Epidermal growth factor receptor (EGFR) gene amplification and mutations are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive tumor growth ...are not well understood. Here, through integrated epigenome and transcriptome analyses of cell lines, genotyped clinical samples, and TCGA data, we show that EGFR mutations remodel the activated enhancer landscape of GBM, promoting tumorigenesis through a SOX9 and FOXG1-dependent transcriptional regulatory network in vitro and in vivo. The most common EGFR mutation, EGFRvIII, sensitizes GBM cells to the BET-bromodomain inhibitor JQ1 in a SOX9, FOXG1-dependent manner. These results identify the role of transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy.
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•Oncogenic EGFRvIII mutation remodels the enhancer landscape in GBM•EGFRvIII induces SOX9 and FOXG1 transcription in GBM•SOX9 and FOXG1 collaborate to activate an oncogenic gene regulatory program•EGFRvIII-dependent transcription sensitizes GBM cells to JQ1
Epidermal growth factor receptor (EGFR) gene amplification and mutations are the most common oncogenic events in glioblastoma (GBM). Through an integrative genomics analysis, Liu et al., identify a role for transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy.
Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of ...interleukin-1β phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely resembled human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1, and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5+ gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1β-IL-6 signaling cascade and Dll1-dependent Notch signaling.
► IL-1β overexpression in the mouse esophagus induces IL-6 dependent BE and EAC ► Bile acids accelerate intestinal metaplasia and dysplasia in this mouse model of BE ► Notch signaling in columnar cells, not goblet cells is associated with carcinogenesis ► BE and EAC likely arise from gastric cardia progenitor cells
In classical inverse linear optimization, one assumes that a given solution is a candidate to be optimal. Real data are imperfect and noisy, so there is no guarantee that this assumption is ...satisfied. Inspired by regression, this paper presents a unified framework for cost function estimation in linear optimization comprising a general inverse optimization model and a corresponding goodness-of-fit metric. Although our inverse optimization model is nonconvex, we derive a closed-form solution and present the geometric intuition. Our goodness-of-fit metric,
ρ
, the
coefficient of complementarity
, has similar properties to
R
2
from regression and is quasi-convex in the input data, leading to an intuitive geometric interpretation. While
ρ
is computable in polynomial time, we derive a lower bound that possesses the same properties, is tight for several important model variations, and is even easier to compute. We demonstrate the application of our framework for model estimation and evaluation in production planning and cancer therapy.
This paper was accepted by Yinyu Ye, optimization.
We search for dynamical substructures in the LAMOST DR3 very metal-poor (VMP) star catalog. After cross-matching with Gaia DR2, there are ∼3300 VMP stars with available high-quality astrometric ...information that have halo-like kinematics. We apply a method based on the self-organizing map StarGO to find groups clustered in the 4D space of orbital energy and angular momentum. We identify 57 dynamically tagged groups (DTGs), which we label DTG-1 to DTG-57. Most of them belong to existing massive substructures in the nearby halo, such as the Gaia Sausage or Sequoia. The stream identified by Helmi et al. is recovered, but the two disjointed portions of the substructure appear to have distinct dynamical properties. The very retrograde substructure Rg5 found previously by Myeong et al. is also retrieved. We report six new DTGs with highly retrograde orbits, two with very prograde orbits, and 12 with polar orbits. By mapping other data sets (APOGEE halo stars, and catalogs of r-process-enhanced and carbon-enhanced metal-poor CEMP stars) onto the trained neuron map, we can associate stars with detailed chemical abundances with the DTGs and look for associations with chemically peculiar stars. The highly eccentric Gaia Sausage groups contain representatives of both debris from the satellite itself (which is -poor) and the Splashed Disk, sent up into eccentric halo orbits from the encounter (and which is -rich). The new prograde substructures also appear to be associated with the Splashed Disk. The DTGs belonging to the Gaia Sausage host two relatively metal-rich r-II stars and six CEMP stars in different subclasses, consistent with the idea that the Gaia Sausage progenitor is a massive dwarf galaxy. Rg5 is dynamically associated with two highly r-process-enhanced stars with Fe/H ∼ −3. This finding indicates that its progenitor might be an ultrafaint dwarf galaxy that has experienced r-process enrichment from neutron star mergers.
The structure and kinematics of the recognized stellar components of the Milky Way are explored, based on well-determined atmospheric parameters and kinematic quantities for 32360 'calibration stars' ...from the Sloan Digital Sky Survey (SDSS) and its first extension, SDSS-II, which included the sub-survey Sloan Extension for Galactic Understanding and Exploration (SEGUE). Full space motions for a sub-sample of 16,920 stars, exploring a local volume within 4 kpc of the Sun, are used to derive velocity ellipsoids for the inner- and outer-halo components of the Galaxy, as well as for the canonical thick-disk and proposed metal-weak thick-disk (MWTD) populations. This new sample of calibration stars represents an increase of 60% relative to the numbers used in a previous analysis. We first examine the question of whether the data require the presence of at least a two-component halo in order to account for the rotational behavior of likely halo stars in the local volume, and whether more than two components are needed. We also address the question of whether the proposed MWTD is kinematically and chemically distinct from the canonical thick disk, and point out that the Galactocentric rotational velocity inferred for the MWTD, as well as its mean metallicity, appear quite similar to the values derived previously for the Monoceros stream, suggesting a possible association between these structures. In addition, we consider the fractions of each component required to understand the nature of the observed kinematic behavior of the stellar populations of the Galaxy as a function of distance from the plane. Scale lengths and scale heights for the thick-disk and MWTD components are determined. Spatial density profiles for the inner- and outer-halo populations are inferred from a Jeans theorem analysis. The full set of calibration stars (including those outside the local volume) is used to test for the expected changes in the observed stellar metallicity distribution function with distance above the Galactic plane in situ, due to the changing contributions from the underlying stellar populations. The above issues are considered, in concert with theoretical and observational constraints from other Milky-Way-like galaxies, in light of modern cold dark matter galaxy formation models.
