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Purpose: Compared with their European American (EA) counterparts, African American (AA) women are more likely to die from breast cancer in the United States. This disparity is greatest in hormone receptor–positive subtypes. Here we uncover biological factors underlying this disparity by comparing functional expression and prognostic significance of master transcriptional regulators of luminal differentiation. Experimental Design: Data and biospecimens from 262 AA and 293 EA patients diagnosed with breast cancer from 2001 to 2010 at a major medical center were analyzed by IHC for functional biomarkers of luminal differentiation, including estrogen receptor (ESR1) and its pioneer factors, FOXA1 and GATA3. Integrated comparison of protein levels with network-level gene expression analysis uncovered predictive correlations with race and survival. Results: Univariate or multivariate HRs for overall survival, estimated from digital IHC scoring of nuclear antigen, show distinct differences in the magnitude and significance of these biomarkers to predict survival based on race: ESR1 [EA HR = 0.47; 95% confidence interval (CI), 0.31–0.72 and AA HR = 0.77; 95% CI, 0.48–1.18]; FOXA1 (EA HR = 0.38; 95% CI, 0.23–0.63 and AA HR = 0.53; 95% CI, 0.31–0.88), and GATA3 (EA HR = 0.36; 95% CI, 0.23–0.56; AA HR = 0.57; CI, 0.56–1.4). In addition, we identify genes in the downstream regulons of these biomarkers highly correlated with race and survival. Conclusions: Even within clinically homogeneous tumor groups, regulatory networks that drive mammary luminal differentiation reveal race-specific differences in their association with clinical outcome. Understanding these biomarkers and their downstream regulons will elucidate the intrinsic mechanisms that drive racial disparities in breast cancer survival.

Isolation of circulating tumor cells (CTCs) from blood provides a minimally-invasive alternative into the basic understanding, diagnosis and prognosis of metastatic cancers. The roles and clinical values of CTCs are under intensive investigation, yet most studies are limited by technical challenges in the comprehensive enrichment of intact and viable CTCs with minimal white blood cells (WBCs) contamination. Here, we report a novel method based on contrast of cell magnetization in biocompatible ferrofluids (a colloidal magnetic nanoparticles suspension), termed as integrated ferrohydrodynamic cell separation (iFCS), that enriches CTCs in a tumor antigen-independent and cell size variation-inclusive manner, and achieves high-throughput (12 mL h(−1)), high recovery rate (99.08% at down to ~;10 cells mL(−1) spike ratio), low WBCs contamination (533 cells for every one milliliter blood processed) and is biocompatible. This method will enable large cohort research to define clinical and diagnostic value of CTC subtypes.

Interactions between the gut microbiota and the host are important for health, where dysbiosis has emerged as a likely component of mucosal disease. The specific constituents of the microbiota that contribute to mucosal disease are not well defined. The authors sought to define microbial components that regulate homeostasis within the intestinal mucosa. Using an unbiased, metabolomic profiling approach, a selective depletion of indole and indole-derived metabolites was identified in murine and human colitis. Indole-3-propionic acid (IPA) was selectively diminished in circulating serum from human subjects with active colitis, and IPA served as a biomarker of disease remission. Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor. Colonization of germ-free mice with wild-type Escherichia coli, but not E. coli mutants unable to generate indole, induced colonic epithelial IL-10R1. Moreover, oral administration of IPA significantly ameliorated disease in a chemically induced murine colitis model. This work defines a novel role of indole metabolites in anti-inflammatory pathways mediated by epithelial IL-10 signaling and identifies possible avenues for utilizing indoles as novel therapeutics in mucosal disease.

Shih-Fan, Chan/0000-0003-2955-9433; Shen, Sheng-Feng/0000-0002-0631-6343; Albrecht, Tomas/0000-0002-9213-0034; Karaardic, Hakan/0000-0001-9839-4201; Wilkins, Matthew/0000-0002-3162-6749 WOS: 000381578200007 PubMed: 27357267 Population divergence in geographic isolation is due to a combination of factors. Natural and sexual selection may be important in shaping patterns of population differentiation, a pattern referred to as 'isolation by adaptation' (IBA). IBA can be complementary to the well-known pattern of 'isolation by distance' (IBD), in which the divergence of closely related populations (via any evolutionary process) is associated with geographic isolation. The barn swallow Hirundo rustica complex comprises six closely related subspecies, where divergent sexual selection is associated with phenotypic differentiation among allopatric populations. To investigate the relative contributions of selection and geographic distance to genome-wide differentiation, we compared genotypic and phenotypic variation from 350 barn swallows sampled across eight populations (28 pairwise comparisons) from four different subspecies. We report a draft whole-genome sequence for H. rustica, to which we aligned a set of 9493 single nucleotide polymorphisms (SNPs). Using statistical approaches to control for spatial autocorrelation of phenotypic variables and geographic distance, we find that divergence in traits related to migratory behaviour and sexual signalling, as well as geographic distance, together explain over 70% of genome-wide divergence among populations. Controlling for IBD, we find 42% of genomewide divergence is attributable to IBA through pairwise differences in traits related to migratory behaviour and sexual signalling alone. By (i) combining these results with prior studies of how selection shapes morphological differentiation and (ii) accounting for spatial autocorrelation, we infer that morphological adaptation plays a large role in shaping population -level differentiation in this group of closely related populations. National Science FoundationNational Science Foundation (NSF) [DEB-CAREER-1149942]; NSFNational Science Foundation (NSF); Royal Society of LondonRoyal Society of London; Ministry of Education, Youth and Sports of the Czech RepublicMinistry of Education, Youth & Sports - Czech Republic [LH14045] We thank C. Alex Buerkle for collaboration on all aspects of this project and the Safran, Kane and Flaxman laboratory groups at the University of Colorado for feedback and advice. We thanks Matthew Evans for collaboration on barn swallows in the UK. Funding for this project was provided by the National Science Foundation (DEB-CAREER-1149942) to R.J.S. M.R.W was supported by an NSF graduate research fellowship and P.N by a Royal Society of London University Research Fellowship. Work in the Czech Republic was funded by the Ministry of Education, Youth and Sports of the Czech Republic (project LH14045). All field and laboratory protocols were compliant with University of Colorado, and Federal animal care and import/export protocols. We are grateful for the excellent reviews provided by Dr. Anna Santure and three anonymous reviewers.