Differential expression and biochemical activity of the immune receptor Tim-3 in healthy and malignant human myeloid cells

The T cell immunoglobulin and mucin domain 3 (Tim-3) is a plasma membrane-associated receptor which is involved in a variety of biological responses in human immune cells. It is highly expressed in most acute myeloid leukaemia (AML) cells and therefore may serve as a possible target for AML therapy. However, its biochemical activities in primary human AML cells remain unclear. We therefore analysed the total expression and surface presence of the Tim-3 receptor in primary human AML blasts and healthy primary human leukocytes isolated from human blood. We found that Tim-3 expression was significantly higher in primary AML cells compared to primary healthy leukocytes. Tim-3 receptor molecules were distributed largely on the surface of primary AML cells, whereas in healthy leukocytes Tim-3 protein was mainly expressed intracellularly. In primary human AML blasts, both Tim-3 agonistic antibody and galectin-9 (a Tim-3 natural ligand) significantly upregulated mTOR pathway activity. This was in line with increased accumulation of hypoxia-inducible factor 1 alpha (HIF-1α) and secretion of VEGF and TNF-α. Similar results were obtained in primary human healthy leukocytes. Importantly, in both types of primary cells, Tim-3-mediated effects were compared with those induced by lipopolysaccharide (LPS) and stem cell factor (SCF). Tim-3 induced comparatively moderate responses in both AML cells and healthy leukocytes. However, Tim-3, like LPS, mediated the release of both TNF-α and VEGF, while SCF induced mostly VEGF secretion and did not upregulate TNF-α release

Second fundamental form of the Prym map in the ramified case

In this paper we study the second fundamental form of the Prym map $P_{g,r}: R_{g,r} \rightarrow {\mathcal A}^{\delta}_{g-1+r}$ in the ramified case $r>0$. We give an expression of it in terms of the second fundamental form of the Torelli map of the covering curves. We use this expression to give an upper bound for the dimension of a germ of a totally geodesic submanifold, and hence of a Shimura subvariety of ${\mathcal A}^{\delta}_{g-1+r}$, contained in the Prym locus.Comment: To appear in Galois Covers, Grothendieck-Teichmueller Theory and Dessins d'Enfants - Interactions between Geometry, Topology, Number Theory and Algebra. Springer Proceedings in Mathematics & Statistics. arXiv admin note: text overlap with arXiv:1711.0342

First Application of Pulse-Shape Analysis to Silicon Micro-Strip Detectors

The method of pulse-shape analysis (PSA) for particle identification (PID) was applied to a double-sided silicon strip detector (DSSD) with a strip pitch of 300 \{mu}m. We present the results of test measurements with particles from the reactions of a 70 MeV 12C beam impinging on a mylar target. Good separation between protons and alpha particles down to 3 MeV has been obtained when excluding the interstrip events of the DSSD from the analysis.Comment: 7 pages, 6 figures, submitted to Nuclear Inst. and Methods in Physics Research

Exploring the links between cancer and placenta development

The development of metastatic cancer is a multistage process, which often requires decades to complete. Impairments in DNA damage control and DNA repair in cancer cell precursors generate genetically heterogeneous cell populations. However, despite heterogeneity most solid cancers have stereotypical behaviours, including invasiveness and suppression of immune responses that can be unleashed with immunotherapy targeting lymphocyte checkpoints. The mechanisms leading to the acquisition of stereotypical properties remain poorly understood. Reactivation of embryonic development processes in cells with unstable genomes might contribute to tumour expansion and metastasis formation. However, it is unclear whether these events are linked to immune response modulation. Tumours and embryos have non-self-components and need to avoid immune responses in their microenvironment. In mammalian embryos, neo-antigens are of paternal origin, while in tumour cells DNA mismatch repair and replication defects generate them. Inactivation of the maternal immune response towards the embryo, which occurs at the placental-maternal interface, is key to ensuring embryonic development. This regulation is accomplished by the trophoblast, which mimics several malignant cell features, including the ability to invade normal tissues and to avoid host immune responses, often adopting the same cancer immunoediting strategies. A better understanding as to whether and how genotoxic stress promotes cancer development through reactivation of programmes occurring during early stages of mammalian placentation could help to clarify resistance to drugs targeting immune checkpoint and DNA damage responses and to develop new therapeutic strategies to eradicate cancer

Excavation at Aguas Buenas, Robinson Crusoe Island, Chile, of a gunpowder magazine and the supposed campsite of Alexander Selkirk, together with an account of early navigational dividers

Excavations were undertaken of a ruined building at Aguas Buenas, identified as an 18th-century Spanish gunpowder magazine. Evidence was also found for the campsite of an early European occupant of the island. A case is made that this was Alexander Selkirk, a castaway here from 1704 to 1709. Selkirk was the model for Defoe’s Robinson Crusoe. A detailed discussion is given of a fragment of copper alloy identifi ed as being from a pair of navigational dividers

