A new gene expression signature, the ClinicoMolecular Triad Classification, may improve prediction and prognostication of breast cancer at the time of diagnosis

Abstract Introduction When making treatment decisions, oncologists often stratify breast cancer (BC) into a low-risk group (low-grade estrogen receptor-positive (ER+)), an intermediate-risk group (high-grade ER+) and a high-risk group that includes Her2+ and triple-negative (TN) tumors (ER-/PR-/Her2-). None of the currently available gene signatures correlates to this clinical classification. In this study, we aimed to develop a test that is practical for oncologists and offers both molecular characterization of BC and improved prediction of prognosis and treatment response. Methods We investigated the molecular basis of such clinical practice by grouping Her2+ and TN BC together during clustering analyses of the genome-wide gene expression profiles of our training cohort, mostly derived from fine-needle aspiration biopsies (FNABs) of 149 consecutive evaluable BC. The analyses consistently divided these tumors into a three-cluster pattern, similarly to clinical risk stratification groups, that was reproducible in published microarray databases (n = 2,487) annotated with clinical outcomes. The clinicopathological parameters of each of these three molecular groups were also similar to clinical classification. Results The low-risk group had good outcomes and benefited from endocrine therapy. Both the intermediate- and high-risk groups had poor outcomes, and their BC was resistant to endocrine therapy. The latter group demonstrated the highest rate of complete pathological response to neoadjuvant chemotherapy; the highest activities in Myc, E2F1, Ras, β-catenin and IFN-γ pathways; and poor prognosis predicted by 14 independent prognostic signatures. On the basis of multivariate analysis, we found that this new gene signature, termed the "ClinicoMolecular Triad Classification" (CMTC), predicted recurrence and treatment response better than all pathological parameters and other prognostic signatures. Conclusions CMTC correlates well with current clinical classifications of BC and has the potential to be easily integrated into routine clinical practice. Using FNABs, CMTC can be determined at the time of diagnostic needle biopsies for tumors of all sizes. On the basis of using public databases as the validation cohort in our analyses, CMTC appeared to enable accurate treatment guidance, could be made available in preoperative settings and was applicable to all BC types independently of tumor size and receptor and nodal status. The unique oncogenic signaling pathway pattern of each CMTC group may provide guidance in the development of new treatment strategies. Further validation of CMTC requires prospective, randomized, controlled trials

PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation

Activation of the Ras–MAPK signal transduction pathway is necessary for biological responses both to growth factors and ECM. Here, we provide evidence that phosphorylation of S298 of MAPK kinase 1 (MEK1) by p21-activated kinase (PAK) is a site of convergence for integrin and growth factor signaling. We find that adhesion to fibronectin induces PAK1-dependent phosphorylation of MEK1 on S298 and that this phosphorylation is necessary for efficient activation of MEK1 and subsequent MAPK activation. The rapid and efficient activation of MEK and phosphorylation on S298 induced by cell adhesion to fibronectin is influenced by FAK and Src signaling and is paralleled by localization of phospho-S298 MEK1 and phospho-MAPK staining in peripheral membrane–proximal adhesion structures. We propose that FAK/Src-dependent, PAK1-mediated phosphorylation of MEK1 on S298 is central to the organization and localization of active Raf–MEK1–MAPK signaling complexes, and that formation of such complexes contributes to the adhesion dependence of growth factor signaling to MAPK

A generalised Euler-Poincaré formula for associahedra

We derive a formula for the number of flip-equivalence classes of tilings of an n-gon by collections of tiles of shape dictated by an integer partition λ. The proof uses the Euler–Poincaré formula; and the formula itself generalises the Euler–Poincaré formula for associahedr

Hide your pain : social threat increases pain reports and aggression, but reduces facial pain expression and empathy

Earlier research studying the effects of social threat on the experience and expression of pain led to mixed results. In this study, female participants (N = 32) came to the lab with 2 confederates. Both confederates administered a total of 10 painful electrocutaneous stimuli to the participant. The framing of the administration was manipulated in a within-subjects design: In the low social threat condition the participant was told that the confederate could choose between 10 and 20 pain stimuli, thus they believed that this confederate chose to administer the minimum allowed number of pain stimuli. In the high social threat condition the confederate had a choice between 1 and 10 stimuli, thus they believed that this confederate chose to administer the maximum allowed number of stimuli. Participants reported on the intensity, unpleasantness, and threat value of the painful stimuli, and their facial expression was recorded. Moreover, aggression and empathy toward the confederates were assessed. As hypothesized, participants reported increased pain intensity, unpleasantness, and threat in the high social threat condition compared to the low social threat condition, but showed less facial pain expression. Finally, participants exhibited increased aggression and reduced empathy toward the confederate in the high social threat condition. Perspective: Social threat reduces painful facial expression, but simultaneously increases pain reports, leading to a double burden of the person in pain. Additionally, social threat affected social relationships by increasing aggression and reducing empathy for the other

