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IL-1α is a dual function cytokine that affects inflammatory and immune responses and plays a pivotal role in cancer. The effects of intracellular IL-1α on the development of triple negative breast cancer (TNBC) in mice were assessed using the CRISPR/Cas9 system to suppress IL-1α expression in 4T1 breast cancer cells. Knockout of IL-1α in 4T1 cells modified expression of multiple genes, including downregulation of cytokines and chemokines involved in the recruitment of tumor-associated pro-inflammatory cells. Orthotopical injection of IL-1α knockout (KO) 4T1 cells into BALB/c mice led to a significant decrease in local tumor growth and lung metastases, compared to injection of wild-type 4T1 (4T1/WT) cells. Neutrophils and myeloid-derived suppressor cells were abundant in tumors developing after injection of 4T1/WT cells, whereas more antigen-presenting cells were observed in the tumor microenvironment after injection of IL-1α KO 4T1 cells. This switch correlated with increased infiltration of CD3+CD8+ and NKp46+cells. Engraftment of IL-1α knockout 4T1 cells into immunodeficient NOD.SCID mice resulted in more rapid tumor growth, with increased lung metastasis in comparison to engraftment of 4T1/WT cells. Our results suggest that tumor-associated IL-1α is involved in TNBC progression in mice by modulating the interplay between immunosuppressive pro-inflammatory cells vs. antigen-presenting and cytotoxic cells.

We prove that for every r > 0 if a nonpositively curved (p, q)-map M contains no flat submaps of radius r, then the area ofM does not exceed Crn for some constant C. This strengthens a theorem of Ivanov and Schupp. We show that an infinite (p, q)-map which tessellates the plane is quasi-isometric to the Euclidean plane if and only if the map contains only finitely many nonflat vertices and faces. We also generalize Ivanov and Schupp's result to a much larger class of maps, namely to maps with angle functions. [ABSTRACT FROM AUTHOR]

Previous studies from our lab demonstrated that the crosstalk between brain-metastasizing melanoma cells and microglia, the macrophage-like cells of the central nervous system, fuels progression to metastasis. In the present study, an in-depth investigation of melanoma-microglia interactions elucidated a pro-metastatic molecular mechanism that drives a vicious melanoma-brain-metastasis cycle. We employed RNA-Sequencing, HTG miRNA whole transcriptome assay, and reverse phase protein arrays (RPPA) to analyze the impact of melanoma-microglia interactions on sustainability and progression of four different human brain-metastasizing melanoma cell lines. Microglia cells exposed to melanoma-derived IL-6 exhibited upregulated levels of STAT3 phosphorylation and SOCS3 expression, which, in turn, promoted melanoma cell viability and metastatic potential. IL-6/STAT3 pathway inhibitors diminished the pro-metastatic functions of microglia and reduced melanoma progression. SOCS3 overexpression in microglia cells evoked microglial support in melanoma brain metastasis by increasing melanoma cell migration and proliferation. Different melanomas exhibited heterogeneity in their microglia-activating capacity as well as in their response to microglia-derived signals. In spite of this reality and based on the results of the present study, we concluded that the activation of the IL-6/STAT3/SOCS3 pathway in microglia is a major mechanism by which reciprocal melanoma-microglia signaling engineers the interacting microglia to reinforce the progression of melanoma brain metastasis. This mechanism may operate differently in different melanomas.

UV-curable particle-free ceramic compositions for stereolithography-based 3D printing technologies present a promising alternative to the commonly used particle-based compositions. So far, such compositions were mainly based on solutions of pre-ceramic polymers which limit their applications to silicon-containing materials. However, the application of particle-free inks for the fabrication of other ceramic materials, in particular dense polycrystalline ones, is very little explored. We present a new and general fabrication approach based on all-solution compositions, by combining sol–gel chemistry and photopolymerization, for obtaining dense 3D ceramic structures by DLP printing. The process is demonstrated here for the fabrication of barium titanate (BaTiO3). By using chelating solvent and monomer, a stable UV-curable solution is obtained. An aging period of 8–14 days was crucial for obtaining dense ceramic objects without any secondary phases. The heat treatment was found to affect the microstructure, density and hardness of the resulting ceramics. The presented process enables obtaining objects free of carbon materials, having a density as high as 98% of the theoretical value, and a hardness of 4.3 GPa.

Previous studies indicated that microglia cells upregulate the expression of aldolase C (ALDOC) in melanoma cells. The present study using brain‐metastasizing variants from three human melanomas explores the functional role of ALDOC in the formation and maintenance of melanoma brain metastasis (MBM). ALDOC overexpression impacted differentially the malignant phenotype of these three variants. In the first variant, ALDOC overexpression promoted cell viability, adhesion to and transmigration through a layer of brain endothelial cells, and amplified brain micrometastasis formation. The cross‐talk between this MBM variant and microglia cells promoted the proliferation and migration of the latter cells. In sharp contrast, ALDOC overexpression in the second brain‐metastasizing melanoma variant reduced or did not affect the same malignancy features. In the third melanoma variant, ALDOC overexpression augmented certain characteristics of malignancy and reduced others. The analysis of biological functions and disease pathways in the ALDOC overexpressing variants clearly indicated that ALDOC induced the expression of tumor progression promoting genes in the first variant and antitumor progression properties in the second variant. Overall, these results accentuate the complex microenvironment interactions between microglia cells and MBM, and the functional impact of intertumor heterogeneity. Since intertumor heterogeneity imposes a challenge in the planning of cancer treatment, we propose to employ the functional response of tumors with an identical histology, to a particular drug or the molecular signature of this response, as a predictive indicator of response/nonresponse to this drug.

Abstract The link between the gut microbiota and social behavior has been demonstrated, however the translational impact of a certain microbiota composition on stable behavioral patterns is yet to be elucidated. Here we employed an established social behavior mouse model of dominance (Dom) or submissiveness (Sub). A comprehensive 16S rRNA gene sequence analysis of Dom and Sub mice revealed a significantly different gut microbiota composition that clearly distinguishes between the two behavioral modes. Sub mice gut microbiota is significantly less diverse than that of Dom mice, and their taxa composition uniquely comprised the genera Mycoplasma and Anaeroplasma of the Tenericutes phylum, in addition to the Rikenellaceae and Clostridiaceae families. Conversely, the gut microbiota of Dom mice includes the genus Prevotella of the Bacteriodetes phylum, significantly less abundant in Sub mice. In addition, Sub mice show lower body weight from the age of 2 weeks and throughout their life span, accompanied with lower epididymis white adipose tissue (eWAT) mass and smaller adipocytes together with substantially elevated expression of inflammation and metabolic-related eWAT adipokines. Finally, fecal microbiota transplantation into germ-free mice show that Sub-transplanted mice acquired Sub microbiota and adopted their behavioral and physiological features, including depressive-like and anti-social behaviors alongside reduced eWAT mass, smaller adipocytes, and a Sub-like eWAT adipokine profile. Our findings demonstrate the critical role of the gut microbiome in determining dominance vs. submissiveness and suggest an association between gut microbiota, the eWAT metabolic and inflammatory profile, and the social behavior mode.