Accumulation of myeloid-derived suppressor cells (MDSC) in melanoma microenvironment is supported by chemokine receptor/chemokine signaling. Although different chemokines were suggested to be ...involved in this process, the role of CCR5 and its ligands is not established. Using a
transgenic mouse melanoma model, we found an accumulation of CCR5
MDSCs in melanoma lesions associated with both increased concentrations of CCR5 ligands and tumor progression. Tumor-infiltrating CCR5
MDSCs displayed higher immunosuppressive activity than their CCR5
counterparts. Upregulation of CCR5 expression on CD11b
Gr1
myeloid cells was induced
by CCR5 ligands and other inflammatory factors. In melanoma patients, CCR5
MDSCs were enriched at the tumor site and correlated with enhanced production of CCR5 ligands. Moreover, they exhibited a stronger immunosuppressive pattern compared with CCR5
MDSCs. Blocking CCR5/CCR5 ligand interactions increased survival of tumor-bearing mice and was associated with reduced migration and immunosuppressive potential of MDSCs in tumor lesions. Our findings define a critical role for CCR5 in recruitment and activation of MDSCs, suggesting a novel strategy for melanoma treatment.
These findings validate the importance of the CCR5/CCR5 ligand axis not only for MDSC recruitment but also for further activation of their immunosuppressive functions in the tumor microenvironment, with potentially broad therapeutic implications, given existing clinically available inhibitors of this axis.
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Glioblastoma is one of the most difficult tumor types to treat with conventional therapy options like tumor debulking and chemo- and radiotherapy. Immunotherapeutic agents like oncolytic viruses, ...immune checkpoint inhibitors, and chimeric antigen receptor T cells have revolutionized cancer therapy, but their success in glioblastoma remains limited and further optimization of immunotherapies is needed. Several oncolytic viruses have demonstrated the ability to infect tumors and trigger anti-tumor immune responses in malignant glioma patients. Leading the pack, oncolytic herpesvirus, first in its class, awaits an approval for treating malignant glioma from MHLW, the federal authority of Japan. Nevertheless, some major hurdles like the blood-brain barrier, the immunosuppressive tumor microenvironment, and tumor heterogeneity can engender suboptimal efficacy in malignant glioma. In this review, we discuss the current status of malignant glioma therapies with a focus on oncolytic viruses in clinical trials. Furthermore, we discuss the obstacles faced by oncolytic viruses in malignant glioma patients and strategies that are being used to overcome these limitations to (1) optimize delivery of oncolytic viruses beyond the blood-brain barrier; (2) trigger inflammatory immune responses in and around tumors; and (3) use multimodal therapies in combination to tackle tumor heterogeneity, with an end goal of optimizing the therapeutic outcome of oncolytic virotherapy.
We investigate the effects of secondary electrons (SEs), induced by electrons impinging on the electrodes, on the characteristics of low-pressure single-frequency capacitively coupled plasmas (CCPs) ...by particle-in-cell/Monte Carlo collisions (PIC/MCC) simulations. In a recent PIC/MCC simulation study, that incorporated a realistic description of the electron-surface interaction, such electron-induced SEs (δ-electrons) were found to have a remarkable impact on the ionization dynamics and the plasma parameters in argon at 0.5 Pa and 6.7 cm gap between SiO2 electrodes (Horváth et al 2017 Plasma Sources Sci. Technol. 26 124001). At such low pressure and at high voltage amplitudes, the ion-induced SEs (γ-electrons) emitted at one electrode can reach the opposite electrode with high energies, where, depending on the surface material and surface conditions, they can induce the emission of a high number of δ-electrons, which can cause significant ionization and a higher plasma density. Here, we study the influence of δ-electrons on the ionization dynamics and plasma parameters at various pressures and voltage amplitudes, assuming different SE yields for ions (γ-coefficient) in single-frequency 13.56 MHz argon discharges. The emission of SEs by electron impact is found to be an important plasma-surface process at low pressures, between 0.5 Pa and 3 Pa. Both the gas pressure and the value of the γ-coefficient are found to affect the role of δ-electrons in shaping the discharge characteristics at different voltage amplitudes. Their effect on the ionization dynamics is most striking at low pressures, high voltage amplitudes and high values of the γ-coefficient. However, in the whole parameter regime investigated here, the realistic description of the electron-surface interaction significantly alters the computed plasma parameters, compared to results obtained based on a simple model for the description of the electron-surface interaction, widely used in PIC/MCC simulations of low-pressure CCPs.