Simple psychological interventions for reducing pain from common needle procedures in adults: Systematic review of randomized and quasi-randomized controlled trials

Background: This systematic review evaluated the effectiveness of simple psychological interventions for managing pain and fear in adults undergoing vaccination or related common needle procedures (ie, venipuncture/venous cannulation). Design/Methods: Databases were searched to identify relevant randomized and quasi-randomized controlled trials. Self-reported pain and fear were prioritized as critically important outcomes. Data were combined using standardized mean difference (SMD) or relative risk (RR) with 95% confidence intervals (CI). Results: No studies involving vaccination met inclusion criteria; evidence was drawn from 8 studies of other common needle procedures (eg, venous cannulation, venipuncture) in adults. Two trials evaluating the impact of neutral signaling of the impending procedure (eg, ready? ) as compared with signaling of impending pain (eg, sharp scratch ) demonstrated lower pain when signaled about the procedure (n=199): SMD=-0.97 (95% CI, -1.26, -0.68), after removal of 1 trial where self-reported pain was significantly lower than the other 2 included trials. Two trials evaluated music distraction (n=156) and demonstrated no difference in pain: SMD=0.10 (95% CI, -0.48, 0.27), or fear: SMD= -0.25 (95% CI, -0.61, 0.10). Two trials evaluated visual distraction and demonstrated no difference in pain (n=177): SMD= -0.57 (95% CI, -1.82, 0.68), or fear (n=81): SMD= -0.05 (95% CI, -0.50, 0.40). Two trials evaluating breathing interventions found less pain in intervention groups (n=138): SMD= -0.82 (95% CI, -1.21, -0.43). The quality of evidence across all trials was very low. Conclusions: There are no published studies of simple psychological interventions for vaccination pain in adults. There is some evidence of a benefit from other needle procedures for breathing strategies and neutral signaling of the start of the procedure. There is no evidence for use of music or visual distraction

The Effects of Forest Fuel-Reduction Treatments in the United States

The current conditions of many seasonally dry forests in the western and southern United States, especially those that once experienced low- to moderate-intensity fire regimes, leave them uncharacteristically susceptible to high-severity wildfire. Both prescribed fire and its mechanical surrogates are generally successful in meeting short-term fuel-reduction objectives such that treated stands are more resilient to high-intensity wildfire. Most available evidence suggests that these objectives are typically accomplished with few unintended consequences, since most ecosystem components (vegetation, soils, wildlife, bark beetles, carbon sequestration) exhibit very subtle effects or no measurable effects at all. Although mechanical treatments do not serve as complete surrogates for fire, their application can help mitigate costs and liability in some areas. Desired treatment effects on fire hazards are transient, which indicates that after fuel-reduction management starts, managers need to be persistent with repeated treatment, especially in the faster-growing forests in the southern United States.Keywords: wildfire, forest conservation, forest management, fire surrogates, fire ecolog

How effective is low vision service provision? A systematic review

Visual impairment is a large and growing socioeconomic problem. Good evidence on rehabilitation outcomes is required to guide service development and improve the lives of people with sight loss. Of the 478 potentially relevant articles identified, only 58 studies met our liberal inclusion criteria, and of these only 7 were randomized controlled trials. Although the literature is sufficient to confirm that rehabilitation services result in improved clinical and functional ability outcomes, the effects on mood, vision-related quality of life (QoL) and health-related QoL are less clear. There are some good data on the performance of particular types of intervention, but almost no useful data about outcomes in children, those of working age, and other groups. There were no reports on cost effectiveness. Overall, the number of well-designed and adequately reported studies is pitifully small; visual rehabilitation research needs higher quality research. We highlight study design and reporting considerations and suggest a future research agenda

Probing the physics of the solar atmosphere with the Multi-slit Solar Explorer (MUSE). I. Coronal heating

