T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a ...prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date.
Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival.
In ER-negative tumours triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive), presence of CD8+ T cells within the tumour was associated with a 28% 95% confidence interval (CI) 16% to 38% reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours hazard ratio (HR) = 0.54; 95% CI 0.37-0.79 versus CD8-negative tumours (HR = 0.87; 95% CI 0.55–1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (Pheterogeneity = 0.04) and approached significance in imputed data (Pheterogeneity = 0.1).
The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative supplementary Figure S1, available at Annals of Oncology online and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes.
NCT00003577.
Relative brain size has long been considered a reflection of cognitive capacities and has played a fundamental role in developing core theories in the life sciences. Yet, the notion that relative ...brain size validly represents selection on brain size relies on the untested assumptions that brain-body allometry is restrained to a stable scaling relationship across species and that any deviation from this slope is due to selection on brain size. Using the largest fossil and extant dataset yet assembled, we find that shifts in allometric slope underpin major transitions in mammalian evolution and are often primarily characterized by marked changes in body size. Our results reveal that the largest-brained mammals achieved large relative brain sizes by highly divergent paths. These findings prompt a reevaluation of the traditional paradigm of relative brain size and open new opportunities to improve our understanding of the genetic and developmental mechanisms that influence brain size.
ABSTRACT Solar flares produce radiation that can have an almost immediate effect on the near-Earth environment, making it crucial to forecast flares in order to mitigate their negative effects. The ...number of published approaches to flare forecasting using photospheric magnetic field observations has proliferated, with varying claims about how well each works. Because of the different analysis techniques and data sets used, it is essentially impossible to compare the results from the literature. This problem is exacerbated by the low event rates of large solar flares. The challenges of forecasting rare events have long been recognized in the meteorology community, but have yet to be fully acknowledged by the space weather community. During the interagency workshop on "all clear" forecasts held in Boulder, CO in 2009, the performance of a number of existing algorithms was compared on common data sets, specifically line-of-sight magnetic field and continuum intensity images from the Michelson Doppler Imager, with consistent definitions of what constitutes an event. We demonstrate the importance of making such systematic comparisons, and of using standard verification statistics to determine what constitutes a good prediction scheme. When a comparison was made in this fashion, no one method clearly outperformed all others, which may in part be due to the strong correlations among the parameters used by different methods to characterize an active region. For M-class flares and above, the set of methods tends toward a weakly positive skill score (as measured with several distinct metrics), with no participating method proving substantially better than climatological forecasts.
We present simultaneous observations of aurorae at Jupiter from the Hubble Space Telescope and Hisaki, in combination with the in situ measurements of magnetic field, particles, and radio waves from ...the Juno Spacecraft in the outer magnetosphere, from ~ 80RJ to 60RJ during 17 to 22 March 2017. Two cycles of accumulation and release of magnetic flux, named magnetic loading/unloading, were identified during this period, which correlate well with electron energization and auroral intensifications. Magnetic reconnection events are identified during both the loading and unloading periods, indicating that reconnection and unloading are independent processes. These results show that the dynamics in the middle magnetosphere are coupled with auroral variability.
Key Points
Accumulation and release of magnetic flux in the middle Jovian magnetosphere modulate auroral intensifications
Magnetic reconnection process occurs independently of Jupiter's global loading and unloading of magnetic flux
We provide direct evidence that unloading of magnetic flux causes enhancements of auroral kilometric emissions
Fundoscopy outside ophthalmology is in decline, and the technical demands of the traditional direct ophthalmoscope examination are likely contributing. Alternative fundoscopy technologies are ...increasingly available, yet valid comparisons between fundoscopy technologies are lacking. We aimed to assess medical students' perceptions of usefulness and ease of use of traditional and contemporary fundus-viewing technologies including smartphone fundoscopy.
One hundred forty-six second-year medical students participated in a cross-sectional, randomised, cross-over study of fundoscopy methods. Medical students completed small group training sessions using six current fundoscopy technologies including: a non-mydriatic fundus camera; two types of direct fundoscopy; and three types of smartphone fundoscopy. A novel survey of perceived usefulness and ease of use was then completed by students.
Repeated-measures ANOVA found students rated both the perceived usefulness (p< 0.001) and ease of use (p< 0.001) of smartphone fundoscopy significantly higher than both the non-mydriatic camera and direct fundoscopy.
Smartphone fundoscopy was found to be significantly more useful and easier to use than other modalities. Educators should optimise student access to novel fundoscopy technologies such as smartphone fundoscopy which may mitigate the technical challenges of fundoscopy and reinvigorate use of this valuable clinical examination.
