252 research outputs found
Engaging stimulatory immune checkpoint interactions in the tumour immune microenvironment of primary liver cancers – how to push the gas after having released the brake
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the first and second most common primary liver cancer (PLC). For decades, systemic therapies consisting of tyrosine kinase inhibitors (TKIs) or chemotherapy have formed the cornerstone of treating advanced-stage HCC and CCA, respectively. More recently, immunotherapy using immune checkpoint inhibition (ICI) has shown anti-tumour reactivity in some patients. The combination regimen of anti-PD-L1 and anti-VEGF antibodies has been approved as new first-line treatment of advanced-stage HCC. Furthermore, gemcibatine plus cisplatin (GEMCIS) with an anti-PD-L1 antibody is awaiting global approval for the treatment of advanced-stage CCA. As effective anti-tumour reactivity using ICI is achieved in a minor subset of both HCC and CCA patients only, alternative immune strategies to sensitise the tumour microenvironment of PLC are waited for. Here we discuss immune checkpoint stimulation (ICS) as additional tool to enhance anti-tumour reactivity. Up-to-date information on the clinical application of ICS in onco-immunology is provided. This review provides a rationale of the application of next-generation ICS either alone or in combination regimen to potentially enhance anti-tumour reactivity in PLC patients.</p
Engaging stimulatory immune checkpoint interactions in the tumour immune microenvironment of primary liver cancers – how to push the gas after having released the brake
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the first and second most common primary liver cancer (PLC). For decades, systemic therapies consisting of tyrosine kinase inhibitors (TKIs) or chemotherapy have formed the cornerstone of treating advanced-stage HCC and CCA, respectively. More recently, immunotherapy using immune checkpoint inhibition (ICI) has shown anti-tumour reactivity in some patients. The combination regimen of anti-PD-L1 and anti-VEGF antibodies has been approved as new first-line treatment of advanced-stage HCC. Furthermore, gemcibatine plus cisplatin (GEMCIS) with an anti-PD-L1 antibody is awaiting global approval for the treatment of advanced-stage CCA. As effective anti-tumour reactivity using ICI is achieved in a minor subset of both HCC and CCA patients only, alternative immune strategies to sensitise the tumour microenvironment of PLC are waited for. Here we discuss immune checkpoint stimulation (ICS) as additional tool to enhance anti-tumour reactivity. Up-to-date information on the clinical application of ICS in onco-immunology is provided. This review provides a rationale of the application of next-generation ICS either alone or in combination regimen to potentially enhance anti-tumour reactivity in PLC patients.</p
Thermal expansion, heat capacity and magnetostriction of RAl (R = Tm, Yb, Lu) single crystals
We present thermal expansion and longitudinal magnetostriction data for cubic
RAl3 (R = Tm, Yb, Lu) single crystals. The thermal expansion coefficient for
YbAl3 is consistent with an intermediate valence of the Yb ion, whereas the
data for TmAl3 show crystal electric field contributions and have strong
magnetic field dependencies. de Haas-van Alphen-like oscillations were observed
in the magnetostriction data of YbAl3 and LuAl3, several new extreme orbits
were measured and their effective masses were estimated. Zero and 140 kOe
specific heat data taken on both LuAl3 and TmAl3 for T < 200 K allow for the
determination of a CEF splitting scheme for TmAl3
Engaging stimulatory immune checkpoint interactions in the tumour immune microenvironment of primary liver cancers – how to push the gas after having released the brake
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the first and second most common primary liver cancer (PLC). For decades, systemic therapies consisting of tyrosine kinase inhibitors (TKIs) or chemotherapy have formed the cornerstone of treating advanced-stage HCC and CCA, respectively. More recently, immunotherapy using immune checkpoint inhibition (ICI) has shown anti-tumour reactivity in some patients. The combination regimen of anti-PD-L1 and anti-VEGF antibodies has been approved as new first-line treatment of advanced-stage HCC. Furthermore, gemcibatine plus cisplatin (GEMCIS) with an anti-PD-L1 antibody is awaiting global approval for the treatment of advanced-stage CCA. As effective anti-tumour reactivity using ICI is achieved in a minor subset of both HCC and CCA patients only, alternative immune strategies to sensitise the tumour microenvironment of PLC are waited for. Here we discuss immune checkpoint stimulation (ICS) as additional tool to enhance anti-tumour reactivity. Up-to-date information on the clinical application of ICS in onco-immunology is provided. This review provides a rationale of the application of next-generation ICS either alone or in combination regimen to potentially enhance anti-tumour reactivity in PLC patients
Calculation of magnetic anisotropy energy in SmCo5
SmCo5 is an important hard magnetic material, due to its large magnetic
anisotropy energy (MAE). We have studied the magnetic properties of SmCo5 using
density functional theory (DFT) calculations where the Sm f-bands, which are
difficult to include in DFT calculations, have been treated within the LDA+U
formalism. The large MAE comes mostly from the Sm f-shell anisotropy, stemming
from an interplay between the crystal field and the spin-orbit coupling. We
found that both are of similar strengths, unlike some other Sm compounds,
leading to a partial quenching of the orbital moment (f-states cannot be
described as either pure lattice harmonics or pure complex harmonics), an
optimal situation for enhanced MAE. A smaller portion of the MAE can be
associated with the Co-d band anisotropy, related to the peak in the density of
states at the Fermi energy. Our result for the MAE of SmCo5, 21.6 meV/f.u.,
agrees reasonably with the experimental value of 13-16 meV/f.u., and the
calculated magnetic moment (including the orbital component) of 9.4 mu_B agrees
with the experimental value of 8.9 mu_B.Comment: Submitted to Phys. Rev.
