Sites of Failure in Breast Cancer Patients with Extracapsular Invasion of Axillary Lymph Node Metastases: No Need for Axillary Irradiation?!

Background and Purpose:: Extracapsular spread (ECS) is frequent, but the specific sites of relapse are seldom given in the literature. In this study it was evaluated, if ECS might be an indicator for axillary irradiation. Patients and Methods:: After a retrospective review of pathology reports, the information about ECS was available in 254 lymph node-positive patients: ECS was absent in 34% (ECS-negative; n = 87) and present in 66% (ECS-positive; n = 167). All patients were irradiated locally, 78 patients got periclavicular and 74 axillary irradiation (median total dose: 50.4 Gy). 240/254 patients (94.5%) received systemic treatment/s. Mean follow-up was 46 months. Results:: The regional relapse rate was 4.6% without ECS versus 9.6% with ECS. The 5-year axillary relapse-free survival was 100% in ECS-negative and 90% in ECS-positive patients (p = 0.01), whereas corresponding values for periclavicular relapse-free survival (with ECS: 91% ± 4%; without ECS: 94% ± 3%; p = 0.77) and local relapse-free survival (with ECS: 86% ± 4%; without ECS: 91% ± 3%; p = 0.69) were not significantly different. χ2-tests revealed a high correlation of ECS with T-stage, number of positive lymph nodes and progesterone receptor status, comparisons with estrogen receptor, grade, or age were not significant. In multivariate analysis number of positive lymph nodes was solely significant for regional failure. Dividing the patients into those with one to three and those with four or more positive lymph nodes, ECS lost its significance for axillary failure. Conclusion:: ECS was accompanied by an enhanced axillary failure rate in univariate analysis, which was no longer true after adjusting for the number of positive lymph node

Key Technologies for Progressing Discovery of Microbiome-Based Medicines

A growing number of experimental and computational approaches are illuminating the “microbial dark matter” and uncovering the integral role of commensal microbes in human health. Through this work, it is now clear that the human microbiome presents great potential as a therapeutic target for a plethora of diseases, including inflammatory bowel disease, diabetes and obesity. The development of more efficacious and targeted treatments relies on identification of causal links between the microbiome and disease; with future progress dependent on effective links between state-of-the-art sequencing approaches, computational analyses and experimental assays. We argue determining causation is essential, which can be attained by generating hypotheses using multi-omic functional analyses and validating these hypotheses in complex, biologically relevant experimental models. In this review we discuss existing analysis and validation methods, and propose best-practice approaches required to enable the next phase of microbiome research

Culturing of ‘unculturable’ human microbiota reveals novel taxa and extensive sporulation

Our intestinal microbiota harbours a diverse bacterial community required for our health, sustenance and wellbeing. Intestinal colonization begins at birth and climaxes with the acquisition of two dominant groups of strict anaerobic bacteria belonging to the Firmicutes and Bacteroidetes phyla. Culture-independent, genomic approaches have transformed our understanding of the role of the human microbiome in health and many diseases. However, owing to the prevailing perception that our indigenous bacteria are largely recalcitrant to culture, many of their functions and phenotypes remain unknown. Here we describe a novel workflow based on targeted phenotypic culturing linked to large-scale whole-genome sequencing, phylogenetic analysis and computational modelling that demonstrates that a substantial proportion of the intestinal bacteria are culturable. Applying this approach to healthy individuals, we isolated 137 bacterial species from characterized and candidate novel families, genera and species that were archived as pure cultures. Whole-genome and metagenomic sequencing, combined with computational and phenotypic analysis, suggests that at least 50-60% of the bacterial genera from the intestinal microbiota of a healthy individual produce resilient spores, specialized for host-to-host transmission. Our approach unlocks the human intestinal microbiota for phenotypic analysis and reveals how a marked proportion of oxygen-sensitive intestinal bacteria can be transmitted between individuals, affecting microbiota heritability

Stunted microbiota and opportunistic pathogen colonization in caesarean-section birth

Immediately after birth, newborn babies experience rapid colonization by microorganisms from their mothers and the surrounding environment1. Diseases in childhood and later in life are potentially mediated by the perturbation of the colonization of the infant gut microbiota2. However, the effects of delivery via caesarean section on the earliest stages of the acquisition and development of the gut microbiota, during the neonatal period (≤1 month), remain controversial3,4. Here we report the disrupted transmission of maternal Bacteroides strains, and high-level colonization by opportunistic pathogens associated with the hospital environment (including Enterococcus, Enterobacter and Klebsiella species), in babies delivered by caesarean section. These effects were also seen, to a lesser extent, in vaginally delivered babies whose mothers underwent antibiotic prophylaxis and in babies who were not breastfed during the neonatal period. We applied longitudinal sampling and whole-genome shotgun metagenomic analysis to 1,679 gut microbiota samples (taken at several time points during the neonatal period, and in infancy) from 596 full-term babies born in UK hospitals; for a subset of these babies, we collected additional matched samples from mothers (175 mothers paired with 178 babies). This analysis demonstrates that the mode of delivery is a significant factor that affects the composition of the gut microbiota throughout the neonatal period, and into infancy. Matched large-scale culturing and whole-genome sequencing of over 800 bacterial strains from these babies identified virulence factors and clinically relevant antimicrobial resistance in opportunistic pathogens that may predispose individuals to opportunistic infections. Our findings highlight the critical role of the local environment in establishing the gut microbiota in very early life, and identify colonization with antimicrobial-resistance-containing opportunistic pathogens as a previously underappreciated risk factor in hospital births

