ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma.

Low-risk gestational trophoblastic neoplasia including choriocarcinoma is often effectively treated with Methotrexate (MTX) as a first line therapy. However, MTX resistance (MTX-R) occurs in at least ≈33% of cases. This can sometimes be salvaged with actinomycin-D but often requires more toxic combination chemotherapy. Moreover, additional therapy may be needed and, for high-risk patients, 5% still die from the multidrug-resistant disease. Consequently, new treatments that are less toxic and could reverse MTX-R are needed. Here, we compared the proteome/phosphoproteome of MTX-resistant and sensitive choriocarcinoma cells using quantitative mass-spectrometry to identify therapeutically actionable molecular changes associated with MTX-R. Bioinformatics analysis of the proteomic data identified cell cycle and DNA damage repair as major pathways associated with MTX-R. MTX-R choriocarcinoma cells undergo cell cycle delay in G1 phase that enables them to repair DNA damage more efficiently through non-homologous end joining in an ATR-dependent manner. Increased expression of cyclin-dependent kinase 4 (CDK4) and loss of p16Ink4a in resistant cells suggested that CDK4 inhibition may be a strategy to treat MTX-R choriocarcinoma. Indeed, inhibition of CDK4/6 using genetic silencing or the clinically relevant inhibitor, Palbociclib, induced growth inhibition both in vitro and in an orthotopic in vivo mouse model. Finally, targeting the ATR pathway, genetically or pharmacologically, re-sensitised resistant cells to MTX in vitro and potently prevented the growth of MTX-R tumours in vivo. In short, we identified two novel therapeutic strategies to tackle MTX-R choriocarcinoma that could rapidly be translated into the clinic.

From solar sneezing to killer electrons: outer radiation belt response to solar eruptions.

Electrons in the outer Van Allen (radiation) belt occasionally reach relativistic energies, turning them into a potential hazard for spacecraft operating in geospace. Such electrons have secured the reputation of satellite killers and play a prominent role in space weather. The flux of these electrons can vary over time scales of years (related to the solar cycle) to minutes (related to sudden storm commencements). Electric fields and plasma waves are the main factors regulating the electron transport, acceleration and loss. Both the fields and the plasma waves are driven directly or indirectly by disturbances originating in the Sun, propagating through interplanetary space and impacting the Earth. This paper reviews our current understanding of the response of outer Van Allen belt electrons to solar eruptions and their interplanetary extensions, i.e. interplanetary coronal mass ejections and high-speed solar wind streams and the associated stream interaction regions. This article is part of the theme issue 'Solar eruptions and their space weather impact'.

Temporal organization of magnetospheric fluctuations unveiled by recurrence patterns in the Dst index.

Magnetic storms constitute the most remarkable large-scale phenomena of nonlinear magnetospheric dynamics. Studying the dynamical organization of macroscopic variability in terms of geomagnetic activity index data by means of complexity measures provides a promising approach for identifying the underlying processes and associated time scales. Here, we apply a suite of characteristics from recurrence quantification analysis (RQA) and recurrence network analysis (RNA) in order to unveil some key nonlinear features of the hourly Disturbance storm-time (Dst) index during periods with magnetic storms and such of normal variability. Our results demonstrate that recurrence-based measures can serve as excellent tracers for changes in the dynamical complexity along non-stationary records of geomagnetic activity. In particular, trapping time (characterizing the typical length of "laminar phases" in the observed dynamics) and recurrence network transitivity (associated with the number of the system's effective dynamical degrees of freedom) allow for a very good discrimination between magnetic storm and quiescence phases. In general, some RQA and RNA characteristics distinguish between storm and non-storm times equally well or even better than other previously considered nonlinear characteristics like Hurst exponent or symbolic dynamics based entropy concepts. Our results point to future potentials of recurrence characteristics for unveiling temporal changes in the dynamical complexity of the magnetosphere.

Reconsidering Planning and Management of Medical Devices Procurement in Public Health Services in Cyprus.

Hospital procurement is a crucial field for any health care system, not only for economic reasons but also for reasons related to the quality and safety of the services provided. That is why the process of procurement is, in most countries, governed by a strict legal framework and policy mechanisms. This study investigates the problems and inefficiencies associated with the procurement of medical devices in public hospitals in Cyprus and formulates empirically documented proposals for improvement. Using the Delphi method, a group of 38 experts approach the procurement system in Cyprus from different angles, achieving high rates of consensus on 35 different statements on the weaknesses and problems of the current medical device procurement system, as well as presenting proposals and recommendations for improvement. The findings are highly valuable for future policy initiatives in Cyprus in the light of the economic crisis and the expected implementation of the new General Health Insurance System (GeSY), which the Government of the Republic of Cyprus and the Troika has agreed.

The four aldehyde oxidases of Drosophila melanogaster have different gene expression patterns and enzyme substrate specificities.

In the genome of Drosophila melanogaster, four genes coding for aldehyde oxidases (AOX1-4) were identified on chromosome 3. Phylogenetic analysis showed that the AOX gene cluster evolved via independent duplication events in the vertebrate and invertebrate lineages. The functional role and the substrate specificity of the distinct Drosophila AOX enzymes is unknown. Two loss-of-function mutant alleles in this gene region, low pyridoxal oxidase (Po(lpo)) and aldehyde oxidase-1 (Aldox-1(n1)) are associated with a phenotype characterized by undetectable AOX enzymatic activity. However, the genes involved and the corresponding mutations have not yet been identified. In this study we characterized the activities, substrate specificities and expression profiles of the four AOX enzymes in D. melanogaster. We show that the Po(lpo)-associated phenotype is the consequence of a structural alteration of the AOX1 gene. We identified an 11-bp deletion in the Po(lpo) allele, resulting in a frame-shift event, which removes the molybdenum cofactor domain of the encoded enzyme. Furthermore, we show that AOX2 activity is detectable only during metamorphosis and characterize a Minos-AOX2 insertion in this developmental gene that disrupts its activity. We demonstrate that the Aldox-1(n1) phenotype maps to the AOX3 gene and AOX4 activity is not detectable in our assays.