Changes in epithelial proportions and transcriptional state underlie major premenopausal breast cancer risks

The human breast undergoes lifelong remodeling in response to estrogen and progesterone, but hormone exposure also increases breast cancer risk. Here, we use single-cell analysis to identify distinct mechanisms through which breast composition and cell state affect hormone signaling. We show that prior pregnancy reduces the transcriptional response of hormone-responsive (HR+) epithelial cells, whereas high body mass index (BMI) reduces overall HR+ cell proportions. These distinct changes both impact neighboring cells by effectively reducing the magnitude of paracrine signals originating from HR+ cells. Because pregnancy and high BMI are known to protect against hormone-dependent breast cancer in premenopausal women, our findings directly link breast cancer risk with person-to-person heterogeneity in hormone responsiveness. More broadly, our findings illustrate how cell proportions and cell state can collectively impact cell communities through the action of cell-to-cell signaling networks

Pulmonary hypertension in infants with congenital heart defects: are leukotrienes involved?

The circulating levels of leukotriene E4 in infants with congenital heart defects, increased pulmonary blood flow and pulmonary arterial hypertension, were determined and compared with infants with decreased pulmonary blood flow (Tetralogy of Fallot). There was no correlation (r=0.38) between the pulmonary arterial pressure (56 ± 4 mmHg) and the leukotriene E4 levels (1.37 ± 0.67 ng/ml blood) measured in peripheral blood samples from the hypertensive group prior to surgery. There was considerable variation in the detectable leukotriene E4 levels in blood samples from different patients. The levels detected in the blood samples between the two groups of patients was similar. These data suggest that neither the surgical repair during cardiopulmonary bypass nor the pulmonary hypertension appeared to modify the leukotriene E4 blood levels in the small number of patients studied

Ice–ocean interaction and calving front morphology at two west Greenland tidewater outlet glaciers

Warm, subtropical-originating Atlantic water (AW) has been identified as a primary driver of mass loss across the marine sectors of the Greenland Ice Sheet (GrIS), yet the specific processes by which this water mass interacts with and erodes the calving front of tidewater glaciers is frequently modelled and much speculated upon but remains largely unobserved. We present a suite of fjord salinity, temperature, turbidity versus depth casts along with glacial runoff estimation from Rink and Store glaciers, two major marine outlets draining the western sector of the GrIS during 2009 and 2010. We characterise the main water bodies present and interpret their interaction with their respective calving fronts. We identify two distinct processes of ice–ocean interaction which have distinct spatial and temporal footprints: (1) homogenous free convective melting which occurs across the calving front where AW is in direct contact with the ice mass, and (2) localised upwelling-driven melt by turbulent subglacial runoff mixing with fjord water which occurs at distinct injection points across the calving front. Throughout the study, AW at 2.8 ± 0.2 °C was consistently observed in contact with both glaciers below 450 m depth, yielding homogenous, free convective submarine melting up to ~200 m depth. Above this bottom layer, multiple interactions are identified, primarily controlled by the rate of subglacial fresh-water discharge which results in localised and discrete upwelling plumes. In the record melt year of 2010, the Store Glacier calving face was dominated by these runoff-driven plumes which led to a highly crenulated frontal geometry characterised by large embayments at the subglacial portals separated by headlands which are dominated by calving. Rink Glacier, which is significantly deeper than Store has a larger proportion of its submerged calving face exposed to AW, which results in a uniform, relatively flat overall frontal geometry

Changes in epithelial proportions and transcriptional state underlie major premenopausal breast cancer risks

The human breast undergoes lifelong remodeling in response to estrogen and progesterone, but hormone exposure also increases breast cancer risk. Here, we use single-cell analysis to identify distinct mechanisms through which breast composition and cell state affect hormone signaling. We show that prior pregnancy reduces the transcriptional response of hormone-responsive (HR+) epithelial cells, whereas high body mass index (BMI) reduces overall HR+ cell proportions. These distinct changes both impact neighboring cells by effectively reducing the magnitude of paracrine signals originating from HR+ cells. Because pregnancy and high BMI are known to protect against hormone-dependent breast cancer in premenopausal women, our findings directly link breast cancer risk with person-to-person heterogeneity in hormone responsiveness. More broadly, our findings illustrate how cell proportions and cell state can collectively impact cell communities through the action of cell-to-cell signaling networks

Regulatory network decoded from epigenomes of surface ectoderm-derived cell types

Developmental history shapes the epigenome and biological function of differentiated cells. Epigenomic patterns have been broadly attributed to the three embryonic germ layers. Here we investigate how developmental origin influences epigenomes. We compare key epigenomes of cell types derived from surface ectoderm (SE), including keratinocytes and breast luminal and myoepithelial cells, against neural crest-derived melanocytes and mesoderm-derived dermal fibroblasts to identify SE differentially methylated regions (SE-DMRs). DNA methylomes of neonatal keratinocytes share many more DMRs with adult breast luminal and myoepithelial cells than with melanocytes and fibroblasts from the same neonatal skin. This suggests that SE origin contributes to DNA methylation patterning, while shared skin tissue environment has limited effect on epidermal keratinocytes. Hypomethylated SE-DMRs are in proximity to genes with SE relevant functions. They are also enriched for enhancer- and promoter-associated histone modifications in SE-derived cells, and for binding motifs of transcription factors important in keratinocyte and mammary gland biology. Thus, epigenomic analysis of cell types with common developmental origin reveals an epigenetic signature that underlies a shared gene regulatory network

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects

MUSCAT: The Mexico-UK Sub-Millimetre Camera for AsTronomy

The Mexico-UK Sub-millimetre Camera for AsTronomy (MUSCAT) is a large-format, millimetre-wave camera consisting of 1,500 background-limited lumped-element kinetic inductance detectors (LEKIDs) scheduled for deployment on the Large Millimeter Telescope (Volc\'an Sierra Negra, Mexico) in 2018. MUSCAT is designed for observing at 1.1 mm and will utilise the full 40' field of view of the LMTs upgraded 50-m primary mirror. In its primary role, MUSCAT is designed for high-resolution follow-up surveys of both galactic and extra-galactic sub-mm sources identified by Herschel. MUSCAT is also designed to be a technology demonstrator that will provide the first on-sky demonstrations of novel design concepts such as horn-coupled LEKID arrays and closed continuous cycle miniature dilution refrigeration. Here we describe some of the key design elements of the MUSCAT instrument such as the novel use of continuous sorption refrigerators and a miniature dilutor for continuous 100-mK cooling of the focal plane, broadband optical coupling to Aluminium LEKID arrays using waveguide chokes and anti-reflection coating materials as well as with the general mechanical and optical design of MUSCAT. We explain how MUSCAT is designed to be simple to upgrade and the possibilities for changing the focal plane unit that allows MUSCAT to act as a demonstrator for other novel technologies such as multi-chroic polarisation sensitive pixels and on-chip spectrometry in the future. Finally, we will report on the current status of MUSCAT's commissioning.Comment: Presented at SPIE Astronomical Telescopes + Instrumentation, 2018, Austin, Texas, United State