STAT1-deficient mice spontaneously develop estrogen receptor alpha-positive luminal mammary carcinomas

Abstract Introduction Although breast cancers expressing estrogen receptor-α (ERα) and progesterone receptors (PR) are the most common form of mammary malignancy in humans, it has been difficult to develop a suitable mouse model showing similar steroid hormone responsiveness. STAT transcription factors play critical roles in mammary gland tumorigenesis, but the precise role of STAT1 remains unclear. Herein, we show that a subset of human breast cancers display reduced STAT1 expression and that mice lacking STAT1 surprisingly develop ERα+/PR+ mammary tumors. Methods We used a combination of approaches, including histological examination, gene targeted mice, gene expression analysis, tumor transplantaion, and immunophenotyping, to pursue this study. Results Forty-five percent (37/83) of human ERα+ and 22% (17/78) of ERα- breast cancers display undetectable or low levels of STAT1 expression in neoplastic cells. In contrast, STAT1 expression is elevated in epithelial cells of normal breast tissues adjacent to the malignant lesions, suggesting that STAT1 is selectively downregulated in the tumor cells during tumor progression. Interestingly, the expression levels of STAT1 in the tumor-infiltrating stromal cells remain elevated, indicating that single-cell resolution analysis of STAT1 level in primary breast cancer biopsies is necessary for accurate assessment. Female mice lacking functional STAT1 spontaneously develop mammary adenocarcinomas that comprise > 90% ERα+/PR+ tumor cells, and depend on estrogen for tumor engraftment and progression. Phenotypic marker analyses demonstrate that STAT1-/- mammary tumors arise from luminal epithelial cells, but not myoepithelial cells. In addition, the molecular signature of the STAT1-/- mammary tumors overlaps closely to that of human luminal breast cancers. Finally, introduction of wildtype STAT1, but not a STAT1 mutant lacking the critical Tyr701 residue, into STAT1-/- mammary tumor cells results in apoptosis, demonstrating that the tumor suppressor function of STAT1 is cell-autonomous and requires its transcriptional activity. Conclusions Our findings demonstrate that STAT1 suppresses mammary tumor formation and its expression is frequently lost during breast cancer progression. Spontaneous mammary tumors that develop in STAT1-/- mice closely recapitulate the progression, ovarian hormone responsiveness, and molecular characteristics of human luminal breast cancer, the most common subtype of human breast neoplasms, and thus represent a valuable platform for testing novel treatments and detection modalities

Considering sex as a biological variable in preclinical research

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154390/1/fsb2fj201600781r.pd

The Three Hundred project: The gas disruption of infalling objects in cluster environments

We analyse the gas content evolution of infalling haloes in cluster environments from The Three Hundred project, a collection of 324 numerically modelled galaxy clusters. The haloes in our sample were selected within 5R200 of the main cluster halo at $z$ = 0 and have total halo mass M200 ≥ 1011h-1MO. We track their main progenitors and study their gas evolution since their crossing into the infall region, which we define as 1-4R200. Studying the radial trends of our populations using both the full phase-space information and a line-of-sight projection, we confirm the Arthur et al. (2019) result and identify a characteristic radius around 1.7R200 in 3D and at R200 in projection at which infalling haloes lose nearly all of the gas prior their infall. Splitting the trends by subhalo status,we show that subhaloes residing in group-mass and low-mass host haloes in the infall region follow similar radial gas-loss trends as their hosts, whereas subhaloes of cluster-mass host haloes are stripped of their gas much further out. Our results show that infalling objects suffer significant gaseous disruption that correlates with time-since-infall, cluster-centric distance, and host mass, and that the gaseous disruption they experience is a combination of subhalo pre-processing and object gas depletion at a radius that behaves like an accretion shock

CMB-S4 Science Book, First Edition

This book lays out the scientific goals to be addressed by the next-generation ground-based cosmic microwave background experiment, CMB-S4, envisioned to consist of dedicated telescopes at the South Pole, the high Chilean Atacama plateau and possibly a northern hemisphere site, all equipped with new superconducting cameras. CMB-S4 will dramatically advance cosmological studies by crossing critical thresholds in the search for the B-mode polarization signature of primordial gravitational waves, in the determination of the number and masses of the neutrinos, in the search for evidence of new light relics, in constraining the nature of dark energy, and in testing general relativity on large scales

