Introduction Lymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor.

The pathogenesis of nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) and its relationship to other lymphomas are largely unknown. This is partly because of the technical challenge of analyzing its rare neoplastic lymphocytic and histiocytic (L&H) cells, which are dispersed in an abundant nonneoplastic cellular microenvironment. We performed a genome-wide expression study of microdissected L&H lymphoma cells in comparison to normal and other malignant B cells that indicated a relationship of L&H cells to and/or that they originate from germinal center B cells at the transition to memory B cells. L&H cells show a surprisingly high similarity to the tumor cells of T cell–rich B cell lymphoma and classical Hodgkin lymphoma, a partial loss of their B cell phenotype, and deregulation of many apoptosis regulators and putative oncogenes. Importantly, L&H cells are characterized by constitutive nuclear factor κB activity and aberrant extracellular signal-regulated kinase signaling. Thus, these findings shed new light on the nature of L&H cells, reveal several novel pathogenetic mechanisms in NLPHL, and may help in differential diagnosis and lead to novel therapeutic strategies.

IntroductionCurrent prognostic gene expression profiles for breast cancer mainly reflect proliferation status and are most useful in ER-positive cancers. Triple negative breast cancers (TNBC) are clinically heterogeneous and prognostic markers and biology-based therapies are needed to better treat this disease.MethodsWe assembled Affymetrix gene expression data for 579 TNBC and performed unsupervised analysis to define metagenes that distinguish molecular subsets within TNBC. We used n = 394 cases for discovery and n = 185 cases for validation. Sixteen metagenes emerged that identified basal-like, apocrine and claudin-low molecular subtypes, or reflected various non-neoplastic cell populations, including immune cells, blood, adipocytes, stroma, angiogenesis and inflammation within the cancer. The expressions of these metagenes were correlated with survival and multivariate analysis was performed, including routine clinical and pathological variables.ResultsSeventy-three percent of TNBC displayed basal-like molecular subtype that correlated with high histological grade and younger age. Survival of basal-like TNBC was not different from non basal-like TNBC. High expression of immune cell metagenes was associated with good and high expression of inflammation and angiogenesis-related metagenes were associated with poor prognosis. A ratio of high B-cell and low IL-8 metagenes identified 32% of TNBC with good prognosis (hazard ratio (HR) 0.37, 95% CI 0.22 to 0.61; P < 0.001) and was the only significant predictor in multivariate analysis including routine clinicopathological variables.ConclusionsWe describe a ratio of high B-cell presence and low IL-8 activity as a powerful new prognostic marker for TNBC. Inhibition of the IL-8 pathway also represents an attractive novel therapeutic target for this disease.

The microbial communities inhabiting the mammalian intestinal tract play an important role in diverse aspects of host biology. However, little is known regarding the forces shaping variation in these communities and their influence on host fitness. To shed light on the contributions of host genetics, transmission and geography to diversity in microbial communities between individuals, we performed a survey of intestinal microbial communities in a panel of 121 house mice derived from eight locations across Western Europe using pyrosequencing of the bacterial 16S rRNA gene. The host factors studied included population structure estimated by microsatellite loci and mitochondrial DNA, genetic distance and geography. To determine whether host tissue (mucosa)-associated communities display properties distinct from those of the lumen, both the caecal mucosa and contents were examined. We identified Bacteroides, Robinsoniella and Helicobacter as the most abundant genera in both the caecal content and mucosa-associated communities of wild house mice. Overall, we found geography to be the most significant factor explaining patterns of diversity in the intestinal microbiota, with a comparatively weaker influence of host population structure and genetic distance. Furthermore, the influence of host genetic distance was limited to the mucosa communities, consistent with this environment being more intimately coupled to the host.

A total of 8,859 DNA sequences encompassing approximately 1.9 million base pairs of the chimpanzee genome were sequenced and compared to corresponding human DNA sequences. Although the average sequence difference is low (1.24%), the extent of changes is markedly different among sites and types of substitutions. Whereas approximately 15% of all CpG sites have experienced changes between humans and chimpanzees, owing to a 23-fold excess of transitions and a 7-fold excess of transversions, substitutions at other sites vary in frequency, between 0.1% and 0.5%. If the nucleotide diversity in the common ancestral species of humans and chimpanzees is assumed to have been about fourfold higher than in contemporary humans, all possible comparisons between autosomes and X and Y chromosomes result in estimates of the ratio between male and female mutation rates of approximately 3. Thus, the relative time spent in the male and female germlines may be a major determinant of the overall accumulation of nucleotide substitutions. However, since the extent of divergence differs significantly among autosomes, additional unknown factors must also influence the accumulation of substitutions in the human genome.

Summary• The family Araceae (3790 species, 117 genera) has one of the oldest fossil records among angiosperms. Ecologically, members of this family range from free-floating aquatics (Pistia and Lemna) to tropical epiphytes. Here, we infer some of the macroevolutionary processes that have led to the worldwide range of this family and test how the inclusion of fossil (formerly occupied) geographical ranges affects biogeographical reconstructions.• Using a complete genus-level phylogeny from plastid sequences and outgroups representing the 13 other Alismatales families, we estimate divergence times by applying different clock models and reconstruct range shifts under different models of past continental connectivity, with or without the incorporation of fossil locations.• Araceae began to diversify in the Early Cretaceous (when the breakup of Pangea was in its final stages), and all eight subfamilies existed before the K ⁄ T boundary. Early lineages persist in Laurasia, with several relatively recent entries into Africa, South America, South-East Asia and Australia.• Water-associated habitats appear to be ancestral in the family, and DNA substitution rates are especially high in free-floating Araceae. Past distributions inferred when fossils are included differ in nontrivial ways from those without fossils. Our complete genus-level time-scale for the Araceae may prove to be useful for ecological and physiological studies.

Non-coding genetic variation is a major driver of phenotypic diversity and allows the investigation of mechanisms that control gene expression. Here, we systematically investigated the effects of >50 million variations from five strains of mice on mRNA, nascent transcription, transcription start sites, and transcription factor binding in resting and activated macrophages. We observed substantial differences associated with distinct molecular pathways. Evaluating genetic variation provided evidence for roles of ∼100 TFs in shaping lineage-determining factor binding. Unexpectedly, a substantial fraction of strain-specific factor binding could not be explained by local mutations. Integration of genomic features with chromatin interaction data provided evidence for hundreds of connected cis-regulatory domains associated with differences in transcription factor binding and gene expression. This system and the >250 datasets establish a substantial new resource for investigation of how genetic variation affects cellular phenotypes.

Motivation: Coalescent-based simulation software for genomic sequences allows the efficient in silico generation of short- and medium-sized genetic sequences. However, the simulation of genome-size datasets as produced by next-generation sequencing is currently only possible using fairly crude approximations.Results: We present the sequential coalescent with recombination model (SCRM), a new method that efficiently and accurately approximates the coalescent with recombination, closing the gap between current approximations and the exact model. We present an efficient implementation and show that it can simulate genomic-scale datasets with an essentially correct linkage structure.Availability and implementation: The open source implementation scrm is freely available at https://scrm.github.io under the conditions of the GPLv3 license.Contact: staab@bio.lmu.de or gerton.lunter@well.ox.ac.uk.Supplementary information: Supplementary data are available at Bioinformatics online.