Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and ...promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects.
Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma.
In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy.
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•Apoptotic lymphoma cells promote tumor growth, angiogenesis, and TAM accumulation•Unbiased “in situ transcriptomics” analysis shows TAMs promote pro-tumor pathways•Apoptotic tumor cells express and process matrix remodeling proteins•The oncogenic potential of apoptotic tumor cells extends beyond lymphoma
Apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. Ford et al. demonstrate apoptotic lymphoma cells can promote tumor growth, angiogenesis, TAM accumulation, and TAM activation to potentiate cancer progression. These results have important implications for apoptosis-inducing anti-cancer therapies.
Abstract
The detection of planetary transits in the light curves of active stars, featuring correlated noise in the form of stellar variability, remains a challenge. Depending on the noise ...characteristics, we show that the traditional technique that consists of detrending a light curve before searching for transits alters their signal-to-noise ratio and hinders our capability to discover exoplanets transiting rapidly rotating active stars. We present
nuance
, an algorithm to search for transits in light curves while simultaneously accounting for the presence of correlated noise, such as stellar variability and instrumental signals. We assess the performance of
nuance
on simulated light curves as well as on the Transiting Exoplanet Survey Satellite light curves of 438 rapidly rotating M dwarfs. For each data set, we compare our method to five commonly used detrending techniques followed by a search with the Box-Least-Squares algorithm. Overall, we demonstrate that
nuance
is the most performant method in 93% of cases, leading to both the highest number of true positives and the lowest number of false-positive detections. Although simultaneously searching for transits while modeling correlated noise is expected to be computationally expensive, we make our algorithm tractable and available as the
JAX
-powered Python package
nuance,
allowing its use on distributed environments and GPU devices. Finally, we explore the prospects offered by the
nuance
formalism and its use to advance our knowledge of planetary systems around active stars, both using space-based surveys and sparse ground-based observations.
The EBF1-PDGFRB gene fusion accounts for <1% of B-cell precursor acute lymphoblastic leukemia (ALL) cases and occurs within the Philadelphia-like ALL subtype. We report 15 EBF1-PDGFRB-positive ...patients from childhood ALL treatment trials (ALL 97/99, UKALL 2003, UKALL 2011) in the United Kingdom. The fusion arose from interstitial deletion of 5q33 (n = 11), balanced rearrangement (n = 2), or complex rearrangement (n = 2). There was a predominance of females (n = 11), median age of 12 years, and median white blood cell count of 48.8 × 109/L. Among 12 patients who achieved complete remission on earlier trials (ALL 97/99 and UKALL 2003), 10 were positive for minimal residual disease (MRD) at the end of induction, and 7 relapsed 18 to 59 months after diagnosis. The majority (9 of 12) remained alive 6 to 9 years after diagnosis. There are reports of EBF1-PDGFRB-positive patients who are refractory to conventional chemotherapy who achieve complete response when treated with the tyrosine kinase inhibitor imatinib. These findings have prompted screening for EBF1-PDGFRB in patients entered onto the current UKALL 2011 trial for whom induction therapy failed, who did not achieve remission by day 29, or who remained MRD positive (>0.5%) at week 14. Two UKALL 2011 patients, positive for EBF1-PDGFRB, received imatinib; 1 died 6 months after a matched unrelated bone marrow transplant as a result of undefined encephalopathy, and the other remained in remission 10 months after diagnosis.
•EBF1-PDGFRB fusion accounts for ∼0.5% of B-cell precursor acute lymphoblastic leukemia and 2.7% of the B-other subtype.•EBF1-PDGFRB-positive patients are MRD positive and are slow early responders who respond to imatinib.
Abstract
SPECULOOS is a ground-based transit survey consisting of six identical 1 m robotic telescopes. The immediate goal of the project is to detect temperate terrestrial planets transiting nearby ...ultracool dwarfs (late M-dwarf stars and brown dwarfs), which could be amenable for atmospheric research with the next generation of telescopes. Here, we report the developments of the northern counterpart of the project—SPECULOOS Northern Observatory, and present its performance during the first three years of operations from mid-2019 to mid-2022. Currently, the observatory consists of one telescope, which is named Artemis. The Artemis telescope demonstrates remarkable photometric precision, allowing it to be ready to detect new transiting terrestrial exoplanets around ultracool dwarfs. Over the period of the first three years after the installation, we observed 96 objects from the SPECULOOS target list for 6000 hr with a typical photometric precision of 0.5%, and reaching a precision of 0.2% for relatively bright non-variable targets with a typical exposure time of 25 s. Our weather downtime (clouds, high wind speed, high humidity, precipitation and/or high concentration of dust particles in the air) over the period of three years was 30% of overall night time. Our actual downtime is 40% because of additional time loss associated with technical problems.
ABSTRACT
We present the discovery of TOI-2136 b, a sub-Neptune planet transiting a nearby M4.5V-type star every 7.85 d, identified through photometric measurements from the Transiting Exoplanet ...Survey Satellite (TESS) mission. The host star is located 33 pc away with a radius of R* = 0.34 ± 0.02 R⊙, a mass of $0.34\pm 0.02 \, \mathrm{M}_{\odot }$, and an effective temperature of 3342 ± 100 K. We estimate its stellar rotation period to be 75 ± 5 d based on archival long-term photometry. We confirm and characterize the planet based on a series of ground-based multiwavelength photometry, high-angular-resolution imaging observations, and precise radial velocities from Canada–France–Hawaii Telescope (CFHT)/SpectroPolarimètre InfraROUge (SPIRou). Our joint analysis reveals that the planet has a radius of 2.20 ± 0.17 R⊕ and a mass of 6.4 ± 2.4 M⊕. The mass and radius of TOI-2136 b are consistent with a broad range of compositions, from water-ice to gas-dominated worlds. TOI-2136 b falls close to the radius valley for M dwarfs predicted by thermally driven atmospheric mass-loss models, making it an interesting target for future studies of its interior structure and atmospheric properties.
