Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?

Phenotypic plasticity, the ability of cells to reversibly alter their phenotypes in response to signals, presents a significant clinical challenge to treating solid tumors. Tumor cells utilize phenotypic plasticity to evade therapies, metastasize, and colonize distant organs. As a result, phenotypic plasticity can accelerate tumor progression. A well-studied example of phenotypic plasticity is the bidirectional conversions among epithelial, mesenchymal, and hybrid epithelial/mesenchymal (E/M) phenotype(s). These conversions can alter a repertoire of cellular traits associated with multiple hallmarks of cancer, such as metabolism, immune evasion, invasion, and metastasis. To tackle the complexity and heterogeneity of these transitions, mathematical models have been developed that seek to capture the experimentally verified molecular mechanisms and act as ‘hypothesis-generating machines’. Here, we discuss how these quantitative mathematical models have helped us explain existing experimental data, guided further experiments, and provided an improved conceptual framework for understanding how multiple intracellular and extracellular signals can drive E/M plasticity at both the single-cell and population levels. We also discuss the implications of this plasticity in driving multiple aggressive facets of tumor progression

Restoration of rotational invariance of bound states on the light front

We study bound states in a model with scalar nucleons interacting via an exchanged scalar meson using the Hamiltonian formalism on the light front. In this approach manifest rotational invariance is broken when the Fock space is truncated. By considering an effective Hamiltonian that takes into account two meson exchanges, we find that this breaking of rotational invariance is decreased from that which occurs when only one meson exchange is included. The best improvement occurs when the states are weakly bound.Comment: 20 pages, 6 figures, uses feynMF; changed typos, clarified use of angular momentu

Pathway and gene-set activation measurement from mRNA expression data: the tissue distribution of human pathways

BACKGROUND: Interpretation of lists of genes or proteins with altered expression is a critical and time-consuming part of microarray and proteomics research, but relatively little attention has been paid to methods for extracting biological meaning from these output lists. One powerful approach is to examine the expression of predefined biological pathways and gene sets, such as metabolic and signaling pathways and macromolecular complexes. Although many methods for measuring pathway expression have been proposed, a systematic analysis of the performance of multiple methods over multiple independent data sets has not previously been reported. RESULTS: Five different measures of pathway expression were compared in an analysis of nine publicly available mRNA expression data sets. The relative sensitivity of the metrics varied greatly across data sets, and the biological pathways identified for each data set are also dependent on the choice of pathway activation metric. In addition, we show that removing incoherent pathways prior to analysis improves specificity. Finally, we create and analyze a public map of pathway expression in human tissues by gene-set analysis of a large compendium of human expression data. CONCLUSION: We show that both the detection sensitivity and identity of pathways significantly perturbed in a microarray experiment are highly dependent on the analysis methods used and how incoherent pathways are treated. Analysts should thus consider using multiple approaches to test the robustness of their biological interpretations. We also provide a comprehensive picture of the tissue distribution of human gene pathways and a useful public archive of human pathway expression data

TESS Discovery of a Transiting Super-Earth in the π\pi Mensae System

We report the detection of a transiting planet around $\pi$ Mensae (HD 39091), using data from the Transiting Exoplanet Survey Satellite (TESS). The solar-type host star is unusually bright (V=5.7) and was already known to host a Jovian planet on a highly eccentric, 5.7-year orbit. The newly discovered planet has a size of $2.04\pm 0.05$ $R_\oplus$ and an orbital period of 6.27 days. Radial-velocity data from the HARPS and AAT/UCLES archives also displays a 6.27-day periodicity, confirming the existence of the planet and leading to a mass determination of $4.82\pm 0.85$ $M_\oplus$. The star's proximity and brightness will facilitate further investigations, such as atmospheric spectroscopy, asteroseismology, the Rossiter--McLaughlin effect, astrometry, and direct imaging.Comment: Accepted for publication ApJ Letters. This letter makes use of the TESS Alert data, which is currently in a beta test phase. The discovery light curve is included in a table inside the arxiv submissio

Spleen tyrosine kinase-mediated autophagy is required for epithelial-mesenchymal plasticity and metastasis in breast cancer

The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here we compare a reversible model of epithelial-mesenchymal transition (EMT) induced by TGF-β to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGF-β-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal-epithelial transition (MET). Genetic knockout of autophagy related 7 (ATG7) or pharmacological inhibition of SYK activity with fostamatib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, the current study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells

The assessment of circulating volume using inferior vena cava collapse index and carotid Doppler velocity time integral in healthy volunteers: a pilot study

