analogous[17,18] to the masses generated by broken symmetries in particle physics and give rise to large momentum-space Berry curvatures[8,19] accompanied by spontaneous quantum Hall effects[7-9]. Though recent experiments[20-23] have provided convincing evidence of strong electronic correlations near the CNP in BLG, the presence of gaps is difficult to establish because of the lack of direct spectroscopic measurements. Here we present transport measurements in ultra-clean double-gated BLG, using source-drain bias as a spectroscopic tool to resolve a gap of ~2 meV at the CNP. The gap can be closed by an electric field E\bot \sim13 mV/nm but increases monotonically with a magnetic field B, with an apparent particle-hole asymmetry above the gap, thus providing the first mapping of the ground states in BLG.Comment: 4 figure

Mott physics and band topology in materials with strong spin-orbit interaction

Recent theory and experiment have revealed that strong spin-orbit coupling can have dramatic qualitative effects on the band structure of weakly interacting solids. Indeed, it leads to a distinct phase of matter, the topological band insulator. In this paper, we consider the combined effects of spin-orbit coupling and strong electron correlation, and show that the former has both quantitative and qualitative effects upon the correlation-driven Mott transition. As a specific example we take Ir-based pyrochlores, where the subsystem of Ir 5d electrons is known to undergo a Mott transition. At weak electron-electron interaction, we predict that Ir electrons are in a metallic phase at weak spin-orbit interaction, and in a topological band insulator phase at strong spin-orbit interaction. Very generally, we show that with increasing strength of the electron-electron interaction, the effective spin-orbit coupling is enhanced, increasing the domain of the topological band insulator. Furthermore, in our model, we argue that with increasing interactions, the topological band insulator is transformed into a "topological Mott insulator" phase, which is characterized by gapless surface spin-only excitations. The full phase diagram also includes a narrow region of gapless Mott insulator with a spinon Fermi surface, and a magnetically ordered state at still larger electron-electron interaction.Comment: 10+ pages including 3+ pages of Supplementary Informatio