Endoglin and MMP14 contribute to Ewing sarcoma spreading by modulation of cell-matrix interactions

Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.E.A.’s laboratory is supported by ISCIII-FEDER (PI20/00003), CIBERONC (CB16/12/00361), PAIDI-Junta de Andalucía (P18-RT-735), Fundación CRIS Contra el Cáncer, Asociación Candela Riera and Asociación Pablo Ugarte. A.T.A. is supported by Juan de la Cierva Incorporación fellowship (IJC-2018-036767-I); P.P.-C. is sponsored by the Fundación María García Estrada. J.O.-P is supported by Ph.D. Grant Plan Propio from the University of Seville. J.D.-M is supported by CIBERONC (CB16/12/00361). C.S.-A. is supported by the European Social Fund and the Junta de Andalucía (Talento Doctores 2020, DOC_01473). This work was supported by grants from the Consejería de Salud (Junta de Andalucía, grants No PI-0036-2017, PI-0040-2017, and PI-0061-2020) awarded to J.D.-M, A.T.A. and C. S.-A., respectively. This work was also supported by the GEIS-Fundación Mari Paz Jiménez Casado (IV beca trienal) granted to J.D.-M, the 13ª GEIS-Beca Buesa granted to A.T.A. and CRIS (Cancer Research Innovation Spain) granted to J.D.-M and E.A. The laboratory of T.G.P.G. is supported by the Barbara and Wilfried Mohr Foundation. The lab of J.A. is supported by the Instituto de Salud Carlos III (ISCIII), grant number PI20CIII/00020; Asociación Pablo Ugarte, grant numbers TRPV205/18, TPI-M 1149/13; Asociación Candela Riera; Asociación Todos Somos Iván & Fundación Sonrisa de Alex, grant reference: TVP333-19.S

Sum rules and dualities for generalized parton distributions: is there a holographic principle?

To leading order approximation, the physical content of generalized parton distributions (GPDs) that is accessible in deep virtual electroproduction of photons or mesons is contained in their value on the cross-over trajectory. This trajectory separates the t-channel and s-channel dominated GPD regions. The underlying Lorentz covariance implies correspondence between these two regions through their relation to GPDs on the cross-over trajectory. This point of view leads to a family of GPD sum rules which are a quark analogue of finite energy sum rules and it guides us to a new phenomenological GPD concept. As an example, we discuss the constraints from the JLab/Hall A data on the dominant u-quark GPD H. The question arises whether GPDs are governed by some kind of holographic principle.Comment: 45 pages, 4 figures, Sect. 2 reorganized for clarity. Typos in Eq. (20) corrected. 4 new refs. Matches published versio

Demonstration of a novel technique to measure two-photon exchange effects in elastic e±pe^\pm p scattering

The discrepancy between proton electromagnetic form factors extracted using unpolarized and polarized scattering data is believed to be a consequence of two-photon exchange (TPE) effects. However, the calculations of TPE corrections have significant model dependence, and there is limited direct experimental evidence for such corrections. We present the results of a new experimental technique for making direct $e^\pm p$ comparisons, which has the potential to make precise measurements over a broad range in $Q^2$ and scattering angles. We use the Jefferson Lab electron beam and the Hall B photon tagger to generate a clean but untagged photon beam. The photon beam impinges on a converter foil to generate a mixed beam of electrons, positrons, and photons. A chicane is used to separate and recombine the electron and positron beams while the photon beam is stopped by a photon blocker. This provides a combined electron and positron beam, with energies from 0.5 to 3.2 GeV, which impinges on a liquid hydrogen target. The large acceptance CLAS detector is used to identify and reconstruct elastic scattering events, determining both the initial lepton energy and the sign of the scattered lepton. The data were collected in two days with a primary electron beam energy of only 3.3 GeV, limiting the data from this run to smaller values of $Q^2$ and scattering angle. Nonetheless, this measurement yields a data sample for $e^\pm p$ with statistics comparable to those of the best previous measurements. We have shown that we can cleanly identify elastic scattering events and correct for the difference in acceptance for electron and positron scattering. The final ratio of positron to electron scattering: $R=1.027\pm0.005\pm0.05$ for $=0.206$ GeV$^2$ and $0.830\leq \epsilon\leq 0.943$