We show that a higher incidence of campylobacteriosis is found in young children (age, <5 years) living in rural, compared with urban, areas. Association of this difference with particular animal ...sources was evaluated using multilocus sequence typing. This evaluation was achieved by comparing Campylobacter isolates originating from these children, retail poultry, and a range of animal sources by use of source attribution and phylogenetic analysis methods. The results indicate that chicken is a major source of infection in young urban children, although not in their rural counterparts, for which ruminant and other avian sources are more important
Abstract Cells in their native microenvironment interact with three-dimensional (3D) nanofeatures. Despite many reports on the effects of substrate nanotopography on cells, the independent effect of ...3D parameters has not been investigated. Recent advances in nanofabrication for precise control of nanostructure pattern, periodicity, shape, and height enabled this systematic study of cell interactions with 3D nanotopographies. Two distinct nanopatterns (posts and grates) with varying three-dimensionalities (50–600 nm in nanostructure height) were created, while maintaining the pattern periodicity (230 nm in pitch) and tip shape (needle- or blade-like sharp tips). Human foreskin fibroblasts exhibited significantly smaller cell size and lower proliferation on needle-like nanoposts, and enhanced elongation with alignment on blade-like nanogrates. These phenomena became more pronounced as the nanotopographical three-dimensionality (structural height) increased. The nanopost and nanograte architectures provided the distinct contact guidance for both filopodia extension and the formation of adhesion molecules complex, which was believed to lead to the unique cell behaviors observed.
Sexual selection is proposed to be an important driver of diversification in animal systems, yet previous tests of this hypothesis have produced mixed results and the mechanisms involved remain ...unclear. Here, we use a novel phylogenetic approach to assess the influence of sexual selection on patterns of evolutionary change during 84 recent speciation events across 23 passerine bird families. We show that elevated levels of sexual selection are associated with more rapid phenotypic divergence between related lineages, and that this effect is restricted to male plumage traits proposed to function in mate choice and species recognition. Conversely, we found no evidence that sexual selection promoted divergence in female plumage traits, or in male traits related to foraging and locomotion. These results provide strong evidence that female choice and male–male competition are dominant mechanisms driving divergence during speciation in birds, potentially linking sexual selection to the accelerated evolution of pre-mating reproductive isolation.
The post-genomics era has brought with it ever increasing demands to observe and characterise variation within biological systems. This variation has been studied at the genomic (gene function), ...proteomic (protein regulation) and the metabolomic (small molecular weight metabolite) levels. Whilst genomics and proteomics are generally studied using microarrays (genomics) and 2D-gels or mass spectrometry (proteomics), the technique of choice is less obvious in the area of metabolomics. Much work has been published employing mass spectrometry, NMR spectroscopy and vibrational spectroscopic techniques, amongst others, for the study of variations within the metabolome in many animal, plant and microbial systems. This review discusses the advantages and disadvantages of each technique, putting the current status of the field of metabolomics in context, and providing examples of applications for each technique employed.
Expression of programmed death ligand 1 (PD-L1) in solid tumours has been shown to predict whether patients are likely to respond to anti-PD-L1 therapies. To estimate the therapeutic potential of ...PD-L1 inhibition in breast cancer, we evaluated the prevalence and significance of PD-L1 protein expression in a large collection of breast tumours.
Correlations between CD274 (PD-L1) copy number, transcript and protein levels were evaluated in tumours from 418 patients recruited to the METABRIC genomic study. Immunohistochemistry was used to detect PD-L1 protein in breast tumours in tissue microarrays from 5763 patients recruited to the SEARCH population-based study (N = 4079) and the NEAT randomised, controlled trial (N = 1684).
PD-L1 protein data was available for 3916 of the possible 5763 tumours from the SEARCH and NEAT studies. PD-L1 expression by immune cells was observed in 6% (235/3916) of tumours and expression by tumour cells was observed in just 1.7% (66/3916). PD-L1 was most frequently expressed in basal-like tumours. This was observed both where tumours were subtyped by combined copy number and expression profiling 39% (17/44) of IntClust 10 i.e. basal-like tumours were PD-L1 immune cell positive; P < 0.001 and where a surrogate IHC-based classifier was used 19% (56/302) of basal-like tumours were PD-L1 immune cell positive; P < 0.001. Moreover, CD274 (PD-L1) amplification was observed in five tumours of which four were IntClust 10. Expression of PD-L1 by either tumour cells or infiltrating immune cells was positively correlated with infiltration by both cytotoxic and regulatory T cells (P < 0.001). There was a nominally significant association between PD-L1 and improved disease-specific survival (hazard ratio 0.53, 95% confidence interval 0.26–1.07; P = 0.08) in ER-negative disease.
Expression of PD-L1 is rare in breast cancer, markedly enriched in basal-like tumours and is correlated with infiltrating lymphocytes. PD-L1 inhibition may benefit the 19% of patients with basal-like tumours in which the protein is expressed.
NCT00003577.
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