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Abstract Background Tumors comprise a complex microenvironment of interacting malignant and stromal cell types. Much of our understanding of the tumor microenvironment comes from in vitro studies isolating the interactions between malignant cells and a single stromal cell type, often along a single pathway. Result To develop a deeper understanding of the interactions between cells within human lung tumors, we perform RNA-seq profiling of flow-sorted malignant cells, endothelial cells, immune cells, fibroblasts, and bulk cells from freshly resected human primary non-small-cell lung tumors. We map the cell-specific differential expression of prognostically associated secreted factors and cell surface genes, and computationally reconstruct cross-talk between these cell types to generate a novel resource called the Lung Tumor Microenvironment Interactome (LTMI). Using this resource, we identify and validate a prognostically unfavorable influence of Gremlin-1 production by fibroblasts on proliferation of malignant lung adenocarcinoma cells. We also find a prognostically favorable association between infiltration of mast cells and less aggressive tumor cell behavior. Conclusion These results illustrate the utility of the LTMI as a resource for generating hypotheses concerning tumor-microenvironment interactions that may have prognostic and therapeutic relevance.

The article presents a study which examined effect of renin overexpression and high-fat feeding on glucose intolerance and angiotensin II (Ang II). The researchers used RenTgMK transgenic mice which are subjected to genotyping, glucose tolerance test, plasma measurement, pancreas histology and immunostaining, stastical analysis and metabolic evaluation. The body weight, fat weight, metabolic levels, insulin resistance and renin-angiotensin system (RAS) reaction are also assessed.

Homologous chromosomes must pair and establish stable connections during prophase I of meiosis to segregate reliably from each other at anaphase I. In most organisms, the stable connections, called chiasmata, arise from crossovers. In Drosophila males, homologs pair and segregate without crossing over. Chiasmata are replaced by a homolog conjunction complex that includes the Stromalin in Meiosis (SNM) and Modifier of Mdg4 in Meiosis (MNM) proteins. MNM is one of 31 alternative splice products of mod(mdg4), all of which share a common 402-amino-acid N terminus and differ at their C termini. Previous data demonstrated that an MNM-specific exon is required for homolog conjunction, but did not address whether the N-terminal common region, which includes a BTB domain that can mediate coalescence of protein-DNA complexes, is also required. Here we describe a mutation in the common region of mod(mdg4), Z3-3401, that causes qualitatively similar phenotypes as the MNM-specific alleles but disrupts X-Y segregation much more drastically than autosomal segregation. The mutant MNM protein in Z3-3401 is expressed throughout prophase I in spermatocytes but the protein is confined to the cytoplasm, suggesting that the Z3-3401 mutation disrupts a signal required for nuclear localization or retention. Z3- 3401 fails to complement a large battery of lethal and semilethal alleles in the common region for meiotic nondisjunction, including an allele containing an amino acid substitution at a conserved residue in the BTB/POZ domain, consistent with a general requirement for the mod(mdg4) common region in homolog segregation. [ABSTRACT FROM AUTHOR]

Polyphenolic components of green tea, such as epigallocatechin-3-gallate (EGCG), have potent anti-inflammatory properties. We previously showed that EGCG inhibits tumor necrosis factor-α (TNF-α)-mediated activation of the nuclear factor-KB (NF-KB) pathway, partly through inhibition of IKB kinase (IKK). The NF-KB pathway may also be activated in response to interleukin-1β (IL-1β) stimulation through a distinct signal transduction pathway. We therefore hypothesized that EGCG inhibits IL-1β-mediated activation of the NF-KB pathway. Because the gene expression of interleukin-8 (IL-8), the major human neutrophil chemoattractant, is dependent on activation of NF-KB, IL-8 gene expression in human lung epithelial (A549) cells treated with human IL-1β was used as a model of IL-1β signal transduction. The EGCG markedly inhibited IL-1β-mediated IL-1β receptor-associated kinase (IRAK) degradation and the signaling events downstream from IRAK degradation: IKK activation, IKBα degradation, and NF-KB activation. In addition, EGCG inhibited phosphorylation of the p65 subunit of NF-KB. The functional consequence of this inhibition was evident by inhibition of IL-8 gene expression. Therefore, the green tea polyphenol EGCG is a potent inhibitor of IL-1β signal transduction in vitro. The proximal mechanisms of this effect involve inhibition of IRAK-dependent signaling and phosphorylation of p65. [ABSTRACT FROM AUTHOR]

Animal and clinical studies have pointed to a potential role of the Renin Angiotensin System (RAS) in diabetes. However, mechanisms underlying this association are not completely understood. The objective of this work is to dissect the mechanisms by which overexpression of RAS mediates glucose intolerance, using a transgenic mouse model overexpressing renin in the liver (RenTg; Caron et al., 2002), resulting in constitutively elevated plasma angiotensin II (Ang II). Twenty week-old RenTg mice exhibit significantly impaired glucose tolerance and fasting insulinemia, despite normal glycemia, leptinemia and adiponectinemia, as compared to their wild type littermates. Although adipokine gene expression did not differ across genotypes, the type 2 Ang II receptor was markedly down-regulated in adipose tissue of RenTg mice. Comparative proteomics of adipose tissue from these mice indicates a genotype-dependent differential expression of several proteins associated with diabetes and glucose metabolism. We are currently studying these candidate proteins to identify their role in RAS-induced diabetes. These studies demonstrate that overexpression of renin impairs glucose tolerance and further support the role of RAS in the pathogenesis of diabetes. Future studies will dissect mechanism(s) and tissue(s) linking RAS to diabetes. [ABSTRACT FROM AUTHOR]

We present an analysis of dihadron correlations using recently developed methods for background subtraction which allow for higher precision measurements with fewer assumptions about the background. These studies indicate that low momentum jets interacting with the medium do not equilibrate with the medium but rather that interactions with the medium lead to more subtle increases in their widths and fragmentation functions, consistent with observations from studies of higher momentum fully reconstructed jets. The away-side shape is not consistent with a Mach cone. The qualitatively different conclusions reached with a more careful consideration of the background subtraction call into question the complete suppression of jets in central collisions observed in earlier studies, indicating that this is also an artifact of the background subtraction. [ABSTRACT FROM AUTHOR]