ABSTRACT
We report on the discovery of Gliese 12 b, the nearest transiting temperate, Earth-sized planet found to date. Gliese 12 is a bright (V = 12.6 mag, K = 7.8 mag) metal-poor M4V star only ...12.162 ± 0.005 pc away from the Solar system with one of the lowest stellar activity levels known for M-dwarfs. A planet candidate was detected by TESS based on only 3 transits in sectors 42, 43, and 57, with an ambiguity in the orbital period due to observational gaps. We performed follow-up transit observations with CHEOPS and ground-based photometry with MINERVA-Australis, SPECULOOS, and Purple Mountain Observatory, as well as further TESS observations in sector 70. We statistically validate Gliese 12 b as a planet with an orbital period of 12.76144 ± 0.00006 d and a radius of 1.0 ± 0.1 R⊕, resulting in an equilibrium temperature of ∼315 K. Gliese 12 b has excellent future prospects for precise mass measurement, which may inform how planetary internal structure is affected by the stellar compositional environment. Gliese 12 b also represents one of the best targets to study whether Earth-like planets orbiting cool stars can retain their atmospheres, a crucial step to advance our understanding of habitability on Earth and across the galaxy.
ABSTRACT
We present the discovery and characterization of an eclipsing binary identified by the Next Generation Transit Survey in the ∼115-Myr-old Blanco 1 open cluster. NGTS J0002−29 comprises three ...M dwarfs: a short-period binary and a companion in a wider orbit. This system is the first well-characterized, low-mass eclipsing binary in Blanco 1. With a low mass ratio, a tertiary companion, and binary components that straddle the fully convective boundary, it is an important benchmark system, and one of only two well-characterized, low-mass eclipsing binaries at this age. We simultaneously model light curves from NGTS, TESS, SPECULOOS, and SAAO, radial velocities from VLT/UVES and Keck/HIRES, and the system’s spectral energy distribution. We find that the binary components travel on circular orbits around their common centre of mass in Porb = 1.098 005 24 ± 0.000 000 38 d, and have masses Mpri = 0.3978 ± 0.0033 M⊙ and Msec = 0.2245 ± 0.0018 M⊙, radii Rpri = 0.4037 ± 0.0048 R⊙ and Rsec = 0.2759 ± 0.0055 R⊙, and effective temperatures $T_{\rm pri}=\mbox{$3372\, ^{+44}_{-37}$}$ K and $T_{\rm sec}=\mbox{$3231\, ^{+38}_{-31}$}$ K. We compare these properties to the predictions of seven stellar evolution models, which typically imply an inflated primary. The system joins a list of 19 well-characterized, low-mass, sub-Gyr, stellar-mass eclipsing binaries, which constitute some of the strongest observational tests of stellar evolution theory at low masses and young ages.
ABSTRACT
HIP 41378 f is a temperate 9.2 ± 0.1 R⊕ planet with period of 542.08 d and an extremely low density of 0.09 ± 0.02 g cm−3. It transits the bright star HIP 41378 (V = 8.93), making it an ...exciting target for atmospheric characterization including transmission spectroscopy. HIP 41378 was monitored photometrically between the dates of 2019 November 19 and 28. We detected a transit of HIP 41378 f with NGTS, just the third transit ever detected for this planet, which confirms the orbital period. This is also the first ground-based detection of a transit of HIP 41378 f. Additional ground-based photometry was also obtained and used to constrain the time of the transit. The transit was measured to occur 1.50 h earlier than predicted. We use an analytic transit timing variation (TTV) model to show the observed TTV can be explained by interactions between HIP 41378 e and HIP 41378 f. Using our TTV model, we predict the epochs of future transits of HIP 41378 f, with derived transit centres of TC, 4 = $2459\,355.087^{+0.031}_{-0.022}$ (2021 May) and TC, 5 = $2459\,897.078^{+0.114}_{-0.060}$ (2022 November).
Multiple sclerosis (MS) is a debilitating affliction of the central nervous system (CNS) that involves demyelination of neuronal axons and neurodegeneration resulting in disability that becomes more ...pronounced in progressive forms of the disease. The involvement of neurodegeneration in MS underscores the need for effective neuroprotective approaches necessitating identification of new therapeutic targets. Herein, we applied an integrated elemental analysis workflow to human MS-affected spinal cord tissue utilising multiple inductively coupled plasma-mass spectrometry methodologies. These analyses revealed shifts in atomic copper as a notable aspect of disease. Complementary gene expression and biochemical analyses demonstrated that changes in copper levels coincided with altered expression of copper handling genes and downstream functionality of cuproenzymes. Copper-related problems observed in the human MS spinal cord were largely reproduced in the experimental autoimmune encephalomyelitis (EAE) mouse model during the acute phase of disease characterised by axonal demyelination, lesion formation, and motor neuron loss. Treatment of EAE mice with the CNS-permeant copper modulating compound CuII(atsm) resulted in recovery of cuproenzyme function, improved myelination and lesion volume, and neuroprotection. These findings support targeting copper perturbations as a therapeutic strategy for MS with CuII(atsm) showing initial promise.
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