The GALEX Ultraviolet Atlas of Nearby Galaxies

We present images, integrated photometry, and surface-brightness and color profiles for a total of 1034 nearby galaxies recently observed by the Galaxy Evolution Explorer (GALEX) satellite in its far-ultraviolet (FUV; λ_(eff) = 1516 Å) and near-ultraviolet (NUV; λ_(eff) = 2267 Å) bands. Our catalog of objects is derived primarily from the GALEX Nearby Galaxies Survey (NGS) supplemented by galaxies larger than 1' in diameter serendipitously found in these fields and in other GALEX exposures of similar of greater depth. The sample analyzed here adequately describes the distribution and full range of properties (luminosity, color, star formation rate [SFR]) of galaxies in the local universe. From the surface brightness profiles obtained we have computed asymptotic magnitudes, colors, and luminosities, along with the concentration indices C31 and C42. We have also morphologically classified the UV surface brightness profiles according to their shape. This data set has been complemented with archival optical, near-infrared, and far-infrared fluxes and colors. We find that the integrated (FUV − K) color provides robust discrimination between elliptical and spiral/irregular galaxies and also among spiral galaxies of different subtypes. Elliptical galaxies with brighter K-band luminosities (i.e., more massive) are redder in (NUV − K) color but bluer in (FUV − NUV) (a color sensitive to the presence of a strong UV upturn) than less massive ellipticals. In the case of the spiral/irregular galaxies our analysis shows the presence of a relatively tight correlation between the (FUV − NUV) color (or, equivalently, the slope of the UV spectrum, β) and the total infrared-to-UV ratio. The correlation found between (FUV − NUV) color and K-band luminosity (with lower luminosity objects being bluer than more luminous ones) can be explained as due to an increase in the dust content with galaxy luminosity. The images in this Atlas along with the profiles and integrated properties are publicly available through a dedicated Web page

Sequence-dependent off-target inhibition of TLR7/8 sensing by synthetic microRNA inhibitors

Anti-microRNA (miRNA) oligonucleotides (AMOs) with 2\u27-O-Methyl (2\u27OMe) residues are commonly used to study miRNA function and can achieve high potency, with low cytotoxicity. Not withstanding this, we demonstrate the sequence-dependent capacity of 2\u27OMe AMOs to inhibit Toll-like receptor (TLR) 7 and 8 sensing of immunostimulatory RNA, independent of their miRNA-targeting function. Through a screen of 29 AMOs targeting common miRNAs, we found a subset of sequences highly inhibitory to TLR7 sensing in mouse macrophages. Interspecies conservation of this inhibitory activity was confirmed on TLR7/8 activity in human peripheral blood mononuclear cells. Significantly, we identified a core motif governing the inhibitory activity of these AMOs, which is present in more than 50 AMOs targeted to human miRNAs in miRBaseV20. DNA/locked nucleic acids (LNA) AMOs synthesized with a phosphorothioate backbone also inhibited TLR7 sensing in a sequence-dependent manner, demonstrating that the off-target effects of AMOs are not restricted to 2\u27OMe modification. Taken together, our work establishes the potential for off-target effects of AMOs on TLR7/8 function, which should be taken into account in their therapeutic development and in vivo application

Recent star formation in nearby galaxies from GALEX imaging:M101 and M51

The GALEX (Galaxy Evolution Explorer) Nearby Galaxies Survey is providing deep far-UV and near-UV imaging for a representative sample of galaxies in the local universe. We present early results for M51 and M101, from GALEX UV imaging and SDSS optical data in five bands. The multi-band photometry of compact stellar complexes in M101 is compared to population synthesis models, to derive ages, reddening, reddening-corrected luminosities and current/initial masses. The GALEX UV photometry provides a complete census of young compact complexes on a approximately 160pc scale. A galactocentric gradient of the far-UV - near-UV color indicates younger stellar populations towards the outer parts of the galaxy disks, the effect being more pronounced in M101 than in M51.Comment: This paper will be published as part of the Galaxy Evolution Explorer (GALEX) Astrophysical Journal Letters Special Issue. Full paper available from http://dolomiti.pha.jhu.edu . Links to full set of papers will be available at http://www.galex.caltech.edu/PUBLICATIONS/ after November 22, 200

GALEX UV Color Relations for Nearby Early-Type Galaxies

We use GALEX/optical photometry to construct color-color relationships for early-type galaxies sorted by morphological type. We have matched objects in the GALEX GR1 public release and the first IR1.1 internal release, with the RC3 early-type galaxies having a morphological type -5.5<T<-1.5 with mean error in T<1.5, and mean error on (B-V)T<0.05. After visual inspection of each match, we are left with 130 galaxies with a reliable GALEX pipeline photometry in the far-UV and near-UV bands. This sample is divided into Ellipticals (-5.5<T<-3.5) and Lenticulars (-3.5<T<-1.5). After correction for the Galactic extinction, the color-color diagrams FUV-NUV vs. (B-V)_{Tc} are plotted for the two subsamples. We find a tight anti-correlation between the FUV-NUV and (B-V)_{Tc} colors for Ellipticals, the UV color getting bluer when the (B-V)_{Tc} get redder. This relationship very likely is an extension of the color-metallicity relationship into the GALEX NUV band. We suspect that the main source of the correlation is metal line blanketing in the NUV band. The FUV-NUV vs B-V correlation has larger scatter for lenticular galaxies; we speculate this reflects the presence of low level star formation. If the latter objects (i.e. those that are blue both in FUV-NUV and B-V) are interpreted as harboring recent star formation activity, this would be the case for a few percent (~4%) of Ellipticals and ~15% of Lenticulars; this would make about 10% of early-type galaxies with residual star formation in our full sample of 130 early-type galaxies. We also plot FUV-NUV vs. the Mg_2 index and central velocity dispersion. We find a tight anti-correlation between FUV-NUV and the Mg_2 index(...).Comment: 25 pages, 5 figures, accepted for publication in ApJS (abstract abridged), typos corrected in section 2.