Tie2-expressing monocytes/macrophages (TEMs) are a distinct subset of proangiogenic monocytes selectively recruited to tumors in breast cancer. Because of the hypoxic nature of solid tumors, we investigated if oxygen, via hypoxia-inducible transcription factors HIF-1a and HIF-2a, regulates TEM function in the hypoxic tumor microenvironment. We orthotopically implanted PyMT breast tumor cells into the mammary fat pads of syngeneic LysMcre, HIF-1a fl/fl /LysMcre, or HIF-2a fl/fl /LysMcre mice and evaluated the tumor TEM population. There was no difference in the percentage of tumor macrophages among the mouse groups. In contrast, HIF-1a fl/fl /LysMcre mice had a significantly smaller percentage of tumor TEMs compared with control and HIF-2a fl/fl /LysMcre mice. Proangiogenic TEMs in macrophage HIF-2a-deficient tumors presented significantly more CD31 + microvessel density but exacerbated hypoxia and tissue necrosis. Reduced numbers of proangiogenic TEMs in macrophage HIF-1a-deficient tumors presented significantly less microvessel density but tumor vessels that were more functional as lectin injection revealed more perfusion, and functional electron paramagnetic resonance analysis revealed more oxygen in those tumors. Macrophage HIF-1a-deficient tumors also responded significantly to chemotherapy. These data introduce a previously undescribed and counterintuitive prohypoxia role for proangiogenic TEMs in breast cancer which is, in part, suppressed by HIF-2a.
Despite modest improvements in survival in recent years, pancreatic adenocarcinoma remains a deadly disease with a 5-year survival rate of only 9%. These poor outcomes are driven by failure of early detection, treatment resistance, and propensity for early metastatic spread. Uncovering innovative therapeutic modalities to target the resistance mechanisms that make pancreatic cancer largely incurable are urgently needed. In this review, we discuss the immune composition of pancreatic tumors, including the counterintuitive fact that there is a significant inflammatory immune infiltrate in pancreatic cancer yet anti-tumor mechanisms are subverted and immune behaviors are suppressed. Here, we emphasize how immune cell interactions generate tumor progression and treatment resistance. We narrow in on tumor macrophage (TAM) spatial arrangement, polarity/function, recruitment, and origin to introduce a concept where interactions with tumor neutrophils (TAN) perpetuate the microenvironment. The sequelae of macrophage and neutrophil activities contributes to tumor remodeling, fibrosis, hypoxia, and progression. We also discuss immune mechanisms driving resistance to standard of care modalities. Finally, we describe a cadre of treatment targets, including those intended to overcome TAM and TAN recruitment and function, to circumvent barriers presented by immune infiltration in pancreatic adenocarcinoma.
Nitrification, the microbial oxidation of ammonia (NH 3 ) to nitrite (NO 2 – ) and NO 2 – to nitrate (NO 3 – ), plays a vital role in ocean nitrogen cycling. Characterizing the distribution of nitrifying organisms over environmental gradients can help predict how nitrogen availability may change with shifting ocean conditions, for example, due to loss of dissolved oxygen (O 2 ). We characterized the distribution of nitrifiers at 5 depths spanning the oxic to hypoxic zone of the offshore Benguela upwelling system above the continental slope off Namibia. Based on 16S rRNA gene amplicon sequencing, the proportional abundance of nitrifiers (ammonia and nitrite oxidizers) increased with depth, driven by an increase in ammonia-oxidizing archaea (AOA; Thaumarchaeota) to up to 33% of the community at hypoxic depths where O 2 concentrations fell to ~25 μM. The AOA community transitioned from being dominated by a few members at oxic depths to a more even representation of taxa in the hypoxic zone. In comparison, the community of NO 2 – -oxidizing bacteria (NOB), composed primarily of Nitrospinae, was far less abundant and exhibited higher evenness at all depths. The AOA:NOB ratio declined with depth from 41:1 in the oxic zone to 27:1 under hypoxia, suggesting potential variation in the balance between NO 2 – production and consumption via nitrification. Indeed, in contrast to prior observations from more O 2 -depleted sites closer to shore, NO 2 – did not accumulate at hypoxic depths near this offshore site, potentially due in part to a tightened coupling between AOA and NOB.
The human microbiome is composed of the symbiotic, commensalistic, and pathogenic bacteria that live on and in different sites of the human body. Recent studies on the human microbiome has provided insights into its implications for human health and physiology. Several recent studies have examined the relationship between human behavior (such has diet) on the microbiome. Other studies have tried to discern the association between human genome and microbiome on human health, focusing on conditions such as Irritable Bowel Disease and Celiac Disease, diet and gut microbiome. In this study, DNA samples were extracted from fecal samples of three healthy individuals and one with Celiac Disease. Microbial diversity and abundance was analyzed using multiplex sequencing targeting the V4-V5 region of the 16S rDNA gene. Bioinformatics analysis of the gut microbial community of the three individuals were determined to genus level taxonomic distinction. Further phylogenetic and statistical analyses of selected show similarities and differences between the microbiota of Celiac and non-Celiac subjects.
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