Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging
. Given the unique effector functions of ...macrophages and their capacity to penetrate tumors
, we genetically engineered human macrophages with CARs to direct their phagocytic activity against tumors. We found that a chimeric adenoviral vector overcame the inherent resistance of primary human macrophages to genetic manipulation and imparted a sustained pro-inflammatory (M1) phenotype. CAR macrophages (CAR-Ms) demonstrated antigen-specific phagocytosis and tumor clearance in vitro. In two solid tumor xenograft mouse models, a single infusion of human CAR-Ms decreased tumor burden and prolonged overall survival. Characterization of CAR-M activity showed that CAR-Ms expressed pro-inflammatory cytokines and chemokines, converted bystander M2 macrophages to M1, upregulated antigen presentation machinery, recruited and presented antigen to T cells and resisted the effects of immunosuppressive cytokines. In humanized mouse models, CAR-Ms were further shown to induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity.
Most stellar remnants so far have been found in binary systems, where they interact with matter from their companions. Isolated neutron stars and black holes are difficult to find as they are dark, ...yet they are predicted to exist in our Galaxy in vast numbers. We explored the OGLE-III data base of 150 million objects observed in years 2001–2009 and found 59 microlensing events exhibiting a parallax effect due to the Earth's motion around the Sun. Combining parallax and brightness measurements from microlensing light curves with expected proper motions in the Milky Way, we identified 13 microlensing events which are consistent with having a white dwarf, neutron star or a black hole lens and we estimated their masses and distances. The most massive of our black hole candidates has 9.3 M⊙ and is at a distance of 2.4 kpc. The distribution of masses of our candidates indicates a continuum in mass distribution with no mass gap between neutron stars and black holes. We also present predictions on how such events will be observed by the astrometric Gaia mission.
ABSTRACT While dozens of stellar-mass black holes (BHs) have been discovered in binary systems, isolated BHs have eluded detection. Their presence can be inferred when they lens light from a ...background star. We attempt to detect the astrometric lensing signatures of three photometrically identified microlensing events, OGLE-2011-BLG-0022, OGLE-2011-BLG-0125, and OGLE-2012-BLG-0169 (OB110022, OB110125, and OB120169), located toward the Galactic Bulge. These events were selected because of their long durations, which statistically favors more massive lenses. Astrometric measurements were made over one to two years using laser-guided adaptive optics observations from the W. M. Keck Observatory. Lens model parameters were first constrained by the photometric light curves. The OB120169 light curve is well fit by a single-lens model, while both OB110022 and OB110125 light curves favor binary lens models. Using the photometric fits as prior information, no significant astrometric lensing signal was detected and all targets were consistent with linear motion. The significant lack of astrometric signal constrains the lens mass of OB110022 to 0.05-1.79 M in a 99.7% confidence interval, which disfavors a BH lens. Fits to OB110125 yielded a reduced Einstein crossing time and insufficient observations during the peak, so no mass limits were obtained. Two degenerate solutions exist for OB120169, which have a lens mass between 0.2-38.8 M and 0.4-39.8 M for a 99.7% confidence interval. Follow-up observations of OB120169 will further constrain the lens mass. Based on our experience, we use simulations to design optimal astrometric observing strategies and show that with more typical observing conditions the detection of BHs is feasible.
In this fourth part of the series presenting the Optical Gravitational Lensing Experiment (OGLE) microlensing studies of the dark matter halo compact objects (MACHOs), we describe results of the ...OGLE-III monitoring of the Small Magellanic Cloud (SMC). Three sound candidates for microlensing events were found and yielded the optical depth τSMC-OIII= 1.30 ± 1.01 × 10−7, consistent with the expected contribution from Galactic disc and SMC self-lensing. We report that event OGLE-SMC-03 is most likely a thick-disc lens candidate, the first of such type found towards the SMC. In this paper we also combined all OGLE Large Magellanic Cloud and SMC microlensing results in order to refine the conclusions on MACHOs. All but one of the OGLE events are most likely caused by the lensing by known populations of stars; therefore, we concluded that there is no need for introducing any special dark matter compact objects in order to explain the observed event rates. Potential black hole event indicates that similar lenses can contribute only about 2 per cent to the total mass of the halo, which is still in agreement with the expected number of such objects.
In the era of precision cosmology, it is essential to determine the Hubble constant to an accuracy of three per cent or better. At present, its uncertainty is dominated by the uncertainty in the ...distance to the Large Magellanic Cloud (LMC), which, being our second-closest galaxy, serves as the best anchor point for the cosmic distance scale. Observations of eclipsing binaries offer a unique opportunity to measure stellar parameters and distances precisely and accurately. The eclipsing-binary method was previously applied to the LMC, but the accuracy of the distance results was lessened by the need to model the bright, early-type systems used in those studies. Here we report determinations of the distances to eight long-period, late-type eclipsing systems in the LMC, composed of cool, giant stars. For these systems, we can accurately measure both the linear and the angular sizes of their components and avoid the most important problems related to the hot, early-type systems. The LMC distance that we derive from these systems (49.97 ± 0.19 (statistical) ± 1.11 (systematic) kiloparsecs) is accurate to 2.2 per cent and provides a firm base for a 3-per-cent determination of the Hubble constant, with prospects for improvement to 2 per cent in the future.
