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Although hormonal therapy (HT) inhibits the growth of hormone receptor-positive (HR+) breast and prostate cancers, HT resistance frequently develops within the complex metastatic microenvironment of the host organ (often the bone), a setting poorly recapitulated in 2D culture systems. To address this limitation, we cultured HR+ breast cancer and prostate cancer spheroids and patient-derived organoids in 3D extracellular matrices (ECM) alone or together with bone marrow stromal cells (BMSC). In 3D monocultures, antiestrogens and antiandrogens induced anoikis by abrogating anchorage-independent growth of HR+ cancer cells but exhibited only modest effects against tumor cells residing in the ECM niche. In contrast, BMSC induced hormone-independent growth of breast cancer and prostate cancer spheroids and restored lumen filling in the presence of HR-targeting agents. Molecular and functional characterization of BMSC-induced hormone independence and HT resistance in anchorage-independent cells revealed distinct context-dependent mechanisms. Cocultures of ZR75-1 and LNCaP with BMSCs exhibited paracrine IL6-induced HT resistance via attenuation of HR protein expression, which was reversed by inhibition of IL6 or JAK signaling. Paracrine IL6/JAK/STAT3-mediated HT resistance was confirmed in patient-derived organoids cocultured with BMSCs. Distinctly, MCF7 and T47D spheroids retained ER protein expression in cocultures but acquired redundant compensatory signals enabling anchorage independence via ERK and PI3K bypass cascades activated in a non-IL6-dependent manner. Collectively, these data characterize the pleiotropic hormone-independent mechanisms underlying acquisition and restoration of anchorage-independent growth in HR+ tumors. Combined analysis of tumor and microenvironmental biomarkers in metastatic biopsies of HT-resistant patients can help refine treatment approaches. SIGNIFICANCE: This study uncovers a previously underappreciated dependency of tumor cells on HR signaling for anchorage-independent growth and highlights how the metastatic microenvironment restores this malignant property of cancer cells during hormone therapy.

Objective: The aim of this study was to identify genetic biomarkers and cellular communications associated with severe asthma in microarray data sets and single cell data sets. The potential gene expression levels were verified in a mouse model of asthma.Methods: We identified differentially expressed genes from the microarray datasets (GSE130499 and GSE63142) of severe asthma, and then constructed models to screen the most relevant biomarkers to severe asthma by machine learning algorithms (LASSO and SVM-RFE), with further validation of the results by GSE43696. Single-cell datasets (GSE193816 and GSE227744) were identified for potential biomarker-specific expression and intercellular communication. Finally, The expression levels of potential biomarkers were verified with a mouse model of asthma.Results: The 73 genes were differentially expressed between severe asthma and normal control. LASSO and SVM-RFE recognized three genes BCL3, DDIT4 and S100A14 as biomarkers of severe asthma and had good diagnostic effect. Among them, BCL3 transcript level was down-regulated in severe asthma, while S100A14 and DDIT4 transcript levels were up-regulated. The transcript levels of the three genes were confirmed in the mouse model. Infiltration of neutrophils and mast cells were found to be increased in severe asthma and may be associated with bronchial epithelial cells through BMP and NRG signalingConclusions: We identified three differentially expressed genes (BCL3, DDIT4 and S100A14) of diagnostic significance that may be involved in the development of severe asthma and these gene expressions could be serviced as biomarker of severe asthma and investigating the function roles could bring new insights into the underlying mechanisms [ABSTRACT FROM AUTHOR]

This study examined spatial and temporal thermal performance and energy consumption. The temperature distribution in the running period was monitored in test rooms with integrated electric- and hot water-heated floors. The short- and long-term energy consumption of the two heating systems were recorded and compared. The results indicated that the integrated electric heating system generated higher temperatures for indoor air and on the exterior surface of the wooden floor than the hot water heating system; meanwhile, the difference in the mean temperatures of the exterior and rear surfaces of the electric-heated floor was 2.44 °C, while that of the hot water-heated test room was 13.25 °C. The efficient structure of the integrated electric heating system saved 22.97% energy compared to the hot water system after short-term (7 h) charging and reaching a dynamic balance, and it efficiently increased the energy utilization rate to 11.81%. After long-term charging, the daily energy consumption of the integrated electric heating system consumed much less energy than the hot water system every month. The integrated electric heating system saved 62.55% and 34.30% of energy in May and January, respectively, and consumed less than half of the energy the hot water system consumed in the less cold months. Therefore, a high-efficiency and energy-saving integrated electric-heated floor could be a potential indoor heating solution. [ABSTRACT FROM AUTHOR]

Climate policies will affect future surface ozone pollution in China. Here, we simulate changes in summertime ozone across China by 2030 under four emission scenarios reflecting different levels of climate action. We also contrast results obtained with two different chemical mechanisms employed in the chemical transport model (WRF‐Chem). With emission reductions in ozone precursors introduced by climate policies, both mechanisms show promising ozone mitigation for most parts of China. However, they disagree starkly in China's three main city clusters, where one mechanism projects worsening ozone pollution by 2030 despite the emission reductions. We analyze possible drivers of this important discrepancy, in particular the role of varying ozone chemical regimes affecting its sensitivity to emission changes. We recommend an intercomparison project to examine this critical modeling uncertainty among other models/mechanisms, which would be invaluable for informing local and regional emission control strategies that are based on single‐model results. Plain Language Summary: Surface ozone pollution is harmful to both human health and ecosystems. Reducing ozone formation through effective emission control strategies has therefore been identified as a pressing need. Chemical transport models (CTMs) are important tools that can help scientists and policymakers assess how effectively the emission reductions may alleviate ozone pollution. However, we show that the predicted effectiveness of emission control strategies for ozone mitigation in areas within the three city clusters of China are strongly dependent on the choice of chemical mechanism commonly employed in CTMs. For example, given emission reductions driven by ambitious climate action, we find that projected ozone pollution in these regions could be improved or worsened by the year 2030 depending on the model mechanism used. Our work underlines the importance of considering and understanding this disagreement when it comes to projecting even near‐term emission‐control strategies. Furthermore, we highlight the potential benefits of conducting a multi‐model/mechanism intercomparison project to better understand how and why different models/mechanisms disagree on the simulated ozone response to emission changes, as to produce more robust mitigation scenario assessments. Key Points: Future emission pathways driven by climate actions are projected to alleviate surface ozone pollution in most parts of China by 2030However, for China's three main city clusters, model projections disagree strongly for two widely used chemical mechanismsThis modeling uncertainty may arise from the inconsistency of categorizing ozone chemical regimes by different chemical mechanisms [ABSTRACT FROM AUTHOR]