•New inverse multi-objective convex optimization methods are proposed.•The proposed methods infer weights quantifying intended trade-offs encoded in data.•A connection between inverse and ...multi-objective optimization is established.•The proposed methods generalize several existing inverse optimization models.•The methods have the potential to improve radiotherapy planning efficiency.
Given an input solution that may not be Pareto optimal, we present a new inverse optimization methodology for multi-objective convex optimization that determines a weight vector producing a weakly Pareto optimal solution that preserves the decision maker’s trade-off intention encoded in the input solution. We introduce a notion of trade-off preservation, which we use as a measure of similarity for approximating the input solution, and show its connection with minimizing an optimality gap. We propose a linear approximation to the inverse model and a successive linear programming algorithm that balance between trade-off preservation and computational efficiency, and show that our model encompasses many of the existing inverse optimization models from the literature. We demonstrate the proposed method using clinical data from prostate cancer radiation therapy.
We present an analysis of the kinematic properties of stellar populations in the Galactic halo, making use of over 100,000 main-sequence turnoff (MSTO) stars observed in the Sloan Digital Sky Survey. ...After dividing the Galactic halo into an inner-halo region (IHR) and outer-halo region (OHR), based on the spatial variation of carbon-to-iron ratios in the sample, we find that stars in the OHR exhibit a clear retrograde motion of −49 4 km s−1 and a more spherical distribution of stellar orbits, while stars in the IHR have zero net rotation (−3 1 km s−1) with a much more radially biased distribution of stellar orbits. Furthermore, we classify the carbon-enhanced metal-poor (CEMP) stars among the MSTO sample in each halo component into CEMP-no and CEMP-s subclasses, based on their absolute carbon abundances, A(C), and examine the spatial distributions and kinematics associated with each subclass. The CEMP-no stars are the majority subclass of CEMP stars in the OHR (∼65%), and the minority subclass in the IHR (∼44%), similar to the results of several previous analyses. The CEMP-no stars in each halo region exhibit slightly higher counterrotation than the CEMP-s stars, but within statistical errors. The CEMP-no stars also show a more spherical distribution of orbits than the CEMP-s stars in each halo region. These distinct characteristics provide strong evidence that numerous low-mass satellite galaxies (similar to the ultra-faint dwarf galaxies) have donated stars to the OHR, while more massive dwarf galaxies provided the dominant contribution to the IHR.
We use the multi-epoch radial velocities acquired by the Apache Point Observatory Galactic Evolution Experiment (APOGEE) survey to perform a large-scale statistical study of stellar multiplicity for ...field stars in the Milky Way, spanning the evolutionary phases between the main sequence (MS) and the red clump. We show that the distribution of maximum radial velocity shifts (ΔRVmax) for APOGEE targets is a strong function of log g, with MS stars showing ΔRVmax as high as ∼300 , and steadily dropping down to ∼30 for log g ∼ 0, as stars climb up the red giant branch (RGB). Red clump stars show a distribution of ΔRVmax values comparable to that of stars at the tip of the RGB, implying they have similar multiplicity characteristics. The observed attrition of high ΔRVmax systems in the RGB is consistent with a lognormal period distribution in the MS and a multiplicity fraction of 0.35, which is truncated at an increasing period as stars become physically larger and undergo mass transfer after Roche Lobe overflow during H-shell burning. The ΔRVmax distributions also show that the multiplicity characteristics of field stars are metallicity-dependent, with metal-poor (Fe/H −0.5) stars having a multiplicity fraction a factor of 2-3 higher than metal-rich (Fe/H 0.0) stars. This has profound implications for the formation rates of interacting binaries observed by astronomical transient surveys and gravitational wave detectors, as well as the habitability of circumbinary planets.
Influenza is a major cause of severe respiratory infections leading to excessive hospitalizations and deaths globally; annual epidemics, pandemics, and sporadic/endemic avian virus infections occur ...as a result of rapid, continuous evolution of influenza viruses. Emergence of antiviral resistance is of great clinical and public health concern. Currently available antiviral treatments include four neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, laninamivir), M2-inibitors (amantadine, rimantadine), and a polymerase inhibitor (favipiravir). In this review, we focus on resistance issues related to the use of neuraminidase inhibitors (NAIs). Data on primary resistance, as well as secondary resistance related to NAI exposure will be presented. Their clinical implications, detection, and novel therapeutic options undergoing clinical trials are discussed.
The Milky Way is a unique laboratory in which stellar properties can be measured and analyzed in detail. In particular, stars in the older populations encode information on the mechanisms that led to ...the formation of our Galaxy. In this article, we analyze the kinematics, spatial distribution, and chemistry of a large number of stars in the solar neighborhood, where all of the main Galactic components are well represented. We find that the thick disk comprises two distinct and overlapping stellar populations with different kinematic properties and chemical compositions. The metal-weak thick disk (MWTD) contains two-times less metal content than the canonical thick disk, and exhibits enrichment of light elements typical of the oldest stellar populations of the Galaxy. The rotational velocity of the MWTD around the Galactic center is ∼150 km s−1, corresponding to a rotational lag of 30 km s−1 relative to the canonical thick disk (∼180 km s−1), with a velocity dispersion of 60 km s−1. This stellar population likely originated from the merger of a dwarf galaxy during the early phases of our Galaxy's assembly, or it is a precursor disk, formed in the inner Galaxy and brought into the solar neighborhood by bar instability or spiral-arm formation mechanisms.
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