Funding: I.D.M. has received support from the UK Science and Technology Facilities Council (Consolidated grant ST/K000950/1), the European Union Horizon 2020 research and innovation program (grant agreement No. 647214), and the Research Council of Norway through its Centres of Excellence scheme, project number 262622.The Multi-slit Solar Explorer (MUSE) is a proposed mission composed of a multislit extreme ultraviolet (EUV) spectrograph (in three spectral bands around 171 Å, 284 Å, and 108 Å) and an EUV context imager (in two passbands around 195 Å and 304 Å). MUSE will provide unprecedented spectral and imaging diagnostics of the solar corona at high spatial (≤0.″5) and temporal resolution (down to ∼0.5 s for sit-and-stare observations), thanks to its innovative multislit design. By obtaining spectra in four bright EUV lines (Fe ix 171 Å, Fe xv 284 Å, Fe xix–Fe xxi 108 Å) covering a wide range of transition regions and coronal temperatures along 37 slits simultaneously, MUSE will, for the first time, “freeze” (at a cadence as short as 10 s) with a spectroscopic raster the evolution of the dynamic coronal plasma over a wide range of scales: from the spatial scales on which energy is released (≤0.″5) to the large-scale (∼170″ × 170″) atmospheric response. We use numerical modeling to showcase how MUSE will constrain the properties of the solar atmosphere on spatiotemporal scales (≤0.″5, ≤20 s) and the large field of view on which state-of-the-art models of the physical processes that drive coronal heating, flares, and coronal mass ejections (CMEs) make distinguishing and testable predictions. We describe the synergy between MUSE, the single-slit, high-resolution Solar-C EUVST spectrograph, and ground-based observatories (DKIST and others), and the critical role MUSE plays because of the multiscale nature of the physical processes involved. In this first paper, we focus on coronal heating mechanisms. An accompanying paper focuses on flares and CMEs.Publisher PDFPeer reviewe

Inter-Homolog Crossing-Over and Synapsis in Arabidopsis Meiosis Are Dependent on the Chromosome Axis Protein AtASY3

In this study we have analysed AtASY3, a coiled-coil domain protein that is required for normal meiosis in Arabidopsis. Analysis of an Atasy3-1 mutant reveals that loss of the protein compromises chromosome axis formation and results in reduced numbers of meiotic crossovers (COs). Although the frequency of DNA double-strand breaks (DSBs) appears moderately reduced in Atasy3-1, the main recombination defect is a reduction in the formation of COs. Immunolocalization studies in wild-type meiocytes indicate that the HORMA protein AtASY1, which is related to Hop1 in budding yeast, forms hyper-abundant domains along the chromosomes that are spatially associated with DSBs and early recombination pathway proteins. Loss of AtASY3 disrupts the axial organization of AtASY1. Furthermore we show that the AtASY3 and AtASY1 homologs BoASY3 and BoASY1, from the closely related species Brassica oleracea, are co-immunoprecipitated from meiocyte extracts and that AtASY3 interacts with AtASY1 via residues in its predicted coiled-coil domain. Together our results suggest that AtASY3 is a functional homolog of Red1. Since studies in budding yeast indicate that Red1 and Hop1 play a key role in establishing a bias to favor inter-homolog recombination (IHR), we propose that AtASY3 and AtASY1 may have a similar role in Arabidopsis. Loss of AtASY3 also disrupts synaptonemal complex (SC) formation. In Atasy3-1 the transverse filament protein AtZYP1 forms small patches rather than a continuous SC. The few AtMLH1 foci that remain in Atasy3-1 are found in association with the AtZYP1 patches. This is sufficient to prevent the ectopic recombination observed in the absence of AtZYP1, thus emphasizing that in addition to its structural role the protein is important for CO formation

The effects of timing of fine needle aspiration biopsies on gene expression profiles in breast cancers

<p>Abstract</p> <p>Background</p> <p>DNA microarray analysis has great potential to become an important clinical tool to individualize prognostication and treatment for breast cancer patients. However, with any emerging technology, there are many variables one must consider before bringing the technology to the bedside. There are already concerted efforts to standardize protocols and to improve reproducibility of DNA microarray. Our study examines one variable that is often overlooked, the timing of tissue acquisition, which may have a significant impact on the outcomes of DNA microarray analyses especially in studies that compare microarray data based on biospecimens taken <it>in vivo </it>and <it>ex vivo</it>.</p> <p>Methods</p> <p>From 16 patients, we obtained paired fine needle aspiration biopsies (FNABs) of breast cancers taken before (PRE) and after (POST) their surgeries and compared the microarray data to determine the genes that were differentially expressed between the FNABs taken at the two time points. qRT-PCR was used to validate our findings. To examine effects of longer exposure to hypoxia on gene expression, we also compared the gene expression profiles of 10 breast cancers from clinical tissue bank.</p> <p>Results</p> <p>Using hierarchical clustering analysis, 12 genes were found to be differentially expressed between the FNABs taken before and after surgical removal. Remarkably, most of the genes were linked to FOS in an early hypoxia pathway. The gene expression of FOS also increased with longer exposure to hypoxia.</p> <p>Conclusion</p> <p>Our study demonstrated that the timing of fine needle aspiration biopsies can be a confounding factor in microarray data analyses in breast cancer. We have shown that FOS-related genes, which have been implicated in early hypoxia as well as the development of breast cancers, were differentially expressed before and after surgery. Therefore, it is important that future studies take timing of tissue acquisition into account.</p