The Three Hundred project: a large catalogue of theoretically modelled galaxy clusters for cosmological and astrophysical applications

We introduce the The Three Hundred project, an endeavour to model 324 large galaxy clusters with full-physics hydrodynamical re-simulations. Here we present the dataset and study the differences to observations for fundamental galaxy cluster properties and scaling relations. We find that the modelled galaxy clusters are generally in reasonable agreement with observations with respect to baryonic fractions and gas scaling relations at redshift z = 0. However, there are still some (model-dependent) differences, such as central galaxies being too massive, and galaxy colours (g − r) being bluer (about 0.2 dex lower at the peak position) than in observations. The agreement in gas scaling relations down to 1013 h−1M⊙ between the simulations indicates that particulars of the sub-grid modelling of the baryonic physics only has a weak influence on these relations. We also include – where appropriate – a comparison to three semi-analytical galaxy formation models as applied to the same underlying dark matter only simulation. All simulations and derived data products are publicly available

Cancer immunoediting by the innate immune system in the absence of adaptive immunity

Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3'methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2, and RAG2x γc mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon γ (IFN-γ), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2x γc mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting

Franchises lost and gained: post-coloniality and the development of women’s rights in Canada

The Canadian constitution is to some extent characterised by its focus on equality, and in particular gender equality. This development of women’s rights in Canada and the greater engagement of women as political actors is often presented as a steady linear process, moving forwards from post-enlightenment modernity. This article seeks to disturb this ‘discourse of the continuous,’ by using an analysis of the pre-confederation history of suffrage in Canada to both refute a simplistic linear view of women’s rights development and to argue for recognition of the Indigenous contribution to the history of women’s rights in Canada. The gain of franchise and suffrage movements in Canada in the late nineteenth and early twentieth century are, rightly, the focus of considerable study (Pauker 2015), This article takes an alternative perspective. Instead, it examines the exercise of earlier franchises in pre-confederation Canada. In particular it analyses why franchise was exercised more widely in Lower Canada and relates this to the context of the removal of franchises from women prior to confederation

CMB-S4: Forecasting Constraints on Primordial Gravitational Waves

CMB-S4---the next-generation ground-based cosmic microwave background (CMB) experiment---is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the Universe, from the highest energies at the dawn of time through the growth of structure to the present day. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semi-analytic projection tool, targeted explicitly towards optimizing constraints on the tensor-to-scalar ratio, $r$, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2--3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments given a desired scientific goal. To form a closed-loop process, we couple this semi-analytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for $r > 0.003$ at greater than $5\sigma$, or, in the absence of a detection, of reaching an upper limit of $r < 0.001$ at $95\%$ CL.Comment: 24 pages, 8 figures, 9 tables, submitted to ApJ. arXiv admin note: text overlap with arXiv:1907.0447

The Three Hundred project : A large catalogue of theoretically modelled galaxy clusters for cosmological and astrophysical applications

We introduce the THE THREE HUNDRED project, an endeavour to model 324 large galaxy clusters with full-physics hydrodynamical re-simulations. Here we present the data set and study the differences to observations for fundamental galaxy cluster properties and scaling relations. We find that the modelled galaxy clusters are generally in reasonable agreement with observations with respect to baryonic fractions and gas scaling relations at redshift z = 0. However, there are still some (model-dependent) differences, such as central galaxies being too massive, and galaxy colours (g − r) being bluer (about 0.2 dex lower at the peak position) than in observations. The agreement in gas scaling relations down to 1013h−1M⊙ between the simulations indicates that particulars of the sub-grid modelling of the baryonic physics only has a weak influence on these relations. We also include – where appropriate – a comparison to three semi-analytical galaxy formation models as applied to the same underlying dark-matter-only simulation. All simulations and derived data products are publicly available.Instituto de Astrofísica de La PlataFacultad de Ciencias Astronómicas y Geofísica