Modified structure of protons and neutrons in correlated pairs

The atomic nucleus is made of protons and neutrons (nucleons), which are themselves composed of quarks and gluons. Understanding how the quark–gluon structure of a nucleon bound in an atomic nucleus is modified by the surrounding nucleons is an outstanding challenge. Although evidence for such modification—known as the EMC effect—was first observed over 35 years ago, there is still no generally accepted explanation for its cause1,2,3. Recent observations suggest that the EMC effect is related to close-proximity short-range correlated (SRC) nucleon pairs in nuclei4,5. Here we report simultaneous, high-precision measurements of the EMC effect and SRC abundances. We show that EMC data can be explained by a universal modification of the structure of nucleons in neutron–proton SRC pairs and present a data-driven extraction of the corresponding universal modification function. This implies that in heavier nuclei with many more neutrons than protons, each proton is more likely than each neutron to belong to an SRC pair and hence to have distorted quark structure. This universal modification function will be useful for determining the structure of the free neutron and thereby testing quantum chromodynamics symmetry-breaking mechanisms and may help to discriminate between nuclear physics effects and beyond-the-standard-model effects in neutrino experiments

Measurement of nuclear transparency ratios for protons and neutrons

This paper presents, for the first time, measurements of neutron transparency ratios for nuclei relative to C measured using the (e,e′n) reaction, spanning measured neutron momenta of 1.4 to 2.4 GeV/c. The transparency ratios were extracted in two kinematical regions, corresponding to knockout of mean-field nucleons and to the breakup of Short-Range Correlated nucleon pairs. The extracted neutron transparency ratios are consistent with each other for the two measured kinematical regions and agree with the proton transparencies extracted from new and previous (e,e′p) measurements, including those from neutron-rich nuclei such as lead. The data also agree with and confirm the Glauber approximation that is commonly used to interpret experimental data. The nuclear-mass-dependence of the extracted transparencies scales as Aα with α=−0.289±0.007, which is consistent with nuclear-surface dominance of the reactions

Measurement of the View the tt production cross-section using eμ events with b-tagged jets in pp collisions at √s = 13 TeV with the ATLAS detector

This paper describes a measurement of the inclusive top quark pair production cross-section (σtt¯) with a data sample of 3.2 fb−1 of proton–proton collisions at a centre-of-mass energy of √s = 13 TeV, collected in 2015 by the ATLAS detector at the LHC. This measurement uses events with an opposite-charge electron–muon pair in the final state. Jets containing b-quarks are tagged using an algorithm based on track impact parameters and reconstructed secondary vertices. The numbers of events with exactly one and exactly two b-tagged jets are counted and used to determine simultaneously σtt¯ and the efficiency to reconstruct and b-tag a jet from a top quark decay, thereby minimising the associated systematic uncertainties. The cross-section is measured to be: σtt¯ = 818 ± 8 (stat) ± 27 (syst) ± 19 (lumi) ± 12 (beam) pb, where the four uncertainties arise from data statistics, experimental and theoretical systematic effects, the integrated luminosity and the LHC beam energy, giving a total relative uncertainty of 4.4%. The result is consistent with theoretical QCD calculations at next-to-next-to-leading order. A fiducial measurement corresponding to the experimental acceptance of the leptons is also presented

Search for strong gravity in multijet final states produced in pp collisions at √s=13 TeV using the ATLAS detector at the LHC

A search is conducted for new physics in multijet final states using 3.6 inverse femtobarns of data from proton-proton collisions at √s = 13TeV taken at the CERN Large Hadron Collider with the ATLAS detector. Events are selected containing at least three jets with scalar sum of jet transverse momenta (HT) greater than 1TeV. No excess is seen at large HT and limits are presented on new physics: models which produce final states containing at least three jets and having cross sections larger than 1.6 fb with HT > 5.8 TeV are excluded. Limits are also given in terms of new physics models of strong gravity that hypothesize additional space-time dimensions