Evidence of Substructure in the Cluster of Galaxies A3558

We investigate the dynamical properties of the cluster of galaxies A3558 (Shapley 8). Studying a region of one square degree ($\sim$ 3 Mpc$^2$) centered on the cluster cD galaxy, we have obtained a statistically complete photometric catalog with positions and magnitudes of 1421 galaxies (down to a limiting magnitude of $B \sim 21$). This catalog has been matched to the recent velocity data obtained by Mazure et al. (1997) and from the literature, yielding a radial velocity catalog containing 322 galaxies. Our analysis shows that the position/velocity space distribution of galaxies shows significant substructure. A central bimodal core detected previously in preliminary studies is confirmed by using the Adaptive Kernel Technique and Wavelet Analysis. We show that this central bimodal subtructure is nevertheless composed of a projected feature, kinematically unrelated to the cluster, plus a group of galaxies probably in its initial merging phase into a relaxed core. The cD velocity offset with respect to the average cluster redshift, reported earlier by several authors, is completely eliminated as a result of our dynamical analysis. The untangling of the relaxed core component also allows a better, more reliable determination of the central velocity dispersion, which in turn eliminates the ``$\beta$-problem'' for A3558. The cluster also shows a ``preferential'' distribution of subclumps coinciding with the direction of the major axis position angle of the cD galaxy and of the central X-ray emission ellipsoidal distribution, in agreement with an anisotropic merger scenario.Comment: 35 pages in latex, 17 figures in Postscript, accepted for publication in the Astrophysical Journa

Mechanisms of immune escape and resistance to checkpoint inhibitor therapies in mismatch repair deficient metastatic colorectal cancers

SIMPLE SUMMARY: A subset of colorectal cancers (CRCs) is characterized by a mismatch repair deficiency that is frequently associated with microsatellite instability (MSI). The compromised DNA repair machinery leads to the accumulation of tumor neoantigens affecting the sensitivity of MSI metastatic CRC to immune checkpoint inhibitors (CPIs), both upfront and in later lines of treatment. However, up to 30% of MSI CRCs exhibit primary resistance to frontline immune based therapy, and an additional subset develops acquired resistance. Here, we first discuss the clinical and molecular features of MSI CRCs and then we review how the loss of antigenicity, immunogenicity, and a hostile tumor microenvironment could influence primary and acquired resistance to CPIs. Finally, we describe strategies to improve the outcome of MSI CRC patients upon CPI treatment. ABSTRACT: Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs

The extended epoch of galaxy formation: age dating of ~3600 galaxies with 2<z<6.5 in the VIMOS Ultra-Deep Survey

We aim at improving constraints on the epoch of galaxy formation by measuring the ages of 3597 galaxies with spectroscopic redshifts 2<z<6.5 in the VIMOS Ultra Deep Survey (VUDS). We derive ages and other physical parameters from the simultaneous fitting with the GOSSIP+ software of observed UV rest-frame spectra and photometric data from the u-band up to 4.5 microns using composite stellar population models. We conclude from extensive simulations that at z>2 the joint analysis of spectroscopy and photometry combined with restricted age possibilities when taking into account the age of the Universe substantially reduces systematic uncertainties and degeneracies in the age derivation. We find galaxy ages ranging from very young with a few tens of million years to substantially evolved with ages up to ~1.5-2 Gyr. The formation redshifts z_f derived from the measured ages indicate that galaxies may have started forming stars as early as z_f~15. We produce the formation redshift function (FzF), the number of galaxies per unit volume formed at a redshift z_f, and compare the FzF in increasing redshift bins finding a remarkably constant 'universal' FzF. The FzF is parametrized with (1+z)^\zeta, with \zeta~0.58+/-0.06, indicating a smooth 2 dex increase from z~15 to z~2. Remarkably this observed increase is of the same order as the observed rise in the star formation rate density (SFRD). The ratio of the SFRD with the FzF gives an average SFR per galaxy of ~7-17Msun/yr at z~4-6, in agreement with the measured SFR for galaxies at these redshifts. From the smooth rise in the FzF we infer that the period of galaxy formation extends from the highest possible redshifts that we can probe at z~15 down to redshifts z~2. This indicates that galaxy formation is a continuous process over cosmic time, with a higher number of galaxies forming at the peak in SFRD at z~2 than at earlier epochs. (Abridged)Comment: Submitted to A&A, 24 page

Closing the knowledge gap on the composition of the asbestos bodies

Asbestos bodies (AB) form in the lungs as a result of a biomineralization process initiated by the alveolar macrophages in the attempt to remove asbestos. During this process, organic and inorganic material deposit on the foreign fibers forming a Fe-rich coating. The AB start to form in months, thus quickly becoming the actual interface between asbestos and the lung tissue. Therefore, revealing their composition, and, in particular, the chemical form of Fe, which is the major component of the AB, is essential to assess their possible role in the pathogenesis of asbestos-related diseases. In this work we report the result of the first x-ray diffraction measurements performed on single AB embedded in the lung tissue samples of former asbestos plant workers. The combination with x-ray absorption spectroscopy data allowed to unambiguously reveal that Fe is present in the AB in the form of two Fe-oxy(hydroxides): ferrihydrite and goethite. The presence of goethite, which can be explained in terms of the transformation of ferrihydrite (a metastable phase) due to the acidic conditions induced by the alveolar macrophages in their attempt to phagocytose the fibers, has toxicological implications that are discussed in the paper