International audienceBackground: Assessment of circulating volume and the requirement for fluid replacement are fundamental to resuscitation but remain largely empirical. Passive leg raise (PLR) may determine fluid responders while avoiding potential fluid overload. We hypothesised that inferior vena cava collapse index (IVCCI) and carotid artery blood flow would change predictably in response to PLR, potentially providing a non-invasive tool to assess circulating volume and identifying fluid responsive patients.Methods: We conducted a prospective proof of concept pilot study on fasted healthy volunteers. One operator measured IVC diameter during quiet respiration and sniff, and carotid artery flow. Stroke volume (SV) was also measured using suprasternal Doppler. Our primary endpoint was change in IVCCI after PLR. We also studied changes in IVCCI after “sniff”, and correlation between carotid artery flow and SV.Results: Passive leg raise was associated with significant reduction in the mean inferior vena cava collapsibility index from 0.24 to 0.17 (p < 0.01). Mean stroke volume increased from 56.0 to 69.2 mL (p < 0.01). There was no significant change in common carotid artery blood flow. Changes in physiology consequent upon passive leg raise normalised rapidly.Discussion: Passive leg raise is associated with a decrease of IVCCI and increase in stroke volume. However, the wide range of values observed suggests that factors other than circulating volume predominate in determining the proportion of collapse with respiration.Conclusion: In contrast to other studies, we did not find that carotid blood flow increased with passive leg raise. Rapid normalisation of post-PLR physiology may account for this

A Tabletop X-Ray Tomography Instrument for Nanometer-Scale Imaging: Integration of a Scanning Electron Microscope with a Transition-Edge Sensor Spectrometer

X-ray nanotomography is a powerful tool for the characterization of nanoscale materials and structures, but is difficult to implement due to competing requirements on X-ray flux and spot size. Due to this constraint, state-of-the-art nanotomography is predominantly performed at large synchrotron facilities. Compact X-ray nanotomography tools operated in standard analysis laboratories exist, but are limited by X-ray optics and destructive sample preparation techniques. We present a laboratory-scale nanotomography instrument that achieves nanoscale spatial resolution while changing the limitations of conventional tomography tools. The instrument combines the electron beam of a scanning electron microscope (SEM) with the precise, broadband X-ray detection of a superconducting transition-edge sensor (TES) microcalorimeter. The electron beam generates a highly focused X-ray spot in a metal target, while the TES spectrometer isolates target photons with high signal-to-noise. This combination of a focused X-ray spot, energy-resolved X-ray detection, and unique system geometry enable nanoscale, element-specific X-ray imaging in a compact footprint. The proof-of-concept for this approach to X-ray nanotomography is demonstrated by imaging 160 nm features in three dimensions in a Cu-SiO2 integrated circuit, and a path towards finer resolution and enhanced imaging capabilities is discussed.Comment: The following article has been submitted to Physical Review Applie

A tabletop x-ray tomography instrument for nanometer-scale imaging: demonstration of the 1,000-element transition-edge sensor subarray

We report on the 1,000-element transition-edge sensor (TES) x-ray spectrometer implementation of the TOMographic Circuit Analysis Tool (TOMCAT). TOMCAT combines a high spatial resolution scanning electron microscope (SEM) with a highly efficient and pixelated TES spectrometer to reconstruct three-dimensional maps of nanoscale integrated circuits (ICs). A 240-pixel prototype spectrometer was recently used to reconstruct ICs at the 130 nm technology node, but to increase imaging speed to more practical levels, the detector efficiency needs to be improved. For this reason, we are building a spectrometer that will eventually contain 3,000 TES microcalorimeters read out with microwave superconducting quantum interference device (SQUID) multiplexing, and we currently have commissioned a 1,000 TES subarray. This still represents a significant improvement from the 240-pixel system and allows us to begin characterizing the full spectrometer performance. Of the 992 maximimum available readout channels, we have yielded 818 devices, representing the largest number of TES x-ray microcalorimeters simultaneously read out to date. These microcalorimeters have been optimized for pulse speed rather than purely energy resolution, and we measure a FWHM energy resolution of 14 eV at the 8.0 keV Cu K$\alpha$ line.Comment: 5 pages, 4 figures, submitted to IEEE Transactions on Applied Superconductivit

Early Navigation Performance of the OSIRIS-REx Approach to Bennu

The New Frontiers-class OSIRIS-REx (Origins, Spectral Interpretation, Resource Identification, Security-Regolith Explorer) mission is the first American endeavor to return a sample from an asteroid. In preparation for retrieving the sample, OSIRIS-REx is conducting a campaign of challenging proximity-operations maneuvers and scientific observations, bringing the spacecraft closer and closer to the surface of near-Earth asteroid (101955) Bennu. Ultimately, the spacecraft will enter a 900-meter-radius orbit about Bennu and conduct a series of reconnaissance flybys of candidate sample sites before being guided into contact with the surface for the Touch and Go sample collection event. Between August and December 2018, the OSIRIS-REx team acquired the first optical observations of Bennu and used them for navigation. We conducted a series of maneuvers with the main engine, Trajectory Correction Maneuver, and Attitude Control System thruster sets to slow the OSIRIS-REx approach to Bennu and achieve rendezvous on December 3, 2018. This paper describes the trajectory design, navigation conops, and key navigation results from the Approach phase of the OSIRIS-REx mission