The first stars are predicted to have formed within 200 million years after the Big Bang, initiating the cosmic dawn. A true first star has not yet been discovered, although stars with tiny amounts ...of elements heavier than helium ('metals') have been found in the outer regions ('halo') of the Milky Way. The first stars and their immediate successors should, however, preferentially be found today in the central regions ('bulges') of galaxies, because they formed in the largest over-densities that grew gravitationally with time. The Milky Way bulge underwent a rapid chemical enrichment during the first 1-2 billion years, leading to a dearth of early, metal-poor stars. Here we report observations of extremely metal-poor stars in the Milky Way bulge, including one star with an iron abundance about 10,000 times lower than the solar value without noticeable carbon enhancement. We confirm that most of the metal-poor bulge stars are on tight orbits around the Galactic Centre, rather than being halo stars passing through the bulge, as expected for stars formed at redshifts greater than 15. Their chemical compositions are in general similar to typical halo stars of the same metallicity although intriguing differences exist, including lower abundances of carbon.
ABSTRACT Eruptions of classical novae are possible sources of lithium formation and gamma-ray emission. Nova remnants can also become Type Ia supernovae (SNe Ia). The contribution of novae to these ...phenomena depends on nova rates, which are not well established for the Galaxy. Here, we directly measure a Galactic bulge nova rate of 13.8 2.6 . This measurement is much more accurate than any previous measurement of this kind thanks to many years' monitoring of the bulge by the Optical Gravitational Lensing Experiment (OGLE) survey. Our sample consists of 39 novae eruptions, ∼1/3 of which are OGLE-based discoveries. This long-term monitoring allows us to not only measure the nova rate but also to study in detail the light curves of 39 eruptions and more than 80 post-nova candidates. We measured orbital periods for 9 post-novae and 9 novae, and in 14 cases we procured the first estimates. The OGLE survey is very sensitive to the frequently erupting recurrent novae. We did not find any object similar to M31 2008-12a, which erupts once a year. The lack of detection indicates that there is only a small number of them in the Galactic bulge.
Context. OGLE-2002-BLG-360 was discovered as a microlensing candidate by the OGLE-III project. The subsequent light curve, however, clearly showed that the brightening of the object could not have ...resulted from the gravitational microlensing phenomenon. Aims. We aim to explain the nature of OGLE-2002-BLG-360 and its eruption observed in 2002−2006. Methods. The observational data primarily come from the archives of the OGLE project, which monitored the object in 2001−2009. The archives of the MACHO and MOA projects also provided us with additional data obtained in 1995−99 and 2000−2005, respectively. These data allowed us to analyse the light curve of the object during its eruption, as well as the potential variability of its progenitor. In the archives of several infrared surveys, namely 2MASS, MSX, Spitzer, AKARI, WISE, and VVV, we found measurements of the object, which allowed us to study the spectral energy distribution (SED) of the object. We constructed a simple model of a star surrounded by a dusty envelope, which was used to interpret the observed SED. Results. Our analysis of the data clearly shows that OGLE-2002-BLG-360 was most probably a red transient, i.e. an object similar in nature to V838 Mon, whose eruption was observed in 2002. The SED in all phases, i.e. progenitor, eruption, and remnant, was dominated by infrared emission, which we interpret as evidence of dust formation in an intense mass outflow. Since 2009 the object has been completely embedded in dust. Conclusions. We suggest that the progenitor of OGLE-2002-BLG-360 was a binary, which had entered the common-envelope phase a long time (at least decades) before the observed eruption, and that the eruption resulted from the final merger of the binary components. We point out similarities between OGLE-2002-BLG-360 and CK Vul, whose eruption was observed in 1670−72, and this strengthens the hypothesis that CK Vul was also a red transient.
We report the discovery of a young stellar bridge that forms a continuous connection between the Magellanic Clouds. This is the most extensive optical survey of this region to date. We find that the ...young population is present mainly in the western half of the MBR, which, together with the newly discovered young population in the eastern Bridge, form a continuous stream of stars connecting both galaxies along delta ~ -73.5 deg. The young population distribution is clumped, with one of the major densities close to the SMC and the other fairly isolated and located approximately mid-way between the Clouds, which we call the OGLE island. We observe a continuity of red clump stars between the Magellanic Clouds which represent an intermediate-age population. We also see only minor mixing of the old populations of the Clouds in the southern part of the Bridge, represented by the lowest part of the red giant branch.
We report the discovery of a new subclass of double-mode RR Lyrae stars in the Large and Small Magellanic Clouds. The sample of 22 pulsating stars has been extracted from the latest edition of the ...Optical Gravitational Lensing Experiment collection of RR Lyrae variables in the Magellanic System. The stars pulsating simultaneously in the fundamental (F) and first-overtone (1O) modes have distinctly different properties than regular double-mode RR Lyrae variables (RRd stars). The P sub( 1O)/P sub( F) period ratios of our anomalous RRd stars are within a range of 0.725-0.738, while 'classical' double-mode RR Lyrae variables have period ratios in the range of ...0.742-0.748. In contrast to the typical RRd stars, in the majority of the anomalous pulsators, the F-mode amplitudes are higher than the 1O-mode amplitudes. The light curves associated with the F-mode in the anomalous RRd stars show different morphology than the light curves of, both, regular RRd stars and single-mode RRab stars. Most of the anomalous double-mode stars show long-term modulations of the amplitudes (Blazhko-like effect). Translating the period ratios into the abundance parameter, Z, we find for our stars Z ... (0.002, 0.005) -- an order of magnitude higher values than typical for RR Lyrae stars. The mass range of the RRd stars inferred from the W sub( I) versus P sub( F) diagram is (0.55-0.75)...M... These parameters cannot be accounted for with single star evolution assuming a Reimers-like mass-loss. Much greater mass-loss caused by interaction with other stars is postulated. We blame the peculiar pulsation properties of our stars to the parametric resonance instability of the 1O-mode to excitation of the F- and 2O-modes as with the inferred parameters of the stars ... (ProQuest: ... denotes formulae/symbols omitted.)
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