Abstract
The two primary observable quantities of an exoplanet—its mass and radius—alone are not sufficient to probe a rocky exoplanet’s interior composition and mineralogy. To overcome this, ...host-star abundances of the primary planet-building elements (Mg, Si, Fe) are typically used as a proxy for the planet’s bulk composition. The majority of small exoplanet hosts, however, do not have available abundance data. Here we present the open-source ExoPlex mass–radius–composition solver. Unlike previous open-source mass–radius solvers, ExoPlex calculates the core chemistry and equilibrium mantle mineralogy for a bulk composition, including effects of mantle FeO content, core light elements, and surface water/ice. We utilize ExoPlex to calculate the planetary radii, surface gravities, and bulk densities for 10
6
model planets up to 2
R
⊕
across these geochemistries, adopting the distribution of FGK stellar abundances to estimate of the range of bulk exoplanet compositions. We outline the 99.7% distribution of radii, surface gravities, and bulk densities that define planets as “nominally rocky.” Planets outside this range require compositions outside those expected from stellar abundance data, likely making them either Fe-enriched super-Mercuries, or volatile-enriched mini-Neptunes. We apply our classification scheme to a sample of 85 well-resolved exoplanets without available host-star abundances. We estimate only nine planets are within the “nominally rocky planet zone” at >70% confidence, while ∼20% and ∼30% of this sample can be reasonably classified as super-Mercuries or volatile-rich, respectively. Our results provide observers with a self-consistent way to classify broadly a planet as likely rocky, Mercury-like, or volatile-enriched, using mass and radius measurements alone.
The influence of exciton–vibrational coupling on the optical and transport properties of molecular aggregates is an old problem that gained renewed interest in recent years. On the experimental side, ...various nonlinear spectroscopic techniques gave insight into the dynamics of systems as complex as photosynthetic antennae. Striking evidence was gathered that in these protein–pigment complexes quantum coherence is operative even at room temperature conditions. Investigations were triggered to understand the role of vibrational degrees of freedom, beyond that of a heat bath characterized by thermal fluctuations. This development was paralleled by theory, where efficient methods emerged, which could provide the proper frame to perform non-Markovian and non-perturbative simulations of exciton–vibrational dynamics and spectroscopy. This review summarizes the state of affairs of the theory of exciton–vibrational interaction in molecular aggregates and photosynthetic antenna complexes. The focus is put on the discussion of basic effects of exciton–vibrational interaction from the stationary and dynamics points of view. Here, the molecular dimer plays a prominent role as it permits a systematic investigation of absorption and emission spectra by numerical diagonalization of the exciton–vibrational Hamiltonian in a truncated Hilbert space. An extension to larger aggregates, having many coupled nuclear degrees of freedom, becomes possible with the Multi-Layer Multi-Configuration Time-Dependent Hartree (ML-MCTDH) method for wave packet propagation. In fact it will be shown that this method allows one to approach the limit of almost continuous spectral densities, which is usually the realm of density matrix theory. Real system–bath situations are introduced for two models, which differ in the way strongly coupled nuclear coordinates are treated, as a part of the relevant system or the bath. A rather detailed exposition of the Hierarchy Equations Of Motion (HEOM) method will be given in terms of a stochastic decoupling ansatz. This method has become the standard in exciton–vibrational theory and illustrative examples will be presented as well as a comparison with ML-MCTDH. Applications will be shown for generic model systems as well as for small aggregates mimicking those formed by perylene bisimide dyes. Further, photosynthetic antenna complexes will be discussed, including spectral densities and the role of exciton–vibrational coupling in two-dimensional electronic spectroscopy.
Abstract
We model the thermal states of both isolated neutron stars and accreting neutron stars in X-ray transients in quiescence and confront them with observations. We use an equation of state ...calculated using realistic two-body and three-body nucleon interactions, and superfluid nucleon gaps obtained using the same microscopic approach in the BCS approximation. Consistency with low-luminosity accreting neutron stars is obtained, as the direct Urca process is operating in neutron stars with mass larger than 1.1 M⊙ for the employed equation of state. In addition, proton superfluidity and sufficiently weak neutron superfluidity, obtained using a scaling factor for the gaps, are necessary to explain the cooling of middle-aged neutron stars and to obtain a realistic distribution of neutron star masses.
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