Harnessing RNA sequencing for global, unbiased evaluation of two new adjuvants for dendritic-cell immunotherapy
Effective stimulation of immune cells is crucial for the success of cancer immunotherapies. Current approaches to evaluate the efficiency of stimuli are mainly defined by known flow cytometry-based cell activation or cell maturation markers. This method however does not give a complete overview of the achieved activation state and may leave important side effects unnoticed. Here, we used an unbiased RNA sequencing (RNA-seq)-based approach to compare the capacity of four clinical-grade dendritic cell (DC) activation stimuli used to prepare DC-vaccines composed of various types of DC subsets; the already clinically applied GM-CSF and Frühsommer meningoencephalitis (FSME) prophylactic vaccine and the novel clinical grade adjuvants protamine-RNA complexes (pRNA) and CpG-P. We found that GM-CSF and pRNA had similar effects on their target cells, whereas pRNA and CpG-P induced stronger type I interferon (IFN) expression than FSME. In general, the pathways most affected by all stimuli were related to immune activity and cell migration. GM-CSF stimulation, however, also induced a significant increase of genes related to nonsense-mediated decay, indicating a possible deleterious effect of this stimulus. Taken together, the two novel stimuli appear to be promising alternatives. Our study demonstrates how RNA-seq based investigation of changes in a large number of genes and gene groups can be exploited for fast and unbiased, global evaluation of clinical-grade stimuli, as opposed to the general limited evaluation of a pre-specified set of genes, by which one might miss important biological effects that are detrimental for vaccine efficacy
Magnetic structure of antiferromagnetic NdRhIn5
The magnetic structure of antiferromagnetic NdRhIn5 has been determined using
neutron diffraction. It has a commensurate antiferromagnetic structure with a
magnetic wave vector (1/2,0,1/2) below T_N = 11K. The staggered Nd moment at
1.6K is 2.6mu_B aligned along the c-axis. We find the magnetic structure to be
closely related to that of its cubic parent compound NdIn3 below 4.6K. The
enhanced T_N and the absence of additional transitions below T_N for NdRhIn5
are interpreted in terms of an improved matching of the
crystalline-electric-field (CEF), magnetocrystalline, and exchange interaction
anisotropies. In comparison, the role of these competing anisotropies on the
magnetic properties of the structurally related compound CeRhIn5 is discussed.Comment: 4 pages, 4 figure
Hypoxia induces a transcriptional early primitive streak signature in pluripotent cells enhancing spontaneous elongation and lineage representation in gastruloids
The cellular microenvironment, together with intrinsic regulators, shapes stem cell identity and differentiation capacity. Mammalian early embryos are exposed to hypoxia in vivo and appear to benefit from hypoxic culture in vitro. Yet, how hypoxia influences stem cell transcriptional networks and lineage choices remain poorly understood. Here, we investigated the molecular effects of acute and prolonged hypoxia on embryonic and extra-embryonic stem cells as well as the functional impact on differentiation potential. We find a temporal and cell type-specific transcriptional response including an early primitive streak signature in hypoxic embryonic stem cells mediated by HIF1α. Using a 3D gastruloid differentiation model, we show that hypoxia-induced T expression enables symmetry breaking and axial elongation in the absence of exogenous WNT activation. When combined with exogenous WNT activation, hypoxia enhances lineage representation in gastruloids, as demonstrated by highly enriched signatures of gut endoderm, notochord, neuromesodermal progenitors and somites. Our findings directly link the microenvironment to stem cell function and provide a rationale supportive of applying physiological conditions in models of embryo development
Valency of rare earths in RIn3 and RSn3: Ab initio analysis of electric-field gradients
In RIn3 and RSn3 the rare earth (R) is trivalent, except for Eu and Yb, which
are divalent. This was experimentally determined in 1977 by perturbed angular
correlation measurements of the electric-field gradient on a 111Cd impurity. At
that time, the data were interpreted using a point charge model, which is now
known to be unphysical and unreliable. This makes the valency determination
potentially questionable. We revisit these data, and analyze them using ab
initio calculations of the electric-field gradient. From these calculations,
the physical mechanism that is responsible for the influence of the valency on
the electric-field gradient is derived. A generally applicable scheme to
interpret electric-field gradients is used, which in a transparent way
correlates the size of the field gradient with chemical properties of the
system.Comment: 10 page
Hijacking of transcriptional condensates by endogenous retroviruses
Most endogenous retroviruses (ERVs) in mammals are incapable of retrotransposition; therefore, why ERV derepression is associated with lethality during early development has been a mystery. Here, we report that rapid and selective degradation of the heterochromatin adapter protein TRIM28 triggers dissociation of transcriptional condensates from loci encoding super-enhancer (SE)-driven pluripotency genes and their association with transcribed ERV loci in murine embryonic stem cells. Knockdown of ERV RNAs or forced expression of SE-enriched transcription factors rescued condensate localization at SEs in TRIM28-degraded cells. In a biochemical reconstitution system, ERV RNA facilitated partitioning of RNA polymerase II and the Mediator coactivator into phase-separated droplets. In TRIM28 knockout mouse embryos, single-cell RNA-seq analysis revealed specific depletion of pluripotent lineages. We propose that coding and noncoding nascent RNAs, including those produced by retrotransposons, may facilitate ‘hijacking’ of transcriptional condensates in various developmental and disease contexts
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